Fibromyalgia is a chronic disorder of hyperalgesia and fatigue among other debilitating manifestations. Current antidepressant-based therapy is hampered by suboptimal tolerability. The main pathomechanism is central sensitization that is largely precipitated by glial neuroinflammation involving NLRP3 inflammasome pathway. Administration of Zn, a relatively tolerable and accessible mineral with established antioxidant and autophagy-promoting properties, was shown effective against fatigue syndromes and NLRP3 inflammasome activation, yet its effect on fibromyalgia remains elusive. The current study investigated the ameliorative efficacy of Zn administration against reserpine-induced fibromyalgia in rats. Sprague-Dawley male rats were randomized into four groups: normal control, reserpine (1 mg/kg, S.C.)-induced fibromyalgia model, and two groups receiving Zn gluconate (30 mg/kg, I.P.) daily either for a week post-induction or for a week pre- and post-induction. Zn administration alleviated reserpine-induced thermal allodynia (P < 0.0001), fatigue, and depression, but not weight loss or reduced food intake. Moreover, Zn reversed reserpine-mediated central neurodegeneration, glial activation (P < 0.01), and NLRP3 inflammasome upregulation as evidenced by significant decline in NF-κB/NLRP3/GSDMD/IL-1β and IL-18 axis with NLRP3 protein level at P < 0.01. Connectedly, Zn showed marked antioxidant and pro-autophagic effects through attenuating reserpine-induced MDA elevation (P < 0.05), total antioxidant capacity decline, Nrf2/HO-1 axis downregulation, and LC3-II: p62 balance reduction (P < 0.001). Post-treatment conferred superior histological protection, while pre-and-post-treatment provided better behavioral outcomes, NLRP3 expression decline, and redox improvements. In conclusion, this study suggests a potential role of Zn supplementation in amelioration of and protection against FM manifestations through controlling central NLRP3-autophagy-oxidative stress network, yet the potentially context- and exposure-dependent effects of Zn warrant further investigations.

Cerebral injury following cardiac arrest (CA) is a primary contributor to patients' mortality and poor neurological outcome. However, there are currently no definitive and effective therapeutic approaches. Emerging evidence has indicated that mesenchymal stem cell (MSC) pretreatment exerted protective effects against cardiac and cerebral injuries in the porcine model of CA. However, given the unpredictable nature of CA, we administered immunity-and-matrix-regulatory cells (IMRCs) derived from human embryonic stem cells (hESCs) following CA to investigate whether IMRCs could alleviate cerebral injury following CA in swine. In vivo, a porcine CA model was established using male domestic white swine. In vitro, CA-induced injury was simulated by subjecting HT22 cells and primary cultures of hippocampal neurons to hypoxia/reoxygenation (H/R). SAT1 overexpression was achieved in HT22 cells via lentiviral transduction and in primary cultures of hippocampal neurons via adeno‑associated virus (AAV) transduction. Following IMRC administration, neurological function, cerebral injury, cell viability, lactate dehydrogenase (LDH) release, and ferroptosis-related indicators were systematically evaluated using a series of experimental assays. IMRC administration significantly decreased ferroptosis-related ferrous iron (Fe[2+]), lipid reactive oxygen species (ROS), malondialdehyde (MDA), and 4‑hydroxynonenal (4‑HNE) at 24, 48, and 72 h following CA, while concomitantly elevating glutathione (GSH) levels and mitigating cerebral injury. Further in vitro studies demonstrated that SAT1 overexpression promoted ALOX15 activation and suppressed GPX4 expression, thereby exacerbating H/R-induced neuronal ferroptosis. Moreover, SAT1 overexpression was found to partially attenuate the protective effects of IMRCs against H/R-induced ferroptosis. In vivo, IMRC administration downregulated the expression of SAT1 and ALOX15, while concurrently upregulating GPX4 levels. Early post-resuscitation administration of IMRCs attenuated cerebral injury following cardiac arrest, and this protective effect was possibly related to the suppression of ferroptosis via regulation of the SAT1/ALOX15/GPX4 signaling pathway.

Neonatal bacterial meningitis (NBM) is a severe neonatal infectious disease associated with a high incidence of neurological sequelae. Lipopolysaccharide (LPS) and inflammatory cytokines aggravate cerebral injury, whereas the mechanism of ferroptosis in the pathogenesis of NBM remains unclear. Melatonin (MT), an endogenous neurohormone, provides anti-ferroptotic neuroprotection in models of cerebral injury; however, its mechanism of action against NBM-related injury through ferroptosis has not been clarified. This study investigated the protective effects mediated by MT in vivo and in vitro. Rat models of LPS-induced inflammatory brain injury were established through intracerebroventricular (i.c.v.) injection, and Escherichia coli (E. coli)-infected cell models were developed to investigate the neuroprotective effects of MT against TFRC-related ferroptosis. CCK-8 assays, Western blotting, transmission electron microscopy (TEM), iron detection, and immunofluorescence, BODIPY staining were used to assess cell viability, inflammatory factors, mitochondrial ultrastructure, iron accumulation, and GPX4 expression. E. coli infection induced typical ferroptotic mitochondrial damage. MT alleviated neuroinflammation and reduced the expression of ferroptosis-related proteins both in vitro and in vivo. MT treatment increased mitochondrial GPX4 expression. The ferroptosis agonist RSL3 reversed the neuroprotective effects of MT. MT inhibited TFRC-related ferroptosis and alleviated neuronal damage. MT protects against E. coli/Lipopolysaccharide induced neuronal injury by regulating TFRC-related ferroptosis, indicating that MT may be a promising therapeutic agent for NBM.

Intracerebral hemorrhage (ICH) creates a sterile perihematomal niche in which erythrocyte lysis, heme and iron toxicity, mitochondrial damage, blood-brain barrier disruption and innate immune activation converge. Which nucleic-acid sensors translate this biochemical stress into inflammatory cell death remains unresolved. Z-DNA-binding protein 1 (ZBP1) can recognize Z-conformation nucleic acids and couple ligand sensing to RIPK1, RIPK3, MLKL, caspase-8 and inflammasome-associated modules. We performed a targeted, evidence-graded narrative search, updated on 29 August 2026, to ask four questions: which components of the proposed pathway are established in ICH, which are transferable from other systems, which remain hypothetical, and what findings would falsify or validate the model? ICH studies demonstrate cytosolic mitochondrial DNA release and increasingly support cGAS-STING and AIM2 activation, while genetic and biochemical studies establish RIPK1-RIPK3-MLKL-dependent necroptotic signaling. However, Z-conformation ligands, ZBP1 ligand binding, ZBP1-containing complex assembly and ZBP1-dependent injury have not been demonstrated in ICH. The two ICH reports involving ZBP1 provide transcriptomic or intervention-associated observations rather than dependency evidence. Human and murine ZBP1 also differ in RIPK1/RIPK3 and RHIM requirements, limiting direct translation from mouse genetics. We therefore frame ZBP1 as a falsifiable candidate mechanism, not an established target, and define validation criteria based on cell-type-specific loss of function, ligand capture, complex formation, pathway epistasis, functional rescue and preservation of hematoma clearance.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Accumulating evidence indicates that β-amyloid oligomers (AβO), the most neurotoxic form of β-amyloid, play a critical role in the pathogenesis of AD by inducing synaptic loss, neuronal death, and neuroinflammation. Therefore, targeting AβO-driven pathological processes through multi-target therapeutic strategies represents a promising approach to treating AD. This study aimed to investigate the neuroprotective effects of Rheum undulatum Linné rhizome (RUL) and the underlying mechanisms of its action against AβO-induced neurotoxicity using integrated in vitro, in vivo, and in silico approaches. RUL treatment protected HT22 and N2a neuronal cells from AβO-induced neurotoxicity and reduced extracellular AβO levels. In AβO-injected mice, oral administration of RUL alleviated memory impairment, preserved synaptic integrity, as evidenced by increased PSD95 and SYP expression, and suppressed microglial and astrocytic activation, as indicated by reduced Iba-1 and GFAP immunoreactivity in the hippocampus. Mechanistically, systems-level network analysis identified p53-related signaling as a central regulatory axis in the AD-associated pathway. These network-level insights were experimentally validated by demonstrating that RUL suppressed p53 phosphorylation, increased the BCL2/Bax ratio, inhibited caspase-3 activation, and reduced pro-inflammatory cytokines, including TNF-α and IL-1β, in the hippocampus. Collectively, these findings demonstrate that RUL exerts neuroprotective effects by preserving synaptic integrity and concurrently suppressing apoptotic and neuroinflammatory pathways through the network-level modulation of AβO-driven pathology, supporting its potential as a multi-target therapeutic candidate for AD.

Aminoglycoside-induced hearing loss is closely associated with oxidative stress and mitochondrial dysfunction in cochlear hair cells, but the upstream epigenetic mechanisms remain incompletely understood. This study investigated whether histone deacetylase 1 (HDAC1) contributes to neomycin-induced cochlear injury through transcriptional repression of NRF2. In HEI-OC1 cells, neomycin increased apoptosis, reactive oxygen species accumulation, mitochondrial depolarization, and mitochondrial superoxide production, accompanied by HDAC1 upregulation and NRF2 suppression. HDAC1 silencing attenuated these alterations and restored NRF2 expression. ChIP-qPCR demonstrated increased HDAC1 occupancy and reduced H3K27ac enrichment at the proximal NRF2 promoter after neomycin exposure, whereas HDAC1 knockdown reversed these changes. Consistently, HDAC1 silencing increased NRF2 promoter activity, while HDAC1 overexpression further suppressed NRF2 transcription and reduced H3K27ac levels. HDAC1 knockdown also restored nuclear NRF2 abundance and increased the downstream antioxidant proteins HO-1 and NQO1. Importantly, NRF2 overexpression partially rescued the reductions in cell viability and ATP content caused by HDAC1 overexpression, supporting a functional role for NRF2 downstream of HDAC1. In vivo, valproic acid partially preserved auditory thresholds, reduced cochlear hair cell apoptosis, restored NRF2 expression, and ameliorated mitochondrial ultrastructural damage in neomycin-treated mice. Collectively, these findings identify HDAC1-associated H3K27ac remodeling at the NRF2 promoter as an epigenetic mechanism contributing to neomycin-induced cochlear hair cell injury and support HDAC1-NRF2 regulation as a potential target for otoprotection.

Chemotherapy-induced cognitive impairment (CICI) is a prevalent and debilitating sequela in cancer patients receiving paclitaxel. Our previous study revealed that glial cells, particularly astrocytes, regulate NLRP3-mediated neuroinflammation, which is crucial to the pathophysiology of cognitive deficits. However, the therapeutic potential of targeting astrocytic NLRP3 for CICI remains largely unexplored. This study sought to determine whether astrocyte-specific NLRP3 knockout (KO) could mitigate paclitaxel-induced cognitive impairment. A mouse model of CICI was established via intraperitoneal injection of paclitaxel. Cognitive function was assessed using the Morris water maze and novel object recognition tests. Immunofluorescence labelling and local field potential (LFP) recordings in the medial prefrontal cortex (mPFC) were used to analyze pathological changes. Astrocyte-specific NLRP3 KO reduced intensities of GFAP, decreased colocalization of cleaved caspase-1 and IL-18 with astrocytes. Besides, the deletion approach significantly mitigated paclitaxel-induced cognitive deficits and increased the expression of synaptic markers, including synaptophysin and postsynaptic density protein 95 (PSD95). Electrophysiologically, astrocytic NLRP3 deletion improved the power of β- and γ-band oscillations and enhanced β-γ phase-amplitude coupling during novel object exploration. Astrocyte-specific NLRP3 knockout confers a protective effect against paclitaxel-induced cognitive dysfunction, potentially through inhibition of NLRP3 inflammasome-mediated pyroptotic signaling in astrocytes and preservation of synaptic integrity within the mPFC.

Administration of ketones is used as a therapeutic option in multiple conditions, including epilepsy, mental health disorders, and brain aging. A proposed mechanism of action involves the modulation of glutamate and GABA, the brain's primary excitatory and inhibitory neurotransmitters, which jointly regulate the excitatory-inhibitory balance. However, the precise mechanism by which ketones influence these neurotransmitters remains unclear. In this study, we hypothesize that ketones modulate glutamate and GABA through the pseudo-malate-aspartate shuttle (PMAS). To test this, we developed a computational model of neurotransmitter cycling centered on the PMAS, simulating the temporal dynamics and steady-state concentrations of glutamate and GABA as functions of ketone metabolism. We then compared the model outputs with MRS data from ketone administration experiments and found agreement with the model predictions, providing quantitative support for the model. Building on this agreement, we performed metabolic control analysis, which identified partial displacement of glucose metabolism through the PMAS as the dominant mechanism underlying the observed reductions in glutamate and GABA and revealed key enzymes that selectively modulate each neurotransmitter. Overall, the model provides researchers and clinicians with a framework for hypothesis testing and treatment optimization, while also serving as a foundation for future model expansions.

Mucopolysaccharidosis type IIIB (Sanfilippo syndrome type B) is a neurodegenerative lysosomal storage disorder characterized by cognitive decline, behavioral abnormalities, and neuroinflammation, for which no effective central nervous system (CNS)-targeted therapy currently exists. Increasing evidence indicates that inflammatory processes contribute substantially to disease progression. In this study, we evaluated the effects of resveratrol on behavioral outcomes and neuroinflammatory markers in an MPS IIIB mouse model, including both sexes. Behavioral analyses demonstrated anxiety-like behavior and memory impairment in MPS IIIB mice. Resveratrol treatment improved cognitive performance, reduced anxiety-related behavior, and normalized exploratory activity. Premature deaths occurred only in untreated MPS IIIB mice. Hematological and biochemical analyses revealed systemic inflammation, erythropoietic stress, metabolic dysregulation, and altered liver-associated parameters. Diseased mice exhibited leukocytosis, elevated pro-inflammatory immune cell populations, increased globulin concentrations, disturbed glucose and lipid metabolism, and sex-dependent alterations in liver and renal markers. Resveratrol partially normalized these abnormalities and reduced inflammatory and hematological disorders. Peripheral and central inflammatory responses were assessed by measurement of IL-1β, IL-6, and c-Fos levels. MPS IIIB mice displayed widespread neuroinflammation in the hippocampus, cortex, and amygdala, with pronounced sex- and region-dependent differences. Females exhibited stronger inflammatory changes in CA1, CA2, and retrosplenial cortical regions, whereas males showed predominant involvement of CA3, dentate gyrus, and motor cortical areas. Resveratrol reduced pro-inflammatory cytokine production and normalized neuronal hyperactivity, particularly in males. Overall, resveratrol modulated neuroinflammatory markers and improved selected behavioral outcomes in MPS IIIB mice, suggesting its potential to ameliorate CNS-related manifestations of Sanfilippo syndrome.

Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand activated nuclear receptor traditionally associated with lipid and glucose metabolism. Emerging evidence, however, identifies PPARγ as a central immunometabolic regulator in the central nervous system (CNS), coordinating mitochondrial function, neuroinflammation, synaptic plasticity, and neurovascular integrity. Beyond its classical metabolic actions, PPARγ regulates microglial activation, astrocytic inflammatory responses, oxidative stress, and mitochondrial biogenesis, thereby influencing neuronal resilience and circuit stability. This narrative review synthesizes knowledge of PPARγ structure, activation, CNS distribution, endogenous ligands, and synthetic agonists, including thiazolidinediones and selective modulators. We highlight how PPARγ controls transcriptional programs related to energy homeostasis, inflammatory signaling, including NF κB dependent pathways, and blood brain barrier function. Attention is devoted to synaptic remodeling and plasticity, positioning PPARγ as a molecular bridge between metabolic state and neuronal adaptability. We propose that PPARγ signaling dysregulation represents a convergent mechanism in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and adrenoleukodystrophy; psychiatric conditions, such as depression and anxiety; and neurooncological processes. Integrating evidence across these conditions supports PPARγ as a master regulator of neuroimmune metabolic coupling in the brain. Finally, we discuss translational challenges and opportunities, including brain penetrant, functionally selective ligands, clarification of cell type specific signaling, and expansion of rigorous clinical trials. Integrating mechanistic, preclinical, and clinical trial evidence, this review critically examines the therapeutic potential of PPARγ across neurodegenerative, psychiatric, and neurooncological CNS conditions, while identifying priorities for future therapeutic development in diverse brain disorders.

Population aging imposes a substantial dementia burden. Chronic cerebral hypoperfusion (CCH) serves as a crucial early pathological basis for Alzheimer's disease (AD) and Vascular Dementia (VaD). Our previous studies have demonstrated that macrophage-derived docosahexaenoic acid metabolite Maresin1 can ameliorate CCH-induced cognitive impairment, though the underlying angiogenesis-related mechanisms remain to be elucidated. We developed a rat model of chronic cerebral hypoperfusion using the bilateral common carotid artery occlusion surgical approach. Cognitive improvements and angiogenic mechanisms by Maresin1 were systematically evaluated using behavioral assessments, immunofluorescence techniques, Western blotting (WB), ELISA, and cerebral blood flow measurements via laser Doppler. Our findings revealed that Maresin1 administration significantly ameliorated CCH-induced cognitive deficits, promoted hippocampal angiogenesis and enhanced cerebral perfusion. Further analysis showed significant enhancement of IGF-1/p-Akt/VEGF/eNOS signaling pathway activation by Maresin1, and the increased VEGF expression was predominantly mediated by perivascular macrophage (pvMΦ) activation. Depletion of pvMΦ using clodronate liposomes suppressed the VEGF upregulation and cognitive improvement mediated by Maresin1. Our research demonstrates that IGF-1/p-Akt/VEGF pathway activation in pvMΦ plays a crucial role in Maresin1-mediated angiogenesis in CCH rats.

Glioblastoma (GBM) is an aggressive and prevalent malignant brain tumor and remains a major public health challenge. Prognosis is poor, with median survival of 14-18 months and fewer than 7% of patients surviving beyond five years, reinforcing the need for new therapeutic strategies. Natural products are a traditional source of bioactive substances, and fruits are rich in phenolic constituents with potential anticancer activity. Psidium cattleianum, a Myrtaceae species native to South America, produces red and yellow fruits rich in vitamin C and phenolics, although biological data on the yellow variety are scarce. Preliminary evidence suggests anti-inflammatory, antioxidant, and antineoplastic activities, but studies in glioma models are limited. This study characterized the phenolic profile and evaluated the activity of a hydroalcoholic extract from yellow Psidium cattleianum (YPC) fruits in GBM and non-tumor cells. LC-MS analysis identified ellagic acid, catechin, and gallic acid as major constituents. Biological activity was assessed in glioma cell lines (C6 and U87MG), primary astrocytes, and fibroblast lines (L929 and MRC5). Cells were treated with extract concentrations ranging from 125 to 2000 µg/mL for 2 to 72 h. The extract significantly reduced proliferation, viability, colony formation and reactive oxygen species levels in glioma cells, while increasing glutathione peroxidase activity. In C6 cells, it also inhibited migration. Astrocytes and fibroblasts remained unaffected by cytotoxicity under the evaluated conditions. These findings demonstrate a selective antineoplastic potential of the YPC extract in glioma cells and support its relevance for further investigation in GBM treatment.

Sleep restriction is associated with neuroinflammation, blood-brain barrier (BBB) dysfunction, and cognitive impairment. Although reduced sleep duration in women is well recognized and the impact of sleep disorders is correlated with a higher incidence of neurodegenerative diseases, its consequences during female aging remain poorly understood. Hence, the aim of this study was to evaluate whether recurrent sleep restriction in female rats accelerates aging-related processes, compared with aged females with normal sleep patterns. Female Wistar rats were subjected to sleep restriction for 10 consecutive days, every three months from 6 to 18 months of age. An additional group of 3-month-old rats underwent a single sleep restriction episode as control. BBB permeability, neuroinflammation, cellular senescence, and recognition memory were assessed. Recurrent sleep restriction increased BBB permeability in the cerebral cortex to tracers of different molecular weights and induced hippocampal increase in TNF-α and IL-1β. In contrast, senescence markers showed age- and region-dependent changes, with no clear effect of recurrent sleep restriction in aged animals. A single sleep restriction episode was sufficient to impair recognition memory, whereas recurrent sleep restriction accelerated age-related cognitive decline. These findings indicate that the BBB dysfunction and neuroinflammatory alterations during sleep restriction depend on age and brain region, as well as the recurrence of these episodes.

Oxidative stress plays a critical role in the methylmercury (MeHg) neurotoxicity, as MeHg induces reactive oxygen species (ROS) generation and impairs antioxidant defense systems. However, the precise molecular mechanisms underlying MeHg-induced neurotoxicity remain elusive. The nuclear factor erythroid 2-related factor 2 (Nrf2) activates antioxidant defense genes in response to acute MeHg exposure. Similarly, the signal transducer and activator of transcription 3 (STAT3), a transcription factor involved in cell growth and anti-apoptotic genes, also contributes to maintaining redox homeostasis. Here, we sought to investigate the roles of Nrf2 and STAT3 in mouse hypothalamic neuronal GT1-7 cells exposed to MeHg. We inhibited STAT3 either pharmacologically with AG490 (a JAK2 inhibitor) or C188-9 (a small-molecule STAT3 SH2 domain inhibitor) or genetically using a lentivirus carrying STAT3 shRNA (vs. scramble control), in GT1-7 cells exposed to 5 µM MeHg. To further dissect the role of Nrf2, the pathway was pharmacologically inhibited using brusatol or activated with sulforaphane (SFN) in GT1-7 cells co-exposed to 5 µM MeHg. Changes in cell viability, reactive species production, and protein and gene expression were analyzed. Our findings reveal that deficits of either the Nrf2 or STAT3 pathways exacerbated MeHg-induced toxicity. Moreover, in MeHg-exposed cells, Nrf2 ablation led to increased STAT3 activity, suggesting a reciprocal and potentially compensatory responses between these two pathways in protecting against MeHg-induced oxidative stress. Our novel findings provide crucial understanding of the molecular mechanisms underlying MeHg neurotoxicity and offer insights into potential therapeutic strategies for mitigating acute MeHg-induced neurotoxicity.