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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

The epidemics of metabolic disease, in the form of obesity and type 2 diabetes, are a growing public health concern. However, incretin-based therapeutics have transformed our ability to address these diseases. While this current generation of incretin analogues show weight regain upon cessation of treatment, the amount of which can depend on the treatment and patient, iterative advancements may improve weight loss durability in the long term. In this review, we discuss the development of glucagon like peptide-1 receptor (GLP-1R) agonists and GLP-1R/ glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonists, and how future generations will leverage this strategy. We focus our review on glucagon receptor (GCGR) agonism, which has recently been combined with both GLP-1R and GLP-1R/GIPR agonism to generate dual (e.g. survodutide, cotatutide, mazdutide, etc) and triple agonists (e.g. retatrutide, etc) for improved body weight loss via energy expenditure stimulation. We rely on largely pre-clinical evidence for action because clinical data is extremely limited for GCGR agonism. Herein, we review mechanisms by which glucagon receptor agonists act to increase energy expenditure. Finally, we discuss future improvements to incretin-based therapeutics, and how they can include strategies that target the GCGR. The purpose of this review is to discuss mechanisms by which GCGR agonism can reduce body weight and put them in the context of the combination with incretin receptor agonists. Mechanistic data has only currently been evaluated in preclinical rodent models and evidence for similar processes in humans is limited. We also provide perspectives about how treatments can improve for future advancement of obesity treatment. Show less

Depressive disorders (DDs), especially treatment-resistant depression (TRD), pose a significant challenge worldwide, largely because their underlying biological mechanisms are complicated and treatments often fall short. There is growing evidence pointing to factors like disrupted neuroplasticity, neuroinflammation, irregularities in the hypothalamic-pituitary-adrenal (HPA) axis, and glutamatergic system imbalances as contributors to the onset and persistence of depressive symptoms. Exosomes (small extracellular vesicles involved in communication between cells) have recently gained attention for their potential role in connecting peripheral and central nervous system (CNS) changes. They carry proteins, lipids, and nucleic acids and are even capable of crossing the blood-brain barrier. Because of this, exosomes might provide a window into molecular changes in the brain and serve as accessible biomarkers of disease status and treatment response. Recent research points out that the contents of exosomes, especially microRNAs (miRNAs) and neurotrophic factors like brain-derived neurotrophic factor (BDNF), might play a part in disrupting synaptic plasticity and could be linked to resistance to antidepressants. At the same time, there is growing interest in using engineered exosomes as targeted drug carriers aimed at the CNS. That said, there are still quite a few hurdles to overcome. Methods vary widely between studies, protocols for isolating exosomes are not sufficiently standardized, safety data are limited, and we do not fully understand how drugs and exosomes interact or how they behave pharmacokinetically. This review brings together current findings regarding exosomes in DDs (with particular emphasis on TRD), highlights their promise for diagnosis and treatment, and sets out some of the main questions that need to be answered before clinical application becomes feasible. Show less

Exercise serves as a potent physiological stimulus influencing brain-derived neurotrophic factor (BDNF), a key molecule involved in neuronal maintenance, synaptic plasticity, and cognitive regulation. However, the temporal dynamics of circulating BDNF in response to varying exercise intensities remain poorly understood. This study investigated serum BDNF kinetics following low- and moderate-intensity continuous exercise (LICE, MICE) and high-intensity interval exercise (HIIE) in young healthy men. Twelve participants completed all three exercise sessions in a randomized crossover design with seven-day washouts. Venous blood samples were collected at baseline, immediately post-exercise, and at 5, 15, 30, 45, and 60 min of recovery. Serum BDNF and blood lactate concentrations were measured, and heart rate was monitored continuously during each exercise session. BDNF levels were significantly higher in HIIE than in both LICE and MICE across all time points (p < 0.001), with no differences between LICE and MICE (p > 0.05). Within-group analysis revealed that HIIE induced a pronounced but transient rise in BDNF, peaking at 15 min post-exercise and returning to baseline by 60 min. These results suggest that HIIE elicits a distinct neurotrophic response pattern shaped by exercise intensity and interval structure. Our findings provide descriptive data on serum BDNF kinetics that may inform future mechanistic research. Trial registration: The study was registered on ClinicalTrials.gov (identifier: NCT07175831 https://clinicaltrials.gov/study/NCT07175831 ) on 15th of September 2025. Show less

Tirzepatide (TZP), a novel dual agonist of glucagon-like peptide (GLP)-1/glucose-dependent insulinotropic polypeptide (GIP) receptors (GLP-1R/GIPR), has been shown to reduce cardiovascular (CV) risk in patients with diabetes or obesity. This study investigated anti-atherosclerotic effects of TZP and the underlying mechanisms using apo E Show less

The induction of nausea and emesis represents a significant barriers to optimizing weight loss medications for the treatment of obesity. Identifying mechanisms that improve tolerability and/or enhance efficacy without induction of emetic neurocircuitry could provide substantial therapeutic benefits. Candidate peptide YY (PYY)-based approaches for obesity treatment are no exception, as PYY-based therapeutics are uniformly associated with nausea and emesis. Recently, interest in glucose-dependent insulinotropic polypeptide receptor (GIPR)-based therapeutics has resurfaced, with some paradoxical findings from several preclinical studies showing that both GIPR agonism and antagonism, when combined with glucagon-like peptide-1 receptor (GLP-1R) agonists, result in greater body weight loss and superior glycemic control compared to GLP-1R agonism alone. Here, we investigated the effects of pharmacological modulation of the GIPR system on the actions of PYY. We found that systemic GIPR agonism attenuated PYY-induced malaise while preserving its anorectic and body weight-lowering effects in rats. Interestingly, GIPR antagonism enhanced PYY-induced hypophagia and body weight loss without compromising its malaise tolerability profile. Furthermore, inhibition of GIPR signaling significantly reduced PYY-induced c-Fos expression in the area postrema (AP) of the hindbrain. Since both NPY2R and GIPR are expressed in the same AP neurons, this suggests a potential neuronal pathway by which GIPR modulates the effects of PYY. Overall, our findings underscore the multifaceted actions of the GIPR system and highlight the therapeutic potential of both GIPR agonism and antagonism in enhancing and improving the effects of PYY-based obesity treatments. Show less

Brain-derived neurotrophic factor (BDNF) has been firmly implicated in the synaptic plasticity of neurons in the central nervous system (CNS), which make BDNF as an important regulator of memory and emotion. In this review we will discuss our knowledge about the multiple intracellular signaling pathways activated by BDNF, and the regulation of intracellular trafficking of BDNF/TrkB in synaptic plasticity, memory and emotion. Alternations in BDNF/TrkB trafficking has been shown to be involved in memory deficits and mood disorders. Future studies could explore targeting the regulation of BDNF/TrkB trafficking to devise BDNF-based therapeutics for human memory and mood disorders. Show less

Aging in dogs is a multifactorial process involving behavioral, cognitive, immunological, and microbiota-related changes, yet distinguishing healthy from pathological aging remains challenging. This exploratory study aimed to evaluate physiological indicators of health by integrating pain evaluation and cognitive testing in senior companion dogs. Eighteen companion dogs aged ≥8 years underwent standardized behavioral and cognitive evaluations (Mini C-BARQ, DISHAA, object choice test), chronic pain assessment (Helsinki Chronic Pain Index), and quality-of-life (QoL) scoring. Hematological parameters, serum brain-derived neurotrophic factor (BDNF), and Th1/Th2 ratios were measured as physiological indicators, while fecal samples were analyzed via 16S rRNA sequencing for microbiota profiling. All dogs scored above the chronic pain threshold (mean HCPI: 28.72), although caregiver-reported QoL ratings suggested good overall wellbeing. Cognitive testing yielded low average scores on the DISHAA (mean: 9.05), with only one dog showing mild cognitive decline; however, mean performance on the object choice test was low (1.94/5). Mean serum BDNF concentration was 0.154 ng/dL (SD: 0.082) and correlated positively with red blood cell (RBC) count and negatively with MCV, MCH, and MCHC ( These preliminary findings highlight potential interactions between pain, microbiota composition, and immune dysregulation, suggesting their possible utility as candidate indicators for differentiating healthy from pathological aging in dogs. Show less

Gene-environment interactions play a critical role in shaping phenotypic heterogeneity in complex psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is a key genetic regulator of stress-sensitive neuroplasticity. Yet, how We conducted a case-control study including 93 patients with first-episode schizophrenia (SZ) and 64 healthy controls. Childhood trauma exposure was assessed using the Childhood Trauma Questionnaire (CTQ), and symptom dimensions were evaluated with the Positive and Negative Syndrome Scale (PANSS). Three Patients with SZ exhibited significantly higher CTQ scores across all trauma subtypes compared with controls (all These findings demonstrate that Show less

Obesity is a chronic disease caused by the accumulation of cholesterol, which often requires long-term management strategies, such as dietary changes, increased physical activity, and psychological support. Obesity associated neurobehavioral disorders are a growing global health concern, emphasizing the need for innovative therapeutic strategies. Our study evaluates the therapeutic efficacy of (Z)-1-(furan-2-yl)-N-(4-(2-nitrophenyl)-6-(p-tolyl)pyrimidin-2-yl)methanimine referred as BN3 derivative, in treating high-fat diet-induced metabolic and behavioral dysfunctions in a zebrafish model. The research focused on reducing oxidative stress, lipid accumulation, and neurobehavioral deficits, which are closely linked to obesity-related metabolic stress. In this study, zebrafish were divided into five separate experimental groups: control group, model of obesity caused by high-fat diets, BN3 (50 µM and 100 µM), and Positive Control (PC) Group treated with Lovastatin 100 µM. Initially, fish were fed a high-fat diet for 14 days and followed by 30 days of exercise and simultaneously administering BN3 treatments via oral gavage. Assessment of biochemical, histopathology, gene expression, and behavioral were carried out. The results indicated that BN3 treatment significantly decreased oxidative stress levels by enhancing the activity of four antioxidant enzymes (Superoxide Dismutase, Catalase, Glutathione Transferase and Glutathione Peroxidase). BN3 also decreased lipid accumulation as evidenced through histological staining analysis, and total cholesterol estimation. BN3 enhanced locomotion, social interaction, and exploratory behaviors, and reduced anxiety, with the 100 µM treatment group exhibiting the same results as the PC. Gene expression analysis indicates that BN3 is modulating pparγ, fas, pik3cd, src-3, and bdnf pathways (metabolic and neuroinflammation pathways). BN3 impacted these multiple metabolic and neurobehavioral impairments associated with obesity through a multisite treatment approach. BN3 demonstrates significant therapeutic potential, assuring further studies to explore its long-term safety, pharmacokinetics, and translational application in managing obesity and related disorders. Show less

Major depressive disorder (MDD) involves multifaceted pathologies including neurotransmission, neuroplasticity, inflammation, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. Growing evidence implicates zinc homeostasis imbalance in MDD, yet a systematic framework integrating it into these mechanisms is lacking. This narrative review synthesizes literature (2000-2024) to elucidate the multidimensional associations between zinc homeostasis and MDD pathology, focusing on zinc's roles in neurotransmitter regulation, BDNF signaling, inflammation, oxidative stress, and HPA axis activity. Epidemiological studies indicate an inverse correlation between serum zinc levels and MDD. Mechanistically, zinc imbalance may disrupt neural signaling via glutamate/GABA/5-HT receptors, impair neurotrophy via BDNF, exacerbate neuroinflammation and oxidative stress, and promote HPA axis hyperactivity. Zinc supplementation shows efficacy in mild-to-moderate MDD and augments conventional antidepressants, especially in treatment-resistant cases. Novel targets like GPR39 and zinc transporters, along with brain-targeted formulations, offer promising therapeutic avenues. Zinc homeostasis is critically involved in MDD's heterogeneous pathology, making it a promising target for precision treatment. However, this potential is tempered by inconsistent data and methodological limitations. Future research should prioritize: standardizing assessment methods; investigating brain region-specific zinc dynamics; developing novel targeted formulations; and exploring gene-environment interactions in zinc signaling. Show less

Lipoprotein lipase (LPL) is a blood vessel lipase that regulates and removes plasma lipoprotein triglycerides from blood circulation. It is important in the control of hypertriglyceridemia. LPL dysregulation can lead to hypertriglyceridemia and increase the risk of atherosclerosis cardiovascular disease. Therefore, the biochemical characterization of LPL could help understand the LPL dysregulation mechanism. However, active LPL enzyme acquisition via bacterial expression is challenging, as studies have reported that LPL could only be co-expressed in the presence of a chaperone. Therefore, this work intends to investigate the possibility of bacterial expression of human LPL (hLPL) with active lipase activity. The hLPL protein has been produced in SHuffle® T7 cells, and the optimal refolding conditions of the hLPL protein have been described here. The addition of 4% glycerol, 0.5-M NaCl, and 0.5-mM CaCl Show less

Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance circulating levels of biologically intact incretins, yet the relative contribution of glucose-dependent insulinotropic polypeptide (GIP) to their metabolic effects remains incompletely understood. While glucagon-like peptide-1 (GLP-1) has long been emphasized in incretin biology, emerging evidence suggests important physiological roles for GIP. This study investigated whether endogenous GIP signaling is indispensable for the glucose-lowering and anti-obesity effects of DPP-4 inhibition. Male Gipr DPP-4 inhibition significantly improved glucose tolerance and attenuated body-weight gain in HFD-fed Gipr Endogenous GIP signaling is essential for both glucose-lowering and anti-obesity actions of DPP-4 inhibitors in mice. GLP-1 elevation alone is insufficient to compensate for GIP receptor deficiency. These findings refined the mechanistic understanding of DPP-4 inhibitors, highlighted the physiological importance of GIP, and suggested context-dependent metabolic actions of incretins. Show less

Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adverse factors in the periodontal microenvironment. Therefore, identifying novel therapeutic targets and elucidating the underlying molecular mechanisms to protect the proliferative and differentiation potential of PDLSCs is of significant importance. PDLSCs were exposed to electronic cigarette extract and various common oral stressors to evaluate the expression of glucagon such as peptide 1 receptor (GLP1R) and gastric inhibitory polypeptide receptor (GIPR). PDLSCs isolated from patients with periodontitis and PDLSCs from a mouse periodontitis model were also analyzed. Functional studies were performed by GLP1R or GIPR knockdown, overexpression, and treatment with single or dual receptor agonists, followed by assessment of cell proliferation and multilineage differentiation capacities. Transcriptome (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA immunoprecipitation sequencing (RIP-seq) were applied to delineate downstream signaling pathways and RNA–protein interactions. Protein synthesis regulation was further investigated by immunoprecipitation of interferon induced protein with tetratricopeptide repeats (IFIT)-associated translation initiation factors. For in vivo validation, wild-type and GLP1R/GIPR double-knockout periodontitis mice were transplanted with CRISPR-Cas9 mCherry-labeled PDLSCs and treated with receptor agonists. Disease severity and PDLSC fate were evaluated by histology and lineage tracing. Finally, a questionnaire-based survey was conducted in 150 patients with periodontitis, including 74 individuals with long-term use (> 1 month) of GLP1R or GLP1R/GIPR dual agonists (e.g., semaglutide, liraglutide, tirzepatide), to assess their periodontal outcomes. GLP1R and GIPR expression were markedly downregulated in PDLSCs exposed to multiple stressors and in PDLSCs isolated from periodontitis specimens. RNA-seq, ChIP-seq, and RIP-seq identified downstream pathways and RNA–protein interactions implicated in receptor-mediated regulation. Functionally, GIPR agonism promoted PDLSC proliferation via activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, whereas GLP1R agonist enhanced multilineage differentiation capacity in vitro. Mechanistically, GLP1R knockdown induced robust upregulation of IFIT1/2/3, while GLP1R agonist suppressed IFIT expression. IFIT1/2/3 were shown to interact with eIF3C and to inhibit translation of differentiation-related mRNAs, linking GLP1R signaling to translational control of PDLSC fate. In vivo, transplantation experiments in both wild-type and GLP1R/GIPR double-knockout periodontitis mice demonstrated that single and dual receptor agonists significantly improved endogenous and exogenous PDLSC-mediated periodontal regeneration. Consistently, a clinical survey of 150 patients with periodontitis (74 receiving GLP1R or dual agonists) revealed significantly better periodontal staging and grading in treated individuals, with longer agonist exposure associated with greater improvement. Our findings uncover the different molecular roles of GIPR and GLP1R in self-renewal capacity and multipotency of PDLSCs, and open new avenues for developing therapeutic targets and strategies in oral tissue engineering and regenerative medicine. The online version contains supplementary material available at 10.1186/s11658-026-00867-2. Show less

Diabetic retinopathy (DR) is a leading cause of vision loss worldwide, driven by chronic metabolic dysregulation that promotes inflammation, oxidative stress, and progressive neurovascular unit dysfunction in the retina. While regular exercise is an effective non-pharmacological strategy to reduce diabetes-related complications, accumulating evidence suggests that its retinal benefits extend beyond systemic metabolic control and are mediated in part by exercise-induced bioactive factors known as exerkines. Secreted from skeletal muscle, adipose tissue, liver, and other organs, exerkines act as endocrine signals linking physical activity to tissue-specific adaptations. This review provides a retina-focused, cell-type-oriented synthesis of current evidence implicating key exercise-responsive exerkines, including irisin, adiponectin, brain-derived neurotrophic factor, fibroblast growth factor-21, apelin, and clusterin, in pathways relevant to DR pathogenesis. We systematically map reported exerkine actions to retinal endothelial cells, pericytes, Müller glia, microglia, neurons, and the retinal pigment epithelium, while explicitly distinguishing findings from retinal or DR-specific models from those extrapolated from extra-ocular systems. We further integrate emerging data on exercise modality-specific exerkine signatures and discuss their translational relevance, limitations, and safety considerations across different stages of DR. In total, this review highlights exerkines as candidate mediators and biomarkers of exercise-retina crosstalk and outlines priorities for mechanistic validation and clinical translation alongside established therapies such as anti-VEGF treatment. Show less

Chromosomal rearrangements involving the Mixed Lineage Leukemia gene (MLL1, KMT2A) are defining a genetically distinct subset in about 10% of human acute leukemias. Translocations involving the KMT2A-locus at chromosome 11q23 are resulting in the formation of a chimeric oncogene, where the N-terminal part of KMT2A is fused to a variety of translocation partners. The most frequently found fusion partners of KMT2A in acute leukemia are the C-terminal parts of AFF1, MLLT3, MLLT1 and MLLT10. Unfortunately, the presence of an KMT2A-rearrangements is associated with adverse outcomes in leukemia patients. Moreover, non-rearranged KMT2A-complexes have been demonstrated to be crucial for disease development and maintenance in NPM1-mutated and NUP98-rearranged leukemia, expanding the spectrum of genetic disease subtypes that are dependent on KMT2A. Recent advances in the development of targeted therapy strategies to disrupt the function of KMT2A-complexes in leukemia have led to the establishment of Menin-KMT2A interaction inhibitors that effectively eradicate leukemia in preclinical model systems and show favorable tolerability and significant efficacy in early-phase clinical trials. Indeed, one Menin inhibitor, Revumenib, was recently approved for the treatment of patients with relapsed or refractory KMT2A-rearranged acute leukemia. However, single agent therapy can lead to resistance. In this Review article we summarize our current understanding about the biology of pathogenic KMT2A-complex function in cancer, specifically leukemia, and give a systematic overview of lessons learned from recent clinical and preclinical studies using Menin inhibitors. Show less

Vicarious trauma, the psychological distress from witnessing others' suffering, is an increasingly recognized precursor to depression and anxiety. However, the underlying neurobiological mechanisms remain poorly understood and appear to be sex-dependent. This study investigated the behavioral, physiological, and molecular consequences of purely psychological stress using a novel rodent model of vicarious learned helplessness (VLH). Male and female C57BL/6J mice were used to establish VLH paradigm. Observer mice witnessed conspecifics receiving inescapable foot shocks through a partitioned chamber allowing multisensory interaction. Following 7 days of conditioning, behavioral assays assessed anxiety and depressive symptoms. Prefrontal cortex tissue was analyzed using RT-qPCR and immunoblotting to identify molecular alterations. Vicarious stress induced depression phenotype in both sexes, characterized by active avoidance deficits, anhedonia and anxiety, comparable to direct physical trauma. Physiological assessments revealed hypothalamic-pituitary-adrenal (HPA) axis hyperactivity with elevated plasma corticosterone in both sexes. While molecular analysis showed shared downregulation of metabotropic glutamate receptor 2 (mGluR2) and elevated Il6 mRNA in the prefrontal cortex, distinct sexual dimorphism emerged. Males displayed specific deficits in neurotrophic support ( Vicarious trauma is sufficient to drive depression-like pathology through distinct molecular trajectories in males and females. These findings are suggestive of the critical necessity for sex-specific therapeutic strategies when treating trauma-related psychiatric disorders. Show less

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and behavioral impairments associated with striatal neuronal loss, for which effective symptom-attenuating therapies remain lacking. Artemisinin (ART), a natural sesquiterpene lactone with established antioxidant and anti-inflammatory actions, has recently gained attention as a potential neuroprotective agent. This study evaluated the therapeutic relevance of ART in a rat model of HD induced by 3-nitropropionic acid (3-NP). 3-NP administration caused severe behavioral deficits, including an 81.8% reduction in rearing and a 74.9% reduction in ambulation (p < 0.0001), a 63.7% decrease in novel object exploration, and a 53.5% decline in Morris water maze target quadrant time versus controls. Biochemically, 3-NP elevated HMGB1 (4.8-fold), TLR4 (6.8-fold), RIPK1 (6.4-fold), RIPK3 (5.2-fold), MLKL (5.5-fold), p38-MAPK (4.2-fold), NF-κB (2.1-fold), and TNF-α (4.5-fold), while reducing GSH (57.6%), Nrf2 (77.7%), Sig1R (86.2%), D2R (64%), XIAP (77.8%), BDNF (57.6%) and SDH (61.44%) (all p < 0.0001). Treatment with ART (100 mg/kg) markedly restored behavioral performance, increasing rearing and ambulation by 3.2- and 2.6-fold, novel object exploration by 2.4-fold, and target quadrant time by 1.7-fold compared to the 3-NP group. At the molecular level, ART reduced HMGB1 (69.2%), TLR4 (60.4%), RIPK1 (66.3%), RIPK3 (66.4%), MLKL (58%), and TNF-α (62.5%), while significantly restoring GSH (2.1-fold), Nrf2 (3.7-fold), Sig1R (5.2-fold), D2R (2.6-fold), XIAP (3.7-fold), BDNF (2.3-fold) and SDH (1.94-fold) relative to 3-NP-treated rats. Collectively, these results demonstrate that ART confers robust neuroprotection against 3-NP-induced HD-like pathology by attenuating oxidative stress, suppressing HMGB1/TLR4/NF-κB signaling, inhibiting necroptosis, and upregulating neuroprotective markers. These findings highlight ART not only as a neuroprotective agent but also as a promising symptom-attenuating therapeutic candidate for Huntington's disease and other neurodegenerative disorders driven by oxidative and inflammatory stress. 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

There is a close connection between aging and osteoarthritis (OA), but the specific mechanisms are still unclear. This study aims to explore the potential connections and molecular mechanisms between OA and aging through multi-omics and genetics methods. Integrating single-cell RNA sequencing (scRNA-seq), bulk RNA-seq data, Mendelian randomization (MR), colocalization analysis, and cell function analysis, this study explores the correlation between OA and aging. Furthermore, it investigates the potential causal relationship between key marker genes and OA. Integrating and analyzing scRNA-seq data from OA, aging, and control groups revealed a significant increase in the proportion of the classical monocyte core subgroup. Differential expression analysis yielded 77 marker genes, and further MR analysis identified four key marker genes (DUSP6, CSTA, CD300E, and GPX1) as causally related to OA, which was confirmed in an independent validation cohort. Reverse MR and Steiger filtering indicated no evidence of reverse causality. DUSP6- and CSTA-classical monocytes may interact with other cell subgroups through the MIF-(CD74 + CD44) signaling pathway. This study revealed the heterogeneity of monocyte subgroups in OA and aging patients, identifying key marker genes with a causal relationship to OA through an integrated multi-omics approach, providing potential molecular targets for the diagnosis and treatment of OA from an aging perspective. Show less

High-calorie diets cause metabolic syndrome, obesity, and emotional disturbances, with neurological consequences. These prevalent conditions impair both peripheral and central nervous system function, elevating depression risk. These complications represent prevalent chronic conditions in modern society. The bioactive compound 6-gingerol demonstrates antioxidant and anti-inflammatory properties. This study investigated 6-gingerol’s protective effects against depression-like behavior and metabolic syndrome induced by a high-fat, high-sucrose diet (HFHS) in rats. Male Sprague-Dawley rats were randomly divided into six groups ( [Image: see text] Show less

Major depressive disorder (MDD) is a multifactorial mental health condition involving genetic, environmental, and neurobiological factors. Conventional antidepressants such as fluoxetine, a selective serotonin reuptake inhibitor, require weeks to exert therapeutic effects, whereas ketamine and esketamine act rapidly via glutamatergic modulation. These drugs may also converge on the inhibition of glycogen synthase kinase 3 beta ( Show less

P2X receptors, a family of ATP-gated ion channels, are increasingly recognized as key contributors to the pathophysiology of major depressive disorder. Among them, P2X7 plays a central role in stress-induced neuroinflammation by driving microglial activation, inflammasome signaling, and downstream reductions in BDNF and neuroplasticity. Additional P2X subtypes, including P2X4, further modulate neuronal and glial communication relevant to mood regulation. Evidence from animal models, human genetic studies, and early therapeutic trials supports the involvement of P2X signaling in depressive phenotypes and highlights P2X7 antagonists as promising candidates for novel antidepressant strategies. Overall, targeting P2X receptors offers a mechanistically distinct approach to understanding and treating depression. Show less

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 nervous system is increasingly recognized as a dynamic and regulatory component of the tumor microenvironment playing critical roles in cancer initiation, progression, metastasis, and resistance to therapy. Recent evidence in cancer neuroscience have revealed a specialized "neural niche" a microanatomical and functional domain enriched in neural inputs and neuromodulatory signals orchestrated through bidirectional communication between tumor, nervus system and immune cellsCancer cells secrete neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) to attract and remodel peripheral innervation. Infiltrating nerve fibers, in turn, release neurotransmitters (e.g., norepinephrine, acetylcholine) and neuropeptides (e.g., substance P, calcitonin gene-related peptide) that influence not only tumor growth, angiogenesis but also immune cell polarization, T cell exhaustion, dendritic cell maturation and myeloid derived suppressor cell recruitment. This neural-immune crosstalk establishes immune suppressive microenvironment that facilitates tumor immune escape and leading to metastatic progression. Perineural invasion (PNI), a distinct pathological process of tumor dissemination, further exemplifies neuroepithelial integration and correlates with recurrence, pain and poor prognosis across multiple solid tumors. Beyond local interactions, chronic stress and systemic neuroendocrine activation via the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic-adrenal-medullary networks, contribute to tumor-promoting immunosuppression through glucocorticoid signaling and sympathetic responses. In this review, we discuss mechanistically integrated and clinical relevant synthesis of tumor-neuron-immune interactions. We emphasize recent conceptual advances, including autonomic balance, systemic neuroendocrine feedback and therapeutic strategies targeting this axis. These insights establish a framework for future translational research and development of neuromodulatory therapies that complement immunotherapy as well as conventional therapeutics. 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