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1.
Int J Mol Sci ; 23(7)2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1785739

ABSTRACT

Di-(2-ethylhexyl) phthalate (DEHP) is a frequently used plasticizer that may be linked to the development of endometriosis, a common gynecological disorder with a profound impact on quality of life. Despite its prevalence, vital access to treatment has often been hampered by a lack of understanding of its pathogenesis as well as reliable disease models. Recently, epithelial-mesenchymal transition (EMT) has been suggested to have a significant role in endometriosis pathophysiology. In this study, we found that DEHP treatment enhanced proliferation, migration, and inflammatory responses, along with EMT and stemness induction in human endometrial and endometriotic cells. The selective transforming growth factor-ß (TGF-ß) receptor type 1/2 inhibitor LY2109761 reversed the DEHP-induced cell proliferation and migration enhancement as well as the increased expression of crucial molecules involved in inflammation, EMT, and stemness, indicating that DEHP-triggered phenomena occur via the TGF-ß/Smad signaling pathway. Our study clearly defines the role of DEHP in the etiology and pathophysiological mechanisms of endometriosis and establishes an efficient disease model for endometriosis using a biomimetic 3D cell culture technique. Altogether, our data provide novel etiological and mechanistic insights into the role of DEHP in endometriosis pathogenesis, opening avenues for developing novel preventive and therapeutic strategies for endometriosis.


Subject(s)
Diethylhexyl Phthalate , Endometriosis , Cell Proliferation , Diethylhexyl Phthalate/metabolism , Diethylhexyl Phthalate/toxicity , Endometriosis/pathology , Epithelial Cells/metabolism , Epithelial-Mesenchymal Transition , Female , Humans , Phthalic Acids , Quality of Life , Signal Transduction , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1/metabolism , Transforming Growth Factors/metabolism
2.
Mol Med Rep ; 25(4)2022 04.
Article in English | MEDLINE | ID: covidwho-1753714

ABSTRACT

Aberrant TGF­ß/Smad7 signaling has been reported to be an important mechanism underlying the pathogenesis of ulcerative colitis. Therefore, the present study aimed to investigate the effects of a number of potential anti­colitis agents on intestinal epithelial permeability and the TGF­ß/Smad7 signaling pathway in an experimental model of colitis. A mouse model of colitis was first established before anti­TNF­α and 5­aminosalicyclic acid (5­ASA) were administered intraperitoneally and orally, respectively. Myeloperoxidase (MPO) activity, histological index (HI) of the colon and the disease activity index (DAI) scores were then detected in each mouse. Transmission electron microscopy (TEM), immunohistochemical and functional tests, including Evans blue (EB) and FITC­dextran (FD­4) staining, were used to evaluate intestinal mucosal permeability. The expression of epithelial phenotype markers E­cadherin, occludin, zona occludens (ZO­1), TGF­ß and Smad7 were measured. In addition, epithelial myosin light chain kinase (MLCK) expression and activity were measured. Anti­TNF­α and 5­ASA treatments was both found to effectively reduce the DAI score and HI, whilst decreasing colonic MPO activity, plasma levels of FD­4 and EB permeation of the intestine. Furthermore, anti­TNF­α and 5­ASA treatments decreased MLCK expression and activity, reduced the expression of Smad7 in the small intestine epithelium, but increased the expression of TGF­ß. In mice with colitis, TEM revealed partial epithelial injury in the ileum, where the number of intercellular tight junctions and the expression levels of E­cadherin, ZO­1 and occludin were decreased, all of which were alleviated by anti­TNF­α and 5­ASA treatment. In conclusion, anti­TNF­α and 5­ASA both exerted protective effects on intestinal epithelial permeability in an experimental mouse model of colitis. The underlying mechanism may be mediated at least in part by the increase in TGF­ß expression and/or the reduction in Smad7 expression, which can inhibit epithelial MLCK activity and in turn reduce mucosal permeability during the pathogenesis of ulcerative colitis.


Subject(s)
Colitis, Ulcerative/metabolism , Smad7 Protein/genetics , Smad7 Protein/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Animals , Cadherins/metabolism , Colitis, Ulcerative/chemically induced , Colon/pathology , Dextran Sulfate/toxicity , Disease Models, Animal , Female , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Intestinal Mucosa/ultrastructure , Male , Mesalamine/administration & dosage , Mice, Inbred C57BL , Myosin-Light-Chain Kinase/metabolism , Occludin/metabolism , Peroxidase/drug effects , Severity of Illness Index , Signal Transduction/drug effects , Tight Junctions/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Zonula Occludens-1 Protein/metabolism
3.
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
4.
Int J Mol Sci ; 23(1)2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1580700

ABSTRACT

Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-ß is intimately involved in the fibrogenic process. When activated, TGF-ß promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 tissue expression) involved in the TGF-ß1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-ß pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-ß inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.


Subject(s)
COVID-19/metabolism , Pulmonary Fibrosis/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Actins/metabolism , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Caveolin 1/metabolism , Collagen Type I/metabolism , Collagen Type III/metabolism , Female , Humans , Hyaluronan Receptors/metabolism , Immunohistochemistry , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/metabolism , Influenza, Human/pathology , Interleukin-4/metabolism , Male , Matrix Metalloproteinase 9/metabolism , Middle Aged , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , Retrospective Studies , Transforming Growth Factor beta1/metabolism
5.
Cells ; 10(9)2021 08 31.
Article in English | MEDLINE | ID: covidwho-1390542

ABSTRACT

The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes ß-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived ß-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing ß-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small-molecule-induced human ß-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.


Subject(s)
Homeostasis , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/enzymology , Insulin/metabolism , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Genes, Reporter , Harmine/pharmacology , Homeostasis/drug effects , Humans , Induced Pluripotent Stem Cells/drug effects , Induced Pluripotent Stem Cells/metabolism , Insulin-Secreting Cells/drug effects , Kinetics , Male , Mice , Models, Biological , NFATC Transcription Factors/metabolism , Organoids/drug effects , Organoids/metabolism , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/metabolism , Rats , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/metabolism
8.
Pharmacol Rep ; 73(3): 712-727, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1195205

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pulmonary injury or multiple-organ injury by various pathological pathways. Transforming growth factor-beta (TGF-ß) is a key factor that is released during SARS-CoV-2 infection. TGF-ß, by internalization of the epithelial sodium channel (ENaC), suppresses the anti-oxidant system, downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), and activates the plasminogen activator inhibitor 1 (PAI-1) and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB). These changes cause inflammation and lung injury along with coagulopathy. Moreover, reactive oxygen species play a significant role in lung injury, which levels up during SARS-CoV-2 infection. DRUG SUGGESTION: Pirfenidone is an anti-fibrotic drug with an anti-oxidant activity that can prevent lung injury during SARS-CoV-2 infection by blocking the maturation process of transforming growth factor-beta (TGF-ß) and enhancing the protective role of peroxisome proliferator-activated receptors (PPARs). Pirfenidone is a safe drug for patients with hypertension or diabetes and its side effect tolerated well. CONCLUSION: The drug as a theoretical perspective may be an effective and safe choice for suppressing the inflammatory response during COVID-19. The recommendation would be a combination of pirfenidone and N-acetylcysteine to achieve maximum benefit during SARS-CoV-2 treatment.


Subject(s)
COVID-19/drug therapy , COVID-19/metabolism , Inflammation/drug therapy , Lung Injury/metabolism , Pyridones/therapeutic use , Signal Transduction/drug effects , Transforming Growth Factor beta/metabolism , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , COVID-19/virology , Humans , Inflammation/metabolism , Lung Injury/virology , SARS-CoV-2/pathogenicity
9.
Nature ; 594(7862): 246-252, 2021 06.
Article in English | MEDLINE | ID: covidwho-1180252

ABSTRACT

The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1-10. Integration of such datasets to obtain a holistic view of virus-host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-ß pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org ) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Host-Pathogen Interactions , Proteome/metabolism , Proteomics , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/metabolism , Animals , Antiviral Agents/pharmacology , Autophagy/drug effects , COVID-19/immunology , COVID-19/virology , Cell Line , Datasets as Topic , Drug Evaluation, Preclinical , Host-Pathogen Interactions/immunology , Humans , Matrix Metalloproteinase Inhibitors/pharmacology , Phosphorylation , Protein Interaction Maps , Protein Kinase Inhibitors/pharmacology , Protein Processing, Post-Translational , Proteome/chemistry , SARS Virus/immunology , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Transforming Growth Factor beta/metabolism , Ubiquitination , Viral Proteins/chemistry , Viral Proteins/metabolism , Viroporin Proteins/metabolism
10.
Sci Immunol ; 5(53)2020 11 06.
Article in English | MEDLINE | ID: covidwho-999190

ABSTRACT

Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-ß present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunologic Memory/immunology , Lung/immunology , Pneumonia, Viral/immunology , SARS-CoV-2/immunology , Age Factors , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , COVID-19/metabolism , COVID-19/virology , Host-Pathogen Interactions/immunology , Humans , Influenza, Human/immunology , Influenza, Human/metabolism , Influenza, Human/virology , Lung/metabolism , Lung/virology , Mice, Inbred C57BL , Orthomyxoviridae/immunology , Orthomyxoviridae/physiology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/virology , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2/physiology , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta/metabolism
11.
Life Sci ; 266: 118883, 2021 Feb 01.
Article in English | MEDLINE | ID: covidwho-974347

ABSTRACT

Coronavirus disease 2019 (COVID-19) has rapidly spread around the world causing global public health emergency. In the last twenty years, we have witnessed several viral epidemics such as severe acute respiratory syndrome coronavirus (SARS-CoV), Influenza A virus subtype H1N1 and most recently Middle East respiratory syndrome coronavirus (MERS-CoV). There were tremendous efforts endeavoured globally by scientists to combat these viral diseases and now for SARS-CoV-2. Several drugs such as chloroquine, arbidol, remdesivir, favipiravir and dexamethasone are adopted for use against COVID-19 and currently clinical studies are underway to test their safety and efficacy for treating COVID-19 patients. As per World Health Organization reports, so far more than 16 million people are affected by COVID-19 with a recovery of close to 10 million and deaths at 600,000 globally. SARS-CoV-2 infection is reported to cause extensive pulmonary damages in affected people. Given the large number of recoveries, it is important to follow-up the recovered patients for apparent lung function abnormalities. In this review, we discuss our understanding about the development of long-term pulmonary abnormalities such as lung fibrosis observed in patients recovered from coronavirus infections (SARS-CoV and MERS-CoV) and probable epigenetic therapeutic strategy to prevent the development of similar pulmonary abnormalities in SARS-CoV-2 recovered patients. In this regard, we address the use of U.S. Food and Drug Administration (FDA) approved histone deacetylase (HDAC) inhibitors therapy to manage pulmonary fibrosis and their underlying molecular mechanisms in managing the pathologic processes in COVID-19 recovered patients.


Subject(s)
COVID-19/complications , Drug Repositioning , Histone Deacetylase Inhibitors/therapeutic use , Pulmonary Fibrosis/drug therapy , Transforming Growth Factor beta/metabolism , Adult , Aged , COVID-19/pathology , COVID-19/therapy , Coronavirus Infections/pathology , Extracellular Matrix/pathology , Extracellular Matrix/virology , Histone Deacetylase Inhibitors/pharmacology , Humans , Middle Aged , Pulmonary Fibrosis/virology , Risk Factors , Signal Transduction , Survivors
12.
Sci Rep ; 10(1): 18689, 2020 10 29.
Article in English | MEDLINE | ID: covidwho-894418

ABSTRACT

The COVID-19 fatality rate is high when compared to the H1N1pdm09 (pandemic Influenza A virus H1N1 subtype) rate, and although both cause an aggravated inflammatory response, the differences in the mechanisms of both pandemic pneumonias need clarification. Thus, our goal was to analyze tissue expression of interleukins 4, 13, (IL-4, IL-13), transforming growth factor-beta (TGF-ß), and the number of M2 macrophages (Sphingosine-1) in patients who died by COVID-19, comparing with cases of severe pneumopathy caused by H1N1pdm09, and a control group without lung injury. Six lung biopsy samples of patients who died of SARS-CoV-2 (COVID-19 group) were used and compared with ten lung samples of adults who died from a severe infection of H1N1pdm09 (H1N1 group) and eleven samples of patients who died from different causes without lung injury (CONTROL group). The expression of IL-4, IL-13, TGF-ß, and M2 macrophages score (Sphingosine-1) were identified through immunohistochemistry (IHC). Significantly higher IL-4 tissue expression and Sphingosine-1 in M2 macrophages were observed in the COVID-19 group compared to both the H1N1 and the CONTROL groups. A different mechanism of diffuse alveolar damage (DAD) in SARS-CoV-2 compared to H1N1pdm09 infections were observed. IL-4 expression and lung remodeling are phenomena observed in both SARS-CoV-2 and H1N1pdm09. However, SARS-CoV-2 seems to promote lung damage through different mechanisms, such as the scarce participation Th1/Th17 response and the higher participation of the Th2. Understanding and managing the aggravated and ineffective immune response elicited by SARS-CoV-2 merits further clarification to improve treatments propose.


Subject(s)
Coronavirus Infections/metabolism , Interleukin-13/metabolism , Interleukin-4/metabolism , Lung/metabolism , Pneumonia, Viral/metabolism , Aged , Aged, 80 and over , Biomarkers/metabolism , COVID-19 , Coronavirus Infections/pathology , Female , Humans , Interleukin-13/genetics , Interleukin-4/genetics , Lung/pathology , Macrophages/metabolism , Male , Middle Aged , Pandemics , Pneumonia, Viral/pathology , Sphingosine/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism
13.
Cell Death Dis ; 11(10): 921, 2020 10 27.
Article in English | MEDLINE | ID: covidwho-894382

ABSTRACT

The immunological mechanisms underlying the clinical presentation of SARS-CoV-2 infection and those influencing the disease outcome remain to be defined. Myeloid-derived suppressor cells (MDSC) have been described to be highly increased during COVID-19, however, their role remains elusive. We performed an in depth analysis of MDSC in 128 SARS-CoV-2 infected patients. Polymorphonuclear (PMN)-MDSC expanded during COVID-19, in particular in patients who required intensive care treatments, and correlated with IL-1ß, IL-6, IL-8, and TNF-α plasma levels. PMN-MDSC inhibited T-cells IFN-γ production upon SARS-CoV-2 peptides stimulation, through TGF-ß- and iNOS-mediated mechanisms, possibly contrasting virus elimination. Accordingly, a multivariate regression analysis found a strong association between PMN-MDSC percentage and fatal outcome of the disease. The PMN-MDSC frequency was higher in non-survivors than survivors at the admission time, followed by a decreasing trend. Interestingly, this trend was associated with IL-6 increase in non-survivors but not in survivors. In conclusion, this study indicates PMN-MDSC as a novel factor in the pathogenesis of SARS-CoV2 infection, and open up to new therapeutic options.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Myeloid-Derived Suppressor Cells/immunology , Pneumonia, Viral/pathology , T-Lymphocytes/immunology , Aged , Area Under Curve , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Female , Humans , Interferon-gamma/metabolism , Interleukin-1beta/blood , Interleukin-6/blood , Male , Middle Aged , Myeloid-Derived Suppressor Cells/cytology , Neutrophils/cytology , Neutrophils/immunology , Neutrophils/metabolism , Nitric Oxide Synthase Type II/metabolism , Pandemics , Peptides/immunology , Peptides/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Proportional Hazards Models , ROC Curve , SARS-CoV-2 , Survival Rate , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Transforming Growth Factor beta/blood , Transforming Growth Factor beta/metabolism
14.
Biomed Pharmacother ; 130: 110548, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-679603

ABSTRACT

Although 70 % of the genome is transcribed to RNA in humans, only ∼2% of these transcripts are translated into proteins. The rest of the transcripts are defined as noncoding RNAs, including Long noncoding RNAs (LncRNAs) and MicroRNAs (miRNAs) that mostly function post-transcriptionally to regulate the gene expression. The outbreak of a novel coronavirus (SARS-CoV) has caused a major public health concern across the globe. The SARS-CoV is the seventh coronavirus that is known to cause human disease. There are currently no promising antiviral drugs with proven efficacy nor are there vaccines for its prevention. As of August 10, 2020, SARS-CoV has been infected more than 13 million cases in more than 213 countries, with an estimated mortality rate of ∼3 %. Thus, it is of utmost important priority to develop novel therapies for COVID-19. It is not fully investigated whether noncoding RNAs regulate signaling pathways that SARS-CoV involved in. Hence, computational analysis of the noncoding RNA interactions and determining importance of key regulatory noncoding RNAs in antiviral defense mechanisms will likely be helpful in developing new drugs to attack SARS-CoV infection. To elucidate this, we utilized bioinformatic approaches to find the interaction network of SARS-CoV/human proteins, miRNAs, and lncRNAs. We found TGF-beta signaling pathway as one of the potential interactive pathways. Furthermore, potential miRNAs/lncRNAs networks that the virus might engage during infection in human host cells have been shown. Altogether, TGF-beta signaling pathway as well as hub miRNAs, and LncRNAs involve during SARS-CoV pathogenesis can be considered as potential therapeutic targets.


Subject(s)
COVID-19/metabolism , COVID-19/virology , MicroRNAs/metabolism , RNA, Long Noncoding/metabolism , SARS-CoV-2/metabolism , COVID-19/genetics , Computational Biology , Computer Simulation , Gene Regulatory Networks , Genome, Human , Genome, Viral , Humans , MicroRNAs/genetics , RNA Processing, Post-Transcriptional , RNA, Long Noncoding/genetics , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , SARS-CoV-2/genetics , Transforming Growth Factor beta/metabolism
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