Molecular Medicine最新文献

{"title":"Distinctive features of blood- and ascitic fluid-derived extracellular vesicles in ovarian cancer patients.","authors":"Francesca Gorini, Camelia Alexandra Coada, Sarah Monesmith, Antonio De Leo, Dario de Biase, Giulia Dondi, Stella Di Costanzo, Francesco Mezzapesa, Ivan Vannini, Mattia Melloni, Sara Bandini, Flora Guerra, Riccardo Di Corato, Pierandrea De Iaco, Patrizia Hrelia, Anna Myriam Perrone, Sabrina Angelini, Gloria Ravegnini","doi":"10.1186/s10020-025-01177-7","DOIUrl":"https://doi.org/10.1186/s10020-025-01177-7","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer (OC) is a highly aggressive malignancy characterized by early dissemination of cancer cells from the surface of the ovary to the peritoneum. To gain a deeper understanding of the mechanisms associated with this intraperitoneal spread, we aimed to characterize the role of extracellular vesicles (EVs) in metastatic colonization in OC.</p><p><strong>Methods: </strong>To this purpose, a total of 150 samples of ascitic fluids, blood serum, tumor and normal tissues from 60 OC patients, were extensively analyzed to characterize the EVs released in blood and ascitic fluids of OC patients, in terms of size, expression of superficial epitopes and abundance of miRNAs biocargo.</p><p><strong>Results: </strong>A statistically significant difference in the size of EVs derived from ascitic fluid and serum was identified. Analysis of surface protein expression highlighted twenty epitopes with a significant difference between the two biological matrices, of which 18 were over- and two were under-expressed in ascitic fluid. With regard to miRNA levels, Principal Component Analysis (PCA) assessed four distinct clusters representing tumor tissue, normal tissue, ascitic fluid, and serum. A prominent difference in circulating miRNAs was observed in serum and ascitic fluid highlighting 98 miRNAs significantly deregulated (P-adj < 0.05) between the two bodily fluids. Deregulated miRNAs and epitopes underline an enrichment in ascites in components contributing to the metastatic spread.</p><p><strong>Conclusion: </strong>The results highlight a clear difference between the two biological fluids, suggesting that tumor selectively releases specific EVs populations in serum or ascites. In this context, it seems that ascites-derived EVs play a major role in modulating EMT and metastatic cascade, which is a key feature of OC.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"143"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018897","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":"Tripartite motif-containing 27 negatively regulates NF-κB activation in bone remodeling.","authors":"Kabsun Kim, Jung Ha Kim, Inyoung Kim, Semun Seong, Hyun Kook, Jeong-Tae Koh, Nacksung Kim","doi":"10.1186/s10020-025-01204-7","DOIUrl":"https://doi.org/10.1186/s10020-025-01204-7","url":null,"abstract":"<p><strong>Background: </strong>Tripartite motif-containing 27 (TRIM27) is highly expressed in the mouse thymus, spleen, and hematopoietic compartment cells and regulates cell proliferation, apoptosis, and innate immune responses. However, the role of TRIM27 in bone remodeling remains unknown. This study aimed to investigate the role of TRIM27 in the differentiation of osteoclasts and osteoblasts.</p><p><strong>Methods: </strong>We measured the effects of overexpression or knockdown of TRIM27 in osteoclasts and osteoblasts using real-time PCR and Western blot analysis to quantify the mRNA and protein levels of marker genes. Additionally, we performed an in vivo analysis of TRIM27 knockout mice through bone mineral density analysis and histological analysis.</p><p><strong>Results: </strong>TRIM27 deficiency decreased bone mineral density by enhancing osteoclast differentiation and inhibiting osteoblast differentiation. Overexpression of TRIM27 in osteoclast precursors suppressed osteoclast formation and resorption activity, and ectopic expression of TRIM27 in osteoblast precursors induced osteoblast differentiation and mineralization. Additionally, we found that TRIM27 attenuated NF-κB activation in both osteoclasts and osteoblasts by interacting with TAB2 and promoting TAB2 degradation through lysosomal-dependent pathways, thereby inhibiting NF-κB signaling.</p><p><strong>Conclusions: </strong>Our results identify TRIM27 as a novel negative regulator of NF-κB in bone remodeling, suggesting that regulating TRIM27 may be useful in developing treatments for musculoskeletal diseases, such as osteoporosis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"141"},"PeriodicalIF":6.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972313","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":"HLA-F regulates the proliferation of trophoblast via PKM2-dependent glycolysis in the pathogenesis of preeclampsia.","authors":"Ruiling Xu, Yu Huang, Wenchi Xie, Dan Luo, Jie Mei, Xinghui Liu, Fulin Liu, Fangyuan Luo","doi":"10.1186/s10020-025-01201-w","DOIUrl":"https://doi.org/10.1186/s10020-025-01201-w","url":null,"abstract":"<p><strong>Background: </strong>The regulatory molecule Human Leukocyte Antigen F (HLA-F) has been implicated in trophoblast proliferation during pregnancy, and reduced levels of this antigen have been identified in trophoblast cells of patients with preeclampsia. This study aimed to analyze the effect and mechanism of HLA-F on the proliferation of trophoblast and the underlying mechanism of reduced HLA-F involved in preeclampsia.</p><p><strong>Methods: </strong>q-PCR, Western blot (WB), and Immunohistochemistry (IHC) were used to detect the expression of HLA-F and Pyruvate Kinase Muscle isoform 2 (PKM2) in placenta tissues. Jar cells were transfected with overexpression lentivirus, specific siRNA, and shRNA to regulate corresponding genes. Immunofluorescence was used to analyze the expression and distribution of HLA-F and PKM2. Extracellular and intracellular lactate, pyruvate, and enzymatic activity of PKM2 were measured using the corresponding assay kits. Cell proliferation was measured by CCK8, MTT, colony formation assay, and Mini patient-derived xenograft (Mini-PDX). Chromatin Immunoprecipitation and deep sequencing (ChIP-seq) and 4-dimensional label-free quantitative proteomics (4D-LFQP-LA) were used to analyze the HLA-F-binding DNA sequences and the differential lactylation proteins in HLA-F-overexpression Jar and its control.</p><p><strong>Results: </strong>The expression of HLA-F is reduced in extravillous trophoblast and villous cytotrophoblast from patients with preeclampsia. Over-expression of HLA-F promoted proliferation while under-expression inhibited it. Further experiments demonstrated that over-expression of HLA-F promoted expression of the PKM2 protein and its enzymatic activity, resulting in enhanced glycolysis in Jar cells. Specifically, we determined that HLA-F regulated the expression of PKM2 by binding the promoter of PKM, and promoted PKM2 enzyme activity by down-regulating the lactylation of residue K305. Moreover, silencing PKM2 with siRNA reduced HLA-F-mediated glycolysis and proliferation in HLA-F-overexpressing Jar cells. Finally, we corroborated these results using a MiniPDX model, with which we confirmed that the PKM2 agonist TEPP-46 promoted the proliferation of ShHLA-F Jar cells.</p><p><strong>Conclusions: </strong>The reduced expression of HLA-F in placental trophoblast cells resulted in the downregulation of both PKM2 transcription and protein expression. Concurrently, the relative upregulation of lactylation at PKM2 K305 contributed to a decline in enzyme activity, further exacerbating glycolysis dysfunction. Collectively, these alterations led to a suppression of trophoblast proliferation capacity and involvement in the pathogenesis of preeclampsia.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"142"},"PeriodicalIF":6.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033746","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":"Diprovocim protects against the radiation-induced damage via the TLR2 signaling pathway.","authors":"Duo Fang, Hainan Zhao, Lu Pei, Kai Jiang, Yuhan Gan, Xuanlu Zhai, Liao Zhang, Ying Cheng, Cong Liu, Jicong Du, Fu Gao","doi":"10.1186/s10020-025-01198-2","DOIUrl":"https://doi.org/10.1186/s10020-025-01198-2","url":null,"abstract":"<p><p>Severe ionizing radiation (IR) causes the acute lethal damage of hematopoietic system and gastrointestinal tract. By establishing a radiation injury model, we found that Diprovocim, a TLR2 agonist, protected mice against the lethal damage of hematopoietic system and gastrointestinal tract. Diprovocim inhibited the IR-induced damage, promoted erythrocyte differentiation and elevated the proportion of hematopoietic stem cells (HSCs) in irradiated mice, and promoted the proliferation and differentiation of intestinal stem cells (ISCs). In addition, the RNA seq results suggested that Diprovocim significantly upregulated the TLR2 signaling pathway, and Diprovocim had no radioprotective effect on TLR2 KO mice, suggesting that Diprovocim activated TLR2 signaling pathway to exert its radioprotective function. The RNA sequencing results also suggested that Diprovocim significantly up-regulated the expression of SOX9. Diprovocim had no radioprotective effect after SOX9 knockdown. In conclusion, we demonstrated that Diprovocim protected the radiation-induced damage and upregulated targeting TLR2-SOX9 axis and that Diprovocim might be a potential high-efficiency selective agent.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"139"},"PeriodicalIF":6.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024540","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":"Genomic subtypes of non-muscle-invasive bladder cancer: guiding immunotherapy decision-making for patients exposed to aristolochic acid.","authors":"Yun Peng, Yuxuan Song, Caipeng Qin, Mengting Ding, Zixiong Huang, Fei Wang, Yuchao HuangFu, Luping Yu, Yiqing Du, Tao Xu","doi":"10.1186/s10020-025-01199-1","DOIUrl":"https://doi.org/10.1186/s10020-025-01199-1","url":null,"abstract":"<p><strong>Background: </strong>The limited genomic data on non-muscle-invasive bladder cancer (NMIBC) hampers our understanding of its carcinogenesis and development. Specifically, Aristolochic acid (AA), a potent human carcinogenic compound from aristolochia plants and commonly found in Chinese herbal medicine, has been extensively documented as being closely associated with the onset and progression of bladder cancer. However, the field of AA-induced NMIBC remains largely unexplored in terms of its genomic and molecular characteristics, as well as clinical therapeutic strategies.</p><p><strong>Methods: </strong>To bridge this knowledge gap, we conducted a comprehensive study using a cohort of 81 NMIBC samples. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) to obtain detailed genomic and transcriptomic data. We subjected these datasets to genomic analysis and subtype analysis to gain valuable insights into NMIBC.</p><p><strong>Results: </strong>By temporally dissecting mutations in NMIBC specimens, we identified a comprehensive mutational landscape of NMIBC and the associations of these mutations with recurrence-free survival. Additionally, we discerned four genomic subtypes of NMIBC: AA-like, FGFR3/HRAS, FGFR3 & chr9Del, and genome instability (GI). The AA-like subtype presented a high frequency of gene mutations along with a pronounced AA mutagenesis signature of SBS22 (Fisher test: P-value 3.5e-4, OR 25.25) even after temporal dissection. The FGFR3/HRAS subtype exhibited FGFR3 or HRAS mutations with few copy number alterations (CNAs). The FGFR3 & chr9Del subtype was characterized by the co-occurrence of chr9p and chr9q deletions as well as FGFR3 mutations, while the GI subtype showed a high frequency of CNAs. Notably, the AA-like and GI subtypes demonstrated better outcomes after immunotherapy, whereas the FGFR3/HRAS subtype showed poorer outcomes.</p><p><strong>Conclusions: </strong>Our findings provide novel perspectives on the genomics of NMIBC, unveiling four prominent genomic subtypes, each showing different outcomes following immunotherapy.</p><p><strong>Trial registration: </strong>No. 2019PHB268-01 (retrospectively registered on February 14, 2020).</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"140"},"PeriodicalIF":6.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010229","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: Integrating network pharmacology, molecular docking and experimental verification to explore the therapeutic effect and potential mechanism of nomilin against triple-negative breast cancer.","authors":"Zhixuan Wu, Haoyi Xiang, Xiaowu Wang, Rongrong Zhang, Yangyang Guo, Liangchen Qu, Jingyao Zhou, Yanyi Xiao","doi":"10.1186/s10020-025-01188-4","DOIUrl":"https://doi.org/10.1186/s10020-025-01188-4","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"137"},"PeriodicalIF":6.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008102","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":"Deficiency of IL-7R attenuates abdominal aortic aneurysms in mice by inhibiting macrophage polarization towards M1 phenotype through the NF-κB pathway.","authors":"Shengnan Xu, Xueyu Han, Yi Yu, Chuan Qu, Bo Yang, Bo Shen, Xin Liu","doi":"10.1186/s10020-025-01209-2","DOIUrl":"https://doi.org/10.1186/s10020-025-01209-2","url":null,"abstract":"<p><strong>Background: </strong>Abdominal aortic aneurysm (AAA) is a common degenerative disease of the abdominal aorta, which can result in extremely high mortality owing to the rupture of the abdominal aorta. The activation of IL-7R has been shown to modulate the inflammatory responses, which play an important role in the progression of AAAs. However, the mechanism of IL-7/IL-7R axis in AAAs is still unclear.</p><p><strong>Aims: </strong>This study aims to investigate the effects of IL-7R on AAAs and the underlying mechanisms involved.</p><p><strong>Methods: </strong>Wild-type C57BL/6 and IL-7R knockout mice were used as experimental subjects. ELISA analysis, histological staining, western blotting and qPCR were performed to explore effects of IL-7R deficiency in the formation and development of elastase-induced AAAs. Transwell, CCK8, and immunofluorescence assays detected the migration and polarization of RAW264.7 macrophages in vitro.</p><p><strong>Result: </strong>We demonstrated that IL-7R was elevated in mice with AAAs. Blocking IL-7R can inhibit the formation of AAAs and reduce aortic dilatation, elastic layer degradation, and inflammatory cell infiltration. Knockout of IL-7R suppressed the migration, infiltration and M1 polarization of macrophages. Moreover, inhibition of the NF-κB signaling pathway by BAY 11-7082 attenuated the macrophage-mediated inflammatory responses caused by IL-7R overexpression.</p><p><strong>Conclusion: </strong>In short, this study showed that IL-7R promotes the infiltration and migration of macrophages by regulating M1 macrophage polarization, possibly in part via activation of the NF-κB pathway, which may be associated with the development of AAAs.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"138"},"PeriodicalIF":6.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064053","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":"Acidosis regulates immune progression in rheumatoid arthritis by promoting the expression of cytokines and co-stimulatory molecules in synovial fibroblasts.","authors":"Xuewen Qian, Zhuoyan Zai, Yuemin Tao, Huifang Lv, Mengjia Hao, Longbiao Zhang, Xiaoyue Zhang, Yayun Xu, Yihao Zhang, Feihu Chen","doi":"10.1186/s10020-025-01181-x","DOIUrl":"https://doi.org/10.1186/s10020-025-01181-x","url":null,"abstract":"<p><strong>Background: </strong>Tissue acidosis is a key characteristic of RA. It remains unclear whether acidosis promotes the formation of the complex adaptive immune landscape mainly characterized by T cell activation in RA by influencing synovial fibroblasts. This study aims to investigate the influence of acidosis on the immune microenvironment of RA by exploring the cytokine secretion and expression of co-stimulatory factors of RA synovial fibroblasts.</p><p><strong>Methods: </strong>The Bulk RNA-seq dataset (GSE89408, Normal = 23, RA = 150) was utilized for cytokine screening and the immune state assessment based on disease stage. RNA-seq was employed to investigate cytokine and co-stimulatory molecule expression following 6 h of acid stimulation, combined with Bulk RNA-seq data to evaluate contributions to RA. Human cytokine arrays were used to confirm cytokine accumulation in supernatants after 12 h of acid stimulation. Proteomics was applied to explore cellular functional states in RASFs under 6 h of acid stress, with joint RNA-seq analysis elucidating transcription factor activation. Validation of select high-throughput data was performed using qRT-PCR and immune-based assays.</p><p><strong>Results: </strong>Bulk RNA-seq and RNA-seq identified 56 differentially expressed cytokines at their intersection. Functional enrichment analysis demonstrated that acid stimulation enhanced cytokine secretion and T cell chemotaxis in RA synovial fibroblasts (RASFs). Cytokine array revealed that acid exposure increased the accumulation of growth factors (e.g., FGF, VEGF) by over twofold and promoted the expression of multiple inflammatory and chemotactic factors. Immune state analysis indicated that acid stimulation induced a complex immune landscape by upregulating co-stimulatory and antigen-presenting molecules. Proteomics showed that acid stress enhanced mitochondrial function and triggered metabolic reprogramming in RASFs. Integrated transcriptomic and proteomic analyses revealed that AP1 regulates gene expression in RASFs, with its activation further confirmed by Western blotting and immunofluorescence.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"136"},"PeriodicalIF":6.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027907","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-chiro-inositol effectively counteracts endometriosis in a mouse model.","authors":"Martina Placidi, Giovanni Casoli, Teresa Vergara, Andrea Bianchi, Domenica Cocciolone, Silvia Zaccardi, Guido Macchiarelli, Maria Grazia Palmerini, Carla Tatone, Arturo Bevilacqua, Giovanna Di Emidio","doi":"10.1186/s10020-025-01178-6","DOIUrl":"https://doi.org/10.1186/s10020-025-01178-6","url":null,"abstract":"<p><strong>Background: </strong>Endometriosis, a common condition affecting 5-10% of women of reproductive age, is the growth of endometrial-like tissue outside the uterus, leading to pain and infertility. Current treatments, such as surgery and hormonal therapy, offer limited long-term benefits. This study investigated the potential of D-chiro inositol (DCI), a natural compound that influences ovarian steroidogenesis, to treat endometriosis and compared its efficacy with a progestin drug such as Dienogest (DG).</p><p><strong>Methods: </strong>We established a non-surgical mouse model of endometriosis in CD1 mice. Uterine horns were removed from donor mice, cut into fragments and inoculated in recipient mice by intraperitoneal injection. Endometriosis progression was assessed at 15, 21 and 28 days after transplantation, with the 28-day window being the most effective. The mice were then randomly assigned to four experimental groups, which received for 28 days: water (EMS); DCI 0.4 mg/die (DCI); DCI 0.2 mg/die and Dienogest 0.33 ng/die (DCI + DG); DG 0.67 ng/die (DG). At the end of the treatments, endometriotic lesions, ovaries and circulating estradiol levels were analyzed.</p><p><strong>Results: </strong>The results showed that treatment with DCI, both alone and in combination with DG, significantly reduced the number, size and vascularization of endometriotic lesions compared to the EMS control group. Histological analysis confirmed a decrease in endometriotic foci across all treatment groups, with the most pronounced effects in the DCI group. To investigate the underlying molecular mechanisms, we found that DCI led to a significant reduction in the expression of Sirt1 and an increase in E-Cadherin, indicating a reduction in EMT transition relevant for lesion development. In addition, DCI decreased cell proliferation and,blood vessel formation, as evaluated by PCNA and CD34, respectively. Futhermore, in the ovary, DCI treatment downregulated the expression of aromatase (Cyp19a1), the enzyme critical for estrogen biosynthesis, and increased the number of primordial to antral follicles, suggesting a beneficial effect on ovarian folliculogenesis.</p><p><strong>Conclusions: </strong>By modulating proliferation, EMT transition and aromatase activity, DCI emerges as a promising compound for endometriosis treatment.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"134"},"PeriodicalIF":6.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11987403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990957","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":"Neuroprotective role of morin hydrate on 3-nitropropionic acid-elicited huntington's disease: in vivo investigation of RIPK1/RIPK3/MLKL necroptosis signaling pathway.","authors":"Eman M Elbaz, Rabab H Sayed, Amany A Abdelkader, Atef Tadros Fahim","doi":"10.1186/s10020-025-01172-y","DOIUrl":"https://doi.org/10.1186/s10020-025-01172-y","url":null,"abstract":"<p><strong>Background: </strong>Huntington's disease (HD) is a rare dominantly inheritable autosomal neurodegenerative disease with unclear pathophysiological pathways. In neurodegenerative disorders, including HD, necroptosis plays a significant role in neuronal death. Morin hydrate (MH), a natural bioactive flavonoid, has various pharmacological properties via orchestrating neuroinflammation, apoptosis, and necroptosis. Up to now, there is no extant data on the impact of MH on the necroptotic pathway in HD.</p><p><strong>Aim: </strong>This research aimed to scrutinize the effect of MH on neurodegeneration initiated by 3-nitropropionic acid (3-NP) administration in rats via modulating necroptosis and apoptosis signaling pathways and compare it with necrosulfonamide (NSA) as a necroptosis inhibitor.</p><p><strong>Methods: </strong>HD was triggered in male wistar rats by intraperitoneal injection of 3-NP (10 mg/kg/day) for 14 days. Intraperitoneal injection of MH (20 mg/kg/day, i.p.) or NSA (1.65 mg/kg/day, i.p.) an hour prior to 3-NP administration for 14 days. At the end of study, rats were weighed, and their locomotor activity was assessed via grip strength and open field tests. Striata of rats were investigated histologically and immunohistochemically by evaluation the expression levels of glial fibrillary acidic protein (GFAP). Striatal tumor necrosis factor-alpha (TNF-α), caspase 3, and 8 levels were quantified through the ELISA technique, while striatal expression of necroptosis-associated proteins; phosphorylated form of receptor interacting protein kinase 1/3(p-RIPK1, p-RIPK3) and phosphorylated form of mixed lineage kinase domain-like protein (p-MLKL) were assessed by the Western blot technique. Striatal succinate dehydrogenase (SDH) activity was assayed colorimetrically. Finally, gene enrichment analysis using ShinyGO was employed.</p><p><strong>Results: </strong>MH and NSA significantly mitigated body weight loss and ameliorated locomotor deterioration, besides reversing histological abnormalities in the striatum of rats. Intriguingly, MH exerted similar effects on specific biomarkers and molecular signals as NSA. MH and NSA inhibited neuroinflammation, apoptosis, and necroptosis by significantly decreasing the striatal (TNF-α), caspase 3, and necroptosis-associated proteins (P-RIPK1, P-RIPK3, and P-MLKL) levels. Besides, MH and NSA also decreased striatal GFAP and increased SDH activity. Gene enrichment analysis revealed a significant interaction between genes. Together, MH exerts a neuroprotective action on 3-NP-elicited HD rats via reducing neuroinflammation, apoptosis, and necroptosis. This study highlights MH as a potential protection against HD, calling for further research to confirm its neuroprotective effects.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"135"},"PeriodicalIF":6.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11987198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993490","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}