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Depressive disorder represents a multifaceted and intricate condition characterized by disturbances in monoaminergic signaling, neurotrophic support mechanisms, and the regulation of inflammatory processes. An increasing body of evidence indicates that natural bioactive compounds may provide adjunctive therapeutic advantages with a reduced incidence of adverse effects in comparison to traditional antidepressants. This review investigates the antidepressant efficacy of Show less

Aberrant microglial activation and impaired adult hippocampal neurogenesis play critical roles in the pathogenesis of depression. Although electroacupuncture (EA) has demonstrated clinical antidepressant efficacy, the underlying mechanisms by which it modulates microglial activity and promotes neurogenesis remain unclear. Male C57BL/6 J mice were subjected to chronic unpredictable mild stress (CUMS) for three weeks. Following this period, the mice were divided into groups receiving either EA at the Yintang (GV29) and Baihui (GV20) acupoints, imipramine (IMI) as a positive control, or no treatment (vehicle control) for an additional 3 weeks. To evaluate depressive-like behaviors, we conducted the sucrose preference test, forced swimming test, and tail suspension test. Anxiety-like behaviors were assessed using the open field test and elevated plus maze. We employed immunofluorescence, Golgi staining, Western blotting, and real-time quantitative PCR (qRT-PCR) to elucidate the effects of EA on microglia-driven hippocampal neurogenesis and BDNF signaling. Notably, loss-of-function experiments utilizing PLX5622 for microglial ablation and ANA-12 for TrkB blockade demonstrated the necessity of both microglia and BDNF signaling for the therapeutic efficacy of EA. EA treatment significantly alleviated CUMS-induced anxiodepressive behaviors. This behavioral recovery was associated with a phenotypic shift in microglia towards a pro-neurogenic state in the hippocampus. Importantly, microglia were essential for the therapeutic effects of EA, as evidenced by their ablation with PLX5622. Furthermore, EA enhanced neurogenesis by orchestrating a multi-step augmentation of BDNF signaling, which involved PKA activation, subsequent release from MeCP2-mediated transcriptional repression, and ultimately increased maturation of BDNF. Our findings demonstrate that EA exerts antidepressant effects by promoting a pro-neurogenic transformation of microglia. Mechanistically, these microglia enhance BDNF function via the PKA/MeCP2/BDNF pathway, thereby facilitating hippocampal neurogenesis and restoring synaptic plasticity, which collectively alleviate depressive symptoms. Show less

The olfactory mucosa has emerged as a promising source of mesenchymal stem cells with neurogenic potential. These cells exhibit neural, glial, and mesenchymal properties, making them attractive candidates for regenerative medicine, particularly in treating neurodegenerative and immunemediated disorders. This systematic review analyzed existing literature on the isolation, characterization, and therapeutic applications of olfactory mucosa mesenchymal stem cells. The review assessed variations in isolation techniques, culture conditions, and differentiation potential, as well as preclinical and clinical applications. Olfactory mucosa mesenchymal stem cells express key neural and mesenchymal markers, including Nestin, SRY-box 2, Olfactory mucosa mesenchymal stem cells represent a promising avenue for neurological and regenerative therapies. Despite their potential, further research is needed to optimize isolation techniques, enhance reproducibility, and navigate regulatory hurdles. Collaborative efforts between researchers, clinicians, and regulatory bodies will be essential to translating OM-MSC research into viable clinical applications. Show less

Temporomandibular disorders (TMD) are multifactorial chronic pain conditions involving the temporomandibular joint, masticatory muscles, and associated structures, with a marked predominance in women. Despite their high prevalence and significant impact on quality of life, the biological mechanisms underlying pain chronification in TMD remain incompletely understood. Growing evidence indicates that persistent TMD-related pain arises from complex interactions among inflammatory signaling, oxidative stress, neuroendocrine dysregulation, and epigenetic modulation of gene expression. This integrative narrative review synthesizes current clinical and preclinical evidence from molecular biology, neuroendocrinology, and epigenetics to elucidate the biomolecular mechanisms involved in chronic TMD pain. Studies consistently report elevated proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α, alongside increased oxidative stress markers, including malondialdehyde and 8-hydroxy-2′-deoxyguanosine, accompanied by reduced antioxidant capacity in saliva and serum. Alterations in neuroendocrine mediators, particularly dysregulation of the hypothalamic–pituitary–adrenal axis and reduced levels of neurotrophic factors such as brain-derived neurotrophic factor and nerve growth factor, appear to contribute to central sensitization and impaired neuroplasticity. In parallel, epigenetic mechanisms—including DNA methylation of pain- and stress-related genes (e.g., Show less

Ischemic stroke triggers hypoxia, inflammation, and oxidative stress. Local oxygen delivery may prevent secondary injuries. Herein, we implanted a catalase-incorporated thiolated gelatin-based oxygen-releasing hydrogel sheet in a rat model of photothrombosis to evaluate early infarct attenuation and feasibility. Male Sprague-Dawley rats were allocated to four groups (n = 6/group): control at 24 h (G1), with hydrogel sheet at 24 h (G2), control at 72 h (G3), and with hydrogel sheet at 72 h (G4). Focal ischemia was induced with Rose Bengal and targeted illumination through a 6.0-mm cranial defect. A hydrogel sheet was applied to the cortex after surgery. The infarct burden was assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining and magnetic resonance imaging (MRI), while mRNA expression levels of tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and superoxide dismutase (SOD) were measured by quantitative reverse transcription PCR. Body weight was monitored as a safety measure. At 24 h, TTC showed a significant infarct reduction in G2 compared with G1. At 72 h, infarct measures did not differ significantly between G4 and G3. MRI and gene expression analyses did not show statistically significant between-group differences and are presented as exploratory outcomes. Weight and perioperative status were similar across groups, indicating short-term tolerability. The hydrogel sheet was associated with reduced TTC-defined infarct burden at 24 h in this model; confirmatory studies will require larger, powered cohorts, longer follow-up with functional testing, and in vivo oxygen release profiling to optimize dose, placement, and exposure time. Show less

Evidence has shown significant sex differences in freezing and darting behaviors in a rat model of aversive learning using fear conditioning. The present study explored sex differences in a rat model of aversive learning using a fear-conditioning method via measuring freezing and darting behaviors. Fear conditioning was induced by three footshocks (0.8 mA, 3 s, 30-s interval) paired with an auditory conditioned stimulus (75 dB, 3 s). Extinction was performed by broadcasting 20 auditory conditioned stimuli (75 dB, 3 s, 30-s interval), with no shocks, in three, or four, of five sessions. Freezing and darting behaviors, locomotor activity and time spent in the center squares (anxiety-like behavior) in the open field test, and brain-derived neurotrophic factor (BDNF) in the infralimbic region of the mPFC (medial prefrontal cortex) were evaluated. The results showed both sexes showed a high rate of freezing, with males showing more freezing. Females were more responsive to extinction. Darting behavior was only observed in females and diminished following extinction. Locomotion and anxiety-like behavior were increased and decreased following extinction learning in both sexes, respectively. BDNF expression level in the infralimbic region of the mPFC was increased following extinction learning, with a greater increase in females. In conclusion, we showed that females have a diverse behavioral response to the anticipation of a threat in a rat model of fear conditioning. The important role of BDNF in the modulation of both freezing and darting behaviors was also shown. Show less

Testicular germ cell tumors (TGCT) are highly heritable malignancies that display increasing incidence worldwide, with rising mortality rates particularly evident among Hispanic men. However, genomic studies of TGCT have largely focused on European cohorts, limiting accurate risk prediction in other populations. We investigated rare germline variants contributing to TGCT susceptibility in a Hispanic cohort. Exome sequencing data (mean depth 60x) from 40 Mexican TGCT patients were analyzed against two ancestry-matched control groups using gene-based aggregation analyses and single-variant association. Top candidate variants were validated and replicated in an independent cohort of 211 TGCT patients, with Mexican individuals from the PAGE study serving as a third control group. Gene-based testing revealed seven genes, including Show less

Biased agonism of the glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptors (GLP-1R/GIPR) yields greater weight loss and better glycemic control than unbiased agonism in preclinical models. To evaluate whether biased agonism translates into improved efficacy for weight loss and glycemic control in clinical settings, we developed and characterized CT-388, a unimolecular peptide-based dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors. In cell-based assays, CT-388 activated GLP-1R and GIPR with both having minimal receptor internalization vs their native ligands. CT-388 improved glycemic control in mice and monkeys, and reduced bodyweight, suppressed appetite, and improved metabolic dysfunction-associated steatohepatitis pathology in mice. In a phase 1, double-blind, randomized, placebo-controlled clinical study (NCT04838405) of CT-388 (subcutaneously administered single doses [0.5-7.5 mg] or 4 once-weekly doses [5-12 mg]) in otherwise healthy participants with overweight or obesity, CT-388 was generally well tolerated with a safety profile consistent with other incretin-based therapies; most treatment-emergent adverse events were mild or moderate. Glycemic parameters were improved during fasting conditions and an oral glucose tolerance test. The mean percent change in bodyweight from baseline to day 29 was -4.7% to -8.0% across CT-388 doses vs -0.5% with placebo. CT-388 pharmacokinetics supported once-weekly dosing. In conclusion, CT-388 demonstrated strong translatability from preclinical to clinical studies with consistent pharmacokinetics and pharmacodynamics across multiple species. In clinical settings, 4 weeks of CT-388 treatment produced clinically meaningful weight loss and improved glycemic control with favorable tolerability. These findings warrant further clinical evaluation of CT-388 for treating obesity and type 2 diabetes. Show less

Selective breeding has substantially improved productive and reproductive traits in pigs. Yet, these traits are biologically interconnected, and selection for one often affects others in unintended ways. While genome-wide association studies (GWAS) have uncovered many loci linked to these traits, they provide limited insight into causal mechanisms. Mendelian randomization (MR) provides a robust framework for inferring causality and identifying shared genetic determinants. Here, we integrated MR, colocalization, and functional genomics to investigate the biological links between growth, carcass composition, and reproduction in pigs. Using average daily gain (ADG) as the exposure, MR revealed potentially significant causal effects (P < 0.05) of ADG on carcass composition traits, including backfat thickness (BFT: Our findings suggest a shared genetic architecture and provide potential evidence of a causal influence of ADG on carcass composition and reproductive traits in pigs. This integrative framework supports the development of multi-trait breeding strategies that enhance productivity while managing inherent trade-offs in regulating complex traits. Show less

Tirzepatide, a single-molecule dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor (R) agonist, has shown superiority in the reduction of blood glucose and body weight, above selective GLP-1R agonists, but the contribution of GIP to these effects remains incompletely understood. To characterize the preclinical and in-human effects of a long-acting GIPR agonist monotherapy in healthy participants and patients with type 2 diabetes (T2D). A long-acting GIPR agonist (LY3537021) was characterized in vitro and in Long-Evans diet-induced obese rats and Wistar rats. Next, a phase 1, randomized, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) study explored the safety, tolerability, pharmacokinetics, and pharmacodynamics of LY3537021 in healthy participants and participants with T2D in Singapore. In vitro, LY3537021 demonstrated potency greater than native GIP and selectivity for the GIPR. In vivo in rats, chronic treatment with LY3537021 resulted in weight loss and improved glycemic control during a glucose tolerance test. The phase 1 clinical study enrolled 85 healthy participants and patients with T2D (SAD, n = 47 [aged 25-64 years]; MAD, n = 38 [aged 25-69 years]; average baseline BMI was 25.9-27.0 kg/m In vivo studies demonstrated that LY3537021 reduced body weight and improved glycemia during a glucose challenge in rats. The phase 1 study demonstrated that the long-acting GIPR agonist LY3537021 was well tolerated, induced weight loss, and improved glucose control in humans. These observations better define the therapeutic benefit of long-acting GIPR agonists and support a distinct contribution of GIP agonism to the benefits observed with multi-agonist peptides that act via the GIPR. Future studies are needed in more diverse populations and in cohorts with overweight/obesity to confirm these findings. GOV: NCT04586907. Show less

The neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a key regulator of synaptic plasticity in hippocampus and cortex of mammalian brains. In the lateral nucleus of the amygdala (LA), BDNF is involved in the control of long-term potentiation (LTP). Here, we show that BDNF is involved in spike-timing dependent potentiation (STDP) of thalamic inputs onto LA projection neurons. Inhibition of BDNF/TrkB signaling with the TrkB scavenger TrkB/FC completely blocked this timing-dependent form of LTP (t-LTP). Disruption of lipid-rafts by depletion of cholesterol from synaptic microdomains with Methyl-β-cyclodextrin (MCD) also prevented induction and expression of t-LTP. These data suggest that BDNF-induced TrkB translocation into synaptic lipid-rafts is required for induction of t-LTP at thalamo-amygdala synapses. Since cholesterol-dependent modulation is not unique for TrkB receptor signaling but has been described for other receptors and ion channels involved in synaptic plasticity, additional studies are required to obtain a more complete picture regarding their role in t-LTP at thalamo-amygdala afferents. Show less

Spinal cord injury (SCI) remains difficult to treat, and current interventions provide limited functional restoration and often require invasive procedures. Existing cell- or extracellular vesicles (EV)-based approaches are frequently administered alongside surgery, limiting therapeutic reach and overall efficacy. In this study, we developed an engineered extracellular vesicle (EV) platform by displaying a single-chain variable fragment (scFv) against integrin αvβ8 (αITGEV) and loading brain-derived neurotrophic factor mRNA (mBDNF). The construct maintained canonical EV identity and morphology, and showed predominant single particle co-positivity for targeting ligand and cargo. In neuron-microglia co-culture, mBDNF@αITGEV preferentially entered both cell types under injury-relevant stress, shifted microglia toward a repair-associated phenotype, reduced TNF-α and IL-1β, increased IL-4 and IL-10, and preserved neuronal architecture. Our results indicate that mBDNF@αITG-EVs significantly promote functional motor recovery by modulating the inflammatory microenvironment and inhibiting neuronal ferroptosis. Mechanistically, the delivery of BDNF mRNA bolstered GPX4 expression and stabilized mitochondrial dynamics, thereby mitigating secondary oxidative damage. This study provides a non-invasive strategy for precision nanomedicine in neuro-regeneration. Collectively, this study supports a non-invasive systemically administered, targeted EV-mRNA therapeutic strategy for spinal cord injury with translational potential. Show less

Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder triggered by a traumatic event. Its core features include intrusive flashbacks, persistent avoidance, negative cognition and mood changes, and heightened arousal. The global lifetime prevalence is approximately 3.9%, exceeding 5.0% in high-income countries and high-trauma-exposed populations. With rising incidence of natural disasters, violent conflicts, and public health incidents worldwide, PTSD has become a serious public health issue threatening people's mental health. However, its pathogenesis remains largely unknown, specific clinical diagnostic biomarkers are lacking, and treatment efficacy varies significantly across individuals. Molecular understanding of its pathophysiology is urgently needed. Brain-derived neurotrophic factor (BDNF), a key neurotrophic factor in the central nervous system, is crucial for regulating neuronal survival, differentiation, and synaptic plasticity. Abnormal synaptic plasticity is closely associated with abnormal fear memory storage and emotional regulation impairments in PTSD patients. DNA methylation, a classic epigenetic regulatory mechanism, can inhibit transcriptional activity by modifying CpG sites in gene promoter regions. Its role in regulating BDNF gene expression has been widely demonstrated. In recent years, more epidemiological and animal studies suggest that BDNF DNA methylation may serve as a key molecular bridge between trauma exposure and the onset of PTSD. Abnormally elevated BDNF promoter methylation levels have been detected in the peripheral blood and in core brain regions(hippocampu,samygdala) of PTSD patients. Furthermore, these methylation levels can predict the risk of developing PTSD after trauma and are significantly correlated with clinical features such as impaired cortisol secretion and generalized fear memory. This study conducted a literature review, with data collected from authoritative Chinese and English databases. Chinese literature was retrieved from CNKI (China National Knowledge Infrastructure) and Wan fang Data; English literature was sourced from PubMed and Web of Science. The search was restricted to articles published prior to December 2025, focusing on case-control studies investigating the association between BDNF DNA methylation and post-traumatic stress disorder (PTSD). This review followed a structured, but not systematic, search strategy. We focus on the specific molecular pathways by which BDNF DNA methylation contributes to PTSD pathogenesis by influencing neural circuit plasticity, hippocampal function, and hypothalamic-pituitary-adrenal (HPA) axis homeostasis. We also summarize its potential for application in the development of diagnostic biomarkers and targeted interventions for PTSD. We also outline cutting-edge research directions driven by emerging technologies such as single-cell sequencing and epigenetic editing. This article aims to provide theoretical references for a deeper understanding of the pathogenesis of PTSD and promote clinical translational research. Show less

Aging is accompanied by a progressive decline in immune function, known as immunosenescence, and by a chronic low-grade inflammatory state, termed inflammaging. Both conditions contribute to increased susceptibility to infections, reduced vaccine responses, and the development of age-related diseases. Emerging evidence suggests that intermittent fasting (IF), a dietary pattern that alternates between periods of fasting and feeding, may influence pathways associated with immune aging across mid-life and older adulthood. This review explores how IF may exert immunoregulatory effects through metabolic remodeling, cellular stress responses, and inflammatory signaling. Preclinical and human studies indicate that IF attenuates pro-inflammatory cytokine production, enhances autophagy, and improves immune cell function, potentially delaying immunosenescence and reducing inflammaging in middle-aged and older populations. Additionally, IF may protect against neuroinflammation and cognitive decline by reducing oxidative stress, activating AMPK-SIRT1 and ketone signaling via β-hydroxybutyrate (BHB), enhancing neuroplasticity, upregulating brain-derived neurotrophic factor, and suppressing pro-inflammatory cytokines, inflammation, and frailty in the aging brain. However, most evidence comes from short- to medium-term studies in selected, relatively healthy populations, with benefits often similar to those of continuous calorie restriction, and there is limited data on long-term safety, adverse effects, and outcomes in frail older adults. By reducing oxidative stress and inflammaging, IF may mitigate frailty in older adults or delay its progression when initiated earlier. By integrating insights from immunometabolism and gerontology, this review highlights the potential role of IF as a non-pharmacological strategy to promote healthy immune aging and support functional outcomes in older adults. However, evidence in frail older adults remains limited, and randomized trials in this population are warranted. Future research should directly compare IF with isocaloric non-fasting regimens, include long-term follow-up, and carefully characterize safety and adherence in high-risk groups before IF can be routinely recommended for immune aging. Show less

The preoptic area (POA) is a well-established regulator of body temperature, but its role in feeding behavior remains underexplored. Our study identifies leptin receptor (Lepr)-expressing neurons in the POA (POA Show less

The melanocortin-4 receptor (MC4R) is highly expressed in the hypothalamus, and mutations in this gene are closely associated with the development of hereditary obesity and early-onset severe obesity in humans. Mc4r has been shown to be involved in the development of dilated cardiomyopathy. However, the current system for the early diagnosis and treatment of heart disease is not well established. In this study, we analyzed the effects of Mc4r knockout on cardiac function, cardiomyocyte morphology, fibrosis, and apoptosis in mice. Moreover, we explored the possible early molecular mechanisms by which Mc4r affects cardiac dysfunction via transcriptome sequencing of cardiac cells combined with bioinformatics analysis. Although the overall heart does not show organic changes, our study suggested that cardiomyocytes already show early abnormal changes at the molecular level. The sequencing results revealed that the genes that were differentially expressed between the two groups of mice were enriched mainly in the p53 signaling pathway and the hypoxia-inducible factor 1 (HIF-1) signaling pathway. We screened 10 key target genes via a protein-protein interaction (PPI) network and module analysis. Drugs targeting key genes were subsequently screened, and angiotensinogen (Agt) and Kit were identified as potential drug targets. We analyze relevant data through bioinformatics to screen for signaling pathways and key hub genes that are enriched in differentially expressed genes (DEGs), as well as molecules targeting the hub genes, in order to provide ideas for early prevention of heart disease caused by Mc4r gene defects or related obesity. Show less

Obesity, a global health catastrophe, arises from complex interactions between environmental factors and genetic predispositions. This review summarizes the current state of knowledge on the genetic basis of obesity and contrasts rare monogenic forms caused by mutations in a single gene with common polygenic forms caused by hundreds of genetic variants with small effects. We highlight important genes in neuroendocrine signaling pathways, particularly the leptin-melanocortin system involving Show less

Hypothalamic inflammation plays a key pathophysiological mechanism linking chronic consumption of a high fat diet (HFD) to the development of obesity and associated metabolic complications. Pilot studies report that oral glutamine (Gln) supplementation might reduce waist circumference and improve metabolic and inflammatory status in obesity patients. Although Gln metabolism plays a key role in intercellular communication in the central nervous system, its potential beneficial effects remain unexplored in these contexts. Here, we aimed to evaluate how stress and glutamine supplementation can modulate the hypothalamic response to HFD in mice using a chronic-restraint stress (CRS) model, which mimics IBS symptoms. From week 12 to week 14, mice received or not Gln diluted in drinking water (2 g/kg/day) and were placed in restraint tubes (2 h/day) for the last four consecutive days of protocol. Male and female obese mice showed a difference in vulnerability to CRS-induced effects. Moreover, mice responded to Gln supplementation in a sex-dependent manner, especially in stress conditions. Hypothalamic pathways regulating energy homeostasis were more impacted in male mice, whereas factors involved in neuroinflammation were more affected in female mice. Gln supplementation led to an increase in Mc4r and Bdnf mRNA levels and GFAP expression in male mice, while upregulated Iba1 and Il6 mRNA levels as well as signs of microgliosis were observed in stressed females. In conclusion, mice with obesity showed sex-specific hypothalamic response to glutamine supplementation and stress. Further investigations should be done to decipher underlying mechanisms. Show less

Marine macroalgae are increasingly recognized as sources of bioactive compounds with potential benefits for metabolic health. This study investigated the chemical composition and metabolic effects of a 70% ethanol extract of the edible red alga Show less

The melanocortin-3 receptor (MC3R) and the melanocortin-4 receptor (MC4R), both expressed in hypothalamic nuclei, are key downstream effectors of leptin signaling and play important roles in energy homeostasis. While pathogenic variants in the MC4R gene represent the most common cause of monogenic obesity, the clinical significance of MC3R variants is less clear. MC4R localizes to the primary cilium, a sensory organelle present on nearly all human cells. To better understand the pathophysiological mechanisms of MC3R variants, we investigated whether MC3R localizes to the primary cilium and assessed the impact of rare MC3R variants identified in individuals with obesity on ciliary expression. Using human RPE cells, human NGN2-induced iNeurons, and primary mouse hypothalamic neurons, we found that, in contrast to MC4R, neither wild type MC3R nor rare MC3R variants localized specifically to the primary cilium in vitro in any cell type, including hypothalamic neurons. These findings suggest that MC3R and MC4R may utilize distinct signaling pathways or that additional factors, such as accessory proteins, are required for MC3R targeting to primary cilia in vivo. Further studies are needed to clarify the role of MC3R variants in monogenic obesity and their broader implications for human disease. Show less

Adolescence represents a critical developmental window during which lifestyle habits profoundly influence long-term health trajectories. This chapter examines the enduring effects of physical activity (PA) initiated during adolescence on musculoskeletal, cardiometabolic, cognitive, and mental health outcomes. Evidence from longitudinal and epidemiological studies consistently demonstrates that regular PA during this period is associated with reduced risks of obesity, type 2 diabetes (T2DM), cardiovascular disease, osteoporosis, and sarcopenia in adulthood. Mechanistic insights highlight the role of PA in enhancing bone mineral development, muscle hypertrophy, metabolic regulation, and neuroplasticity, partially mediated by factors such as brain-derived neurotrophic factor (BDNF). The chapter further addresses the influence of mediating and moderating variables, including genetic predisposition, biological sex, maturational timing, and sociocultural determinants, in shaping individual responses to exercise. Finally, it underscores the necessity of integrated, multilevel public health strategies and school-based interventions tailored to adolescent needs, aimed at promoting equitable, sustainable engagement in PA. By synthesizing current evidence, this chapter emphasizes the lifelong preventive and therapeutic potential of adolescent PA for reducing the global burden of noncommunicable diseases. Show less

Class B1 GPCRs are crucial to maintaining homeostasis along a multitude of vital biochemical pathways. Understanding the activation mechanism of these proteins at both a family and clade-specific level is particularly relevant for designing multi-target agonists, as exemplified by recently designed dual-agonists for GLP-1R and GIPR, for treating obesity. Here, we use 6 milliseconds of unbiased all-atom MD simulations of GCGR, GLP1R, PAC1R, SCTR, PTH1R and CALCR from the four different clades of Class B1 GPCRs to establish the universal mechanism of their activation. We show that the activation of Class B1 GPCRs involves a clade-independent intermediate state characterized by the outward movement of helix 6. We use a combination of Markov state models and transition path theory to show that the activation of these proteins occurs at a millisecond timescale. We identify characteristic molecular locks that are conserved at a clade-level, showcasing the uniqueness among the activation mechanisms of these proteins. We show that these proteins show similar inactive and active states, but show unique activation mechanisms at a residue level. These sites can be targeted directly or allosterically to design therapeutics targeting a specific clade of proteins. Thus, this study provides an integrated atomistic view of the activation for Class B1 GPCRs from a mechanistic, thermodynamic and kinetic perspective. Show less

This study aimed to evaluate the therapeutic potential of stem cells from human exfoliated deciduous teeth (SHED) against depression and to elucidate the underlying mechanisms involving neuroinflammation and synaptic plasticity in a rat model of chronic unpredictable mild stress (CUMS). A robust rat model of depression was established using chronic unpredictable mild stress (CUMS) paradigm. CUMS-exposed rats received intracerebroventricular transplantation of SHED at three doses (0.5×10 SHED transplantation rapidly ameliorated CUMS-induced behavioral deficits, showing efficacy comparable to fluoxetine but with a notably faster onset. Mechanistically, SHED potently attenuated neuroinflammation by reducing hippocampal and cortical levels of pro inflammatory cytokines and by promoting a phenotypic shift in microglia from the M1 to the M2 state, as evidenced by morphology and marker expression. Transcriptomic analysis revealed that SHED treatment upregulated gene sets related to postsynaptic density, while downregulating the NOD like receptor (NLRP3 inflammasome) signaling pathway. At the molecular level, SHED enhanced the expression of key synaptic protein (PSD95) and restored the impaired BDNF/TrkB signaling axis in stress-vulnerable brain regions. SHED exerts rapid and potent antidepressant effects in the CUMS model through a convergent dual mechanism: suppressing neuroinflammation via microglial reprogramming and inflammasome inhibition, and enhancing structural and functional synaptic plasticity. These robust preclinical findings strongly support SHED as a novel, mechanism-based, cell therapeutic strategy for major depressive disorder. Show less

Chronic obesity is associated with impaired bone health. However, few investigations have been conducted to assess bone physiology in early-onset obesity. In this study, we measured specific bone turnover and metabolic biomarkers in children with severe obesity with biallelic loss-of-function variants of the leptin (LEP), leptin receptor (LEPR), or melanocortin 4 receptor (MC4R) genes. Thirty-nine children aged 0.3-8.8 years with a BMI SDS ≥ 3, previously identified with pathogenic variants in LEP, LEPR, or MC4R, were recruited for the current study. Additionally, 13 age-matched children with severe obesity who tested negative for variants in known obesity-related genes were included, and another 13 unrelated age-matched children with normal body weight served as the control group. Serum osteocalcin, osteopontin, osteoprotegerin, and sclerostin levels were assessed using multi-analyte profiling. Serum leptin, insulin, and cortisol levels were determined using ELISA. Serum levels of osteocalcin and osteopontin, specific markers of bone formation, were significantly lower in children with LEP and LEPR biallelic variants than in the control group. In contrast, the values of these two biomarkers in children with MC4R deficiency were significantly higher than those in the other groups. No differences were observed in the bone resorption markers osteoprotegerin and sclerostin. Hyperleptinemia was more pronounced in children with LEPR deficiency. Serum insulin concentrations were elevated in individuals with MC4R deficiency, whereas serum cortisol levels were significantly higher in children with LEP deficiency than in all other groups. Our data demonstrate that osteogenic activity (but not resorption activity) is differentially affected in children with complete genetic disruption of the leptin-signaling pathway. Children with MC4R deficiency showed higher osteogenic markers, but children with LEP and LEPR deficiencies showed the opposite. Our results support the usefulness of bone turnover biomarkers for the assessment and management of bone health in different types of obesity. Show less

Survivors with chronic sequelae of carbon monoxide (CO) poisoning after the 1963 Miike-Mikawa coal mine disaster can exhibit persistent higher brain dysfunction in late life. We examined whether serum metabolic alterations remained detectable ~60 years later and assessed serum brain-derived neurotrophic factor (BDNF). In this cross-sectional case-control study, outpatients with chronic CO-poisoning sequelae (CO; n = 14) and former miners without CO exposure (CON; n = 16), all aged ≥ 75 years, underwent targeted serum metabolomics (1183 metabolites) and clinical assessments. Between-group differences were evaluated using Welch's Relative to controls, the CO group showed higher valine, alanine, and betaine and lower 3-hydroxybutyric acid, inosine, and hypoxanthine; these contrasts persisted with concordant direction after matching. Serum BDNF was lower in the CO group (unadjusted trend) and was significantly reduced after age/MMSE adjustment ( Six decades after exposure, chronic CO sequelae were associated with a reproducible serum profile combining amino-acid elevations with relative suppression of ketone-body and purine-related metabolites, suggesting enduring alterations in systemic substrate handling and bioenergetics. If replicated in larger cohorts, such signatures-potentially alongside BDNF-should be regarded as hypothesis-generating; biomarker development would require external validation, longitudinal tracking, and assessment of intervention responsiveness before any clinical use is considered. Show less

An increasing number of stroke survivors are burdened by persistent disabilities, requiring long-term rehabilitation. However, the extent of functional gain is highly variable, severely impairing patients' quality of life. This variability highlights a critical gap in current prognostic tools, which rely primarily on clinical and neuroimaging data. The aim of this review is to synthesize the current literature on serum biomarkers in stroke survivors and to evaluate their prognostic value for rehabilitation outcomes. Our synthesis indicates that biomarkers reflecting distinct pathophysiological processes are emerging as key prognostic indicators. Markers of inflammation such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), and Interleukin-1 beta (IL-1β), and neuro-glial injury, including S100 Calcium-Binding Protein B (S100B), Neuron-Specific Enolase (NSE), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament Light Chain (NfL), are consistently associated with poorer functional outcomes. Conversely, markers of neuroplasticity, such as Brain-Derived Neurotrophic Factor (BDNF) and Insulin-like Growth Factor-1 (IGF-1), serve as potential indicators of recovery potential, although their predictive accuracy remains inconsistent across studies. Furthermore, emerging biomarkers of synaptic activity, such as Syntaxin-1a (STX1A) and Synaptosomal-Associated Protein, 25kDa (SNAP-25), and neuromuscular junction integrity, such as C-terminal Agrin Fragment (CAF), offer novel insights into brain-periphery communication, though their clinical utility is still under investigation. While promising, the translation of these biomarkers into clinical practice is hindered by methodological limitations, including assay heterogeneity and lack of large-scale validation. Future standardization of these molecular signatures is a critical step toward implementing precision medicine in stroke rehabilitation. Show less