INT69322

Context Info Confidence 0.54 First Reported 1997 Last Reported 2010 Negated 0 Speculated 1 Reported most in Abstract Documents 70 Total Number 71 Disease Relevance 42.92 Pain Relevance 22.71

cytosol (MAPK14) nucleoplasm (MAPK14) signal transduction (MAPK14) nucleus (MAPK14) response to stress (MAPK14) cytoplasm (MAPK14)

Anatomy Link Frequency chondrocytes 3 macrophages 3 brain 2 monocytes 2 T cells 2 MAPK14 (Homo sapiens)

Pain Link Frequency Relevance Heat Paracetamol 40 99.98 Arthritis 140 99.96 Inflammation 756 99.76 rheumatoid arthritis 305 99.74 intrathecal 26 99.74 aspirin 34 99.36 Osteoarthritis 1944 99.24 Inflammatory mediators 52 99.08 Pain 111 99.02 dexamethasone 19 98.76

Disease Link Frequency Relevance Heat Stress 105 100.00 Arthritis 168 99.96 Rheumatoid Arthritis 396 99.74 Reprotox - General 1 59 99.56 Apoptosis 586 99.38 INFLAMMATION 844 99.36 Nociception 1 99.32 Osteoarthritis 1905 99.24 Fever 82 99.24 Acute Coronary Syndrome 13 99.24

Sentences Mentioned In

Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

Both pain states are disrupted by intrathecal CNI-1493, a p38 mitogen-activated protein (MAP) kinase inhibitor.

Negative_regulation (inhibitor) of p38 associated with pain and intrathecal

1) Confidence 0.54 Published 2001 Journal J Pain Section Abstract Doc Link 14622812 Disease Relevance 0.74 Pain Relevance 0.82

Systemic administration of CNI-1493, a p38 mitogen-activated protein kinase inhibitor, blocks intrathecal human immunodeficiency virus-1 gp120-induced enhanced pain states in rats.

Negative_regulation (inhibitor) of p38 associated with pain, acquired immune deficiency syndrome or hiv infection and intrathecal

2) Confidence 0.54 Published 2001 Journal J Pain Section Title Doc Link 14622812 Disease Relevance 0.92 Pain Relevance 1.00

VX-702, a novel p38 mitogen-activated protein kinase (MAPK) inhibitor, is currently under investigation in ACS patients with unstable angina to evaluate its safety and efficacy during percutaneous coronary intervention (PCI).

Negative_regulation (inhibitor) of p38 associated with acute coronary syndrome and angina

3) Confidence 0.52 Published 2004 Journal Thromb. Haemost. Section Abstract Doc Link 15583748 Disease Relevance 0.59 Pain Relevance 0.14

Understanding the intercellular signalling pathways involved in nociception may lead to novel drugs, such as p38 mitogen-activated protein (MAP) kinase inhibitors, being used in the treatment of cough in the future.

Negative_regulation (inhibitors) of p38 associated with nociception and cough

4) Confidence 0.45 Published 2007 Journal Pulm Pharmacol Ther Section Abstract Doc Link 17189707 Disease Relevance 0.87 Pain Relevance 0.31

Among them, compound 4a, (S)-2-(4-fluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole (R-132811), achieved the most promising results in various in vitro and in vivo tests including several rheumatoid arthritis models ((i) inhibition of p38alpha, p38beta, p38gamma, and p38delta MAP kinases: IC(50)=0.034, 0.572, >10, and >10 microM, respectively; (ii) inhibition of TNFalpha, IL-1beta, IL-6, and IL-8 production in human whole blood: IC(50)=0.026, 0.020, 0.88, and 0.016 microM, respectively; (iii) inhibition of LPS induced TNFalpha, IL-1beta and IL-6 production in mice: ID(50)=0.93, 8.63, and 0.11 mg/kg, p.o., respectively; (iv) inhibition of anti-collagen antibody-induced arthritis in mice: ID(50)=2.22 mg/kg, p.o.; (v) inhibition of collagen-induced arthritis in mice: ID(50)=2.38 mg/kg, p.o.; (vi) prophylactic effect on adjuvant-induced arthritis in rats: ID(50)=3.1 mg/kg, p.o.; (vii) therapeutic effect on adjuvant-induced arthritis in rats: ID(50)=4.9 mg/kg, p.o.; (viii) analgesic effect on adjuvant-induced arthritic pain in rats: ID(50)=2.9 mg/kg, p.o.).

Negative_regulation (inhibition) of p38alpha in blood associated with pain, analgesic, rheumatoid arthritis and arthritis

5) Confidence 0.42 Published 2010 Journal Bioorg. Med. Chem. Lett. Section Abstract Doc Link 20637613 Disease Relevance 0.55 Pain Relevance 0.46

A number of compounds that inhibit the p38alpha MAPK have entered clinical trials for the treatment of rheumatoid arthritis and psoriasis, but side effects have prevented their progression to Phase III clinical trials.

Negative_regulation (inhibit) of p38alpha associated with psoriasis and rheumatoid arthritis

6) Confidence 0.41 Published 2009 Journal Curr. Opin. Cell Biol. Section Abstract Doc Link 19217767 Disease Relevance 0.59 Pain Relevance 0.21

SB203580, a p38 mitogen-activated protein kinase inhibitor, and RNA inhibition of p53 inhibited the sulindac-induced apoptosis.

Negative_regulation (inhibitor) of p38 associated with apoptosis

7) Confidence 0.40 Published 2007 Journal Apoptosis Section Abstract Doc Link 17136320 Disease Relevance 1.25 Pain Relevance 0.06

Whether CNI-1493, or any other p38 MAP kinase inhibitor, can cross the blood-brain barrier to affect spinal cord function is unknown.

Negative_regulation (inhibitor) of p38 MAP kinase in brain associated with spinal cord

8) Confidence 0.40 Published 2001 Journal J Pain Section Abstract Doc Link 14622812 Disease Relevance 0.74 Pain Relevance 0.82

These studies provide the first evidence that systemic p38 MAP kinase inhibitors can prevent centrally mediated exaggerated pain states.

Negative_regulation (inhibitors) of p38 MAP kinase associated with pain

9) Confidence 0.39 Published 2001 Journal J Pain Section Abstract Doc Link 14622812 Disease Relevance 0.91 Pain Relevance 1.19

These studies provide the first evidence that systemic p38 MAP kinase inhibitors can prevent centrally mediated exaggerated pain states.

Negative_regulation (inhibitors) of p38 MAP kinase associated with pain

10) Confidence 0.39 Published 2001 Journal J Pain Section Abstract Doc Link 14622812 Disease Relevance 0.91 Pain Relevance 1.19

Interestingly, we show contrasting effects of p38 MAPK inhibition as compared to aspirin inhibition on platelet aggregation in response to collagen.

Negative_regulation (inhibition) of p38 in platelet associated with aspirin

11) Confidence 0.38 Published 2004 Journal Thromb. Haemost. Section Abstract Doc Link 15583748 Disease Relevance 0.21 Pain Relevance 0.28

In a rodent model of inflammatory arthritis, p38-MAPK inhibition suppressed the inflammation and bone destruction [9].

Negative_regulation (inhibition) of p38 associated with inflammation and arthritis

12) Confidence 0.36 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2991031 Disease Relevance 0.85 Pain Relevance 0.67

It is well documented that activation of the runt-related transcription factor RUNX-2 is mediated by activated p38-MAPK as inhibition of p38-MAPK abrogates its activity and the expression of cartilage degrading enzymes in chondrocytes [16].

Negative_regulation (inhibition) of p38 in chondrocytes

13) Confidence 0.36 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2991031 Disease Relevance 0.49 Pain Relevance 0.25

However, it is not known whether the inhibition of p38-MAPK - RUNX-2 pathway is related to the antioxidant activity of PE or one or more of the bioavailable constituents of PE exert this inhibitory effect by interfering with the kinase activity of p38-MAPK or both.

Spec (whether) Negative_regulation (inhibition) of p38

14) Confidence 0.36 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2991031 Disease Relevance 0.71 Pain Relevance 0.36

Inhibition of p38-MAPK with the commonly used pharmacological agent SB203580 reduces proinflammatory cytokine production in monocytes/macrophages, neutrophils, and T lymphocytes [8].

Negative_regulation (Inhibition) of p38 in monocytes associated with cytokine

15) Confidence 0.36 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2991031 Disease Relevance 1.06 Pain Relevance 0.76

Thus, our results suggest that PE or PE-derived compounds may be useful in blocking the activation of MKK3 and might provide the benefit of p38-MAPK inhibition and its downstream targets such as RUNX-2 without the direct inhibition of p38-MAPK in OA.

Negative_regulation (inhibition) of p38 associated with osteoarthritis

16) Confidence 0.36 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2991031 Disease Relevance 0.79 Pain Relevance 0.42

-induced DNA binding activity of RUNX-2 was also inhibited by PE in primary human OA chondrocytes and correlated with the inhibition of p38?

Negative_regulation (inhibition) of p38 in chondrocytes associated with osteoarthritis

17) Confidence 0.36 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2991031 Disease Relevance 0.83 Pain Relevance 0.44

Inhibition of prostaglandin endoperoxide synthase-2 expression in stimulated human monocytes by inhibitors of p38 mitogen-activated protein kinase.

Negative_regulation (inhibitors) of p38 in monocytes

18) Confidence 0.32 Published 1997 Journal J. Immunol. Section Title Doc Link 9144511 Disease Relevance 0.08 Pain Relevance 0.16

The inhibition of p38 kinase is associated with a suppression of the ET-1-induced stimulation of both enzymes, whereas the inhibitions of adenyl cyclase-dependent PKA kinase is associated with a partial suppression of the ET-1-induced stimulation of MMP-13 production only.

Negative_regulation (inhibition) of p38 kinase

19) Confidence 0.29 Published 2005 Journal Arthritis Res Ther Section Body Doc Link PMC1065327 Disease Relevance 0.14 Pain Relevance 0.07

At this time (45 min), both p38 kinase and Akt phosphorylated forms were diminished.

Negative_regulation (diminished) of p38 kinase

20) Confidence 0.29 Published 2005 Journal Arthritis Res Ther Section Body Doc Link PMC1065327 Disease Relevance 0.39 Pain Relevance 0.04

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