Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021831 (enteropathy)
 4,403 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small intestinal ulceration, bleeding, and inflammation are major adverse effects associated with the use of diclofenac (DCF) or other nonsteroidal anti-inflammatory drugs (NSAIDs). The underlying mechanisms of DCF enteropathy are poorly understood, but there is increasing evidence that topical effects are involved. The aim of this study was to explore the role of c-Jun-N-terminal kinase (JNK) in DCF-induced enterocyte death because JNK not only regulates mitochondria-mediated apoptosis but also is a key node where many of the proximal stress signals converge. Male C57BL/6J mice were injected intraperitoneally with DCF or vehicle (Solutol HS-15), and the extent of small intestinal ulceration was determined. A single dose of DCF (60 mg/kg) produced numerous ulcers in the third and fourth quartiles of the jejunum and ileum, with maximal effects after 18 h and extensive recovery after 48 h. To study the molecular pathways leading to enterocyte injury, we isolated villi-enriched mucosal fractions from DCF-treated mice. Immunoblot studies with a phosphospecific JNK antibody revealed that JNK1/2 (p46) was activated at 6 h, leading to phosphorylation of the downstream target c-Jun. The levels of the JNK-regulated proapoptotic transcription factor C/EBP homologous protein (CHOP) were also increased after DCF. The selective JNK inhibitor SP600125 (30 mg/kg ip), given both 1 h before and 1 h after DCF, blocked JNK kinase activity and afforded significant protection against DCF enteropathy. In conclusion, these data demonstrate that the JNK pathway is critically involved in the pathogenesis of DCF-induced enteropathy and suggest a potential application of JNK inhibitors in the prevention of NSAID-induced enteropathy.
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PMID:Protection from diclofenac-induced small intestinal injury by the JNK inhibitor SP600125 in a mouse model of NSAID-associated enteropathy. 2050 47

Small intestinal ulceration is a frequent and potentially serious condition associated with nonselective cyclooxygenase 1/2 inhibitors (nonsteroidal anti-inflammatory drugs, NSAIDs) including diclofenac (DCF). An initial topical effect involving mitochondria has been implicated in the pathogenesis, but the exact mechanisms of NSAID-induced enteropathy are unknown. We aimed at investigating whether DCF caused enterocyte demise via the mitochondrial permeability transition (mPT) and whether inhibition of critical mPT regulators might protect the mucosa from DCF injury. Cultured enterocytes (IEC-6) exposed to DCF readily underwent mPT-mediated cell death. We then targeted mitochondrial cyclophilin D (CypD), a key regulator of the mPT, in a mouse model of NSAID enteropathy. C57BL/6J mice were treated with an ulcerogenic dose of DCF (60 mg/kg, ip), followed (+ 1 h) by a non-cholestatic dose (10 mg/kg, ip) of the CypD inhibitor, cyclosporin A (CsA). CsA greatly reduced the extent of small intestinal ulceration. To avoid potential calcineurin-mediated effects, we used the non-immunosuppressive cyclosporin analog, D-MeAla(3)-EtVal(4)-cyclosporin (Debio 025). Debio 025 similarly protected the mucosa from DCF injury. To exclude drug-drug interactions, we exposed mice genetically deficient in mitochondrial CypD (peptidyl-prolyl cis-trans isomerase F [Ppif(-/-)]) to DCF. Ppif-null mice were largely protected from the ulcerogenic effects of DCF, whereas their wild-type littermates developed typical enteropathy. Enterocyte injury was preceded by upregulation of the proapoptotic transcription factor C/EBP homologous protein (Chop). Chop-null mice were refractory to DCF enteropathy, suggesting a critical role of endoplasmic reticulum stress induced by DCF. In conclusion, mitochondrial CypD plays a key role in NSAID-induced enteropathy, lending itself as a potentially new therapeutic target for cytoprotective intervention.
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PMID:Pharmacologic targeting or genetic deletion of mitochondrial cyclophilin D protects from NSAID-induced small intestinal ulceration in mice. 2066