The lifetime prevalence of depression is significantly higher in women. But the lack of ideal antidepressant severely limits therapies for female specific depressive disorders like perinatal depressio Show more
The lifetime prevalence of depression is significantly higher in women. But the lack of ideal antidepressant severely limits therapies for female specific depressive disorders like perinatal depression. Herein, we evaluated whether vitamin C (ascorbic acid), a widely used nutritional supplement and perinatal therapeutic agent, could serve as a potential treatment for female-related depressive disorders using a chronic restraint stress (CRS) mouse model. C57BL/6 adult female mice were submitted to a 14-day CRS paradigm to induce depression-like behaviors. The antidepressant potential of vitamin C (200 mg/kg, i.p., a single dose) were assessed in CRS-exposed female mice that exhibited depression-like phenotype. Furthermore, we explored the underlying mechanisms through RNA sequencing, western blotting, and pharmacological interventions. Vitamin C rapidly ameliorated depression-like phenotypes in CRS-exposed female mice within 24 h. The sucrose preference test indicated that the antidepressant effect of vitamin C lasted for more than 72 h. Transcriptome sequencing analysis revealed that vitamin C reversed CRS-induced transcriptional alterations in 104 genes in the medial prefrontal cortex (mPFC) of female mice, including the dopamine receptor D2 (D2R). Western blotting confirmed that CRS suppressed the D2R-ERK1/2-CREB-BDNF pathway in the mPFC, which was effectively rescued by vitamin C. The antidepressant effect of vitamin C was antagonized by the D2R antagonist sulpiride. Additionally, protein-protein interaction network analysis revealed functional linkages between D2R and other vitamin C-regulated stress-sensitive genes. Our findings suggest that vitamin C may serve as an ideal candidate for the treatment of depression in females, potentially through the restoration of the D2R-BDNF pathway. Show less
This study aims to evaluate 5-(but-1-en-1-yl)-1,2,3-trimethoxybenzene (BETMB) as a novel dual-target anti-seizure agent for refractory epilepsy and elucidate the synergistic neuroelectrophysiological Show more
This study aims to evaluate 5-(but-1-en-1-yl)-1,2,3-trimethoxybenzene (BETMB) as a novel dual-target anti-seizure agent for refractory epilepsy and elucidate the synergistic neuroelectrophysiological mechanism between Na Whole-cell patch-clamp recordings characterized BETMB's dual-target activity. Antiseizure efficacy was assessed in maximal electroshock (MES), pentylenetetrazole (PTZ), and kainic acid (KA) models. Cognitive function in chronic KA mice was evaluated using the Morris water maze (MWM). Histopathological, immunohistochemical, and Western blot analyses explored neuroprotection. Synergy between Na BETMB acted as a GABA BETMB is a promising dual-target therapy for refractory epilepsy, supported by the first electrophysiological evidence that dual modulation of GABA Show less
Chronic heart failure (CHF) impairs cognitive function. Xijiaqi Formula (XJQ), a traditional Chinese medicine (TCM) used clinically to treat CHF, demonstrates potential for improving cognition in CHF Show more
Chronic heart failure (CHF) impairs cognitive function. Xijiaqi Formula (XJQ), a traditional Chinese medicine (TCM) used clinically to treat CHF, demonstrates potential for improving cognition in CHF patients. However, its precise mechanism in treating post-CHF cognitive dysfunction remains unclear. This study systematically investigates XJQ's effects on post-CHF cognitive dysfunction and the underlying mechanisms. The components of XJQ were identified through liquid chromatography-mass spectrometry. CHF was induced in rats via ligation of the left anterior descending coronary artery, followed by six weeks of XJQ treatment. Cardiac function was evaluated through echocardiography and hemodynamic parameters, while cognitive function was assessed using Morris water maze (MWM) and open field tests (OFT). XJQ treatment enhanced both cardiac and cognitive functions in CHF rats. Network pharmacology identified 12 core active components of XJQ and indicated its effect on cognitive dysfunction involved regulating synapses, inflammation, and phosphodiesterase 4 (PDE4)-dependent cyclic adenosine monophosphate (cAMP) signaling. XJQ inhibited microglial and astrocyte activation, decreased proinflammatory cytokines, and mitigated neuronal damage. Notably, XJQ promoted synaptic repair and dendritic growth by downregulating PDE4 and upregulating cAMP, protein kinase A (PKA), cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), PSD95, and synapsin I levels. Molecular docking and Bio-layer interferometry assays confirmed direct binding of quercetin, kaempferol, isorhamnetin, and darutoside to PDE4. In conclusion, XJQ alleviates neuroinflammation and enhances synaptic plasticity to improve cognitive dysfunction in CHF rats via the PDE4/cAMP/PKA/CREB signaling pathway. These findings provide valuable insight into the heart-brain axis. Show less
The high global prevalence of anxiety disorders, coupled with the limitations of existing treatments, constitutes a severe public health challenge. Chronic stress, as a core environmental trigger, has Show more
The high global prevalence of anxiety disorders, coupled with the limitations of existing treatments, constitutes a severe public health challenge. Chronic stress, as a core environmental trigger, has garnered increasing attention for its mechanism of mediating brain-derived neurotrophic factor (BDNF) imbalance through neuroinflammation. BDNF dysregulation may contribute to anxiety disorders, particularly in subtypes with heightened neuroinflammation. The objective of this review is to comprehensively and methodically explores the potential role of the "M1-like microglia-A1-like astrocyte axis (M1-A1 axis)" in linking chronic stress to BDNF dysregulation in anxiety disorders, and to provide a theoretical basis for intervention strategies targeting this axis. By synthesizing recent relevant clinical and preclinical evidence, this review integrates evidence from molecular to systems levels, focusing on the activation mechanisms of neuroinflammation under chronic stress, the crosstalk between glial cells, and their regulatory network on BDNF. Chronic stress is associated with peripheral and central cascades through hypothalamic-pituitary-adrenal (HPA) axis activation and gut microbiota disruption. Within the central nervous system (CNS), stress induces microglial polarization toward the pro-inflammatory microglial subpopulations (hereinafter referred to as M1-like microglia). The signals released by M1-like microglia, such as Interleukin-1 alpha (IL-1α), Tumor Necrosis Factor-alpha (TNF-α), and Complement Component 1q (C1q) (ITC), drive astrocytes to transform into the neurotoxic astrocyte states (hereinafter referred to as A1-like astrocyte), forming the "M1-A1 axis". This axis contributes to BDNF dysregulation through the following mechanisms: (1) Release of pro-inflammatory cytokines inhibits BDNF transcription and translation; (2) Induction of astrocytic lactate metabolism disruption, which impairs neuronal energy supply and acidifies the microenvironment, further amplifying inflammation and affecting BDNF expression; (3) Compromise of the blood-brain barrier(BBB)enables peripheral immune cells to penetrate into the CNS, and these cells work in synergy with central glial cells to amplify inflammation. The reduction in BDNF and the imbalance in the ratio of its precursor to mature form ultimately lead to impaired synaptic plasticity in brain regions like the hippocampus (HIP) and amygdala, precipitating anxiety-like behaviors. Existing pharmacological interventions are inadequate to reverse this pathological process. The M1-A1 axis may serve as a key node linking chronic stress to BDNF dysregulation and anxiety disorders. Targeting the phenotypic transformation of glial cells, repairing the BBB, or modulating glial cell metabolism (e.g., lactate shuttle) may represent potential strategies requiring further validation. Future research should focus on the spatiotemporal dynamics of this axis and its clinical translation. Show less
DNA double-strand break repair has emerged as a vital pathway to repair DNA damage seriously related to the risk of colorectal cancer (CRC). To explore valid susceptible biomarkers of CRC via investig Show more
DNA double-strand break repair has emerged as a vital pathway to repair DNA damage seriously related to the risk of colorectal cancer (CRC). To explore valid susceptible biomarkers of CRC via investigating the association of single nucleotide polymorphisms in DSBR genes with CRC risk, seven polymorphisms located in 3'-untranslated regions of DSBR genes including RAD51 rs11852786, RAD51B rs963917, BRCA1 rs12516 and rs8176318, BRCA2 rs15869, XRCC4 rs2035990 and XRCC5 rs2440 were detected and analyzed in a CRC case-control study (cases (202) and also controls (202)). The PolymiRTs and miRSNP database were used to predict the microRNAs that can bind to 3'UTR SNPs. Since long non-coding RNA as a miRNA "sponge" played the role of competing endogenous RNA, DAVID database was used to find the lncRNAs that can bind to the candidate miRNA seed sequences. BRCA1 rs12516 minor A allele was found to be linked with a higher risk of CRC than its major G allele (OR = 2.716, 95%CI: 1.394-5.292, P = 0.003). The stratified analyses demonstrated rs12516 AA genotype with a more elevated risk of CRC in male (OR = 3.089, 95% CI:1.315 ~ 7.255) or age > 50 population (OR = 3.318, 95%CI:1.571 ~ 7.006) than its GG genotype. BRCA1 rs12516 A allele created a novel miR-4704-5p binding target, and there was a negative correlation between miR-4704-5p and BRCA1 expression (r =-0.7199, P = 0.0440). Based on the theory of ceRNA network, it was predicted that lncRNA BDNF-AS can competitively bind to miR-4704-5p, whose expression was exhibited to be negatively correlated with BDNF-AS (r=-0.3481, P = 0.0375). On the contrary, BDNF-AS expression showed a positive correlation with BRCA1 mRNA level in colorectal tissue carrying rs12516 of A allele (adjacent tissue: r = 0.7269, P = 0.0411; cancer tissue: r = 0.7134, P = 0.0469). ROC curve showed both BDNF-AS (AUC = 0.651, P = 0.0277) and miR-4704-5p (AUC = 0.7215, P = 0.0012) can distinguish CRC tissues from their adjacent tissues. BRCA1 rs12516 is characterized as a potential biomarker associated with CRC risk, via a possible functional ceRNA network of BDNF-AS, miR-4704-5p and BRCA1. The interaction of a lower expression of BDNF-AS, a higher expression of miR-4704-5p and rs12516 A allele could together increase the risk of colorectal cancer. Show less
Chronic pain, marked by nociceptive sensitization and maladaptive neuroplasticity, affects 30% of the global population with escalating socioeconomic burdens. Epidemiological data show a 2-3-fold incr Show more
Chronic pain, marked by nociceptive sensitization and maladaptive neuroplasticity, affects 30% of the global population with escalating socioeconomic burdens. Epidemiological data show a 2-3-fold increase in neuropsychiatric co-morbidities among individuals with chronic pain, where epigenetic dysregulation serves as a key mechanism linking ongoing pain to emotional disorders. This review systematically explores epigenetic signatures in supraspinal integration hubs, notably the limbic-paralimbic networks and prefrontal regulatory circuits. The identified epigenetic signatures encompass dysregulation of DNA methyltransferases (DNMTs), RNA modifications, histone post-translational modifications and locus-specific alterations, including aberrant methylation at the brain-derived neurotrophic factor (BDNF), opioid μ receptor and transient receptor potential ankyrin 1 (TRPA1) gene loci. Additionally, they involve dysfunction of the glucocorticoid receptor (GR)/corticotropin-releasing factor (CRF) axis via epigenetic modulation. Building on these findings, we evaluate therapeutic strategies addressing epigenetic dysregulation. While preclinical data demonstrate the efficacy of histone deacetylase (HDAC) and DNMT inhibitors, clinical translation faces significant barriers, including limited blood-brain barrier permeability. Notably, our analysis highlights the benefits of combining pharmacological interventions with non-invasive neuromodulation for enhanced co-morbidity management. Looking forward, this review proposes innovative approaches that leverage CRISPR-based chromatin editing platforms, biomimetic nanocarriers for neuron-specific delivery and closed-loop neuromodulation integrating real-time biomarker feedback, collectively establishing a precision medicine framework for pain or neuropsychiatric co-morbidities. Show less
Current treatments for depression have focused on improving the dysregulated monoamine neurotransmitter systems in the brain. However, the conventional antidepressants based on the monoamine hypothesi Show more
Current treatments for depression have focused on improving the dysregulated monoamine neurotransmitter systems in the brain. However, the conventional antidepressants based on the monoamine hypothesis usually exert side effects and unsatisfactory responses. MicroRNAs (miRNAs) are smaller noncoding RNA which are highly expressed in the brain and play important roles in the development of neurological disorders. In this study we investigated the role of miRNAs in the occurrence of depression. A rat depression model was established by exposure to chronic mild stress (CMS) over 4 weeks. In the next week, the sucrose preference test (SPT), the forced swimming test (FST), and the open field test (OFT) were used to evaluate the depression-like behaviors. Then the rats were euthanized and total RNA was isolated from rat mPFC. We showed that the level of microRNA-129-5p (miR-129-5p) was significantly increased in the mPFC of CMS rats. Overexpression of miR-129-5p in the mPFC by bilateral microinjection of lenti-miR-129-5p virus (OE-miR-129-5p) induced the depression-like behaviors in control rats, accompanied with the impairment in neuronal structures and a decrease in synaptic plasticity. In contrast, knockdown of miR-129-5p in the mPFC by bilateral microinjection of lenti-miR-129-5p sponge virus (KD-miR-129-5p) ameliorated the depression-like behaviors in CMS rats, along with the improvement in neuronal structures and an increase in synaptic plasticity. Furthermore, we demonstrated that miR-129-5p targeted to the brain-derived neurotrophic factor (BDNF) in the mPFC to contribute to the development of depression. This study suggests that miR-129-5p in the mPFC impairs the neuronal structures and reduces the synaptic plasticity after the exposure to CMS, which underlies the development of CMS-induced depression-like behaviors in rats. Show less
Hyposalivation affects cognitive function. However, its impact on hippocampus-dependent memory remains unclear. Saliva contains brain-derived neurotrophic factor (BDNF), which is also synthesized in t Show more
Hyposalivation affects cognitive function. However, its impact on hippocampus-dependent memory remains unclear. Saliva contains brain-derived neurotrophic factor (BDNF), which is also synthesized in the hippocampus and can pass through the blood-brain barrier (BBB) to influence hippocampal plasticity. Therefore, we hypothesized that hyposalivation reduces peripheral BDNF availability, leading to decreased hippocampal BDNF levels and cognitive impairment. In this study, this relationship was investigated using an in vivo model of sialadenectomy-induced hyposalivation. A total of 24 8-week-old male ddY mice were divided into control and extraction (EXT) groups. The EXT group underwent submandibular and sublingual salivary gland extractions, whereas the control group underwent a sham operation. Saliva was collected at baseline (0 weeks) and at 2- and 3-weeks postoperatively. Cognitive function was assessed using the Y-maze, fear conditioning (FC), novel object recognition (NOR), and object location tests (OLT). Anxiety-like behavior was evaluated using the open field test (OFT) and elevated plus-maze (EPM) tests. Hippocampi were collected at 3 weeks post-operation for BDNF quantification using enzyme-linked immunosorbent assay, and its concentration in subregions of the hippocampus was determined by semi-quantitative analysis. Hyposalivation significantly impaired spatial working memory in the Y-maze test and contextual fear memory in the FC, both of which are hippocampus-dependent. NOR showed only a transient deficit at 24 h during the 2-week period (no significant difference in 3-week post-operation), whereas long-term spatial memory measured by the OLT exhibited a persistent 24-h impairment at both 2 and 3 weeks, indicating reduced long-term spatial memory rather than accelerated decay. No significant differences were observed in anxiety-like behavior. Although sialoadenectomy significantly reduced salivary secretion and total salivary BDNF output, the concentration of BDNF in saliva in both groups remained unchanged at 2- and 3-weeks post-operation. However, hippocampal BDNF levels were significantly lower in the EXT group than in the control group. These findings suggest that hyposalivation may selectively impair hippocampus-related spatial memory without affecting recognition memory or anxiety-related behaviors. Show less
Yue Hu, Tahir Ali, Shengnan Mou+6 more · 2026 · Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · Springer · added 2026-04-24
Astrocyte-derived extracellular vesicles (ADEVs) have emerged as a novel research tool in the field of central nervous system disorders. However, significant differences in yield and purity exist amon Show more
Astrocyte-derived extracellular vesicles (ADEVs) have emerged as a novel research tool in the field of central nervous system disorders. However, significant differences in yield and purity exist among extracellular vesicles (EVs) isolated by different methods, leading to considerable heterogeneity in clinical study outcomes. Therefore, establishing appropriate normalization strategies to enhance comparability across results is a key prerequisite for their clinical translation. This study included 15 patients with major depressive disorder (MDD) and 15 healthy controls (HCs). ADEVs were isolated from plasma using ultracentrifugation combined with immunoaffinity capture. Subsequently, the levels of brain-derived neurotrophic factor (BDNF), five EV biomarkers (CD9, CD63, CD81, Alix, and TSG101), and particle counts in ADEVs were quantified. In addition, plasma lipoprotein levels were measured. Our results demonstrated a lack of significant correlation between particle counts and the levels of five EV biomarkers in plasma ADEVs, whereas strong correlations were observed among the five biomarkers themselves. Normalization of BDNF levels to CD81 or CD9 revealed a significant decrease in the MDD group, whereas normalization to EV particle counts or other EV biomarkers did not show such differences. Notably, plasma levels of apolipoprotein B (APOB), low-density lipoprotein (LDL), and total cholesterol (TC) significantly interfered with the measurement of particle counts. In summary, under conventional EV isolation and detection conditions, our findings support the use of EV biomarker levels rather than particle counts as a normalization method for quantifying target proteins of ADEVs in plasma. [Image: see text] The online version contains supplementary material available at 10.1186/s12888-026-07796-6. Show less
Alzheimer's disease (AD) and osteoporosis are common age-related degenerative diseases. Emerging evidence suggests that amyloid-β (Aβ) deposition may contribute to the pathogenesis of both conditions. Show more
Alzheimer's disease (AD) and osteoporosis are common age-related degenerative diseases. Emerging evidence suggests that amyloid-β (Aβ) deposition may contribute to the pathogenesis of both conditions. This study investigated whether probucol could alleviate AD-associated bone loss and Aβ42-induced osteoblast dysfunction, and further explored the underlying mechanisms. Female mice were divided into four groups (n = 5 per group): C57BL/6 wild-type (WT), WT treated with probucol (WT + PBC), APP/PS1 transgenic (AD) mice, and AD treated with probucol (AD+PBC). Bone mineral density (BMD) was assessed by micro-CT. Levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) along with bone metabolism markers including fibroblast growth factor 23 (FGF23), sclerostin, and brain-derived neurotrophic factor (BDNF) in bone and brain tissues were measured by ELISA. FOXO3a was knocked down in the bone marrow of APP/PS1 mice via stereotactic injection of lentiviral vectors. Expression of APP and FOXO3a in bone tissue was evaluated using RT-qPCR and Western blotting (WB). Mitochondrial damage in osteoblasts and neuronal cells was assessed by transmission electron microscopy (TEM). In vitro study, osteoblast differentiation and mineralization deficits were evaluated using Alizarin Red staining. WB was used to measure the expression of AKT, FOXO3a, autophagy and apoptosis related proteins. Probucol attenuated bone loss and mitochondrial damage in both APP/PS1 and FOXO3a-knockdown APP/PS1 mice, and improved cognitive impairment and neuronal ultrastructure in APP/PS1 mice. Furthermore, probucol attenuated Aβ42-induced osteoblast differentiation and mineralization via the AKT/FOXO3a signaling pathway in vitro. These findings demonstrate that probucol ameliorates AD-associated bone loss and Aβ42-induced osteoblast impairments by regulating AKT/FOXO3a signaling pathway. Show less
Docosahexaenoic acid (DHA) is indispensable for neurological health, yet its therapeutic potential is hampered by poor bioavailability and non-specific brain distribution. We hypothesized that co-admi Show more
Docosahexaenoic acid (DHA) is indispensable for neurological health, yet its therapeutic potential is hampered by poor bioavailability and non-specific brain distribution. We hypothesized that co-administering DHA with specific molecular carriers - eicosapentaenoic acid (EPA) or phosphatidylserine (PS) - would exploit distinct cellular transport pathways to achieve region-specific brain enrichment and associated neuroprotection. By dietary intervention using C57BL/6J mice, we employed regional lipidomics, ELISA, and western blotting to assess brain fatty acid incorporation, neurotrophic factor levels, inflammatory signaling, and transporter expression following supplementation with DHA alone or in combination with EPA or PS. Lipidomic analyses revealed striking, carrier-dependent spatial modulation of DHA. Co-administration with EPA enriched the cortex and striatum, while PS co-administration preferentially targeted the hippocampus and cortex. Mechanistically, both carrier-DHA complexes enhanced the expression of the key blood-brain barrier (BBB) transporter MFSD2A. Functionally, this precision delivery activated distinct neuroprotective programs. PS + DHA robustly upregulated the CREB-BDNF neurotrophic pathway, while EPA + DHA uniquely suppressed the NF-κB pathway, demonstrating potent anti-inflammatory effects. These results demonstrate that the choice of molecular carrier dictates both the spatial distribution of DHA and the nature of the ensuing neuroprotective response. Our findings establish that dietary co-supplementation with specific lipid carriers enables precise spatial delivery of DHA by engaging specific transporters, thereby activating distinct neuroprotective programs in a region-specific manner. This work provides a mechanistic framework for a precision nutrition strategy, tailoring DHA formulations to target specific neuroanatomical and cellular vulnerabilities in neurological disorders. Show less
The trend of global population aging is closely associated with a rising incidence of neurodegenerative diseases (NDs), including stroke, Alzheimer disease, Parkinson disease, and depression. These co Show more
The trend of global population aging is closely associated with a rising incidence of neurodegenerative diseases (NDs), including stroke, Alzheimer disease, Parkinson disease, and depression. These conditions, characterized by progressive neuronal loss, currently pose a significant challenge due to the lack of curative therapies. Brain-derived neurotrophic factor (BDNF) serves as a critical regulator of synaptic plasticity, a fundamental mechanism believed to underpin essential cognitive and motor functions such as learning, memory formation, and recovery. Decreased BDNF and deficits in BDNF signaling leads to the pathogenesis of NDs. Numerous studies support the therapeutic potential of acupuncture in managing NDs. Its beneficial effects are largely attributed to the ability to elevate BDNF expression and potentiate associated neurotrophic signaling. Beyond direct BDNF modulation, acupuncture exerts regulatory effects on specific micro-RNAs (miRNAs). This includes miRNAs that directly target BDNF transcripts for posttranscriptional control, as well as others that independently influence molecules critical for maintaining synaptic plasticity. The binding of acupuncture-elevated BDNF to its high-affinity receptor, Tropomyosin-related kinase B (Trk-B), initiates the activation of key downstream signaling cascades, including phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) and phospholipase C-γ (PLCγ) pathways which are involved in synaptic plasticity, survival, proliferation and differentiation of neurons. In this review, we present the effects of acupuncture on BDNF, miRNAs and the downstream signal transduction pathways of BDNF in NDs and the review may partly elucidate the biological molecular mechanisms of acupuncture in the therapy of NDs. Show less
Unhealthy diets characterized by high salt, fat, and fructose content are established risk factors for metabolic and cardiovascular disorders and may have indirect effects on cognitive function. Howev Show more
Unhealthy diets characterized by high salt, fat, and fructose content are established risk factors for metabolic and cardiovascular disorders and may have indirect effects on cognitive function. However, the combined impact of a high-salt, high-fat, and high-fructose diet (HSHFHFD) on systemic physiology and brain health remains to be fully elucidated. Sprague-Dawley (SD) rats received a customized high-salt, high-fat diet supplemented with 30% fructose water for 18 weeks. Physiological and brain parameters were assessed, in combination with multi-omics analyses including brain proteomics and metabolomics, serum metabolomics, and gut microbiota profiling. HSHFHFD significantly elevated blood glucose, blood pressure, and serum levels of TG, TC, and LDL in rats. Serum metabolomic profiling identified over 100 differentially abundant metabolites in the Model group. Proteomics, metabolomics, and gut microbiome integration revealed pronounced alterations in both brain proteomic and metabolomic profiles, with 155 differentially expressed proteins associated with glial cell proliferation and 65 differential metabolites linked to fatty acid and amino acid metabolism, among others. Experimental validation confirmed marked upregulation of GFAP and Bax protein, concomitant with downregulation of ZO-1 and occludin. Furthermore, HSHFHFD perturbed the CREB signaling pathway, leading to diminished BDNF expression. The levels of inflammatory factors, including IL-6, IL-10, IL-1β and TNFα, were significantly elevated in the brain. Oxidative stress was evident, as indicated by elevated malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) activity, and altered NAD HSHFHFD-induced depletion of gut Show less
Ginsenoside Rd, a protopanaxadiol abundant in Panax ginseng and Panax notoginseng, possesses well-documented neuroprotective properties but suffers from low bioavailability. Here, we engineered nanopa Show more
Ginsenoside Rd, a protopanaxadiol abundant in Panax ginseng and Panax notoginseng, possesses well-documented neuroprotective properties but suffers from low bioavailability. Here, we engineered nanoparticles from zein, chitosan-α-lipoic acid copolymer, and sodium alginate for the delivery of ginsenoside Rd (Rd) and evaluated their efficacy in alleviating scopolamine-induced memory impairment in a mouse model. The results demonstrated that the nanoparticles successfully encapsulated Rd, with an encapsulation efficiency of approximately 73.23 %, and exhibited a hollow spherical morphology. Additionally, the carrier exhibited exceptional stability under varying temperature and salt ion conditions, along with the ability to be readily redispersed. The incorporation of Rd into nanoparticles significantly improved its antioxidant efficacy, as well as its stability and sustained release profile in the gastrointestinal environment. In vivo experiments demonstrated that Rd-loaded nanoparticles significantly improved scopolamine-induced memory deficits, oxidative stress, cholinergic system dysfunction, and neuronal damage in the hippocampal region of mice, outperforming the effects of ginsenoside Rd alone. Western blot results indicated that Rd-loaded nanoparticles improved memory-impaired mice by upregulating p-CaMKII, p-CREB, and BDNF protein expression through modulating the long-term potentiation pathway. We further found that Rd-loaded nanoparticles treatment increased the richness and diversity of gut microbiota. This study provides a promising strategy for the effective treatment of improving learning memory. Show less
Major depressive disorder (MDD) involves multifaceted pathologies including neurotransmission, neuroplasticity, inflammation, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Growing evidenc Show more
Major depressive disorder (MDD) involves multifaceted pathologies including neurotransmission, neuroplasticity, inflammation, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Growing evidence implicates zinc homeostasis imbalance in MDD, yet a systematic framework integrating it into these mechanisms is lacking. This narrative review synthesizes literature (2000-2024) to elucidate the multidimensional associations between zinc homeostasis and MDD pathology, focusing on zinc's roles in neurotransmitter regulation, BDNF signaling, inflammation, oxidative stress, and HPA axis activity. Epidemiological studies indicate an inverse correlation between serum zinc levels and MDD. Mechanistically, zinc imbalance may disrupt neural signaling via glutamate/GABA/5-HT receptors, impair neurotrophy via BDNF, exacerbate neuroinflammation and oxidative stress, and promote HPA axis hyperactivity. Zinc supplementation shows efficacy in mild-to-moderate MDD and augments conventional antidepressants, especially in treatment-resistant cases. Novel targets like GPR39 and zinc transporters, along with brain-targeted formulations, offer promising therapeutic avenues. Zinc homeostasis is critically involved in MDD's heterogeneous pathology, making it a promising target for precision treatment. However, this potential is tempered by inconsistent data and methodological limitations. Future research should prioritize: standardizing assessment methods; investigating brain region-specific zinc dynamics; developing novel targeted formulations; and exploring gene-environment interactions in zinc signaling. Show less
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with systemic manifestations, including cognitive impairment linked to gut‒brain axis dysregulation. While probiotic therapies show prom Show more
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with systemic manifestations, including cognitive impairment linked to gut‒brain axis dysregulation. While probiotic therapies show promise, their mechanisms in mitigating neuropsychiatric comorbidities remain unclear. Here, we investigated the therapeutic potential of Show less
Major depressive disorder is a severe mental health condition characterized by persistent depressed mood and loss of interest. Current first-line pharmacotherapies often exhibit limited therapeutic pe Show more
Major depressive disorder is a severe mental health condition characterized by persistent depressed mood and loss of interest. Current first-line pharmacotherapies often exhibit limited therapeutic performance and adverse side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising, safe, and noninvasive alternative intervention with demonstrated neuromodulatory efficacy. Nevertheless, its mechanisms remain unclear. This study investigated whether the antidepressant properties of taVNS are associated with the microbiota-gut-brain axis, focusing on the potential crosstalk between differentially expressed hippocampal proteins and the gut microbiota. A chronic unpredictable mild stress (CUMS) rat model of depression was established, and taVNS was administered for 14 days. Hippocampal proteomic profiling was performed using data-independent acquisition. Fecal metagenomic sequencing was conducted to characterize alterations in gut microbial communities. Key signaling pathways were validated using Western blot, qRT-PCR, HE staining, and transmission electron microscopy, all of which were employed to systematically assess behavioral, proteomic, microbial, and molecular changes. Proteomics and molecular analyses revealed that taVNS upregulated hippocampal expression of glutamate ionotropic receptor N-methyl-D-aspartate type subunit 1 (GluN1) and brain-derived neurotrophic factor (BDNF), while simultaneously restoring mitogen-activated protein kinase (MAPK) signaling activity. Metagenomic profiling demonstrated that taVNS increased the abundance of TaVNS significantly alleviated depression-like behaviors in CUMS-exposed rats. The underlying mechanism may involve the restoration of synaptic function of glutamatergic neurons by regulating the GluN1/MAPK/BDNF signaling pathway. In addition, taVNS reshaped the gut microbiota, markedly increasing the abundance of Show less
Docosahexaenoic acid (DHA), one of the most critical polyunsaturated fatty acids, is vital for the neurological growth and cognitive function of infants and children. Approximately 98% of DHA in breas Show more
Docosahexaenoic acid (DHA), one of the most critical polyunsaturated fatty acids, is vital for the neurological growth and cognitive function of infants and children. Approximately 98% of DHA in breast milk exists as triglycerides, with 60% esterified at the sn-2 position. To demonstrate the necessity of mimicking the form of DHA present in breast milk in nutritional food for young children, this study administered diets with varying sn-2 DHA contents (10%, 30%, and 50%) to four groups of mice and analyzed their behavioral performance, brain DHA concentration, expression of brain fatty acid transport proteins, histopathology, and expression of synaptic-related proteins in the hippocampus after 4 weeks. The results showed that compared with the control group, mice in the 50% sn-2 DHA group exhibited superior learning and memory capabilities in behavioral tests, with the most pronounced behavioral improvements in mice, which correlated with higher brain DHA accumulation (from 0.870 ± 0.055 mg/g brain to 1.809 ± 0.132 mg/g brain, p < 0.05), increased levels of MFSD2A (1.40-fold, p > 0.05), FABP5 (2.36-fold, p < 0.05), FATP1 (1.47-fold, p < 0.05), and ACSL6 (1.48-fold, p < 0.05), improved hippocampal neuron morphology, and enhanced the level of BDNF (1.55-fold, p < 0.05), SYN (1.45-fold, p < 0.05), and PSD-95 (1.57-fold, p < 0.05). These findings establish a foundation for developing DHA nutritional supplements. Show less
Lead (Pb) accumulation in the hippocampus and the resulting oxidative stress contribute to memory impairments, highlighting the hippocampus as a primary target for Pb neurotoxicity. Selenium-containin Show more
Lead (Pb) accumulation in the hippocampus and the resulting oxidative stress contribute to memory impairments, highlighting the hippocampus as a primary target for Pb neurotoxicity. Selenium-containing peptides TSeMMM and SeMDPGQQ are able to alleviate Pb-induced oxidative neurological damage and the specific microRNAs involved in the memory protection by the two peptides need to be explored. In this study, mouse memory impairment models were constructed through the administration of 20 mg kg Show less
Lactoferrin (LF) plays a positive role in attenuating aging. In this study, LF obtained using different processing methods (freeze-dried: F and spray-dried: S) and its gastrointestinal digesta (XF and Show more
Lactoferrin (LF) plays a positive role in attenuating aging. In this study, LF obtained using different processing methods (freeze-dried: F and spray-dried: S) and its gastrointestinal digesta (XF and XS) were supplemented in d-gal-induced mice to explore their antiaging effects. The results showed that LF and its digesta (LFs) effectively ameliorated cognitive decline. Mechanistically, LFs prevented neuronal and synaptic injury by restoring redox balance, inhibiting the activation of microglia and astrocytes, and activating the cAMP-response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathway. Additionally, LFs increased the tight junction proteins and mucin-2, regulated the gut microbiota, particularly enriching bacteria in Firmicutes and restoring the Firmicutes/Bacteroidota ratio to maintain intestinal homeostasis. Meanwhile, LFs altered phospholipids (PLs) and other metabolites involved in glycerophospholipid metabolism such as arachidonic acid. Correlation analysis showed a significant association among metabolites, microbiota, and behaviors. These results indicated that LF and especially its digesta exert antiaging effects through multitarget pathways involving neuronal protection, neuroinflammation suppression, and microbiota-gut-brain axis regulation. Show less
Substance use disorder is characterized by compulsive seeking behavior that is associated with aberrant synaptic plasticity in mature neurons. Environmental enrichment (EE) has been shown to increase Show more
Substance use disorder is characterized by compulsive seeking behavior that is associated with aberrant synaptic plasticity in mature neurons. Environmental enrichment (EE) has been shown to increase adult hippocampal neurogenesis and exert beneficial effects on addictive behaviors. However, the mechanisms of EE's effects on methamphetamine (METH)-induced synaptic plasticity in mature and newborn neurons remain unclear. We reported that EE decreased METH-induced seeking behavior with a decrease in the activity of mature granule cells and an increase in the number of newborn granule cells. Furthermore, the aberrant glutamatergic transmission in hippocampal mature and newborn granule cells was differentially regulated by EE. Moreover, EE restored the normal synaptic plasticity, accompanied by enhancement of brain derived neurotrophic factor (BDNF) expression. Importantly, the intervention of BDNF reversed the effects of EE on METH-induced reinstatement behavior and glutamatergic transmission in both mature and newborn cells. Finally, specifically knocking out the newborn neurons reversed the changes of EE in abnormal plasticity of mature neurons, as well as in seeking and cognitive behaviors. Taken together, regulating synaptic plasticity of mature and newborn neurons is involved in METH-induced seeking behavior and cognitive impairments, which highlights a critical role of adult neurogenesis in the treatment of METH addiction. Show less
Depression is a debilitating psychiatric disorder with high prevalence and suicide risk, imposing significant burdens on global health. Against this global health burden, the active ingredients of Gek Show more
Depression is a debilitating psychiatric disorder with high prevalence and suicide risk, imposing significant burdens on global health. Against this global health burden, the active ingredients of Gekko gecko Linnaeus (AIGG), a traditional Chinese medicine (TCM), have shown empirical antidepressant effects. However, their specific pharmacological mechanisms remain unclear. This study systematically elucidated the antidepressant mechanisms of AIGG by integrating GC-MS-based component analysis, network pharmacology, molecular docking, and a corticosterone (CORT)-induced depressive mouse model. GC-MS identified 10 bioactive compounds (including fatty acids) in AIGG. Network pharmacology screening of 51 potential targets revealed significant enrichment in synaptic transmission and cAMP pathways. Molecular docking confirmed strong binding affinities between AIGG-derived compounds and key targets. In vivo experiments demonstrated that AIGG significantly reversed depression-like behaviors in both forced swim and tail suspension tests, suppressed Interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and elevated β-nerve growth factor (β-NGF) levels, attenuated neuroinflammatory infiltration and neuronal apoptosis in brain tissue, and upregulated protein expression of protein kinase cAMP-activated catalytic subunit alpha (PRKACA), brain-derived neurotrophic factor (BDNF), and postsynaptic density protein 95 (PSD95). The study confirmed that AIGG alleviates depression by activating the cAMP-PRKACA-BDNF axis to restore synaptic plasticity, providing a novel natural product-based strategy for treatment of the resistant depression. Show less
This study investigated the neuroprotective effects and mechanisms of cycloastragenol (CAG) on oxidative stress and neurological function in cerebral ischemia-reperfusion injury (CIRI) and oxygen-gluc Show more
This study investigated the neuroprotective effects and mechanisms of cycloastragenol (CAG) on oxidative stress and neurological function in cerebral ischemia-reperfusion injury (CIRI) and oxygen-glucose deprivation/reoxygenation (OGD/R) models. In vivo, rats were given oral CAG daily for 28 days before CIRI induction. Cerebral infarction and hippocampal injury were assessed using TTC, Nissl, and HE staining. Neurological scores, morris water maze, grip strength tests, and brain water content were used to evaluate functional outcomes. Oxidative stress was determined by biochemical assays, DHE staining, and transmission electron microscopy, while Western blotting was performed to measure neuroprotective proteins. In vitro, primary neurons were treated with CAG and subjected to OGD/R. Cell viability was tested by CCK-8 assay, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry, ROS levels were quantified, and MDA, SOD, and GSH were measured biochemically. Western blot further evaluated BDNF and NeuN expression to confirm in vivo findings. In vivo, CAG reduced infarct volume and edema, improved neurological deficits, preserved the structural integrity of neurons in the hippocampal CA1 region. CAG also promoted motor function recovery, markedly reduced MDA levels, increased SOD and GSH activity, and upregulated BDNF and NeuN expression. In vitro, CAG enhanced cell viability in the OGD/R model, reduced apoptosis, restored mitochondrial membrane potential, and significantly suppressed oxidative stress induced by ischemia-reperfusion. CAG effectively alleviated injury caused by cerebral and cellular ischemia-reperfusion by maintaining redox homeostasis, inhibiting oxidative stress, and promoting the expression of neuroprotective proteins, demonstrating promising neuroprotective potential. Show less
Kaempferol, a natural dietary flavonoid, has shown neuroprotective potential. However, its mechanisms of protection against age-related cognitive decline, especially those mediated
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-est Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen-cholinergic-NGF axis: E Show less
Depression is a major global health burden, and current treatments are limited by delayed onset and incomplete efficacy, highlighting the need for novel, mechanism-based therapies. Chronic restraint s Show more
Depression is a major global health burden, and current treatments are limited by delayed onset and incomplete efficacy, highlighting the need for novel, mechanism-based therapies. Chronic restraint stress (CRS) induces behavioral, hormonal, and synaptic changes relevant to depression, but the role of adiponectin signaling remains unclear. Here, we examined whether the adiponectin receptor agonist AdipoRon exerts antidepressant-like effects via brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling in mice subjected to 14 days of CRS. CRS produced anxiety- and depression-like behaviors, elevated plasma corticosterone, reduced circulating adiponectin, and selectively decreased hippocampal adiponectin and adiponectin receptor 2 (AdipoR2), accompanied by reduced PSD-95 and GluA1 in CA3 and the dentate gyrus (DG). AdipoRon treatment (20 mg/kg, days 8-14) prevented behavioral deficits, normalized corticosterone and adiponectin levels, and restored hippocampal AdipoR2, PSD-95, and GluA1 expression in CA3 and DG. AdipoRon also reversed CRS-induced decreases in hippocampal phosphorylated AMPK (p-AMPK), PPARα, BDNF, and phosphorylated TrkB (p-TrkB), with p-AMPK/AMPK and PPARα levels positively correlating with BDNF. Immunofluorescence confirmed BDNF recovery in CA3 and DG. Importantly, pretreatment with the TrkB antagonist ANA-12 abolished the behavioral, hormonal, and molecular effects of AdipoRon, indicating that its actions require BDNF-TrkB activation. These findings suggest that AdipoRon mitigates CRS-induced deficits via hippocampal AdipoR2-AMPK-PPARα-BDNF-TrkB signaling and highlight AdipoR2 as a promising target for depression therapy under chronic stress. Show less
Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poor Show more
Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poorly understood. We integrated genome-wide association study (GWAS) data for CKM components (cardiovascular disease [CVD], chronic kidney disease [CKD], metabolic syndrome), CKM-related cardiovascular events, and sarcopenia diagnostic criteria from European-ancestry cohorts, and conducted meta-analyses harmonizing each phenotype across at least three studies. We employed Mendelian Randomization (MR) to assess potential causal links and genetic correlation analyses (global and local) to quantify shared heritability. Multi-omics analyses included two sequential phases: Phase 1 identified and validated novel shared CKM-sarcopenia genes through integrated methylation (n = 1980) and expression (n = 31,684) analyses, followed by cross-validation using two complementary transcriptome-wide association studies (TWAS). Phase 2 prioritized druggable targets through proteomic analysis across five independent cohorts (deCODE, n = 35,559; UK Biobank Pharma Proteomics Project (UKB-PPP), n = 54,219; Fenland, n = 10,708; FinnGen Olink, n = 619; FinnGen Somascan, n = 828) and integrated colocalization. MR suggested genetically predicted associations between sarcopenia and CKM; genetically slower walking pace was associated with higher CVD risk (OR = 0.85, P = 9.56 × 10 Ambient air pollution likely promotes CKM-sarcopenia comorbidity chiefly via inflammatory signaling and epigenetic modifications. Our multi-omics integration reveals convergent pathways, candidate driver genes, and differential methylation sites that link these conditions. We propose these targets for environmental mitigation and molecular intervention, which require validation in diverse populations. Show less
Early pregnancy loss (EPL), a spontaneous death of the embryo or foetus occurring within the first trimester, is a major challenge for human reproduction with profound adverse consequences for women's Show more
Early pregnancy loss (EPL), a spontaneous death of the embryo or foetus occurring within the first trimester, is a major challenge for human reproduction with profound adverse consequences for women's health. Currently, reliable blood-based biomarkers for EPL remain limited. Therefore, there is an urgent need to discover novel biomarkers for EPL using a multi-omics-based approach to facilitate early detection and timely management. In the discovery cohort, 40 patients with EPL and 40 healthy pregnancies (HP) at 7-13 weeks of gestation were enrolled. Serum proteins and metabolites were assayed by Olink® technology and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS), respectively. Biomarkers were defined by false discovery rate (FDR) < 0.05 and fold change (FC) > 1.2. Random forest (RF) and logistic regression (LR) models incorporating selected biomarkers were employed to develop diagnostic models for EPL. In the external validation cohort, we prospectively enrolled 142 pregnancies at 7-10 gestational weeks, including 47 subjects who subsequently developed EPL and 95 pregnancies with full-term birth. Serum levels of selected biomarkers were quantified by ELISA. The combined proteomics and metabolomics screening identified 26 proteins and 21 metabolites significantly changed in the EPL group and tightly associated with EPL-related clinical phenotypes, with functional enrichment in immunoregulation and lipid oxidation processes. Moreover, integrating serum levels of angiopoietin-like 4 (ANGPTL4), programmed death-ligand 1 (PD-L1), neutrophil%, and lymphocyte% achieved an AUC of 0.944 (95% CI: 0.835-1.000) in the random forest model and 0.954 (95% CI: 0.875-1.000) in the logistic regression model to discriminate EPL from HP. Importantly, this four-biomarker model achieved an AUC of 0.857 (95% CI: 0.747-0.968) in the random survival forest model and a C-index of 0.804 (95% CI: 0.685-0.973) in the validation cohort for EPL prediction. Our integrative omics study reveals a panel of potential circulating biomarkers for EPL, which further offer mechanistic insights into EPL pathogenesis, including impaired maternal immune tolerance and dysregulated lipid metabolism pathways. Moreover, the newly identified biomarkers exhibit promising diagnostic and predictive performance for EPL, underscoring its clinical translational value for human reproduction and maternal-foetal health. This study was supported by Research Grants Council (RGC) Germany/Hong Kong Joint Research Scheme (G-CUHK415/25), 1+1+1 CUHK-CUHK(SZ)-GDST Joint Collaboration Fund (2025A0505000077), CUHK HOPE BWCH Collaborative Medical Research Fund (CF2025002), Shenzhen Medical Research Fund (C2501040), and Shenzhen Science and Technology Program (RCYX20210609104608036). Show less