👤 Chuan-Ling Wu

Transcriptomics provides mechanistic insights into chemical toxicity and serves as a hypothesis-generating tool for prioritizing potential adverse outcomes. Here, we introduced a transcriptomics-guided outcome prediction (T-GOP) framework, a hypothesis-informed approach that uses transcriptomic enrichment to prioritize end points for targeted experimental validation. As a case study, the ecotoxicological effects of the PFOS alternative, sodium Show less

Schizophrenia primarily depends on pharmacotherapy, which has demonstrated limited efficacy in enhancing cognitive impairments. High-definition transcranial direct current stimulation (HD-tDCS) and computerized cognitive remediation therapy (CCRT) hold potential for improving cognitive impairments. This study aims to investigate the effects of combining HD-tDCS with CCRT on cognition and to explore the mechanisms of this approach in schizophrenia. This is the protocol of a randomized controlled trial. Schizophrenia patients will be randomly assigned to one of 4 groups: HD-tDCS + CCRT group (Group 1), HD-tDCS group (Group 2), CCRT group (Group 3), and a control group (Group 4). The central electrode will be personalized using magnetic resonance imaging (MRI)-guided localization in the medial prefrontal cortex (mPFC). CCRT includes 6 therapeutic modules and 10 distinct tasks. Both HD-tDCS and CCRT will be administered once daily, 5 days per week, for 4 consecutive weeks, culminating in a total of 20 sessions. Assessments will occur at baseline (T0), after 10 sessions (T1), after 20 sessions (T2), and after 6 months of follow-up (T3). The primary outcome measure is the change in cognition. We will employ multimodal MRI, serum concentrations of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) to explore the underlying mechanisms. An involvement of mPFC and synaptic plasticity in response to HD-tDCS and CCRT is hypothesized. The study will provide empirical evidence for the effectiveness of combined therapy at an individual level, explore its mechanisms, and may ultimately result in personalized medicine. ChiCTR2500102731, https://www.chictr.org.cn/hvshowprojectEN.html?id=276964&v=1.0. Show less

Acetylation, a key post-translational modification, is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among HDACs, HDAC6-a class II deacetylase with predominant cytoplasmic localization-plays a unique role in cellular processes that extend beyond histone modification. It is ubiquitously expressed throughout the central and peripheral nervous systems and is integral to key physiological functions including protein quality control, autophagy, mitochondrial transport, and oxidative stress responses. Notably, under pathological conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, and peripheral nerve injury, HDAC6 undergoes nuclear translocation and contributes to epigenetic dysregulation by modulating the transcription of genes such as brain-derived neurotrophic factor, thereby impairing synaptic integrity and function. This dual role-cytoplasmic in protein homeostasis and nuclear in transcriptional regulation-highlights the HDAC6 paradox in neurological disorders. This review summarizes recent understanding of HDAC6's structure, expression, and functions within the nervous system, and discuss how targeting HDAC6 with selective inhibitors offers a promising therapeutic strategy for mitigating neurological disease pathogenesis. The goal is to provide insights that bridge HDAC6's roles in protein quality control and epigenetic regulation, fostering further exploration of HDAC6 inhibition in neurologic therapeutics. Show less

Post-stroke depression (PSD) affects 29-52% of stroke survivors, with inflammation as a key pathophysiological mechanism. Hyperbaric oxygen therapy (HBOT) may modulate neurorestoration, but clinical evidence is limited. While meta-analytic evidence suggests HBOT may benefit PSD symptoms, high-quality randomized controlled trials employing rigorous sham-control and concurrently investigating neurotrophic mechanisms remain scarce. In this randomized, double-blind, sham-controlled trial, 61 PSD patients were allocated to HBOT (n=29) or Sham-HBOT (n=32) groups, respectively. HAMD, NIHSS and MBI scores and serum Brain-Derived Neurotrophic Factor (BDNF), and beta-Nerve Growth Factor (beta-NGF), were evaluated at baseline as well as 2 and 4 weeks after HBOT intervention. The primary outcome was the change in the 17-item Hamilton Depression Rating Scale (HAMD-17) score from baseline to week 4, analyzed in the modified intention-to-treat population. The trial was registered (ChiCTR2100053522). HAMD scores decreased significantly in the HBOT group vs sham-group at weeks 2 (p=0.017) and 4 (p<0.01). Serum BDNF and beta-NGF, levels were significantly elevated in the HBOT group (all p<0.01). Reductions in HAMD scores correlated with increases in BDNF (r = 0.66, p < 0.05) and beta-NGF (r = 0.47, p =0.01). HAMD scores decreased significantly in the HBOT group compared to the sham-group, with the between-group difference reaching significance at week 2 (p=0.017) and week 4 (p<0.001). Exploratory subgroup analyses by stroke type (ischemic vs hemorrhagic) and age (dichotomized at the median of 65 years) were conducted and these analyses revealed no significant interaction between treatment group and either stroke subtype or age subgroup on the change in HAMD-17 scores (all p > 0.05), suggesting a consistent trend of HBOT effect across these subgroups within this limited sample. This preliminary trial suggests that a 4-week course of HBOT may alleviate depressive symptoms in PSD patients, an effect associated with increased serum BDNF and β-NGF levels. Given the limited sample size and short follow-up, its long-term efficacy and clinical positioning require validation in larger trials with extended follow-up. Show less

Depression is one of the most prevalent and disabling non-motor symptoms in Parkinson's disease (PD), forming a bidirectional relationship with motor dysfunction that worsens quality of life. Pharmacological treatments exhibit limited and inconsistent efficacy, and may lead to adverse interactions. Acupuncture may improve both depressive and motor symptoms by regulating the neuro-immune-endocrine network, but high-quality evidence remains insufficient. This study aims to evaluate the efficacy and safety of acupuncture as an adjunctive therapy for depression in PD and to explore potential biological correlates of clinical changes using predefined serum biomarkers. In this single-center, evaluator-blinded, randomized controlled trial, 88 patients with PD and comorbid depression will be randomly assigned to an acupuncture group or a waitlist control group. The primary outcome is the change in the Montgomery-Asberg Depression Rating Scale (MADRS) score. Secondary outcomes include motor function, anxiety, sleep quality, and overall quality of life. Exploratory analyses will assess serum inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and kynurenine/tryptophan (KYN/TRP) ratio. We hypothesize that adjunctive acupuncture may improve depressive and motor symptoms compared with the control. Exploratory analyses will examine whether clinical changes are associated with changes in relevant biomarkers. This study will provide rigorous evidence for acupuncture as an adjunctive therapy, offering a non-pharmacological strategy to optimize the comprehensive management of PD and disrupt the bidirectional emotion-motor interplay. https://www.chictr.org.cn/, identifier ChiCTR2500113443. Show less

To investigate the therapeutic mechanisms of miR-9-5p-overexpressing human umbilical cord mesenchymal stromal cells (hUC-MSCs) in neonatal rat models of hypoxic-ischemic brain damage (HIBD). Fresh neonatal umbilical cords were collected to isolate and culture human umbilical cord mesenchymal stromal cells (hUC-MSCs). Recombinant adenovirus was used to amplify miR-9-5p and transduce hUC-MSCs, generating miR-9-5p-overexpressing cells. Functional assessments included: ELISA to evaluate secretory function (e.g., neurotrophic and anti-inflammatory factors), real-time cell analysis to measure proliferation capacity, Transwell and Dunn chamber assays to assess chemotactic migration ability. Healthy 7-day-old Sprague-Dawley (SD) rats of both sexes were randomly allocated into four groups (n = 12/group, with 4 rats per group assigned to TTC staining, Western blot, or Morris water maze assay, respectively): Sham-operated control group (mock surgery), Hypoxic-ischemic brain damage (HIBD) model group, miR-9-5p-hUC-MSCs treatment group, and Adenovirus-transduced hUC-MSCs (Ad-hUC-MSCs) treatment group. The HIBD model was induced in groups 2-4. At 24 h post-modeling, 1×10 Spindle-shaped and polygonal adherent cells emerged within 3-5 days following umbilical cord tissue block inoculation, with flow cytometric analysis confirming their identity as mesenchymal stromal cells (MSCs). Compared to the Ad-hUC-MSCs treatment group, miR-9-5p enhanced the secretion of neuroreparative and anti-inflammatory factors (e.g., NGF, BDNF, IL-6) in hUC-MSCs while suppressing pro-inflammatory cytokines (e.g., IL-1, IL-2) (p < 0.05). Furthermore, miR-9-5p significantly promoted hUC-MSCs proliferation and augmented the chemotactic migratory capacity of miR-9-5p-hUC-MSCs. At 48 h post-transplantation in the miR-9-5p-hUC-MSCs group, the sham-operated controls showed no detectable cerebral infarction, whereas the model group exhibited distinct pale infarct foci occupying 33.15% ± 4.38% of total brain volume (vs. controls, p < 0.05), indicating severe cerebral injury. Both miR-9-5p-hUC-MSCs and Ad-hUC-MSCs treatments markedly reduced infarct volumes to 14.85% ± 2.79% and 19.11% ± 4.57%, respectively, with the miR-9-5p-hUC-MSCs group demonstrating a statistically superior therapeutic effect compared to Ad-hUC-MSCs (p < 0.05). Transplantation of either Ad-hUC-MSCs or miR-9-5p-hUC-MSCs significantly improved short- and long-term neurobehavioral outcomes in hypoxic-ischemic brain damage (HIBD) rats. At 48 h post-HIBD induction, upregulated expression of Beclin-2 and Caspase-3 proteins was observed in brain tissue. Notably, these elevated protein levels were attenuated following treatment with miR-9-5p-hUC-MSCs or Ad-hUC-MSCs. MiR-9-5p enhances the secretion of immunomodulatory factors and improves the migratory and proliferative capacities of hUC-MSCs. Overexpression of miR-9-5p promotes in vivo homing of hUC-MSCs, which mitigate cerebral injury and exert neuroprotective and reparative effects through dual mechanisms: modulating immune responses and providing neurotrophic support. Furthermore, hUC-MSCs significantly reduce cerebral infarct volume in hypoxic-ischemic brain damage (HIBD) rats and downregulate levels of apoptotic proteins (Beclin-2 and Caspase-3) in brain tissue, demonstrating potent cerebroprotective effects. Show less

4-Methylethcathinone (4-MEC), a synthetic cathinone with psychostimulant properties, is increasingly abused as a "designer drug". However, its molecular mechanisms, particularly those related to neuroplasticity regulation, remain poorly understood. Caveolin-1 (CAV1) is a scaffolding protein of membrane lipid rafts and has been confirmed to organize multiple synaptic signaling proteins to regulate synaptic signaling and neuroplasticity. Herein, we investigated whether CAV1 modulates 4-MEC-induced alterations in the BDNF-TrkB signal pathway and neuroplasticity markers in human SH-SY5Y neuroblastoma cells and a mouse-conditioned place preference (CPP) model. Using qRT-PCR and Western blotting, we demonstrated that 4-MEC significantly upregulated CAV1 mRNA and protein levels, as well as components of the BDNF-TrkB signaling pathway and neuroplasticity markers (GAP43, MAP2, SYP). siRNA-mediated CAV1 knockdown abolished 4-MEC-induced increases in these proteins and neuroplasticity-related mRNAs, whereas CAV1 overexpression potentiated these effects. Additionally, molecular docking predicted potential binding sites between 4-MEC and CAV1. Meanwhile, protein docking also predicted the potential binding sites between CAV1 and TrkB, and co-immunoprecipitation confirmed their physical interactions in SH-SY5Y cells. In the mice exposed to 4-MEC in the CPP paradigm, we observed similar upregulation of CAV1, BDNF-TrkB signaling pathway components, and neuroplasticity markers in the brain. These findings identify CAV1 as a potential critical mediator of 4-MEC's neuroadaptive effects through the BDNF-TrkB signal pathway to regulate neuroplasticity. It suggests a possible novel molecular target for synthetic cathinone toxicity, with potential implications for forensic research. Show less

The neurotrophic factor (NTF) family has recently expanded its role beyond neurological conditions, but its involvement in acute inflammatory lung diseases remains largely unclear. Using well-established acute lung injury (ALI) and sepsis models, we demonstrate that brain-derived neurotrophic factor (BDNF), a key NTF, is impaired in pulmonary epithelial cells and negatively correlates with the inflammatory response. Raising the BDNF level alleviates inflammatory lung injury, but these effects are absent in macrophage-deleted mice. Both in vivo and in vitro results show BDNF inhibits macrophage inflammation, and further proteomics analysis identifies macrophage TLR4 as a receptor that BDNF antagonizes via direct binding. The BDNF fragment (aa 104-115) is critical for BDNF-TLR4 interaction, and the corresponding synthetic BDNF-derived dodecapeptide (BDP-12) retains TLR4-antagonistic and anti-inflammatory effects both in vitro and in vivo, without pro-proliferative side effects. In conclusion, our findings reveal that epithelial-derived BDNF prevents macrophage inflammation by directly targeting TLR4 and highlights BDP-12 as a potential therapeutic agent for acute inflammatory diseases. Show less

This study explored the molecular mechanisms by which T7 peptide-modified liposomal irisin (T7@Lipo@Irisin) alleviates perioperative neurocognitive disorders (PND) via regulation of the AMPK/PGC-1α metabolic pathway. T7@Lipo@Irisin nanoparticles were prepared by thin-film hydration and ultrasonic dispersion and showed favorable physicochemical performance, with an encapsulation efficiency of approximately 85%. Serum analysis of healthy donors (n = 10) and PND patients (n = 6) showed higher IL-6 and TNF-α and lower brain-derived neurotrophic factor (BDNF) in PND. In vitro, T7@Lipo@Irisin restored mitochondrial membrane potential, reduced reactive oxygen species (ROS) accumulation, enhanced Neuro-2a hippocampal neuron viability, and activated the AMPK/PGC-1α axis under oxidative stress. In a PND mouse model, it improved Garcia neurological scores, preserved neuronal morphology, and decreased apoptosis. Multi-omic integration of scATAC-seq/scRNA-seq and TMT-based proteomics demonstrated enhanced neuro-glial crosstalk, epigenetic activation of metabolic/antioxidant genes (e.g., Sirt1, Nfe2l2), and upregulated pathways (mitochondrial function, NAD-dependent metabolism, synaptic homeostasis). Proteomics confirmed upregulation of SIRT1, NDUFS2, and BDNF, forming a network linked to energy metabolism and neural repair. Collectively, T7@Lipo@Irisin mitigates PND by activating AMPK/PGC-1α to enhance mitochondrial function and stabilize the neuro-microenvironment. Show less

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, in which mitochondrial dysfunction plays a critical role. The mitochondrial calcium uniporter (MCU) is a key regulator of mitochondrial calcium (mCa Show less

Tianwang Buxin Dan (TWBXD) is a classical Chinese formula traditionally prescribed to "nourish Yin, calm the mind and relieve bowel stagnation" in disorders characterized by heart-kidney disharmony, insomnia, anxiety, and constipation. However, the mechanistic basis associating its gut-regulating and emotion-modulating effects along the gut-brain axis remains unclear. To investigate whether TWBXD ameliorates functional constipation comorbid with emotional disturbances by modulating mitogen-activated protein kinase/Extracellular Signal-Regulated Kinase/c-Jun N-terminal Kinase (MAPK/ERK/JNK) signaling, hypothalamic-pituitary-adrenal (HPA)-axis activity, and autophagy-related mitochondrial integrity in the colon and hippocampus. A diphenoxylate-induced rat model of functional constipation with anxiety/depression-like behavior was treated with low, medium, or high doses of TWBXD. Intestinal transit, fecal parameters, and distal colonic transit were also assessed. Emotional behaviors were evaluated using open-field and elevated plus-maze tests. Colonic and hippocampal histopathology and ultrastructure were examined using hematoxylin and eosin staining, Nissl staining, and transmission electron microscopy. Serum corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and corticosterone (CORT) levels were measured using enzyme-linked immunosorbent assay. MAPK/ERK/JNK-related proteins and brain-derived neurotrophic factor (BDNF) were analyzed by Western blotting. The major chemical constituents of TWBXD were characterized using ultra-high-performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS). TWBXD dose-dependently improved intestinal transit, fecal moisture, and body weight gain, and alleviated anxiety-/depression-like behaviors. TWBXD preserved colonic mucosal architecture and hippocampal neuronal integrity, mitigated mitochondrial swelling and excessive autophagic vacuole formation, downregulated colonic phosphorylated ERK (p-ERK), phosphorylated JNK, and phosphorylated p38, restored hippocampal BDNF expression while normalizing p-ERK levels, and reduced serum CRF, ACTH, and CORT levels. TWBXD exerts multi-target therapeutic effects on functional constipation with emotional disturbances by suppressing MAPK/ERK/JNK overactivation, normalizing HPA-axis hyperactivity, and protecting mitochondrial structure and autophagy along the gut-brain axis, providing mechanistic support for its traditional use in gut-brain-related disorders. Show less

Aurantii Fructus (AF)is a traditional Chinese medicine historically used to regulate Qi and alleviate emotional distress, suggesting potential psychotropic effects. This study investigates its therapeutic value for depression based on this traditional indication. To evaluate the rapid antidepressant-like effect of a single acute dose of AF extract in a chronic unpredictable mild stress (CUMS) mouse model and elucidate its underlying molecular mechanisms through integrated transcriptomic and metabolomic analyses. AF flavonoid content was quantified by HPLC. Male mice underwent a 4-week CUMS protocol. A single oral dose of AF was administered 2 h prior to behavioral testing (NSF, TST, SPT, and OFT), with ketamine serving as a positive control. Hippocampal transcriptome analysis was performed by RNA sequencing, and serum metabolites were profiled via LC-MS in both positive and negative ion modes. Pearson correlation analysis assessed relationships between key targets and behavioral outcomes. Pathway involvement was functionally validated in a separate experiment using a hypoxanthine synthesis inhibitor. AF contained narirutin (1.32 mg/g), hesperidin (3.19 mg/g), neohesperidin (22.89 mg/g), naringenin (0.03 mg/g), and nobiletin (0.08 mg/g). Acute AF administration rapidly reversed CUMS-induced depressive-like behaviors, significantly decreasing latency to feed and increasing food consumption in the NSF test, reducing immobility time in the TST, and elevating sucrose preference in the SPT, without altering locomotor activity. Transcriptomic analysis revealed specific downregulation of hippocampal caspase-4 expression by AF. Metabolomic profiling showed AF normalized elevated serum hypoxanthine levels. Serum hypoxanthine levels negatively correlated with hippocampal caspase-4 expression and behavioral improvements, whereas caspase-4 expression positively correlated with behavioral deficits. Pharmacological inhibition of hypoxanthine synthesis abolished AF's antidepressant effects and prevented its normalization of hippocampal caspase-4, NF-κB, GDNF, and BDNF expression. Acute AF produces rapid, ketamine-like antidepressant effects by targeting the hypoxanthine-caspase-4 pathway. This study reveals a novel purinergic mechanism underlying AF's traditional use for emotional disorders and offers a promising therapeutic strategy for rapid-acting antidepressant development. Show less

Depression, a complex global disorder with unmet therapeutic needs, imposes profound societal burdens. Yueju Pill (YJP), a classic TCM formula targeting 'six stagnations', synergistically integrates five herbs (Atractylodes, Cyperus, Ligusticum, Gardenia and Massa Medicata) to restore Qi-blood homeostasis. Contemporary evidence delineates its multitarget antidepressant efficacy: normalising monoaminergic neurotransmission and the tryptophan-kynurenine pathway, potentiating neurotrophic support (BDNF/eEF2) for neuroplasticity, antagonising neuroinflammation via microglial M1-to-M2 polarisation and NF-κB/MAPK inhibition, mitigating oxidative stress and mitochondrial dysfunction and enhancing synaptic plasticity through glial/neuronal gene regulation (e.g., GADD45g/PHGDH). This synthesis of TCM principles with mechanistic evidence positions YJP as a holistic, systems-level therapeutic candidate, advocating for rigorous clinical validation and integration into precision psychiatry. Show less

This study evaluated the efficacy of combining personalized acupuncture with accelerated deep transcranial magnetic stimulation (adTMS) for mild cognitive impairment (MCI). In this randomized, double-blind, controlled trial, 120 MCI patients were assigned to a Combined group (personalized acupuncture + active adTMS), a Single Stimulation group (active adTMS + sham acupuncture), or a Placebo group (sham TMS + sham acupuncture). The primary outcome was the change in Montreal Cognitive Assessment (MoCA) score at 12 weeks. Secondary outcomes included P300 latency, magnetic resonance spectroscopy (MRS) NAA/Cr ratio, serum brain-derived neurotrophic factor (BDNF), C-reactive protein (CRP), interleukin-6 (IL-6), and the Modified Barthel Index (MBI). The Combined group showed a significantly greater improvement in MoCA scores (3.2 ± 1.3 points) compared to the Single Stimulation (1.9 ± 1.2 points; mean difference 1.3, 95 % CI 0.4 to 2.2) and Placebo groups (1.1 ± 1.0 points; mean difference 2.1, 95 % CI 1.2 to 3.0). The Combined group also demonstrated greater reductions in P300 latency and increases in NAA/Cr ratio and serum BDNF levels than the other groups. The combination of personalized acupuncture and adTMS significantly improves cognitive function in MCI patients, supported by positive changes in electrophysiological and metabolic markers. This integrative approach represents a promising non-pharmacological strategy for MCI.Trial registration: International Traditional Medicine Clinical Trials Registry (ITMCTR2025000652). Show less

Alzheimer's disease is a common neurodegenerative disease characterized by progressive memory loss, cognitive decline, and behavioral changes. Blood-based biomarkers have recently gained significant attention due to their accessibility and cost-effectiveness. This review highlights the latest progress in multiple key areas of bloodbased biomarkers for Alzheimer's disease. For early diagnosis, blood-based biomarkers such as amyloid-β and phosphorylated tau can identify Alzheimer's disease even before clinical symptoms emerge. Dynamic changes in blood-based biomarkers, including p-tau217 and neurofilament light chain, reflect disease progression and correlate with cognitive decline, enabling continuous monitoring of Alzheimer's disease progression. Additionally, bloodbased biomarkers such as p-tau181 and glial fibrillary acidic protein aid in differential diagnosis by distinguishing Alzheimer's disease from other dementias such as frontotemporal dementia. Blood-based biomarkers related to nerve repair have opened up new avenues for tracking nerve regeneration and therapeutic response, especially brain-derived neurotrophic factor. Furthermore, advanced detection technologies such as single-molecule array and immunoprecipitation-mass spectrometry have significantly improved the sensitivity and specificity of bloodbased biomarkers, facilitating their clinical translation. In summary, blood-based biomarkers hold strong potential to improve early diagnosis, monitor progression, differential diagnosis, and evaluate therapies in Alzheimer's disease. This review provides a comprehensive and updated evaluation of the translational potential of bloodbased biomarkers, emphasizing their practical utility in clinical settings and offering insights into future directions for large-scale application. This review emphasizes the need to prioritize the allocation of scientific resources, expedite the transition of blood-based biomarkers to clinical implementation, and ultimately achieve precise treatment of Alzheimer's disease using these biomarkers. Show less

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration and increasingly associated with gut microbiota alterations. Roseburia intestinalis (R. intestinalis) is consistently reduced in PD; however, its functional contribution remains unknown. We performed two complementary mouse experiments using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model. In the primary intervention experiment, mice received live or heat-killed R. intestinalis, followed by behavioral assessments and multi-layer analyses, including immunofluorescence, western blotting, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, 16S rRNA sequencing, metabolomics, and transcriptomics. In a separate mechanistic experiment, subdiaphragmatic vagotomy was introduced to interrogate vagus-dependent gut-brain communication, with key behavioral and inflammatory endpoints assessed. Live R. intestinalis improved rotarod, pole, and grip strength performance and preserved tyrosine hydroxylase-positive neurons in the substantia nigra; however, these effects were not observed in the heat-killed group. Live R. intestinalis treatment also reduced glial reactivity, restored brain-derived neurotrophic factor expression, and maintained blood-brain barrier integrity. Systemically, R. intestinalis lowered serum lipopolysaccharide, tumor necrosis factor-α, and interleukin-6 levels; preserved colonic structure; and restored mucin-secreting goblet cell function. MPTP-induced dysbiosis was partially corrected. Metabolomic profiling revealed restoration of several acyl-carnitines and higher acetic acid levels. Transcriptomic analysis showed increased immediate early genes after MPTP, and the elevated c-Fos in the substantia nigra was partially normalized by R. intestinalis. Importantly, vagotomy abolished the central neuroprotective and anti-inflammatory effects but did not affect peripheral cytokine suppression, indicating both vagus-dependent and vagus-independent pathways. R. intestinalis supplementation alleviated motor impairments, reduced neuroinflammation, preserved dopaminergic neurons, and improved intestinal and metabolic alterations in mice with an MPTP-induced PD model. Its protective actions may involve both central and peripheral mechanisms, potentially including gut-brain communication pathways. R. intestinalis may be a promising candidate for microbiota-based strategies against PD. Show less

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive loss of cognitive function. Its main pathological features include accumulation of Amyloid-beta (Aβ) plaques, excessive phosphorylation of microtubule-associated protein tau (tau protein), and neuroinflammation. In recent years, studies have confirmed intestinal flora is closely connected to AD. Gut-brain axis has an important part in AD. Intestinal flora can achieve signal communication between gut and brain through metabolic, immune, neural, and endocrine pathways, thereby slowing down AD. It has been discovered that exercise is not only beneficial to physical health but also has a positive impact on the brain function. In recent years, more and more studies have found exercise can alleviate AD through the following four major pathways: regulating the diversity of intestinal flora, strengthening the blood-brain barrier (BBB), regulating immune homeostasis, and upregulating the brain-derived neurotrophic factor (BDNF). In this review, we have summarized intestinal flora in AD and systematically expounded potential regulatory pathways of exercise in modulating intestinal flora for AD. This provides a more theoretical basis for subsequent research targeting "gut-brain axis" to regulate AD. At the same time, this review also summarizes differences in different exercise types on improving intestinal flora for alleviating AD, providing new ideas and strategies for AD. Show less

Major depressive disorder (MDD) is a leading cause of global morbidity and mortality. Although pharmacological treatments are widely used, their effects are often limited, and nearly half of patients show resistance to current antidepressants, including those unresponsive to all available therapies. These challenges highlight the need to better understand the neurobiological mechanisms driving MDD and to develop novel therapeutic strategies, especially those involving natural compounds with multitarget actions. Baicalin, a bioactive flavonoid from Show less

Post-stroke neurogenic bladder dysfunction impairs patients' quality of life, yet current treatments offer limited effectiveness. This study investigated the therapeutic effects and underlying mechanisms of human amniotic fluid stem cell-derived extracellular vesicle (hAFSC-EV) on bladder dysfunction and neurovascular plasticity after cerebral ischemia. Thirty-six female rats underwent bilateral ovariectomy and were assigned to sham-operated or 90-min middle cerebral artery occlusion (MCAO) groups, with or without a single injection of hAFSC-EVs. Magnetic resonance imaging (MRI), cystometry, blood-brain barrier (BBB) permeability, and markers of neurogenesis and angiogenesis in ischemic brain were assessed. Bladder levels of brain-derived neurotrophic factor (BDNF), β3-adrenoceptor, adenylate cyclase, and M2- and M3-muscarinic receptors were evaluated at 7 and 28 days post-MCAO or sham-operation. Compared with untreated rats, hAFSC-EV treatment significantly reduced cerebral infarct volume and BBB leakage, and enhanced microvessel and vascular density, along with angiogenesis. Neural markers such as BDNF, nestin, and doublecortin were significantly upregulated at 7 and/or 28 days post-MCAO. hAFSC-EV treatment ameliorated MCAO-induced bladder dysfunction by reducing peak voided volume, intercontraction interval, and bladder capacity, along with improving residual urine volume. hAFSC-EV treatment significantly increased bladder expression of BDNF and M3-muscarinic receptors, and recovers the expressions of M2, β3-adrenoceptor, and adenylate cyclase to near control levels at 7 and 28 days post-MCAO. hAFSC-EV treatment improves neurogenic bladder dysfunction and cerebral ischemia post-MCAO, potentially through reducing infarct volume and BBB disruption, enhancing neurogenesis and angiogenesis in the ischemic brain, and modulating the expression of bladder BDNF, β3-adrenoceptor, adenylate cyclase and muscarinic receptors. Show less

Limited data support the beneficial effects of fecal microbiota transplantation (FMT) against intracranial ischemic injury under chronic cerebral hypoperfusion (CCH). However, a comprehensive understanding is lacking, hindering its clinical translation. In the present study, we evaluated microbial, metabolic, cellular, and behavioral alterations to explore the roles and mechanisms of FMT in hippocampal neurogenesis under CCH. Rats underwent bilateral common carotid artery occlusion to induce CCH. Intestinal microbiota (IM) and fecal/hippocampal metabolites were assessed by 16S ribosomal RNA sequencing and untargeted liquid chromatography-mass spectrometry, respectively. Potential molecular pathways and differentially expressed genes in the hippocampus were identified by RNA sequencing and verified by western blot, immunofluorescence, and dual-luciferase reporter assays. Neurogenesis was quantified by BrdU/DCX, BrdU/nestin, BrdU/GFAP, and BrdU/NeuN labeling. Cognitive function was evaluated with the Morris water maze. FMT altered IM composition by enriching Verrucomicrobiae, Ruminococcaceae, Akkermansiaceae, Turicibacter, Akkermansia, Verrucomicrobiales, Oscillospirales, Verrucomicrobiota, and Akkermansia_muciniphila. These shifts were associated with significantly elevated metabolites in tryptophan- and arginine-related pathways, including fecal L-tryptophan and hippocampal L-arginine, L-glutamine, indolepyruvate, indoleacetaldehyde, and kynurenic acid. Furthermore, FMT potentiated the Wnt3a/β-catenin/Neurog2/BDNF pathway, promoting hippocampal neurogenesis. FMT-induced activation of Wnt3a/β-catenin/Neurog2 signaling also up-regulated hippocampal C3 expression, contributing to neurogenesis and cognitive recovery under CCH. These findings provide evidence that FMT exerts protective effects against CCH insult through Wnt3a-mediated neurogenesis. 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 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

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 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

Insomnia and anxiety are highly comorbid, severely compromising quality of life. Efficacy of current pharmacological interventions for this dual condition remains limited. Zhi-Gan Formula (ZG), consisting of Zhi-Zi-Chi Decoction and Ganmai Dazao Decoction, two classic Traditional Chinese Medicine (TCM) formulae clinically widely used for insomnia or anxiety, holds promise as a therapeutic option for insomnia-anxiety comorbidity. This study aimed to assess ZG's sleep-promoting and anxiolytic efficacy, and investigate the novel mechanism through which pituitary adenylate cyclase-activating polypeptide (PACAP) in the medial prefrontal cortex (mPFC) modulates comorbid sleep and anxiety conditions. Mice received 4-chloro-DL-phenylalanine (PCPA) injections and were subsequently administered ZG or diazepam. Behaviors were assessed using the pentobarbital-induced sleep test, open-field test (OFT), and elevated plus-maze test (EPM). Key pathways were identified via network pharmacology analysis and validated using long-term potentiation (LTP) recordings and protein quantification. Viral-mediated PACAP knockdown vectors were transfected into the mPFC. PCPA administration induced insomnia and anxiety-like behaviors. ZG administered for 3 days significantly shortened sleep latency, prolonged sleep duration, and alleviated anxiety-like behaviors, whereas diazepam only partially improved anxiety-like behaviors. Network pharmacology analysis suggested ZG's engagement in neuropeptide-receptor interactions and synaptic transmission pathways. Assessments of synaptic plasticity showed that ZG improved mPFC LTP and the expression of synaptic proteins (PSD95, synapsin-1, BDNF) impaired in the model mice. Moreover, the expression of the neuropeptide PACAP and downstream eEF2 signaling for synaptic protein synthesis were all improved by ZG. Crucially, perfusion of a PACAP agonist in the mPFC brain slices from sleep-deprived mice rescued LTP deficits. Finally, mPFC PACAP knockdown abolished the therapeutic effects and the enhanced expressions of the synaptic proteins by ZG. ZG alleviated insomnia-anxiety comorbidity by restoring synaptic plasticity in the mPFC via the PACAP-eEF2-BDNF pathway, which may also shed light on the development of a novel therapeutic approach for the treatment of sleep-anxiety comorbidity. 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. 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

Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of 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 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

This study was designed to explore the effects of esketamine on cognitive deficits and blood-brain barrier (BBB) dysfunction in sepsis-associated encephalopathy (SAE). An in vivo SAE model was generated through the administration of lipopolysaccharide (LPS), and LPS-induced cognitive impairment in rats was evaluated using the Morris water maze (MWM) test. BBB disruption in vivo was assessed by measuring brain water content together with Evans blue dye penetration, while LPS-induced endothelial hyperpermeability in vitro was examined through FITC-dextran leakage. The protein expression of claudin-3 and ZO-1 was determined by western blotting. In addition, the levels of pro-inflammatory cytokines, cell apoptosis, autophagy, and the activity of the BDNF/TrkB pathway were examined. Rapamycin (Rap, an autophagy inducer) and K252a (a BDNF inhibitor) were used to determine whether the protective effects of esketamine were associated with autophagy and BDNF/TrkB signaling. Esketamine treatment significantly improved the LPS-induced cognitive dysfunction and neurological injury observed in vivo, and it also inhibited the production of pro-inflammatory cytokines and reduced cell apoptosis both in vivo and in LPS-treated hCMEC/D3 cells. Importantly, esketamine alleviated BBB hyperpermeability in vivo and prevented LPS-induced endothelial leakage in vitro. Moreover, esketamine suppressed LPS-induced autophagy, and the influence of esketamine on claudin-3 and ZO-1 expression was reversed when Rap was applied. Esketamine activated the BDNF/TrkB pathway, and the protective effects of esketamine on BBB integrity and autophagy in response to LPS were abolished by K252a. Taken together, these findings indicate that esketamine protects the BBB against SAE by activating the BDNF/TrkB pathway and inhibiting autophagy, providing a potential therapeutic strategy for SAE. Show less