Chemistry (Weinheim an der Bergstrasse, Germany), Jan 19, 2015
The mechanism of the nitrene-group transfer reaction from an organic azide to isonitrile catalyze... more The mechanism of the nitrene-group transfer reaction from an organic azide to isonitrile catalyzed by a Zr(IV) d(0) complex carrying a redox-active ligand was studied by using quantum chemical molecular-modeling methods. The key step of the reaction involves the two-electron reduction of the azide moiety to release dinitrogen and provide the nitrene fragment, which is subsequently transferred to the isonitrile substrate. The reducing equivalents are supplied by the redox-active bis(2-iso-propylamido-4-methoxyphenyl)-amide ligand. The main focus of this work is on the mechanism of this redox reaction, in particular, two plausible mechanistic scenarios are considered: 1) the metal center may actively participate in the electron-transfer process by first recruiting the electrons from the redox-active ligand and becoming formally reduced in the process, followed by a classical metal-based reduction of the azide reactant. 2) Alternatively, a non-classical, direct ligand-to-ligand charge-...
The anti-inflammatory cytokine interleukin (IL)-10 is synthesized in the central nervous system (... more The anti-inflammatory cytokine interleukin (IL)-10 is synthesized in the central nervous system (CNS) and acts to limit clinical symptoms of stroke, multiple sclerosis, Alzheimer's disease, meningitis, and the behavioral changes that occur during bacterial infections. Expression of IL-10 is critical during the course of most major diseases in the CNS and promotes survival of neurons and all glial cells in the brain by blocking the effects of proinflammatory cytokines and by promoting expression of cell survival signals. In order to assess functional importance of this cytokine in viral encephalitis we have exploited an experimental model of Japanese encephalitis (JE). We report for the first time that in Japanese encephalitis, there is a progressive decline in level of IL-10. The extent of progressive decrease in IL-10 level following viral infection is inversely proportional to the increase in the level of proinflammatory cytokines as well as negative consequences that follows viral infection.
While a number of studies have documented the neurotropism of Japanese encephalitis virus (JEV), ... more While a number of studies have documented the neurotropism of Japanese encephalitis virus (JEV), little is known regarding the molecular mechanism of neuronal death following viral infection. The tumor necrosis factor receptor (TNFR)-associated death domain (TRADD) has been suggested to be the crucial signal adaptor that mediates all intracellular responses from TNFR-1. Using mouse (Neuro2a) and human (SK-N-SH) neuroblastoma cell lines, we have shown that the altered expression of TNFR-1 and TRADD following JEV infection regulates the downstream apoptotic cascades. Activation of TRADD led to mitochondria-mediated neuronal apoptosis. As TRADD-knockout animals or deficient cell lines are unavailable, it has been difficult to definitively address the physiological role of TRADD in diseases pathology following JEV infection. We circumvented this problem by silencing TRADD expression with small-interfering RNA (siRNA) and have found that TRADD is required for TNFR-1-initiated neuronal apoptosis following in vitro infection with JEV. Interestingly, siRNA against TRADD also decreased the viral load in Neu-ro2a cells. Furthermore, siRNA against TRADD increased the survival of JEV-infected mice by altering the expression of pro apoptotic versus antiapoptotic molecules. These studies show that the engagement of TNFR-1 and TRADD following JEV infection plays a crucial role in neuronal apoptosis.
Objective: Deltoid contracture is not uncommon in India. Contractures of deltoid often do not hav... more Objective: Deltoid contracture is not uncommon in India. Contractures of deltoid often do not have defi nite etiology. We have critically analyzed the condition as regards the etiopathogenesis and its surgical results. Materials and Methods: Nineteen patients with deltoid contracture operated between June 1990 and September 2001 were enrolled for a unicentric retrospective study. The surgery was indicated in patients with abduction deformity of more than 30° at the shoulder. The etiology of deltoid contracture was idiopathic (n = 13) intramuscular injection in deltoid muscle (n = 5) and blunt trauma (n = 1). All were operated by distal release (incision near the insertion of the deltoid muscle). The average follow-up was of 9.5 years (range 6-17 years). They were evaluated based on parameters like pain, persistence of deformity, range of shoulder movements and strength of deltoid. Results: All patients recovered painless full range of shoulder motion except one. The correction of deformity was achieved in all patients and there was no loss of strength of deltoid compared to the opposite side. Histology of excised tissue showed features of chronic infl ammation. The complications observed were hypertrophic scar (n = 1), painful terminal restriction of shoulder movements (n = 1) and prominent vertebral border of scapula (n = 1). Conclusion: Deltoid contracture has features of chronic infl ammation, and the intramuscular deltoid injection is the most incriminating factor in its etiopathogenesis. The condition can be effectively managed surgically by distal release of the deltoid muscle combined with excision of the muscular fi brotic contracture band.
While a number of studies have documented the importance of microglia in central nervous system (... more While a number of studies have documented the importance of microglia in central nervous system (CNS) response to injury, infection and disease, little is known regarding its role in viral encephalitis. We therefore, exploited an experimental model of Japanese Encephalitis, to better understand the role played by microglia in Japanese Encephalitis Virus (JEV) infection. Lectin staining performed to assess microglial activation indicated a robust increase in reactive microglia following infection. A difference in the topographic distribution of activated, resting, and phagocytic microglia was also observed. The levels of various proinflammatory mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (Cox-2), IL-6, IL-1b, TNF-a, and MCP-1 that have been implicated in microglial response to an activational state was significantly elevated following infection. These cytokines exhibited region selective expression in the brains of infected animals, with the highest expression observed in the hippocampus. Moreover, the expression of neuronal specific nuclear protein NeuN was markedly downregulated during progressive infection indicating neuronal loss. In vitro studies further confirmed that microglial activation and subsequent release of various proinflammatory mediators induces neuronal death following JEV infection. Although initiation of immune responses by microglial cells is an important protective mechanism in the CNS, unrestrained inflammatory responses may result in irreparable brain damage. Our findings suggest that the increased microglial activation following JEV infection influences the outcome of viral pathogenesis. It is likely that the increased microglial activation triggers bystander damage, as the animals eventually succumb to infection. V
Homepage: http://baik.chem.indiana.edu/ [**] We thank the NSF (0116050 and CHE-0645381) for finan... more Homepage: http://baik.chem.indiana.edu/ [**] We thank the NSF (0116050 and CHE-0645381) for financial support. We also thank the Research Corporation for a Scialog Award (M.H.B.).
Uploads
Papers by Soumya Ghosh