Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by persistent neuroinflammation, oxidative imbalance, cognitive decline, Aβ buildup, tau phosphorylation, and synaptic dysfunction. Despite progress in understanding AD’s development, effective treatments are still limited. Isorhapontigenin (ISO), a methoxylated stilbenoid similar to resveratrol, shows neuroprotective, anti-inflammatory, and antioxidative effects. In this study, we explored ISO’s therapeutic potential in a mouse model of AD-like pathology induced by LPS, focusing on TLR4/RAGE-triggered NF-κB signaling pathway and related neuroinflammatory responses, oxidative stress, GSK3β signaling, tau pathology, Aβ accumulation, glial activation, and synaptic health. Western blot and immunofluorescence techniques were used to measure the levels of TLR4/RAGE signaling components, glial markers (GFAP and Iba-1), p-NF-κB signaling pathway activation, proinflammatory cytokines ( TNF-α, COX-2, and IL-1β), oxidative stress indicators (Nrf2 and HO-1), neurodegeneration markers (p-GSK3β, p-tau, and Aβ), and synaptic proteins (PSD-95, SNAP-23, and SYP). Nissl staining helped assess neuronal density and structure. BV2 microglial cells were treated similarly in vitro, followed by viability tests and Apotox-Glo™ triplex assays, along with protein expression analysis. The levels of TLR4, RAGE, GFAP, and Iba-1 increased in the LPS-treated group, along with proinflammatory mediators, ROS, LPO, and neurodegenerative markers. Yet, ISO treatment significantly reduced their expression. Moreover, LPS lowered Nrf2 and HO-1 levels, reduced p-GSK3β, and decreased synaptic proteins, indicating oxidative damage and synaptic failure. ISO reversed these changes by restoring p-GSK3β, activating Nrf2/HO-1, and boosting synaptic protein levels, followed by behavioral improvement as evidenced by reduced escape latency and increased spontaneous alternations in the Morris water maze (MWM) and Y-maze tests. Additionally, ISO preserved neuronal and synaptic integrity and provided consistent neuroprotection in BV2 cells. Overall, these results demonstrate that ISO reduces LPS-induced AD-like pathology by activating TLR4/RAGE-driven p-NF-κB, decreasing neuroinflammation, enhancing Nrf2/HO-1 activity, inhibiting GSK3β, lowering Aβ and p-Tau accumulation, preserving synaptic health, and prominent improvement in spatial memory, emphasizing its potential as an AD treatment.
HMGB1 (high mobility group box 1 protein) refers to a chromatin-associated protein localized in the cytosol to be secreted to the extracellular milieu from multiple cell types including immune and non-immune cells. In this context, HMGB1 functions as a proinflammatory cytokine. Microglia as the main resident immune cells in the brain actively express and secrete HMGB1. Accumulative evidence suggests that HMGB1, released not only by microglia but also astrocytes and endothelial cells, plays a central role in mediating inflammatory signaling and driving the progression of neuroinflammation. In this review, we aim to discuss the critical role and key implications of HMGB1 in neuroinflammation, focusing on the most recent studies and discoveries in this area.
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA sensor that mediates innate immunity by inducing type I interferons (IFN-I) and proinflammatory cytokines. Although its role in antiviral defense and tumor immunity has been well established, emerging evidence suggests that it is also closely involved in demyelinating diseases of both the central and peripheral nervous systems (PNS). Such diseases, exemplified by multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), are characterized by immune-mediated inflammation, oxidative stress, mitochondrial dysfunction, and impaired myelin regeneration. This review systematically examines the diverse roles of the cGAS-STING pathway in demyelination. We summarize how moderate activation of this pathway promotes protective inflammation and autophagy, facilitating debris clearance and supporting remyelination during the early stages of disease. In contrast, excessive or sustained activation exacerbates neuroinflammation, hinders remyelination, and promotes progressive axonal injury. The involvement of cGAS-STING in T cell polarization, reactive oxygen species (ROS)-mediated injury, and antiviral responses further underscores its dual role in both disease initiation and progression. Understanding the context-dependent effects of cGAS-STING signaling in demyelinating diseases offers valuable insights for developing targeted therapeutic strategies. However, this review also emphasizes that most current evidence is derived from cellular and animal models. Given that the effects of cGAS-STING signaling are highly context dependent and may vary among different demyelinating diseases, disease stages, and cell types, further clinically relevant studies are required to validate its therapeutic potential.
Mitochondrial oxidative stress is a major factor of neurological diseases by generating and accumulating ROS, LPO, and 4-HNE in the brain. Here, cadmium chloride (CdCl2) is injected into mice (5 mg/kg per mouse, I.P.) to establish an animal model and to analyze elevated oxidative stress, neuroinflammation, apoptosis, reduced body weight, and synaptic impairment. The therapeutic agent Cistanoside A (CA) was administered to the CdCl2-treated mice group at a dose of 60 mg/kg per mouse for 4 weeks, P.O. The CdCl2 + CA-treated mice group reversed the elevated levels of ROS, LPO, GSH, and SOD in the mice brain homogenates and improved the levels of endogenous antioxidant biomarkers (Nrf2 and HO-1). Similarly, CA reduced neuroinflammation, as analyzed with GFAP, Iba-1, p-NFKB, IL-1β, and TNF-α in the CdCl2 + CA co-treated group. Furthermore, CA preserved neuronal integrity and morphology in the mouse brain, as analyzed via western blot (i.e., Bax and Bcl2), Nissl staining, Hematoxylin Eosin staining, and immunohistochemistry. In silico, our therapeutic agent CA shows strong interaction with the active site of Keap-1 and enhances the activity of NRF2 to inhibit CdCl2-induced oxidative stress and downstream signaling. Accumulatively, the therapeutic agent CA (60 mg/kg per mouse) potentially reversed oxidative stress, neuroinflammation, and the progression of neurodegeneration in the mouse CdCl2-injected neurotoxic model.
Temporal lobe epilepsy (TLE) is the most prevalent form of drug-resistant epilepsy and is driven by persistent neuroinflammatory cascades wherein interactions between inflammatory mediators and hormones play a crucial role. Kisspeptin (Kiss1), a neuropeptide known to modulate synaptic transmission in the hippocampus, has an unclear role in pathophysiology of epilepsy. To investigate this, a lithium–pilocarpine TLE rat model was established. Expression profiles of Kiss1, Kiss1r, and key neuroinflammatory molecules were assessed in the hippocampus, anterior temporal lobe (ATL), and neocortex at the transcript and protein levels. Neuroinflammatory markers were correlated with the expression of Kiss1 and its receptor under epileptic conditions. The cellular localization of Kiss1r with microglia (Iba1), astrocytic (Gfap), and neuronal (NeuN) markers was examined in TLE. Additionally, kisspeptin-10 (Kp-10) was administered to TLE rats, and its effects on cytoarchitecture, neuroinflammation, and long-term memory were evaluated. The results demonstrated significant downregulation of Kiss1 and Kiss1r mRNA across brain regions (P < 0.05). At the protein level, Kiss1 was significantly downregulated in the hippocampus and ATL but remained unchanged in the neocortex. Kiss1r levels increased in the hippocampus, decreased in the ATL, and remained unchanged in the neocortex. Kp-10 administration led to restoration of cellular alterations in the hippocampus of TLE rats. Kp-10 treatment upregulated the levels of anti-inflammatory cytokine Il-10 in the hippocampus and ATL. A downregulation in the levels of pro-inflammatory cytokine Il-1β in the hippocampus, but no alteration in ATL was seen upon Kp-10 treatment. Novel object recognition test indicated improved memory discrimination in Kp-10-treated TLE rats. These findings suggest that chronic neuroinflammation in TLE disrupts the kisspeptin signalling system, further aggravating disease pathology. Conversely, exogenous Kp-10 administration attenuated neuroinflammation, enhanced cognitive function and survival rate, highlighting a potential neuroprotective role of kisspeptin in TLE pathogenesis.
Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) are two prevalent chronic conditions that interact bidirectionally, with their high comorbidity posing a serious global health challenge. Recent studies highlight the gut-brain axis, particularly the gut microbiota-astrocyte axis, as a key mechanism underlying this comorbidity. The review reveals a common gut dysbiosis pattern in both T2DM and MDD, marked by reduced short-chain fatty acids (SCFAs)-producing bacteria and elevated lipopolysaccharide (LPS)-associated pro-inflammatory bacteria. Nevertheless, the two diseases present opposing astrocytic states: overactivation in T2DM and inhibition in MDD. In the progression from T2DM to secondary MDD, microbiota dysbiosis induces astrocyte hyperactivation in the hippocampus and hypothalamus, which in turn reduces glutamine synthetase (GS) and brain-derived neurotrophic factor (BDNF), exacerbates neuroinflammation, promotes insulin resistance (IR) and hypothalamic–pituitary–adrenal (HPA) axis overactivation, and disrupts the glutamate-glutamine (Glu-Gln) cycle, ultimately culminating in MDD. Conversely, as MDD progresses to secondary T2DM, microbiota dysbiosis suppresses astrocyte activation in the hippocampus and prefrontal cortex, which similarly aggravates neuroinflammation, promotes IR, and disrupts the Glu-Gln cycle, thereby contributing to T2DM. Together, these results advance our knowledge of the bidirectional interplay between T2DM and MDD, while simultaneously identifying potential nodes for therapeutic modulation.
Spinal cord injury (SCI) causes permanent sensorimotor deficits due to the inhibitory extracellular microenvironment that forms post-injury, hindering regeneration. The extracellular matrix (ECM) plays a critical role in neural development and repair, with the developmental spinal cord ECM being enriched in pro-regenerative molecules and containing relatively low levels of inhibitory components. In contrast, the ECM of the adult injured spinal cord is characterized by an abundance of growth-inhibitory molecules. Human pluripotent stem cell-derived spinal cord organoids have emerged as promising in vitro models for studying spinal cord development and disease; however, their application is limited by incomplete structural and functional maturation. The incorporation of developmental ECM components into organoid cultures has been shown to promote maturation, neuronal connectivity, and functional integration. This review provides a comprehensive overview of the regenerative properties of developmental spinal cord ECM and discusses its applications in organoid engineering and SCI repair, including decellularized ECM biomaterials, hydrogels, synthetic analogs, and combinatorial approaches. Collectively, developmental ECM-based strategies represent a promising platform for the development of precision regenerative therapies aimed at enhancing functional recovery after SCI.
( +)-Borneol (Bor) has been shown to enhance drug penetration across the blood-brain barrier (BBB); yet its mechanisms of action and adjuvant effects on Alzheimer’s disease (AD) drugs remain insufficiently investigated. This study systematically explored the adjuvant effects of Bor and its underlying mechanisms by employing AB wild-type zebrafish and APP transgenic zebrafish models. Results demonstrated that Bor at concentrations of 0.05 mM or lower exhibited no toxicity toward AB wild-type zebrafish, whereas 0.01 and 0.05 mM Bor significantly increased the expression of green fluorescent protein (GFP) in the zebrafish brain. Genetic analyses revealed that Bor downregulated genes encoding tight junction proteins and P-glycoprotein (P-gp). Drug treatment experiments showed that Bor enhanced the efficacy of AD therapeutic agents, including Zhenbaopill (ZBP, a traditional medicinal preparation) and the synthetic drug 8e. Specifically, Bor ameliorated AD-related behavioral impairments, inhibited cerebral apoptosis, restored the expression of AD-associated genes, normalized the activities of acetylcholine (ACh)-related enzymes, and downregulated both the mRNA and protein levels of Claudin 5. In summary, Bor enhances BBB permeability by regulating the expression of genes encoding BBB-related proteins, thereby increasing the brain concentration and bioavailability of AD drugs with anticholinesterase activity. An appropriate dose of Bor may thus contribute to enhancing the therapeutic efficacy of AD drugs.
Traumatic brain injury (TBI) is a major cause of long-term neurological disability worldwide, and effective therapeutic strategies remain limited. Cottonseed oil (CSO), a plant-derived oil rich in polyunsaturated fatty acids, has been reported to exert protective effects in ischemia-related injuries; however, its role and underlying mechanisms in TBI remain unclear. Here, we established a controlled cortical impact (CCI) model in mice and administered CSO by oral gavage prior to injury. Neurological function was assessed using the modified neurological severity score, rotarod, and balance beam tests, and neuronal injury was evaluated by histological and biochemical analyses. CSO administration significantly improved neurological and motor function, attenuated neuronal damage and apoptosis, enhanced cerebral blood perfusion, preserved blood-brain barrier (BBB) integrity, and reduced brain edema. CSO modulated the expression of AQP4, VEGFA, and BDNF, and markedly suppressed glial activation and pro-inflammatory cytokine production. In vitro, CSO alleviated H2O2-induced cellular injury in HT22 cells by reducing reactive oxygen species accumulation and restoring antioxidant defenses. Mechanistically, the neuroprotective effects of CSO were associated with activation of the AKT/GSK-3β signaling pathway, characterized by enhanced phosphorylation of AKT (Ser473) and inhibitory phosphorylation of GSK-3β (Ser9). Pharmacological inhibition of AKT with MK2206 abolished CSO-induced AKT/GSK-3β pathway activation, reduced cell viability, and restored the elevation of IL-1β and IL-6 levels in vitro, confirming that the anti-neuroinflammatory effects of CSO are mediated at least in part through the AKT/GSK-3β signaling axis. Collectively, these findings demonstrate that CSO exerts significant neuroprotective effects in experimental TBI by preserving neurovascular integrity, attenuating neuroinflammation, and activating the AKT/GSK-3β pathway, highlighting CSO as a promising preventive strategy for TBI.
Epilepsy is a prevalent neurological disorder characterized by an incompletely understood etiology and a substantial unmet therapeutic need, particularly for drug-resistant forms. This review examines the potential role of mitochondria-associated endoplasmic reticulum membranes (MAMs) as emerging signaling hubs in epileptogenesis. We systematically analyze how MAMs regulate core cellular processes-including calcium signaling, lipid metabolism, mitochondrial dynamics, autophagy, and oxidative stress-and how dysregulation of these processes may contribute to seizure initiation and progression. Furthermore, we evaluate existing interventions, such as phytotherapeutics and the ketogenic diet, from the perspective of modulation of MAMs. The review also highlights novel strategies targeting MAMs, including small-molecule approaches, nanodelivery systems, and neuromodulation technologies, which offer promising avenues for precise therapeutic intervention. By consolidating current molecular and genetic evidence, we identify MAMs as a critical hub in epilepsy and propose that targeting their integrity and function may represent a strategy to overcome drug resistance and modify disease progression. By integrating current knowledge of MAMs biology with epilepsy pathophysiology, this work provides a mechanistic framework to guide future research. It offers insights for the development of targeted molecular therapies for epilepsy.
Peripheral nerve injury (PNI) presents a significant clinical challenge often resulting in long-term functional disability. Following injury, successful regeneration heavily depends on the cellular plasticity of Schwann cells (SCs) to undergo dedifferentiation, proliferate, and guide axonal growth. Recently, the pineal hormone melatonin has emerged as a promising therapeutic candidate due to its potent antioxidant properties and ability to modulate SC biological behavior. However, its exact molecular mechanisms and direct impact on SC proliferation remain fragmented across literature. Following PRISMA 2020 guidelines and registered on PROSPERO (CRD420261373030), a systematic search was conducted across Medline via PubMed, Scopus, and Web of Science up to April 1, 2026. Original in vitro and in vivo studies evaluating melatonin’s effects on SC proliferation and PNI models were included. Data extraction focused on signaling pathways, histological outcomes, and functional recovery. Risk of bias was assessed using QUIN for in vitro and SYRCLE for in vivo studies. Twenty-six studies (12 in vivo, 3 in vitro, 11 mixed) were analyzed. In vitro, melatonin administration was frequently associated with dose-dependent mitogenic responses in RSC96 and primary SCs, operating primarily via MT1 receptor interaction and downstream activation of the Ras/Raf/ERK-MAPK and Shh signaling pathways. It supported SC dedifferentiation alongside Sox2 upregulation and alternative FAK activation, while preserving cell viability under oxidative stress via Parkin-mediated mitophagy. In vivo, melatonin treatment was correlated with increased myelin sheath thickness, higher axon density, and elevated SC infiltration across sciatic, cranial, and brachial plexus models. These structural changes were accompanied by functional recovery trends, higher CMAP amplitudes, and reduced lipid peroxidation markers (lowered MDA/MPO). Advanced delivery platforms, including 3D-printed scaffolds and electrospun magnetic nanoparticles, achieved sustained local melatonin release in experimental models. Preclinical evidence indicates that melatonin modulates Schwann cell proliferation, migration, and cytoprotection through receptor-dependent and antioxidant mechanisms. These findings offer a foundational, evidence-based rationale for further investigation in large-animal models and prospective clinical trial designs.
Faithful genome duplication during neurogenesis relies on the licensing of surplus replication origins, and hypomorphic variants in MCM3 have been associated with microcephaly and related growth disorders. Using in utero electroporation in embryonic mouse cortex, we show that acute partial depletion of MCM3 disrupts cortical progenitor development. MCM3 knockdown reduced EdU incorporation and PCNA positivity among GFP-positive cells in the VZ, indicating decreased S-phase engagement or impaired cell-cycle progression. It also increased replication-stress-associated signals, including γ-H2AX and p-RPA2(T21), but did not induce detectable cleaved caspase-3 activation. These changes were accompanied by a reduction in the population of electroporated neural progenitors, leading to decreased neuronal output. In addition, MCM3-depleted neuronal progeny showed altered radial distribution and reduced callosal axon extension. Together, these findings support a role for MCM3 in maintaining progenitor proliferative capacity and genome-stress tolerance during cortical development, and provide mechanistic insight into how partial MCM3 deficiency may contribute to microcephaly-related neurodevelopmental disorders.
Neurons respond to nutrient deprivation by activating autophagic pathways that promote survival under subsequent metabolic stress. Here, we show that short-term nutrient deprivation or pharmacological inhibition of mTORC1 enhances neuronal resistance to glutamate-induced excitotoxicity in primary cerebellar cultures characterized by a rapid decline in p62/SQSTM1 levels and a decrease in procaspase-3 levels, suggesting a potential mechanism for enhanced cell survival. Importantly, extracellular vesicles (EVs) secreted by the neurons during transient nutrient deprivation protect naïve recipient neurons by activating Akt and reducing excitotoxic cell death, indicating that these vesicles transmit pro-survival signals. Our findings uncover a stress-induced intercellular communication mechanism with therapeutic potential in neuroprotection, ischemic preconditioning, and vesicle-based interventions.
Parkinson’s disease (PD) is increasingly recognized as a disorder of glial dysfunction, wherein astrocytes transition from homeostatic supporters to active drivers of neurodegeneration. This review synthesizes recent evidence to propose a novel dual-pathway failure model in which internalized alpha-synuclein orchestrates a self-amplifying cycle of astrocytic toxicity. Pathological alpha-synuclein simultaneously suppresses key cytoprotective systems, the Nrf2-mediated antioxidant response and TFEB-regulated autophagy-lysosomal degradation, while hyperactivating neuroinflammatory signaling via NF-κB/MAPK and the recently implicated cGAS-STING axis, triggered by mitochondrial DNA release. This imbalance fosters chronic oxidative stress, proteostatic collapse, and sustained neuroinflammation. Ferroptosis, a form of necrotic cell death characterized by iron dependency and lipid peroxidation, may represent a likely downstream consequence of astrocytic death when protective failure (Nrf2/TFEB suppression) overlaps with toxic activation (cGAS-STING/NF-κB signaling) and disturbances in iron and lipid homeostasis. The concurrent failure of antioxidant defenses and the buildup of labile iron and peroxidizable lipids could establish a conducive environment for ferroptotic membrane rupture, potentially resulting in secondary neuronal damage. This gliocentric model reframes PD pathogenesis as a feed-forward loop of neurotoxicity originating in astrocytic reprogramming. Therapeutically, breaking this cycle via STING inhibition, Nrf2/TFEB activation, and anti-ferroptotic agents represents a promising but still experimental avenue for intervention aimed at restoring astrocyte homeostasis and potentially halting neurodegeneration. However, it is critical to note that the evidence supporting these approaches is derived almost exclusively from preclinical models, with no approved therapies targeting these astrocytic pathways currently available for PD patients.
Spinal cord injury (SCI) induces secondary damage characterized by metabolic disturbance, excessive inflammation, and progressive neurological dysfunction. Every-other-day fasting (EODF) has shown neuroprotective potential, but the mechanisms underlying its effects in SCI remain unclear. We investigated whether EODF prehabilitation attenuates SCI-associated secondary injury through SREBF1-associated metabolic–immune remodeling. Female C57BL/6 J mice underwent EODF for 4 weeks before SCI induction, and adeno-associated virus-mediated SREBF1 knockdown was used to assess the functional contribution of SREBF1. EODF was well tolerated, significantly improved locomotor recovery, reduced lesion cavity formation, and attenuated histopathological damage after SCI. EODF also had stage-dependent effects on SREBF1 expression, suppressing its aberrant early protein elevation while promoting coordinated regulation at later stages. In parallel, EODF partially restored altered omega-3 and omega-6 fatty acid profiles, attenuated TLR4/MyD88 signaling, reduced TNF-α, increased IL-10, shifted macrophage/microglia-associated markers toward a less proinflammatory profile, and reduced the proportion of TUNEL-positive cells. These protective effects were markedly attenuated by SREBF1 knockdown. Overall, our findings indicate that EODF prehabilitation mitigates SCI-associated secondary injury and support SREBF1-associated metabolic–immune remodeling as a functionally relevant mechanism underlying this protection. The results further suggest that temporal regulation of metabolic–inflammatory coupling may contribute to spinal cord resilience after injury.
Ischemic stroke (IS) is accompanied by blood–brain barrier (BBB) disruption and neuroinflammatory activation, but the upstream regulatory mechanisms remain incompletely defined. Here, integrated single-cell RNA sequencing, regulatory network analysis, and machine-learning screening identified Chemokine-like factor 1 (CKLF1) as a candidate endothelial regulator associated with IS. Functional validation showed that CKLF1 upregulation impaired endothelial barrier integrity, reduced tight-junction protein expression, enhanced apoptosis-associated activity, and activated PI3K/AKT/mTOR signaling under ischemic stress. CKLF1 also promoted chemokine amplification, microglial pro-inflammatory activation, and peripheral neutrophil recruitment. In a tMCAO/R mouse model, pharmacological inhibition of CKLF1 improved neurological outcomes, reduced infarct volume, preserved BBB integrity, and attenuated inflammatory activation, particularly when combined with CCL2 blockade. Conversely, CKLF1⁺ extracellular vesicle (EV)-related treatment aggravated BBB permeability and neuroinflammation. These findings support CKLF1 as a mediator of post-stroke endothelial injury and immune-inflammatory crosstalk and suggest that CKLF1-targeted intervention may represent a potential strategy for limiting BBB disruption after IS. Schematic illustration of CKLF1-mediated BBB disruption and chemokine network regulation mechanisms following IS.
M itochondria act as the energetic hub of eukaryotic cells, orchestrating cellular energy metabolism via oxidative phosphorylation and the tricarboxylic acid (TCA) cycle, thereby subjecting them to continuous environmental stress. To address these challenges, mitochondria have developed a sophisticated array of quality-control mechanisms that provide adaptive resilience. These quality-control pathways encompassing mitochondrial biogenesis, dynamic remodeling, and mitophagy collectively safeguard cellular homeostasis. Among them, mitophagy plays a continuous role in surveying, identifying, and eliminating dysfunctional mitochondria, thereby preserving the integrity of the mitochondrial network and ensuring optimal bioenergetic function. When mitophagy is dysregulated, a cascade of protein homeostatic collapse and metabolic failure ensues, disrupting physiological cellular processes. Moreover, mitophagy plays a role in the development and progression of various pathologies, including neurodegenerative disorders, cardiovascular diseases, and cancer. In the context of neurodegeneration, aberrant mitophagy aggravates disease progression at the molecular, organellar, and cellular levels. Given that neuronal metabolism critically relies on oxidative phosphorylation, which primarily occurs within mitochondria, mitochondrial functional integrity directly determines neuronal energy supply and physiological capacity. Consequently, impaired mitophagy has been identified as a key determinant in the etiology of neurodegenerative diseases. This review systematically elucidates the key molecular mechanisms regulating mitophagy and how these mechanisms contribute to the onset and progression of neurodegenerative diseases. It also summarizes potential therapeutic agents targeting mitophagy to improve neurodegenerative disorders.
In long-lived neurons, precise control of mitochondrial gene expression is critical for maintaining bioenergetic capacity and preventing dysfunction linked to neurodegeneration. This control is executed by nuclear-encoded mitochondrial central dogma (NEM-CD) genes, yet their tissue-specific regulation, particularly in large mammalian brains, remains poorly defined. We conducted a comparative transcriptomic analysis of 214 NEM-CD genes across four buffalo tissues (brain/cerebellum, heart, kidney, and ovary) to elucidate organ-specific regulatory strategies. RNA sequencing and differential expression analysis revealed a definitive quantitative hierarchy (kidney > heart > brain > ovary), with tissue identity explaining 46.36
Alzheimer’s disease (AD) is a progressive neurological condition marked by memory impairment and cognitive deterioration. Early diagnosis remains difficult due to the absence of reliable peripheral biomarkers. Circulating microRNAs (miRNAs) have recently gained attention as non-invasive indicators measurable in blood. Among these, microRNA-146a is of particular interest because of its role in inflammatory signaling and its altered expression in AD. This article highlights the diagnostic potential and biological function of microRNA-146a as a peripheral biomarker for Alzheimer’s disease. The current study aimed to examine the expression and clinical relevance of microRNA-146a and to assess its possible influence on disease progression in Alzheimer’s disease patients. Blood samples were collected after obtaining signed informed consent (No. 3912/2022 MRB) from 50 AD patients and from 50 healthy controls (HC); the miRNA content was screened by RT-PC. The expression of miRNA-146a is significantly greater in the Alzheimer’s disease group (4.369 ± 3.168 -fold change) than in the control group (1.056 ± 0.702) (p < 0.001). In order to evaluate miR146a expression efficiency, a receiver operating characteristic (ROC) curve showed miR146a exhibited strong discriminative capability, with an AUC of 0.906 (95
Neuropathic pain (NP) presents a significant challenge for patients with chronic diseases, characterized by spontaneous pain and hyperalgesia, with recent studies highlighting the involvement of the gut microbiota in its pathogenesis. Increasing evidence suggests that melatonin mitigates systemic inflammation and remodels gut microbiota. The present study further explored the mechanism by which oral melatonin ameliorates pain-related behavior following peripheral nerve injury. In this study, mice with chronic constriction injury (CCI) were orally administered melatonin (100 mg/kg) for 14 days. Pain behaviors were evaluated using mechanical allodynia and thermal hyperalgesia tests. Gut microbiota profiles were assessed via 16S rRNA sequencing, and microbiota-dependent effects were verified through antibiotic treatment (ABX) and fecal microbiota transplantation (FMT). Linoleic acid (LA) levels in serum and spinal cord were measured using liquid chromatography–mass spectrometry (LC–MS), and protein expression of NLRP3, caspase-1, and GSDMD in spinal cord tissue was examined by immunoblotting. Melatonin treatment significantly increased the mechanical pain threshold and prolonged thermal withdrawal latency in CCI mice. It also remodeled the dysbiotic gut microbiota, and these protective effects were abolished by antibiotic treatment but restored by FMT. Protein analysis revealed upregulation of NLRP3 and GSDMD in CCI mice, both of which were suppressed following melatonin administration. Moreover, melatonin-induced microbiota modulation elevated LA levels in serum and spinal cord. Supplementation with LA alone alleviated NP and inhibited NLRP3, caspase-1, and GSDMD activation. These findings suggest that oral melatonin treatment effectively ameliorates NP in CCI mice associated with the neuroinflammation and microbiota-metabolites-brain axis.
