TRANSDISCIPLINARY APPROACH IN FREE RADICAL THEORY OF AGING. CONTRIBUTION OF NIKOLAY M. EMANUEL AND HIS SCIENTIFIC SCHOOL TO GERONTOLOGY

Работа представляет собой обзор научных исследований влияния антиоксидантов-геропротекторов на старение экспериментальных животных и репликативное старение диплоидных клеток человека, выполненных в отделе кинетики химических и биологических процессов «ХИМБИО» Института химической физики АН СССР под руководством академика Николая Марковича Эмануэля в 1960- 1980- е гг. В работах Н.М. Эмануэля и сотрудников было установлено неизвестное ранее явление взаимодействия ингибиторов свободнорадикальных реакций в процессах окисления органических веществ, заключающееся в регенерации более эффективного ингибитора вследствие переноса атома водорода к его радикалу от молекулы менее эффективного ингибитора. Антиоксиданты поливалентны и могут влиять одновременно на многие процессы старения. Данные научной школы Н.М. Эмануэля по увеличению средней продолжительности жизни на 25,3 % и максимальной продолжительности мышей на 55,8 % под действием антиоксидантов, полученные в результате хорошо обоснованных экспериментальных и теоретических исследований, явились весомым аргументом в пользу свободнорадикальной теории старения. The work is aimed to review the results of scientific studies of the effect of antioxidants-geroprotectors on the aging of experimental animals and the replicative aging of human diploid cells, carried out in the Department of Kinetics of Chemical and Biological Processes «KHIMBIO» of the Institute of Chemical Physics of the USSR Academy of Sciences under the leadership of academician Nikolay Markovich Emanuel in the 1960-1980s after pioneer work by D. Harman. By N.M. Emanuel and colleagues, it was established a previously unknown phenomenon of radical interaction of inhibitors in the oxidation of organic substances, which consists in the regeneration of a more effective inhibitor due to the transfer of a hydrogen atom to its free radical from a molecule of a less effective inhibitor. Antioxidants are polyvalent and can simultaneously affect many stages of aging processes. Data from the N.M. Emanuel scientific school on the increase of the average lifespan of mice by 25,3 % and their maximum lifespan by 55,8 % using antioxidants, discovered at the Institute of Chemical Physics of the USSR Academy of Sciences as a result of well-founded experimental and theoretical studies, became a powerful argument in favor of the free radical theory of aging in 1970-ties. This was further promoted by approaches based on the theory of reliability, the damage theory, and as well as an approach based on oxidative activation of the Nrf2 signaling pathway, which maintains the «nucleophilic tone» of protective oxidoreductases.

STRUCTURAL DETERMINATION OF L-ASPARAGINASE II OF STREPTOMYCES ALBIDOFLAVUS AND INTERACTION ANALYSIS WITH L-ASPARAGINE AND CEFOTAXIME

Objective: L-Asparaginase enzyme possesses a crucial role in the treatment of various hematologic malignancies. The current study focuses on homology modeling and interaction analysis of L-Asparaginase proteins belonging to Streptomyces albidoflavus (S. albidoflavus) with the essential ligand L-Asparagine and subsequent analysis with essential β-lactam antibiotic Cefotaxime. Methods: The process of understanding Asparaginase interactions primarily involved structure determination of WP_096097608, WP_095730301, which is achieved by GalaxyTBM, I-TASSER and SWISS-MODEL. Further, the S. albidoflavus Asparaginase proteins are subjected to GalaxySite and Autodock Vina of PyRx analysis. Results: The GalaxyTBM predicted structures of both the proteins are found promising on various validation studies. The two Asparaginase proteins exhibited high binding affinities of-6.8 and-6.5 kcal/mol with Cefotaxime and-5.1 and-4.9 kcal/mol towards Asparagine. The protein WP_096097608 residues forming hydrogen bonds with L-Asparagine are also analysed to involve in interaction with Cefotaxime on individual docking analysis. Conclusion: The current findings details the two S. albidoflavus Asparaginase proteins affinity towards L-Asparagine, hence can be assessed further for immunogenicity studies. In addition to the above findings, an attempt is made to find the L-Asparaginase binding possibilities with non-metals that identified an essential β-lactam antibiotic Cefotaxime to be an effective inhibitor. This study helps in understanding the interactions of L-Asparaginase with Cefotaxime, as intake of antibiotics between the phases of chemotherapy is observed to treat various infections and also as an antibiotic to microbes that utilize Asparaginase as a vital enzyme.

Protamine Sulfate Neutralization Profile of Various Dosages of Bovine, Ovine and Porcine UFHs and Their Depolymerized Derivatives in Non-Human Primates

Introduction: Currently used unfractionated heparins (UFHs) and low molecular weight heparins (LMWHs) are derived from porcine intestinal mucosa. However, heparins have also been manufactured from tissues of other mammalian species such as cow (Bovine) and sheep (Ovine). Protamine sulphate (PS) is an effective inhibitor of heparin and is used clinically to neutralize both LMWH and UFH. In this study, we determined the PS neutralization profile of these agents in non-human primate model using anti-Xa and anti-IIa methods. Material and Methods: UFHs obtained from bovine, ovine and porcine mucosal tissues and their respective depolymerized LMWHs were administered at both, gravimetric (0.5 mg/kg) and potency adjusted (100 U/kg) dosages regimen intravenously to individual groups of primates in cross over studies. PS was administered at a fixed dosage and the relative neutralization of these anticoagulants was measured utilizing amidolytic anti-Xa and anti-IIa methods. Results: These studies have demonstrated that, the equi-gravimetric dosages of BMH, PMH and OMH have comparable PS neutralization profiles. At potency adjusted dosages, all UFHs were completely neutralized by PS. Although comparable, the LMWHs were not fully neutralized by PS in both the anti-Xa and anti-IIa assays. PS was more efficient in neutralizing the anti-IIa effects of LMWHs. Conclusion: Heparins of diverse origins showed comparable neutralization profiles by PS in the amidolytic anti-Xa and anti-IIa assays.

1’-Ribose Cyano Substitution Allows Remdesivir to Effectively Inhibit Nucleotide Addition and Proofreading during SARS-CoV-2 Viral RNA Replication

COVID-19 has recently caused a global health crisis and an effective interventional therapy is urgently needed. Remdesivir is one effective inhibitor for SARS-CoV-2 viral RNA replication. It supersedes other NTP...