👤 Jindian Shi

The development of glucagon-like peptide 1 (GLP1) receptor agonists, including semaglutide and tirzepatide, has transformed the clinical management of overweight and obesity. However, substantial inter-person variability exists in both weight loss efficacy and the incidence of side effects Show less

The global prevalence and incidence of metabolic dysfunction-associated fatty liver disease (MAFLD), including its progressive form metabolic dysfunction-associated steatohepatitis (MASH), are steadily rising, making them the most common chronic liver diseases worldwide. However, therapeutic options for MAFLD are currently limited. Glucolipid dysregulation drives MAFLD pathogenesis through intertwined glucose metabolic imbalance and lipid accumulation. Patients with type 2 diabetes mellitus (T2DM) are particularly prone to developing MASH and are at a higher risk of progressing to cirrhosis and hepatocellular carcinoma. The coexistence of MAFLD and T2DM correlates with clinical prognosis and elevates the risk of extrahepatic complications. Given the close association between MAFLD and T2DM, glucagon-like peptide-1 receptor agonists (GLP-1RAs), which have been approved for the treatment of T2DM and obesity, were the first to be investigated in patients with MAFLD/MASH. Recently, beyond GLP-1RAs, novel combination agents integrating glucose-dependent insulinotropic peptide receptor (GIPR) and/or glucagon receptor (GCR) agonists have also been explored. A large number of phase II randomized clinical trials have demonstrated significant improvements in body weight, insulin resistance, and liver parameters. Thus, GLP-1RAs and dual/triple agonists are promising for MAFLD/MASH, especially in those with obesity or T2DM. This study explores mechanisms and clinical evidence of incretin-based therapies for MAFLD by targeting its core pathogenesis-glucolipid disorders. With growing evidence, it also forecasts the broad clinical prospects on MAFLD treatment. Show less

Dietary diversity plays a crucial role in maintaining physical function. This study explored the association and potential mechanisms between dietary diversity and gait characteristics measured by wearable devices in older adults. This cross-sectional study included 861 older adults aged 60 years or above. Dietary diversity score (DDS) was assessed using a standard food frequency questionnaire. A multi-sensor gait system was used to measure periodic, kinetic, and spatiotemporal gait parameters during a 12-meter walking test. The coefficient of variation (CV) was calculated for each parameter to assess gait stability. Multivariable linear regression models were conducted to examine the relationship between DDS and gait parameters, adjusting for demographics, lifestyle factors, cognitive function, and comorbidities. Participants had a mean age of 70.25 ± 6.19 years, with 58.30% being female. After adjusting for all covariates, each 1-SD increase in DDS was positively associated with Z-scores of landing control force (β = 0.072, SE = 0.033, P = 0.033), foot-off angle (β = 0.076, SE = 0.033, P = 0.021), gait speed (β = 0.086, SE = 0.033, P = 0.008), step length (β = 0.068, SE = 0.031, P = 0.032), and stride length (β = 0.078, SE = 0.033, P = 0.013). Furthermore, higher DDS was negatively associated with the CVs of initial limb support time, step time, stride time, ground reaction force, landing control force, foot-off angle, gait speed, and step length (all P < 0.05). We also identified biomarkers simultaneously related to both DDS and gait characteristics, including albumin, leptin, myostatin, brain-derived neurotrophic factor, insulin-like growth factor-1, high-sensitivity C-reactive protein, interleukin-6, and glutathione reductase. Higher DDS is associated with superior kinetic and spatiotemporal gait vigor performance and enhanced gait stability. Pathways involving nutritional status, energy metabolism, inflammatory regulation, antioxidant defense, and neural function may underpin this association. Show less

Depression has emerged as a concerning factor in colon cancer progression and treatment, yet its underlying mechanisms and therapeutic targets remain poorly defined. This study aimed to elucidate how depression affects colon cancer progression and chemotherapeutic response, and to explore potential molecular targets and therapeutic interventions involving the traditional Chinese medicine formula Sinisan (SNS) and its bioactive component Quercetin. A mouse model combining depression and colon cancer was established to evaluate behavioral alterations, tumor progression, and pathological features. RNA sequencing was performed to screen the differentially expressed genes. The effects of corticosterone (CORT) on proliferation, colony formation, migration, and GSTM2 expression were examined in HCT116 cells, followed by functional validation through GSTM2 overexpression and inhibition assays. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) were used to validate the binding of Quercetin to GSTM2. The therapeutic efficacy of SNS and Quercetin was assessed with respect to depressive symptoms, serum BDNF levels, NLRP3 inflammasome activity, and the potency of 5-fluorouracil (5-FU) chemotherapy. Mice with depression and colon cancer exhibited aggravated depressive behaviors and accelerated tumor progression. RNA-sequencing and network pharmacology analyses identified GSTM2 as a promising candidate target in colon cancer treatment, which was markedly down-regulated in the DP-CC group. CORT enhanced proliferation, colony formation, and migration of HCT116 cells while simultaneously suppressing GSTM2 expression. Conversely, GSTM2 levels negatively correlated with cell proliferation, colony formation, and chemoresistance in HCT116 cells. Treatment with SNS alleviated depressive symptoms, elevated serum BDNF, reduced NLRP3 inflammasome activity, and potentiated the efficacy of 5-FU chemotherapy. Quercetin, a bioactive component of SNS, bound to GSTM2 through hydrogen-bond and van-der-Waals interactions, up-regulated GSTM2 expression, and mitigated CORT-induced proliferation, colony formation, and chemoresistance. Our findings suggest that depression promotes colon-cancer progression by down-regulating GSTM2, whereas SNS restores GSTM2 expression and enhances chemotherapeutic response. Show less

Microglia-neuron contacts have been shown to regulate neural network activity through the formation and elimination of synapses. The pathogenesis of major depressive disorder is accompanied by a decline in brain-derived neurotrophic factor (BDNF) signaling, associated with increased microglia activity that disrupts cognitive function. The actions of both typical and rapid-acting antidepressant drugs, which have been shown to increase BDNF signaling through the tropomyosin receptor kinase B (TrkB) receptor, decrease microglia activation and the levels of pro-inflammatory cytokines. Examining the link between BDNF signaling and the microglial pro-inflammatory response, we demonstrate that TrkB signaling elicits the neuronal secretion of CD22 (Siglec-2), a sialic acid-binding immunoglobulin-type lectin, to inhibit microglial activation and alleviate depression-like symptoms. In a male chronic mild stress (CMS) mouse model of depression decreased expression of the postsynaptic scaffolding protein PSD-95 and Gαi1/3 were found to compromise TrkB signaling leading to reduced CD22 levels in hippocampal tissue. Restoration of TrkB-Gαi1/3-Akt signaling with dSyn3, a peptidomimetic compound targeting the PDZ3 domain of PSD-95, enhanced CD22 expression to inhibit microglial activation, promote dendritic spine formation and rapidly mitigate depression-like symptoms. Furthermore, hippocampal overexpression of CD22 in neurons was sufficient to reduce microglial activation and depressive-like behaviors in male CMS mice. S-ketamine, a rapid-acting antidepressant, increased CD22 expression to mitigate depression-like symptoms. While neuronal knockdown of CD22 in the hippocampus did not significantly impair the rapid (within 4 h) antidepressant effects typically observed with S-ketamine or dSyn3 administration, strikingly, knockdown of CD22 attenuated the long-acting (within 3 days) antidepressant effects of S-ketamine or dSyn3, as evidenced by sustained immobility in the TST (tail suspension test) and FST (forced swim test), and a lack of improvement in sucrose preference. In contrast, a single dose of fluoxetine failed to increase CD22 expression or inhibit microglia activity. These results suggest that rapidly-acting anti-depressant drugs enhance TrkB-induced neuronal expression and secretion of CD22 to promote the homeostatic state of microglia required for antidepressant actions. In male depression mice, dSyn3 facilitates BDNF-induced TrkB-PSD-95-Gαi1/3 complex formation to increase Akt-mTOR activation as well as synaptic and spine density in the hippocampus. TrkB signaling increases CD22 expression and secretion from neurons blocking microglial activation in the hippocampal region of male CMS mice. Show less

Early-life stress (ELS) is a key risk factor for adolescent depression. Si-Ni-San (SNS), a classic traditional Chinese medicine formula, has shown antidepressant potential, yet its effects on the dorsal raphe nucleus (DRN)-nucleus accumbens (NAc) serotonergic circuit remain unclear. This study aimed to investigate whether SNS alleviates adolescent depression by restoring DRN-NAc serotonergic circuit function and to identify the serotonin receptor mediating its synaptic effects in the NAc. Firstly, the antidepressant efficacy of SNS was evaluated in a mouse model of ELS. Subsequently, its underlying mechanism was explored through integrated neurophysiological, molecular, and pharmacological analyses. Depressive- and anxiety-like behaviors were assessed using behavioral tests (sucrose preference, tail suspension, forced swim, open field, and elevated plus maze). In vivo electrophysiolog was employed to monitor DRN neuronal activity. Chemogenetic manipulation was employed to regulate the DRN-NAc serotonergic circuit, while 5-HT4R function was assessed through pharmacological intervention and viral knockdown. Synaptic and molecular mechanisms were examined using Western blotting, qPCR, ELISA, and immunofluorescence. SNS alleviated depressive-like behaviors, enhanced neural activity and low-frequency oscillations in the DRN, and restored 5-hydroxytryptamine (5-HT) levels in the NAc. Mechanistically, SNS upregulated tryptophan hydroxylase 2 (TPH2) while downregulating indoleamine 2,3-dioxygenase 1 (IDO1), thus promoting 5-HT synthesis. Critically, the antidepressant effects of SNS were blocked by either chemogenetic inhibition of the DRN-NAc serotonergic circuit or pharmacological blockade of 5-HT4R in the NAc. Meanwhile, the knockdown of 5-HT4R abolished the ameliorative effects of SNS on depressive-like behaviors and associated synaptic remodeling, including the upregulation of brain-derived neurotrophic factor, postsynaptic density protein 95, and mushroom spine density. These results demonstrate that SNS alleviates depressive-like behaviors in adolescent male mice by restoring DRN-NAc serotonergic circuit function, enhancing 5-HT bioavailability, and promoting 5-HT4R-dependent synaptic plasticity in the NAc, revealing a circuit- and receptor-specific therapeutic mechanism. Show less

Cellular and synaptic plasticity in ventral tegmental area (VTA) play a key role in alcohol use disorder (AUD). Here, we first delineated the in vivo dynamics of dopamine (DA) neuron activity in VTA during chronic intermittent ethanol exposure: initial sensitization was followed by a phase of attenuated and dysregulated response upon the first high-concentration exposure, culminating in stable hyper-responsiveness. Chronic ethanol exposure impaired long-term potentiation of GABAergic synapses (LTP Show less

This narrative review systematically synthesizes recent clinical and pre-clinical evidence to elucidate the latest neurobiological mechanisms underlying acupuncture for post-stroke insomnia combined with cognitive impairment (PS-ICI). PS-ICI is characterized pathologically by a hippocampal-prefrontal circuitry-mediate "sleep-cognition vicious cycle" and clinically by concurrent cognitive decline and sleep-architecture disruption, both of which markedly impede post-stroke neurological recovery. Grounded in the Traditional Chinese Medicine (TCM) principle of "regulating Shen and re-animating the brain, "acupuncture exerts bidirectional modulation on cognition and sleep, significantly improving core functional outcomes and activities of daily living. Up-to-date studies confirm that synergistic, multi-dimensional effects are achieved through regulation of the BDNF-TrkB-PI3K/Akt signaling axis, preservation of neurovascular unit integrity, restoration of gut-brain axis homeostasis, normalization of circadian immune rhythms, and reshaping of default-mode network (DMN) plasticity. Given the high heterogeneity of included studies, a qualitative integrative approach was employed. Current evidence is nevertheless limited by small sample sizes, short follow-up durations, and substantial heterogeneity in acupuncture parameters (frequency and point selection); future work must therefore focus on dissecting inter-pathway interactions, standardizing therapeutic protocols, and integrating multi-omic technologies to propel acupuncture toward precision, evidence-based management of PS-ICI. Show less

Chronic toxoplasmosis has been increasingly associated with behavior disorders, including depression-like behaviors, while the underlying mechanisms remain poorly understood. In this study, we demonstrated that chronic toxoplasmosis induced depression-like behaviors in mice, which were observed together with neuroinflammation, neuronal injury, and suppression of the BDNF-TrkB pathway. Treatment with the TrkB agonist 7,8-DHF alleviated these behavioral deficits by restoring BDNF-TrkB signaling, preserving neuronal function, and reducing neuroinflammation through inhibition of NF-κB and MAPK pathways. Additionally, 7,8-DHF also reduced astrocyte overactivation and protected blood-brain barrier structure integrity. These findings highlight that disruption of BDNF-TrkB signaling contributes to T. gondii-induced behavioral abnormalities and that targeting this pathway may represent a promising therapeutic strategy against neuroinflammation and neuronal damage associated with chronic infection. Show less

Acute spinal cord injury (SCI) results in irreversible neurological deficits. We hypothesized that local transplantation of bone marrow mesenchymal stem cells (BMSCs) combined with erythropoietin (EPO) would inhibit glial scarring and accelerate functional recovery. To quantify the therapeutic efficacy and underlying mechanisms of BMSCs+EPO versus BMSCs alone in a rat model of acute SCI. Forty SD rats (T10 Allen 60 g·cm impact) were randomized to sham, SCI, SCI+BMSCs, or SCI+BMSCs+EPO ( At 4 weeks, BBB scores in the BMSCs+EPO group reached 12.7 ± 1.5, representing a 54% increase over the BMSCs-alone group (8.3 ± 0.7, BMSCs+EPO exerts synergistic neuroprotective effects, achieving superior locomotor recovery compared with BMSCs monotherapy, and represents a promising adjuvant strategy for acute SCI. Show less

Evidence proved that electroacupuncture (EA) combined with antidepressants can improve the antidepressant effectiveness for depressed patients. However, the clinical mechanisms of EA remain unclear. This study aimed to observe the mechanism of EA as an adjunct therapy to escitalopram oxalate (EO) on depressed patients. This study was designed as a single-blinded, double-dummy randomized controlled trial. 61 participants were diagnosed with mild-to-moderate depression according to the International Classification of Diseases 10th Edition (ICD-10, F32) were randomly allocated to receive EA + EO placebo, EO + sham EA, or EA + EO for six weeks treatment. The clinical assessment including depression severity, quality of life (QOL) and clinical safety. Biological indicators of immune-inflammation, the brain-derived neurotrophic factor and glucocorticoid inducible genes in peripheral blood of participants were measured by using enzyme linked immunosorbent assay and real-time polymerase chain reaction respectively before and after treatment. Three interventions improved the depression severity and QOL (P < 0.05), and no inter-group difference was found in the 6th week (P > 0.05). Anxiety psychic and somatic general symptoms in the EA + EO group were improved significantly than those of the other two groups (P < 0.05). After six-week treatment of EA + EO, blood SGK1 mRNA, GILZ mRNA, and BDNF levels were increased significantly ( 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

Neuroinflammation driven by dysfunctional microglial responses represents a critical early pathogenic process, particularly in the context of Alzheimer's disease (AD). The natural flavonoid fisetin possesses anti-inflammatory characteristics; however, the exact mechanisms via which it mitigates microglial dysfunction in AD are not fully elucidated. This work employed a combination of in vivo and in vitro approaches, utilizing male APP/PS1 mice and ADDL-stimulated primary microglia. Behavioral tests, immunohistochemistry, molecular profiling, and mitochondrial function assays were conducted. This research combines network pharmacology, molecular docking, and cellular thermal shift assays (CETSA) to offer predictive insights. Fisetin treatment improved cognitive performance in APP/PS1 mice, concurrently reducing amyloid pathology and plaque-associated microglial clustering. In primary microglia, fisetin potently inhibited ADDL-induced pro-inflammatory activation, mitochondrial ROS overproduction, and membrane depolarization. PI3K was identified as a signaling node potentially involved in fisetin-mediated regulation of microglial inflammatory responses. Accordingly, fisetin constrained microglial inflammatory signaling, at least in part through modulation of the PI3K-Akt-NF-κB axis, thereby limiting NF-κB nuclear translocation and pro-inflammatory cytokine release in both the mouse hippocampus and cultured primary microglia. Furthermore, conditioned medium from fisetin-treated microglia alleviated neuronal damage and restored the expression of BDNF and PSD95 in primary neurons. The collective findings, along with experimental studies utilizing the PI3K inhibitor (LY294002), indicate that PI3K may act as a molecular target of fisetin, underscoring its potential therapeutic significance in regulating early inflammatory processes in AD. Show less

Substance use disorders (SUDs) present a global health challenge with high relapse rates. Emerging evidence implicates gut microbiota dysbiosis in SUD pathophysiology via the gut-brain axis. This 24-week randomized controlled trial investigated whether precision exercise interventions could modulate the gut microbiota-emotion axis to improve psychological outcomes in individuals undergoing compulsory drug rehabilitation. Thirty male participants were randomized to a precision exercise group (n = 15; individualized aerobic + resistance training, 4-5 sessions/week) or control group (n = 15; standard rehabilitation activities). Multi-dimensional assessments included weekly fecal (16S rRNA sequencing), urine (SCFAs via GC-MS), and saliva samples (cortisol, serotonin, BDNF via ELISA), alongside psychological evaluations (SCL-90-R, POMS) and physiological measures. The exercise group exhibited significant increases in gut microbial diversity (Shannon index: +18.2%, p < 0.001; Cohen's d = 2.14) and enrichment of beneficial taxa (e.g., Faecalibacterium, Bifidobacterium; LDA >3.5). Urinary SCFAs increased markedly (butyrate: 3.12-fold, p < 0.001), correlating with elevated salivary BDNF (+82%, p < 0.001) and reduced cortisol (-41.1%, p < 0.001). Psychological outcomes improved substantially: SCL-90-R Global Severity Index decreased by 43.3% (p < 0.001), and 78.6% of exercise participants achieved clinically meaningful improvement. Machine learning models predicted treatment response (AUC = 0.91) using baseline microbiome features. Precision exercise restores gut microbiota homeostasis, enhances neuroactive metabolite production, and improves emotional regulation in SUD recovery. The gut microbiota-emotion axis represents a viable target for non-pharmacological interventions, with microbiome profiles enabling personalized treatment strategies. 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

Gliomas are the most common primary malignant tumors of the central nervous system. Mounting evidence highlights the crucial role of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) in glioma treatment response. This study aimed to investigate the association between single-nucleotide polymorphisms (SNPs) of YTHDF1 and cognitive dysfunction (CD) following radiotherapy for glioma. A total of 323 glioma patients were enrolled pre-radiotherapy and followed up for 3 months post-radiotherapy. They were categorized into glioma patients with CD (group, YTHDF1 mRNA expression was significantly higher in the CD group than in the non-CD group. Among the four analyzed SNPs, only rs6090311 exhibited significant differences in both genotype and allele frequencies between the two groups, while rs6011668, rs68041888 and rs6122103 showed no significant variations. After controlling for potential confounders, including WHO grade, tumor volume, BDNF levels, and radiotherapy dose, carriers of the G allele (A/G + G/G genotypes) at rs6090311 demonstrated a significantly lower risk of developing post-radiotherapy CD (OR = 0.319, 95% CI: 0.111-0.916). YTHDF1 overexpression is associated with post-radiotherapy CD in glioma patients, and the rs6090311 G allele may act as a protective genetic marker for this complication. Show less

Alzheimer's disease (AD) is a common neurodegenerative disorder wherein reactive oxygen species (ROS) and Amyloid-β-protein (Aβ) play critical roles. Inspired by traditional Chinese charcoal drug and the anti-inflammatory properties of some carbon dots, we developed Radix Isatidis derived carbon dots (RI-CDs) via a hydrothermal method. The RI-CDs can cross the blood-brain barrier (BBB) and were thus evaluated for AD therapy. In vitro, RI-CDs scavenged ROS, inhibited Aβ Show less

Lilium brownii is a plant that can be used for medicinal and food purposes. 1-O-p-coumaroyl-3-O-feruloyl glycerol (CF) is a phenolic acid glycerol dimer isolated from Lilium brownii. This study aims to evaluate the neuroprotective effects of CF and elucidate the possible molecular mechanisms underlying its neuroprotective effects through in vivo and in vitro models of Parkinson's disease. 1-methyl-4-phenylpyridinium ions (MPP Following CF administration, the apoptosis rate and reactive oxygen species (ROS) levels in PC12 cells were significantly reduced. CF markedly upregulated the expression of proteins including dopamine, tyrosine hydroxylase, brain-derived neurotrophic factor (BDNF), while simultaneously downregulating the expression of proteins such as α-synuclein. Molecular docking results demonstrated favorable affinity between CF and proteins including p62. This compound not only ameliorated motor and cognitive impairments in Parkinson's disease mice but also markedly increased neuronal numbers within the substantia nigra region of these animals. CF exerts a neuroprotective effect in Parkinson's disease by modulating the p62-Keap1-Nrf2 signalling pathway. Show less

Current monoaminergic antidepressants demonstrate limited efficacy and delayed onset, necessitating novel treatment strategies. Previous studies have identified salt-inducible kinase 1 (SIK1) in the paraventricular nucleus (PVN) as an important regulator of depression pathogenesis by controlling nuclear translocation of cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) and activity of the hypothalamus-pituitary-adrenal (HPA) axis. The current study investigated the antidepressant-like efficacy of phanginin A, a newly discovered potent SIK1 activator, in male C57BL/6 J mice. Two well-validated depression models (chronic social defeat stress and chronic unpredictable mild stress) were established to examine the efficacy of phanginin A treatment against chronic stress-induced HPA hyperactivity and depression-like behaviors including desperate mood, anhedonia, and social avoidance. Western blotting, immunofluorescence, and co-immunoprecipitation were then conducted to evaluate the biological changes in not only the SIK1-CRTC1 signaling in PVN neurons but also the hippocampal brain derived neurotrophic factor (BDNF) signaling and adult neurogenesis among all groups. To further determine the antidepressant mechanism of phanginin A, model mice were re-examined following genetic knockdown of SIK1 in the PVN. Phanginin A administration suppressed depression-like behaviors in both models, normalized chronic stress-induced alteration in the SIK1-CRTC1 signaling in PVN neurons, and rescued chronic stress-induced impairments in hippocampal BDNF signaling and adult neurogenesis. Knockdown of SIK1 in the PVN abrogated the antidepressant-like actions of Phanginin A in male mice. Our findings further establish SIK1 in the PVN as an antidepressant target and support phanginin A as a potential antidepressant candidate. 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 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

This study examined how different photoperiods affect net energy partitioning and explored the mechanisms via blood biochemistry, gut microbiota, and fecal metabolites. Twelve healthy crossbred pigs (47.7 ± 7.5 kg) were randomly allocated to two groups and subjected to a self-controlled crossover design. Following an 8-day baseline under a normal photoperiod (12L:12D, 12 h light:12 h dark), pigs were assigned to two photoperiod treatment groups: prolonged photoperiod (18L:6D, 18 h light:6 h dark; P group) and shortened photoperiod (6L:18D, 6 h light:18 h dark; S group). Measurements during the baseline (12L:12D) and treatment phases are designated as N1/P (for the P group) and N2/S (for the S group), respectively. The treatment periods were interspersed with the baseline 12L:12D photoperiod and repeated six times. It was observed that, compared to N2, shortened photoperiod (S) had significantly higher net energy deposition, net energy for protein deposition, and net energy for fat deposition ( Show less

Acute alcohol consumption is known to exert widespread physiological effects, yet the immediate impacts on metabolic biomarkers remain incompletely understood. The present randomized controlled trial was conducted to investigate the acute effects of a single episode of alcohol ingestion on various biomarkers in healthy individuals. A total of 45 male participants were recruited and randomized into an alcohol group (n = 40) and a control group (n = 5) at an 8:1 ratio. Volunteers in the alcohol group ingested 40% Absolut vodka within 15 min. Blood pressure, heart rate, and blood oxygen saturation were measured at 0 h, 1 h, 3 h, 5 h, 12 h, and 24 h. Venous blood samples were drawn at 0 h, 1 h, 5 h, 12 h, and 24 h after alcohol intake. Our results showed that levels of liver function markers, including α-fucosidase (AFU), albumin (ALB), and alkaline phosphatase (ALP), were significantly increased in the alcohol group compared to the control group. The 24-h area under curve (AUC) of AFU, ALB, and ALP were significantly higher in the alcohol group. The liver fibrosis maker collagen type Ⅳ (Ⅳ-C) tended to be higher at 1 h and 12 h in the alcohol group compared to the control group. Lipid levels, including triglycerides (TG), apolipoprotein A1 (APOA1), and the APOA1/APOB, were significantly elevated after alcohol ingestion, particularly at 5 h and 12 h. The 24 h-AUC of TG, APOA1, and APOA1/APOB were higher in the alcohol group than in the control group. Additionally, cardiac function indicators, including heart rate, systolic blood pressure (SBP), and diastolic blood pressure (DBP), were significantly elevated in the alcohol group. SBP and DBP remained higher 24 h after alcohol ingestion compared to the control group. This study demonstrated that even a single episode of binge drinking could induce significant alterations of biomarkers related to liver function, cardiac function, and lipid profiles. These findings provided valuable insights into the short-term impact of alcohol on health and highlighted the importance of further research to explore the long-term implications of repeated acute alcohol exposure. Given the very small control group, these results should be interpreted as preliminary and confirmed in larger, more balanced randomized trials. The online version contains supplementary material available at 10.1038/s41598-026-40028-1. Show less

Low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL are generally considered normal. We tested the controversial hypothesis that a subset of individuals with 'normal' LDL-C levels may have a non-negligible risk of coronary artery disease (CAD) due to inherited factors, including monogenic variants and polygenic risk scores (PGS). A retrospective analysis of a prospective cohort from the Genomic Health Initiative at Endeavor Health, including 7880 participants without a prior diagnosis of CAD and not on statins at recruitment. Participants were stratified by baseline LDL-C levels and followed for incident CAD. The association of CAD risk with carrier status for pathogenic/likely pathogenic (P/LP) variants in Among participants, 31.2 % had LDL-C <100 mg/dL (normal), 39.5 % had LDL-C 100-129 mg/dL, and 29.3 % had LDL-C ≥130 mg/dL. Over a median follow-up of 8 years, CAD was diagnosed in 5.3 %, 6.9 %, and 7.6 % of participants in these LDL-C groups, respectively. Among those with normal LDL-C, CAD incidence rose to 9.5 % in individuals with high genetic risk (P/LP variants and/or high PGS). Genetic risk was significantly associated with CAD in multivariable models ( Individuals with 'normal' LDL-C levels can have substantial CAD risk if they carry high genetic risk. These findings underscore the importance of incorporating genetic information into CAD risk assessment, even among those with traditionally normal lipid profiles. Show less

To elucidate the molecular basis of intramuscular fat (IMF) variation in yellow-feathered broilers, we selected 10 high-IMF (HF) and 10 low-IMF (LF) breast muscle samples from a total of 214 samples, after z-score filtering for LC-MS lipidomics and RNA-seq analyses. Lipidomics identified 94 differentially expressed lipids (DELs; 83 upregulated, 11 downregulated in HF), predominantly triglycerides (TGs, 20.2%), phosphatidylethanolamines (PEs, 15.3%), phosphatidylcholines (PCs, 12.1%), and sphingomyelins (SMs, 8.4%). LION/web enrichment indicated an unsaturated lipid-rich phenotype, characterized by fatty acids containing ≥ 2 double bonds and membrane structural components. RNA-seq revealed 423 differentially expressed genes (DEGs; 312 upregulated, 111 downregulated in HF), enriched in plasma membrane, cell periphery, retinol metabolism, and steroid hormone biosynthesis pathways. RT-qPCR validation of nine lipid metabolism-related DEGs confirmed the RNA-seq trends. Cross-omics Pearson correlation between these DEGs and the top 20 DELs identified PLIN1, SCD, and APOB as central regulatory hubs strongly associated with multiple polyunsaturated TGs and PCs. Functional overlap across omics layers suggests coordinated membrane remodeling and unsaturated lipid deposition in HF breast muscle, providing a data-driven framework for future mechanistic validation and breeding strategies. Show less

The comparative efficacy and safety profiles of PCSK9 inhibitors in familial hypercholesterolemia (FH), including genotype-dependent treatment responses, remain unclear. This systematic review was conducted in accordance with the Preferred Reporting Items for Meta-Analyses guidelines. A network meta-analysis of randomized clinical trials evaluating the use of PCSK9 inhibitors for the treatment of FH patients, including subgroup analyses of efficacy, was performed. Fifteen randomized clinical trials (n = 2954 patients) were included. All PCSK9 inhibitors significantly improved lipid parameters compared to control. In heterozygous FH (HeFH) populations, ongericimab showed the greatest reductions in LDL-C (mean difference [MD]: -74.98 %), ApoB (MD: -64.64 %), and Lp(a) (MD: -59.66 %), with SUCRA rankings of 68.7 %, 63.6 %, and 95.0 %, respectively. However, these results are based on a single trial and require further validation. No significant lipid-lowering effects were observed in HoFH patients. In terms of safety, lerodalcibep showed the most favorable profile for injection-site reactions and ALT >3 × ULN, with SUCRA values of 98.5 % and 96.7 %, respectively. Inclisiran was associated with a significantly higher risk of injection-site reactions. PCSK9 inhibitors generally show favorable efficacy and safety in FH patients. However, comparative rankings and point estimates should be interpreted with caution due to funnel plot asymmetry for LDL-C and imbalances in trial data. Ongericimab demonstrated promising results in HeFH, but further validation is required. Inclisiran's efficacy may be underestimated due to short-term follow-up. Monotherapy with PCSK9 inhibitors has limited efficacy in HoFH patients, highlighting the need for combination therapies. Show less