المؤلفون: Jin Young Choi, Hee Won Byeon, Seong Ok Park, Erdenebileg Uyangaa, Koanhoi Kim, Seong Kug Eo

المصدر: Journal of Neuroinflammation, Vol 21, Iss 1, Pp 1-22 (2024)

مصطلحات موضوعية: NADPH oxidase 2, Japanese encephalitis, Macrophages, Reactive oxygen species, ROS scavenger, Neurology. Diseases of the nervous system, RC346-429

الوصف: Abstract Background Macrophages play a pivotal role in the regulation of Japanese encephalitis (JE), a severe neuroinflammation in the central nervous system (CNS) following infection with JE virus (JEV). Macrophages are known for their heterogeneity, polarizing into M1 or M2 phenotypes in the context of various immunopathological diseases. A comprehensive understanding of macrophage polarization and its relevance to JE progression holds significant promise for advancing JE control and therapeutic strategies. Methods To elucidate the role of NADPH oxidase-derived reactive oxygen species (ROS) in JE progression, we assessed viral load, M1 macrophage accumulation, and cytokine production in WT and NADPH oxidase 2 (NOX2)-deficient mice using murine JE model. Additionally, we employed bone marrow (BM) cell-derived macrophages to delineate ROS-mediated regulation of macrophage polarization by ROS following JEV infection. Results NOX2-deficient mice exhibited increased resistance to JE progression rather than heightened susceptibility, driven by the regulation of macrophage polarization. These mice displayed reduced viral loads in peripheral lymphoid tissues and the CNS, along with diminished infiltration of inflammatory cells into the CNS, thereby resulting in attenuated neuroinflammation. Additionally, NOX2-deficient mice exhibited enhanced JEV-specific Th1 CD4 + and CD8 + T cell responses and increased accumulation of M1 macrophages producing IL-12p40 and iNOS in peripheral lymphoid and inflamed extraneural tissues. Mechanistic investigations revealed that NOX2-deficient macrophages displayed a more pronounced differentiation into M1 phenotypes in response to JEV infection, thereby leading to the suppression of viral replication. Importantly, the administration of H2O2 generated by NOX2 was shown to inhibit M1 macrophage polarization. Finally, oral administration of the ROS scavenger, butylated hydroxyanisole (BHA), bolstered resistance to JE progression and reduced viral loads in both extraneural tissues and the CNS, along with facilitated accumulation of M1 macrophages. Conclusion In light of our results, it is suggested that ROS generated by NOX2 play a role in undermining the control of JEV replication within peripheral extraneural tissues, primarily by suppressing M1 macrophage polarization. Subsequently, this leads to an augmentation in the viral load invading the CNS, thereby facilitating JE progression. Hence, our findings ultimately underscore the significance of ROS-mediated macrophage polarization in the context of JE progression initiated JEV infection.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1742-2094Test

الوصول الحر: https://doaj.org/article/2b3e874e1b5c432586e4138dff43d0f1Test

المؤلفون: Xin Shi, Panpan Li, Marc Herb, Hanhan Liu, Maoren Wang, Xiaosha Wang, Yuan Feng, Tim van Beers, Ning Xia, Huige Li, Verena Prokosch

المصدر: Journal of Neuroinflammation, Vol 21, Iss 1, Pp 1-23 (2024)

مصطلحات موضوعية: NADPH oxidase 2, Deletion, Pharmacological inhibition, Oxidative stress, Neurodegeneration, Neuroinflammation, Neurology. Diseases of the nervous system, RC346-429

الوصف: Abstract Background NADPH oxidase (NOX), a primary source of endothelial reactive oxygen species (ROS), is considered a key event in disrupting the integrity of the blood-retinal barrier. Abnormalities in neurovascular-coupled immune signaling herald the loss of ganglion cells in glaucoma. Persistent microglia-driven inflammation and cellular innate immune system dysregulation often lead to deteriorating retinal degeneration. However, the crosstalk between NOX and the retinal immune environment remains unresolved. Here, we investigate the interaction between oxidative stress and neuroinflammation in glaucoma by genetic defects of NOX2 or its regulation via gp91ds-tat. Methods Ex vivo cultures of retinal explants from wildtype C57BL/6J and Nox2 −/− mice were subjected to normal and high hydrostatic pressure (Pressure 60 mmHg) for 24 h. In vivo, high intraocular pressure (H-IOP) was induced in C57BL/6J mice for two weeks. Both Pressure 60 mmHg retinas and H-IOP mice were treated with either gp91ds-tat (a NOX2-specific inhibitor). Proteomic analysis was performed on control, H-IOP, and treatment with gp91ds-tat retinas to identify differentially expressed proteins (DEPs). The study also evaluated various glaucoma phenotypes, including IOP, retinal ganglion cell (RGC) functionality, and optic nerve (ON) degeneration. The superoxide (O2 -) levels assay, blood-retinal barrier degradation, gliosis, neuroinflammation, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative PCR were performed in this study. Results We found that NOX2-specific deletion or activity inhibition effectively attenuated retinal oxidative stress, immune dysregulation, the internal blood-retinal barrier (iBRB) injury, neurovascular unit (NVU) dysfunction, RGC loss, and ON axonal degeneration following H-IOP. Mechanistically, we unveiled for the first time that NOX2-dependent ROS-driven pro-inflammatory signaling, where NOX2/ROS induces endothelium-derived endothelin-1 (ET-1) overexpression, which activates the ERK1/2 signaling pathway and mediates the shift of microglia activation to a pro-inflammatory M1 phenotype, thereby triggering a neuroinflammatory outburst. Conclusions Collectively, we demonstrate for the first time that NOX2 deletion or gp91ds-tat inhibition attenuates iBRB injury and NVU dysfunction to rescue glaucomatous RGC loss and ON axon degeneration, which is associated with inhibition of the ET-1/ERK1/2-transduced shift of microglial cell activation toward a pro-inflammatory M1 phenotype, highlighting NOX2 as a potential target for novel neuroprotective therapies in glaucoma management.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1742-2094Test

الوصول الحر: https://doaj.org/article/8cefb59a93cf49a6b18fe067964ea100Test

المؤلفون: Zhan, Yongqiang, Xu, Dongwei, Tian, Yizhu, Qu, Xiaoye, Sheng, Mingwei, Lin, Yuanbang, Ke, Michael, Jiang, Longfeng, Xia, Qiang, Kaldas, Fady M, Farmer, Douglas G, Ke, Bibo

المصدر: JHEP reports : innovation in hepatology. 4(9)

مصطلحات موضوعية: ALT, alanine aminotransferase, APAF1, apoptotic peptidase activating factor 1, ASK1, apoptosis signal-regulating kinase 1, AST, aspartate aminotransferase, Apoptosis, BMM, bone marrow-derived macrophage, CXCL-10, C-X-C motif chemokine ligand 10, CYLD, cyclindromatosis, ChIP, chromatin immunoprecipitation, DAMP, damage-associated molecular pattern, DUB, deubiquitinating enzyme, ER, endoplasmic reticulum, ES, embryonic stem, G3BP1, G3BP1, Ras GTPase-activating protein-binding protein 1, GCLC, glutamate-cysteine ligase catalytic subunit, GCLM, glutamate-cysteine ligase regulatory subunit, IHC, immunohistochemistry, INF-β, interferon-β, IR, ischaemia/reperfusion, IRF3, IRF3, interferon regulatory factor 3, IRF7, IFN-regulating transcription factor 7, IRI, ischaemia/reperfusion injury, Innate immunity, KO, knockout, LPS, lipopolysaccharide, Liver inflammation, Lyz2, Lysozyme 2, MCP-1, monocyte chemoattractant protein 1, NOX2, NADPH oxidase 2, NOX4, NADPH oxidase 4, NQO1, NAD(P)H quinone dehydrogenase 1, NRF2, nuclear factor (erythroid-derived 2)-like 2, NS, non-specific, Necroptosis, OASL1, 2′, 5′oligoadenylate synthetase-like 1, PAMP, pathogen-derived molecular pattern, RIPK3, receptor-interacting serine/threonine-protein kinase 3, ROS, reactive oxygen species, STING, STING, stimulator of interferon genes, TBK1, TANK-binding kinase 1, TLR4, Toll-like receptor 4, TNF-α, tumour necrosis factor-alpha, TRX, thioredoxin, TSS, transcription start sites, TXNIP, thioredoxin-interacting protein, TXNIPFL/FL, floxed TXNIP, TXNIPM-KO, myeloid-specific TXNIP KO, UTR, untranslated region, sALT, serum ALT, sAST, serum AST, siRNA, small interfering RNA, Liver Disease, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being

الوصف: Background & aimsThe stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress.MethodsA mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice.ResultsThe TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-β (IFN-β) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2',5' oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis.ConclusionsMacrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases.Lay summaryLiver inflammation and injury induced by ischaemia and reperfusion (the absence of blood flow to the liver tissue followed by the resupply of blood) is a significant cause of hepatic dysfunction and failure following liver transplantation, resection, and haemorrhagic shock. Herein, we uncover an underlying mechanism that contributes to liver inflammation and cell death in this setting and could be a therapeutic target in stress-induced liver inflammatory injury.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/54g9807fTest

المؤلفون: Yuqi Gao, Rui Hua, Kezheng Peng, Yuemiao Yin, Chenye Zeng, Yannan Guo, Yida Wang, Liyuan Li, Xue Li, Ying Qiu, Zhao Wang

المصدر: Food Science and Human Wellness, Vol 12, Iss 4, Pp 1081-1101 (2023)

مصطلحات موضوعية: Starchy carbohydrates, Nonalcoholic fatty liver disease, NADPH oxidase 2, Fatty acid influx, Nutrition. Foods and food supply, TX341-641

الوصف: Nonalcoholic fatty liver disease (NAFLD) is a high-incidence lipid disorder that affects more than a quarter of the population worldwide, and dietary intervention is the recognized treatment. Starch is the main component of staple foods that are consumed daily, and the effects, metabolic pathway, and molecular mechanism of starch in the context of NAFLD remain unclear. Our study showed that a high-starch carbohydrate diet (HCD) led to the occurrence and exacerbation of NAFLD in mice. Transcriptomics and metabonomic analyses showed that the increased fatty acid influx mediated by NADPH oxidase 2 (NOX2) exacerbated NAFLD. Knocking down NOX2 specifically alleviated HCD-induced NAFLD in vivo and in vitro. Moreover, the large amounts of ROS produced by NOX2 further exacerbated insulin resistance and increased lipolysis in perirenal white adipose tissue (periWAT), thereby providing fatty acids for hepatic lipid synthesis. In addition, the interaction between AMPKα1 and p47phox was the pathway that mediated the high expression of NOX2 induced by a HCD. Our study systematically demonstrated the effect of a HCD on NAFLD. Elevated fatty acid influx is a unique molecular regulatory pathway that mediates HCD-induced NAFLD exacerbation, which is different from the effect of simple sugars. Additionally, NOX2 was suggested to be a specific and effective drug target for NAFLD.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2213453022002452Test; https://doaj.org/toc/2213-4530Test

الوصول الحر: https://doaj.org/article/d0c4aab398b646c3b0e2b55caf678fd7Test

المؤلفون: Côco, Larissa Zambom, Aires, Rafaela, Carvalho, Glaucimeire Rocha, Belisário, Eduarda de Souza, Yap, Michelle Khai Khun, Gobbi Amorim, Fernanda, Conde-Aranda, Javier, Nogueira, Breno Valentim, Vasquez, Elisardo Corral, Pereira, Thiago de Melo Costa, Campagnaro, Bianca Prandi

المصدر: Cells, 12 (24), 2799 (2023-12-08)

مصطلحات موضوعية: anti-inflammatory, bioprospection, gastroprotection, oxidative stress, Antioxidants, Interleukin-10, NADPH Oxidase 2, Tumor Necrosis Factor-alpha, Reactive Oxygen Species, Peptides, Mice, Animals, Male, Antioxidants/pharmacology, Antioxidants/therapeutic use, Tumor Necrosis Factor-alpha/adverse effects, Reactive Oxygen Species/adverse effects, Peptides/therapeutic use, Stomach Ulcer/chemically induced, Stomach Ulcer/prevention & control, Stomach Ulcer/drug therapy, Kefir, Stomach Ulcer, Biochemistry, Genetics and Molecular Biology (all), General Medicine, Physical, chemical, mathematical & earth Sciences, Chemistry, Physique, chimie, mathématiques & sciences de la terre, Chimie

الوصف: The present study was conducted to evaluate the protective effect of milk kefir against NSAID-induced gastric ulcers. Male Swiss mice were divided into three groups: control (Vehicle; UHT milk at a dose of 0.3 mL/100 g), proton pump inhibitor (PPI; lansoprazole 30 mg/kg), and 4% milk kefir (Kefir; 0.3 mL/100 g). After 14 days of treatment, gastric ulcer was induced by oral administration of indomethacin (40 mg/kg). Reactive oxygen species (ROS), nitric oxide (NO), DNA content, cellular apoptosis, IL-10 and TNF-α levels, and myeloperoxidase (MPO) enzyme activity were determined. The interaction networks between NADPH oxidase 2 and kefir peptides 1-35 were determined using the Residue Interaction Network Generator (RING) webserver. Pretreatment with kefir for 14 days prevented gastric lesions. In addition, kefir administration reduced ROS production, DNA fragmentation, apoptosis, and TNF-α systemic levels. Simultaneously, kefir increased NO bioavailability in gastric cells and IL-10 systemic levels. A total of 35 kefir peptides showed affinity with NADPH oxidase 2. These findings suggest that the gastroprotective effect of kefir is due to its antioxidant and anti-inflammatory properties. Kefir could be a promising natural therapy for gastric ulcers, opening new perspectives for future research.

العلاقة: https://www.mdpi.com/2073-4409/12/24/2799/pdfTest; urn:issn:2073-4409

الوصول الحر: https://orbi.uliege.be/handle/2268/314220Test

المؤلفون: Youn, Ji Youn, Zhang, Yixuan, Wu, Yusi, Cannesson, Maxime, Cai, Hua

مصطلحات موضوعية: Lung, Emerging Infectious Diseases, Tobacco Smoke and Health, Clinical Research, Tobacco, Infectious Diseases, Estrogen, Cancer, Prevention, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Aetiology, Development of treatments and therapeutic interventions, Cardiovascular, Respiratory, Good Health and Well Being, Angiotensin-Converting Enzyme 2, COVID-19, Chemokine CCL2, Endothelial Cells, Estrogens, Female, Humans, Interleukin-6, Male, NADPH Oxidase 2, Reactive Oxygen Species, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Up-Regulation, COVID-19 Drug Treatment, IL-6, SARS CoV-2 spike protein, Endothelial cells, Oxidative stress, NOX2, ACE2, MCP-1, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Pharmacology and Pharmaceutical Sciences

الوصف: The outbreak of COVID-19 has remained uncontained with urgent need for robust therapeutics. We have previously reported sex difference of COVID-19 for the first time indicating male predisposition. Males are more susceptible than females, and more often to develop into severe cases with higher mortality. This predisposition is potentially linked to higher prevalence of cigarette smoking. Nonetheless, we found for the first time that cigarette smoking extract (CSE) had no effect on angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) expression in endothelial cells. The otherwise observed worse outcomes in smokers is likely linked to baseline respiratory diseases associated with chronic smoking. Instead, we hypothesized that estrogen mediated protection might underlie lower morbidity, severity and mortality of COVID-19 in females. Of note, endothelial inflammation and barrier dysfunction are major mediators of disease progression, and development of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. Therefore, we investigated potential protective effects of estrogen on endothelial cells against oxidative stress induced by interleukin-6 (IL-6) and SARS-CoV-2 spike protein (S protein). Indeed, 17β-estradiol completely reversed S protein-induced selective activation of NADPH oxidase isoform 2 (NOX2) and reactive oxygen species (ROS) production that are ACE2-dependent, as well as ACE2 upregulation and induction of pro-inflammatory gene monocyte chemoattractant protein-1 (MCP-1) in endothelial cells to effectively attenuate endothelial dysfunction. Effects of IL-6 on activating NOX2-dependent ROS production and upregulation of MCP-1 were also completely attenuated by 17β-estradiol. Of note, co-treatment with CSE had no additional effects on S protein stimulated endothelial oxidative stress, confirming that current smoking status is likely unrelated to more severe disease in chronic smokers. These data indicate that estrogen can serve as a novel therapy for patients with COVID-19 via inhibition of initial viral responses and attenuation of cytokine storm induced endothelial dysfunction, to substantially alleviate morbidity, severity and mortality of the disease, especially in men and post-menopause women. Short-term administration of estrogen can therefore be readily applied to the clinical management of COVID-19 as a robust therapeutic option.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/81q088sfTest

المؤلفون: Hegyi, Bence, Fasoli, Anna, Ko, Christopher Y, Van, Benjamin W, Alim, Chidera C, Shen, Erin Y, Ciccozzi, Marisa M, Tapa, Srinivas, Ripplinger, Crystal M, Erickson, Jeffrey R, Bossuyt, Julie, Bers, Donald M

المصدر: Circulation Research. 129(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Action Potentials, Adult, Aged, Animals, Arrhythmias, Cardiac, Biomarkers, Blood Glucose, Calcium Signaling, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Case-Control Studies, Diabetes Mellitus, Experimental, Excitation Contraction Coupling, Female, Glycosylation, Heart Rate, Humans, Male, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Transgenic, Middle Aged, Mutation, Myocardial Contraction, Myocytes, Cardiac, NADPH Oxidase 2, Phosphorylation, Protein Processing, Post-Translational, Mice, acetylglucosamine, action potential, electrophysiology, hyperglycemia, phosphorylation, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences

الوصف: [Figure: see text].

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0bh572jzTest

المؤلفون: Wu X, Ji D, Wang Z, Yu W, Du Q, Hu W, Zheng Y, Dong X, Chen F

المصدر: Neuropsychiatric Disease and Treatment, Vol Volume 19, Pp 1027-1042 (2023)

مصطلحات موضوعية: nadph oxidase 2, biomarker, aneurysmal subarachnoid hemorrhage, disease severity, delayed cerebral ischemia, prognosis, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429

الوصف: Xiaoyu Wu,1,* Danfei Ji,1,* Zefan Wang,1,* Wenhua Yu,2 Quan Du,2 Wei Hu,3 Yongke Zheng,3 Xiaoqiao Dong,2 Fanghui Chen4 1The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Neurosurgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Department of Intensive Care Unit, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Emergency Department, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoqiao Dong; Fanghui Chen, Email dxqhyy@163.com; wangxiaoleihzsy@163.comBackground: NADPH oxidase 2 (NOX2) is highly expressed in injured brain tissues. We determined serum NOX2 levels of aneurysmal subarachnoid hemorrhage (aSAH) patients and further investigated correlation of serum NOX2 levels with disease severity, delayed cerebral ischemia (DCI) plus prognosis after aSAH.Methods: Serum NOX2 levels were measured in 123 aSAH patients and 123 healthy controls. World Federation of Neurological Surgeons scale (WFNS) score and modified Fisher (mFisher) score were utilized to assess disease severity. Modified Rankin scale (mRS) score was used to evaluate the clinical prognosis at 90 days after aSAH. Relations of serum NOX2 levels to DCI and 90-day poor prognosis (mRS score of 3– 6) were analyzed using multivariate analysis. Receiver operating characteristic curve (ROC) was built to evaluate the prognostic predictive capability.Results: Serum NOX2 levels in aSAH patients, compared with healthy controls, were significantly increased, and were independently correlated with WFNS score, mFisher score and post-stroke 90-day mRS score. Patients with poor prognosis or DCI had significantly higher serum NOX2 levels than other remainders, and serum NOX2 levels independently predicted 90-day poor prognosis and DCI. Serum NOX2 had high prognosis and DCI predictive abilities, and their areas under ROC curve were similar to those of WFNS score and mFisher score.Conclusion: Serum NOX2 levels are significantly associated with hemorrhage severity, poor 90-day prognosis and DCI in aSAH patients. Hence, complement NOX2 may serve as a potential prognostic biomarker after aSAH.Keywords: NADPH oxidase 2, biomarker, aneurysmal subarachnoid hemorrhage, disease severity, delayed cerebral ischemia, prognosis

وصف الملف: electronic resource

العلاقة: https://www.dovepress.com/elevated-serum-nox2-levels-contribute-to-delayed-cerebral-ischemia-and-peer-reviewed-fulltext-article-NDTTest; https://doaj.org/toc/1178-2021Test

الوصول الحر: https://doaj.org/article/3ed77ce310354d7482c4acf0bb3aa224Test

المؤلفون: Maritza J. Romero, Qian Yue, Bhupesh Singla, Jürg Hamacher, Supriya Sridhar, Auriel S. Moseley, Chang Song, Mobarak A. Mraheil, Bernhard Fischer, Markus Zeitlinger, Trinad Chakraborty, David Fulton, Lin Gan, Brian H. Annex, Gabor Csanyi, Douglas C. Eaton, Rudolf Lucas

المصدر: Frontiers in Immunology, Vol 14 (2023)

مصطلحات موضوعية: Epithelial sodium channel (ENaC), SARS-CoV2 spike protein, receptor binding domain (RBD), human ACE-2, endothelial dysfunction, NADPH oxidase 2 (NOX2), Immunologic diseases. Allergy, RC581-607

الوصف: IntroductionAlthough both COVID-19 and non-COVID-19 ARDS can be accompanied by significantly increased levels of circulating cytokines, the former significantly differs from the latter by its higher vasculopathy, characterized by increased oxidative stress and coagulopathy in lung capillaries. This points towards the existence of SARS-CoV2-specific factors and mechanisms that can sensitize the endothelium towards becoming dysfunctional. Although the virus is rarely detected within endothelial cells or in the circulation, the S1 subunit of its spike protein, which contains the receptor binding domain (RBD) for human ACE2 (hACE2), can be detected in plasma from COVID-19 patients and its levels correlate with disease severity. It remains obscure how the SARS-CoV2 RBD exerts its deleterious actions in lung endothelium and whether there are mechanisms to mitigate this.MethodsIn this study, we use a combination of in vitro studies in RBD-treated human lung microvascular endothelial cells (HL-MVEC), including electrophysiology, barrier function, oxidative stress and human ACE2 (hACE2) surface protein expression measurements with in vivo studies in transgenic mice globally expressing human ACE2 and injected with RBD.ResultsWe show that SARS-CoV2 RBD impairs endothelial ENaC activity, reduces surface hACE2 expression and increases reactive oxygen species (ROS) and tissue factor (TF) generation in monolayers of HL-MVEC, as such promoting barrier dysfunction and coagulopathy. The TNF-derived TIP peptide (a.k.a. solnatide, AP301) -which directly activates ENaC upon binding to its a subunit- can override RBD-induced impairment of ENaC function and hACE2 expression, mitigates ROS and TF generation and restores barrier function in HL-MVEC monolayers. In correlation with the increased mortality observed in COVID-19 patients co-infected with S. pneumoniae, compared to subjects solely infected with SARS-CoV2, we observe that prior intraperitoneal RBD treatment in transgenic mice globally expressing hACE2 significantly increases fibrin deposition and capillary leak upon intratracheal instillation of S. pneumoniae and that this is mitigated by TIP peptide treatment.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1241448/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/601f9caadea24ac78d5e6a33f31a23e1Test

المؤلفون: Sarkar, Sutapa, Saha, Punnag, Seth, Ratanesh K, Mondal, Ayan, Bose, Dipro, Kimono, Diana, Albadrani, Muayad, Mukherjee, Avik, Porter, Dwayne E, Scott, Geoff I, Xiao, Shuo, Brooks, Bryan, Ferry, John, Nagarkatti, Mitzi, Nagarkatti, Prakash, Chatterjee, Saurabh

مصطلحات موضوعية: Medical Physiology, Biomedical and Clinical Sciences, Chronic Liver Disease and Cirrhosis, Digestive Diseases, Liver Disease, Oral and gastrointestinal, Animals, Cell Line, Enzyme Inhibitors, Fibrosis, Intestinal Mucosa, Intestines, Lactic Acid, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microcystins, NADPH Oxidase 2, Non-alcoholic Fatty Liver Disease, Phosphorylation, MC-LR, PP2A inhibitor, Lactate, Dysbiosis, Peroxynitrite, NOX2, NAFLD, Environmental Sciences, Biological Sciences, Medical and Health Sciences, Toxicology, Medical physiology, Pharmacology and pharmaceutical sciences

الوصف: Clinical studies implicated an increased risk of intestinal fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Our previous studies have shown that microcystin-LR (MC-LR) exposure led to altered gut microbiome and increased abundance of lactate producing bacteria and intestinal inflammation in underlying NAFLD. This led us to further investigate the effects of the MC-LR, a PP2A inhibitor in activating the TGF-β fibrotic pathway in the intestines that might be mediated by increased lactate induced redox enzyme NOX2. Exposure to MC-LR led to higher lactate levels in circulation and in the intestinal content. The higher lactate levels were associated with NOX2 activation in vivo that led to increased Smad2/3-Smad4 co-localization and high alpha-smooth muscle actin (α-SMA) immunoreactivity in the intestines. Mechanistically, primary mouse intestinal epithelial cells treated with lactate and MC-LR separately led to higher NOX2 activation, phosphorylation of TGFβR1 receptor and subsequent Smad 2/3-Smad4 co-localization inhibitable by apocynin (NOX2 inhibitor), FBA (a peroxynitrite scavenger) and DMPO (a nitrone spin trap), catalase and superoxide dismutase. Inhibition of NOX2-induced redox signaling also showed a significant decrease in collagen protein thus suggesting a strong redox signaling induced activation of an ectopic fibrotic manifestation in the intestines. In conclusion, the present study provides mechanistic insight into the role of microcystin in dysbiosis-linked lactate production and subsequently advances our knowledge in lactate-induced NOX2 exacerbation of the cell differentiation and fibrosis in the NAFLD intestines.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6h9479gfTest