Metabolic brain disease最新文献

{"title":"Coenzyme Q₁₀ supplementation restores mitochondrial respiration in patients with primary CoQ₁₀ deficiency caused by novel COQ2 and COQ4 variants.","authors":"Achanya S Jayan, Priya Nataraj, Arun Kumar Gangadharan, Olivia Thomas, Rekha Mangat, Cibin T Raghavan, Srinivas Gopala, Soumya Sundaram, Madhusoodanan Urulangodi","doi":"10.1007/s11011-026-01983-w","DOIUrl":"10.1007/s11011-026-01983-w","url":null,"abstract":"<p><p>Primary coenzyme Q10 deficiencies (COQ10D) are rare mitochondrial disorders caused by pathogenic variants in genes involved in coenzyme Q₁₀ (CoQ₁₀) biosynthesis, leading to impaired mitochondrial respiration and heterogeneous neurological phenotypes. In this study, we identified and functionally characterized novel recessive variants in COQ2 and COQ4 using whole-exome sequencing. One proband carried a homozygous COQ2 variant (c.1039 A > G; p.Ser347Gly), while the second harbored compound heterozygous COQ4 variants (c.238 C > T; p.Arg80Cys and c.380del; p.Tyr127PhefsTer7). Variant segregation was confirmed by Sanger sequencing, and in silico protein modelling predicted deleterious structural effects. Mitochondrial function was assessed in freshly isolated platelets from probands, family members, and healthy controls using high-resolution respirometry. The COQ2 proband showed increased proton leak and reduced ATP-linked respiration, indicating uncoupled oxidative phosphorylation, whereas the COQ4 proband, already receiving CoQ₁₀, showed near-normal mitochondrial function. Following three months of CoQ₁₀ supplementation, the COQ2 proband showed significant improvement in ATP synthesis and reduced proton leak, accompanied by clinical neurological improvement. mRNA expression analysis revealed feedback regulation, while protein levels of ETC complexes I-V remained unchanged. Importantly, CoQ₁₀ supplementation in healthy individuals did not alter mitochondrial respiration, confirming the specificity of therapeutic benefit in COQ10Ds. Overall, in addition to expanding the genetic spectrum of COQ10Ds, this study also provides functional evidence that defective mitochondrial function in these conditions is, at least in part, reversible with targeted CoQ₁₀ therapy, underscoring the importance of early genetic diagnosis and timely initiation of CoQ₁₀ supplementation.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920353","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":"Hyperglycemia associated brain dysfunction: rodent models for studying diabetic cognitive deficits.","authors":"Brianna M Balsamo, Darrin H Brager","doi":"10.1007/s11011-026-01979-6","DOIUrl":"10.1007/s11011-026-01979-6","url":null,"abstract":"<p><p>Diabetes and chronic hyperglycemia exert a profound impact on the central nervous system, significantly increasing the risk of cognitive impairment and neurodegenerative disease. This neurological decline is driven by a complex interplay of molecular and cellular mechanisms, including dysregulated insulin signaling, impaired cerebral glucose metabolism, excitotoxic glutamate accumulation, oxidative stress, and neuroinflammation. Collectively, these metabolic stressors compromise synaptic integrity and plasticity, promoting pathological hallmarks such as amyloid-beta accumulation, tau hyperphosphorylation, and neuronal atrophy. Structural and functional abnormalities are particularly prevalent in the hippocampus and prefrontal cortex, regions essential for learning and memory. Researchers utilize a diverse array of rodent model systems, including chemically induced, diet-induced, genetic, and autoimmune models, to study specific disease facets. No single model, however, perfectly replicates the complexity of human diabetes; instead, models vary in their face, construct, and predictive validity. While some systems offer high translational relevance, others provide superior mechanistic clarity. Consequently, the strategic selection of animal models is crucial for accurately characterizing diabetes-associated neurological dysfunction and facilitating the translation of preclinical findings into effective human clinical interventions. In this review we discuss the major diabetic rodent models and synthesize the current evidence linking diabetes and hyperglycemia to neurological dysfunction in the context of the rodent model(s) best suited for investigating specific impairments. Understanding how metabolic disease influences neuronal and molecular pathways that are critical for cognition and being able to study them in a translational model is essential for identifying early therapeutic targets and reducing the growing neurological burden of diabetes.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13558288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920343","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":"Therapeutics candidates and repurposing strategies to target parkinson's disease pathology: current evidence and future directions.","authors":"Yarava Dhanush, N D Nizamuddin, Satrasala Neelima, S Kalpana, Kalyan Kumar Arla, Vakkalagadda Siva Ganesh, P Chandana Sree, Chennuru Rohitha","doi":"10.1007/s11011-026-01961-2","DOIUrl":"10.1007/s11011-026-01961-2","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, affecting over 8.5 million individuals globally. Its pathophysiology is multifactorial, encompassing progressive loss of dopaminergic neurons in the substantia nigra, accumulation of misfolded alpha-synuclein, mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired proteostasis. Despite decades of research, current treatments remain predominantly symptomatic, with levodopa and dopamine replacement therapies failing to halt neurodegeneration. Given the high cost and low success rate of de novo drug development, both repurposed approved drugs and mechanistically targeted investigational therapeutics have emerged as promising approaches as a strategically rational alternative that leverages established safety profiles, known pharmacokinetics, and abbreviated regulatory pathways. This review aimed to comprehensively examine the current evidence for repurposed drugs, clinically investigated therapeutic candidates, and repositioning strategies targeting the principal pathological hallmarks of Parkinson's disease: (1) alpha-synuclein aggregation and propagation, (2) oxidative stress, (3) neuroinflammation, (4) mitochondrial dysfunction, (5) lysosomal and proteasomal dysfunction, and (6) dopaminergic neurodegeneration. The review further sought to identify recurring translational challenges, propose mechanistic frameworks for rational combination therapy, and outline future directions for trial design and biomarker integration. A narrative review of published preclinical studies, clinical trials, and recent literature was conducted, focusing on repurposed compounds with mechanistic plausibility and evidence of CNS penetration relevant to PD pathology. Evidence from Phase 1-3 clinical trials and post-mortem neuropathological analyses was synthesised across each pathological hallmark. Compounds were evaluated for mechanistic specificity, pharmacokinetic suitability, and clinical translation status. Across six pathological hallmarks, repurposed agents showed disease-relevant activity, with variable clinical translation. Ambroxol, a GCase pharmacological chaperone, achieved ~ 30-34% brain penetration, increased cerebrospinal fluid alpha-synuclein in a Phase 2 trial (n = 17) regardless of GBA mutation status, and is now in Phase 3 (ASPro-PD, n = 330). N-acetylcysteine restored depleted brain glutathione, scavenged reactive oxygen species, preserved VMAT2 and tyrosine hydroxylase expression, and improved motor outcomes, with positive dopamine transporter imaging in clinical studies. Doxycycline, a BBB-penetrant antibiotic, suppressed microglial MMP-3 and MMP-9 and downregulated TNF-α, IL-1β, iNOS, and COX-2 in preclinical PD models. Metformin and its mitochondria-targeted analog Mito-Met activated AMPK signalling and reversed mitochondrial dysfunction in PD models; however, Mito-Q10 failed in a one-year clinical trial, highlighting that ~ 70% ","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920282","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":"Postbiotics as a therapeutic frontier in Parkinson's disease: Insights into molecular pathways and neuroprotective effects.","authors":"Anjali Kumari, Khadga Raj Aran","doi":"10.1007/s11011-026-01978-7","DOIUrl":"10.1007/s11011-026-01978-7","url":null,"abstract":"<p><p>Parkinson's disease (PD) is an aging neurodegenerative disease associated with dopaminergic neuronal impairment, mitochondrial dysfunction, oxidative stress, chronic neuroinflammation, and pathological deposits of misfolded α-synuclein. Gut microbiota (GM) is a general contributing factor in PD pathogenesis via the microbiota-gut-brain bidirectional axis. Gut dysbiosis facilitates intestinal permeability, systemic inflammation, disrupted metabolism of neurotransmitters and amplified α-synuclein aggregation, deteriorates motor and non-motor symptoms. These bioactive metabolites and structural components that beneficial microorganisms generate, known as postbiotics, have been highlighted as having the capacity to regulate neuroinflammation, mitochondrial functionality, synaptic signaling, gut and blood-brain barrier integrity. Short-chain fatty acids (SCFAs), bioactive peptides, bacterial lysates, and exopolysaccharides are compounds with potent neuroprotective and anti-inflammatory properties that are applicable to PD. Preclinical evidence shows that postbiotics, especially butyrate, have the ability to alleviate oxidative stress, inhibit microglial activation, prevent α-synuclein aggregation, and improve behavioral performance in PD models. The emerging clinical evidence also indicates that the optimization of endogenous postbiotic synthesis positively influences gastrointestinal (GI) symptoms and decreases inflammatory biomarkers, and changes GM in PD patients. This review summarizes the mechanistic activities of postbiotics on pathways involved in the pathogenesis of PD and synthesizes recent findings of the therapeutic usefulness of postbiotics. Overall, postbiotics may represent a promising therapeutic strategy for targeting neurodegenerative processes in PD, although their safety, efficacy, optimal dosing, and clinical utility require further investigations. Further studies of specific postbiotic interventions and strategies targeting the microbiota-gut-brain axis are needed to determine their potential to improve the quality of life of patients with PD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920300","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":"Isoniazid impairs memory function in male Swiss mice by elevating pro-inflammatory cytokines and disruption of hippocampal, and prefrontal cortex neuronal morphology.","authors":"Miracle Olamide Gefu, Paul Ademola Adeleke, Blessing Oluwafemi Ajiboye, Gbemisayo Adetomiwa Abbas, Favour Boluwatife Jegede, Clinton Ijirigho, Abayomi Mayowa Ajayi, Solomon Umukoro","doi":"10.1007/s11011-026-01981-y","DOIUrl":"10.1007/s11011-026-01981-y","url":null,"abstract":"<p><p>Isoniazid (INH), a first-line antibiotic for tuberculosis treatment, is known for its efficacy but also for its potential to cause neurotoxic side effects, which include peripheral neuropathy, seizures, and in rare cases, psychosis. This study aimed to evaluate the neurotoxic effects of INH on memory function and its underlying mechanisms in male Swiss mice. Eighteen male Swiss mice (n = 6 per group) were treated orally with INH at doses of 5, 10, and 20 mg/kg for 28 days. The behavioral tests for memory using Y-maze and Morris water maze were conducted afterwards. The brain tissues of the animals were processed for determination of oxidative stress/antioxidant markers, pro-inflammatory cytokines, and neurotransmitter enzymes (acetylcholinesterase and glutamate decarboxylase).The histomorphology of the hippocampus and prefrontal cortex regions of the brains of the animals was done using the Hematoxylin and Eosin staining techniques. The results of the study showed that INH produced a reduction in memory function, with significant impairments at higher doses in the Morris water maze test. Biochemical analyses revealed increased lipid peroxidative product, reduced antioxidant defenses, and elevated pro-inflammatory cytokines in the hippocampus and prefrontal cortex of mice treated with INH. It also produced neurotransmitter enzymes dysregulations of the discrete brain regions of mice treated with INH. The histomorphorological studies revealed that INH produced structural changes in the hippocampus and prefrontal cortex and marked loss of viable neuronal cells. The results obtained from these studies suggest that INH treatment causes memory impairment. These findings highlight the need for strategies to minimize cognitive side effects in patients with tuberculosis on INH therapy.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906862","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":"Phenotypic shift of astrocytes from A1 to A2 induced by fasudil improves demyelination recovery in cuprizone-treated mice.","authors":"Kun Xu, Ting Yang, Hao-Ran Dong, Tai-Song Yin, Jun-Jun Yin, Li-Juan Song, Bao-Guo Xiao, Jin-Zhu Yin, Chun-Sheng Liu, Cun-Gen Ma, Xin-Yi Li, Zhi-Bin Ding","doi":"10.1007/s11011-026-01935-4","DOIUrl":"10.1007/s11011-026-01935-4","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS), characterized by neuroinflammation, demyelination, and subsequent axonal degeneration. Astrocytes (ASTs) play a dual role in MS pathogenesis, adopting either neurotoxic A1 or neuroprotective A2 phenotypes, which respectively inhibit or promote myelin repair. Fasudil (FSD), a Rho kinase inhibitor, has demonstrated potential in modulating AST phenotypes and facilitating remyelination. In this study, we investigated whether FSD treatment transformed astrocytes from A1 to A2 phenotype in cuprizone-induced demyelinating mice. Our results showed that FSD markedly suppressed A1 AST activation while enhancing A2 AST activation. Concurrently, FSD decreased pro-inflammatory chemokines such as CXCL1 and CXCL10, and increased A2-associated neurotrophic factors including BDNF and FGF2. These alterations fostered a favorable microenvironment that inhibited inflammatory responses and supported oligodendrocyte precursor cell (OPCs) differentiation and maturation, thereby ameliorated CPZ-induced demyelination. The study further revealed that these phenotypic transformation was mediated through the inhibition of NF-κB and LCN2 signaling pathways. This work identifies FSD as a promising therapeutic candidate for inhibiting demyelination through the regulation of AST polarization via specific signaling mechanism.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906874","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":"L-carnitine modulates molecular responses associated with inflammation, endoplasmic reticulum stress, and neurotrophic signaling in cerebral cortex of neonatal Gcdh^-/- mice exposed to glutaric and quinolinic acids.","authors":"Ediandra Tissot Castro, Ângela Zanatta, Andrey Vinicios Soares Carvalho, Amanda Uggeri de Moraes, Carlos Alexandre Netto, Guilhian Leipnitz, Alexandre Umpierrez Amaral, Carmen Regla Vargas, Rafael Teixeira Ribeiro, Moacir Wajner","doi":"10.1007/s11011-026-01973-y","DOIUrl":"10.1007/s11011-026-01973-y","url":null,"abstract":"<p><p>Glutaric acidemia type 1 (GA I) is caused by deficient activity of glutaryl-CoA dehydrogenase, leading to predominant accumulation of glutaric acid (GA) in the brain. GA I patients present progressive neurological deterioration whose pathophysiology is only partially elucidated. We investigated whether intracerebral GA administration, alone or combined with quinolinic acid (QA), a pro-inflammatory intermediate of the kynurenine pathway, could alter the expression of genes associated with inflammatory signaling, endoplasmic reticulum (ER) stress, and neurotrophic support in cerebral cortex of wild-type (WT) and Gcdh^-/- mice. We also tested the effects of L-carnitine (Carn) on these parameters. GA alone increased mRNA levels of the genes encoding NF-κB (NFKB1), COX-2 (PTGS2), iNOS (NOS2), and TLR2 (TLR2) in both genotypes, while reducing those of IL-10 (IL10) and VEGF-A (VEGFA) only in Gcdh^-/- mice. Combined QA + GA treatment produced a larger response, including increased TNF-α (TNF), IL-1β (IL1B), IL-6 (IL6), NLRP3 (NLRP3), CHOP (DDIT3) and PERK (EIF2AK3) mRNA levels in the Gcdh^-/- mice, besides reducing IκBα (NFKBIA), IL-10 (IL10) and BDNF (BDNF) expression in both genotypes, and VEGF-A (VEGFA) in the Gcdh^-/- mice. We also found that lysine (Lys) and QA treatment elevated TNF-α, IL-1β, and IL-6 protein levels in Gcdh^-/- mice. Carn prevented or attenuated most transcriptional alterations induced by QA + GA and reduced cytokine protein elevations elicited by Lys + QA administration. These findings indicate that Carn modulates acute molecular responses related to inflammation, ER stress, and neurotrophic factors in the cerebral cortex of the GAI mouse model.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13546310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148897474","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":"Full-spectrum cannabidiol-rich oil modulates behavior and neurochemical alterations in a rodent model of maple syrup urine disease.","authors":"Isabela da Silva Lemos, Sasckia Duarte, Meline Oliveira Dos Santos Morais, Carolina Giassi Alano, Laura Schmidt Quinsani, Rafaela Tezza Matiola, Flávia Saccon Niero, Lucas Candido Pedro, Zilli Réus, Flavia Karine Rigo, Rafael Mariano de Bitencourt, Emilio Luiz Streck","doi":"10.1007/s11011-026-01958-x","DOIUrl":"10.1007/s11011-026-01958-x","url":null,"abstract":"<p><p>Maple Syrup Urine Disease (MSUD) is caused by a genetic mutation in the branched-chain α-ketoacid dehydrogenase complex, resulting to accumulation of branched-chain amino acids (BCAAs) that affect the central nervous system and cause neurochemical alterations and behavioral changes. In this line, full-spectrum cannabidiol (CBD)-rich oil has emerged as a potential therapeutic strategy. Therefore, this study aims to evaluate the effects of two doses of the compound full-spectrum CBD-rich oil in a BCAA-induced MSUD rat model, against behavioral, cholinergic, inflammatory, and oxidative stress parameters. For this, animals were divided into six groups: control group, CBD 3.5 mg/kg group, CBD 7.5 mg/kg group, BCAA group, BCAA + CBD 3.5 mg/kg group, and BCAA + CBD 7.5 mg/kg group. The treatment was administered over 21 days; after that, the animals were subjected to open-field and object recognition tests. Next, we extracted the cerebral cortex to analyze cholinergic function, inflammation, and oxidative stress. The results show that the open-field test revealed no differences in crossings and rearings across all groups. In object recognition test, control and CBD 3.5 groups showed improved short- and long-term memory compared to training. The CBD 7.5 and BCAA + CBD 3.5 groups showed improvement only in short-term memory. BCAA control and BCAA + 7.5 did not present differences. In the cholinergic system, BCAA control showed decreased choline acetyltransferase (ChAT) activity, which was reversed by CBD treatment at both doses. The BCAA + CBD 7.5 shows increased ChAT activity compared to control group. While acetylcholinesterase (AChE) was reduced in the CBD 7.5 groups and increased in the BCAA control group, both CBDs reversed this increase in BCAA control group. Inflammatory cytokines show increased interleukin-1β in BCAA control group, and the CBD treatment decreases its levels compared to BCAA and saline control groups. Interleukin-6 increases in BCAA control group, and CBD 3.5 reverses it. Tumoral necrosis factor-alpha was reduced in BCAA + CBD 3.5 and BCAA + CBD 7.5 compared to control and BCAA control groups. Further, under oxidative stress, BCAA control increases 2,7-dichlorofluorescein oxidation and thiobarbituric acid levels, which were reversed by CBD treatment. Sulfhydryl content was decreased in CBD 7.5, BCAA control group, BCAA + CBD 3.5, and BCAA + CBD 7.5 compared to control group. Superoxide dismutase activity increased across all groups, whereas catalase activity decreased in the BCAA control group; treatment with CBD 7.5 reversed this reduction. Overall, we conclude that full-spectrum CBD-rich oil shows therapeutic potential for MSUD, although optimal dosing and treatment duration require further investigation.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888169","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":"Da chuanxiong formula improves vascular remodeling via promoting angiogenesis and vasodilation mediated by PI3K/Akt/eNOS signaling.","authors":"Jiale Gao, Tianyu Lou, Beibei Huang, Xiuying Guo, Hao Wu, Jie Liu, Yueting Li, Menghan Feng, Lirong Liu, Hongbin Xiao","doi":"10.1007/s11011-026-01974-x","DOIUrl":"10.1007/s11011-026-01974-x","url":null,"abstract":"<p><p>Vascular cognitive impairment (VCI) is a vast disease with chronic cerebral hypoperfusion (CCH) being the major driver. In our previous study, we have verified that Da ChuanXiong (DCX) formula could alleviate VCI, and obviously upregulate the decreased cerebral blood flow, indicating its potential benefits on vascular remodeling. This study aims to explore the pro-angiogenic and vasodilatory effects of DCX formula after CCH injuries, and clarify its pharmacodynamic substances and potential mechanisms. The rat model of CCH was established by bilateral common carotid artery occlusion. CD31⁺ immunofluorescent staining and quail chorioallantoic membrane (qCAM) experiments were conducted to assess the angiogenic effect of DCX. Isolated vascular ring experiments and NO assay in qCAM were performed to evaluate the vasodilatory effect of DCX. Then we analyzed the chemical components absorbed in the blood of DCX under CCH conditions by UPLC-Q-TOF/MS, and further combined network pharmacology, molecular docking to predict the potential mechanisms and effective components. Western blot was performed in CCH rats to verify the possible mechanisms and in vitro pharmacodynamic verification experiment was conducted for innovative active ingredients in DCX. Our results revealed that DCX obviously increased the number of CD31⁺ cells in the hippocampus and brain cortex of CCH rats, and significantly increased the vascular areas in qCAM. DCX significantly dilated the pre-constricted vascular ring and increased NO contents in qCAM. Besides, Senkyunolide A, Butylphthalide, Ferulic acid, Senkyunolide I, Levistilide A, Ligustilide, Senkyunolide H and Gastrodin were identified as the 8 major blood-absorbed compounds of DCX under CCH condition. Next, network pharmacology and molecular docking revealed NOS3 and PI3K/Akt signaling as the critical targets and pathway of DCX improving vascular remodeling against CCH injuries, which was further validated by western blot. Moreover, we firstly discovered that Senkyunolide A and Senkyunolide H could obviously promote cell migration and enhance the tube formation ability of HUVECs in vitro. Taken together, DCX formula effectively enhanced the angiogenesis and vasodilation via activating PI3K/Akt/eNOS signaling, which might be the important pathways for DCX promoting vascular remodeling against CCH injuries. Notably, Senkyunolide A and Senkyunolide H were firstly identified as innovative components responsible for the pro-angiogenic effects of DCX.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"41 1","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888167","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":"ADAM10's combined influence on the diagnostic usefulness of IL 22, IL 10, IL-17 A, and IL-17D in autism spectrum disorders: Predicted role on gut leakiness as co-morbidity.","authors":"Afaf El-Ansary, Hanan A Alfawaz, Ahmed Dewedar, Ramesa Shafi Bhat, Geir Bjørklund, Laila Y Al-Ayadhi","doi":"10.1007/s11011-026-01965-y","DOIUrl":"10.1007/s11011-026-01965-y","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with increasing global prevalence but a lack of reliable diagnostic biomarkers. Emerging evidence suggests that immune dysregulation, gut-brain axis dysfunction, and increased intestinal permeability play key roles in ASD pathophysiology. This study investigated the combined diagnostic value of ADAM10 and cytokines (IL-10, IL-22, IL-17 A, and IL-17D). Multivariable logistic regression produces an improved ROC curve that improves diagnostic accuracy over individual markers by combining numerous predictors into a single risk score (linear predictor). The technique, which frequently raises individual marker AUCs, entails modelling a binary result, calculating the probability, and visualizing ROC based on the projected probabilities. In this case-control study, plasma levels of ADAM10, IL-10, IL-22, IL-17 A, and IL-17D were measured in 37 male children with ASD and 37 age-matched controls. Group comparisons, correlation analyses, and receiver operating characteristic (ROC) curve analyses, including combined ROC models, were performed. ADAM10, IL-22, and IL-17 A levels were significantly reduced in children with ASD compared to controls, whereas IL-10 and IL-17D showed no significant differences. ADAM10, IL-17 A, and IL-22 demonstrated good diagnostic performance, with AUC values of 0.886, 0.855, and 0.812, respectively. In contrast, IL-10 and IL-17D showed poor discriminatory ability, with AUC values of 0.524 and 0.599, respectively. Combined ROC analysis markedly improved diagnostic accuracy, with all panels including ADAM10 achieving AUC values above 0.90, and some reaching as high as 0.988, with high sensitivity and specificity. The combination of ADAM10 with selected cytokines significantly enhances diagnostic performance compared to individual markers, supporting a link between immune dysregulation, barrier dysfunction, and gut permeability in ASD.</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":"148874370","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}