A phenoxy-bridged trinuclear Ni(ii) complex: synthesis, structural elucidation and molecular docking with viral proteins

A novel phenoxy-bridged trinuclear nickel(ii) complex [Ni3(mu-L)2(bipy)3](1) (where H3L= (E)-2-hydroxy-N-(2-hydroxy-3,5-diiodophenyl)-3,5-diiodobenzohydrazonic acid, bipy = 2,2'-bipyridyl) has been designed and synthesized as a potential antivirus drug candidate. The trinuclear Ni(ii) complex [Ni3(mu-L)2(bipy)3](1) was fully characterized via single crystal X-ray crystallography. The unique structure of the trinuclear nickel(ii) complex crystallized in a trigonal crystal system with P3221 space group and revealed distorted octahedral coordination geometry around each Ni(ii) ion. The X-ray diffraction analysis established the existence of a new kind of trinuclear metal system containing nickel(ii)-nickel(ii) interactions with an overall octahedral-like geometry about the nickel(ii) atoms. The non-bonded Ni-Ni distance seems to be 3.067 and 4.455 A from the nearest nickel atoms. The detailed structural analysis and non-covalent supramolecular interactions are also investigated by single crystal structure analysis and computational approaches. Hirshfeld surfaces (HSs) and 2D fingerprint plots (FPs) have been explored in the crystal structure to investigate the intermolecular interactions. The preliminary analysis of redox and magnetic characterization was conducted using cyclic voltammetry measurements and a vibrating sample magnetometer (VSM), respectively. This unique structure shows good inhibition performance for SARS-CoV-2, Omicron and HIV viruses. For insight into the potential application of the Ni(ii) coordination complex as an effective antivirus drug, we have examined the molecular docking of the trinuclear Ni(ii) complex [Ni3(mu-L)2(bipy)3](1) with the receptor binding domain (RBD) from SARS-CoV-2 (PDB ID: 7MZF), Omicron BA.3 variant spike (PDB ID: 7XIZ), and HIV protease (PDB ID: 7WCQ) viruses. This structure shows good inhibition performance for SARS-CoV-2, Omicron S protein and HIV protease viruses;the binding energies (DELTAG) and the respective Ki/Kd (inhibition/dissociation constants) correlation values are -8.9 (2.373 muM or 2373 nM), -8.1 (1.218 muM or 1218 nM) and -7.9 (0.874 muM or 874 nM), respectively. The results could be used for rational drug design against SARS-CoV-2 Omicron variant and HIV protease viruses.Copyright © 2023 The Royal Society of Chemistry.

Redox stress in COVID-19: Implications for hematologic disorders.

COVID-19 is the respiratory illness caused by the beta coronavirus SARS-CoV-2. COVID-19 is complicated by an increased risk for adverse thrombotic events that promote organ failure and death. While the mechanism of action for SARS-CoV-2 is still being understood, how SARS-CoV-2 infection impacts the redox environment in hematologic conditions is unclear. In this review, the redox mechanisms contributing to SARS-CoV-2 infection, coagulopathy and inflammation are briefly discussed. Specifically, sources of oxidant generation by hematopoietic and non-hematopoietic cells are identified with special emphasis on leukocytes, platelets, red cells, and endothelial cells. Furthermore, reactive cysteines in SARS-CoV-2 are also discussed with respect to oxidative cysteine modification and current therapeutic implications. Lastly, sickle cell disease will be discussed as a hematologic disorder with a pre-existing prothrombotic redox condition that complicates treatment strategies for COVID-19. An understanding of the redox mechanism may identify potential targets for COVID-19-mediated thrombosis in hematologic disorders.

Antiviral Activity of Interferon Alpha-2b and Taurine Combination Against SARS-CoV-2 in vitro

Interferons (IFN) have antiviral activity against many viruses, including SARS-CoV-2. A combination of IFN-a2b and the antioxidant taurine is widely used in the Russian Federation, and its antiviral activity has not been studied before. The aim of this study was to determine the antiviral activity of interferon drugs, in combination with taurine and without it. The study included cytotoxicity and antiviral activity assays of IFN-a2b preparations, when stored according to the instructions at 2-8°C, and after 1 month storage at the temperature of 20-26°C in a pre-opened state. The combination of IFN alpha-2b with taurine has a higher antiviral activity compared to IFN alpha-2b mono-preparation by more than 25% at a «low» and 85% at a «high» multiplicity of infection. Selectivity index for combinations of IFN-a2b (50,000 IU/dose) + taurine (1 mg/ml) and IFN-a2b (10,000 IU/ml) + taurine (0.8 mg/ml) was more than 600 units, whereas for the IFN-a2b (10,000 IU/ml) it was 200 units. Antiviral activity does not change after one month at room temperature. The combination of interferon with taurine at high concentrations was less toxic than interferon. The results obtained demonstrate practicability of interferon alpha-2b and taurine combination use for treatment and prevention of COVID-19.

OCCUPATIONAL AND ENVIRONMENTAL INFLUENCES ON HYPERTENSION

In this brief review I shall try to discuss several topics related to hypertension which maybe associated with occupational and environmental effects. Effects of dietary sodium will not be discussed as these are extensively discussed elsewhere. Occupational stress is difficult to define but there seems to be a relationship between high demands and relatively low control, and blood pressure in both men and women despite different professional distribution. Noise, a relatively less recognized stressor that may be associated with hypertension Both industrial noise and urban noise. Recently due to the Covid19 lockdown and reduction of aircraft noise in relevant areas a reduction of bloodpressure was noted. Seasonal variation with rise of blood pressure during cold and perhaps shorter daytime light seasons, and subsequent reduction in the summer with its higher temperatures and longer light hours is one environmental factor. Air pollution, especially that associated with high level small particulate matter equal to, or smaller than 0.25 μm, was associated with hypertension in several studies, with quite and ethnic and geographic variability. High altitude exposure (higher than 2500 m), involves hypoxemia (in addition to radiation, cold temperatures, and dehydration because of dryness of inhaled air), resulting in renin angiotensin system activation and sympathetically induced vascular contraction, and elevation of pulse rate and blood-pressure at rest and an exaggerated increase during exercise. Immigration seems to be associated with hypertension through different mechanisms in different populations. Mechanisms of these effects are not well understood though some must be mediated through sympathetic activation, others through the renin angiotensin system though, hypoxemia, altered redox state and inflammation all might participate along with other mechanisms.

PET imaging of innate immunity activation In Vivo with redox-tuned 4-[ 18F]fluoro-1-naphthol

High redox potential reactive oxygen and nitrogen species (ROS/RNS), such as O2 free radicals, superoxide, and hypochlorous acid, generated by activities of the NADPH oxidase-2 (NOX2)/myeloperoxidase (MPO) axis and related enzymes, are key effector molecules of innate immunity in physiological and diseased inflammatory states. Other lower energy species (H2O2, NO) provide adjuvant signaling functions. NOX2- and MPO-derived high energy radicals are known to oxidize naphthol species, wherein the naphthol products bind to proximate proteins and activated myeloid cells. Herein, we present 4-[18F]fluoro-1-naphthol ([18F]4FN), a novel redox-tuned radiopharmaceutical that selectively detects by positron emission tomography (PET) high energy radicals produced by activated innate immunity. The products of human MPO plus H2O2 , but not H2O2 alone, rapidly and completely oxidized [18F]4FN. All-trans-retinoic acid-differentiated HL-60 'neutrophil-like' human cells activated with phorbol-12-myristate-13-acetate (PMA) retained [ 18F]4FN 5-fold over unstimulated cells. 4-ABAH, an MPO-specific inhibitor, or DPI, a broad oxidase inhibitor, blocked cellular retention by >95%. [18F]4FN PET/CT imaging readily discriminated foci of inflammation in vivo in three distinct murine models of acute inflammation: endotoxin-induced whole-body toxic shock, PMA-induced mild contact dermatitis of the ear, and lipopolysaccharide (LPS)-induced ankle arthritis. Mechanistically, in mice in vivo, 4-ABAH reduced inflammationinduced [18F]4FN retention, and Cybb-/- (Nox2-/-) gene-deletion strongly and significantly abrogated PMA-induced [18F]4FN retention. Thus, [18F]4FN shows promise as a robust redox-tuned reporter for imaging activation states of innate immunity by PET/CT, is ready for translation. [18F]4FN PET imaging may find application in a variety of inflammatory states associated with cancer therapy, immunotherapy-related adverse events, as well as other diseases, including arthritis, hepatitis, atherosclerosis, COVID-19, as well as up-staging and monitoring multi-organ inflammation.

Association between Seminal Oxidation-Reduction Potential and Sperm DNA Fragmentation-A Meta-Analysis.

Seminal oxidative stress and sperm DNA damage are potential etiologies of male factor infertility. The present study aims to evaluate the relationship between oxidation-reduction potential (ORP), a measure of oxidative stress, and sperm DNA fragmentation (SDF) by conducting a systematic review and meta-analysis of relevant clinical data. A literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The COVIDENCE tool was used to screen and identify studies evaluating seminal ORP and SDF. Studies (n = 7) that measured seminal ORP and SDF of 3491 semen samples were included in the analysis. The fixed-effects model revealed a significant pooled correlation coefficient (r = 0.24; p < 0.001) between seminal ORP and SDF. Furthermore, subgroup analyses indicated that the pooled correlation coefficient between ORP and sperm chromatin dispersion (SCD) assay was less than other SDF assays (0.23 vs. 0.29). There was a moderate level of heterogeneity (I2 = 42.27%) among the studies, indicating a lack of publication bias. This is the first meta-analysis to reveal a positive correlation between seminal ORP and SDF. Furthermore, this study indicates the role of oxidative stress in the development of sperm DNA damage and thus warrants prospectively exploring the clinical value of these sperm function tests.

Oxidative Stress and Biochemical Parameters among Recovered COVID-19 Patients: A Case-control Study

Introduction: The Coronavirus Disease-2019 (COVID-19) pandemic has spread rapidly, infecting more than 194 million and killing more than 4 million people worldwide. Algeria has not escaped this scourge;according to World Health Organization (WHO), 162,155 confirmed cases and 4,063 deaths have been recorded from 3rdJanuary 2020 to 26thJuly 2021. Recent studies have indicated the critical role of an altered immune system, and oxidative stress in the pathological process contributing to several complications during COVID-19 disease. Aim: To determine blood markers, oxidant/antioxidant status and biochemical parameters in patients highly recovered from COVID-19 and compare with those who have never contracted COVID-19;considered as controls. Materials and Methods: The present case-control study was conducted in Tiaret, Algeria, between May 2021 and June 2021. Thirty healthy volunteers who had never contracted COVID-19 and 16 volunteers who recovered from COVID-19 in the last six months were included in the study. Blood samples were taken after 8 to 12 hours of fasting, the blood markers and biochemical parameters were evaluated. The participant with chronic diseases (diabetes, hypertension, cardiovascular diseases, kidney disease) was excluded. Student's t-test was performed for statistical comparison between the two groups. Statistical analysis was performed using Excel Microsoft 2010 software. Results. The control group consisted of 46.7% male (n=14) and 53.3% females (n=16). While, the case group consisted of 62.5% males (n=10) and 37.5% females (n=6). The plasma levels of Low Density Lipoprotein-Cholesterol (LDL-C), p-value=0.004∗∗and creatinine increased very significantly in the cases compared to the controls. While, total cholesterol, p-value=0.04∗and Glutamate Pyruvate Transaminase (GPT), p-value=0.03∗ increased significantly in the case group on comparision to the control group. On the other hand, erythrocyte Malondialdehyde (MDA) levels, p-value=0.009∗∗increased very significantly in the case group compared to controls. The erythrocyte activity catalase decreased highly significantly in the case group compared to the controls. But erythrocyte Reduced glutathione (GSH) decreased very significantly in group cases compared to controls. Conclusion: The findings in the present study confirmed the persistence of metabolic alterations and oxidative stress in COVID-19 patients after recovery. Antioxidant supplementation is recommended to improve redox status and reduce oxidative stress after recovery.

Oxidative Stress Status and its correlation with Redox Status as Measured By An Electrochemical (PAOT®) Methodology: A Pilot Study in Critical COVID-19 Pneumonia Survivors

Background: In most serious COVID-19 forms which required prolonged stay in intensive care unit, pulmonary, cardiovascular, renal, neurological and psychological sequelae have been reported after the infection. All these complications can be sustained by chronic inflammatory problems and/ or increased oxidative stress. Material and Methods: Biomarkers of the systemic oxidative stress status (OSS) including enzymatic and non-enzymatic antioxidants, total antioxidant capacity of plasma (PAOT®-Sore), trace elements, oxidative damage to lipids and inflammation markers, were investigated in 12 patients admitted to a revalidation center for post-19 COVID pneumonia. Results: From blood samples collected two months after hospital discharge and one month after admission to the revalidation center, vitamin C, thiol proteins, reduced glutathione, gamma-tocopherol and beta carotene were significantly decreased compared to reference values. By contrast, lipid peroxides and markers of inflammation (neutrophils, myeloperoxidase) were significantly higher than the norms. Lipid peroxides was strongly correlated with Cu (r = 0.95, P < 0.005) and Cu/Zn ratio (0.66, P = 0.020). Using an electrochemical method (PAOT®), total antioxidant capacity (TAC) evaluated in saliva and urine negatively correlated with copper and lipid peroxides. Similar findings were obtained for PAOT®-skin score. Conclusions: Systemic OSS was strongly altered in patients admitted in revalidation after C0VID-19 infection. This suggests the need for supplementing these patients with antioxidants.

COVID-19: Melatonin as a potential adjuvant treatment.

This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients. Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death. Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients. Additional experiments and clinical studies are required to confirm this speculation.