American journal of physiology. Cell physiology最新文献

{"title":"Polymeric nanoparticle-mediated siRNA delivery into primary human bronchial airway cells.","authors":"Michael A Thompson, Samantha K Hamrick, Niyati A Borkar, Preetham Ravi, Yagiz Anil Cicek, Victor Lehot, Ritabrita Goswami, Harini Nagaraj, Nourina Nasim, Vincent M Rotello, Christina M Pabelick, Y S Prakash","doi":"10.1152/ajpcell.00127.2026","DOIUrl":"10.1152/ajpcell.00127.2026","url":null,"abstract":"<p><p>Small interfering RNAs (siRNAs) are powerful tools to target cellular protein expression, making them promising candidates for therapeutic applications. siRNA-based approaches to target detrimental mechanisms in airway diseases such as asthma and chronic obstructive pulmonary disease are highly appealing. However, such delivery systems must be nontoxic, protect siRNAs from degradation, and enable intracellular uptake that accesses cytosolic RNA machinery. The present study examines the mechanisms by which guanidinium-functionalized poly(oxanorbornene)imide polymer (PONI-Guan) nanoparticles can effectively and safely deliver siRNA in human bronchial epithelial (BEC) and airway smooth muscle cells (ASM). PONI-Guan polymers were engineered to self-assemble with siRNA through electrostatic interactions. Primary BEC and ASM cells were preincubated with methyl-β-cyclodextrin, dynasore, dansylcadaverine chlorpromazine, latrunculin B, or cytochalasin D followed by incubation with nanoparticles at a single concentration but different guanidinium/phosphate ratios (G/P). BEC and ASM treated with methyl-β-cyclodextrin and dynasore demonstrated significant decrease in nanoparticle uptake. In addition, BEC showed decreased uptake with latrunculin B. Minimal BEC toxicity was observed with 20, 30, and 40 G/P ratios; ASM showed some toxicity with 40 G/P. Transepithelial electrical resistance readings were stable with 20 and 30 G/P, whereas 40 G/P showed significant but transient changes, with barrier integrity restored in ∼6 h. Furthermore, 30 G/P did not induce markers of necrosis, apoptosis, or inflammation in BEC or ASM. Transfection of BDNF siRNA in ASM and Arginase 1 and 2 siRNA in BEC showed significant decrease in corresponding mRNA and protein expression. Overall, these data indicate that PONI-Guan polymers can deliver siRNA safely and effectively in bronchial cells, primarily through caveolar or macropinocytosis uptake, offering a promising tool for future siRNA-based therapies.<b>NEW & NOTEWORTHY</b> siRNA delivery to target cellular processes is an appealing area in lung diseases such as asthma. To realize this potential requires efficient, targeted cytosolic delivery without cellular toxicity or siRNA degradation. We demonstrate the efficacy of PONI-Guan nanoparticles in accessing airway epithelial and smooth muscle cells with specific siRNA targeting of mRNAs of interest while maintaining barrier integrity and avoiding cellular toxicity.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C783-C796"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13537270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700487","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":"Sex-divergent skeletal muscle remodeling emerges early in cancer cachexia.","authors":"Chris Karagiannis, Alastair A E Saunders, Rachel E Thomson, María Guillán-Fresco, Wayne X Du, Craig A Goodman, Paul Gregorevic","doi":"10.1152/ajpcell.00271.2026","DOIUrl":"10.1152/ajpcell.00271.2026","url":null,"abstract":"<p><p>Cancer cachexia is characterized by progressive skeletal muscle wasting and dysfunction, yet the early events that precede overt muscle wasting remain poorly defined. Here, we utilized a time-coursed C26 carcinoma model in male and female mice to define the precachectic transcriptomic, proteostatic, immune, and metabolic adaptations between sexes. Males progressed more rapidly to cachexia and exhibited earlier impairments in body composition and grip strength, with shifts in muscle fiber size distribution detectable before changes in muscle mass. Transcriptomic analysis of the tibialis anterior muscle identified >6,000 differentially expressed genes, with >60% showing sex-specific regulation at the precachectic stage. Proteostasis pathways were transcriptionally altered in both sexes; however, global muscle protein synthesis was suppressed earlier in males, preceding both measurable muscle mass loss and robust induction of specific E3 ubiquitin ligases. Transcripts related to innate immunity were preferentially elevated in males and accompanied by increased infiltration of myeloid cells, whereas systemic immune profiles showed limited concordant changes. Females showed preferential enrichment of insulin resistance and metabolic remodeling pathways, accompanied by early impairment of insulin handling and reduced muscle glycogen content at severe cachexia. These results show that cachexia progression in this model is sexually dimorphic, and skeletal muscle undergoes extensive remodeling before overt wasting. Males exhibit earlier functional decline and muscle immune remodeling, whereas females show earlier metabolic vulnerability with impaired insulin handling. These findings define sex-divergent precachectic windows that may guide early biomarker discovery and therapeutic strategies aimed at preventing progression and improving quality of life in patients with cancer.<b>NEW & NOTEWORTHY</b> By modeling cancer-associated cachexia over a time-course in male and female mice, we show that skeletal muscle remodeling begins before overt wasting is evident. The precachectic interval is marked by suppressed protein synthesis, muscle-local immune remodeling, extracellular matrix disruption, and metabolic vulnerability, with several responses differing by sex. These findings suggest that key features of cachexia emerge early in the disease time-course and may inform clinical approaches for detecting disease before significant muscle wasting occurs.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C533-C549"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468363","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":"Isoform-specific modulation of PI3K/Akt1 signaling by Orai channels in estrogen receptor-positive breast cancer.","authors":"Alvaro Macías-Díaz, Jose J Lopez, Manuel Fuentes-Mateos, Tarik Smani, Juan A Rosado","doi":"10.1152/ajpcell.00333.2026","DOIUrl":"10.1152/ajpcell.00333.2026","url":null,"abstract":"<p><p>The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is a fundamental intracellular axis that integrates extracellular stimuli to orchestrate essential cellular processes. The activation of Akt1 represents a key determinant of aggressiveness in estrogen receptor-positive (ER+) breast cancer, a process closely associated with Ca²⁺-signaling remodeling mediated by Orai1 and Orai3. In ER+ breast cancer cells, Orai3 plays a predominant role in store-operated Ca²⁺ entry (SOCE), whereas Orai1 indirectly regulates SOCE and contributes to store-independent Ca²⁺ influx pathways. Here we investigated the regulation of Akt1 activation by Orai3 and Orai1 and characterized the underlying intracellular mechanisms in ER+ breast cancer cells. Our findings reveal distinct, opposing roles for Orai1 and Orai3. Orai3 overexpression in wild-type cells, as well as 2-aminoethoxydiphenyl borate (2-APB)-mediated stimulation of Orai1-knockout (O1KO) MCF-7 cells, enhanced Akt1 phosphorylation, whereas Orai3 knockdown attenuated this effect. This 2-APB-induced activation was impaired by calmodulin-dependent protein kinase kinase (CaMKK) inhibition in a concentration-dependent manner. Conversely, Orai1 deficiency (O1KO) or shRNA-mediated knockdown resulted in enhanced Akt1 phosphorylation, whereas Orai1 overexpression attenuated it. Expression of the pore-dead Orai1E106Q mutant in O1KO cells failed to affect Akt phosphorylation, indicating that Ca²⁺ influx is essential for this modulation. Mechanistically, Orai1 knockout or knockdown attenuated the expression of adenylyl cyclase 8 (AC8), whereas Orai1 expression enhanced AC8 levels through a Ca²⁺-influx-dependent mechanism. Finally, silencing AC8 impaired Orai1-mediated inhibition of Akt phosphorylation. Overall, these findings demonstrate an unprecedented functional antagonism between Orai1 and Orai3 in ER+ breast cancer cells, where distinct signaling pathways mediate their opposing effects on Akt1 phosphorylation.<b>NEW & NOTEWORTHY</b> Orai1 and Orai3 exert opposing effects on the PI3K/Akt1 pathway, revealing a complex regulatory mechanism to coordinate cellular processes, such as survival, in ER+ breast cancer cells. Although Orai3 promotes Akt1 activation via CaMKK to drive tumor progression, Orai1 acts as a modulator on this axis through an AC8/cAMP-dependent mechanism. These findings highlight the functional diversity of Orai proteins and identify them as potential therapeutic targets for modulating Akt1-driven aggressiveness in breast cancer.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C691-C704"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148710941","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":"AMITO: an open-access application for assisted analysis of mitochondria in transmission electron microscopy images.","authors":"Elyse Hucteau, Thomas J Hureau, Allan F Pagano, Joris Mallard","doi":"10.1152/ajpcell.00300.2026","DOIUrl":"10.1152/ajpcell.00300.2026","url":null,"abstract":"<p><p>Analysis of mitochondrial morphology and ultrastructure from transmission electron microscopy images is essential for understanding cellular adaptations in both physiological and pathological conditions. However, these investigations remain time-consuming, poorly standardized, and therefore highly variable. We developed an open-access, standalone MATLAB-based application [Analysis of MITOchondria (AMITO)] that can be run without a license and integrates analyses within a single user-friendly interface. AMITO demonstrated excellent agreement with conventional manual image analysis software, high intra- and interexperimenter reproducibility, and substantial reduction in analysis time. Therefore, AMITO provides a reliable, efficient, and accessible tool to ensure robustness and reproducibility in mitochondrial assessment.<b>NEW & NOTEWORTHY</b> AMITO is an open-access, standalone application for mitochondrial analysis from TEM images that combines automated and manual workflows within a single user-friendly interface. Validated against conventional FIJI analysis, AMITO demonstrated excellent reproducibility while substantially reducing analysis time and experimenter-dependent variability. By integrating morphology and ultrastructure quantification without requiring programming expertise, AMITO provides a reliable and accessible solution to improve robustness, efficiency, and reproducibility in mitochondrial research.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C834-C847"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787134","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":"Maternal obesity disrupts trophoblast differentiation and causes female-specific labyrinth defects in the mouse placenta.","authors":"Li-Wei Chen, Zhongyun Kou, Md Nazmul Hossain, Chaeyoung Shin, Sharmeen Islam, Xinrui Li, Jeanene Marie de Avila, Min Du","doi":"10.1152/ajpcell.00357.2026","DOIUrl":"10.1152/ajpcell.00357.2026","url":null,"abstract":"<p><p>Maternal obesity (MO) alters the intrauterine environment and increases the risk of a variety of developmental outcomes; however, the effects on placental cell population and development remain unclear. In this study, we investigated the impact of MO on placental cellular composition, development, and morphology in C57BL/6J mice fed a control or high-fat diet. Single-cell RNA sequencing of <i>embryonic day</i> (E) <i>13.5</i> placentas identified 16 transcriptionally distinct cell populations and revealed a reduction in the trophoblast progenitor cell population in MO placentas. MO suppressed trophoblast genes involved in placental development and mitochondrial oxidative phosphorylation, accompanied by decreased protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key regulator of mitochondrial biogenesis. Furthermore, MO reduced the expression of <i>Hand1</i> and <i>Tfap2c</i>, transcription factors involved in trophoblast differentiation and placental development, whereas increasing prolactin-family gene expression and STAT5 phosphorylation. At E17.5, MO caused female-specific reductions in placental weight and labyrinth zone area, along with increased <i>Tnf</i> expression and sustained suppression of <i>Hand1</i> in female placentas. These findings suggest that MO disrupts trophoblast differentiation and placental metabolic function during midgestation, which may contribute to placental vulnerability later in pregnancy.<b>NEW & NOTEWORTHY</b> Using placental single-cell RNA sequencing at <i>embryonic day</i> (E) <i>13.5</i>, we found that maternal obesity (MO) was associated with a lower observed trophoblast proportion and downregulation of placental-development and oxidative-phosphorylation programs. These changes occurred alongside reduced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) protein and activated JAK-STAT signaling. At <i>embryonic day 17.5</i>, female placentas from obese dams showed reduced weight and labyrinth area, revealing sex-dependent placental vulnerability.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C594-C604"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13499971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648218","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":"Murine pancreatic tumors induce pathological remodeling of muscles critical to chewing and swallowing.","authors":"Sarah M Duckett, Jeremy B Ducharme, Martin M Schonk, Daria Neyroud, Sarah M Judge, Andrew R Judge","doi":"10.1152/ajpcell.00390.2026","DOIUrl":"10.1152/ajpcell.00390.2026","url":null,"abstract":"<p><p>Cancer cachexia is a debilitating syndrome defined by involuntary weight loss due to loss of muscle mass, with or without loss of fat mass. Cachexia is particularly prevalent in pancreatic cancer, affecting up to 70% of patients at diagnosis, and is associated with reduced physical function, impaired treatment tolerance, and worsened survival. Skeletal muscle, including muscles involved in respiration and locomotion, exhibits extensive pathological remodeling in cachexia, including myofiber atrophy and transcriptional reprogramming. Whether muscles that are critical to chewing and swallowing respond similarly remains unknown. To address this gap, we collected masseter (chewing) and digastric (swallowing) muscles from cachectic mice bearing orthotopic KPC pancreatic tumors (<i>n</i> = 8) and cancer-free Sham controls (<i>n</i> = 8). Hematoxylin and eosin staining revealed increased mononuclear cell content, centralized nuclei, and expanded interstitial spaces in both muscles of KPC mice. Myofiber cross-sectional area was reduced by 42% in the masseter and 23% in the digastric. RNA sequencing revealed distinct transcriptional responses between these muscles. The masseter muscle showed enrichment of catabolic signaling pathways, including proteolytic and stress-response programs, alongside downregulation of extracellular matrix and growth-related programs. In contrast, the digastric muscle exhibited robust upregulation of immune and inflammatory pathways, including innate and adaptive immune signaling, with minimal overlap between muscles. Collectively, these findings demonstrate that pancreatic cancer drives pathological remodeling and atrophy in muscles central to chewing and swallowing while eliciting distinct, muscle-specific transcriptional responses, changes that could negatively affect food and nutrient intake and thereby contribute to cachexia progression.<b>NEW & NOTEWORTHY</b> To the best of our knowledge, this is the first study to examine how pancreatic cancer affects muscles involved in chewing and swallowing. Pancreatic cancer causes myofiber atrophy and pathological remodeling in the masseter and digastric muscles while driving distinct transcriptional programs, including catabolic signaling in the masseter and immune-inflammatory remodeling in the digastric. These findings identify feeding muscles as an underexplored component of cancer cachexia with potential relevance to nutritional decline in pancreatic cancer.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C550-C557"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13528807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618099","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":"Electron microscopic analysis of the mouse and human alveolar epithelial glycocalyx using high-pressure freezing and freeze substitution.","authors":"Vladimir Gluhovic, Elena Lopez-Rodriguez, Ilayda Yavuz, Sara Timm, Marko Vukovic, Anna Löwa, Andreas C Hocke, Wolfgang M Kuebler, Matthias Ochs, Shailey Gale Twamley","doi":"10.1152/ajpcell.00029.2026","DOIUrl":"10.1152/ajpcell.00029.2026","url":null,"abstract":"<p><p>Alveolar epithelial cells (AECs) are covered apically by the alveolar lining layer (ALL). The alveolar epithelial glycocalyx (AEGCX), which is part of the ALL, consists of a mixture of glycoproteins, proteoglycans, and glycosaminoglycans. In comparison with the endothelial glycocalyx (GCX), much less is known about the composition and structure of the AEGCX, although it is presumed to be involved in many cellular processes. The challenges of in vivo visualization of the AEGCX, coupled with the distorting effects of aldehyde fixation, make it difficult to accurately determine its structural organization and molecular composition. In this study, we aimed to improve the preservation of the ultrastructure of the AEGCX by using high-pressure freezing combined with freeze substitution (HPF/FS) for transmission electron microscopy (TEM) analysis. HPF is a type of cryopreservation that uses both liquid nitrogen and high pressure. By using HPF/FS to preserve commercially available human primary AECs, human alveolar-like organoids, monolayers of human organoid-derived alveolar-like epithelial cells, and ex vivo tissue from both mice and human lungs, we observed two distinct regions on the apical surface via TEM: an inner GCX-like layer along the cell membrane followed by a loosely arranged outer layer. Our data show a bilayered structure on the surface of AECs. To minimize freeze-induced damage during HPF, a protein-rich cryoprotectant was introduced to stabilize the sample. By processing control samples of protein-rich cryoprotectants lacking cells, we found that HPF/FS preserves components of the cryoprotectant, as confirmed by TEM analysis. This implies that HPF/FS preserves not only cellular-derived constituents but also components found in the cryoprotectant, which may interfere with interpretation of the outer surface layer.<b>NEW & NOTEWORTHY</b> The structure of the AEGCX is not fully understood. To avoid formaldehyde-induced disruption of the AEGCX, we preserved samples by HPF/FS for TEM analysis. We uncovered two morphologically distinct regions on the apical surface of AECs. An inner GCX-like layer along the membrane followed by an associated outer layer. We found that cryoprotectants used during HPF to avoid freezing induced damage interfere with the outer layer, potentially misleading interpretations of its structure.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C573-C585"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534720","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":"Microbiome-associated metabolites, valerobetaine and homocarnitine, inhibit carnitine transport via OCTN2.","authors":"Jaclyn Weinberg, Jennifer Jeon, William J Crandall, Choon-Myung Lee, Zachery R Jarrell, Gahyun Lim, Ho Young Lee, Young-Mi Go, Dean P Jones","doi":"10.1152/ajpcell.00317.2026","DOIUrl":"10.1152/ajpcell.00317.2026","url":null,"abstract":"<p><p>The intestinal microbiome-derived metabolite, valerobetaine (δ-valerobetaine), promotes obesity, hepatic steatosis, and impaired cognition in mice and is associated with obesity, fatty liver disease, diabetes, and cardiovascular disease in humans. Mechanistic studies show that valerobetaine decreases systemic carnitine and inhibits mitochondrial fatty acid oxidation. Valerobetaine and its mammalian hydroxylation product, homocarnitine, share close structural homology with carnitine, which is mainly transported by the organic cation transporter 2 (OCTN2). To determine whether reductions in systemic carnitine induced by valerobetaine and homocarnitine result from interactions with OCTN2, we performed in vitro uptake studies using HEK293 cells overexpressing human OCTN2 coupled with metabolite measurement by mass spectrometry. OCTN2 overexpression increased the uptake rates of both homocarnitine and valerobetaine relative to control cells. Meldonium, an OCTN2 substrate and inhibitor, reduced uptake of both metabolites in a concentration-dependent manner. Saturating uptake kinetics were observed for valerobetaine, whereas homocarnitine exhibited linear uptake across the concentration range tested (1-100 µM). Both metabolites exhibited lower transport efficiency compared with the carnitine precursor γ-butyrobetaine and showed relatively lower potency in inhibition of carnitine uptake. Together, these findings identify homocarnitine and valerobetaine as modulators of carnitine transport and provide a mechanistic basis by which these microbiome-derived metabolites lower systemic carnitine levels and impair mitochondrial fatty acid oxidation.<b>NEW & NOTEWORTHY</b> This study uses transport physiology, ectopic gene expression, and mass spectrometry-based detection methods to show that the microbiome-derived valerobetaine and its mammalian metabolic product, homocarnitine, are transported by OCTN2, an important carnitine transporter. Moreover, both valerobetaine and homocarnitine inhibit carnitine transport, providing a mechanism to explain the systemic decrease in carnitine, global impairment of mitochondrial fatty acid oxidation, and association of valerobetaine with several pathophysiological processes, including obesity, hepatic steatosis, and cognitive decline.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C586-C593"},"PeriodicalIF":5.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534771","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":"Elevated circulating bile acids alleviate acute pancreatitis by restoring mitochondrial function via acinar cell uptake.","authors":"Haiyan Chen, Yudan Fan, Na Huang, Qian Wang, Bo Wang, Jin Sun, Shu Zhang, Jun Li","doi":"10.1152/ajpcell.00172.2026","DOIUrl":"10.1152/ajpcell.00172.2026","url":null,"abstract":"<p><p>Acute pancreatitis (AP) is commonly linked to bile acid (BA) dyshomeostasis, yet the causal role of elevated circulating BAs and the functional significance of their uptake by pancreatic acinar cells in AP progression remain unclear and controversial. A cerulein (CER)-induced rat model of AP was established, and pathological elevation of circulating BAs was achieved via intraperitoneal injection of sodium taurocholate (50 mg/kg). Targeted metabolomics was used to quantify BA profiles in serum and pancreatic tissue. In vitro experiments on pancreatic acinar cells were conducted to assess BA uptake and its effects on cell survival. Mitochondrial function was evaluated via confocal microscopy, RNA sequencing, and biochemical assays for membrane potential, adenosine triphosphate (ATP), and reactive oxygen species. Systemic Na-TC administration increased serum and pancreatic total BA levels to concentrations comparable to biliary pancreatitis. Under these clinically relevant BA elevations, Na-TC treatment significantly attenuated CER-induced pancreatic histopathological damage, inflammation, and oxidative stress. In vitro, Na-TC (10-200 μM) reduced CER-induced acinar cell apoptosis/necrosis, but this protection was abrogated by the BA transporter inhibitor rifamycin sodium salt. RNA sequencing and functional analyses revealed that BA uptake upregulated mitochondrial electron transport chain subunits, enhanced oxidative phosphorylation, restored mitochondrial membrane potential, and increased ATP production. These findings challenge the traditional view of circulating BA toxicity in AP and indicate that at levels comparable to those observed in biliary pancreatitis, uptake of a certain amount of BAs by pancreatic acinar cells is beneficial rather than harmful.<b>NEW & NOTEWORTHY</b> This study challenges the view that elevated circulating bile acids (BAs) are toxic in acute pancreatitis. We demonstrate that at clinically relevant levels, uptake of BAs into pancreatic acinar cells via specific transporters is protective. It enhances mitochondrial oxidative phosphorylation, restores ATP production, and reduces cell death, revealing a novel beneficial role for intracellular BAs.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C252-C266"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148256986","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":"Correction for Pan et al., volume 312, 2017, p. C248-C258.","authors":"","doi":"10.1152/ajpcell.00296.2016_COR","DOIUrl":"https://doi.org/10.1152/ajpcell.00296.2016_COR","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"331 2","pages":"C495-C496"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629298","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}