Cyclic di-GMP and cyclic di-AMP are second messengers produced by a wide variety of bacteria. They influence bacterial cell survival, biofilm formation, virulence and bacteria-host interactions. However, many of their cellular targets and biological effects are yet to be determined. A chemical proteomics approach revealed that Mycobacterium smegmatis RecA (MsRecA) possesses a high-affinity cyclic di-AMP binding activity. We further demonstrate that both cyclic di-AMP and cyclic di-GMP bind specifically to the C-terminal motif of MsRecA and Mycobacterium tuberculosis RecA (MtRecA). Escherichia coli RecA (EcRecA) was devoid of cyclic di-AMP binding but have cyclic di-GMP binding activity. Notably, cyclic di-AMP attenuates the DNA strand exchange promoted by MsRecA as well as MtRecA through the disassembly of RecA nucleoprotein filaments. However, the structure and DNA strand exchange activity of EcRecA nucleoprotein filaments remain largely unaffected. Furthermore, M. smegmatis ΔdisA cells were found to have undetectable RecA levels due to the translational repression of recA mRNA. Consequently, the ΔdisA mutant exhibited enhanced sensitivity to DNA-damaging agents. Altogether, this study points out the importance of sequence diversity among recA genes, the role(s) of cyclic di-AMP and reveals a new mode of negative regulation of recA gene expression, DNA repair and homologous recombination in mycobacteria.

Inflammation is one of the mechanisms involved in the acute kidney injury (AKI) caused by cisplatin (CP)-induced nephrotoxicity. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) has powerful antioxidant activity. We investigated its potential nephroprotective effects and the underlying mechanisms that may add further benefits to its clinical usefulness in a CP-induced AKI model. Male Swiss albino mice were divided randomly into four groups: control, CP (20 mg/kg intraperitoneally), tempol (100 mg/kg/day, per os) + CP, and tempol only treatments. Blood samples were collected to analyze renal function parameters. Immunoblotting and immunohistochemical analysis were used to assess the level and localization of inflammatory markers. Tempol afforded protection to animals from CP-induced elevation of inflammatory markers as indicated by reduced expression of nuclear factor-kappa B, cyclooxygenase-2, and tumor necrosis factor-α in kidney tissue. Histological findings and analysis of kidney function markers corroborated with these findings confirming a nephroprotective role for tempol. In conclusion, this study provides important evidence for the promising anti-inflammatory effects of tempol which appears to contribute significantly to its nephroprotective action.

There is a global concern about adverse health effects of endocrine-disrupting chemicals (EDCs). Bisphenol A (BPA), an estrogenic and obesogenic compound, used in the plastic and medical industry has a dominant position among EDCs as far as human health and regulatory scenario are concerned. Due to its omnipresence across the biosphere, population of all age groups and health status is unavoidably exposed to BPA. Transgenerational exposure to BPA and its effects have also been recognized. However, there is no report on the transgenerational effect of BPA on metabolically disordered parents, such as obese ones. We studied effect of BPA exposure in F0 generation and its impact on F1 generation and factored parental obesity in transgenerational effect of concurrent exposure to low dose BPA (10 ppm × 180 days) in Wistar rats in a one-generation study protocol. The exposed F0 generation animals were crossed and F1 generation was analyzed 35 days after birth for indications of reproductive toxicity. We observed changes in hormone levels and disturbance in glucose and lipid homeostasis. Animals showed increased serum cholesterol and triglycerides along with higher birth weight and rapid weight gain. Histopathological evidence confirmed the presence of regressive and inflammatory changes in the ovary and testis. The test group showed metabolic disturbances in comparison to control group. Our study showed the additive effect of parental obesity in transgenerational reproductive toxicity of BPA. Female animals of F1 generation of BPA-treated obese parents showed more insulin resistance than males with similar exposure scenario. Our study highlights the confounding role of metabolic disorders such as obesity in the transgenerational toxicity of BPA, which otherwise itself is implicated in the aetiology of such metabolic disorders, directly or indirectly.

No abstract

No abstract