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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

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

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

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

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

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

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 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

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

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

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 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

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

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

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

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

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

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

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

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

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

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

Genome-wide association studies (GWASs) have identified hundreds of obesity-associated SNPs, but establishing their causality remains challenging. Here, we demonstrate that rs11676272, located in the ADCY3 gene, is a functional causal variant for obesity susceptibility. Bioinformatic analyses and dual-luciferase reporter assays indicate that the rs11676272 region may act as a human-gained enhancer regulating ADCY3 expression. In HEK293T cells, CRISPR-Cas9-mediated single-nucleotide editing of rs11676272 (T > C) reduces ADCY3 expression. Moreover, the rs11676272-T allele is preferentially bound by the transcription factor E2F3 to upregulate ADCY3 expression, whereas the rs11676272-C risk allele loses this binding. In vivo, the rs11676272 T > C variant in human ADCY3 (hADCY3) knock-in mice accelerates weight gain under high-fat diet conditions and shortens primary cilia in the ventromedial hypothalamus (VMH). CRISPRa-mediated activation of the hADCY3 promoter region rescues ciliary length in both the VMH and hypothalamic arcuate nucleus of Mut-hADCY3 mice. Our data reveal a causal role for rs11676272 in obesity, offering insight into potential therapeutic strategies. 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

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