Polyphenols have been shown to exhibit neuroprotective effects suppress neuroinflammation and activate antioxidant mechanisms.
A polyphenol found in pomegranate fruit, punicalagin, inhibits neuroinflammation in LPS-activated rat primary microglia by suppressing the production of pro-inflammatory cytokines (TNF- and IL-6), and PGE2 after 24 h of stimulation with LPS.
Punicalagin, which is a polyphenol – a form of chemical compound found in pomegranate fruit, can inhibit inflammation in specialised brain cells known as microglia. This inflammation leads to the destruction of more and more brain cells, making the condition of Alzheimer’s sufferers progressively worse . Recent results suggest that punicalagin inhibits neuroinflammation in microglia through interference with NF-[kappa]B signalling.
It is recommended to consume juice products that are 100 per cent pomegranate, meaning that approximately 3.4 per cent will be punicalagin. Unfortunately, most of the anti-oxidant compounds are found in the outer skin of the pomegranate, not in the soft part of the fruit. Pomegranate may be useful in neuroinflammatory conditions other than Alzheimer’s disease, including cancer and Parkinson’s disease.
Bottom Line: EAT YOU pomegranates! Punicalagin is good for your brain. The juice is the best was to get the most of the phytonutrient. It’s role in reducing the risk of Alzheimer’s disease and other inflammatory conditions is still being evaluated, but seems very promising.
Below is Nonsense relating to neuroinflammation, studies involving Punicalagin, and cytokines in the CNS:
Cytokines are polypeptides (proteins) that cause inflammation, immune activation, cellular differentiation, and death. They include interferons (INF) , tumor necrosis factor (TNF) , interleukins(IL) , chemokines, and growth factors. None of these are present to any degree in healthy tissues, but rather are induced by cell damage and tissue injury.
In the CNS, Tumor necrosis factor alpha (TNFa), Interleukin-1 (IL-1), and Transforming Growth Factor Beta (TGFb) are primarily the main cytokines. Each of these cytokines binds a specific receptor, which activates a process or signaling pathway, which include the NfkB and MAPK (mitogen activated protein kinase) pathways.
In the CNS, other cytokines include:
- Chemokines (fractalkine, IL-8, RANTES)
- Neuropoietic cytokines (IL-6, IL-11)
In a very basic categorization, the pro-inflammatory cytokines are : IL-1, TNF-a, IL-6, and the anti-inflammatory cytokines are IL-1ra (IL-1 receptor antagonist), IL-10, and TGFb
It has been noted that TNFa and IL-1 increase in the brain prior to neuronal death, and there are increased cytokines in stroke. The presence of IL-6 and TNFa are found to be increased in areas of tissue injury and in tissues in which there were poor clinical outcomes.
Some cytokines are synergistic – i.e. IL1 and TNFa or INFg (gamma) cause neurotoxicity when they are around together. TNFa may have a dose-dependent neurotoxicity.
TNFa/IL-1 increase ischemic injury in the brain.
TGFb/IL-10/IL-1ra reduce neurological injury.
Chronic IL-6 expression is neurotoxic in mice.
Endogenous IL-1 expression induces neurodegeneration
IL-1ra inhibits brain damage caused by injury or excitotoxins.
If you inhibit IL-1ra, it has been found that ischemic damage occurs more frequently, hence IL-1ra is protective in the brain. If you block it, then you lose protection.
TGFB2 receptor (which binds protective TGFB), will induce damage in the brain by removing the protective TGFB, but having too much TGFb causes autoimmune encephalitis. Thus too much of a good thing can cause problems as well!
SO again :
IL-1 = neurodegenerative
IL-10 = protective against injury
TNFa/IL-6 cause damage, but sometimes inhibit damage. It’s not always just they cytokines presence but WHEN they are present that counts. Il-1 and TNFa protect neurons if they are present BEFORE an injury, but if delivered at the time of injury, they cause destruction.
Different cells in the brain secrete cytokines. Glia, endothelial cells (lining of blood vessels), microglia, and neurons express TNFa, which in turn induces IL-10 that feeds back to decrease TNFa production (negative feedback). There is a TNF alpha binding protein that influences and decreases TNFa and also fractalkins that cause microglia to secrete less TNFa as well. All of these create feedbacks to limit cytokine production in complicated ways.
When damage occurs, the microglia (structural cells in the brain) first produce IL-1b(beta). The damage to cells causes extracelular ATP to be released and that activates P2X7 receptors that cause decreased intracellular potassium. This results in caspase 1 activation that causes the production of IL-1B, which in turn KILLS microglia and macrophages in the brain.
Also, during injury, TNFa release causes TGFb/IL6 expression.
Injury causes IL-1 to induce TNFa, IL-6, TGFb expression as well!
Infection and inflammation in the brain or periphery cause increased CNS cytokines and further inflammation. Hence peripheral inflammation affects CNS inflammation as well.
Excitotoxic amino acids also regulate cytokines after CNS injury as below:
Postsynaptic Density Protein 95 binds NMDA receptor subunit NR2 and Kainate recptor GLUR6 – which then phosphorylates C-JUn-N terminal kinase (JNK) and activates JUN. JUN promotes IL-1, IL-6, TNFa, INFa/g production.
Of note Cannabomids INHIBIT TNFa and IL-1 release from glial cells and are anti-inflammatory.
Neurons depend on glial cells for survival. Glial cells (astrocytes) produce neurotropins and growth factors (nerve growth factor (NGF), BDNF, GDNF)
Cytokines affect blood flow in the CNS as well indirectly. IL-1 induces neovasculariztion. IL-1 and TNFa damage the blood brain barrier and allow migration of molecules in and out of the CNS. They also cause NO (Nitric oxide) to be released, which is neurotoxic. They also upregulate adhesion molecules for leukocytes, that then enter the brain. What follows in vasogenic edema (swelling).
IL-1, IL-6, and TNFa also mediate fevers, endocrine reactions, and cardiovascular changes. This causes increased neuronal loss by alterations in blood flow and inflammation.
The COX-2 enzyme pathway and subsequent generation of prostaglandins play a significant role in neuroinflammation. mPGES-1 is the terminal enzyme for the biosynthesis of PGE2 (prostoglandin) during inflammation, and is functionally coupled with COX-2. This enzyme is markedly induced by pro-inflammatory stimuli and is down-regulated by antiinflammatory glucocorticoids – mPGES-1 inhibitors produced inhibition of PGE2 production
The transcription factor NF-B plays a crucial role in neuro-inflammation.
In resting cells, NF-B is sequestered in the cytoplasm by the inhibitory IB protein. When activated by a variety of stimuli that includes LPS (lipopolysacharride), IB is phosphorylated by IKK. Phosphorylated IB then undergoes ubiquitinisation and degradation . Dissociation and degradation of IB activates the translocation of NF-B subunit from the cytosol to the nucleus. The translocated subunit thereafter facilitates the transcription of several pro-inflammatory genes, including those encoding pro-inflammatory cytokines, and COX-2. Furthermore, microglial NF-B activation has been linked to brain damage
Punicalagin significantly inhibited LPS-induced NF-B signalling in microglia by suppressing the phosphorylation of IKK, IB and nuclear p65
Punicalagin produced a modest suppressive action on the phosphorylation of p38 and JNK MAPKs following LPS activation
Treatment with LPS in primary astrocytes triggered the synthesis of inflammatory cytokines, through MAPKs signalling pathways. Of particular interest is the role of p38, which has been shown to be a critical mediator of LPS-induced inflammation .
It appears that the effects of punicalagin on neuroinflammation are mediated mainly through targeting NF-B signalling, while MAPKmediated actions are minimal. Studies have shown that the TLR-4-mediated TRAF- 6/IKK/NF-B pathway has been well established as a signalling pathway responsible for inflammatory responses.
In addition to NF-B activation, TLR-4 can also initiate MAPK signalling
Punicalagin inhibited TRAF-6 protein expression, suggesting that this compound may inhibit the IKK/IB/NF-B signalling pathway, as well as p38 and JNK MAPK via selective inhibition of TRAF-6
Treatment with LPS in primary astrocytes triggered the synthesis of inflammatory cytokines, through MAPKs signalling pathways.
Punicalagin inhibits neuroinflammation in LPS-activated rat primary microglia (1) <– punicalagin inhibited COX- 2 and mPGES-1 after 24 h of LPS stimulation, suggesting that punicalagin acts to reduce PGE2 production by interfering with both COX-2 and mPGES-1 enzymatic activities in LPS-activated microglia.
Graphics from NATURE –
Xu, X., Yin, P., Wan, C., Chong, X. et al., Punicalagin inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4-mediated MAPKs and NF-B activation. Inflammation 2014, 37, 956–965. Punicalagin inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4-mediated MAPKs and NF-B activation
Punicalagin Inhibits Inflammation in LPS-Induced RAW264 7 macrophages <– punicalagin (25–100 M) suppressed NO, PGE2, TNF-, IL-6 and IL-1 production from LPS stimulated RAW 264.7 cells.
Winand, J., Schneider, Y. J., The anti-inflammatory effect of a pomegranate husk extract on inflamed adipocytes and macrophages cultivated independently, but not on the inflammatory vicious cycle between adipocytes and macrophages. Food Funct. 2014, 5, 310–318. The anti-inflammatory effect of a pomegranate husk extract on inflamed adipocytes and macrophages cultivated independently, but not on the inflammatory vicious cycle between adipocytes and macrophage <–Demonstrated the inhibitory effects of punicalagin on TNF- and NO production in LPS-stimulated RAW 264.7 cells, as well as IL-6 production in LPS-stimulated 3T3-L1 adipocytes.
The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer <<– The p38 MAPK signaling cascade is involved in various biological responses other than inflammation such as cell proliferation, differentiation, apoptosis and invasion. The p38 MAPK, originally referred as cytokine-suppressive anti-inflammatory drug binding protein (CSBP). p38 MAPK is activated by pro-inflammatory cytokines such as interleukins and TNF-α. Stimulation of receptors that initiate this cascade include GPCR, cytokine receptors, Toll-like receptors, growth factor receptors, and receptors associated with environmental stress such as heat shock, radiation and ultraviolet light. p38 MAPK is activated by upstream MAPK kinases (MKK) p38 MAPK pathway plays a central role in the expression and activity of pro-inflammatory cytokines such as TNF-α, IL-1, IL-2, IL-6, IL-7, and IL-8 and plays a regulatory role in cell proliferation and differentiation in the immune system. It also regulates the expression of several MMPs involved in inflammation such as MMP-2, MMP-9, and MMP-13.
p38 MAPK inhibitors have been shown to reduce LPS-induced TNF-α production (Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function.)
(CYTOKINES AND ACUTE neurodegenration) <<- Brain inflammation has been implicated in the pathogenesis of neurodegeneration in common neurological diseases such as stroke and Alzheimer’s disease
b-Amyloid Fibrils Activate Parallel Mitogen-Activated Protein kinase pathways in microglia < – Noted that p38 MAPK was upregulated in the brains of a transgenic mouse model of Alzheimer’s disease. Fibrillar forms of b-amyloid (Ab), which are the primary constituents of senile plaques, have been shown to activate tyrosine kinase-dependent signal transduction cascades, resulting in inflammatory responses in microglia.
There is involvement of p38 MAPK in cancer cell invasion. Of note, p38α and p38β were found to play important roles in cell differentiation and invasion of several different cancer cells such as breast cancer, squamous carcinoma cell, colon cancer, and ovarian cancer
Cannabinoids and Neuroprotection in Global and Focal Cerebral ischemia <–CANNABINOIDS inhibit IL-1 and TNFα expression and release from glia, and have anti-inflammatory and neuroprotective actions in vitro and in vivo
Common pathways of neuronal cell death have been identified in response to diverse insults, such as ischaemia, trauma or excitotoxicity. These include early disruption of ion homeostasis, excessive neuronal activation, seizures and spreading depression, massive release and impaired uptake of neurotransmitters such as glutamate, intracellular entry of Ca2+, and release of nitric oxide and free radicals. More recently, further factors have been identified, including activation of genes that initiate or execute apoptosis, and the influence of glial and endothelial cells, extracellular matrix and invading immune cells. There is evidence that specific cytokines can act at most, if not all, of these steps, and probably have multiple actions on several cells or systems involved in neurodegeneration.
Increased expression of p38 MAPK and extracellular-signal-regulated kinase (ERK) has been found in ischaemic brain tissue after MCAo. Selective inhibitors of these pathways markedly reduce the ischemic injury in rodents. TNFR1 and TNFR2 (Tumor necrosis factor receptors) belong to the low-affinity neurotrophin receptor gene superfamily. TNFα elicits its biological effects on multiple cell types in the CNS through these receptors.
TGFβ- mediated signalling is also regulated through crosstalk with other signal transduction pathways, including MAPK.
So, IL-1ra, or a small molecule antagonist of IL-1 receptors, might be beneficial in acute neurodegenerative conditions. Studies are currently evaluating this.
Relton, J. K. & Rothwell, N. J. Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res. Bull. 29, 243–246 (1992). The first study to report that inhibition of endogenous IL-1 limits neuronal death induced by cerebral ischaemia or excitotoxicity in vivo.
Prehn, J. H., Backhauss, C. & Krieglstein, J. Transforming growth factor-β 1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. J. Cereb. Blood Flow Metab. 13, 521–525 (1993). An early study showing neuroprotective effects of TGFβ in vivo against cerebral ischaemia, and in vitro against glu
Chao, C. C., Hu, S., Ehrlich, L. & Peterson, P. K. Interleukin-1 and tumor necrosis factor-α synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methylD-aspartate receptors. Brain. Behav. Immun. 9, 355–365 (1995). An early study showing interactions between cytokines to influence neuronal death in vitro, using human fetal brain cell cultures composed of neurons and glia.
Nawashiro, H., Martin, D. & Hallenbeck, J. M. Inhibition of tumor necrosis factor and amelioration of brain infarction in mice. J. Cereb. Blood Flow Metab. 17, 229–232 (1996). An early study indicating that endogenous TNFα mediates ischaemic brain damage in vivo. TNFbinding protein — a naturally occurring inhibitor of TNF — reduced damage caused by focal cerebral ischaemia in mice.
Scherbel, U. et al. Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc. Natl Acad. Sci. USA 96, 8721–8726 (1999). This study might provide an explanation for seemingly conflicting reports indicating that endogenous TNFα is either neurotoxic (based largely on acute interventions) or neuroprotective (based largely on stadies on genetically modified animals). It reports that functional outcomes in TNFα-null mice were improved early after brain injury compared with wild type mice, but TNFα-null mice showed permanent deficits and reduced recovery.
Ferrari, D., Chiozzi, P., Falzoni, S., Hanau, S. & Di Virgilio, F. Purinergic modulation of interleukin-1β release from microglial cells stimulated with bacterial endotoxin. J. Exp. Med. 185, 579–582 (1997). An early study showing that IL-1β is released from microglia by activation of purinergic, P2X7 receptors. Bacterial LPS is required for activation of microglial IL-1β expression, whereas ATP induced cleavage and release.
Ohtsuki, T., Ruetzler, C. A., Tasaki, K. & Hallenbeck, J. M. Interleukin-1 mediates induction of tolerance to global ischemia in gerbil hippocampal CA1 neurons. J. Cereb. Blood Flow Metab. 16, 1137–1142 (1996). The first demonstration that endogenous IL-1 can mediate ischaemic tolerance. Pre-treatment of gerbils three days before global ischaemia reduced brain injury. IL-1 was induced by a brief period of ‘preconditionary’ ischaemia.
Carrié, A. et al. A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nature Genet. 23, 25–31 (1999). A direct link between one of the recently identified members of the IL-1/Toll receptor family in brain function. Cognitive function in patients with X-linked mental retardation is strongly associated with a nonsense mutation in a gene identified as IL-1-receptor-like protein (IL-1R AcPL).
Venters, H. D. et al. A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc. Natl Acad. Sci. USA 96, 9879–9884 (1999). This study provided a potential explanation for indirect effects of the proinflammatory cytokine TNFα on neuronal survival through modification of the signalling pathway of a protective growth factor, IGF. This mechanism might apply to other neurotoxic cytokines.
Loddick, S. A., MacKenzie, A. & Rothwell, N. J. An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat. Neuroreport 7, 1465–1468 (1996). The first study reporting that inhibition of caspase activity protects against neuronal death (ischaemic brain damage) in vivo
Legos, J. J. et al. SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia. Brain Res. 892, 70–77 (2001). The first study to show that selective inhibition of p38 MAPK, which is involved in IL-1 and TNFα signalling,
Troy, C. M., Stefanis, L., Prochiantz, A., Greene, L. A. & Shelanski, M. L. The contrasting roles of ICE family proteases and interleukin-1β in apoptosis induced by trophic factor withdrawal and by copper/zinc superoxide dismutase down-regulation. Proc. Natl Acad. Sci. USA 93, 5635–5640 (1996). An early study reporting the contribution of ICE (caspase 1) to apoptosis in a neuronal cell line (PC12 cells) and indicating that ICE acts through modification of superoxide dismutase 1.
Giulian, D., Woodward, J., Young, D. G., Krebs, J. F. & Lachman, L. B. Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularisation. J. Neurosci. 8, 2485–2490 (1988). One of the first reports of IL-1 actions on nerve cells that might be relevant to neurodegeneration and repair
- 1. Ono K, Han J. The p38 signal transduction pathway: activation and function. Cell Signal 2000;12:1-13 [CrossRef], [PubMed],[Web of Science ®]
- 2. Yu L, Hébert MC, Zhang YE. TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J 2002;21:3749-59 [CrossRef], [PubMed], [Web of Science ®]
- 3. Pearson G, Robinson F, Beers Gibson T, Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 2001;22:153-83 [CrossRef], [PubMed], [Web of Science ®]
- 4. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene 2007;26:3279-90 [CrossRef],[PubMed], [Web of Science ®]
- 5. Schindler JF, Monahan JB, Smith WG. p38 pathway kinases as anti-inflammatory drug targets. J Dent Res 2007;86:800-11[CrossRef], [PubMed], [Web of Science ®]
- 6. Kaminska B. MAPK signalling pathways as molecular targets for anti-inflammatory therapy: from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta 2005;1754:253-62 [CrossRef], [PubMed], [Web of Science ®]
- 7. Lee JC, Laydon JT, McDonnell PC, A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature1994;372:739-46 [CrossRef], [PubMed], [Web of Science ®]
- 8. Newton R, Holden N. Inhibitors of p38 mitogen-activated protein kinase: potential as anti-inflammatory agents in asthma? BioDrugs 2003;17:113-29 [CrossRef], [PubMed], [Web of Science ®]
- 9. Hale KK, Trollinger D, Rihanek M, Manthey CL. Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and delta in inflammatory cell lineages. J Immunol 1999;162:4246-52 [PubMed], [Web of Science ®]
- 10. Beardmore VA, Hinton HJ, Eftychi C, Generation and characterization of p38 beta (MAPK11) gene-targeted mice. Mol Cell Biol 2005;25:10454-64 [CrossRef], [PubMed], [Web of Science ®]
- 11. Perregaux DG, Dean D, Cronan M, Inhibition of interleukin-1 beta production by SKF86002: evidence of two sites of in vitro activity and of a time and system dependence. Mol Pharmacol 1995;48:433-42 [PubMed], [Web of Science ®]
- 12. Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 2001;81:807-69 [PubMed], [Web of Science ®]
- 13. Raingeaud J, Gupta S, Rogers JS, Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 1995;270:7420-26 [CrossRef],[PubMed], [Web of Science ®]
- 14. Sugden PH, Clerk A. Stress-responsive mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res 1998;83:345-52 [CrossRef], [PubMed], [Web of Science ®]
- 15. Sweeney G, Somwar R, Ramlal T, An inhibitor of p38 mitogen-activated protein kinase prevents insulin-stimulated glucose transport but not glucose transporter translocation in 3T3-L1 adipocytes and L6 myotubes. J Biol Chem 1999;274:10071-8[CrossRef], [PubMed], [Web of Science ®]
- 16. Heidenreich KA, Kummer JL. Inhibition of p38 mitogen-activated protein kinase by insulin in cultured fetal neurons. J Biol Chem 1996;271:9891-4 [CrossRef], [PubMed], [Web of Science ®]
- 17. Jiang Y, Gram H, Zhao M, Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. J Biol Chem 1997;272:30122-8 [CrossRef], [PubMed], [Web of Science ®]
- 18. Hu MC, Wang YP, Mikhail A. Murine p38-delta mitogen-activated protein kinase, a developmentally regulated protein kinase that is activated by stress and proinflammatory cytokines. J Biol Chem 1999;274:7095-102 [CrossRef], [PubMed], [Web of Science ®]
- 19. Cuenda A, Cohen P, Buee-Scherrer V, Goedert M. Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO J1997;16:295-305 [CrossRef], [PubMed], [Web of Science ®]
- 20. Enslen H, Raingeaud J, Davis RJ. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem 1998;273:1741-8 [CrossRef], [PubMed], [Web of Science ®]
- 21. Han J, Lee JD, Jiang Y, Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem1996;271:2886-91 [CrossRef], [PubMed], [Web of Science ®]
- 22. Stein B, Brady H, Yang MX, Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. J Biol Chem 1996; 271:11427-33 [CrossRef], [PubMed], [Web of Science ®]
- 23. Moriguchi T, Kuroyanagi N, Yamaguchi K, A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem 1996;271:13675-9 [CrossRef], [PubMed], [Web of Science ®]
- 24. Moriguchi T, Toyoshima F, Gotoh Y, Purification and identification of a major activator for p38 from osmotically shocked cells. Activation of mitogen-activated protein kinase Kinase 6 by osmotic shock, tumor necrosis factor-? and H2O2 J Biol Chem1996;271:26981-8 [CrossRef], [PubMed], [Web of Science ®]
- 25. Yamauchi J, Tsujimoto G, Kaziro Y, Itoh H. Parallel regulation of mitogen-activated protein kinase kinase 3 (MKK3) and MKK6 in Gq-signaling cascade. J Biol Chem 2001;276:23362-72 [CrossRef], [PubMed], [Web of Science ®]
- 26. Bagrodia S, Dérijard B, Davis RJ, Cerione RA. Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation. J Biol Chem 1995;270:27995-8 [CrossRef], [PubMed], [Web of Science ®]
- 27. Zhang S, Han J, Sells MA, Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1. J Biol Chem 1995;270:23934-6 [CrossRef], [PubMed], [Web of Science ®]
- 28. Kim MS, Lee EJ, Kim HR, Moon A. p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer Res 2003;63:5454-61 [PubMed], [Web of Science ®]
- 29. Nick JA, Avdi NJ, Young SK, Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP. J Clin Invest 1997;99:975-86 [CrossRef], [PubMed], [Web of Science ®]
- 30. Zhang Y, Neo SY, Han J, RGS16 attenuates galphaq-dependent p38 mitogen-activated protein kinase activation by platelet-activating factor. J Biol Chem 1999;274:2851-7 [CrossRef], [PubMed], [Web of Science ®]
- 31. Kotlyarov A, Neininger A, Schubert C, MAPKAP kinase 2 is essential for LPS-induced TNFalpha biosynthesis. Nat Cell Biol1999;1:94-7 [CrossRef], [PubMed], [Web of Science ®]
- 32. Hegen M, Gaestel M, Nickerson-Nutter CL, MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis. J Immunol 2006;177:1913-17 [CrossRef], [PubMed], [Web of Science ®]
- 33. Ben-Levy R, Hooper S, Wilson R, Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr Biol 1998;8:1049-57 [CrossRef], [PubMed], [Web of Science ®]
- 34. Engel K, Kotlyarov A, Gaestel M. Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation. EMBO J 1998;17:3363-71 [CrossRef], [PubMed], [Web of Science ®]
- 35. McLaughlin MM, Kumar S, McDonnell PC, Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem 1996;271:8488-92 [CrossRef], [PubMed], [Web of Science ®]
- 36. New L, Jiang Y, Zhao M, PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J 1998;17:3372-84 [CrossRef],[PubMed], [Web of Science ®]
- 37. Zhu T, Lobie PE. Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by growth hormone: resultant transcriptional activation of ATF-2 and CHOP, cytoskeletal re-organization and mitogenesis. J Biol Chem2000;275:2103-14 [CrossRef], [PubMed], [Web of Science ®]
- 38. Han J, Jiang Y, Li Z, Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature1997;386:296-9 [CrossRef], [PubMed], [Web of Science ®]
- 39. Wang XZ, Ron D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science 1996;272:1347-9 [CrossRef], [PubMed], [Web of Science ®]
- 40. Yang SH, Galanis A, Sharrocks AD. Targeting of p38 mitogen-activated protein kinases to MEF2 transcription factors. Mol Cell Biol 1999;19:4028-37 [CrossRef], [PubMed], [Web of Science ®]
- 41. Vermeulen L, De Wilde G, Van Damme P, Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J 2003;22:1313-24 [CrossRef], [PubMed], [Web of Science ®]
- 42. Song H, Ki SH, Kim SG, Moon A. Activating transcription factor 2 mediates matrix metalloproteinase-2 transcriptional activation induced by p38 in breast epithelial cells. Cancer Res 2006;66:10487-96 [CrossRef], [PubMed], [Web of Science ®]
- 43. Carter AB, Knudtson KL, Monick MM, The p38 mitogen-activated protein kinase is required for NF-kappaB-dependent gene expression. The role of TATA-binding protein (TBP). J Biol Chem 1999;274:30858-63 [CrossRef], [PubMed], [Web of Science ®]
- 44. Campbell J, Ciesielski CJ, Hunt AE, A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. J Immunol 2004;173:6928-37 [CrossRef], [PubMed], [Web of Science ®]
- 45. Underwood DC, Osborn RR, Bochnowicz S, SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol 2000;279:L895-902 [PubMed], [Web of Science ®]
- 46. Pietersma A, Tilly BC, Gaestel M, p38 mitogen activated protein kinase regulates endothelial VCAM-1 expression at the post-transcriptional level. Biochem Biophys Res Commun 1997;230:44-8 [CrossRef], [PubMed], [Web of Science ®]
- 47. Craxton A, Shu G, Graves JD, p38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes. J Immunol 1998;161:3225-36 [PubMed], [Web of Science ®]
- 48. Ridley SH, Sarsfield SJ, Lee JC, Actions of IL-1 are selectively controlled by p38 mitogenactivated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J Immunol 1997;158:3165-73 [PubMed], [Web of Science ®]
- 49. Mbalaviele G, Anderson G, Jones A, Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. J Pharmacol Exp Ther 2006;317:1044-53 [CrossRef], [PubMed], [Web of Science ®]
- 50. Barnes PJ. Novel signal transduction modulators for the treatment of airway diseases. Pharmacol Ther 2006;109:238-45[CrossRef], [PubMed], [Web of Science ®]
- 51. Haddad EB, Birrell M, McCluskie K, Role of p38 MAP kinase in LPS-induced airway inflammation in the rat. Br J Pharmacol2001;132:1715-24 [CrossRef], [PubMed], [Web of Science ®]
- 52. Escott KJ, Belvisi MG, Birrell MA, Effect of the p38 kinase inhibitor, SB 203580, on allergic airway inflammation in the rat. Br J Pharmacol 2000;131:173-6 [CrossRef], [PubMed], [Web of Science ®]
- 53. Fujita M, Igarashi T, Kurai T, Correlation between dry eye and rheumatoid arthritis activity. Am J Ophthalmol 2005;140:808-13 [CrossRef], [PubMed], [Web of Science ®]
- 54. Sweeney SE, Firestein GS. Signal transduction in rheumatoid arthritis. Curr Opin Rheumatol 2001;16:231-7 [CrossRef]
- 55. Kumar S, Blake SM, Emery JG. Intracellular signaling pathways as a target for the treatment of rheumatoid arthritis. Curr Opin Pharmacol 2001;1:307-13 [CrossRef], [PubMed]
- 56. Badger AM, Bradbeer JN, Votta B, Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock, and immune function. J Pharmacol Exp Ther 1996;279:1453-61 [PubMed], [Web of Science ®]
- 57. Jackson JR, Bolognese B, Hillegass L, Pharmacological effects of SB 220025, a selective inhibitor of P38 mitogen-activated protein kinase, in angiogenesis and chronic inflammatory disease models. J Pharmacol Exp Ther 1998;284:687-92 [PubMed],[Web of Science ®]
- 58. Badger AM, Griswold DE, Kapadia R, Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum 2000;43:175-83 [CrossRef], [PubMed], [Web of Science ®]
- 59. Wada Y, Nakajima-Yamada T, Yamada K, R-130823, a novel inhibitor of p38 MAPK, ameliorates hyperalgesia and swelling in arthritis models. Eur J Pharmacol 2005;506:285-95 [CrossRef], [PubMed], [Web of Science ®]
- 60. Wadsworth SA, Cavender DE, Beers SA, RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase. J Pharmacol Exp Ther 1999;291:680-7 [PubMed], [Web of Science ®]
- 61. Summers RW, Elliott DE, Qadir K, Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Am J Gastroenterol 2003;98:2034-41 [CrossRef], [PubMed], [Web of Science ®]
- 62. Hollenbach E, Neumann M, Vieth M, Inhibition of p38 MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease. FASEB J 2004;18:1550-2 [PubMed], [Web of Science ®]
- 63. Allan SM, Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci 2001;2:734-44 [CrossRef], [PubMed],[Web of Science ®]
- 64. McDonald DR, Bamberger ME, Combs CK, Landreth GE. Beta-amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. J Neurosci 1998;18:4451-60 [PubMed], [Web of Science ®]
- 65. Legos JJ, Erhardt JA, White RF, SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia. Brain Res 2001;892:70-7 [CrossRef], [PubMed], [Web of Science ®]
- 66. Barone FC, Irving EA, Ray AM, SB 239063, a second-generation p38 mitogen activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia. J Pharmacol Exp Ther 2001;296:312-21 [PubMed], [Web of Science ®]
- 67. Barone FC, Irving EA, Ray AM, Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia. Med Res Rev 2001;21:129-45 [CrossRef], [PubMed], [Web of Science ®]
- 68. Koistinaho M, Kettunen MI, Goldsteins G, Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation. Proc Natl Acad Sci2002;99:1610-5 [CrossRef], [PubMed], [Web of Science ®]
- 69. Maroney AC, Finn JP, Connors TJ, Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J Biol Chem 2001;276:25302-8 [CrossRef], [PubMed], [Web of Science ®]
- 70. Rust W, Kingsley K, Petnicki T, Heat shock protein 27 plays two distinct roles in controlling human breast cancer cell migration on laminin-5. Mol Cell Biol Res Commun 1999;1:196-02 [CrossRef], [PubMed]
- 71. Simon C, Simon M, Vucelic G, The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1-dependent promoter activation. Exp Cell Res 2001;271:344-55 [CrossRef], [PubMed], [Web of Science ®]
- 72. Nemoto T, Kubota S, Ishida H, Ornithine decarboxylase, mitogen-activated protein kinase and matrix metalloproteinase-2 expressions in human colon tumors. World J Gastroenterol 2005;11:3065-9 [CrossRef], [PubMed], [Web of Science ®]
- 73. Davidson B, Givant-Horwitz V, Lazarovici P, Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK): co-expression in metastatic serous ovarian carcinoma. Clin Exp Metastasis 2003;20:621-31 [CrossRef], [PubMed], [Web of Science ®]
- 74. Morooka T, Nishida E. Requirement of p38 mitogen-activated protein kinase for neuronal differentiation in PC12 cells. J Biol Chem 1998;273:24285-8 [CrossRef], [PubMed], [Web of Science ®]
- 75. Junttila MR, Ala-Aho R, Jokilehto T, p38alpha and p38delta mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells. Oncogene 2007;26:5267-79 [CrossRef], [PubMed], [Web of Science ®]
- 76. Lim SJ, Lee YJ, Lee E. p38MAPK inhibitor SB203580 sensitizes human SNU-C4 colon cancer cells to exisulind-induced apoptosis. Oncol Rep 2006;16:1131-5 [PubMed], [Web of Science ®]
- 77. Guo X, Ma N, Wang J, Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells. BMC Cancer 2008;8:375 [CrossRef], [PubMed]
- 78. Yasui H, Hideshima T, Ikeda H, BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (HSP) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/HSP27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth. Br J Haematol 2007;136:414-23 [CrossRef], [PubMed], [Web of Science ®]
- 79. Shin I, Kim S, Song H, H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells. J Biol Chem 2005; 280: 14675-83 [CrossRef], [PubMed], [Web of Science ®]
- 80. Tryggvason K. Type IV collagenase in invasive tumors. Breast Cancer Res 1993;24:209-18 [CrossRef], [Web of Science ®]
- 81. Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 1991;64:327-36 [CrossRef], [PubMed], [Web of Science ®]
- 82. Xu L, Chen S, Bergan RC. MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Oncogene 2006;25:2987-98 [CrossRef],[PubMed], [Web of Science ®]
- 83. Denkert C, Siegert A, Leclere A, An inhibitor of stress-activated MAP-kinases reduces invasion and MMP-2 expression of malignant melanoma cells. Clin Exp Metastasis 2002;19:79-85 [CrossRef], [PubMed], [Web of Science ®]
- 84. Johansson N, Ala-aho R, Uitto V, Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase. J Cell Sci 2000;113:227-35 [PubMed], [Web of Science ®]
- 85. Han YC, Zeng XX, Wang R, Correlation of p38 mitogen-activated protein kinase signal transduction pathway to uPA expression in breast cancer. Ai Zheng 2007;26:48-53 [PubMed]
- 86. Zhou HY, Pon YL, Wong AS. Synergistic effects of epidermal growth factor and hepatocyte growth factor on human ovarian cancer cell invasion and migration: role of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. Endocrinology 2007;148:5195-208 [CrossRef], [PubMed], [Web of Science ®]
- 87. Simon C, Goepfert H, Boyd D. Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. Cancer Res 1998;58:1135-9 [PubMed], [Web of Science ®]
- 88. Yao J, Xiong S, Klos K, Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-beta1 in human breast cancer cells. Oncogene 2001;20:8066-74 [CrossRef], [PubMed], [Web of Science ®]
- 89. She QB, Chen N, Dong Z. ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. J Biol Chem 2000;275:20444-9 [CrossRef], [PubMed], [Web of Science ®]
- 90. She QB, Bode AM, Ma WY, Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. Cancer Res 2001;61:1604-10 [PubMed], [Web of Science ®]
- 91. Bradham C, McClay DR. p38 MAPK in development and cancer. Cell Cycle 2006;5:824-8 [Taylor & Francis Online],[PubMed], [Web of Science ®]
- 92. Iyoda K, Sasaki Y, Horimoto M, Involvement of the p38 mitogen-activated protein kinase cascade in hepatocellular carcinoma. Cancer 2003;97:3017-26 [CrossRef], [PubMed], [Web of Science ®]
- 93. Corrèze C, Blondeau JP, Pomérance M. p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells. Eur J Endocrinol 2005;153:123-33 [CrossRef], [PubMed], [Web of Science ®]
- 94. Chang HL, Wu YC, Su JH, Protoapigenone, a novel flavonoid, induces apoptosis in human prostate cancer cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase 1/2. J Pharmacol Exp Ther 2008;325:841-9[CrossRef], [PubMed], [Web of Science ®]
- 95. Croons V, Martinet W, Herman AG, The protein synthesis inhibitor anisomycin induces macrophage apoptosis in rabbit atherosclerotic plaques through p38 mitogen-activated protein kinase. J Pharmacol Exp Ther 2009;329:856-64 [CrossRef],[PubMed], [Web of Science ®]
- 96. Elenitoba-Johnson KS, Jenson SD, Abbott RT, Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. Proc Natl Acad Sci U S A 2003;100:7259-64[CrossRef], [PubMed], [Web of Science ®]
- 97. Karahashi H, Nagata K, Ishii K, Amano F. A selective inhibitor of p38 MAP kinase, SB202190, induced apoptotic cell death of a lipopolysaccharide-treated macrophage-like cell line, J774.1. Biochem Biophys Acta 2000;1502:207-23 [PubMed], [Web of Science ®]
- 98. Navas TA, Nguyen AN, Hideshima T, Inhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo. Leukemia2006;20:1017-27 [CrossRef], [PubMed], [Web of Science ®]
- 99. Lantos I, Bender PE, Razgaitis KA, Antiinflammatory activity of 5,6-diaryl-2,3-dihydroimidazo[2,1-b]thiazoles. Isomeric 4-pyridyl and 4-substituted phenyl derivatives. J Med Chem 1984;27:72-5 [CrossRef], [PubMed], [Web of Science ®]
- 100. Saccani S, Pantano S, Natoli G. p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol 2002;3:69-75 [CrossRef], [PubMed], [Web of Science ®]
- 101. Pargellis C, Tong L, Churchill L, Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Biol2002;9:268-72 [CrossRef], [PubMed]
- 102. Karaman MW, Herrgard S, Treiber DK, A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 2008;26:127-32 [CrossRef], [PubMed], [Web of Science ®]
- 103. Fabian MA, Biggs WH, Treiber DK, A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol2005;23:329-36 [CrossRef], [PubMed], [Web of Science ®]
- 104. Zack D, Campagnuolo GS, Middleton S, 66th American College of Rheumatology Annual Scientific Meeting, Orlando, 2003. J Clin Rheumatol 2002;8:207 [CrossRef], [PubMed]
- 105. Boehringer Ingelheim Pharmaceuticals Inc. Method for administering BIRB 796 BS. WO/2003/049742; 2003
- 106. Hill RJ, Dabbagh K, Phippard D, Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. J Pharmacol Exp Ther 2008;327:610-9 [CrossRef], [PubMed], [Web of Science ®]
- 107. Kim ES, Kim MS, Moon A. Transforming growth factor (TGF)-beta in conjunction with H-ras activation promotes malignant progression of MCF10A breast epithelial cells. Cytokine 2005;21(29):84-91 [CrossRef]
- 108. Kim ES, Kim MS, Moon A. TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 2004;25:1375-82 [PubMed], [Web of Science ®]
- 109. Kim ES, Sohn YW, Moon A. TGF-beta-induced transcriptional activation of MMP-2 is mediated by activating transcription factor (ATF)2 in human breast epithelial cells. Cancer Lett 2007;252:147-56 [CrossRef], [PubMed], [Web of Science ®]
- 110. Song H, Moon A. Glial cell-derived neurotrophic factor (GDNF) promotes low-grade Hs683 glioma cell migration through JNK, ERK-1/2 and p38 MAPK signaling pathways. Neurosci Res 2006;56:29-38 [CrossRef], [PubMed], [Web of Science ®]
- 111. Dominguez C, Powers DA, Tamayo N. p38 MAP kinase inhibitors: many are made, but few are chosen. Curr Opin Drug Discov Devel 2005;8:421-30 [PubMed], [Web of Science ®]
- 112. Lee MR, Dominguez C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem 2005;12:2979-94 [CrossRef], [PubMed], [Web of Science ®]
- 113. Mongin-Bulewski C. Drug Discovery Technology 2002 (Part V) – Overnight Report. Boston MA, USA. IDdb Meeting Report. 4-9 August 2002
- 114. Gruenbaum LM, Schwartz R, Woska JR, Inhibition of pro-inflammatory cytokine production by the dual p38/JNK2 inhibitor BIRB796 correlates with the inhibition of p38 signaling. Biochem Pharmacol 2009;77:422-32 [CrossRef], [PubMed], [Web of Science ®]
- 115. Branger J, van den Blink B, Weijer S, Inhibition of coagulation, fibrinolysis, and endothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. Blood 2003;101:4446-8 [CrossRef], [PubMed], [Web of Science ®]
- 116. Schreiber S, Feagan B, D’Haens G, Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006;4:325-34 [CrossRef], [PubMed],[Web of Science ®]
- 117. Cohen SB, Cheng TT, Chindalore V, Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthritis Rheum 2009;60:335-44[CrossRef], [PubMed], [Web of Science ®]
- 118. Alten RE, Zerbini C, Jeka S, Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy. Ann Rheum Dis 2009: published online 8 Apr 2009, doi:10.1136/ard.2008.104802
- 119. Pusztai L, Mendoza TR, Reuben JM, at al. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine 2004;25:94-102 [CrossRef], [PubMed], [Web of Science ®]
- 120. Fijen JW, Zijlstra JG, De Boer P, Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers. Clin Exp Immunol 2001;124:16-20 [CrossRef],[PubMed], [Web of Science ®]
- 121. Behr TM, Berova M, Doe CP, p38 mitogen-activated protein kinase inhibitors for the treatment of chronic cardiovascular disease. Curr Opin Investig Drugs 2003;4:1059-64 [PubMed]
- 122. Braddock M. Inflammation in drug discovery and development SRI’s seventh international meeting. San Diego, CA, USA. IDdb Meeting Report. 20-21 February 2003
- 123. GlaxoSmithKline. P38 mitogen-activated protein (MAP) kinase inhibitor (SB681323) study in patients with neuropathic pain. ClinicalTrials.gov, Bethesda, MD: National Library of Medicine. Available from:http://www.clinicaltrials.gov/ct2/show/NCT00390845 [Last accessed May 2009]
- 124. GlaxoSmithKline Product development pipeline. GlaxoSmithKline Inc. February 2009. Available from:www.gsk.com/investors/pp_pipeline_standard.htm [Last accessed May 2005]
- 125. Pargellis C, Regan J. Inhibitors of p38 mitogen-activated protein kinase for the treatment of rheumatoid arthritis. Curr Opin Investig Drugs 2003;4:566-71 [PubMed]
- 126. Tong MD, Daniels DO, Montano T, SCIO-469, a novel p38A MAPK inhibitor, provides efficacy in acute postsurgical dental pain. Clin Pharm Ther 2004;75:3 [CrossRef]
- 127. Genovese MC, Cohen SB, Wofsy D, A randomized, double-blind, placebo-controlled phase 2 study of an oral p38 alpha MAPK inhibitor, SCIO-469, in patients with active rheumatoid arthritis. San Francisco: 72th American College of Rheumatology Annual Scientific Meeting, 24-29 October 2008
- 128. Fitzgerald CE, Patel SB, Becker JW, Structural basis for p38? MAP kinase quinazoline and pyridol-pyrimidine inhibitor specificity Nat Struct Biol 2003;10:764-69
- 129. Weisman M, Furst D, Schiff M, A double-blind, placebo controlled trial of VX-745, an oral p38 mitogen-activated protein kinase (MAPK) inhibitor in patients with rheumatoid arthritis(RA). FRI0018. Stockholm: European League Against Rheumatism, Annual Congress, Jun 12-15, 2002
- 130. Vertex Pharmaceuticals Inc. Vertex moves to re-allocate resources from VX-745 in p38MAP kinase program to accelerate development of second generation drug candidates VX-702 and VX-850. Press Release 2001
- 131. Vertex Pharmaceuticals Inc. Preliminary Phase IIa data for VX-702 demonstrate tolerability and reduction in C-reactive protein in cardiovascular patients. Rome: European Society of Cardiology’s Acute Cardiac Care Symposium, 17-20 October 2004
- 132. Damjanov N, Kauffman R, Spencer-Green GT. Safety and efficacy of VX-702, a p38 MAP kinase inhibitor, in rheumatoid arthritis. OP-0246. Paris: European League Against Rheumatism, Annual Congress, Jun 11-14, 2008
- 133. Damjanov N, Kauffman R, Spencer-Green GT. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: Results of two randomized, double-blind, placebo-controlled clinical studies. Arthritis Rheum2009;60:1232-41 [CrossRef], [PubMed], [Web of Science ®]
- 134. Wang Y, Singh R, Lefkowitch JH, Tumor necrosis factor-induced toxic liver injury results from JNK2 dependent activation of caspase-8 and the mitochondrialdeath pathway. J Biol Chem 2006;281:15258-67 [CrossRef], [PubMed], [Web of Science ®]
- 135. Muniyappa H, Das KC. Activation of c-Jun N-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: a MLK-3-MKK7-dependent mechanism. Cell Signal 2008;20:675-83 [CrossRef], [PubMed], [Web of Science ®]
- 136. Heinrichsdorff J, Luedde T, Perdiguero E, p38alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver failure. EMBO Rep 2008;9:1048-54 [CrossRef], [PubMed], [Web of Science ®]
- 137. Whitmarsh AJ, Yang SH, Su MS, Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors. Mol Cell Biol 1997;17:2360-71 [PubMed], [Web of Science ®]
- 138. Brancho D, Tanaka N, Jaeschke A, Mechanism of p38 MAP kinase activation in vivo. Genes Dev 2003;17:1969-78[CrossRef], [PubMed], [Web of Science ®]
- 139. Ventura JJ, Tenbaum S, Perdiguero E, p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nat Genet 2007;39:750-8 [CrossRef], [PubMed], [Web of Science ®]
- 140. Gaestel M, Kotlyarov A, Kracht M. Targeting innate immunity protein kinase signalling in inflammation. Nat Rev Drug Discov 2009;8:480-99 [CrossRef], [PubMed], [Web of Science ®]
- 141. Ronkina N, Kotlyarov A, Dittrich-Breiholz O, The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK. Mol Cell Biol2007;27:170-81 [CrossRef], [PubMed], [Web of Science ®]
- 142. Ananieva O, Darragh J, Johansen C, The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nat Immunol 2008;9:1028-36 [CrossRef], [PubMed], [Web of Science ®]
- 143. Brook M, Tchen CR, Santalucia T, Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. Mol Cell Biol2006;26:2408-18 [CrossRef], [PubMed], [Web of Science ®]
- 144. Cohen P. Targeting protein kinases for the development of anti-inflammatory drugs. Curr Opin Cell Biol 2009;21:317-24[CrossRef], [PubMed], [Web of Science ®]
- 145. Mayer RJ, Callahan JF. p38 MAP kinase inhibitors: a future therapy for inflammatory diseases. Drug Discov Today2006;3:49-54 [CrossRef]
 van Marum, R. J., Current and future therapy in Alzheimer’s disease. Fundam. Clin. Pharmacol. 2008, 22, 265–274.  Morales, I., Guzman-Mart ´ ´ınez, L., Cerda-Troncoso, C., Far´ıas, G. A. et al., Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014, 8, 112.  Hu, N., Yu, J. T., Tan, L., Wang, Y. L. et al., Nutrition and the risk of Alzheimer’s disease. Biomed. Res. Int. 2013, 2013, 524820.  Lin, C. C., Hsu, Y. F., Lin, T. C., Effects of punicalagin and punicalin on carrageenan-induced inflammation in rats. Am. J. Chin. Med. 1999, 27, 371–376.  Adams, L. S., Seeram, N. P., Aggarwal, B. B., Takada, Y. et al., Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J. Agric. Food. Chem. 2006, 54, 980–985.  Xu, X., Yin, P., Wan, C., Chong, X. et al., Punicalagin inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4-mediated MAPKs and NF-B activation. Inflammation 2014, 37, 956–965.  Bhatia, H. S., Candelario-Jalil, E., de Oliveira, A. C., Olajide, O. A. et al., Mangiferin inhibits cyclooxygenase-2 expression and prostaglandin E2 production in activated rat microglial cells. Arch. Biochem. Biophys. 2008, 477, 253–258.  Olajide, O. A., Bhatia, H. S., de Oliveira, A. C., Wright, C. W. et al., Inhibition of neuroinflammation in LPS-activated microglia by cryptolepine. Evid. Based Complement Alternat. Med. 2013, 2013, 459723. Vinet, J., Weering, H. R., Heinrich, A., Kalin, R. E. et al., Neu- ¨ roprotective function for ramified microglia in hippocampal excitotoxicity. J. Neuroinflammation 2012, 9, 27.  Olajide, O. A., Velagapudi, R., Okorji, U. P., Sarker, S. D. et al., Picralima nitida seeds suppress PGE2 production by interfering with multiple signalling pathways in IL-1-stimulated SKN-SH neuronal cells. J. Ethnopharmacol. 2014, 152, 377–383.  Fiebich, B. L., Lieb, K., Engels, S., Heinrich, M., Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells. J. Neuroimmunol. 2002, 132, 18–24.  Munoz, L., Ammit, A. J., Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease. Neuropharmacology 2010, 58, 561–568.  Winand, J., Schneider, Y. J., The anti-inflammatory effect of a pomegranate husk extract on inflamed adipocytes and macrophages cultivated independently, but not on the inflammatory vicious cycle between adipocytes and macrophages. Food Funct. 2014, 5, 310–318.  Kudo, I., Murakami, M., Prostaglandin E synthase, a terminal enzyme for prostaglandin E2 biosynthesis. J. Biochem. Mol. Biol. 2005, 38, 633–638.  Wang, J., Limburg, D., Carter, J., Mbalaviele, G. et al., Selective inducible microsomal prostaglandin E(2) synthase- 1 (mPGES-1) inhibitors derived from an oxicam template. Bioorg. Med. Chem. Lett. 2010, 20, 1604–1609.  Baeuerle, P. A., Baltimore, D., NF-kappa B: ten years after. Cell. 1996, 87, 13–20.  Huang, C. Y., Fujimura, M., Noshita, N., Chang, Y. Y. et al., SOD1 down-regulates NF-kappaB and c-Myc expression in mice after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 2001, 21, 163–173.  Zhang, W., Potrovita, I., Tarabin, V., Herrmann, O. et al., Neuronal activation of NF-kappaB contributes to cell death in cerebral ischemia. J. Cereb. Blood Flow Metab. 2005, 25, 30– 40.  Gu, J. H., Ge, J. B., Li, M, Wu, F. et al., Inhibition of NF- B activation is associated with anti-inflammatory and antiapoptotic effects of Ginkgolide B in a mouse model of cerebral ischemia/reperfusion injury. Eur. J. Pharm. Sci. 2012, 47, 652–660.  Sastre, M., Walter, J., Gentleman, S. M., Interactions between APP secretases and inflammatory mediators. J. Neuroinflammation 2008, 5, 25.  Gong, P., Xu, X., Shi, J., Ni, L. et al., Phosphorylation of mitogen- and stress-activated protein kinase-1 in astrocytic inflammation: a possible role in inhibiting production of in- flammatory cytokines. PLoS One 2013, 8, e81747.  Yong, H. Y., Koh, M. S., Moon, A., The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin. Investig. Drugs 2009, 18, 1893.  Liu, S. L., Kielian, T., Microglial activation by Citrobacter koseri is mediated by TLR4-and MyD88-dependent pathways. J. Immunol. 2009, 183, 5537–5547.  Butler, M. P., Hanly, J. A., Moynagh, P. N., Pellino3 is a novel upstream regulator of p38 MAPK and activates CREB in a p38-de