Metabolic brain disease最新文献

{"title":"Amino acid patterns predict white matter integrity measures in the brain in patients across the Alzheimer's disease continuum.","authors":"Farshad Goharmanesh, Maryam Masmoie, Hamide Nasiri, Sayedeh-Fatemeh Sadat-Madani, Sara Montazeri Namin, Maryam Damizadeh, Shayan Shakeri, Fatemeh Sodeifian, Ali Rajabpour-Sanati, Bahar Bahrainian, Yasaman Mohammadi, Ali Shushtari, Mahsa Mayeli","doi":"10.1007/s11011-025-01647-1","DOIUrl":"10.1007/s11011-025-01647-1","url":null,"abstract":"<p><p>Alzheimer's disease (AD), the leading cause of dementia, poses a growing global health challenge due to its rising prevalence and socioeconomic impact. Investigating metabolic alterations associated with white matter integrity (WMI) could provide critical insights into AD pathogenesis and identify potential therapeutic targets. This cross-sectional study explored the associations between amino acid (AA) profiles, assessed via ultra-high-performance liquid chromatography (UHPLC), and WMI metrics derived from diffusion tensor imaging (DTI) in individuals across the AD continuum. A total of 176 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included and grouped into cognitively normal (CN) individuals (n = 54), patients with mild cognitive impairment (MCI, n = 88), and AD patients (n = 34). WMI was evaluated using DTI-derived metrics, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD). AA profiling was conducted using an appropriate panel. Regression analyses, adjusted for age, gender, and education, was used to identify significant associations between AA levels and WMI. Distinct AA alterations were associated with white matter microstructural integrity across study groups. In CN individuals, higher levels of arginine, glycine, and threonine correlated with decreased FA and increased MD, indicating reduced white matter integrity. Conversely, in AD patients, aspartate, glutamate, and histidine exhibited opposite associations, showing positive correlations with FA and negative correlations with MD, suggesting potential neuroprotective or compensatory mechanisms. These findings underscore the associations between AA patterns and white matter integrity and their potential role as AD progression markers. Further investigations into these AA metabolism pathways may identify novel biomarkers for early diagnosis and targets for therapeutic interventions.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 6","pages":"227"},"PeriodicalIF":3.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326273","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":"Elucidating neural molecular mechanisms underlying metabolic disorders-induced neuropsychiatric disorders in mice on prolonged high fructose diet.","authors":"Sachin Singh, Nitesh Kumar Singh, Kottapalli Srividya, Unis Ahmad Bhat, Divya Tej Sowpati, Sumana Chakravarty, Arvind Kumar","doi":"10.1007/s11011-025-01648-0","DOIUrl":"10.1007/s11011-025-01648-0","url":null,"abstract":"<p><p>Metabolic disorders (MetDs), driven mostly by lifestyle changes are growing at an alarming rate, and have cardiovascular and cerebrovascular consequences, eventually leading to various neuropsychiatric disorders. Considering a dearth of studies, we modeled MetDs-like conditions in C57BL/6 Ncrl mice on prolonged 60% high fructose diet (Hfr) for 56 weeks. The metabolic assessments revealed significant changes in various MetDs-related physiological and biochemical parameters in the Hfr group compared to the control (Ctrl) group such as reduced lean mass, hyperlipidemia, elevated liver function markers (SGPT, SGOT), and kidney function markers (creatinine, alkaline phosphatase). However, hyperglycemia and glucose intolerance were not observed. Interestingly, the prolonged Hfr diet accelerated the onset of aging. But just 10 days of chronic unpredictable mild stress (CUMS) resulted in mild insulin intolerance as shown by the oral glucose tolerance test (OGTT). Further, these animals developed neuropsychiatric disorders-like phenotype. Transcriptomic analysis of the prefrontal cortex (PFC) region led to uncovering of hundreds of differentially expressed genes (DEGs) between the groups, including the known markers: pro-inflammatory cytokines (IL1B, IL6, TNFα) chemokines (CXCl10,12, CCL4,8), innate immune regulators (TLR4), neuroinflammatory regulators (NLRP3,4), neurotrophic and angiogenic factor (VEGF), thus correlating with MetD-induced neuropsychiatric (cognitive and affective) disorders. The pathway analysis of the DEGs highlighted perturbations of various signaling pathways already implicated in neuropsychiatric disorders. Furthermore, dysregulation of a few key epigenetic regulators including the critical metabolic sensor SIRT6 and its neuroinflammatory and immune target genes, supports our hypothesis that epigenetic dysregulation underlies lifestyle changes (high-calorie diet and chronic stress)-induced susceptibility to diseases.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 6","pages":"226"},"PeriodicalIF":3.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317475","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":"Bilirubin: a game-changer in alzheimer's therapy? Unveiling its neuroprotective and disease-modifying potential.","authors":"Ramandeep Kaur Sidhu, Yukti Mittal, Khadga Raj Aran","doi":"10.1007/s11011-025-01653-3","DOIUrl":"10.1007/s11011-025-01653-3","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurological disease characterised by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTS), oxidative stress, and neuroinflammation resulting in cognitive decline. Bilirubin is considered to be a by-product of heme metabolism and has emerged as a powerful endogenous antioxidant with significant neuroprotective activities. This article focuses on the multidirectional role of bilirubin in AD, underlining its capability to alleviate oxidative stress, reduce neuroinflammation, inhibit Aβ fibrillation and tau hyperphosphorylation, and maintain synaptic and mitochondrial function. The antioxidant activity of bilirubin, which involves the bilirubin-biliverdin redox cycle, scavenges ROS and promotes cellular defence mechanisms. In addition, bilirubin modulates inflammatory signalling pathways like NF-κB and TLR4 to downregulate pro-inflammatory cytokine release. It also induces Aβ clearance and prevents tau pathology by controlling kinase and phosphatase function, thus ensuring neuronal integrity. Despite its therapeutic promise, the role of bilirubin in AD is multifaceted, with reports from studies being conflicting regarding its levels in patients. While physiological levels have neuroprotective properties, higher levels are neurotoxic, and this emphasizes the requirement for accurate therapeutic dosing. The challenges of blood-brain barrier (BBB) permeability, heterogeneity in bilirubin metabolism, and the absence of large-scale clinical trials need to be overcome to apply preclinical observations to clinical applications. Future studies must aim at maximising bilirubin-based treatments, such as bilirubin analogues, HO-1 inducers, and nanocarrier systems, in addition to non-pharmacological methods such as dietary and lifestyle changes. Standardisation of bilirubin assessment and determining its potential as a diagnostic biomarker are also critical. Overall, bilirubin is a potential therapeutic target for AD, but additional research is necessary to optimize its potential while minimising risks.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 6","pages":"224"},"PeriodicalIF":3.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302486","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":"Human placental extract rescues hippocampal damage associated with cognitive impairment in diabetic male rats through antioxidative, anti-inflammatory, and neuromodulatory activities.","authors":"Shreen Matar, Rehab A Gomaa, Abeer El Wakil, Amina Essawy","doi":"10.1007/s11011-025-01646-2","DOIUrl":"10.1007/s11011-025-01646-2","url":null,"abstract":"<p><p>Memory and cognitive impairment have emerged as significant comorbidities associated with diabetes, yet effective treatment remains elusive. Various studies have shown that human placental extract (HPE) is rich in bioactive molecules that exhibit anti-inflammatory, antioxidant, anti-apoptotic, and immunomodulatory properties. However, the impact of HPE on memory and cognitive decline is not well understood. This study aimed to investigate the therapeutic effects of HPE on memory and cognitive dysfunction induced by streptozotocin (STZ) in rats, while also exploring the underlying mechanisms. To induce type 2 diabetes mellitus (T2DM), rats were first fed a high-fat diet for two weeks, followed by a single intraperitoneal injection of STZ (40 mg/kg body weight) and subsequently treated with HPE (20 mg/kg body weight per day) for 14 days. The results of our behavioral tests demonstrated that HPE significantly enhanced learning, memory, and cognitive function in rats subjected to STZ administration. Specifically, HPE increased the discrimination index in the novel object recognition test from a negative value in STZ rats to a positive value in treated rats and improved spontaneous alternation in the T-maze from 41.25 ± 8.25% to 74.50 ± 8.50%. Additionally, HPE notably improved serum levels of insulin, glucose, the homeostatic model assessment of insulin resistance (HOMA-IR), and lipid profiles compared to untreated diabetic rats. It also modulated oxidative stress markers, antioxidants, as well as pro-inflammatory cytokines and neurochemicals levels in hippocampal tissue, underscoring its antioxidant and anti-inflammatory properties. Notably, HPE treatment improved the neurological morphology of the hippocampus and reduced DNA damage. The percentage of tailed cells dropped from 25.67 ± 0.33 in diabetic rats to 13.67 ± 0.88 with HPE treatment. In summary, HPE exhibits neuroprotective effects and could serve as a promising therapeutic strategy for addressing neurodegenerative symptoms associated with T2DM in a rat model.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 6","pages":"225"},"PeriodicalIF":3.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302487","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":"Adropin ameliorates behavioral seizures and the relevant neuroinflammation, oxidative stress, and neural damage in a rat model of pentylenetetrazole-induced seizure potentially by reducing the activation of NF-κB/IkB-α signaling pathway.","authors":"Shaafah Namulodi, Ibrahim Ethem Torun, Fahri Bayiroglu, Mehmet Salih Kaya, Erkan Kilinc","doi":"10.1007/s11011-025-01654-2","DOIUrl":"10.1007/s11011-025-01654-2","url":null,"abstract":"<p><p>This study aimed to investigate the effects of adropin on seizure activity, neuroinflammation, oxidative stress, and cognitive function in a rat model of pentylenetetrazole (PTZ)-induced seizure. Male Wistar rats were randomly assigned to six groups (n = 7/each group), as follows: control, PTZ, adropin (2 µg/kg or 10 µg/kg) + PTZ, L-NAME + adropin + PTZ, and valproic acid + PTZ groups. Anticonvulsant medicine valproic acid was administered as positive control. Non-selective nitric oxide synthase inhibitor L-NAME was administered together with adropin to elucidate whether adropin exerts its possible effects through the nitric oxide pathway. Behavioral epileptic seizures, biochemical markers of neuroinflammation and relevant pathway, oxidative stress, cognitive function and neural survival/damage were assessed. Adropin (10 µg/kg) reduced PTZ-induced seizure severity and duration, and mitigated cortical and hippocampal pro-inflammatory (IL-1β, IL-6, TNF-α and related transcription factors pNF-κB-p65 and pIκBα), oxidant (MDA) and neural damage (GFAP) markers while elevating anti-inflammatory (IL-10), antioxidant (SOD) and neural survival (BDNF) markers. Combining adropin and L-NAME also exhibited similar effects to adropin alone. In other words, blocking systemic nitric oxide production did not alter the effects of adropin. However, adropin did not significantly improve cognitive performance in the passive avoidance test. Valproic acid, as a positive control, reversed the PTZ-induced effects. These findings suggest that adropin exhibits anticonvulsant, anti-inflammatory, antioxidant and neuroprotective properties in PTZ-induced seizure model potentially through modulation of NF-κB/IkB-α signalling. Therefore, adropin may be a multi-faceted and promising agent in the prevention and management of epileptic seizures in the future.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"222"},"PeriodicalIF":3.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285499","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":"Blood-brain barrier dysfunction in hepatic encephalopathy: pathophysiology, diagnostic assessment and therapeutic perspectives.","authors":"Loic Le Guennec, Sarah Mouri, Dominique Thabut, Nicolas Weiss","doi":"10.1007/s11011-025-01645-3","DOIUrl":"10.1007/s11011-025-01645-3","url":null,"abstract":"<p><p>Hepatic encephalopathy (HE) is defined as the spectrum of neurological and neuro-psychological disturbances that complicate liver insufficiency and/or portosystemic shunt and is associated with excess mortality, impaired quality of life and a higher risk of traffic accidents. In addition to hyperammonaemia, systemic inflammation is now recognised as a pivotal precipitant of HE. Accumulating evidence over the past three decades indicates that dysfunction of the blood-brain barrier (BBB)-the multicellular interface that regulates molecular, immune and haemodynamic exchanges between brain and blood-also plays a central pathogenic role. In experimental and clinical HE, cytokine- and ammonia-driven loss of tight-junction proteins (claudin-5, occludin, ZO-1/-2), astrocytic aquaporin-4 mislocalisation, pericyte structural injury and impaired glymphatic flow converge to increase vascular permeability and promote cytotoxic and vasogenic oedema. Concurrent activation of microglia and up-regulation of endothelial adhesion molecules facilitate leukocyte recruitment, whereas NF-κB-dependent re-programming of ATP-binding cassette and solute-carrier transporters alters cerebral handling of xenobiotics, bile acids and amino acids. A better understanding of these interconnected mechanisms opens the way to BBB-directed interventions such as Angiopoietin-1 analogues, sphingosine-1-phosphate-receptor modulators or claudin-5 peptidomimetics that could complement classic ammonia-lowering therapies. This review critically examines how BBB dysfunction contributes to the pathogenesis of HE and summarizes emerging therapeutic approaches targeting the barrier.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"223"},"PeriodicalIF":3.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285500","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":"Immunomodulatory and behavioral effects of ayahuasca and N, N-dimethyltryptamine in a rat model of lipopolysaccharide-induced depression.","authors":"Daniel do Nascimento Sousa, Monique de Azevedo, Maria Lucília Santos, Tatiana Karla Dos Santos Borges, Daniela Mara de Oliveira, Eloisa Dutra Caldas","doi":"10.1007/s11011-025-01650-6","DOIUrl":"10.1007/s11011-025-01650-6","url":null,"abstract":"<p><p>Ayahuasca (Aya) is an Amazonian beverage traditionally used as medicine by Indigenous people in South America to treat various illnesses and have shown a potential to treat depression. This study aimed to investigate the antidepressant effects of fluoxetine, Aya and N, N dimethyl tryptamine (DMT), a component of the beverage, focusing on the modulation of inflammatory serum cytokine profiles and behavior of Wistar rats subjected to lipopolysaccharide (LPS)-induced depression. In total, 126 rats were randomly assigned to seven groups: saline control, LPS, fluoxetine, three ayahuasca groups (dosed at 0.5, 1, and 2 times the usual ritualistic dose, Aya0.5, Aya1 and Aya2), and one DMT treatment group. The rats received LPS every other day from day 1 to 13 and fluoxetine, Aya and DMT daily from day 2 to 14. At day 15, the rats were submitted to open field and forced swimming tests, plasma samples were collected and the animals were euthanized. The LPS group showed lower body weight grain and higher plasma levels of pro-inflammatory cytokines IL-1α (p < 0.001), TNF-α, and IL-12p70 compared to control, which were significantly reduced by the treatment groups (p < 0.05 up to p < 0.0001), indicating a potential for modulation of the inflammatory state seen in depression. The Aya2 group exhibited increased locomotion in the open field arena compared to the fluoxetine (p < 0.05) and DMT (p < 0.01) groups, with a significantly higher percentage of entries into the center than the control group (p < 0.01). Furthermore, treatments with fluoxetine, Aya, and DMT significantly increased swimming time compared to the LPS group (p < 0.01), and fluoxetine and the Aya0.5 groups displayed higher climbing times compared to LPS and control (p < 0.05). Although the LPS model did not consistently induce depressive-like behaviors, the results highlight the potential of ayahuasca and DMT to modulate the immune system and reduce pro-inflammatory cytokine levels associated with depression, which could have significant implications for treating inflammation-related aspects of depression.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"220"},"PeriodicalIF":3.2,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266722","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":"Tirzepatide: a novel therapeutic approach for Alzheimer's disease.","authors":"Ghadah H Alshehri, Hayder M Al-Kuraishy, Huda Jaber Waheed, Ali I Al-Gareeb, Safaa A Faheem, Athanasios Alexiou, Marios Papadakis, Gaber El-Saber Batiha","doi":"10.1007/s11011-025-01649-z","DOIUrl":"10.1007/s11011-025-01649-z","url":null,"abstract":"<p><p>Tirzepatide (TRZ) is a dual agonist of glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptors that were recently approved for the treatment of type 2 diabetes (T2D) and obesity. Of note is that T2D and obesity, by inducing peripheral low-grade inflammation and oxidative stress, provoke the development of central neuroinflammation and oxidative stress. Together, T2D and obesity are regarded as potential risk factors implicated in the development and progression of Alzheimer's disease (AD), which is the most common neurodegenerative disease and represents the most typical cause of dementia. Hence, targeting low-grade inflammation and oxidative stress in T2D and obesity by TRZ may reduce AD neuropathology. In addition, TRZ can inhibit the production of amyloid beta (Aβ) and associated neuroinflammation, oxidative stress, and neuronal apoptosis. However, the underlying neuroprotective mechanism of TRZ against AD is not entirely explained. Consequently, this mini-review aims to discuss the possible molecular mechanism of TRZ in AD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"221"},"PeriodicalIF":3.2,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266723","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":"Unraveling novel mechanisms of ATP-Binding cassette (ABC) transporter in insulin Resistance-induced amyloidogenesis.","authors":"Akhil Sharma, Ashi Mannan, Thakur Gurjeet Singh","doi":"10.1007/s11011-025-01642-6","DOIUrl":"10.1007/s11011-025-01642-6","url":null,"abstract":"<p><p>Insulin resistance (IR) impairs glucose uptake and metabolism, whereas amyloidogenesis, the formation of abnormal protein aggregation, forming insoluble fibrils called amyloids, which are linked with numerous neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Huntington disease's (HD), Parkinson's disease (PD) and Prion's disease. This review explores how IR promotes amyloidogenesis by disrupting cholesterol homeostasis and enhancing Amyloid beta (Aβ) production and aggregation. Specifically, we examine the role of ATP-binding cassette (ABC) transporters in cholesterol homeostasis along with their impact on insulin signaling pathways, highlights how their dysregulation can lead to IR, a significant contributor to the development of amyloidogenesis, a key factor in causing NDDs. We explore the novel molecular mechanisms linking IR and Aβ aggregation, focusing on the interplay between ABC transporters and Amyloid precursor protein (APP) processing. Furthermore, we also explore emerging evidence linking ABC transporters to oxidative stress, inflammation and mitochondrial dysfunction critical factors in the development of amyloidogenesis. Additionally, this review also discusses potential therapeutic strategies targeting ABC transporters to mitigate IR and reduce amyloid burden by various mechanisms including Insulin receptors/IRS-1 signaling, Phosphatidylinositol3kinase-Protein kinase-B (PI3K/AKT), Mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase (JNK), Glycogen synthase kinase 3 (GSK3), mammalian Target of Rapamycin (mTOR), Insulin-Degrading Enzyme (IDE), Advanced glycation end products (AGEs), Glucose transporters (GLUTs), Apolipoprotein E (ApoE), Peroxisome proliferator-activated receptors (PPARs), Adiponectin, Mitochondrial dysfunctioning, AMP-activated protein kinase (AMPK) Wingless-related integration site/beta-catenin (Wnt/β-catenin) and Sirtuin1 (SIRT1). These insights provide new possibilities for developing targeted therapies against neurodegenerative diseases associated with IR and amyloid accumulation.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"218"},"PeriodicalIF":3.2,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248765","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":"Targeting NOX inhibitors in neurodegeneration: a therapeutic perspective.","authors":"Sifat Kaur, Reet Verma, Veerta Sharma, Thakur Gurjeet Singh","doi":"10.1007/s11011-025-01644-4","DOIUrl":"10.1007/s11011-025-01644-4","url":null,"abstract":"<p><p>Neurodegenerative diseases are characterized by progressive neuronal loss, cognitive decline, and motor dysfunction driven by oxidative stress and neuroinflammation. NADPH oxidases (NOX) are a major source of reactive oxygen species (ROS) in the central nervous system, contributing to oxidative damage, mitochondrial dysfunction, and neuroinflammatory responses. Overactivation of NOX enzymes, particularly NOX-1, NOX-2, and NOX-4, has been implicated in neuronal injury and disease progression. NOX inhibitors have shown promise in pre-clinical models by reducing ROS production, modulating neuroinflammatory pathways, and preserving neuronal integrity. Despite these encouraging findings, clinical research remains in early stages, with ongoing studies focused on evaluating NOX inhibitors in neurodegeneration. NOX inhibition represents a promising therapeutic strategy for neurodegeneration. However, challenges such as achieving isoform selectivity, improving drug bioavailability, and overcoming blood-brain barrier penetration must be addressed for successful clinical translation. This review provides a therapeutic perspective on NOX inhibition in neurodegenerative diseases, discussing the current state of pre-clinical and clinical research, highlighting key challenges, and proposing directions for future research aimed at optimizing NOX-targeted therapies for clinical application.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"219"},"PeriodicalIF":3.2,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248764","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}