Amritpal Singh

Animal models of acute renal failure

The animal models are pivotal for understanding the characteristics of acute renal failure (ARF) and development of effective therapy for its optimal management. Since the etiology for induction of renal failure is multifold, therefore, a large number of animal models have been developed to mimic the clinical conditions of renal failure. Glycerol-induced renal failure closely mimics the rhabdomyolysis; ischemia-reperfusion-induced ARF simulate the hemodynamic changes-induced changes in renal functioning; drug-induced such as gentamicin, cisplatin, NSAID, ifosfamide-induced ARF mimics the renal failure due to clinical administration of respective drugs; uranium, potassium dichromate-induced ARF mimics the occupational hazard; S-(1,2-dichlorovinyl)-L-cysteine-induced ARF simulate contaminated water-induced renal dysfunction; sepsis-induced ARF mimics the infection-induced renal failure and radiocontrast-induced ARF mimics renal failure in patients during use of radiocontrast media at the time of cardiac catheterization. Since each animal model has been created with specific methodology, therefore, it is essential to describe the model in detail and consequently interpret the results in the context of a specific model.

Effect of mast cell stabilizers in hyperhomocysteinemia-induced cardiac hypertrophy in rats.

The present study has been designed to investigate the effect of sodium cromoglycate and ketotifen, mast cell stabilizers in hyperhomocysteinemia-induced cardiac hypertrophy in rats. Methods: Rats were administered L-methionine (1.7 g/kg/day PO) for 8 weeks to produce hyperhomocysteinemia. Sodium cromoglycate (24 mg/kg/day IP) and ketotifen (1mg/kg/day IP) treatments were started from first day of administration of L-methionine and continued for 8 weeks. The development of cardiac hypertrophy was assessed in terms of measuring mean arterial blood pressure (MABP), ratio of left ventricular (LV) weight to body weight (LVW/BW), LV wall thickness (LVWT), LV protein content, and LV collagen content. Further, the oxidative stress in heart was assessed by measuring lipid peroxidation, superoxide anion generation, and reduced glutathione (GSH). Moreover, the cardiomyocyte diameter and LV mast cell density were determined using hematoxylin-eosin and toluidine blue staining, respectively. Results: The L-methionine administration produced hyperhomocysteinemia, which significantly increased MABP, oxidative stress, and density of mast cells and consequently produced cardiac hypertrophy by increasing cardiomyocyte diameter, LVW/BW, LVWT, LV protein and collagen content. However, sodium cromoglycate and ketotifen treatments significantly attenuated hyperhomocysteinemia-induced oxidative stress and pathological cardiac hypertrophy without significantly altering MABP. Moreover, sodium cromoglycate and ketotifen treatments did not affect serum homocysteine levels. Conclusions: Thus, it may be concluded that hyperhomocysteinemia-induced cardiac hypertrophy is associated with an increase in oxidative stress and density of mast cells in heart. Sodium cromoglycate and ketotifen may have attenuated hyperhomocysteinemia-induced pathological cardiac hypertrophy, possibly by reducing oxidative stress and preventing the degranulation and increase in density of mast cells.

Impact of obesity on hypertension-induced cardiac remodeling: role of oxidative stress and its modulation by gemfibrozil treatment in rats

This study investigated the possible synergistic role of obesity in hypertension-induced cardiac remodeling and its modulation by gemfibrozil treatment in rats. Male Wistar rats were fed a high-fat diet (HFD) for 90 days. Normal rats were subjected to hypertension by partial abdominal aortic constriction (PAAC) for 28 days. In the HFD+PAAC control group, rats on HFD were subjected to PAAC on the 62nd day and were sacrificed on the 90th day. HFD and PAAC individually resulted in significant cardiac hypertrophy and fibrosis along with increased oxidative stress and mean arterial blood pressure (MABP) in rats as evidenced by various morphological, biochemical, and histological parameters. Moreover, the HFD + PAAC control group showed marked cardiac remodeling compared to rats subjected to HFD or PAAC alone. The HFD+gemfibrozil and HFD+PAAC+gemfibrozil groups showed significant reduction in cardiac remodeling along with reduction in oxidative stress and MABP. Hence, it may be concluded that oxidative stress plays a key role in obesity-mediated synergistic effects on induction and progression of PAAC-induced cardiac remodeling, and its deleterious effects could be reversed by gemfibrozil treatment in rats through its antioxidant activity.

Pharmacological investigations of Punica granatum in glycerol-induced acute renal failure in rats.

Objective: The present study was designed to investigate the ameliorative potential and possible mechanism of hydroalcoholic extract of flowers of P. granatum in glycerol-induced acute renal failure (ARF) in rats. Materials and Methods: The rats were subjected to rhabdomyolytic ARF by single intramuscular injection of hypertonic glycerol (50% v/v; 8 ml/kg) and the animals were sacrificed after 24 hours of glycerol injection. The plasma creatinine, blood urea nitrogen, creatinine clearance, and histopathological studies were performed to assess the degree of renal injury. Results: Pretreatment with hydroalcoholic extract of flowers of P. granatum (125 and 250 mg/kg p.o. twice daily for 3 days) significantly attenuated hypertonic glycerol-induced renal dysfunction in a dose-dependent manner. BADGE (Bisphenol-A-diglycidyl ether) (30 mg/kg), a peroxisome proliferator-activated receptor (PPAR)-γ antagonist, and N(omega)-nitro-l-arginine-methyl ester (L-NAME) (10, 20, and 40 mg/kg), nitric oxide synthase inhibitor, were employed to explore the mechanism of renoprotective effects of Punica granatum. Administration of BADGE (30 mg/kg) and L-NAME (40 mg/kg) abolished the beneficial effects of P. granatum in glycerol-induced renal dysfunction. Conclusion: Hydroalcoholic extract of flowers of P. granatum has ameliorative potential in attenuating myoglobinuric renal failure and its renoprotective effects involve activation of PPAR-γ and nitric oxide-dependent signaling pathway.

A Study on the Antioxidant Activity of Pyridylselenium Compounds and their Slow Release from Poly(acrylamide) Hydrogels

Abstract The antioxidant activity of pyridylselenium compounds has been evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical and nitric oxide (NO) scavenging methods. Pyridylselenium compounds have shown far superior (100–1000 times) antioxidant property than ebselen. The control release of bis(2-pyridyl) diselenide from poly(acrylamide) hydrogels has been studied in order to evaluate its release mechanism and diffusion coefficient. The later study also demonstrates that the pyridylselenium loading into the polymer matrix increases the magnitude and the rate of the radical scavenging activity of the poly(acrylamide) hydrogels. GRAPHICAL ABSTRACT

Ameliorative role of rosiglitazone in hyperhomocysteinemia-induced experimental cardiac hypertrophy.

The present study has been designed to explore the beneficial effect of rosiglitazone, a peroxisome proliferator activated receptor-γ agonist, in hyperhomocysteinemia-induced cardiac hypertrophy in rats. The hyperhomocysteinemia was induced in rats by feeding L-methionine (1.7 g/kg per day orally) for 8 weeks. The development of cardiac hypertrophy was assessed by measuring ratio of left ventricular weight to body weight, left ventricular wall thickness, cardiomyocyte diameter, and mean arterial blood pressure. The extent of fibrosis was checked by biochemical and histological assessment of collagen deposition. Moreover, the oxidative stress in heart was measured in terms of an increase in thiobarbituric acid reactive substances, superoxide anion generation, and decrease in reduced glutathione levels. The treatment with rosiglitazone (5 and 10 mg/kg per day orally) started from the first day of administration of L-methionine significantly abolished hyperhomocysteinemia-induced increase in left ventricular weight to body weight ratio, left ventricular wall thickness, cardiomyocyte diameter, collagen deposition, and oxidative stress without affecting serum homocysteine levels in rats. At high dose, rosiglitazone markedly reduced mean arterial blood pressure but at low dose, a significant reduction in mean arterial blood pressure was not observed in hyperhomocysteinemic rats. Hence, our results suggest that rosiglitazone provides benefit in hyperhomocysteinemia-induced cardiac hypertrophy and fibrosis in a dose-dependent manner and its protective action is independent of change in mean arterial blood pressure and serum homocysteine levels in rats.

A mechanistic study of the synthesis, single crystal X-ray data and anticarcinogenic potential of bis(2-pyridyl)selenides and -diselenides

The reaction of bis(organyl)diselenide with a reducing agent, such as LiAlH4, NaBH4, Li(C2H5)3BH, etc., generally leads to cleavage of the Se–Se bond resulting in the formation of the corresponding organylselenols/selenolates. However, this work for the first time demonstrates the scisson of the C(pyridine)–Se bond in bis(2-pyridyl)diselenides with LiAlH4. The reaction affords analytically pure bis(2-pyridyl)selenides in near quantitative yields. The reaction pathway involves the formation of a selenated aluminato complex followed by the scission of the C(pyridine)–Se bond and generation of LiAlSeH2. The generation of LiAlSeH2 was established by experimental and NMR analysis. The mechanism of the reaction has been supported by theoretical analysis. Single crystal X-ray structure determination of bis(3-methyl-2-pyridyl)selenide (2e) was performed and it shows that the molecules are self-assembled in a 2D-network of C–H⋯N hydrogen bonds and π⋯π stacking interactions. The synthesized compounds were also evaluated against the Raji cancer cell line (acute lymphoid leukemia).

FT-IR, NMR, molecular structure, and HOMO-LUMO studies of 3,5-dimethyl-2-pyridylselenium compounds by density functional theory

GRAPHICAL ABSTRACT ABSTRACT The present study explores various quantum chemical models to better understand the molecular properties of pyridylselenium compounds. We have carried out theoretical and experimental analyses of bis(3,5-dimethyl-2-pyridyl)diselenide (1), 3,5-dimethyl-2,6-bis(methylselenenyl) pyridine (2) and 3,5-dimethyl-2-(methylselenenyl)pyridine (3). The study demonstrates the effect of structural variations on molecular properties of these compounds. Density functional theory (DFT) has been used to calculate vibrational wavenumbers and intensity of vibrational bands and the results obtained are in excellent agreement with the experimental FT-IR data. The 1H and 13C NMR chemical shifts were calculated using GIAO method in gas phase and solvent phase of CDCl3 by taking IEFPCM method and correlations have been developed which accurately predicts the chemical shift values of various organoselenium compounds. The HOMO-LUMO energies in the gas and solvent phase were calculated by using B3LYP/6-311++G(d,p) level of theory. The HOMO-LUMO energy gaps in different molecules were compared and correlated with their biological activity.