In silico prediction of potential inhibitors for SARS-CoV-2 Omicron variant using molecular docking and dynamics simulation-based drug repurposing

Journal of Molecular Modeling -     

Role of selenium against lead toxicity in male rats

Male albino rats were intramuscularly administered a single dose of lead acetate (100 μmol/kg b.wt). Another group of rats were injected with sodium selenite (10 μmol/kg b.wt) before lead intoxication. After 3 and 24 hours, lead treatment resulted in significant increases in acid and alkaline phosphatases, GOT and GPT, total proteins, and cholesterol in serum. The total triglycerides in serum was decreased after 24 hours of intoxication. Lead treatment also produced significant elevation of lipid peroxidation in liver and kidney. The antioxidant capacity of hepatic and renal cells in terms of the activities of superoxide dismutase, glutathione reductase, and glutathione content was diminished. It appears from these results that lead may exert its toxic effect via peroxidative damage to renal and hepatic cell membranes after 24 hours. Selenium administration prior to lead injection produced pronounced prophylactic action against lead effects, and it is observed that selenium enhances the endogenous antioxidant capacity of the cells by increasing the activities of the superoxide dismutase and glutathione reductase and the glutathione content. As a result, the lipid peroxidation was decreased in both liver and kidney. © 1998 John Wiley & Sons, Inc. J Biochem Mol Toxicol 12: 345–349, 1998     

A sulfenic acid enzyme intermediate is involved in the catalytic mechanism of peptide methionine sulfoxide reductase from Escherichia coli

Methionine oxidation into methionine sulfoxide is known to be involved in many pathologies and to exert regulatory effects on proteins. This oxidation can be reversed by a ubiquitous monomeric enzyme, the peptide methionine sulfoxide reductase (MsrA), whose activity in vivo requires the thioredoxin-regenerating system. The proposed chemical mechanism of Escherichia coli MsrA involves three Cys residues (positions 51, 198, and 206). A fourth Cys (position 86) is not important for catalysis. In the absence of a reducing system, 2 mol of methionine are formed per mole of enzyme for wild type and Cys-86 --> Ser mutant MsrA, whereas only 1 mol is formed for mutants in which either Cys-198 or Cys-206 is mutated. Reduction of methionine sulfoxide is shown to proceed through the formation of a sulfenic acid intermediate. This intermediate has been characterized by chemical probes and mass spectrometry analyses. Together, the results support a three-step chemical mechanism in vivo: 1) Cys-51 attacks the sulfur atom of the sulfoxide substrate leading, via a rearrangement, to the formation of a sulfenic acid intermediate on Cys-51 and release of 1 mol of methionine/mol of enzyme; 2) the sulfenic acid is then reduced via a double displacement mechanism involving formation of a disulfide bond between Cys-51 and Cys-198, followed by formation of a disulfide bond between Cys-198 and Cys-206, which liberates Cys-51, and 3) the disulfide bond between Cys-198 and Cys-206 is reduced by thioredoxin-dependent recycling system process.     

E. coli methionine sulfoxide reductase with a truncated N terminus or C terminus, or both, retains the ability to reduce methionine sulfoxide

The monomeric peptide methionine sulfoxide reductase (MsrA) catalyzes the irreversible thioredoxin-dependent reduction of methionine sulfoxide. The crystal structure of MsrAs from Escherichia coli and Bos taurus can be described as a central core of about 140 amino acids that contains the active site. The core is wrapped by two long N- and C-terminal extended chains. The catalytic mechanism of the E. coli enzyme has been recently postulated to take place through formation of a sulfenic acid intermediate, followed by reduction of the intermediate via intrathiol-disulfide exchanges and thioredoxin oxidation. In the present work, truncated MsrAs at the N- or C-terminal end or at both were produced as folded entities. All forms are able to reduce methionine sulfoxide in the presence of dithiothreitol. However, only the N-terminal truncated form, which possesses the two cysteines located at the C-terminus, reduces the sulfenic acid intermediate in a thioredoxin-dependent manner. The wild type displays a ping-pong mechanism with either thioredoxin or dithiothreitol as reductant. Kinetic saturation is only observed with thioredoxin with a low K(M) value of 10 microM. Thus, thioredoxin is likely the reductant in vivo. Truncations do not significantly modify the kinetic properties, except for the double truncated form, which displays a 17-fold decrease in k(cat)/K(MetSO). Alternative mechanisms for sulfenic acid reduction are also presented based on analysis of available MsrA sequences.     

Improvement of β-glucosidase production by co-culture of Aspergillus niger and A. oryzae under solid state fermentation through feeding process

Eleven different Aspergillus strains were evaluated for their ability to produce β-glucosidase using sugar cane bagasse as a sole carbon source under solid state fermentation (SSF). The most potent strains, A. niger NRC 7 (674.6 U/g ds) and A. oryzae NRRL 447 (83 U/g ds), were used in a mixed culture to enhance β-glucosidase production by co-culturing under SSF. In mixed culture, β-glucosidase of the two strains (814 U/g ds) was nearly 1.2- and 9.8-fold than that of monocultures of A. niger NRC 7A and A. oryzae NRRL 447, respectively. Optimization of the culture parameters, initial pH value, moisture content, inoculum size and ratios of the two strains. and incubation time exhibited a significant increase in β-glucosidase production (1,893 U/g ds) than before optimization. Single feeding with citrate-phosphate buffer, succinate buffer, casein. and soybean flour individually after the third day of the fermentation time and controlling the moisture content at 90 % (w/w) induced β-glucosidase production. Maximum enzyme production increased up to 2.1-fold compared to 2,188 U/g ds during normal batch culture. Among nitrogen sources, soybean flour gave the highest β-glucosidase (4,578 U/g ds). while urea reduced β-glucosidase production (1,693 U/g ds). However, the combination of buffers with soybean flour through two fed cycles resulted in a decrease of the enzyme than single fed with buffers or soybean flour alone.     

Attenuation of the acute adriamycin-induced cardiac and hepatic oxidative toxicity by N-(2-mercaptopropionyl) glycine in rats

The protective effect of the synthetic aminothiol, N-(2-mercaptopropionyl) glycine (MPG) on adriamycin (ADR) induced acute cardiac and hepatic oxidative toxicity was evaluated in rats. ADR toxicity, induced by a single intraperitoneal injection (15 mg/kg), was indicated by an elevation in the level of serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), creatine kinase isoenzyme (CK-MB), and lactic dehydrogenase (LDH). ADR produced significant elevation in thiobarbituric acid reactive substances (TBARS), indicating lipid peroxidation, and significantly inhibited the activity of superoxide dismutase (SOD) in heart and liver tissues. In contrast, a single injection of ADR did not affect the cardiac or hepatic glutathione (GSH) content and cardiac catalase (CAT) activity but elevated hepatic CAT. Pretreatment with MPG, (2.5 mg/kg) intragastrically, significantly reduced TBARS concentration in both heart and liver and ameliorated the inhibition of cardiac and hepatic SOD activity. In addition, MPG significantly decreased the serum level of GOT, GPT, CK-MB, and LDH of ADR treated rats. These results suggest that MPG exhibited antioxidative potentials that may protect heart and liver against ADR-induced acute oxidative toxicity. This protective effect might be mediated, at least in part, by the high redox potential of sulfhydryl groups that limit the activity of free radicals generated by ADR.     

Neuropathological and Cognitive Effects Induced by CuO-NPs in Rats and Trials for Prevention Using Pomegranate Juice

Copper oxide nanoparticles (CuO‐NPs) are extensively utilized in several industries and in pharmaceutical production. This excess exposure elevates the concern about its expected poisonous impacts on humans and animals. Pomegranate juice (PJ) is a natural source of polyphenols and exhibits potent antioxidant activities. Our experiment intended to explore the neurobehavioral and toxicopathological impacts of CuO-NPs and to explain the mechanistic role of PJ to reduce their toxicity. Thirty Wistar albino rats received the subsequent materials through oral gavage, every day for 28d: (1) normal saline, (2) 3 mL/kg bwt PJ, (3) 6 mL/kg bwt PJ, (4) 300 mg/kg bwt CuO-NPs, (5) CuO-NPs?+?3 mL/kg bwt PJ, (6) CuO-NPs?+?6 mL/kg bwt PJ. Continuous exposure to CuO-NPs caused a significant elevation of MDA levels and reduction of total antioxidant capacity associated with remarkable pathological alterations in all brain regions including cerebrum, hippocampus and cerebellum. Progressive decline of memory along with cognitive and psychiatric disturbances were observed in rats exposed to CuO-NPs not in PJ co-treated rats. Continuous exposure to CuO-NPs caused over expression of the immunohistochemical markers of caspase-3, iNOS and GFAP altogether with DAN fragmentation and down-regulation of HO-1 and Nrf2 gene in the whole brain tissues. Conversely, rats co-treated with PJ showed dose dependent improvements in the entire toxicological, behavioral, and pathological parameters. We showed that PJ had the ability to reduce the oxidative stress damage via up-regulation of HO-1 and Nrf2 genes in the brain. So that PJ had the ability to protect the brain and DNA from further damage.