American journal of physiology. Cell physiology最新文献

{"title":"hUC-MSC-derived extracellular vesicles protect lung tissue from cigarette smoke-induced injury by upregulating the METTL3-mediated m⁶A modification.","authors":"Jun Wen, Jianwei Xu, Ying Li, Lijuan Ma, Jie Wang, Shan Huang, Xue Yi","doi":"10.1152/ajpcell.00222.2025","DOIUrl":"10.1152/ajpcell.00222.2025","url":null,"abstract":"<p><p>Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD), a prevalent and incurable lung disease. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) exhibit therapeutic potential in treating COPD. However, the precise mechanism underlying their beneficial effects in lung epithelial cells exposed to cigarette smoke remains incompletely understood. In this study, we purified hUC-MSC-EVs and assessed their influence on viability, apoptosis, and pyroptosis in BEAS-2B human bronchial epithelial cells treated with cigarette smoke extract (CSE). Our data revealed that CSE-treated BEAS-2B cells uptake hUC-MSC-EVs, which significantly improved cell viability and suppressed apoptosis and pyroptosis. Mechanistically, hUC-MSC-EVs partially restored the decreased <i>N</i>⁶-methyladenosine (m⁶A) modification, a key regulator of COPD, in CSE-treated BEAS-2B cells by upregulating the m⁶A writer METTL3. Depletion of METTL3 abolished the protective effect of hUC-MSC-EVs against CSE-induced damage in BEAS-2B cells. The levels of METTL3 were also positively associated with the Wnt/β-catenin pathway. In addition, we investigated the protective effect of hUC-MSC-EVs on lung tissues in a COPD rat model, confirming the regulation of METTL3 expression and the Wnt/β-catenin pathway by hUC-MSC-EVs in vivo. These findings collectively validate the protective effect of hUC-MSC-EVs on lung epithelial cells exposed to cigarette smoke and highlight the therapeutic potential of targeting the METTL3-Wnt axis in COPD treatment.<b>NEW & NOTEWORTHY</b> hUC-MSC-EVs partially restored the decreased m⁶A modification in cigarette smoke extract (CSE)-treated BEAS-2B cells by upregulating METTL3. Depletion of METTL3 abolished the protective effect of hUC-MSC-EVs against CSE-induced damage in BEAS-2B cells. hUC-MSC-EVs regulate the expression of METTL3 and Wnt/β-catenin pathway in vivo. Therefore, hUC-MSC-EVs have a protective effect on lung epithelial cells exposed to cigarette smoke, and targeting the METTL3-Wnt axis has therapeutic potential in chronic obstructive pulmonary disease.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C426-C439"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473778","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":"IRBIT and LIMA1 associate with and are necessary for epithelial cell SLC26A3 (DRA) stimulation by cAMP/ATP.","authors":"Rafiquel Sarker, Tatiana B Boronia, Robert N Cole, Varsha Singh, Ruxian Lin, George McNamara, Mark Donowitz","doi":"10.1152/ajpcell.00046.2025","DOIUrl":"10.1152/ajpcell.00046.2025","url":null,"abstract":"<p><p>The epithelial brush border (BB) Cl^-/[Formula: see text] exchanger SLC26A3 [down-regulated in adenoma (DRA)] is part of two separate intestinal transport processes, neutral NaCl absorption (linked to NHE3) and anion secretion (interacting with CFTR). There is a gap in understanding the regulation of DRA in digestive physiology and in the secretory diarrheal diseases, in which there is elevation of cAMP and/or Ca²⁺. The acute stimulatory regulation of DRA in Caco-2 cells by elevated cAMP (forskolin) and Ca²⁺ (ATP) was studied. As previously reported, DRA was maximally stimulated similarly by forskolin, ATP, and their combination at concentrations that alone maximally stimulated DRA (not additive) and also by their combination at concentrations that alone had no effect (called synergistic stimulation). DRA was phosphorylated at baseline on a single amino acid (S⁵⁶³) and this markedly decreased with acute cAMP/ATP stimulation. Immunoprecipitation (IP) of DRA identified two associating proteins, inositol 1,4,5-trisphosphate receptor-binding protein released with inositol 1,4,5-trisphosphate (IRBIT) and LiM domain and actin-binding protein 1 (LIMA1), which were shown involved in the cAMP/Ca²⁺ stimulation. KD of IRBIT1 or LIMA1 reduced the cAMP plus ATP stimulation of DRA but did not alter basal DRA activity. Maximum ATP, but not maximum forskolin stimulation of DRA, was IRBIT dependent. Also, the elevation in intracellular Ca²⁺ by cAMP/ATP was IRBIT dependent. IRBIT and LIMA1 bound DRA under basal conditions, and the amount bound increased with cAMP/ATP stimulation. cAMP/ATP stimulation increased the coprecipitation of LIMA1 with both IRBIT and DRA. With acute stimulation, there was also more BB DRA, IRBIT, but not LIMA1. These results identify a DRA-IRBIT-LIMA1 complex that is involved in acute stimulation of DRA activity.<b>NEW & NOTEWORTHY</b> Insights into acute DRA regulation relevant to secretory diarrhea studied synergistic cAMP and Ca²⁺-induced DRA stimulation. DRA was phosphorylated under baseline conditions, which decreased with acute stimulation. Acute stimulation, but not basal activity, required the presence of both IRBIT and LIMA1 (an actin-binding scaffold), involved more plasma membrane DRA, and also increased DRA association with IRBIT and LIMA1, indicating a role for a DRA-IRBIT-LIMA1 plasma membrane complex in acute DRA stimulation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C560-C573"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493411","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":"NKT cell deficiency exacerbates adenine-induced renal fibrosis through enhanced Treg infiltration and TGF-β expression.","authors":"Yoshihiro Kuno, Hiroki Ishikawa, Ryuichi Nagashima, Yasunari Matsuzaka, Chikara Kohda, Takeo Isozaki, Hirotaka Kuwata, Masayuki Iyoda","doi":"10.1152/ajpcell.00373.2025","DOIUrl":"10.1152/ajpcell.00373.2025","url":null,"abstract":"<p><p>Natural killer T (NKT) cells are immunoregulatory lymphocytes known for their roles in infection and tumor immunity, but their involvement in renal fibrosis remains unclear. In this study, we investigated the role of NKT cells in adenine-induced renal fibrosis using CD1d-knockout (CD1dKO) mice, which lack NKT cells, and wild-type (WT) controls. Both CD1dKO and WT mice developed renal dysfunction following 5 wk of being fed an adenine-rich diet; however, CD1dKO mice exhibited significantly greater weight loss, elevated serum blood urea nitrogen and creatinine levels, and increased expression of fibrosis- and inflammation-related genes, including <i>Acta2</i>, <i>Col1a1</i>, <i>Tgfb1</i>, <i>Fn1</i>, and <i>Il1b</i>, <i>Il6</i>, <i>Tnf</i>. Histological analysis revealed markedly enlarged fibrotic areas in the kidneys of CD1dKO mice. Flow cytometry demonstrated increased infiltration of CD25⁺ Foxp3⁺ regulatory T cells (Tregs) in CD1dKO mice compared with WT controls. Given that Tregs are a major source of TGF-β, these results suggest that the absence of NKT cells promotes a profibrotic immune environment through enhanced Treg accumulation and TGF-β expression. Our findings showed that NKT cells play a protective role in limiting renal fibrosis progression by modulating immune cell infiltration, particularly enhanced Treg accumulation, and cytokine production. Targeting NKT cell pathways may represent a novel therapeutic approach for the treatment of chronic kidney disease and fibrosis.<b>NEW & NOTEWORTHY</b> This study reveals a protective role for natural killer T (NKT) cells in adenine-induced renal fibrosis. Using CD1d-deficient mice lacking NKT cells, we demonstrate that their absence leads to worsened fibrosis, heightened inflammation, and increased regulatory T cell infiltration. These findings suggest that NKT cells mitigate fibrotic progression by modulating immune responses and highlight a potential therapeutic target in chronic kidney disease.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C471-C479"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551728","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":"B0092 tumor-bearing mice are a new model for the study of cachexia in head and neck cancer.","authors":"Patrick D Livingston, Ana Luiza Labbate Bonaldo, Nicholas A Jamnick, Natalia M Weinzierl, Caleb J Gammon, Chandler S Callaway, Schuyler Lee, Bifeng Gao, Andrew Goodspeed, Robson F Carvalho, Christian D Young, David J Orlicky, Douglas J Adams, Leah J Novinger, Andrea Bonetto","doi":"10.1152/ajpcell.00374.2025","DOIUrl":"10.1152/ajpcell.00374.2025","url":null,"abstract":"<p><p>Head and neck cancer (HNC) accounts for ∼4% of all cancers but causes ∼15,000 deaths annually in the United States. Over 40% of HNC patients present with cachexia, a severe comorbidity associated with skeletal muscle defects, worsened treatment response, and poor outcomes. The mechanisms behind HNC cachexia remain unclear, partly due to limited small animal models. This study characterizes functional and molecular features of cachexia in a novel preclinical model using tobacco-induced B0092 oral squamous cell carcinoma in C57BL/6J mice. C2C12 myotubes were exposed to various concentrations of B0092 conditioned media (CM) to assess effects on myotube diameter and expression of muscle-specific ubiquitin ligases (MuRF-1 and atrogin-1). C57BL/6J male and female mice were implanted with B0092 cells (5 × 10⁵ cells) to investigate musculoskeletal effects of HNC. RNA sequencing of muscle identified gene signatures associated with cachexia. Myotubes treated with B0092 CM showed atrophy already at 25% CM (-21%, <i>P</i> < 0.01), along with elevated MuRF-1 (+81%, <i>P</i> < 0.05) and atrogin-1 (+27%, <i>P</i> < 0.05). B0092 tumor growth in male mice led to muscle atrophy, reduced strength (-36%, <i>P</i> < 0.001), and lower bone mineral density (-8%, <i>P</i> < 0.01). Muscle atrophy correlated with increased MuRF-1 (+1.96-fold, <i>P</i> < 0.05) and atrogin-1 (+1.97-fold, <i>P</i> < 0.05). Female mice exhibited moderate cachexia despite similar tumor size. RNA sequencing of muscle in male B0092 hosts revealed mitochondrial dysfunction and upregulation of proteasome- and translation-related pathways, supporting a shift toward protein degradation and impaired energy metabolism. These findings suggest that B0092-bearing mice are valuable to uncover novel molecular pathways and potential therapeutic targets for HNC cachexia.<b>NEW & NOTEWORTHY</b> This study introduces a novel preclinical model for head and neck cancer (HNC) cachexia using B0092 oral squamous cell carcinoma in C57BL/6J mice. Key findings include muscle atrophy, systemic musculoskeletal effects, and critical gene signatures associated with skeletal muscle wasting. These insights pave the way for potential therapeutic targets to mitigate cachexia in patients with HNC, offering a promising avenue for improving patient outcomes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C646-C658"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gestational chronic intermittent hypoxia triggers maternal inflammation and disrupts placental stress responses.","authors":"Jennifer J Gardner, Reneé de Nazaré Oliveira da Silva, Jessica L Bradshaw, Steve Mabry, E Nicole Wilson, Nataliia Hula, Selina M Tucker, Isabelle K Gorham, Desirae Escalera, Leslie Lopez, Nicole R Phillips, Rebecca L Cunningham, Styliani Goulopoulou","doi":"10.1152/ajpcell.00446.2025","DOIUrl":"10.1152/ajpcell.00446.2025","url":null,"abstract":"<p><p>Gestational hypoxia is associated with placental cellular responses, including oxidative stress and inflammation. Circulating cell-free mitochondrial DNA (ccf-mtDNA) is a marker of cell stress that can be transported within extracellular vehicles (EVs), eliciting proinflammatory responses. We hypothesized that systemic exposure to chronic intermittent hypoxia (CIH) during late pregnancy would increase maternal inflammation, alter circulating EV characteristics, and disrupt placental stress responses. Pregnant rats were exposed to CIH (<i>n</i> = 8) or Normoxia (<i>n</i> = 9) during <i>gestational days 15</i>-<i>20</i> (GD 15-20; term 22-23 days). On GD20, ccf-mtDNA and EV-associated mtDNA (EV-mtDNA) were quantified with real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR), whereas maternal circulating cytokines were quantified using a MILLIPLEX cytokine array. Systemic oxidative stress was measured by plasma advanced oxidation protein products (AOPPs). Placental stress responses were evaluated by examining the balance between proinflammatory and antioxidant gene expression and the activation of proteins involved in apoptotic and autophagic processes. CIH exposure increased placental weights (<i>P</i> = 0.015) and reduced placental efficiency (<i>P</i> = 0.0006) without affecting fetal biometrics (<i>P</i> > 0.05). Absolute ccf-mtDNA and EV-mtDNA content were unchanged (<i>P</i> > 0.05), but EV concentrations were reduced (<i>P</i> = 0.011) in response to CIH, suggesting an increase in EV-mtDNA per EV. Maternal interleukin-18 (IL-18) concentrations increased in the CIH group (<i>P</i> = 0.047). Placental mRNA expression of <i>catalase</i> (<i>P</i> = 0.048) and <i>sod2</i> (<i>P</i> = 0.038) was upregulated, whereas autophagy-related proteins Beclin-1 (<i>P</i> = 0.006) and p62 (<i>P</i> = 0.023) were also increased in response to CIH, with no changes in LC3A/B expression (<i>P</i> > 0.05). Gestational CIH disrupts maternal EV and inflammatory profiles, reduces placental efficiency, and modulates placental antioxidant and autophagic mechanisms, without impairing fetal growth in rats.<b>NEW & NOTEWORTHY</b> Late-gestation exposure to even mild, short-term, chronic intermittent hypoxia (CIH) is sufficient to initiate maternal inflammation and disrupt key placental stress response mechanisms, despite occurring after placental development is largely complete. These findings highlight a novel temporal maternal and placental vulnerability in late pregnancy and identify novel targets for understanding the pathophysiology of hypoxia-related pregnancy complications.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C630-C645"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional reassessment of Nav1.5 T559A reveals loss-of-function in a variant commonly used as wild type.","authors":"Dario Melgari, Marco Villa, Anthony Frosio, Serena Calamaio, Luigi Anastasia, Carlo Pappone, Ilaria Rivolta","doi":"10.1152/ajpcell.00424.2025","DOIUrl":"10.1152/ajpcell.00424.2025","url":null,"abstract":"<p><p><i>SCN5A</i> encodes the α-subunit of the cardiac voltage-gated sodium channel Nav1.5 that plays a fundamental role in the excitability and functionality of the human heart. Nav1.5 T559A is a rare variant that has never been functionally characterized nor clinically described. However, it is present in the hH1a <i>SCN5A</i> clone that has been used as a wild-type control over the years. In this work, we performed a functional electrophysiological characterization of T559A by comparing it with the reverted channel T559. When expressed in a heterologous system, T559A resulted in a significant reduction in sodium current density, suggesting a loss-of-function effect of the mutation. Also, mutation reversion slightly but significantly accelerated the kinetics of both channel activation and inactivation. Thus, caution should be exercised in choosing the most appropriate control and genetic background in functional studies.<b>NEW & NOTEWORTHY</b> This work represents the first functional characterization of the Nav1.5 T559A channel variant that has been widely used as a control wild type over the past decades. We found that the substitution T559A caused a loss-of-function reduction of current density, with smaller effects on channel kinetics and voltage-dependence.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C585-C591"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607152","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":"Epigenetic modulation of cisplatin sensitivity by the M6A-linked ceRNA network in non-small cell lung cancer.","authors":"Qi Wang, He Yan, Jing Zhang, Jie Zhang, Xiaomin Su, Zhenzhong Su","doi":"10.1152/ajpcell.00881.2024","DOIUrl":"10.1152/ajpcell.00881.2024","url":null,"abstract":"<p><p>Cisplatin resistance significantly impedes effective treatment of non-small cell lung cancer (NSCLC). This study investigates the role of the N6-methyladenosine (M6A)-related circFUT8/miR-185-5p/HNRNPC competing endogenous RNA (ceRNA) axis in NSCLC cisplatin resistance. Bioinformatics analysis identified HNRNPC, a critical M6A modification-related gene, as a promoter of NSCLC proliferation and metastasis. Our in vitro and in vivo experiments reveal that circFUT8 upregulates HNRNPC by sponging miR-185-5p, thus enhancing NSCLC cell proliferation, migration, and invasion while reducing apoptosis and sensitivity to cisplatin. These findings highlight the circFUT8/miR-185-5p/HNRNPC axis as a potential target to overcome chemoresistance in NSCLC.<b>NEW & NOTEWORTHY</b> This study identifies the N6-methyladenosine (M6A)-linked circFUT8/miR-185-5p/HNRNPC competing endogenous RNA (ceRNA) network as a key regulator of cisplatin resistance in non-small cell lung cancer (NSCLC). By revealing how circFUT8 modulates HNRNPC through miR-185-5p, this work provides insights into the molecular mechanisms of chemoresistance. The findings suggest potential therapeutic strategies targeting the circFUT8/miR-185-5p/HNRNPC axis to overcome cisplatin resistance in NSCLC, opening new avenues for improved treatment outcomes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C481-C499"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061937","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":"Kir2.1 channels drive macrophage migration through enhancing store-operated Ca²⁺ entry.","authors":"Yoshiaki Suzuki, Taiju Katayama, Yu Fujita, Tsukasa Koide, Yuuki Sawai, Kazuki Maeda, Rubii Kondo, Wayne R Giles, Yuji Imaizumi, Hisao Yamamura","doi":"10.1152/ajpcell.00901.2024","DOIUrl":"10.1152/ajpcell.00901.2024","url":null,"abstract":"<p><p>Kir2.1 is an inwardly rectifying K⁺ channel that is essential for the generation and regulation of the resting membrane potential in many types of cells such as cardiac myocytes. It is known that Kir2.1 is also expressed in macrophages, but its role in macrophage function remains unclear. In this study, we aimed to reveal the significance of Kir2.1 in bone marrow-derived macrophages (BMDMs) using siRNA and selective inhibitors that target Kir2.1. Inwardly rectifying K⁺ currents were consistently observed in mouse BMDMs, and were suppressed by Kir2.1 knockdown or superfusion with BaCl₂ (Ba²⁺). Inhibition of Kir2.1 depolarized the resting membrane potential of BMDMs, and this primary response reduced both the resting cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) and store-operated Ca²⁺ entry. Furthermore, inhibition of Kir2.1 by Ba²⁺ or siRNA and/or inhibition of Ca²⁺ release-activated Ca²⁺ (CRAC) channels by YM58483 attenuated the increase in [Ca²⁺]_cyt that was induced by the endogenous agonist ATP. Importantly, inhibition of Kir2.1 by Ba²⁺ or ML133 had no effect on differentiation of bone marrow progenitors to macrophages, M2 polarization, phagocytic activity, or cell proliferation. On the other hand, the inhibition of Kir2.1, CRAC channel, Ca²⁺/calmodulin-dependent kinase (CaMK), CaMK kinase (CaMKK), or Pyk2 suppressed BMDM migration. ATP stimulation promoted BMDM migration, but this effect was attenuated by the inhibition of Kir2.1, CRAC channels, and CaMK. These results suggest that Kir2.1 can hyperpolarize the membrane potential of macrophages, increasing Ca²⁺ influx through CRAC channels and activating CaMK and Pyk2, thereby increasing macrophage motility.<b>NEW & NOTEWORTHY</b> In bone marrow-derived macrophages, Kir2.1 regulates the resting membrane potential and can enhance Ca²⁺ influx through Ca²⁺ release-activated Ca²⁺ (CRAC) channels after Ca²⁺ store depletion or ATP stimulation. Changes in Kir2.1-mediated K⁺ currents have minimal effects on macrophage differentiation, M2 polarization, phagocytosis, and proliferation. In contrast, Kir2.1 promoted migration by promoting Ca²⁺ influx through CRAC channels and subsequent CaMK and Pyk2 activation. Thus, Kir2.1 can control macrophage motility by modulating membrane potential and intracellular Ca²⁺ signaling.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C413-C425"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537768","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":"Adipocyte-specific modulation of 11β-HSD enzymes for the treatment of obesity in male mice.","authors":"Merc Emil Matienzo, Junhyeong Lee, Sangyi Lim, Edzel Evallo, Chang-Min Lee, Keon Kim, Min-Jung Park, Dong-Il Kim","doi":"10.1152/ajpcell.00978.2024","DOIUrl":"10.1152/ajpcell.00978.2024","url":null,"abstract":"<p><p>Glucocorticoids (GCs) are potent regulators of energy balance and adipose tissue function, making them attractive targets for obesity treatments. The local activation and inactivation of GCs are mediated by two key enzymes: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates active GCs, and type 2 (11β-HSD2), which inactivates them. In this study, we explored the therapeutic potential of modulating adipose GC metabolism by targeting 11β-HSD enzymes using adeno-associated virus (AAV)-based gene delivery systems. Specifically, we used AAV-double floxed inverted orientation (DIO)-mediated overexpression of 11β-HSD2 and CRISPR-Cas9-mediated knockout of 11β-HSD1 in adipocytes. Adipocyte-specific overexpression of 11β-HSD2 suppressed GC-responsive gene expression but did not prevent diet-induced obesity, enhance thermogenic capacity under cold exposure, or improve GC-driven metabolic dysfunction. In contrast, adipocyte-specific deletion of 11β-HSD1 reduced adiposity and ameliorated hepatic steatosis in high-fat diet-fed male mice. However, these metabolic benefits were not observed in female mice, indicating a possible sex-specific response to adipose GC modulation. These findings suggest that although 11β-HSD2 overexpression alone is insufficient to counteract GC-related metabolic dysfunction, inhibition of 11β-HSD1 may offer modest metabolic benefits in males. Overall, this study highlights the sex-dependent roles of 11β-HSD isoenzymes in adipose GC regulation and their therapeutic potential in obesity.<b>NEW & NOTEWORTHY</b> This study used advanced AAV-based strategies to modulate GC activity specifically in adipose tissues. Adipocyte-specific overexpression of 11β-HSD2 via AAV-DIO delivery did not mitigate the metabolic phenotypes in mice with excess GCs or obesity. In contrast, inducible knockout of 11β-HSD1 in adipocytes improved high-fat diet-induced adiposity and hepatic steatosis. These findings provide an additional understanding of 11β-HSD activity in adipose tissues.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C530-C539"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607151","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":"Hugh Davson: the scientist and his science.","authors":"Bonnie L Blazer-Yost, J Gordon McComb","doi":"10.1152/ajpcell.00399.2025","DOIUrl":"10.1152/ajpcell.00399.2025","url":null,"abstract":"<p><p>Each year, the American Physiological Society and its various sections award named lectureships which honor the legacy of physiologists who have been instrumental in establishing important and enduring scientific principles. However, as the decades pass and many layers are added to the founding principles, the original science of these important luminaries begins to dim as we forget how important the original discoveries were to our current endeavors. In that context, we would like to highlight some of the important contributions of Hugh Davson (1909-1996). One of us (J.G.M.) considers Dr. Davson a significant mentor; the other of us (B.L.B-Y.) is honored to be awarded the 2025 Davson lectureship of the Cell and Molecular Physiology Section. In this historical perspective, the authors wish to review the legacy of Hugh Davson from the perspective of both the scientist and his science. When pressed to acknowledge the scientific contributions of Hugh Davson, most physiologists, particularly those of a certain age, will cite the Davson-Danielli model of the plasma membrane. However, the current authors would like to acknowledge Dr. Davson's enduring contributions in another area, that of his fundamental studies of the ocular and cerebrospinal fluids that form the basis of our current research in this important aspect of fluid electrolyte homeostasis in the brain.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C675-C681"},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641556","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}