Discovery and pharmacological evaluation of indole derivatives as potent and selective RORγt inverse agonist for multiple autoimmune conditions.

Targeting nuclear receptor RORγ is recognized to be beneficial in multiple autoimmune disorders. We disclosed new indole analogues as potent RORγ inverse agonists. RO-2 as one of the potent and orally bioavailable compounds was evaluated in various models of autoimmune disorder. It showed potent suppression of downstream markers of RORγt activity in murine and human primary cells, ex vivo PD assay and in multiple animal models of autoimmune diseases. The results indicate the potential of these indole analogues as orally bioavailable small molecule inverse agonists of RORγt, efficacious in various Th17 driven models of autoimmune disorders.

Therapeutic potential of matrix metalloprotease inhibitors in neuropathic pain.

IMPORTANCE OF THE FIELD: Millions of people suffer from neuropathic pain (NP), but the treatment is empirical and results in transient relief in only a few patients. This is primarily because of the poor understanding of the molecular mechanism underlying NP. Following nerve injury, there is a differential and temporal pattern of MMPs expression that coincides with changes in levels of pro-inflammatory cytokines, suggesting that MMPs not only act as mediators for neuroinflammation but might also be directly involved in pain associated with nerve damage. AREAS COVERED IN THIS REVIEW: The present review describes the different mechanisms of NP. The main focus of the review is to highlight the importance of MMPs in NP and their inhibition as a novel approach for treating NP. WHAT THE READER WILL GAIN: A comprehensive overview of the role of MMPs in the pathogenesis of NP and the potential of MMP inhibition as a therapeutic intervention for NP. TAKE HOME MESSAGE: Targeted therapy using specific MMP inhibitors, siRNAs, peptide inhibitors and monoclonal antibodies can provide a better way of treatment by blocking a single MMP and can reduce the side effects of broad-spectrum MMP inhibitors.

Prostaglandin E(2) synthase inhibition as a therapeutic target.

BACKGROUND: Most NSAIDs function by inhibiting biosynthesis of PGE(2) by inhibition of COX-1 and/or COX-2. Since COX-1 has a protective function in the gastro-intestinal tract (GIT), non-selective inhibition of both cycloxy genases leads to moderate to severe gastro-intestinal intolerance. Attempts to identify selective inhibitors of COX-2, led to the identification of celecoxib and rofecoxib. However, long-term use of these drugs has serious adverse effects of sudden myocardial infarction and thrombosis. Drug-mediated imbalance in the levels of prostaglandin I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) with a bias towards TXA(2) may be the primary reason for these events. This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug. METHODS: Recently, the focus of research has shifted to enzymes downstream of COX in the prosta glandin biosynthetic pathway such as prostaglandin E(2) synthases. Microsomal prostaglandin E(2) synthase-1 (mPGES-1) specifically isomerizes PGH(2) to PGE(2), under inflammatory conditions. In this review, we examine the biology of mPGES-1 and its role in disease. Progress in designing molecules that can selectively inhibit mPGES-1 is reviewed. CONCLUSION: mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.

Crucial role of cytosolic tryparedoxin peroxidase in Leishmania donovani survival, drug response and virulence.

Leishmania donovani, the causative agent of visceral leishmaniasis, uses a cascade of enzymes that include cytosolic tryparedoxin peroxidase (cTXNPx) for detoxification of peroxides, an event pivotal for survival of digenic parasites living in two disparate biological environments. In this study, we observed an increase in promastigote cTXNPx levels after exposure to H(2)O(2) and this group did not show any cell death; however, exposure to a combination of H(2)O(2) and nitric oxide resulted in significant reduction of cTXNPx levels accompanied by high cell death. The protective relationship between higher levels of cTXNPx and survival was further substantiated by the improved ability of L. donovani promastigotes overexpressing cTXNPx to withstand exposure to H(2)O(2) and nitric oxide combination as compared with vector transfectants. In addition, cTXNPx transfectants demonstrated increased virulence, causing higher parasite burden in macrophages as compared with vector transfectants. Interestingly, the cTXNPx transfectants as promastigotes or amastigotes were resistant to clearance by the anti-leishmanial drug antimony, suggesting a cTXNPx link to drug response. Mechanistically, cTXNPx overexpression was protective against changes in Ca(2+) homeostasis but not against mitochondrial hyperpolarization brought about by exposure to H(2)O(2) and nitric oxide. Therefore, this study provides a link between cTXNPx expression to survival, virulence and drug response in L. donovani.

Determination of gibberellins in fermentation broth produced by Fusarium verticilliodes MTCC 156 by high-performance liquid chromatography tandem mass spectrometry.

A method for the detection of gibberellins produced by Fusarium verticilliodes is described using HPLCMS/MS (HPLC tandem MS). A Hypersil (5 microm) octadecylsilane column with methanol/water as eluent in the ratio 3:1 at a flow rate of 0.5 ml/min was used. In the HPLCMS, GA(3) (gibberellic acid; m / z 346.3) eluted at retention time tr=3.08 min, with the corresponding mass chromatogram having peaks at m / z 346.7 and 328.8 corresponding to the M+ and M+-H2O ions respectively. The ethyl acetate extract from the broth, subjected to HPLCMS analysis under similar conditions, showed a constituent with tr=2.13 min, the mass chromatogram of which exhibited peaks at m / z 348.9 and 331.9 corresponding to the MH+ and MH+-H2O ions respectively. Comparison of the MS and MS/MS results (direct infusion) of an authentic sample of GA3 and the ethyl acetate extract from the broth revealed the formation of reduced GA3 in the broth. The present study, utilizing HPLCMS/MS, describes an improved methodology for the unambiguous determination and estimation of gibberellins from fermentation broth.