Pub Date : 2025-10-16DOI: 10.1016/j.yexmp.2025.105003
Shuai-Jie Huang , Ping Huang , Nan-Nan Song , Xian-Hui Jia , Hong-Li Gao , Zhi-Yuan Lu , Xiao-Lan Wen
Homozygous familial hypercholesterolemia (HoFH) is a rare autosomal recessive disorder characterized by variants in genes involved in the regulation of low-density lipoprotein cholesterol (LDL-C) metabolism. The genetic basis of HoFH is complex, with biallelic variants in the low-density lipoprotein receptor (LDLR) gene being the most prevalent. Early diagnosis and appropriate lipid-lowering therapy (LLT) are essential for patients with HoFH to prevent the premature onset of atherosclerotic cardiovascular disease (ASCVD). Effective and timely reduction of LDL-C levels is crucial for the success of LLT. Nevertheless, the majority of patients with HoFH exhibit resistance to conventional LLT due to insufficient or absent activity of LDL-R, rendering the management of HoFH challenging. Recent advancements have introduced novel pharmacological agents for treating HoFH (e.g. evolocumab, alirocumab, inclisiran and bempedoic acid), including cholesterol-lowering strategies that function independently of LDL-R such as lomitapide and evinacumab offering significant promise for managing this condition. However, disparities in the treatment of HoFH persist across different regions and countries. In this context, the review provides a comprehensive overview of established treatment modalities and emerging therapeutic agents for individuals with HoFH.
{"title":"Breaking barriers: Innovative therapies for managing homozygous familial hypercholesterolemia","authors":"Shuai-Jie Huang , Ping Huang , Nan-Nan Song , Xian-Hui Jia , Hong-Li Gao , Zhi-Yuan Lu , Xiao-Lan Wen","doi":"10.1016/j.yexmp.2025.105003","DOIUrl":"10.1016/j.yexmp.2025.105003","url":null,"abstract":"<div><div>Homozygous familial hypercholesterolemia (HoFH) is a rare autosomal recessive disorder characterized by variants in genes involved in the regulation of low-density lipoprotein cholesterol (LDL-C) metabolism. The genetic basis of HoFH is complex, with biallelic variants in the low-density lipoprotein receptor (<em>LDLR</em>) gene being the most prevalent. Early diagnosis and appropriate lipid-lowering therapy (LLT) are essential for patients with HoFH to prevent the premature onset of atherosclerotic cardiovascular disease (ASCVD). Effective and timely reduction of LDL-C levels is crucial for the success of LLT. Nevertheless, the majority of patients with HoFH exhibit resistance to conventional LLT due to insufficient or absent activity of LDL-R, rendering the management of HoFH challenging. Recent advancements have introduced novel pharmacological agents for treating HoFH (e.g. evolocumab, alirocumab, inclisiran and bempedoic acid), including cholesterol-lowering strategies that function independently of LDL-R such as lomitapide and evinacumab offering significant promise for managing this condition. However, disparities in the treatment of HoFH persist across different regions and countries. In this context, the review provides a comprehensive overview of established treatment modalities and emerging therapeutic agents for individuals with HoFH.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105003"},"PeriodicalIF":3.7,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312639","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":"2025-10-16","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 : 2025-10-11DOI: 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":"2025-10-11","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 : 2025-10-09DOI: 10.1016/j.yexmp.2025.105000
Samaneh Haghighi , Arezoo Haghighi , Zoltán S. Zádori , Krisztián Kovács , Anna Manzéger , Gábor Kökény
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic effects, although the possible COX-independent impact on the kidneys is largely unknown. Kidney damage is often associated with defective autophagy and autophagy dysregulation has been associated with kidney fibrosis and the pro-fibrotic EGR1 transcription factor activation. The non-selective COX inhibitor indomethacin (IND) can be nephrotoxic, but the impact of selective COX-2 inhibitor celecoxib (CEL) or the non-selective naproxen (NAP) on renal autophagy and EGR1 remain obscure. Here, we investigated the dose-dependent effect of CEL and NAP administration on human proximal tubule epithelial (HK-2) cells and murine inner medullary collecting duct (IMCD) cells in comparison to the effects of IND. To elucidate chronic renal effects, we also treated rats similarly for two weeks. We found that high doses of CEL and NAP, but not IND, disrupted autophagy, increased oxidative stress, and activated pro-fibrotic pathways in both HK-2 and IMCD cells with induced EGR1, accompanied by ACTA2 upregulation. We found similar effects in the renal medulla of rats treated with high-dose CEL and NAP. In addition, autophagy dysfunction was evident through increased LC3-II/I and p62 accumulation. Histology confirmed dose-dependent tubular damage and nuclear EGR1 accumulation in CEL and NAP treated rats, accompanied by induced HMOX1 and AKT phosphorylation. Our study reveals dose-dependent tubulotoxic effects of NSAIDs unrelated to their COX-selectivity, suggesting an interplay between pro-fibrotic transcription factor EGR1, autophagy pathways and oxidative stress. These findings underscore the need for meticulous dose optimization especially in kidney disease patients in order to reduce nephrotoxicity.
{"title":"Celecoxib and naproxen disrupt autophagy and activate EGR1 in kidney tubules","authors":"Samaneh Haghighi , Arezoo Haghighi , Zoltán S. Zádori , Krisztián Kovács , Anna Manzéger , Gábor Kökény","doi":"10.1016/j.yexmp.2025.105000","DOIUrl":"10.1016/j.yexmp.2025.105000","url":null,"abstract":"<div><div>Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic effects, although the possible COX-independent impact on the kidneys is largely unknown. Kidney damage is often associated with defective autophagy and autophagy dysregulation has been associated with kidney fibrosis and the pro-fibrotic EGR1 transcription factor activation. The non-selective COX inhibitor indomethacin (IND) can be nephrotoxic, but the impact of selective COX-2 inhibitor celecoxib (CEL) or the non-selective naproxen (NAP) on renal autophagy and EGR1 remain obscure. Here, we investigated the dose-dependent effect of CEL and NAP administration on human proximal tubule epithelial (HK-2) cells and murine inner medullary collecting duct (IMCD) cells in comparison to the effects of IND. To elucidate chronic renal effects, we also treated rats similarly for two weeks. We found that high doses of CEL and NAP, but not IND, disrupted autophagy, increased oxidative stress, and activated pro-fibrotic pathways in both HK-2 and IMCD cells with induced EGR1, accompanied by ACTA2 upregulation. We found similar effects in the renal medulla of rats treated with high-dose CEL and NAP. In addition, autophagy dysfunction was evident through increased LC3-II/I and p62 accumulation. Histology confirmed dose-dependent tubular damage and nuclear EGR1 accumulation in CEL and NAP treated rats, accompanied by induced HMOX1 and AKT phosphorylation. Our study reveals dose-dependent tubulotoxic effects of NSAIDs unrelated to their COX-selectivity, suggesting an interplay between pro-fibrotic transcription factor EGR1, autophagy pathways and oxidative stress. These findings underscore the need for meticulous dose optimization especially in kidney disease patients in order to reduce nephrotoxicity.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105000"},"PeriodicalIF":3.7,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145267323","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 : 2025-10-09DOI: 10.1016/j.yexmp.2025.105002
Francesco Sessa , Marco Carotenuto , Davide Ferorelli , Massimiliano Esposito , Cristoforo Pomara , Monica Salerno
Fetal Alcohol Spectrum Disorders (FASD) encompass a continuum of neurodevelopmental and physical impairments resulting from prenatal alcohol exposure (PAE). Despite widespread recognition of ethanol's teratogenic effects, the clinical variability observed in FASD suggests a multifactorial etiology involving genetic, biochemical, epigenetic, and environmental influences. This review provides an integrative analysis of how genetic polymorphisms in key alcohol-metabolizing enzymes (ADH1B, ADH1C, ALDH2, CYP2E1, and CAT) modulate maternal and fetal susceptibility to ethanol and its toxic metabolite, acetaldehyde. These polymorphisms influence enzymatic activity, oxidative stress responses, and detoxification efficiency, thereby shaping fetal exposure and risk.
The review further explores maternal–fetal genotype interactions, gene–environment dynamics, and the timing of exposure as critical modulators of FASD outcomes. Epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation, are examined as mediators of long-term gene expression changes and neurodevelopmental disruption. Novel insights are provided into the roles of the 5-HTTLPR and orexin systems in neuropsychiatric vulnerability.
By synthesizing molecular, genetic, and clinical perspectives, this review advocates for a precision medicine approach to FASD prevention and management. It discusses the potential of genetic screening, predictive modeling, and theranoMiRNAs for risk stratification and early intervention. Importantly, it also addresses the translational challenges, including cost, feasibility, and the risk of false positives/negatives, that must be overcome to move from theory to clinical practice. These insights support the development of personalized, ethically grounded strategies to reduce fetal harm and improve outcomes in genetically and environmentally susceptible populations.
{"title":"Genetic and epigenetic determinants of fetal alcohol spectrum disorders: Toward a precision medicine approach","authors":"Francesco Sessa , Marco Carotenuto , Davide Ferorelli , Massimiliano Esposito , Cristoforo Pomara , Monica Salerno","doi":"10.1016/j.yexmp.2025.105002","DOIUrl":"10.1016/j.yexmp.2025.105002","url":null,"abstract":"<div><div>Fetal Alcohol Spectrum Disorders (FASD) encompass a continuum of neurodevelopmental and physical impairments resulting from prenatal alcohol exposure (PAE). Despite widespread recognition of ethanol's teratogenic effects, the clinical variability observed in FASD suggests a multifactorial etiology involving genetic, biochemical, epigenetic, and environmental influences. This review provides an integrative analysis of how genetic polymorphisms in key alcohol-metabolizing enzymes (ADH1B, ADH1C, ALDH2, CYP2E1, and CAT) modulate maternal and fetal susceptibility to ethanol and its toxic metabolite, acetaldehyde. These polymorphisms influence enzymatic activity, oxidative stress responses, and detoxification efficiency, thereby shaping fetal exposure and risk.</div><div>The review further explores maternal–fetal genotype interactions, gene–environment dynamics, and the timing of exposure as critical modulators of FASD outcomes. Epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation, are examined as mediators of long-term gene expression changes and neurodevelopmental disruption. Novel insights are provided into the roles of the 5-HTTLPR and orexin systems in neuropsychiatric vulnerability.</div><div>By synthesizing molecular, genetic, and clinical perspectives, this review advocates for a precision medicine approach to FASD prevention and management. It discusses the potential of genetic screening, predictive modeling, and theranoMiRNAs for risk stratification and early intervention. Importantly, it also addresses the translational challenges, including cost, feasibility, and the risk of false positives/negatives, that must be overcome to move from theory to clinical practice. These insights support the development of personalized, ethically grounded strategies to reduce fetal harm and improve outcomes in genetically and environmentally susceptible populations.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105002"},"PeriodicalIF":3.7,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145267321","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":"2025-10-03","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}
Pub Date : 2025-09-25DOI: 10.1016/j.yexmp.2025.104998
Cai Zhang , Jingyuan Gao , Lu Chen , Lei Xing , Limin Li , Xiaoli Hou , Faming Tian
Osteoarthritis (OA) represents a prevalent chronic joint disorder, which is pathologically characterized by cartilage degeneration. At present, effective therapeutic interventions for OA remains relatively infrequent, highlighting the urgent need for a deeper exploration of the underlying mechanisms of the disease and the development of novel, more effective treatments. A growing body of research has increasingly highlighted the pivotal role of signal transducer and activator of transcription 3 (STAT3), a critical downstream effector protein activated by a diverse array of cytokines, in mediating various physiological and pathological processes. STAT3 has been implicated in the pathophysiological progression of OA, influencing key aspects of disease development. This review concentrated on the notable role and molecular mechanisms of STAT3 signalling in the degeneration of cartilage and dysfunction of the subchondral bone, while synthesizing the most recent evidence regarding the therapeutic potential of targeting the STAT3 pathway for OA management. By concentrating on the inhibition of STAT3 signalling pathway, this review aimed to contribute to the translation of these findings into innovative, clinically relevant treatment strategies for OA.
{"title":"Cell-specific functions of STAT3 in osteoarthritis and its therapeutic potential","authors":"Cai Zhang , Jingyuan Gao , Lu Chen , Lei Xing , Limin Li , Xiaoli Hou , Faming Tian","doi":"10.1016/j.yexmp.2025.104998","DOIUrl":"10.1016/j.yexmp.2025.104998","url":null,"abstract":"<div><div>Osteoarthritis (OA) represents a prevalent chronic joint disorder, which is pathologically characterized by cartilage degeneration. At present, effective therapeutic interventions for OA remains relatively infrequent, highlighting the urgent need for a deeper exploration of the underlying mechanisms of the disease and the development of novel, more effective treatments. A growing body of research has increasingly highlighted the pivotal role of signal transducer and activator of transcription 3 (STAT3), a critical downstream effector protein activated by a diverse array of cytokines, in mediating various physiological and pathological processes. STAT3 has been implicated in the pathophysiological progression of OA, influencing key aspects of disease development. This review concentrated on the notable role and molecular mechanisms of STAT3 signalling in the degeneration of cartilage and dysfunction of the subchondral bone, while synthesizing the most recent evidence regarding the therapeutic potential of targeting the STAT3 pathway for OA management. By concentrating on the inhibition of STAT3 signalling pathway, this review aimed to contribute to the translation of these findings into innovative, clinically relevant treatment strategies for OA.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 104998"},"PeriodicalIF":3.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155169","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":"2025-09-15","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 : 2025-09-04DOI: 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":"2025-09-04","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 : 2025-09-01Epub Date: 2025-08-09DOI: 10.1016/j.yexmp.2025.104991
Vera Paar, Xuanchao Feng, Kristen Kopp, Fitore Marmullaku, Uta C Hoppe, Lukas J Motloch, Michael Lichtenauer
Drug eluting stents (DES) are a first-line treatment for ischemic heart diseases. Due to their direct contact with the blood stream, late stent thromboses are a common complication. Thrombosis and inflammation are tightly linked to each other, and are characterized by the activation of inflammatory cells and the secretion of cytokines and chemokines. To date, the influence of DES on the activation of the inflammatory cascade and its corresponding players has not yet been investigated. We performed an in vitro study to observe any potential response of isolated human peripheral blood mononuclear cells (PBMCs) to the structure and drug-coating of different DES. PBMCs from healthy volunteers were incubated with different DES types for 48 h. We measured the secretion of cytokines and chemokines, as well as cell adhesion molecules, and selected growth factors by ELISA. DES were found to significantly increase the cytokine and chemokine secretion of IL-1β, IL-6, IL-8, and ICAM-1, as well as the growth factors ANG and FGF-basic. We further showed that zotarolimus presents with the lowest inflammation-associated protein expression. Our data further revealed that the inflammatory reaction is highly dependent on the DES size, material, and the polymer type of the DES coating. Finally, we tendentially showed that thinner alloys are associated with a lower inflammatory reaction. Our results indicate that DES may potentially lead to an increased inflammatory reaction, considering the different DES designs and properties. This would potentially help to further improve composition and drug selection.
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