Life sciences最新文献

{"title":"Pulmonary neuroendocrine cell as a therapeutic strategy in pulmonary hypertension: Great expectations or Bleak House?","authors":"Yunhua Yang ,&nbsp;Yurong Zhang ,&nbsp;Shaoxin Gong ,&nbsp;Na Liang ,&nbsp;Nanping Li ,&nbsp;Gangkai Tan ,&nbsp;Xiaoyong Lei ,&nbsp;Aiping Wang","doi":"10.1016/j.lfs.2026.124194","DOIUrl":"10.1016/j.lfs.2026.124194","url":null,"abstract":"<div><div>Pulmonary hypertension (PH) is a cardiovascular disease with a poor prognosis, mainly attributed to irreversible pulmonary vascular remodeling. Although there are already mature clinical diagnosis and treatment guidelines, the mortality rate of PH remains unacceptably high, highlighting the urgent need for innovative treatment strategies. Pulmonary neuroendocrine cells (PNECs) are rare pulmonary epithelial cells distributed in the airways and have physiological functions such as regulating chemical sensation and tissue repair. The proliferation phenomenon of PNECs in chronic lung diseases, notably COPD and asthma, as well as its identity as a progenitor cell of lung neuroendocrine carcinoma, jointly emphasize the therapeutic potential of targeting PNECs. Emerging evidence indicates that PNECs can regulate the tension of micro vessels around the bronchioles through paracrine neuropeptide signaling and lead to vascular pathological remodeling, making it a potential therapeutic target for PH. This review systematically describes the pathophysiological contribution of PNECs to PH development, with particular attention to the homeostasis regulation of pulmonary vascular wall cells such as pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) by their paracrine bioactive substances. We further explored the therapeutic strategies and challenges of regulating pulmonary vascular remodeling driven by PNECs, with the expectation of achieving precise PH management.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124194"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LEAP2 acts in hepatocytes and at central level, alleviates steatosis and inflammation but resistance in obese and aging","authors":"Marta V. Miguéns ,&nbsp;Carmen Quintela-Vilariño ,&nbsp;Sabela Casado ,&nbsp;Tadeu de Oliveira-Diz ,&nbsp;Timo D. Müller ,&nbsp;Rubén Nogueiras ,&nbsp;Carlos Diéguez ,&nbsp;Sulay Tovar","doi":"10.1016/j.lfs.2026.124219","DOIUrl":"10.1016/j.lfs.2026.124219","url":null,"abstract":"<div><h3>Scope</h3><div>Global increase in obesity and metabolic syndrome has led to a marked rise in comorbidities, with liver disease emerging as a major concern. Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over 30% of the population, making it the most prevalent liver disorder worldwide. Hepatic steatosis, hallmark of MAFLD, can progress to inflammation, fibrosis, steatohepatitis, and cirrhosis. Despite advances in elucidating its mechanisms, no effective pharmacological therapy exists to reverse disease progression. Ghrelin signaling axis has been implicated in energy and lipid homeostasis, and the recent identification of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous ghrelin receptor antagonist and inverse agonist has generated interest in its potential role in liver metabolism. The primary objective of this study was to evaluate LEAP2 on hepatocyte lipid metabolism and determine its capacity to prevent diet- and age-induced steatosis in vivo.</div></div><div><h3>Methods and results</h3><div>We investigated LEAP2 actions on hepatocyte lipid metabolism using human and mouse hepatocyte cultures, also we did in vivo studies in mice with chronic central LEAP2 administration in models of diet-induced and age-related steatosis.</div><div>LEAP2 inhibited lipid accumulation in hepatocytes and reduced hepatic lipid deposition in mice fed a standard diet. However, LEAP2 did not prevent high-fat diet–induced steatosis in young mice although it attenuated hepatic inflammation. In aged animals, LEAP2 failed to suppress age-associated inflammation and steatosis.</div></div><div><h3>Conclusion</h3><div>LEAP2 has been identified as a novel regulator of hepatic lipid metabolism with the potential to counteract inflammation-associated steatosis, although its effects on age-related steatosis appear limited. Targeting the LEAP2–ghrelin axis may represent a promising therapeutic strategy; however, further studies are required to determine its efficacy in diet-induced hepatic disease.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124219"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compressive stress induces cartilage endplate degeneration through the Piezo1/YAP-TEAD/NLRP3 axis","authors":"Tong Cao ,&nbsp;Fushuai Peng ,&nbsp;Wei Wang ,&nbsp;Xingzhi Jing ,&nbsp;Fei Chen ,&nbsp;Mingtong Sun ,&nbsp;Jiaju Ma ,&nbsp;Wei Yang ,&nbsp;Zhihao Xu ,&nbsp;Zhenghao Xie ,&nbsp;Jun Dong ,&nbsp;Tao Li","doi":"10.1016/j.lfs.2026.124195","DOIUrl":"10.1016/j.lfs.2026.124195","url":null,"abstract":"<div><h3>Aims</h3><div>To investigate the potential mechanisms by which compressive stress induces degeneration of cartilage endplate, and to elucidate the specific roles of mechanosensitive protein Piezo1, YAP, and NLRP3 in this process. A pressure-inflammation model of chondrocytes is proposed.</div></div><div><h3>Materials and methods</h3><div>Firstly, a bipedal standing mouse model was established to investigate the effect of mechanical stress on cartilage endplate degeneration and calcification. Next, cells were subjected to compression stress and western blot analysis as well as Bulk RNAseq were employed to detect the expression changes of Piezo1, YAP, NLRP3, ASC, and IL-1β. Additionally, intracellular Ca²⁺ levels, cytoskeleton and mitochondrial membrane potential were assessed. At last, Piezo1 chondrocyte conditional knockout mice were established to illustrate the role of Piezo1 in mechanical stress induced cartilage endplate degeneration.</div></div><div><h3>Key findings</h3><div>The bipedal standing mouse model demonstrated that compressive stress promotes cartilage endplate degeneration. The in vitro experiments demonstrated that compressive stress promoted degeneration of cartilage endplate via Piezo1-induced NLRP3 activation. Compressive stress activate Piezo1, triggering Ca²⁺ influx and promoting cytoskeletal polymerization, which facilitated nuclear translocation of YAP. Subsequently, YAP-TEAD complex formation activated the NLRP3 inflammasome, leading to enhanced expression of IL-1β, MMP13, MMP3, RUNX2, and COL10, while suppressing expression of COL2 and SOX9.</div></div><div><h3>Significance</h3><div>Our study reveals the role of Piezo1/YAP-TEAD/NLRP3 axis in pressure stress-induced cartilage endplate degeneration. This signaling axis not only regulates inflammation, ossification, and oxidative stress responses in chondrocytes but also promotes chondrocyte apoptosis through mitochondrial dysfunction. These findings provide novel molecular mechanisms for understanding the role of mechanical stress in cartilage degeneration.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124195"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145933862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Galectin-9 in human trophoblast cells: Implications for maternal-fetal immune balance and pregnancy complications","authors":"Xuqing He ,&nbsp;Penghao Li ,&nbsp;Jingliang Xu ,&nbsp;Jingxian Zhang ,&nbsp;Yungang Liu ,&nbsp;Ju Huang ,&nbsp;Xinrui Chi ,&nbsp;Qiaoxin Zhang ,&nbsp;Yanrong Chen ,&nbsp;Jin Huang ,&nbsp;Hui Wang ,&nbsp;Zhengping Zhuang ,&nbsp;Jiang Gu","doi":"10.1016/j.lfs.2025.124173","DOIUrl":"10.1016/j.lfs.2025.124173","url":null,"abstract":"<div><h3>Introduction</h3><div>Galectin-9 (Gal-9) is a multifunctional protein belonging to the β-galactoside-binding lectin family playing crucial roles in immune regulation of tumor and pregnancy. However, its roles in placental pathophysiology such as preeclampsia have not been well understood. In this study the involvement of Gal-9 in trophoblast functioning and sustained immune balance were explored.</div></div><div><h3>Methods</h3><div>Immortalized human trophoblast cells (HTR-8/SVneo) were subjected to chemical hypoxia (induced by CoCl₂) and oxidative stress (induced by HMGB1), then treated with HIF-1α knockdown or specific inhibitors. Subsequently, Gal-9 and IgG4 (another newly established immune regulator of pregnancy) levels were analyzed with immunofluorescence assay and Western blotting, and in human placental tissues with immunohistochemistry; moreover, the invasiveness of HTR-8/SVneo cells co-cultured with peripheral blood mononuclear cells (PBMCs) was evaluated with transwell assay, and IgG4 determined with ELISA and Western blotting.</div></div><div><h3>Results</h3><div>Both chemical hypoxia and oxidative stress induced Gal-9 expression in HTR-8/SVneo cells, which were initiated by the elevation of HIF-1 and apoptosis signal-regulating kinase 1 (ASK1), respectively. Interestingly, IgG4 secretion from PBMCs co-cultured with HTR-8/SVneo was dependent on the duration of hypoxia: it was enhanced up to day 5 but inhibited by day 7, with persistent elevation of Gal-9 but apoptosis of PBMCs under prolonged hypoxia.</div></div><div><h3>Conclusion</h3><div>Hypoxia and oxidative stress upregulate trophoblast Gal-9 through distinct mechanisms. Hypoxia duration affects IgG4 production in co-cultures—enhanced short-term but suppressed long-term—implying pathological placental hypoxia may increase Gal-9, reduce IgG4, and disrupt maternal-fetal immune balance. This newly discovered regulatory pathway of Gal-9 in the placenta during pregnancy may contribute to the pathogenesis of pregnancy-associated diseases including PE.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124173"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “SNHG8/miR-873-3p/CDK6 axis triggers proliferation and migration of smooth muscle cells in intimal hyperplasia” [Life Sci. 379 (2025) 123878]","authors":"Jiaying Sun ,&nbsp;Jing Qi ,&nbsp;Jianyao Su ,&nbsp;Jiye Wan","doi":"10.1016/j.lfs.2026.124198","DOIUrl":"10.1016/j.lfs.2026.124198","url":null,"abstract":"","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124198"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emodin induces oxidative stress and Ferroptosis in hepatocellular carcinoma cells through the miR-4465/NFE2L3/HMGCR/GPX4 signaling axis","authors":"Zhiran Ding ,&nbsp;Menghua Zheng ,&nbsp;Bingbing Mou ,&nbsp;Yu Li ,&nbsp;Boxin Qin ,&nbsp;Lu Qiu ,&nbsp;Xuesong Yang ,&nbsp;Yonggang Ren","doi":"10.1016/j.lfs.2026.124200","DOIUrl":"10.1016/j.lfs.2026.124200","url":null,"abstract":"<div><h3>Aims</h3><div>Emodin, a natural anthraquinone, exerts antitumor effects by increasing reactive oxygen species (ROS) and inducing apoptosis, autophagy, and cell-cycle arrest. However, its potential to induce ferroptosis, a distinct iron-dependent cell death, in hepatocellular carcinoma (HCC) remains unexplored.</div></div><div><h3>Materials and methods</h3><div>The anti-proliferative effect of Emodin was assessed in human HCC cell lines HepG2 and MHCC97H. Ferroptosis was evaluated following treatment with 40 μM Emodin for 24 h, measuring ROS, lipid peroxidation, glutathione levels, and mitochondrial morphology. Molecular mechanisms were investigated via reverse transcription polymerase chain reaction (RT-qPCR), western blot, and functional rescue experiments. A HepG2 xenograft model (25 and 50 mg/kg Emodin, intraperitoneal.) and immunohistochemistry were used to confirm the findings in vivo.</div></div><div><h3>Key findings</h3><div>Emodin inhibited HCC cell proliferation and induced ferroptosis, characterized by ROS accumulation, lipid peroxidation, and reduced glutathione levels, mitochondrial membrane potential, and glutathione peroxidase 4 (GPX4) expression. Mechanistically, Emodin upregulated microRNA-4465 (miR-4465), which directly targeted and suppressed the NFE2 like bZIP transcription factor 3 (NFE2L3). This led to inhibition of the NFE2L3/3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)/GPX4 signaling axis. Overexpression of NFE2L3 rescued cells from Emodin-induced ferroptosis. In the xenograft model, Emodin significantly suppressed tumor growth and downregulated the NFE2L3/HMGCR/GPX4 pathway in tumor tissues.</div></div><div><h3>Significance</h3><div>Our study demonstrates that Emodin induces ferroptosis through the miR-4465/NFE2L3/HMGCR/GPX4 axis in HCC, revealing NFE2L3's role in ferroptosis and suggesting Emodin as a promising therapeutic candidate.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124200"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sinomenine ameliorates myocardial ischemia/reperfusion injury by inhibiting mitochondrial oxidative stress-mediated PANoptosis and ferroptosis via α7nAChR","authors":"Jia-Rong Yang ,&nbsp;Fu-Qin Tan ,&nbsp;Chen-Jie Cheng,&nbsp;Meng-Wan Zhang,&nbsp;Jian-Guang Yu","doi":"10.1016/j.lfs.2026.124199","DOIUrl":"10.1016/j.lfs.2026.124199","url":null,"abstract":"<div><h3>Aims</h3><div>To elucidate the cardioprotective effect of sinomenine (SIN) against myocardial ischemia/reperfusion injury (MIRI) and to investigate the role of the α7 nicotinic acetylcholine receptor (α7nAChR) and its downstream mechanisms.</div></div><div><h3>Materials and methods</h3><div>A murine MIRI model and cardiomyocyte hypoxia/reoxygenation (H/R) models were employed. Key parameters measured included myocardial infarct size, cardiac function, lactate dehydrogenase (LDH) activity, cell viability, adenosine triphosphate (ATP) content, 4-hydroxynonenal (4-HNE) level, α7nAChR expression, mitochondrial reactive oxygen species (ROS), and markers of PANoptosis and ferroptosis. The role of α7nAChR was verified using its antagonist methyllycaconitine and specific siRNA. The mitochondrial antioxidant mito-TEMPO served as a positive control in key cellular assays.</div></div><div><h3>Key findings</h3><div>SIN reduced myocardial infarct size, serum LDH, and cardiomyocyte apoptosis, while improving cardiac function and increasing myocardial ATP and α7nAChR expression in MIRI mice, with concordant reductions in oxidative stress marker 4-HNE. In H/R-injured cardiomyocytes, SIN restored cell viability, decreased LDH release, preserved ATP, attenuated oxidative stress (4-HNE, mitochondrial ROS), and upregulated α7nAChR. SIN concurrently suppressed PANoptosis (apoptosis, necroptosis, pyroptosis) and ferroptosis. The efficacy of SIN in reducing mitochondrial ROS and cell death was comparable to mito-TEMPO. All protective effects of SIN were abolished by inhibition of α7nAChR.</div></div><div><h3>Significance</h3><div>This study provides the first evidence linking SIN's cardioprotection to the concurrent inhibition of PANoptosis and ferroptosis via α7nAChR activation. We demonstrate that SIN protects against MIRI by activating α7nAChR, thereby improving mitochondrial function, reducing oxidative stress, and suppressing integrated cell death pathways, identifying α7nAChR as a promising target for MIRI.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124199"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exogenous hydrogen sulphide alleviates diabetes-associated cognitive decline by inhibiting ferroptosis through Nrf2/GPX4 signalling pathway","authors":"Wei Hua ,&nbsp;Yilei Sun ,&nbsp;Mingze Sun ,&nbsp;Yiying Liu ,&nbsp;Hongxue Sun ,&nbsp;Huinan Chen ,&nbsp;Shuainan Ma","doi":"10.1016/j.lfs.2026.124220","DOIUrl":"10.1016/j.lfs.2026.124220","url":null,"abstract":"<div><h3>Aims</h3><div>Neuronal ferroptosis affects the pathogenesis of diabetes-associated cognitive decline (DACD). Exogenous hydrogen sulphide (H₂S) treatment ameliorates cognitive deficits in diabetic mice. This study aimed to explore whether H₂S exerts neuroprotective effects by suppressing ferroptosis through activation of Nrf2/GPX4 signalling pathway.</div></div><div><h3>Materials and methods</h3><div>STZ-induced diabetic mice received NaHS or NaHS combined with the Nrf2 inhibitor ML385, after which cognitive functions were evaluated using the Morris water maze test. Hippocampal neuronal damage and mitochondrial morphological changes were identified using transmission electron microscopy, haematoxylin and eosin (H&amp;E) staining, Nissl staining, and immunofluorescence staining. The expression levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and iron were determined using assay kits. Western blotting was performed to evaluate the expression of the Nrf2/GPX4 axis, iron transport-related proteins, and GSH synthesis enzymes.</div></div><div><h3>Key findings</h3><div>Exogenous H₂S treatment ameliorated cognitive deficits by mitigating hippocampal neuronal loss and improving synaptic ultrastructural integrity. The levels of ROS, MDA, and iron were reduced, whereas SOD, GSH, and Nrf2/GPX4 expression were increased following NaHS administration. Exogenous H₂S also ameliorated mitochondrial impairment and suppressed ferroptosis in the hippocampal neurones. However, these neuroprotective effects were abolished by ML385. Diabetic mice cotreated with ML385 and NaHS exhibited prolonged escape latency and reduced time in the target quadrant. Additionally, ML385 co-administration with NaHS exacerbated neuronal damage, oxidative stress, synaptic ultrastructural abnormalities, and iron dysregulation, while downregulating Nrf2/GPX4 expression and inhibiting ferroptosis suppression.</div></div><div><h3>Significance</h3><div>Exogenous H₂S treatment alleviates DACD by suppressing ferroptosis via activation of the Nrf2/GPX4 signalling pathway.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124220"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sinapic acid balances the excitatory and inhibitory neurotransmitter systems to mitigate post-traumatic stress disorder-like behaviors","authors":"Chang Hyeon Kong ,&nbsp;Keontae Park ,&nbsp;Ju Eun Han ,&nbsp;Ho Jung Bae ,&nbsp;Se Jin Park ,&nbsp;Seo Yun Jung ,&nbsp;Dong Hyun Kim ,&nbsp;Jong Hoon Ryu","doi":"10.1016/j.lfs.2026.124201","DOIUrl":"10.1016/j.lfs.2026.124201","url":null,"abstract":"<div><div>Post-traumatic stress disorder (PTSD) is a mental illness that can occur in individuals who have experienced trauma. Sinapic acid has been reported to be effective for anxiety as a GABA_A receptor agonist, and has been reported to improve cognitive impairment by modulating the GABA/glutamate ratio, but there are no reports associated with PTSD. In the present study, we investigated the effects of sinapic acid in a mouse model of PTSD induced by a single prolonged stress (SPS) protocol.</div><div>We examined the therapeutic effects of sinapic acid on emotional and cognitive impairment in the SPS mouse model. We also explored the effects of sinapic acid on fear memory extinction. Western blot was employed to investigate how sinapic acid exerts its pharmacological activities.</div><div>Sinapic acid ameliorated PTSD-like behaviors in a SPS mouse model. Notably, in the case of cognitive dysfunction, paroxetine failed to improve, but sinapic acid restored cognitive function. Additionally, sinapic acid did not increase locomotor behavior, while paroxetine increased. Furthermore, sinapic acid normalized the overactivated GluN2B-containing NMDA receptor signaling pathway in the amygdala and the hypothalamus. The mitigation of fear memory deficits by sinapic acid was exerted by sub-effective dose of GluN2B-containing NMDA receptor antagonist and abolished by GABA_A receptor antagonist.</div><div>Our findings suggest that sinapic acid could serve as a potential therapeutic agent for PTSD by balancing excitatory and inhibitory neurotransmitter systems due to its action on GluN2B-containing NMDA receptors and GABA_A receptors.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124201"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New insights in the chronic kidney disease-associated osteoarthritis progression: Role of uremic toxin indoxyl sulfate-induced chondrocyte senescence and ferroptosis","authors":"Yao-Pang Chung ,&nbsp;Ya-Wen Chen ,&nbsp;Chun-Fa Huang ,&nbsp;Te-I Weng ,&nbsp;Rong-Sen Yang ,&nbsp;Shing-Hwa Liu","doi":"10.1016/j.lfs.2026.124211","DOIUrl":"10.1016/j.lfs.2026.124211","url":null,"abstract":"<div><h3>Aims</h3><div>Epidemiological data have shown a notably high co-occurrence of osteoarthritis (OA) and chronic kidney disease (CKD). The pathological mechanisms for CKD-associated OA still remain to be clarified. Uremic toxin Indoxyl Sulfate (IS), accumulated in CKD, may play a role in OA pathology. This study aimed to clarify the role of IS in CKD-associated OA and investigated the involvement of chondrocyte senescence and ferroptosis through the crosstalk between calcium and iron metabolism.</div></div><div><h3>Materials and methods</h3><div>Human chondrocytes were treated with IS and co-treated with either calcium chelator BAPTA or iron chelator Deferoxamine (DFO). Cellular senescence and ferroptosis were assessed. An adenine-induced CKD mouse model was utilized to evaluate OA features and molecular mechanisms with or without oral adsorbent AST-120 (reducing IS levels) or DFO treatment.</div></div><div><h3>Key findings</h3><div>IS exposure elevated intracellular iron and calcium, triggering chondrocyte lipid peroxidation, senescence and ferroptosis via the calpain-1/interleukin-1α signaling axis, which could be reversed by both BAPTA and DFO treatment. IS-increased intracellular iron levels could be reversed by DFO, but not BAPTA. In vivo, reducing IS levels with AST-120 or iron chelation with DFO alleviated cartilage degradation and iron accumulation. Protein expression patterns in the joint tissues mirrored those observed in cell culture.</div></div><div><h3>Significance</h3><div>Our findings demonstrate for the first time that IS promotes both calcium influx and iron accumulation, leading to enhanced chondrocyte lipid peroxidation, senescence and ferroptosis. These effects may underlie the mechanistic link between CKD and OA comorbidity. IS may thus represent a critical bridge between kidney dysfunction and joint degeneration.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124211"},"PeriodicalIF":5.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}