American journal of physiology. Cell physiology最新文献

{"title":"BHLHE40-mediated upregulation of CAV1 decreases the radiosensitivity of nasopharyngeal carcinoma.","authors":"Ying Bin, Lanhua Wu, Youchang Du, Xingyue Qiu, Yaoyi Huang, Min Kang, Li Jiang","doi":"10.1152/ajpcell.01069.2024","DOIUrl":"10.1152/ajpcell.01069.2024","url":null,"abstract":"<p><p>Radical radiotherapy remains the standard treatment for nonmetastatic nasopharyngeal carcinoma (NPC). However, a considerable proportion of patients still experience therapeutic failure due to the emergence of radioresistance. The molecular mechanisms underlying this resistance are not fully elucidated, underscoring the need for new biomarkers and therapeutic targets to increase radiosensitivity and improve treatment outcomes. Gene and protein expression were assessed using real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry. Cell viability, proliferation, and apoptosis were evaluated using the cell counting kit-8 assay, colony formation assay, and flow cytometry, respectively. The binding of basic helix-loop-helix family member e40 (BHLHE40) to the caveolin-1 (CAV1) promoter was examined using chromatin immunoprecipitation and a dual luciferase assay. An in vivo NPC xenograft mouse model was also established. CAV1 reduced the radiosensitivity of NPC by activating the protein kinase B (Akt) signaling pathway. BHLHE40 contributed to NPC progression by transcriptionally upregulating CAV1. In addition, exosomes secreted by radioresistant NPC cells promoted angiogenesis in human umbilical vein endothelial cells in a CAV1-dependent manner. This study demonstrated that BHLHE40 reduces NPC radiosensitivity by activating CAV1 and the Akt pathway, with CAV1-containing exosomes enhancing angiogenesis and further accelerating NPC progression. These findings suggest that targeting CAV1 could be a promising therapeutic strategy in NPC, offering a new approach to overcoming radioresistance and enhancing treatment efficacy.<b>NEW & NOTEWORTHY</b> This study reveals that BHLHE40 reduces NPC radiosensitivity by transcriptionally activating CAV1, which in turn activates the Akt pathway. In addition, CAV1-containing exosomes secreted by radioresistant NPC cells promote angiogenesis, further accelerating tumor progression. These findings provide new insights into the molecular mechanisms of NPC radioresistance and suggest that targeting CAV1 could be a promising therapeutic strategy to enhance radiosensitivity and improve treatment outcomes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C2095-C2110"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum for Foster et al., volume 328, 2025, p. C1220-C1233.","authors":"","doi":"10.1152/ajpcell.00332.2024_COR","DOIUrl":"https://doi.org/10.1152/ajpcell.00332.2024_COR","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 6","pages":"C2111"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunoproteasome subunit PSMB8 promotes skeletal muscle regeneration by regulating macrophage phenotyping switch in mice.","authors":"Yanhong Zhang, Shiyao Hong, Fan Zhang, Kexin Yao, Shuhui Jin, Shijuan Gao, Yan Liu, Yulin Li, Congcong Zhang","doi":"10.1152/ajpcell.00965.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00965.2024","url":null,"abstract":"<p><p>Immunoproteasomes regulate the degradation of ubiquitin-coupled proteins and cell differentiation. However, its precise role in skeletal muscle regeneration remains unclear. In this study, we found that expression of the immunoproteasome subunit, PSMB8, increased significantly in young muscles after cardiotoxin-induced injury, whereas its expression was downregulated in injured aged mice. Genetic knockout or pharmacological inhibition of the immunoproteasome subunit, PSMB8, resulted in impaired muscle regeneration and increased interstitial fibrosis. PSMB8 inhibition by short interfering RNA (siRNA) or inhibitor decreased the differentiation ability of myoblasts. There was increased infiltration of inflammatory cells, especially Ly6C^hi proinflammatory macrophages, in <i>Psmb8</i> deficient muscles. In vitro, <i>Psmb8-</i>deficient macrophages expressed higher levels of proinflammatory cytokines and lower levels of anti-inflammatory cytokines after phagocytosis of myoblast debris, which was associated with increased activation of the NF-κB signaling pathway. Inhibition of the NF-κB pathway improves the regeneration ability and attenuates interstitial fibrosis in <i>Psmb8-</i>deficient muscles after injury. The overexpression of <i>Psmb8</i> by adenovirus could also improve the regenerative ability of aged muscles.<b>NEW & NOTEWORTHY</b> The immunoproteasome subunit, PSMB8, is essential for efficient muscle regeneration and may be a new therapeutic target for age-related muscle atrophy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 6","pages":"C1716-C1729"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orai channel pharmacological manipulation reduces metabolic flexibility in cardiac fibroblasts.","authors":"Patricia da Silva Pantoja Newman, Amandeep Bajwa, Agnese De Mario, Cristina Mammucari, Salvatore Mancarella","doi":"10.1152/ajpcell.00822.2024","DOIUrl":"10.1152/ajpcell.00822.2024","url":null,"abstract":"<p><p>Cardiac fibroblasts (CFs) play a crucial role in regulating normal heart function and are also involved in the pathological remodeling of the heart that occurs due to hypertension, myocardial infarction, and heart failure. Metabolic changes in fibroblasts are key drivers in the progression of these diseases. Calcium (Ca²⁺) signaling and Ca²⁺ ion channels control many functions of fibroblasts. Orai Ca²⁺ channels are abundantly expressed in fibroblasts; however, their exact role is not yet fully understood. This study examined the role of Orai Ca²⁺ channels in maintaining Ca²⁺ homeostasis within organelles and in energy production in CFs. We found that chronic inhibition of Orai activity altered the expression levels of major metabolic enzymes, affecting the overall cell metabolism. Orai channels are required to refill the endoplasmic reticulum (ER) store. Acute Orai channel activity inhibition reduced Ca²⁺ content in the ER and mitochondria and was associated with the impaired ability to use glucose as a primary energy source. These results have significant implications for understanding the role of Orai-dependent Ca²⁺ entry in maintaining organellar Ca²⁺ homeostasis and cellular metabolic flexibility, sparking further research in this area.<b>NEW & NOTEWORTHY</b> We show that Orai actively contributes to organellar Ca²⁺ concentration and energy homeostasis of the cardiac fibroblast. These findings can have a significant impact during fibrogenesis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1880-C1892"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomechanical platelet activation: diseases that require a new class of antiplatelet therapeutics.","authors":"Riya Gupta, Fahad Alkhalfan, Jason Wheeler, Scott J Cameron","doi":"10.1152/ajpcell.00228.2025","DOIUrl":"10.1152/ajpcell.00228.2025","url":null,"abstract":"<p><p>Mechanisms of platelet activation have traditionally been investigated through the activation of biochemical pathways through cell surface agonists such as adenosine diphosphate, thrombin, and collagen. However, recent research has identified another crucial mechanism, biomechanical activation, where external physical forces directly influence platelet reactivity. This paradigm shift underscores the complex interplay between biochemical and biomechanical stimuli in platelet activation. This review aims to understand the molecular mechanisms underlying biomechanical activation and the implications for treating thrombotic disorders.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1831-C1836"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organ fibrosis: beyond collagen I expression. Fibroblast phenotype and basement membrane proteins.","authors":"Rachel M Biggs, Amy D Bradshaw","doi":"10.1152/ajpcell.00077.2025","DOIUrl":"10.1152/ajpcell.00077.2025","url":null,"abstract":"<p><p>The prevalence of fibrotic disease and its contribution to organ failure have wide-ranging consequences in terms of both morbidity and mortality and are particularly relevant in chronic conditions that afflict aging populations. The paucity of treatment options for those with fibrosis-dependent complications illustrates the challenge and underlying complexity of controlling and reducing extracellular matrix (ECM) content once fibrosis has been established. Legitimately, a major focus of research in fibrosis has centered on transcriptional regulation of fibrillar collagen, particularly collagen I, and factors that induce the expression of genes encoding the fibrillar collagens. However, knowledge that other facets of extracellular matrix biology, in addition to fibrillar collagen content, also make significant contributions to fibrosis is appreciated with emerging significance. Herein, a summary of some recent advances in uncovering critical fibroblast activation states, ECM organization, and composition of fibrotic ECM, including basement membrane components, is discussed. In addition, evidence in support of distinct fibroblast phenotypes in fibrotic tissues, which once established, limit regression of fibrosis despite alleviation of the initiating pathology, is given. As the capacity to reduce established fibrosis has the potential for profound translational significance across organs, more research into each of these important processes is merited.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C2023-C2031"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into Hippo-YAP pathway activation for enhanced DFU healing.","authors":"Shaochun Zhang, Ye Wang, Xuesong Xiong, Jili Xing, Ke Jing","doi":"10.1152/ajpcell.01067.2024","DOIUrl":"10.1152/ajpcell.01067.2024","url":null,"abstract":"<p><p>With the increasing prevalence of diabetes, diabetic foot ulcers (DFUs) have become a global health challenge, significantly impacting patients' quality of life and placing a substantial burden on healthcare systems. Among various immune cell subsets, M2-polarized macrophages play a pivotal role in tissue repair and inflammation resolution. This study uses single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing to comprehensively investigate the role of the TFAP2A-LIFR-Hippo-YAP signaling axis in regulating macrophage M2 polarization and its critical function in DFU wound healing. Through scRNA-seq analysis, we identified nine major immune cell subsets in DFU samples, with macrophages emerging as key regulatory cells. In vitro experiments further confirmed that TFAP2A promotes macrophage M2 polarization (evidenced by increased expression of the M2 marker ARG1) and ameliorates endothelial dysfunction by enhancing tube formation, improving migration capacity, and upregulating relevant proteins such as VCAM-1. Moreover, TFAP2A serves as a central regulatory gene for macrophage function in DFU by upregulating LIFR expression and activating the Hippo-YAP signaling pathway, thereby inducing M2 polarization and mitigating endothelial dysfunction. Mouse model experiments further demonstrated that the TFAP2A-LIFR-Hippo-YAP signaling axis accelerates DFU wound healing through the induction of macrophage M2 polarization. This study unveils a novel immunoregulatory role of TFAP2A in DFU and provides a promising therapeutic target for the treatment of chronic diabetic wounds.<b>NEW & NOTEWORTHY</b> This study provides unprecedented insights into diabetic foot ulcer healing by demonstrating the novel immunoregulatory role of the TFAP2A-LIFR-Hippo-YAP signaling axis. Leveraging single-cell and bulk transcriptomics, we identify TFAP2A as a crucial regulator of macrophage M2 polarization, essential for wound healing and angiogenesis. These findings offer valuable mechanistic understanding and present TFAP2A as a promising therapeutic target for improving outcomes in chronic diabetic wounds.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1921-C1940"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stromal heterogeneity in the adult lung delineated by single-cell genomics.","authors":"Tatsuya Tsukui, Dean Sheppard","doi":"10.1152/ajpcell.00285.2025","DOIUrl":"10.1152/ajpcell.00285.2025","url":null,"abstract":"<p><p>Stromal cells in the lung provide structural support to other cells and play critical roles in inflammation, repair, and fibrosis after injury. Recent technological advancements in single-cell genomics have tremendously improved our knowledge of stromal heterogeneity in the lung. Stromal heterogeneity in single-cell RNA sequencing data is often conserved across different studies despite the different annotation strategies. Spatial analyses suggest that each stromal subset is characterized by unique anatomic locations in the adult lung. This review overviews the stromal heterogeneity delineated by single-cell RNA sequencing studies and highlights the functional characteristics and locations of each population.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1964-C1972"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage heme oxygenase-1 modulates peroxynitrite-mediated vascular injury and exacerbates abdominal aortic aneurysm development.","authors":"Liangliang Jia, Yufei Wang, Chunna Jin, Yuankun Ma, Yidong Wang, Liuguang Song, Jian Shen, Yao Xie, Meixiang Xiang","doi":"10.1152/ajpcell.00525.2023","DOIUrl":"https://doi.org/10.1152/ajpcell.00525.2023","url":null,"abstract":"<p><p>Inflammatory reactions mediated by macrophages are profoundly related to the depletion of smooth muscle cells (SMCs) in abdominal aortic aneurysm (AAA) development. The findings from our previous investigation indicate that heme oxygenase-1 (HO-1) in macrophages exacerbates proinflammatory responses and oxidative damage. Therefore, the aim of this work was to gain insight into the function of HO-1 derived from macrophages and elucidate the underlying molecular mechanisms involved in AAA development. In this study, we discovered a dramatic increase in HO-1 expression in the infiltrated macrophages in experimental calcium phosphate-induced AAA tissues. Myeloid conditional HO-1-deficient mice displayed slower luminal area enlargement, as well as diminished inducible nitric oxide synthase (iNOS)-positive M1 macrophage activation, peroxynitrite generation, and SMCs apoptosis in aneurysmal tissues compared with littermate controls. Furthermore, we showed that inhibiting HO-1 eliminated the protein expression of iNOS induced by lipopolysaccharide/interferon-γ in bone marrow-derived macrophages, whereas the mRNA expression remained unaffected. Suppressing iNOS in macrophages alleviated SMCs apoptosis by decreasing nitric oxide generation in a coculture system in vitro. In summary, our study illustrates that macrophage-derived HO-1 strengthens AAA development through boosting the production of iNOS-dependent peroxynitrite and the deterioration of SMCs. These findings reveal potential therapeutic targets for resolving aneurysmal diseases.<b>NEW & NOTEWORTHY</b> This article illustrates the role of macrophage-derived heme oxygenase-1 (HO-1) in the development of abdominal aortic aneurysm (AAA). HO-1 deletion in macrophages hindered AAA development by reducing inducible nitric oxide synthase (iNOS)-dependent peroxynitrite production and smooth muscle cells (SMCs) apoptosis in vivo. Mechanistically, inhibition of HO-1 reduced the stimulated iNOS protein production in macrophages by lipopolysaccharide/interferon-γ. Moreover, suppressing iNOS in macrophages prevented SMCs apoptosis by decreasing nitric oxide generation in vitro.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 6","pages":"C1808-C1821"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIB1: a multifaceted regulator of cardiometabolic health.","authors":"Valeria Prete, Paola Di Pietro, Angela Carmelita Abate, Eleonora Venturini, Concetta Iside, Carmine Vecchione, Albino Carrizzo","doi":"10.1152/ajpcell.00231.2025","DOIUrl":"10.1152/ajpcell.00231.2025","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. The rising prevalence of CVD is primarily driven by several risk factors, including dyslipidemia, atherosclerosis, diabetes, and obesity. Many current studies are focused on unraveling the underlying pathophysiological mechanisms that govern these risk factors, with the main goal of identifying novel biomarkers and therapeutic targets to prevent the onset of CVD in the population. In recent decades, genome-wide association studies (GWASs) have linked the 8q24 locus containing the TRIB1 (Tribbles homolog 1) gene to various cardiometabolic traits in humans, such as plasma triglycerides, LDL cholesterol, HDL cholesterol, total cholesterol, adiponectin, and glycated hemoglobin levels. Emerging research has investigated the role of Trib1 in regulating plasma lipid levels, inflammation, and insulin signaling, opening new avenues for the potential therapeutic role of Trib1 in CVD risk assessment. Accordingly, this review aims to explore the crucial role of Trib1 as a therapeutic biomarker in CVDs, with a focus on its association with lipid metabolism, atherosclerosis, obesity, and diabetes, analyzing in vitro and in vivo studies and offering insights into its underlying molecular mechanisms.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1973-C1981"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}