Molecular Medicine最新文献

{"title":"Endocrine and metabolic alterations in response to systemic inflammation and sepsis: a review article.","authors":"Syed Faizan Mehdi, Muhammad Hamza Qureshi, Salman Pervaiz, Karishma Kumari, Edwin Saji, Mahnoor Shah, Ahmad Abdullah, Kamran Zahoor, Hafiza Amna Qadeer, Disha Kumari Katari, Christine Metz, Lopa Mishra, Derek LeRoith, Kevin Tracey, Michael J Brownstein, Jesse Roth","doi":"10.1186/s10020-025-01074-z","DOIUrl":"10.1186/s10020-025-01074-z","url":null,"abstract":"<p><p>Severe sepsis is cognate with life threatening multi-organ dysfunction. There is a disturbance in endocrine functions with alterations in several hormonal pathways. It has frequently been linked with dysfunction in the hypothalamic pituitary-adrenal axis (HPA). Increased cortisol or cortisolemia is evident throughout the acute phase, along with changes in the hypothalamic pituitary thyroid (HPT) axis, growth hormone-IGF-1 axis, insulin-glucose axis, leptin, catecholamines, renin angiotensin aldosterone axis, ghrelin, glucagon, hypothalamic pituitary gonadal (HGA) axis, and fibroblast growth factor-21. These changes and metabolic alterations constitute the overall response to infection in sepsis. Further research is essential to look into the hormonal changes that occur during sepsis, not only to understand their potential relevance in therapy but also because they may serve as prognostic indicators.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"16"},"PeriodicalIF":6.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007736","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":"D-mannose promotes diabetic wound healing through inhibiting advanced glycation end products formation in keratinocytes.","authors":"Jialiang Luo, Tianxing Wu, Jing Zhang, Zhicheng Liang, Weijie Shao, Di Wang, Lei Li, Daming Zuo, Jia Zhou","doi":"10.1186/s10020-025-01070-3","DOIUrl":"10.1186/s10020-025-01070-3","url":null,"abstract":"<p><strong>Background: </strong>Diabetic chronic foot ulcers pose a significant therapeutic challenge around the world, resulting in adverse effects and complications in patients. D-mannose is enriched in cirtus peel and exerts beneficial effects among various diseases, especially against inflammation-related disorders.</p><p><strong>Methods: </strong>Here, we examined the potential effect of D-mannose during wound healing process in streptozotocin (STZ)-induced diabetes mice in vivo and by culturing keratinocytes under high glucose condition in vitro. The skin lesion healing was recorded in photos and evaluated by histochemical staining. What's more, the advanced glycation end products (AGEs) concentration in blood and mice skin was quantified. Apoptotic cells were assessed by flow cytometry and Western blotting. Inflammatory cytokines and cellular differential gene expression levels were measured by real-time PCR. The expression of the AMPK/Nrf2/HO-1 signaling-related molecules was determined by Western blotting.</p><p><strong>Results: </strong>We first found that topical supplementation of D-mannose remarkably improved skin wound healing in diabetes mice. Furthermore, both in vivo and in vitro experiments demonstrated that D-mannose reduced the AGEs generation. Mechanistically, D-mannose inhibited AGEs, then upregulated AMPK/Nrf2/HO-1 signaling in the context of high glucose to maintain keratinocyte normal functions, which positively influenced macrophage and fibroblast to accelerate diabetic wound healing. Noteworthily, these protective effects of D-mannose were abolished by the pretreatment with inhibitors of AGEs or AMPK.</p><p><strong>Conclusion: </strong>As far as we know, this is the first study exploring the protective role of D-mannose on diabetic wound healing via topical supplementation. We find that D-mannose protects keratinocytes from high glucose stimulation via inhibition of AGEs formation as well as orchestrates inflammatory microenvironment in diabetic wounded skin, suggesting its supplementation as a potential therapy to promote refractory wound healing in diabetic patients.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"15"},"PeriodicalIF":6.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008670","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":"Microbially produced imidazole propionate impairs prostate cancer progression through PDZK1.","authors":"Shengkai Jin, Yuhua Zhou, Jing Lv, Yichen Lu, Yuwei Zhang, Menglu Li, Ninghan Feng","doi":"10.1186/s10020-025-01073-0","DOIUrl":"https://doi.org/10.1186/s10020-025-01073-0","url":null,"abstract":"<p><strong>Background: </strong>A close relationship exists between castration-resistant prostate cancer (CRPC) and histidine metabolism by gut microbes. However, the effects of the histidine metabolite imidazole propionate (IMP) on prostate cancer (PCa) and its underlying mechanisms are not well understood.</p><p><strong>Methods: </strong>We first assessed the effects of IMP on cell proliferation and migration at the cellular level. Subsequently, we investigated the mechanism of action of IMP using transcriptome sequencing, qPCR, and Western blot analysis. Finally, we validated our findings in vivo using a mouse model.</p><p><strong>Results: </strong>Histidine had no effect on PCa cell proliferation; however, IMP significantly inhibited the proliferation and migration of PC3 and DU145 cells. Mechanistic studies indicate that IMP exerts its effects by upregulating PDZK1 expression, which subsequently inhibits the phosphorylation of the PI3K-AKT pathway.</p><p><strong>Conclusions: </strong>In conclusion, IMP significantly inhibits the progression of PCa, offering new insights into potential treatments for CRPC.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"14"},"PeriodicalIF":6.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007824","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":"Nootkatone inhibits the progression of glioblastoma by activating the ATF4-CHOP-CHAC1 pathway.","authors":"Qian Wang, Xiumin Xue, Zhichao Chen, Wei Zhang, Yiming Qian, Danni Chen, Lin Lin, Yinfeng Yuan, Weiqiao Zhao, Zhihui Huang, Yongjie Wang","doi":"10.1186/s10020-025-01064-1","DOIUrl":"https://doi.org/10.1186/s10020-025-01064-1","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) represents a primary brain tumor that is widely prevalent, and clinical drugs available for its treatment exhibit varying degrees of resistance. Nootkatone (NKT) is a functional sesquiterpene sourced from traditional Chinese medicine --Alpinia Oxyphylla Miq and has been reported to have a diverse range of pharmacological properties. However, it remains unknown whether there are effects of NKT on GBM. In this study, we found that NKT inhibited the growth of GBM cells in a dose-dependent manner in vitro. Subsequently, we observed that NKT suppressed the migration and arrested cell cycle at G2/M phase of GBM cells. Furthermore, NKT induced the death of GBM cells accompanied by an increase in reactive oxygen species (ROS) production. Mechanistically, we found that NKT inhibited the progression of GBM cells through activating the ATF4-CHOP-CHAC1 pathway in GBM cells. Furthermore, NKT-induced inhibition of migration and proliferation in GBM cells was partially restored by ATF4 or CHAC1 knockdown. Finally, we found that NKT inhibited the growth of tumor in GBM orthotopic mice model through activation of ATF4-CHOP-CHAC1 axis. Taken together, our findings show that NKT suppresses the growth and migration of GBM cells by activating the ATF4-CHOP-CHAC1 pathway, which in turn prevents the tumorigenesis of GBMs and provides a novel perspective for the development of drugs against GBM.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"13"},"PeriodicalIF":6.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007942","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 systemic evolutionary theory of the origin of cancer (SETOC): an update.","authors":"Antonio Mazzocca, Giovanni Ferraro, Giovanni Misciagna","doi":"10.1186/s10020-025-01069-w","DOIUrl":"10.1186/s10020-025-01069-w","url":null,"abstract":"<p><p>The Systemic Evolutionary Theory of the Origin of Cancer (SETOC) is a recently proposed theory founded on two primary principles: the cooperative and endosymbiotic process of cell evolution as described by Lynn Margulis, and the integration of complex systems operating in eukaryotic cells, which is a core concept in systems biology. The SETOC proposes that malignant transformation occurs when cells undergo a continuous adaptation process in response to long-term injuries, leading to tissue remodeling, chronic inflammation, fibrosis, and ultimately cancer. This process involves a maladaptive response, wherein the 'endosymbiotic contract' between the nuclear-cytoplasmic system (derived from the primordial archaeal cell) and the mitochondrial system (derived from the primordial α-proteobacterium) gradually breaks down. This ultimately leads to uncoordinated behaviors and functions in transformed cells. The decoupling of the two cellular subsystems causes transformed cells to acquire phenotypic characteristics analogous to those of unicellular organisms, as well as certain biological features of embryonic development that are normally suppressed. These adaptive changes enable cancer cells to survive in the harsh tumor microenvironment characterized by low oxygen concentrations, inadequate nutrients, increased catabolic waste, and increased acidity. De-endosymbiosis reprograms the sequential metabolic functions of glycolysis, the TCA cycle, and oxidative phosphorylation (OxPhos). This leads to increased lactate fermentation (Warburg effect), respiratory chain dysfunction, and TCA cycle reversal. Here, we present an updated version of the SETOC that incorporates the fundamental principles outlined by this theory and integrates the epistemological approach used to develop it.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"12"},"PeriodicalIF":6.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979223","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":"Decreased expression of LEF1 caused defective decidualization by inhibiting IL-11 expression in patients with adenomyosis.","authors":"Jingru Duan, Xiaowei Zhou, Hanfei Zhu, Mingjuan Zhou, Mengyu Liu, Yan Zhou, Wenzhu Li, Bufang Xu, Aijun Zhang","doi":"10.1186/s10020-024-01054-9","DOIUrl":"10.1186/s10020-024-01054-9","url":null,"abstract":"<p><p>Reduced lymphoid enhancer-binding factor 1 (LEF1) expression in patients with adenomyosis during the mid-secretory phase leads to impaired endometrial receptivity, affecting embryo implantation. This study investigated the molecular mechanisms underlying reduced endometrial receptivity in 25 adenomyosis patients and 25 controls. Functional experiments were conducted using human endometrial stromal cells (HESCs) and TERT-immortalized HESCs(T-HESCs), with final validation performed using a mouse model. Western blot and quantitative real-time polymerase chain reaction (RT-qPCR) analyses revealed that patients with adenomyosis showed a marked decrease in LEF1 expression in the stromal cells of the endometrium during the mid-secretory phase. In vitro experiments demonstrated that LEF1 knockdown in stromal cells led to impaired decidualization. Transcriptome sequencing, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) experiments showed that LEF1 could bind to the promoter region of interleukin (IL)-11 and promote its transcription, and IL-11 expression was also found to be downregulated in adenomyosis patients. Overexpression of IL-11 rescued the impaired decidualization caused by decreased LEF1 expression. In the in vitro co-culture model, LEF1/IL-11 knockdown led to a reduction in embryo implantation area, which was partially restored upon IL-11 overexpression. In the adenomyosis mouse model, we observed a decrease in LEF1 expression and a reduction in implantation sites compared to control mice, accompanied by impaired decidualization and receptivity. Notably, supplementation with IL-11 restored the number of implantation sites. The decrease in fertility due to reduced endometrial receptivity in adenomyosis patients is a significant clinical issue in assisted reproductive technology. This research provides insights into one potential molecular mechanism underlying this decreased receptivity, with a specific focus on the reduced expression of LEF1 in the endometrial stromal cells during the mid-secretory phase in adenomyosis patients. Our findings offer new perspectives for clinical strategies to improve endometrial receptivity in patients with adenomyosis, potentially enhancing their chances of successful pregnancy.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"10"},"PeriodicalIF":6.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142965742","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 eCIRP inhibitor attenuates fibrosis and ferroptosis in ischemia and reperfusion induced chronic kidney disease.","authors":"Fangming Zhang, Zhijian Hu, Asha Jacob, Max Brenner, Ping Wang","doi":"10.1186/s10020-025-01071-2","DOIUrl":"10.1186/s10020-025-01071-2","url":null,"abstract":"<p><strong>Background: </strong>Chronic kidney disease (CKD) is a leading cause of death in the United States, and renal fibrosis represents a pathologic hallmark of CKD. Extracellular cold-inducible RNA-binding protein (eCIRP) is a stress response protein involved in acute inflammation, tissue injury and regulated cell death. However, the role of eCIRP in chronic inflammation and tissue injury has not been elucidated. We hypothesize that eCIRP is involved in renal ischemia/reperfusion (RIR)-induced CKD and that C23, an antagonist to eCIRP, is beneficial in attenuating renal fibrosis and ferroptosis in RIR-induced CKD.</p><p><strong>Methods: </strong>C57BL/6 (WT) or CIRP^-/- mice underwent renal injury with total blockage of blood perfusion by clamping bilateral renal pedicles for 28 min. In the WT mice at the time of reperfusion, they were treated with C23 (8 mg/kg) or vehicle. Blood and kidneys were harvested for further analysis at 21 days thereafter. In a separate cohort, mice underwent bilateral RIR and treatment with C23 or vehicle and were then subjected to left nephrectomy 72 h thereafter. Mice were then monitored for additional 19 days, and glomerular filtration rate (GFR) was assessed using a noninvasive transcutaneous method.</p><p><strong>Results: </strong>In the RIR-induced CKD, CIRP^-/- mice showed decreased collagen deposition, fibronectin staining, and renal injury as compared to the WT mice. Administration of C23 ameliorated renal fibrosis by decreasing the expression of active TGF-β1, α-SMA, collagen deposition, fibronectin and macrophage infiltration to the kidneys. Furthermore, intervention with C23 significantly decreased renal ferroptosis by reducing iron accumulation, increasing the expression of glutathione peroxidase 4 (GPX4) and lipid peroxidation in the kidneys of RIR-induced CKD mice. Treatment with C23 also attenuated BUN and creatinine. Finally, GFR was significantly decreased in RIR mice with left nephrectomy and C23 treatment partially prevented their decrease.</p><p><strong>Conclusion: </strong>Our data show that eCIRP plays an important role in RIR-induced CKD. Treatment with C23 decreased renal inflammation, alleviated chronic renal injury and fibrosis, and inhibited ferroptosis in the RIR-induced CKD mice.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"11"},"PeriodicalIF":6.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142965680","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 role and mechanism of HMGB1-mediated Notch1/Hes-1 pathway in anxiety and depression-like behaviors in mice with chronic rhinosinusitis.","authors":"Fangwei Zhou, Yiting Jiang, Yangsong Li, Jianyao Li, Tian Zhang, Guodong Yu","doi":"10.1186/s10020-024-01057-6","DOIUrl":"10.1186/s10020-024-01057-6","url":null,"abstract":"<p><strong>Background: </strong>Chronic rhinosinusitis (CRS) is a global health issue, with some patients experiencing anxiety and depression-like symptoms. This study investigates the role of HMGB1 in anxiety and depression-like behaviors associated with the microglial Notch1/Hes-1 pathway in CRS mice.</p><p><strong>Methods: </strong>A CRS mouse model was developed, and behavioral assessments were conducted to evaluate anxiety and depression-like behaviors. Techniques including ¹⁸F-FDG PET, Nissl staining, and immunofluorescence were used to assess hippocampal metabolic activity in CRS mice. Western Blot and RT-qPCR were employed to measure HMGB1 and Notch1/Hes-1 expression in the hippocampus, while ELISA determined inflammatory cytokine levels. The study also examined the effects of metformin on these behaviors and its mechanisms.</p><p><strong>Results: </strong>CRS mice exhibited increased anxiety and depression-like behaviors, accompanied by enhanced hippocampal metabolic activity. HMGB1-siRNA treatment reduced these behaviors. Hippocampal glucose metabolism was markedly higher in CRS mice than in controls. Nissl staining revealed hippocampal neuron damage, and immunofluorescence indicated microglial activation in CRS mice. Reducing HMGB1 expression inhibited Notch1/Hes-1 pathway activation. In microglia, HMGB1 knockdown suppressed the Notch1/Hes-1 pathway, reducing inflammatory cytokine secretion. Metformin improved neuropsychiatric symptoms in CRS mice by inhibiting the Notch1/Hes-1 pathway after HMGB1 downregulation.</p><p><strong>Conclusion: </strong>HMGB1 activates the microglial Notch1/Hes-1 pathway in CRS mice, promoting neuroinflammation and anxiety and depression-like behaviors. Metformin alleviates these effects.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"8"},"PeriodicalIF":6.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951804","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":"Multi‑omics identification of a novel signature for serous ovarian carcinoma in the context of 3P medicine and based on twelve programmed cell death patterns: a multi-cohort machine learning study.","authors":"Lele Ye, Chunhao Long, Binbing Xu, Xuyang Yao, Jiaye Yu, Yunhui Luo, Yuan Xu, Zhuofeng Jiang, Zekai Nian, Yawen Zheng, Yaoyao Cai, Xiangyang Xue, Gangqiang Guo","doi":"10.1186/s10020-024-01036-x","DOIUrl":"https://doi.org/10.1186/s10020-024-01036-x","url":null,"abstract":"<p><strong>Background: </strong>Predictive, preventive, and personalized medicine (PPPM/3PM) is a strategy aimed at improving the prognosis of cancer, and programmed cell death (PCD) is increasingly recognized as a potential target in cancer therapy and prognosis. However, a PCD-based predictive model for serous ovarian carcinoma (SOC) is lacking. In the present study, we aimed to establish a cell death index (CDI)-based model using PCD-related genes.</p><p><strong>Methods: </strong>We included 1254 genes from 12 PCD patterns in our analysis. Differentially expressed genes (DEGs) from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) were screened. Subsequently, 14 PCD-related genes were included in the PCD-gene-based CDI model. Genomics, single-cell transcriptomes, bulk transcriptomes, spatial transcriptomes, and clinical information from TCGA-OV, GSE26193, GSE63885, and GSE140082 were collected and analyzed to verify the prediction model.</p><p><strong>Results: </strong>The CDI was recognized as an independent prognostic risk factor for patients with SOC. Patients with SOC and a high CDI had lower survival rates and poorer prognoses than those with a low CDI. Specific clinical parameters and the CDI were combined to establish a nomogram that accurately assessed patient survival. We used the PCD-genes model to observe differences between high and low CDI groups. The results showed that patients with SOC and a high CDI showed immunosuppression and hardly benefited from immunotherapy; therefore, trametinib_1372 and BMS-754807 may be potential therapeutic agents for these patients.</p><p><strong>Conclusions: </strong>The CDI-based model, which was established using 14 PCD-related genes, accurately predicted the tumor microenvironment, immunotherapy response, and drug sensitivity of patients with SOC. Thus this model may help improve the diagnostic and therapeutic efficacy of PPPM.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"5"},"PeriodicalIF":6.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951799","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":"Ubiquitin specific peptidase 11 knockdown slows Huntington's disease progression via regulating mitochondrial dysfunction and neuronal damage depending on PTEN-mediated AKT pathway.","authors":"Bai Gao, Yuchen Jing, Xi Li, Shuyan Cong","doi":"10.1186/s10020-024-01061-w","DOIUrl":"10.1186/s10020-024-01061-w","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial dysfunction and neuronal damage are major sign of cytopathology in Huntington's disease (HD), a neurodegenerative disease. Ubiquitin specific peptidase 11 (USP11) is a deubiquitinating enzyme involved in various physiological processes through regulating protein degradation. However, its specific role in HD is unclear.</p><p><strong>Methods: </strong>To interfere with USP11 expression, adeno-associated viruses 2 containing USP11-specific shRNA were injected into the bilateral striatum of 12-week-old R6/1 and WT mice. In vitro, the inducible PC12 cell model of HD was used in which the expression of an N-terminal truncation of huntingtin, with either wild type (Q23) or expanded polyglutamine (Q74) can be induced by the doxycycline. USP11 was knocked down to study its role in HD. The protein expression patterns in Q74 cells were quantified by label-free proteomics to further explore the target protein of USP11. Detecting the association between USP11 and Phosphatase and Tensin Homolog (PTEN) through Co-IP.</p><p><strong>Results: </strong>Herein, USP11 was found to be upregulated in the striatum of R6/1 mice (an HD model with gradual development of symptoms) in an age-dependent manner. The spontaneous HD was alleviated by silencing USP11, as evidenced by improved locomotor activity and spatial memory, attenuated striatal atrophy in R6/1 mice, reduced accumulation of mutant huntingtin protein, and restored mitochondrial function in vitro and in vivo. The results of label-free proteomics revealed a significant change in the protein expression profile. Through functional enrichment, we focused on PTEN, known as a negative regulator of the AKT pathway. We demonstrated that USP11 downregulation promoted ubiquitination modification of PTEN and activated the AKT pathway, and PTEN overexpression reversed the effects of USP11 knockdown.</p><p><strong>Conclusions: </strong>Collectively, USP11 knockdown protects R6/1 mouse neurons from oxidative stress by alleviating mitochondrial dysfunction, thereby preventing the HD progression. This is achieved by inhibiting PTEN expression, which in turn activates the AKT pathway. This study suggests that USP11-PTEN-AKT signaling pathway may be a new attractive therapeutic target for HD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"7"},"PeriodicalIF":6.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11715466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951844","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}