This study identifies antioxidants superoxide dismutase and reduced glutathione, and oxidative stress as important determinants of neuropathological and behavioural consequences of CCI-induced neuropathy, and NAC may be a potential candidate for alleviation of neuropathic pain.

In the current study, we examined whether subchronic exposure via drinking water to low doses of a mixture of metals (arsenic, cadmium, lead, mercury, chromium, manganese, iron, and nickel), found as contaminants in various water sources of India, and to concentrations equivalent to WHO maximum permissible limits (MPL) in drinking water for individual metals, can alter systemic physiology of male rats. Data on water contamination with metals in India were collected from the literature and metals were selected on the basis of their frequency of occurrence and contamination level above MPL. Male Wistar rats were exposed to the mixture at 0, 1, 10, and 100 times the mode concentrations (the most frequently occurring concentration) of the individual metals via drinking water for 90 days. One more group of rats was exposed to the mixture at a concentration equivalent to the MPL (WHO) in drinking water for individual metals. Toxic potential of the mixture was evaluated by assessing general toxicological end points, serum chemistry and histopathology of vital organs. The mixture decreased body weight and water consumption and increased weights of brain, liver, and kidneys with 10x and 100x doses. After 30 days of exposure, no appreciable changes were found in any blood clinical markers. After 60 days, only the 100x dose, while after 90 days both 10x and 100x doses increased activities of aspartate aminotransferase and alkaline phosphatase and levels of urea nitrogen and creatinine and decreased total protein and albumin levels, but alanine aminotransferase activity and glucose level were not affected. At 10x and 100x exposure levels, qualitatively similar, but dose-dependent vascular, degenerative, and necrotic changes were observed in brain, liver, and kidney. The results indicate that subchronic exposure to the metal mixture affected general health of male rats by altering the functional and structural integrity of kidney, liver, and brain at 10 and 100 times the mode concentrations of the individual metals in Indian water sources, but exposure at mode concentrations of contemporary water contamination levels or at concentrations equivalent to the MPL for individual metals in drinking water may not cause any health hazards in male rats.

The identification of new molecular components of the DNA damage signaling cascade opens novel avenues to enhance the efficacy of chemotherapeutic drugs. High-mobility group protein 1 (HMGB1) is a DNA damage sensor responsive to the incorporation of nonnatural nucleosides into DNA; several nuclear and cytosolic proteins are functionally integrated with HMGB1 in the context of DNA damage response. The functional role of HMGB1 and HMGB1-associated proteins (high-mobility group protein B2, HMGB2; glyceraldehyde-3-phosphate dehydrogenase, GAPDH; protein disulfide isomerase family A member 3, PDIA3; and heat shock 70 kDa protein 8, HSPA8) in DNA damage response was assessed in human carcinoma cells A549 and UO31 by transient knockdown with short interfering RNAs. Using the cell proliferation assay, we found that knockdown of HMGB1-associated proteins resulted in 8-fold to 50-fold decreased chemosensitivity of A549 cells to cytarabine. Western blot analysis and immunofluorescent microscopy were used to evaluate genotoxic stress markers in knocked-down cancer cells after 24 to 72 hours of incubation with 1 μmol/L of cytarabine. Our results dissect the roles of HMGB1-associated proteins in DNA damage response: HMGB1 and HMGB2 facilitate p53 phosphorylation after exposure to genotoxic stress, and PDIA3 has been found essential for H2AX phosphorylation (no γ-H2AX accumulated after 24-72 hours of incubation with 1 μmol/L of cytarabine in PDIA3 knockdown cells). We conclude that phosphorylation of p53 and phosphorylation of H2AX occur in two distinct branches of the DNA damage response. These findings identify new molecular components of the DNA damage signaling cascade and provide novel promising targets for chemotherapeutic intervention.

Exposure of animals and humans to different metal components through contaminated drinking water can result in a wide range of adverse clinical conditions. Toxicological consequences arising from the concurrent repeated exposure to multiple metal contaminants are not known. The purpose of the present study was to evaluate the oxidative stress-inducing potential of a mixture of eight metals (arsenic, cadmium, lead, mercury, chromium, nickel, manganese, iron), representative of groundwater contamination in different areas of India, in erythrocytes of male rats subchronically exposed to environmentally relevant doses via drinking water. The selection of these metals, as determined by literature survey of groundwater contamination in India, was primarily based on the frequency of their occurrence and contamination level above World Health Organization maximum permissible limit (MPL) in drinking water. Male albino Wistar rats were exposed to the metal mixture at 0, 1, 10, and 100 times the mode concentrations (the most frequently occurring concentration) of the individual metals in drinking water for 90 days. In addition, one group of rats was also exposed to the mixture at a concentration equal to the MPL of individual components. The oxidative stress in erythrocytes was evaluated by assessing the magnitude of malondialdehyde production and reduced glutathione (GSH) content and the activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione reductase (GR) after 30, 60, and 90 days of exposure. MPL and 1x dose levels did not cause any changes. The mixture at 10x and 100x doses caused dose- and time-dependent effects. After 30 days, the 10x dose did not cause any changes except increase in SOD activity. The 100x dose increased the activities of SOD, catalase and GR and the GSH level, but caused no alterations in lipid peroxidation (LPO) and GPx activity. After 60 days, the 10x dose did not cause any changes. The 100x dose increased LPO and decreased all the antioxidant parameters, except GSH. After 90 days, both 10x and 100x levels elevated LPO. The 10x dose decreased GSH level and activities of SOD and catalase, but not of GPx and GR, whereas the 100x dose decreased all the antioxidative systems. Overall, the present study demonstrates that the subchronic exposure of male rats to the mixture of metals via drinking water results in induction of oxidative stress and concomitant reduction in antioxidative defense system in erythrocytes at 10 and 100 times the mode concentrations of the individual metals in contaminated groundwater.

Bacterial cellulose (BC) is a naturally occurring nanofibrous biomaterial which exhibits unique physical properties and is amenable to chemical modifications. To explore whether this versatile material can be used in the treatment of osteochondral defects (OCD), we developed and characterized novel BC-based nanocomposite scaffolds, for example, BC-hydroxyapatite (BC-HA) and BC-glycosaminoglycans (BC-GAG) that mimic bone and cartilage, respectively. In vitro biocompatibility of BC-HA and BC-GAG scaffolds was established using osteosarcoma cells, human articular chondrocytes, and human adipose-derived mesenchymal stem cells. On subcutaneous implantation, the scaffolds allowed tissue ingrowth and induced no adverse immunological reactions suggesting excellent in vivo biocompatibility. Implantation of acellular bilayered scaffolds in OCD created in rat knees induced progressive regeneration of cartilage tissue, deposition of extracellular matrix, and regeneration of subchondral bone by the host cells. The results of micro-CT revealed that bone mineral density and ratio of bone volume to tissue volume were significantly higher in animals receiving bilayered scaffold as compared to the control animals. To the best of our knowledge, this study proves for the first time, the functional performance of acellular BC-based bilayered scaffolds. Thus, this strategy has great potential for clinical translation and can be used in repair of OCD.