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Familial partial lipodystrophy type 3 (FPLD3) is a rare autosomal dominant disorder caused by mutations in peroxisome proliferator-activated receptor gamma(PPARG), which encodes the key adipogenic transcription factor peroxisome proliferator-activated receptor gamma(PPARγ). Clinical diagnosis is challenging due to phenotypic overlap with common metabolic syndromes. We identified a novel PPARG variant in a Chinese family and performed comprehensive functional characterization to elucidate its pathogenic mechanism. The proband, a 15-year-old boy presenting with atypical fat distribution, severe insulin resistance, hypertriglyceridemia, and pancreatitis, underwent clinical evaluation and whole-exome sequencing. The identified variant was confirmed by Sanger sequencing. Its functional impact was assessed through in silico modeling, luciferase reporter assays, protein stability analysis (cycloheximide chase), and evaluation of mitochondrial function (JC-1 staining) and adipocyte gene expression in cellular models. A heterozygous PPARG c.634C>T (p.Arg212Trp, R212W) variant was identified and segregated with the phenotype. Functional studies revealed that the R212W mutant exhibits a partial loss of transcriptional activity (~40% of wild-type) while retaining ligand sensitivity. Crucially, we demonstrated that the mutant protein has significantly reduced stability due to accelerated degradation. In adipocyte models, R212W expression led to impaired mitochondrial membrane potential, depleted cellular ATP levels, and downregulated expression of key metabolic genes (glucose transporter 4[GLUT4], adiponectin[ADIPOQ], fatty acid binding protein 4[FABP4], lipoprotein lipase[LPL], perilipin 1[PLIN1]). These functional deficits were partially rescued by treatment with the PPARγ agonist rosiglitazone. We report a novel pathogenic PPARG R212W variant associated with FPLD3. Our data extend beyond a simple loss-of-function model by establishing a multi-faceted pathogenic mechanism involving protein destabilization, mitochondrial dysfunction, and cellular bioenergetic failure. The partial rescue by rosiglitazone suggests a potential therapeutic avenue. This study underscores the importance of integrating clinical phenotyping with deep functional analysis to diagnose and understand rare monogenic lipodystrophies. Show less

This study examined whether baseline levels of 14 serum biomarkers predicted antidepressant remission differently by sex at 12 weeks and 12 months. In a prospective cohort, 1,086 outpatients with depressive disorders received stepwise antidepressant treatment following a naturalistic protocol. Baseline serum samples were analyzed for biomarkers from six systems: immune (high-sensitivity C-reactive protein, tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, interleukin-4, interleukin-10), metabolic (leptin, ghrelin, total cholesterol), neurotrophic (brain-derived neurotrophic factor), neurotransmitter (serotonin), endocrine (cortisol), and nutritional (folate, homocysteine). Remission, defined as a Hamilton Depression Rating Scale scores ≤ 7, was assessed at 12 weeks and 12 months. Logistic regression models with biomarker-by-sex interaction and stratified analyses were used, adjusting for clinical covariates. Higher baseline serotonin predicted 12-week remission in males but not in females. At 12 months, lower leptin and higher folate predicted remission only in males, while lower cortisol predicted remission only in females. These showed significant biomarker-sex interactions. No sex-specific interactions were found for immune markers. Baseline serum biomarkers across biological systems showed sex-specific associations with treatment outcomes. Neurotransmitter, metabolic, endocrine, and nutritional markers may offer predictive value for sex-tailored, biomarker-informed treatment strategies in depression. Show less

The fat mass and obesity-associated (FTO) gene, though widely studied in human obesity and livestock lipid accumulation, remains poorly understood in bovine adipogenesis. This study investigated its role in bovine adipocytes via overexpression, given its high expression in Guanling cattle adipose tissue. Results demonstrated that FTO significantly increased triglyceride content, adiponectin secretion, and lipid droplet accumulation (P < 0.01). It also upregulated key adipogenic markers (PPARγ, C/EBPβ, FABP4, LPL; P < 0.05). Transcriptomic analysis revealed that FTO promotes adipocyte differentiation and lipogenesis through regulating multiple lipid metabolic pathways. These findings reveal that FTO positively regulates bovine adipocyte differentiation by modulating lipid metabolic networks, thereby filling a critical gap in the understanding of FTO-mediated lipid metabolism in ruminants. Show less

Autophagy is integral to the rapid proliferation of esophageal squamous cell carcinoma (ESCC), and its regulation presents a promising avenue for therapeutic intervention. Recent studies have elucidated the interplay between autophagy and glucose metabolism, while there is a paucity of anticancer drugs that concurrently target these 2 biological processes. In this study, we identified a natural compound, Show less

Efficient, spatially selective delivery of adeno-associated virus (AAV) therapeutics to deep brain structures remains a major challenge to gene therapy for Alzheimer's disease (AD), owing to limited transport across the blood-brain barrier (BBB) and poor penetration to target neurons. Here, we establish an integrated, noninvasive imaging and therapy platform that combines microbubble-enhanced focused ultrasound (MB-FUS) with positron emission tomography/computed tomography (PET/CT) to transiently modulate the BBB, enhance region-specific AAV delivery following systemic dosing, and longitudinally track transduction in vivo. Optimized MB-FUS achieved targeted hippocampal delivery of systemically administered AAV9 in healthy mice, resulting in a 10-fold enhancement of neuronal transduction as compared to non-FUS controls. Importantly, longitudinal PET reporter gene imaging in the 5xFAD AD model demonstrated robust brain AAV transduction that remained stable for at least seven months. Finally, to assess therapeutic impact, we used brain-derived neurotrophic factor (BDNF) as a test cargo. MB-FUS-facilitated delivery elevated BDNF expression in targeted regions and produced short-term improvements in synaptic signaling in 5xFAD mice. Collectively, these results highlight MB-FUS as a next-generation delivery platform to overcome barriers to AAV therapeutic delivery in Alzheimer's disease and position longitudinal PET assessment as a critical, translatable tool for monitoring and optimizing gene therapy. Show less

Alzheimer's disease (AD) is the most widespread neurodegenerative disease, strongly linked to amyloid depositions in the brain consisting of amyloid β (Aβ) peptides. The likelihood of developing late-onset Alzheimer's disease (LOAD) is influenced by the specific isoforms of apolipoprotein E (ApoE), with ApoE4 being the strongest known genetic risk factor for LOAD. Strong evidence suggests that ApoE impacts AD by modulating Aβ aggregation and clearance, although the precise molecular mechanisms remain incompletely understood. Microscale thermophoresis (MST) is a powerful technique for characterizing molecular interactions in solution, which has been used to determine various binding constants, although not the binding of ApoE to Aβ peptides. MST results show that ApoE isoforms bind Aβ1-40 and Aβ1-42 with low micromolar affinity. For Aβ1-42, ApoE3 shows the strongest binding ( Show less

Atherosclerosis is a leading cause of worldwide cardiovascular morbidity and mortality, and endothelial ferroptosis has emerged as a key mechanism in driving vascular injury. This study aimed to investigate whether quercetin (QCT), a natural dietary flavonoid with potent anti-oxidant activity, protects against atherosclerosis-associated endothelial dysfunction by modulating ferroptosis. In order to test this, ApoE[Formula: see text] mice fed a high-fat diet were treated with QCT or ferrostatin-1, and their aortic plaque burden, stability, and macrophage infiltration were then assessed. To evaluate ferroptosis, human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low-density lipoprotein (Ox-LDL), with or without QCT, and their reactive oxygen species (ROS), Fe[Formula: see text] accumulation, and heme oxygenase-1 (HMOX-1) expression were measured. While functional assays examined endothelial barrier integrity and monocyte adhesion, gene modulation studies explored the role of phosphofurin acidic cluster sorting protein 2 (PACS2). QCT treatment markedly reduced plaque area, necrotic core size, and macrophage infiltration while enhancing plaque stability. Show less

COVID-19 is associated with cardiometabolic complications, including lipid abnormalities, but its effect on lipoprotein(a) [Lp(a)] remains unclear. This pilot cohort study was conducted at an academic tertiary hospital and a primary healthcare facility (6 July-31 August 2021). It included a cross-sectional baseline comparison of patients hospitalised with COVID-19, diabetic controls, and healthy controls, with COVID-19 patients additionally followed for three months post-discharge. The study evaluated the relationship between lipid profiles, Lp(a), disease severity, and recovery. Among 169 participants, patients with COVID-19 ( The online version contains supplementary material available at 10.1038/s41598-026-37439-5. Show less

Elevated lipoprotein(a) [Lp(a)] is an independent and causal risk factor for atherosclerotic cardiovascular disease. Increasingly, prevention societies recommend testing Lp(a) at least once for all adults. A quality improvement (QI) initiative aimed to increase the rates of Lp(a) ordering for patients was piloted in the general cardiology fellows' clinic at an urban academic medical center. QI project interventions focused on provider education and inclusion of electronic health record-based tools. Over a period of 10 months, the proportion of patients with an Lp(a) order increased from 10.1% to 20.9%, and the proportion of patients with an Lp(a) result increased from 7.0% to 11.2%. Ahead of results from ongoing clinical trials testing Lp(a)-targeted therapies, health systems can use QI methods to assess current Lp(a) ordering practices, identify patients who may benefit from future Lp(a)-targeted therapy, and plan for rapid expansion of Lp(a) testing. Show less

The efficacy of antidepressants is influenced by a combination of genetic, individual, and environmental factors. This study aimed to investigate the association between the miR-182 rs76481776 polymorphism and the response to antidepressant treatment in major depressive disorder (MDD) patients, and its underlying molecular mechanisms. This study enrolled 180 MDD patients and 180 healthy controls. The rs76481776 genotype was determined using TaqMan-based qPCR. The severity of depression and treatment response were assessed using the Hamilton Depression Rating Scale (HAMD). The expression of miR-182 and The T allele of rs76481776 was a significant risk factor for MDD (OR = 2.182, 95% CI: 1.424-3.345, The T allele of rs76481776 diminished the therapeutic efficacy of antidepressants by up-regulating miR-182 expression and subsequently suppressing Show less

Major Depressive Disorder (MDD) is a debilitating psychiatric disorder that is a leading cause of disability worldwide. Although treatment with antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs), has demonstrated clinical efficacy, the "trial and error" approach in choosing the most effective antidepressant treatment for each patient allows for only a subset of patients to achieve response to the first line of treatment. Circular RNAs (circRNAs), are highly stable and brain-enriched non-coding RNAs that are mainly derived from the backsplicing and covalent joining of exons and introns of protein-coding genes. They are known to be important for brain development and function, cross the blood-brain-barrier, and be highly sensitive to changes in both synaptic activity and neuronal receptor signaling. Here we present evidence that expression of the brain-enriched circRNA, CDR1as, is associated with symptomatic response to SSRI treatment, and regulated by serotonin and Brain-Derived Neurotrophic Factor (BDNF) receptor activity. We present data using circRNA-specific PCR in baseline whole blood samples from two independent cohorts, drawn from the Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) and the Biomarkers of ANTidepressant RESponse (ANTARES) clinical studies, showing that before treatment CDR1as is differentially expressed between future symptomatic responders and non-responders to treatment with the SSRI sertraline. Additional data from naturalistic antidepressant response studies further highlight the association between CDR1as and antidepressant effects of SSRIs as a class. In addition, we show that CDR1as levels are altered following sertraline treatment in responders with the trajectory of change post-treatment associated with long-term remission. Furthermore, we report that levels of CDR1as in the blood can specifically predict remission with SSRI treatment, but not response/remission with Placebo or Bupropion treatments. Lastly, we provide evidence in animal mechanistic and neuronal culture studies, suggesting mouse Cdr1as is strongly regulated by 5-HT2A and BDNF receptor signaling. Taken together, our data identify a brain-enriched circRNA associated with known mechanisms of antidepressant response that can serve as a blood biomarker for predicting response and remission with SSRI treatment. Show less

Circulating lipoprotein(a) [Lp(a)] levels are highly heritable and linked to atherosclerotic cardiovascular disease, yet clinical measurement rates remain low (<1%) in the United States. The high heritability of Lp(a) across populations makes genetic prediction an attractive approach for closing this testing gap, but existing polygenic scores transfer poorly across populations. Haplotype-based prediction models, which use standard genome-wide genotype data to capture common-, rare-, and structural-variation at the LPA locus, could bridge this gap, enabling opportunistic identification of individuals with elevated Lp(a) levels across diverse populations within existing large, genotyped cohorts. This study sought to develop and validate a haplotype-based prediction model using genome-wide genotype data to identify individuals with elevated Lp(a) levels across diverse populations. We developed an Among PMBB (n = 1856), MGBB (n = 1401), and BioMe (n = 1686) participants with available genotype and Lp(a) measurements, average age was 60 years, and 51% were female. Overall r A haplotype-based genetic model effectively identified individuals with elevated Lp(a) levels across diverse populations, with potential utility for opportunistic screening among cohorts where genotype data is available, but Lp(a) testing rates are low. Show less

Osteoporosis has emerged as a growing public health concern due to its high prevalence and substantial economic burden on both individuals and society. Recent studies have identified the serum uric acid to high-density lipoprotein cholesterol ratio (UHR) as a novel predictive biomarker for various diseases. However, its association with bone mineral density (BMD) remains unclear. This study evaluated the association of the UHR and forearm BMD (FR-BMD) in a middle-aged and elderly cohort. We also assessed the interaction effects of age, sex, and body mass index (BMI). A total of 4,958 adults aged ≥50 years were enrolled from health examinees at Heze Municipal Hospital (2022-2025). We collected demographic data, serum lipids, and uric acid levels. Measurements of FR-BMD were performed on the left distal radius (1/3 site) utilizing dual-energy X-ray absorptiometry. Multivariate linear regression analyses evaluated the UHR-BMD relationship, supplemented by subgroup analyses and interaction tests. Nonlinear associations were assessed using generalized additive models with smoothing curves. After adjusting for age, sex, BMI, Alb, ALP, ALT, BUN, TP, Scr, Lp(a), TC, GGT and hypertension, a higher UHR was significantly associated with lower FR-BMD [β=-0.076, 95%CI(-0.138~-0.015), P = 0.015]. Significant interaction effects were observed for age and sex ( The association of UHR with FR-BMD is significantly modified by age and sex in middle-aged and elderly populations. Nonlinear relationships exist in males <60 years, females ≥60 years and non-overweight individuals. The potential of UHR as a novel indicator for bone health assessment in select populations is highlighted by our results. 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

Near-infrared (NIR)-II fluorescence imaging at 1000-1700 nm is widely used for deep-tissue visualisation and disease theranostics in the brain, with NIR-II theranostics greatly improving imaging resolution, imaging depth, and therapeutic efficacy. However, the extreme lack of molecular design in NIR-II fluorophores has slowed the discovery of bright candidates and restricted their efficacious application in brain theranostics. Here, we develop a covalent bond locking (CBL) strategy that enables the feasible design of bright NIR-II fluorophores by effectively restricting the twisted intramolecular charge transfer state. These spirofluorophores incorporate terminally spiro-donor groups, which leads to a higher molar extinction coefficient and improved quantum yield than non-spirofluorophores do. With bright and stable NIR-II fluorescence advantages, we demonstrate that CBL nanoparticles (NPs) of spirofluorophores achieve multiscale high-resolution NIR-II angiography via one-photon fluorescence and two-photon fluorescence bioimaging simultaneously. With apolipoprotein E (ApoE) modification, CBL@ApoE NPs achieve enhanced blood-brain barrier permeability, facilitating superior brain glioma theranostics. This work proposes a CBL strategy to engineer highly bright NIR-II fluorescent fluorophores, providing a reliable nanoplatform for deep brain theranostics that can be effectively delivered across biological barriers to target brain tumors. Show less

Melanocortin-2 receptor accessory protein-2 (MRAP2) modulates the activity of hypothalamic melanocortin-4 (MC4R) and growth hormone-secretagogue (GHSR) receptors, which suppress and promote appetite, respectively. We investigate whether obesity-associated variants of MRAP2 alter their ability to modulate MC4R and GHSR signalling as a possible mechanistic link to the development of obesity. Functional effects of five obesity-associated MRAP2 variants were analysed in HEK293 cells by co-expressing wild-type or variant MRAP2 with MC4R or GHSR. Endpoints included cell-surface and total expression, and ligand-induced second-messenger responses, β-arrestin-2 recruitment, and alternative G-protein activation. MRAP2 decreased basal MC4R cell-surface expression while GHSR cell-surface expression was not affected. In MC4R/MRAP2 expressing cells, maximal α-MSH-induced cAMP and β-arrestin-2 recruitment responses were increased. Similarly, ghrelin-induced Ca2+-mobilization in GHSR/MRAP2 expressing cells was increased, but β-arrestin-2 recruitment was suppressed. MRAP2 did not bias G-protein activation by either receptor, although previous reports show MRAP2 biases MC4R signalling towards Gαq/11. The variants did not significantly affect the ability of MRAP2 to modulate MC4R and GHSR signalling. Our results indicate that MRAP2 potentiates the ligand responsiveness of MC4R and GHSR, but has differential effects on β-arrestin-2 recruitment. The MRAP2 variants had no significant effects on the signalling endpoints tested. This suggests that, despite their association with obesity, the variants may be functionally benign, or that the absence of effects reflects limitations inherent to our cellular model. In addition, since MRAP2 can modulate multiple receptors and differentially modulate their signalling, we cannot rule out their influence on body weight regulation via other mechanisms. Show less

Global studies have shown a bidirectional association of gestational diabetes mellitus (GDM) with postpartum depression (PPD). Despite high GDM prevalence in Pakistan (3.3%-17.8%), no prior studies have explored its link with PPD. In this study, association between GDM and risk of developing PPD was investigated and risk factors for PPD were identified using the gold-standard Edinburgh Postnatal Depression Scale (EPDS). Evidence suggests that PPD has strong genetic basis. The BDNF gene is a known candidate for PPD pathogenesis, while the orexin system is linked to arousal, energy metabolism, with emerging role in neuropsychiatric disorders. This study is the first study to explore association of orexin SNP ORX1 10914456 with PPD together with the BDNF SNP rs6265 (Val/Met66), among participants with and without GDM diagnosis. Among 1,000 women approached in hospitals of Islamabad, Rawalpindi, 800 met inclusion criteria (400 GDM, 400 non-GDM controls) and were genotyped for BDNF and orexin SNPs. Participants completed the EPDS 1 week postpartum. Using a cutoff of ≥13, 84.9% of GDM patients and 18% of non-GDM controls scored ≥13 on EPDS (χ2 = 78.337, p < 0.00001). Multivariate logistic regression revealed GDM diagnosis, BMI >25, fasting plasma glucose >126 mg/dL, 31-39-week gestation, <12 years of education, and urban locality as significant risk factors for PPD. GDM diagnosis increased odds of PPD by 2.5-fold (OR = 2.5, 95% CI: 21.48-4.31, p < 0.0001). The orexin SNP Orx1 10914456, CC genotype and BDNF SNP rs6265, AA genotype increased the odds of having higher EPDS scores in GDM patients by 3.11 (OR = 3.11, 95% CI: 1.29-7.47, p < 0.001) and 3.3 (OR = 3.3, 95% CI: 1.31-8.13, p = 0.04, p < 0.05), respectively, in comparison to other genotypic variants. Our study supports orexin and BDNF system-targeted therapies for PPD. Show less

Primary cilia orchestrate several signaling pathways, and their disruption results in pleiotropic disorders called ciliopathies. Bardet-Beidl syndrome (BBS), one ciliopathy, provides insights into cilia function in many tissues. Using a mouse model of BBS, Bbs4 knockout (Bbs4 Show less

Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in men. Androgen deprivation therapy (ADT) has been widely used as the first-line treatment for PCa. However, most PCa will progress to castration-resistant PCa (CRPC) that resists ADT 1 to 3 years after the treatment. Steroidogenesis from cholesterol is one of the mechanisms leading to ADT resistance. In PCa cells, low-density lipoprotein (LDL) mediated uptake is the major venue to acquire cholesterol. However, the mechanism of regulating this process is not fully understood. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that is ectopically expressed in PCa cells and promotes PCa progression by activating downstream signaling pathways. To comprehensively determine the roles of FGFR1 in PCa, we generated FGFR1-null DU145 cells and compared the transcriptomes of FGFR1-null and wild-type cells. We found that ablation of FGFR1 reduced the expression of genes promoting LDL uptake and de novo synthesis of cholesterol, thereby reducing the overall cholesterol pool in PCa cells. Detailed mechanistic studies further revealed that FGFR1 boosted the activation of sterol regulatory element-binding protein 2 (SREBP2) through ERK-dependent phosphorylation and cleavage, which, in turn, increased the expression of low-density lipoprotein receptor (LDLR) and enzymes involved in de novo cholesterol synthesis. Furthermore, in silico analyses demonstrated that high expression of FGFR1 was associated with high LDLR expression and clinicopathological features in PCa. Collectively, our data unveiled a previously unrecognized therapeutic avenue for CRPC by targeting FGFR1-driven cholesterol uptake and de novo synthesis. Show less

Brain-derived neurotrophic factor (BDNF) is a neurotrophin with crucial roles in the developing and adult nervous system, contributing to neuronal survival, differentiation, and synaptic plasticity. The pleiotropic functions of BDNF require stringent spatiotemporal control of its expression, making BDNF one of the most thoroughly studied activity-regulated genes. Over the years, substantial evidence has accumulated, providing insights into BDNF gene structure, numerous mRNA variants, their different localization patterns and translational efficiencies, as well as the functions of the BDNF protein in different tissues. This review aims to summarize the current understanding of the mechanisms governing BDNF expression at transcriptional, posttranscriptional, and translational levels, offering an integrated perspective of BDNF regulation. Show less

The serotonin receptor 7 (5-HT7R) has been indicated as a key modulator of neuronal structure and function, playing critical roles in synaptic plasticity, dendritic spine formation, and cytoskeletal remodeling. 5-HT7R activation promotes neurite outgrowth, enhances long-term potentiation (LTP), stimulates local protein synthesis at synapses, and regulates mitochondrial functions, and the mTOR pathway. These properties make the 5-HT7R a compelling candidate for therapeutic intervention in neurodevelopmental disorders characterized by synaptic dysfunctions. Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of the maternal UBE3A gene, resulting in impairments of synaptic plasticity, dendritic spine density, protein synthesis, mitochondrial activity and mTOR signaling. Intriguingly, many of the processes altered in AS are the ones that are positively regulated by 5-HT7R activation. For instance, AS animal models exhibit reduced LTP and altered dendritic morphology and 5-HT7R stimulation enhances synaptic strength and spine formation in the brain of wild type rodents. Moreover, BDNF/TrkB function signaling is impaired and mitochondrial integrity is disrupted in AS and 5-HT7R agonists enhance the altered BDNF/TrkB signalling and restore mitochondrial dysfunctions in Rett syndrome (RTT) mice model. Interestingly, recent evidence demonstrates that pharmacological activation of 5-HT7Rs increases synaptic protein synthesis, restores LTP, enhances dendritic spine density, and improves cognitive function in an AS mouse model. These encouraging results open the way to future studies using neurons and brain organoids generated from iPSCs obtained from AS patients, which represent novel tools in preclinical research. Overall, 5-HT7R stimulation, by counteracting the molecular alterations associated with the loss of UBE3A, may represent a novel approach to restore neural function in the mature brain, leading to translational applications in AS patients, and possibly also in other synaptopathies. Clinical trial number: not applicable. Show less

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disorder that complicates the identification of effective therapeutic targets. The potential of stem cells and neurotrophins as promising candidates has become increasingly evident, owing to their neuroprotective and anti-inflammatory properties. In this study, a preclinical evaluation of the safety and biodistribution of mesenchymal stromal/stem cells (MSCs) combined with neurotrophin-releasing polyelectrolyte nanoparticles (NTs) was conducted in a porcine intrathecal delivery model relevant to ALS therapy development. Four groups of male pigs were administered saline with NTs, adipose-derived stem cells (ASCs) with NTs, Wharton's jelly-derived MSCs (WJ-MSCs) with NTs, or spinal puncture only. The safety of the treatment was assessed using magnetic resonance imaging (MRI), haematological and biochemical analyses, cerebrospinal fluid profiling, and histology. No adverse effects or significant systemic alterations were observed. It is noteworthy that C-reactive protein levels diminished following NT and NT-MSC administration, suggesting a systemic anti-inflammatory effect. The migration of MSCs was facilitated by cerebrospinal fluid, leading to their accumulation around the spinal cord and brain parenchyma. The present findings demonstrate short-term safety and biodistribution patterns following intrathecal administration of MSCs combined with neurotrophin-releasing nanoparticles in a large-animal model. These preliminary observations provide a pilot framework for future efficacy studies in disease-specific ALS models. This work establishes a translational platform for the development of future ALS therapies, with subsequent studies focused on efficacy testing in disease-specific models that more accurately reflect the slow, heterogeneous, multisystem nature of human ALS. Show less

Amyloid-β (Aβ) PET imaging is a core biomarker and is considered sufficient for the biological diagnosis of Alzheimer's disease (AD). However, it is typically reduced to a binary Aβ™/Aβ+ classification. In this study, we aimed to identify subgroups along the continuum of Aβ accumulation including subgroups within Aβ- and Aβ+. We used a total of 3,110 of Aβ PET scans from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) datasets to develop Show less

Stress is defined as a disruption of homeostasis that elicits adaptive responses aimed at restoring physiological balance. However, when stress becomes chronic or overwhelming, maladaptive changes may occur, contributing to endocrine, behavioral, and neuropsychiatric dysfunctions. Beyond the classical neuroendocrine axes, such as the sympatho-adrenomedullary and hypothalamic-pituitary-adrenal (HPA) axes, the renin-angiotensin system has also being implicated in stress modulation. Previous studies have shown that angiotensin-(1-7), acting through its receptor Mas, exerts a modulatory effect on the stress response, attenuating anxiety- and depression-like behaviors induced by various stressors. Here we investigated the impact of genetic deletion of Mas on the consequences of chronic unpredictable stress (CUS) exposure. Over 21 consecutive days, mice were subjected to random stressors, after which endocrine, behavioral and neurochemical assessments were performed. Mas knockout (KO) mice exposed to CUS exhibited significantly elevated corticosterone and blood glucose levels compared to stressed wild-type mice. In behavioral tests, stressed Mas KO mice displayed the highest immobility times in the forced swimming test, indicating enhanced depressive-like behavior. Anxiety-like behavior was also heightened in Mas KO mice, as evidenced by a significant reduction in the percentage of time spent in the open arms of the elevated plus maze test. Neurochemical analysis revealed a marked reduction in brain-derived neurotrophic factor (BDNF) levels in key brain regions of stressed Mas KO animals. Together, these findings suggest that Mas plays a critical role in the neurobiology of stress, since its absence exacerbates HPA axis hyperactivity, depression- and anxiety-like behaviors, as well as BDNF reduction. Overall, these results highlight the potential neuroprotective role of Mas in stress-related disorders. Show less

In recent years, young adults have navigated multiple, simultaneous crises - COVID-19, war in Ukraine, economic turbulence, climate change, and rapid AI growth - which pose complex mental-health risks. Drawing on multisystemic resilience models and the dual-factor model of mental health, we examine how individual (emotion-regulation difficulties), relational (attachment, social support), and contextual resources (social engagement, place attachment, socioeconomic status) relate to distinct emotional-response profiles and their change across three waves (July 2023, February 2024, September 2024) in a representative Polish sample ( The online version contains supplementary material available at 10.1186/s12992-026-01199-8. Show less

Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neuroprotective axis in which macrophages deploy apolipoprotein E (APOE) to transfer intracellular lipids to neighboring cells, especially fibroblasts. Genetic ablation of The online version contains supplementary material available at 10.1186/s12974-026-03756-9. Show less

Post-traumatic stress disorder (PTSD) is a chronic psychiatric condition linked with abnormal fear responses, oxidative imbalance, inflammation, and neuronal injury. The present work examined the protective effects of morin hydrate (MH), a natural flavonoid known for its antioxidant and neuroprotective properties, in a stress-re-stress (SRS) rat model of PTSD. Male Wistar rats were exposed to repeated stress cues and then treated with vehicle, paroxetine (10 mg/kg, p.o.), or MH (15 and 30 mg/kg, p.o.). Behavioral outcomes were assessed using fear conditioning, elevated plus maze, open field, Y-maze, novel object recognition, forced swim, and sucrose preference tests. Animals exposed to SRS developed pronounced fear retention, anxiety-like and depressive behaviors, and cognitive impairment. Treatment with MH, especially at 30 mg/kg, improved exploratory activity, reduced immobility, and enhanced memory performance. Biochemical studies showed reduced lipid peroxidation and restoration of glutathione, superoxide dismutase, and catalase. MH also lowered pro-inflammatory cytokines (TNF-α, IL-1β) and increased hippocampal brain-derived neurotrophic factor (BDNF). Histological analysis confirmed preservation of neuronal density in CA1 and CA2 regions of the hippocampus. In summary, MH produced behavioral, biochemical, and structural improvements in the SRS model, suggesting its value as a natural therapeutic candidate for PTSD. Show less

This study investigated longitudinal plasma serotonin dynamics across the Alzheimer's disease (AD) continuum (cognitively normal [CN], mild cognitive impairment [MCI], and AD) to determine whether baseline serotonin and its 24-month change are associated with CSF amyloid-β (Aβ42), tau biomarkers, amyloid PET burden, structural brain integrity, and cognitive decline. Data from 959 ADNI participants (CN = 306, MCI = 421, AD = 232) with baseline and 24-month follow-up were analyzed. Measures included plasma serotonin, CSF biomarkers (Aβ42, total tau, p-tau181), florbetapir PET, MRI (hippocampal volume, cortical thickness), and cognitive tests (MMSE, ADAS-Cog 11, CDR-SB). Group differences were tested using ANOVA or Kruskal-Wallis, and associations were examined via partial correlations and mixed-effects models adjusted for age, sex, education, and APOE ε4, with FDR correction. The results revealed that baseline plasma serotonin levels showed a stepwise decline across the clinical continuum (CN > MCI > AD; p ≤ 0.05), consistent with progressive serotonergic dysregulation. In AD participants, higher baseline serotonin was significantly associated with less amyloid pathology and preserved brain structure, including higher CSF Aβ42 (β = 0.28, FDR p = 0.01), lower florbetapir PET SUVR (β = -0.31, FDR p = 0.02), and larger hippocampal volume (β = 0.33, FDR p = 0.02). Higher serotonin was also linked to better cognitive performance (MMSE: β = 0.22, FDR p = 0.02; ADAS-Cog 11: β = -0.24, FDR p = 0.02). Longitudinally, decreases in serotonin over 24 months in AD were associated with worsening amyloid burden (ΔPET SUVR: β = -0.29, FDR p = 0.02) and accelerated hippocampal atrophy (β = 0.32, FDR p = 0.01). Baseline serotonin predicted smaller 24-month declines in CSF Aβ42 (β = 0.28, FDR p = 0.01) and reduced hippocampal volume loss (β = 0.31, FDR p = 0.01). In CN and MCI groups, associations between serotonin and AD biomarkers or cognitive outcomes were not significant after FDR correction. On the whole, lower plasma serotonin levels are linked to amyloid pathology, hippocampal neurodegeneration, and cognitive decline in AD, supporting serotonin's potential as a stage-specific biomarker and mechanistic contributor to disease progression. Integrative longitudinal studies are needed to clarify causality and evaluate serotonergic pathways as therapeutic targets. Show less

Major depressive disorder (MDD) is a highly prevalent psychiatric illness for which rapid-acting antidepressants such as ketamine provide only transient benefit. Because κ-opioid receptor (KOR) signaling contributes to stress-related dysphoria and impaired neuroplasticity, we examined whether KOR antagonism could prolong ketamine's antidepressant-like effects in a mouse model of adolescent chronic unpredictable stress (CUS). Male Show less