Molecular Medicine最新文献

{"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}

{"title":"Warburg effect and lactylation in cancer: mechanisms for chemoresistance.","authors":"Wenjie Zhang, Min Xia, Jiahui Li, Gaohua Liu, Yan Sun, Xisha Chen, Jing Zhong","doi":"10.1186/s10020-025-01205-6","DOIUrl":"https://doi.org/10.1186/s10020-025-01205-6","url":null,"abstract":"<p><p>In the clinical management of cancers, the emergence of chemoresistance represents a profound and imperative \"pain point\" that requires immediate attention. Understanding the mechanisms of chemoresistance is essential for developing effective therapeutic strategies. Importantly, existing studies have demonstrated that glucose metabolic reprogramming, commonly referred to as the Warburg effect or aerobic glycolysis, is a major contributor to chemoresistance. Additionally, lactate, a byproduct of aerobic glycolysis, functions as a signaling molecule that supports lysine lactylation modification of proteins, which also plays a critical role in chemoresistance. However, it is insufficient to discuss the role of glycolysis or lactylation in chemoresistance from a single perspective. The intricate relationship between aerobic glycolysis and lactylation plays a crucial role in promoting chemoresistance. Thus, a thorough elucidation of the mechanisms underlying chemoresistance mediated by aerobic glycolysis and lactylation is essential. This review provides a comprehensive overview of these mechanisms and further outlines that glycolysis and lactylation exert synergistic effects, promoting the development of chemoresistance and creating a positive feedback loop that continues to mediate this resistance. The close link between aerobic glycolysis and lactylation suggests that the application of glycolysis-related drugs or inhibitors in cancer therapy may represent a promising anticancer strategy. Furthermore, the targeted application of lactylation, either alone or in combination with other treatments, may offer new therapeutic avenues for overcoming chemoresistance.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"146"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035711","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":"SNORA47 affects stemness and chemotherapy sensitivity via EBF3/RPL11/c-Myc axis in luminal A breast cancer.","authors":"Qilin Han, Ying Zhou, Zixian Dong, Weitao Wang, Menghan Wang, Mengyang Pang, Xinyue Song, Bo Chen, Ang Zheng","doi":"10.1186/s10020-025-01216-3","DOIUrl":"https://doi.org/10.1186/s10020-025-01216-3","url":null,"abstract":"<p><p>Chemotherapy sensitivity is an important factor that restricts the prognosis of breast cancer, and breast cancer stem cells (BCSCs) are the root cause of chemotherapy sensitivity. SNORA47, a member of the small nucleolar RNAs, has not been documented in the context of breast cancer, although it has been reported in lung cancer. In this study, high SNORA47 expression was linked to unfavorable survival outcomes among patients with Luminal A breast cancer in The Cancer Genome Atlas (TCGA). Among Luminal A patients, an elevated expression of SNORA47 correlated with high TNM stage (P = 0.049). SNORA47 was strongly associated with breast cancer stemness phenotype and tumor sensitivity in vivo and in vitro. Our findings demonstrated that SNORA47, through its interaction with early B-cell factor 3(EBF3), facilitated the translocation of ribosomal protein L11(RPL11), which as a modulator that subsequently regulates the expression levels of the oncogene c-Myc. These discoveries provided novel insights into the molecular mechanisms of breast cancer progression and suggested potential therapeutic targets for overcoming drug sensitivity by disrupting the SNORA47-EBF3-RPL11 axis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"150"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034256","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":"Pemafibrate modulates peroxisome proliferator-activated receptor alpha and prevents alcohol-associated liver disease in rats.","authors":"Takashi Saito, Joseph George, Kazuaki Ozaki, Mutsumi Tsuchishima, Mikihiro Tsutsumi","doi":"10.1186/s10020-025-01210-9","DOIUrl":"https://doi.org/10.1186/s10020-025-01210-9","url":null,"abstract":"<p><strong>Background and aims: </strong>Alcohol-associated liver disease (ALD) with steatosis or steatohepatitis that could progress to liver cirrhosis is a common problem in chronic alcohol consumption. Pemafibrate is a novel, highly specific peroxisome proliferator-activated receptor-α (PPARα) modulator, which regulates the expression of the target genes related to lipid and glucose metabolism. Here, we evaluated the effect of pemafibrate to prevent ALD and steatosis in rats.</p><p><strong>Methods: </strong>The animals were treated with liquid diet containing ethanol (36% of total calories) or an isocaloric carbohydrate diet for 4 weeks. Subsequently, both groups were fed with either 0.5% aqueous methylcellulose solution (MC) or MC containing 0.3 mg/kg body weight of pemafibrate orally twice a day along with the liquid diet for another 4 weeks. A set of animals were sacrificed at the 4th week before the start of pemafibrate treatment and the remaining animals at the end of 8 weeks. Blood and liver samples were collected for biochemical and histopathological evaluations.</p><p><strong>Results: </strong>Treatment with pemafibrate prevented inflammation and steatosis in the hepatic tissue. Furthermore, pemafibrate administration markedly increased hepatic NAD and NADH levels, reduced both serum and hepatic triglyceride levels, and upregulated the expression of molecules involved in lipid metabolism.</p><p><strong>Conclusions: </strong>The results of the present study demonstrated that pemafibrate modulates target genes related to hepatic lipid metabolism and prevents deposition of fat globules in the liver during chronic alcohol feeding in rats. Therefore, pemafibrate could be used as a potent therapeutic agent to prevent steatosis and related adverse events in ALD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"145"},"PeriodicalIF":6.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972319","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":"Calpain inhibition as a novel therapeutic strategy for aortic dissection with acute lower extremity ischemia.","authors":"Qiwen Tan, Xiaokang Wang, Wanchuang Xu, Kun Song, Yifan Xiong, Zhentong Jiang, Jingjing Li, Yunsheng Yu, Wenxue Ye, Zhenya Shen, Xiaomei Teng","doi":"10.1186/s10020-025-01212-7","DOIUrl":"https://doi.org/10.1186/s10020-025-01212-7","url":null,"abstract":"<p><strong>Background: </strong>Aortic dissection (AD) patients with malperfusion present significant challenges and are associated with high postoperative mortality rates. Limited data exist regarding the management of patients with AD and acute lower extremity ischemia. Early diagnosis of the extent of malperfusion and timely intervention are critical for improving patient prognosis.</p><p><strong>Methods: </strong>A total of 104 patients diagnosed with AD were enrolled in this observational retrospective study, of which 11 (10.6%) presented with lower limb ischemia (LLI). A comparative analysis was conducted on the clinical data of the AD group and the AD + LLI group. Plasma concentrations of SBDP145, a specific indicator of Calpain activity, were quantified in Control, AD, and AD + LLI groups using ELISA. To explore the role of Calpain in LLI and AD, pharmacological inhibition with Calpeptin and transgenic mice overexpressing calpastatin (Tg-CAST) were utilized in mouse models. RNA sequencing and functional assays were employed to identify the downstream effectors of Calpain.</p><p><strong>Results: </strong>Patients in the AD + LLI group exhibited significantly elevated leukocyte counts, percentages of neutrophils and lymphocytes, as well as increased serum levels of AST, creatinine, total cholesterol, low-density lipoprotein, uric acid, and creatine kinase compared to those in the AD group. Furthermore, the mean calcium ion concentration and Ca²⁺-dependent Calpain activation were significantly higher in the AD + LLI patients. Both endogenous and exogenous Calpain inhibitors effectively promoted the restoration of blood flow to ischemic hind limbs by inhibiting the inflammatory response and promoting vascular regeneration. Additionally, Calpain inhibition prevented the onset and progression of AD. RNA sequencing and Western Blot assays demonstrated that Calpain inhibition significantly increased levels of Fabp3, which is involved in the ischemia-induced fatty acid metabolism pathway.</p><p><strong>Conclusions: </strong>Inhibition of Calpain has been demonstrated to decrease the incidence of AD and enhance the restoration of blood flow perfusion in ischemic lower extremities. This effect may be mediated by the upregulation of Fabp3. These findings highlight the potential for targeted interventions against Calpain as a novel therapeutic strategy in the treatment of cardiovascular disease.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"144"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034238","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}