Amitava Khan

Promising role of ferulic acid, atorvastatin and their combination in ameliorating high fat diet-induced stress in mice.

AIMS The present study evaluated a comparative and combined hepatoprotective effect of atorvastatin (AS) and ferulic acid (F) against high fat diet (HFD) induced oxidative stress in terms of hyperlipidemia, anti-oxidative status, lipid peroxidation and inflammation. MAIN METHODS Male Swiss albino mice were given a diet containing high fat (H) (23.9% wt/wt), supplemented with AS (10mg/kg) or F (100mg/kg) and both (10 and 100mg/kg) for 8weeks. The control mice (C) were fed with normal diet. KEY FINDINGS The H mice exhibited increased body weight; hyperlipidemia; serum level of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6); hepatic lipid profile; lipid accumulation; reactive oxygen species (ROS) of hepatocytes, lipid peroxidation and liver antioxidant capacity was decreased. Immunofluorescent and Western blot assay revealed activation of nuclear factor kappa B (NF-κB) signaling pathway. The addition of F or AS and both in the diet significantly counteracted HFD induced body weight gain; hyperlipidemia; TNF-α, IL-6; hepatic lipid profile; fatty infiltration; NF-κB signaling pathway; ROS; lipid peroxidation and moreover elevated levels of hepatic antioxidant enzymes activity were observed. SIGNIFICANCE Simultaneous treatment with AS, F and their combination protected against HFD induced weight gain and oxidative stress. The protection may be attributed to the hypolipidemic and free radical scavenging activity of AS or F and their combination. This study illustrates that AS and F have relatively similar hypolipidemic, antioxidative, anti-inflammatory actions and the AS+F combination along with HFD has shown outstanding effects as compared to other treated groups.

Naringin inhibits gamma radiation-induced oxidative DNA damage and inflammation, by modulating p53 and NF-κB signaling pathways in murine splenocytes

Abstract The adverse effects of ionizing radiation occur due to the generation of reactive oxygen species (ROS). The aim of this study was to identify the protective effects of naringin (NG), a citrus flavonoid, on ionizing radiation (IR)-induced differential stress response, with an exploration of the mechanisms involved in this process. Isolated murine splenocytes were incubated in the presence and in the absence of different concentrations of NG (50 and 100 μM) for 1 h prior to 6 Gy γ-irradiation, and the molecular mechanisms of action were determined through biochemical, immunoblot, flow cytometric, and immunofluorescence studies. Pretreatment with NG significantly prevented IR-induced intracellular ROS generation, thereby preventing the formation of cellular TBARS and the development of cellular nitrite. NG significantly reduced nuclear DNA damage with respect to the irradiated splenocytes, through the inhibition of DNA-PKcs and p-γH2AX. The reduced cell viability as a result of irradiation was recovered by NG through modulation of the redox-regulated cell signaling system. NG pretreatment resulted in significant inhibition of IR-induced G1/S phase cell cycle arrest through the modulation of p53-dependent p21/WAF1, cyclin E, and CDK2 activation. The results also demonstrated that NG blocked the IR-induced p38 function and reversed IR-mediated differential stress response through inhibition of the NF-κB pathway. Thus, the p38/NF-κB pathway participated in the IR-induced inflammatory development, leading to upregulation of CRP, MCP-1, and iNOS2 gene expression. However, NG pretreatment reversed the inflammatory development through downregulation of NF-κB, and regulated the expression of CRP, MCP-1, and iNOS2. The above results provide a theoretical basis for the preventive use of NG against radiation-induced multiple cellular anomalies.

Gossypetin, a naturally occurring hexahydroxy flavone, ameliorates gamma radiation-mediated DNA damage

Abstract Purpose: To evaluate the protective effect of gossypetin (GTIN) against gamma (γ)-radiation-mediated DNA damage. Materials and methods: Increasing concentrations (10–150 μM) of GTIN were incubated with supercoiled DNA 1 h prior exposure to γ-radiation in the range of 5-Gy absorbed dose from Co60 γ source. To establish the effective protective concentration of GTIN, supercoiled DNA was pre-incubated with 50 μM of GTIN for 1 h followed by exposure of 5, 10 and 20 Gy doses of γ-radiation. Moreover, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical, hydroxyl radical, nitric oxide (NO) scavenging, metal chelating activity and ferric reducing antioxidant power (FRAP) of GTIN were measured and compared with standards. The flowcytometric analysis and radiation-induced genomic DNA damage by comet assay were employed to estimate the level of intracellular reactive oxygen species (ROS) using isolated murine hepatocytes. Results: GTIN was able to effectively scavenge different free radicals in in vitro situations. It could significantly prevent radiation induced supercoiled and genomic DNA damage with reduced comet parameters. It also acted as a potent scavenger of the radiation induced ROS. Conclusions: GTIN ameliorated radiation-induced oxidative stress and DNA damage by its free-radical scavenging activity.

Dinuclear zinc(II) complexes with compartmental ligands: syntheses, structures, and bioactivities as artificial nuclease

Four water-soluble dinuclear Zn(II) complexes (1–4) of compartmental ligand L = 2,6-bis(R-iminomethyl)-4-R′-phenolate (where R = N-ethylpiperidine or R = N-ethylpyrrolidine, R′ = methyl or tert-butyl) have been synthesized, characterized, and their DNA cleavage activity and cytotoxicity toward HepG2 cancerous cells are evaluated. The dinuclear complexes are formed by a pentadentate-substituted phenolate ligand chelating the metal ions separated by ca 3.27 Å. Each metal is a distorted trigonal bipyramid, completing the coordination sphere through acetate. The X-ray structural determination of 2 shows that the complex is counterbalanced by half (formulation [Zn2L2(CH3CO2)2][(Zn(SCN)4]0.5), while in 1 and 3 two crystallographically-independent complexes are present in the unit cell with a . Among the four complexes only the 4-tert-butyl-phenolato derivatives (3 and 4) show DNA cleavage activity in in-vivo conditions and appear to be promising toward metal complexes to be used as anticancer agents. The cytotoxicity of the complexes, investigated through MTT assay, suggests that 4 is a better choice as artificial nuclease.

Naringin ameliorates radiation-induced hepatic damage through modulation of Nrf2 and NF-κB pathways

Understanding the mechanism of ionizing radiation (IR)-induced systemic stress and its modulation by phytocomponents has great significance for the development of novel phyto-radioprotectors. The present study was intended to evaluate the radioprotective effect of naringin (NG), a citrus flavonoid on the modulation of IR-induced activation of the redox-regulated signaling system in murine liver. On the basis of survival analysis, mice were treated with 75 mg kg−1 body weight of NG for three consecutive days before irradiation (6 Gy). Pretreatment with NG significantly prevented the IR-induced generation of intracellular reactive oxygen species (ROS), along with the formation of hepatic thiobarbituric acid reactive substances (TBARS) and cellular nitrite. NG also showed significant reduction in IR-induced nuclear DNA damage through the inhibition of DNA-dependent protein kinase (DNA-PK). Further, the IR-induced cell death was arrested in the presence of NG through the inhibition of p53 mediated stress-activated protein kinase/Jun amino-terminal kinase (SAPK/JNK) pathways and modulation of other molecules of apoptosis pathways. Moreover, NG supported the intracellular defense mechanisms, by maintaining the endogenous antioxidants probably through phosphoinositide 3-kinase/protein kinase-B (PI3K/Akt) guided transcriptional activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, NG inhibited IR-induced inflammation through suppression of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) followed by the alteration of pro inflammatory factors. Taken together, these results suggested that NG reversed the IR-induced redox-imbalance in murine liver, probably by the inhibition of ROS/p38-MAPK/NF-κB, along with the activation of the PI3K/Akt/Nrf2 pathway and the reduction of apoptosis by interfering with the p53/SAPK/JNK/Bax pathway.

Ferulic acid (FA) abrogates γ-radiation induced oxidative stress and DNA damage by up-regulating nuclear translocation of Nrf2 and activation of NHEJ pathway

Abstract The present study was aimed to evaluate the radioprotective effect of ferulic acid (FA), a naturally occurring plant flavonoid in terms of DNA damage and damage related alterations of repair pathways by gamma radiation. FA was administered at a dose of 50 mg/kg body weight for five consecutive days prior to exposing the swiss albino mice to a single dose of 10 Gy gamma radiation. Ionising radiation induces oxidative damage manifested by decreased expression of Cu, Zn-SOD (SOD stands for super oxide dismutase), Mn-SOD and catalase. Gamma radiation promulgated reactive oxygen species (ROS) mediated DNA damage and modified repair pathways. ROS enhanced nuclear translocation of p53, activated ATM (ataxia telangiectasia-mutated protein), increased expression of GADD45a (growth arrest and DNA-damage-inducible protein) gene and inactivated Non homologous end joining (NHEJ) repair pathway. The comet formation in irradiated mice peripheral blood mononuclear cells (PBMC) reiterated the DNA damage in IR exposed groups. FA pretreatment significantly prevented the comet formation and regulated the nuclear translocation of p53, inhibited ATM activation and expression of GADD45a gene. FA promoted the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and activated NHEJ repair pathway to overcome ROS mediated oxidative stress and DNA damage. Therefore, the current study stated that FA can challenge the oxidative stress by (i) inducing nuclear translocation of Nrf2, (ii) scavenging ROS, and (iii) activating NHEJ DNA repair process.

Smokeless tobacco consumption impedes metabolic, cellular, apoptotic and systemic stress pattern: A study on Government employees in Kolkata, India

Smokeless tobacco (SLT) remains a threat amongst a large population across the globe and particularly in India. The oral use of tobacco has been implicated to cause physiological stress leading to extreme toxicological challenge. The study included 47 SLT-users and 44 non-users providing a spectrum of pathophysiological, clinico-biochemical, antioxidant parameters, cell cycle progression study of PBMC and morphological changes of red blood cells (RBC). The expressions of p53, p21, Bax, Bcl-2, IL-6, TNF- α, Cox-2, iNOS were analyzed from thirteen representative SLT-users and twelve non-users. Difference in CRP, random glucose, serum cholesterol, TG, HLDL-C, LDL-C, VLDL-C, neutrophil count, monocyte count, ESR, SOD (PBMC) and TBARS (RBC membrane) were found to be statistically significant (p < 0.05) between the studied groups. The current study confers crucial insight into SLT mediated effects on systemic toxicity and stress. This has challenged the metabolic condition leading to a rise in the inflammatory status, increased apoptosis and RBC membrane damage. The above findings were substantiated with metabolic, clinical and biochemical parameters. This is possibly the first ever in-depth report and remains an invaluable document on the fatal effects of SLT.

Gossypetin ameliorates ionizing radiation-induced oxidative stress in mice liver--a molecular approach.

Abstract Radioprotective action of gossypetin (GTIN) against gamma (γ)-radiation-induced oxidative stress in liver was explored in the present article. Our main aim was to evaluate the protective efficacy of GTIN against radiation-induced alteration of liver in murine system. To evaluate the effect of GTIN, it was orally administered to mice at a dose of 30 mg/kg body weight for three consecutive days prior to γ-radiation at a dose of 5 Gy. Radioprotective efficacy of GTIN were evaluated at physiological, cellular, and molecular level using biochemical analysis, comet assay, flow cytometry, histopathology, immunofluorescence, and immunoblotting techniques. Ionizing radiation was responsible for augmentation of hepatic oxidative stress in terms of lipid peroxidation and depletion of endogenous antioxidant enzymes. Immunoblotting and immunofluorescence studies showed that irradiation enhanced the nuclear translocation of nuclear factor kappa B (NF-κB) level, which leads to hepatic inflammation. To investigate further, we found that radiation induced the activation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK)-mediated apoptotic pathway and deactivation of the NF-E2-related factor 2 (Nrf2)-mediated redox signaling pathway, whereas GTIN pretreatment ameliorated these radiation-mediated effects. This is the novel report where GTIN rationally validated the molecular mechanism in terms of the modulation of cellular signaling system’ instead of ‘ This is the novel report where GTIN is rationally validated in molecular terms to establish it as promising radioprotective agents. This might be fruitful especially for nuclear workers and defense personnel assuming the possibility of radiation exposure.