Copyright (c) 2011-2012, Selventa. All rights reserved.

Table 1. Genes relatively overexpressed in gemcitabine-sensitive pancreatic cancer cell lines

a(CHEBI:gemcitabine) -> r(HGNC:SERPINF2)

tscript(p(MGI:Srf)) -| p(MGI:Cfl1,pmod(P,S,3))

At the posttranslational level, cofilin, a key regulator of actin dynamics, displays dramatically elevated inhibitory phosphorylation at Ser-3.

TNF-alpha (P also increased angiotensinogen and angiotensin II in isolated adipocytes.

p(HGNC:TNF) -> tscript(complex(NCH:"Nfkb Complex"))

TNF-{alpha} induces transcription of AGT via the transcription factor nuclear factor-{kappa}B, which is known to be involved in the production of numerous proinflammatory markers.

Although both PKCbetaII and PKCepsilon can phosphorylate cTnI

kin(p(PFM:"Prkc Family")) -> p(MGI:Tnni3,pmod(P,S))

Protein kinase C (PKC)-induced phosphorylation of cardiac troponin I (cTnI)

Fig. 4. Genes regulated during capillary tube formation. upregulated

bp(GO:angiogenesis) -| r(HGNC:"MT-ND4L")

p(MGI:Vegfa) -| (path(MESHD:Hyperoxia) -> bp(GO:"cell death"))
path(MESHD:Hyperoxia) -> bp(GO:"cell death")

VEGF also conferred protection via an A1-dependent mechanism

bp(GO:"complement activation") -> path(SDIS:"tissue damage")

TNFR1 promotes systemic immune responses and renal T cell death, while intrinsic cell TNFR2 plays a critical role in complement-dependent tissue injury.

bp(GO:"response to hypoxia") -> r(EGID:104263)

Table 3. Genes changed after hypoxia that are unique to HIF1A WT upregulated

bp(GO:"response to hypoxia") -> r(MGI:Pim3)

table 2 - genes changed after hypoxia common to HIF1A WT and HIF1A del upregulated by hypoxia

bp(GO:"response to hypoxia") -> r(MGI:Sesn1)

bp(GO:"response to hypoxia") -> r(MGI:Smad1)

p(HGNC:TP53,sub(Y,220,C)) =| tscript(p(HGNC:TP53))

path(SDIS:"blood flow") -| bp(MESHPP:"Insulin Resistance")

Glucose uptake into various tissues has been reported to be enhanced by insulin-mediated vasodilation and the decrease in local blood flow to lead to the development of insulin resistance [1] and [2].

bp(GO:"response to hypoxia") -| r(HGNC:PPARG)

Both hypoxia-mimetic deferoxamine mesylate (DFO) and TGF-beta1 inhibited adipocyte differentiation (1.0% versus the control at 15 microm DFO and 1.4% versus the control at 1 ng/ml TGF-beta1) and adipocyte gene expression (peroxisome proliferator-activated receptor-gamma2 and lipoprotein lipase) in human MSCs after 21 days of treatment. Hypoxia (2% O(2)) and DFO (but not TGF-beta1) increased hypoxia-inducible factor-1alpha as shown by Western blotting.

TABLE 3. The list of uterine genes significantly increased and decreased by acute P4 treatment upregulated

TABLE 4. The list of genes significantly increased and decreased uterine genes by chronic P4 treatment upregulated

Table 2. HOXA10-modulated genes in human CD34+ cord blood cells upregulated

tscript(p(HGNC:HOXA9)) -> r(HGNC:MAPK12)

tscript(p(HGNC:HOXA9)) -> r(HGNC:PPP1R13L)

tscript(p(HGNC:HOXA9)) -> r(HGNC:STK17B)

Among the selected genes, 11 (ATF-4, c-maf, SGK-1, PBEF, ATPase 8, NADH dehydrogenase 4, STK6, TRAF4-associated factor 1, molybdopterin synthase, CKS1, and CIDE-B) have not been previously reported to be sensitive to ()NO.

a(CHEBI:"nitric oxide") -> r(HGNC:CDKN1A)

PTIO-mediated increase in nitrosating species remarkably enhanced ()NO-dependent induction of IL-8, p21/Cip1, and MKP-1 and built a specific gene expression profile.

gtp(p(PFH:"RAS Family")) -> r(HGNC:SPP1)

high levels of Bcr-Abl activate a signaling cascade involving the sequential activation of Ras, phosphatidylinositol-3 kinase, atypical protein kinase C, Raf-1, and mitogen-activated protein kinase kinase, leading to the ultimate expression of OPN.

kin(p(HGNC:PRKCI)) -> kin(p(PFH:"MEK1/2 Family"))

activation of EGF-R by EGF triggers signaling through the MAP kinase pathway during in vitro maturation

Moreover, overexpressed Daxx positively modulates FAS-ligand and TGFbeta-induced apoptosis.

p(HGNC:PLCG1,pmod(P,Y,783)) => cat(p(HGNC:PLCG1))

PLC gamma is phosphorylated by activated FGFR, resulting in PLC gamma activation, stimulation of phosphatidyl inositol hydrolysis and generation of two second messengers, diacylglycerol and inositol (1,4,5) P3. Tyrosine phosphorylation of PLCgamma by FGFR4 is weaker than that seen by other isoforms of FGFR.Three tyrosine residues in PLC gamma have been identified as sites of receptor tyrosine kinase phosphorylation. Mutagenesis indicates that the phosphorylation at Tyr 783 is essential for IP3 formation, phosphorylation of Tyr 771 is dispensable, and phosphorylation of Tyr 1254 is necessary to achieve maximal IP3 formation.

kin(p(HGNC:FGFR1)) -> bp(GO:"cell proliferation")

Activation of FGFR1 or FGFR2 by angiogenic FGFs (including FGF1, FGF2, and FGF4) leads to endothelial cell proliferation [16].Recently, also the FGF8b isoform has been shown to stimulate endothelial cell proliferation in vitro [17].

kin(p(HGNC:FGFR2)) -> bp(GO:angiogenesis)

Also, FGFs modulate the expression of uPA receptor on the endothelial cell surface, thus allowing the localization of the proteolytic activity at the leading edge of the cell at the front of migration [22]. Furthermore, FGF1 and FGF2 induce the expression of the plasminogen activator inhibitor (PAI)-1 in cultured endothelial cells leading to a fine modulation of the proteolytic balance [23-25].

FGF2 [50] and FGF8b [17] can enhance endothelial cell reorganization onMatrigel.The process requires the activation of the proteolytic machinery, including type IV collagenase(s) and TIMPs production [51] as well as uPA and PAI-1 upregulation [52], a6b1 integrin receptor engagement [53], PECAM-1 [54], and activation of the small GTPase Rac [55].

complex(a(CHEBI:ganglioside),p(HGNC:FGF1)) =| p(HGNC:FGF1)

Gangliosides bind FGF1, FGF2, and FGF4 via negatively charged Neu-Ac residues [147,148]. In the extracellular environment, gangliosides compete with free heparin for the binding to the growth factor. On endothelial cells, free gangliosides prevent the binding of FGF2 to FGFRs and HSPGs, thus inhibiting FGF2-mediated cell proliferation [147]. Ganglioside GM1 is expressed on the endothelial cell surface and binds FGF2 with an affinity that is significantly higher than that of its free counterpart (Table 1). Under these conditions, GM1 acts as a functional FGF2 co-receptor.

complex(a(CHEBI:ganglioside),p(HGNC:FGF2)) =| p(HGNC:FGF2)

complex(p(HGNC:SDC2),p(HGNC:FGF7)) => p(HGNC:FGF7)

In general, free heparin/HSPGs sequester FGFs in the extracellular environment and act as FGF antagonists. On the contrary, cellassociated HSPGs can directly activate a signal transduction pathway in response to FGF2 [124], promote FGF2 internalization [125,126], and are required for a correct presentation of FGFs to FGFRs, leading to the formation of productive HSPGs/FGF/FGFR ternary complexes [121].

bp(GO:"inflammatory response") -> bp(GO:angiogenesis)

Inflammation may promote FGF-dependent angiogenesis (Fig. 4). Inflammatory cells, including mononuclear phagocytes [204,205], CD4+ and CD8+ T lymphocytes [206,207], and mast cells [208] can express FGF2.

cat(complex(p(HGNC:ITGAV),p(HGNC:ITGB3))) -> bp(GO:"cell migration")
p(HGNC:FGF2) -> (cat(complex(p(HGNC:ITGAV),p(HGNC:ITGB3))) -> bp(GO:"cell migration"))

Moreover, FGF2-mediated chemotaxis on fibronectincoated substrata can be attenuated by avb3 integrin inhibitors [34].

bp(GO:"response to osmotic stress") -> p(HGNC:FGF2)

Moreover, osmotic shock and shear stress induce the release of FGF2 from endothelial cells [209,210]. FGF2 production and release from endothelial cells are also triggered by IFN-a plus IL-2 [211], IL-1b [212], and nitric oxide (NO) [213].

On the other hand, PTX3, synthesized locally by endothelial cells in response to IL-1b and TNF-a, binds FGF2 and acts as a natural angiogenesis inhibitor (see above), thus allowing a fine tuning of FGF2 pro-angiogenic activity in inflammation.

complex(p(HGNC:PTX3),p(HGNC:FGF2)) =| p(HGNC:FGF2)

PTX3 binds FGF2, but not FGF1 and FGF4, with high affinity [166]. In endothelial cells, PTX3 prevents the binding of FGF2 to cell surface FGFRs and HSPGs, with a consequent inhibition of cell proliferation and migration, and inhibits FGF2-dependent neovascularization in the CAM assay.

Several experimental evidences point to the possibility that FGF2 induces neovascularization indirectly by activation of the VEGF/ VEGFR system. Indeed: (i) VEGFR-2 antagonists inhibit both VEGF and FGF2-induced angiogenesis in vitro and in vivo [98]; (ii) expression of dominant-negative FGFR1 or FGFR2 in glioma cells results in a decrease in tumor vascularization paralleled by VEGF down-regulation [99]; (iii) both endogenous and exogenous FGF2 modulate VEGF expression in endothelial cells [82]; (iv) in the mouse cornea, the quiescent endothelium of vessels of the limbus express both VEGF mRNA and protein only after FGF2 treatment. In the same model, systemic administration of anti-VEGF-A neutralizing antibodies dramatically reduces FGF2-induced vascularization [82]; (v) VEGFR-1-blocking antibodies or the expression of a dominant-negative VEGFR-1 result in a significant reduction of FGF2-induced cell extensions and capillary morphogenesis [56]; (vi) FGF2 upregulates the expression of both FGFRs and VEGFRs in endothelial cells [100].

Stimulation of endothelial cells by FGF2 causes also the shedding of cell surface membrane vesicles containing MMP-2 and MMP-9 together with the two MMP inhibitors TIMP-1 and TIMP-2. These vesicles stimulate capillary-like structure formation when added to endothelial cells seeded on a solubilized basement membrane preparation (Matrigel) [26].

kin(p(HGNC:ERBB4)) => p(HGNC:STAT5A,pmod(P,S,779))

Here we show that STAT5A regulation by ERBB4 is also mediated through STAT5A serine phosphorylation. Using a reverse-phase high performance liquid chromatography tandem mass spectrometry analysis of proteolytically digested STAT5A coexpressed with ERBB4, we identified STAT5A serine phosphorylations at the previously described Ser-779 and at the novel Ser-127/Ser-128. Immunohistochemistry of wild-type and ERBB4-null mammary glands at late pregnancy showed that ERBB4 expression was required for STAT5A phosphorylation at Ser-779.

However, the expression of Otx2 (37), Ctgf (38), and Ebaf (39) were significantly decreased, whereas Hrc (40) was increased in Sox15-null ES cells.

p(HGNC:PLCG1,pmod(P,Y,771)) => cat(p(HGNC:PLCG1))

Despite extensive overlap in the molecules recruited to the active receptors, there is some preferential modulation of signalling pathways. Tumour cells that express EGFR with kinase-domain mutations preferentially activate the pro-survival PI3K?AKT and signal transducer and activator of transcription (STAT) pathways67. Although EGFR has no consensus sequence for the p85 adaptor subunit of PI3K, it couples to this pathway through GAB1, which binds growth-factorreceptor- bound protein 2 (GRB2).

kin(p(HGNC:EGFR)) => p(HGNC:PLCG1,pmod(P,Y,771))

p(HGNC:EREG) => complex(p(HGNC:ERBB4),p(HGNC:ERBB2))

Figure 1 | ERBB receptors, ligands, dimers and downstream signalling pathways. a | Members of the epidermal growth factor (EGF) family of growth factors are ligands for the ERBB receptors. Ligand binding to ERBB receptors induces the formation of receptor homo- and heterodimers and the activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues within the cytoplasmic tail. These phosphorylated residues serve as docking sites for a range of proteins, the recruitment of which leads to the activation of intracellular signalling pathways. None of the ligands bind ERBB2, but ERBB2 is the preferred dimerization partner for all the other ERBB receptors. ERBB3 has impaired kinase activity and only acquires signalling potential when it is dimerized with another ERBB receptor, such as ERBB2. Overexpression of ERBB2 in tumours leads to constitutive activation of ERBB2, presumably because of increased receptor concentrations at the plasma membrane. Many of these tumours contain phosphorylated ERBB3, which couples ERBB2 to the phosphatidylinositol 3-kinase (PI3K)?AKT pathway128.

p(HGNC:NRG1) => complex(p(HGNC:ERBB3),p(HGNC:ERBB2))

p(HGNC:TGFA) => complex(p(HGNC:EGFR),p(HGNC:EGFR))

complex(p(HGNC:EGFR),p(HGNC:ERBB2)) => kin(p(HGNC:ERBB2))

kin(p(HGNC:BUB1B)) -| bp(MESHPP:Apoptosis)

Evasion from apoptosis is a hallmark of cancer, and recent success using targeted therapeutics underscores the importance of identifying anti-apoptotic survival pathways. Here we utilize RNA interference (RNAi) to systematically screen the kinase and phosphatase component of the human genome.

kin(p(HGNC:CAMK1G)) -| bp(MESHPP:Apoptosis)

kin(p(HGNC:CAMK2D)) -| bp(MESHPP:Apoptosis)

kin(p(HGNC:CHKA)) -| bp(MESHPP:Apoptosis)

kin(p(HGNC:JAK1)) -| bp(MESHPP:Apoptosis)

kin(p(HGNC:NEK3)) -| bp(MESHPP:Apoptosis)

kin(p(HGNC:PFKFB2)) -| bp(MESHPP:Apoptosis)

kin(p(HGNC:PRKCQ)) -| bp(MESHPP:Apoptosis)

kin(p(HGNC:RPS6KL1)) -| bp(MESHPP:Apoptosis)

kin(p(HGNC:TNK2)) -| bp(MESHPP:Apoptosis)

phos(p(HGNC:DUSP19)) -| bp(MESHPP:Apoptosis)

phos(p(HGNC:G6PC)) -> bp(MESHPP:Apoptosis)

phos(p(HGNC:PPP1R7)) -> bp(MESHPP:Apoptosis)

phos(p(HGNC:PPP2CA)) -| bp(MESHPP:Apoptosis)

phos(p(HGNC:PPP2R3A)) -| bp(MESHPP:Apoptosis)

phos(p(HGNC:PPP2R4)) -> bp(MESHPP:Apoptosis)

phos(p(HGNC:PTPN5)) -| bp(MESHPP:Apoptosis)

phos(p(HGNC:PTPRN2)) -| bp(MESHPP:Apoptosis)

phos(p(HGNC:PTPRO)) -| bp(MESHPP:Apoptosis)

phos(p(HGNC:SBF1)) -| bp(MESHPP:Apoptosis)

phos(p(HGNC:INPP5K)) -| bp(MESHPP:Apoptosis)

o biochemically characterize the transcriptional activity of GCMa/1, we set up an in vitro transcription system for human GCMa/1 (hGCMa/1). Using G-free reporter constructs carrying multiple copies of wild-type or mutant GCMa-binding site (GBS) in front of a synthetic TATA box, we observed specific transcriptional activities of recombinant hGCMa/1 proteins prepared from a baculovirus--insect cell or Escherichia coli expression system. We further characterized GCMa/1-mediated transcriptional activation on the native syncytin promoter. Using G-free reporter constructs containing the native syncytin promoter, a TATA box downstream of the proximal GBS in the syncytin promoter was shown to be essential for the transcription activation directed by hGCMa/1.

path(SDIS:"TLR signaling") -> kin(p(HGNC:IKBKB))

Again, the activation of these kinases in obesity highlights the overlap of metabolic and immune pathways; these are the same kinases, particularly IKK and JNK, that are activated in the innate immune response by Toll-like receptor (TLR) signaling in response to LPS, peptidoglycan, double-stranded RNA, and other microbial products

a(CHEBI:lipopolysaccharide) -> kin(p(HGNC:MAPK8))

bp(MESHPP:Obesity) positiveCorrelation kin(p(HGNC:PRKCQ))

a(SCHEM:"serum glucose") -> a(CHEBI:"reactive oxygen species")

Due to increased delivery of glucose to adipose tissue, endothelial cells in the fat pad may take up increasing amounts of glucose through their constitutive glucose transporters. Increased glucose uptake by endothelial cells in hyperglycemic conditions causes excess production of ROS in mitochondria, which inflicts oxidative damage and activates inflammatory signaling cascades inside endothelial cells (101).

bp(MESHPP:Obesity) positiveCorrelation kin(p(HGNC:MAPK8))

In obesity, JNK activity is elevated in liver, muscle, and fat tissues, and loss of JNK1 prevents the development of insulin resistance and diabetes in both genetic and dietary mouse models of obesity

p(HGNC:MYD88) -> path(MESHD:Atherosclerosis)

Indeed, lack of MyD88, a critical mediator of TLR signaling, reduces atherosclerosis in apoE minus mice

a(CHEBI:"nitric oxide") -| bp(GO:"insulin receptor signaling pathway")

Overproduction of nitric oxide also appears to contribute to impairment of both muscle cell insulin action and beta cell function in obesity

kin(p(HGNC:IKBKB)) -| bp(GO:"insulin receptor signaling pathway")

Several serine/threonine kinases are activated by inflammatory or stressful stimuli and contribute to inhibition of insulin signaling, including JNK, inhibitor of NF-kB kinase (IKK), and PKC-theta

p(MGI:Hyou1) -| bp(MESHPP:"Insulin Resistance")

Targeting of JNK using a synthetic inhibitor and/or an inhibitory peptide has been demonstrated to improve insulin action in obese mice and reduce atherosclerosis in the apoE-deficient rodent model (52, 53). These results directly demonstrate the therapeutic potential of JNK inhibitors in diabetes. TZDs, high-affinity ligands of PPARg, which are given clinically as insulin-sensitizing agents, likely improve insulin action through multiple mechanisms, including both activating lipid metabolism and reducing production of inflammatory mediators such as TNFalpha It has recently been demonstrated that mice in which the chaperone ORP150 is transgenically or adenovirally overexpressed exhibited reduced ER stress and improved insulin tolerance compared with controls, whereas reduction of the expression of this molecule in liver results in increased ER stress and insulin resistance

a(SCHEM:cytokine) -> kin(p(PFH:"MAPK JNK Family"))

The 3 members of the JNK group of serine/threonine kinases, JNK-1, -2, and -3, JNK has recently emerged as a central metabolic regulator, playing an important role in the development of insulin resistance in obesity In response to stimuli such as ER stress, cytokines, and fatty acids, JNK is activated, whereupon it associates with and phosphorylates IRS-1 on Ser307, impairing insulin action

kin(p(PFH:"MAPK JNK Family")) -> p(HGNC:IRS1,pmod(P,S))

p(HGNC:ADIPOQ) -> bp(GO:"fatty acid oxidation")

This phosphorylation reduces both tyrosine phosphorylation of IRS-1 in response to insulin and the ability of IRS-1 to associate with the insulin receptor and thereby inhibits downstream signaling and insulin action

p(HGNC:IL10) -| bp(MESHPP:"Insulin Resistance")

p(HGNC:IL1R1) -| (p(HGNC:LEP) -| path(SDIS:"food intake"))

p(HGNC:IL1R1) -| (p(HGNC:LEP) -> bp(GO:"fatty acid oxidation"))
p(HGNC:LEP) -> bp(GO:"fatty acid oxidation")

p(HGNC:IL6) -> bp(MESHPP:"Insulin Resistance")

bp(GO:"inflammatory response") -> p(HGNC:RETN)

bp(MESHPP:Obesity) positiveCorrelation p(HGNC:CCL2)

bp(MESHPP:Obesity) positiveCorrelation p(HGNC:IL6)

a(SCHEM:"serum glucose") -> p(HGNC:IL1B)

bp(GO:"inflammatory response") -> bp(MESHPP:"Insulin Resistance")

even in the absence of obesity, infusion of animals with inflammatory cytokines or lipids can cause insulin resistance

These results establish that PTP1B promotes integrin-mediated responses in fibroblasts by dephosphorylating the inhibitory pTyr(527) and thereby activating the Src kinase.

phos(p(HGNC:PTPN1)) -> p(HGNC:MAPK1,pmod(P,Y))

We show that down-regulation of PTP1B activity with small molecule inhibitors suppresses cell spreading and migration to fibronectin, increases Tyr(527) phosphorylation in Src, and decreases phosphorylation of FAK, p130(Cas), and ERK1/2.

kin(p(HGNC:GSK3B)) => p(HGNC:LGALS3,pmod(P))

Analysis of the human gal-3 sequence reveled a structural similarity to beta-catenin as it also contains the consensus sequence (S92XXXS96) for glycogen synthase kinase-3beta (GSK-3beta) phosphorylation and can serve as its substrate.

a(SCHEM:Progestins) -> cat(p(HGNC:FASN))

We found that in estrogen receptor (ER)- and progesterone receptor (PR)-positive MCF-7 human breast cancer cells, synthetic progestins used in oral contraceptives including norethynodrel (NOR) and norethindrone, induced a dose-dependent increase of FAS enzymatic activity, with a maximum response (> or = 4-fold) occurring at a concentration of 10(-8) M. FAS activity was only slightly stimulated after exposure to two other progestins, medroxy-progesterone acetate (MPA) and megestrol acetate (MGA), which are used in postmenopausal hormone replacement therapy and high-dose progestin treatment therapy. Western blot analyses showed that NOR-induced stimulation of FAS activity correlated closely with NOR-induced up-regulation of FAS protein expression

p(MGI:Vegfa) -> tscript(p(PFM:"Notch Family"))

The current model of arterial-venous identity proposes that binding of vascular endothelial growth factor to its heterodimeric receptor--Flk1 and neuropilin 1 (NP-1; also called Nrp1)--activates the Notch signalling pathway in the endothelium, causing induction of ephrin B2 expression and suppression of ephrin receptor B4 expression

cat(p(MGI:Vegfa)) -> tscript(p(PFM:"Notch Family"))

tscript(p(PFM:"Notch Family")) -> r(MGI:Efnb2)

cat(p(HGNC:HSD11B1)) -> tscript(p(HGNC:NR3C1))

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) locally regenerates active cortisol from inactive cortisone amplifying glucocorticoid receptor activation

a(CHEBI:testosterone) -> bp(GO:"cell proliferation")

These data show that Par4 has an important role in tumour suppression, with a particular relevance in the endometrium and prostate.

cat(p(RGD:Alox15)) -| kin(p(RGD:Pdgfrb))

Conversely, the receptors for transforming growth factor-beta and platelet-derived growth factor, which contributed to down-regulation of sPLA2-IIA expression, were decreased following 12/15-LOX overexpression

cat(p(RGD:Alox12)) -| kin(p(RGD:Pdgfrb))

complex(p(HGNC:CYTH3),p(HGNC:THRA)) =| tscript(p(HGNC:THRA))

Thyroid hormone receptors (TRs) bind to response elements (TREs) located in the promoter region of target genes and modulate their transcription. We reconfirmed the interaction between TRs and GRP1 in yeast and glutathione-S-transferase pull-down assays, and determined the areas of TRs and GRP1 involved in the interaction. Coimmunoprecipitation studies demonstrated that the interaction between GRP1 and TRs takes place in the cytoplasm and the nucleus of mammalian cells.

addition of GRP1 diminishes the formation of TR/TR homodimers and TR/retinoid X receptor heterodimers on TREs, which could explain the effect of GRP1 on transcription.

In response to IFN-gamma, C/EBP-beta undergoes phosphorylation at a critical ERK1/2 phosphorylation motif.

Apart from counteracting matrix metalloproteinases, tissue inhibitor of metalloproteinases-3 (TIMP-3) has proapoptotic properties.

tsc-22 mRNA is expressed in almost all organs of mice and humans and its expression is induced in a variety of cell lines by many different factors including TGF-beta, phorbol ester, serum, and progestin

gtp(p(MGI:Cdc42)) -> bp(GO:"nuclear migration")

By direct imaging of wound-edge fibroblasts after triggering MTOC reorientation with soluble factors, we found instead that the nucleus moved away from the leading edge to reorient the MTOC, while the MTOC remained stationary. Rearward nuclear movement was coupled with actin retrograde flow and was regulated by a pathway involving Cdc42, MRCK, myosin, and actin.

bp(GO:"response to radiation") -> tloc(p(HGNC:ITGA6),GOCCACC:"GO:0005886",GOCCACC:"GO:0005622")

By immunofluorescence, we could demonstrate that UVB leads to a dose-dependent internalization of alpha6-integrin

bp(GO:"response to radiation") -| surf(p(HGNC:ITGA6))
complex(NCH:"Laminin 1 Complex") -| (bp(GO:"response to radiation") -| surf(p(HGNC:ITGA6)))

In the presence of LM-1, the UVB-induced down-regulation of alpha6-integrin in melanocytes was significantly reduced

We were able to demonstrate that the alpha6-integrin subunit is selectively and reversibly down-regulated by UVB

p(HGNC:WNT3A) -> complex(p(HGNC:RHOA),p(HGNC:DVL2),p(HGNC:DVL3),p(HGNC:PRKCA))

PKCa, PCKb, and PKCmu were associated with both Dvl-2 (Figure 8A) and Dvl-3 (Figure 8B), suggesting that several PKCs are likely included in the Dvl/RhoA complex.

(1) the levels of Her2, but not of EGFR, as well as the uPA secretion, cell motility and Matrigel invasion were statistically higher in AR negative than in AR positive PCa cells;

(2) the uPA secretion and uPA Rexpression were positively related to Matrigel invasion; (3) the EGF was able to stimulate chemotaxis and Matrigel invasion in a dose-dependent manner;

complex(p(HGNC:PLAU),p(HGNC:PLAUR)) => cat(p(HGNC:PLAU))

(4) the EGF-induced cell migration was statistically higher inAR negative than in AR positive cells with a similar increase with respect to basal value (about 2.6 fold); (5) the Matrigel invasion was statistically higher in AR negative than in AR positive PCa cells also if the increment of Matrigel invasion after EGF treatment was statistically higher in AR positive respect to AR negative cells; (6) the EGF induced uPA secretion and its membrane uptake through the increment of uPAR;

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> path(SDIS:metastasis)
phos(p(HGNC:PTEN)) -| (kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> path(SDIS:metastasis))

(7) these effects were blocked by EGFR/Her2 tyrosine kinase inhibitors with IC(50) lower than those needed to inhibit cell proliferation and required PI3K/Akt, MAPK and PI-PLC activities as verified by inhibition experiments. inhibition of PI3K blocked the EGF-induced invasiveness in PTEN positive cells but not in PTEN negative cells,

a(CHEBI:wortmannin) -| (p(EGID:183) -> cat(complex(NCH:"Na/K Exchanging ATPase Complex")))
p(EGID:183) -> cat(complex(NCH:"Na/K Exchanging ATPase Complex"))

The treatment of cells with PKC-iota antisense oligodeoxynucleotides inhibited the effects of Ang II on the Na+/K+ATPase activity. Additionally, the effect of Ang II on Na+/K+ATPase activity was also blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002, and by the actin depolymerizing agents, cytochalasin D.

We demonstrated previously that in serum-starved MCF-7 breast cancer cell line, Ang II increased Na+/K+ATPase activity and activated the protein kinase C zeta (PKC-zeta) (Muscella et al., 2002 J Endocrinol 173:315-323; 2003 J Cell Physiol 197:61-68.).

We show that Cdc2 inhibits EGF-mediated ERK activation through direct interaction and phosphorylation of several ERK pathway proteins, including the guanine nucleotide exchange factor, Sos-1, and Raf-1 kinase.

kin(p(EGID:5424)) -| (p(HGNC:EGF) -> kin(p(HGNC:MAPK1)))

a(SCHEM:"trans10,cis12-Octadecadienoate") -| r(MGI:Idh2)

Gene expression was measured during t10c12-CLA-induced body fat reduction in a polygenic obese line of mice. Adult mice (n = 185) were allotted to a 2 x 2 factorial experiment consisting of either nonobese (ICR-control) or obese (M16-selected) mice fed a 7% fat, purified diet containing either 1% linoleic acid (LA) or 1% t10c12-CLA. Body weight (BW) by day 14 was 12% lower in CLA- compared with LA-fed mice (P of epididymal, mesenteric, and brown adipose tissues, as a percentage of BW, in both lines by 30, 27, and 58%, respectively, and increased liver weight/BW by 34% (P per day) from epididymal adipose (days 5 and 14) of the obese mice to analyze gene expression profiles using Agilent mouse oligo microarray slides representing 20,000 genes. Numbers of genes differentially expressed by greater than or equal to twofold in epididymal adipose (days 5 and 14) were 29 and 125, respectively. It was concluded that, in adipose tissue, CLA increased expression of uncoupling proteins (1 and 2), carnitine palmitoyltransferase system, tumor necrosis factor-alpha (P caspase-3 but decreased expression of peroxisome proliferator-activated receptor-gamma, glucose transporter-4, perilipin, caveolin-1, adiponectin, resistin, and Bcl-2 (P candidate genes that will be useful in elucidating mechanisms of adipose delipidation.

a(SCHEM:"trans10,cis12-Octadecadienoate") -| r(MGI:Rxrg)

a(SCHEM:"trans10,cis12-Octadecadienoate") -| r(MGI:Retn)

a(SCHEM:"trans10,cis12-Octadecadienoate") -| r(MGI:Pfkfb3)

a(SCHEM:"trans10,cis12-Octadecadienoate") -> r(MGI:Cpt1a)

a(SCHEM:"trans10,cis12-Octadecadienoate") -> r(MGI:Gpam)

a(SCHEM:"trans10,cis12-Octadecadienoate") -> r(MGI:Slc25a20)

Notably, stress-induced transcription factors such as ATF3, ATF4, CHOP, and C/EBP beta were robustly up-regulated, yet exhibited unique kinetic patterns. Genes involved in the synthesis and modification of proteins (various tRNA synthetases), protein degradation (e.g., ubiquitin, Herpud1, Sqstm1), and oxidative stress (Hmox1, Por) could be subgrouped into distinct kinetic profiles as well.

p(HGNC:AKT2,pmod(P,T,309)) => kin(p(HGNC:AKT2))

Upon stimulation with insulin, AKT is recruited to cellular membranes by binding of its amino terminal pleckstrin (PH) domain to membrane bound phosphatidylinositol 3,4,5, trisphosphate (PIP3) [3]. The membrane bound form of AKT then becomes phosphorylated on two regulatory residues, a threonine within the activation loop (Thr308 in AKT1,Thr309 in AKT2, Thr305 in AKT3) and a serine in the C-terminus of the enzyme (Ser473 in AKT1,Ser474 in AKT2, Ser472 in AKT3), and both phosphorylations are considered to be required for AKT to reach maximum kinase activity [1]. The kinase responsible for phosphorylation of Thr308/309/305 has been identified as phosphoinositide-dependent kinase 1 (PDK1) [3].

cat(p(MGI:Prdx6)) -| bp(GO:"response to oxidative stress")

Prdx6 stably overexpressed in cells protected against oxidative stress, whereas antisense treatment resulted in oxidant stress

kin(p(HGNC:MAPK1)) => p(HGNC:CAD,pmod(P,T,456))

kin(p(HGNC:MAPK3)) => p(HGNC:CAD,pmod(P,T,456))

GnRH-induced phosphorylation of MAPK/ERK kinase 1 and c-Raf kinase was blocked by Cam inhibition

p(MGI:Map2k1,pmod(P)) => kin(p(MGI:Map2k1))

gtp(p(HGNC:CDC42)) => cat(p(HGNC:IQGAP1))

Activated Rac1 and Cdc42 form a tripartite complex with IQGAP1 and APC (Watanabe et al., 2004). The depletion of IQGAP1 or APC by RNAi inhibits formation of an actin meshwork at the leading edge, as well as cell migration, immobilization of the plus-ends of microtubules and polarization of the MTOC.

This reflects a need for Foxo3a to maintain neutrophil vitality during inflammation by suppressing Fas ligand; because Foxo3a can bind and suppress the Fasl promoter,

p(HGNC:APOE) -| path(SDIS:"LDL oxidation")

Taken together, these results localized the antioxidant domain of apoE to its receptor binding domain and the basic amino acids in this domain are important for its antioxidant activity.

p(HGNC:APOE) -| a(CHEBI:"reactive oxygen species")

phos(p(HGNC:PTPRF)) -> kin(p(PFH:"AKT Family"))

Knock-down of LAR induced post-receptor insulin resistance with the insulin-induced activation of PKB/Akt and MAP kinases markedly inhibited.

cat(p(HGNC:ADIPOR2)) -> tscript(p(HGNC:PPARA))

We showed that AdipoR1 and AdipoR2 serve as receptors for globular and full-length adiponectin and mediate increased AMP-activated protein kinase, peroxisome proliferator-activated receptor-alpha ligand activities, and glucose uptake and fatty-acid oxidation by adiponectin

suppression of ING4 further induces HIF transcriptional activity

In the presence of cortisone (1 to 10 nM), there was significant cortisol production, which was dose dependently augmented (2- to 6-fold, p 0.001) by 1,25-dihydroxyvitamin D3 (0.1 to 10 nM). 1,25-Dihydroxyvitamin D3 dose dependently increased 11beta-HSD 1 expression up to 2-fold (p 0.01) in both the presence and absence of cortisone. In contrast, 1,25-dihydroxyvitamin D3 dose dependently decreased adipocyte AT1 expression (by 30% to 50%, p 0.001) in both the presence and absence of cortisone, suggesting compensatory down-regulation of AT(1)

a(CHEBI:calcitriol) -> a(SCHEM:Hydrocortisone)

bp(MESHPP:Obesity) negativeCorrelation phos(p(EGID:54704))

At T0 in ObS, PDHt was normal, whereas PDHa and PDP1 activity was below normal at all Mg/Ca concentrations.

a(CHEBI:"trichostatin A") -| r(HGNC:ADAMTS9)

The HDAC inhibitors trichostatin A and sodium butyrate potently inhibit cartilage degradation in an explant assay. These compounds decrease the level of collagenolytic enzymes in explant-conditioned culture medium and also the activation of these enzymes. In cell culture, these effects are explained by the ability of HDAC inhibitors to block the induction of key MMPs (e.g. MMP-1 and MMP-13) by proinflammatory cytokines at both the mRNA and protein levels. The induction of aggrecan-degrading enzymes (e.g. ADAMTS4, ADAMTS5, and ADAMTS9) is also inhibited at the mRNA level.

a(CHEBI:"trichostatin A") -| r(HGNC:MMP13)

Here, we show that estrogen receptor alpha (ERalpha) coimmunoprecipitates with CSN5/Jab1, a subunit of the COP9 signalosome (CSN), and that overexpression of CSN5/Jab1 causes an increase in ligand-induced ERalpha degradation

p(MGI:Raf1,pmod(P,S,43)) =| kin(p(MGI:Raf1))

Phosphorylation at Raf-1 S43 and S259 by PKA only weakly inhibited EGF activation of Raf-1 and ERK when cells maintained high Raf-1 S338 phosphorylation. Raf-1 inhibition in suspension was not due to excessive negative regulation on inhibitory sites S43 and S259, as these serines were largely dephosphorylated in suspended cells.

p(MGI:Raf1,pmod(P,S,338)) -> kin(p(MGI:Mapk1))

Restoration of phosphorylation at S338, either by expression of highly active PAK or by expression of an S338 phospho-mimetic Raf-1 mutation, led to a partial rescue of ERK activation in suspended cells.

p(MGI:Raf1,pmod(P,S,338)) -> kin(p(MGI:Mapk3))

p(MGI:Tnf) -> complex(p(MGI:Bid),p(MGI:Mtch2))

Activation of the TNF-R1 receptor results in the cleavage of BID into truncated BID (tBID), which translocates to the mitochondria and induces the activation of BAX or BAK. In TNF-alpha-activated FL5.12 cells, tBID becomes part of a 45-kDa cross-linkable mitochondrial complex. Here we describe the biochemical purification of this complex and the identification of mitochondrial carrier homolog 2 (Mtch2) as part of this complex.

ASB3 expression and activities are required for (i) TNF-R2 ubiquitination both in vivo and in vitro, (ii) TNF-R2 proteolysis via the proteasome pathway, and (iii) the inhibition of TNF-R2-mediated Jun N-terminal protein kinase (JNK) activation.

complex(p(MGI:Prkcz),p(MGI:Pawr)) -| (kin(p(MGI:Prkcz)) -> tscript(complex(NCM:"Nfkb Complex")))
kin(p(MGI:Prkcz)) -> tscript(complex(NCM:"Nfkb Complex"))

A luciferase reporter assay showed that ceramide analogs activate nuclear factor (NF)-kappaB unless PAR-4-dependent inhibition of PKCzeta suppresses NF-kappaB activation.

a(CHEBI:ceramide) -> p(MGI:Prkcz,pmod(P))

Ceramide and its analogs activated PKCzeta prior to binding to PAR-4, as determined by increased levels of phosphorylated PKCzeta and glycogen synthase kinase-3beta and emergence of a PAR-4-to-phosphorylated PKCzeta fluorescence resonance energy transfer signal that co-localizes with ceramide.

complex(p(MGI:Prkcz),p(MGI:Pawr)) -| kin(p(MGI:Prkcz))

We have reported that ceramide mediates binding of atypical protein kinase C (PKC) zeta to its inhibitor protein, PAR-4 (prostate apoptosis response-4), thereby inducing apoptosis in differentiating embryonic stem cells.

kin(p(PFH:"EGFR/ERBB Family")) -> tscript(p(HGNC:CREB1))

Both in vitro and in vivo DNA binding assay revealed that the CREB binding activity was low in EGF-starved cells, whereas it was induced within 30 min after EGF treatment

cat(p(HGNC:CXCR4)) -| bp(MESHPP:Apoptosis)
p(HGNC:CXCL12) -> (cat(p(HGNC:CXCR4)) -| bp(MESHPP:Apoptosis))

TC14012 and TN14003 antagonized the antiapoptotic effect of synthetic CXCL12 and stromal cell-mediated protection of CLL cells from spontaneous apoptosis.

At a functional level, leptin up-regulates the IL-1beta, IL-6, IL-12, TNF-alpha, and MIP-1alpha production.

p(HGNC:LEP) -> complex(p(HGNC:IL12A),p(HGNC:IL12B))

bp(GO:"response to UV") -> bp(MESHPP:Apoptosis)

Finally, we found that leptin partly protects DCs from spontaneous and UVB-induced apoptosis.

Furthermore, we found that leptin down-regulates IL-10 production by DCs and drives naive T cell polarization toward Th1 phenotype.

Expression of {Cell surface} CD14, B7-1, CCR5, and CXCR4 was down-regulated on PK1-treated monocytes when compared with monocytes treated with a control or Csf-1

kin(p(HGNC:MAP3K5)) => kin(p(HGNC:MAP2K4))

Glucose deprivation rapidly increases the interaction between ASK1 and JIP3, and the consequently activated ASK1 phosphorylates SEK1 on the Thr-261 residue.

tscript(p(HGNC:PPARGC1A)) -> bp(GO:"regulation of membrane potential")

Endothelial cells that overexpress PGC-1alpha show reduced accumulation of reactive oxygen species (ROS), increased mitochondrial membrane potential, and reduced apoptotic cell death both in basal and oxidative stress conditions

Furthermore, HSA augments intracellular glutathione levels and influences activation of the ubiquitous transcription factor nuclear factor-kappa B using both in vitro and in vivo protocols.32

cat(p(HGNC:ADIPOQ)) -| (p(HGNC:TNF) -> path(SDIS:"monocyte adherence"))
p(HGNC:TNF) -> path(SDIS:"monocyte adherence")

Adiponectin dose dependently suppresses TNF-A-stimulated adherence of monocytes to cultured human endothelial cells. This effect results from inhibition of the expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and intercellular adhesion molecule-1 (ICAM-1). TNF-A increases, whereas adiponectin reduces, the amount of these proteins and their respective mRNAs in endothelial cells [56].

Insulin down-regulated resistin expression in 3T3-L1 adipocytes

a(SCHEM:"serum leptin") -> kin(p(PFR:"MAPK Erk1/3 Family"))

Leptin administration to culture media to reach physiological and pathophysiologic concentrations dose-dependently increases both migration and proliferation of rat vascular smooth muscle cells [25] through activation of phosphatidylinositol-3-kinase and mitogen-activated protein kinases.

a(SCHEM:"serum leptin") -> path(SDIS:"macrophage TNF secretion")

in vitro administration of leptin to lipopolysaccharide (LPS)- activated macrophages collected from ob-/ob- and db-/db- mice substantially potentiates secretion of tumor necrosis factor and interleukins-2 and -6. These results indicate that leptin is involved in the regulation of immune function and cytokine secretion in ob/ob mice.

kin(p(HGNC:MAPK8)) => p(HGNC:FOXO4,pmod(P))

JNK then phosphorylates cytoplasmic FOXO proteins at the C-terminal sites that are distinct from the Akt phosphorylation sites. JNK-induced phosphorylation initiates nuclear import of FOXO proteins and activation of their transcriptional regulatory potential.

Oxidative stress... leads to an activation of the small GTPase Ral, which in turn is instrumental in the phosphorylation and activation of the Jun N-terminal kinase JNK.

Transcriptional control by FOXO also extends to the regulation of pro-apoptotic genes Bim and Fas Ligand and to the stress response genes like GADD45, Mn superoxide dismutase and catalase.

a(CHEBI:glutathione) -| a(CHEBI:"reactive oxygen species")

In the process of reducing high intracellular glucose to sorbitol, the aldose reductase consumes the cofactor NADPH (6). But as shown in Fig. 2, NADPH is also the essential cofactor for regenerating a critical intracellular antioxidant, reduced glutathione. By reducing the amount of reduced glutathione, the polyol pathway increases susceptibility to intracellular oxidative stress.

a(SCHEM:"Advanced Glycation End Product") -> bp(GO:"inflammatory response")

The third mechanism, shown on the right of Fig. 3, is that these AGE precursors diffuse out of the cell and modify circulating proteins in the blood such as albumin. These modified circulating proteins can then bind to AGE receptors and activate them, thereby causing the production of inflammatory cytokines and growth factors,

a(SCHEM:"D-Glucose, anhydrous") -> a(SCHEM:Diacylglycerol)

hyperglycemia inside the cell increases the synthesis of a molecule called diacylglycerol

kin(p(PFH:"PRKC Family")) -> r(HGNC:EDN1)

it has a variety of effects on gene expression, examples of which are shown in the row of open boxes in Fig. 4.

kin(p(PFH:"PRKC Family")) -> r(HGNC:FN1)

a(SCHEM:Diacylglycerol) => kin(p(PFH:"PRKC Family"))

which is a critical activating cofactor for the classic isoforms of protein kinase-C, -beta, -delta, and -alpha

a(CHEBI:spironolactone) -> tscript(p(MGI:Nr1i2))

Two PXR ligands [pregnenolone-16alpha-carbonitrile (PCN) and spironolactone] increased Oatp1a4 mRNA expression in liver,

complex(p(HGNC:ARHGDIB),p(HGNC:CDC42)) =| gtp(p(HGNC:CDC42))

Both RhoGDI and D4GDI (hereafter referred to collectively as GDIs) are cytosolic and form 1:1 complexes with Rho family GTPases, although several Rho family members have been reported to not effectively bind to GDIs (Table 1). First, they inhibit the dissociation of GDP from Rho proteins, maintaining the GTPase in an inactive form and preventing GTPase activation by GEFs (Box 1). Second, they are able to interact with the GTP-bound form of the Rho GTPase to inhibit GTP hydrolysis, blocking both intrinsic and GAP-catalyzed GTPase activity and preventing interactions with effector targets.

complex(p(HGNC:ARHGDIB),p(HGNC:RAC1)) =| gtp(p(HGNC:RAC1))

p(HGNC:SNN) -| kin(p(PFH:"MAPK Erk1/3 Family"))

In addition, we present the evidence that Snn overexpression results in reduced extracellular regulated kinase activation and increased p38 activation.

bp(GO:"response to hypoxia") -> tscript(p(MGI:Hif1a))

Here, we demonstrate that p38alpha-/- cells fail to activate HIF-1 under hypoxic conditions.

kin(p(MGI:Mapk14)) -> (bp(GO:"response to hypoxia") -> tscript(p(MGI:Hif1a)))

As shown in Fig. 5F, the mRNA expression levels of most lipogenic genes including G6PD, 6PGD, ME, ADD1/SREBP1c, and FAS and those of adipogenic genes including PPARgamma, C/EBPalpha, and aP2 were greatly decreased in G6PD-11i-infected 3T3-L1 cells, indicating that a certain amount of G6PD appears to be required for the execution of both adipogenesis and lipogenesis in adipocytes.

Surprisingly, the expression of certain adipocytokines such as tumor necrosis factor alpha and resistin was increased, whereas that of adiponectin was decreased in G6PD overexpressed adipocytes

tscript(p(HGNC:HMGA1)) -> surf(p(HGNC:INSR))

Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity.

tscript(p(MGI:Hmga1)) -> sec(a(SCHEM:"serum insulin"))

Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes.

kin(p(HGNC:MAP3K5)) -> p(HGNC:PDCD6,pmod(P))

We also found that apoptosis signal-regulating kinase 1 (ASK1) strongly phosphorylated ALG-2. Importantly, Raf-1 blocks the ASK1-dependent ALG-2 phosphorylation

p(MGI:Thbs1) -| bp(GO:"monocyte extravasation")

TSP-1-/- mice had markedly increased macrophage and myofibroblast density

tscript(p(HGNC:TP53)) -| gtp(p(HGNC:HRAS))

Supplementary Figure 3 Cluster of upregulated genes that correlate with INK4A locus [inactivation].

tscript(p(MGI:Cebpa)) -> bp(GO:"cell differentiation")

The first transcription factors found to participate in adipogenesis were members of the bZIP family of CCAAT/enhancer binding proteins (C/EBPs), specifically C/EBPa, C/EBPb, and C/EBPd. Upon the addition of adipogenic cocktail to 3T3-L1 pre-adipocytes, there is a rapid and transient elevation in C/EBPb and C/EBPd [7,9] The appearance of these proteins is followed rapidly by the expression of C/EBPa, and by the nuclear hormone receptor peroxisome proliferator-activated receptor g (PPARg). These two factors remain elevated for the rest of the differentiation process and indeed for the life of the mature adipocyte. C/EBPa and PPARg are the most critical factors yet discovered for adipogenesis, as will be discussed below. For the moment, suffice it to say that virtually every single downstream target gene whose expression defines the adipocyte appears to be regulated by one or both of these proteins. All of the aforementioned factors, C/EBPa, C/EBPb, C/EBPd, and PPARg, can induce or accelerate differentiation in non-adipogenic NIH-3T3 cells [7].

Of the 80 protein spots showing significant changes in protein levels after oncogenic transformation by RAS, we successfully identified 32 of them from 34 protein spots by peptide mass fingerprinting.

gtp(p(HGNC:HRAS)) -> path(SDIS:"anchorage-independent growth")

While T29 cells, stably transfected with SV40 T/t antigens and hTERT, are fully immortalized, only the addition of oncogenic RAS leads to the malignant transformation of T29H cells as demonstrated by the capability of anchorage-independent growth and tumor formation in nude mice.

gtp(p(HGNC:HRAS)) -> path(SDIS:"tumor growth")

path(SDIS:"food intake") -| r(HGNC:PTPRA)

path(SDIS:"food intake") -| r(HGNC:RFC1)

path(SDIS:"food intake") -| r(HGNC:RARS)

path(SDIS:"food intake") -| r(HGNC:RNASE4)

path(SDIS:"food intake") -| r(HGNC:UGDH)

path(SDIS:"food intake") -> r(HGNC:GLB1)

path(SDIS:"food intake") -> r(HGNC:LYPLA1)

By using specific inhibitors for PI3K (LY294002) and ERK MAPKs (PD98059), we demonstrate that LY294002 either alone or in conjunction with PD98059 inhibited IL-10-induced phosphorylation of STAT-1 and consequently CD14 expression.

cat(p(MGI:Ctss)) -> (p(MGI:Ifng) -> bp(GO:"inflammatory response"))
p(MGI:Ifng) -> bp(GO:"inflammatory response")

Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-gamma-induced DNA injury, apoptosis, emphysema, inflammation, and protease accumulation.

CD200 (OX2) is a membrane glycoprotein that interacts with a structurally related receptor (CD200R) involved in the regulation of macrophage function.

kin(p(PFH:"PRKA Family")) => p(HGNC:GRK1,pmod(P,S,21))

kin(p(PFH:"PRKA Family")) => p(HGNC:GRK7,pmod(P,S,23))

tscript(p(HGNC:RB1)) -> bp(GO:"cell differentiation")

It [pRB] also coactivates certain non-E2F transcription factors and promotes differentiation.

kin(p(HGNC:MAPK3)) => p(HGNC:RPS3,pmod(P,T,42))

down-regulation of SphK2 in these cells completely eliminated migration toward EGF

p(HGNC:EGF) -> p(HGNC:EPHA2,pmod(P,Y,588))

The fold increase of these EphA2 tyrosines are just below the cutoff used.

p(HGNC:EGF) -> p(HGNC:EPHA2,pmod(P,Y,594))

kin(p(HGNC:EGFR)) -> p(HGNC:CTNND1,pmod(P,Y,321))

This is taken from supplemental table 2 from PMID 15951569 Cut-offs were 2.25 for increase and 0.5 for decrease LLID were found by converting from GI assession numbers in DAVID Spreadsheet is saved in the project folder for Cell Signaling Project # bduckworth

kin(p(HGNC:EGFR)) -> p(HGNC:CAV1,pmod(P,Y,14))

kin(p(HGNC:EGFR)) -> p(HGNC:EFNB2,pmod(P,Y,330))

kin(p(HGNC:EGFR)) -> p(HGNC:ITSN2,pmod(P,Y,552))

kin(p(HGNC:EGFR)) -> p(HGNC:NCK1,pmod(P,Y,105))

kin(p(HGNC:EGFR)) -> p(HGNC:STAM2,pmod(P,Y,374))

kin(p(HGNC:EGFR)) -> p(HGNC:TNK2,pmod(P,Y,857))

kin(p(HGNC:EGFR)) -> p(HGNC:TNK2,pmod(P,Y,858))

kin(p(HGNC:EGFR)) -> p(HGNC:TNS3,pmod(P,S,536))

kin(p(HGNC:EGFR)) -> p(HGNC:TNS3,pmod(P,Y,540))

kin(p(HGNC:MAPK3)) => p(HGNC:GRB10,pmod(P,S,476))

kin(p(PFR:"Prkc Family")) -> path(SDIS:"tumor growth")

4]. On the whole, these data are consistent with the known role of PKC isoenzymes in tumour cell proliferation, invasion and metastasis. Moreover, PKC has been implicated in the pathogenesis of asthma

a(SCHEM:Sirolimus) -| p(HGNC:EIF4EBP1,pmod(P))

rapamycin inhibited phospho-RPS6 and 4E-BP1

a(SCHEM:Sirolimus) -| p(HGNC:RPS6,pmod(P))

PRL stimulated (100 ng/ml for 15 min) the phosphorylation of paxillin by Fak in T47D cells.

ICBP90 expression was strongly decreased after TCR triggering concomitantly to cyclin D3 and topoisomerase IIalpha expression decreases. Cell stimulation with PMA and/or calcium ionophore A23187 down-regulated ICBP90 expression.

Northern and Western blot analysis detected significantly higher levels of IGF-1 in cells overexpressing GH.

tscript(p(HGNC:NR4A3)) -> bp(GO:"inflammatory response")

NR4A nuclear receptors as potential transcriptional mediators of inflammatory signals in activated macrophages

tscript(complex(NCH:"Nfkb Complex")) -> r(HGNC:NR4A1)

Several lines of evidence point to the NF-kappaB signaling pathway as a principal mediator of inducible NR4A expression in macrophages

a(SCHEM:"Oxidized Low Density Lipoprotein") -> r(HGNC:NR4A2)

Treatment of macrophages with lipopolysaccharide (LPS), cytokines, or oxidized lipids triggers the transcriptional induction of Nur77 (NR4A1), Nurr1 (NR4A2), and NOR1 (NR4A3) expression.

cat(p(HGNC:PRMT1)) -> tscript(p(HGNC:PPARGC1A))

PGC-1alpha coactivator activity is potentiated by arginine methylation by protein arginine methyltransferase 1 (PRMT1), another nuclear receptor coactivator.

bp(GO:"response to osmotic stress") -> r(HGNC:AKR1B1)

The cellular response to osmotic stress ensures that the concentration of water inside the cell is maintained within a range that is compatible with biologic function. Single cell organisms are particularly dependent on mechanisms that permit adaptation to osmotic stress because each individual cell is directly exposed to the external environment. Mammals, however, limit osmotic stress by establishing an internal aqueous environment in which intravascular water and electrolytes are subject to sensitive and dynamic, organism-based homeostatic regulation. Recent studies of NFAT5/TonEBP, an essential mammalian osmoregulatory transcription factor, demonstrate the unexpected yet critical significance of cell-based osmotic regulation in vivo. These results highlight the fundamental importance of maintaining intracellular water homeostasis in the face of varying cellular metabolic activity and distinct tissue microenvironments.

Biologically, SAK RNA interference (RNAi) silencing induced apoptosis, whereas SAK overexpression attenuated p53-induced apoptosis.

Both EGFR and GRPR are activated in NSCLC by their corresponding ligands, TGF-a and GRP, in an autocrine manner.

tscript(p(HGNC:BHLHE40)) -| r(HGNC:PER2)

From full text of Table 1 and following up on references in table 1: A list of potential BHLHB2- and BHLHB3-target genes

tscript(p(HGNC:BHLHE40)) =| r(HGNC:PCK2)

From full text table 4: Reagents regulating expression of the BHLHB2 and BHLHB3 genes

a(CHEBI:glucocorticoid) -| r(HGNC:BHLHE40)

bp(GO:"cell differentiation") -> r(HGNC:ATP2A3)

We report that SERCA3 expression increased along the crypts as cells differentiated in normal colonic mucosa

Supplemental Table 1 - genes regulated by progesterone at 48h up genes

a(CHEBI:progesterone) -> r(HGNC:HSD11B2)

tscript(p(HGNC:MITF)) -> (a(SCHEM:"cyclic AMP") -> r(HGNC:HIF1A))

melanocyte-specific transcription factor, microphthalmia-associated transcription factor (MITF), binds to the Hif1a promoter and strongly stimulates its transcriptional activity. Further, MITF \"silencing\" abrogates the cAMP effect on Hif1a expression, and overexpression of MITF in human melanoma cells is sufficient to stimulate HIF1A mRNA

p(HGNC:AKT2,pmod(P,S,474)) => kin(p(HGNC:AKT2))

After PIP3 binding, Akt1 is activated by phosphorylation on two critical residues, namely threonine %308 (T308) and serine 473 (S473); similar activation residues (S472 and S474, %respectively) are highly conserved in Akt2 and Akt3 Phosphoinositol-3-phosphate (PIP3) is a product of phosphoinositol 3-kinase enzymatic activity and has been shown to be a prerequisite lipid modulator of Akt activity Akt activity can be regulated by the PTEN tumour suppressor gene, which negatively regulates PIP3 levels PIP3 has been described as a downstream component of a wide range of receptors, including the c-Met receptor [5], the epidermal growth factor receptor family [6], fibroblast growth factor receptor [7], insulin growth factor receptor [8] and platelet-derived growth factor receptor

phos(p(HGNC:PTEN)) =| a(SCHEM:"Phosphatidylinositol-3,4,5-trisphosphate")

Akt activity can be regulated by the PTEN tumour suppressor gene, which negatively regulates PIP3 levels

kin(p(HGNC:FGFR1)) -> complex(a(SCHEM:"Phosphatidylinositol-3,4,5-trisphosphate"),p(PFH:"AKT Family"))

PIP3 has been described as a downstream component of a wide range of receptors, including the c-Met receptor [5], the epidermal growth factor receptor family [6], fibroblast growth factor receptor [7], insulin growth factor receptor [8] and platelet-derived growth factor receptor

title := \"Epithelium-specific ets transcription factor 2 upregulates cytokeratin 18 expression in pulmonary epithelial cells through an interaction with cytokeratin 18 intron 1.\" Multiple interactions between the ETS domain and putative DNA binding sites within K18 intron 1 were observed,

Fra-1 and JAB1 (COPS5) levels are markedly increased in Nrf1 and Nrf2 null cells.

Glutamate-cysteine ligase catalytic subunit (GCLC) is regulated transcriptionally by Nrf1 and Nrf2.tert-Butylhydroquinone (TBH) induces human GCLC via Nrf2-mediated trans activation of the antioxidant-responsive element (ARE). Interestingly, TBH also induces rat GCLC, but the rat GCLC promoter lacks ARE. This study examined the role of Nrf1 and Nrf2 in the transcriptional regulation of rat GCLC. The baseline and TBH-mediated increase in GCLC mRNA levels and rat GCLC promoter activity were lower in Nrf1 and Nrf2 null (F1 and F2) fibroblasts than in wild-type cells.Overexpression of Nrf1 and Nrf2 in respective cells restored the rat GCLC promoter activity and response to TBH but not if the AP-1 and NF-kappaB binding sites were mutated.

tscript(complex(NCM:"Nfkb Complex")) => r(MGI:Gclc)

Nrf2 overexpression alone also induced the rat GCLC promoter activity and, in conjunction with TBH treatment, resulted in a synergistic induction of the rat GCLC promoter activity. However, this induction is blocked significantly if the AP-1 site or the NF-kappaB site is mutated and completely prevented if both sites are mutated.

tscript(p(MGI:Nfe2l2)) -> tscript(complex(NCM:"AP-1 Complex"))

By using oligonucleotide expression microarray analysis and analyzing the promoters of p63-induced genes, we have identified novel p63-specific response elements (p63-REs) in the promoter regions of EVPL and SMARCD3. # TABLE 1. List of genes induced over fourfold by TAp63y in 293 inducible cells

tscript(p(HGNC:TP63)) -> r(HGNC:COL17A1)

tscript(p(HGNC:TP63)) -> r(HGNC:CDC42EP4)

tscript(p(HGNC:TP63)) -> r(HGNC:PRICKLE3)

tscript(p(HGNC:TP63)) -> r(HGNC:RAP1GAP)

TNF-alpha, IL-1beta, IL-6 and IFN-gamma could induce the secretion of C3 and Bf of A549 cells. RA alone had no effect on secretion of C3 and Bf of A549 cells but could notably enhance the secretion of C3 and Bf of A549 cells induced by the cytokines

a(SCHEM:Tretinoin) -> (p(HGNC:TNF) -> p(HGNC:CFB))

a(CHEBI:"zinc protoporphyrin") -| cat(p(MGI:Hmox1))

NO-mediated increase in MnSOD activity was partly abolished by HO-1 inhibitor Zn(II) protoporphyrin IX (ZnPP)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> sec(p(PFH:"HSPA Family"))

After 24 h there was a significant increase in HSP70 in the culture media of oxLDL treated macrophages compared to untreated controls (P < 0.05, Fig. 2A and B).

OxLDLsup increased intracellular IL-12 production in naïve macrophages (P < 0.05; Fig. 5), and pre-treatment of the oxLDLsup with neutralizing antibodies against HSP70 inhibited this increase.

a(SCHEM:"Oxidized Low Density Lipoprotein") -> r(HGNC:HMOX1)

The results from the DNA microarray scan show that 5 of the 17 up regulated genes after 6 h of oxLDL treatment belonged to the heat shock protein (HSP) family (Fig. 1A). Three of these genes belonged to the HSP70 family (HSP70-1A, -1B and HSP70 6). The two remaining HSP genes were DNAJB1 (member of the HSP40 family) and heme oxygenase 1 (HMOX1, also referred to as HSP32).

a(CHEBI:lipopolysaccharide) -> r(HGNC:IL1R1)

Figure 1 Gene expression in peripheral blood neutrophils stimulated by several mediators in vitro. (RT-PCR) Peripheral blood neutrophils were incubated with several physiological stimuli for 3 hours in vitro at 37?C (TNFa, 100 U/ml; GM-CSF, 0.1 nM; IL-8, 10 nM; fMLP, 1 mM; LPS, 10 ng/ml). Expression of indicated genes was measured by real time RT-PCR.

a(CHEBI:lipopolysaccharide) -> r(HGNC:IL1R2)

TFE3 and TFEB regulate endogenous WT1, Snail, and Smad7 expression in 3T3 cells. A, RT-PCR analyses indicate that overexpressed TFE3 and TFEB induce WT1 expression and decrease Snail expression in 3T3 cells; inhibition of endogenous TFE3 and TFEB represses Smad7 expression.

cat(p(HGNC:LPL)) -> tscript(p(HGNC:STAT1))

(Stat1). The anti-inflammatory response of LPL in suppressing TNF-alpha-induced gene expression was a result of its inhibition of NF-kappaB activity by the abrogation of IkappaB-alpha degradation and phosphorylation of the p65 subunit.

kin(p(HGNC:JAK2)) -> tscript(p(HGNC:STAT1))

complex(p(MGI:Mib1),p(MGI:Dll1)) -| p(MGI:Dll1)

Mind bomb 1 (Mib1) has been identified as a ubiquitin ligase that promotes the endocytosis of Delta. In accordance with the pan-Notch defects in Mib1-/- embryos, Mib1 interacts with and regulates all of the Notch ligands, jagged 1 and jagged 2, as well as Dll1, Dll3 and Dll4.

a(CHEBI:"reactive oxygen species") -> a(SCHEM:"8-Oxo-7,8-dihydrodeoxyguanine")

8-Oxo-7,8-dihydroguanine (8-oxoGua) is produced in cells by reactive oxygen species

p(HGNC:KRAS,sub(Q,61,H)) => gtp(p(HGNC:KRAS))

a(CHEBI:lipopolysaccharide) -> p(HGNC:TLR2)

cells were exposed to LPS (1 ?g/ml) which led to an increased expression of TLR2 on AM from nonsmokers (18.35 ± 4.24 vs. 13.98 ± 2.54 rMFI [A] p < 0.04; 21.1 ± 6.23 vs. 12.07 ± 3.5 [B] p < 0.04). In contrast, cells of smokers and COPD patients did not respond to LPS stimulation with increased TLR2 expression

path(SDIS:"Type II diabetes") positiveCorrelation r(MGI:Sod1)

GPx-1 and SOD-1 showed elevated mRNA expression in the KKAy mice in the kidney and heart,

bp(MESHPP:Obesity) positiveCorrelation p(MGI:Nampt)

The significance of endogenous visfatin controlling whole-body insulin sensitivity is reinforced by the phenotype of lean, heterozygous visfatin-knockout mice, which revealed mild but reproducible hyperglycaemia. Subsequent analysis of this insulin-mimetic effect revealed two surprising findings: that the effects of visfatin are mediated by the insulin receptor itself, with remarkably similar affinities to those of insulin but through a distinct binding site, and that this insulin-sensitizing effect of visfatin might be additive to the effect of insulin, suggesting that visfatin activates insulin-receptor-activated pathways through a novel mechanism. What is the physiological relevance of visfatin for the metabolic syndrome? The discovery of this curious new adipokine has great potential to significantly enhance our understanding of the metabolic syndrome. However, as with most new discoveries, these findings need to be reproduced. Indeed, there is already an indication that the correlation between visfatin gene expression and the metabolic syndromemight not be universal to all models [8]. Novel findings also raise several newquestions that need to be addressed before their true significance can be appreciated. It will be necessary to determine the contribution of visfatin originating from visceral adipose tissue to the control of global insulin sensitivity. Although the affinity of visfatin for the insulin receptor appears to be similar to insulin, its concentration in plasma is much lower (3-10% of the insulin concentration) under physiological conditions. It is also not regulated by fasting and feeding. This raises doubts about the physiological importance of the systemic insulinsensitizing effects of visfatin. However, the dramatic elevation of visfatin levels in the visceral adipose tissue of obese mice suggests that it has a significant role in the pathophysiology of obesity.

p(HGNC:NAMPT) -| bp(MESHPP:"Insulin Resistance")

When delivered directly to diabetic mice, visfatin also improved insulin sensitivity in vivo, decreasing glucose and insulin levels [2].

IRF5 associates with both Myd88 and TRAF-6 and ligands for TLR4 and TLR9 promote nuclear translocation of IRF5 in a Myd88-dependent manner [61] (Figure 3). However, many of the downstream mediators of the IRF5 pathway await identification. Although IRF-5 is phosphorylated by TBK1 and IKK-i, this phosphorylation does not lead to IRF-5 nuclear translocation or activation [62]. The Myd88 activation of IRF-5...

a(SCHEM:"Oxidized Low Density Lipoprotein") -> r(MGI:Stmn1)

TABLE I Differentially expressed proteins in oxLDL-treated J774 or J774-CE macrophages

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:12332)

TABLE I - Differentially expressed proteins in oxLDL-treated J774. All identified proteins gave Mascot total scores greater than 200, which was calculated from the expression 10 log(p) where p is the probability that the match is a random event (p 1020). Individual peptide scores of 40 or greater represented extensive homology, and at least two of these CID spectra from each analysis were visually inspected to verify the peptide sequence. Typical sequence coverage was at least 20%.

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:11461)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:17886)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:18655)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:18746)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:20655)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:233016)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:107146)

TABLE II - Up-regulated mRNA in oxLDL-treated J774 macrophages. The statistical significance of the differential expression for each transcript was determined by the Wilcoxon signed rank test. Each probe set in the differentially expressed sample was compared with its counterpart, and a p value was calculated to determine the degree of change. A value of p less than 0.002 denoted an increase in transcript, and a value of p greater than 0.998 denoted a decrease in transcript. All of the differentially expressed transcripts reported here were determined to be increased or decreased in the oxLDL-treated sample of at least one sample pair (J774 untreated/oxLDL-treated or J774-CE untreated/ oxLDL-treated) according to this statistical test.

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:20706)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:52822)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:59010)

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:108052)

TABLE III - Down-regulated mRNA in oxLDL-treated J774 macrophages. The statistical significance of the differential expression for each transcript was determined by the Wilcoxon signed rank test. Each probe set in the differentially expressed sample was compared with its counterpart, and a p value was calculated to determine the degree of change. A value of p less than 0.002 denoted an increase in transcript, and a value of p greater than 0.998 denoted a decrease in transcript. All of the differentially expressed transcripts reported here were determined to be increased or decreased in the oxLDL-treated sample of at least one sample pair (J774 untreated/oxLDL-treated or J774-CE untreated/ oxLDL-treated) according to this statistical test.

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:22040)

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:276950)

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:327978)

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:55932)

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:65963)

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:98660)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:211666)

TABLE IV - Differential regulation of antioxidant response genes in oxLDL-treated J774 macrophages. The statistical significance of the differential expression for each transcript was determined by the Wilcoxon signed rank test. Each probe set in the differentially expressed sample was compared with its counterpart, and a p value was calculated to determine the degree of change. A value of p less than 0.002 denoted an increase in transcript, and a value of p greater than 0.998 denoted a decrease in transcript. All of the differentially expressed transcripts reported here were determined to be increased or decreased in the oxLDL-treated sample of at least one sample pair (J774 untreated/oxLDL-treated or J774-CE untreated/ oxLDL-treated) according to this statistical test.

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:50493)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:77974)

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:110454)

TABLE V - Differential regulation of immune response mRNA transcripts in oxLDL-treated J774 macrophages. The statistical significance of the differential expression for each transcript was determined by the Wilcoxon signed rank test. Each probe set in the differentially expressed sample was compared with its counterpart, and a p value was calculated to determine the degree of change. A value of p less than 0.002 denoted an increase in transcript, and a value of p greater than 0.998 denoted a decrease in transcript. All of the differentially expressed transcripts reported here were determined to be increased or decreased in the oxLDL-treated sample of at least one sample pair (J774 untreated/oxLDL-treated or J774-CE untreated/ oxLDL-treated) according to this statistical test.

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:16019)

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:170744)

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:21810)

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:23962)

a(SCHEM:"Oxidized Low Density Lipoprotein") -| p(EGID:67775)

a(SCHEM:"Oxidized Low Density Lipoprotein") -> p(EGID:21939)

SIRT1 binds acetylated FOXO4 and restores its activity. Thus SIRT1 activates FOXO1 and FOXO4, which promote cell-cycle arrest by inducing p27kip

SIRT1 represses PPAR-gamma, a key regulator of adipogenesis, by docking with its cofactors NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors)

Although it has been clearly established that negative feedback loops have a fundamental role in the regulation of epidermal growth factor receptor (EGFR) signalling in flies, their role in the regulation of mammalian EGFR has been inferred only recently from in vitro studies. Here, we report on the forced expression of RALT/MIG-6, a negative feedback regulator of ErbB receptors, in mouse skin. Conversely, knockdown of RALT by RNA interference enhanced ErbB mitogenic signalling. Thus, RALT behaves as a suppressor of EGFR signalling in mouse skin.

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> path(SDIS:"adipose glucose import")

Finally, activation of Akt induces an increase in the concentration of cellular fatty acids as well as phosphoglycerides, the components of cellular membranes.

kin(p(HGNC:AKT1)) -> tscript(p(HGNC:SREBF1))

We also show that Akt leads to the accumulation of nuclear SREBP-1 but not SREBP-2, and that activation of SREBP is required for Akt-induced activation of the FAS promoter.

Id2 protein is selectively upregulated by UVB... which revealed that UVB alters the expression of three of the four human inhibitor of differentiation/DNA binding (Id) proteins that comprise a class of helix-loop-helix family of transcription factors involved in proliferation, differentiation, apoptosis, and carcinogenesis. These results were verified by RT-PCR and immunoblot analysis of control and UVB-irradiated primary and immortalized keratinocytes. Whereas Id1 was downregulated in both cell types, Id2 expression was upregulated in primary HFK, but not immortalized cells. In contrast, Id3 expression was significantly increased only in immortalized cells.

bp(GO:"response to UV-B") -| r(HGNC:ID1)

bp(GO:"response to UV-B") -> r(HGNC:ID2)

bp(GO:"response to UV-B") -> r(HGNC:ID3)

p(MGI:Olr1) -> path(SDIS:"fatty acid import")

Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake

a(CHEBI:rosiglitazone) -> path(SDIS:"fatty acid import")

a(CHEBI:rosiglitazone) -| tscript(p(MGI:Ncor2))

SMRT and NCo-R were recruited to the 3 distinct regions in the OLR1 promoter containing the PPREs. Rosiglitazone treatment released corepressor binding in all 3 regions

bp(GO:"cell differentiation") -| r(MGI:Brd3)

we identified three conserved but uncharacterized genes encoding bromodomain containing 3 (BRD3), protein lysine methyltransferase (PLM), and kelch domain containing 2 (KLHDC2), which were downregulated during endothelial differentiation. An RNA blot study showed that these genes were markedly expressed in undifferentiated ES cells, whereas the expression was reduced upon endothelial differentiation;

bp(GO:"cell differentiation") -| r(MGI:Klhdc2)

p(MGI:Nmu) -> bp(GO:"cellular extravasation")

Moreover, intraplantar injection of NMU into paws induced early inflammatory responses such as mast cell degranulation, vasodilation, and plasma extravasation in WT mice but not in WBB6F(1)-W/W(v) mice

EGR-p65 complexes strongly activated transcription of the promoters of the human genes encoding the cytokines interleukin 2, tissue necrosis factor alpha and ICAM-1. The EGR-p65 complexes increased reporter-gene activity about 100-fold and thus exceeded the transcriptional activities of the p65 homodimer and the p65/p50 heterodimers.

path(SDIS:"viral infection") -> r(HGNC:FGG)

TABLE 1. Increase in the mRNA levels of fibrinogen and fibrinogen-related genes, as well as other cellular genes, in 3a-expressing stable A549 cell lines, clones U1 and U2, as determined by oligonucleotide microarray analysis

path(SDIS:"viral infection") -> r(HGNC:FGL1)

path(SDIS:"viral infection") -> r(HGNC:FXYD2)

path(SDIS:"viral infection") -> r(HGNC:S100P)

path(SDIS:"viral infection") -> r(HGNC:TM4SF20)

path(SDIS:"viral infection") -> r(HGNC:UPK1B)

path(SDIS:"viral infection") -> r(HGNC:VCAN)

Figure 5 Changes in gene expression in taf4-/- cells

kin(p(PFR:"MAPK Erk1/3 Family")) -> r(RGD:Tgfb1)

We show that PDGF-BB induces TSP-1 and TGF-beta1 via the src kinase pathway whereas TNF-a utilizes the MAPK/Erk pathway

cat(p(HGNC:CMA1)) -> bp(MESHPP:Apoptosis)

RESULTS: Most of the cells in the incubation with chymase were detached by 24 hr. However, chymase-mediated apoptosis was a slower process and was only detected after incubation of cells with chymase for 36 to 48 hr.

kin(complex(NCH:"AMP Activated Protein Kinase Complex")) -| cat(p(HGNC:ACACA))

Activation of AMPK leads to phosphorylation, and thus inhibition, of acetyl coenzyme A carboxylase.

Although extensively studied in cachexia, autoimmune disease, rheumatoid arthritis, sepsis, and other inflammatory disorders, the role of TNF-alpha and its association with obesity and diabetes is less understood. Infusion of TNF-alpha in rats impaired insulin-stimulated whole body glucose disposal (43).

p(HGNC:IL6) -| (p(HGNC:IRS1,pmod(P,Y)) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex")))
p(HGNC:IRS1,pmod(P,Y)) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))

Although the exact mechanism of resistin function has yet to be identified, Steppan et al. (100) observed increased circulating resistin levels in diet-induced and genetic models of obesity. Inhibition of resistin in these models restored insulin action, whereas administration of resistin inhibited insulin action in control animals. Surprisingly, the evidence linking resistin to diabetes and obesity in humans is less clear. Serum content of resistin is unaffected by obesity and insulin resistance in humans (37). Lee et al. (66) compared BMI, fat mass, and insulin action to resistin levels in 243 subjects (male and female) and observed no relationship. There was also no difference in resistin between lean and obese insulin-resistant subjects. Serum resistin can be elevated in Type 2 diabetes patients, but there was no relationship between adiposity and insulin (70), whereas others have reported no difference in obese, obese diabetic, and nonobese subjects (37). Although there are conflicting reports as to the relationship of resistin to adiposity (5), most investigations agree that resistin is not related to insulin resistance (107). To date, there is no information on the interaction between exercise and resistin. Because the role of resistin in regulating insulin action is unclear at this time, there appears to be little rationale to investigate the influence of exercise on this particular adipocytokine. Interleukin (IL-6). IL-6 is a multifunctional cytokine secreted by numerous cell types including immune cells, skeletal muscle, and adipose tissue. In an effort to determine function, Kim et al. (58) pretreated mice with IL-6 before a hyperinsulinemic- euglycemic clamp. IL-6 blunted skeletal muscle glucose disposal as well as IRS-1-associated phosphatidylinositol 3-kinase activity (58).

a(SCHEM:"serum insulin") -> path(SDIS:"muscle glucose import")
p(HGNC:IL6) -| (a(SCHEM:"serum insulin") -> path(SDIS:"muscle glucose import"))

a(SCHEM:Diacylglycerol) -> kin(p(HGNC:PRKCE))

TNF-alpha mediates insulin resistance via serine phosphorylation of insulin receptor substrate (IRS-1) in skeletal muscle, which inhibits the ability of insulin to stimulate GLUT-4 translocation to the cell membrane and therefore reduces glucose uptake (43). Conversely, inhibition of TNF-alpha results in increased insulin-stimulated IRS-1 tyrosine phosphorylation (10, 43). The ability of TNF-alpha to serine phosphorylate IRS-1 may be mediated via diacylglycerol (DAG). Incubating intact rat skeletal muscle strips with TNF-alpha significantly increased palmitate incorporation into DAG (7). This is important because DAGs are known activators of conventional and novel protein kinase C isoforms that serine phosphorylate, and thus inhibit, IRS-1.

complex(p(PFH:"NOTCH Family"),p(HGNC:RBPJ)) -> tscript(p(PFH:"NOTCH Family"))

Jagged1 on tumor cells binds to Notch receptor(s) on endothelial cells. Upon ligand binding, the Notch intracellular domain (NICD) is released from the endothelial cell plasma membrane by the secretase-dependent proteolytic cleavages of Notch receptor. The NICD then translocates to the nucleus, where it interacts with the CSL (named for mammalian CBF1/RBP, Drosophila Su(H), and C. elegans Lag-1) transcription repressor to activate the transcription of target genes.The basic-helix-loop-helix proteins (bHLH) Hairy/Enhancer of Split (Hes1, -5, and -7) and Hes-related proteins (Hey1, -2, and -L) are the best-characterized downstream targets.

tscript(p(PFH:"NOTCH Family")) -> r(HGNC:HEY2)

sec(p(HGNC:HGF)) -> kin(p(PFH:"MAPK Erk1/3 Family"))

The tumor associated growth factors HGF, EGF, and TGFA, produced by tumor cells and or stromal cells, induce Jagged1 expression in tumor cells probably in endothelial cells as well through MAPK pathway.

cat(p(HGNC:FTH1)) -| a(CHEBI:"reactive oxygen species")

when H-ferritin is expressed in L929 cells under a TNF-inducible system, the TNF-induced LIP and subsequent ROS production and cell death were all prevented

cat(p(HGNC:FTH1)) -| bp(GO:"cell death")

bp(GO:"response to hypoxia") -> r(HGNC:PFKFB4)

Our studies clearly demonstrated that PFKFB4 mRNA is also expressed in mammary gland malignant cells (MCF-7 and T47D cell lines) in normoxic conditions and that hypoxia strongly induces it expression.

bp(GO:"response to hypoxia") -> r(HGNC:LEP)

Indeed, the proportion of cardiac output that goes to adipose tissue is decreased in obesity, and the obese do not show the post-prandial increase in blood flow which occurs in lean individuals (Karpe et al. 2002). Activation of a transcription factor, hypoxia inducible factor-1 (HIF-1), through the stimulation of the expression of the HIF-1a subunit - the molecular sensor of hypoxia (Semenza 2001, Wenger 2002, Hopfl et al. 2004) - may be the mechanism through which low oxygen tension links to inflammation (Trayhurn & Wood 2004). The target genes for HIF-1 include VEGF and leptin, and expression of both of these has been shown to be stimulated in 3T3-L1 adipocytes in response to hypoxia (Lolmede et al. 2003).

It was previously identified as pre-B cell colony-enhancing factor (PBEF), a 52 000 mol. wt cytokine expressed in lymphocytes, and importantly it appears to be an insulin mimetic, both binding to and activating the insulin receptor (Fukuhara et al. 2005).

cat(p(HGNC:AZGP1)) -> cat(p(HGNC:ADRB3))

Such an action is not only surprising in itself, but also in relation to the augmented expression in visceral adipose tissue given the particular association between this fat depot and the metabolic syndrome. Zinc-a2-glycoprotein, the third novel adipokine, is a 43 000 mol. wt glycoprotein which is synthesized by certain malignant tumours and which has been used as a marker for cancer. The protein stimulates lipid loss in cachexia, and this occurs through the activation of lipolysis (Hirai et al. 1998, Todorov et al. 1998, Sanchez et al. 1999) via b3-adrenoceptors (Russell et al. 2002).

bp(GO:"response to cold") -| r(HGNC:LEP)

There have been few reports on the effects of either acute or chronic cold exposure on adipokine production, but substantial changes would be predicted, not least because of the sympathetic activation in WAT. One of the earliest studies on leptin showed that acute exposure of mice to the cold induced a major suppression of ob gene expression in WAT (Trayhurn et al.

bp(GO:"inflammatory response") -> sec(p(HGNC:NGF))

This suggests that NGF is an inflammatory response protein in adipocytes, a view supported by the subsequent observation that NGF secretion by 3T3-L1 cells is dramatically upregulated by prostaglandin PGD2 and by the J series prostaglandins, PGJ2 and D12-PGJ2 (Bullo et al. 2005).

bp(MESHPP:Obesity) positiveCorrelation sec(p(HGNC:NAMPT))

Visfatin is especially intriguing in that this adipokine is highly enriched in visceral fat, in both animals and humans, and its circulating levels are also increased in obesity (Fukuhara et al. 2005).

bp(MESHPP:Obesity) positiveCorrelation sec(p(HGNC:APLN))

and has now been found to be secreted from adipocytes (Boucher et al. 2005). It is synthesized as a 77 amino acid preproprotein, which is cleaved to a 55 amino acid product and then to further products, the biologically active form apparently being apelin-36 (Tatemoto et al. 1998). Apelin expression and circulating levels are increased in hyperinsulinaemia-associated obesities, including in humans, and in cell culture its expression rises after adipocyte differentiation.

kin(complex(NCH:"p85/p110 PI3Kinase Complex")) -> kin(p(PFH:"AKT Family"))

Co-transfection of Akt (myc-Akt) and ASK1 induced a high level of ASK1 phosphorylation, which was decreased approximately 40% by either the phosphoinositide 3-kinase inhibitor LY294002 or cotransfection of ASK1 with a kinase-dead Akt construct (myc-AktKD), suggesting that Akt phosphorylates ASK1 in cells.

Specific depletion of JDP2 resulted in p53-independent cell death that resembles apoptosis and was evident at 72 h.

cat(p(RGD:Adrb3)) -| a(SCHEM:Triacylglycerol)

KTO-7924 for 28 days significantly decreased RP WAT weight, plasma triglyceride, free fatty acid, and insulin, and improved insulin resistance

cat(p(RGD:Adrb3)) -| bp(MESHPP:"Insulin Resistance")

cat(p(RGD:Adrb3)) -| a(SCHEM:"serum triacylglycerol")

kin(p(PFR:"Akt Family")) -> p(RGD:Vcp,pmod(P,S,352))

significant increase in Akt activation in rat CA1 hippocampal region extracts Active recombinant Akt phosphorylated recombinant VCP in vitro. Site-directed mutagenesis studies identified Ser352, Ser746, and Ser748 as Akt phosphorylation sites on VCP.

a(SCHEM:Thiazolidinedione) -> r(RGD:Serpina12)

Recently, there has been a worldwide increase in the incidence of obesity associated with a metabolic syndrome known as type 2 diabetes, the development of which seems to be as a result of high-caloric diet intake and physical inactivity (1, 2); and predicted estimates suggest that the population with this syndrome may double to ~300 million by the year 2025 (3). One of the critical determinants for the development of this obesity may be an increase in the regional distribution of body fat, i.e., abdominal obesity. The latter often shows clustering of atherogenic risk factors (4, 5), i.e., hypertension, dyslipidemia, alterations in coagulation and inflammatory cytokine profiles, and hyperinsulinemic insulin resistance. As a consequence, there is an expected increase in morbidity and mortality of cardiovascular disease (6-9). Vigorous efforts have been made to delineate the relationship between increased adiposity and insulin resistance. In this regard, some molecules, including free fatty acids, leptin (10, 11), TNF-alpha (12, 13), acylation-stimulating protein (14, 15), adiponectin (16, 17), and resistin (18), which are secreted by the adipocytes, may modulate the sensitivity of insulin, the action of which activates multiple signaling events after phosphorylation of insulin receptor and several other molecules in type 2 diabetes (19, 20). To address the causal relationship between insulin resistance and obesity, various animal models, e.g., Otsuka Long-Evans Tokushima fatty (OLETF) rats, have been used by many investigators. The OLETF rat is an animal model of type 2 diabetes, which is characterized by abdominal obesity, insulin resistance, hypertension, and dyslipidemia (21). Previously, we isolated a ~135-bp cDNA fragment during differential screening of the genes upregulated in visceral adipose tissues of obese OLETF rats and down-regulated in nonobese and diabetes-resistant Long-Evans Tokushima Otsuka (LETO) rats (22). This cDNA fragment exhibited partial homology with the serine protease inhibitor belonging to the serine protease inhibitor (serpin) family. In this study, we describe the isolation of the full-length cDNA of this potential inhibitor, designated as \"vaspin\" (visceral adipose tissue-derived serpin). In addition, preparation of its putative protein and characterization of its biological properties by using in vitro and in vivo rat and mouse model systems are included in this communication. Vaspin Is a Visceral Adipose Tissue-Derived Serpin. The rat, mouse, and human vaspin cDNAs had ORFs of 1,236, 1,242, and 1,245 nucleotides, respectively (Fig. 1A). The putative proteins included 412, 414, and 415 amino. The analysis of the deduced amino acid sequence of rat, mouse, and human orthologs predicted a hydrophobic N-terminal signal peptide (underscored), and N-terminal Edman sequencing revealed that mouse vaspin protein begins at the Leu-21 residue. The reactive loop site (boxed) extends from 364 to 379 residues (Fig. 1A). Homology analyses indicated that vaspin has 40.5% identity with alpha1-antitrypsin. Automated protein structure homologymodeling by SWISS-MODEL (http://swiss-model.expasy.org) predicted the presence of three beta-sheets (blue), nine alpha-helices (red), and one reactive center loop (yellow), features characteristic of serpin gene family (Fig. 1B). A single transcript was observed in visceral WATs of 30-wk-old obese OLETF rats [VIS(OLTEF)], and it was absent in 6-wk-old lean LETO rats [VIS(LETO)] and in subdermal (SUB) and brown fatty tissues (Fig. 1C). No vaspin mRNA expression was observed in other nonadipose tissues from OLETF rats, suggesting its role in abdominal obesity as observed in this metabolic syndrome. Similarly, no mRNA transcript was observed in nonadipose tissues from human and mouse organs (data not shown). Regulation of Vaspin Gene Expression in Genetically Obese OLETF Rats. To investigate the regulation of vaspin gene exp...

a(SCHEM:"serum insulin") -> r(RGD:Serpina12)

at 30 wk of age and maintained its levels up to 50 wk, while reducing in visceral WATs, i.e., retroperitoneal and MES fat (Fig. 2E). Similarly, insulin therapy up-regulated expression of vaspin in SUB WATs along with a partial reduction in visceral WATs at 30 wk of age.

a(SCHEM:"serum insulin") -> kin(complex(NCM:"p85/p110 PI3Kinase Complex"))

Fenretinide treatment did not affect food intake, body weight or the development of obesity on the high-fat diet (not shown). Mice on a high-fat diet developed marked insulin resistance (Fig. 4d) and glucose intolerance (Fig. 4e). Fenretinide treatment improved insulin sensitivity (Fig. 4d) and normalized glucose tolerance (Fig. 4e). Similar results were obtained in ob/ob mice treated with fenretinide (not shown). Thus, both genetic and pharmacological interventions that decrease serum RBP4 levels improve insulin sensitivity. RBP4 impairs insulin signalling in muscle To understand how RBP4 alters insulin sensitivity, we studied insulin signalling in muscle and liver of Rbp4-/- mice and mice overexpressing human RBP4 (RBP4-Tg mice). Basal phosphoinositide 3-kinase (PI(3)K) activity was similar in all genotypes (Fig. 5a-d). Insulin resulted in a 26-fold increase in PI(3)K activity in muscle of control mice, but its effect was reduced by 30% in RBP4-Tg mice (Fig. 5a).

path(SDIS:"food intake") -> (p(MGI:Rbp4) -> a(SCHEM:"serum insulin"))

Rosiglitazone treatment also completely normalized the elevated serum RBP4 levels in adipose-Glut4-/- mice (Fig. 2c). The dramatic effect of this insulin-sensitizing anti-diabetic agent on serum RBP4 levels raises the possibility that elevation of RBP4 might play a causative role in insulin resistance and type 2 diabetes. Increased RBP4 causes insulin resistance Transgenic mice expressing human RBP4 driven by the mouse muscle creatine kinase (Mck) promoter (RBP4-Tg) have an ,3-fold increase in serum RBP4 levels compared with non-transgenic mice19, similar to the elevation observed in serum of adipose-Glut4-/- mice (see Supplementary Fig. 2). RBP4-Tg mice develop normally. Growth curves are similar to wild-type mice until at least 16 weeks of age (not shown). Insulin levels are higher in fed RBP4-Tg mice compared with wild-type mice, indicating insulin resistance (see Supplementary Table 2), which is also evident in insulin tolerance tests (Fig. 3a). There are no differences in glucose, free fatty acid, leptin, adiponectin or resistin levels in fed RBP4-Tg mice compared with controls (see Supplementary Table 2).

p(MGI:Slc2a4) -| bp(MESHPP:"Insulin Resistance")

There was no difference in the magnitude of serum RBP4 elevation between the obese and obese-diabetic groups, suggesting that obesity and insulin resistance, but not hyperglycaemia, are associated with elevated serum RBP4 in humans. Rosiglitazone reverses RBP4 elevation The anti-diabetic agent rosiglitazone is a peroxisome proliferator activated receptor-gamma (PPARg) agonist that improves insulin sensitivity17. Treatment of adipose-Glut4-/- mice with rosiglitazone for three weeks completely reversed their insulin resistance and glucose intolerance18.

a(CHEBI:aldosterone) -> bp(MESHPP:"Insulin Resistance")

Aldosterone dose-dependently inhibited expression of uncoupling protein-1 (UCP-1) by 30% (p dose-dependently impaired insulin-induced glucose uptake by about 25% (p 0.01).

a(CHEBI:aldosterone) -> bp(GO:"inflammatory response")

On a transcriptional level, mRNA of the proinflammatory adipokines leptin and monocyte chemoattractant protein-1 (MCP-1) was increased by 5,000% and 40%, respectively, by aldosterone exposure (p demonstrates that aldosterone directly impacts on major adipose functions including stimulation of proinflammatory adipokines.

kin(p(HGNC:MAPK1)) => p(HGNC:GSK3B,pmod(P,T,43))

kin(p(HGNC:MAPK3)) => p(HGNC:GSK3B,pmod(P,T,43))

phos(p(HGNC:PTPMT1)) -> sec(p(EGID:3630))

Knockdown of PTPMT1 expression in the pancreatic insulinoma cell line INS-1 832/13 alters the mitochondrial phosphoprotein profile and markedly enhances both ATP production and insulin secretion.

kin(p(HGNC:MAP3K3)) => kin(p(HGNC:MAP2K1))

from Gene MAP3K3: This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse Mekk3. Its catalytic domain is closely related to those of several other kinases, including mouse Mekk2, tobacco NPK, and yeast Ste11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed. This protein directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively; it does not regulate the p38 pathway. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NFKB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed.

kin(p(HGNC:MAP3K3)) -> kin(p(HGNC:MAPK1))

hKSR-2 also regulates the activity of MEKK3 (another MAP3K family member) in HEK-293T cells. We demonstrate that hKSR-2 is a negative regulator of MEKK3-mediated activation of MAP kinase (specifically ERK and JNK) and NF-kappaB pathways, and concurrently inhibits MEKK3-mediated interleukin-8 production.

We found that association of FIP200 with the TSC1-TSC2 complex correlated with its ability to increase cell size and up-regulate S6 kinase phosphorylation

complex(p(HGNC:RB1CC1),p(HGNC:TSC1),p(HGNC:TSC2)) -> bp(GO:"cell growth")

a(SCHEM:"Advanced Glycation End Product") -> a(SCHEM:"serum glucose")

75% of HAGE-HF mice were diabetic and exhibited higher body weight (P< 0.001), fasting glucose (P < 0.001), insulin (P< 0.001), and serum AGEs (P < 0.01) than control mice, while none of the LAGE-HF mice were diabetic despite a similar rise in body weight and plasma lipids.

cat(p(MGI:Dgat1)) -| bp(MESHPP:"Insulin Resistance")

... improved insulin sensitivity in the face of moderate obesity that is observed in transgenic mice overexpressing DGAT in adipose tisuue

The suppressor of cytokine signalling (SOCS) protein family negatively regulates cytokine action. In this study, we investigated the effects of estrogen (E2) on SOCS-3 expression in T47D and MCF-7 human breast cancer cells. Real-time PCR analysis of E2-treated T47D cells revealed a ligand and time-dependent increase in of SOCS-3 mRNA levels. Cloning of a 1.7 kb fragment of the human SOCS-3 5' flanking sequence, and subsequent analysis of potential transcription factor-binding sites identified an incomplete ERE motif located -1493 to -1489 upstream of the start site. Transient transfection of the cloned fragment in MCF-7 cells showed that both E2 and genistein treatment caused an increase in reporter gene activity, which was inhibited by co-treatment with ICI 182,780. Chromatin immunoprecipitation analysis revealed an E2 and time-dependent recruitment of ERalpha to the E2 responsive region of the human SOCS-3 promoter. In summary, this study shows that ERalpha directly regulates human SOCS-3 promoter activity in human breast cancer cells, thus modulating cytokine activity.

a(SCHEM:"cyclic AMP") -| p(HGNC:CFL1,pmod(P))

. Pretreatment of cultures with tautomycin, a protein phosphatase type 1 inhibitor, blocked the effect of cAMP on 1) the dephosphorylation of cofilin, 2) the decrease in RLC phosphorylation, and 3) the decrease in isometric tension.

p(HGNC:SUMO1) -| tscript(complex(NCH:"AP-1 Complex"))

lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229 sumoylation entails lower AP-1 transactivation activity

p(HGNC:SUMO2) -| tscript(complex(NCH:"AP-1 Complex"))

bp(MESHPP:Obesity) positiveCorrelation r(HGNC:C1QTNF5)

The analyses indicated that the inflammation/immune response category was over-represented, and that most inflammation-related genes were upregulated in adipocytes of obese subjects. Quantitative real-time PCR confirmed the transcriptional upregulation of representative inflammation-related genes (CCL2 and CCL3) encoding the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein 1alpha. The differential expression levels of eight positional candidate genes, including inflammation-related THY1 and C1QTNF5,

tscript(p(HGNC:FOXO3)) -> p(HGNC:TNFSF10)

A study found that FOXO3a induces apoptosis in LAPC4 prostate cancer cells via the up-regulation of its direct target tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (8).

tscript(p(MGI:Trp53)) -> bp(MESHPP:Apoptosis)

In p53-competent cells, Ckap2 does not induce tetraploidy but activates p53-mediated cell cycle arrest and apoptosis.

Yes-associated protein (YAP), also containing WW domains, was shown to associate with p73 and enhance its transcriptional activity.

a(SCHEM:Superoxides) -> a(CHEBI:"hydrogen peroxide")
cat(p(HGNC:SOD2)) -> (a(SCHEM:Superoxides) -> a(CHEBI:"hydrogen peroxide"))

Superoxide dismutases (SODs) are the only enzyme family with activity against superoxide radicals (resulting in hydrogen peroxide production). These enzymes include manganese SOD (MnSOD), copper zinc SOD (CuZnSOD), and extracellular SOD (ECSOD).21?23 All of them are widely expressed in human lung.24 CuZnSOD, which is mainly a cytosolic enzyme, is evenly distributed intracellularly but is also found in the nucleus and lysosomes.25

cat(p(HGNC:SOD1)) -> a(CHEBI:"hydrogen peroxide")

cat(p(HGNC:SOD1)) -> (a(SCHEM:Superoxides) -> a(CHEBI:"hydrogen peroxide"))

path(SDIS:"acute phase reaction") -| r(HGNC:ACADM)

mRNA levels of PGC-1alpha, ERRalpha, and MCAD are markedly reduced in the liver, heart, and kidney of mice during the lipopolysaccharide (LPS)-induced APR

path(SDIS:"acute phase reaction") -| r(HGNC:PPARGC1A)

a(CHEBI:glucocorticoid) -> r(RGD:Sftpa1)

S1 mapping of precursor transcripts has confirmed the stimulating effect of glucocorticoids on SP-A rat gene transcription in vivo.

Here we show that the genetic loss of Akt1, but not Akt2, in mice results in defective ischemia and VEGF-induced angiogenesis

p(HGNC:FLT4,pmod(P)) -> kin(complex(NCH:"p85/p110 PI3Kinase Complex"))

Functional and biochemical anlaysis of the E-R3 chimera also identified the contribution of tyrosines 1230/1231 to VEGFR-3- dependent proliferation, migration and survival. Our data show that these tyrosine residues activate the classic PI3K/AKT and ERK pathways upon GRB2 direct recruitment to the receptor. This site must collaborate with Y1337, which was previously shown to recruit SHC and indirectly GRB2.

a(CHEBI:dexamethasone) -| (kin(p(PFH:"AKT Family")) =| kin(p(HGNC:GSK3B)))
kin(p(PFH:"AKT Family")) =| kin(p(HGNC:GSK3B))

Dexamethasone treatment decreased the ability of insulin to stimulate glucose uptake, glycogen synthesis and glycogen synthase fractional activity. In addition, the dephosphorylation of glycogen synthase by insulin was blocked. These defects were paralleled by reduced insulin-stimulated protein kinase B (PKB) and GSK-3 phosphorylation. We demonstrated that chronic dexamethasone treatment impairs insulin-stimulated PKB and GSK-3 phosphorylation, which may contribute to insulin resistance in skeletal muscles.

a(CHEBI:dexamethasone) -| (kin(p(HGNC:INSR)) -| kin(p(HGNC:GSK3B)))

a(CHEBI:dexamethasone) -| (kin(p(MGI:Insr)) -> kin(p(PFM:"Akt Family")))
kin(p(MGI:Insr)) -> kin(p(PFM:"Akt Family"))

kin(p(HGNC:INSR)) -> p(HGNC:GSK3B,pmod(P,S))

tscript(p(HGNC:NR3C1)) -| (kin(p(PFH:"AKT Family")) =| kin(p(HGNC:GSK3B)))

in response to malathion three genes with increased expression after treatment in all four cell strains. These genes were two aldo-keto reductases (AKR1C1 and AKR1C2) and an estrogen-responsive gene (EBBP). Decreased expression of six RNA species was seen at various time points in all cell strains analyzed: plasminogen activator (PLAT), centromere protein F (CPF), replication factor C (RFC3), thymidylate synthetase (TYMS), a putative mitotic checkpoint kinase (BUB1)

p(HGNC:AR) -> bp(GO:"cell proliferation")

Here we show that lysine-specific demethylase 1 (LSD1; also known as BHC110) co-localizes with the androgen receptor in normal human prostate and prostate tumour. LSD1 interacts with androgen receptor in vitro and in vivo, and stimulates androgen-receptor-dependent transcription. Conversely, knockdown of LSD1 protein levels abrogates androgen-induced transcriptional activation and cell proliferation.

a(CHEBI:"hydrogen peroxide") -> p(HGNC:HRAS)

To this end, we employed 1) PD 98059 and U0126 (2 h and 15 min of incubation, respectively), which inhibit MEK (MAPKK); and 2) a dominant-negative MEK variant that inhibits cellular MEK (see \"Materials and Methods\"). The results, shown in Fig. 3, A-C, demonstrate that induction of Ha-Ras by H2O2 was abolished by MEK inhibition.

CYNOMOLGUS MONKEYS were exposed to ciprofibrate at various dose levels for either 4 or 15 days, and the liver transcriptional profiles were examined using Affymetrix human GeneChips. Data taken from Supplementary table 4. 27 genes upregulated and 22 genes downregulated. Probesets with p > 0.01 were selected as differentially expressed.

a(CHEBI:lipopolysaccharide) -> r(HGNC:G0S2)

LPS stimulates a vigorous inflammatory response from circulating leukocytes that varies greatly from individual to individual. The goal of this study was to use an unbiased approach to identify differences in gene expression that may account for the high degree of interindividual variability in inflammatory responses to LPS in the normal human population. We measured LPS-induced cytokine production ex vivo in whole blood from 102 healthy human subjects and identified individuals who consistently showed either very high or very low responses to LPS (denoted lps(high) and lps(low), respectively). Comparison of gene expression profiles between the lps(high) and lps(low) individuals revealed 80 genes that were differentially expressed in the presence of LPS and 21 genes that were differentially expressed in the absence of LPS (p confirmed using real-time RT-PCR. Functional relevance for one gene confirmed to be expressed at a higher level in lps(high), adipophilin, was inferred when reduction in adipophilin mRNA by small interfering RNA in the human monocyte-like cell line THP-1 resulted in a modest but significant reduction in LPS-induced MCP-1 mRNA expression. These data illustrate a novel approach to the identification of factors that determine interindividual variability in innate immune inflammatory responses and identify adipophilin as a novel potential regulator of LPS-induced MCP-1 production in human monocytes.

a(CHEBI:lipopolysaccharide) -> r(HGNC:IL12B)

p(HGNC:IL13) -> path(SDIS:"tight junction permeability")

IL-13 had a dose-dependent effect on transepithelial resistance of HT-29/B6 monolayers (reduction to 60% +/- 4%), whereas IL-4 had no effect. This was due to an increased number of apoptotic cells (5.6-fold +/- 0.9-fold) and an increased expression of the pore-forming tight junction protein claudin-2 to 295% +/- 37%, both of which contributed equally. Finally, epithelial restitution velocity decreased from 15.1 +/- 0.6 to 10.6 +/- 0.5 microm/h after treatment with IL-13.

tport(p(HGNC:LDLR)) -| a(SCHEM:"Oxidized Low Density Lipoprotein")

In FH patients, elevation in serum LDL-cholesterol levels secondary to the LDL receptor defect results in the formation of oxidized or otherwise modified LDL, and in their uptake by the macrophage scavenger receptors, leading to massive lipid accumulation and foam cell formation [10].

Protein levels of cyclins (D1, E, A), E2F1, and E2F4 were all elevated in the epidermis of BK5.IGF-1 mice. Also, immunoprecipitation experiments demonstrated an increase in cdk4/cyclin D1 and cdk2/cyclin E complex formation,

p(MGI:Igf1) -> p(PFM:"Gsk3 Family",pmod(P,S,9))

Western blot analyses with epidermal lysates showed that signaling components downstream of PI3K/Akt were altered in epidermis of BK5.IGF-1 mice. Increased phosphorylation of GSK-3 (Ser(9/21)), TSC2(Thr(1462)), and mTOR(Ser(2448)) was observed.

kin(p(HGNC:MAP2K1)) -> kin(p(HGNC:MAPK8))

Furthermore, we have found that constitutively activated MEK activates JNK. We have corroborated these findings in studies with isolated protein components from a human astrocyte (U-251) cell line; that is, JNK phosphorylates raf but not the reverse; MEK phosphorylates JNK but not the reverse.

a(SCHEM:"Very Low Density Lipoprotein") -> r(HGNC:IL1B)

# GeneRif: VLDL induces IL-1beta mRNA expression, caspase-1 activation, and IL-1beta release from macrophages

Table 1. Functional classification of target genes bound by ER alpha in MCF-7 cells in the presence of estradiol

Table 1. Functional classification of target genes bound by ER{alpha} in MCF-7 cells in the presence of estradiol

bp(MESHPP:Obesity) positiveCorrelation r(HGNC:ALOX5AP)

TABLE 2. Immune response regulated by obesity [obesity vs. lean microarray]

bp(MESHPP:Obesity) positiveCorrelation r(HGNC:CCL2)

bp(MESHPP:Obesity) positiveCorrelation r(HGNC:CD74)

bp(MESHPP:Obesity) positiveCorrelation r(HGNC:CXCL2)

bp(MESHPP:Obesity) positiveCorrelation r(HGNC:CXCR4)

bp(MESHPP:Obesity) positiveCorrelation r(HGNC:"HLA-DPA1")

bp(MESHPP:Obesity) positiveCorrelation r(HGNC:LYST)

bp(MESHPP:Obesity) positiveCorrelation r(HGNC:SELE)

Here, we report that Smac inhibits clonogenic tumor growth by blocking random migration and proliferation and by enhancing apoptosis in a cell density and cell type dependent manner in SH-EP neuroblastoma cells.

The age-related increase of lep gene expression could be, in part, responsible for these changes

p(HGNC:CLIP1) -| bp(GO:"cell proliferation")

Restin, a member of melanoma-associated antigen superfamily gene, was first cloned from differentiated leukemia cell induced by all trans-retinoic acid, and was able to inhibit cell proliferation

tscript(p(HGNC:ATF3)) -> bp(GO:"cell proliferation")

The results showed that only ATF3 had a strong interaction with Restin. It is interesting to know that ATF3 was an important transcription factor for G1 cell cycle initiation in physiological stress response. It was possible that the inhibition of cell proliferation by Restin might be related with the inhibition of ATF3 activity.

a(SCHEM:Hydrocortisone) -| bp(GO:angiogenesis)

Endogenous glucocorticoids, including those generated locally by 11betaHSD1, exert tonic inhibition of angiogenesis

treatment of LAN-1 cells with 5-aza-C reactivates the expression of CASP8 mRNA (Fig. 6E) and allows the binding of N-Myc to E-box sites (Fig. 6F)

cat(p(HGNC:CMKLR1)) -> bp(GO:"macrophage activation")

direct CMKLR1-positive plasmacytoid dendritic cell and tissue macrophage recruitment to sterile sites of tissue damage, as well as trafficking to sites of infectious and allergic inflammation.

p(HGNC:LOXL2) -> (tscript(p(HGNC:SNAI1)) -| p(PFH:"CDH Family"))
tscript(p(HGNC:SNAI1)) -| p(PFH:"CDH Family")

Here we show that lysyl-oxidase-like 2 and 3 (LOXL2 and LOXL3), two members of the lysyl-oxidase gene family, interact and cooperate with Snail to downregulate E-cadherin expression. Snail's lysine residues 98 and 137 are essential for Snail stability, functional cooperation with LOXL2/3 and induction of EMT

p(HGNC:SERTAD2) -> tscript(p(HGNC:TP53))

Expression of SEI-1, SEI-2 or SEI-3 strongly stimulates p53-dependent gene activation in HeLa and U2OS cells

Foxa2 occupied its binding sites in all three target genes... Therefore, the decreased activation of the PEPCK, TAT, and IGFBP-1 genes in Foxa2-deficient hepatocytes that we observed solely in the fasted state (Figure 2) indicates that Foxa2 is essential to the transcriptional response to food deprivation.

p(HGNC:CTNNB1,pmod(P,Y,654)) => tscript(p(HGNC:CTNNB1))

(from text) The phosphorylation of tyrosine 654 increases the ability of ?-catenin to bind the basal transcription factor TATA-binding protein, and mutation of Y654 to glutamate results in enhanced transcriptional activity [33]

kin(p(HGNC:EGFR)) => p(HGNC:CTNNB1,pmod(P,Y,654))

The binding of beta-catenin to these partners is regulated by phosphorylation of at least three critical tyrosine residues. Each of these residues is targeted by one or more specific kinases: Y142 by Fyn, Fer and cMet; Y489 by Abl; and Y654 by Src and the epidermal growth factor receptor.

Here we report that a 14-3-3-binding protein, TAZ (transcriptional coactivator with PDZ-binding motif), coactivates Runx2-dependent gene transcription while repressing PPARgamma-dependent gene transcription.

kin(p(PFH:"PRKC Family")) -> r(HGNC:EGR1)

HGF-induced expression of Egr-1, PDGFA, and VEGF was suppressed by pharmacologic and siRNA inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) and protein kinase C (PKC) pathways.

KO of onecut-2 decreases expression of a2m and follistatin in day 12.5 embryos.

found that sepsis evoked 1) a downregulation of genes encoding all examined electron transport chain components

path(MESHD:Sepsis) -| r(RGD:"Atp5h-ps1")

composite(a(SCHEM:Diosgenin),a(SCHEM:"Ethinyl estradiol")) -| r(RGD:Abcg5)

Hepatic Abcg5 and Abcg8 mRNA expression decreased in ethinyl estradiol and diosgenin-ethinyl estradiol groups compared with the control group and

composite(a(SCHEM:Diosgenin),a(SCHEM:"Ethinyl estradiol")) -> r(RGD:Abcc3)

Hepatic Mrp3 mRNA expression was remarkably increased in the D, EE and DE groups in comparison with the control group (531%, 321% and 1160% of control, respectively, P < 0.01). H

cat(p(MGI:Ednra)) -> a(SCHEM:"8-Isoprostane")

ET(A) receptor antagonist BQ-123. In AhR null mice, BQ-123 significantly reduced elevated plasma 8-isoprostane, a systemic end product of phospholipid oxidation by ROS,

Stable elevated expression of PLD2 also increased Myc expression and provided a Myc-dependent survival signal in the absence of E2.

p(HGNC:BARD1) -| (p(HGNC:BRCA1) -> bp(GO:"cell death"))

This model for reciprocal regulation of nuclear transport by NES masking is unique in the literature, although it is certainly possible that other heterodimers are regulated in a similar fashion. It is not yet known whether BRCA2 is regulated by nuclear-cytoplasmic shuttling. Functional implications of nuclear-cytoplasmic shuttling of BRCA1 and BARD1 Howdoes the nuclear shuttling ofBRCA1andBARD1regulate their function, and when does it occur? These questions are only now starting to be addressed. The only activity of either BRCA1orBARD1that is yet known to be influenced by nuclear import/export is their ability to induce apoptosis when overexpressed; apoptotic activity of both BRCA1(45) and of BARD1(51) is inhibited by at least 50% when the two proteins are co-expressed in cells.

kin(p(HGNC:MAP2K1)) -> kin(p(HGNC:IKBKB))

Endocrine therapy with an estrogen receptor (ER)-targeted antiestrogen, such as tamoxifen, or estrogen ablation by aromatase inhibitors is clinically indicated for the management of all forms of ER-positive breast cancer. However, 30-50% of ER-positive breast cancer cases fail to benefit clinically from endocrine therapy alone, and recent molecular evidence suggests that 'crosstalk' pathways originating from activated receptor tyrosine kinases and/or other proliferative and survival signals may be contributing to this endocrine resistance. Molecular identification and validation of candidate ER crosstalking pathways will likely lead to clinically important prognostic markers and targets for the application of novel therapeutics in combination with standard endocrine agents. This review focuses on a critical survival and proliferation pathway involving activation of nuclear factor-kappaB (NFkappaB), a family of ubiquitously expressed transcription factors that for nearly two decades have been known to be critical regulators of mammalian immune and inflammatory responses, and more recently have been associated with chemotherapy resistance. With the demonstration that activation of NFkappaB is absolutely required for normal mammary gland development, NFkappaB involvment in human breast cancers was initially explored and linked to the development of hormone-independent (ER-negative) breast cancer. Newer clinical evidence now implicates NFkappaB activation, particularly DNA-binding by the p50 subunit of NFkappaB, as a potential prognostic marker capable of identifying a high-risk subset of ER-positive, primary breast cancers destined for early relapse despite adjuvant endocrine therapy with tamoxifen. Furthermore, initial preclinical studies suggest that treatment strategies designed to prevent or interrupt activation of NFkappaB in cell-line models of these more aggressive, ER-positive breast cancers can restore their sensitivity to such standard endocrine agents as tamoxifen.

p(HGNC:AKT1,pmod(P,S)) => kin(p(HGNC:AKT1))

CXCR4 was localized to lipid rafts in PC cells and initiated Akt phosphorylation.

p(HGNC:RALBP1) -> (p(HGNC:TNF) -> kin(p(HGNC:IKBKB)))

Rip1 is required for IkappaB kinase activation in response to tumor necrosis factor alpha (TNF-alpha) and has been implicated in the Toll-like receptor 3 (TLR3) response to double-stranded RNA.

cat(p(HGNC:TLR3)) => complex(p(HGNC:TLR3),p(HGNC:MAP3K7))

Upon TLR3 activation, Rip1 is also modified by polyubiquitin chains and is recruited to TLR3 along with Traf6 and the ubiquitin-activated kinase Tak1.

We now demonstrate that PTN stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (PK) C substrate domain of beta-adducin through activation of either PKC alpha or beta.

tscript(p(HGNC:FOXO4)) -> bp(MESHPP:Apoptosis)

By using viral-mediated MEOX2 gene silencing and transfer, we show that restoring expression of the protein it encodes, GAX, in BECs from individuals with Alzheimer disease stimulates angiogenesis, transcriptionally suppresses AFX1 forkhead transcription factor-mediated apoptosis and increases the levels of a major amyloid-beta peptide (Abeta) clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP), at the blood-brain barrier

tscript(p(HGNC:MEOX2)) -| (tscript(p(HGNC:FOXO4)) -> bp(MESHPP:Apoptosis))

Stearoyl-CoA desaturase-2 gene expression is required for lipid synthesis during early skin and liver development.\" There are four known stearoyl-CoA desaturase (SCD) enzyme isoforms in mouse and two in humans that are required for the biosynthesis of monounsaturated fatty acids, mainly oleate.

Among these are the suppression of listericidal activity, the inhibition of phagocyte oxidase-mediated oxidative burst, and the suppression of important IFN-gamma-induced genes, including Ccl5, Cxcl10, Cxcl9, Irf2, Fcgr1, Fcgr3, and Tlr2

tscript(p(MGI:Atf4)) -| tscript(p(MGI:Creb1))

in the hippocampus of GCN2(-/-) mice, the expression of ATF4 is reduced and CREB activity is increased

bp(GO:"response to UV") -> p(MGI:Egfr,pmod(P,Y,1173))

EGFR was rapidly activated in mouse epidermis following exposure to UV, as detected by the phosphorylation of EGFR on tyrosine residues 992, 1045, 1068 and 1173.

kin(p(PFH:"AKT Family")) -> p(HGNC:RNF11,pmod(P,T,135))

RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies.

p(MGI:Pdx1) -| bp(GO:"cell proliferation")

Pdx1 repression was associated with increased cell proliferation predominantly in the exocrine pancreas and upregulation of genes implicated in pancreas regeneration.

We have previously demonstrated that p100H mutant mice, which lack a functional Sox6 gene, exhibit skeletal and cardiac muscle degeneration and develop cardiac conduction abnormalities soon after birth. To understand the role of Sox6 in skeletal muscle development, we identified muscle-specific genes differentially expressed between wild-type and p100H mutant skeletal muscles and investigated their temporal expression in the mutant muscle. We found that, in the mutant skeletal muscle, slow fiber and cardiac isoform genes are expressed at significantly higher levels, whereas fast fiber isoform genes are expressed at significantly lower levels than wild-type. Onset of this aberrant fiber type-specific gene expression in the mutant coincides with the beginning of the secondary myotube formation, at embryonic day 15-16 in mice. Together with our earlier report, demonstrating early postnatal muscle defects in the Sox6 null-p100H mutant, the present results suggest that Sox6 likely plays an important role in muscle development.

OBJECTIVE: To examine the effect of a high-fat diet on gene expression in adipose tissues and to determine induction kinetics of adipose monocyte chemoattractant protein-1 and -3 (MCP-1 and MCP-3) in diet-induced obesity (DIO) and the effect of a lack of MCP-1 signaling on DIO susceptibility and macrophage recruitment into adipose tissue. RESEARCH METHODS AND PROCEDURES: Obese and lean adipose tissues were profiled for expression changes. The time-course of MCP-1 and MCP-3 expression was examined by reverse transcriptase-polymerase chain reaction. Plasma MCP-1 levels were determined by enzyme-linked immunosorbent assay (ELISA). Chemokine receptor-2 (CCR2) knockout mice were placed on the high-fat diet to determine DIO susceptibility. Macrophage infiltration in adipose tissue was examined by immunohistochemistry with F4/80 antibody. RESULTS: DIO elevated adipose expression of many inflammatory genes, including MCP-1 and MCP-3. Adipose MCP-1 and MCP-3 mRNA levels increased within 7 days of starting a high-fat diet, with elevation of plasma MCP-1 detected after 4 weeks on the diet. The induction of MCP-1 and MCP-3 expression preceded that of tumor necrosis factor-alpha. The elevated plasma MCP-1 concentration in obese mice was partially reversed by treatment with AM251. No change in DIO susceptibility and macrophage accumulation in adipose tissue were observed in CCR2 knockout mice, which lack the MCP-1 receptor CCR2. DISCUSSION: A high-fat diet elevated adipose expression of inflammatory genes, including early induction of MCP-1 and MCP-3, supporting the view that obese adipose tissues contribute to systemic inflammation. However, despite increased MCP-1 in obesity, disruption of MCP-1 signaling did not confer resistance to DIO in mice or reduce adipose tissue macrophage infiltration.

a(SCHEM:"Dietary Lipid") -> r(MGI:Il2rg)

a(SCHEM:"Dietary Lipid") -> r(MGI:Traf1)

complex(p(HGNC:PDGFB),p(HGNC:PDGFB)) -> p(HGNC:ACTB,pmod(P,Y))

Mass spectral identification of radiolabeled c-Src-as1 substrates revealed several direct targets of c-Src upon PDGF stimulation: PDGFR (from one-dimensional gel), vimentin, tubulin-{beta}5, {beta}- and {gamma}-actin, and myosin light chain 2-A

complex(p(HGNC:PDGFB),p(HGNC:PDGFB)) -> p(HGNC:MYL7,pmod(P,Y))

complex(p(HGNC:PDGFB),p(HGNC:PDGFB)) -> bp(GO:chemotaxis)

complex(p(HGNC:PDGFB),p(HGNC:PDGFB)) -> kin(p(HGNC:FYN))

exposure to PDGF resulted in a marked increase in c-Src, Fyn, and Yes kinase activities

the observed 70% decrease in chemotactic response can be solely attributed to c-Src inhibition.

Altered growth was found to be due in part to cell cycle arrest and induction of apoptosis.

Increased expression of CYLD in BT549 cells induced apoptosis, while its suppression by small interfering RNA inhibited cell death in BAF57 expressing BT549 cells.

p(MGI:Rela,pmod(A,K,310)) => tscript(p(MGI:Rela))

These findings indicate that the acetylation of RelA at lysine 310 is importantly regulated by prior phosphorylation of serines 276 and 536. Such phosphorylated and acetylated forms of RelA display enhanced transcriptional activity.

p(HGNC:TGFB1) -> complex(p(HGNC:SMAD2),p(HGNC:SMAD3),p(HGNC:SMAD4))

In response to transforming growth factor beta (TGF-beta), Smad4 forms complexes with activated Smad2 and Smad3, which accumulate in the nucleus,

kin(p(HGNC:CHEK1)) -| bp(MESHPP:Apoptosis)

The ubiquitination of Chk1 is mediated by E3 ligase complexes containing Cul1 or Cul4A. Treatment of cells with the anticancer agent camptothecin (CPT) triggers Chk1 destruction, which blocks recovery from drug-induced S phase arrest and leads to cell death.

cat(p(HGNC:CNR2)) -> bp(MESHPP:Apoptosis)

Results show that stimulation of the CB2 receptor leads to p38 MAPK activation and that inhibition of this kinase attenuates CB2 receptor-induced caspase activation and apoptosis.

Collectively, these studies suggest that the persistent single-strand breaks formed upon PARP-1 inhibition, which promote the collapse of replication forks and would normally be repaired by homologous recombination, cannot be repaired effectively in the absence of functional BRCA1 or BRCA2. This results in the accumulation of chromosomal abnormalities, cell cycle arrest in G2/M, and apoptosis

cat(p(MGI:Tnfrsf1b)) -> p(MGI:Mapk1,pmod(P))

Intestinal fibrosis is an incurable complication of Crohn's disease involving increased numbers of collagen-producing myofibroblasts. Tumor necrosis factor (TNF) alpha has defined proinflammatory roles in Crohn's disease but its role in fibrosis is unclear. We tested the hypothesis that TNFalpha increases collagen accumulation and proliferation in intestinal myofibroblasts and has additive effects in combination with insulin-like growth factor (IGF) I. The mechanisms, TNF receptor isoform, and downstream signaling pathways were examined. Intestinal myofibroblasts from wild-type (WT) mice or mice homozygous for disruption of genes encoding TNFR1 (TNFR1-/-), TNFR2 (TNFR2-/-), or both (TNFR1/2-/-), were treated with TNFalpha, IGF-I, or both. In WT cells, TNFalpha and IGF-I stimulated type I collagen accumulation and DNA synthesis in an additive manner. IGF-I, but not TNFalpha, stimulated type I collagen gene activation. TNFalpha, but not IGF-I, induced tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and reduced matrix metalloproteinases-2 activity and collagen degradation. TNFalpha also activated ERK1/2. These responses to TNFalpha were absent in TNFR2-/- and TNFR1/2-/- myofibroblasts, whereas TNFR1-/- cells showed similar responses to WT. Inhibition of ERK1/2 diminished TNFalpha induced DNA synthesis in WT and TNFR1-/- cells. Differences in TNFalpha-induced STAT3/DNA binding activity and not NFkappaB and AP-1 transcriptional activation correlated with impaired collagen accumulation/TIMP-1 induction in TNFR2(-/-) cells. Constitutively active STAT3 rescued TIMP-1 expression in TNFR2-/- cells. We conclude that TNFalpha and IGF-I may additively contribute to fibrosis during intestinal inflammation. TNFR2 is a primary mediator of fibrogenic actions of TNFalpha acting through ERK1/2 to stimulate proliferation and through STAT3 to stimulate TIMP-1 and inhibit collagen degradation.

kin(p(PFM:"MAPK Erk1/3 Family")) -> tscript(p(MGI:Stat3))

bp(GO:"double-strand break repair") -| a(SCHEM:"double-stranded DNA break")

Our findings suggest a role for RECQL4 in the repair of DNA double-strand breaks by homologous recombination and shed new light onto RECQL4's function in human cells.

complex(p(HGNC:RAD51),p(HGNC:RECQL4)) -> bp(GO:"double-strand break repair")

Both the growth-stimulating activity of low-dose NO for endothelial cells and suppression of TSP1 expression were ERK-dependent. Conversely, exogenous TSP1 suppressed NO-mediated pERK

kin(p(HGNC:MAPK1)) -> bp(GO:"cell growth")

p(HGNC:TP53,sub(P,309,S)) =| tscript(p(HGNC:TP53))

cat(p(MGI:Ticam1)) -> tscript(p(MGI:Irf3))

TLR3 and TLR4 activate IRF3 and NF-kappaB through the TRIF-dependent pathway

cat(p(MGI:Tlr3)) -> tscript(p(MGI:Irf3))

SMAD1 phosphorylation was examined in C-28/I2 chondrocytes treated with BMP2(100ng/ml). It was phosphorylated after treatment with BMP2 for 1 hour.

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by phenylalanine hydroxylase (PAH) deficiency. Accumulation of phenylalanine leads to severe mental and psychomotor retardation, and hypopigmentation of skin and hair...Our data indicated that 12 genes were significantly up-regulated in PKU. Four are involved in defense and inflammatory responses of neutrophils (NE, MPO, NGP, and CRAMP), three other overexpressed genes are related to extracellular matrix organization and degradation (COL1A1, COL1A2, and MMP13); the remainder were a nociceptor in sensory neurons (MrgA1), a structural gene of P lysozyme (Lzp-s), an immunoglobulin alpha heavy chain constant region gene (Igh-2), an osteocalcin-related protein precursor (Bglap-rs1), and a membrane-spanning 4 domain, subfamily A, member 3 (Ms4a3).

a(CHEBI:"reactive oxygen species") -> p(RGD:Cav1,pmod(P,Y))

The nonreceptor tyrosine kinase, proto-oncogene cAbl is a substrate of Src and is a major mediator for ROS-dependent tyrosine phosphorylation of Cav1.

kin(p(PFH:"PRKA Family")) => p(HGNC:PDE3A,pmod(P,S,312))

Forskolin did not promote the binding of 14-3-3 proteins to PDE3A (Figures 2A and 5A). However, using the pSer312-PDE3A antibodies, we found that forskolin stimulated the phosphorylation of PDE3A at Ser312 (Figures 5A and 5C). This residue lies within a sequence SHRRTS312LPCIP that conforms to a consensus site for PKA. The forskolin-stimulated phosphorylation of Ser312 was inhibited by the PKA inhibitor H-89 (Figure 5C), and by mimosine and aphidicolin (Figure 5A), but not by inhibitors of PI3K (LY 294002), mTOR (mammalian target of rapamycin) (rapamycin) or the MAPK cascade (U0126) (Figure 5C; see [35] for inhibitor specificities), nor by H-7 (results not shown).

kin(p(PFH:"PRKC Family")) => p(HGNC:PDE3A,pmod(P,S,428))

PDE3A (phosphodiesterase 3A) was identified as a phosphoprotein that co-immunoprecipitates with endogenous 14-3-3 proteins from HeLa cell extracts, and binds directly to 14-3-3 proteins in a phosphorylation-dependent manner (Ser428). Among cellular stimuli tested, PMA promoted maximal binding of PDE3A to 14-3-3 proteins. While p42/p44 MAPK (mitogen-activated protein kinase), SAPK2 (stress-activated protein kinase 2)/p38 and PKC (protein kinase C) were all activated by PMA in HeLa cells, the PMA-induced binding of PDE3A to 14-3-3 proteins was inhibited by the non-specific PKC inhibitors Ro 318220 and H-7, but not by PD 184352, which inhibits MAPK activation, nor by SB 203580 and BIRB0796, which inhibit SAPK2 activation.

kin(p(HGNC:RET)) => p(HGNC:PTK2,pmod(P,Y,576))

RESULTS: Immunoprecipitated, mutant RET from cells or the recombinant RET kinase domain was able to directly phosphorylate tyrosine residues on FAK. Specifically Y576/577, Y861, and Y925, but not the autophosphorylation site Y397 of FAK, were phosphorylated by RET.

a(CHEBI:aldosterone) -> bp(GO:"response to oxidative stress")

Aldosterone seems to induce cardiac inflammation and gene expression via oxidative stress that is inhibited by N-acetylcysteine but not by tempol.

Reduction of AIF expression by RNA interference inhibited large-scale DNA fragmentation and conferred significant protection against MPP+ toxicity.

tscript(p(MGI:Sp1)) -> bp(GO:angiogenesis)

Furthermore, knocking down Sp1 expression significantly impaired the angiogenic potential of tumor cells in vitro and suppressed angiogenesis in vivo animal models.

Incubation of murine aortic ECs with recombinant resistin increased monocyte chemoattractant protein (MCP)-1 and soluble vascular cell adhesion molecule (sVCAM)-1 protein levels in the conditioned medium.

cat(p(HGNC:MSRA)) -| bp(GO:"response to oxidative stress")

MsrA (methionine sulphoxide reductase A) is an antioxidant repair enzyme that reduces oxidized methionine to methionine. Moreover, the oxidation of methionine residues in proteins is considered to be an important consequence of oxidative damage to cells.

ATF5, a transcriptional activator, stimulates asparagine synthetase promoter/reporter gene transcription

path(MESHD:Fibrosis) positiveCorrelation r(HGNC:ADAM10)

TABLE 2. UPREGULATED GENES IN IDIOPATHIC PULMONARY FIBROSIS

path(MESHD:Fibrosis) positiveCorrelation r(HGNC:COL18A1)

path(MESHD:Fibrosis) positiveCorrelation r(HGNC:COL7A1)

path(MESHD:Fibrosis) positiveCorrelation r(HGNC:HEPH)

path(MESHD:Fibrosis) positiveCorrelation r(HGNC:IL13RA2)

path(MESHD:Fibrosis) positiveCorrelation r(HGNC:MYBPC1)

path(MESHD:Fibrosis) positiveCorrelation r(HGNC:MYLK)

path(MESHD:Fibrosis) positiveCorrelation r(HGNC:SPP1)

path(MESHD:Fibrosis) positiveCorrelation r(HGNC:TNN)

path(MESHD:Fibrosis) positiveCorrelation r(HGNC:UBIAD1)

cat(p(MGI:Sirt1)) =| tscript(p(MGI:Mef2d))

Instead, the NAD+-dependent deacetylase SIRT1 can potently induce MEF2 deacetylation

bp(GO:"response to hypoxia") -| r(HGNC:KCNK5)

Thus, we have cloned the TASK-2 promoter, demonstrated that its transcriptional activity is dependent upon pO(2), shown that deletion of overlapping consensus binding sites for NF-kappaB/Elk-1 ablates this O(2) sensitivity, and proved that Elk-1 binds preferentially to this site. Furthermore, the consequences of chronic hypoxia on natively expressed TASK-2 are decreased steady-state mRNA and cell depolarization showing that TASK-2 contributes to the excitability of this important lung cell type.

p(HGNC:RAF1,pmod(P,S,621)) -> (p(PFH:"14-3-3 Family") =| kin(p(HGNC:RAF1)))
p(PFH:"14-3-3 Family") =| kin(p(HGNC:RAF1))

Phosphorylation. Raf is principally activated by phosphorylation of specific amino acid residues as shown for each isoform in Figure 4. From an evolutionary standpoint, the Raf activation sites are highly conserved from yeast to humans. Several amino acids in Raf, particularly serine (S) 259 and S621, which bind 14-3-3 and maintain C-Raf in a closed auto-inhibited conformation, are phosphorylated in the basal state.

p(PFH:"RAS Family",pmod(F)) => gtp(p(PFH:"RAS Family"))

Raf may also be activated by Ras-independent elements and, in turn, propagates signals through diverse effectors that mediate proliferation, angiogenesis, metastases, and survival.5 Raf may be activated by signaling upstream or constitutively. Constitutive activation of Raf and Ras are indistinguishable in their potential to induce malignant transformation.6-8 Activating raf mutations have been identified in melanoma, thyroid, colon, and other cancers (Table 1).9-43 Furthermore, the disappointing clinical results of farnesyltransferase (FTase) inhibitors (FTIs) that were developed based on a flawed premise that they would effectively target malignancies with a high incidence of Ras mutation has led to scrutiny of signaling elements downstream of Ras, such as Raf, as therapeutic targets.44 This review highlights relevant information about the biology of Raf and novel strategies directed at exploiting this knowledge to more effectively treat malignant diseases. SIGNALING THROUGH THE MAPK PATHWAY The molecular mechanisms and signaling pathways that regulate cell proliferation and survival are receiving considerable attention as potential targets for anticancer strategies. 45,46 Recently, there has been a notable increase in efforts directed at targeting the MAPK pathway, which integrates a wide array of proliferative signals initiated by receptor tyrosine kinases (RTKs) and G protein- coupled receptors.47,48 The network of signals emanating from the MAPK pathway are transmitted by proteins that serve as chemical switches, cycling between phosphorylated (activated) and dephosphorylated (inactivated) states.49 These on and off switches are regulated by kinases and phosphatases, respectively. Activated signaling elements, in turn, phosphorylate amino acid residues on downstream signaling proteins in a cascade-like and expansive manner.50 Not only does the centrality of the MAPK pathway render its components important targets for therapeutic development, but many genes that encode for its critical signaling elements undergo mutations, constitutively activating downstream signaling elements and conferring the potential for transformation and autonomous growth.50-52 In addition to efforts directed at Ras, therapeutic strategies directed at the MAPK pathway are targeting the cascade of downstream effector proteins including Raf, MAPK kinase (MAPKK; also called MEK or extracellular signal-regulated kinase [ERK] kinase), and ERK. The Raf/MEK/ERK module (Fig 1) of the MAPK pathway, which is immediately downstream of Ras, may be less redundant and innately resistant to therapeutic manipulations compared with Ras (as discussed in the next section). The Unfilled Promise of Targeting Ras The Raf/MEK/ERK module of the MAPK pathway has been the focus of considerable attention because therapeutic efforts directed at Ras, which is situated at the apex of the MAPK pathway, have been disappointing.44 Ras belongs to a superfamily of guanine nucleotide triphosphatases (GTPases) that transmit proliferative and survival signals to the MAPK, phosphatidylinositol 3-kinase (PI3K), and other pathways (Figs 1 and 2). Three ras proto-oncogenes encode four 21-kd proteins, called p21ras or Ras (H-Ras, N-Ras, K-Ras4A, and K-Ras4B, resulting from two alternatively spliced K-Ras gene products), that are localized to the inner surface of the cell membrane.44 Of the three ras genes, K-ras mutations are most commonly found in solid malignancies, whereas N-ras mutations are encountered less often, and H-ras mutations are rarely encountered.53,54 Ras isoforms impart distinct biologic effects as a result of the potential of these proteins to differentially activitate critical effectors.55 After synthesis as inactive cytosolic propeptides, Ras undergoes a series of post-translational modifications at its carboxyl terminus that increase its hydrophobicity.56,57 These modifications render Ras functional and capable of lo...

The Rho family of small GTPases, consisting of Rho, Rac, and cyclin-dependent kinase (Cdc) 42, regulate cytoskeletal organization during the cell cycle and also mediate Ras-induced activation of Raf, especially C-Raf.134-136 These GTPases do not directly bind to Raf but, instead, signal by activating downstream kinases. Rho signals by activating the serine/threonine protein kinases N1 and N2 and Rho-associated kinase 1, whereas Rac and Cdc42 signal through p21-activated kinase (PAK).134-136

kin(p(HGNC:RAF1)) => p(HGNC:BCL2,pmod(P))

This action releases activated NF-kB, which is then translocated to the nucleus where it mediates transcription of antiapoptotic factors.155,166 Other antiapoptotic effects of C-Raf are mediated by a mitochondrial pool of the protein, which, on stimulation, localizes to the mitochondrial membrane where the protein interacts with and phosphorylates Bcl-2, Bcl-2-associated athanogene, and other pro-apoptotic regulators, abrogating their pro-apoptotic effects.

p(HGNC:EPO) -> p(HGNC:RAF1,pmod(P,Y,341))

Y341 is phosphorylated by the Src family of non-RTKs, Janus kinase, and erythropoietin.

kin(p(PFH:"PRKA Family")) =| kin(p(HGNC:RAF1))

and phosphorylation by protein kinases A (PKA) and B (PKB/Akt),

a(SCHEM:"cyclic AMP") -> (gtp(p(HGNC:RAP1A)) -> kin(p(HGNC:RAF1)))

as shown in Figure 2.95-98 In essence, the activation status of Raf depends on the integration of both activating and inhibitory stimuli, the net result of which determines the downstream messages. THE RAF FAMILY OF GENES AND PROTEINS The raf family of genes was first identified as oncogenes in retroviruses that are the causative vectors of tumors in mice and chicken.99,100 The first raf gene to be identified, v-raf, the transforming gene of the mouse sarcoma virus 3611, induces fibrosarcomas and erythroleukemia in newborn mice, and C-raf (also called raf-1) is its proto-oncogene homolog.101,102 A-raf was found next by screening a mouse spleen cDNA library at low stringency with a v-raf probe. Next, v-Rmil was identified as the transforming gene in the avian retrovirus Mill Hill No. 2 (MH2) from a spontaneous ovarian tumor and found to be homologous to v-raf.99 C-Rmil corresponded to a third mammalian raf gene, B-raf, which was also shown to be an oncogene.103,104 However, initial attempts to identify activated versions of raf in human cancers failed to demonstrate unique DNA rearrangements in any specific tumor type, which, in retrospect, can be attributed to the lack of requisite sensitivity of early assays to detect single point mutations. Furthermore, most early efforts were directed at C-raf, rather than at the more oncogenic B-raf. The mammalian raf family consists of the following three genes: A-raf, B-raf, and C-raf, which are located on chromosomes Xp11, 7q32, and 3p25, respectively. The raf proto-oncogenes encode three 68- to 74-kd cytosolic proteins, termed A-Raf, B-Raf, and C-Raf (Raf-1), which share highly conserved amino-terminal regulatory regions and catalytic domains at the carboxyl terminus (Fig 4).10 As serine/threonine kinases, Raf proteins phosphorylate serine and threonine residues on essential modulatory proteins downstream of Ras. Each Raf species has a distinct expression profile in tissues, which suggests that individual Raf isoforms perform clearly defined functions.4 C-Raf is ubiquitously expressed in most tissues. Both A- and B-Raf have more restricted expression profiles than C-Raf, with A-Raf overexpressed in urogenital tissues (eg, kidney, ovary, prostate, and epididymis) and B-Raf overexpressed in neural, testicular, splenic, and hematopoietic tissues.105 Unlike A-raf and C-raf, B-raf undergoes differential splicing in exons 8b and 10a, and its spliced variants are translated into 10 B-Raf isoforms.106,107 Both A-Raf and C-Raf undergo localization to the mitochondria, which supports the notion that Raf regulates apoptosis, but the specific proportions of Raf isoforms that are localized to the mitochondria are not known.108-112 This localization may be a result of isoform-specific lipid- or protein-binding partners, which recruit Raf to distinct membrane rafts. From a functional standpoint, although all Raf proteins are serine/threonine kinases and capable of activating the MAPK cascade, they have distinct downstream phosphorylation targets and play unique roles in signaling.113 Their distinct roles are supported by Raf knockout studies, in which mice lacking each of the three Raf proteins have disparate phenotypes.113,114 B-raf knockouts die in utero by day 12, usually as a result of massive internal hemorrhage, whereas A-raf and C-raf knockouts die postpartum with extensive intestinal distension (A-raf knockout) or failure of lung maturation (C-raf knockout). Additional support for the diverse functionality of Raf family members is provided by the disparate responses of B-Raf and C-Raf to identical stimuli, as well as the distinct messages that each isoform relays downstream to Rap1, which is a small GTPase that functions as both an activator and repressor of Raf.115 For example, Rap1- mediated stimulation of B-Raf by cyclic adenosine monophosphate (cAMP) phosphorylates ERK, whereas stimulation of C-Raf inhibits ERK phosphorylation.115

p(HGNC:EGF) -> kin(p(PFH:"MAPK p38 Family"))

senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I)

cat(p(HGNC:SIRT1)) -> (p(HGNC:IGF1) -> kin(p(PFH:"MAPK Erk1/3 Family")))
p(HGNC:IGF1) -> kin(p(PFH:"MAPK Erk1/3 Family"))

cat(p(HGNC:PTGS2)) -> a(SCHEM:"15-deoxy-D12,14-prostaglandin J2")

COX-2 inhibitors...in the vasculature prevents the accumulation of COX-2- derived 15d-PGJ2, which is associated with the atheroprotective nature of laminar flow.

path(SDIS:"acute phase reaction") -| r(RGD:Cebpa)

The AP reaction was accompanied by a decrease of the relative concentration of C/EBP alpha and an increase of C/EBP beta

CD2 or CD28 stimulation, but not CD3/TCR stimulation, induces Dok phosphorylation.

path(SDIS:"Type I diabetes") positiveCorrelation p(HGNC:CSF2)

Unstimulated monocytes of at-risk/type 1 diabetic humans and macrophages of the NOD mouse have markedly elevated autocrine GM-CSF production and persistent STAT5 phosphorylation.

a(SCHEM:"serum insulin") -| a(SCHEM:"cyclic AMP")

Acute insulin treatment activates phosphodiesterase 3B, reduces cAMP levels and quenches beta-adrenergic receptor signalling.

a(SCHEM:"serum insulin") -| cat(p(PFH:"ADRB Family"))

cat(p(HGNC:ADRB2)) -> a(SCHEM:"cyclic AMP")

In adipocytes, stimulation of beta-adrenergic receptors increases cyclic AMP levels and activates protein kinase A (PKA), which stimulates lipolysis by phosphorylating hormone-sensitive lipase and perilipin.

kin(p(PFH:"PRKA Family")) -> p(EGID:5346,pmod(P,S))

kin(p(PFH:"PRKA Family")) -> path(SDIS:"adipocyte lipolysis")

tscript(p(HGNC:E2F8)) -| tscript(p(PFH:"E2F Family"))

The E2F family of transcription factors are downstream effectors of the retinoblastoma protein, pRB, pathway and are essential for the timely regulation of genes necessary for cell-cycle progression. Here we describe the characterization of human and murine E2F8, a new member of the E2F family. Sequence analysis of E2F8 predicts the presence of two distinct E2F-related DNA binding domains suggesting that E2F8 and, the recently, identified E2F7 form a subgroup within the E2F family. We show that E2F transcription factors bind the E2F8 promoter in vivo and that expression of E2F8 is being induced at the G1/S transition. Purified recombinant E2F8 binds specifically to a consensus E2F-DNA-binding site indicating that E2F8, like E2F7, binds DNA without the requirement of co-factors such as DP1. E2F8 inhibits E2F-driven promoters suggesting that E2F8 is transcriptional repressor like E2F7. Ectopic expression of E2F8 in diploid human fibroblasts reduces expression of E2F-target genes and inhibits cell growth consistent with a role for repressing E2F transcriptional activity. Taken together, these data suggest that E2F8 has an important role in turning of the expression of E2F-target genes in the S-phase of the cell cycle.

Fas ligand mRNA levels were increased in HBP1 transfectants, suggesting involvement of the Fas/Fas ligand pathway.

rmEP reduced IL-18 expression in WT- and EP –/–-derived keratinocytes at 8 h after stimulation, and there was no obvious difference between WT and EP –/– (Fig. 3D).

GbetaL binds strongly to mTOR near its kinase domain and is required for maximal mTOR activity.
path(SDIS:"food intake") -> kin(p(EGID:2475))
under nutrient-rich conditions the raptor-mTOR interaction is in a low stability state associated with high mTOR kinase activity.
[Effect of AOB, a fermented-grain food supplement, on oxidative stress in type 2 diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
Gene-disease associations inferred from animal model manually asserted gene-disease associations.
DisGeNET evidence - PREDICTED
[Erectile dysfunction in young non-obese type II diabetic Goto-Kakizaki rats is associated with decreased eNOS phosphorylation at Ser1177.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Peripheral mechanisms of erectile dysfunction in a rat model of chronic cocaine use.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Left ventricular SERCA2a gene down-regulation does not parallel ANP gene up-regulation during post-MI remodelling in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The influences of insulin and food intake on intestinal ornithine transcarbamylase activity in diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Streptozotocin-induced diabetes in the rat is associated with changes in vaginal hemodynamics, morphology and biochemical markers.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: mechanisms for aquaporin 2 down-regulation and cellular proliferation.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Nitric oxide differentially regulates renal ATP-binding cassette transporters during endotoxemia.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Hyperhomocysteinemia and myocardial expression of brain natriuretic peptide in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Impaired alveolar epithelial cell differentiation in the hypoplastic lung in nitrofen-induced congenital diaphragmatic hernia.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[11C-NMSP/ 18F-FDG microPET to monitor neural stem cell transplantation in a rat model of traumatic brain injury.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Early changes in insulin receptor signaling and pain sensation in streptozotocin-induced diabetic neuropathy in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Inducible transgenic rat model for diabetes mellitus based on shRNA-mediated gene knockdown.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Gene expression profiles of livers from thermally injured rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[alpha(2)-Macroglobulin: a novel cytochemical marker characterizing preneoplastic and neoplastic rat liver lesions negative for hitherto established cytochemical markers.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Selective COX-2 inhibition markedly slows disease progression and attenuates altered prostanoid production in Han:SPRD-cy rats with inherited kidney disease.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Expression of netrin-1, slit-1 and slit-3 but not of slit-2 after cerebellar and spinal cord lesions.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Expression of neuregulin and ErbB3 and ErbB4 after a traumatic lesion in the ventral funiculus of the spinal cord and in the intact primary olfactory system.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Prolonged c-Jun expression in the basolateral amygdala following bulbectomy: possible implications for antidepressant activity and time of onset.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Myocardial ischemia induces differential regulation of KATP channel gene expression in rat hearts.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Poloxamer 407-mediated alterations in the activities of enzymes regulating lipid metabolism in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Leptin deficiency and beta-cell dysfunction underlie type 2 diabetes in compound Akt knockout mice.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Postinjury administration of pituitary adenylate cyclase activating polypeptide (PACAP) attenuates traumatically induced axonal injury in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The antiinflammatory effects of adenosine receptor agonists on the carrageenan-induced pleural inflammatory response in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Adenosine A1 receptor agonists reduce hyperalgesia after spinal cord injury in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Adenosine A2A receptor activation reduces lung injury in trauma/hemorrhagic shock.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Upregulation of arterial serotonin 1B and 2B receptors in deoxycorticosterone acetate-salt hypertension.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Complement activation following optic nerve crush in the adult rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Involvement of dipeptidyl peptidase IV in immune complex-mediated glomerulonephritis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Effect of hypothyroidism on the expression of three microtubule-associated proteins (1A, 1B and 2) in developing rat cerebellum.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Local and systemic expression of inducible nitric oxide synthase in comparison with that of cyclooxygenase-2 in rat carrageenin-induced pleurisy.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Overexpression of IFN-induced protein 10 and its receptor CXCR3 in myasthenia gravis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Disruption of endothelial-cell caveolin-1alpha/raft scaffolding during development of monocrotaline-induced pulmonary hypertension.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Experimental arthritis: effect on growth parameters and total skeletal calcium.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Expression of interleukin-17 in ischemic brain tissue.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Increased renal collagen cross-linking and lipid accumulation in nephropathy of Zucker diabetic fatty rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Role of atypical protein kinase C in activation of sterol regulatory element binding protein-1c and nuclear factor kappa B (NFkappaB) in liver of rodents used as a model of diabetes, and relationships to hyperlipidaemia and insulin resistance.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Warm ischemia-induced alterations in oxidative and inflammatory proteins in hepatic Kupffer cells in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Pentylenetetrazole kindling induces neuronal cyclin B1 expression in rat hippocampus.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Metallothioneins and zinc dysregulation contribute to neurodevelopmental damage in a model of perinatal viral infection.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Role of complement regulatory membrane proteins in ischaemia-reperfusion injury of rat gastric mucosa.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Differential expression and signaling of IFN-gamma in the conjunctiva between Lewis and Brown Norway rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Dynamics of gene expression for immediate early- and late genes after seizure activity in aged rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Activation of caspase 8 in the pituitaries of streptozotocin-induced diabetic rats: implication in increased apoptosis of lactotrophs.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Activation of cell death pathway after a brief period of global ischemia in diabetic and non-diabetic animals.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[IL-17 induces myocardial fibrosis and enhances RANKL/OPG and MMP/TIMP signaling in isoproterenol-induced heart failure.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Elevated levels of inhibin-A and immunoreactive inhibin in aged male Wistar rats with testicular Leydig cell tumor.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[GeneChip analysis after acute spinal cord injury in rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Pyruvate kinase activation and lipoperoxidation after selective hepatic ischemia in Wistar rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Anti-inflammatory and antimicrobial effect of lectin from Lonchocarpus sericeus seeds in an experimental rat model of infectious peritonitis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Triptolide inhibits CC chemokines expressed in rat adjuvant-induced arthritis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Blockade of endothelin ET(A)/ET(B) receptors favors a role for endothelin during acute Trypanosoma cruzi infection in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[alpha -Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Modification of adenosine A1 and A2A receptor density in the hippocampus of streptozotocin-induced diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Characterization of adenosine-A1 receptor-mediated antilipolysis in rats by tissue microdialysis, 1H-spectroscopy, and glucose clamp studies.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Effects of leptin on airway inflammation and the expression of Th1/Th2 cytokines in asthmatic rats].]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The relationship of blood glucose and the expression of insulin-like growth factor-1 receptor mRNA in diabetic cardiomyopathy: a preliminary study with rats].]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Complement activation contributes to hypoxic-ischemic brain injury in neonatal rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Intravenous immunoglobulin protects against experimental thrombotic microangiopathy.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Enzymes of purine metabolism in cancer.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Cholecystokinin octapeptide: a potential growth factor for pancreatic beta cells in diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[2-Methoxyestradiol inhibits the up-regulation of AQP4 and AQP1 expression after spinal cord injury.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Role of low-affinity nerve growth factor receptor inhibitory antibody in reducing pain behavior and calcitonin gene-related Peptide expression in a rat model of wrist joint inflammatory pain.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Peripheral participation of cholecystokinin in the morphine-induced peripheral antinociceptive effect in non-diabetic and diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The timing of re-institution of good blood glucose control affects apoptosis and expression of Bax and Bcl-2 in the retina of diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Apoptosis and its pathway in early post-implantation embryos of diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Contribution of anaphylatoxin C5a to late airway responses after repeated exposure of antigen to allergic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Shengmai-san-mediated enhancement of regenerative responses of spinal cord axons after injury in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The role of hyperglycemia in FAT/CD36 expression and function.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Protective effect of iridoid glucosides from Boschniakia rossica on acute liver injury induced by carbon tetrachloride in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Positioned to inhibit: netrin-1 and netrin receptor expression after spinal cord injury.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Altered expression of hepatic CYP2E1 and CYP4A in obese, diabetic ob/ob mice, and fa/fa Zucker rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Degeneration of dopaminergic neurons triggers an expression of individual enzymes of dopamine synthesis in non-dopaminergic neurons of the arcuate nucleus in adult rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Characterizing a rat Brca2 knockout model.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Oligohydramnios decreases platelet-derived growth factor expression in fetal rat lungs.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Intrauterine growth restriction due to uteroplacental insufficiency decreased white matter and altered NMDAR subunit composition in juvenile rat hippocampi.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Age and meloxicam attenuate the ischemia/reperfusion-induced down-regulation in the NMDA receptor genes.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Fluoroquinolones reduce carrageenan-induced edema in rats and the involvement of the glucocorticoid receptor system.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Immunohistochemical characterization of glomerular PDGF B-chain and PDGF beta-receptor expression in diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Analysis of early changes in the articular cartilage transcriptisome in the rat meniscal tear model of osteoarthritis: pathway comparisons with the rat anterior cruciate transection model and with human osteoarthritic cartilage.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Early and sharp nitric oxide production and anoxic depolarization in the rat hippocampus during transient forebrain ischemia.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Involvement of nitric oxide in spatial memory deficits in status epilepticus rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Vascular proliferation and transforming growth factor-beta expression in pre- and early stage of diabetes mellitus in Otsuka Long-Evans Tokushima fatty rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The role of NOS in the impairment of spatial memory and damaged neurons in rats injected with amyloid beta 25-35 into the temporal cortex.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Overexpression of inducible nitric oxide synthase and cyclooxygenase-2 in rat zinc-deficient lung: Involvement of a NF-kappaB dependent pathway.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Expression of iNOS mRNA associated with suppression of colonic contraction in rat colitis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[iNOS expression in rat aorta is increased after spinal cord transection: a possible cause of orthostatic hypotension in man.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Spatial coordination of cell-adhesion molecules and redox cycling of iron in the microvascular inflammatory response to pulmonary injury.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Differential regulation of hepatic apolipoprotein A-I and A-II gene expression by thyroid hormone in rat liver.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Expression of VEGF, iNOS, and eNOS is increased in cochlea of diabetic rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Effect of oxytocin on acupuncture analgesia in the rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Additive effects of medroxyprogesterone acetate and 5-fluorouracil derivative on 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Studies on biochemical markers in cryoinfarction in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Long-term effects of B-type natriuretic peptide infusion after acute myocardial infarction in a rat model.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Expression of galectin-1, a new component of slit diaphragm, is altered in minimal change nephrotic syndrome.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Upregulation of glial cell line-derived neurotrophic factor and artemin mRNA in the auditory nerve of deafened rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[GTP-binding protein mediated phospholipase A2 activation in rat liver during the progression of sepsis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Changes in protein kinase C in early cardiomyopathy and in gracilis muscle in the BB/Wor diabetic rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Expression and role of early growth response gene-1 in experimental silicosis of rat].]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Protective effect of mycophenolate mofetil on mercuric chloride-induced nephrotoxicity in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Curcumin protects intestinal mucosal barrier function of rat enteritis via activation of MKP-1 and attenuation of p38 and NF-B activation.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Protective effects of grape seed proanthocyanidin extracts on cerebral cortex of streptozotocin-induced diabetic rats through modulating AGEs/RAGE/NF-kappaB pathway.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[IGF-1 expression in infarcted myocardium and MGF E peptide actions in rat cardiomyocytes in vitro.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[P2X7 receptor immunoreactive profile confined to resting and activated microglia in the epileptic brain.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Alterations of intermedin and its receptor system in oleic acid-induced acute lung injury of rats].]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The role of an epithelial neutrophil-activating peptide-78-like protein in rat adjuvant-induced arthritis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Nerve growth factor in the developing and adult lacrimal glands of rat with and without inherited retinitis pigmentosa.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The Clara cells and CCSP may participate in the pathogenesis of asthma in the rat asthma remodel.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Different forms of obesity as a function of diet composition.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[L-type calcium channel blocker suppresses calcineurin signal pathway and development of right ventricular hypertrophy.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Recruitment of the Sonic hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Airway remodeling in allergen-challenged Brown Norway rats: distribution of proteoglycans.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Comparison between single and combined treatment with candesartan and pioglitazone following transient focal ischemia in rat brain.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase c-{alpha} and -{beta}.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Differential induction of protein kinase C isoforms at the cardiac hypertrophy stage and congestive heart failure stage in Dahl salt-sensitive rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Time course of expression of intermediate filament protein vimentin, nestin and desmin in rat renal glomerular injury.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Expression of different isoforms of protein kinase C in the rat hippocampus after pilocarpine-induced status epilepticus with special reference to CA1 area and the dentate gyrus.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Molecular cloning of the rat NADH:ubiquinone oxidoreductase subunit and its up-regulation in the facial muscle after denervation: detected by means of differential display.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[UCP2 and UCP3 gene expression, heart function and oxygen cost of myocardial work changes during aging and ischemia-reperfusion].]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Contribution of delta1-opioid receptors in regulation of cardiac resistance to ischemia-reperfusion].]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Hypotensive hemorrhage increases calcium uptake capacity and Bcl-XL content of liver mitochondria.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Nutrient-driven incretin secretion into intestinal lymph is different between diabetic Goto-Kakizaki rats and Wistar rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Distribution and expression of tissue inhibitors of metalloproteinase in dorsal root entry zone and dorsal column after dorsal root injury.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[A crucial role of nitric oxide in acute lung injury secondary to the acute necrotizing pancreatitis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Protein kinase C isozymes in hypertension and hypertrophy: insight from SHHF rat hearts.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Altered cardiac endothelin receptors and protein kinase C in deoxycorticosterone-salt hypertensive rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Renal cortical regulation of COX-1 and functionally related products in early renovascular hypertension (rat).]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The dynamic detection of NO during stroke and reperfusion in vivo.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Intrauterine growth restriction and shallower implantation site in rats with maternal hyperinsulinemia are associated with altered NOS expression.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Role of myocardial neuronal nitric oxide synthase-derived nitric oxide in beta-adrenergic hyporesponsiveness after myocardial infarction-induced heart failure in rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Calcification of aortic smooth muscle cells isolated from spontaneously hypertensive rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Cyclophosphamide induced cystitis: role of nitric oxide synthase, cyclooxygenase-1 and 2, and NK(1) receptors.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Role of perfusion medium, oxygen and rheology for endoplasmic reticulum stress-induced cell death after hypothermic machine preservation of the liver.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Characterisation and chromosomal localisation of the rat alpha- and beta-adducin-encoding genes.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Cardioprotective effect of 5-lipoxygenase gene (ALOX5) silencing in ischemia-reperfusion.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Liver cirrhosis induces renal and liver phospholipase A2 activity in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Role of lipocortin-1 in the anti-hyperalgesic actions of dexamethasone.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Myocyte apoptosis during acute myocardial infarction in rats is related to early sarcolemmal translocation of annexin A5 in border zone.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Inhibition of Rho kinase by fasudil hydrochloride attenuates lung injury induced by intestinal ischemia and reperfusion.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Uncoupled endothelial nitric oxide synthase and oxidative stress in a rat model of pregnancy-induced hypertension.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Phosphorylated endothelial NOS Ser1177 via the PI3K/Akt pathway is depressed in the brain of stroke-prone spontaneously hypertensive rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Its dual influence on insulin secretion in vivo at different peptide concentrations, and the abundance of macrophages expressing daintain/AIF1 in the pancreatic islets of prediabetic rats, suggest that daintain/AIF1 may have a role in connection with the pathogenesis of insulin-dependent diabetes mellitus.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Allelic variants in the GABA(A)alpha6 receptor subunit gene (GABRA6) is associated with abdominal obesity and cortisol secretion.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Changes of intermedin/adrenomedullin 2 and its receptors in the right ventricle of rats with chronic hypoxic pulmonary hypertension].]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Decreased FKBP12.6 expression and enhanced endothelin receptor signaling associated with arrhymogenesis in myocardial infarction rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Gas6 regulates mesangial cell proliferation through Axl in experimental glomerulonephritis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Endogenous neurosteroids modulate epileptogenesis in a model of temporal lobe epilepsy.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Nicotine-induced prenatal overexposure to maternal glucocorticoid and intrauterine growth retardation in rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Expression and localization of mesothelin in developing rat pancreas.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Serum KL-6 as a novel disease marker in adolescent and adult cystic fibrosis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Dietary and hormonal regulation of aldolase B gene expression.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Study of iron metabolism disturbances in an animal model of insulin resistance.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Differential cytokine activity and morphology during wound healing in the neonatal and adult rat skin.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Paraventricular nucleus corticotrophin releasing hormone contributes to sympathoexcitation via interaction with neurotransmitters in heart failure.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Activities of cerebral dihydropteridine reductase and tyrosine hydroxylase in chronic uremia in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Selective losses of brainstem catecholamine neurons after hypoxia-ischemia in the immature rat pup.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Time-dependent changes in the expression of thyroid hormone receptor alpha 1 in the myocardium after acute myocardial infarction: possible implications in cardiac remodelling.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Genes that affect cholesterol synthesis, cholesterol absorption, and chylomicron assembly: the relationship between the liver and intestine in control and streptozotosin diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Upregulation of pancreatic polypeptide-sensitive neuropeptide Y (NPY) receptors in estrogen-induced hypertrophy of the anterior pituitary gland in the Fischer-344 rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Effects of sulfur dioxide on the expressions of MUC5AC and ICAM-1 in airway of asthmatic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Gene for pain modulatory neuropeptide NPFF: induction in spinal cord by noxious stimuli.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Preventive effect of Notch signaling inhibition by a gamma-secretase inhibitor on peritoneal dialysis fluid-induced peritoneal fibrosis in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Environment matters: synaptic properties of neurons born in the epileptic adult brain develop to reduce excitability.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Melatonin preserves fetal growth in rats by protecting against ischemia/reperfusion-induced oxidative/nitrosative mitochondrial damage in the placenta.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Transcriptional and posttranscriptional regulation of apolipoprotein E, A-I, and A-II gene expression in normal rat liver and during several pathophysiologic states.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Study on the expressions and roles of renal heat shock protein 72 and Toll-like receptor 4 in hepatorenal syndrome in rat].]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Expression of toll-like receptor 2 and 4 in intestinal mucosa in experimental severe acute pancreatitis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Protective effect of bicyclol on liver injury induced by hepatic warm ischemia/reperfusion in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Antiarthritic activity of an orally active C5a receptor antagonist against antigen-induced monarticular arthritis in the rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Effect of biliary obstruction and internal biliary drainage on hepatic cytochrome P450 isozymes in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The potential role of transcription factor aryl hydrocarbon receptor in downregulation of hepatic cytochrome P-450 during sepsis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Endothelin levels increase in rat focal and global ischemia.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Effect of pyrrolidine dithiocarbamate on hepatic vascular stress gene expression during ischemia and reperfusion.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Involvement of NO and MEK/ERK pathway in enhancement of endothelin-1-induced mesenteric artery contraction in later-stage type 2 diabetic Goto-Kakizaki rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[A role for enhanced integrin and FAK expression in uremia-induced parathyroid hyperplasia.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Activation of signaling molecules and matrix metalloproteinases in right ventricular myocardium of rats with pulmonary hypertension.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Astrocytes and neurons: different roles in regulating adenosine levels.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Hyperoxia increases protein mass of 5-lipoxygenase and its activating protein, flap, and leukotriene B(4) output in newborn rat lungs.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Inhibition of diabetic nephropathy by a decoy peptide corresponding to the `handle` region for nonproteolytic activation of prorenin.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Protein nitration in rat lungs during hyperoxia exposure: a possible role of myeloperoxidase.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Abnormal PTEN expression in portal hypertensive gastric mucosa: a key to impaired PI 3-kinase/Akt activation and delayed injury healing?]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Beneficial effects of magnolol in a rodent model of endotoxin shock.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Suppression of hepatic cytochrome p450-mediated drug metabolism during the late stage of sepsis in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Hypothermia after cardiac arrest does not alter serum inflammatory markers.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Down-regulation of genes related to the adrenergic system may contribute to splanchnic vasodilation in rat portal hypertension.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Cooperative effect of angiotensin AT(1) and endothelin ET(A) receptor antagonism limits the brain damage after ischemic stroke in rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Differential expression of alpha- and beta-enolase genes during rat heart development and hypertrophy.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Taurine rescues vascular endothelial dysfunction in streptozocin-induced diabetic rats: correlated with downregulation of LOX-1 and ICAM-1 expression on aortas.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Pancreatic gene expression is altered during acute experimental pancreatitis in the rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Intrinsic fibroblast-mediated remodeling of damaged collagenous matrices in vivo.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Effects of various diuretics on cardiac function in rats with heart failure].]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Fetal adrenal gland alterations in a rat model of adverse intrauterine environment.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Potential contributory role of H-Ras, a small G-protein, in the development of retinopathy in diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The effect of simvastatin on the serum monocyte chemoattractant protein-1 and intracellular adhesion molecule-1 levels in diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Independent alterations in the central and peripheral somatosensory pathways in rat diabetic neuropathy.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[In vivo characterization of the molecular-genetic changes in gastric mucosa during the development of acute gastritis and stress ulceration.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Megestrol acetate inhibits the expression of cytoplasmic aromatase through nuclear C/EBP in reperfusion injury-induced ischemic rat hippocampus.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Oxidative stress-induced, poly(ADP-ribose) polymerase-dependent upregulation of ET-1 expression in chronic diabetic complications.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Tumor necrosis factor-alpha gene expression in diabetic nephropathy: relationship with urinary albumin excretion and effect of angiotensin-converting enzyme inhibition.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Tissue-specific expression and splicing of the rat polycystic kidney disease 1 gene.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Stobadine protects rat kidney against ischaemia/reperfusion injury.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[FTY720 attenuates lesional interleukin-17(+) cell accumulation in rat experimental autoimmune neuritis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The effect of caffeic acid phenethyl ester (CAPE) against cholestatic liver injury in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Prevention of diabetes: effect of mycophenolate mofetil and anti-CD25 on onset of diabetes in the DRBB rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Stretch-activated signaling of nerve growth factor secretion in bladder and vascular smooth muscle cells from hypertensive and hyperactive rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Identification of two nuclear factor of activated T-cells (NFAT)-response elements in the 5'-upstream regulatory region of the ET-1 promoter.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Strain difference in susceptibility to experimental autoimmune encephalomyelitis in rats correlates with T(H)1 and T(H)17-inducing cytokine profiles.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Methylprednisolone inhibits IFN-gamma and IL-17 expression and production by cells infiltrating central nervous system in experimental autoimmune encephalomyelitis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Gene expression profile related to inflammation in rat model of traumatic deep vein thrombosis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Extracellular signal-regulated kinase-mediated IL-1-induced cortical neuron damage during traumatic brain injury.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Crosstalk between thrombosis and inflammation in lung reperfusion injury.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Melanin-concentrating hormone induces insulin resistance through a mechanism independent of body weight gain.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Characterization of a novel peripheral nervous system myelin protein (PMP-22/SR13).]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[DHEA administration increases brown fat uncoupling protein 1 levels in obese OLETF rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Increased melatonin synthesis in pineal glands of rats in streptozotocin induced type 1 diabetes.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Changes of serum neuron specific enolase in rats with septic shock].]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Enhancement of erbB2 and erbB3 expression during oral oncogenesis in diabetic rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Frequent induction of mammary carcinomas following neu oncogene transfer into in situ mammary epithelial cells of susceptible and resistant rat strains.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Myofibroblast transdifferentiation of mesothelial cells is mediated by RAGE and contributes to peritoneal fibrosis in uraemia.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Alteration in erythropoietin-induced cardioprotective signaling by postinfarct ventricular remodeling.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Sepsis-induced muscle growth hormone resistance occurs independently of STAT5 phosphorylation.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Molecular characterization and functional regulation of a novel rat liver-specific organic anion transporter rlst-1.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Increased 5-HT2C receptor binding in the brain stem and cerebral cortex during liver regeneration and hepatic neoplasia in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Estrogen receptor antagonist fulvestrant (ICI 182,780) inhibits the anti-inflammatory effect of glucocorticoids.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Estrogen receptor hormone agonists limit trauma hemorrhage shock-induced gut and lung injury in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Diabetes increases both N-ras and ets-1 expression during rat oral oncogenesis resulting in enhanced cell proliferation and metastatic potential.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Microarray studies on effects of Pneumocystis carinii infection on global gene expression in alveolar macrophages.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Pituitary and hypothalamic somatostatin receptor subtype messenger ribonucleic acid expression in the food-deprived and diabetic rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Nicorandil protects against lethal ischemic ventricular arrhythmias and up-regulates endothelial nitric oxide synthase expression and sulfonylurea receptor 2 mRNA in conscious rats with acute myocardial infarction.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Urea transporter UT-A1 and aquaporin-2 proteins decrease in response to angiotensin II or norepinephrine-induced acute hypertension.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Donor simvastatin treatment abolishes rat cardiac allograft ischemia/reperfusion injury and chronic rejection through microvascular protection.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Role of macrophages in nephrolithiasis in rats: an analysis of the renal interstitium.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Forkhead class O transcription factor 3a activation and Sirtuin1 overexpression in the hypertrophied myocardium of the diabetic Goto-Kakizaki rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Unilateral ureteral obstruction evokes renal tubular apoptosis via the enhanced oxidative stress and endoplasmic reticulum stress in the rat.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Melatonin protects against oxidative damage in a neonatal rat model of bronchopulmonary dysplasia.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Hyperbaric oxygenation pretreatment induces catalase and reduces infarct size in ischemic rat myocardium.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Testicular steroidogenesis is decreased by hyperthermia in old rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Aberrant methylation of the THRB gene in tissue and plasma of breast cancer patients.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Long-term inhibition of the central alpha(2B)-adrenergic receptor gene via recombinant AAV-delivered antisense in hypertensive rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[The combined use of prostaglandin I2 analogue (OP-2507) and thromboxane A2 synthetase inhibitor (OKY-046) strongly inhibits atherosclerosis of aortic allografts in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Inhibition of ALK5 signaling induces physeal dysplasia in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Venous thrombosis-associated inflammation and attenuation with neutralizing antibodies to cytokines and adhesion molecules.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Adenosine protected against pulmonary edema through transporter- and receptor A2-mediated endothelial barrier enhancement.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Differential regulation of CXCL12 and PACAP mRNA expression after focal and global ischemia.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Identification of genes enhanced by protein-calorie malnutrition by differential display polymerase chain reaction (expression of fibrinogen B beta chain, B cell translocation gene 1 and thyroid hormone responsive protein genes).]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[DeltaPKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Significance of insulin signaling in liver regeneration triggered by portal vein ligation.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Growth pattern switch of renal cells and expression of cell cycle related proteins at the early stage of diabetic nephropathy.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Mechanism of hexachlorobenzene-induced porphyria in rats. Effect of phenobarbitone pretreatment.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Brief episode of ischemia activates protective genetic program in rat heart: a gene chip study.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Overexpression of the PC3/TIS21/BTG2 mRNA is part of the stress response induced by acute pancreatitis in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Mediators of ischemic preconditioning identified by microarray analysis of rat spinal cord.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Extracellular signal-regulated kinase activation during renal ischemia/reperfusion mediates focal adhesion dissolution and renal injury.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Subcellular redistribution of focal adhesion kinase and its related nonkinase in hypertrophic myocardium.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Hepatic and skeletal muscle glycogen metabolism in rats with short-term cholestasis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy: role of M-CAT element within the promoter.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Involvement of GADD153 and cardiac ankyrin repeat protein in cardiac ischemia-reperfusion injury.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Peripubertal hyperinsulinemia upregulates phosphatidylinositol 3-kinase/akt pathway in rat ovaries.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Ischemia-induced enhancement of CFTR expression on the plasma membrane in neonatal rat ventricular myocytes.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Protective role of heme oxygenase 1 in the intestinal tissue injury in hemorrhagic shock in rats.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[A shift in the Bax/Bcl-2 balance may activate caspase-3 and modulate apoptosis in experimental glomerulonephritis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Synergistic inhibition of tumor growth in a murine mammary adenocarcinoma model by combinational gene therapy using IL-12, pro-IL-18, and IL-1beta converting enzyme cDNA.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Attenuation of endogenous oxidative stress-induced cell death by cytochrome P450 inhibitors in primary cultures of rat hepatocytes.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Streptozotocin-induced diabetes increases the interaction of Bad/Bcl-XL and decreases the binding of pBad/14-3-3 in rat testis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Regulation of rat pancreatic CCKB receptor and somatostatin expression by insulin.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Increased expression of cyclin G1 and p21WAF1/CIP1 in neurons following transient forebrain ischemia: comparison with early DNA damage.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Myocardial ischemia and reperfusion reduce the levels of cyclic ADP-ribose in rat myocardium.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Danshensu protects vascular endothelia in a rat model of hyperhomocysteinemia.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Overexpression of cyclin D1 and cyclin E in 1,2-dimethylhydrazine dihydrochloride-induced rat colon carcinogenesis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Altered CD38 expression in thioacetamide-induced rat model of liver cirrhosis.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.
[Effect of vitamin A on the CD44 expression in the small intestine of rats with obstructive jaundice.]. Sentence from MEDLINE/PubMed, a database of the U.S. National Library of Medicine.