Experimental and molecular pathology最新文献

{"title":"Platelet-derived growth factor-C contributes to kidney inflammation in experimental hypertension with little effect on the peritubular capillary network","authors":"Ina V. Martin ,&nbsp;Christian Dippel ,&nbsp;Eva M. Buhl ,&nbsp;Robert Göllinger ,&nbsp;Katja Ermert ,&nbsp;Jürgen Floege ,&nbsp;Eleni Stamellou ,&nbsp;Ute Raffetseder ,&nbsp;Rafael Kramann ,&nbsp;Tammo Ostendorf","doi":"10.1016/j.yexmp.2025.104994","DOIUrl":"10.1016/j.yexmp.2025.104994","url":null,"abstract":"<div><h3>Background and aims</h3><div>Platelet-Derived Growth Factor (PDGF)-C plays a significant role in kidney fibrosis, angiogenesis, and hypertension. While its involvement in the healing of damaged glomerular capillaries is well recognized, its function in kidney peritubular capillaries (PTCs) remains less understood. Therefore, this study investigates the role of PDGF-C in PTCs under both homeostatic conditions and experimentally angiotensin II (AngII)-induced hypertension.</div></div><div><h3>Materials and methods</h3><div>We utilized mice with systemic PDGF-C antagonism or conditional deletion of endothelial-derived PDGF-C (<em>Cdh5-cre::Pdgfc</em>^{<em>flox/flox</em>}) in an AngII-induced hypertension model. The PTC network, glycocalyx, and inflammatory parameters in the kidneys were analyzed and quantified using qPCR, electron microscopy, and fluorescence microscopy.</div></div><div><h3>Results</h3><div>Systemic antagonism of PDGF-C in the AngII model reduced peritubular accumulation of PDGF receptor-expressing mesenchymal cells and the expression of <em>Ccl2</em>, <em>Plat</em> and <em>Nos3</em>, while PTC density and glycocalyx-regulating genes remained unaffected. Conditional deletion of endothelial cell-derived PDGF-C did not affect peritubular accumulation of mesenchymal cells, blood pressure or genes associated with angiogenesis; it also had no impact on the PTC network or glycocalyx. Notably, a reduction in inflammatory infiltrates was observed in the hypertensive <em>Cdh5-cre::Pdgfc</em>^{<em>flox/flox</em>} -mice.</div></div><div><h3>Conclusion</h3><div>Despite influencing certain parameters critical for endothelial homeostasis, such as PDGFR⁺ pericyte recruitment following systemic PDGF-C antagonism during hypertension, PDGF-C has minimal effects on the PTC network. Conversely, both systemic and endothelial cell-derived PDGF-C modulate the inflammatory response associated with hypertension in the kidney. Our findings help mitigate safety concerns about pharmacological PDGF-C targeting and its impact on peritubular capillaries.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104994"},"PeriodicalIF":3.7,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907621","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}

{"title":"Peroxidasin expression is increased in intratumoural capillaries and in proximal tubular cells adjacent to clear cell renal cell carcinoma.","authors":"Roberto Silva ,&nbsp;Jorge Reis Almeida ,&nbsp;Ana Rita Coelho ,&nbsp;Isabel Brandão ,&nbsp;Bárbara Gomes ,&nbsp;Inês Soares Alencastre ,&nbsp;João Paulo Oliveira","doi":"10.1016/j.yexmp.2025.104993","DOIUrl":"10.1016/j.yexmp.2025.104993","url":null,"abstract":"<div><div>Peroxidasin (PXDN), is a heme peroxidase with a critical role in the crosslinking of type IV collagen, being essential for basement membrane integrity. Overexpression of PXDN has been associated with poor clinical outcomes in many cancers; however, little is currently known about its role in renal cell carcinoma (RCC). In this study, we characterized the expression of PXDN in tumour tissue and adjacent non-neoplastic tissue from cases of clear cell renal cell carcinoma (ccRCC), chromophobe RCC (chRCC), and renal oncocytoma using immunohistochemistry. Our results revealed increased PXDN expression in the intratumoural capillaries of ccRCC compared to other tumour types, including oncocytoma. Additionally, there was a notable increase in PXDN expression in the proximal tubular epithelial cells of non-neoplastic adjacent parenchyma in ccRCC cases compared to the same region in oncocytomas. These findings suggest, for the first time, that PXDN may play a role in tumour angiogenesis, potentially promoting metastases and malignancy. Furthermore, PXDN may be involved in the crosstalk between the tumour and adjacent tissues, a mechanism warranting further investigation.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104993"},"PeriodicalIF":3.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144866366","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}

{"title":"Research progress of sarcopenia: Diagnostic advancements, molecular mechanisms, and therapeutic strategies","authors":"Hao-lin Wang ,&nbsp;Long-long Liu ,&nbsp;Ze-yu Tan ,&nbsp;Yuan Zhou ,&nbsp;Jing Zhang ,&nbsp;Lin Zhai ,&nbsp;Qian Xie ,&nbsp;Rong-hua Liu","doi":"10.1016/j.yexmp.2025.104992","DOIUrl":"10.1016/j.yexmp.2025.104992","url":null,"abstract":"<div><div>Muscle atrophy or loss is an important sign of human aging. As the aging society approaches and human lifespan prolongs, sarcopenia has emerged as one of the significant risks influencing the quality of life of the elderly. Sarcopenia is a progressive geriatric syndrome characterized by the deterioration of skeletal muscle mass and function, which can result in an increased risk of falls, fractures, restricted physical activity, disability, mortality, and a remarkable escalation in the risk of cardiovascular diseases among the elderly. This work synthesizes recent advances in sarcopenia research, critically evaluating diagnostic frameworks, histopathological hallmarks, and molecular pathways driving disease progression. Additionally, we provide an in-depth analysis of evidence-based exercise and nutritional interventions, identifying key research gaps. These insights offer valuable references for future research on sarcopenia and clinical management, as well as lifestyle interventions such as exercise and nutrition.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104992"},"PeriodicalIF":3.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144829736","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}

{"title":"The interplay involving oxidative stress and autophagy: Mechanisms, implications, and therapeutic opportunities","authors":"Noha A. Gouda ,&nbsp;Assem Zhakupova ,&nbsp;Ahmed M. Abdelaal ,&nbsp;Firdos Ahmad ,&nbsp;Ahmed Elkamhawy","doi":"10.1016/j.yexmp.2025.104989","DOIUrl":"10.1016/j.yexmp.2025.104989","url":null,"abstract":"<div><div>Reactive oxygen species (ROS) are extremely reactive molecules produced during cellular metabolism, which play important roles in signaling and immune responses. Excessive ROS accumulation results in oxidative stress and cellular damage. As a result, autophagy (a cellular recycling process) is induced to overcome oxidative stress conditions by eliminating impaired cellular components. By selectively targeting and degrading dysfunctional mitochondria and peroxisomes through mitophagy and pexophagy, respectively, cells can effectively reduce ROS accumulation. Conversely, oxidative stress can disrupt autophagy, impairing protein aggregate clearance and thereby exacerbating ROS accumulation. In this review, we discuss the complex correlation between oxidative stress and autophagy, highlighting the mechanisms of regulation and their pathological implications. Additionally, we discuss the latest advances and challenges in developing autophagy-modulating therapies.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104989"},"PeriodicalIF":3.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757616","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}

{"title":"Twenty-eight-day perfluorooctanoate exposure does not affect immune cell populations in naïve mice","authors":"Candice Limper ,&nbsp;Crystal Silliman ,&nbsp;Ethan Cho ,&nbsp;Amanda Ng ,&nbsp;Steven Yang ,&nbsp;Zachary Hammer ,&nbsp;Isabella Ciocca ,&nbsp;Brian Imbiakha ,&nbsp;Amie Redko ,&nbsp;Colleen M. Lau ,&nbsp;Sue Chang ,&nbsp;Julie Sahler ,&nbsp;Avery August","doi":"10.1016/j.yexmp.2025.104990","DOIUrl":"10.1016/j.yexmp.2025.104990","url":null,"abstract":"<div><div>Perfluorooctanoate (C₇F₁₅CO₂⁻, PFOA) is a perfluorinated compound widely used in the production of industrial products, such as non-stick cookware and firefighting foams. Although its production has been phased out in the United States, PFOA remains prevalent in the environment due to its persistence and resistance to degradation. As a result, trace levels of PFOA is detectable in water, soil, biota, and the general population. Environmental and toxicological concerns have emerged due to potential health risks associated with PFOA exposure, including effects on the immune system. Basic underlying knowledge gaps exist for potential effects of PFOA on baseline immune cell maintenance in the absence of overt liver hypertrophy. In this study, we assessed the immune-related effects of 28-day daily PFOA exposure in adult naïve mice, using doses of 20 ng/kg/day, 200 ng/kg/day, 2 μg/kg/day, and 40 μg/kg/day, resulting in mean serum PFOA concentrations of non-detectable, 6.979 ng/mL, 80.03 ng/mL, and 1773 ng/mL respectively, representative of levels seen in the general human population (∼1.5 ng/mL), community-exposed residents (∼225 ng/mL), and occupational workers (∼2000 ng/mL). Evaluation of immune cell populations in bone marrow, thymus, spleen, liver, and lymph nodes, along with serum antibodies indicate that 28 days of PFOA exposure had no effect on proportion and number of immune cell populations nor serum antibodies, except for a slight decrease in serum IgE at the highest dose. By contrast, mice receiving CTX, a known immune suppressant, exhibited a wide array of biological responses, which were absent from PFOA-treated mice. These findings contribute to understanding the potential immune effects of environmentally relevant PFOA exposure.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104990"},"PeriodicalIF":3.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723708","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}

{"title":"NVP-BEZ235 enhances autophagy and ameliorates cognitive deficits by targeting tauopathies","authors":"Ifat Alsharif","doi":"10.1016/j.yexmp.2025.104988","DOIUrl":"10.1016/j.yexmp.2025.104988","url":null,"abstract":"<div><div>Tauopathies are a class of neurodegenerative disorders characterized by the abnormal accumulation of hyperphosphorylated tau (p-tau) and the formation of neurofibrillary tangles. Autophagy, a fundamental cellular degradation pathway, plays a pivotal role in maintaining proteostasis by facilitating the clearance of misfolded and aggregated proteins. In tauopathies, however, autophagic processes are often impaired, contributing to the pathological buildup of p-tau. NVP-BEZ235, a dual inhibitor of the mammalian target of rapamycin (mTOR) and PI3K, has previously been evaluated in phase I clinical trials for solid tumors and lymphomas. In this study, we investigated the therapeutic potential of NVP-BEZ235 in tauopathy models, both in vitro and in vivo. In SH-SY5Y cells stably expressing human P301L-mutant tau (SH-Tau), NVP-BEZ235 treatment induced a time-dependent increase in LC3B-II and a decrease in p62 levels, consistent with enhanced autophagic activity. Autophagic flux analysis further confirmed the promotion of autophagy upon mTOR pathway inhibition. NVP-BEZ235 significantly reduced tau phosphorylation at multiple residues, including Ser262, Ser396, Ser404, and Thr231, without eliciting cytotoxic effects. In a transgenic mouse model of tauopathy (P301S), chronic treatment with NVP-BEZ235 (20 mg/kg/day for two months) resulted in a marked reduction of both RIPA-soluble and -insoluble p-tau species in the brain. Spatial learning and memory, assessed through Morris water maze and novel object recognition tests, were significantly improved in treated mice. Furthermore, NVP-BEZ235 administration reduced neuroinflammatory markers and pro-inflammatory cytokine levels (TNF-α, IL-1β, IL-6), while also enhancing autophagic markers in brain tissue. Hematological analysis and organ histology revealed no signs of systemic toxicity. Collectively, these findings demonstrate that NVP-BEZ235 facilitates tau clearance by enhancing autophagy through mTOR inhibition, thereby mitigating cognitive deficits and neuroinflammation in tauopathy models. This study supports the therapeutic potential of NVP-BEZ235 as a promising candidate for the treatment of tau-related neurodegenerative diseases.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104988"},"PeriodicalIF":2.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144696821","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}

{"title":"Daidzin suppresses melanogenesis through ERK and AKT signaling pathways mediated MITF proteasomal degradation","authors":"Jinpeng Lv ,&nbsp;Kun Zou ,&nbsp;Chuanwei Yin ,&nbsp;Wenhui Xu ,&nbsp;Duo Meng ,&nbsp;Huansha Zhang ,&nbsp;Wenhao Yu ,&nbsp;Peiwen Jiang ,&nbsp;Changjun Yun ,&nbsp;Hui Xue ,&nbsp;Nan Hu ,&nbsp;Rongyin Gao","doi":"10.1016/j.yexmp.2025.104986","DOIUrl":"10.1016/j.yexmp.2025.104986","url":null,"abstract":"<div><div>Daidzin, a prominent isoflavone found in soybeans, <em>Pueraria lobata</em>, and various legumes, has been extensively investigated for its diverse pharmacological activities, which include anticancer, antioxidant, anti-inflammatory, antiepileptic, and alcohol detoxification properties. Previous studies have shown that the dichloromethane fraction of <em>Pueraria lobata</em> stem (DCM-PLS) exhibits significant anti-melanogenic activity, with daidzin identified as the principal active compound. However, the precise role of daidzin in pigmentation remains incompletely understood. This study aimed to investigate the effects of daidzin on pigmentation and to elucidate the underlying mechanisms. Our findings revealed that daidzin not only inhibited basal melanin production but also reduced melanin synthesis induced by α-MSH, ACTH, and UV exposure. The effects of daidzin were primarily mediated through the activation of the extracellular signal-regulated protein kinase (ERK) and protein kinase B (AKT) pathways. Upon activation, these pathways facilitated the ubiquitination and degradation of Melanocytes Inducing Transcription Factor (MITF), resulting in decreased expression of tyrosinase, TRP-1, and TRP-2, ultimately inhibiting melanogenesis. Importantly, our research further demonstrated that daidzin reduced pigmentation in both zebrafish and human skin explants, highlighting its potential application as a therapeutic approach for disorders related to skin pigmentation.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104986"},"PeriodicalIF":2.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144680738","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}

{"title":"Modulating cellular deformability via 3D dextran hydrogel cultivation to regulate the microcirculation of mesenchymal stem cells in murine spleen and liver","authors":"Xiaolu Zhu ,&nbsp;Zheng Wang ,&nbsp;Yuanping Shi ,&nbsp;Shuang Yao ,&nbsp;Fengliang He ,&nbsp;Xiuli Cong ,&nbsp;Fang Teng","doi":"10.1016/j.yexmp.2025.104987","DOIUrl":"10.1016/j.yexmp.2025.104987","url":null,"abstract":"<div><div>For mesenchymal stem cell (MSC) therapy to be effective, the vascular system may be used to deliver and steer the cells to the target tissue. However, the expanded MSCs in petri dishes typically exhibit limited deformability and commonly excluded by the capillary networks when homing to the downstream organs via microcirculation. Here, we propose to utilize specially designed 3D dextran hydrogels and tuning the microscopic heterogeneity of hydrogel composition to make the administrated cells mechanically comply with the structure and mechanics of the capillary. The deformability of cells cultured in petri dishes, microcosmically homogeneous (HOM), and heterogeneous (HET) dextran hydrogels was investigated in vitro by measuring cell moduli through atomic force microscope (AFM), analyzing the expression of cytoskeletal protein via flow cytometry and fluorescent imaging. The in vitro experimental results demonstrate a progressive increase in cell deformability from 2D dishes, to HOM-hydrogel derived cells, and then to HET-hydrogel derived cells. The in vivo mouse experiment indicates the cells could deform accordingly and pass through easily with reduced resistance inside the mouse organs. It is suggested that the main destination of hMSC microcirculation could be selected between the spleen and liver of mice, by tuning cell mechanics that depends on the stimulus from HOM or HET hydrogel, which lays a potential foundation for the mechanically modified MSC therapy targeting organ lesions.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104987"},"PeriodicalIF":2.8,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662203","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}

{"title":"Treatment with YKL-05-099, a salt inducible kinase (SIK) inhibitor, attenuates salt-sensitive hypertension: The molecular outcomes of SIK in the kidney","authors":"Dayene S. Gomes ,&nbsp;Bruna Visniauskas ,&nbsp;Prasad V.G. Katakam ,&nbsp;Rosilane Taveira-da-Silva ,&nbsp;Jennifer Lowe ,&nbsp;Zoe Vallotton ,&nbsp;Minolfa C. Prieto ,&nbsp;Lucienne S. Lara","doi":"10.1016/j.yexmp.2025.104977","DOIUrl":"10.1016/j.yexmp.2025.104977","url":null,"abstract":"<div><div>Salt-inducible kinase (SIK) is a serine/threonine kinase that acts as an intracellular Na⁺ sensor, playing a role in salt-sensitive hypertension. We aimed to evaluate the therapeutic potential of YKL-05-099, a selective SIK inhibitor, in protecting kidney function and attenuating salt-sensitive hypertension. Male adult C57BL/6 J mice were randomly assigned to either a normal sodium (0.5 % NaCl; NS) or high‑sodium diet (4 % NaCl; HS) and further divided into two subgroups – receiving either intraperitoneal injection of saline or SIK inhibitor (SIKi; YKL-05-099, 20 mg/Kg/day). Blood pressure was measured by radiotelemetry for 15 days. On days 7 and 14, mice were placed in metabolic cages for 24 h urine collection. At the end of the treatment, blood and kidneys were collected for renal function assessment, and the renal cortex was extracted for biochemical analysis. HS intake led to a salt-sensitive hypertension model, as seen by increased systolic blood pressure (SPB), kidney damage and impairment in renal function. In the HS, SIKi treatment blocked the elevated SIK activity in the renal cortex, preventing kidney damage, proteinuria, and increased SBP. The Na⁺ balance was positive due, partly, to a higher (Na⁺+K⁺)-ATPase activity in the HS. SIKi treatment exerted an anti-inflammatory effect by attenuating HS-dependent macrophage infiltration and ROS production and decreasing the metalloprotease activity. Consequently, the kidney damage biomarker monocyte chemotactic protein type 1 excretion was enhanced. In conclusion, SIK inhibition rescued HS mice from salt-sensitive hypertension and kidney insufficiency by blocking inflammation, metalloprotease activity, and oxidative stress.</div></div><div><h3>Significance</h3><div>Salt-sensitive hypertension is a major contributor to chronic kidney disease and cardiovascular morbidity worldwide. Despite its prevalence, the underlying mechanisms linking high salt intake to renal injury remain incompletely understood, and targeted therapies are lacking. This study identifies salt-inducible kinase (SIK) as a key mediator of salt-induced renal dysfunction and systemic hypertension. By using a selective SIK inhibitor (YKL-05-099), we demonstrate that pharmacological inhibition of SIK effectively prevents kidney damage, inflammation, oxidative stress, and high blood pressure in a preclinical model of salt-sensitive hypertension. These findings highlight SIK as a promising therapeutic target for preserving renal function and managing salt-induced hypertension, paving the way for novel interventions in salt-related cardiovascular and renal diseases.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104977"},"PeriodicalIF":2.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656118","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}

{"title":"Small intestinal bacteria accelerate aspirin-induced small intestinal injuries","authors":"Fumio Kakizaki ,&nbsp;Teruo Miyazaki ,&nbsp;Hajime Ueda ,&nbsp;Junichi Iwamoto ,&nbsp;Akira Honda ,&nbsp;Tadashi Ikegami","doi":"10.1016/j.yexmp.2025.104984","DOIUrl":"10.1016/j.yexmp.2025.104984","url":null,"abstract":"<div><h3>Background</h3><div>Small intestinal mucosal injuries are observed during treatment with enteric-coated, low-dose aspirin (LDA) through uncertain mechanism(s). Because aspirin (acetylsalicylic acid, ASA) is an acetylated form of the highly cytotoxic salicylic acid (SA), we hypothesized that SA deacetylated by esterases in the small intestine directly causes mucosal injuries. This study explored the mechanism(s) of ASA deacetylation to SA in the small intestinal environment.</div></div><div><h3>Methods</h3><div>ASA was added to the x, and deacetylation of added ASA and cell damage were evaluated. To explore the ASA deacetylation mechanism(s) in the intestinal environment, ASA was incubated with different pH phosphate buffers (4.01–9.10), pancreatic enzymes, homogenates of pancreas and IEC-6 cell, and caecum bacterial suspension (CBS). ASA and CBS were co-injected into the murine duodenum, and small intestinal damage was evaluated after an hour by histological observation.</div></div><div><h3>Results</h3><div>Intestinal cell damage was caused dependently on the deacetylation rate of added ASA to SA in the cell and culture media. In vitro, almost ASA was not deacetylated by incubation with different pH buffer, pancreatic enzymes, or IEC-6 cell homogenate, but deacetylation of ASA was significantly promoted with CBS. ASA deacetylation by bacterial esterases(s) was confirmed by adding an esterase-specific inhibitor, potassium fluoride. Furthermore, severe injuries throughout the entire murine small intestine were found after co-injection of ASA and CBS, but not after ASA alone.</div></div><div><h3>Conclusions</h3><div>Enteric-coated, LDA-induced mucosal injuries in the small intestine are mainly caused by direct cytotoxicity of SA deacetylated by enterobacterial esterase in the small intestine.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"143 ","pages":"Article 104984"},"PeriodicalIF":2.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614742","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}