T. M. Jeena, C. Rakshitha, Akarsha B. Jain, Vaishnavi, Fathima Razana, Aleena Varughese, M. Fathimath Muneesa, Yashodhar P. Bhandary
{"title":"Therapeutic Potential of Lentiviral miR-200a Mimics in Regulating Fibrinolysis and EMT Markers During Pulmonary Fibrosis","authors":"T. M. Jeena, C. Rakshitha, Akarsha B. Jain, Vaishnavi, Fathima Razana, Aleena Varughese, M. Fathimath Muneesa, Yashodhar P. Bhandary","doi":"10.1096/fba.2025-00276","DOIUrl":"10.1096/fba.2025-00276","url":null,"abstract":"<p>Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by the excessive accumulation of collagen-rich extracellular matrix (ECM), leading to the replacement of normal lung architecture. This pathological remodeling is primarily caused by the epithelial-to-mesenchymal transition (EMT), in which epithelial cells lose their polarity and adhesion and acquire mesenchymal characteristics that encourage the deposition of ECM and the growth of fibrotic tissue. The disruption of ECM homeostasis caused by dysregulated MMP-2 and MMP-9 activity in IPF paradoxically promotes abnormal tissue remodeling and fibrosis. IPF's unknown etiology, delayed diagnosis, and lack of effective treatments point to a crucial knowledge gap regarding ECM- and EMT-driven fibrosis. The microRNA-200 (miR-200) family has been found to be important EMT regulators in recent research, suggesting that they may be able to influence the course of fibrosis. Hereby the current study provides an insight on the role of miR-200a in regulating MMP-2 and MMP-9 in bleomycin (BLM)-induced lung fibrosis using both in vitro (A549 cells) and in vivo (C57BL/6 mice) models. A549 cells were transfected with a synthetic miR-200a mimic, and MMP expression was analyzed using RT-qPCR. In vivo, mice were intranasally administered a lentiviral vector expressing miR-200a prior to BLM induction, followed by tissue analysis at days 14 and 21 using histological stains and immunofluorescence. Gene and protein expression were quantified via RT-qPCR and western blotting. Our findings indicate that miR-200a mitigates fibrosis by downregulating MMPs and PAI-1 while upregulating uPA and uPAR, suggesting a protective role of miR-200a and its potential as a therapeutic target for pulmonary fibrosis.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 4","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13088896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ryan H. Cunnington, Nisha Singh, Marziyeh Shafizadeh, John W. Hanrahan, Shyamala Dakshinamurti, Prashen Chelikani
{"title":"Severe Hypoxia Reduces Adenylyl Cyclase 6 Expression and Function in Bronchial Epithelial Cells","authors":"Ryan H. Cunnington, Nisha Singh, Marziyeh Shafizadeh, John W. Hanrahan, Shyamala Dakshinamurti, Prashen Chelikani","doi":"10.1096/fba.2025-00309","DOIUrl":"10.1096/fba.2025-00309","url":null,"abstract":"<p>Hypoxia is associated with a range of maladies, inflammation, and impaired immunity. The airway epithelial barrier contends with constant exposure to microbes but can be weakened with hypoxia and diseases, such as cystic fibrosis (CF). People with CF (pwCF) have defective cystic fibrosis transmembrane conductance regulator (CFTR) function leading to reduced immune function, excess mucous accumulation, and chronic infection. CFTR is a cAMP-dependent anion channel that is regulated in part by adenylyl cyclase 6 (AC6). G protein-coupled receptors (GPCRs) such as the chemosensory bitter taste receptors (T2Rs) have been shown to alter inhibitory G proteins and cAMP levels. T2Rs also mediate innate immunity responses and detect quorum sensing molecules (QSMs) through T2R14. The impact of hypoxia on these processes, in human airways, has not yet been characterized. We analyzed protein expression and functional endpoints at normal (21%), mild (10%), and severe (1%) oxygen levels to establish the effects of hypoxia on these processes in human bronchial epithelial cells. Our results show that severe hypoxia leads to decreased AC6 expression without altering Gαi/Gαs/T2R14 compared to wild-type controls. Hypoxia induced ligand and oxygen dependent effects on T2R14 functional responses to fungal QSMs, farnesol, and tyrosol. IL-5 release was increased in QSM treated CF cells at 1% oxygen. Severe hypoxia inhibited forskolin-induced currents due to CFTR and reduced cAMP. These results demonstrate expression level and functional alterations due to hypoxia in airway epithelia, including evidence that reduced AC6 expression and function in severe hypoxia is associated with CFTR dysfunction, establishing a potential link between these proteins and the functional outcome of airway epithelial response to hypoxia.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 4","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13088891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A TLR8 Variant Identified From Whole Exome Sequencing as a Sepsis-Prone Mutation","authors":"Fahd Alhamdan, Stefano Gianoli, Xioahui Han, Sophia Koutsogiannaki","doi":"10.1096/fba.2026-00049","DOIUrl":"10.1096/fba.2026-00049","url":null,"abstract":"<p>Sepsis remains a leading cause of morbidity and mortality worldwide, with outcomes highly influenced by host immune responses. While environmental and pathogen-related factors are well recognized, the contribution of host genomic variants to sepsis susceptibility and severity is increasingly appreciated. Because approximately 85% of known disease-causing mutations reside in the exome, whole exome sequencing (WES) offers a powerful strategy to uncover pathogenic variants in critically ill patients and to identify potential inborn errors of immunity that may modulate disease course. In the present study, we performed WES on 31 sepsis patients across different age groups, stratified into pre-school-aged children, school-aged children, and adults, and identified multiple genes harboring high- or medium-impact variants. Of particular interest, a high-impact TLR8 variant (rs3764880: A>G; p.Met1Val) was observed across all the age groups and predominantly in individuals with bacterial sepsis. Single-cell RNA sequencing of peripheral blood mononuclear cells demonstrated that TLR8 was highly expressed in non-classical monocytes, with transcription levels markedly elevated in carriers of the variant. Functional studies revealed that this TLR8 variant enhanced IFN-β secretion upon ligand stimulation, suggesting that dysregulated TLR8 signaling might modulate host inflammatory responses during bacterial sepsis. Given the established role of IFN-β in exacerbating sepsis severity, these findings support a model in which the TLR8 rs3764880 variant contributes to sepsis pathophysiology by amplifying IFN-β-mediated monocyte responses. This study underscores the importance of integrating genomic and functional immunologic analyses to identify host determinants of sepsis, highlights TLR8 as a potential biomarker and therapeutic target, and provides a framework for precision medicine approaches to predict and modulate outcomes in bacterial sepsis.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 4","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13080694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147698081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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