Pub Date : 2025-12-01Epub Date: 2025-10-11DOI: 10.1016/j.yexmp.2025.105001
Xiaoyu Zhang, Fanyan Meng, Zhidan Wang, Shuang Ren, Jie Zhang
The research has found that the incidence of rheumatoid arthritis (RA) combined with Type 2 Diabetes Mellitus (T2DM) and insulin resistance (IR) is higher than that in the general population. This indicates that there is an association mechanism between RA and abnormal glucose metabolism. IR is one of the main causes of T2DM, and high blood glucose levels are one of the main symptoms of T2DM. Therefore, revealing the intrinsic mechanism between RA and the abnormal glucose metabolism in T2DM becomes the key to treating RA complicated with T2DM. This article summarizes the mechanism of RA combined with T2DM, which is mainly caused by the disorder of glucose metabolism and the persistent presence of inflammatory mediators. The synovial hyperplasia, angiogenesis and bone destruction of RA interact with the abnormal glucose metabolism. Therefore, elaborating the intrinsic connection and interaction mechanism between abnormal glucose metabolism and RA, and summarizing the abnormal glucose metabolism phenomenon of increased prevalence of T2DM in RA patients in clinical practice, can provide a reference for future in-depth research on treatment plans related to abnormal glucose metabolism in RA.
{"title":"The association between abnormal glucose metabolism and rheumatoid arthritis","authors":"Xiaoyu Zhang, Fanyan Meng, Zhidan Wang, Shuang Ren, Jie Zhang","doi":"10.1016/j.yexmp.2025.105001","DOIUrl":"10.1016/j.yexmp.2025.105001","url":null,"abstract":"<div><div>The research has found that the incidence of rheumatoid arthritis (RA) combined with Type 2 Diabetes Mellitus (T2DM) and insulin resistance (IR) is higher than that in the general population. This indicates that there is an association mechanism between RA and abnormal glucose metabolism. IR is one of the main causes of T2DM, and high blood glucose levels are one of the main symptoms of T2DM. Therefore, revealing the intrinsic mechanism between RA and the abnormal glucose metabolism in T2DM becomes the key to treating RA complicated with T2DM. This article summarizes the mechanism of RA combined with T2DM, which is mainly caused by the disorder of glucose metabolism and the persistent presence of inflammatory mediators. The synovial hyperplasia, angiogenesis and bone destruction of RA interact with the abnormal glucose metabolism. Therefore, elaborating the intrinsic connection and interaction mechanism between abnormal glucose metabolism and RA, and summarizing the abnormal glucose metabolism phenomenon of increased prevalence of T2DM in RA patients in clinical practice, can provide a reference for future in-depth research on treatment plans related to abnormal glucose metabolism in RA.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105001"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145267322","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 : 2025-12-01Epub Date: 2025-11-25DOI: 10.1016/j.yexmp.2025.105012
Victoria Chirico , Tabea Lenkeit , Seyma Büyücek , Katharina Möller , Florian Lutz , Florian Viehweger , Martina Kluth , Claudia Hube-Magg , Christian Bernreuther , Guido Sauter , Andreas H. Marx , Ronald Simon , Till Krech , Stefan Steurer , Christoph Fraune , Sarah Minner , Natalia Gorbokon , Maximilian Lennartz , Eike Burandt , Anne Menz , Nina Schraps
CBP (CREB-binding protein) is a ubiquitously expressed major histone modifier involved in the regulation of thousands of genes. In cancer, loss-of-function and overexpression can occur. To clarify the role of CBP expression, a tissue microarray containing 14,966 samples from 134 different tumor entities and 608 samples of 76 different normal tissues was analyzed by immunohistochemistry. In normal tissues, strong nuclear CBP staining was ubiquitously seen except of few cell types. Among 12,255 evaluable tumors, CBP staining was completely absent (CBP deficiency) in 226 (1.84 %) while 232 (1.89 %) showed only faint to moderate staining of a minority of cancer cells (substantial reduction, SR), 384 (3.13 %) weak, 3079 (25.12 %) moderate, and 8334 (68.00 %) strong CBP positivity. CBP deficiency or SR was common in endometrioid endometrial carcinoma (22.8 %), hepatocellular carcinoma (19.0 %), urothelial carcinoma (up to 17.4 %), serous endometrial carcinoma (12.5 %), and chromophobe renal cell carcinoma (RCC; 10.7 %). Less than 10 % CBP deficient or SR cases were seen in >50 additional tumor categories. Among tumors with CBP expression, reduced expression was linked to high pT (p < 0.0001), high UICC stage (p = 0.0005) and poor grade (p < 0.0001) in clear cell RCC, high UICC stage (p = 0.0409) and distant metastasis (p = 0.0022) in papillary RCC, advanced pT stage (p = 0.0003) in colorectal carcinoma and invasive disease (p < 0.0001) and L1 status (p = 0.0154) in urothelial carcinoma. High CBP expression was related to nodal metastasis in pancreatic adenocarcinoma (p = 0.0201). In conclusion, CBP deficiency is a rare event in many different tumor types. Reduced or absent CBP expression is linked to aggressive cancer phenotypes.
{"title":"Prevalence and clinical significance of CBP deficiency and disturbed CBP expression in human cancer","authors":"Victoria Chirico , Tabea Lenkeit , Seyma Büyücek , Katharina Möller , Florian Lutz , Florian Viehweger , Martina Kluth , Claudia Hube-Magg , Christian Bernreuther , Guido Sauter , Andreas H. Marx , Ronald Simon , Till Krech , Stefan Steurer , Christoph Fraune , Sarah Minner , Natalia Gorbokon , Maximilian Lennartz , Eike Burandt , Anne Menz , Nina Schraps","doi":"10.1016/j.yexmp.2025.105012","DOIUrl":"10.1016/j.yexmp.2025.105012","url":null,"abstract":"<div><div>CBP (CREB-binding protein) is a ubiquitously expressed major histone modifier involved in the regulation of thousands of genes. In cancer, loss-of-function and overexpression can occur. To clarify the role of CBP expression, a tissue microarray containing 14,966 samples from 134 different tumor entities and 608 samples of 76 different normal tissues was analyzed by immunohistochemistry. In normal tissues, strong nuclear CBP staining was ubiquitously seen except of few cell types. Among 12,255 evaluable tumors, CBP staining was completely absent (CBP deficiency) in 226 (1.84 %) while 232 (1.89 %) showed only faint to moderate staining of a minority of cancer cells (substantial reduction, SR), 384 (3.13 %) weak, 3079 (25.12 %) moderate, and 8334 (68.00 %) strong CBP positivity. CBP deficiency or SR was common in endometrioid endometrial carcinoma (22.8 %), hepatocellular carcinoma (19.0 %), urothelial carcinoma (up to 17.4 %), serous endometrial carcinoma (12.5 %), and chromophobe renal cell carcinoma (RCC; 10.7 %). Less than 10 % CBP deficient or SR cases were seen in >50 additional tumor categories. Among tumors with CBP expression, reduced expression was linked to high pT (<em>p</em> < 0.0001), high UICC stage (<em>p</em> = 0.0005) and poor grade (<em>p</em> < 0.0001) in clear cell RCC, high UICC stage (<em>p</em> = 0.0409) and distant metastasis (<em>p</em> = 0.0022) in papillary RCC, advanced pT stage (<em>p</em> = 0.0003) in colorectal carcinoma and invasive disease (p < 0.0001) and L1 status (<em>p</em> = 0.0154) in urothelial carcinoma. High CBP expression was related to nodal metastasis in pancreatic adenocarcinoma (<em>p</em> = 0.0201). In conclusion, CBP deficiency is a rare event in many different tumor types. Reduced or absent CBP expression is linked to aggressive cancer phenotypes.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105012"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620295","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 : 2025-12-01Epub Date: 2025-10-31DOI: 10.1016/j.yexmp.2025.105006
Luiz Filipe Gonçalves-Oliveira , Juliana Figueiredo Peixoto , Bernardo Acácio Santini Pereira , Nathalia Silva Carlos Oliveira , Flávia de Oliveira Cardoso , Davyson de Lima Moreira , Franklin Silva-Souza , Carlos Roberto Alves
The development of innovative treatments for American Cutaneous Leishmaniasis is crucial due to severe side effects of current treatment and the emergence of non-responder parasites. To address such a challenge the incorporation of epoxy-α-lapachone (ELAP) into a microemulsion (ME), named ELAP-ME, represents a promising therapeutic approach. In previous studies, ELAP-ME demonstrated efficacy in controlling infection in the BALB/c-Leishmania (Leishmania) amazonensis model, advancing in the technology readiness level with a drug prototype. To further validate its potential as a drug prototype, the histopathological effects of ELAP-ME were investigated in healthy BALB/c mice as a preclinical approach stage. Mice were administered with a fixed dose of ELAP-ME microemulsion (∼7 μg/kg) and evaluated at different short-term after administration (4, 12, and 24 h). Histopathological analysis of the liver, kidney, lung, heart, and brain revealed only mild alterations. These findings confirm the low toxicity profile of ELAP-ME, highlighting its safety and supporting its continued advancement as a pharmacological alternative for the treatment of leishmaniasis.
{"title":"Histopathological analysis reveals mild to moderate changes in BALB/c mice after short-term administration of a microemulsion loaded with epoxy-α-lapachone","authors":"Luiz Filipe Gonçalves-Oliveira , Juliana Figueiredo Peixoto , Bernardo Acácio Santini Pereira , Nathalia Silva Carlos Oliveira , Flávia de Oliveira Cardoso , Davyson de Lima Moreira , Franklin Silva-Souza , Carlos Roberto Alves","doi":"10.1016/j.yexmp.2025.105006","DOIUrl":"10.1016/j.yexmp.2025.105006","url":null,"abstract":"<div><div>The development of innovative treatments for American Cutaneous Leishmaniasis is crucial due to severe side effects of current treatment and the emergence of non-responder parasites. To address such a challenge the incorporation of epoxy-α-lapachone (ELAP) into a microemulsion (ME), named ELAP-ME, represents a promising therapeutic approach. In previous studies, ELAP-ME demonstrated efficacy in controlling infection in the BALB/c-<em>Leishmania</em> (<em>Leishmania</em>) <em>amazonensis</em> model, advancing in the technology readiness level with a drug prototype. To further validate its potential as a drug prototype, the histopathological effects of ELAP-ME were investigated in healthy BALB/c mice as a preclinical approach stage. Mice were administered with a fixed dose of ELAP-ME microemulsion (∼7 μg/kg) and evaluated at different short-term after administration (4, 12, and 24 h). Histopathological analysis of the liver, kidney, lung, heart, and brain revealed only mild alterations. These findings confirm the low toxicity profile of ELAP-ME, highlighting its safety and supporting its continued advancement as a pharmacological alternative for the treatment of leishmaniasis.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105006"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421453","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 : 2025-12-01Epub Date: 2025-09-04DOI: 10.1016/j.yexmp.2025.104995
Angelo Santoro , Yuri Vincenzo Ferrara , Alfonso De Angelis
Cystinosis is a autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene, which encodes cystinosin, a cystine transporter. The defective function of cystinosin leads to cystine accumulation in the lysosome, resulting in progressive multi-organ damage. Cystinosis manifests early in life, with nephropathic cystinosis typically presenting in infancy with renal Fanconi syndrome, leading to chronic kidney disease and end-stage renal disease if untreated. Diagnosis relies on clinical evaluation, corneal examination, leukocyte cystine quantification, and CTNS genetic testing. In the present review, both cysteamine-based and non-cysteamine therapeutic approaches for the treatment of cystinosis are discussed. Cysteamine therapy, reduces intracellular cystine levels and delays disease progression, significantly improving patient outcomes. However, cysteamine requires lifelong adherence and has limitations, including gastrointestinal side effects and frequent dosing. Kidney transplantation remains a therapeutic option for end-stage renal disease, although extra-renal complications persist. Novel therapeutic strategies are under investigation to address these limitations, including improved cysteamine formulations, prodrugs, and small molecules. Additional approaches include gene therapy, stem cell-based interventions, mRNA-based treatments, and the targeted degradation of cystine crystals. Continued research and multidisciplinary management are essential to enhancing the prognosis and quality of life for individuals affected by cystinosis.
{"title":"Therapeutic strategies in cystinosis: A focus on cysteamine and beyond","authors":"Angelo Santoro , Yuri Vincenzo Ferrara , Alfonso De Angelis","doi":"10.1016/j.yexmp.2025.104995","DOIUrl":"10.1016/j.yexmp.2025.104995","url":null,"abstract":"<div><div>Cystinosis is a autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene, which encodes cystinosin, a cystine transporter. The defective function of cystinosin leads to cystine accumulation in the lysosome, resulting in progressive multi-organ damage. Cystinosis manifests early in life, with nephropathic cystinosis typically presenting in infancy with renal Fanconi syndrome, leading to chronic kidney disease and end-stage renal disease if untreated. Diagnosis relies on clinical evaluation, corneal examination, leukocyte cystine quantification, and CTNS genetic testing. In the present review, both cysteamine-based and non-cysteamine therapeutic approaches for the treatment of cystinosis are discussed. Cysteamine therapy, reduces intracellular cystine levels and delays disease progression, significantly improving patient outcomes. However, cysteamine requires lifelong adherence and has limitations, including gastrointestinal side effects and frequent dosing. Kidney transplantation remains a therapeutic option for end-stage renal disease, although extra-renal complications persist. Novel therapeutic strategies are under investigation to address these limitations, including improved cysteamine formulations, prodrugs, and small molecules. Additional approaches include gene therapy, stem cell-based interventions, mRNA-based treatments, and the targeted degradation of cystine crystals. Continued research and multidisciplinary management are essential to enhancing the prognosis and quality of life for individuals affected by cystinosis.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 104995"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144989487","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 : 2025-12-01Epub Date: 2025-06-04DOI: 10.1016/j.yexmp.2025.104974
Qiuhong Wang , Manhua Li , Xunlei Zhang , Hua Huang , Jianfei Huang , Jing Ke , Haifang Ding , Jinzhang Xiao , Xiaohang Shan , Qingqing Liu , Bojun Bao , Lei Yang
{"title":"Corrigendum to “Upregulation of CDK7 in gastric cancer cell promotes tumor cell proliferation and predicts poor prognosis” [Experimental and Molecular Pathology 100 (2016) 514–521]","authors":"Qiuhong Wang , Manhua Li , Xunlei Zhang , Hua Huang , Jianfei Huang , Jing Ke , Haifang Ding , Jinzhang Xiao , Xiaohang Shan , Qingqing Liu , Bojun Bao , Lei Yang","doi":"10.1016/j.yexmp.2025.104974","DOIUrl":"10.1016/j.yexmp.2025.104974","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 104974"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224873","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}
The endothelial glycocalyx, a carbohydrate-rich layer lining the vascular endothelium, plays a critical role in maintaining vascular homeostasis by regulating permeability, leukocyte adhesion, and inflammatory signaling. Its degradation has been implicated in endothelial dysfunction and organ damage in various diseases. Biomarkers derived from glycocalyx components, particularly Syndecan-1 (SDC-1) and heparan sulfate (HS), can be detected in blood and urine, providing a potential window into vascular injury. In this narrative review, we explore the clinical potential of glycocalyx-derived biomarkers, with a focus on SDC-1, in a broad spectrum of conditions, including sepsis, coronavirus disease, acute respiratory distress syndrome, kidney diseases, cardiovascular disorders, autoimmune diseases, cancer, trauma, and pregnancy-related complications. We highlight the pathophysiological mechanisms of glycocalyx degradation, assess the diagnostic and prognostic utility of SDC-1, and summarize emerging therapeutic strategies to preserve glycocalyx integrity. Given their strong association with disease severity and outcomes, glycocalyx-derived biomarkers may enable earlier diagnosis, improved risk stratification, and personalized treatment, supporting more informed clinical decision-making across diverse medical conditions.
{"title":"Glycocalyx shedding as a clinical biomarker in critical illness","authors":"Ayako Inoda , Keiko Suzuki , Hiroyuki Tomita , Hideshi Okada","doi":"10.1016/j.yexmp.2025.104997","DOIUrl":"10.1016/j.yexmp.2025.104997","url":null,"abstract":"<div><div>The endothelial glycocalyx, a carbohydrate-rich layer lining the vascular endothelium, plays a critical role in maintaining vascular homeostasis by regulating permeability, leukocyte adhesion, and inflammatory signaling. Its degradation has been implicated in endothelial dysfunction and organ damage in various diseases. Biomarkers derived from glycocalyx components, particularly Syndecan-1 (SDC-1) and heparan sulfate (HS), can be detected in blood and urine, providing a potential window into vascular injury. In this narrative review, we explore the clinical potential of glycocalyx-derived biomarkers, with a focus on SDC-1, in a broad spectrum of conditions, including sepsis, coronavirus disease, acute respiratory distress syndrome, kidney diseases, cardiovascular disorders, autoimmune diseases, cancer, trauma, and pregnancy-related complications. We highlight the pathophysiological mechanisms of glycocalyx degradation, assess the diagnostic and prognostic utility of SDC-1, and summarize emerging therapeutic strategies to preserve glycocalyx integrity. Given their strong association with disease severity and outcomes, glycocalyx-derived biomarkers may enable earlier diagnosis, improved risk stratification, and personalized treatment, supporting more informed clinical decision-making across diverse medical conditions.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 104997"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145227163","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}
Metabolic reprogramming is a common phenomenon that is observed in diverse cancer types. Clear cell renal cell carcinoma (ccRCC) is termed a metabolic disease due to its dysregulated lipid and glucose metabolism. Among kidney cancers, ccRCC is the most malignant form of cancer, defined by the large accumulation of lipid droplets. These lipid droplets, although they provide energy and induction of metastasis, also act as a buffer by preventing ferroptosis. Ferroptosis is an iron-dependent type of regulated cell death, which is characterized by the accumulation of toxic lipid peroxides. Ferroptosis has emerged to play an important part in tumor progression and cancer therapy. Due to a lack of diagnostic markers and resistance towards therapy, ccRCC is a difficult cancer type to overcome. However, studies have shown the importance of ferroptosis in ccRCC treatment by targeting various pathways. This paper helps in understanding the mechanism of ferroptosis and the evidence observed in ccRCC. This paper aims to understand the current trend of ferroptosis in ccRCC and produce a potential therapy for ccRCC through ferroptosis.
{"title":"Mechanism and importance of ferroptosis in clear cell renal cell carcinoma treatment","authors":"Manvi Agarwal Neeraj , Songmi Noh , JeeHoon Chae , JunJeong Choi","doi":"10.1016/j.yexmp.2025.105004","DOIUrl":"10.1016/j.yexmp.2025.105004","url":null,"abstract":"<div><div>Metabolic reprogramming is a common phenomenon that is observed in diverse cancer types. Clear cell renal cell carcinoma (ccRCC) is termed a metabolic disease due to its dysregulated lipid and glucose metabolism. Among kidney cancers, ccRCC is the most malignant form of cancer, defined by the large accumulation of lipid droplets. These lipid droplets, although they provide energy and induction of metastasis, also act as a buffer by preventing ferroptosis. Ferroptosis is an iron-dependent type of regulated cell death, which is characterized by the accumulation of toxic lipid peroxides. Ferroptosis has emerged to play an important part in tumor progression and cancer therapy. Due to a lack of diagnostic markers and resistance towards therapy, ccRCC is a difficult cancer type to overcome. However, studies have shown the importance of ferroptosis in ccRCC treatment by targeting various pathways. This paper helps in understanding the mechanism of ferroptosis and the evidence observed in ccRCC. This paper aims to understand the current trend of ferroptosis in ccRCC and produce a potential therapy for ccRCC through ferroptosis.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105004"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312634","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 : 2025-12-01Epub Date: 2025-11-20DOI: 10.1016/j.yexmp.2025.105009
Amy May Lin Quek , Ooiean Teng , Ju-Hea Park , Bernadette Guek Cheng Er , Erle Chuen Hian Lim , Raymond Chee Seong Seet
Previous studies indicate that stroke recovery is worse in patients with prior COVID-19, suggesting persistent biological perturbations. We investigated lingering renin-angiotensin system (RAS) and inflammatory alterations after COVID-19 to uncover mechanisms driving impaired ischemic stroke recovery. We conducted a prospective observational cohort study comparing clinical and molecular profiles of ischemic stroke patients with and without recent COVID-19 infection to age-matched healthy controls. Plasma angiotensin-(1–7), angiotensin II, and soluble ACE2 were quantified, high-throughput proteomic profiling was performed using the Olink® Explore platform, and RNA sequencing was conducted to identify molecular mechanisms related to COVID-19-associated stroke and stroke outcomes (90-day modified Rankin Scale (mRS)). A total of 189 participants (38 COVID-19-associated stroke, 77 non-COVID-19 stroke, and 74 healthy controls) were enrolled. COVID-19-associated stroke patients exhibited significantly higher proportions of cryptogenic strokes (21.1 % vs 10.4 %), earlier hospital presentation (mean 185 vs 310 min), greater use of endovascular thrombectomy (97.4 % vs. 52.6 %), yet poorer functional outcomes (mRS ≥3) at 3 months (73 % vs. 47 %, all p < 0.05). Both stroke groups showed elevated angiotensin-(1–7) levels compared to controls, but angiotensin II levels were notably higher only in non-COVID-19 stroke patients. Proteomic analysis revealed sustained elevation of interferon-gamma (IFN-γ) signaling in COVID-19-associated stroke patients. Reduced AKT3 levels emerged as a significant predictor of poor outcomes, independent of renin-angiotensin biomarkers (adjusted OR 0.40; 95 % CI 0.16–0.94). Stroke patients with low AKT3 levels and poor outcomes exhibited significant upregulation of ribosomal proteins (RPS15, RPS4X, RPS7, RPS18, RPSA, RPS27A, RPS13, RPS23), reflecting heightened translational stress. Persistent RAS and inflammatory dysregulation following COVID-19 may contribute to worse stroke recovery. Future studies should validate and investigate the therapeutic implications of these findings.
{"title":"Persistent renin-angiotensin system and inflammatory dysregulation following COVID-19 impairs ischemic stroke recovery","authors":"Amy May Lin Quek , Ooiean Teng , Ju-Hea Park , Bernadette Guek Cheng Er , Erle Chuen Hian Lim , Raymond Chee Seong Seet","doi":"10.1016/j.yexmp.2025.105009","DOIUrl":"10.1016/j.yexmp.2025.105009","url":null,"abstract":"<div><div>Previous studies indicate that stroke recovery is worse in patients with prior COVID-19, suggesting persistent biological perturbations. We investigated lingering renin-angiotensin system (RAS) and inflammatory alterations after COVID-19 to uncover mechanisms driving impaired ischemic stroke recovery. We conducted a prospective observational cohort study comparing clinical and molecular profiles of ischemic stroke patients with and without recent COVID-19 infection to age-matched healthy controls. Plasma angiotensin-(1–7), angiotensin II, and soluble ACE2 were quantified, high-throughput proteomic profiling was performed using the Olink® Explore platform, and RNA sequencing was conducted to identify molecular mechanisms related to COVID-19-associated stroke and stroke outcomes (90-day modified Rankin Scale (mRS)). A total of 189 participants (38 COVID-19-associated stroke, 77 non-COVID-19 stroke, and 74 healthy controls) were enrolled. COVID-19-associated stroke patients exhibited significantly higher proportions of cryptogenic strokes (21.1 % vs 10.4 %), earlier hospital presentation (mean 185 vs 310 min), greater use of endovascular thrombectomy (97.4 % vs. 52.6 %), yet poorer functional outcomes (mRS ≥3) at 3 months (73 % vs. 47 %, all <em>p</em> < 0.05). Both stroke groups showed elevated angiotensin-(1–7) levels compared to controls, but angiotensin II levels were notably higher only in non-COVID-19 stroke patients. Proteomic analysis revealed sustained elevation of interferon-gamma (IFN-γ) signaling in COVID-19-associated stroke patients. Reduced AKT3 levels emerged as a significant predictor of poor outcomes, independent of renin-angiotensin biomarkers (adjusted OR 0.40; 95 % CI 0.16–0.94). Stroke patients with low AKT3 levels and poor outcomes exhibited significant upregulation of ribosomal proteins (RPS15, RPS4X, RPS7, RPS18, RPSA, RPS27A, RPS13, RPS23), reflecting heightened translational stress. Persistent RAS and inflammatory dysregulation following COVID-19 may contribute to worse stroke recovery. Future studies should validate and investigate the therapeutic implications of these findings.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105009"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573409","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}
Liver fibrosis results from chronic liver injury and is characterized by excessive accumulation of extracellular matrix due to sustained wound-healing responses. Although histological evaluation remains the gold standard for fibrosis assessment, its subjectivity can limit reproducibility. In this study, we evaluated an automated image analysis software, MorphoQuant, for liver fibrosis quantification in a rat model of CCl4-induced liver injury. Male Wistar rats were treated with CCl4 or vehicle for six weeks, and fibrosis severity was assessed using both the conventional Ishak staging system and automated quantification of collagen proportionate area (CPA). Automated CPA strongly correlated with Ishak stage, liver index, and plasma aminotransferase levels. Additionally, CPA values were significantly associated with the expression of fibrosis-related genes and macrophage infiltration, highlighting the software's ability to assess both fibrosis progression and inflammatory responses. These findings support the use of MorphoQuant as a robust, reader-independent tool that enhance analytical consistency in preclinical models of liver fibrosis.
{"title":"Automated quantification of collagen proportionate area correlates with molecular and histological markers of fibrosis in CCl4-treated rats","authors":"Bernie Efole , Mathilde Mouchiroud , Alexandra Dubé , Andréa Allaire , Sébastien M. Labbé , Cindy Serdjebi , Olivier Barbier , Alexandre Caron","doi":"10.1016/j.yexmp.2025.104996","DOIUrl":"10.1016/j.yexmp.2025.104996","url":null,"abstract":"<div><div>Liver fibrosis results from chronic liver injury and is characterized by excessive accumulation of extracellular matrix due to sustained wound-healing responses. Although histological evaluation remains the gold standard for fibrosis assessment, its subjectivity can limit reproducibility. In this study, we evaluated an automated image analysis software, MorphoQuant, for liver fibrosis quantification in a rat model of CCl4-induced liver injury. Male Wistar rats were treated with CCl4 or vehicle for six weeks, and fibrosis severity was assessed using both the conventional Ishak staging system and automated quantification of collagen proportionate area (CPA). Automated CPA strongly correlated with Ishak stage, liver index, and plasma aminotransferase levels. Additionally, CPA values were significantly associated with the expression of fibrosis-related genes and macrophage infiltration, highlighting the software's ability to assess both fibrosis progression and inflammatory responses. These findings support the use of MorphoQuant as a robust, reader-independent tool that enhance analytical consistency in preclinical models of liver fibrosis.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 104996"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060865","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 : 2025-09-01Epub Date: 2025-07-24DOI: 10.1016/j.yexmp.2025.104988
Ifat Alsharif
Tauopathies are a class of neurodegenerative disorders characterized by the abnormal accumulation of hyperphosphorylated tau (p-tau) and the formation of neurofibrillary tangles. Autophagy, a fundamental cellular degradation pathway, plays a pivotal role in maintaining proteostasis by facilitating the clearance of misfolded and aggregated proteins. In tauopathies, however, autophagic processes are often impaired, contributing to the pathological buildup of p-tau. NVP-BEZ235, a dual inhibitor of the mammalian target of rapamycin (mTOR) and PI3K, has previously been evaluated in phase I clinical trials for solid tumors and lymphomas. In this study, we investigated the therapeutic potential of NVP-BEZ235 in tauopathy models, both in vitro and in vivo. In SH-SY5Y cells stably expressing human P301L-mutant tau (SH-Tau), NVP-BEZ235 treatment induced a time-dependent increase in LC3B-II and a decrease in p62 levels, consistent with enhanced autophagic activity. Autophagic flux analysis further confirmed the promotion of autophagy upon mTOR pathway inhibition. NVP-BEZ235 significantly reduced tau phosphorylation at multiple residues, including Ser262, Ser396, Ser404, and Thr231, without eliciting cytotoxic effects. In a transgenic mouse model of tauopathy (P301S), chronic treatment with NVP-BEZ235 (20 mg/kg/day for two months) resulted in a marked reduction of both RIPA-soluble and -insoluble p-tau species in the brain. Spatial learning and memory, assessed through Morris water maze and novel object recognition tests, were significantly improved in treated mice. Furthermore, NVP-BEZ235 administration reduced neuroinflammatory markers and pro-inflammatory cytokine levels (TNF-α, IL-1β, IL-6), while also enhancing autophagic markers in brain tissue. Hematological analysis and organ histology revealed no signs of systemic toxicity. Collectively, these findings demonstrate that NVP-BEZ235 facilitates tau clearance by enhancing autophagy through mTOR inhibition, thereby mitigating cognitive deficits and neuroinflammation in tauopathy models. This study supports the therapeutic potential of NVP-BEZ235 as a promising candidate for the treatment of tau-related neurodegenerative diseases.
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