Chinmoy S. Dey

Bio: Chinmoy S. Dey is an academic researcher from Indian Institute of Technology Delhi. The author has contributed to research in topics: Insulin receptor & Insulin resistance. The author has an hindex of 25, co-authored 65 publications receiving 2355 citations. Previous affiliations of Chinmoy S. Dey include Council of Scientific and Industrial Research & Department of Biotechnology.

Possible Mechanism of Miltefosine-Mediated Death of Leishmania donovani

Abstract: Miltefosine causes leishmanial death, but the possible mechanism(s) of action is not known. The mode of action of miltefosine was investigated in vitro in Leishmania donovani promastigotes as well as in extra- and intracellular amastigotes. Here, we demonstrate that miltefosine induces apoptosis-like death in L. donovani based on observed phenomena such as nuclear DNA condensation, DNA fragmentation with accompanying ladder formation, and in situ labeling of DNA fragments by the terminal deoxyribonucleotidyltransferase-mediated dUTP-biotin nick end labeling method. Understanding of miltefosine-mediated death will facilitate the design of new therapeutic strategies against Leishmania parasites.

Metformin enhances insulin signalling in insulin-dependent and -independent pathways in insulin resistant muscle cells

Abstract: 1 Metformin lowers blood glucose levels in type 2 diabetic patients. To evaluate the insulin sensitizing action of metformin on skeletal muscle cells, we have used C2C12 skeletal muscle cells differentiated in chronic presence or absence of insulin. 2 Metformin was added during the last 24 h of differentiation of the C2C12 myotubes. Insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) was determined. 3 Chronic insulin treatment resulted in 60 and 40% reduction in insulin-stimulated tyrosine phosphorylation of IR and IRS-1, respectively. Treatment with metformin was able to increase the tyrosine phosphorylation of IR and IRS-1 by 100 and 90% respectively. 4 Chronic insulin treatment drastically reduced (45%) insulin-stimulated phosphatidyl inositol 3-kinase (PI 3-kinase) activity. Metformin treatment restored PI 3-kinase activity in insulin-resistant myotubes. 5 Insulin-stimulated glucose uptake was impaired in chronically insulin-treated myotubes. Metformin increased basal glucose uptake to significant levels (P<0.05), but metformin did not increase insulin-stimulated glucose transport. 6 All the three mitogen-activated protein kinases (MAPK) were activated by insulin in sensitive myotubes. The activation of p38 MAPK was impaired in resistant myotubes, while ERK and JNK were unaffected. Treatment with metformin enhanced the basal activation levels of p38 in both sensitive and resistant myotubes, but insulin did not further stimulate p38 activation in metformin treated cells. 7 Treatment of cells with p38 inhibitor, SB203580, blocked insulin- and metformin-stimulated glucose uptake as well as p38 activation. 8 Since the effect of metformin on glucose uptake corresponded to p38 MAPK activation, this suggests the potential role p38 in glucose uptake. 9 These data demonstrate the direct insulin sensitizing action of metformin on skeletal muscle cells.

Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline

Abstract: While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE e4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE e4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.

Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis

Abstract: Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and cancer cells as well as some pathogenic bacteria and fungi. For 10 years it has been licensed in India for the treatment of visceral leishmaniasis (VL), a fatal neglected parasitic disease. It is the first and still the only oral drug that can be used to treat VL and cutaneous leishmaniasis (CL). The standard 28 day miltefosine monotherapy regimen is well tolerated, except for mild gastrointestinal side effects, although its teratogenic potential severely hampers its general use in the clinic and roll-out in national elimination programmes. The pharmacokinetics of miltefosine are mainly characterized by its long residence time in the body, resulting in extensive drug accumulation during treatment and long elimination half-lives. At the moment, different combination therapy strategies encompassing miltefosine are being tested in multiple controlled clinical trials in various geographical areas of endemicity, both in South Asia and East Africa. We here review the most salient pre-clinical and clinical pharmacological aspects of miltefosine, its mechanism of action against Leishmania parasites and other pathogens, and provide a systematic overview of the efficacy and safety data from all clinical trials of miltefosine, either alone or in combination, in the treatment of VL and CL.

Induction ofc-fos expressionthrough JNK-mediated TCF/Elk-1 phosphorylation

Abstract: Growth factors induce c‐fos transcription by stimulating phosphorylation of transcription factor TCF/Elk‐1, which binds to the serum response element (SRE). Under such conditions Elk‐1 could be phosphorylated by the mitogen‐activated protein kinases (MAPKs) ERK1 and ERK2. However, c‐fos transcription and SRE activity are also induced by stimuli, such as UV irradiation and activation of the protein kinase MEKK1, that cause only an insignificant increase in ERK1/2 activity. However, both of these stimuli strongly activate two other MAPKs, JNK1 and JNK2, and stimulate Elk‐1 transcriptional activity and phosphorylation. We find that the JNKs are the predominant Elk‐1 activation domain kinases in extracts of UV‐irradiated cells and that immunopurified JNK1/2 phosphorylate Elk‐1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity. Finally, we show that UV irradiation, but not serum or phorbol esters, stimulate translocation of JNK1 to the nucleus. As Elk‐1 is most likely phosphorylated while bound to the c‐fos promoter, these results suggest that UV irradiation and MEKK1 activation stimulate TCF/Elk‐1 activity through JNK activation, while growth factors induce c‐fos through ERK activation.

Drug resistance and treatment failure in leishmaniasis: A 21st century challenge

Abstract: Reevaluation of treatment guidelines for Old and New World leishmaniasis is urgently needed on a global basis because treatment failure is an increasing problem. Drug resistance is a fundamental determinant of treatment failure, although other factors also contribute to this phenomenon, including the global HIV/AIDS epidemic with its accompanying impact on the immune system. Pentavalent antimonials have been used successfully worldwide for the treatment of leishmaniasis since the first half of the 20th century, but the last 10 to 20 years have witnessed an increase in clinical resistance, e.g., in North Bihar in India. In this review, we discuss the meaning of “resistance” related to leishmaniasis and discuss its molecular epidemiology, particularly for Leishmania donovani that causes visceral leishmaniasis. We also discuss how resistance can affect drug combination therapies. Molecular mechanisms known to contribute to resistance to antimonials, amphotericin B, and miltefosine are also outlined.