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":"2026-03-01","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 : 2026-03-01Epub Date: 2025-12-11DOI: 10.1016/j.yexmp.2025.105016
Lenka Vaňková , Jiří Polívka , Věra Křížková , Samuel Vokurka , Ondřej Fiala , Monika Holubová , Kristýna Pivovarčíková , Inka Třešková , Tereza Knížková , Jan Říčař , Radek Kučera , Martin Pešta
Immunotherapy by immune checkpoint inhibitors (ICIs) revolutionized the treatment of melanoma patients. Tumor-infiltrating immune cells (TIICs) play a crucial role in antitumor immunity activated by ICIs. However, ICIs treatment may be associated with serious immune-related adverse events (irAEs). The aim of the study was to identify the key immune cells and molecules of the tumor microenvironment responsible for the treatment effects and risk of irAEs through immunohistochemical quantification of TIICs. We analyzed metastases (FFPE) of 28 melanoma patients treated with ICIs. Multilevel sampling and stereological quantification were used to assess TIICs identified immunohistochemically by the markers CD1a, CD1d, CD3, CD4, CD8, CD20, CD56, CD68, FOXP3, including immune checkpoint molecules LAG3, PD1, PD-L1. In lymph node metastases, higher infiltration of PD-L1, CD8-positive cells and lower infiltration of CD1a-positive cells predicted response to ICIs (P ≤ 0.05, P ≤ 0.05, P ≤ 0.05, resp.). In all metastasis's subtypes, higher expression of PD-L1 was predictor of response to immunotherapy (P ≤ 0.05). Lower PD-L1 expression (P ≤ 0.05) and lower CD3 expression (P ≤ 0.001) were associated with irAEs. Higher infiltration of CD8-positive T lymphocytes was associated with longer progression-free survival (P = 0.0166) as well as overall survival (P = 0.0454). Stereological quantification of specific immune cells in melanoma metastases, such as T-lymphocytes (CD3), cytotoxic T-lymphocytes (CD8), dendritic cells (CD1a) and PD-L1-positive cells, may predict ICIs treatment efficacy or the risk of irAEs. High infiltration of metastatic tissue by CD8-positive T cells is important for long-term favorable therapeutic response to ICIs.
{"title":"Stereological quantification of tumor infiltrating immune cells as predictor of immunotherapy in metastatic melanoma","authors":"Lenka Vaňková , Jiří Polívka , Věra Křížková , Samuel Vokurka , Ondřej Fiala , Monika Holubová , Kristýna Pivovarčíková , Inka Třešková , Tereza Knížková , Jan Říčař , Radek Kučera , Martin Pešta","doi":"10.1016/j.yexmp.2025.105016","DOIUrl":"10.1016/j.yexmp.2025.105016","url":null,"abstract":"<div><div>Immunotherapy by immune checkpoint inhibitors (ICIs) revolutionized the treatment of melanoma patients. Tumor-infiltrating immune cells (TIICs) play a crucial role in antitumor immunity activated by ICIs. However, ICIs treatment may be associated with serious immune-related adverse events (irAEs). The aim of the study was to identify the key immune cells and molecules of the tumor microenvironment responsible for the treatment effects and risk of irAEs through immunohistochemical quantification of TIICs. We analyzed metastases (FFPE) of 28 melanoma patients treated with ICIs. Multilevel sampling and stereological quantification were used to assess TIICs identified immunohistochemically by the markers CD1a, CD1d, CD3, CD4, CD8, CD20, CD56, CD68, FOXP3, including immune checkpoint molecules LAG3, PD1, PD-L1. In lymph node metastases, higher infiltration of PD-L1, CD8-positive cells and lower infiltration of CD1a-positive cells predicted response to ICIs (<em>P</em> ≤ 0.05, P ≤ 0.05, P ≤ 0.05, resp.). In all metastasis's subtypes, higher expression of PD-L1 was predictor of response to immunotherapy (P ≤ 0.05). Lower PD-L1 expression (P ≤ 0.05) and lower CD3 expression (<em>P</em> ≤ 0.001) were associated with irAEs. Higher infiltration of CD8-positive T lymphocytes was associated with longer progression-free survival (<em>P</em> = 0.0166) as well as overall survival (<em>P</em> = 0.0454). Stereological quantification of specific immune cells in melanoma metastases, such as T-lymphocytes (CD3), cytotoxic T-lymphocytes (CD8), dendritic cells (CD1a) and PD-L1-positive cells, may predict ICIs treatment efficacy or the risk of irAEs. High infiltration of metastatic tissue by CD8-positive T cells is important for long-term favorable therapeutic response to ICIs.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105016"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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":"2026-03-01","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 : 2026-03-01Epub Date: 2025-12-06DOI: 10.1016/j.yexmp.2025.105014
Hyo Jung Shin , In Soo Kim , Minwoo Kim , Seung Yeon Jung , Dong Woon Kim , Joon Won Kang
Microglia, the resident immune cells of the brain, play a critical role in maintaining homeostasis. In this study, we investigated changes in microglial phenotype associated with seizure susceptibility. Kainic acid (KA) was injected intraperitoneally, and when seizures reached Racine stage 4/5, administration was stopped, and mice were monitored for 60 min. Only mice that showed behavioral convulsive status epilepsy (SE) in the first experiment received a second KA injection 2 weeks later. Using this model, we observed changes in brain tissue and microglial phenotype according to seizure susceptibility. We also analyzed gene expression patterns associated with microglial phagocytosis in a publicly available hippocampal transcriptome microarray dataset (GSE88992) from mice injected with KA. After the initial low-dose KA repeat injection, the number of injections required to induce SE during the secondary injection was compared with the initial injection, and mice were categorized into seizure-resistant (SR, n = 26, no SE), seizure-tolerant (ST, n = 11, SE after ≥2 injections), and seizure-susceptible (SS, n = 15, SE after ≤2 injections) groups. Neuronal loss was observed in all seizure groups, but the extent varied across hippocampal regions. Microglial phenotypes in the hippocampus showed significant differences between groups. Immunofluorescence staining further confirmed that triggering receptor expressed on myeloid cells (TREM2) expression was increased in microglia in the SS group. Using a model that classifies seizure resistance, tolerance, and susceptibility, we observed significant differences in microglial phenotypes and TREM2 expressions between groups. This study highlights the role of microglia in the progression from first seizures to subsequent seizures, a critical step in the development of epilepsy.
小胶质细胞是大脑的常驻免疫细胞，在维持体内平衡中起着关键作用。在这项研究中，我们研究了与癫痫易感性相关的小胶质细胞表型的变化。腹腔注射Kainic acid (KA)，当癫痫发作达到拉辛期4/5时，停止给药，并监测小鼠60 min。只有在第一次实验中表现出行为惊厥状态癫痫（SE）的小鼠在2周后接受第二次KA注射。使用该模型，我们观察到脑组织和小胶质细胞表型根据癫痫易感性的变化。我们还分析了注射KA小鼠的海马转录组微阵列数据集（GSE88992）中与小胶质细胞吞噬相关的基因表达模式。初始低剂量KA重复注射后，比较二次注射诱导SE所需的注射次数，并将小鼠分为抗癫痫组（SR, n = 26，无SE）、耐癫痫组（ST, n = 11，注射≥2次SE）和癫痫敏感组（SS, n = 15，≤2次SE）。在所有的癫痫发作组中都观察到神经元的丧失，但海马区域的程度不同。海马小胶质细胞表型组间差异有统计学意义。免疫荧光染色进一步证实，SS组小胶质细胞中髓系细胞触发受体（TREM2）表达增加。通过对癫痫抵抗、耐受性和易感性进行分类的模型，我们观察到各组间小胶质细胞表型和TREM2表达的显著差异。这项研究强调了小胶质细胞在癫痫发作过程中的作用，这是癫痫发展的关键一步。
{"title":"Seizure susceptibility relates to microglial TREM2 expression and morphology in a multiple repeated low-dose kainic acid model","authors":"Hyo Jung Shin , In Soo Kim , Minwoo Kim , Seung Yeon Jung , Dong Woon Kim , Joon Won Kang","doi":"10.1016/j.yexmp.2025.105014","DOIUrl":"10.1016/j.yexmp.2025.105014","url":null,"abstract":"<div><div>Microglia, the resident immune cells of the brain, play a critical role in maintaining homeostasis. In this study, we investigated changes in microglial phenotype associated with seizure susceptibility. Kainic acid (KA) was injected intraperitoneally, and when seizures reached Racine stage 4/5, administration was stopped, and mice were monitored for 60 min. Only mice that showed behavioral convulsive status epilepsy (SE) in the first experiment received a second KA injection 2 weeks later. Using this model, we observed changes in brain tissue and microglial phenotype according to seizure susceptibility. We also analyzed gene expression patterns associated with microglial phagocytosis in a publicly available hippocampal transcriptome microarray dataset (GSE88992) from mice injected with KA. After the initial low-dose KA repeat injection, the number of injections required to induce SE during the secondary injection was compared with the initial injection, and mice were categorized into seizure-resistant (SR, <em>n</em> = 26, no SE), seizure-tolerant (ST, <em>n</em> = 11, SE after ≥2 injections), and seizure-susceptible (SS, <em>n</em> = 15, SE after ≤2 injections) groups. Neuronal loss was observed in all seizure groups, but the extent varied across hippocampal regions. Microglial phenotypes in the hippocampus showed significant differences between groups. Immunofluorescence staining further confirmed that triggering receptor expressed on myeloid cells (TREM2) expression was increased in microglia in the SS group. Using a model that classifies seizure resistance, tolerance, and susceptibility, we observed significant differences in microglial phenotypes and TREM2 expressions between groups. This study highlights the role of microglia in the progression from first seizures to subsequent seizures, a critical step in the development of epilepsy.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105014"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We report the synthesis and pharmacological evaluation of UG-635, a novel 25-nitro vitamin D analogue bearing a 20-epimeric configuration. Cytotoxicity studies in SH-SY5Y neuroblastoma and HepG2 hepatocarcinoma cells showed that UG-635 is well tolerated at low concentrations but reduces viability at higher doses. Importantly, UG-635 demonstrated protective effects against oxidative stress in neuronal cells and exhibited anti-proliferative activity in breast cancer (MCF7) and osteoblast (MC3T3-E1) models, with efficacy comparable to calcitriol. Structural and crystallographic analyses revealed efficient binding to the vitamin D receptor (VDR), stabilizing its active conformation through favorable interactions with anchoring histidines. These findings highlight UG-635 as a promising vitamin D analogue with potential pharmacological relevance in cancer and neurodegenerative disease contexts, combining anti-proliferative and cytoprotective properties.
{"title":"25-nitro-20-epi-vitamin D analogue with anti-proliferative and cytoprotective properties: Biological and pharmacological evaluation","authors":"Uxía Gómez-Bouzó , Carole Peluso-Iltis , Sandra Barreiro , Carlos Fernandes , Lieve Verlinden , Annemieke Verstuyf , Fernanda Borges , Natacha Rochel , Generosa Gómez , Yagamare Fall","doi":"10.1016/j.yexmp.2026.105036","DOIUrl":"10.1016/j.yexmp.2026.105036","url":null,"abstract":"<div><div>We report the synthesis and pharmacological evaluation of <strong>UG-635</strong>, a novel 25-nitro vitamin D analogue bearing a 20-epimeric configuration. Cytotoxicity studies in SH-SY5Y neuroblastoma and HepG2 hepatocarcinoma cells showed that <strong>UG-635</strong> is well tolerated at low concentrations but reduces viability at higher doses. Importantly, <strong>UG-635</strong> demonstrated protective effects against oxidative stress in neuronal cells and exhibited anti-proliferative activity in breast cancer (MCF7) and osteoblast (MC3T3-E1) models, with efficacy comparable to calcitriol. Structural and crystallographic analyses revealed efficient binding to the vitamin D receptor (VDR), stabilizing its active conformation through favorable interactions with anchoring histidines. These findings highlight <strong>UG-635</strong> as a promising vitamin D analogue with potential pharmacological relevance in cancer and neurodegenerative disease contexts, combining anti-proliferative and cytoprotective properties.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105036"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283197","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 : 2026-03-01Epub Date: 2026-02-16DOI: 10.1016/j.yexmp.2026.105034
Letizia Penolazzi , Alice Zaramella , Anna Chierici , Paola Bisaccia , Maria Pina Notarangelo , Anna Maria Tolomeo , Elisabetta Lambertini , Anna Alessia Saponaro , Tommaso Colangelo , Michela Pozzobon , Roberta Piva
{"title":"Corrigendum to “Wharton's jelly-derived nanovesicles for targeting intervertebral disc degeneration” [Experimental and Molecular Pathology 144 (2025) 105011]","authors":"Letizia Penolazzi , Alice Zaramella , Anna Chierici , Paola Bisaccia , Maria Pina Notarangelo , Anna Maria Tolomeo , Elisabetta Lambertini , Anna Alessia Saponaro , Tommaso Colangelo , Michela Pozzobon , Roberta Piva","doi":"10.1016/j.yexmp.2026.105034","DOIUrl":"10.1016/j.yexmp.2026.105034","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105034"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146206865","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 : 2026-03-01Epub Date: 2026-02-05DOI: 10.1016/j.yexmp.2026.105031
Lingtong Zhi , Yuqing Wang , Zixing Zhao , Yabin Guo , Kaiwen Wang , Wenhui He , Changjiang Guo , Zhiyuan Niu , Wuling Zhu , Xuan Zhang
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":"10.1016/j.yexmp.2026.105031","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105031"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","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 : 2026-03-01Epub 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":"2026-03-01","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 : 2026-03-01Epub Date: 2025-12-05DOI: 10.1016/j.yexmp.2025.105013
André Anastácio Santos , David Pires , Vanda Marques , Nicole Alesina , Pedro Miguel Rodrigues , Ana Catarina Bravo , Catarina Gouveia , Susana Saraiva , Luís Correia , Ricardo Crespo , João Pereira da Silva , Marília Cravo , Jesus Maria Banales , Joana Torres , Cecília Maria Pereira Rodrigues
Background
Primary sclerosing cholangitis (PSC) is a chronic liver disease frequently associated with inflammatory bowel disease (IBD) and increased risk of colorectal cancer (CRC). Despite the strong association, the underlying mechanisms linking PSC-IBD, gut inflammation, and neoplastic potential remain unclear. This study explores the role of miR-21-5p dysregulation, gut microbiota dysbiosis, and pro-oncogenic markers in shaping the inflammatory and neoplastic microenvironment in PSC-IBD patients.
Methods
A case-control study was conducted, including PSC patients with concomitant IBD (n = 14) and control individuals without diagnosed PSC and IBD (n = 20). miR-21-5p levels were evaluated in serum, fecal samples, and colonic biopsies via qPCR. Gut microbiota composition was analyzed using 16S rRNA sequencing. Pro-oncogenic and inflammatory markers in colonic tissue were assessed via qPCR. In vitro studies were performed using cholangiocyte (H69), colorectal cancer (HCT116), and primary monocyte models to investigate the role of miR-21-5p.
Results
miR-21-5p was significantly upregulated in the right colon, serum, and fecal samples of PSC-IBD patients compared to controls. Gut microbiota analysis revealed dysbiosis, characterized by an increased Bacteroidota/Bacillota ratio and reduction in bile acid-metabolizing bacteria, including Clostridium sensu stricto 1, Ruminococcaceae UCG-002, and Christensenellaceae_R7_group. Colonic tissue analysis showed increased expression of EMT-related transcription factors TWIST1 and SNAIL, inflammatory cytokines IL-8, CCL2, and COX2, and the stem cell marker LGR5. In vitro studies confirmed miR-21-5p role in upregulating does markers in monocytes and CRC cells.
Conclusion
This study found a link between miR-21-5p dysregulation and gut microbiota dysbiosis, colonic inflammation, and pro-oncogenic signaling in PSC-IBD patients. These findings highlight miR-21-5p as a potential modulator of disease progression and neoplastic risk.
{"title":"miR-21-5p dysregulation is associated with gut microbiota dysbiosis and pro-oncogenic markers in primary sclerosing cholangitis with concomitant inflammatory bowel disease","authors":"André Anastácio Santos , David Pires , Vanda Marques , Nicole Alesina , Pedro Miguel Rodrigues , Ana Catarina Bravo , Catarina Gouveia , Susana Saraiva , Luís Correia , Ricardo Crespo , João Pereira da Silva , Marília Cravo , Jesus Maria Banales , Joana Torres , Cecília Maria Pereira Rodrigues","doi":"10.1016/j.yexmp.2025.105013","DOIUrl":"10.1016/j.yexmp.2025.105013","url":null,"abstract":"<div><h3>Background</h3><div>Primary sclerosing cholangitis (PSC) is a chronic liver disease frequently associated with inflammatory bowel disease (IBD) and increased risk of colorectal cancer (CRC). Despite the strong association, the underlying mechanisms linking PSC-IBD, gut inflammation, and neoplastic potential remain unclear. This study explores the role of miR-21-5p dysregulation, gut microbiota dysbiosis, and pro-oncogenic markers in shaping the inflammatory and neoplastic microenvironment in PSC-IBD patients.</div></div><div><h3>Methods</h3><div>A case-control study was conducted, including PSC patients with concomitant IBD (<em>n</em> = 14) and control individuals without diagnosed PSC and IBD (<em>n</em> = 20). miR-21-5p levels were evaluated in serum, fecal samples, and colonic biopsies <em>via</em> qPCR. Gut microbiota composition was analyzed using 16S rRNA sequencing. Pro-oncogenic and inflammatory markers in colonic tissue were assessed <em>via</em> qPCR. <em>In vitro</em> studies were performed using cholangiocyte (H69), colorectal cancer (HCT116), and primary monocyte models to investigate the role of miR-21-5p.</div></div><div><h3>Results</h3><div>miR-21-5p was significantly upregulated in the right colon, serum, and fecal samples of PSC-IBD patients compared to controls. Gut microbiota analysis revealed dysbiosis, characterized by an increased <em>Bacteroidota</em>/<em>Bacillota</em> ratio and reduction in bile acid-metabolizing bacteria, including <em>Clostridium sensu stricto 1</em>, <em>Ruminococcaceae UCG-002</em>, and <em>Christensenellaceae_R7_group</em>. Colonic tissue analysis showed increased expression of EMT-related transcription factors <em>TWIST1</em> and <em>SNAIL</em>, inflammatory cytokines <em>IL-8</em>, <em>CCL2</em>, and <em>COX2</em>, and the stem cell marker <em>LGR5</em>. <em>In vitro</em> studies confirmed miR-21-5p role in upregulating <em>does</em> markers in monocytes and CRC cells.</div></div><div><h3>Conclusion</h3><div>This study found a link between miR-21-5p dysregulation and gut microbiota dysbiosis, colonic inflammation, and pro-oncogenic signaling in PSC-IBD patients. These findings highlight miR-21-5p as a potential modulator of disease progression and neoplastic risk.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105013"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-06DOI: 10.1016/j.yexmp.2025.105021
Darab Ghadimi , Sophia Blömer , Aysel Şahin Kaya , Sandra Krüger , Christoph Röcken , Heiner Schäfer , Jumpei Uchiyama , Shigenobu Matsuzaki , Wilhelm Bockelmann
Diet and nutrition affect almost every biological process, including multiple chronic diseases, diabetes, and some cancers. However, there are still significant gaps in our understanding of the importance of nutrition and healthy diets in syntrophy with respect to cross-feeding of the microbe-microbe and the microbe-host in the pathobiology of the infectious-inflamed intestinal milieu caused by anaerobic opportunistic bacteria such as Fusobacterium nucleatum (F. nucleatum). We examined the immune outcomes of three-member folate syntrophy and cross-feeding between F. nucleatum bacteria, endogenous folate-producing gut bacteria, and host cells at the host-pathogen interface using a triple co-culture model. T84, THP-1, and Huh7 cells were inoculated with F. nucleatum for 6 h in regular DMEM, DMEM with 9.5 μM folic acid, or with/without a mixture of Bifidobacterium longum subsp. infantis (B. infantis) and Escherichia coli Nissle 1917 (EcN). Cytokine secretion, cometabolite levels (ammonia, indoles), cell viability, and barrier integrity were assessed. F. nucleatum-induced folate depletion was associated with increased IL-1β and IL-6 and decreased IL-22, along with reduced transepithelial electrical resistance (TEER) and cell viability in T84 cells. Folate supplementation mitigated these effects. The mixture of B. infantis and EcN reduced F. nucleatum-induced pro-inflammatory cytokines, increased IL-22, and improved TEER and cell viability. These protective effects were enhanced by the addition of folate. F. nucleatum also elevated ammonia and reduced indoles, effects reversed by B. infantis and EcN. In addition to the intrinsic pathogenicity of harmful bacteria, folate deprivation, microbe–microbe folate syntrophy, and microbe–host folate cross-feeding contribute to the pathobiology of anaerobic opportunistic bacteria and influence the physiological fate of host cells. A combination of B. infantis and EcN modulates the infectious-inflamed interface through a cytoprotective effect and mechanical competitive extrusion of pathogenic F. nucleatum. These results provide potential insights into the mechanisms of early-onset colorectal cancer, and evidently, require future studies using patient-derived organoids and in vivo systems to improve clinical relevance.
{"title":"Assessing the role of folate syntrophy and folate cross-feeding in the pathobiology of infectious-inflamed milieu caused by Fusobacterium nucleatum","authors":"Darab Ghadimi , Sophia Blömer , Aysel Şahin Kaya , Sandra Krüger , Christoph Röcken , Heiner Schäfer , Jumpei Uchiyama , Shigenobu Matsuzaki , Wilhelm Bockelmann","doi":"10.1016/j.yexmp.2025.105021","DOIUrl":"10.1016/j.yexmp.2025.105021","url":null,"abstract":"<div><div>Diet and nutrition affect almost every biological process, including multiple chronic diseases, diabetes, and some cancers. However, there are still significant gaps in our understanding of the importance of nutrition and healthy diets in syntrophy with respect to cross-feeding of the microbe-microbe and the microbe-host in the pathobiology of the infectious-inflamed intestinal milieu caused by anaerobic opportunistic bacteria such as <em>Fusobacterium nucleatum</em> (<em>F. nucleatum</em>). We examined the immune outcomes of three-member folate syntrophy and cross-feeding between <em>F. nucleatum</em> bacteria, endogenous folate-producing gut bacteria, and host cells at the host-pathogen interface using a triple co-culture model. T84, THP-1, and Huh7 cells were inoculated with <em>F. nucleatum</em> for 6 h in regular DMEM, DMEM with 9.5 μM folic acid, or with/without a mixture of <em>Bifidobacterium longum</em> subsp. <em>infantis</em> (<em>B. infantis</em>) and <em>Escherichia coli</em> Nissle <em>1917</em> (EcN). Cytokine secretion, cometabolite levels (ammonia, indoles), cell viability, and barrier integrity were assessed. <em>F. nucleatum-</em>induced folate depletion was associated with increased IL-1β and IL-6 and decreased IL-22, along with reduced transepithelial electrical resistance (TEER) and cell viability in T84 cells. Folate supplementation mitigated these effects. The mixture of <em>B. infantis</em> and EcN reduced <em>F. nucleatum</em>-induced pro-inflammatory cytokines, increased IL-22, and improved TEER and cell viability. These protective effects were enhanced by the addition of folate. <em>F. nucleatum</em> also elevated ammonia and reduced indoles, effects reversed by <em>B. infantis</em> and EcN. In addition to the intrinsic pathogenicity of harmful bacteria, folate deprivation, microbe–microbe folate syntrophy, and microbe–host folate cross-feeding contribute to the pathobiology of anaerobic opportunistic bacteria and influence the physiological fate of host cells. A combination of <em>B. infantis</em> and EcN modulates the infectious-inflamed interface through a cytoprotective effect and mechanical competitive extrusion of pathogenic <em>F. nucleatum</em>. These results provide potential insights into the mechanisms of early-onset colorectal cancer, and evidently, require future studies using patient-derived organoids and in vivo systems to improve clinical relevance.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"145 ","pages":"Article 105021"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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