Metabolic brain disease最新文献

{"title":"Genetic and structural characterisation of alzheimer's disease associated variants in an Eastern Indian cohort.","authors":"Dipanwita Sadhukhan, Adreesh Mukherjee, Izaz Monir Kamal, Shreyosi Maitra, Brahmachari Somnath Vedeshachaitanya, Bidisha Bhattacharyya, Atanu Biswas, Saikat Chakrabarti, Arindam Biswas","doi":"10.1007/s11011-026-01929-2","DOIUrl":"10.1007/s11011-026-01929-2","url":null,"abstract":"<p><p>Alzheimer's disease (AD) shows substantial clinical heterogeneity often caused by genetic variants contributing to both familial and early-onset forms. However, the genetic landscape of AD in the diverse Indian population remains further characterised. To identify probable pathogenic variants associated with AD, representing individuals from Eastern India and to assess their potential structural effects using molecular dynamics (MD) simulations. Whole-exome sequencing was performed in 29 radiologically confirmed AD patients. Variants identified were screened using standard in silico prediction tools and categorised according to their involvement in amyloid precursor protein (APP)-related and non-APP pathways. Molecular dynamics simulations of filtered variants in PSEN1, SORL1, and ABCA7 genes were conducted using GROMACS 2024 to assess conformational stability, flexibility (RMSD, RMSF), compactness (Rg), and solvent accessibility (SASA). Thirty-six variants across 18 genes were identified, including five pathogenic variants and 31 variants of uncertain significance. Frequently affected genes included ABCA7 (8 variants), SORL1 (3 variants), PSEN1 (two novel variants), and APP (London mutation, Val717Ile). Most patients (83.3%) had a positive family history, with a mean age at onset of 54.17 ± 11.74 years, presenting with typical AD, posterior cortical atrophy, or frontal variants. MD simulations revealed increased rigidity, altered electrostatic interactions, and disrupted ATP-binding dynamics in mutant proteins compared with wild type. This study identifies novel and known AD-associated variants in an Indian cohort and demonstrates their potential structural impact. Integrating genetic and structural analyses provides valuable insights into AD pathogenesis in underrepresented populations.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148397395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic mutations and synaptic dysfunctions in social interaction disorders: insights from invertebrate models to humans.","authors":"Victor Ebube Anadu, Toheeb O Oyerinde, Tolulope J Gbayisomore, David A Oyeniran, Francis T Adeniran, Olayemi K Ijomone, Omamuyovwi M Ijomone","doi":"10.1007/s11011-026-01921-w","DOIUrl":"10.1007/s11011-026-01921-w","url":null,"abstract":"<p><p>Abnormal social interactions are key features of various neurodevelopmental and neuropsychiatric disorders, including autism, attention-deficit/hyperactivity disorder, and schizophrenia. Social interaction behaviours are highly conserved and have evolved across species. Studying social behaviours is crucial as it determines an organism's survival, development, and reproduction. Research over the years has demonstrated how genetic mutations influence synaptic architecture and function, revealing their contributions to these social abnormalities. Furthermore, specific genes, known as cell adhesion molecules (CAM), play important roles in the formation, maturation, and functioning of the synapses, and mutations in these genes alter normal synaptic formation and functioning, consequently disrupting behavioural outcomes. In biological systems, normal synaptogenesis has functional implications for social behaviours necessary for social bonding and cooperation. This review integrates findings from studies across various model organisms-including the C. elegans, Drosophila melanogaster, Zebrafish, and rodents- to elucidate how alterations in synaptic function disrupt social interaction. We extensively discuss how mutations in CAM genes alter key conserved synaptic pathways, leading to neurochemical alterations that contribute to social deficits common in neurodevelopmental disorders, as well as therapeutic strategies inspired by animal studies, including the use of drugs and gene therapies in the management and treatment of the symptoms observed in social interaction disorders.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crocin alleviates \"short-term\" Cadmium-induced brain and lung toxicities: investigation of key neuropeptides GLP-1 and spexin as biomarkers.","authors":"Ghadha Ibrahim Fouad","doi":"10.1007/s11011-026-01918-5","DOIUrl":"10.1007/s11011-026-01918-5","url":null,"abstract":"<p><p>Cadmium is a highly neurotoxic heavy metal that impacts the functions of several organs through stimulating excessive oxidative stress. Polyphenols were evidenced to mitigate heavy metal-induced neurotoxicity and pulmonary toxicity. Crocin (CN) is a carotenoid compound extracted from Crocus sativus L. This study explored the protective activities of CN against Cadmium chloride (CdCl₂)-induced neurotoxicity and lung injury. Thirty-two female albino Wistar rats, 6-8 weeks-old, were allocated into four groups: Negative control, CdCl₂-intoxicated rats (two successive intraperitoneal doses of 1 and 3 mg/kg body weight), CN group, and treated CdCl₂ rats with CN (50 mg/kg body weight, orally). Hanging-wire test was used to assess the muscular coordination. Biochemically, lipid peroxidation and glutathione (GSH) contents in the brain and lung homogenates, serum iron and phosphorus levels, serum Glucagon-like Peptide-1 (GLP-1) and spexin (SPX) levels were measured, along with histopathological investigation of cerebellar and pulmonary tissues. CdCl₂ rats demonstrated loss of neuromuscular coordination and imbalance in the hanging-wire test. Furthermore, CdCl₂ rats exhibited increased lipid peroxidation, GSH decline, disruption of iron and phosphorus levels, and reduction of GLP-1 and SPX levels. Concomitant treatment of CdCl₂-rats with CN, for two weeks, restored the muscular strength, mitigated oxidative stress, regulated iron and phosphorus levels, modulated GLP-1 and SPX, and ameliorated the histopathological features in the cerebellum and the lungs. We concluded that CN exerted neuroprotective and pulmonary protective potentials against CdCl₂-induced toxicity, and that GLP-1 and SPX could be regarded as biomarkers of heavy metals-associated neurotoxicity and lung toxicity.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Supra-additive neuroprotective effects of berberine-metformin combination in diabetic encephalopathy: Chou-Talalay synergy quantification, AMPK-Nrf2 axis modulation, and pharmacokinetic verification.","authors":"Wessam M Filfilan, Mohamed E Elbeeh","doi":"10.1007/s11011-026-01910-z","DOIUrl":"10.1007/s11011-026-01910-z","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) increases the risk of hippocampal neurodegeneration and cognitive decline. Berberine and metformin independently activate AMPK and may engage Nrf2-mediated antioxidant defenses, yet their combined neuroprotective interaction has not been formally quantified using validated synergy frameworks, nor has its pharmacokinetic basis been verified. Streptozotocin-nicotinamide diabetic rats were allocated to twelve groups (n = 13/group) receiving berberine (50, 100, 150 mg/kg/day) or metformin (100, 200, 300 mg/kg/day) monotherapy, fixed-ratio 1:2 combinations, or vehicle controls (including a non-diabetic combination group) orally for six weeks. The novel object recognition (NOR) discrimination index served as the predefined primary endpoint for Chou-Talalay combination index (CI) analysis. Hippocampal mechanistic (n = 6/group) and satellite LC-MS/MS pharmacokinetic (n = 6/group) analyses were performed. Diabetes impaired NOR discrimination index (37.2 ± 3.8% vs. 68.4 ± 3.2%; p < 0.001). The reference combination (100 + 200 mg/kg) restored NOR to 67.1 ± 3.6% with CI = 0.65 (95% CI: 0.43-0.91), synergism maintained across the full effect range. All six neuroinflammatory endpoints achieved Benjamini-Hochberg-corrected significance (p_adj = 0.006-0.043; Tier 2). Non-diabetic combination animals showed reduced AMPK activation magnitude (1.53 vs. 2.31-fold; P_adj = 0.067; Tier 3, hypothesis-generating). LC-MS/MS verified bioequivalent drug exposure. Berberine-metformin co-treatment is associated with CI-quantified supra-additive recognition memory recovery in diabetic encephalopathy, with neuroinflammatory suppression as the most statistically robust mechanistic correlate. Pharmacokinetic findings are consistent with a pharmacodynamic rather than pharmacokinetic basis. Causal involvement of the AMPK-Nrf2 axis remains correlative pending direct loss-of-function validation.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electroacupuncture-modulated DHCR24 facilitates spinal cord injury recovery by attenuating apoptosis and neuroinflammation via the Wnt signaling pathway.","authors":"Chunlei Li, Yuan Li, Tongyan Liu, Yue Zong, Lingyun Zhou","doi":"10.1007/s11011-026-01919-4","DOIUrl":"10.1007/s11011-026-01919-4","url":null,"abstract":"<p><p>Spinal cord injury (SCI) is a highly disabling condition affecting the central nervous system (CNS). Neuroinflammation and neuronal apoptosis are two critical factors in the pathological process of SCI. Although electroacupuncture (EA) has been reported to alleviate neuroinflammation in brain injury, the underlying molecular mechanism remains unclear. Transcriptome sequencing of spinal cord tissues was performed to identify potential key factors and pathways involved in EA post-SCI. DHCR24, a cholesterol synthesis regulator, was selected as a key candidate and DHCR24 was downregulated after SCI (log₂FC = -1.6, P < 0.01), and this downregulation was notably reversed by EA treatment (log₂FC = 1.04, P < 0.01). We investigated the neuroprotective effect of DHCR24 against neuron death and neuroinflammation in SCI, with a particular focus on its effects on the Wnt signaling pathway. SCI-induced DHCR24 downregulation was associated with decreased expression of the axonal regeneration marker NF and increased activation of Iba1/CCR7-positive microglia, accompanied by enhanced neuronal apoptosis and inflammatory factor release. Importantly, functional validation experiments demonstrated that DHCR24 was required for the therapeutic effects of EA. Complementary in vitro studies in LPS/IFN-γ-stimulated BV2 microglia cells confirmed the role of DHCR24 in microglial polarization and neuronal survival, likely via Wnt signaling activation. Integrating transcriptomic and mechanistic evidence, we demonstrate that DHCR2 promotes Wnt pathway activation, reduces neuronal apoptosis and neuroinflammation, and ultimately enhances spinal cord repair. This study provides evidence supporting the potential clinical application of EA in SCI recovery and identifies DHCR24 may be a key mechanistic target underlying its therapeutic effects.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gestational deltamethrin exposure exacerbates post-traumatic epileptiform activity and social deficits, diminishing the therapeutic efficacy of curcumin in rats.","authors":"Kamendra Kumar, Prince Kumar, Pavan Kumar, Deepak Sharma","doi":"10.1007/s11011-026-01923-8","DOIUrl":"10.1007/s11011-026-01923-8","url":null,"abstract":"<p><p>Gestational exposure to the neurotoxic insecticide deltamethrin (DLT) is suspected to increase susceptibility to neurological disorders, but its impact on secondary brain injuries and therapeutic interventions remains poorly understood. This study investigates whether prenatal DLT exposure exacerbates post-traumatic epileptogenesis in offspring and evaluates whether it compromises the neuroprotective efficacy of curcumin. Pregnant rats were exposed to DLT during gestation, and post-traumatic epileptiform activity was subsequently induced in the offspring using a focal FeCl₃ cortical injury model. Following oral curcumin administration, subjects were evaluated utilizing electrocorticography, behavioral assays, Golgi staining, and immunohistochemistry. We found that gestational DLT exposure significantly exacerbated injury pathology, evidenced by heightened neuronal hyperexcitability, severe social behavioral deficits, reduced dendritic complexity, profound loss of synaptic markers (PSD95 and SYP), upregulation of voltage-gated sodium channels (NaV1.1 and NaV1.6), and aggravated glial activation. Crucially, while curcumin treatment successfully attenuated molecular, histological, and electrophysiological pathologies, prior DLT exposure exacerbated the epileptic phenotype and severely interfered with curcumin's overall therapeutic efficacy, preventing absolute cellular markers from fully returning to unexposed recovery levels. Furthermore, prior DLT exposure actively blunted curcumin's ability to rescue complex social behavioral deficits. These findings demonstrate that early-life environmental toxicant exposure increases vulnerability to post-traumatic epileptogenesis and establishes a severely aggravated pathological baseline that limits the overall restorative capacity of subsequent interventions.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The protective role of melatonin on the brain in a rat model of Alzheimer's disease.","authors":"Sarah S Mostafa, Rabab A Mohammed, Asmaa Y Abbas, Manal A Othman","doi":"10.1007/s11011-026-01915-8","DOIUrl":"10.1007/s11011-026-01915-8","url":null,"abstract":"<p><p>Alzheimer's disease is an age-related neurodegenerative disorder characterized by progressive cognitive decline and multiple biochemical and structural abnormalities in the brain. Accumulating evidence suggests that aluminum exposure may contribute to neurodegenerative process including those observed in AD and was linked to neuronal damage and cognitive impairment. Melatonin (Mel) is a neurohormone that regulates circadian rhythm and possesses antioxidant, anti-inflammatory and neuroprotective properties. The current study investigated the potential protective roles of Mel in a rat model of AD induced by aluminum chloride (AlCl₃). Forty adult male rats were divided into 4 experimental groups: a control group, an AlCl3-treated group, an AlCl₃+Mel-treated group, and a Mel-only group. AlCl₃ was administered orally for four weeks. Cognitive performance and spatial learning were assessed using Morris water maze test. Plasma levels of the pro inflammatory cytokines; interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured using enzyme linked immunosorbent assay. Histopathological examination of the frontal cortex was performed using hematoxylin and eosin staining, and immunohistochemistry was conducted using the neuronal marker NeuN, microglial marker Iba1, and inflammatory markers IL-6 and TNF-α. Mel treatment significantly improved learning and memory performance in the Morris water maze test. It also reduced plasma levels of IL-6 and TNF-α. Using immunohistochemistry, Mel increased NeuN expression, while reducing Iba1, IL-6 and TNF-α expression. These findings showed that Mel attenuated frontal cortical neurodegeneration and neuroinflammation in this model of AD, suggesting that Mel may represent a promising neuroprotective therapeutic strategy for AD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective effects of 2-(2-nitrophenyl)-1,3-thiazolidine-4-carboxylic acid in a rotenone-induced Parkinson's disease rat model: Modulation of oxidative stress, behavioral dysfunction, and iron accumulation.","authors":"Shaheen Kousar, Shazia Perveen, Imran Haider, Sumaira Kanwal, Sana Javaid, Ahmed O Abbas, Hesham Hassanien, Abdallah Tageldein Mansour, Mohamed Ashour, Mohamed Shawky","doi":"10.1007/s11011-026-01905-w","DOIUrl":"10.1007/s11011-026-01905-w","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, oxidative stress, and abnormal iron accumulation in the substantia nigra. Targeting redox imbalance and metal dysregulation represents a promising therapeutic strategy. This study evaluated the neuroprotective potential of 2-(2-nitrophenyl)-1,3-thiazolidine-4-carboxylic acid (2,2Np-1,3TZD-4-CA) in a rotenone-induced rat model of PD. Forty-two male Sprague-Dawley rats were randomly assigned to seven experimental groups, including controls, rotenone-treated animals, compound-treated groups, and combined treatment groups. Behavioral performance was assessed using pole, inverted screen, rotarod, Y-maze, open field, and tail suspension tests. Oxidative stress markers (SOD, CAT, MDA, GSH, GPx) were measured, along with brain iron analysis and histopathological examination. Treatment with 2,2Np-1,3TZD-4-CA significantly improved rotenone-induced behavioral impairments and restored antioxidant enzyme activities (P < 0.05). Moreover, the compound reduced elevated brain iron levels and ameliorated histopathological alterations in neural tissues (P < 0.05), indicating attenuation of oxidative and metabolic damage. These findings demonstrate that 2,2Np-1,3TZD-4-CA exerts marked neuroprotective effects, likely mediated through regulation of oxidative stress and iron homeostasis, suggesting its potential therapeutic relevance for Parkinson's disease.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interplay between gut microbiota and Alzheimer's disease: mechanistic insights from dysbiosis to disease modulation.","authors":"Kakali Das, Rupjan Khatun, Sanjana Begum, Koushik Bhattacharyya, Madhushree Datta, Dipankar Saha, Anupam Sarma, Prachi Mehta, Bhrigu Kumar Das","doi":"10.1007/s11011-026-01922-9","DOIUrl":"10.1007/s11011-026-01922-9","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a chronic, progressive, neurodegenerative condition marked by memory loss and cognitive decline. It is characterized by neuropathological features such as amyloid plaque accumulation, neurofibrillary tangles of tau protein, and inflammatory changes in the brain. Recent research emphasizes how gut microbes influence the onset and progression of AD primarily through the gut-brain connection, a bidirectional communication system. The human gastrointestinal tract (GI) contains trillions of bacteria, primarily Bacteroidetes, Firmicutes, and Actinobacteria, which play vital roles in digestion, metabolic regulation, and immune modulation. However, factors such as diet, lifestyle, and environmental exposure can disrupt microbial balance, weaken intestinal barrier function, and initiate systemic inflammation. Such dysbiosis has been linked to defective regulation of the amyloid precursor protein (APP), leading to increased deposition of amyloidogenic peptides (Aβ). Moreover, the enteric nervous system, which expresses APP, may serve as an initial site of amyloid deposition, affecting gastrointestinal motility and inflammatory susceptibility. The gut microbiota also produces key bioactive compounds, including neurotransmitters such as serotonin, dopamine, acetylcholine, histamine, and gamma-aminobutyric acid (GABA), which influence the central nervous system (CNS) through neural, immune, and endocrine pathways. An imbalance in these neuroactive molecules may disrupt synaptic signaling and contribute to Alzheimer's-related cognitive dysfunction. Therefore, improving our understanding of gut-brain communication may advance knowledge of AD development and support the creation of new therapies. This review highlights the strong association between intestinal microbes and Alzheimer's pathogenesis, emphasizing microbiota modulation through probiotics, prebiotics, postbiotics, synbiotics, and antibiotics as potential therapeutic approaches, supported by emerging clinical trial evidence.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut-brain axis modulation by fecal microbiota transplantation improves dual-organ injury after cerebral ischemia-reperfusion via Caspase-8 dependent inhibition of necroptosis.","authors":"Zhangfeng Shen, Dongdong Xu, Ke Wang, Yuhao Chen, Qian Dou, Shengyu Jin, Bing Hu","doi":"10.1007/s11011-026-01917-6","DOIUrl":"10.1007/s11011-026-01917-6","url":null,"abstract":"<p><p>The pathological features of cerebral ischemia-reperfusion (CIR) include necroptosis activation. This study investigated how healthy fecal microbiota transplantation (H-FMT) improves CIR and intestinal barrier damage. Rats subjected to middle cerebral artery occlusion and reperfusion (MCAO/R) were treated with H-FMT and/or a Cysteine-aspartic acid protease-8 (Caspase-8) inhibitor. Survival and body weight were monitored throughout the experiment. Neurological function, tissue damage, inflammatory cytokines, and Caspase-8/Receptor-interacting protein kinase 1 (RIPK1)-Receptor-interacting protein kinase 3 (RIPK3)-Mixed lineage kinase domain-like protein (MLKL) expression were assessed. Ultrastructural changes were examined by transmission electron microscopy (TEM), p-RIPK1/p-RIPK3 expression by immunohistochemistry (IHC), and gut microbiota by 16 S sequencing. H-FMT significantly ameliorated neurological deficits and intestinal barrier disruption, reduced infarct volume and neuronal loss, and attenuated mitochondrial damage. These effects were accompanied by reduced apoptosis and inflammation, increased Caspase-8 activation, and suppressed RIPK1-RIPK3-MLKL phosphorylation. IHC confirmed reduced p-RIPK1/p-RIPK3 signals after H-FMT. 16 S sequencing revealed that H-FMT restored microbial diversity, reduced pathogenic Proteobacteria, and enriched beneficial Lactobacillus, which positively correlated with Caspase-8 activation. Our findings suggest that H-FMT alleviates CIR injury by activating Caspase-8 and suppressing necroptosis. However, due to the small sample size, these results should be considered preliminary.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13315487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148345959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}