Dijendra Nath Roy

Superoxide anion mediated mitochondrial dysfunction leads to hepatocyte apoptosis preferentially in the periportal region during copper toxicity in rats

Chronic exposure to copper induces hepatocellular apoptosis with greater injury in the periportal region compared to the perivenous region. Here we have identified the factors responsible for the development of regional damage in the liver under in vivo conditions. Enhanced production of reactive oxygen species (ROS) with predominance of superoxide radical (O(2)(-)) indicates the contribution of redox imbalance in the process. This may be linked with copper catalyzed oxidation of GSH to GSSG resulting in the generation of O(2)(-). Downregulation of Cu-Zn SOD in consequence of the degradation of this enzyme, causes decreased dismutation of O(2)(-), that further contributes to the enhanced level of O(2)(-) in the periportal region. Decreased functioning of Mn SOD activity, reduction in mitochondrial thiol/disulphide ratio and generation of O(2)(-) were much higher in the mitochondria from periportal region, which point to the involvement of this organelle in the regional hepatotoxicity observed during copper exposure. This was supported by copper-mediated enhanced mitochondrial dysfunction as evident from ATP depletion, collapse of mitochondrial membrane potential (MMP) and induction of mitochondrial permeability transition (MPT). Results suggest the active participation of O(2)(-) in inducing mitochondrial dysfunction preferentially in the periportal region that eventually leads to the development of hepatotoxicity due to copper exposure under in vivo condition.

SUMO Modification of Stra13 Is Required for Repression of Cyclin D1 Expression and Cellular Growth Arrest

Stra13, a basic helix-loop-helix (bHLH) transcription factor is involved in myriad biological functions including cellular growth arrest, differentiation and senescence. However, the mechanisms by which its transcriptional activity and function are regulated remain unclear. In this study, we provide evidence that post-translational modification of Stra13 by Small Ubiquitin-like Modifier (SUMO) dramatically potentiates its ability to transcriptionally repress cyclin D1 and mediate G1 cell cycle arrest in fibroblast cells. Mutation of SUMO acceptor lysines 159 and 279 located in the C-terminal repression domain has no impact on nuclear localization; however, it abrogates association with the co-repressor histone deacetylase 1 (HDAC1), attenuates repression of cyclin D1, and prevents Stra13-mediated growth suppression. HDAC1, which promotes cellular proliferation and cell cycle progression, antagonizes Stra13 sumoylation-dependent growth arrest. Our results uncover an unidentified regulatory axis between Stra13 and HDAC1 in progression through the G1/S phase of the cell cycle, and provide new mechanistic insights into regulation of Stra13-mediated transcriptional repression by sumoylation.

14‐Deoxyandrographolide desensitizes hepatocytes to tumour necrosis factor‐alpha‐induced apoptosis through calcium‐dependent tumour necrosis factor receptor superfamily member 1A release via the NO/cGMP pathway

Andrographis paniculata (AP) has been found to display hepatoprotective effect, although the mechanism of action of the active compounds of AP in this context still remains unclear. Here, we evaluated the hepatoprotective efficacy of 14‐deoxyandrographolide (14‐DAG), a bioactive compound of AP, particularly its role in desensitization of hepatocytes to tumour necrosis factor‐alpha (TNF‐α)‐induced signalling of apoptosis.

Combination therapy with andrographolide and d-penicillamine enhanced therapeutic advantage over monotherapy with d-penicillamine in attenuating fibrogenic response and cell death in the periportal zone of liver in rats during copper toxicosis

Long treatment regime with d-penicillamine is needed before it can exert clinically meaningful benefits in the treatment of copper toxicosis. The consequence of long-term d-penicillamine treatment is associated with numerous side effects. The limitations of d-penicillamine monotherapy prompted us to search for more effective treatment strategies that could decrease the duration of d-penicillamine therapy. The present study was designed to evaluate the therapeutic potential of d-penicillamine in combination with another hepatoprotective drug, andrographolide in treatment of copper toxicosis in rats. d-penicillamine treatment led to the excretion of copper through urine. Addition of andrographolide to d-penicillamine regime appeared to increase protection of liver by increasing the biliary excretion of copper and reduction in cholestatic injury. The early removal of the causative agent copper during combination treatment was the most effective therapeutic intervention that contributed to the early rectification of fibrosis in liver. Combination treatment reduced Kupffer cells accumulation and TNFα production in liver of copper exposed rats. In particular, andrographolide mediated the anti-inflammatory effect by inhibiting the cytokine production. However, another possible mechanism of cytoprotection of andrographolide was decreasing mitochondrial production of superoxide anions that resulted in better restoration of mitochondrial dysfunction during combination therapy than monotherapy. Furthermore, ROS inhibition by combination regimen resulted in significant decline in activation of caspase cascade. Inhibition of caspases attenuated apoptosis of hepatocytes, induced by chronic copper exposure. In summary, this study suggested that added benefit of combination treatment over use of either agent alone in alleviating the hepatotoxicity and fibrosis associated with copper toxicosis.

The insect repellents: A silent environmental chemical toxicant to the health

In recent years, a large number of insect repellents have been developed with the idea of consumer benefits. In addition to already known advantageous application of insect repellents, there is increasing concern about the potential toxicity in environment leading to health caused by random use of these compounds. An increasing number of evidence suggests that insect repellents may trigger undesirable hazardous interactions with biological systems with a potential to generate harmful effects including intermediate metabolites. Biotransformation followed by bioaccumulation (vice e versa) may be an important phenomenon for toxic response of this chemicals. In this review, we have summarized the current state of knowledge on the insect repellent toxicity, including biochemical pathway alteration under in vitro and in vivo conditions considering different classes of organisms, from lower to higher vertebrate. Furthermore, we have tried to incorporate the effects of insect repellent in light of some clinical reports. We hope this review would provide useful information on potential side effects of uncontrolled use of insect repellents.

Nanomaterial and toxicity: what can proteomics tell us about the nanotoxicology?

Abstract 1. In the last few years, a substantial scientific work is focused to identify the potential toxicity of nanomaterials by studying the cellular pathways under in vitro and in vivo conditions. Owing to high surface area to volume ratio nanoparticles (NPs) can pass through cell membranes which might be responsible for creating adverse interactions in biological systems. Simultaneously, researchers are also interested to assess the fate of NP inside the living system, which may lead to altered protein expression as well as protein corona formation. 2. According to published reports, NP-mediated toxicity involves altered cellular system including cell morphology, cell differentiation, cell metabolism, cell mobility, cellular immunity, which is derived from the side effects of nanoformulation and leading to apoptosis and necrosis. These results indicate the existence of potential toxic effect of these particles to human health. 3. The advent of proteomics with sophisticated technical improvement coupled with advanced bioinformatics has led to identify altered proteins due to nanomaterial exposure that could provide a new avenue to biomarker discovery. 4. This review aims to provide the current status of safe production and use of nanomaterials.

IL-9 Signaling Pathway: An Update

Since the discovery of IL-9 almost three decades back as a growth factor, we have come a long way to understand its pleiotropic functions in the immune system. Despite its many functions, IL-9 still remains as an understudied cytokine. In the last decade, renewed emphasis has been provided to understand the biology of IL-9. Any growth factor or cytokine signals via its cognate receptor to mediate biological functions. In this chapter, we discuss the IL-9 signal transduction in different cell types, which would then exert its distinct functions.