Natural Killer (NK) cells play a crucial role in the body's innate immune system, distinguished by their ability to target a wide array of tumors through diverse killing strategies. Following the intense focus on T cells, NK cells have emerged as a key player in immunotherapy. Recent advancements in NK cell-based cancer treatments, including adoptive cell therapy, immune checkpoint inhibition, recombinant cytokine therapies, and nanomedicines, have demonstrated promising outcomes both in vitro and in vivo. As research into NK cell-based therapies intensifies, evidence is mounting that NK cells undergo phenotypic changes, acquiring characteristics of exhaustion. Key features comprise reduced proliferative capacity, diminished cytokine production, altered receptor expression, as well as compromised lymph node homing and Tumor Microenvironment (TME) persistence. NK cell exhaustion not only reduces NK cell efficacy and number in solid tumor therapies, but it also plays a crucial role in treatment resistance and tumor cell evasion. Understanding the mechanisms behind NK cell exhaustion and developing strategies to counteract it within the suppressive TME are of paramount importance. In this review, we delineate the maturation and development of NK cells, emphasize the phenotypic characteristics and underlying mechanisms of NK cell exhaustion, systematically review the methods to mitigate NK cell exhaustion, and thoroughly discuss the current limitations of NK cell immunotherapy. Ultimately, we aim to provide potential solutions and future directions for enhancing NK cell-based cancer treatments.
{"title":"Mechanisms and strategies for reversing NK cell exhaustion in tumor immunotherapy.","authors":"Lingtong Zhi, Yuqing Wang, Zixing Zhao, Yabin Guo, Kaiwen Wang, Wenhui He, Changjiang Guo, Zhiyuan Niu, Wuling Zhu, Xuan Zhang","doi":"10.1016/j.yexmp.2026.105031","DOIUrl":"https://doi.org/10.1016/j.yexmp.2026.105031","url":null,"abstract":"<p><p>Natural Killer (NK) cells play a crucial role in the body's innate immune system, distinguished by their ability to target a wide array of tumors through diverse killing strategies. Following the intense focus on T cells, NK cells have emerged as a key player in immunotherapy. Recent advancements in NK cell-based cancer treatments, including adoptive cell therapy, immune checkpoint inhibition, recombinant cytokine therapies, and nanomedicines, have demonstrated promising outcomes both in vitro and in vivo. As research into NK cell-based therapies intensifies, evidence is mounting that NK cells undergo phenotypic changes, acquiring characteristics of exhaustion. Key features comprise reduced proliferative capacity, diminished cytokine production, altered receptor expression, as well as compromised lymph node homing and Tumor Microenvironment (TME) persistence. NK cell exhaustion not only reduces NK cell efficacy and number in solid tumor therapies, but it also plays a crucial role in treatment resistance and tumor cell evasion. Understanding the mechanisms behind NK cell exhaustion and developing strategies to counteract it within the suppressive TME are of paramount importance. In this review, we delineate the maturation and development of NK cells, emphasize the phenotypic characteristics and underlying mechanisms of NK cell exhaustion, systematically review the methods to mitigate NK cell exhaustion, and thoroughly discuss the current limitations of NK cell immunotherapy. Ultimately, we aim to provide potential solutions and future directions for enhancing NK cell-based cancer treatments.</p>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"105031"},"PeriodicalIF":3.7,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131572","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 : 2026-02-03DOI: 10.1016/j.yexmp.2026.105030
Jiaxiang Zhang, Yu Yun, Weigang Duan
The high incidence of hyperuricemia (HUA) is largely attributed to imbalances between uric acid production, distribution, and excretion. HUA can lead to renal fibrosis, which in turn causes a progressive decline in kidney function and the development of serious conditions such as chronic kidney disease (CKD). Therefore, the effective prevention and treatment of HUA-induced renal fibrosis is of critical importance. Elevated serum uric acid acts as a key trigger for HUA-induced renal fibrosis, while uric acid accumulation in kidney tissues, especially in the medulla, may play an even essential role in this process. However, few studies have focused on the role of tissue uric acid, even though increased tissue uric acid can activate macrophages and mediate chronic inflammation as well as other mechanisms that initiate or worsen renal fibrosis. Moreover, current clinical drug interventions yield unsatisfactory outcomes and are often associated with numerous adverse effects, emphasizing the urgent need for new therapeutic agents. In recent years, the use of clinically relevant uricase-deficient animal models in pharmacological studies has increased, potentially representing the forefront of research in HUA-induced renal fibrosis. However, a comprehensive review of these studies is still needing. This review explains how uric acid affects the kidney and induces renal fibrosis, summarizes the underlying mechanisms to inform clinical diagnosis, treatment, and drug development, and consolidates the current status of clinical therapies and pharmacological research using uricase-deficient animal models, with the aim of identifying promising agents for the effective prevention and treatment of HUA-induced renal fibrosis.
{"title":"Hyperuricemia-induced renal fibrosis: Mechanisms and advances in pharmacological studies using uricase-deficient animal models.","authors":"Jiaxiang Zhang, Yu Yun, Weigang Duan","doi":"10.1016/j.yexmp.2026.105030","DOIUrl":"https://doi.org/10.1016/j.yexmp.2026.105030","url":null,"abstract":"<p><p>The high incidence of hyperuricemia (HUA) is largely attributed to imbalances between uric acid production, distribution, and excretion. HUA can lead to renal fibrosis, which in turn causes a progressive decline in kidney function and the development of serious conditions such as chronic kidney disease (CKD). Therefore, the effective prevention and treatment of HUA-induced renal fibrosis is of critical importance. Elevated serum uric acid acts as a key trigger for HUA-induced renal fibrosis, while uric acid accumulation in kidney tissues, especially in the medulla, may play an even essential role in this process. However, few studies have focused on the role of tissue uric acid, even though increased tissue uric acid can activate macrophages and mediate chronic inflammation as well as other mechanisms that initiate or worsen renal fibrosis. Moreover, current clinical drug interventions yield unsatisfactory outcomes and are often associated with numerous adverse effects, emphasizing the urgent need for new therapeutic agents. In recent years, the use of clinically relevant uricase-deficient animal models in pharmacological studies has increased, potentially representing the forefront of research in HUA-induced renal fibrosis. However, a comprehensive review of these studies is still needing. This review explains how uric acid affects the kidney and induces renal fibrosis, summarizes the underlying mechanisms to inform clinical diagnosis, treatment, and drug development, and consolidates the current status of clinical therapies and pharmacological research using uricase-deficient animal models, with the aim of identifying promising agents for the effective prevention and treatment of HUA-induced renal fibrosis.</p>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"105030"},"PeriodicalIF":3.7,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118309","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}
Skin cancer represents a significant global healthcare challenge, with rising incidence and persistent gaps in effective long-term management. Recent evidence has identified the endocannabinoid system as an emerging therapeutic target offering novel pharmacological approaches for the prevention and treatment of various skin cancers. Cannabinoids, through modulation of the endocannabinoid system, have demonstrated antitumor activity by inhibiting tumor proliferation, angiogenesis, invasion, and metastasis and by inducing apoptosis and autophagy in malignant cells. This review synthesizes the most recent preclinical evidence on phytocannabinoids, endocannabinoids, and synthetic cannabinoids in melanoma and non-melanoma skin cancers, delineating receptor-dependent and receptor-independent mechanisms. Additionally, emerging cannabinoid-based delivery strategies, particularly cannabidiol formulations designed to enhance skin penetration and therapeutic efficacy, are critically examined. Despite encouraging preclinical findings, clinical translation remains limited by scarce skin-cancer-specific trials, variability in cannabinoid preparations, and uncertainties around dosing and safety. Consequently, robust mechanistic studies and well-designed clinical trials are required to validate cannabinoids' therapeutic potential and guide their integration into future skin cancer treatment paradigms.
{"title":"Cannabinoids and skin cancer: Mechanistic insights, therapeutic potential, and translational perspectives","authors":"Ashutosh Pareek , Rashi Gupta , Aaushi Pareek , Jenny Wilkerson , Lance R. McMahon , Gautam Sethi , Anil Chuturgoon","doi":"10.1016/j.yexmp.2026.105027","DOIUrl":"10.1016/j.yexmp.2026.105027","url":null,"abstract":"<div><div>Skin cancer represents a significant global healthcare challenge, with rising incidence and persistent gaps in effective long-term management. Recent evidence has identified the endocannabinoid system as an emerging therapeutic target offering novel pharmacological approaches for the prevention and treatment of various skin cancers. Cannabinoids, through modulation of the endocannabinoid system, have demonstrated antitumor activity by inhibiting tumor proliferation, angiogenesis, invasion, and metastasis and by inducing apoptosis and autophagy in malignant cells. This review synthesizes the most recent preclinical evidence on phytocannabinoids, endocannabinoids, and synthetic cannabinoids in melanoma and non-melanoma skin cancers, delineating receptor-dependent and receptor-independent mechanisms. Additionally, emerging cannabinoid-based delivery strategies, particularly cannabidiol formulations designed to enhance skin penetration and therapeutic efficacy, are critically examined. Despite encouraging preclinical findings, clinical translation remains limited by scarce skin-cancer-specific trials, variability in cannabinoid preparations, and uncertainties around dosing and safety. Consequently, robust mechanistic studies and well-designed clinical trials are required to validate cannabinoids' therapeutic potential and guide their integration into future skin cancer treatment paradigms.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105027"},"PeriodicalIF":3.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074127","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 : 2026-01-29DOI: 10.1016/j.yexmp.2026.105028
S. Klingenstein , J. Grünig , P.H. Neckel , B. Hirt , S. Liebau , M. Klingenstein
Summary
The human nose is a complex sensory organ responsible for air filtration, moisture regulation, heat exchange, and odor detection. To resolve its cellular and structural heterogeneity—including regions traditionally associated with respiratory and olfactory functions—we applied multiround multiplex immunofluorescence to human postmortem nasal samples. We optimized a manual workflow combining autofluorescence quenching and efficient antibody stripping for frontal nasal and olfactory bulb sections. Multiple published protocols were systematically tested and adapted, with particular emphasis on preserving tissue integrity at bone–soft tissue interfaces. Using this approach, we performed multiplex staining on full nasal sections with five antibodies across three rounds, followed by a validation round with GFAP. Marker panels included K5 (basal cells), TUBB3 (neuronal elements), ANXA1 and E-cadherin (epithelial borders), COLIV (basement membrane), and GFAP (glial/ensheathing cells).
This optimized method enables spatial mapping of distinct cell types within intact human nasal tissue and provides a robust platform for future studies on epithelial organization and structural remodeling in health and disease.
{"title":"Optimized manual multiplex immunofluorescence protocol for human nasal tissue","authors":"S. Klingenstein , J. Grünig , P.H. Neckel , B. Hirt , S. Liebau , M. Klingenstein","doi":"10.1016/j.yexmp.2026.105028","DOIUrl":"10.1016/j.yexmp.2026.105028","url":null,"abstract":"<div><h3>Summary</h3><div>The human nose is a complex sensory organ responsible for air filtration, moisture regulation, heat exchange, and odor detection. To resolve its cellular and structural heterogeneity—including regions traditionally associated with respiratory and olfactory functions—we applied multiround multiplex immunofluorescence to human postmortem nasal samples. We optimized a manual workflow combining autofluorescence quenching and efficient antibody stripping for frontal nasal and olfactory bulb sections. Multiple published protocols were systematically tested and adapted, with particular emphasis on preserving tissue integrity at bone–soft tissue interfaces. Using this approach, we performed multiplex staining on full nasal sections with five antibodies across three rounds, followed by a validation round with GFAP. Marker panels included K5 (basal cells), TUBB3 (neuronal elements), ANXA1 and E-cadherin (epithelial borders), COLIV (basement membrane), and GFAP (glial/ensheathing cells).</div><div>This optimized method enables spatial mapping of distinct cell types within intact human nasal tissue and provides a robust platform for future studies on epithelial organization and structural remodeling in health and disease.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105028"},"PeriodicalIF":3.7,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074125","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 dysfunction-associated steatotic liver disease (MASLD) is closely associated with obesity. Excess cholesterol, the hepatic and circulating levels of which are regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9), exacerbates MASLD. Data on hepatic and circulating PCSK9 protein expression in MASLD are inconsistent, and PCSK9 levels in different adipose tissues have not been well studied. Here, we used two MASLD mouse models that develop hepatic steatosis, one with weight gain and one with weight loss. These models enable distinguishing between the effects of obesity and MASLD. In the high-fat diet model, hepatic PCSK9 protein was normal. PCSK9 protein was increased in the serum and epididymal fat of the mice. In mice fed a methionine-choline-deficient diet, PCSK9 protein was normal in the liver, brown fat, subcutaneous fat, epididymal, and perirenal adipose tissue. Serum PCSK9 levels were reduced, suggesting that the lower fat mass of these mice contributed to the reduction. It is noteworthy that PCSK9 expression was low in adipocytes compared to hepatocytes. In addition, stromal vascular cells residing within adipose tissue contribute to PCSK9 protein levels in adipose tissue. PCSK9 protein was similar in subcutaneous, epididymal, and perirenal adipose tissue and was lowest in brown adipose tissue, indicating a more prominent expression in white adipose tissues. The current study shows that PCSK9 is expressed in both white and brown adipose tissues, and suggests that obesity rather than liver steatosis is associated with higher serum PCSK9 levels.
{"title":"Preliminary evidence that adipose tissue contributes to serum proprotein convertase subtilisin/kexin type 9 levels in murine models of metabolic liver injury","authors":"Sabrina Krautbauer , Florian Weber , Gerhard Liebisch , Christa Buechler","doi":"10.1016/j.yexmp.2026.105029","DOIUrl":"10.1016/j.yexmp.2026.105029","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with obesity. Excess cholesterol, the hepatic and circulating levels of which are regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9), exacerbates MASLD. Data on hepatic and circulating PCSK9 protein expression in MASLD are inconsistent, and PCSK9 levels in different adipose tissues have not been well studied. Here, we used two MASLD mouse models that develop hepatic steatosis, one with weight gain and one with weight loss. These models enable distinguishing between the effects of obesity and MASLD. In the high-fat diet model, hepatic PCSK9 protein was normal. PCSK9 protein was increased in the serum and epididymal fat of the mice. In mice fed a methionine-choline-deficient diet, PCSK9 protein was normal in the liver, brown fat, subcutaneous fat, epididymal, and perirenal adipose tissue. Serum PCSK9 levels were reduced, suggesting that the lower fat mass of these mice contributed to the reduction. It is noteworthy that PCSK9 expression was low in adipocytes compared to hepatocytes. In addition, stromal vascular cells residing within adipose tissue contribute to PCSK9 protein levels in adipose tissue. PCSK9 protein was similar in subcutaneous, epididymal, and perirenal adipose tissue and was lowest in brown adipose tissue, indicating a more prominent expression in white adipose tissues. The current study shows that PCSK9 is expressed in both white and brown adipose tissues, and suggests that obesity rather than liver steatosis is associated with higher serum PCSK9 levels.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105029"},"PeriodicalIF":3.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074126","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 : 2026-01-20DOI: 10.1016/j.yexmp.2026.105026
Olivia Hiatt, Benjamin D. Davidson, Logan Beck, Katelyn A. Sturgis, Ethan Evans, Elizabeth Thurmond, Madeline Boyer, Benjamin T. Bikman, Paul R. Reynolds, Juan A. Arroyo
Pregnancy is a vulnerable period where maternal exposure to environmental toxicants like secondhand smoke (SHS) and electronic cigarette (eCig) aerosols can harm maternal and fetal health. This study examines the differential impacts of SHS and eCig exposure on maternal lung tissue during late gestation, focusing on inflammation, apoptosis, and oxidative stress. Pregnant C57BL/6 mice were exposed to SHS or eCig aerosols for four or six days from embryonic day 12.5 or 14.5, with lung tissues collected on day 18.5 for analysis. Bronchoalveolar lavage fluid and lung tissue were assessed for inflammation, apoptosis, and oxidative stress. SHS exposure caused pronounced immune activation and mitochondrial-mediated apoptosis, while eCig exposure induced a milder inflammatory response with evidence of epithelial remodeling and oxidative imbalance. Collectively, both exposures disrupted maternal pulmonary homeostasis, with SHS producing stronger inflammatory effects. Unlike SHS, eCig exposure caused transient apoptosis with partial preservation of anti-apoptotic pathways (Bcl-2, IGF-1), while SHS exhibited stronger pro-inflammatory effects, eCig exposure still contributed to oxidative stress and immune dysregulation. These findings underscore the risks of both exposures during pregnancy, emphasizing the need for stringent public health policies regulating eCig use to protect maternal and fetal health.
{"title":"Maternal lung inflammation and apoptosis following gestational exposure to secondhand smoke and E-cigarette vapor: Implications for maternal-fetal health","authors":"Olivia Hiatt, Benjamin D. Davidson, Logan Beck, Katelyn A. Sturgis, Ethan Evans, Elizabeth Thurmond, Madeline Boyer, Benjamin T. Bikman, Paul R. Reynolds, Juan A. Arroyo","doi":"10.1016/j.yexmp.2026.105026","DOIUrl":"10.1016/j.yexmp.2026.105026","url":null,"abstract":"<div><div>Pregnancy is a vulnerable period where maternal exposure to environmental toxicants like secondhand smoke (SHS) and electronic cigarette (eCig) aerosols can harm maternal and fetal health. This study examines the differential impacts of SHS and eCig exposure on maternal lung tissue during late gestation, focusing on inflammation, apoptosis, and oxidative stress. Pregnant C57BL/6 mice were exposed to SHS or eCig aerosols for four or six days from embryonic day 12.5 or 14.5, with lung tissues collected on day 18.5 for analysis. Bronchoalveolar lavage fluid and lung tissue were assessed for inflammation, apoptosis, and oxidative stress. SHS exposure caused pronounced immune activation and mitochondrial-mediated apoptosis, while eCig exposure induced a milder inflammatory response with evidence of epithelial remodeling and oxidative imbalance. Collectively, both exposures disrupted maternal pulmonary homeostasis, with SHS producing stronger inflammatory effects. Unlike SHS, eCig exposure caused transient apoptosis with partial preservation of anti-apoptotic pathways (Bcl-2, IGF-1), while SHS exhibited stronger pro-inflammatory effects, eCig exposure still contributed to oxidative stress and immune dysregulation. These findings underscore the risks of both exposures during pregnancy, emphasizing the need for stringent public health policies regulating eCig use to protect maternal and fetal health.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105026"},"PeriodicalIF":3.7,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017982","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 : 2026-01-16DOI: 10.1016/j.yexmp.2026.105025
Kyeong-Min Lee , Yeo Jin Hwang
Chronic Kidney disease (CKD), in which renal fibrosis is the defining pathological feature, poses significant global health and economic challenges. Despite its high clinical prevalence, effective therapies to prevent or reverse renal fibrosis remain scarce. Metixene hydrochloride hydrate (MHH), an anticholinergic drug once used for Parkinson's disease, has not been evaluated for renal fibrosis. Here, we investigated whether MHH mitigates renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model and evaluated its effects on transforming growth factor-β1 (TGF-β1) signaling in renal cells. MHH did not affect the cell viability of NRK-49F cells at concentrations ranging from 0.5 to 5 μM. In vitro, MHH effectively suppressed TGF-β1-induced PAI-1 expression (both mRNA and protein) and secretion in renal fibroblasts, as well as PAI-1 secretion and protein expression in renal glomerular endothelial cells. Furthermore, TGF-β1 stimulated the mRNA and protein expressions of key renal fibrotic factors, including collagen type I, fibronectin, and alpha-smooth muscle actin, in NRK-49F cells. MMH significantly inhibited the expression of these renal fibrotic factors in these cells. UUO kidneys exhibited markedly increased tubular atrophy and interstitial fibrosis, as well as increased expression of renal fibrotic markers. MHH treatment significantly mitigated these pathological parameters and expression of renal fibrotic markers. Mechanistically, MHH suppressed TGF-β1-induced Smad3 phosphorylation both in vitro and in vivo. Our findings indicate that MHH exerts potent antifibrotic effects by downregulating the TGF-β1/Smad3 signaling pathway and suppressing the expression of fibrotic factors in renal cells and obstructed kidneys. Therefore, MHH could be repositioned as a therapeutic agent for renal fibrosis in various kidney diseases.
{"title":"Metixene hydrochloride hydrate mitigates kidney tubulointerstitial fibrosis by inhibiting Smad3 phosphorylation","authors":"Kyeong-Min Lee , Yeo Jin Hwang","doi":"10.1016/j.yexmp.2026.105025","DOIUrl":"10.1016/j.yexmp.2026.105025","url":null,"abstract":"<div><div>Chronic Kidney disease (CKD), in which renal fibrosis is the defining pathological feature, poses significant global health and economic challenges. Despite its high clinical prevalence, effective therapies to prevent or reverse renal fibrosis remain scarce. Metixene hydrochloride hydrate (MHH), an anticholinergic drug once used for Parkinson's disease, has not been evaluated for renal fibrosis. Here, we investigated whether MHH mitigates renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model and evaluated its effects on transforming growth factor-β1 (TGF-β1) signaling in renal cells. MHH did not affect the cell viability of NRK-49F cells at concentrations ranging from 0.5 to 5 μM. In vitro, MHH effectively suppressed TGF-β1-induced PAI-1 expression (both mRNA and protein) and secretion in renal fibroblasts, as well as PAI-1 secretion and protein expression in renal glomerular endothelial cells. Furthermore, TGF-β1 stimulated the mRNA and protein expressions of key renal fibrotic factors, including collagen type I, fibronectin, and alpha-smooth muscle actin, in NRK-49F cells. MMH significantly inhibited the expression of these renal fibrotic factors in these cells. UUO kidneys exhibited markedly increased tubular atrophy and interstitial fibrosis, as well as increased expression of renal fibrotic markers. MHH treatment significantly mitigated these pathological parameters and expression of renal fibrotic markers. Mechanistically, MHH suppressed TGF-β1-induced Smad3 phosphorylation both in vitro and in vivo. Our findings indicate that MHH exerts potent antifibrotic effects by downregulating the TGF-β1/Smad3 signaling pathway and suppressing the expression of fibrotic factors in renal cells and obstructed kidneys. Therefore, MHH could be repositioned as a therapeutic agent for renal fibrosis in various kidney diseases.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105025"},"PeriodicalIF":3.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972766","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 : 2026-01-13DOI: 10.1016/j.yexmp.2026.105023
Matteo Micucci , Michela Battistelli , Sabrina Burattini , Riham Osman , Francesco Onesimo , Michele Mari , Michele Retini , Ilaria Versari , Barbara Pagliarani , Andrea Tarozzi , Giovanni Zappia , Federico Gianfanti , Letizia Pruccoli
Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra and the presence of misfolded α-synuclein in the brain. Mitochondrial dysfunction and oxidative stress are factors contributing to the death of these neurons. Coenzyme Q10 (CoQ10) serve as an antioxidant and cofactor for mitochondrial enzymes, and its deficiency can exacerbate neurodegenerative processes in PD. However, the clinical efficacy of CoQ10 is limited by its low bioavailability and instability. Ubiquinol diacetate (CoQ10 Ac), an esterified form of CoQ10, shows improved pharmacokinetic properties and potential as a prodrug, converting into the reduced antioxidant form of CoQ10 by esterases in the body. This study aimed to investigate the antioxidant and neuroprotective effects of CoQ10 Ac compared to CoQ10 in SH-SY5Y cell line and Caenorhabditis elegans models of PD. CoQ10 Ac showed higher antioxidant activity than CoQ10 at both extracellular and intracellular levels, particularly in the membrane and cytosolic compartments. It exhibited superior neuroprotection against 6-hydroxydopamine toxicity, showing a greater ability to reduce the activation of caspase-3 and PARP1 compared to CoQ10. Both compounds decreased the increased ratio of mitochondrial fission protein, DRP1, to fusion protein, OPA1, induced by 6-hydroxydopamine in SH-SY5Y cells, enhancing OPA1 levels and promoting antiapoptotic death. However, CoQ10 Ac was more effective than CoQ10 in preserving mitochondrial structural integrity and mass. Additionally, both compounds significantly inhibited the aggregation of α-synuclein induced by 6-hydroxydopamine. Furthermore, CoQ10 Ac showed stronger neuroprotective effects than CoQ10 in C. elegans models of PD. It demonstrated greater anti-aggregant activity in C. elegans expressing human α-synuclein, suggesting higher bioavailability. These findings highlight CoQ10 Ac as a promising prodrug candidate and support further investigation in in vivo PD models.
{"title":"Antioxidant and neuroprotective effects of ubiquinol diacetate: Insights from SH-SY5Y cell line and Caenorhabditis elegans models of Parkinson's disease","authors":"Matteo Micucci , Michela Battistelli , Sabrina Burattini , Riham Osman , Francesco Onesimo , Michele Mari , Michele Retini , Ilaria Versari , Barbara Pagliarani , Andrea Tarozzi , Giovanni Zappia , Federico Gianfanti , Letizia Pruccoli","doi":"10.1016/j.yexmp.2026.105023","DOIUrl":"10.1016/j.yexmp.2026.105023","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra and the presence of misfolded α-synuclein in the brain. Mitochondrial dysfunction and oxidative stress are factors contributing to the death of these neurons. Coenzyme Q10 (CoQ10) serve as an antioxidant and cofactor for mitochondrial enzymes, and its deficiency can exacerbate neurodegenerative processes in PD. However, the clinical efficacy of CoQ10 is limited by its low bioavailability and instability. Ubiquinol diacetate (CoQ10 Ac), an esterified form of CoQ10, shows improved pharmacokinetic properties and potential as a prodrug, converting into the reduced antioxidant form of CoQ10 by esterases in the body. This study aimed to investigate the antioxidant and neuroprotective effects of CoQ10 Ac compared to CoQ10 in SH-SY5Y cell line and <em>Caenorhabditis elegans</em> models of PD. CoQ10 Ac showed higher antioxidant activity than CoQ10 at both extracellular and intracellular levels, particularly in the membrane and cytosolic compartments. It exhibited superior neuroprotection against 6-hydroxydopamine toxicity, showing a greater ability to reduce the activation of caspase-3 and PARP1 compared to CoQ10. Both compounds decreased the increased ratio of mitochondrial fission protein, DRP1, to fusion protein, OPA1, induced by 6-hydroxydopamine in SH-SY5Y cells, enhancing OPA1 levels and promoting antiapoptotic death. However, CoQ10 Ac was more effective than CoQ10 in preserving mitochondrial structural integrity and mass. Additionally, both compounds significantly inhibited the aggregation of α-synuclein induced by 6-hydroxydopamine. Furthermore, CoQ10 Ac showed stronger neuroprotective effects than CoQ10 in <em>C. elegans</em> models of PD. It demonstrated greater anti-aggregant activity in <em>C. elegans</em> expressing human α-synuclein, suggesting higher bioavailability. These findings highlight CoQ10 Ac as a promising prodrug candidate and support further investigation in <em>in vivo</em> PD models.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105023"},"PeriodicalIF":3.7,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972767","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 : 2026-01-13DOI: 10.1016/j.yexmp.2026.105024
Hui-Ching Wang , Chi-Wen Luo , Sin-Hua Moi , Ya-Hui Chang , Shu-Jyuan Chang , Yu-Hsuan Hung , Tzu-Yi Chen , Yi-Zi Chen , Chiao-Ying Lai , Yu-Ci Yang , Chun-Chieh Wu , Li-Tzong Chen , Mei-Ren Pan
Background
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy with limited biomarkers for early detection. Recurrence and metastasis after surgical resection remain major causes of mortality, highlighting the urgent need for novel therapeutic strategies.
Methods
We integrated clinical database analyses and functional assays in PDAC cell lines and mouse models to investigate the role of the SKP2-CDK6 axis in tumor progression, metastasis, and gemcitabine resistance.
Results
Elevated CDK6 expression correlated with poorer progression-free and overall survival in PDAC patients and was associated with advanced stage and lymph node metastasis. SKP2 expression positively correlated with CDK6, and mechanistic studies revealed that SKP2 may transcriptionally regulate CDK6. Inhibition of CDK6 suppressed tumor growth and metastasis in vitro and in vivo, and reduced epithelial-mesenchymal transition. Combining a CDK6 inhibitor with gemcitabine significantly reduced colony formation in gemcitabine-resistant PDAC cells, suggesting a synergistic anticancer effect.
Conclusions
The SKP2-CDK6 axis may drive PDAC progression and chemoresistance. Co-targeting SKP2 and CDK6 in combination with gemcitabine may represent a promising therapeutic approach, warranting further preclinical and clinical evaluation to improve outcomes for patients with PDAC.
{"title":"Exploring the characteristics of the SKP2-CDK6 axis in pancreatic cancer cell metastasis and its clinical significance","authors":"Hui-Ching Wang , Chi-Wen Luo , Sin-Hua Moi , Ya-Hui Chang , Shu-Jyuan Chang , Yu-Hsuan Hung , Tzu-Yi Chen , Yi-Zi Chen , Chiao-Ying Lai , Yu-Ci Yang , Chun-Chieh Wu , Li-Tzong Chen , Mei-Ren Pan","doi":"10.1016/j.yexmp.2026.105024","DOIUrl":"10.1016/j.yexmp.2026.105024","url":null,"abstract":"<div><h3>Background</h3><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy with limited biomarkers for early detection. Recurrence and metastasis after surgical resection remain major causes of mortality, highlighting the urgent need for novel therapeutic strategies.</div></div><div><h3>Methods</h3><div>We integrated clinical database analyses and functional assays in PDAC cell lines and mouse models to investigate the role of the SKP2-CDK6 axis in tumor progression, metastasis, and gemcitabine resistance.</div></div><div><h3>Results</h3><div>Elevated CDK6 expression correlated with poorer progression-free and overall survival in PDAC patients and was associated with advanced stage and lymph node metastasis. SKP2 expression positively correlated with CDK6, and mechanistic studies revealed that SKP2 may transcriptionally regulate CDK6. Inhibition of CDK6 suppressed tumor growth and metastasis in vitro and in vivo, and reduced epithelial-mesenchymal transition. Combining a CDK6 inhibitor with gemcitabine significantly reduced colony formation in gemcitabine-resistant PDAC cells, suggesting a synergistic anticancer effect.</div></div><div><h3>Conclusions</h3><div>The SKP2-CDK6 axis may drive PDAC progression and chemoresistance. Co-targeting SKP2 and CDK6 in combination with gemcitabine may represent a promising therapeutic approach, warranting further preclinical and clinical evaluation to improve outcomes for patients with PDAC.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105024"},"PeriodicalIF":3.7,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972768","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 : 2026-01-10DOI: 10.1016/j.yexmp.2025.105018
Ifat Alsharif
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