Metabolic brain disease最新文献

Emerging evidence suggests that TBI triggers ferroptosis, and dexmedetomidine (Dex) has a neuroprotective effect. This study aimed to explore the underlying mechanism of function of Dex in ferroptosisi after TBI. TBI model was established using the modified Feeney's weight drop injury method. Our experiment included the assessment of lesion volume by hematoxylin and eosin (HE) staining, the evaluation of the expression levels of ferroptosis-related proteins NRF2, HO-1, GPX4, FPN1, and TRFC by Western blotting (WB), the morphological changes via transmission electron microscopy (TEM), the increase in reactive oxygen species (ROS) through the measurement of malondialdehyde (MDA), the expression of HO-1 and GPX4 in the hippocampal tissues by immunofluorescence staining (IF), the behavioral assay by the Morris water maze (MWM) test and the open field test (OFT). Dex could alleviate the cognitive impairment in TBI mice and reduce ferroptosis after TBI. Dex could promote the nuclear translocation of NRF2 and enhance the expression of downstream HO-1, xCT, and GPX4, thereby inhibiting ferroptosis of neuronal cells. In addition, ML385 inhibited the expression of NRF2 and then reversed the neuroprotective effect of Dex. Dex alleviates ferroptosis and oxidative stress responses after TBI in mice through the NRF2/HO-1/GPX4 pathway, thus relieving the cognitive impairment in mice after TBI.

Major depressive disorder (MDD) is a common psychiatric illness with chronic poor mood, cognitive impairment, and neurovegetative symptoms. Genetic, environmental, and neurochemical variables are involved. A recent study shows that microRNAs (miRNAs), tiny, non-coding RNAs that regulate gene expression, play a major role in MDD development and progression. These miRNAs affect depression-related neuroplasticity, inflammation, stress, and synaptic function. Dysregulation of miR-124, miR-135, and miR-16 affects neurotransmitter signaling and neurotrophic support, particularly serotonin, dopamine, and brain-derived neurotrophic factor (BDNF), and increases neuroinflammation. These chemical abnormalities can affect mood-regulating brain circuits, prolonging and worsening depression. MiRNA anomalies alter MDD susceptibility and treatment response. MiRNAs can be found in blood and other tissues, making them promising diagnostic biomarkers and therapeutic efficacy predictors for more individualized MDD management. Experimental miRNA mimics and antagomirs are being tested to fix gene expression aberrations more precisely than standard antidepressants. This review summarizes MDD miRNA information, emphasizing their pathogenic and therapeutic roles. MiRNA-based diagnostics and therapeutics have promising potential. However, molecularly targeted interventions must address off-target effects and miRNA regulation network complexity to enhance MDD outcomes.

Cromolyn has anti-inflammatory and neuroprotective effects. However, its influence on microglial cell viability and death pathways remains largely unexplored. This study aimed to elucidate the cellular and molecular mechanisms underlying the effects of cromolyn exposure on microglial viability, with a particular focus on ferroptosis and ferritinophagy. HMC3 microglial cells were treated with cromolyn for 24, 48, and 72 h. Cell viability, nuclear morphology, cell cycle, MDA, GSH, and intracellular iron levels were assessed. Western blot analysis evaluated the expression of ferroptosis-related (GPX4, ACSL4, SLC7A11) and autophagy-associated (NCOA4, FTH1) proteins. Functional validation was performed using ferroptosis and autophagy inhibitors, and NCOA4-silencing. Cromolyn induced time- and dose-dependent cytotoxicity (IC₅₀ at 48 h = 9.4 µM), with prominent G0/G1 cell cycle arrest and nuclear abnormalities emerging at 48 h. At 72 h, excessive cell death limited mechanistic analyses. Cromolyn triggered ferroptosis via the GPX4-regulated pathway, evidenced by increased MDA, iron accumulation, and altered expression of GPX4, ACSL4, and SLC7A11. This ferroptotic response was mechanistically linked to NCOA4-mediated ferritinophagy, leading to GPX4 suppression and lipid peroxidation. NCOA4 knockdown rescued cell viability, restored FTH1 levels, and reduced lipid peroxidation. Our findings suggest, for the first time, that cromolyn may regulate microglial survival through an NCOA4-dependent ferritinophagy-ferroptosis axis. Given the dual roles of microglia in neuroinflammation and neurodegeneration, these data highlight both the therapeutic potential and risks of cromolyn in neurodegenerative disorders.

Whole-brain radiotherapy (WBRT) is a prevalent technique for managing multiple intracranial metastases, however, the cognitive damage in long-term survivors due to WBTR is a critical concern that impacts patients' quality of life. Panax ginseng, a bioactive compound recognized for its neuroprotective benefits, also enhances cognitive functions, including memory and learning. This study aims to examine the potential protective effects of Panax ginseng supplementation on cognitive dysfunction and the levels of neurogenesis-related proteins in the hippocampus of rats that underwent WBRT, which was delivered as 3 fractions of 6 Gy (total dose 18 Gy) using a linear accelerator. Thirty-six male Sprague-Dawley rats were divided into three groups: radiation, ginseng treatment, and control. After 60 days of Panax ginseng administration (100 mg/kg), behavior tests (Morris water maze and novel object recognition) were performed, followed by western blot analysis of the hippocampus. Results indicated that Panax ginseng supplementation ameliorated radiation-induced cognitive impairments. Additionally, western blot analyses revealed that Panax ginseng promoted neuronal recovery and neuroplasticity processes in the hippocampus, simultaneously exhibiting a neuroprotective mechanism by reducing apoptosis and neurotoxicity markers. Panax ginseng ameliorates cognitive dysfunction after WBRT by enhancing neurogenesis and diminishing cell death in the hippocampus.

This study investigates the neuroprotective potential of Coenzyme Q₁₀ (CoQ₁₀) in aging rats, with emphasis on its roles in modulating autophagy and reducing inflammaging. Male Wistar rats, both young (4 months) and aged (24 months), were orally administered CoQ₁₀ at a dose of 20 mg/kg body weight for 28 days. Biochemical analysis revealed a significant enhancement in antioxidant defenses, as evidenced by elevated ferric reducing antioxidant power (FRAP), reduced glutathione (GSH), and increased activities of superoxide dismutase (SOD) and catalase (CAT). In parallel, levels of oxidative stress biomarkers-including malondialdehyde (MDA), advanced oxidation protein products (AOPP), protein carbonyls (PCO), and nitric oxide (NO)-were significantly reduced. CoQ₁₀ supplementation also restored mitochondrial function, as indicated by increased activities of electron transport chain complexes in the brain. Gene expression analysis via reverse transcriptase-polymerase chain reaction (RT-PCR) showed up-regulation of autophagy markers Beclin-1 and ULK-1, alongside down-regulation of pro-inflammatory cytokines IL-6 and TNF-α, suggesting a reduction in neuroinflammation. Histopathological analysis supported these findings, demonstrating improved structural integrity of brain cells in CoQ₁₀-treated rats. Overall, these results indicate that CoQ₁₀ exerts multifaceted neuroprotective effects through enhancement of antioxidant defenses, restoration of mitochondrial function, activation of autophagy, and suppression of inflammation, thereby offering a promising intervention to mitigate age-associated neurodegeneration.

Introduction: Postoperative neurocognitive disorders (POCD) is a common post-surgical complication that severely impacts patients' quality of life, with perioperative anesthesia exposure recognized as a key contributing factor. This study focused on sevoflurane-induced cognitive dysfunction which is a model isolating anesthesia-related mechanisms of POCD, to investigate the therapeutic effect of mitoquinone (mitoQ), a mitochondrial-targeted antioxidant, in counteracting anesthesia-driven cognitive decline.

Materials and methods: Aged C57 male mice (18 weeks old) were treated with mitoQ prior to sevoflurane exposure, spatial learning ability was assessed in each group using a water maze, mitochondrial function, oxidative stress, inflammation, autophagy, and apoptosis were observed in the brain tissues and various cell lines of the mice using WB, immunofluorescence, or flow cytometry, and metabolism of the HT22 cells was detected using the Seahorse MDA and SOD kits to detect the level of oxidative stress in HT22 cells.

Results: Behavioral experiments demonstrated that sevoflurane exposure resulted in spatial memory dysfunction in mice, and mitoQ treatment attenuated this cognitive dysfunction; mechanistically, mitoQ reduced Mfn1, Mfn2 expression in HT22 cells of the SEV treatment group in a dose-dependent manner, increased Drp1 and Fis1 expression to maintain mitochondrial function, and inhibited excessive autophagy by reducing LC3 and P62 expression to inhibit excessive autophagy, reduced NLRP3 and ASC protein expression in BV2 cells of SEV treatment group to attenuate inflammation, and thus reduced Cleaved caspase1 and GSDMD expression in whole brain tissues, suggesting that apoptosis was attenuated.

Conclusion: MitoQ attenuates apoptosis by modulating mitochondrial dynamics, oxidative stress, inflammation, and autophagy to achieve therapeutic prevention of sevoflurane-induced cognitive dysfunction in aged mice are confirmatory of the potential of mitoQ in preventing POCD in elderly patients.

Recent studies emphasize the pivotal role of endoplasmic reticulum (ER) stress in Alzheimer's disease (AD), highlighting the need for further investigation into this critical link. In response to ER stress, cells increase reactive oxygen species (ROS) production, leading to heightened oxidative stress. This interplay has sparked interest in antioxidant molecules such as squalene (SQ) as potential therapeutic agents. The primary objective of this study was to examine the impact of SQ on the unfolded protein response (UPR) pathway triggered by ER stress in an in vitro AD model. Herein, molecular docking analysis was performed to evaluate SQ interactions with target proteins, followed by in vitro assays. Human bone marrow-derived mesenchymal stem cells were differentiated into neuronal-like cells and characterized via immunostaining. The cells were then exposed to Aβ_1-42 toxicity to establish an in vitro AD model. To assess the effects of SQ treatment following Aβ_1-42 exposure, UPR-related proteins (BIP, p-PERK, PERK, eIF2α, p-eIF2α, ATF4, CHOP) were analysed by Western blotting; ROS levels were quantified to evaluate oxidative stress, and a TUNEL assay was performed to assess apoptosis. Our findings indicate that SQ alters protein expression within the UPR pathway in the AD experimental model. Notably, amyloid-β levels were significantly reduced in the SQ-treated group (p˂0.001). Furthermore, SQ reduced ROS levels. These results suggest that SQ holds potential as a therapeutic agent for mitigating amyloid-β toxicity.

Alzheimer's disease (AD) is the most common cause of dementia. The disease spreads over the world and has an impact on human health and welfare. The patients suffer from cognitiv disability in addition to economic and social effects. It is urgently necessary to find effective medication for cognitive decline because it appears to be a central focus of neurological and neurodegenerative illnesses. Cognitive decline is an intriguing pathophysiological state. Such underlying causes of cognitive impairment linked to neurodegeneration include oxidative damage and diminished cholinergic neurotransmission. The approved therapies for neurodegenerative diseases like AD are known to have undesirable side effects and merely offer symptomatic alleviation. Honeybee products have long been recognized for their therapeutic and health-improving properties. The antioxidant and anti-inflammatory activities of bee products and their ingredients are promising agents for AD. The current review aimed to collect and expose the different studies conducted on the neuroprotective potential of honeybee products such as bee venom and propolis or their active components chrysin, ferulic acid, and quercetin in combination with the conventional anti-AD or anti-dementia treatments such as donepezil and rivastigmine. Additionally, the active component chitosan was found to form effective nanoparticles in treating the neurodegenerative diseases in concern. Although the studies collected on this topic were few, they highlighted the potential synergistic effect of honeybee products in treating AD. In conclusion, bee products combined with donepezil and rivastigmine can be considered a potential neuroprotective agent against AD. Further studies are needed to support the preclinical studies and promote the clinical trials.

Ventral tegmental area (VTA) is typically involved in heroin reward, but it is still unclear whether the VTA or neural projections containing VTA are also involved in conditioned cues (CS)-induced heroin-seeking behavior. In present study, rats were first trained to self-administer heroin for 14 days, then undergone withdrawal for another 14 days. Subsequently, part of rats were assessed CS-induced heroin-seeking behaviors and tested c-Fos protein expression in brain areas after microinjection with saline, neostigmine or tetrodotoxin (TTX) into the VTA. Part of rats were tested CS-induced heroin-seeking behaviors after chemogenetic inhibition of the dopaminergic projection from VTA to paraventricular thalamus (PVT) by stimulating with clozapine N-oxide (CNO). We found that CS-induced heroin-seeking behaviors could be enhanced by microinjection with neostigmine, but weakened by microinjection with TTX, into the VTA. The expression of c-Fos immunoreactive neurons were increased in the PVT and nucleus accumbens (NAc) after neostigmine treatment, but decreased in the PVT, NAc and lateral habenula (LHb) after TTX treatment. Chemogenetic inhibition of the dopaminergic projection from VTA to PVT could significantly inhibit CS-induced heroin-seeking behaviors of rats. Our results suggest that stimulating VTA promotes CS-induced heroin-seeking behavior, and the underlying neural circuits may involve the projection from VTA to PVT.