Pub Date : 2026-01-10DOI: 10.1016/j.yexmp.2025.105018
Ifat Alsharif
{"title":"Corrigendum to \"NVP-BEZ235 enhances autophagy and ameliorates cognitive deficits by targeting tauopathies\" [Experimental and Molecular Pathology 143 (2025) 104988].","authors":"Ifat Alsharif","doi":"10.1016/j.yexmp.2025.105018","DOIUrl":"https://doi.org/10.1016/j.yexmp.2025.105018","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":" ","pages":"105018"},"PeriodicalIF":3.7,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.yexmp.2026.105022
Lenka Doubravská, Marie Macůrková
Myotubularin-related proteins (MTMRs) comprise a family of lipid phosphatases using phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate as their substrate. Several members have a well-established role in the pathogenesis of human myopathies and neuropathies. There is a growing body of evidence that the portfolio of diseases where MTMRs play a role should be extended to cancer. MTMRs are thus closing the gap on their functional counterparts, the phosphatidylinositol kinases. MTMRs do not contribute to cancer initiation through driver mutations, but their expression in tumours is frequently altered, leading to defects in cell proliferation, migration or cell death. In some instances, MTMR misexpression contributes to resistance to cancer treatment. In this review we summarize the current knowledge with the emphasis on the molecular mechanisms underlying the MTMR function in cancer pathogenesis.
{"title":"The role of myotubularin-related lipid phosphatases in cancer pathogenesis","authors":"Lenka Doubravská, Marie Macůrková","doi":"10.1016/j.yexmp.2026.105022","DOIUrl":"10.1016/j.yexmp.2026.105022","url":null,"abstract":"<div><div>Myotubularin-related proteins (MTMRs) comprise a family of lipid phosphatases using phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate as their substrate. Several members have a well-established role in the pathogenesis of human myopathies and neuropathies. There is a growing body of evidence that the portfolio of diseases where MTMRs play a role should be extended to cancer. MTMRs are thus closing the gap on their functional counterparts, the phosphatidylinositol kinases. MTMRs do not contribute to cancer initiation through driver mutations, but their expression in tumours is frequently altered, leading to defects in cell proliferation, migration or cell death. In some instances, MTMR misexpression contributes to resistance to cancer treatment. In this review we summarize the current knowledge with the emphasis on the molecular mechanisms underlying the MTMR function in cancer pathogenesis.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105022"},"PeriodicalIF":3.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.yexmp.2025.105021
Darab Ghadimi , Sophia Blömer , Aysel Şahin Kaya , Sandra Krüger , Christoph Röcken , Heiner Schäfer , Jumpei Uchiyama , Shigenobu Matsuzaki , Wilhelm Bockelmann
Diet and nutrition affect almost every biological process, including multiple chronic diseases, diabetes, and some cancers. However, there are still significant gaps in our understanding of the importance of nutrition and healthy diets in syntrophy with respect to cross-feeding of the microbe-microbe and the microbe-host in the pathobiology of the infectious-inflamed intestinal milieu caused by anaerobic opportunistic bacteria such as Fusobacterium nucleatum (F. nucleatum). We examined the immune outcomes of three-member folate syntrophy and cross-feeding between F. nucleatum bacteria, endogenous folate-producing gut bacteria, and host cells at the host-pathogen interface using a triple co-culture model. T84, THP-1, and Huh7 cells were inoculated with F. nucleatum for 6 h in regular DMEM, DMEM with 9.5 μM folic acid, or with/without a mixture of Bifidobacterium longum subsp. infantis (B. infantis) and Escherichia coli Nissle 1917 (EcN). Cytokine secretion, cometabolite levels (ammonia, indoles), cell viability, and barrier integrity were assessed. F. nucleatum-induced folate depletion was associated with increased IL-1β and IL-6 and decreased IL-22, along with reduced transepithelial electrical resistance (TEER) and cell viability in T84 cells. Folate supplementation mitigated these effects. The mixture of B. infantis and EcN reduced F. nucleatum-induced pro-inflammatory cytokines, increased IL-22, and improved TEER and cell viability. These protective effects were enhanced by the addition of folate. F. nucleatum also elevated ammonia and reduced indoles, effects reversed by B. infantis and EcN. In addition to the intrinsic pathogenicity of harmful bacteria, folate deprivation, microbe–microbe folate syntrophy, and microbe–host folate cross-feeding contribute to the pathobiology of anaerobic opportunistic bacteria and influence the physiological fate of host cells. A combination of B. infantis and EcN modulates the infectious-inflamed interface through a cytoprotective effect and mechanical competitive extrusion of pathogenic F. nucleatum. These results provide potential insights into the mechanisms of early-onset colorectal cancer, and evidently, require future studies using patient-derived organoids and in vivo systems to improve clinical relevance.
{"title":"Assessing the role of folate syntrophy and folate cross-feeding in the pathobiology of infectious-inflamed milieu caused by Fusobacterium nucleatum","authors":"Darab Ghadimi , Sophia Blömer , Aysel Şahin Kaya , Sandra Krüger , Christoph Röcken , Heiner Schäfer , Jumpei Uchiyama , Shigenobu Matsuzaki , Wilhelm Bockelmann","doi":"10.1016/j.yexmp.2025.105021","DOIUrl":"10.1016/j.yexmp.2025.105021","url":null,"abstract":"<div><div>Diet and nutrition affect almost every biological process, including multiple chronic diseases, diabetes, and some cancers. However, there are still significant gaps in our understanding of the importance of nutrition and healthy diets in syntrophy with respect to cross-feeding of the microbe-microbe and the microbe-host in the pathobiology of the infectious-inflamed intestinal milieu caused by anaerobic opportunistic bacteria such as <em>Fusobacterium nucleatum</em> (<em>F. nucleatum</em>). We examined the immune outcomes of three-member folate syntrophy and cross-feeding between <em>F. nucleatum</em> bacteria, endogenous folate-producing gut bacteria, and host cells at the host-pathogen interface using a triple co-culture model. T84, THP-1, and Huh7 cells were inoculated with <em>F. nucleatum</em> for 6 h in regular DMEM, DMEM with 9.5 μM folic acid, or with/without a mixture of <em>Bifidobacterium longum</em> subsp. <em>infantis</em> (<em>B. infantis</em>) and <em>Escherichia coli</em> Nissle <em>1917</em> (EcN). Cytokine secretion, cometabolite levels (ammonia, indoles), cell viability, and barrier integrity were assessed. <em>F. nucleatum-</em>induced folate depletion was associated with increased IL-1β and IL-6 and decreased IL-22, along with reduced transepithelial electrical resistance (TEER) and cell viability in T84 cells. Folate supplementation mitigated these effects. The mixture of <em>B. infantis</em> and EcN reduced <em>F. nucleatum</em>-induced pro-inflammatory cytokines, increased IL-22, and improved TEER and cell viability. These protective effects were enhanced by the addition of folate. <em>F. nucleatum</em> also elevated ammonia and reduced indoles, effects reversed by <em>B. infantis</em> and EcN. In addition to the intrinsic pathogenicity of harmful bacteria, folate deprivation, microbe–microbe folate syntrophy, and microbe–host folate cross-feeding contribute to the pathobiology of anaerobic opportunistic bacteria and influence the physiological fate of host cells. A combination of <em>B. infantis</em> and EcN modulates the infectious-inflamed interface through a cytoprotective effect and mechanical competitive extrusion of pathogenic <em>F. nucleatum</em>. These results provide potential insights into the mechanisms of early-onset colorectal cancer, and evidently, require future studies using patient-derived organoids and in vivo systems to improve clinical relevance.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105021"},"PeriodicalIF":3.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A significant gap exists between preclinical findings in animal models and their translation to diabetes therapeutics. Although several generic drugs are currently available, an effective and precise control of glycemia is challenging, and side effects due to both hyperglycemia and drugs are common. This is partly due to our incomplete understanding of disease mechanisms. It is now appreciated that, due to its simplicity and well-conserved genetic pathways, Drosophila disease modeling is an excellent choice for studying diabetes and its complications. Here, we review knowledge about conserved glucose sensing mechanisms, energy homeostasis pathways, and diabetes modeling in Drosophila. We discuss how hyperglycemia-induced metabolic deregulations cause diabetic complications. Further through the lens of Drosophila, we highlight molecular mechanisms underlying vascular and emerging diabetic complications, including neurodegeneration and cancer. We conclude with the thought that diabetes modeling in Drosophila could prove beneficial in large-scale screening of drugs for diabetes and its complications.
{"title":"Understanding diabetes and its complications through the lens of Drosophila","authors":"Supriya Bevinakoppamath , Anju Srinivas , Chandan Gowda Umesha , Akila Prashant , Amanjot Singh , Vinay Kumar Rao","doi":"10.1016/j.yexmp.2025.105017","DOIUrl":"10.1016/j.yexmp.2025.105017","url":null,"abstract":"<div><div>A significant gap exists between preclinical findings in animal models and their translation to diabetes therapeutics. Although several generic drugs are currently available, an effective and precise control of glycemia is challenging, and side effects due to both hyperglycemia and drugs are common. This is partly due to our incomplete understanding of disease mechanisms. It is now appreciated that, due to its simplicity and well-conserved genetic pathways, Drosophila disease modeling is an excellent choice for studying diabetes and its complications. Here, we review knowledge about conserved glucose sensing mechanisms, energy homeostasis pathways, and diabetes modeling in Drosophila. We discuss how hyperglycemia-induced metabolic deregulations cause diabetic complications. Further through the lens of Drosophila, we highlight molecular mechanisms underlying vascular and emerging diabetic complications, including neurodegeneration and cancer. We conclude with the thought that diabetes modeling in Drosophila could prove beneficial in large-scale screening of drugs for diabetes and its complications.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105017"},"PeriodicalIF":3.7,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.yexmp.2025.105016
Lenka Vaňková , Jiří Polívka , Věra Křížková , Samuel Vokurka , Ondřej Fiala , Monika Holubová , Kristýna Pivovarčíková , Inka Třešková , Tereza Knížková , Jan Říčař , Radek Kučera , Martin Pešta
Immunotherapy by immune checkpoint inhibitors (ICIs) revolutionized the treatment of melanoma patients. Tumor-infiltrating immune cells (TIICs) play a crucial role in antitumor immunity activated by ICIs. However, ICIs treatment may be associated with serious immune-related adverse events (irAEs). The aim of the study was to identify the key immune cells and molecules of the tumor microenvironment responsible for the treatment effects and risk of irAEs through immunohistochemical quantification of TIICs. We analyzed metastases (FFPE) of 28 melanoma patients treated with ICIs. Multilevel sampling and stereological quantification were used to assess TIICs identified immunohistochemically by the markers CD1a, CD1d, CD3, CD4, CD8, CD20, CD56, CD68, FOXP3, including immune checkpoint molecules LAG3, PD1, PD-L1. In lymph node metastases, higher infiltration of PD-L1, CD8-positive cells and lower infiltration of CD1a-positive cells predicted response to ICIs (P ≤ 0.05, P ≤ 0.05, P ≤ 0.05, resp.). In all metastasis's subtypes, higher expression of PD-L1 was predictor of response to immunotherapy (P ≤ 0.05). Lower PD-L1 expression (P ≤ 0.05) and lower CD3 expression (P ≤ 0.001) were associated with irAEs. Higher infiltration of CD8-positive T lymphocytes was associated with longer progression-free survival (P = 0.0166) as well as overall survival (P = 0.0454). Stereological quantification of specific immune cells in melanoma metastases, such as T-lymphocytes (CD3), cytotoxic T-lymphocytes (CD8), dendritic cells (CD1a) and PD-L1-positive cells, may predict ICIs treatment efficacy or the risk of irAEs. High infiltration of metastatic tissue by CD8-positive T cells is important for long-term favorable therapeutic response to ICIs.
{"title":"Stereological quantification of tumor infiltrating immune cells as predictor of immunotherapy in metastatic melanoma","authors":"Lenka Vaňková , Jiří Polívka , Věra Křížková , Samuel Vokurka , Ondřej Fiala , Monika Holubová , Kristýna Pivovarčíková , Inka Třešková , Tereza Knížková , Jan Říčař , Radek Kučera , Martin Pešta","doi":"10.1016/j.yexmp.2025.105016","DOIUrl":"10.1016/j.yexmp.2025.105016","url":null,"abstract":"<div><div>Immunotherapy by immune checkpoint inhibitors (ICIs) revolutionized the treatment of melanoma patients. Tumor-infiltrating immune cells (TIICs) play a crucial role in antitumor immunity activated by ICIs. However, ICIs treatment may be associated with serious immune-related adverse events (irAEs). The aim of the study was to identify the key immune cells and molecules of the tumor microenvironment responsible for the treatment effects and risk of irAEs through immunohistochemical quantification of TIICs. We analyzed metastases (FFPE) of 28 melanoma patients treated with ICIs. Multilevel sampling and stereological quantification were used to assess TIICs identified immunohistochemically by the markers CD1a, CD1d, CD3, CD4, CD8, CD20, CD56, CD68, FOXP3, including immune checkpoint molecules LAG3, PD1, PD-L1. In lymph node metastases, higher infiltration of PD-L1, CD8-positive cells and lower infiltration of CD1a-positive cells predicted response to ICIs (<em>P</em> ≤ 0.05, P ≤ 0.05, P ≤ 0.05, resp.). In all metastasis's subtypes, higher expression of PD-L1 was predictor of response to immunotherapy (P ≤ 0.05). Lower PD-L1 expression (P ≤ 0.05) and lower CD3 expression (<em>P</em> ≤ 0.001) were associated with irAEs. Higher infiltration of CD8-positive T lymphocytes was associated with longer progression-free survival (<em>P</em> = 0.0166) as well as overall survival (<em>P</em> = 0.0454). Stereological quantification of specific immune cells in melanoma metastases, such as T-lymphocytes (CD3), cytotoxic T-lymphocytes (CD8), dendritic cells (CD1a) and PD-L1-positive cells, may predict ICIs treatment efficacy or the risk of irAEs. High infiltration of metastatic tissue by CD8-positive T cells is important for long-term favorable therapeutic response to ICIs.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105016"},"PeriodicalIF":3.7,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-06DOI: 10.1016/j.yexmp.2025.105014
Hyo Jung Shin , In Soo Kim , Minwoo Kim , Seung Yeon Jung , Dong Woon Kim , Joon Won Kang
Microglia, the resident immune cells of the brain, play a critical role in maintaining homeostasis. In this study, we investigated changes in microglial phenotype associated with seizure susceptibility. Kainic acid (KA) was injected intraperitoneally, and when seizures reached Racine stage 4/5, administration was stopped, and mice were monitored for 60 min. Only mice that showed behavioral convulsive status epilepsy (SE) in the first experiment received a second KA injection 2 weeks later. Using this model, we observed changes in brain tissue and microglial phenotype according to seizure susceptibility. We also analyzed gene expression patterns associated with microglial phagocytosis in a publicly available hippocampal transcriptome microarray dataset (GSE88992) from mice injected with KA. After the initial low-dose KA repeat injection, the number of injections required to induce SE during the secondary injection was compared with the initial injection, and mice were categorized into seizure-resistant (SR, n = 26, no SE), seizure-tolerant (ST, n = 11, SE after ≥2 injections), and seizure-susceptible (SS, n = 15, SE after ≤2 injections) groups. Neuronal loss was observed in all seizure groups, but the extent varied across hippocampal regions. Microglial phenotypes in the hippocampus showed significant differences between groups. Immunofluorescence staining further confirmed that triggering receptor expressed on myeloid cells (TREM2) expression was increased in microglia in the SS group. Using a model that classifies seizure resistance, tolerance, and susceptibility, we observed significant differences in microglial phenotypes and TREM2 expressions between groups. This study highlights the role of microglia in the progression from first seizures to subsequent seizures, a critical step in the development of epilepsy.
小胶质细胞是大脑的常驻免疫细胞，在维持体内平衡中起着关键作用。在这项研究中，我们研究了与癫痫易感性相关的小胶质细胞表型的变化。腹腔注射Kainic acid (KA)，当癫痫发作达到拉辛期4/5时，停止给药，并监测小鼠60 min。只有在第一次实验中表现出行为惊厥状态癫痫（SE）的小鼠在2周后接受第二次KA注射。使用该模型，我们观察到脑组织和小胶质细胞表型根据癫痫易感性的变化。我们还分析了注射KA小鼠的海马转录组微阵列数据集（GSE88992）中与小胶质细胞吞噬相关的基因表达模式。初始低剂量KA重复注射后，比较二次注射诱导SE所需的注射次数，并将小鼠分为抗癫痫组（SR, n = 26，无SE）、耐癫痫组（ST, n = 11，注射≥2次SE）和癫痫敏感组（SS, n = 15，≤2次SE）。在所有的癫痫发作组中都观察到神经元的丧失，但海马区域的程度不同。海马小胶质细胞表型组间差异有统计学意义。免疫荧光染色进一步证实，SS组小胶质细胞中髓系细胞触发受体（TREM2）表达增加。通过对癫痫抵抗、耐受性和易感性进行分类的模型，我们观察到各组间小胶质细胞表型和TREM2表达的显著差异。这项研究强调了小胶质细胞在癫痫发作过程中的作用，这是癫痫发展的关键一步。
{"title":"Seizure susceptibility relates to microglial TREM2 expression and morphology in a multiple repeated low-dose kainic acid model","authors":"Hyo Jung Shin , In Soo Kim , Minwoo Kim , Seung Yeon Jung , Dong Woon Kim , Joon Won Kang","doi":"10.1016/j.yexmp.2025.105014","DOIUrl":"10.1016/j.yexmp.2025.105014","url":null,"abstract":"<div><div>Microglia, the resident immune cells of the brain, play a critical role in maintaining homeostasis. In this study, we investigated changes in microglial phenotype associated with seizure susceptibility. Kainic acid (KA) was injected intraperitoneally, and when seizures reached Racine stage 4/5, administration was stopped, and mice were monitored for 60 min. Only mice that showed behavioral convulsive status epilepsy (SE) in the first experiment received a second KA injection 2 weeks later. Using this model, we observed changes in brain tissue and microglial phenotype according to seizure susceptibility. We also analyzed gene expression patterns associated with microglial phagocytosis in a publicly available hippocampal transcriptome microarray dataset (GSE88992) from mice injected with KA. After the initial low-dose KA repeat injection, the number of injections required to induce SE during the secondary injection was compared with the initial injection, and mice were categorized into seizure-resistant (SR, <em>n</em> = 26, no SE), seizure-tolerant (ST, <em>n</em> = 11, SE after ≥2 injections), and seizure-susceptible (SS, <em>n</em> = 15, SE after ≤2 injections) groups. Neuronal loss was observed in all seizure groups, but the extent varied across hippocampal regions. Microglial phenotypes in the hippocampus showed significant differences between groups. Immunofluorescence staining further confirmed that triggering receptor expressed on myeloid cells (TREM2) expression was increased in microglia in the SS group. Using a model that classifies seizure resistance, tolerance, and susceptibility, we observed significant differences in microglial phenotypes and TREM2 expressions between groups. This study highlights the role of microglia in the progression from first seizures to subsequent seizures, a critical step in the development of epilepsy.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105014"},"PeriodicalIF":3.7,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-05DOI: 10.1016/j.yexmp.2025.105013
André Anastácio Santos , David Pires , Vanda Marques , Nicole Alesina , Pedro Miguel Rodrigues , Ana Catarina Bravo , Catarina Gouveia , Susana Saraiva , Luís Correia , Ricardo Crespo , João Pereira da Silva , Marília Cravo , Jesus Maria Banales , Joana Torres , Cecília Maria Pereira Rodrigues
Background
Primary sclerosing cholangitis (PSC) is a chronic liver disease frequently associated with inflammatory bowel disease (IBD) and increased risk of colorectal cancer (CRC). Despite the strong association, the underlying mechanisms linking PSC-IBD, gut inflammation, and neoplastic potential remain unclear. This study explores the role of miR-21-5p dysregulation, gut microbiota dysbiosis, and pro-oncogenic markers in shaping the inflammatory and neoplastic microenvironment in PSC-IBD patients.
Methods
A case-control study was conducted, including PSC patients with concomitant IBD (n = 14) and control individuals without diagnosed PSC and IBD (n = 20). miR-21-5p levels were evaluated in serum, fecal samples, and colonic biopsies via qPCR. Gut microbiota composition was analyzed using 16S rRNA sequencing. Pro-oncogenic and inflammatory markers in colonic tissue were assessed via qPCR. In vitro studies were performed using cholangiocyte (H69), colorectal cancer (HCT116), and primary monocyte models to investigate the role of miR-21-5p.
Results
miR-21-5p was significantly upregulated in the right colon, serum, and fecal samples of PSC-IBD patients compared to controls. Gut microbiota analysis revealed dysbiosis, characterized by an increased Bacteroidota/Bacillota ratio and reduction in bile acid-metabolizing bacteria, including Clostridium sensu stricto 1, Ruminococcaceae UCG-002, and Christensenellaceae_R7_group. Colonic tissue analysis showed increased expression of EMT-related transcription factors TWIST1 and SNAIL, inflammatory cytokines IL-8, CCL2, and COX2, and the stem cell marker LGR5. In vitro studies confirmed miR-21-5p role in upregulating does markers in monocytes and CRC cells.
Conclusion
This study found a link between miR-21-5p dysregulation and gut microbiota dysbiosis, colonic inflammation, and pro-oncogenic signaling in PSC-IBD patients. These findings highlight miR-21-5p as a potential modulator of disease progression and neoplastic risk.
{"title":"miR-21-5p dysregulation is associated with gut microbiota dysbiosis and pro-oncogenic markers in primary sclerosing cholangitis with concomitant inflammatory bowel disease","authors":"André Anastácio Santos , David Pires , Vanda Marques , Nicole Alesina , Pedro Miguel Rodrigues , Ana Catarina Bravo , Catarina Gouveia , Susana Saraiva , Luís Correia , Ricardo Crespo , João Pereira da Silva , Marília Cravo , Jesus Maria Banales , Joana Torres , Cecília Maria Pereira Rodrigues","doi":"10.1016/j.yexmp.2025.105013","DOIUrl":"10.1016/j.yexmp.2025.105013","url":null,"abstract":"<div><h3>Background</h3><div>Primary sclerosing cholangitis (PSC) is a chronic liver disease frequently associated with inflammatory bowel disease (IBD) and increased risk of colorectal cancer (CRC). Despite the strong association, the underlying mechanisms linking PSC-IBD, gut inflammation, and neoplastic potential remain unclear. This study explores the role of miR-21-5p dysregulation, gut microbiota dysbiosis, and pro-oncogenic markers in shaping the inflammatory and neoplastic microenvironment in PSC-IBD patients.</div></div><div><h3>Methods</h3><div>A case-control study was conducted, including PSC patients with concomitant IBD (<em>n</em> = 14) and control individuals without diagnosed PSC and IBD (<em>n</em> = 20). miR-21-5p levels were evaluated in serum, fecal samples, and colonic biopsies <em>via</em> qPCR. Gut microbiota composition was analyzed using 16S rRNA sequencing. Pro-oncogenic and inflammatory markers in colonic tissue were assessed <em>via</em> qPCR. <em>In vitro</em> studies were performed using cholangiocyte (H69), colorectal cancer (HCT116), and primary monocyte models to investigate the role of miR-21-5p.</div></div><div><h3>Results</h3><div>miR-21-5p was significantly upregulated in the right colon, serum, and fecal samples of PSC-IBD patients compared to controls. Gut microbiota analysis revealed dysbiosis, characterized by an increased <em>Bacteroidota</em>/<em>Bacillota</em> ratio and reduction in bile acid-metabolizing bacteria, including <em>Clostridium sensu stricto 1</em>, <em>Ruminococcaceae UCG-002</em>, and <em>Christensenellaceae_R7_group</em>. Colonic tissue analysis showed increased expression of EMT-related transcription factors <em>TWIST1</em> and <em>SNAIL</em>, inflammatory cytokines <em>IL-8</em>, <em>CCL2</em>, and <em>COX2</em>, and the stem cell marker <em>LGR5</em>. <em>In vitro</em> studies confirmed miR-21-5p role in upregulating <em>does</em> markers in monocytes and CRC cells.</div></div><div><h3>Conclusion</h3><div>This study found a link between miR-21-5p dysregulation and gut microbiota dysbiosis, colonic inflammation, and pro-oncogenic signaling in PSC-IBD patients. These findings highlight miR-21-5p as a potential modulator of disease progression and neoplastic risk.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105013"},"PeriodicalIF":3.7,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.yexmp.2025.105011
Letizia Penolazzi , Alice Zaramella , Anna Chierici , Paola Bisaccia , Maria Pina Notarangelo , Anna Maria Tolomeo , Elisabetta Lambertini , Anna Alessia Saponaro , Tommaso Colangelo , Michela Pozzobon , Roberta Piva
The present study was designed to characterize the matrix-bound nanovesicles (MBVs) in decellularized Wharton's jelly matrix (DWJ). We have previously used DWJ as a biomaterial demonstrating its efficacy in restoring the functional properties of human intervertebral disc (IVD) cells lost following degeneration (IDD), for which there is currently no cure.
MBVs were isolated by ultracentrifugation from DWJ, characterized by transmission electron microscopy, nanoparticle tracking assay, and surface marker expression. MBVs uptake into cells was assessed by CalceinAM labeling. Nitric oxide production was evaluated by Griess assay. The response of IVD cells was assessed by cell motility (wound scratch assay) and protein expression (immunocytochemistry). MBVs were subjected to human growth factors array to evaluate different growth factors and global miRNA profiling (obtained from miRNA libraries, sequencing-NextSeq system and the GeneGlobe Data Analysis).
MBVs were readily internalized by cells without affecting the viability. MBVs suppressed the acquisition of the M1 phenotype in LPS-stimulated macrophages, positively influence the cell migration of IVD cells and the expression of molecular markers associated with the restoration of the chondrocyte-like phenotype. A preliminary analysis of growth factor content and miRNA expression profiling suggest that MBVs carry a cargo functionally relevant for the IVD cell metabolism.
The discovery of MBVs in DWJ leads to considering them as an integral component of DWJ-based scaffolds designed to repair or regenerate a damaged tissue. The pro-discogenic properties of MBVs demonstrate that there are grounds for expanding the study of DWJ-derived MBVs for potential therapeutic applications in the treatment of IDD.
{"title":"Wharton's jelly-derived nanovesicles for targeting intervertebral disc degeneration","authors":"Letizia Penolazzi , Alice Zaramella , Anna Chierici , Paola Bisaccia , Maria Pina Notarangelo , Anna Maria Tolomeo , Elisabetta Lambertini , Anna Alessia Saponaro , Tommaso Colangelo , Michela Pozzobon , Roberta Piva","doi":"10.1016/j.yexmp.2025.105011","DOIUrl":"10.1016/j.yexmp.2025.105011","url":null,"abstract":"<div><div>The present study was designed to characterize the matrix-bound nanovesicles (MBVs) in decellularized Wharton's jelly matrix (DWJ). We have previously used DWJ as a biomaterial demonstrating its efficacy in restoring the functional properties of human intervertebral disc (IVD) cells lost following degeneration (IDD), for which there is currently no cure.</div><div>MBVs were isolated by ultracentrifugation from DWJ, characterized by transmission electron microscopy, nanoparticle tracking assay, and surface marker expression. MBVs uptake into cells was assessed by CalceinAM labeling. Nitric oxide production was evaluated by Griess assay. The response of IVD cells was assessed by cell motility (wound scratch assay) and protein expression (immunocytochemistry). MBVs were subjected to human growth factors array to evaluate different growth factors and global miRNA profiling (obtained from miRNA libraries, sequencing-NextSeq system and the GeneGlobe Data Analysis).</div><div>MBVs were readily internalized by cells without affecting the viability. MBVs suppressed the acquisition of the M1 phenotype in LPS-stimulated macrophages, positively influence the cell migration of IVD cells and the expression of molecular markers associated with the restoration of the chondrocyte-like phenotype. A preliminary analysis of growth factor content and miRNA expression profiling suggest that MBVs carry a cargo functionally relevant for the IVD cell metabolism.</div><div>The discovery of MBVs in DWJ leads to considering them as an integral component of DWJ-based scaffolds designed to repair or regenerate a damaged tissue. The pro-discogenic properties of MBVs demonstrate that there are grounds for expanding the study of DWJ-derived MBVs for potential therapeutic applications in the treatment of IDD.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105011"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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