Methods: This review is a synthesis and stringent evaluation of recent experimental, clinical and genetic studies relating mitochondrial dysfunction and Parkinson's disease (PD). We examined information on bioenergetics, mitochondrial dynamics, calcium homeostasis, and interactions between neurons and glia. The molecular and therapeutic importance of therapies, such as mitophagy modulators, bioenergetic enhancers, and mitochondrial antioxidants, was investigated.

Result: The absence of Complex I, excess ROS, mitochondrial DNA damage, and nonfunctioning fusionfission cycles leads to neurodegeneration. The glial metabolic abnormalities worsen the oxidative stress and neuroinflammation, weakening the support of the neurons. The effects of impaired mitophagy are the accumulation of dysfunctional mitochondria, and the effects of calcium overload disrupt energy metabolism. Neuroprotective effects of such substances as spermidine, urolithin A, resveratrol, α-lipoic acid, MitoQ, SkQ1, or CoQ10 have been shown using preclinical research. Sacrifices such as exercising and proper dieting enable the mitochondria to perform better and become stronger.

Discussion: Mitochondrial dysfunction enhances the progression of PD through oxidative stress, bioenergetic breakdown, and inflammatory signalling. Attention to these related systems is an entire way to alter the direction of a disease.

Conclusion: PD can be treated using an increase in mitochondrial quality control, redox regulation, and metabolic efficiency. Continued studies in the framework of precision medicine are required to validate the safety and effectiveness of mitochondrial-targeted medications.]]> https://www.benthamscience.com/article/1471202026-07-17 Background: The sodium pump α3 subunit (ATP1A3) is associated with various brain's physiological and pathological mechanisms. However, its molecular mechanisms and cellular targets in glioblastoma (GBM) are poorly understood.

Methods: Bioinformatics and phosphor-proteomics analysis, target fishing experiment, confocal immunofluorescence, molecular cloning, and western blot techniques were carried out to elucidate probable downstream signaling pathways. Then GBM xenografts were established to assess potential molecular mechanisms of ATP1A3 associated with its in vivo anti-glioma impacts.

Results: The mechanistic analyses indicated that the antagonism between ATP1A3 and small nuclear ribonucleoprotein polypeptide G (SNRPG) could suppress GBM growth. ATP1A3 inhibits SNRPGinduced GBM epithelial-mesenchymal transition, and SNRPG decreases ATP1A3 by increasing phosphorylation at S643. As a negative feedback loop, ATP1A3 overexpression causes a reduction of SNRPG-induced invasion-metastasis cascades via regulating KLF9. Furthermore, by using artificial intelligence (AI) techniques, we have also exerted the design and application of a synthetic peptide (ATP1A3-S643 peptide), which could be the potential inhibitor of ATP1A3 phosphorylation. To better explore the anti-glioma effect of ATP1A3 activation, a bioengineering nanomedicine capable of ondemand ATP1A3 activator delivery to the brain for GBM has also been developed in this work, which exhibited an improved therapeutic efficacy in the ATP1A3-targeted treatment of glioma.

Conclusion: ATP1A3 is a potential anti-glioma treatment target, and its activation critically depends on its antagonizing interaction with SNRPG.]]> https://www.benthamscience.com/article/1566772026-07-17 https://www.benthamscience.com/article/1548732026-07-17 Introduction: Chemotherapy-related cognitive impairment (CRCI) has been identified as one of the primary adverse effects of chemotherapy. Doxorubicin (DOX) is an anthracycline chemotherapeutic agent recognized as a fundamental component of chemotherapy. Nevertheless, limited research has been conducted to elucidate the neurotoxic mechanisms of DOX-mediated CRCI. We investigated the neurotoxic mechanisms of DOX by utilizing network toxicology and transcriptomic methods.

Methods: DOX-induced CRCI animal models were successfully established. Spatial learning and memory were assessed using the Morris water maze (MWM) test. The levels of neuronal and synapserelated proteins in the cortex and hippocampus were detected. To elucidate the molecular mechanisms underlying DOX-induced neurotoxicity, an integrated approach combining network toxicology with transcriptomic profiling was employed. Lastly, the neurotherapeutic potential of LY294002 in relieving DOX-induced BBB disruption, neuronal cell loss, and cognitive impairment was evaluated.

Results: Our findings demonstrate that DOX induces spatial learning and memory deficits and promotes neuronal cell loss, primarily by disrupting the blood-brain barrier (BBB) via the PI3K-AKT signaling pathway. Notably, we identified a significant upregulation of vascular endothelial growth factor (VEGF) within astrocytes in mice following DOX exposure.

Discussion: Pharmacological inhibition of PI3K with LY294002 significantly reduced VEGF expression, mitigated BBB disruption and neuronal loss, and consequently alleviated DOX-associated cognitive impairment.

Conclusion: DOX exerts neurotoxic effects by promoting VEGF oversecretion through the upregulation of the PI3K-AKT pathway. Inhibition of the PI3K-AKT pathway effectively mitigates these effects, thereby alleviating DOX-induced BBB disruption, neuronal cell loss, and cognitive impairment.]]> https://www.benthamscience.com/article/1506722026-07-17 Introduction: Recent evidence increasingly supports a potential role of Perivascular Macrophages (PVMs), a unique subpopulation of brain immune cells, in the pathogenesis of Alzheimer’s disease (AD). Strategically positioned at the brain-vasculature interface, PVMs sense the redox status, modulate immunity, and potentially influence ferroptosis—an iron-dependent form of regulated cell death increasingly implicated in AD. However, whether the involvement of PVMs in AD pathology specifically entails mechanisms related to the crosstalk between immunometabolism and ferroptosis, and the precise molecular pathways linking PVMs, immunometabolism, and ferroptosis to AD, remains unclear.

Methods: We first obtained single-cell RNA sequencing data of PVMs from AD patients and control subjects via the GEO database, identified Differentially Expressed Genes (DEGs), and applied Mendelian Randomization (MR), with robustness validated via leave-one-out analysis to pinpoint key genes among the DEGs with causal relevance to AD. Next, we identified ferroptosis-related genes within these key genes and examined their associations with immune cell infiltration and immunometabolic signaling pathways, while also predicting their regulatory transcription factors to inform potential therapeutic strategies.

Results: We identified 149 DEGs in PVMs between AD and control groups, which were primarily enriched in immune and metabolic pathways. MR analysis established eight genes (ACSL1, SPATA6, RAB31, NIBAN1, HDAC4, GRAMD1B, GCC2, and DENND3) as causally and negatively associated with AD risk (IVW analysis identified all P < 0.05, with robustness confirmed by leave-one-out analysis), with ACSL1 being recognized as a known ferroptosis driver. Immune cell infiltration analysis revealed significant differences in monocyte and neutrophil proportions in AD, with DENND3 identified as the sole gene significantly correlated with monocyte abundance. The Key genes demonstrated distinct associations with immunometabolic pathways: GRAMD1B expression was positively associated with PI3K/AKT/mTOR signaling, whereas both NIBAN1 and SPATA6 showed enrichment in cells with high Notch signaling activity. ACSL1 exhibited robust associations with multiple pathways implicated in ferroptosis, including the IL-6/JAK/STAT3, interferon-γ, TGF-β, bile acid metabolism, and cholesterol homeostasis pathways, suggesting potential mechanisms that mediate the crosstalk between immunometabolism and ferroptosis. Transcription factor analysis highlighted shared regulation by CEBPD and the SP1/2/3/4 family, indicating convergent transcriptional control of these genes.

Conclusion: This study identifies eight key genes in PVMs that may protect against AD through mechanisms involving the interplay between immunometabolism and ferroptosis. Our findings provide novel insights into the function of PVMs in AD pathophysiology and suggest potential therapeutic targets for this devastating neurodegenerative disease.]]> https://www.benthamscience.com/article/1540052026-07-17Introduction: Chronic cerebral ischemia (CCI) induces hippocampal neuronal injury, with mitochondrial dysfunction emerging as a pivotal pathological driver of ischemic brain damage. Enhancing mitochondrial biogenesis (MB) represents a promising reparative strategy to restore neuronal homeostasis. Rhodiola sacra (RS), a traditional Tibetan herb, exhibits neuroprotective potential against ischemic injury; however, its underlying mechanisms, particularly its association with MB, remain unclear. This study aims to investigate the protective effects of RS on neuronal apoptosis and mitochondrial dysfunction in CCI rats and oxygen-glucose deprivation (OGD)-exposed cells, with a focus on elucidating the role of SIRT1 in mediating these effects.

Methods: The CCI rat model was established through bilateral common carotid artery occlusion. Spatial learning and memory abilities were evaluated using the Morris water maze. Hippocampal neuronal apoptosis was assessed via TUNEL staining, and mitochondrial damage was examined using transmission electron microscopy. Flow cytometry was employed to detect cell apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) levels. Immunofluorescence staining was used to visualize the mitochondrial permeability transition pore (mPTP). Intracellular ATP levels were measured using a luminol-based chemiluminescence assay, and mitochondrial DNA (mtDNA) content was quantified by qPCR. Additionally, small interfering RNA (siRNA) was utilized to verify the critical role of SIRT1 in mediating the protective effects.

Results: RS significantly improved spatial learning and memory, attenuated hippocampal neuronal apoptosis, and increased mitochondrial content in CCI rats. In SH-SY5Y cells exposed to OGD, salidroside, a key active component of RS, reduced apoptosis and restored mitochondrial function, as evidenced by elevated MMP, ATP, and mtDNA levels, along with suppressed ROS and mPTP activity. Mechanistically, salidroside upregulated SIRT1 expression, which correlated with enhanced MB markers. Notably, inhibition of SIRT1 abolished the anti-apoptotic effects and MB activation induced by salidroside.

Discussion: These findings highlight RS as a promising therapeutic agent for ischemic brain injury, targeting SIRT1 to restore MB.

Conclusion: RS mitigates neuronal apoptosis and mitochondrial dysfunction in CCI through SIRT1- dependent MB activation.

Methods: This prospective cohort study enrolled 320 consecutive adult MMD patients. Sleep quality, anxiety, depression, and insomnia symptoms were evaluated using the PSQI, SAS, SDS, and AIS, respectively. Two independent reviewers assessed clinical and radiological outcomes. Multivariate logistic regression was employed to identify independent risk factors for sleep disorders.

Results: Of the 320 patients (184 females, mean age 45±11 years), 52.1% with sleep disorders had poor functional outcomes (mRS≥2) at admission, which persisted in 55.1% at 3 months post- EDAS. Multivariate analysis revealed that female gender (OR: 5.37, 95% CI: 2.30-12.56), older age (OR: 1.05, 95% CI: 1.01-1.09), headache (OR: 9.25, 95% CI: 1.96-43.67), alcohol consumption (OR: 3.94, 95% CI: 1.68-9.22), anxiety (OR: 4.18, 95% CI: 1.44-12.16), depression (OR: 21.22, 95% CI: 2.53-177.90), higher admission and postoperative mRS scores, and impaired hemodynamic parameters (TTP, rCBV, rCBF) were independent risk factors. Sleeping pill use was a protective factor (OR: 0.16, 95% CI: 0.06-0.42).

Discussion and Conclusion: Sleep disorders are common and adversely impact functional recovery in MMD, yet remain underrecognized. The identified multivariable risk profile underscores the necessity of integrating routine sleep screening and comprehensive management into standard MMD care to improve patient prognosis.

Methods: Male SHRs (15 days old) received either ipsapirone (a 5-HT1A agonist) or MDL100907 (a 5-HT2A antagonist) from postnatal day (PND) 15 to 42, in parallel with similarly aged Wistar Kyoto rats (WKY). After eight weeks of undisturbed observation, we assessed hyperlocomotor activity, anxiety, and impulsivity. On PND 122, rats were sacrificed, and the striatum and prefrontal cortex (PFC) were analyzed for DA-D1, DA-D2, 5-HT1A, and 5-HT2A receptor proteins and DA levels.

Results: The results showed that both treatments had lasting positive effects on ADHD behaviors, linked to increased 5-HT1A and 5-HT2A receptors in the PFC and striatum. Ipsapirone (5-HT1A agonist) did not alter DA receptor expression but reduced DA levels, while the 5-HT2A antagonist reduced DA-D2 and increased DA-D1 expression, with enhanced DA content levels. In the striatum, both treatments increased DA-D2 and reduced DA-D1 receptors, but the 5-HT1A agonist lowered DA content.

Discussion: Striatal DA-D2 dysregulation appears to contribute to hyperlocomotor activity, while attentional impairments are associated with enhanced striatal DA-D2 receptor expression. Enhancing 5-HT activity either through 5-HT2A antagonists or 5-HT1A agonists effectively alleviates core ADHD symptoms in SHRs, likely by indirectly modulating DA signaling. These serotonergic agents may influence DA pathway activity via cortical mechanisms, providing therapeutic benefits without the long-term adverse effects typically associated with direct DA receptor blockade.

Conclusion: These findings suggest that dysregulation of 5-HT1A and DA-D2 receptors may contribute to ADHD, and monotherapy with either a 5-HT1A receptor stimulator or a 5-HT2A receptor inhibitor can effectively alleviate core ADHD symptoms long-term, likely through indirect DA system modulation.s]]>