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The third SARS-CoV-2 pandemic wave causing Omicron variant has comparatively higher replication rate and transmissibility than the second wave-causing Delta variant. The exact mechanism behind the differential properties of Delta and Omicron in respect to infectivity and virulence is not properly understood yet. This study reports the analysis of different mutations within the receptor binding domain (RBD) of spike glycoprotein and non-structural protein (nsp) of Delta and Omicron strains. We have used computational studies to evaluate the properties of Delta and Omicron variants in this work. Q498R, Q493R and S375F mutations of RBD showed better docking scores for Omicron compared to Delta variant of SARS-CoV-2, whereas nsp3_L1266I with PARP15 (7OUX), nsp3_L1266I with PARP15 (7OUX), and nsp6_G107 with ISG15 (1Z2M) showed significantly higher docking score. The findings of the present study might be helpful to reveal the probable cause of relatively milder form of COVID-19 disease manifested by Omicron in comparison to Delta variant of SARS-CoV-2 virus.

Background: COVID-19 is a global threat as a result of the incessant spread of SARS-CoV-2, necessitating the rapid availability of effective antiviral medications to protect our society. For SARSCoV-2, a group of peptides has already been indicated, although their effectiveness has yet to be shown.SARS-CoV-2 is an enveloped virus with hydrophobic fusion protein and spike glycoproteins. Methods: Here, we have compiled a list of amphiphilic peptides that have been published, as well astheir in-silico docking studies with the SARS-CoV-2 spike glycoprotein. Results: The findings demonstrated that spike protein and amphiphilic peptides with increased bindingaffinity create a complex. It was also observed that PalL1 (ARLPRTMVHPKPAQP), 10AN1(FWFTLIKTQAKQPARYRRFC), THETA defensin (RCICGRGICRLL), and mucroporin M1(LFRLIKSLIKRLVSAFK) showed the binding free energy of more than -1000 kcal/mol. Molecular pIand hydrophobicity are also important factors of peptides to enhance the binding affinity with spike proteinof SARS-CoV-2. Conclusion: In light of these findings, it is crucial to compare the in-vitro to in-vivo efficacy of amphiphilicpeptides in order to produce an efficient anti-SARS-CoV-2 peptide therapy that might assistcontrol the present pandemic scenario.

This protocol demonstrates how to establish primary epithelial cell cultures in vitrofrom healthy human tissue and human cancer samples using ROCK inhibitor and irradiated feeder cells.

Lambda-cyhalothrin, a third generation type II pyrethroid, is used predominantly in agriculture production and animal husbandry. A study was conducted to investigate lambda-cyhalothrin induced oxidative streßs, morphological changes of erythrocytes and other hematological biomarkers in rat and its amelioration by taurine, 2-amino ethane-sulfonic acid, a ß-amino acid. Rats were randomly divided into six groups and lambda-cyhalothrin was orally administered at two dose levels (10.83 and 15.17 mg/kg body wt), singly or combined with pretreated taurine (50 mg/kg body wt) for consecutive 14 days. Treatment of Lambda-cyhalothrin resulted in an increase in malondialdehyde, oxidized glutathione level and depletion of reduced glutathione level, superoxide dismutase, catalase, glutathione-s-transferase and glutathione peroxidase in erythrocyte compared to control. Scanning electron microscopic studies showed a marked alteration in the morphology of Lambda-cyhalothrin treated erythrocytes. Lambdacyhalothrin exposure also showed a significant decrease in erythrocyte count, hemoglobin percentage, haematocrit and red cell indices, whereas a significant increase in white blood cells and lymphocyte count was observed. However, pretreatment with taurine significantly restored the above said parameters. These findings revealed that lambda-cyhalothrin exposure produced oxidative stress, morphological changes of erythrocytes and other hematological biomarkers and its amelioration was accomplished by taurine through its reactive oxygen species scavenging activity.

Cypermethrin is an active pesticide that has been used for more than three decades which controls a wide variety of pests in agriculture. The present study designed to evaluate the protective role of zinc in attenuating cypermethrin induced haematological toxicity and oxidative stress in erythrocytes of male rat. Wistar male rats received oral cypermethrin at two dose levels and zinc alone or zinc pre-treatment with cypermethrin for consecutive 14 days. The toxic effects of cypermethrin were observed on various haematological parameters. Administration of cypermethrin resulted in enhanced malondialdehyde level, depletion of reduced glutathione content and antioxidant enzymes of rat erythrocytes. However pre-treatment of zinc in combination with cypermethrin improved haematological status and restored the oxidative markers to their normal levels. Based upon these data, the present study reveals that zinc treatment attenuates cypermethrin exposed haematotoxicity.

Diosgenin (DGN) is a natural bioactive steroidal saponin from therapeutic herbs and it exhibits potential anticancer efficacy. Here, we report the preparation of poly lactide-co-glycolide (PLGA)-encapsulated diosgenin nanoparticles (PLGA-DGN NPs) and characterization of their physicochemical nature, and morphology as well as inspect their drug-loading capability, in vitrodrug release, pharmacokinetics, bio-distribution, safety profile. The in vitroand in vivoantineoplastic activities of PLGA-DGN NPs were also examined against the MCF-7 breast cancer cell line and in the Ehrlich ascites carcinoma (EAC) tumor xenograft model, respectively. The results displayed an appropriate size (∼147 nm), spherical shape, and a narrow polydispersity index. The nanoparticles showed a high encapsulation efficacy (78%), loading capacity (8%), good colloidal stability, and an initial burst release at an acidic medium. The nanoparticles exhibited significant cytotoxic activity at their IC50dose compared to diosgenin. PLGA-DGN NPs facilitated cellular internalization of DGN in human breast cancer MCF-7 cells and extended the blood circulation time showing an excellent pharmacokinetic profile. Bio-distribution study revealed that PLGA-DGN NPs could significantly enhance DGN accumulation in tumor tissue. The safety profile of the PLGA-DGN NPs was confirmed in histopathologic, hematologic, and immunologic parameters of Swiss albino mice. At the same time, an effective antiangiogenic, and antiproliferative potential of PLGA-DGN NPs were exhibited in mice tumor xenograft model by showing tumor regression and down-regulating CD31 and Ki-67 expression. Therefore, PLGA-DGN NPs could be utilized as a promising anticancer drug, opening up a new avenue for further research.

•A method of monitoring lesion-specific recruitment of proteins in vivois described.•Recruitment of repair enzymes to abasic sites is monitored by co-localization.•Repair protein recruitment is consistent with known protein–protein relationships.•Cells demonstrated complete repair of abasic sites by 90min.

•The repair kinetics of two common cyclic DNA adducts derived lipid peroxidation, Acr-dG and HNE-dG, in human colon cells was studied.•This study is the first to measure DNA repair rates by both DNA repair synthesis and LC–MS/MS methods.•Acr-dG, like HNE-dG, is repaired by NER pathway, but it is repaired at a much slower rate compared to HNE-dG.•HNE-dG can inhibit the repair of Acr-dG if both are present in the same DNA.•These results provide an explanation for the higher levels of Acr-dG than HNE-dG observed in vivo.

In both bacteria and eukaryotes the alkylated, oxidized, and deaminated bases and depurinated lesions are primarily repaired via an endogenous preventive pathway, i.e. base excision repair (BER). Radiation therapy and chemotherapy are two important modes of cancer treatment. Many of those therapeutic agents used in the clinic have the ability to induce the DNA damage; however, they may also be highly cytotoxic, causing peripheral toxicity and secondary cancer as adverse side effects. In addition, the damage produced by the therapeutic agents can often be repaired by the BER proteins, which in effect confers therapeutic resistance. Efficient inhibition of a particular BER protein(s) may increase the efficacy of current chemotherapeutic regimes, which minimizes resistance and ultimately decreases the possibility of the aforementioned negative side effects. Therefore, pharmacological inhibition of DNA damage repair pathways may be explored as a useful strategy to enhance chemosensitivity. Various agents have shown excellent results in preclinical studies in combination chemotherapy. Early phase clinical trials are now being carried out using DNA repair inhibitors targeting enzymes such as PARP, DNA-PK or MGMT. In the case of BER proteins, elimination of N-Methylpurine DNA glycosylase (MPG) or inhibition of AP-endonuclease (APE) increased sensitivity of cancer cells to alkylating chemotherapeutics. MPG-/- embryonic stem cells and cells having MPG knock-down by siRNA are hypersensitive to alkylating agents, whereas inhibition of APE by small molecule inhibitors sensitized cancer cells to alkylating chemotherapeutics. Thus, MPG and other BER proteins could be potential targets for chemosensitization.

The cyclic 1, N -propanodeoxyguanosine adducts, derived from α,β-unsaturated aldehydes or enals, including acrolein (Acr), crotonaldehyde (Cro), and trans -4-hydroxy-2-nonenal (HNE), have been detected as endogenous DNA lesions in rodent and human tissues. Collective evidence has indicated that the oxidative metabolism of polyunsaturated fatty acids (PUFAs) is an important pathway for endogenous formation of these adducts. In a recent study, we examined the specific role of different types of fatty acids, ω-3 and ω-6 PUFAs, in the formation of cyclic adducts of Acr, Cro, and HNE. Our studies showed that the incubation of deoxyguanosine 5′-monophosphate with ω-3 or ω-6 fatty acids under oxidative conditions in the presence of ferrous sulfate yielded different amounts of Acr, Cro, and HNE adducts, depending on the types of fatty acids. We observed that Acr- and Cro-dG adducts are primarily formed from ω-3, and the adducts derived from longer chain enals, such as HNE, were detected exclusively from ω-6 fatty acids. Acr adducts are also formed from ω-6 fatty acids, but to a lesser extent; the yields of Acr adducts are proportional to the number of double bonds present in the PUFAs. Two previously unknown cyclic adducts, one from pentenal and the other from heptenal, were detected as products from ω-3 and ω-6 fatty acids, respectively. Because ω-6 PUFAs are known to be involved in the promotion of tumorigenesis, we investigated the role of HNE adducts in p53 gene mutation by mapping the HNE binding to the human p53 gene with UvrABC nuclease and determined the formation of HNE-dG adducts in the gene. The results showed that HNE-dG adducts are preferentially formed in a sequence-specific manner at the third base of codon 249 in the p53 gene, a mutational hotspot in human cancers. The DNA repair study using plasmid DNA containing HNE-dG adducts as a substrate in HeLa cell extracts showed that HNE adducts are readily repaired, and that nucleotide excision repair appears to be a major pathway involved. Together, results of these studies provide a better understanding of the involvement of different PUFAs in DNA damage and their possible roles in tumorigenesis.