Alzheimer's disease is a multifaceted neurodegenerative condition marked by the build-up of amyloid plaques and neurofibrillary tangles that lead to progressive cognitive impairment. Neuroinflammation, especially the activation of microglia, plays a pivotal part in driving this pathology. Microglia are the brain's resident immune cells and can adopt a spectrum of activation states that support either neuroprotection or neurodegeneration. Evidence shows that their phenotypes are highly dynamic and shaped by environmental influences and pathological signals. During the early phases of the disease, microglia tend to assume anti-inflammatory roles that facilitate plaque clearance and promote tissue recovery. Prolonged or dysregulated activation, however, shifts them toward a pro-inflammatory state that amplifies neuronal damage. Several molecular pathways including JAK STAT, PI3K AKT, and MAPK are central to regulating these processes and have emerged as promising therapeutic targets. This review summarizes current insights into microglial phenotypic transitions, the signaling mechanisms governing their activation, and the therapeutic potential of modulating neuroinflammation. Enhancing the neuroprotective capacity of microglia, suppressing chronic inflammatory responses, and targeting key receptors such as TREM2 and P2 × 7 represent potential strategies. A deeper understanding of microglial interactions with other glial cells and the molecular drivers of their activation may provide new avenues for slowing or halting the progression of Alzheimer's disease and related neurodegenerative disorders.

Sepsis-associated encephalopathy (SAE) is a serious sepsis complication with high mortality. Animal models, including cecal ligation and puncture (CLP), lipopolysaccharide (LPS) injection, and peritoneal contamination and infection (PCI), are known to trigger distinct inflammatory responses with differential hippocampal impact. This study aimed to comprehensively compare the hippocampal transcriptomic profiles and validate key findings through independent experimentation. Transcriptomic datasets GSE253309 (CLP), GSE226120 (LPS), and GSE167610 (PCI) were retrieved from the GEO database. Bioinformatics analyses were employed to identify DEGs and enriched pathways. WGCNA pinpointed characteristic modules, and PPI networks were constructed and analyzed. Critically, an independent CLP-induced SAE mouse model was established, and hippocampal RNA sequencing was performed for confirmation. DEG analysis revealed 381, 533, and 85 significant DEGs in the CLP, LPS, and PCI datasets, respectively. CLP and LPS models shared a robust signature of neuroinflammation, significantly enriching GO terms related to immune response and inflammatory response, and KEGG pathways such as TNF, NF-κB, IL-17. In stark contrast, the PCI model was predominantly associated with cell migration, aldarate metabolism, and enriched in metabolic pathways, including bile secretion, ascorbate and aldarate metabolism. Cross-dataset analysis identified 29 common DEGs, from which a PPI network of 16 hub genes was constructed. Importantly, independent validation confirmed a strong concordance (r = 0.576) between the CLP-seq discovery cohort and the experimental CLP-seq data. Lcn2, S100a8, S100a9, Lrg1 and the TNF/IL-17 signaling pathways were robustly verified. CLP and LPS models demonstrate convergent hippocampal transcriptomic profiles distinct from PCI. Lcn2, S100a8, S100a9, Lrg1 and the TNF and IL-17 signaling pathways are highly reliable core features in SAE.

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by continuous cognitive deterioration, primarily resulting from the accumulation of amyloid-β (Aβ) plaques and tau-induced neurofibrillary tangles (NFTs). Recent studies have also highlighted histone deacetylase 3 (HDAC3) as a critical suppressor of synaptic plasticity. Although pharmacological inhibition of HDAC3 has been shown to facilitate long-term potentiation (LTP), the precise relationship between HDAC3 activity and AMPA receptor signaling, key components in LTP induction and maintenance, remains insufficiently understood. Electroacupuncture (EA), known to modulate epigenetic markers like H3K9/H3K27 acetylation and HDAC3/4 activity, may offer therapeutic potential by targeting these pathways. Here, we investigated EA's effects on AD-related pathology in APP/PS1 transgenic mice, focusing on HDAC3-AMPA receptor interactions in synaptic plasticity. Behavioral assays (Morris water maze) and electrophysiological recordings revealed that EA improved spatial learning ability and reinstated LTP in APP/PS1 transgenic mice. Mechanistically, EA reduced hippocampal HDAC3 expression while upregulating GluR1/GluR2 subunits and increasing acetylated H3K9K14/H3 levels, suggesting HDAC3-mediated transcriptional regulation of AMPA receptor genes. Co-immunoprecipitation assays further supported HDAC3's physical interaction with AMPA receptor components. Crucially, conditional knockout of HDAC3 in neurons rescued both LTP impairments and memory deficits, reinforcing its pivotal role in synaptic dysfunction. Our findings unveil a novel epigenetic mechanism whereby EA mitigates AD-associated synaptic damage by suppressing HDAC3 and enhancing AMPA receptor-dependent plasticity, highlighting HDAC3 as a promising therapeutic target for AD intervention.

TANK binding kinase 1 (TBK1) is serine/threonine protein kinase member of the inhibitor of nuclear factor-kB kinase family, with links to the etiology of familial as well as idiopathic Amyotrophic Lateral Sclerosis. It contributes to several regulatory cellular processes such as autophagy, inflammation and apoptosis. Reduction or loss of TBK1 kinase activity is associated with increased risk of ALS, and so understanding the molecular basis of this activity is an important research priority. In this current study, the role of the E168 residue, located adjacent to the active site of TBK1, has been assessed using a combination of artificial and naturally occurring variants found at this codon - evaluated using multiple readouts for TBK1 kinase activity. The results suggest that the negative charge resulting from the presence of a glutamic acid at this codon is a constitutive activator of TBK1 activity.

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid proliferation, therapy resistance, and extensive invasion, largely driven by epithelial-mesenchymal transition (EMT). Longikaurin A (LK-A), a natural kaurane diterpenoid, has demonstrated promising anti-cancer properties, yet its role in EMT regulation within GBM remains unclear. This study aimed to systematically investigate the inhibitory effects of LK-A on TGF-β1-induced EMT and to elucidate the underlying molecular mechanisms contributing to its anti-invasive potential in GBM. LK-A inhibited EMT-associated phenotypic changes, including reduced expression of mesenchymal markers (N-cadherin, Vimentin) and increased expression of epithelial markers (ZO-1, Occludin), alongside suppression of key EMT transcription factors (Snail, Twist1). Functionally, LK-A impaired EMT-induced cell migration, invasion, and glioma stem cell-like traits, evidenced by decreased gliosphere formation and downregulation of stemness markers such as Sox2 and Oct4. Mechanistic analyses revealed that LK-A triggered reactive oxygen species (ROS) accumulation, leading to the activation of the JNK/p38 MAPK signaling cascade. Pharmacological inhibition of JNK or ROS scavenging reversed the anti-EMT effects of LK-A, confirming that EMT suppression is mediated through ROS-dependent JNK activation. In vivo, LK-A significantly suppressed tumor growth, EMT marker expression, and stemness in xenograft models. Collectively, these findings identify LK-A as a potent regulator of EMT and glioma stemness via ROS/JNK signaling. This work provides new mechanistic insight into the anti-tumor effects of LK-A and highlights its potential as a promising therapeutic strategy for combating GBM aggressiveness.

This study investigates the influence of sex on region-specific neural vulnerability following global cerebral ischemia using a Bilateral Common Carotid Artery Occlusion (BCCAo) mouse model that mimics severe ischemic brain stroke condition in humans. Comprehensive behavioral assessments, neuropathological analyses, and molecular profiling were conducted across multiple time points post-ischemia in male and female CD1 mice. Both sexes exhibited early motor deficits, cortical-striatal mitochondrial dysfunction, inflammation, and cell death at day 1, with gradual behavioral recovery. However, the hippocampus demonstrated a clear sex-specific divergence: males exhibited delayed yet prolonged inflammation, apoptotic cell death, and increased autophagy/mitophagy activity, while females were largely protected despite hypoxic and inflammatory gene expression. Molecular assays revealed prolonged upregulation of hypoxia-inducible factor 1α (HIF-1α), IL-1β, IL-6, TNF-α, and apoptotic markers in males, especially in the hippocampus, alongside increased expression of autophagy (Beclin-1, LC3-II, ATG7) and mitophagy (PINK1, BNIP3L) regulators and a shift in mitochondrial dynamics favoring fission.

Alzheimer's disease (AD), an irreversible, degenerative disorder, affects the central nervous system. However, its accurate pathology remains unclear, and studies on treatment modalities are ongoing. Picroside II (PII) is an active compound in the medicinal herb Rhizoma coptis. It has strong effects, including antioxidation, anti-inflammatory, antiapoptotic, and neuroprotective effects. In this study, we analyzed how PII affects cognitive impairment in mice with AD and its underlying mechanism. PII at doses of 20 or 40 mg/kg was given to APP/PS1 mice through intraperitoneal injection for 2 months. Moreover, we carried out the Morris water maze test to evaluate cognitive function. Immunofluorescence analysis was performed to observe cortical Aβ plaque deposition, neuronal loss, and inflammatory cell expression. An enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of the cortical inflammatory factors tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Western blotting and quantitative polymerase chain reaction (qPCR) were performed to measure NLRP3, ASC, GSDMD, and caspase-1 expression. PII improved cognitive function, reduced Aβ plaque deposition and glial activation, and alleviated cortical neuronal loss in APP/PS1 mice. Furthermore, PII decreased the levels of cortical inflammatory factors (TNF-α, IL-6, and IL-1β). In addition, it suppressed NLRP3, ASC, GSDMD, and caspase-1 expression at the mRNA and protein levels. PII enhances the cognitive function of APP/PS1 mice by reducing inflammation and pyroptosis via the suppression of the NLRP3/caspase-1/GSDMD pathway. Therefore, PII is a candidate anti-AD therapeutic agent.

Mitochondrial diseases (MDs) are heterogeneous multisystemic disorders often caused by genetic defects in either nuclear or mitochondrial DNA. Although next-generation sequencing technologies have dramatically expanded the number of variants associated with these diseases, many remain variants of unknown significance (VUS). This review explores the utility of zebrafish (Danio rerio) as a vertebrate model system for studying mitochondrial dysfunction, with a focused analysis on the application of morpholino oligonucleotides (MOs) to functionally characterize and interpret VUS. MO-induced knockdown produces a transient suppression of target genes during zebrafish early development, recapitulating key MD phenotypes. Furthermore, rescue experiments involving co-injection of MO and either wild-type or mutant mRNA have proven useful to functionally assess the pathogenicity of specific variants. Specifically, while wild-type mRNA rescues the morphant phenotype, failure of mutant mRNA to do so confirms the variant's pathogenic effect. This approach has successfully linked previously uncharacterized genes to MD and helped reclassify ambiguous variants. The use of MO-based strategies in zebrafish remains a valuable tool for variant interpretation and functional validation, bridging the gap between genomic data and clinical action, and ultimately reducing the diagnostic odyssey. Overall, this review places MO knockdown and rescue assays in zebrafish as a robust and versatile platform to address functional genomics in MD research.

Tauopathies, including Alzheimer's disease (AD), are neurodegenerative diseases characterized by abnormal tau aggregation in neurons and glial cells. Various tauopathy mouse models have been developed, including PS19, a tau-overexpressing transgenic mouse model with the P301S mutation, in which glial activation has been reported prior to the accumulation of tau. In this mouse model, tau pathology was improved by the administration of the immunosuppressant FKB506, suggesting that inflammatory responses promote the progression of tau pathology. Our previous studies have shown that the inhibition of Collapsin response mediator protein 2 (CRMP2) phosphorylation suppresses inflammation and ameliorates pathological progression in spinal cord injury and MPTP-induced Parkinson's disease models using CRMP2KI/KI mice, in which the phosphorylation site Ser522 was replaced with Ala. Therefore, we compared glial cell activation in male PS19 and PS19; CRMP2KI/KI mice using morphometric analysis at 5 months of age, before the onset of tau pathology. We found that the morphological changes caused by the activation of microglia and astrocytes were normalized by suppressing CRMP2 phosphorylation compared with those in PS19 mice. Cox-2 expression in hippocampal neurons was increased in PS19 mice, but this increase was suppressed in PS19; CRMP2KI/KI mice, suggesting that the suppression of CRMP2 phosphorylation in neurons is also involved in this process. These results suggest that the inhibition of CRMP2 phosphorylation may improve neuroinflammation in tauopathy.

Tramadol withdrawal presents a significant clinical challenge, characterized by neurobehavioral impairments linked to neuroinflammation, oxidative stress and neurotransmitter dysregulation. The TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducer 14 (Fn14) pathway and downstream effectors like cAMP response element binding protein (CREB) are implicated, but effective targeted therapies are lacking. Aurintricarboxylic acid (ATA), a TWEAK inhibitor, exhibits neuroprotective potential. This study aims to evaluate the therapeutic efficacy of ATA in mitigating the tramadol withdrawal-induced neurobehavioral alterations in mice model, focusing on the role of TWEAK/Fn14 pathway and CREB phosphorylation. Swiss albino mice were subjected to chronic tramadol administration (50 mg/kg, s.c.) for 57 days, with withdrawal precipitated with naloxone (5 mg/kg, i.p.) on day 57. Behavioural assessments included withdrawal severity score (WSS), jumping frequency, and hyperalgesia. Biochemical analyses measured the level of oxidative stress markers (TBARS, SOD, GSH and catalase), inflammatory biomarkers (TNF-α, IL-6, IL-1β), and neurotransmitters (glutamate, dopamine and serotonin). ATA (5 mg/kg and 10 mg/kg i.p.) dose-dependently reduced the WSS, jumping frequency and hyperalgesia. It also mitigated the oxidative stress, neuroinflammation, and glutamate level, while restoring the neurotransmitter level. Notably, pretreatment with CREB inhibitor (666 - 15) (10 mg/kg i.p) significantly attenuated the protective effect of ATA, underscoring the pivotal role of CREB phosphorylation in its mechanism. Our findings demonstrate that ATA offers significant neuroprotection against tramadol withdrawal, primarily by inhibiting the TWEAK/Fn14 pathway and subsequently promoting the CREB phosphorylation. This study highlights ATA as a promising therapeutic candidate for managing tramadol withdrawal syndrome by targeting oxidative stress, neuroinflammation, and its downstream effectors.

The recently discovered family of heat-resistant obscure (Hero) proteins represents a novel class with chaperone-like activity and unique protective properties. These proteins may contribute to cellular survival in ischemic stroke (IS) conditions. Herein, we aimed to investigate the expression dynamics of six Hero genes during the acute and subacute phases of IS. Peripheral blood samples were collected from IS patients in the acute (day 1, n = 47) and subacute (day 7, n = 41) phases, along with healthy controls (n = 42). Gene expression was assessed via quantitative PCR. Statistical analysis included group comparisons, multivariate regression modelling, and correlation analysis. In the acute phase, C9orf16 (P = 0.006), C11orf58 (P = 0.00001), and SERBP1 (P = 0.006) were significantly downregulated compared to controls. By day 7, SERBP1 expression normalized, while C9orf16 (P = 0.002) and C11orf58 (P = 0.0004) remained downregulated. Multivariate regression identified C11orf58 expression as a potential biomarker of IS. Expression levels of SERBP1 and C11orf58 negatively correlated with infarct size during both the acute (R = - 0.59, P = 0.00012; R = - 0.49, P = 0.004) and subacute phases (R = - 0.54, P = 0.0024; R = - 0.44, P = 0.032). eQTL analysis showed that SERBP1 SNPs were associated with reduced expression only in controls. Our findings underscore the potential relevance of Hero proteins as biomarkers or therapeutic targets in IS, warranting further investigation into their mechanistic involvement in neuroprotection and recovery.

Autoimmune diseases occur when the immune system mistakenly attacks the body's own tissues, affecting millions of people and often requiring long-term treatment. Current therapies, such as immunosuppressants and biologics, help manage symptoms but can cause serious side effects. A promising new approach involves engineered microbiota-a method that modifies gut bacteria to influence immune function and potentially ease autoimmune conditions. The gut microbiome is crucial in regulating immunity, and imbalances in its composition have been linked to diseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS), and inflammatory bowel disease (IBD). Engineered microbiota works by altering microbial communities, either by adding new strains, genetically modifying existing bacteria, or using carefully selected groups of microbes to control inflammation and immune responses. Recent studies in both animal models and human trials suggest this approach could help restore immune tolerance, reduce inflammation, and repair the gut barrier. However, challenges remain, including ensuring safety, long-term effectiveness, and meeting regulatory standards. Despite being in its early stages, engineered microbiota holds great promise as a future treatment for autoimmune diseases, paving the way for more precise and personalized therapies that leverage the power of the microbiome to improve health.

Hypertension is a significant risk factor for cognitive decline and dementia, yet the underlying mechanisms linking hypertension to cognitive impairments remain poorly understood. Central acetylcholine (ACh) receptors play a crucial role in the regulation of cognitive function. This study aimed to investigate the effects of hypertension on the mRNA levels of ACh receptors in the hippocampus and medial prefrontal cortex (mPFC). We induced hypertension in mice by continuous Angiotensin II (Ang II) infusion and evaluated cardiovascular parameters as well as cognitive performance using behavioral tests, including the Y-maze, object location task, and Morris water maze. Our findings indicated a significant increase in systolic blood pressure (SBP) and heart weight in Ang II-treated mice without affecting body weight or heart rate. Behavioral assessments revealed notable cognitive deficits characterized by reduced alternation in the Y-maze, impaired object recognition, and increased escape latency in the Morris water maze. Furthermore, quantitative real-time PCR analysis demonstrated reductions in the mRNA levels of muscarinic ACh receptor (Chrm1) and nicotinic ACh receptors (Chrnα4, Chrnα7 and Chrnβ2) in the hippocampus as well as Chrm1, Chrnα5 and Chrnα7 in the mPFC. In addition, correlations were observed between SBP and mRNA levels of labile ACh receptors in mice. Our findings elucidate the critical relationship between hypertension-induced cognitive impairment and the altered mRNA levels of ACh receptors, providing a foundation for future research aimed at restoring cholinergic function and developing therapeutic strategies to mitigate cognitive decline in hypertensive patients.

The composition of intestinal microbial communities plays a crucial role in maintaining immune homeostasis, influencing both innate and adaptive immune responses. Growing evidence indicates that bidirectional communication between gut bacteria and host immune cells contributes to the development of autoimmune diseases. Disruptions in microbial diversity, known as dysbiosis, are linked to an increased susceptibility to autoimmune disorders such as rheumatoid arthritis (RA), multiple sclerosis (MS), and lupus erythematosus. This review examines the mechanistic connections between microbial dysregulation and abnormal immune activation, focusing on key signaling pathways. Pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Janus kinase/signal transducers and activators of transcription (JAK/STAT), and Toll-like receptor (TLR) networks act as immunological gatekeepers, and their dysregulation-induced by microbial metabolites or shifts in microbial composition-can lead to chronic inflammation and the breakdown of self-tolerance. Additionally, bacterial fermentation products, including short-chain fatty acids (SCFAs), exert immunomodulatory effects by influencing T-cell differentiation and cytokine profiles. Emerging therapeutic strategies targeting microbial restoration, such as precision probiotics, microbiota transplantation, and tailored nutritional interventions, aim to restore immune balance. This review underscores the gut microbiota as a dynamic regulator of immune signaling.

It is now widely accepted that the development of neurodegenerative diseases depends on and affects many pathological processes, both in the brain and the periphery. Inflammatory, cardiovascular, metabolic, cerebrovascular, autoimmune, and other environmental factors have been extensively studied and shown to contribute notably to the onset, pathogenesis, and clinical outcome of Alzheimer´s disease (AD), Parkinson´s disease (PD), cerebral amyloid angiopathy (CAA), multiple sclerosis, and other neurological disorders. Likewise, AD-induced changes in other tissues outside the central nervous system, such as abnormalities observed in the liver, spleen, or lungs, have been documented and extensively studied, leading to a better understanding of brain-periphery crosstalk in neurodegenerative diseases and the development of novel diagnostic and therapeutic approaches. In this study, we documented striking differences in the periphery in two frequently used, well-established APP transgenic mouse models of AD: 3xTg-AD mice, harboring three human genes (APP, tau, and Psen1), and Tg-SwDI mice, expressing human APP with the Swedish and vasculotropic Dutch/Iowa mutations in the brain. We documented splenomegaly, immunoglobulin-associated spleen amyloidosis, and an increase in the percentage of neutrophils in the spleen and macrophages in the liver in 3xTg-AD mice but not in age-matched Tg-SwDI mice, which are commonly used as an AD/CAA model. Our data suggest that the results observed in any transgenic mouse strain should be taken into account with caution. A detailed knowledge of pathological characteristics recapitulated in a particular strain can help to determine which mice are more appropriate for studying a specific mechanism or therapeutic approach.

The persistence of deleterious substances at lesion sites severely impedes neuronal survival and axonal regeneration following central nervous system (CNS) injury or in neurodegenerative disorders. Therefore, clearing these harmful components and establishing a regeneration-permissive microenvironment are crucial for functional recovery. In this study, primary olfactory ensheathing cells (OECs) isolated from adult SD rats were pharmacologically treated with fisetin, a pharmacological agent. To model CNS injury conditions, neural debris was generated through mechanical disruption of primary neural cells. Neurons exposed to this hostile environment were then treated with conditioned medium from fisetin-activated OECs. Subsequent assessments using qRT-PCR, Western blot, CCK-8 assays, immunofluorescence, and ELISA revealed that fisetin significantly enhanced OEC activation, increasing proliferation and viability. Critically, fisetin-treated OECs markedly mitigated debris-induced neurotoxicity, thereby promoting neuronal survival and neurite outgrowth, which was associated with the upregulated anti-inflammatory cytokines (IL-4, IL-10, TGF-β) and neurotrophic factors (BDNF, GDNF, NGF). Mechanistically, fisetin-activated OECs facilitated neuronal growth via the PI3K/Akt/CREB pathway, suggesting that fisetin potentiates OEC-mediated neuroprotection and neurite regeneration in degenerative environments. These findings may highlight the therapeutic potential of combining OECs therapy with fisetin for CNS injuries and neurodegenerative diseases.

Doxorubicin (DOX) is an effective chemotherapeutic agent, but its clinical utility is limited by its neurotoxic side effects. This study investigates the neuroprotective effects of phosphocreatine (PCr) against DOX-induced neurotoxicity in Sprague-Dawley rats. Forty rats were randomly assigned to four groups: control, DOX (2 mg/kg), DOX + PCr (20 mg/kg), and DOX + PCr (50 mg/kg). Parameters assessed included body weight, oxidative stress markers (MDA, SOD, GSH), and neurofunctional indicators (nNOS, BDNF). Mitochondrial respiration was evaluated using high-resolution respirometry, measuring state 3 and state 4 respiration, the respiratory control ratio (RCR), and ADP/O ratio. Western blotting was used to analyze apoptosis-related proteins (Bax, Bcl-2, cleaved caspase-3, pro-caspase-3, pro-caspase-9, cytochrome c) and signaling molecules (NF-κB, PGC-1α). PCr treatment significantly reduced oxidative stress, as evidenced by lower MDA levels and elevated GSH and SOD. It also modulated apoptotic signaling by decreasing pro-apoptotic proteins (Bax, cleaved caspase-3) and increasing anti-apoptotic Bcl-2. Moreover, PCr enhanced mitochondrial function and biogenesis, while attenuating neuroinflammation through regulation of the NF-κB/PGC-1α pathway. These findings suggest that PCr protects against DOX-induced neurotoxicity by improving mitochondrial bioenergetics, reducing oxidative damage, and inhibiting neuronal apoptosis. PCr may represent a promising therapeutic strategy to mitigate chemotherapy-associated neurotoxicity.

Excessive pro-inflammatory polarization of microglia is a critical driver of secondary inflammation following spinal cord injury (SCI). Jaceosidin, a natural flavonoid with established anti-inflammatory properties, has not been extensively studied in the context of post-SCI inflammation regulation. Given the fundamental role of glycolysis in cellular energy metabolism and its crucial involvement in inflammatory processes, this study investigated the effects of Jaceosidin. We demonstrated that Jaceosidin significantly attenuated the inflammatory response in lipopolysaccharide-stimulated microglia in vitro. Subsequent in vitro and in vivo experiments revealed that Jaceosidin shifted microglial polarization away from the inflammatory state and suppressed glycolytic flux. Mechanistically, Jaceosidin directly targeted and inhibited the activity of pyruvate kinase M2 (PKM2), a key glycolytic enzyme. Intervention with Jaceosidin in a mouse SCI model resulted in reduced microglial activation at the injury site, diminished tissue damage, and significantly improved motor and autonomic nerve function recovery. In conclusion, our findings indicate that Jaceosidin mitigates microglial inflammation and promotes functional recovery after SCI by inhibiting PKM2 activity and dampening glycolysis. As a natural phytochemical derived from traditional Chinese medicine, Jaceosidin presents a promising novel therapeutic strategy for the clinical management of spinal cord injury.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by motor neuron degeneration, muscle weakness, paralysis, and eventual death, with TAR DNA-binding protein 43 (TDP-43) pathology observed in almost all cases. Mouse models based on TDP-43 are thus essential for studying ALS and developing therapeutic approaches. The TDP-43 rNLS8 mouse model expresses a human TDP-43 transgene with a mutated nuclear localization sequence (hTDP-43 ΔNLS), but this is normally suppressed by the presence of doxycycline (Dox). Disease is initiated by removal of Dox, which replicates key ALS features, including TDP-43 pathology, neuromuscular junction denervation, motor neuron loss, and reduced survival. However, this model has a rapid disease progression which limits its use for extended preclinical studies and investigation of early disease mechanisms. To overcome these limitations, we explored whether maintaining low Dox concentrations in the diet (10-20 mg/kg) could slow disease progression. Our findings demonstrate that this approach significantly reduced hTDP-43 ΔNLS expression (up to 4.8-fold), which delayed disease onset by four weeks. Disease progression, assessed by rotarod performance, grip strength, and neurological scores, was extended from six to 15 weeks, with a threefold increase in survival. Despite slower progression, at the end stage, mice displayed similar levels of neuroinflammation, motor neuron loss, as Dox off mice. These findings highlight slower-progressing TDP-43 rNLS8 mice as a robust model for preclinical and early disease mechanism studies.

Depression is a leading global cause of disability. Emerging evidence highlights glutamatergic dysfunction, particularly impaired NMDA receptor signaling, as a key contributor to its neurobiology. Hydrogen sulfide (H₂S), once regarded solely as toxic, is now recognized for its role in regulating synaptic plasticity, inflammation, and neuronal survival. This review synthesizes recent findings on the antidepressant effects of H₂S. In animal models, H₂S administration improves depression-like behaviors while modulating key pathways such as PI3K/AKT/mTOR, Sirt1, and the cGAS-STING pathway. These benefits extend across models of stress, neuropathic pain, diabetes, and sleep deprivation. Among H₂S donors, sodium hydrosulfide (NaHS) demonstrated the most consistent antidepressant effects in preclinical studies. Clinical studies further show that individuals with major depression exhibit lower plasma H₂S levels, with symptom severity inversely correlated to H₂S concentration. Together, these findings support a multifaceted role for H₂S in mood regulation and highlight its promise as both a therapeutic candidate and a potential biomarker in depressive disorders, though translational studies remain needed.

Long-term hyperglycemia and insulin dysfunction deteriorate peripheral nerve functions, leading to sensory loss, spontaneous pain, and hypersensitivity (i.e., allodynia and hyperalgesia). Evidence indicates glucose-induced upregulation of the Wnt/β-catenin mechanism in diabetic peripheral neuropathy (DPN). Eriodictyol (Ed) has shown protective effects against glucotoxicity. The present study explored the bioactivity of Ed in streptozotocin (STZ) induced DPN and the role of the Wnt/β-catenin pathway. Ed or gabapentin (Gpn), or methyl vanillate (MV) was administered in Wistar rats for 4 weeks, starting 6 weeks after STZ administration. Ed ameliorated the mean body weight and mitigated polydipsia and polyphagia in DPN rats. The data indicated that Ed attenuated hyperglycemia, glycosylated hemoglobin (HbA1c) levels, and HOMA-IR, and enhanced circulating insulin levels and HOMA-β against STZ-induced DPN. MV (Wnt/β-catenin activator) caused a significant increase in STZ-induced hyperglycemia, HbA1c, HOMA-IR, and further decreased the insulin levels and HOMA-β in STZ-treated rats. Ed attenuated oxidative stress, inflammatory expression, level of advanced glycation end products, and nuclear factor kappa B in the sciatic nerve of STZ-treated neuropathic rats, and MV further potentiated these markers triggered by STZ. Interestingly, Ed and Gpn attenuated mRNA expression of Wnt1/β-catenin in the sciatic nerve of neuropathic rats. Hyperalgesia and allodynia were significantly ameliorated in Ed or Gpn-treated rats against DPN. Furthermore, Ed ameliorated the biochemical biomarkers, histopathological characteristics, and nociceptive-like responses in STZ and MV-treated rats. It is concluded that Ed can alleviate the pathogenic course of DPN. Wnt/β-catenin pathway might be involved in the eriodyctiol-triggered mitigation of nociceptive-like responses in diabetic rats.