Life sciences最新文献

{"title":"Exposure to low-dose CuO nanoparticles improves fear extinction memory and enhance intrinsic excitability in the infralimbic cortex of male mice","authors":"Rahma Ammar ,&nbsp;Laura E. Maglio ,&nbsp;Mariem Naffeti ,&nbsp;María Covadonga Aguado Ballano ,&nbsp;Marta Callejo-Móstoles ,&nbsp;Yassine Chtourou ,&nbsp;Hamadi Fetoui ,&nbsp;David Fernández de Sevilla","doi":"10.1016/j.lfs.2025.123982","DOIUrl":"10.1016/j.lfs.2025.123982","url":null,"abstract":"<div><h3>Aims</h3><div>Nanomaterials have gained considerable attention for diverse medical applications, particularly in neurology. Copper oxide nanoparticles (CuO-NPs) exhibit unique nanoscale properties that enable close interactions with neuronal cells, highlighting their potential as therapeutic agents for modulating synaptic plasticity and improving cognitive function. We aimed to investigate whether low-dose CuO-NPs can enhance fear extinction memory and increase intrinsic excitability in the infralimbic cortex (IL) of male mice.</div></div><div><h3>Materials and methods</h3><div>Adult male mice were subjected to fear conditioning using auditory cues paired with footshocks. Following the administration of a low dose of CuO-NPs, behavioral performance was assessed by measuring freezing responses during extinction. Whole-cell patch-clamp recordings were then performed on IL pyramidal neurons to evaluate intrinsic excitability and AMPA/NMDA ratio. Transmission electron microscopy (TEM) was applied after 2 and 24 h to assess the ability of CuO-NPs to reach the brain.</div></div><div><h3>Key findings</h3><div>We demonstrated via TEM that CuO-NPs efficiently cross the blood-brain barrier within 24 h' post-administration. Using cued fear conditioning, we subsequently found that a single intraperitoneal injection of CuO-NPs enhanced fear extinction memory, as evidenced by a significant reduction in freezing behavior compared to control animals. Patch-clamp analysis confirmed that CuO-NPs increased the excitability of IL pyramidal neurons and induced a sustained reduction in fast, medium, and slow post-spike after hyperpolarizations. Additionally, we demonstrated that CuO-NPs increased <em>N</em>-methyl-<span>d</span>-aspartate receptor-mediated synaptic currents, suggesting an enhanced synaptic plasticity in the infralimbic cortex.</div></div><div><h3>Significance</h3><div>Our findings offer new insights into the potential use of CuO-NPs for modulating fear extinction memory.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"381 ","pages":"Article 123982"},"PeriodicalIF":5.1,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145120481","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":"The gut microbiota and cardiovascular disease: Exploring the role of microbial dysbiosis and metabolites in pathogenesis and therapeutics","authors":"Amin Mohsenzadeh ,&nbsp;Sahar Pourasgar ,&nbsp;Amirali Mohammadi ,&nbsp;Mahdis Nazari ,&nbsp;Soroush Nematollahi ,&nbsp;Yeganeh Karimi ,&nbsp;Parisa Firoozbakhsh ,&nbsp;Hossein Mohsenzadeh ,&nbsp;Kasra Kamali ,&nbsp;Reza Elahi","doi":"10.1016/j.lfs.2025.123981","DOIUrl":"10.1016/j.lfs.2025.123981","url":null,"abstract":"<div><div>The gut microbiota, a dynamic ecosystem of microorganisms inhabiting the human body, plays a pivotal role in modulating host physiology and immune function, with intense implications for the cardiovascular system. Cardiovascular diseases (CVDs) stand out as the leading cause of mortality worldwide. Gut microbiome dysbiosis is implicated in diverse CVDs, such as hypertension, atherosclerosis, coronary artery disease, heart failure, and myocardial infarction, through mechanisms mediated by microbial-derived metabolites. Key compounds include trimethylamine N-oxide (TMAO) (linked to plaque instability), short-chain fatty acids (SCFAs) (which regulate blood pressure and endothelial function), phenylacetylglutamine (PAGln) (a promoter of thrombotic pathways), and bile acids (influencing lipid metabolism). These metabolites serve as both biomarkers of CVD risk and therapeutic targets. Emerging strategies to modulate the gut microbiota, such as precision probiotics, dietary interventions (e.g., fiber-rich or polyphenol-heavy diets), and pharmacologic inhibitors of microbial enzymes (e.g., TMA lyase blockers), highlight the potential for microbiome-directed therapies. However, challenges remain in elucidating causal microbial pathways, standardizing interventions across diverse populations, and translating preclinical findings into clinical practice. In this mechanistic and translational review, we synthesize current evidence on the bidirectional relationship between gut microbial dysbiosis and CVDs. We explore how modifiable factors, including diet, pharmacotherapy, and early-life microbial colonization, reshape gut communities, driving systemic inflammation, metabolic dysfunction, and vascular pathology. Future research must prioritize longitudinal human studies, multi-omics integration, and randomized trials to harness the gut microbiota's full potential in CVD prevention and personalized treatment.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"381 ","pages":"Article 123981"},"PeriodicalIF":5.1,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131262","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":"Effects of apelin on age-associated neovascularization impairment in peripheral artery disease","authors":"Junyu Chen ,&nbsp;Minghong Chen ,&nbsp;Yu Liu ,&nbsp;Xuerui Wang ,&nbsp;Meilian Yao ,&nbsp;Jing Chen ,&nbsp;Jian Zhang ,&nbsp;Qunyong Peng","doi":"10.1016/j.lfs.2025.123980","DOIUrl":"10.1016/j.lfs.2025.123980","url":null,"abstract":"<div><h3>Aims</h3><div>Peripheral artery disease (PAD) is a prevalent vascular condition in the elderly. Aging induces senescence and dysfunction of endothelial cells (ECs), which contributes to impaired neovascularization. This study aims to investigate the therapeutic potential of apelin in restoring neovascularization in older patients with PAD.</div></div><div><h3>Materials and methods</h3><div>We measured plasma apelin levels of young and elderly patients with PAD, as well as in mice following hindlimb ischemia (HLI). Aged mice were treated with apelin or vehicle. Blood flow recovery was monitored using Laser Doppler imaging. To evaluate neovascularization, we performed micro-CT-based vascular angiography, whole-mount, and immunofluorescence staining. In addition, the effects of apelin on ECs were assessed by measuring reactive oxygen species, senescence-associated β-galactosidase staining, and performing a series of functional assays.</div></div><div><h3>Key findings</h3><div>Here, we report for the first time that plasma apelin levels are significantly reduced in older PAD patients and are closely associated with relevant clinical parameters. A similar reduction was also observed in mice following HLI. In aged mice with HLI, apelin treatment markedly enhanced blood flow recovery. Further analysis demonstrated that apelin promotes neovascularization after ischemia. Both <em>in vivo</em> and <em>in vitro</em> experiments confirmed that apelin facilitates neovascularization by improving endothelial function and mitigating ECs senescence <em>via</em> activation of APJ.</div></div><div><h3>Significance</h3><div>This study integrates clinical observations with experimental evidence, highlighting the therapeutic potential of apelin in promoting neovascularization and enhancing its translational relevance for the treatment of PAD in the elderly.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"381 ","pages":"Article 123980"},"PeriodicalIF":5.1,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109768","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":"Obesity-aggravated erythrocyte injury in ischaemia-reperfusion: Interlinked oxidative stress, metabolic reprogramming, and cytoskeletal destabilisation","authors":"Xiaochen Wang ,&nbsp;Rui Li ,&nbsp;Yuanbing You ,&nbsp;Yidi Gao ,&nbsp;Tiantian Wang ,&nbsp;Jingkang Li ,&nbsp;Qiong Zhang","doi":"10.1016/j.lfs.2025.123975","DOIUrl":"10.1016/j.lfs.2025.123975","url":null,"abstract":"<div><div>Anaemia in obese patients who underwent major vascular surgery is closely associated with ischaemia-reperfusion injury (IRI)-driven erythrocyte damage and haemolysis. However, the obesity-specific mechanisms remain unknown. We investigated the interplay among oxidative stress, metabolic reprogramming, and cytoskeletal destabilisation in red blood cells (RBCs) during aortic IRI under obese conditions. Using a high-fat diet-induced obese mouse model subjected to abdominal aortic clamping–reperfusion, we systematically dissected the hierarchical mechanisms linking obesity to erythrocyte vulnerability during IRI. The key findings were<strong>—</strong>oxidative amplification<strong>—</strong>obese mice exhibited a pronounced intraerythrocytic reactive oxygen species surge post-IRI, accompanied by a compensatory upregulation of antioxidant enzymes (catalase and glutathione peroxidase). However, persistent accumulation of oxidative stress markers (malondialdehyde, 8-hydroxy-2′-deoxyguanosine, and carbonylated proteins) indicated overwhelming oxidative stress. Metabolic iron dysregulation<strong>—</strong>elevated Fe³⁺ and methaemoglobin levels and NADPH/ATP depletion indicated concurrent iron homeostasis disruption and metabolic crisis, respectively. RBCs glycolytic reprogramming is characterized by imbalanced glycolytic flux with accumulation of intermediates (glucose-6-phosphate [G6P] and fructose-6-phosphate), despite compensatory activation of the pentose phosphate pathway (PPP) and Rapoport-Luebering shunt (RLS). Structural destabilisation: critical cytoskeletal protein expression including expression of Band 3, glycophorin C, α/β-spectrin, and adducin, was significantly downregulated, with tropomodulin 1 and tropomyosin displaying the most prominent reductions, resulting in membrane fragility and haemolysis (elevated levels of haemoglobin, bilirubin, and circulating methaemoglobin). Collectively, we identified an ‘oxidative–metabolic–structural collapse’ axis that mediates obesity-aggravated erythrocyte injury during IRI, providing a mechanistic foundation for developing perioperative erythrocyte-protective strategies in metabolic syndrome with potential to improve cardiovascular surgery outcomes.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"380 ","pages":"Article 123975"},"PeriodicalIF":5.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103035","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":"CREB-dependent neurobehavioral alterations via TAAR1 receptor modulation in a chronic unpredictable stress model","authors":"Ojashvi Sharma ,&nbsp;Amarjot Kaur Grewal ,&nbsp;Amit Kumar ,&nbsp;Varinder Singh ,&nbsp;Thakur Gurjeet Singh ,&nbsp;Tanveer Singh ,&nbsp;Sheikh F. Ahmad ,&nbsp;Haneen A. Al-Mazroua","doi":"10.1016/j.lfs.2025.123978","DOIUrl":"10.1016/j.lfs.2025.123978","url":null,"abstract":"<div><div>CUS disrupts brain cellular and molecular physiology, leading to neurotransmitter and neuroendocrine dysregulation, resulting in neurobehavioral changes like anxiety, depression, and cognitive impairment. Numerous neurobiological pathways regulating neurotransmitter systems, are implicated in mood regulation and stress response, notably the TAAR1 receptor have been documented to play a major role in neuropshychiatric diseases. This research investigates CREB-dependent neurobehavioral alterations via TAAR1 receptor modulation with RO5256390 in Chronic Unpredictable Stress Model. For evaluating the impact of CUS and pharmacological interventions on neurobehavioral changes, Swiss albino mice of either sex were subjected to various stressors for 8 weeks. The behavioral traits for anxiety, depression and memory impairment were assessed by EPM, SPT, TST and MWM. The level of corticosterone dopamine, serotonin; biochemical parameters of oxidative stress, inflammatory mediators; acetylcholinesterase (AChE) activity and histological changes in hippocampus and cortex were also examined. Administration of RO5256390 (0.5, 1 and 2 mg/kg i.p), improved behavioral and biochemical parameters in CUS-exposed mice, most likely, by modulating the activity of TAAR1. Fluoxetine (20 mg/kg, p.o) was employed as a standard reference drug in CUS induced mice to facilitate clinical comparison. It was also observed that neuroprotective effects of RO5256390 were significantly abolished by pre-treatment with 666–15 (10 mg/kg, i.p.), a CREB inhibitor, which signifies the involvement of CREB signaling in attenuating the protective mechanism of RO5256390. Therefore, this study highlights the critical role of TAAR1-CREB pathway in neuroprotection and therapeutic potential of RO5256390 in alleviating neurobehavioral changes associated with CUS.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"381 ","pages":"Article 123978"},"PeriodicalIF":5.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103070","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":"Nerve implantation to the muscle after neuroma formation enables pain relief and motor function recovery with reinnervation in rats","authors":"Jinju Kwon ,&nbsp;Jaeseok Kim ,&nbsp;Young Wook Yoon ,&nbsp;Junesun Kim","doi":"10.1016/j.lfs.2025.123972","DOIUrl":"10.1016/j.lfs.2025.123972","url":null,"abstract":"<div><h3>Aims</h3><div>Neuroma formation after peripheral nerve injury inhibits functional recovery and contributes to neuropathic pain. This study aimed to evaluate whether nerve implantation into denervated muscle, even after neuroma formation, could promote motor and sensory functional restoration.</div></div><div><h3>Materials and methods</h3><div>A rat tibial nerve injury model was used. The tibial nerve was ligated and transected to induce neuroma, followed by nerve implantation into the gastrocnemius muscle at 12 days post-injury. Mechanical hypersensitivity was assessed by von Frey testing, and motor function was evaluated using the tibial nerve functional index (TFI). Histological analysis of neuromuscular junctions (NMJ), immunofluorescence of synaptophysin (SYP) in the spinal cord, and electromyography (EMG) were performed to assess reinnervation and synaptic recovery.</div></div><div><h3>Key findings</h3><div>Nerve implantation significantly reduced mechanical hypersensitivity beginning at 1-week post-implantation and maintained analgesic effects up to 30 weeks. Muscle atrophy was attenuated, and CSA was preserved in the implanted group. NMJ morphology was partially restored, and EMG confirmed partial recovery of neurophysiological muscle contraction beginning at 8 weeks and more clearly at 12 weeks. SYP expression in the ventral horn was significantly preserved at 30 weeks, indicating central modulation of motor signaling. Improvement in TFI supported motor restoration.</div></div><div><h3>Significance</h3><div>This study demonstrates that delayed nerve implantation into denervated muscle after neuroma formation can achieve motor and sensory recovery through reinnervation. These findings provide insights into the potential effects on nerve-muscle reconstruction treatment for peripheral nerve injury and establish an experimental basis for future clinical application with mechanism studies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"381 ","pages":"Article 123972"},"PeriodicalIF":5.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103080","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":"Chronic administration of the hydrogen sulfide prodrug SG1002 partially protects against erectile dysfunction resulting from long-term androgen deprivation","authors":"Colin M. Ihrig ,&nbsp;Clifford J. Pierre ,&nbsp;Tooyib A. Azeez ,&nbsp;Justin D. La Favor","doi":"10.1016/j.lfs.2025.123976","DOIUrl":"10.1016/j.lfs.2025.123976","url":null,"abstract":"<div><h3>Aims</h3><div>Androgen deprivation therapy is a common treatment strategy for prostate cancer, although erectile dysfunction (ED) often coincides as an undesirable side-effect. Hydrogen sulfide (H₂S) is an endogenous gasotransmitter with vasodilatory, anti-inflammatory, and antioxidant-like properties. H₂S therapies are being developed for cardiovascular disease management, although the properties of H₂S may also protect the erectile system.</div></div><div><h3>Materials and methods</h3><div>14-week-old male C57Bl/6 mice were subjected to sham surgery or castration, with castrated mice remaining untreated or treated orally with low- or high-doses of the H₂S prodrug SG1002 over the five-week intervention. Erectile function was assessed by intracavernous pressure and mean arterial pressure during cavernous nerve stimulation. Vascular reactivity of the corpus cavernosum (CC), internal pudendal artery (IPA), and internal iliac artery (IIA) were assessed by dose-dependent responses to vasodilatory, vasocontractile, and neurogenic stimuli in myograph systems. CC contents of proteins related to cellular autophagy, antioxidant defense, and mitochondrial dynamics were assessed by immunoblotting. Fibrotic remodeling was assessed by Masson's trichrome staining.</div></div><div><h3>Key findings</h3><div>SG1002 provided a moderate protection on erectile function against long-term androgen deprivation. Castration-induced alterations of several mechanisms of vasodilation and vasoconstriction of the CC and IPA were substantial, while alterations of the IIA modest, with subtle effects of SG1002 treatment across the vascular beds. SG1002 partially protected against castration-induced fibrotic remodeling of the IPA.</div></div><div><h3>Significance</h3><div>H₂S therapy provides a modest but potentially clinically relevant protection of erectile function and health of the erectile structures against the harshly damaging effects of chronic androgen deprivation.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"380 ","pages":"Article 123976"},"PeriodicalIF":5.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103068","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":"Smarca4 ablation in myeloid cells attenuates non-alcoholic fatty liver disease in mice","authors":"Xiulian Miao ,&nbsp;Yan Guo ,&nbsp;Shanwen Gong ,&nbsp;Jun Miao ,&nbsp;Lingling Sun ,&nbsp;Jing Zhuang","doi":"10.1016/j.lfs.2025.123977","DOIUrl":"10.1016/j.lfs.2025.123977","url":null,"abstract":"<div><h3>Aims</h3><div>Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and chronic inflammation. Intercellular crosstalk between hepatocytes and macrophages contributes to NAFLD pathogenesis. We investigated how ablation of Brg1 (encoded by <em>Smarca4</em>), a component of the chromatin remodeling complex, in macrophages might influence NAFLD pathogenesis in mice.</div></div><div><h3>Methods and materials</h3><div><em>Brg1</em>^f/f mice were crossed to <em>LyzM</em>-Cre mice to achieve myeloid cell specific Brg1 deletion. NAFLD was induced by feeding the mice with a high-fat high-carbohydrate (HFHC) diet.</div></div><div><h3>Key findings</h3><div>Brg1 expression was up-regulated in macrophages from the mice fed the HFHC diet compared to the control diet and in peripheral blood monocytic cells from the NAFLD patients compared to the healthy individuals. Co-culture with macrophages promoted lipid accumulation in hepatocytes whereas deletion or pharmaceutical inhibition of Brg1 in macrophages disrupted macrophage-hepatocyte crosstalk. Consistently, Brg1 ablation in myeloid cells attenuated NAFLD pathogenesis in mice. Importantly, administration of a small-molecule Brg1 inhibitor PFI-3 ameliorated NAFLD in mice. RNA-seq identified C<img>C motif chemokine ligand 7 (CCL7) as a downstream target for Brg1 in macrophages.</div></div><div><h3>Significance</h3><div>Our data suggest that Brg1 might contribute to NAFLD by mediating the macrophage-hepatocyte crosstalk to pivot hepatocytes to a pro-NAFLD phenotype.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"381 ","pages":"Article 123977"},"PeriodicalIF":5.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102726","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":"Zinc protoporphyrin-triggered ferroptosis plays a critical role in renal proximal tubular cell damage and chronic kidney disease","authors":"Li-Ting Tsai ,&nbsp;Ching-Chia Wang ,&nbsp;Chieh-Yun Liu ,&nbsp;Chih-Kang Chiang ,&nbsp;Shing-Hwa Liu","doi":"10.1016/j.lfs.2025.123974","DOIUrl":"10.1016/j.lfs.2025.123974","url":null,"abstract":"<div><h3>Background</h3><div>Chronic kidney disease (CKD) represents a significant global health concern. Zinc protoporphyrin (ZnPP), a byproduct formed during disrupted iron metabolism, is frequently elevated in individuals with renal dysfunction. The contribution of ZnPP to kidney pathology remains inadequately understood. Here, we investigated the role of ZnPP in CKD progression in vitro and in vivo.</div></div><div><h3>Methods</h3><div>A adenine-induced CKD mouse model and the renal tubular epithelial cell lines (HK-2 and NRK-52E) were used. In some experiments, CKD mice were treated with the N,N,N′,N′-tetrakis (2-pyridinylmethyl)-1,2-ethanediamine (TPEN), a potent zinc chelator as a ZnPP inhibitor. The ferroptosis-related signaling molecules were determined.</div></div><div><h3>Results</h3><div>ZnPP accumulation, iron overload, ferroptotic activity, and kidney damage, including fibrosis, in CKD mouse kidneys were observed. In vitro, ZnPP exposure increased intracellular labile iron and reactive oxygen species, ultimately inducing ferroptosis in tubular cells. ZnPP disrupted iron regulation by enhancing iron uptake through the upregulation of transferrin and divalent metal transporter 1, while suppressing iron storage and export via reduced expression of ferritin heavy chain and ferroportin. The iron chelator deferoxamine significantly mitigated ZnPP-induced iron accumulation, oxidative stress, and cell death. ZnPP also markedly increased heme oxygenase (HO) activity and HO-1 protein expression in renal tubular cells. Administration of TPEN substantially reduced renal ZnPP levels and alleviated ferroptosis and kidney injury in CKD mice.</div></div><div><h3>Conclusion</h3><div>These findings highlight ZnPP as a previously unrecognized driver of ferroptosis via HO-1 overactivation and dysregulated iron metabolism in CKD, and suggest that targeting ZnPP-mediated pathways may offer a novel therapeutic strategy for CKD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"380 ","pages":"Article 123974"},"PeriodicalIF":5.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086425","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":"Melatonin ameliorates myocardial ischemia/reperfusion injury via regulating the ubiquitin-proteasome system","authors":"Qiang Sun ,&nbsp;Wenjun Fan ,&nbsp;Fang Liu ,&nbsp;Ailing Zhong ,&nbsp;Danmei Huang ,&nbsp;Yanmei Zhang ,&nbsp;Fenfei Gao ,&nbsp;Jinyu Li ,&nbsp;Bin Wang","doi":"10.1016/j.lfs.2025.123973","DOIUrl":"10.1016/j.lfs.2025.123973","url":null,"abstract":"<div><h3>Aims</h3><div>Melatonin exerts cardioprotection in myocardial ischemia/reperfusion injury (MIRI) through anti-apoptotic effects. However, the underlying mechanisms remain incompletely elucidated. Growing evidence suggests that dysregulation of the ubiquitin-proteasome system (UPS) is closely associated with apoptotic. The aim of this study was to investigate whether melatonin can ameliorate MIRI by regulating UPS to inhibit apoptosis.</div></div><div><h3>Materials and methods</h3><div>MIRI model and hypoxia/reoxygenation (H/R)-treated H9c2 cells were utilized in this research. Myocardial apoptosis was assessed using western blotting, TUNEL assay, and flow cytometry, with parallel measurements of proteasome subunits and ubiquitinated proteins levels. Echocardiography was employed to assess cardiac function, while Evans blue-TTC staining quantified infarct size.</div></div><div><h3>Key findings</h3><div>Melatonin activated the JAK2/STAT3 pathway, increased proteasome subunits, and reduced the levels of ubiquitinated proteins, thereby improving UPS function to attenuate cardiomyocyte apoptosis and restore cardiac function. Melatonin's anti-apoptotic effects were inhibited by the proteasome inhibitor bortezomib (BTZ). The JAK2 signaling inhibitor AG490 counteracted melatonin-induced upregulation of proteasome subunits and reduction of ubiquitinated proteins, consequently reversing both its anti-apoptotic and cardioprotective effects.</div></div><div><h3>Significance</h3><div>Melatonin confers cardioprotection against MIRI via JAK2/STAT3-dependent UPS activation and subsequent apoptosis inhibition. This provides new insights into the molecular basis of melatonin's cardioprotective properties.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"380 ","pages":"Article 123973"},"PeriodicalIF":5.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081054","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}