Use of Thiols in the Treatment of COVID-19: Current Evidence

There is a possible role for oxidative stress, a state characterized by an altered balance between the production of free radicals or reactive oxygen species (ROS) and antioxidant defences, in coronavirus disease 2019 (COVID-19), the genesis of which is quite complex. Excessive oxidative stress could be responsible for the alveolar damage, thrombosis, and red blood cell dysregulation observed in COVID-19. Apparently, deficiency of glutathione (GSH), a low-molecular-weight thiol that is the most important non-enzymatic antioxidant molecule and has the potential to keep the cytokine storm in check, is a plausible explanation for the severe manifestations and death in COVID-19 patients. Thiol drugs, which are considered mucolytic, also possess potent antioxidant and anti-inflammatory properties. They exhibit antibacterial activity against a variety of medically important bacteria and may be an effective strategy against influenza virus infection. The importance of oxidative stress during COVID-19 and the various pharmacological characteristics of thiol-based drugs suggest a possible role of thiols in the treatment of COVID-19. Oral and intravenous GSH, as well as GSH precursors such as N-acetylcysteine (NAC), or drugs containing the thiol moiety (erdosteine) may represent a novel therapeutic approach to block NF-kB and address the cytokine storm syndrome and respiratory distress observed in COVID-19 pneumonia patients

Serum Bilirubin Levels in Overweight and Obese Individuals: The Importance of Anti-Inflammatory and Antioxidant Responses

Obesity is a chronic condition involving low-grade inflammation and increased oxidative stress; thus, obese and overweight people have lower values of serum bilirubin. Essentially, bilirubin is a potent endogenous antioxidant molecule with anti-inflammatory, immunomodulatory, antithrombotic, and endocrine properties. This review paper presents the interplay between obesity-related pathological processes and bilirubin, with a focus on adipose tissue and adipokines. We discuss potential strategies to mildly increase serum bilirubin levels in obese patients as an adjunctive therapeutic approach.

Melatonin as a Novel Supplement to COVID 19 Therapies

The COVID-19 disease continues its rampage on the human population all over the world. The pathogenesis mechanisms involve various inflammatory and altered immune responses and oxidative processes, leading to complications like cytokines storm and death in vulnerable cases. Therefore, in this review, we summarize current evidence on melatonin therapy for viral infections with focus on possible underlying mechanisms of melatonin actions. Since this pandemic crisis elapses time, researchers worldwide are busy trying new solutions to overcome the heavy toll of the COVID-19 illness morbidity and mortality. One such drug with growing recognition is melatonin. Melatonin is a well-known anti-inflammatory and antioxidant molecule which helps in promoting adaptive immunity. Melatonin improves sleep and anxiety and also can prevent fibrosis. It is a readily available over-the-counter medication that can be manufactured easily in bulk, hence inexpensive to a patient from a developing nation like India. It can be orally administered and has a wide margin of safety. This article reviews the various facets, merits, demerits, and rationale of the re-use use of molecule melatonin, which is yet to be recognized.

Trimethoxy Crown Chalcones as Multifunctional Class of Monoamine Oxidase Enzyme Inhibitors

Background: Chalcones with methoxy substituents are considered as a promising framework for the inhibition of monoamine oxidase (MAO) enzymes. Methods: A series of nine trimethoxy substituted chalcones (TMa-TMi) was synthesized and evaluated as a multifunctional class of MAO inhibitors. All the synthesized compounds were investigated for their in vitro MAO inhibition, kinetics, reversibility, blood-brain barrier (BBB) permeation, and cytotoxicity and antioxidant potentials. Results: In the present study, compound (2E)-3-(4-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (TMf) was provided with an MAO-A inhibition constant value equal to 3.47±0.09 μM and with a selectivity of 0.008. Thus, it was comparable to that of moclobemide, a well known potent hMAO-A inhibitor (SI=0.010). Compound (2E)-3-(4-bromophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (TMh) showed good MAO-B inhibition, with an inhibition constant of 0.46±0.009 μM. The PAMPA assay demonstrated that all the synthesized derivatives can cross the BBB successfully. The cytotoxicity studies revealed that TMf and TMh have 88.22 and 80.18 % cell viability at 25 µM. Compound TMf appeared as the most promising antioxidant molecule with IC50 values, relative to DPPH and H2O2 radical activities, equal to 6.02±0.17 and 7.25±0.07 μM. To shed light on the molecular interactions of TMf and TMh towards MAO-A and MAO-B, molecular docking simulations and MM/GBSA calculations have been carried out. Conclusion: The lead molecules TMf and TMh with multi-functional nature can be further employed for the treatment of various neurodegenerative disorders and depressive states.

Fisetin Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells via the Inhibition of YAP

Mesenchymal stem cells (MSCs) are self-renewal and capable of differentiating to various functional cell types, including osteocytes, adipocytes, myoblasts, and chondrocytes. They are, therefore, regarded as a potential source for stem cell therapy. Fisetin is a bioactive flavonoid known as an active antioxidant molecule that has been reported to inhibit cell growth in various cell types. Fisetin was shown to play a role in regulating osteogenic differentiation in animal-derived MSCs; however, its molecular mechanism is not well understood. We, therefore, studied the effect of fisetin on the biological properties of human MSCs derived from chorion tissue and its role in human osteogenesis using MSCs and osteoblast-like cells (SaOs-2) as a model. We found that fisetin inhibited proliferation, migration, and osteogenic differentiation of MSCs as well as human SaOs-2 cells. Fisetin could reduce Yes-associated protein (YAP) activity, which results in downregulation of osteogenic genes and upregulation of fibroblast genes. Further analysis using molecular docking and molecular dynamics simulations suggests that fisetin occupied the hydrophobic TEAD pocket preventing YAP from associating with TEA domain (TEAD). This finding supports the potential application of flavonoids like fisetin as a protein–protein interaction disruptor and also suggesting an implication of fisetin in regulating human osteogenesis.

Thioredoxin 1 (TRX1) Overexpression Cancels the Slow Force Response (SFR) Development

The stretch of cardiac muscle increases developed force in two phases. The first phase occurs immediately after stretch and is the expression of the Frank–Starling mechanism, while the second one or slow force response (SFR) occurs gradually and is due to an increase in the calcium transient amplitude. An important step in the chain of events leading to the SFR generation is the increased production of reactive oxygen species (ROS) leading to redox sensitive ERK1/2, p90RSK, and NHE1 phosphorylation/activation. Conversely, suppression of ROS production blunts the SFR. The purpose of this study was to explore whether overexpression of the ubiquitously expressed antioxidant molecule thioredoxin-1 (TRX1) affects the SFR development and NHE1 phosphorylation. We did not detect any change in basal phopho-ERK1/2, phopho-p90RSK, and NHE1 expression in mice with TRX1 overexpression compared to wild type (WT). Isolated papillary muscles from WT or TRX1-overexpressing mice were stretched from 92 to 98% of its maximal length. A prominent SFR was observed in WT mice that was completely canceled in TRX1 animals. Interestingly, myocardial stretch induced a significant increase in NHE1 phosphorylation in WT mice that was not detected in TRX1-overexpressing mice. These novel results suggest that magnification of cardiac antioxidant defense power by overexpression of TRX1 precludes NHE1 phosphorylation/activation after stretch, consequently blunting the SFR development.

Alpha Lipoic Acid as a Potential Treatment for COVID-19 - A Hypothesis

SARS-CoV-2 infection has led to COVID-19 outbreak worldwide. To date, a specific antiviral drug does not exist to treat the disease and control the virus. In this paper, we have explored the potential utility of alpha lipoic acid, an anti-inflammatory and antioxidant molecule, for treatment. Alpha lipoic acid exhibits strong antioxidant properties and modulates the immune system by regulating T cell activation making it a useful therapeutic candidate for cytokine storm triggering SARS-CoV-2 infection. In the present communication, we focused on the therapeutic potential of ALA with respect to its potential role on reducing the severity of symptoms and the adverse effects of other antiviral drugs used. We consider different mechanisms by which modulating ACE2 levels after virus replication and preventing cytokine storm and also focus on a new therapeutic venue that utilizes ALA.

Molecular Mechanism and Role of Translational Values of Heat Shock Protein (HSP27) in Various Disease

HSP27, also known as HSPB1, was first discovered with a molecular weight 27kDa belonging to the four member gene family. Elevated levels of HSP27 are seen when different unfavorable conditions prevail such as increase in temperature and oxidative stress or exposure to heavy metals or organic solvents. They possess ATP-independent chaperone like activity which helps in maintaining protein homeostasis. It can also form large oligomers (300-600 kDa) containing different numbers of subunits. It is composed of total 205 amino acids. HSP27 undergoes post-translational modifications i.e. phosphorylation thereby converting large oligomers into dimers. It can act as an anti-apoptotic and antioxidant molecule during oxidative stress. The elevated form of HSP27 is also seen in some cancer belongs to breast, ovary, prostate, brain, colorectal, hepatocellular carcinoma, lung, liver, and cervical regions. Keeping in view of molecular roles of HSP27 signaling in various pathways, we have proposed their translational values in different diseases. In addition, we have also reported the existing scientific data on the HSP27 as the potential cancer biomarker and their therapeutic targets for improved prognosis and treatment in different diseases.

Corticohippocampal Neuroenergetics and histomorphology in aluminium-induced neurotoxicity: Putative therapeutic roles of ascorbic acid and nicotine

Alzheimer’s disease (AD) is the most common cause of dementia and is hallmarked by β-amyloid plaque and neurofibrillary tangles deposition in the central nervous system. The complex mechanism that underlies AD pathogenesis has made the development of a definitive cure futile. Exploring the possible therapeutic advantages of combining two neuromodulatory molecules with different mechanisms of neuroprotection is an interesting way of drug discovery. Ascorbic acid (AA), a potent antioxidant molecule, and nicotine (NIC), an allosteric modulator of nAChRs, have both been documented to independently proffer neuroprotection in experimental and clinical neurodegenerative cases. This study elucidated the putative therapeutic advantages of combining ascorbic acid and nicotine as a treatment regimen against the aluminium-induced Alzheimer-like corticohippocampal histopathology, anxiety, and perturbed neuroenergetics in rats induced withRats treated with 100 mg/kg aluminium chloride for 28 days presented with significantly increased stretch attend posture frequency and centre square entry. Aluminium significantly depleted the activities of glucose-6-phosphate dehydrogenase (G6PDH) while increasing lactate levels. Corticohippocampal histomorphology of these animals showed poor histoarchitecture, increased congophilic and argentophilic densities that were coupled with increased anti-NSE immunopositivity. Animals post-treated with NIC (10mg/kg) and AA (100mg/kg) for 28 days presented with reduced anxiety level and improved corticohippocampal histomorphology. AA normalized G6PDH and lactate levels while the congophilic density was reduced by NIC. Corticohippocampal argentophilic density anti-NSE immunopositivity were also normalized by AA+NIC.The findings from this study have shown that a combination of ascorbic acid and nicotine effectively mitigated aluminium-induced corticohippocampal histopathology and perturbed neuroenergetics.