Small Molecular Weight Inhibitors of Stress-Activated and Mitogen- Activated Protein Kinases

Malemud, Charles J.

doi:10.2174/138955706777435670

Cited by 26 publications

(17 citation statements)

References 80 publications

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“…This potential pharmacologic therapy could occur not only by suppressing JAK/STAT signaling, but also by dampening downstream nuclear events such as cytokine gene amplification and matrix metalloproteinase (MMP) gene expression, as well as by altering cell survival and apoptosis pathways that are regulated, in part, by 'cross-talk' between JAK/STAT and the SAP/MAPK and PI3K/Akt pathways (Fig. 2) [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Targeting JAK/STAT Signaling Pathway in Inflammatory Diseases

Malemud¹,

Pearlman²

2009

CST

116

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In immune-mediated chronic inflammation the balance between pro-inflammatory and anti-inflammatory cytokines is skewed so that elevated levels of circulating pro-inflammatory cytokines of the interleukin (IL), interferon (IFN) protein families and TNF-is favored. Several of the pro-inflammatory IL-family cytokines, including most prominently, IL-6, IL-12, IL-17, IL-23, as well as IFN-, activate the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway where phosphorylated (i.e. activated) STAT proteins become potent transcription factors for specific STAT-target genes. Moreover, 'cross-talk' between JAK/STAT signaling, SAP/MAPK and the phosphatidyl inositide-3-kinase (PI3K) pathway has been demonstrated. Thus, activation of the SAP/MAPK and PI3K pathways by JAK/STAT can initiate pleiotypic cellular responses that regulate cellular proliferation, survival, development and apoptosis. Further, inflammatory responses typically seen in rheumatoid arthritis, irritable bowel disease, chronic heart failure and diseases of the eye appear to accelerate when the JAK/STAT pathway itself becomes dysregulated. Of note, the outcomes of several human clinical trials demonstrated efficacy in reducing some objective markers of chronic inflammation by inhibiting IL-6-mediated signaling. In addition, evidence from one of these trials showed that suppression of IL-6 signaling also dampened STAT phosphorylation. This result suggested that the targeting of JAK/STAT signaling with small molecule inhibitors may also suppress chronic inflammatory responses.

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Section: Introductionmentioning

confidence: 99%

Targeting JAK/STAT Signaling Pathway in Inflammatory Diseases

Malemud¹,

Pearlman²

2009

CST

116

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“…MAPKs mediate several cell functions, including phosphorylation of transcription factors NF-κB and AP-1 and transcription of proinflammatory and chemotactic cytokines [19][20][21][22]. Furthermore, this pathway can be blocked by small molecule, pharmacological MAPK inhibitors [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

C-Jun NH2 terminal kinase (JNK) is an essential mediator of Toll-like receptor 2-induced corneal inflammation

Adhikary

Sun

Pearlman

2008

Journal of Leukocyte Biology

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TLRs play an important role in the host inflammatory response to bacteria and bacterial products by activating a cascade of intracellular events leading to production of proinflammatory and chemotactic cytokines. To determine the role of MAPKs in TLR-induced corneal inflammation, we stimulated human corneal epithelial (HCE) cells with TLR2 ligands, tripalmitoyl-S-glyceroCys-(Lys)4 (Pam3Cys) or inactivated Staphylococcus aureus, and examined the time course of expression of MAPKs and the effect of MAPK inhibition on IkBα degradation and CXC chemokine production. We found that S. aureus and Pam3Cys stimulate phosphorylation of JNK, p38 MAPK, and ERK within 4 h and that blockade of JNK, but not p38 or ERK phosphorylation, had an inhibitory effect on IkBα degradation and CXC chemokine production. To determine if JNK is also important in TLR2-induced corneal inflammation in vivo, we examined JNK1 −/− mice and pharmacological inhibitors in a murine model of TLR2-induced corneal inflammation which is characterized by neutrophil recruitment to the corneal stroma and development of corneal haze. We found that corneal inflammation was significantly impaired in JNK1 −/− mice compared with control mice, and in mice treated with the JNK inhibitor compared with vehicle control. Taken together with results from HCE cells, these findings demonstrate that JNK has an essential role in TLR2-induced corneal inflammation.

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“…Additional studies have provided evidence indicating that activation of ERK and the antiapoptotic B-cell CLL/lymphoma 2 (bcl-2) play a role in growth factormediated neuroprotection from 6-hydroxydopamine (6-OHDA) toxicity in a dopaminergic cells (Zigmond 2006), hypoxia in cortical neurons (Ma and Quirion 2005), protection from stroke (Mehta et al 2007), and a variety of oxidative stressors (McCubrey et al 2006). Similar findings have been reported regarding inflammation (Malemud 2006).…”

Section: Resultsmentioning

confidence: 63%

Aging modifies brain region-specific vulnerability to experimental oxidative stress induced by low dose hydrogen peroxide

Crivello

Rosenberg

Shukitt‐Hale

et al. 2007

AGE

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Our previous studies demonstrated a significant decline in brain function and behavior in Fischer 344 (F344) rats with age. The present study was designed to test the hypothesis that dysregulation in calcium homeostasis (as assessed through (45)Ca flux) may contribute to the increase in age-related vulnerability to oxidative stress in brain regions, and result in a deficit in behavior-mediated signaling. Crude membrane (P-2) and more purified synaptosomal fractions were isolated from the striatum, hippocampus, and frontal cortex of young (6 months) and old (22 months) F344 rats and were assessed for calcium flux and extracellular-regulated kinase activity 1 (ERK) under control and oxidative stress conditions induced by low dose hydrogen peroxide (final concentration 5 microM). The level of oxidative stress responses was monitored by measuring reactive oxygen species (ROS) and glutathione (GSH). The results showed a significant difference in oxidative stress responses between young and old rats in evaluated brain regions. Old rats showed higher sensitivity to oxidative stress than young rats. The present findings show the differential effects of oxidative stress on calcium flux in brain regions with age that are dependent upon the brain areas examined and the fraction assessed. The accumulation of ROS and the decrease in GSH in the frontal cortex were sufficient to decrease ERK activity in old rats. This is the first study, to our knowledge, that demonstrates age-related differential sensitivity to oxidative stress expressed as a function of behavior-mediated signaling and stress levels among different fractions isolated from brain regions controlling behavior.

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Small Molecular Weight Inhibitors of Stress-Activated and Mitogen- Activated Protein Kinases

Cited by 26 publications

References 80 publications

Targeting JAK/STAT Signaling Pathway in Inflammatory Diseases

Targeting JAK/STAT Signaling Pathway in Inflammatory Diseases

C-Jun NH2 terminal kinase (JNK) is an essential mediator of Toll-like receptor 2-induced corneal inflammation

Aging modifies brain region-specific vulnerability to experimental oxidative stress induced by low dose hydrogen peroxide

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