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1.
Nutrients ; 14(5)2022 Mar 05.
Article in English | MEDLINE | ID: covidwho-1732145

ABSTRACT

BACKGROUND: Pulmonary fibrosis (PF) is a chronic, progressive, and, ultimately, terminal interstitial disease caused by a variety of factors, ranging from genetics, bacterial, and viral infections, to drugs and other influences. Varying degrees of PF and its rapid progress have been widely reported in post-COVID-19 patients and there is consequently an urgent need to develop an appropriate, cost-effective approach for the prevention and management of PF. AIM: The potential "therapeutic" effect of the tocotrienol-rich fraction (TRF) and carotene against bleomycin (BLM)-induced lung fibrosis was investigated in rats via the modulation of TGF-ß/Smad, PI3K/Akt/mTOR, and NF-κB signaling pathways. DESIGN/METHODS: Lung fibrosis was induced in Sprague-Dawley rats by a single intratracheal BLM (5 mg/kg) injection. These rats were subsequently treated with TRF (50, 100, and 200 mg/kg body wt/day), carotene (10 mg/kg body wt/day), or a combination of TRF (200 mg/kg body wt/day) and carotene (10 mg/kg body wt/day) for 28 days by gavage administration. A group of normal rats was provided with saline as a substitute for BLM as the control. Lung function and biochemical, histopathological, and molecular alterations were studied in the lung tissues. RESULTS: Both the TRF and carotene treatments were found to significantly restore the BLM-induced alterations in anti-inflammatory and antioxidant functions. The treatments appeared to show pneumoprotective effects through the upregulation of antioxidant status, downregulation of MMP-7 and inflammatory cytokine expressions, and reduction in collagen accumulation (hydroxyproline). We demonstrated that TRF and carotene ameliorate BLM-induced lung injuries through the inhibition of apoptosis, the induction of TGF-ß1/Smad, PI3K/Akt/mTOR, and NF-κB signaling pathways. Furthermore, the increased expression levels were shown to be significantly and dose-dependently downregulated by TRF (50, 100, and 200 mg/kg body wt/day) treatment in high probability. The histopathological findings further confirmed that the TRF and carotene treatments had significantly attenuated the BLM-induced lung injury in rats. CONCLUSION: The results of this study clearly indicate the ability of TRF and carotene to restore the antioxidant system and to inhibit proinflammatory cytokines. These findings, thus, revealed the potential of TRF and carotene as preventive candidates for the treatment of PF in the future.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Tocotrienols , Animals , Bleomycin/toxicity , Carotenoids/adverse effects , Humans , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/prevention & control , Rats , Rats, Sprague-Dawley , SARS-CoV-2 , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Tocotrienols/adverse effects , Transforming Growth Factor beta/metabolism
2.
Drug Discov Today ; 27(3): 848-856, 2022 03.
Article in English | MEDLINE | ID: covidwho-1729681

ABSTRACT

Coronavirus disease 2019 (COVID-19) has emerged as a serious threat to global health. The disregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) cell signaling pathway observed in patients with COVID-19 has attracted attention for the possible use of specific inhibitors of this pathway for the treatment of the disease. Here, we review emerging data on the involvement of the PI3K/Akt/mTOR pathway in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the clinical studies investigating its tailored inhibition in COVID-19. Current in silico, in vitro, and in vivo data convergently support a role for the PI3K/Akt/mTOR pathway in COVID-19 and suggest the use of specific inhibitors of this pathway that, by a combined mechanism entailing downregulation of excessive inflammatory reactions, cell protection, and antiviral effects, could ameliorate the course of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Animals , COVID-19/metabolism , Humans
3.
Eur Rev Med Pharmacol Sci ; 26(2): 695-709, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1675568

ABSTRACT

In 2009, obesity was identified for the first time as a risk factor for increased disease severity and mortality in patients infected with the H1N1 influenza A virus. During the current COVID-19 pandemic, overweight and obesity have been described as independent risk factors of disease severity and mortality due to COVID-19. Excess visceral fat is associated with systemic chronic microinflammation, changes in adipokine release, and oxidative stress. These disturbances result in an impaired immune response, including dysfunction in lymphocyte action and antibody production. Moreover, obesity is a cause of endothelial dysfunction, pro-coagulation state, and enhanced expression of angiotensin-converting enzyme 2 (ACE-2), which contributes to the infection itself and the severity of the disease. We analyzed both the impact of obesity on the severity of COVID-19 and the potential mechanism that influences this severity. Moreover, we discuss the effect of obesity complications on the severity of disease and mortality of patients with COVID-19. Furthermore, we summarize the effectiveness of COVID-19 vaccination in patients with obesity. Finally, we analyzed the effect of the COVID-19 pandemic on mood disturbances and emotional eating and, as a consequence, the development of obesity or an increase in its severity. In summary, the studies conducted during the COVID-19 pandemic indicate that effective obesity treatment should be initiated at once. In addition, the data confirm the need to organize efficient obesity treatment systems for the sake of not only the individual but also society.


Subject(s)
COVID-19/pathology , Influenza, Human/pathology , Obesity/complications , Adipokines/metabolism , Angiotensin-Converting Enzyme 2/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , COVID-19/complications , COVID-19/epidemiology , COVID-19/mortality , Humans , Influenza A Virus, H1N1 Subtype/isolation & purification , Influenza, Human/complications , Influenza, Human/epidemiology , Meta-Analysis as Topic , Obesity/epidemiology , Oxidative Stress , Pandemics , Risk Factors , Severity of Illness Index , Survival Analysis , TOR Serine-Threonine Kinases/metabolism
5.
Sci Rep ; 11(1): 24442, 2021 12 24.
Article in English | MEDLINE | ID: covidwho-1577650

ABSTRACT

Therapeutic interventions targeting viral infections remain a significant challenge for both the medical and scientific communities. While specific antiviral agents have shown success as therapeutics, viral resistance inevitably develops, making many of these approaches ineffective. This inescapable obstacle warrants alternative approaches, such as the targeting of host cellular factors. Respiratory syncytial virus (RSV), the major respiratory pathogen of infants and children worldwide, causes respiratory tract infection ranging from mild upper respiratory tract symptoms to severe life-threatening lower respiratory tract disease. Despite the fact that the molecular biology of the virus, which was originally discovered in 1956, is well described, there is no vaccine or effective antiviral treatment against RSV infection. Here, we demonstrate that targeting host factors, specifically, mTOR signaling, reduces RSV protein production and generation of infectious progeny virus. Further, we show that this approach can be generalizable as inhibition of mTOR kinases reduces coronavirus gene expression, mRNA transcription and protein production. Overall, defining virus replication-dependent host functions may be an effective means to combat viral infections, particularly in the absence of antiviral drugs.


Subject(s)
Coronavirus/metabolism , Respiratory Syncytial Virus, Human/metabolism , TOR Serine-Threonine Kinases/metabolism , Viral Proteins/metabolism , A549 Cells , Coronavirus/drug effects , Coronavirus/genetics , Gene Expression Regulation, Viral/drug effects , Humans , Protein Biosynthesis/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , RNA Interference , RNA, Small Interfering/metabolism , Rapamycin-Insensitive Companion of mTOR Protein/antagonists & inhibitors , Rapamycin-Insensitive Companion of mTOR Protein/genetics , Rapamycin-Insensitive Companion of mTOR Protein/metabolism , Regulatory-Associated Protein of mTOR/antagonists & inhibitors , Regulatory-Associated Protein of mTOR/genetics , Regulatory-Associated Protein of mTOR/metabolism , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/drug effects , Respiratory Syncytial Virus, Human/isolation & purification , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/genetics , Viral Proteins/genetics
6.
Biomed Pharmacother ; 144: 112230, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1517059

ABSTRACT

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has become a serious challenge for medicine and science. Analysis of the molecular mechanisms associated with the clinical manifestations and severity of COVID-19 has identified several key points of immune dysregulation observed in SARS-CoV-2 infection. For diabetic patients, factors including higher binding affinity and virus penetration, decreased virus clearance and decreased T cell function, increased susceptibility to hyperinflammation, and cytokine storm may make these patients susceptible to a more severe course of COVID-19 disease. Metabolic changes induced by diabetes, especially hyperglycemia, can directly affect the immunometabolism of lymphocytes in part by affecting the activity of the mTOR protein kinase signaling pathway. High mTOR activity can enhance the progression of diabetes due to the activation of effector proinflammatory subpopulations of lymphocytes and, conversely, low activity promotes the differentiation of T-regulatory cells. Interestingly, metformin, an extensively used antidiabetic drug, inhibits mTOR by affecting the activity of AMPK. Therefore, activation of AMPK and/or inhibition of the mTOR-mediated signaling pathway may be an important new target for drug therapy in COVID-19 cases mostly by reducing the level of pro-inflammatory signaling and cytokine storm. These suggestions have been partially confirmed by several retrospective analyzes of patients with diabetes mellitus hospitalized for severe COVID-19.


Subject(s)
COVID-19/drug therapy , Diabetes Mellitus/drug therapy , Hypoglycemic Agents/therapeutic use , Immunity, Cellular/drug effects , Metformin/therapeutic use , Severity of Illness Index , COVID-19/epidemiology , COVID-19/immunology , COVID-19/metabolism , Diabetes Mellitus/epidemiology , Diabetes Mellitus/immunology , Diabetes Mellitus/metabolism , Humans , Hypoglycemic Agents/pharmacology , Immunity, Cellular/physiology , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/metabolism , Metformin/pharmacology , Mortality/trends , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/immunology , TOR Serine-Threonine Kinases/metabolism
7.
Front Endocrinol (Lausanne) ; 12: 731974, 2021.
Article in English | MEDLINE | ID: covidwho-1485049

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing a worldwide epidemic. It spreads very fast and hits people of all ages, especially patients with underlying diseases such as diabetes. In this review, we focus on the influences of diabetes on the outcome of SARS-CoV-2 infection and the involved mechanisms including lung dysfunction, immune disorder, abnormal expression of angiotensin-converting enzyme 2 (ACE2), overactivation of mechanistic target of rapamycin (mTOR) signaling pathway, and increased furin level. On the other hand, SARS-CoV-2 may trigger the development of diabetes. It causes the damage of pancreatic ß cells, which is probably mediated by ACE2 protein in the islets. Furthermore, SARS-CoV-2 may aggravate insulin resistance through attacking other metabolic organs. Of note, certain anti-diabetic drugs (OADs), such as peroxisome proliferator-activated receptor γ (PPARγ) activator and glucagon-like peptide 1 receptor (GLP-1R) agonist, have been shown to upregulate ACE2 in animal models, which may increase the risk of SARS-CoV-2 infection. However, Metformin, as a first-line medicine for the treatment of type 2 diabetes mellitus (T2DM), may be a potential drug benefiting diabetic patients with SARS-CoV-2 infection, probably via a suppression of mTOR signaling together with its anti-inflammatory and anti-fibrosis function in lung. Remarkably, another kind of OADs, dipeptidyl Peptidase 4 (DPP4) inhibitor, may also exert beneficial effects in this respect, probably via a prevention of SARS-CoV-2 binding to cells. Thus, it is of significant to identify appropriate OADs for the treatment of diabetes in the context of SARS-CoV-2 infections.


Subject(s)
COVID-19/epidemiology , COVID-19/metabolism , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Lung/drug effects , Lung/metabolism , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism
8.
Immunol Lett ; 240: 1-8, 2021 12.
Article in English | MEDLINE | ID: covidwho-1433399

ABSTRACT

Some COVID-19 patients suffer complications from anti-viral immune responses which can lead to both a dangerous cytokine storm and development of blood-borne factors that render severe thrombotic events more likely. The precise immune response profile is likely, therefore, to determine and predict patient outcomes and also represents a target for intervention. Anti-viral T cell exhaustion in the early stages is associated with disease progression. Dysregulation of T cell functions, which precedes cytokine storm development and neutrophil expansion in alveolar tissues heralds damaging pathology.T cell function, cytokine production and factors that attract neutrophils to the lung can be modified through targeting molecules that can modulate T cell responses. Manipulating T cell responses by targeting the PI3K/Akt/mTOR pathway could provide the means to control the immune response in COVID-19 patients. During the initial anti-viral response, T cell effector function can be enhanced by delaying anti-viral exhaustion through inhibiting PI3K and Akt. Additionally, immune dysregulation can be addressed by enhancing immune suppressor functions by targeting downstream mTOR, an important intracellular modulator of cellular metabolism. Targeting this signalling pathway also has potential to prevent formation of thrombi due to its role in platelet activation. Furthermore, this signalling pathway is essential for SARS-cov-2 virus replication in host cells and its inhibition could, therefore, reduce viral load. The ultimate goal is to identify targets that can quickly control the immune response in COVID-19 patients to improve patient outcome. Targeting different levels of the PI3K/Akt/mTOR signalling pathway could potentially achieve this during each stage of the disease.


Subject(s)
COVID-19/drug therapy , Phosphatidylinositol 3-Kinase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , SARS-CoV-2/pathogenicity , TOR Serine-Threonine Kinases/metabolism , Animals , COVID-19/enzymology , COVID-19/immunology , COVID-19/virology , Fibrinolytic Agents/therapeutic use , Host-Pathogen Interactions , Humans , Molecular Targeted Therapy , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , SARS-CoV-2/immunology , Viral Load
9.
Nat Commun ; 12(1): 652, 2021 01 28.
Article in English | MEDLINE | ID: covidwho-1397868

ABSTRACT

Injury and loss of oligodendrocytes can cause demyelinating diseases such as multiple sclerosis. To improve our understanding of human oligodendrocyte development, which could facilitate development of remyelination-based treatment strategies, here we describe time-course single-cell-transcriptomic analysis of developing human stem cell-derived oligodendrocyte-lineage-cells (hOLLCs). The study includes hOLLCs derived from both genome engineered embryonic stem cell (ESC) reporter cells containing an Identification-and-Purification tag driven by the endogenous PDGFRα promoter and from unmodified induced pluripotent (iPS) cells. Our analysis uncovers substantial transcriptional heterogeneity of PDGFRα-lineage hOLLCs. We discover sub-populations of human oligodendrocyte progenitor cells (hOPCs) including a potential cytokine-responsive hOPC subset, and identify candidate regulatory genes/networks that define the identity of these sub-populations. Pseudotime trajectory analysis defines developmental pathways of oligodendrocytes vs astrocytes from PDGFRα-expressing hOPCs and predicts differentially expressed genes between the two lineages. In addition, pathway enrichment analysis followed by pharmacological intervention of these pathways confirm that mTOR and cholesterol biosynthesis signaling pathways are involved in maturation of oligodendrocytes from hOPCs.


Subject(s)
Genetic Heterogeneity , Genetic Variation , Induced Pluripotent Stem Cells/metabolism , Oligodendrocyte Precursor Cells/metabolism , Single-Cell Analysis/methods , Transcriptome/genetics , Astrocytes/cytology , Astrocytes/metabolism , Cell Differentiation/genetics , Cell Line , Cell Lineage/genetics , Cholesterol/biosynthesis , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Gene Regulatory Networks/genetics , Humans , Induced Pluripotent Stem Cells/cytology , Oligodendrocyte Precursor Cells/cytology , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Signal Transduction/genetics , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism
10.
Biochim Biophys Acta Mol Basis Dis ; 1867(12): 166260, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1377661

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection-induced inflammatory responses are largely responsible for the death of novel coronavirus disease 2019 (COVID-19) patients. However, the mechanism by which SARS-CoV-2 triggers inflammatory responses remains unclear. Here, we aimed to explore the regulatory role of SARS-CoV-2 spike protein in infected cells and attempted to elucidate the molecular mechanism of SARS-CoV-2-induced inflammation. METHODS: SARS-CoV-2 spike pseudovirions (SCV-2-S) were generated using the spike-expressing virus packaging system. Western blot, mCherry-GFP-LC3 labeling, immunofluorescence, and RNA-seq were performed to examine the regulatory mechanism of SCV-2-S in autophagic response. The effects of SCV-2-S on apoptosis were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Western blot, and flow cytometry analysis. Enzyme-linked immunosorbent assay (ELISA) was carried out to examine the mechanism of SCV-2-S in inflammatory responses. RESULTS: Angiotensin-converting enzyme 2 (ACE2)-mediated SCV-2-S infection induced autophagy and apoptosis in human bronchial epithelial and microvascular endothelial cells. Mechanistically, SCV-2-S inhibited the PI3K/AKT/mTOR pathway by upregulating intracellular reactive oxygen species (ROS) levels, thus promoting the autophagic response. Ultimately, SCV-2-S-induced autophagy triggered inflammatory responses and apoptosis in infected cells. These findings not only improve our understanding of the mechanism underlying SARS-CoV-2 infection-induced pathogenic inflammation but also have important implications for developing anti-inflammatory therapies, such as ROS and autophagy inhibitors, for COVID-19 patients.


Subject(s)
COVID-19/metabolism , Inflammation/metabolism , Spike Glycoprotein, Coronavirus/immunology , Animals , Apoptosis/immunology , Autophagy/physiology , Cell Line , Chlorocebus aethiops , Endothelial Cells/metabolism , HEK293 Cells , Humans , Inflammation/immunology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , SARS-CoV-2/pathogenicity , Signal Transduction/immunology , Spike Glycoprotein, Coronavirus/metabolism , TOR Serine-Threonine Kinases/metabolism , Vero Cells
11.
Pharmacol Res ; 172: 105784, 2021 10.
Article in English | MEDLINE | ID: covidwho-1322310

ABSTRACT

It is becoming progressively more understandable that pharmaceutical targeting of drug-resistant cancers is challenging because of intra- and inter-tumor heterogeneity. Interestingly, naturally derived bioactive compounds have unique ability to modulate wide-ranging deregulated oncogenic cell signaling pathways. In this review, we have focused on the available evidence related to regulation of PI3K/AKT/mTOR, Wnt/ß-catenin, NF-κB and TRAIL/TRAIL-R by fisetin in different cancers. Fisetin has also been shown to inhibit the metastatic spread of cancer cells in tumor-bearing mice. We have also summarized how fisetin regulated autophagy in different cancers. In addition, this review also covers fisetin-mediated regulation of VEGF/VEGFR, EGFR, necroptosis and Hippo pathway. Fisetin has entered into clinical trials particularly in context of COVID19-associated inflammations. Furthermore, fisetin mediated effects are also being tested in clinical trials with reference to osteoarthritis and senescence. These developments will surely pave the way for full-fledge and well-designed clinical trials of fisetin in different cancers. However, we still have to comprehensively analyze and fully unlock pharmacological potential of fisetin against different oncogenic signaling cascades and non-coding RNAs. Fisetin has remarkable potential as chemopreventive agent and future studies must converge on the identification of additional regulatory roles of fisetin for inhibition and prevention of cancers.


Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Flavonols/administration & dosage , Nanostructures/administration & dosage , Neoplasms/drug therapy , Animals , Chemoprevention , Humans , Intercellular Signaling Peptides and Proteins/metabolism , NF-kappa B/metabolism , Neoplasms/metabolism , Neoplasms/prevention & control , Receptors, Vascular Endothelial Growth Factor/metabolism , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , beta Catenin/metabolism
12.
J Neurosci ; 41(25): 5338-5349, 2021 06 23.
Article in English | MEDLINE | ID: covidwho-1282334

ABSTRACT

Clinical reports suggest that the coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome (SARS)-coronavirus-2 (CoV-2) has not only taken millions of lives, but has also created a major crisis of neurologic complications that persist even after recovery from the disease. Autopsies of patients confirm the presence of the coronaviruses in the CNS, especially in the brain. The invasion and transmission of SARS-CoV-2 in the CNS is not clearly defined, but, because the endocytic pathway has become an important target for the development of therapeutic strategies for COVID-19, it is necessary to understand endocytic processes in the CNS. In addition, mitochondria and mechanistic target of rapamycin (mTOR) signaling pathways play a critical role in the antiviral immune response, and may also be critical for endocytic activity. Furthermore, dysfunctions of mitochondria and mTOR signaling pathways have been associated with some high-risk conditions such as diabetes and immunodeficiency for developing severe complications observed in COVID-19 patients. However, the role of these pathways in SARS-CoV-2 infection and spread are largely unknown. In this review, we discuss the potential mechanisms of SARS-CoV-2 entry into the CNS and how mitochondria and mTOR pathways might regulate endocytic vesicle-mitochondria interactions and dynamics during SARS-CoV-2 infection. The mechanisms that plausibly account for severe neurologic complications with COVID-19 and potential treatments with Food and Drug Administration-approved drugs targeting mitochondria and the mTOR pathways are also addressed.


Subject(s)
COVID-19/complications , Nervous System Diseases/virology , Neurons/virology , Animals , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Humans , Mitochondria/metabolism , Mitochondria/virology , Nervous System Diseases/drug therapy , Nervous System Diseases/metabolism , Nervous System Diseases/pathology , Neurons/metabolism , SARS-CoV-2/pathogenicity , TOR Serine-Threonine Kinases/metabolism
13.
Nutr Diabetes ; 11(1): 20, 2021 06 23.
Article in English | MEDLINE | ID: covidwho-1281688

ABSTRACT

Defences to pathogens such as SarCoV2 in mammals involves interactions between immune functions and metabolic pathways to eradicate infection while preventing hyperinflammation. Amino acid metabolic pathways represent with other antimicrobial agent potential targets for therapeutic strategies. iNOS-mediated production of NO from Arg is involved in the innate inflammatory response to pathogens and NO overproduction can induce hyperinflammation. The two Arg-catabolising enzymes Arg1 and IDO1 reduce the hyperinflammation by an immunosuppressive effect via either Arg starvation (for Arg1) or via the immunoregulatory activity of the Arg-derived metabolites Kyn (for IDO1). In response to amino acid abundance mTOR activates the host protein translation and Coronaviruses use this machinery for their own protein synthesis and replication. In contrast GCN2, the sensor of amino acid starvation, activates pathways that restrict inflammation and viral replication. Gln depletion alters the immune response that become more suppressive, by favouring a regulatory T phenotype rather than a Th1 phenotype. Proliferating activated immune cells are highly dependent on Ser, activation and differentiation of T cells need enough Ser and dietary Ser restriction can inhibit their proliferation. Cys is strictly required for T-cell proliferation because they cannot convert Met to Cys. Restricting Met inhibits both viral RNA cap methylation and replication, and the proliferation of infected cells with an increased requirement for Met. Phe catabolism produces antimicrobial metabolites resulting in the inhibition of microbial growth and an immunosuppressive activity towards T lymphocytes.


Subject(s)
Amino Acids/metabolism , Immunity, Innate , Infections/therapy , Animals , Anti-Infective Agents/therapeutic use , Arginine/metabolism , Humans , Infections/metabolism , Inflammation/metabolism , Nitric Oxide Synthase Type II/metabolism , Signal Transduction , T-Lymphocytes/metabolism , TOR Serine-Threonine Kinases/metabolism , Virus Replication
14.
RNA ; 27(9): 1025-1045, 2021 09.
Article in English | MEDLINE | ID: covidwho-1269913

ABSTRACT

Viruses rely on the host translation machinery to synthesize their own proteins. Consequently, they have evolved varied mechanisms to co-opt host translation for their survival. SARS-CoV-2 relies on a nonstructural protein, Nsp1, for shutting down host translation. However, it is currently unknown how viral proteins and host factors critical for viral replication can escape a global shutdown of host translation. Here, using a novel FACS-based assay called MeTAFlow, we report a dose-dependent reduction in both nascent protein synthesis and mRNA abundance in cells expressing Nsp1. We perform RNA-seq and matched ribosome profiling experiments to identify gene-specific changes both at the mRNA expression and translation levels. We discover that a functionally coherent subset of human genes is preferentially translated in the context of Nsp1 expression. These genes include the translation machinery components, RNA binding proteins, and others important for viral pathogenicity. Importantly, we uncovered a remarkable enrichment of 5' terminal oligo-pyrimidine (TOP) tracts among preferentially translated genes. Using reporter assays, we validated that 5' UTRs from TOP transcripts can drive preferential expression in the presence of Nsp1. Finally, we found that LARP1, a key effector protein in the mTOR pathway, may contribute to preferential translation of TOP transcripts in response to Nsp1 expression. Collectively, our study suggests fine-tuning of host gene expression and translation by Nsp1 despite its global repressive effect on host protein synthesis.


Subject(s)
Host-Pathogen Interactions/genetics , Protein Biosynthesis , Proteins/chemistry , Proteins/genetics , Viral Nonstructural Proteins/genetics , 5' Untranslated Regions , Autoantigens/genetics , Autoantigens/metabolism , Gene Expression Regulation , HEK293 Cells , Humans , Protein Folding , Pyrimidines , RNA, Messenger/genetics , Ribonucleoproteins/genetics , Ribonucleoproteins/metabolism , Ribosomes/genetics , Ribosomes/virology , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Viral Nonstructural Proteins/metabolism
15.
Immunology ; 164(3): 467-475, 2021 11.
Article in English | MEDLINE | ID: covidwho-1266332

ABSTRACT

A number of mechanisms have been proposed to explain the well-established link between diabetic status and an increased susceptibility to infection. Notably, diabetes has been shown to be one of the strongest factors influencing healthcare outcome in COVID-19 infections. Though it has long been noted that lymphocytes upregulate insulin receptors following immune activation, until recently, this observation has received little attention. Here, we point out key findings implicating dysregulated insulin signalling in immune cells as a possible contributing factor in the immune pathology associated with diabetes. Mechanistically, insulin, by activating the PI3K/Akt/mTOR pathway, regulates various aspects of both myeloid cells and lymphocytes, such as cell survival, metabolic reprogramming and the polarization and differentiation of immune cells. PI3K signalling is also supressed by immune checkpoint proteins, suggesting that insulin signalling may antagonize peripheral tolerance. Remarkably, it has also recently been shown that, following insulin binding, the insulin receptor translocates to the nucleus where it plays a key role in regulating the transcription of various immune-related genes, including pathways involved in viral infections. Taken together, these observations suggest that dysregulated insulin signalling may directly contribute to a defective immune response during COVID-19 infections.


Subject(s)
Blood Glucose/metabolism , COVID-19/metabolism , Diabetes Mellitus, Type 1/metabolism , Insulin/metabolism , Lymphocytes/metabolism , SARS-CoV-2/pathogenicity , Animals , Biomarkers/blood , COVID-19/immunology , COVID-19/physiopathology , COVID-19/virology , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/physiopathology , Host-Pathogen Interactions , Humans , Immune Checkpoint Proteins/metabolism , Insulin Resistance , Lymphocytes/immunology , Lymphocytes/virology , Phosphatidylinositol 3-Kinase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptor, Insulin/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism
16.
Transplant Proc ; 53(4): 1187-1193, 2021 May.
Article in English | MEDLINE | ID: covidwho-1081930

ABSTRACT

BACKGROUND: Kidney transplant recipients (KTR) are considered high-risk for morbidity and mortality from coronavirus disease 2019 (COVID-19). However, some studies did not show worse outcomes compared to non-transplant patients and there is little data about immunosuppressant drug levels and secondary infections in KTR with COVID-19. Herein, we describe our single-center experience with COVID-19 in KTR. METHODS: We captured KTR diagnosed with COVID-19 between March 1, 2020 and May 18, 2020. After exclusion of KTR on hemodialysis and off immunosuppression, we compared the clinical course of COVID-19 between hospitalized KTR and non-transplant patients, matched by age and sex (controls). RESULTS: Eleven KTR were hospitalized and matched with 44 controls. One KTR and 4 controls died (case fatality rate: 9.1%). There were no significant differences in length of stay or clinical outcomes between KTR and controls. Tacrolimus or sirolimus levels were >10 ng/mL in 6 out of 9 KTR (67%). Bacterial infections were more frequent in KTR (36.3%), compared with controls (6.8%, P = .02). CONCLUSIONS: In our small case series, unlike earlier reports from the pandemic epicenters, the clinical outcomes of KTR with COVID-19 were comparable to those of non-transplant patients. Calcineurin or mammalian target of rapamycin inhibitor (mTOR) levels were high. Bacterial infections were more common in KTR, compared with controls.


Subject(s)
COVID-19/diagnosis , Kidney Transplantation , Adult , Aged , Antiviral Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , COVID-19/virology , Case-Control Studies , Female , Graft Rejection/prevention & control , Humans , Immunosuppressive Agents/therapeutic use , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/therapy , Length of Stay , Male , Middle Aged , Pandemics , SARS-CoV-2/isolation & purification , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/metabolism , Tacrolimus/therapeutic use , Treatment Outcome
17.
Aging (Albany NY) ; 12(24): 26263-26278, 2020 12 27.
Article in English | MEDLINE | ID: covidwho-1000742

ABSTRACT

Inflammaging constitutes the common factor for comorbidities predisposing to severe COVID-19. Inflammaging leads to T-cell senescence, and immunosenescence is linked to autoimmune manifestations in COVID-19. As in SLE, metabolic dysregulation occurs in T-cells. Targeting this T-cell dysfunction opens the field for new therapeutic strategies to prevent severe COVID-19. Immunometabolism-mediated approaches such as rapamycin, metformin and dimethyl fumarate, may optimize COVID-19 treatment of the elderly and patients at risk for severe disease.


Subject(s)
Autoimmunity , COVID-19/immunology , COVID-19/metabolism , Energy Metabolism , Host-Pathogen Interactions , Immunosenescence , SARS-CoV-2/immunology , Biomarkers , COVID-19/complications , COVID-19/virology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Enhancer Elements, Genetic , Humans , Promoter Regions, Genetic , SARS-CoV-2/genetics , Signal Transduction , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , TOR Serine-Threonine Kinases/metabolism
18.
J Med Virol ; 93(4): 1843-1846, 2021 04.
Article in English | MEDLINE | ID: covidwho-971501

ABSTRACT

In this commentary, we shed light on the role of the mammalian target of rapamycin (mTOR) pathway in viral infections. The mTOR pathway has been demonstrated to be modulated in numerous RNA viruses. Frequently, inhibiting mTOR results in suppression of virus growth and replication. Recent evidence points towards modulation of mTOR in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We discuss the current literature on mTOR in SARS-CoV-2 and highlight evidence in support of a role for mTOR inhibitors in the treatment of coronavirus disease 2019.


Subject(s)
COVID-19/drug therapy , RNA Viruses/physiology , SARS-CoV-2/physiology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/virology , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Middle East Respiratory Syndrome Coronavirus/physiology , RNA Viruses/genetics , RNA Viruses/pathogenicity , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Virus Replication
19.
Curr Neurovasc Res ; 17(5): 765-783, 2020.
Article in English | MEDLINE | ID: covidwho-922756

ABSTRACT

Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.


Subject(s)
Circadian Clocks/genetics , Metabolic Diseases/genetics , Niacinamide/genetics , Sirtuin 1/genetics , TOR Serine-Threonine Kinases/genetics , Animals , Humans , Metabolic Diseases/diagnosis , Metabolic Diseases/metabolism , Niacinamide/metabolism , Sirtuin 1/metabolism , TOR Serine-Threonine Kinases/metabolism
20.
Vet Microbiol ; 244: 108684, 2020 May.
Article in English | MEDLINE | ID: covidwho-827805

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) has caused, and continues to cause, severe economic losses to the swine industry worldwide. The pathogenic mechanism and immune regulatory interactions between PEDV and the host remain largely unknown. In this study, the interaction between autophagy and PEDV replication in intestinal porcine epithelial (IPEC-J2) cells was investigated. The effects of the structural and nonstructural proteins of PEDV on the autophagy process and the autophagy-related signaling pathways were also examined. The results shown that PEDV replication increased the autophagy flux in IPEC-J2 cells, and that autophagy was beneficial to PEDV replication, which may be one of the reasons for the rapid damage to intestinal epithelial cells and the enhanced virulence of PEDV in both newborn piglets and finishing pigs. When autophagy was pharmacologically induced by rapamycin, PEDV replication increased from 8.5 × 105 TCID50/mL to 8.8 × 106 TCID50/mL in IPEC-J2 cells. When autophagy was pharmacologically suppressed by hydroxychloroquine, PEDV replication decreased from 8.5 × 105 TCID50/mL to 7.9 × 104 TCID50/mL. To identify which PEDV proteins were the key inducers of autophagy, all 4 structural proteins and 17 nonstructural proteins of PEDV were eukaryotic expressed. It was found that the nonstructural protein 6 (nsp6) and ORF3 of PEDV were able to induce significant autophagy in IPEC-J2 cells, but the other proteins were unable to induce autophagy. It was indicated that nsp6-induced autophagy mainly occurred via the PI3K/Akt/mTOR signaling pathway. The results accelerate the understanding of the biology and pathogenesis of PEDV infection and provide new insights into the development of effective therapeutic strategies.


Subject(s)
Autophagy , Porcine epidemic diarrhea virus/pathogenicity , Signal Transduction , Viral Nonstructural Proteins/genetics , Virus Replication , Animals , Cell Line , Epithelial Cells/pathology , Epithelial Cells/virology , Host-Pathogen Interactions , Intestines/cytology , Intestines/virology , Oncogene Protein v-akt/genetics , Oncogene Protein v-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Porcine epidemic diarrhea virus/physiology , Swine , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Viral Nonstructural Proteins/metabolism
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