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1.
Int J Mol Sci ; 23(1)2021 Dec 21.
Article in English | MEDLINE | ID: covidwho-1580702

ABSTRACT

Right ventricular (RV) and left ventricular (LV) dysfunction is common in a significant number of hospitalized coronavirus disease 2019 (COVID-19) patients. This study was conducted to assess whether the improved mitochondrial bioenergetics by cardiometabolic drug meldonium can attenuate the development of ventricular dysfunction in experimental RV and LV dysfunction models, which resemble ventricular dysfunction in COVID-19 patients. Effects of meldonium were assessed in rats with pulmonary hypertension-induced RV failure and in mice with inflammation-induced LV dysfunction. Rats with RV failure showed decreased RV fractional area change (RVFAC) and hypertrophy. Treatment with meldonium attenuated the development of RV hypertrophy and increased RVFAC by 50%. Mice with inflammation-induced LV dysfunction had decreased LV ejection fraction (LVEF) by 30%. Treatment with meldonium prevented the decrease in LVEF. A decrease in the mitochondrial fatty acid oxidation with a concomitant increase in pyruvate metabolism was noted in the cardiac fibers of the rats and mice with RV and LV failure, respectively. Meldonium treatment in both models restored mitochondrial bioenergetics. The results show that meldonium treatment prevents the development of RV and LV systolic dysfunction by enhancing mitochondrial function in experimental models of ventricular dysfunction that resembles cardiovascular complications in COVID-19 patients.


Subject(s)
Cardiotonic Agents/pharmacology , Methylhydrazines/pharmacology , Animals , COVID-19/complications , COVID-19/drug therapy , Cardiotonic Agents/therapeutic use , Cardiotoxicity/drug therapy , Disease Models, Animal , Endothelium/drug effects , Heart Failure/drug therapy , Heart Failure/metabolism , Heart Ventricles/drug effects , Hydrogen Peroxide/metabolism , Lung/drug effects , Male , Methylhydrazines/therapeutic use , Mice, Inbred C57BL , Mitochondria/drug effects , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Reperfusion Injury/drug therapy , Stroke Volume/drug effects , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Right/drug therapy
2.
J Enzyme Inhib Med Chem ; 36(1): 659-668, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1109085

ABSTRACT

Human intestinal epithelial cell line-6 (HIEC-6) cells and primary human hepatocytes (PHHs) were treated with 3-amidinophenylalanine-derived inhibitors of trypsin-like serine proteases for 24 hours. It was proven that treatment with MI-1900 and MI-1907 was tolerated up to 50 µM in HIEC-6. These inhibitors did not cause elevations in extracellular H2O2 levels and in the concentrations of interleukin (IL)-6 and IL-8 and did not alter occludin distribution in HIEC-6. It was also found that MI-1900 and MI-1907 up to 50 µM did not affect cell viability, IL-6 and IL-8 and occludin levels of PHH. Based on our findings, these inhibitors could be safely applicable at 50 µM in HIEC-6 and in PHH; however, redox status was disturbed in case of PHH. Moreover, it has recently been demonstrated that MI-1900 prevents the replication and spread of the new SARS-CoV-2 in infected Calu-3 cells, most-likely via an inhibition of the membrane-bound host protease TMPRSS2.


Subject(s)
Antiviral Agents/pharmacology , Epithelial Cells/drug effects , Hepatocytes/drug effects , Phenylalanine/pharmacology , Protease Inhibitors/pharmacology , Serine Endopeptidases/metabolism , Cell Line , Cell Survival/drug effects , Epithelial Cells/cytology , Epithelial Cells/enzymology , Gene Expression Regulation/drug effects , Hepatocytes/cytology , Hepatocytes/enzymology , Humans , Hydrogen Peroxide/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , Intestinal Mucosa/cytology , Intestinal Mucosa/drug effects , Intestinal Mucosa/enzymology , Occludin/genetics , Occludin/metabolism , Oxidation-Reduction/drug effects , Phenylalanine/analogs & derivatives , Primary Cell Culture , Serine Endopeptidases/genetics
3.
Free Radic Biol Med ; 165: 184-190, 2021 03.
Article in English | MEDLINE | ID: covidwho-1056615

ABSTRACT

Several recent reviews have suggested a role of oxidative stress in the pathophysiology of COVID-19, but its interplay with disease severity has not been revealed yet. In the present study, we aimed to investigate the association between the severity of COVID-19 and oxidative stress parameters. Clinical data of 77 patients with COVID-19 admitted to the hospital were analyzed and divided into moderate (n = 44) and severe (n = 33) groups based on their clinical condition. Production of oxidant (hydrogen peroxide) and defense antioxidants (total antioxidant capacity, reduced and oxidized glutathione, glutathione s-transferase), and oxidative damage (malondialdehyde, carbonyl, and sulfhydryl) were assessed using the serum samples. The results revealed that severe patients who presented high serum leukocyte count and CRP level stayed for a longer period in the hospital. However, there was no correlation observed between the oxidative stress parameters and degree of COVID-19 severity in the present study. In conclusion, these results indicate that the disease severity may not be a detrimental factor contributing to the changes in the redox profile of hospitalized patients with COVID-19.


Subject(s)
COVID-19/metabolism , Oxidative Stress/physiology , SARS-CoV-2/physiology , Adult , Aged , Brazil/epidemiology , COVID-19/epidemiology , Cohort Studies , Disease Progression , Disease Susceptibility , Female , Glutathione/metabolism , Glutathione Transferase/metabolism , Humans , Hydrogen Peroxide/metabolism , Male , Middle Aged , Prospective Studies
4.
Adv Mater ; 33(8): e2005477, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1039151

ABSTRACT

Besides the pandemic caused by the coronavirus outbreak, many other pathogenic microbes also pose a devastating threat to human health, for instance, pathogenic bacteria. Due to the lack of broad-spectrum antibiotics, it is urgent to develop nonantibiotic strategies to fight bacteria. Herein, inspired by the localized "capture and killing" action of bacteriophages, a virus-like peroxidase-mimic (V-POD-M) is synthesized for efficient bacterial capture (mesoporous spiky structures) and synergistic catalytic sterilization (metal-organic-framework-derived catalytic core). Experimental and theoretical calculations show that the active compound, MoO3 , can serve as a peroxo-complex-intermediate to reduce the free energy for catalyzing H2 O2 , which mainly benefits the generation of •OH radicals. The unique virus-like spikes endow the V-POD-M with fast bacterial capture and killing abilities (nearly 100% at 16 µg mL-1 ). Furthermore, the in vivo experiments show that V-POD-M possesses similar disinfection treatment and wound skin recovery efficiencies to vancomycin. It is suggested that this inexpensive, durable, and highly reactive oxygen species (ROS) catalytic active V-POD-M provides a promising broad-spectrum therapy for nonantibiotic disinfection.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Biomimetic Materials/chemical synthesis , Oxides/chemical synthesis , Peroxidase/chemistry , Anti-Bacterial Agents/pharmacology , Biocompatible Materials/chemistry , Biomimetic Materials/pharmacology , Catalysis , Humans , Hydrogen Peroxide/metabolism , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Molecular Dynamics Simulation , Molybdenum/pharmacology , Oxides/pharmacology , Peroxidase/metabolism , Sterilization , Vancomycin/pharmacology
5.
J Biol Chem ; 295(39): 13458-13473, 2020 09 25.
Article in English | MEDLINE | ID: covidwho-1023994

ABSTRACT

My interest in biological chemistry proceeded from enzymology in vitro to the study of physiological chemistry in vivo Investigating biological redox reactions, I identified hydrogen peroxide (H2O2) as a normal constituent of aerobic life in eukaryotic cells. This finding led to developments that recognized the essential role of H2O2 in metabolic redox control. Further research included studies on GSH, toxicological aspects (the concept of "redox cycling"), biochemical pharmacology (ebselen), nutritional biochemistry and micronutrients (selenium, carotenoids, flavonoids), and the concept of "oxidative stress." Today, we recognize that oxidative stress is two-sided. It has its positive side in physiology and health in redox signaling, "oxidative eustress," whereas at higher intensity, there is damage to biomolecules with potentially deleterious outcome in pathophysiology and disease, "oxidative distress." Reflecting on these developments, it is gratifying to witness the enormous progress in redox biology brought about by the science community in recent years.


Subject(s)
Hydrogen Peroxide/metabolism , Glutathione/metabolism , Humans , Oxidation-Reduction , Oxidative Stress
6.
Cells ; 9(6)2020 06 13.
Article in English | MEDLINE | ID: covidwho-603067

ABSTRACT

There is no vaccine or specific antiviral treatment for COVID-19, which is causing a global pandemic. One current focus is drug repurposing research, but those drugs have limited therapeutic efficacies and known adverse effects. The pathology of COVID-19 is essentially unknown. Without this understanding, it is challenging to discover a successful treatment to be approved for clinical use. This paper addresses several key biological processes of reactive oxygen, halogen and nitrogen species (ROS, RHS and RNS) that play crucial physiological roles in organisms from plants to humans. These include why superoxide dismutases, the enzymes to catalyze the formation of H2O2, are required for protecting ROS-induced injury in cell metabolism, why the amount of ROS/RNS produced by ionizing radiation at clinically relevant doses is ~1000 fold lower than the endogenous ROS/RNS level routinely produced in the cell and why a low level of endogenous RHS plays a crucial role in phagocytosis for immune defense. Herein we propose a plausible amplification mechanism in immune defense: ozone-depleting-like halogen cyclic reactions enhancing RHS effects are responsible for all the mentioned physiological functions, which are activated by H2O2 and deactivated by NO signaling molecule. Our results show that the reaction cycles can be repeated thousands of times and amplify the RHS pathogen-killing (defense) effects by 100,000 fold in phagocytosis, resembling the cyclic ozone-depleting reactions in the stratosphere. It is unraveled that H2O2 is a required protective signaling molecule (angel) in the defense system for human health and its dysfunction can cause many diseases or conditions such as autoimmune disorders, aging and cancer. We also identify a class of potent drugs for effective treatment of invading pathogens such as HIV and SARS-CoV-2 (COVID-19), cancer and other diseases, and provide a molecular mechanism of action of the drugs or candidates.


Subject(s)
Antiviral Agents/chemistry , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Heterocyclic Compounds/therapeutic use , Hydrocarbons, Halogenated/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Animals , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus Infections/metabolism , Humans , Hydrogen Peroxide/metabolism , Lysosomes/drug effects , Pandemics , Phagocytosis , Pneumonia, Viral/metabolism , Respiratory Burst/drug effects , Signal Transduction
7.
Med Hypotheses ; 144: 109999, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-598567

ABSTRACT

The majority of fatalities thus far in the COVID-19 pandemic have been attributed to pneumonia. As expected, the fatality rate reported in China is higher in people with chronic pulmonary disease (6.3%) and those who have cancer (5.6%). According to the American College of Cardiology Clinical Bulletin "COVID-19 Clinical Guidance for the CV Care Team", there is a significantly higher fatality rate in people who are elderly (8.0% 70-79 years; 14.8% ≥80 years), diabetic (7.3%), hypertensive (6.0%), or have known cardiovascular disease (CVD) (10.5%). We propose a biological reason for the higher mortality risk in these populations that is apparent. We further present a set of pathophysiological reasons for the heightened danger that could lead to therapies for enhanced management and prevention.


Subject(s)
COVID-19/epidemiology , Immunity, Innate , Pandemics , Adult , Aging/immunology , COVID-19/etiology , COVID-19/immunology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/immunology , Child , Diabetes Mellitus/epidemiology , Diabetes Mellitus/immunology , Disease Susceptibility , Humans , Hydrogen Peroxide/metabolism , Hypertension/epidemiology , Hypertension/immunology , Hypochlorous Acid/metabolism , Lung/blood supply , Lung/immunology , Microcirculation , Microvessels/physiopathology , Neutrophils/immunology , Neutrophils/metabolism , Peroxidase/metabolism , Risk Factors , United States/epidemiology
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