ABSTRACT
Obesity is associated with several diseases, including mental health. Adipose tissue is distributed around the internal organs, acting in the regulation of metabolism by storing and releasing fatty acids and adipokine in the tissues. Excessive nutritional intake results in hypertrophy and proliferation of adipocytes, leading to local hypoxia in adipose tissue and changes in these adipokine releases. This leads to the recruitment of immune cells to adipose tissue and the release of pro-inflammatory cytokines. The presence of high levels of free fatty acids and inflammatory molecules interfere with intracellular insulin signaling, which can generate a neuroinflammatory process. In this review, we provide an up-to-date discussion of how excessive obesity can lead to possible cognitive dysfunction. We also address the idea that obesity-associated systemic inflammation leads to neuroinflammation in the brain, particularly the hypothalamus and hippocampus, and that this is partially responsible for these negative cognitive outcomes. In addition, we discuss some clinical models and animal studies for obesity and clarify the mechanism of action of anti-obesity drugs in the central nervous system.Copyright © 2023 Wolters Kluwer Medknow Publications. All rights reserved.
ABSTRACT
Objective: COVID19 is associated with vascular inflammation. IFN-alpha (IFNa) and IFN-lambda3 (IFNl3) are potent cytokines produced in viral infections. Their effects involve interferon-stimulated genes (ISGs) and may influence expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. We hypothesized that S1P-induced immune/inflammatory responses in endothelial cells (EC) are mediated via IFN-activated pathways Design and methods: Human ECs were stimulated with S1P (1 mg/mL), IFNa (100ng/mL) or IFNl3 (100IU/mL). Because ACE2, ADAM17 and TMPRSS2 are important for SARS-CoV-2 infection, we used inhibitors of ADAM17 (marimastat, 3.8 nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50 mM). Gene and protein expression was investigated by real-time PCR and immunoblotting, respectively. Vascular function was assessed in mesenteric arteries from wild-type (WT) normotensive and hypertensive (LinA3) mice and in ISG15-deficient (ISG15KO) mice. Results: S1P increased expression of IFNa (3-fold), IFNl3 (4-fold) and ISGs (2-fold) in EC (p < 0.05). EC responses to IFNa (ISG15: 16-fold) were greater than to IFNl3 (ISG15: 1.7-fold) (p < 0.05). S1P increased gene expression of IL-6 (1.3-fold), TNFa (6.2-fold) and IL-1b (3.3-fold), effects that were amplified by IFNs. Only the ADAM17 inhibitor marimastat inhibited S1P effects. IFNa and IFNl3 increase protein expression of ADAM17 (27%) and TMPRSS2 (38%). No changes were observed on ACE2 expression. This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). EC production of IL-6 was increased by IFNa (1,230pg/mL) and IFNl3 (1,124pg/mL) vs control (591pg/mL). Nitric oxide generation and eNOS phosphorylation (Ser1177) were reduced by IFNa (40%) and IFNl3 (40%). Vascular functional responses demonstrated that endothelium-dependent vasorelaxation (% Emax) in vessels from WT-mice stimulated with IFNa (67%) and IFNl3 (71%) were reduced vs control (82%) (p < 0.05). Responses were not altered in vessels from ISG15KO mice. Increased contraction was observed only in vessels from hypertensive mice treated with IFNa (9.1 ± 0.5mN vs control: 7.3 ± 0.3mN) (p < 0.05). Conclusions: In ECs, S1P, IFNa and IFNl3 increased ISG15 and IL-6 by mechanisms dependent on ADAM17. IFNs amplifies endothelial cell inflammatory responses and induced vascular dysfunction through ISG15-dependent mechanisms, with augmented effects in hypertension. Our findings demonstrate that S1P induces immune/inflammatory responses that may be important in endotheliitis associated with COVID-19. This may be especially important in the presence of cardiovascular risk factors, including hypertension.
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Purpose: The field of osteoarthritis (OA) biology is rapidly evolving and brilliant progress has been made this year as well. Methods: Landmark studies of OA biology published in 2021 and early 2022 were selected through PubMed searches and classified by their molecular mechanisms, and it was largely divided into the intra-cellular mechanisms and the inter-compartment or inter-cellular interaction in OA progression. Results: The intra-cellular mechanisms involving OA progression included 1) Piezo1/TRPV4-mediated calcium signaling, 2) low grade inflammation by TLR-CD14-LBP complex and IKKβ-NFkB signaling, 3) PGRN/TNFR2/14-3-3ε/Elk-1 anabolic cascade, 4) G protein-coupled receptor (GPCR) signaling, 5) mechanical loading-cilia/Ift88-hedgehog signaling, 6) mitochondrial fission by ERK1/2-DRP1 pathway, and 7) hypoxia-DOT1L-H3K79 methylation pathway. The studies on inter-compartment or inter-cellular interaction in OA progression included the following subjects: 1) the anabolic role of Lubricin, a proteoglycan from superficial zone cells, 2) osteoclast-chondrocyte interaction via exosomal miRNA and sphingosine 1-phosphate (S1P), 3) αV integrin-mediated TGFβ activation by mechanical loading, 4) TGFβ-mediated suppression of sclerostin in osteocytes, 5) catabolic role of Flightless I as a DAMPs-triggering molecule, and 6) catabolic role of paracrine signaling from fat. Conclusions: Despite the disastrous Covid-19 pandemic situation, many outstanding studies have expanded the boundary of OA biology. They give us not only critical insight on pathophysiology, but also clue for the treatment of OA.
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Objective: The Chinese herbal formula Huo-Xiang-Zheng-Qi (HXZQ) is effective in preventing and treating coronavirus disease 19 (COVID-19) infection;however, its mechanism remains unclear. This study used network pharmacology and molecular docking techniques to investigate the mechanism of action of HXZQ in preventing and treating COVID-19. Methods: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was used to search for the active ingredients and targets of the 10 traditional Chinese medicines (TCMs) of HXZQ prescription (HXZQP). GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmacogenomics Knowledge Base (PharmGKB), Therapeutic Target Database (TTD), and DrugBank databases were used to screen COVID-19-related genes and intersect them with the targets of HXZQP to obtain the drug efficacy targets. Cytoscape 3.8 software was used to construct the drug-active ingredient–target interaction network of HXZQP and perform protein–protein interaction (PPI) network construction and topology analysis. R software was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, AutoDock Vina was utilized for molecular docking of the active ingredients of TCM and drug target proteins. Results: A total of 151 active ingredients and 250 HXZQP targets were identified. Among these, 136 active ingredients and 67 targets of HXZQP were found to be involved in the prevention and treatment of COVID-19. The core proteins identified in the PPI network were MAPK1, MAPK3, MAPK8, MAPK14, STAT3, and PTGS2. Using GO and KEGG pathway enrichment analysis, HXZQP was found to primarily participate in biological processes such as defense response to a virus, cellular response to biotic stimulus, response to lipopolysaccharide, PI3K-Akt signaling pathway, Th17 cell differentiation, HIF-1 signaling pathway, and other signaling pathways closely related to COVID-19. Molecular docking results reflected that the active ingredients of HXZQP have a reliable affinity toward EGFR, MAPK1, MAPK3, MAPK8, and STAT3 proteins. Conclusion: Our study elucidated the main targets and pathways of HXZQP in the prevention and treatment of COVID-19. The study findings provide a basis for further investigation of the pharmacological effects of HXZQP.
ABSTRACT
Objective: COVID19-associated immunopathology is associated with increased production of interferon (IFN)-alpha (IFNα) and lambda3 (IFNL3). Effects of IFNs are mediated by interferon-stimulated genes (ISGs) and influence expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. Increasing evidence indicates vascular inflammation in cardiovascular sequelae of COVID19. We hypothesized that S1P-induced immune/inflammatory responses in endothelial cells (EC) are mediated via IFNα and IFNL3. Design and method: Human ECs were stimulated with S1P (1 μg/mL), IFNα (100ng/mL) or IFNL3 (100IU/mL). Because ACE2, metalloproteinase domain-17 (ADAM17) and type-II transmembrane serine protease (TMPRSS2) are important for SARS-CoV-2 infection, cells were treated with inhibitors of ADAM17 (marimastat, 3.8 nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50 μM). Gene and protein expression was investigated by real-time PCR immunoblotting, respectively. Vascular function was assessed in mesenteric arteries from wild-type (WT) normotensive and hypertensive mice and in ISG15-deficient (ISG15KO) mice. Results: EC stimulated with S1P increased expression of IFNα (3-fold), IFNL3 (4-fold) and ISG (2-fold)(p < 0.05). EC exhibited higher responses to IFNα (ISG15: 16-fold) than to IFNL3 (ISG15: 1.7-fold)(p < 0.05). S1P increased gene expression of IL-6 (1.3-fold), TNFα (6.2-fold) and IL-1β (3.3-fold), effects that were maximized by IFNs. Only marimastat inhibited S1P effects. IL-6 was increased by IFNα (1,230pg/mL) and IFNL3 (1,124pg/mL) vs control (591pg/ mL). This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). Nitric oxide production and eNOS phosphorylation (Ser1177) were reduced by IFNα and (40%) and IFNL3 (40%). Reduced endothelium relaxation maximal response (%Emax) was observed in vessels from WTmice stimulated with IFNα (67%) and IFNL3 (71%) vs control (82%)(p < 0.05) but not in vessels from ISG15KO mice. Increased contraction was observed only in vessels from hypertensive mice treated with IFNα (9.1 ± 0.5mN vs control: 7.3 ± 0.3mN, p < 0.05). Conclusions: In ECs, S1P, IFNα and IFNL3 increased ISG15 and IL-6, processes that involve ADAM17. Inflammation induced by S1P was amplified by IFNs. IFNs induce vascular dysfunction through ISG15-dependent mechanisms, with augmented effects in hypertension. Our findings demonstrate that S1P induces immune/inflammatory responses that may be important in endotheliitis associated with COVID-19. This is especially important in the presence of cardiovascular risk factors, including hypertension.
ABSTRACT
Background: Human cardiac pericytes (PC) were proposed as the main cellular target for SARS-CoV-2 in the heart due to high transcriptional levels of the angiotensin-converting enzyme 2 (ACE2) receptor. Emerging reports indicate CD147/Basigin (BSG), highly expressed in endothelial cells (EC), is an alternative SARS-CoV-2 receptor. To date, the mechanism by which the virus infects and disrupts the heart vascular cells was not identified yet. Moreover, cleaved Spike (S) protein molecules could be released into the bloodstream from the leaking pulmonary epithelial-endothelial barrier in patients with severe COVID-19, opening to the possibility of non-infective diseases in organs distant from the primary site of infection. Purposes: (1) to confirm that human primary cardiac PC express ACE2 and CD147;(2) to verify if PC are permissible to SARS-CoV-2 infection;(3) to investigate if the recombinant SARS-CoV-2 S protein alone, without the other viral elements, can trigger molecular signalling and induce functional alterations in PC;(4) to explore which viral receptor is responsible for the observed events. Methods and results: Cardiac PC express both the ACE2 and CD147 receptors at mRNA and protein level. Incubation of PC for up to 5 days with SARS-CoV-2 expressing the green fluorescent protein (GFP) did not show any evidence of cell infection or viral replication. Next, we exposed the PC to the recombinant S protein (5.8 nM) and confirmed that the protein engaged with cellular receptors (western blot analysis of S protein in treated and control PC). Incubation with the S protein increased PC migration (wound closure assay, P<0.01 vs ctrl) and reduced the formation of tubular structures between PC and EC in a Matrigel assay (P<0.01 vs ctrl). Moreover, the S protein promoted the production of pro-inflammatory factors typical of the cytokine storm in PC (ELISA measurement of MCP1, IL-6, IL-1β, TNFα, P<0.05 vs ctrl), and induced the secretion of proapoptotic factors responsible for EC death (Caspase 3/7 assay, P<0.05 vs ctrl). Signalling studies revealed that the S protein triggers the phosphorylation/ activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in cardiac PC. The neutralization of CD147, using a blocking antibody, prevented ERK1/2 activation in PC, and was reflected into a partial rescue of the cell functional behaviour (migration and pro-angiogenic capacity). In contrast, blockage of CD147 failed to prevent the pro-inflammatory response in PC. Conclusions: We propose the novel hypothesis that COVID-19 associated heart's microvascular dysfunction is prompted by circulating S protein molecules rather than by the direct coronavirus infection of PC. Besides, we propose CD147, and not ACE2, as the leading receptor mediating S protein signalling in cardiac PC.
ABSTRACT
Recently an outbreak that emerged in Wuhan, China in December 2019, spread to the whole world in a short time and killed >1,410,000 people. It was determined that a new type of beta coronavirus called severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) was causative agent of this outbreak and the disease caused by the virus was named as coronavirus disease 19 (COVID19). Despite the information obtained from the viral genome structure, many aspects of the virus-host interactions during infection is still unknown. In this study we aimed to identify SARS-CoV-2 encoded microRNAs and their cellular targets. We applied a computational method to predict miRNAs encoded by SARS-CoV-2 along with their putative targets in humans. Targets of predicted miRNAs were clustered into groups based on their biological processes, molecular function, and cellular compartments using GO and PANTHER. By using KEGG pathway enrichment analysis top pathways were identified. Finally, we have constructed an integrative pathway network analysis with target genes. We identified 40 SARS-CoV-2 miRNAs and their regulated targets. Our analysis showed that targeted genes including NFKB1, NFKBIE, JAK1-2, STAT3-4, STAT5B, STAT6, SOCS1-6, IL2, IL8, IL10, IL17, TGFBR1-2, SMAD2-4, HDAC1-6 and JARID1A-C, JARID2 play important roles in NFKB, JAK/STAT and TGFB signaling pathways as well as cells' epigenetic regulation pathways. Our results may help to understand virus-host interaction and the role of viral miRNAs during SARS-CoV-2 infection. As there is no current drug and effective treatment available for COVID19, it may also help to develop new treatment strategies.