Molecular Medicine最新文献

{"title":"Preclinical evaluation of AAV9-coSMN1 gene therapy for spinal muscular atrophy: efficacy and safety in mouse models and non-human primates.","authors":"Wenhao Ma, Zhijie Wu, Tianyi Zhao, Yan Xia, Jing Qin, Xue Tian, Xin Li, Jun He, Yan Zhang, Lina Zhang, Li Li, Zheyue Dong, Zhichun Feng, Xiaoyan Dong, Wang Sheng, Xiaobing Wu","doi":"10.1186/s10020-025-01207-4","DOIUrl":"https://doi.org/10.1186/s10020-025-01207-4","url":null,"abstract":"<p><strong>Background: </strong>Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by the loss of motor neurons in the spinal cord. Our team has initiated clinical trials using adeno-associated virus serotype 9 (AAV9) vectors carrying a codon-optimized human SMN1 (coSMN1) gene, delivered via intrathecal (IT) injection. Here, we present the preclinical research that laid the groundwork for these trials, offering comprehensive data on the efficacy and safety of AAV9-coSMN1 in both murine models and non-human primates.</p><p><strong>Material and method: </strong>We developed a codon-optimized hSMN1 expression cassette and analyzed SMN protein levels using Western blot and immunofluorescence. Taiwanese SMA-like mouse model was employed to assess tail length preservation, as well as to examine motor neuron and skeletal muscle pathological phenotypes through immunofluorescence and histopathological staining. Serum biomarkers in both mice and cynomolgus monkeys were measured using a blood chemistry analyzer. The in-vivo biodistribution of AAV9-coSMN1 and toxicological profile were investigated through quantitative Polymerase Chain Reaction(qPCR) and histopathological staining.</p><p><strong>Results: </strong>Codon optimization of hSMN1 led to enhanced gene expression and increased SMN protein levels in vitro. AAV9-coSMN1 demonstrated significant therapeutic efficacy in a Type 3 SMA mouse model, effectively rescuing motor neurons, preserving tail integrity, and improving skeletal muscle histopathology. In vivo studies, both mice and cynomolgus monkeys revealed widespread CNS distribution following a single intracerebroventricular or intrathecal injection, with no observed toxic inflammatory responses in the dorsal root ganglia. Peripheral organs also showed detectable levels of the vector gene, indicating effective systemic distribution.</p><p><strong>Conclusion: </strong>The preclinical evaluation confirms that AAV9-coSMN1 is a safe and effective therapeutic candidate for SMA, with potential applicability across various phenotypes. The study provides critical data supporting its advancement to clinical trials, underscoring its promise for broader neurological applications.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"158"},"PeriodicalIF":6.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: S-propargyl-cysteine attenuates temporomandibular joint osteoarthritis by regulating macrophage polarization via Inhibition of JAK/STAT signaling.","authors":"Wenyi Cai, Antong Wu, Zhongxiao Lin, Wei Cao, Janak L Pathak, Richard T Jaspers, Rui Li, Xin Li, Kaihan Zheng, Yufu Lin, Na Zhou, Xin Zhang, Yizhun Zhu, Qingbin Zhang","doi":"10.1186/s10020-025-01214-5","DOIUrl":"https://doi.org/10.1186/s10020-025-01214-5","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"156"},"PeriodicalIF":6.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PYK2 promotes cell proliferation and epithelial-mesenchymal transition in endometriosis by phosphorylating Snail1.","authors":"Lu Liu, Lan Liu, Chenjing Yue, Shiyu Du, Jiayu Liu, Zhenhai Yu","doi":"10.1186/s10020-025-01218-1","DOIUrl":"https://doi.org/10.1186/s10020-025-01218-1","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Endometriosis can lead to decreased endometrial receptivity, reduced rates of implantation, and diminished ovarian reserve. Currently, more than 50% of infertile women are found to suffer from endometriosis. However the etiology and pathogenesis of endometriosis are still poorly understood. Epithelial-mesenchymal transition (EMT) has been confirmed to be involved in endometriosis. PYK2 is a non-receptor tyrosine kinase that affects cell proliferation, survival, and migration by regulating intracellular signaling pathways. PYK2 plays a regulatory role in the EMT process by affecting the expression of genes associated with EMT through the influence of transcription factors. Snail1 (Snail1) plays a key role in the EMT process and is highly expressed in endometriosis tissues. On the other hand, Snail1 affects the invasive and metastatic ability of endometriosis cells mainly by regulating the EMT process. However, the upstream mechanisms that regulate the process of Snail1 protein stability in endometriosis are not clear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We identified a non-receptor tyrosine kinase, proline-rich tyrosine kinase 2 (PYK2 or PTK2B), and examined the expression of PYK2 in endometriosis. The relevant plasmids were constructed. This study enrolled 20 patients with laparoscopically confirmed endometriosis meeting ASRM diagnostic criteria, collecting ectopic lesions (14 ovarian endometriotic cysts and 6 deep infiltrating nodules) along with matched eutopic endometrial tissues (15 proliferative phase, 5 secretory phase) as controls. All tissue specimens underwent immunohistochemical analysis. Human endometrial stromal cells (HESC) were isolated from normal endometrium of 3 control patients for in vitro meconium induction. Ectopic endometrial stromal cells (EESC) were obtained from 5 ectopic lesions. Protein extracts from both ectopic tissues and cells were subjected to Western blot and co-immunoprecipitation (Co-IP) interaction validation. Functional assays (proliferation/migration/invasion) were performed using EESC and 11Z cell lines with triplicate biological replicates. Co-IP experiments were performed to verify the interaction between PYK2 and Snail1, as well as to determine the specific location of this interaction. Additionally, we examined the effect of PYK2 on endometriosis cells in vitro and whether VS-6063 inhibits the biological functions of endometriosis cells. Endometriosis models were established in 20 five-week-old female C57BL/6 mice, randomly allocated into experimental (n = 10) and control (n = 10) groups. Statistical analyses were conducted using GraphPad Prism 7.0, employing parametric tests for normally distributed data and non-parametric methods otherwise, with Benjamini-Hochberg correction for multiple comparisons.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;PYK2 is highly expressed in endometriosis tissues. It acts as a new binding partner of Snail1 and enhances EMT in endometriosis by increasing the","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"155"},"PeriodicalIF":6.0,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interplay of iron, oxidative stress, and α-synuclein in Parkinson's disease progression.","authors":"Yan Chen, Xixi Luo, Yukun Yin, Elizabeth Rosalind Thomas, Kezhi Liu, Wenjun Wang, Xiang Li","doi":"10.1186/s10020-025-01208-3","DOIUrl":"https://doi.org/10.1186/s10020-025-01208-3","url":null,"abstract":"<p><p>The irreversible degeneration of dopamine neurons induced by α-synuclein (α-syn) aggregation in the substantia nigra is the central pathological feature of Parkinson's disease (PD). Neuroimaging and pathological autopsy studies consistently confirm significant iron accumulation in the brain of PD patients, suggesting a critical role for iron in disease progression. Current research has established that iron overload induces ferroptosis in dopaminergic neurons, evidence indicates that the impact of iron on PD pathology extends beyond ferroptosis. Iron also plays a regulatory role in modulating α-syn, affecting its aggregation, spatial conformation, post-translational modifications, and mRNA stability. Iron-induced α-syn aggregation can contribute to dopaminergic neurodegeneration through additional mechanisms, potentially creating a feedback loop in which α-syn further enhances iron accumulation, thus perpetuating a vicious cycle of neurotoxicity. Given α-syn's intrinsically disordered structure, targeting iron metabolism presents a promising therapeutic strategy for PD. Therefore, the development of iron chelators, alone or in combination with other therapeutic drugs, may offer a beneficial approach to alleviating PD symptoms and slowing disease progression.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"154"},"PeriodicalIF":6.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formononetin ameliorates depression-like behaviors through rebalancing microglia M1/M2 polarization and inhibiting NLRP3 inflammasome: involvement of activating PPARα-mediated autophagy.","authors":"Shuaijun Peng, Pan Su, Liming Liu, Zibo Li, Yuan Liu, Lei Tian, Ming Bai, Erping Xu, Yucheng Li","doi":"10.1186/s10020-025-01217-2","DOIUrl":"https://doi.org/10.1186/s10020-025-01217-2","url":null,"abstract":"<p><strong>Background: </strong>The dysregulation of neuroinflammation triggered by imbalance of microglia M1/M2 polarization is a key pathogenic factor and closely associated with occurrence of depression. Formononetin (FMN), a natural non-steroidal isoflavonoid, has been confirmed to exhibit remarkable anti-inflammatory efficacy, but the impact of FMN on depression and the underlying antidepressant mechanisms are still not fully understood. This study aimed to investigate whether the antidepressant effect of FMN is involved in modulating microglia polarization, and if so, what are the underlying mechanisms.</p><p><strong>Methods: </strong>Lipopolysaccharide (LPS)-induced depressive mice were used to study antidepressant mechanisms of FMN. Microglia cell line BV2 stimulated by LPS was employed to investigate pharmacological mechanisms of FMN. Effects of FMN on neuronal damage were detected by H&E, Nissl and Golgi staining. The efficacy of FMN were evaluated by immunostaining and western blots in vivo and vitro. In addition, molecular docking, luciferase reporter assay, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used to confirm the direct target of FMN.</p><p><strong>Results: </strong>Our results showed that FMN significantly reverses depression-like behaviors, alleviates neuroinflammation and neuronal damage, rebalances M1/M2 polarization, inhibits NLRP3 inflammasome and enhances microglial autophagy level in prefrontal cortex of LPS-induced depressive mice. In vitro assays, results unraveled that autophagy inhibitor chloroquine (CQ) blocks effects of FMN on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization. Moreover, PPARα is identified as a direct target of FMN and FMN can activate PPARα-mediated autophagy. Furtherly, combination PPARα agonist (WY14643) with FMN had no significant additive effects on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization, whereas PPARα antagonist (GW6471) abrogated these pharmacologic effects of FMN in BV2. Importantly, GW6471 exhibited similar pharmacologic effects to abolish antidepressant effect of FMN in LPS-induced depressive mice.</p><p><strong>Conclusion: </strong>Our study firstly demonstrated that FMN can rebalance microglia M1/M2 polarization and inhibit NLRP3 inflammasome, with the involvement of activating PPARα-mediated autophagy to ameliorate depression-like behaviors, which provides a novel view to elucidate antidepressant mechanisms of FMN and also offers a potential therapeutic target for depression.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"153"},"PeriodicalIF":6.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights into biomarkers and risk stratification to predict hepatocellular cancer.","authors":"Katrina Li, Brandon Mathew, Ethan Saldanha, Puja Ghosh, Adrian R Krainer, Srinivasan Dasarathy, Hai Huang, Xiyan Xiang, Lopa Mishra","doi":"10.1186/s10020-025-01194-6","DOIUrl":"https://doi.org/10.1186/s10020-025-01194-6","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the third major cause of cancer death worldwide, with more than a doubling of incidence over the past two decades in the United States. Yet, the survival rate remains less than 20%, often due to late diagnosis at advanced stages. Current HCC screening approaches are serum alpha-fetoprotein (AFP) testing and ultrasound (US) of cirrhotic patients. However, these remain suboptimal, particularly in the setting of underlying obesity and metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH), which are also rising in incidence. Therefore, there is an urgent need for novel biomarkers that can stratify risk and predict early diagnosis of HCC, which is curable. Advances in liver cancer biology, multi-omics technologies, artificial intelligence, and precision algorithms have facilitated the development of promising candidates, with several emerging from completed phase 2 and 3 clinical trials. This review highlights the performance of these novel biomarkers and algorithms from a mechanistic perspective and provides new insight into how pathological processes can be detected through blood-based biomarkers. Through human studies compiled with animal models and mechanistic insight in pathways such as the TGF-β pathway, the biological progression from chronic liver disease to cirrhosis and HCC can be delineated. This integrated approach with new biomarkers merit further validation to refine HCC screening and improve early detection and risk stratification.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"152"},"PeriodicalIF":6.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An engineered miniACE2 protein secreted by mesenchymal stromal cells effectively neutralizes multiple SARS-CoV- 2 variants in vitro.","authors":"Sara Moreno-Jiménez, Gina Lopez-Cantillo, Jenny Andrea Arevalo-Romero, Ana María Perdomo-Arciniegas, Andrea Marisol Moreno-Gonzalez, Bellaneth Devia-Mejia, Bernardo Armando Camacho, Paulino Gómez-Puertas, Cesar A Ramirez-Segura","doi":"10.1186/s10020-025-01190-w","DOIUrl":"https://doi.org/10.1186/s10020-025-01190-w","url":null,"abstract":"<p><p>SARS-CoV- 2 continues to evolve, producing novel Omicron subvariants through recombinant lineages that acquire new mutations, undermining existing antiviral strategies. The viral fitness and adaptive potential of SARS-CoV- 2 present significant challenges to emergency treatments, particularly monoclonal antibodies, which demonstrate reduced efficacy with the emergence of each new variant. Consequently, immunocompromised individuals, who are more susceptible to severe manifestations of COVID- 19 and face heightened risks of critical complications and mortality, remain vulnerable in the absence of effective emergency treatments. To develop translational approaches that can benefit this at-risk population and establish broader therapeutic strategies applicable across variants, we previously designed and engineered in silico miniACE2 decoys (designated BP2, BP9, and BP11). These decoys demonstrated promising efficacy in neutralizing Omicron subvariants. In this study, we leveraged the therapeutic potential of mesenchymal stromal cells (MSCs) for tissue repair and immunomodulation in lung injuries and used these cells as a platform for the secretion of BP2. Our innovative assays, which were conducted with the BP2 protein secreted into the culture supernatant of BP2-MSCs, demonstrated the potential for neutralizing SARS-CoV- 2, including Omicron subvariants. The development of these advanced therapeutic platforms holds significant promise for scalability to effectively mitigate the impact of severe COVID- 19, contributing to broader and more resilient treatment strategies against the evolving landscape of SARS-CoV- 2 variants.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"151"},"PeriodicalIF":6.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evobrutinib mitigates neuroinflammation after ischemic stroke by targeting M1 microglial polarization via the TLR4/Myd88/NF-κB pathway.","authors":"Yixiang Jiang, Ning Wang, Jingyi Liu, Jiayi Li, Lulu Chang, Changxin Yang, Zhengyi Chen, Wei Huang, Jing Wang, Xiujuan Lang, Xijun Liu, Yumei Liu, Bo Sun, Hulun Li","doi":"10.1186/s10020-025-01203-8","DOIUrl":"https://doi.org/10.1186/s10020-025-01203-8","url":null,"abstract":"<p><strong>Background: </strong>Evobrutinib, a third-generation Bruton's tyrosine kinase (BTK) inhibitor, shows great promise for treating neuroinflammatory diseases due to its small molecular size, ease of absorption, and ability to cross the blood-brain barrier. Although previous studies have confirmed significant BTK expression in microglia, the potential of Evobrutinib to treat ischemic stroke by modulating microglial function and its underlying mechanisms remain to be elucidated.</p><p><strong>Methods: </strong>Male C57BL/6 mice with cerebral ischemia was established to evaluate the effects of oral Evobrutinib treatment. Assessments included TTC staining, behavioral experiments, and pathological examinations were used to evaluate cerebral ischemic injury. Western Blot, flow cytometry, and qPCR were employed to monitor changes in BTK and pBTK expression in microglia and the impact of Evobrutinib on neuroinflammation following the stroke. In vitro, primary microglia were generated to determine the effects of Evobrutinib on the TLR4/ Myd88/NF-κB pathway and on the polarization of microglial subtypes.</p><p><strong>Results: </strong>The expression of BTK and pBTK is upregulated in microglia under conditions of cerebral ischemia and oxygen-glucose deprivation (OGD). Evobrutinib treatment not only reduced infarct volume in mice but also ameliorated pathological damage and facilitated neurological function recovery. Flow cytometry revealed that Evobrutinib decreased inflammatory cell infiltration and promoted M2 microglia polarization post-stroke. In vitro studies demonstrated that Evobrutinib downregulated the proportion of pro-inflammatory microglia and curtailed the secretion of inflammatory factors under OGD conditions. Mechanistically, Evobrutinib attenuated the OGD-induced upregulation of TLR4/Myd88/NF-κB expression, an effect that was further enhanced by the addition of the TLR4 pathway inhibitor TAK242.</p><p><strong>Conclusions: </strong>Evobrutinib inhibits the expression and activation of BTK in microglia, reducing M1 microglia-mediated neuroinflammation and alleviating ischemic injury following stroke. This effect is mechanistically linked to the inhibition of TLR4/Myd88/NF-κB-mediated M1 polarization of microglia.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"148"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial Piezo1 stimulates angiogenesis to offer protection against intestinal ischemia-reperfusion injury in mice.","authors":"Cuifen Wang, Shangfei Luo, Yameng Yan, Jinze Li, Weipin Niu, Tianying Hong, Kai Hao, Xin Sun, Jiali Liu, Ran An, Jing Li","doi":"10.1186/s10020-025-01197-3","DOIUrl":"https://doi.org/10.1186/s10020-025-01197-3","url":null,"abstract":"<p><strong>Background: </strong>Intestinal ischemia-reperfusion (I/R) injury, which occurs in the ileum and not only leads to intestinal tissue damage, but also may trigger systemic inflammatory responses, is a prevalent pathological condition that is typically associated with acute intestinal ischemia, surgical procedures, or trauma. However, the precise underlying pathogenic mechanisms have not yet been fully uncovered. In this study, we explored the specific roles and underlying mechanisms by which endothelial Piezo1 is involved in intestinal I/R injury.</p><p><strong>Methods: </strong>We evaluated the roles of Piezo1 using both in vivo mouse intestinal ischemia-reperfusion (I/R) injury and in vitro hypoxia-reoxygenation (H/R) models. The expression of Piezo1 was assessed using immunofluorescence and RT-qPCR. In vivo and in vitro experiments involving endothelial knockout and activation of Piezo1 with the specific agonist Yoda1 were conducted to observe the effects on angiogenesis and injury.</p><p><strong>Results: </strong>We found that in post-intestinal I/R mice, Piezo1 expression was markedly increased and was mainly abundant in ileum endothelial cells. Specific knockout of endothelial Piezo1 exhibited a more severe phenotype characterized by accelerating damage to the ileum structure, increasing inflammatory response, and inhibiting angiogenesis. Yoda1-mediated activation of Piezo1 significantly ameliorated intestinal I/R injury. Activation of Piezo1 induced by Yoda1 or H/R promoted angiogenesis in Human Umbilical Vein Endothelial Cells (HUVECs), which was inhibited by GsMTx4. Piezo1 mediated endothelial angiogenesis was linked to an increase of extracellular Ca²⁺ influx, which in turn enhanced hypoxia-inducible factor 1 alpha (HIF-1α) signaling pathway.</p><p><strong>Conclusions: </strong>Our findings indicate that Piezo1 plays a crucial role in protecting against intestinal I/R injury by promoting angiogenesis in endothelial cells, possibly through the activation of the Ca²⁺/HIF-1α/VEGF signaling pathway. This suggests that targeting endothelial Piezo1 channels could be a therapeutic strategy for ileum I/R injury.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"147"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The influence of the gut microbiota on B cells in autoimmune diseases.","authors":"Lun He, Xin Li, Shan Jiang, Yanhua Ou, Shanshan Wang, Na Shi, Zhongshan Yang, Jia-Li Yuan, Gregg Silverman, Haitao Niu","doi":"10.1186/s10020-025-01195-5","DOIUrl":"https://doi.org/10.1186/s10020-025-01195-5","url":null,"abstract":"<p><p>Mounting evidence shows that gut microbiota communities and the human immune system coexist and influence each other, and there are a number of reports of a correlation between specific changes in gut microbiota and the occurrence of autoimmune diseases. B lymphocytes play a central role in the regulation of both gut microbiota communities and in autoimmune diseases. Here, we summarize evidence of the influence of gut microbiota-B cell pathways on autoimmune diseases and how B cells regulate microorganisms, which provides mechanistic insights with relevance for identification of potential therapeutic targets and related fields.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"149"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}