Journal of Molecular Medicine-Jmm最新文献

{"title":"Oral pyrophosphate protects Abcc6^-/- mice against vascular calcification induced by chronic kidney disease.","authors":"Elise Bouderlique, Jennifer Kervadec, Ellie Tang, Jeremy Zaworski, Amélie Coudert, Isabelle Rubera, Christophe Duranton, Edmat Khan, Jean-Philippe Haymann, Georges Leftheriotis, Michel Daudon, Emmanuel Letavernier","doi":"10.1007/s00109-024-02468-y","DOIUrl":"10.1007/s00109-024-02468-y","url":null,"abstract":"<p><p>One of the hallmarks of chronic kidney disease (CKD) is the development of vascular calcification. Inorganic pyrophosphate is a potent inhibitor of calcification, and previous studies have reported low plasma pyrophosphate levels in hemodialysis patients. A long-term mouse model of CKD-accelerated vascular calcification was developed to study pyrophosphate metabolism and to test whether oral pyrophosphate supplementation attenuates the propensity for arterial calcification. CKD was induced by repeated injections of aristolochic acid in wild-type and Abcc6^-/- mice, which tend to develop vascular calcifications. CKD accelerated the development of vascular calcifications in Abcc6^-/- mice, in the aorta and small renal arteries, and decreased circulating pyrophosphate levels. Oral pyrophosphate supplementation for 6 months attenuated CKD-induced vascular calcification in this model. These results show that oral pyrophosphate may be of interest in preventing vascular calcification in patients with CKD. KEY MESSAGES: Chronic kidney disease accelerates the development of vascular calcification in pyrophosphate-deficient mice. Oral pyrophosphate supplementation for 6 months attenuates chronic kidney disease-induced vascular calcification in a mouse model. Oral pyrophosphate may be of interest in preventing vascular calcification in patients with chronic kidney disease.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"1217-1227"},"PeriodicalIF":4.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141972226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New CRISPR/Cas9-based Fgfr2^C361Y/+ mouse model of Crouzon syndrome exhibits skull and behavioral abnormalities.","authors":"Ying Ying Yue, Chen-Zhi Lai, Xiao-Shuang Guo, Chang-Sheng Yang, Yu Wang, Guo-Dong Song, Xiao-Lei Jin","doi":"10.1007/s00109-024-02476-y","DOIUrl":"10.1007/s00109-024-02476-y","url":null,"abstract":"<p><p>Crouzon syndrome (CS), a syndromic craniosynostosis, is a craniofacial developmental deformity caused by mutations in fibroblast growth factor receptor 2 (FGFR2). Previous CS mouse models constructed using traditional gene editing techniques faced issues such as low targeting efficiency, extended lineage cycles, and inconsistent and unstable phenotypes. In this study, a CRISPR/Cas9-mediated strategy was employed to induce a functional augmentation of the Fgfr2 point mutation in mice. Various techniques, including bone staining, micro-CT, histological methods, and behavioral experiments, were employed to systematically examine and corroborate phenotypic disparities between mutant mice (Fgfr2^C361Y/+) and their wild-type littermates. Confirmed via PCR-Sanger sequencing, we successfully induced the p.Cys361Tyr missense mutation in the Fgfr2 IIIc isoform of the extracellular domain (corresponding to the p.Cys342Tyr mutation in humans) based on Fgfr2-215 transcript (ENSMUST00000122054.8). Fgfr2^C361Y/+ mice exhibited characteristics consistent with the phenotypic features associated with CS, including skull-vault craniosynostosis, skull deformity, shallow orbits accompanied by exophthalmos, midface hypoplasia with malocclusion, and shortened skull base, notably without any apparent limb defects. Furthermore, mutant mice displayed behavioral abnormalities encompassing deficits in learning and memory, social interaction, and motor dysfunction, without anxiety-related disorders. Histopathological examination of the hippocampal region revealed structural abnormalities, suggesting possible brain development impairment secondary to craniosynostosis. In conclusion, we constructed a novel gene-edited Fgfr2^C361Y/+ mice strain based on CRISPR/Cas9, which displayed skull and behavioral abnormalities, serving as a new model for studying genetic molecular mechanisms and exploring treatments for CS. KEY MESSAGES: CRISPR/Cas9 crafted a Crouzon model by enhancing Fgfr2-C361Y in mice. Fgfr2^C361Y/+ mice replicate CS phenotypes-craniosynostosis and midface anomalies. Mutant mice show diverse behavioral abnormalities, impacting learning and memory. Fgfr2^C361Y/+ mice offer a novel model for cranial suture studies and therapeutic exploration.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"1255-1266"},"PeriodicalIF":4.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular targets in bone cancer pain: a systematic review of inflammatory cytokines.","authors":"Jacinta Ruivo, Isaura Tavares, Daniel H Pozza","doi":"10.1007/s00109-024-02464-2","DOIUrl":"10.1007/s00109-024-02464-2","url":null,"abstract":"<p><p>Bone cancer pain (BCP) profoundly impacts patient's quality of life, demanding more effective pain management strategies. The aim of this systematic review was to investigate the role of inflammatory cytokines as potential molecular targets in BCP. A systematic search for animal rodent models of bone cancer pain studies was conducted in PubMed, Scopus, and Web of Science. Methodological quality and risk of bias were assessed using the SYRCLE RoB tool. Twenty-five articles met the inclusion criteria, comprising animal studies investigating molecular targets related to inflammatory cytokines in BCP. A low to moderate risk of bias was reported. Key findings in 23 manuscripts revealed upregulated classic pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17, IL-18, IL-33) and chemokines in the spinal cord, periaqueductal gray, and dorsal root ganglia. Interventions targeting these cytokines consistently mitigated pain behaviors. Additionally, it was demonstrated that glial cells, due to their involvement in the release of inflammatory cytokines, emerged as significant contributors to BCP. This systematic review underscores the significance of inflammatory cytokines as potential molecular targets for alleviating BCP. It emphasizes the promise of targeted interventions and advocates for further research to translate these findings into effective therapeutic strategies. Ultimately, this approach holds the potential to enhance the patient's quality of life.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"1063-1088"},"PeriodicalIF":4.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11358194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based humanization of a therapeutic antibody for multiple myeloma.","authors":"Stephen F Marino, Oliver Daumke","doi":"10.1007/s00109-024-02470-4","DOIUrl":"10.1007/s00109-024-02470-4","url":null,"abstract":"<p><p>The optimal efficacy of xenogeneically generated proteins intended for application in humans requires that their own antigenicity be minimized. This necessary adaptation of antibodies to a humanized version poses challenges since modifications even distant from the binding sites can greatly influence antigen recognition and this is the primary feature that must be maintained during all modifications. Current strategies often rely on grafting and/or randomization/selection to arrive at a humanized variant retaining the binding properties of the original molecule. However, in terms of speed and efficiency, rationally directed approaches can be superior, provided the requisite structural information is available. We present here a humanization procedure based on the high-resolution X-ray structure of a chimaeric IgG against a marker for multiple myeloma. Based on in silico modelling of humanizing amino acid substitutions identified from sequence alignments, we devised a straightforward cloning procedure to rapidly evaluate the proposed sequence changes. Careful inspection of the structure allowed the identification of a potentially problematic amino acid change that indeed disrupted antigen binding. Subsequent optimization of the antigen binding loop sequences resulted in substantial recovery of binding affinity lost in the completely humanized antibody. X-ray structures of the humanized and optimized variants demonstrate that the antigen binding mode is preserved, with surprisingly few direct contacts to antibody atoms. These results underline the importance of structural information for the efficient optimization of protein therapeutics. KEY MESSAGES: Structure-based humanization of an IgG against BCMA, a marker for Multiple Myeloma. Identification of problematic mutations and unexpected modification sites. Structures of the modified IgG-antigen complexes verified predictions. Provision of humanized high-affinity IgGs against BCMA for therapeutic applications.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"1151-1161"},"PeriodicalIF":4.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11358308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141762225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil-secreted S100A8/A9 participates in fatty liver injury and fibrosis by promoting myofibroblast migration.","authors":"Na Chang, Yuran Liu, Weiyang Li, Yuehan Ma, Xuan Zhou, Xinhao Zhao, Lin Yang, Liying Li","doi":"10.1007/s00109-024-02469-x","DOIUrl":"10.1007/s00109-024-02469-x","url":null,"abstract":"<p><p>Fatty liver, which is induced by abnormal lipid metabolism, is one of the most common causes of chronic liver disease globally and causes liver fibrosis. During this process, bone marrow-derived mesenchymal stromal cells (BMSCs) and hepatic stellate cells (HSCs) migrate toward the injured liver and participate in fibrogenesis by transdifferentiating into myofibroblasts. S100A8/A9 is a powerful inducer of cell migration and is involved in liver injury. But there are few reports about the effects of S100A8/A9 on BMSC/HSC migration. In the current study, we found that S100A8/A9 expression was increased during fatty liver injury/fibrogenesis. Moreover, S100A8/A9 expression had a positive correlation with fibrosis marker gene expressions in the injured liver. S100A8/A9 was mainly produced by neutrophils in the fibrotic liver. In vitro, neutrophil-secreted S100A8/A9 promoted BMSC/HSC migration via remodeling of microfilaments. Using specific siRNA and inhibitor, we proved that S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. Moreover, S100A8/A9 knock-down alleviated liver injury and fibrogenesis in vivo, while injection of S100A9 neutralizing antibody performed similar roles. We proved that S100A8/A9 was involved in liver injury and fibrogenesis via inducing BMSC/HSC migration. Our research reveals a new mechanism underlying BMSC/HSC migration in liver fibrosis and suggests S100A8/A9 as a potential therapeutic target of liver fibrosis. KEY MESSAGES: S100A8/A9 is secreted by neutrophils and increased in fatty liver injury. Neutrophil-secreted S100A8/A9 is a mediator of BMSC/HSC migration in vitro. S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. S100A8/A9 blockade alleviates liver injury and fibrogenesis in vivo.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"1117-1133"},"PeriodicalIF":4.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141591909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of α7 nAChR-autophagy axis of deciduous tooth pulp stem cells in regulating IL-1β in the process of physiological root resorption of deciduous teeth.","authors":"Tiankai Di, Yujiang Chen, Zhifei Zhou, Jiajia Liu, Yang Du, Chao Feng, Bin Zhu, Lulu Wang","doi":"10.1007/s00109-024-02466-0","DOIUrl":"10.1007/s00109-024-02466-0","url":null,"abstract":"<p><p>Physiological root resorption of deciduous teeth is a normal phenomenon occurring during the developmental stages of children. Previous research has indicated the pivotal role of the inflammatory microenvironment in this process, although the specific mechanisms remain unclear. This study is aimed at elucidating the involvement of the alpha7 nicotinic acetylcholine receptors (α7 nAChR)-autophagy axis in the regulation of the inflammatory microenvironment during physiological root resorption in deciduous teeth. Samples were collected from deciduous teeth at various stages of physiological root resorption, and deciduous dental pulp stem cells (DDPSCs) were isolated and cultured during the mid-phase of root resorption. The findings revealed a substantial infiltration of the pulp of deciduous teeth at the mid-phase of root resorption, characterized by elevated expression levels of α7 nAChR and IL-1β. Significantly increased IL-1β and α7 nAChR expressions were observed in DDPSCs during the mid-phase of root resorption, with α7 nAChR demonstrating a regulatory effect on IL-1β. Moreover, evidence suggested that mechanical stress may act as a trigger, regulating autophagy and IL-1 expression via α7 nAChR. In conclusion, mechanical stress was identified as a regulator of autophagy in DDPSCs through α7 nAChR, influencing the expression of IL-1β and contributing to the formation of the inflammatory microenvironment. This mechanism plays a crucial role in the physiological root resorption of deciduous teeth. KEY MESSAGES: The pulp of deciduous teeth at mid-phase of root resorption was heavily infiltrated with high expression of α7nAChR and IL-1β. α7 nAChR acts as an initiating factor to regulate IL-1β through autophagy in DDPSCs. Mechanical stress can regulate autophagy of DDPSCs through α7 nAChR and thus affect IL-1β expression and inflammatory microenvironment formation in physiological root resorption in deciduous teeth.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"1135-1149"},"PeriodicalIF":4.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141604442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin improves cognitive dysfunction through SIRT1/NLRP3 pathway-mediated neuroinflammation in db/db mice.","authors":"Tian Hu, Jun-Wen Wei, Jia-Yi Zheng, Qing-Yi Luo, Xin-Rui Hu, Qun Du, Ye-Feng Cai, Shi-Jie Zhang","doi":"10.1007/s00109-024-02465-1","DOIUrl":"10.1007/s00109-024-02465-1","url":null,"abstract":"<p><p>Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system. Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of metformin and related mechanisms. Behavioral tests indicated that metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress-induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study, metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1β, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion, metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"1101-1115"},"PeriodicalIF":4.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The caspase-inhibitor Emricasan efficiently counteracts cisplatin- and neomycin-induced cytotoxicity in cochlear cells.","authors":"Larissa Nassauer, Juliane W Schott, Jennifer Harre, Athanasia Warnecke, Michael Morgan, Melanie Galla, Axel Schambach","doi":"10.1007/s00109-024-02472-2","DOIUrl":"10.1007/s00109-024-02472-2","url":null,"abstract":"<p><p>Cisplatin is a chemotherapeutic agent widely used to treat solid tumors. However, it can also be highly ototoxic, resulting in high-frequency hearing loss. Cisplatin causes degeneration of hair cells (HCs) and spiral ganglion neurons (SGNs) in the inner ear, which are essential components of the hearing process and cannot be regenerated in mammals. As the affected cells primarily die by apoptosis, we tested several anti-apoptotic small molecules to protect these cells from drug-induced toxicity. We found that the general caspase inhibitor Emricasan could significantly counteract the toxic effects of cisplatin in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, phoenix auditory cells, and primary SGNs. Importantly, the anti-cytotoxic effect in neuronal cells was even more pronounced than the effect of sodium thiosulfate (STS), which is currently the only approved prevention option for cisplatin-induced ototoxicity. Finally, we tested the protective effect of Emricasan treatment in the context of another ototoxic drug, i.e., the aminoglycoside antibiotic neomycin, and again found a significant increase in cell viability when the cultures were co-treated with Emricasan. These results suggest a promising strategy to prevent ototoxicity in patients by temporarily blocking the apoptotic pathway when applying cisplatin or aminoglycoside antibiotics. KEY MESSAGES: Anti-apoptotic small molecules can reduce cisplatin-induced toxicity. Emricasan can effectively exert its anti-apoptotic effect on cochlear cells. Strong protection from cisplatin- and neomycin-induced cytotoxicity with Emricasan. Sodium thiosulfate and Emricasan provide similar protective effects to cisplatin-treated cells. Emricasan is more potent than sodium thiosulfate in reducing neomycin-induced cytotoxicity.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"1163-1174"},"PeriodicalIF":4.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11358181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs role in telomere length maintenance and telomerase activity in tumor cells.","authors":"Stéfanne Bortoletto, Emanuelle Nunes-Souza, Rafael Marchi, Mayara Oliveira Ruthes, Larissa M Okano, Maria Vitoria Tofolo, Ariana Centa, Aline S Fonseca, Daiane Rosolen, Luciane R Cavalli","doi":"10.1007/s00109-024-02467-z","DOIUrl":"10.1007/s00109-024-02467-z","url":null,"abstract":"<p><p>MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of the human telomerase reverse transcriptase (hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells. Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"1089-1100"},"PeriodicalIF":4.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective role of M₃ muscarinic acetylcholine receptor in indomethacin-induced small intestinal injury.","authors":"Yoko Igarashi-Hisayoshi, Eikichi Ihara, Xiaopeng Bai, Yoshimasa Tanaka, Haruei Ogino, Takatoshi Chinen, Yasushi Taguchi, Yoshihiro Ogawa","doi":"10.1007/s00109-024-02474-0","DOIUrl":"10.1007/s00109-024-02474-0","url":null,"abstract":"<p><p>EP₄ prostanoid receptor (EP₄R) contributes to the intestinal epithelial Cl^- secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M₃ muscarinic acetylcholine receptor (M₃R) also contributes to the intestinal epithelial Cl^- secretion, it remains unclear whether M₃R is involved in NSAID-induced enteropathy due to a lack of selective agents. The present study explored how M₃R is involved in the regulation of the intestinal epithelial Cl^- secretion and its pathophysiological role in NSAID-induced enteropathy. Using the novel highly-selective M₃ positive allosteric modulator PAM-369 that we recently developed, we evaluated the role of M₃R in the intestinal epithelial secretion ex vivo by measuring the short circuit current (Isc) of intestinal epithelium with a Ussing chamber system and examined whether or not M₃R protects against small intestinal injury in indomethacin-treated mice. Both the PGE₁ derivative misoprostol and carbachol similarly increased the Isc in a concentration-dependent manner. The Isc increases were abolished either by receptor antagonists (an EP₄R antagonist and a M₃R antagonist, respectively) or by removal of extracellular Cl^-. PAM-369 enhanced the carbachol-induced Isc by potentiating M₃R, which could contribute to enhanced intestinal epithelial secretion. Treatment with PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. Importantly, the M₃R expression was significantly up-regulated, and PAM-369 potentiation of M₃R was augmented in indomethacin-treated mice compared to untreated mice. These findings show that M₃R plays a role in maintaining the intestinal epithelial secretion, which could contribute to protection against indomethacin-induced small intestinal injury. M₃R is a promising target for treating or preventing NSAID-induced enteropathy. KEY MESSAGES: PAM-369, the M₃ positive allosteric modulator, was used to potentiate M₃R. PAM-369 enhanced carbachol-induced Isc in mouse ileum. PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. M₃R is a promising target for treating or preventing NSAID-induced enteropathy.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":" ","pages":"1175-1186"},"PeriodicalIF":4.8,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}