Type 2 diabetes mellitus is associated with an increased risk of cognitive dysfunction and neurodegenerative changes, contributing to the emerging concept of “Type 3 Diabetes,” characterized by impaired cerebral insulin signaling and altered brain glucose metabolism. However, the metabolic processes connecting systemic metabolic dysfunction with cerebral insulin resistance remain incompletely understood. This review examines carbonyl stress, particularly methylglyoxal and other reactive dicarbonyls, as potential links between dysregulated glucose metabolism and impaired cerebral insulin signaling. We evaluate MGO generation and glyoxalase-mediated detoxification, evidence linking carbonyl stress with insulin-signaling abnormalities and interactions among AGE-RAGE signaling, oxidative stress and neuroinflammation. Particular emphasis is placed on distinguishing evidence from peripheral insulin-responsive tissues, vascular compartments and neuronal models, given the limited direct in vivo evidence establishing MGO as a cause of cerebral insulin resistance. The review further considers potential consequences for neuronal metabolism, synaptic function, and neurodegenerative vulnerability, alongside emerging therapeutic strategies targeting carbonyl metabolism and related pathways, including intranasal nanocarrier-mediated delivery. Overall, carbonyl stress represents a biologically plausible but not yet established molecular link between diabetes-associated metabolic dysfunction and neurodegenerative vulnerability, warranting brain-specific studies to determine its causal and therapeutic relevance. Proposed mechanistic framework illustrating carbonyl stress as a potential molecular link between chronic hyperglycemia, cerebral insulin signaling impairment, and neurodegenerative vulnerability in the context of Type 3 Diabetes
The protective effects of Hua-Feng-Dan recipes against chronic cerebral hypoperfusion-induced ischemia were examined; RNA-seq and 16 S-rRNA-seq were used to explore the molecular mechanisms. Male Sprague-Dawley rats underwent unilateral common carotid artery ligation surgery to establish chronic cerebral hypoperfusion (CCH) models. Then, the CCH rats were treated with various Hua-Feng-Dan recipes in diet for 20 days. Finally, behavioral tests were performed, followed by histopathology. Hippocampal RNA was isolated for RNA-seq and RT-qPCR analyses; Colon bacterial DNA was isolated for 16 S rRNA-seq and bioinformatics. The CCH rats exhibited cognition deficits evidenced by Behavioral tests. The neurons in the hippocampus CA1 area were damaged. Hua-Feng-Dan recipes as Reduced_H (0.5 g/kg), Original, and Nonferment improved behavioral deficits and morphological changes, while Reduced_L (0.25 g/kg) was ineffective. RNA-seq revealed distinct gene expression pattern among groups. Ingenuity pathway analysis of differentially expressed genes revealed Hua-Feng-Dan recipes ameliorated Canonical pathways involved in cytosolic Ca2+ overload, disruption of IGF homeostasis and Neutrophil degranulation; attenuated CCH-activated Upstream regulators such as IL1B, IL6, TNF, IGF1, and glucose metabolism. CCH-decreased Firmicutes/Bacteroidetes ratio were recovered by Hua-Feng-Dan recipes. CCH-increased Prevotellaceae and decreased Lachnospiraceae were attenuated; CCH-increased ASV1 and decreased ASV39 were brought to normal after Hua-Feng-Dan treatments. Similar to the efficacy against CCH, Reduced_L was ineffective in transcriptome and gut microbiota analysis. Hua-Feng-Dan recipes (Reduced_H, Original, and Nonferment) are effective against CCH-induced chronic cerebral ischemia, while Reduced_L was ineffective. The mechanisms of the protection are related to transcriptome regulation in the hippocampus, and modulation of CCH-disrupted gut dysbiosis.
Huntington’s disease (HD) is traditionally regarded as a progressive neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene, resulting in selective striatal neuronal degeneration and progressive motor, cognitive, and psychiatric impairment. However, accumulating evidence indicates that HD is a systemic disorder involving profound metabolic, mitochondrial, and immune dysfunction in peripheral organs, particularly the liver. Emerging studies suggest that hepatic mitochondrial dysfunction induced by mutant huntingtin remodels the hepatic secretome through altered secretion of hepatokines, extracellular vesicles, complement proteins, inflammatory cytokines, and metabolic mediators. These circulating factors may disrupt blood-brain barrier integrity, promote microglial immunometabolic reprogramming, enhance complement-mediated synaptic pruning, and amplify chronic neuroinflammation, thereby accelerating neurodegeneration. This review summarizes current evidence supporting the liver–brain axis in HD and discusses how hepatic metabolic dysfunction contributes to central nervous system pathology. Furthermore, we highlight therapeutic strategies aimed at restoring hepatic mitochondrial homeostasis, modulating hepatokines, extracellular vesicles, exosomal microRNAs, and complement signaling to interrupt pathological liver-to-brain communication. Finally, we discuss emerging translational approaches, including multi-omics technologies, engineered extracellular vesicles, gene-editing platforms, and precision medicine, that may facilitate the development of disease-modifying therapies. By integrating peripheral metabolic regulation with central neuroimmune mechanisms, this review presents the hepatic secretome microglia axis as a potential conceptual framework for understanding HD pathogenesis and identifies liver targeted interventions as promising therapeutic opportunities beyond conventional neuron centric strategies.
Ammonia plays a pivotal role in the pathogenesis of hepatic encephalopathy (HE). Astrocytes are the principal site of ammonia detoxification in the brain, where ammonia is incorporated with glutamate to generate glutamine. After entering mitochondria, glutamine sequentially catabolized, leading to the re-release of ammonia and the generation of oxidative stress, thereby disrupting mitochondrial function. MitoQ, a mitochondria-targeted antioxidant, has been shown to protect against mitochondrial oxidative injury. This study investigated the therapeutic effects and underlying mechanisms of MitoQ in thioacetamide (TAA)-induced HE. MitoQ treatment alleviated TAA-induced behavioral abnormalities and reduced aberrant astrocyte activation in hippocampus. TAA-induced HE exhibited disrupted mitochondrial quality regulation in hippocampus, characterized by increased p-DRP1 expression, decreased OPA1 expression, and activation of PINK1, Parkin, and LC 3B, while these abnormalities were restored following mitochondria-targeted therapy. Primary astrocytes were isolated and exposed to 5 mM ammonium chloride to establish an in vitro hyperammonemic model, followed by treatment with 100 nM MitoQ. MitoQ reduced intracellular reactive oxygen species (ROS) and restored mitochondrial membrane potential in ammonia-exposed astrocytes. Transcriptomic analysis further indicated that oxidative phosphorylation, regulation of autophagy, and mitochondrial function were among the key pathways involved in the protective effects of MitoQ in astrocytes under hyperammonemic conditions. Importantly, PINK1 knockdown abolished the protective effects of MitoQ, suggesting that the PINK1/Parkin pathway is required for MitoQ-mediated mitochondrial protection. Together, these findings demonstrate that MitoQ attenuates TAA-induced HE by restoring mitochondrial homeostasis and suppressing astrocytic oxidative stress, at least partly through a PINK1/Parkin-dependent mechanism.
While the excitation-inhibition imbalance theory has long dominated epilepsy research, the role of cerebral ammonia dysregulation remains underexplored. Herein, we integrated bioinformatics with multi-level experimental validation utilizing tissues from epilepsy patients, a kainic acid-induced chronic mouse model, and an in vitro magnesium-free neuronal model. Five core genes (SOD1, SIRT5, ALB, GFAP, and PLA2G2A) were identified to form a promising predictive model for epilepsy. Cerebral ammonia levels were significantly elevated across all models, accompanied by downregulation of SOD1, SIRT5, and NeuN, alongside significant hippocampal neuronal loss. Network pharmacology and molecular docking identified NAD⁺ as the top compound targeting both SOD1 and SIRT5. Functional studies revealed that overexpression of SOD1 or SIRT5, as well as NAD⁺ treatment, effectively reduced ammonia accumulation, increased neuronal viability, and restored NeuN expression. Notably, neither genetic overexpression nor NAD⁺ treatment directly altered baseline neuronal firing, indicating that their neuroprotective efficacy is mediated through mitigation of ammonia toxicity rather than direct suppression of hyperexcitability. Collectively, these findings suggest that cerebral ammonia dysregulation is associated with dysfunction of the SOD1-SIRT5 axis, which may contribute to AICD in epilepsy, and that restoring this axis via SOD1/SIRT5 overexpression or NAD⁺ reduces ammonia accumulation and promotes neuronal survival.
