American journal of physiology. Cell physiology最新文献

{"title":"Mechanism of shear stress-induced ATP release in ventricular myocytes: roles of pannexin and mitochondria.","authors":"Tran Quoc Dat, Hieu Trong Huynh, Phuong Kim Luong, Tran Nguyet Trinh, Thi Van Anh Vu, Qui Anh Le, Sun-Hee Woo","doi":"10.1152/ajpcell.00330.2025","DOIUrl":"10.1152/ajpcell.00330.2025","url":null,"abstract":"<p><p>Shear stress induces atrial Ca²⁺ waves via connexin43 (Cx43)-mediated ATP release. Here, we examined whether ventricular myocytes release ATP under shear stress and the underlying and regulatory mechanisms. A bioluminescence assay and the \"sniffer patch\" were used to measure ATP release from multiple and single murine ventricular myocytes, respectively, in combination with laminar flow or micro-puffing. Shear stress (∼16 dyn/cm²) induced transient ATP release from myocyte batches, peaking at ∼7 × 10^-18 mols/µm²-membrane within 2 s. This response was abolished by the application of La³⁺ but was not affected by Gap19 treatment or zero external Ca²⁺. In addition, shear-induced ATP release was not different between control and cardiac-specific Cx43-conditional knockout (Cx43-cKO) ventricular cells, suggesting no role for Cx43. Shear-induced ATP release was suppressed by probenecid, low concentrations of carbenoxolone, or the pannexin (Panx) 1 inhibitory peptide ¹⁰Panx1 by 60-75%, suggesting a major role for Panx. Pharmacological screening further revealed a partial (30-40%) role of 9-anthracenecarboxylic acid-sensitive, tamoxifen-insensitive Cl^- channels in ATP release. The sniffer patch, using a P2X7 receptor-overexpressing HEK293 cell positioned at a local region of the ventricular cell, showed a rapid development of shear-induced currents, approximated to be ∼1-10 µM ATP. The Cx43-cKO did not affect these sniffer cell currents. This shear response was suppressed by mitochondrial uncoupling or inhibition of the electron transport chain by 70-80% but was rather enhanced by Mito-TEMPO. Our data suggest that shear stress induces ATP release from murine ventricle cells mainly via Panx and that mitochondrial oxidative phosphorylation may be required for this response.<b>NEW & NOTEWORTHY</b> In this study, we demonstrated shear stress-induced ATP release from ventricular myocytes for the first time using the sniffer patch technique and a bioluminescence assay, incorporating cardiac connexin 43 conditional knockout and pharmacological interventions. Our data also provide new evidence that pannexin primarily mediates ATP release in ventricular myocytes under shear stress and that mitochondrial oxidative phosphorylation is a prerequisite for this shear stress-mediated ATP release.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C924-C935"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833643","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":"MALDI-MSI reveals shared lipid signatures in sarcoid-like granulomas of mice and in a human case.","authors":"Junwoo Kim, Yuben Moodley, Nick S R Lan, Shelley Waters, Dana Hicks, Hoi Sze Yeung, Nicola Gray, Julien Wist, Felicity Lee, Benjamin Allanson, Lokesh Yagnik, Faridh Raja Mohamed, Silvia Lee, Girish Dwivedi","doi":"10.1152/ajpcell.00395.2025","DOIUrl":"10.1152/ajpcell.00395.2025","url":null,"abstract":"<p><p>Sarcoidosis is a complex inflammatory disease of unknown cause, with diagnosis often complicated by a lack of definitive biomarkers. This study used matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) to spatially profile lipids in sarcoid-like granulomatous tissues from animal and human samples. <i>ApoE</i>^-/- mice (<i>n</i> = 23) were fed a cholate-containing high-fat diet for 16 wk, inducing sarcoid-like granulomas. Granulomas were characterized through hematoxylin-eosin, Masson's trichrome, and immunofluorescence staining, whereas lipidomic profiling of mouse hearts (<i>n</i> = 10) and lymph nodes (<i>n</i> = 10) was performed using MALDI-MSI. A comparative analysis was performed using a human sarcoid-like granulomatous lymph node. The mouse model exhibited granulomas, characterized by lipid-laden macrophages, fibrosis, and perivascular lymphocyte clusters. Human lymph nodes with sarcoid-like granulomas demonstrated hallmarks of sarcoidosis, including foamy histiocytes, non-necrotizing granulomas, and Langhans giant cells containing silicone and asteroid bodies. MALDI-MSI identified over 30 lipids that were consistently detected in murine heart and lymph node tissues. Of these, eight key lipids belong to the lysophosphatidylinositol, phosphatidic acid, phosphatidylinositide, and phosphatidylserine classes, which were also detected in human lymph nodes. To our knowledge, this is the first application of MALDI-MSI in spatial lipidomic profiling in a sarcoid-like animal model and human sarcoid-like granulomatous tissue. MALDI-MSI revealed distinct yet shared lipidomic profiles in both sarcoid-like animal and human tissues. This finding provides a new perspective on sarcoidosis pathogenesis and warrants future mechanistic study and validation.<b>NEW & NOTEWORTHY</b> This is the first study to apply MALDI-MSI to characterize the spatial lipidomic landscape of granulomatous inflammation in both a murine sarcoid-like model and a rare human case. Our work reveals distinct yet shared lipidomic profiles in both sarcoid-like animal and human tissues, including region-specific lipid alterations within granulomas. By integrating spatial imaging with lipidomics, this study bridges a critical gap in our understanding of the metabolic and structural composition of granulomatous inflammation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C768-C778"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641557","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":"Microenvironmental and structural regulation of BMP signaling: insights into the prodomain-growth factor interface.","authors":"Chara E S Spanou, Gerhard Sengle","doi":"10.1152/ajpcell.00500.2025","DOIUrl":"10.1152/ajpcell.00500.2025","url":null,"abstract":"<p><p>Bone morphogenetic proteins (BMPs) are extracellular, pluripotent cytokines that regulate diverse cellular processes. Despite their critical roles, the mechanisms controlling their bioavailability within the extracellular microenvironment remain poorly understood. This review highlights recent advances in BMP regulation at the prodomain-growth factor interface, focusing on intra- and extracellular mechanisms that govern BMP activation. By modulating receptor accessibility, this interface serves as a key determinant of BMP activity. Major regulatory processes include propeptide convertase processing, interactions with glycosaminoglycans, targeting to supramolecular extracellular matrix scaffolds, and activation through proteolytic cleavage of BMP prodomains. A deeper understanding of these mechanisms provides new therapeutic insights into conditions associated with dysregulated BMP signaling, including cardiovascular disease and cancer.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C744-C753"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726519","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":"PLCγ has a dual role in capsaicin-triggered neurogenic inflammation promoting mechanical hypersensitivity and edema in male mice.","authors":"Alexandre M do Nascimento, Ana M Rodrigues, Heloisa E G Ramos, Beatriz C de Moraes, Raphael S Santos, Camila S Dale, Deborah Schechtman","doi":"10.1152/ajpcell.00154.2025","DOIUrl":"10.1152/ajpcell.00154.2025","url":null,"abstract":"<p><p>Understanding the signaling mechanisms leading to neurogenic inflammation, a process found in chronic pain, psoriasis and migraine, is key for the development of more effective analgesics. A key player in the onset of this inflammation is transient receptor potential cation channel, subfamily V, member 1 (TRPV1), an ion channel abundant at the free terminals of nociceptors, which can be directly activated by capsaicin (CAP), acidic pH or noxious heat, and indirectly through phospholipase C-γ (PLCγ), which promotes cleavage of the inhibitory phosphatidylinositol-4,5-bisphosphate from the channel. In turn, PLCγ is activated via its phosphorylation by growth factor receptor tyrosine kinases, such as the high affinity nerve growth factor receptor, tropomyosin kinase A (TrkA). We previously developed a permeable phosphopeptide (TAT-pQYP) that binds to PLCγ, preventing lipase anchoring to TrkA, and hence its phosphorylation/activation, and showed that PLCγ is key for mechanical hypersensitivity in CFA-induced inflammation. Herewith, we investigate the role of PLCγ in an acute model of inflammatory nociception induced by the subcutaneous injection of CAP in the hind paw of male mice. This model elicited a two phase response, the first related to TRPV1's sensitization and the latter to neurogenic inflammation. TAT-pQYP did not alter the TRPV1-mediated chemonociceptive response and neurogenic signaling itself, but it was able to disrupt PLCγ signaling, reverting nerve growth factor/TrkA-dependent mechanical hypersensitivity in nociceptors, and returning paw diameter to baseline levels by disrupting vascular endothelial growth factor A/endothelial nitric oxide synthase signaling in endothelial cells. Altogether, our results show that TAT-pQYP disrupts PLCγ signaling in CAP-triggered neurogenic inflammation, leading to an anti-inflammatory and antinociceptive effect without interfering with TRPV1 chemosensitivity and neuropeptides activity. PLCγ represents a potential target to relieve neurogenic inflammation-dependent pain while preserving TRPV1's physiological activity.<b>NEW & NOTEWORTHY</b> When activated, TRPV1 promotes neurogenic inflammation via neuropeptide signaling. However, drugs designed to directly block TRPV1 may impair its nociceptive roles, essential for tissue preservation. In this work, pain and swelling caused by neurogenic inflammation were mitigated after blocking PLCγ's activity, modulating TRPV1's activity without affecting normal chemosensitivity. This suggests that blocking PLCγ could be a new approach for the development of painkillers maintaining the physiological detection of harmful stimuli.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C821-C833"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820291","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":"Asymmetric FGF receptor dimerization: implications for FGF23 biology and drug discovery.","authors":"Mohammed S Razzaque, Moosa Mohammadi","doi":"10.1152/ajpcell.01020.2024","DOIUrl":"10.1152/ajpcell.01020.2024","url":null,"abstract":"<p><p>Fibroblast growth factor 23 (FGF23) requires both αKlotho and heparan sulfate proteoglycans (HSPGs) as obligatory coreceptors to bind, dimerize, and activate its FGF receptors (FGFRs) in the kidney, thereby regulating mineral ion and vitamin D homeostasis. Cryogenic electron microscopy studies reveal that FGF23 signaling proceeds through an asymmetric 1:2:1:1 FGF23-FGFR-αKlotho-HS assembly. According to this structural model, αKlotho simultaneously anchors FGF23 and one FGFR chain, referred to as the primary receptor (FGFR^P), to form a 1:1:1 FGF23-FGFR^P-αKlotho triplex, which boosts FGF23-FGFR^P interaction. Subsequently, the HS coreceptor aids the triplex in recruiting a second FGFR chain, or secondary receptor (FGFR^S), leading to asymmetric receptor dimerization. This recruitment is driven by the interactions of FGF23 and FGFR^P from the triplex with the secondary receptor, with no direct involvement from αKlotho. This model outlines the possibility of heterodimerization among the renal cognate receptors of FGF23 (namely, FGFR1c, FGFR3c, and FGFR4), which may introduce signaling diversity affecting phosphate and vitamin D regulation. In addition, it proposes that kidney-specific HS structures could cooperate with renal αKlotho to home FGF23 to renal tissues. The proposed FGF23 signaling assembly provides a framework for further investigation and may inform the development of FGF23 antagonists or partial agonists for treating disorders associated with phosphate and vitamin D dysregulation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C904-C910"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870895","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":"Reversible oxidative modifications partially cause myofibrillar active and passive force decline in early phase of immobilization.","authors":"Daiki Watanabe, Takaaki Mishima, Taku Hamada","doi":"10.1152/ajpcell.00554.2025","DOIUrl":"10.1152/ajpcell.00554.2025","url":null,"abstract":"<p><p>Muscle immobilization leads to a decrease in muscle fiber size and contractile function, partly due to a decline in myofibrillar force. In this study, we examined the effects of reversible oxidative modifications on the decline of myofibrillar function during the early phase of immobilization. One leg of male C57BL6 mice was immobilized for 3 days and 7 days, whereas the contralateral leg was used as a nontreated (NT) control. After the given immobilization periods, mechanically skinned fibers were prepared from the gastrocnemius muscle, and myofibrillar active and passive forces were assessed. Myofibrillar specific force decreased after 7 days of immobilization, although myofibrillar Ca²⁺ sensitivity remained unchanged. The decreased specific force was partially restored by a treatment with dithiothreitol (DTT), a reducing agent, only when applied to nonactivated fibers, not activated fibers. In addition, 3-morpholinosydnonimine and peroxynitrite (ONOO^-) decreased maximal force in nonactivated fibers from NT but not immobilized (Im) muscles. Myofibrillar passive force decreased after 7 days of immobilization. DTT treatment increased passive force in both NT and Im fibers, with a greater improvement seen in Im fibers. Furthermore, treatment with oxidized glutathione before DTT treatment decreases passive force in both NT and Im fibers, with a greater reduction seen in NT fibers. These results suggest that reversible oxidative modifications partially contribute to the impairments in both myofibrillar active and passive forces, at least in the early phase of immobilization. Specifically, ONOO^- and <i>S</i>-glutathionylation likely play an important role in active and passive force, respectively.<b>NEW & NOTEWORTHY</b> Muscle disuse negatively affects muscle quality, in part due to an impairment of myofibril. This study was the first to reveal that reducing treatment can partially restore the decreased myofibrillar maximal force and passive force observed during the early phase of immobilization. Furthermore, the results suggest that peroxynitrite-induced modification and <i>S</i>-glutathionylation of titin likely contribute to the decreases in active and passive forces, respectively. This study provides valuable insights for the population affected by muscle immobilization.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C939-C952"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938903","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":"Methyl-CpG-binding domain as a protein interaction partner in promoter regulation and neurodevelopment through evolutionary expanded entanglement.","authors":"Stephanie M Bilinovich, Surya B Chhetri, Jackson T Mitchell, Gage O Leighton, Vladislav Jdanov, Jacob K Zieba, Taylor W Cook, Krysta L Engel, Robert M Vaughan, Humza Bhatti, Sadie L Heeringa, Amy M Wilstermann, Sophie Vanderweele, Akansha S Das, Emily C Sherry, Stephen A Duncan, Katie L Uhl, David C Hinds, Mark Mackiewicz, Sarah K Meadows, Kimberly M Newberry, E Christopher Partridge, Sara G Cline, C Joy Shepard, D Casey Smith, Antonio Bradley, Daniel Vogt, Daniel B Campbell, Lucas Pozzo-Miller, Caleb P Bupp, Austin J Goodyke, Surender Rajasekaran, Rebecca C Knickmeyer, Benjie Blair, Connie M Krawczyk, Timothy J Triche, Richard M Myers, Eric M Mendenhall, David C Williams, Jeremy W Prokop","doi":"10.1152/ajpcell.00749.2024","DOIUrl":"10.1152/ajpcell.00749.2024","url":null,"abstract":"<p><p>There is increasing evidence that the methyl-binding domain (MBD) is a protein-protein interaction motif that can function independently of methylated DNA binding. The MBD proteins found throughout plants and invertebrates duplicated into multiple vertebrate DNA and non-DNA-binding members (MBD1, MBD2, MBD3, MBD4, MBD5, MBD6, MECP2, BAZ2A, BAZ2B, SETDB1, and SETDB2). Although many invertebrate species possess MBD proteins that can bind and recognize DNA methylation, the DNA-binding function has been independently lost multiple times, with only minor alterations to the protein interaction residues. The nucleosome remodeling and deacetylase (NuRD) complex, which interacts with MBD2/3 and is colocalized with MBD1/4 ChIP-Seq, is maintained in species where MBD2/3 cannot bind to DNA. NuRD ChIP-seq data from HepG2 cell line, human induced pluripotent stem cells (iPSCs), and human iPSC-derived liver cells suggest that the NuRD complex is highly localized to nonmethylated CpG-rich housekeeping gene promoter elements, which are essential in organogenesis and maintained within the <i>Drosophila melanogaster</i> MBD2/3 non-DNA-binding system. Integration of MBD interaction proteins and NuRD gene expression from >115 million cells of single-cell RNA-seq, along with thousands of bulk tissue profiles, highlights a critical role of MBD3, MECP2, and GATAD2B in brain development and intellectual disability syndromes that is maintained throughout invertebrate neural development and likely involves evolutionary expanded entanglement as the vertebrate MBD proteins expanded. This work suggests that MBD has a largely unexplored role as a critical protein interaction motif that is evolutionarily conserved for regulating enhancers and promoters.<b>NEW & NOTEWORTHY</b> The evolution of the methyl-binding domain (MBD) suggests a shared function in gene regulation, from plants to humans, with the conservation of non-DNA-interacting amino acids critical for protein-protein interactions. The MBD-regulated NuRD complex localizes to promoters of housekeeping genes with hypomethylated CpG islands. Expression profiles suggest a shared role for NuRD complex components in neurodevelopment, where the MBD3 and GATAD2B subcomplex of NuRD may be underexplored due to its non-DNA-binding biology.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C848-C867"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717289","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":"Pericytes in tissue fibrosis.","authors":"Izabela Tuleta, Nikolaos G Frangogiannis","doi":"10.1152/ajpcell.00403.2025","DOIUrl":"10.1152/ajpcell.00403.2025","url":null,"abstract":"<p><p>Pericytes are mural cells, embedded within the microvascular basement membrane and primarily involved in preservation of vessel integrity and regulation of vascular permeability and blood flow. Their study poses major challenges due to the absence of specific and reliable markers for their identification. Emerging evidence suggests that, in addition to their involvement in the regulation of microvascular responses, pericytes may also play a central role in repair, inflammation, and fibrosis in many different organs. Following injury, pericytes may dissociate from endothelial cells, acquiring inflammatory and profibrotic phenotypes. Fibrogenic activation of pericytes has been reported in many different pathologic conditions and may involve stimulation by inflammatory cytokines, transforming growth factor-β, or platelet-derived growth factor-BB. Activated pericytes may stimulate fibrosis by secreting fibroblast-activating growth factors, by producing proteins involved in extracellular matrix remodeling, and by depositing structural and matricellular matrix proteins. Conflicting findings have been reported on the phenotypic plasticity of pericytes and their capacity to convert to fibroblasts and myofibroblasts. Organ-specific differences in pericyte populations and differences in sensitivity and specificity of the pericyte fate mapping and fibroblast identification strategies may account for the conflicting observations reported in various studies. This review manuscript deals with the fate, role, and mechanisms of activation of pericytes in tissue fibrosis. We discuss both the general mechanisms of pericyte activation and the organ-specific roles of pericytes in fibrotic conditions involving the kidney, liver, lung, heart, and central nervous system. Understanding the role of pericytes is important to develop effective therapies for fibrotic conditions.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C868-C886"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833644","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":"Strategies for overcoming ABC transporter-mediated multidrug resistance in colorectal cancer.","authors":"Ralph A de Groot, Daan Reedijk, Quentin Faucher, Silvia M Mihăilă, Rosalinde Masereeuw","doi":"10.1152/ajpcell.00412.2025","DOIUrl":"10.1152/ajpcell.00412.2025","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with multidrug resistance (MDR) significantly limiting the effectiveness of chemotherapy. A major contributor to MDR is the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (<i>ABCB1/</i>P-gp), breast cancer resistance protein (<i>ABCG2/</i>BCRP), and multidrug resistance-associated proteins (<i>ABCC/</i>MRPs). These transporters actively efflux chemotherapeutic agents, reducing their intracellular drug accumulation and efficacy. This review outlines both clinical and emerging strategies that aim to overcome ABC transporter-mediated resistance in CRC. Herein, we detail the functional role of ABC transporters in CRC, followed by clinically tested approaches, such as pharmacological inhibitors, natural compound inhibitors, as well as nanoparticle-based drug delivery systems, that have been explored to circumvent resistance. In addition, we discuss emerging preclinical approaches, including CRISPR/Cas9 gene-editing, RNA interference, epigenetic modulators, and gut microbiome-targeted interventions, that hold promise for future therapeutic translation. By integrating clinically validated and experimental strategies, this review highlights the importance of a multimodal approach to effectively circumvent MDR in CRC and optimize personalized treatment strategies to improve clinical outcomes.<i>ABC transporters; chemoresistance; colorectal cancer; multidrug resistance; therapies</i>.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C699-C717"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641558","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":"Rhbg interaction with CA-IV and its effects on NH₃/NH₄⁺ and CO₂ transport.","authors":"He Zhou, Solange Abdulnour-Nakhoul, L Lee Hamm, Nazih L Nakhoul","doi":"10.1152/ajpcell.00099.2025","DOIUrl":"10.1152/ajpcell.00099.2025","url":null,"abstract":"<p><p>Renal Rhesus type B glycoprotein (Rhbg) is a glycosylated mammalian NH₃/NH₄⁺ transporter expressed in α-intercalated cells of the collecting duct. Carbonic anhydrase-IV (CA-IV) is also expressed in the mammalian kidney, where it catalyzes the reversible hydration of CO₂. This study aims to demonstrate: <i>1</i>) whether Rhbg and CA-IV proteins physically interact; and <i>2</i>) if this interaction functionally affects transport of NH₃/NH₄⁺ and possibly CO₂. We measured transport of NH₄⁺, NH₃, and CO₂ in four groups of <i>Xenopus</i> oocytes. In the first group, we coexpressed Rhbg with CA-IV and compared the measurements to three groups of oocytes expressing either Rhbg or CA-IV or injected with H₂O. We used ion-selective microelectrodes to measure surface pH, to monitor NH₃ transport, and intracellular pH to monitor NH₄⁺ and CO₂ transport. We also used a two-electrode voltage clamp to measure current changes caused by electrogenic NH₄⁺ transport. These parameters measured NH₃/NH₄⁺ and CO₂ transport in oocytes expressing Rhbg and/or CA. Our results indicate that: <i>1</i>) Rhbg and CA-IV were coimmunoprecipitated, suggesting a physical interaction; and <i>2</i>) coexpressing CA-IV with Rhbg: <i>i</i>) inhibited electrogenic NH₄⁺ transport by Rhbg in the presence and absence of CO₂; <i>ii</i>) reduced NH₃ transport by Rhbg only in the presence of CO₂; and <i>iii</i>) had no detectable effect on CO₂ transport by Rhbg. We demonstrated for the first time that Rhbg and CA-IV physically interact, and this interaction has inhibitory effects on Rhbg function but not CA-IV. The interaction of Rhbg and CA-IV is important to explain their role in renal acid-base homeostasis.<b>NEW & NOTEWORTHY</b> Our study revealed the complex regulation of NH₃/NH₄⁺ transport, highlighting the roles of Rhbg, CA-IV, and environmental factors such as CO₂ concentration. These interactions are critical to our understanding of NH₃/NH₄⁺ transport and regulation. Our findings lay a strong foundation for future investigations into the molecular dynamics among these transport proteins and their physiological significance. These studies are essential to fully understand how these mechanisms influence renal ammonia handling, urinary acidification, and systemic pH balance.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C887-C903"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854248","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}