Journal of Clinical Investigation最新文献_第4页

Histamine H1 receptor inverse agonists improve structure and pain in an osteoarthritis mouse model. 组胺H1受体逆激动剂改善骨关节炎小鼠模型的结构和疼痛。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-08-28 DOI: 10.1172/JCI183588

Ichiro Kurakazu, Merissa Olmer, Hannah Swahn, Kevin Myers, Chelsea Kenvisay, Yukio Akasaki, Yasuharu Nakashima, Martin K Lotz

{"title":"Histamine H1 receptor inverse agonists improve structure and pain in an osteoarthritis mouse model.","authors":"Ichiro Kurakazu, Merissa Olmer, Hannah Swahn, Kevin Myers, Chelsea Kenvisay, Yukio Akasaki, Yasuharu Nakashima, Martin K Lotz","doi":"10.1172/JCI183588","DOIUrl":"https://doi.org/10.1172/JCI183588","url":null,"abstract":"Osteoarthritis (OA) is the most common joint disease. Controlling the complex pathogenesis is challenging, thus disease-modifying OA drugs are not available. Forkhead box O (FOXO) transcription factors contribute to cartilage homeostasis through autophagy and oxidative stress resistance. Here, we sought to discover FOXO activators and found that cyproheptadine, a histamine H1 receptor (HRH1) inverse agonist, promoted FOXO3 nuclear translocation and increased FOXO target genes while suppressing inflammation. In a murine OA model, cyproheptadine reduced structural joint tissue damage and pain behaviors. Mechanistically, the inhibition of HRH1 constitutive activity mediated the effects of cyproheptadine on calcium balance between endoplasmic reticulum (ER) and cytoplasm, and FOXO activation was part of this mechanism. The anti-inflammatory effect of cyproheptadine involved the inhibition of protein kinase C/NF-κB pathway. HRH1 inhibition also suppressed osteogenesis in mesenchymal stem cells and nerve growth factor expression, which are mechanisms of osteophyte formation and pain behaviors. Moreover, cyproheptadine suppressed ER stress-induced lipogenesis by upregulating insulin-induced gene 1. Our findings suggest that HRH1 constitutive activity controls important OA-promoting mechanisms and indicate that HRH1 inverse agonists are promising drug repurposing candidates for structure and pain improvement in OA.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clonal expansion of alveolar fibroblast progeny drives pulmonary fibrosis in mouse models. 肺泡成纤维细胞后代克隆扩增驱动小鼠肺纤维化模型。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-08-28 DOI: 10.1172/JCI191826

Christopher Molina, Tatsuya Tsukui, Imran S Khan, Xin Ren, Wenli Qiu, Michael Matthay, Paul Wolters, Dean Sheppard

{"title":"Clonal expansion of alveolar fibroblast progeny drives pulmonary fibrosis in mouse models.","authors":"Christopher Molina, Tatsuya Tsukui, Imran S Khan, Xin Ren, Wenli Qiu, Michael Matthay, Paul Wolters, Dean Sheppard","doi":"10.1172/JCI191826","DOIUrl":"10.1172/JCI191826","url":null,"abstract":"Pulmonary fibrosis has been called a fibroproliferative disease but the functional importance of proliferating fibroblasts to pulmonary fibrosis has not been systematically examined. In response to alveolar injury, resting alveolar fibroblasts differentiate into fibrotic fibroblasts that express high levels of collagens. However, what role, if any, proliferation plays in the accumulation of fibrotic fibroblasts remains unclear. Through EdU incorporation, genetic lineage tracing, and single cell RNA sequencing, we resolve the proliferation dynamics of lung fibroblasts during post-injury fibrogenesis. Our data show substantial DNA replication in progeny of alveolar fibroblasts in two models of pulmonary fibrosis. By genetically labeling individual cells, we observe clonal expansion of alveolar fibroblast descendants principally in regions of fibrotic remodeling. The transcriptome of proliferating fibroblasts closely resembles that of fibrotic fibroblasts, suggesting that fibroblasts can first differentiate into fibrotic fibroblasts and then proliferate. Genetic ablation of proliferating fibroblasts and selective inhibition of cytokinesis in alveolar fibroblast descendants significantly mitigates pulmonary fibrosis and rescues lung function. Furthermore, fibroblasts in precision-cut lung slices from human fibrotic lungs exhibit higher proliferation rates than those in non-diseased lungs. This work establishes fibroblast proliferation as a critical driver of pulmonary fibrosis and suggests that specifically targeting fibroblast proliferation could be a new therapeutic strategy for fibrotic diseases.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reduced heparan sulfate levels in cerebrospinal fluid reflect brain neuron correction in Sanfilippo B mice. Sanfilippo B小鼠脑脊液中硫酸肝素水平的降低反映了脑神经元的校正。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-08-28 DOI: 10.1172/JCI195268

Steven Q Le, Alexander Sorensen, Soila Sukupolvi, Gianna Jewhurst, Grant L Austin, Balraj Doray, Jonathan D Cooper, Patricia I Dickson

引用次数: 0

Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2. Molnupiravir临床试验模拟表明聚合酶链反应低估了对SARS-CoV-2的抗病毒效力。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-08-28 DOI: 10.1172/JCI192052

Shadisadat Esmaeili, Katherine Owens, Ugo Avila-Ponce de Leon, Joseph F Standing, David M Lowe, Shengyuan Zhang, James A Watson, William Hk Schilling, Jessica Wagoner, Stephen J Polyak, Joshua T Schiffer

{"title":"Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2.","authors":"Shadisadat Esmaeili, Katherine Owens, Ugo Avila-Ponce de Leon, Joseph F Standing, David M Lowe, Shengyuan Zhang, James A Watson, William Hk Schilling, Jessica Wagoner, Stephen J Polyak, Joshua T Schiffer","doi":"10.1172/JCI192052","DOIUrl":"10.1172/JCI192052","url":null,"abstract":"Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes. Model simulations suggest lower antiviral potency against pre-omicron SARS-CoV-2 variants than against omicron. We estimate that in vitro assays underestimate in vivo potency 6-7 fold against omicron variants. Our model suggests that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA is underestimated by ~0.4 log10 in the two trials conducted while omicron variants dominated. Viral area under the curve estimates differ significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in vitro assays are unreliable for estimating in vivo antiviral drug potency and suggest that virologic endpoints for respiratory virus clinical trials should be catered to the drug mechanism of action.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Myeloid-mesenchymal crosstalk drives ARG1-dependent profibrotic metabolism via ornithine in lung fibrosis. 髓-间充质串扰通过鸟氨酸在肺纤维化中驱动arg1依赖性纤维化代谢。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-08-28 DOI: 10.1172/JCI188734

Preeti Yadav, Javier Gómez Ortega, Prerna Dabral, Whitney Tamaki, Charles Chien, Kai-Chun Chang, Nivedita Biswas, Sixuan Pan, Julia Nilsson, Xiaoyang Yin, Aritra Bhattacharyya, Kaveh Boostanpour, Tanay Jujaray, Jasper T Wang, Tatsuya Tsukui, Christopher J Molina, Vincent C Auyeung, Dean Sheppard, Baosheng Li, Mazharul Maishan, Hiroki Taenaka, Michael A Matthay, Rieko Muramatsu, Lenka Maliskova, Arnab Ghosh, Walter L Eckalbar, Ari B Molofsky, Stanley J Tamaki, Trever G Bivona, Adam R Abate, Allon Wagner, Satish K Pillai, Paul J Wolters, Kevin M Tharp, Mallar Bhattacharya

{"title":"Myeloid-mesenchymal crosstalk drives ARG1-dependent profibrotic metabolism via ornithine in lung fibrosis.","authors":"Preeti Yadav, Javier Gómez Ortega, Prerna Dabral, Whitney Tamaki, Charles Chien, Kai-Chun Chang, Nivedita Biswas, Sixuan Pan, Julia Nilsson, Xiaoyang Yin, Aritra Bhattacharyya, Kaveh Boostanpour, Tanay Jujaray, Jasper T Wang, Tatsuya Tsukui, Christopher J Molina, Vincent C Auyeung, Dean Sheppard, Baosheng Li, Mazharul Maishan, Hiroki Taenaka, Michael A Matthay, Rieko Muramatsu, Lenka Maliskova, Arnab Ghosh, Walter L Eckalbar, Ari B Molofsky, Stanley J Tamaki, Trever G Bivona, Adam R Abate, Allon Wagner, Satish K Pillai, Paul J Wolters, Kevin M Tharp, Mallar Bhattacharya","doi":"10.1172/JCI188734","DOIUrl":"10.1172/JCI188734","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung remodeling and collagen deposition that leads to respiratory failure. Myeloid cells are abundant in IPF lung and in murine lung fibrosis, but their functional effects are incompletely understood. Using mouse and human lung models, we show that ornithine produced by myeloid cells expressing Arginase 1 (ARG1) serves as a substrate for proline and collagen synthesis by lung fibroblasts. The predominant ARG1-expressing myeloid cells in mouse lung were macrophages, but in IPF lung, high-dimensional imaging revealed ARG1 to be expressed mainly in neutrophils. Small-molecule ARG1 inhibition suppressed both ornithine levels and collagen expression in cultured, precision-cut IPF lung slices and in murine lung fibrosis. These results were confirmed in macrophage-specific Arg1 KO mice. Furthermore, we find that this pathway is regulated by cell-to-cell crosstalk, starting with purinergic signaling: Extracellular ATP (eATP) receptor P2RX4 was necessary for fibroblast IL-6 expression, which in turn was necessary for ARG1 expression by myeloid cells. Taken together, our findings define an immune-mesenchymal circuit that governs profibrotic metabolism in lung fibrosis.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A smooth muscle cell lncRNA controls angiogenesis in chronic limb-threatening ischemia through miR-143-3p/HHIP signaling. 平滑肌细胞lncRNA通过miR-143-3p/ hip信号传导控制慢性肢体缺血血管生成。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-08-28 DOI: 10.1172/JCI188559

Ming Zhai, Anurag Jamaiyar, Jun Qian, Winona W Wu, Emre Bektik, Vinay Randhawa, Camila De Oliveira Vaz, Arvind K Pandey, Akm Khyrul Wara, Madhur Sachan, Yi Hu, Jéssica L Garcia, Claire E Alford, Terence E Ryan, Wenhui Peng, Mark W Feinberg

{"title":"A smooth muscle cell lncRNA controls angiogenesis in chronic limb-threatening ischemia through miR-143-3p/HHIP signaling.","authors":"Ming Zhai, Anurag Jamaiyar, Jun Qian, Winona W Wu, Emre Bektik, Vinay Randhawa, Camila De Oliveira Vaz, Arvind K Pandey, Akm Khyrul Wara, Madhur Sachan, Yi Hu, Jéssica L Garcia, Claire E Alford, Terence E Ryan, Wenhui Peng, Mark W Feinberg","doi":"10.1172/JCI188559","DOIUrl":"https://doi.org/10.1172/JCI188559","url":null,"abstract":"Peripheral artery disease (PAD) often advances to chronic limb-threatening ischemia (CLTI), resulting in severe complications such as limb amputation. Despite the potential of therapeutic angiogenesis, the mechanisms of cell-cell communication and transcriptional changes driving PAD are not fully understood. Profiling long non-coding RNAs (lncRNAs) from gastrocnemius muscles of human subjects with or without CLTI revealed that a vascular smooth muscle cell (SMC)-enriched lncRNA CARMN, was reduced with CLTI. This study explored how a SMC lncRNA-miRNA signaling axis regulates angiogenesis in limb ischemia. CARMN knockout (KO) mice exhibited reduced capillary density and impaired blood flow recovery and tissue necrosis following limb ischemia. We found that CARMN KO SMC supernatants inhibited endothelial cell (EC) proliferation, spheroid sprouting, and network formation. RNA-sequencing identified downregulation of the Hedgehog signaling pathway in CARMN KO models and revealed that CARMN regulates this pathway through its downstream miRNA, miR-143-3p, which targets Hedgehog-interacting protein (HHIP), an antagonist of Hedgehog signaling. Delivery of HHIP-specific siRNA or miR-143-3p mimics rescued EC angiogenic defects and improved blood flow recovery in both CARMN KO and WT mice. These findings underscore the critical role of CARMN in modulating angiogenesis through the miR-143-3p-HHIP-Hedgehog signaling axis, providing insights into SMC-EC interactions and potential therapeutic strategies for CLTI.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Peripherally administered androgen receptor-targeted antisense oligonucleotide rescues spinal pathology in a murine SBMA model. 外周给药雄激素受体靶向反义寡核苷酸拯救脊髓病理小鼠SBMA模型。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-08-28 DOI: 10.1172/JCI182955

Changwoo Lee, Zhigang Yu, Curtis J Kuo, Leon Tejwani, Rosalie M Grijalva, Eunwoo Bae, Hien T Zhao, Janghoo Lim, Andrew P Lieberman

{"title":"Peripherally administered androgen receptor-targeted antisense oligonucleotide rescues spinal pathology in a murine SBMA model.","authors":"Changwoo Lee, Zhigang Yu, Curtis J Kuo, Leon Tejwani, Rosalie M Grijalva, Eunwoo Bae, Hien T Zhao, Janghoo Lim, Andrew P Lieberman","doi":"10.1172/JCI182955","DOIUrl":"10.1172/JCI182955","url":null,"abstract":"Degeneration of the neuromuscular system is a characteristic feature of spinal and bulbar muscular atrophy (SBMA), a CAG/polyglutamine (polyQ) expansion disorder caused by mutation in the androgen receptor (AR). Using a gene targeted mouse model of SBMA, AR113Q mice, we demonstrate age-dependent degeneration of the neuromuscular system that initially manifests with muscle weakness and atrophy and progresses to include denervation of neuromuscular junctions and lower motor neuron soma atrophy. Using this model, we tested the hypothesis that therapeutic intervention targeting skeletal muscle during this period of disease progression arrests degeneration of the neuromuscular system. To accomplish this, AR-targeted antisense oligonucleotides were administered subcutaneously to symptomatic AR113Q mice to reduce expression of polyQ AR in peripheral tissues but not in the spinal cord. This intervention rescued muscle atrophy, neuromuscular junction innervation, lower motor neuron soma size, and survival in aged AR113Q mice. Single-nucleus RNA sequencing revealed age-dependent transcriptional changes in the AR113Q spinal cord during disease progression which were mitigated by peripheral AR gene silencing. Our findings underscore the intricate interplay between peripheral tissues and the central nervous system in SBMA and emphasize the therapeutic effectiveness of peripheral gene knockdown in symptomatic disease.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Incretin receptor agonism rapidly inhibits AgRP neurons to suppress food intake in mice. 肠促胰岛素受体激动作用迅速抑制AgRP神经元抑制小鼠的食物摄入。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-08-26 DOI: 10.1172/JCI186652

Hayley E McMorrow, Andrew B Cohen, Carolyn M Lorch, Nikolas W Hayes, Stefan W Fleps, Joshua A Frydman, Jessica L Xia, Ricardo J Samms, Lisa R Beutler

{"title":"Incretin receptor agonism rapidly inhibits AgRP neurons to suppress food intake in mice.","authors":"Hayley E McMorrow, Andrew B Cohen, Carolyn M Lorch, Nikolas W Hayes, Stefan W Fleps, Joshua A Frydman, Jessica L Xia, Ricardo J Samms, Lisa R Beutler","doi":"10.1172/JCI186652","DOIUrl":"https://doi.org/10.1172/JCI186652","url":null,"abstract":"The incretin receptor agonists semaglutide and tirzepatide have transformed the medical management of obesity. The neural mechanisms by which incretin analogs regulate appetite remain incompletely understood, and dissecting this process is critical for the development of next-generation anti-obesity drugs that are more targeted and tolerable. Moreover, the physiologic functions of incretins in appetite regulation and gut-brain communication have remained elusive. Using in vivo fiber photometry, we discovered distinct pharmacologic and physiologic roles for the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We showed that GIP, but not GLP-1, was required for normal nutrient-mediated inhibition of hunger-promoting AgRP neurons. By contrast, both GIP and GLP-1 analogs at pharmacologic doses were sufficient to inhibit AgRP neurons. The magnitude of neural inhibition was proportional to the effect of each incretin on food intake, and dual GIP and GLP-1 receptor agonism more potently inhibited AgRP neurons and suppressed food intake than either agonist alone. Our results have revealed a role for endogenous GIP in gut-brain appetite regulation and indicate that incretin analogs act in part via AgRP neurons to mediate their anorectic effects.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hypercapnia promotes maladaptive airway and vascular remodeling in mice. 高碳酸血症促进小鼠气道和血管重构的不适应。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-08-26 DOI: 10.1172/JCI196928

Masahiko Shigemura, Felix L Nunez-Santana, S Marina Casalino-Matsuda, David Kirchenbuechler, Radmila Nafikova, Fei Chen, Zhan Yu, Yuliana V Sokolenko, Estefani Diaz, Suchitra Swaminathan, Suror Mohsin, Rizaldy P Scott, Lynn C Welch, Chitaru Kurihara, Emilia Lecuona, G R Scott Budinger, Peter H S Sporn, Jacob I Sznajder, Ankit Bharat

引用次数: 0

Cell and molecular profiles in peripheral nerves shift toward inflammatory phenotypes in diabetic peripheral neuropathy. 糖尿病周围神经病变中周围神经的细胞和分子特征向炎症表型转移。

IF 13.6 1区医学

Journal of Clinical Investigation Pub Date : 2025-08-19 DOI: 10.1172/JCI184075

Diana Tavares-Ferreira, Breanna Q Shen, Juliet M Mwirigi, Stephanie Shiers, Ishwarya Sankaranarayanan, Akshitha Sreerangapuri, Miriam B Kotamarti, Nikhil N Inturi, Khadijah Mazhar, Eroboghene E Ubogu, Geneva L Thomas, Trapper Lalli, Shai M Rozen, Dane K Wukich, Theodore J Price

{"title":"Cell and molecular profiles in peripheral nerves shift toward inflammatory phenotypes in diabetic peripheral neuropathy.","authors":"Diana Tavares-Ferreira, Breanna Q Shen, Juliet M Mwirigi, Stephanie Shiers, Ishwarya Sankaranarayanan, Akshitha Sreerangapuri, Miriam B Kotamarti, Nikhil N Inturi, Khadijah Mazhar, Eroboghene E Ubogu, Geneva L Thomas, Trapper Lalli, Shai M Rozen, Dane K Wukich, Theodore J Price","doi":"10.1172/JCI184075","DOIUrl":"10.1172/JCI184075","url":null,"abstract":"Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus caused by metabolic toxicity to peripheral axons. We aimed to gain deep mechanistic insight into the disease using transcriptomics on tibial and sural nerves recovered from lower leg amputations in a mostly diabetic population and control sural nerves from cross facial nerve graft surgery. First, comparing DPN versus control sural nerves revealed inflammatory activation and sensory changes in DPN. Second, when comparing mixed sensory and motor tibial and purely sensory sural nerves, we identified key pathway differences in affected DPN nerves, with distinct immunological features observed in sural nerves. Third, spatial transcriptomics of sural nerves revealed shifts in immune cell types associated with axonal loss progression. We also found clear evidence of neuronal transcript changes, like PRPH, in nerves with axonal loss, suggesting perturbed RNA transport into distal sensory axons. This motivated further investigation into neuronal mRNA localization in peripheral nerve axons, generating evidence of robust localization of mRNAs such as SCN9A and TRPV1 in human sensory axons. Our work provides insight into altered cellular and transcriptomic profiles in human nerves in DPN and highlights sensory axon mRNA transport as a potential contributor to nerve degeneration.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0