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1.
Aging Cell ; 21(4): e13575, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1788808

ABSTRACT

Dopamine (DA) signaling via G protein-coupled receptors is a multifunctional neurotransmitter and neuroendocrine-immune modulator. The DA nigrostriatal pathway, which controls the motor coordination, progressively degenerates in Parkinson's disease (PD), a most common neurodegenerative disorder (ND) characterized by a selective, age-dependent loss of substantia nigra pars compacta (SNpc) neurons, where DA itself is a primary source of oxidative stress and mitochondrial impairment, intersecting astrocyte and microglial inflammatory networks. Importantly, glia acts as a preferential neuroendocrine-immune DA target, in turn, counter-modulating inflammatory processes. With a major focus on DA intersection within the astrocyte-microglial inflammatory network in PD vulnerability, we herein first summarize the characteristics of DA signaling systems, the propensity of DA neurons to oxidative stress, and glial inflammatory triggers dictating the vulnerability to PD. Reciprocally, DA modulation of astrocytes and microglial reactivity, coupled to the synergic impact of gene-environment interactions, then constitute a further level of control regulating midbrain DA neuron (mDAn) survival/death. Not surprisingly, within this circuitry, DA converges to modulate nuclear factor erythroid 2-like 2 (Nrf2), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless (Wnt)/ß-catenin signaling, a key pathway for mDAn neurogenesis, neuroprotection, and immunomodulation, adding to the already complex "signaling puzzle," a novel actor in mDAn-glial regulatory machinery. Here, we propose an autoregulatory feedback system allowing DA to act as an endogenous Nrf2/Wnt innate modulator and trace the importance of DA receptor agonists applied to the clinic as immune modifiers.


Subject(s)
Dopamine , Parkinson Disease , Aged , Brain/metabolism , Dopamine/metabolism , Dopaminergic Neurons/metabolism , GA-Binding Protein Transcription Factor , Humans , NF-E2-Related Factor 2/metabolism , Neuroglia/metabolism , Parkinson Disease/metabolism
2.
J Cell Mol Med ; 26(7): 1979-1993, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1774827

ABSTRACT

Acute kidney injury (AKI) is a substantial worldwide public health concern with no specific and effective therapies in clinic. NAD+ is a pivotal determinant of cellular energy metabolism involved in the progression of AKI; however, its mechanism in kidney injury remains poorly understood. Sirtuin 1 (SIRT1) is an NAD+ -dependent deacetylase associated with renal protection and acute stress resistance. In this study, we have investigated the role of NAD+ in AKI and the potential mechanism(s) involved in its renoprotective effect. NAD+ was notably decreased and negatively correlated with kidney dysfunction in AKI, restoring NAD+ with NMN significantly ameliorates LPS-induced oxidative stress and apoptosis and attenuates renal damage. We also found that the protection of NAD+ is associated with SIRT1 expressions and performs in a SIRT1-dependent manner. Inhibition of SIRT1 blunted the protective effect of NAD+ and up-regulated the activity of glycogen synthase kinase-3ß (GSK-3ß) that was concomitant with mitigated Nrf2 nuclear accumulation, thereby exacerbates AKI. These findings suggest that NAD+ /SIRT1/GSK-3ß/Nrf2 axis is an important mechanism that can protect against AKI which might be a potential therapeutic target for the treatment of AKI.


Subject(s)
Acute Kidney Injury , Glycogen Synthase Kinase 3 beta , NAD , NF-E2-Related Factor 2 , Sirtuin 1 , Acute Kidney Injury/metabolism , Endotoxins , Glycogen Synthase Kinase 3 beta/metabolism , Humans , NAD/metabolism , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Sirtuin 1/genetics , Sirtuin 1/metabolism
3.
Int J Mol Sci ; 23(4)2022 Feb 17.
Article in English | MEDLINE | ID: covidwho-1701976

ABSTRACT

Selenium has been extensively evaluated clinically as a chemopreventive agent with variable results depending on the type and dose of selenium used. Selenium species are now being therapeutically evaluated as modulators of drug responses rather than as directly cytotoxic agents. In addition, recent data suggest an association between selenium base-line levels in blood and survival of patients with COVID-19. The major focus of this mini review was to summarize: the pathways of selenium metabolism; the results of selenium-based chemopreventive clinical trials; the potential for using selenium metabolites as therapeutic modulators of drug responses in cancer (clear-cell renal-cell carcinoma (ccRCC) in particular); and selenium usage alone or in combination with vaccines in the treatment of patients with COVID-19. Critical therapeutic targets and the potential role of different selenium species, doses, and schedules are discussed.


Subject(s)
COVID-19/drug therapy , Neoplasms/drug therapy , Selenium/therapeutic use , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , COVID-19/virology , DNA Repair/drug effects , Drug Resistance, Neoplasm/drug effects , Humans , NF-E2-Related Factor 2/chemistry , NF-E2-Related Factor 2/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Selenium/chemistry , Selenium/metabolism , Selenium/pharmacology
4.
Int J Mol Sci ; 22(16)2021 Aug 05.
Article in English | MEDLINE | ID: covidwho-1662662

ABSTRACT

Nuclear factor erythroid 2-related factor (Nrf2) is a transcriptional activator of the cell protection gene that binds to the antioxidant response element (ARE). Therefore, Nrf2 protects cells and tissues from oxidative stress. Normally, Kelch-like ECH-associated protein 1 (Keap1) inhibits the activation of Nrf2 by binding to Nrf2 and contributes to Nrf2 break down by ubiquitin proteasomes. In moderate oxidative stress, Keap1 is inhibited, allowing Nrf2 to be translocated to the nucleus, which acts as an antioxidant. However, under unusually severe oxidative stress, the Keap1-Nrf2 mechanism becomes disrupted and results in cell and tissue damage. Oxide-containing atmospheric environment generally contributes to the development of respiratory diseases, possibly leading to the failure of the Keap1-Nrf2 pathway. Until now, several studies have identified changes in Keap1-Nrf2 signaling in models of respiratory diseases, such as acute respiratory distress syndrome (ARDS)/acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and asthma. These studies have confirmed that several Nrf2 activators can alleviate symptoms of respiratory diseases. Thus, this review describes how the expression of Keap1-Nrf2 functions in different respiratory diseases and explains the protective effects of reversing this expression.


Subject(s)
NF-E2-Related Factor 2/metabolism , Respiratory Tract Diseases/metabolism , Animals , Antioxidants/metabolism , Humans , Oxidative Stress/physiology , Signal Transduction/physiology
5.
ChemMedChem ; 17(5): e202100732, 2022 03 04.
Article in English | MEDLINE | ID: covidwho-1661603

ABSTRACT

Naturally occurring compounds represent a vast pool of pharmacologically active entities. One of such compounds is andrographolide, which is endowed with many beneficial properties, including the activity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). To initiate a drug repurposing or hit optimization campaign, it is imperative to unravel the primary mechanism(s) of the antiviral action of andrographolide. Here, we showed by means of a reporter gene assay that andrographolide exerts its anti-SARS-CoV-2 effects by inhibiting the interaction between Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2-related factor 2 (NRF2) causing NRF2 upregulation. Moreover, we demonstrated that subtle structural modifications of andrographolide could lead to derivatives with stronger on-target activities and improved physicochemical properties. Our results indicate that further optimization of this structural class is warranted to develop novel COVID-19 therapies.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Diterpenes/chemistry , SARS-CoV-2/drug effects , Animals , COVID-19/drug therapy , COVID-19/virology , Cell Line , Chlorocebus aethiops , Humans , Kelch-Like ECH-Associated Protein 1/metabolism , Molecular Docking Simulation , Molecular Structure , NF-E2-Related Factor 2/metabolism , SARS-CoV-2/physiology , Vero Cells , Virus Replication
7.
Inflammopharmacology ; 29(5): 1347-1355, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1557643

ABSTRACT

The natural pathway of antioxidant production is mediated through Kelch-like erythroid cell-derived protein with Cap and collar homology [ECH]-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2) system. Keap1 maintains a low level of Nrf2 by holding it in its protein complex. Also, Keap1 facilitates the degradation of Nrf2 by ubiquitination. In other words, Keap1 is a down-regulator of Nrf2. To boost the production of biological antioxidants, Keap1 has to be inhibited and Nrf2 has to be released. Liberated Nrf2 is in an unbound state, so it travels to the nucleus to stimulate the antioxidant response element (ARE) present on the antioxidant genes. AREs activate biosynthesis of biological antioxidants through genes responsible for the production of antioxidants. In some cases of coronavirus disease 2019 (COVID-19), there is an enormous release of cytokines. The antioxidant defense mechanism in the body helps in counteracting symptoms induced by the cytokine storm in COVID-19. So, boosting the production of antioxidants is highly desirable in such a condition. In this review article, we have compiled the role of Keap1-Nrf2 system in antioxidant production. We further propose its potential therapeutic use in managing cytokine storm in COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/therapy , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/therapy , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Antioxidants/therapeutic use , Disease Management , Humans , Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors , NF-E2-Related Factor 2/agonists , Oxidative Stress/drug effects , Oxidative Stress/physiology
8.
Clin Immunol ; 233: 108879, 2021 12.
Article in English | MEDLINE | ID: covidwho-1527619

ABSTRACT

COVID-19 is a pandemic requiring immediate solution for treatment because of its complex pathophysiology. Exploration of novel targets and thus treatment will be life savers which is the need of the hour. 2 host factors- TMPRSS2 and ACE2 are responsible for the way the virus will enter and replicate in the host. Also NRF2 is an important protein responsible for its anti-inflammatory role by multiple mechanisms of action like inhibition of NF-kB, suppression of pro-inflammatory genes, etc. NRF2 is deacetylated by Sirtuins and therefore both have a direct association. Absence of SIRT indicates inhibition of NRF2 expression and thus no anti-oxidative and anti-inflammatory protection for the cell. Therefore, we propose that NRF2 activators and/or SIRT activators can be evaluated to check their efficacy in ameliorating the symptoms of COVID-19.


Subject(s)
COVID-19/immunology , NF-E2-Related Factor 2/immunology , SARS-CoV-2/immunology , Sirtuins/immunology , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , COVID-19/virology , Host-Pathogen Interactions/immunology , Humans , NF-E2-Related Factor 2/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/immunology , Serine Endopeptidases/metabolism , Sirtuins/metabolism , Virus Attachment
9.
Mech Ageing Dev ; 199: 111551, 2021 10.
Article in English | MEDLINE | ID: covidwho-1492370

ABSTRACT

Polyphenols are chemopreventive through the induction of nuclear factor erythroid 2 related factor 2 (Nrf2)-mediated proteins and anti-inflammatory pathways. These pathways, encoding cytoprotective vitagenes, include heat shock proteins, such as heat shock protein 70 (Hsp70) and heme oxygenase-1 (HO-1), as well as glutathione redox system to protect against cancer initiation and progression. Phytochemicals exhibit biphasic dose responses on cancer cells, activating at low dose, signaling pathways resulting in upregulation of vitagenes, as in the case of the Nrf2 pathway upregulated by hydroxytyrosol (HT) or curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Here, the importance of vitagenes in redox stress response and autophagy mechanisms, as well as the potential use of dietary antioxidants in the prevention and treatment of multiple types of cancer are discussed. We also discuss the possible relationship between SARS-CoV-2, inflammation and cancer, exploiting innovative therapeutic approaches with HT-rich aqueous olive pulp extract (Hidrox®), a natural polyphenolic formulation, as well as the rationale of Vitamin D supplementation. Finally, we describe innovative approaches with organoids technology to study human carcinogenesis in preclinical models from basic cancer research to clinical practice, suggesting patient-derived organoids as an innovative tool to test drug toxicity and drive personalized therapy.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Drug Development , NF-E2-Related Factor 2/metabolism , Organoids/drug effects , Oxidative Stress/drug effects , Polyphenols/pharmacology , Vitamin D/pharmacology , Animals , Antineoplastic Agents, Phytogenic/pharmacology , COVID-19/drug therapy , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Humans , NF-E2-Related Factor 2/genetics , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Organoids/metabolism , Oxidation-Reduction , Oxidative Stress/genetics
10.
Life Sci ; 291: 120111, 2022 Feb 15.
Article in English | MEDLINE | ID: covidwho-1487890

ABSTRACT

The Nrf2 transcription factor governs the expression of hundreds genes involved in cell defense against oxidative stress, the hallmark of numerous diseases such as neurodegenerative, cardiovascular, some viral pathologies, diabetes and others. The main route for Nrf2 activity regulation is via interactions with the Keap1 protein. Under the normoxia the Keap1 binds the Nrf2 and targets it to the proteasomal degradation, while the Keap1 is regenerated. Upon oxidative stress the interactions between Nrf2 and Keap1 are interrupted and the Nrf2 activates the transcription of the protective genes. Currently, the Nrf2 system activation is considered as a powerful cytoprotective strategy for treatment of different pathologies, which pathogenesis relies on oxidative stress including viral diseases of pivotal importance such as COVID-19. The implementation of this strategy is accomplished mainly through the inactivation of the Keap1 "guardian" function. Two approaches are now developing: the Keap1 modification via electrophilic agents, which leads to the Nrf2 release, and direct interruption of the Nrf2:Keap1 protein-protein interactions (PPI). Because of theirs chemical structure, the Nrf2 electrophilic inducers could non-specifically interact with others cellular proteins leading to undesired effects. Whereas the non-electrophilic inhibitors of the Nrf2:Keap1 PPI could be more specific, thereby widening the therapeutic window.


Subject(s)
Antioxidant Response Elements/physiology , Kelch-Like ECH-Associated Protein 1/metabolism , Molecular Targeted Therapy/methods , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/drug therapy , COVID-19/metabolism , Host-Pathogen Interactions/physiology , Humans , Ozone/therapeutic use , Protein Interaction Maps/drug effects , Signal Transduction
11.
Oxid Med Cell Longev ; 2021: 5513868, 2021.
Article in English | MEDLINE | ID: covidwho-1467753

ABSTRACT

COVID-19 is a widespread global pandemic with nearly 185 million confirmed cases and about four million deaths. It is caused by an infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which primarily affects the alveolar type II pneumocytes. The infection induces pathological responses including increased inflammation, oxidative stress, and apoptosis. This situation results in impaired gas exchange, hypoxia, and other sequelae that lead to multisystem organ failure and death. As summarized in this article, many interventions and therapeutics have been proposed and investigated to combat the viral infection-induced inflammation and oxidative stress that contributes to the etiology and pathogenesis of COVID-19. However, these methods have not significantly improved treatment outcomes. This may partly be attributable to their inability at restoring redox and inflammatory homeostasis, for which molecular hydrogen (H2), an emerging novel medical gas, may complement. Herein, we systematically review the antioxidative, anti-inflammatory, and antiapoptotic mechanisms of H2. Its small molecular size and nonpolarity allow H2 to rapidly diffuse through cell membranes and penetrate cellular organelles. H2 has been demonstrated to suppress NF-κB inflammatory signaling and induce the Nrf2/Keap1 antioxidant pathway, as well as to improve mitochondrial function and enhance cellular bioenergetics. Many preclinical and clinical studies have demonstrated the beneficial effects of H2 in varying diseases, including COVID-19. However, the exact mechanisms, primary modes of action, and its true clinical effects remain to be delineated and verified. Accordingly, additional mechanistic and clinical research into this novel medical gas to combat COVID-19 complications is warranted.


Subject(s)
COVID-19 , Hydrogen/therapeutic use , Oxidative Stress/drug effects , SARS-CoV-2/metabolism , Signal Transduction/drug effects , COVID-19/drug therapy , COVID-19/metabolism , Humans , Inflammation/drug therapy , Inflammation/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism
12.
Signal Transduct Target Ther ; 5(1): 218, 2020 10 03.
Article in English | MEDLINE | ID: covidwho-1387198

Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Cardiac Glycosides/pharmacology , Gene Expression Regulation/drug effects , Host-Pathogen Interactions/drug effects , Animals , Antiviral Agents/chemistry , Betacoronavirus/pathogenicity , Biological Products/chemistry , Biological Products/pharmacology , Bufanolides/chemistry , Bufanolides/pharmacology , COVID-19 , Cardiac Glycosides/chemistry , Cell Survival/drug effects , Chlorocebus aethiops , Chloroquine/chemistry , Chloroquine/pharmacology , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Digoxin/chemistry , Digoxin/pharmacology , High-Throughput Screening Assays , Host-Pathogen Interactions/genetics , Humans , Janus Kinases/antagonists & inhibitors , Janus Kinases/genetics , Janus Kinases/metabolism , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism , NF-E2-Related Factor 2/antagonists & inhibitors , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , NF-kappa B/metabolism , Pandemics , Phenanthrenes/chemistry , Phenanthrenes/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2 , Signal Transduction , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/genetics , Sodium-Potassium-Exchanging ATPase/metabolism , Vero Cells , Virus Replication/drug effects
13.
Inflammopharmacology ; 29(5): 1347-1355, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1349298

ABSTRACT

The natural pathway of antioxidant production is mediated through Kelch-like erythroid cell-derived protein with Cap and collar homology [ECH]-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2) system. Keap1 maintains a low level of Nrf2 by holding it in its protein complex. Also, Keap1 facilitates the degradation of Nrf2 by ubiquitination. In other words, Keap1 is a down-regulator of Nrf2. To boost the production of biological antioxidants, Keap1 has to be inhibited and Nrf2 has to be released. Liberated Nrf2 is in an unbound state, so it travels to the nucleus to stimulate the antioxidant response element (ARE) present on the antioxidant genes. AREs activate biosynthesis of biological antioxidants through genes responsible for the production of antioxidants. In some cases of coronavirus disease 2019 (COVID-19), there is an enormous release of cytokines. The antioxidant defense mechanism in the body helps in counteracting symptoms induced by the cytokine storm in COVID-19. So, boosting the production of antioxidants is highly desirable in such a condition. In this review article, we have compiled the role of Keap1-Nrf2 system in antioxidant production. We further propose its potential therapeutic use in managing cytokine storm in COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/therapy , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/therapy , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Antioxidants/therapeutic use , Disease Management , Humans , Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors , NF-E2-Related Factor 2/agonists , Oxidative Stress/drug effects , Oxidative Stress/physiology
14.
Int J Mol Sci ; 22(15)2021 Jul 26.
Article in English | MEDLINE | ID: covidwho-1325685

ABSTRACT

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known transcription factor best recognised as one of the main regulators of the oxidative stress response. Beyond playing a crucial role in cell defence by transactivating cytoprotective genes encoding antioxidant and detoxifying enzymes, Nrf2 is also implicated in a wide network regulating anti-inflammatory response and metabolic reprogramming. Such a broad spectrum of actions renders the factor a key regulator of cell fate and a strategic player in the control of cell transformation and response to viral infections. The Nrf2 protective roles in normal cells account for its anti-tumour and anti-viral functions. However, Nrf2 overstimulation often occurs in tumour cells and a complex correlation of Nrf2 with cancer initiation and progression has been widely described. Therefore, if on one hand, Nrf2 has a dual role in cancer, on the other hand, the factor seems to display a univocal function in preventing inflammation and cytokine storm that occur under viral infections, specifically in coronavirus disease 19 (COVID-19). In such a variegate context, the present review aims to dissect the roles of Nrf2 in both cancer and COVID-19, two widespread diseases that represent a cause of major concern today. In particular, the review describes the molecular aspects of Nrf2 signalling in both pathological situations and the most recent findings about the advantages of Nrf2 inhibition or activation as possible strategies for cancer and COVID-19 treatment respectively.


Subject(s)
COVID-19/metabolism , NF-E2-Related Factor 2/metabolism , Neoplasms/metabolism , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/metabolism , Antioxidants/chemistry , Antioxidants/metabolism , COVID-19/drug therapy , Humans , NF-E2-Related Factor 2/chemistry , Neoplasms/drug therapy , Signal Transduction
15.
Front Immunol ; 12: 653110, 2021.
Article in English | MEDLINE | ID: covidwho-1305643

ABSTRACT

To characterize transcriptomic changes in endothelial cells (ECs) infected by coronaviruses, and stimulated by DAMPs, the expressions of 1311 innate immune regulatomic genes (IGs) were examined in 28 EC microarray datasets with 7 monocyte datasets as controls. We made the following findings: The majority of IGs are upregulated in the first 12 hours post-infection (PI), and maintained until 48 hours PI in human microvascular EC infected by middle east respiratory syndrome-coronavirus (MERS-CoV) (an EC model for COVID-19). The expressions of IGs are modulated in 21 human EC transcriptomic datasets by various PAMPs/DAMPs, including LPS, LPC, shear stress, hyperlipidemia and oxLDL. Upregulation of many IGs such as nucleic acid sensors are shared between ECs infected by MERS-CoV and those stimulated by PAMPs and DAMPs. Human heart EC and mouse aortic EC express all four types of coronavirus receptors such as ANPEP, CEACAM1, ACE2, DPP4 and virus entry facilitator TMPRSS2 (heart EC); most of coronavirus replication-transcription protein complexes are expressed in HMEC, which contribute to viremia, thromboembolism, and cardiovascular comorbidities of COVID-19. ECs have novel trained immunity (TI), in which subsequent inflammation is enhanced. Upregulated proinflammatory cytokines such as TNFα, IL6, CSF1 and CSF3 and TI marker IL-32 as well as TI metabolic enzymes and epigenetic enzymes indicate TI function in HMEC infected by MERS-CoV, which may drive cytokine storms. Upregulated CSF1 and CSF3 demonstrate a novel function of ECs in promoting myelopoiesis. Mechanistically, the ER stress and ROS, together with decreased mitochondrial OXPHOS complexes, facilitate a proinflammatory response and TI. Additionally, an increase of the regulators of mitotic catastrophe cell death, apoptosis, ferroptosis, inflammasomes-driven pyroptosis in ECs infected with MERS-CoV and the upregulation of pro-thrombogenic factors increase thromboembolism potential. Finally, NRF2-suppressed ROS regulate innate immune responses, TI, thrombosis, EC inflammation and death. These transcriptomic results provide novel insights on the roles of ECs in coronavirus infections such as COVID-19, cardiovascular diseases (CVD), inflammation, transplantation, autoimmune disease and cancers.


Subject(s)
Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Endothelial Cells/physiology , Inflammation/immunology , Middle East Respiratory Syndrome Coronavirus/physiology , NF-E2-Related Factor 2/metabolism , SARS-CoV-2/physiology , Alarmins/immunology , Animals , Datasets as Topic , Endothelial Cells/virology , Gene Expression Profiling , Humans , Immunity, Innate , Immunization , Mice , Myelopoiesis , Oxidative Stress , Thromboembolism
16.
IUBMB Life ; 74(1): 24-28, 2022 01.
Article in English | MEDLINE | ID: covidwho-1296787

ABSTRACT

Research on oxidants and electrophiles has shifted from focusing on damage to biomolecules to the more fine-grained physiological arena. Redox transitions as excursions from a steady-state redox set point are continually ongoing in maintenance of redox balance. Current excitement on these topics results from the fact that recent research provided mechanistic insight, which gives rise to more concrete and differentiated questions. This Commentary focuses on redox eustress and the feedback restoration of steady state as concepts in active maintenance of physiological health, with brief discussion of redox stress response to viral infection, exemplified by COVID-19.


Subject(s)
COVID-19/metabolism , Homeostasis , Oxidation-Reduction , SARS-CoV-2 , COVID-19/immunology , Feedback, Physiological , Hormesis , Host Microbial Interactions/immunology , Host Microbial Interactions/physiology , Humans , Immunity, Innate , Models, Biological , NF-E2-Related Factor 2/metabolism , Oxidative Stress , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
17.
World J Gastroenterol ; 27(22): 2944-2962, 2021 Jun 14.
Article in English | MEDLINE | ID: covidwho-1268364

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 is a global pandemic and poses a major threat to human health worldwide. In addition to respiratory symptoms, COVID-19 is usually accompanied by systemic inflammation and liver damage in moderate and severe cases. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the expression of antioxidant proteins, participating in COVID-19-mediated inflammation and liver injury. Here, we show the novel reciprocal regulation between NRF2 and inflammatory mediators associated with COVID-19-related liver injury. Additionally, we describe some mechanisms and treatment strategies.


Subject(s)
COVID-19 , Inflammation Mediators , Liver Diseases/virology , NF-E2-Related Factor 2 , COVID-19/pathology , Humans , Inflammation Mediators/metabolism , Liver/metabolism , Liver/pathology , NF-E2-Related Factor 2/metabolism , Oxidative Stress , SARS-CoV-2 , Signal Transduction
18.
Immunopharmacol Immunotoxicol ; 43(3): 309-318, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1242073

ABSTRACT

BACKGROUND: Depression affects people feeling to be anxious, worried, and restless. They also lose interest in activities, concentrating and appetite, they finally may attempt suicide. Depression is the second chronic disease, as a source of the global burden of disease, after heart disease. Its prevalence elevated seven times during the COVID-19. AIM: The current study was designed to evaluate camphor neuroprotective role against rats' ciprofloxacin-induced depression. MATERIALS AND METHODS: Depression was induced by administration of ciprofloxacin (50 mg/kg; orally) for 21 days. Wister albino male rats were divided into five groups. Group I (normal control): rats were given normal saline. Group II: rats received camphor (10 mg/kg; i.p.) for 21 days. Group III (depression control): rats received ciprofloxacin only. Groups IV and V: rats received camphor (5 and 10 mg/kg; i.p.) for 21 days concurrent with ciprofloxacin. Behavior tests as forced swimming test, activity cage, and rotarod were estimated. Oxidative stress and antioxidant biomarkers as malondialdehyde (MDA), nitric oxide (NO), catalase, and nuclear factor erythroid 2-related factor 2 (Nrf-2) besides inflammatory biomarkers as Toll-like receptor 4 (TLR4) and tumor necrosis factor alpha (TNF-α) as well as neurotransmitters were determined. Finally, histopathological examination was done. RESULTS: Camphor increased catalase and Nrf-2 activities, decreased NO, MDA, TNF-α, TLR4 serum levels, and elevating brain contents of serotonin, dopamine, gamma-amino butyric acid (GABA) and P190-RHO GTP protein with normal neuronal cells of the frontal cortex. CONCLUSION: Camphor has neuroprotective effect via modulation of Nrf-2 and TLR4 against ciprofloxacin-induced depression in rats.


Subject(s)
Camphor/pharmacology , Ciprofloxacin/adverse effects , Depression , NF-E2-Related Factor 2/metabolism , Neuroprotective Agents/pharmacology , Toll-Like Receptor 4/metabolism , Animals , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/pathology , Ciprofloxacin/pharmacology , Depression/chemically induced , Depression/drug therapy , Depression/metabolism , Male , Rats , Rats, Wistar , SARS-CoV-2/metabolism
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