Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is mounting evidence that the vanilloid (capsaicin) receptor; transient receptor potential channel, vanilloid subfamily member 1 (TRPV1), is subjected to multiple interacting levels of control. The first level is by reversible phosphorylation catalyzed by intrinsic kinases (e.g. protein kinase A and C) and phosphatases (e.g. calcineurin), which plays a pivotal role in receptor sensitization vs. tachyphylaxis. In addition, this mechanism links TRPV1 to intracellular signaling by various important endogenous as well as exogenous substances such as bradykinin, ethanol, nicotin and insulin. It is not clear, however, whether phosphorylation per se is sufficient to liberate TRPV1 under the inhibitory control of phosphatydylinositol-4,5-bisphosphate. The second level of control is by forming TRPV1 heteromers and their association with putative regulatory proteins. The next level of regulation is by subcellular compartmentalization. The membrane form of TRPV1 functions as a nonselective cation channel. On the endoplasmic reticulum, TRPV1 is present in two differentially regulated forms, one of which is inositol triphosphate-dependent whereas the other is not. These three TRPV1 compartments provide a versatile regulation of intracellular Ca(2+) levels. Last, there is a complex and poorly understood regulation of TRPV1 activity via control of gene expression. Factors that downregulate TRPV1 expression include vanilloid treatment and growth factor (notably, nerve growth factor) deprivation. By contrast, TRPV1 appears to be upregulated during inflammatory conditions. Interestingly, following experimental nerve injury and in animal models of diabetic neuropathy TRPV1 is present on neurons that do not normally express TRPV1. Combined, these findings imply an important role for aberrant TRPV1 expression in the development of neuropathic pain and hyperalgesia. In humans, disease-related changes in TRPV1 expression have already been described (e.g. inflammatory bowel disease and irritable bowel syndrome). The mechanisms that regulate TRPV1 gene expression under pathological conditions are unknown but a better understanding of these pathways has obvious implications for rational drug development.
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PMID:Biochemical pharmacology of the vanilloid receptor TRPV1. An update. 1512 91

Approximately half of the children with ulcerative colitis (UC) have refractory, relapsing or steroid-dependent disease. UC in children is more extensive than in adults, presents more often with severe attacks and carries a more aggressive disease course. Therefore, although a step-up approach is usually recommended in UC, aggressive therapy will often be indicated in children since steroid dependency should never be tolerated. It is vital to ensure that in every resistant case, the symptoms are truly related to the inflammatory disease activity and not to other conditions such as poor adherence to treatment, infections, adverse reactions to drugs, irritable bowel syndrome, lactose intolerance, celiac disease and bacterial overgrowth. The clinician should be ready to escalate therapy in a timely manner but only after ensuring optimization of current treatments. Optimization may include, among others, appropriate dosage, utilization of assays that determine thiopurine, calcineurin inhibitors and anti-tumor necrosis factor levels, introduction of combination therapy when indicated (enemas and immunomodulators) and a long enough time for treatment to become effective. Colectomy is always a valid option and should be discussed before major treatment escalations. Experimental therapies can be considered when all else fails and the family prefers to avoid colectomy. The management of refractory and relapsing disease is particularly challenging in children, and this review summarizes the available evidence to guide treatment decisions in this setup.
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PMID:Relapsing and refractory ulcerative colitis in children. 2496 90

Immunomodulator (thiopurines) and calcineurin inhibitors (cyclosporine, tacrolimus) have been used in IBD treatment. Thiopurines such as azathioprine and 6-mercaptopur- ine are used in steroid refractory and steroid dependent UC patients. They are also concomitant used both in CD and UC with other drugs including anti-TNFa monoclonal Ab mainly as maintenance therapy. Calcineurin inhibitors, cyclosporine and tacrolimus, are used in moderate to severe refractory UC patients. Adverse effects of thiopruine include bone marrow suppression, liver dysfunction, hair loss, and infectious disease. Recently, it was reported that the risk of acute onset leukopenia in thioprine use is associated with NUDT 15 gene variant, especially in Asian population. Renal dysfunction and infectious disease (e. g. pneumocystis) should be concerned in the patientg treated with calcineurin inhibitors.
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PMID:Immunomodulator and calcineurin inhibitors on inflammatory bowel disease. 3056 83

TRPV1 is phosphorylated and functionally upregulated by protein kinases, and negatively regulated by phosphatases including calcineurin. Since the clinical use of calcineurin-inhibiting immunosuppressants is commonly associated with chronic diarrhea, we examined if tacrolimus, a calcineurin inhibitor, promotes TRPV1-dependent colonic hypersensitivity in mice. Intracolonic administration of capsaicin, a TRPV1 agonist, caused referred hyperalgesia in the lower abdomen, an effect prevented by capsazepine, a TRPV1 blocker. Tacrolimus accelerated the intracolonic capsaicin-induced referred hyperalgesia. Similarly, intracolonic capsaicin caused spinal ERK phosphorylation, a marker for nociceptor excitation, an effect promoted by tacrolimus. Thus, tacrolimus may aggravate TRPV1-related colonic pain accompanying irritable bowel syndrome.
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PMID:Tacrolimus, a calcineurin inhibitor, promotes capsaicin-induced colonic pain in mice. 3215 41