Metabolic brain disease最新文献

{"title":"Hepatic-targeted low-intensity pulsed ultrasound attenuates cerebral amyloidosis via upregulating insulin-degrading enzyme.","authors":"Sicheng He, Xinbin Han, Jianghao Chen, Chenghai Li, Junfen Li, Yiqing Zhou, Wenjing Mao, Xinyi Zhang, Yu Chen, Jun Zhan, Yan Wang","doi":"10.1007/s11011-026-01959-w","DOIUrl":"10.1007/s11011-026-01959-w","url":null,"abstract":"<p><p>This study aimed to investigate whether low-intensity pulsed ultrasound (LIPUS) targeted at the liver can alleviate cerebral Aβ pathology by improving peripheral metabolism and enhancing hepatic Aβ clearance in a comorbid mouse model. 5xFAD transgenic mice were fed a high-fat diet (HFD) to induce peripheral IR. Mice received hepatic LIPUS intervention for four weeks. Outcomes were assessed using metabolic tests, in vivo and ex vivo fluorescence imaging of Aβ trafficking, neuropathological analysis, proteomics, and the Morris water maze. LIPUS ameliorated HFD-induced IR, hepatic steatosis, and pancreatic islet hyperplasia. It upregulated hepatic expression of Aβ-clearance proteins (IDE, LRP-1), enhanced peripheral Aβ catabolism, and reduced Aβ infiltration into the brain. Consequently, LIPUS attenuated cerebral Aβ deposition, neuronal apoptosis, and partially rescued spatial learning and memory deficits. Proteomic analysis confirmed systemic upregulation of metabolic and clearance pathways. Hepatic LIPUS modulates the peripheral metabolism-central clearance axis, reducing brain Aβ burden and improving cognitive function. This non-invasive approach presents a novel strategy for AD, particularly in the context of metabolic dysfunction.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874340","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":"Phosphatidylethanolamine-mediated metabolic membrane remodeling in obesity-associated Alzheimer's disease: mechanisms, neuroimmune crosstalk, and therapeutic potential.","authors":"Mumtaz Ahmad, Moh Aijaz, Mohamamd Anas Ansari, Muhammad Afzal","doi":"10.1007/s11011-026-01960-3","DOIUrl":"10.1007/s11011-026-01960-3","url":null,"abstract":"<p><p>Alzheimer's disease is increasingly recognized as a multifactorial neurodegenerative disorder characterized by complex interactions among metabolic dysfunction, chronic inflammation, mitochondrial impairment, and lipid dysregulation. Although the amyloid cascade hypothesis has long dominated Alzheimer's disease research, limited clinical success of amyloid-targeted therapies has highlighted the need for broader mechanistic frameworks integrating systemic metabolic and cellular dysfunction. Emerging evidence suggests that obesity-associated phospholipid remodeling, particularly dysregulation of phosphatidylethanolamine (PE), may critically influence neurodegenerative progression through alterations in membrane dynamics, mitochondrial homeostasis, autophagy, oxidative stress, and neuroimmune signaling. This review critically examines the molecular and cellular mechanisms underlying PE-mediated adipose-brain crosstalk in obesity-associated Alzheimer's disease, with emphasis on mitochondrial dysfunction, blood-brain barrier disruption, ferroptosis, membrane remodeling, and microglial activation. The review further discusses how altered PE metabolism may impair synaptic integrity, promote lipotoxicity, and enhance neuronal vulnerability under chronic metabolic stress. Current evidence, however, remains constrained by methodological heterogeneity, inconsistent lipidomic findings, and substantial reliance on experimental animal models, limiting translational interpretation. In addition, this review proposes the concept of a \"metabolic membrane remodeling axis\" as an integrative framework linking obesity-driven phospholipid dysregulation with neuroimmune and neurodegenerative progression. A deeper understanding of PE-driven neuroimmunometabolic dysfunction may facilitate biomarker discovery and support the development of lipid-targeted therapeutic strategies for obesity-associated Alzheimer's disease.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874398","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 and cognitive-enhancing effects of γ-Oryzanol in bile duct ligation-induced hepatic encephalopathy in rats.","authors":"Elias Kargar-Abargouei, Elaheh Zare, Maryam Arab Firouzjaei, Esmaeel Ghani","doi":"10.1007/s11011-026-01970-1","DOIUrl":"10.1007/s11011-026-01970-1","url":null,"abstract":"<p><p>Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome characterized by a spectrum of symptoms ranging from mild cognitive and motor disturbances to severe coma. γ-Oryzanol (ORY), a natural compound derived from rice bran, has demonstrated potential to enhance memory and cognitive function in preclinical studies. This study investigated the neuroprotective and cognitive-enhancing effects of γ-oryzanol in a rat model of HE induced by bile duct ligation (BDL). Male Wistar rats underwent BDL surgery and received either γ-oryzanol (100 mg/kg) or vehicle via oral gavage for subchronic 28 days. Four experimental groups were included: sham-operated, sham + ORY, BDL, and BDL + ORY. Cognitive function was assessed using the Novel Object Recognition (NOR) test and Y-maze. Blood samples were analyzed for oxidative stress markers (antioxidant status, lipid peroxidation, thiol levels), liver function markers (bilirubin, albumin, AST, ALT, ALP, LDH), and prefrontal cortex tissues were examined histologically. BDL induction significantly impaired cognitive performance and increased oxidative stress and neuronal damage in the prefrontal cortex. γ-Oryzanol treatment effectively restored cognitive function, reduced oxidative stress, and attenuated neuronal damage without significantly altering liver enzyme levels. These findings suggest that γ-oryzanol exerts neuroprotective effects in HE possibly through antioxidant-related pathways, although this mechanism was not consistently supported by all oxidative stress markers. The protective effects appeared largely independent of major liver function improvement.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874351","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":"Harnessing the neuroprotective potential of estrogen in Parkinson's disease: an insight into molecular mechanisms and therapeutic approaches.","authors":"Ashmit Kaur, Aarti Sharma, Shubham Upadhayay","doi":"10.1007/s11011-026-01969-8","DOIUrl":"10.1007/s11011-026-01969-8","url":null,"abstract":"<p><p>Parkinson's disease (PD) is the world's fastest-growing neurodegenerative disorder, presenting a significant burden on patients, caretakers, and healthcare systems. Despite advances in symptomatic management, disease-modifying therapies remain inaccessible, underscoring the need to focus on prevention and neuroprotection. Estrogen has emerged as a potential neuroprotective agent due to its diverse effects on neuronal survival and function. This review examines the neuroprotective role of estrogen in the pathogenesis of PD. A comprehensive literature search was conducted using the PubMed, Scopus, and Web of Science databases, with a focus on studies published within the last 10 years. The combinatorial keyword strategies, including \"estrogen,\" \"parkinson's disease,\" \"estrogen receptor alpha (ERα),\" \"estrogen receptor beta (ERβ)\", \"G-protein coupled estrogen receptor 1 (GPER1),\" \"neurodegeneration,\" \"oxidative stress,\" \"neuroinflammation,\" \"neuroprotection,\" and \"preclinical studies.\" Findings indicate that estrogen deficiency promotes Parkinson's-like pathology, which includes oxidative stress, mitochondrial impairment, synaptic dysfunction, and neuroinflammation. Activating ERα, ERβ, and GPER1 through both genomic and non-genomic mechanisms slows disease progression by reducing oxidative damage, inflammatory cytokine release, and neurodegeneration. Preclinical evidence suggests that several natural, synthetic, and semisynthetic estrogen compounds protect neurons by modulating PI3K/Akt, MAPK/ERK, and NF-κB signalling pathways, thereby reducing dopaminergic neuronal loss and improving behavioural outcomes. Estrogen protects the brain from neurotoxic insults, while a deficiency of estrogen exacerbates oxidative stress, mitochondrial dysfunction, and neuroinflammation. While activation of ERα, ERβ, and GPER promotes antioxidant, anti-inflammatory, and anti-apoptotic effects, reducing PD pathogenesis. These findings support estrogen receptors as potential therapeutic targets for PD management.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865950","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":"Intensity-dependent effects of interval training on brain mitophagy, metabolic signaling pathways, and neuroinflammation in a rat model of type 2 diabetes.","authors":"Babak Esmealy, Kosar Zeinizadeh, Elaheh Piralaiy, Farnaz Derakhti, Mahdi Hayati","doi":"10.1007/s11011-026-01944-3","DOIUrl":"10.1007/s11011-026-01944-3","url":null,"abstract":"<p><p>Type 2 diabetes mellitus impairs brain metabolic and mitochondrial homeostasis, yet the intensity-dependent neuroprotective effects of exercise remain poorly defined. This study examined the intensity‑dependent effects of interval training on brain mitophagy, metabolic signaling, oxidative stress, and neuroinflammation in a type 2 diabetes model. Fifty male rats were assigned to five groups (n = 10 each): healthy control (HC), diabetic control (DC), diabetic + low-intensity interval training (LIIT), diabetic + moderate-intensity interval training (MIIT), and diabetic + high-intensity interval training (HIIT). Following the intervention, hippocampal and cortical tissues were analyzed for metabolic signaling markers (AMPK, ULK1, mTOR), mitophagy-related proteins (PINK1, Parkin, LC3-II/I, p62), oxidative and antioxidant indices (MDA, SOD, CAT, TAC), pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and lipid peroxidation (4-HNE). Statistical significance was set at p < 0.05. MIIT and HIIT activated AMPK-ULK1 signaling and suppressed mTOR in the hippocampus and cortex, leading to enhanced mitophagy, particularly in the hippocampus. These adaptations were accompanied by improved redox balance, reduced lipid peroxidation, and attenuated neuroinflammation, with effects increasing in an intensity-dependent manner (LIIT < MIIT < HIIT). Interval training may support neuroprotective adaptations in type 2 diabetes, with moderate- and high-intensity protocols potentially offering greater benefits than low intensity. Still, these effects require confirmation in broader experimental contexts.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857475","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":"Effects of imbalanced gut microbial on mice with type a hepatic encephalopathy through the gut-liver-brain axis.","authors":"Xiaoya Yang, Jiayuan Huang, Lei Wu, Tianyu Xu, Guoqiao Quan, Yuange Li, Tao Liu, Lingping Kong, Xingxiang He, Zhaoming Liu, Wenrui Xie","doi":"10.1007/s11011-026-01964-z","DOIUrl":"10.1007/s11011-026-01964-z","url":null,"abstract":"<p><strong>Background and aims: </strong>The relationship between type A hepatic encephalopathy, a highly lethal disease, and gut microbiota remains unclear, and research on this topic is limited. The objective of our study was to investigate the correlation between an imbalance in the gut microbiota and type A hepatic encephalopathy and the impact of fecal microbiota transplantation.</p><p><strong>Methods: </strong>We established a mouse model of gut microbiota disorder and type A hepatic encephalopathy. Feces from grades III and IV type A hepatic encephalopathy mice were transplanted into healthy mice. Antibiotic administration, intestinal symbiosis, and pathogenicity experiments were conducted. Behavioral, biochemical, pathological, 16 S rRNA gene amplicon sequencing analyses, and correlation analyses were performed.</p><p><strong>Results: </strong>Antibiotic treatment caused a gut microbiota imbalance in mice. The degree of thioacetamide-induced type A hepatic encephalopathy was significantly aggravated after oral antibiotic administration, leading to a decline in the survival curve, accompanied by behavioral, biochemical, and pathological changes, as well as decreased Rikenellaceae levels. Transplanting feces from type A hepatic encephalopathy mice into healthy mice resulted in thioacetamide-like behavioral, biochemical, and tissue changes, as well as a significant decline in the abundance of the gut microbiota, an increase in the abundance of Prevotellaceae NK3B31, and a decrease in the abundance of Akkermansia muciniphila and Odoribacter. Additionally, significant correlations were observed between the abundances of the four intestinal microbial species and the majority of measured indicators in mice with type A hepatic encephalopathy. Notably, Akkermansia muciniphila exhibited particularly strong associations with these indicators. Although significant between-group differences were observed for Bacillus, Paenibacillus, Candidatus Saccharimonas, Escherichia-Shigella, UCG_002, Acinetobacter, and Proteus, no significant correlations were detected between these microbial taxa and any of the measured indicators.</p><p><strong>Conclusions: </strong>Gut microbiota disorder aggravates lesions in thioacetamide-induced type A hepatic encephalopathy mice. Transplanting feces from mice with type A hepatic encephalopathy causes healthy mice to exhibit type A hepatic encephalopathy symptoms.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857541","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":"Sex-specific effects of therapeutic hypothermia on short- and long-term microglial and astrocytic reactivity after severe neonatal hypoxia-ischemia.","authors":"Ricardo Ribeiro Nunes, João Vitor Miotto Tauffer, Bianca Büchele Martins, Isadora D'Ávila Tassinari, Carlos Alexandre Netto, Ana Helena Paz, Luciano Stürmer de Fraga","doi":"10.1007/s11011-026-01957-y","DOIUrl":"10.1007/s11011-026-01957-y","url":null,"abstract":"<p><p>Therapeutic hypothermia (TH) is the standard treatment to reduce mortality and neurological impairments after neonatal hypoxia-ischemia (HI). However, TH does not fully suppress neuroinflammation, leading to persistent neuroinflammatory responses that may exacerbate brain injury and limit TH efficacy. In addition, the influence of sexual dimorphism on these outcomes remains poorly understood. We investigated short- and long-term microglial and astrocytic reactivity in male and female neonatal rats following HI and TH treatment. At postnatal day 7 (PND7), male and female pups underwent right common carotid occlusion followed by exposure to hypoxia (8% O₂). TH was induced by reducing body temperature to 32°C for 5 h. Brains were collected at PND8 or PND21 to assess brain injury volume, brain water content, and microglial and astrocytic reactivity based on Iba-1 and GFAP mean fluorescence intensity. Behavioral impairments were evaluated using negative geotaxis, olfactory discrimination, and cylinder tests. TH did not reduce injury volume but attenuated neuronal cell loss in males and reduced brain edema in females. In males, microglial reactivity was reduced by TH at PND8 and PND21 and astrocytic reactivity only at PND8. Olfactory discrimination was impaired in females and prevented by TH, whereas motor performance deficits and developmental impairments were not prevented by TH. Our results reinforce that the neuroprotective efficacy of TH is limited in severe HI injury and that, despite reducing early neuroinflammation, TH fails to prevent long-term neuroinflammatory responses. Notably, the early anti-inflammatory effects were only observed in males, underscoring the need for additional therapeutic strategies, particularly for females.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857303","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}

{"title":"L-theanine from Camellia sinensis (L.) attenuates 3-NP-induced Huntington's disease-like alterations by remedying behavioral patterns and modulating neurotransmitters across three distinct brain regions: evidence from in-vivo and in-silico approaches.","authors":"Susankar Kushari, Dipankar Saha, Bhrigu Kumar Das, Sunayana Baruah, Kumar Saurav Dey, Suman Kumar, Trishna Das, Jashabir Chakraborty","doi":"10.1007/s11011-026-01967-w","DOIUrl":"10.1007/s11011-026-01967-w","url":null,"abstract":"<p><p>Huntington's disease (HD) is a neurological condition with limited treatment. Its hallmarks are progressive loss of neurons, chorea, cognitive, motor, and metabolic impairments. The current study uses 3-nitropropionic acid (3-NP) to cause HD-like indications in rats. L-theanine (L-TH), an active component of Camellia sinensis, has already been shown to possess anti-inflammatory and anti-oxidant effects. The impact of the isolated phytoconstituent, L-TH, on 3-NP-induced changes in three distinct brain regions was assessed in the current study. The animals received a 7-day pretreatment consisting of normal saline, extract of C. sinensis (100 and 200 mg/kg b.w., i.p.), L-TH (10 mg/kg b.w., i.p.), and standard Tetrabenazine (TBZ, 25 mg/kg, b.w., i.p.). The administration of 3-NP (10 mg/kg b.w., i.p.) to the treatment groups began on the 8th day of the protocol and continued until the 21st day. The brain homogenates underwent biochemical and neurochemical assessments. In conclusion, L-TH improved behavioral outcomes and attenuated 3-NP-induced neurochemical alterations in brain homogenates. Histopathological analysis revealed lower levels of tissue damage in the L-TH-treated group compared to the 3-NP group. Molecular docking studies further indicated favorable interactions of L-TH with the HTT protein. These findings suggest that L-TH may attenuate 3-NP-induced Huntington's disease-like alterations in rats. However, additional studies using genetic HD models and molecular mechanisms are required to confirm its therapeutic efficacy and underlying mode of action.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148857233","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":"Characterizing the molecular mechanisms underlying aluminium-induced disruptions in neuronal survival pathways.","authors":"Kankipati Sravya, Arpitha Rao, P Harshitha, Aluru Parithathvi, Herman Sunil Dsouza","doi":"10.1007/s11011-026-01953-2","DOIUrl":"10.1007/s11011-026-01953-2","url":null,"abstract":"<p><p>Aluminium, an omnipresent environmental pollutant, has been recognized for its neurotoxic effects, particularly its ability to promote neuronal death. More research evidence links aluminium exposure to death through molecular mechanisms. This review delves into the mechanisms underlying aluminium-induced neurotoxicity, including programmed cell death pathways such as apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis. Aluminium exposure leads to disruption of oxidative homeostasis and induction of endoplasmic reticulum stress, mitochondrial dysfunction and DNA damage, which in turn trigger different cell death pathways. Substantial changes in key signalling pathways, such as the IL-1β/JNK, PI3K/Akt/mTOR, Nrf2/Ho-1, System Xc-/GPX4, and NLRP3 inflammasome activation pathways, were observed. Overall, these intertwined pathways highlight aluminium as a potent modulator of neuronal survival pathways, driving neurodegeneration through multifactorial mechanisms. A thorough understanding of these changes provides a fundamental explanation of the role of aluminium toxicity in the etiology of neurodegenerative diseases and provides a foundation for treatment.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840711","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}

{"title":"Advanced glycation end products and PTSD: molecular insights and dietary approaches for neuropsychiatric health.","authors":"Km Deeksha, Krishan Kumar Verma, Anjali Saini","doi":"10.1007/s11011-026-01963-0","DOIUrl":"10.1007/s11011-026-01963-0","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Post-Traumatic Stress Disorder is a complex psychiatric condition characterized by persistent fear, emotional dysregulation, cognitive impairment, hyperarousal, and chronic stress. Although PTSD is typically triggered by exposure to traumatic events, the underlying biological mechanisms contributing to its development and progression remain incompletely understood. Glycation, a non-enzymatic biochemical process leading to the formation of Advanced Glycation End Products (AGEs), has emerged as a potential mechanistic link between chronic stress, neuroinflammation, and stress-related neuropsychiatric disorders, including PTSD. This review explores the role of glycation and deglycation in the pathophysiology of PTSD. It examines how chronic psychological stress contributes to AGE accumulation, neuroinflammation, oxidative damage, and neuronal dysfunction. Additionally, the review discusses diagnostic biomarkers, potential therapeutic targets, dietary and nutritional interventions, and hormonal therapies that may help restore glycation-deglycation balance and improve clinical outcomes in individuals with PTSD. A comprehensive review of the literature was conducted to evaluate the molecular and physiological mechanisms underlying PTSD, with particular emphasis on glycation-related pathways. Studies investigating the roles of AGEs, their receptors, endogenous deglycation systems, dietary factors, and pharmacological interventions were analysed. The review also assessed emerging precision medicine approaches and nutritional strategies aimed at reducing AGE formation and mitigating stress-induced neurobiological alterations. Chronic psychological stress may disrupt the physiological balance between glycation and deglycation, leading to carbonyl stress, excessive AGE formation, mitochondrial dysfunction, oxidative stress, and persistent neuroinflammation. AGEs activate the receptor for advanced glycation end products (RAGE), triggering inflammatory signalling pathways such as NF-κB and promoting neuronal injury. Key molecular targets linking PTSD and glycation include RAGE, hypoxia-inducible factor-1 alpha (HIF-1α), KEAP1/Nrf2 signalling, FKBP5-glucocorticoid receptor pathways, the glyoxalase system (GLO1 and GLO2), and DJ-1/PARK7. Biomarker studies reveal alterations across neuroendocrine, inflammatory, genetic, epigenetic, psychophysiological, and neuroanatomical pathways in PTSD. Nutritional interventions rich in polyphenols, antioxidants, omega-3 fatty acids, probiotics, vitamins, and anti-inflammatory compounds may reduce AGE formation, enhance endogenous deglycation mechanisms, and improve neurobiological resilience. Emerging hormonal therapies, including glucocorticoids, DHEA, allopregnanolone, estrogen, testosterone, oxytocin, vasopressin antagonists, and IGF-1 modulation, may further complement conventional PTSD treatment strategies. Dysregulation of glycation and deglycation pathways represents a promising mechanistic framework for underst","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148829152","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}