Search Results (59)

Mammals exhibit unique and highly variable mechanisms for the establishment and maintenance of pregnancy. Ruminants (e.g., sheep, cows, and goats) have novel mechanisms whereby the conceptus (embryo and its extra-embryonic membranes) signals for the establishment of pregnancy and exhibits unique metabolic pathways favoring conceptus development. Embryos of ruminants reach the spherical blastocyst stage at 5 to 10 mm in diameter and then elongate rapidly to elongated filamentous conceptuses of greater than 250 mm as they make contact with the uterine luminal epithelium (LE) for implantation. During conceptus elongation the trophectoderm cells secrete interferon tau (IFNT), a novel pregnancy recognition signal for ruminants to ensure maintenance of a functional corpus luteum (CL) to secrete progesterone (P4) required for pregnancy. P4 induces uterine epithelia cells to express the endogenous Jaagsiekte Retrovirus (enJSRV) that may transactivate toll-like receptors 7 and 8 in the conceptus trophectoderm to induce secretion of IFNT, a classical viral–antiviral mechanism. IFNT silences expression of receptors for estradiol (E2) and oxytocin (OXTR), which abrogates the mechanism whereby oxytocin from CL and posterior pituitary would otherwise induce large pulses of prostaglandin F_2α (PGF) by uterine epithelia to cause regression of the CL and its secretion of P4. IFNT has another novel role in silencing expression of not only ESR1 and OXTR, but all classical interferon-stimulated genes in the uterine LE and superficial glandular epithelium (sGE), but with P4 increasing expression of genes for transport of nutrients such as glucose and arginine into the uterine lumen to support conceptus development. Ruminant conceptuses convert glucose to fructose, a novel hexose sugar that cannot be transported back to the maternal circulation. Fructose is converted to fructose-1-PO4 for metabolism, not via the pathway for glycolysis but via the novel fructolysis pathway uninhibited by low pH, citrate, or ATP as is the case for glycolysis. Thus, fructose and its metabolites support the pentose cycle, hexosamine biosynthesis pathway, one-carbon metabolism, and the citric acid cycle for all cells of the conceptus. Arginine is another key nutrient transported into the uterine lumen by the uterine LE/sGE in response to P4 and IFNT. Arginine is metabolized to generate nitric oxide, polyamines, and creatine, essential for conceptus growth and development, while enhancing production of IFNT as a novel pregnancy recognition signal, and upregulating expression of genes in the uterine LE/sGE for transport of nutrients. Fructose is the major hexose sugar supporting major metabolic pathways required for conceptus growth and development in ruminants. Full article

This study aimed to investigate the molecular binding mechanisms of bromocriptine toward histamine-associated targets, exploring both antagonist-like and other potential interaction modes that may support therapeutic repurposing. Network pharmacology was applied to identify histamine-related pathways and prioritize potential protein targets. CXCR4, GHSR, and OXTR were selected based on combined docking scores and pharmacophore modeling evidence. Molecular dynamics (MD) simulations over 100 ns assessed structural stability, flexibility, compactness, and solvent exposure. Binding site contact analysis and MM/PBSA free binding energy calculations were conducted to characterize binding energetics and interaction persistence. Bromocriptine exhibited stable binding to all three receptors, engaging key residues implicated in receptor modulation (e.g., Asp187 in CXCR4, Asp99 in GHSR, Arg232 in OXTR). The MM/PBSA ΔG_binding values of bromocriptine were −22.67 ± 3.70 kcal/mol (CXCR4 complex), −22.11 ± 3.55 kcal/mol (GHSR complex), and −21.43 ± 2.41 kcal/mol (OXTR complex), stronger than standard agonists and comparable to antagonists. Contact profiles revealed shared and unique binding patterns across targets, reflecting their potential for diverse modulatory effects. Bromocriptine demonstrates high-affinity binding to multiple histamine-associated GPCR targets, potentially exerting both inhibitory and modulatory actions. These findings provide a molecular basis for further experimental validation and therapeutic exploration in histamine-related conditions. Full article

Background/Objectives: Lower urinary tract symptoms (LUTS), such as frequency, urgency, nocturia, and urge incontinence, are commonly linked to overactive bladder (OAB) and benign prostatic hyperplasia (BPH). Oxytocin receptor (OXTR) upregulation has been proposed to enhance bladder and prostate contractility, while obesity is a recognized risk factor for LUTS, OAB, and BPH. This study aimed to investigate whether the OXTR antagonist atosiban attenuates spontaneous and oxytocin-induced contractions in bladder and prostate tissues from obese and non-obese rats. Methods: Bladder and prostate tissues were obtained from obese and non-obese rats and studied in in vitro organ bath preparations. The effects of atosiban (1 µM and 10 µM) on spontaneous contractility and oxytocin-induced responses were examined. Immunohistochemistry was performed to evaluate OXTR expression in the bladder. Results: Atosiban significantly reduced spontaneous contractions in the bladder (p < 0.0001 in obese; p < 0.01 in non-obese) and prostate (p < 0.01 in obese; p < 0.0001 in non-obese). Oxytocin-induced bladder contractions were significantly increased in obese rats but were attenuated by atosiban at 10 µM (p < 0.05), an effect absent in non-obese rats. Immunohistochemical analysis confirmed elevated OXTR expression in both epithelial and stromal compartments of the bladder in obese rats (p < 0.05). Conclusions: These findings indicate that oxytocin contributes to bladder and prostate hypercontractility, particularly in obesity. Targeting OXTR with atosiban may represent a novel therapeutic strategy for the management of LUTS, OAB, and BPH. Full article

The neuropeptide oxytocin (OXT) is involved in social bonding, reproduction, and childbirth. Its activity is mediated by the oxytocin receptor (OXTR), also expressed in the skin. OXT alleviates dermal fibroblast senescence, and OXT levels correlate with visible skin aging. OXT inhibits nociceptive signaling and promotes neuronal plasticity. Here, we demonstrate OXT-like benefits of OXTR activation for skin touch sensoriality and nociception, as well as visible skin health and beauty indicators, using an aqueous extract of Hyacinthus orientalis bulbs. OXTR activation was evaluated in a Chinese hamster ovary (CHO) cell model. Nociception and innervation benefits were investigated in keratinocyte/sensory neuron coculture models. A placebo-controlled clinical study evaluated gentle touch receptivity, nociception, skin tone, elasticity, and wrinkling. The extract activated OXTR and enhanced dermal fibroblast proliferation in vitro. In the keratinocyte-neuron coculture, the HO extract lowered nociceptive CGRP release below that of the unstimulated and OXT controls and promoted neuronal survival and dendricity. An organ-on-a-chip coculture showed decreased electrical activity and increased neuronal peripherin. Clinically, we observed selective left-side frontal alpha-wave activation, indicating pleasant sensation, reduced nociception, enhanced skin glow, improved elasticity, and reduced wrinkling. This extract thus shows high value for holistic wellbeing solutions, enhancing the skin’s receptivity to pleasant sensations and promoting well-aging. Full article

Background/Objectives: Borderline personality disorder (BPD) is a complex psychiatric condition marked by emotional dysregulation, interpersonal instability, and impulsivity. Despite the advances in psychotherapy and pharmacotherapy, many patients show a partial or unstable response. Recent research suggests that oxytocin, a neuropeptide involved in social cognition and emotional regulation, may offer novel therapeutic avenues. Methods: We systematically synthesize evidence from PubMed, PsycINFO, Web of Science, and Google Scholar on oxytocin’s role in BPD, prioritizing studies on neurobiology, emotion regulation, clinical interventions, and adjunctive therapy models. Thirty studies were included and critically appraised using PRISMA and Cochrane’s tools. Due to methodological heterogeneity, no meta-analysis was conducted; instead, the findings were integrated through a narrative synthesis approach. Results: Evidence supports oxytocin’s modulatory effects on amygdala reactivity, prefrontal–limbic connectivity, and hypothalamic–pituitary–adrenal axis function. Intranasal oxytocin appears beneficial for emotional regulation and interpersonal sensitivity, particularly in individuals with early trauma. The reported effect sizes ranged from small (Cohen’s d ≈ 0.40) to large (d ≈ 0.83), though some trials reported null or adverse effects, such as increased hypermentalization. Heterogeneous responses were influenced by factors such as sex, trauma history, and OXTR gene variants. Conclusions: Although intranasal oxytocin shows promise in modulating core neurobiological systems implicated in BPD and enhancing emotion regulation and social cognition, its clinical effects remain variable and context-dependent. The evidence supports cautious exploration of oxytocin as an adjunct to psychotherapeutic interventions rather than as a standalone treatment. Future research should focus on biomarker-informed, stratified trials that account for trauma history, genetic variation, and sex differences to clarify its therapeutic potential. Full article

Mesothelioma is characterized by the inactivation of tumor suppressor genes, with frequent mutations in neurofibromin 2 (NF2), BRCA1-associated protein 1 (BAP1), and cyclin-dependent kinase inhibitor 2A (CDKN2A). These mutations lead to disruptions in the Hippo signaling pathway and histone methylation, thereby promoting tumor growth. NF2 mutations result in Merlin deficiency, leading to uncontrolled cell proliferation, whereas BAP1 mutations impair chromatin remodeling and hinder DNA damage repair. Emerging molecular targets in mesothelioma include mesothelin (MSLN), oxytocin receptor (OXTR), protein arginine methyltransferase (PRMT5), and carbohydrate sulfotransferase 4 (CHST4). MSLN-based therapies, such as antibody–drug conjugates and immunotoxins, have shown efficacy in clinical trials. OXTR, upregulated in mesothelioma, is correlated with poor prognosis and represents a novel therapeutic target. PRMT5 inhibition is being explored in tumors with MTAP deletions, commonly co-occurring with CDKN2A loss. CHST4 expression is associated with improved prognosis, potentially influencing tumor immunity. Immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in some cases; however, resistance mechanisms remain a challenge. Advances in multi-omics approaches have improved our understanding of mesothelioma pathogenesis. Future research will aim to identify novel therapeutic targets and personalized treatment strategies, particularly in the context of epigenetic therapy and combination immunotherapy. Full article

One of the most frequent forms of maternal morbidity following childbirth is postpartum depression. Postpartum depression (PPD), a disabling condition as a major public health concern, has a significant negative impact on the child’s emotional, mental as well as intellectual development if left undiagnosed and untreated, which can later have long-term complications. The oxytocin system is an excellent candidate gene system in the maternal context. Differences in vulnerability of mothers for the onset of postpartum psychiatric disorders could be influenced by individual differences in the genetic profile of each one. In this original research, we aimed to explore if there are any possible contributions of genetic variation on both the oxytocin receptor gene (OXTR) and the oxytocin gene (OXT) to the occurrence of postpartum depression, aiming to provide the latest evidence and determine which genetic polymorphisms significantly create a susceptibility for this condition. A total of 100 mothers were preliminarily genotyped before they completed the Edinburgh Postnatal Depression Scale Questionnaire (EPDS) at 6 weeks postpartum. DNA was extracted from peripheral blood samples of the participants (N = 100) and evaluated for the oxytocin gene (OXT_rs2740210; OXT_rs4813627) and oxytocin receptor gene (OXTR_ rs237885) single nucleotide polymorphisms. The results highlighted a significant interaction between the oxytocin OXT_rs2740210 genotype and maternal postpartum depression in mothers with the CC genotype but not in those with AA/AC genotypes. This reveals that an interaction of vulnerable genotypes (CC genotype of OXT_rs2740210, C allele in genotype of OXT_rs2740210, G allele in genotype of OXT_rs4813627) with an environmental burden or other risk factors would predispose the mothers to develop postpartum depression. We found no significant association between the interaction effect of the oxytocin receptor gene OXTR_rs237885 genotype depending on the occurrence of maternal postpartum depression. These findings prove the implication of the oxytocinergic system gene variants in vulnerability for postpartum depression and indicate the need for future studies adopting a multilevel approach in order to increase understanding. Full article

Sensory processing abnormalities have been noted since the first clinical description of autism in 1940. However, it was not until the release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) in 2013 that sensory challenges were considered as symptoms of autism spectrum disorder (ASD). Multisensory processing is of paramount importance in building a perceptual and cognitive representation of reality. For this reason, deficits in multisensory integration may be a characteristic of ASD. The neurohormone oxytocin (Oxt) is involved in the etiology of ASD, and there are several ongoing clinical trials regarding Oxt administration in ASD patients. Recent studies indicate that Oxt triggers muscle contraction modulating thermogenesis, while abnormal thermoregulation results in sensory deficits, as in ASD. Activation of the Oxt system through exposure to cold stress regulates the expression of oxytocin receptor (Oxtr) in the brain and circulating Oxt, and if this mechanism is pathologically disrupted, it can lead to sensory processing abnormalities since Oxt acts as a master gene that regulates thermogenesis. This review will describe the sensory deficits characteristic of ASD together with the recent theories regarding how the modulation of Oxt/Oxtr in the brain influences sensory processing in ASD. Full article

Background: Adolescent non-suicidal self-injury (NSSI) has emerged as a progressively widespread and significant public health concern on a global scale. Research has increasingly documented a positive linkage between deviant peer affiliation and adolescent NSSI; however, there is little known about the underlying moderating or mediating mechanism of NSSI. According to the gene × environment interaction perspective, the current study investigated the intermediary function of depression in linking deviant peer affiliation to NSSI among adolescents, while also considering the moderating effect of the OXTR gene rs53576 polymorphism on this intermediary process. Methods: A total of 469 adolescents (Mean_age = 12.81 years; SD = 0.47 years) anonymously finished the study questionnaires. This study used structural equation modeling analysis to verify a moderated mediation model. Gender, age, and family financial difficulties were used as covariates. Results: Mediation analyses suggested that the positive connection between deviant peer affiliation and adolescent NSSI was mediated by depression. Moreover, the moderated mediation analyses revealed that deviant peer affiliation increased depression levels, which in turn contributed to increased NSSI among adolescents with the AA genotype. Nevertheless, the correlation failed to reach statistical significance among adolescents possessing the GA and GG genotypes. Conclusions: These findings emphasize depression’s potential as a bridge linking deviant peer affiliation to adolescent NSSI. The AA genotype of the OXTR gene rs53576 emerges as a critical risk factor in the enhancement of this indirect effect. This study provides valuable perspectives for designing intervention strategies aimed at reducing adolescent NSSI. Full article

Oxytocin (OXT) is a neurohypophysial nonapeptide that exerts its effects mainly through the oxytocin receptor (OXTR). Several studies have pointed out the role of OXT in the modulation of stem cell (SC) fate and properties. SCs are undifferentiated cells characterized by a remarkable ability to self-renew and differentiate into various cell types of the body. In this review, we focused on the role of OXT in SC differentiation. Specifically, we summarize and discuss the scientific research examining the effects of OXT on mesodermal SC-derived lineages, including cardiac, myogenic, adipogenic, osteogenic, and chondrogenic differentiation. The available studies related to the effects of OXT on SC differentiation provide little insights about the molecular mechanism mediated by the OXT–OXTR pathway. Further research is needed to fully elucidate these pathways to effectively modulate SC differentiation and develop potential therapeutic applications in regenerative medicine. Full article

The development of fetal organs can be impacted by systemic changes in maternal circulation, with the placenta playing a pivotal role in maintaining pregnancy homeostasis and nutrient exchange. In clinical obstetrics, oxytocin (OXT) is commonly used to induce labor. To explore the potential role of OXT in the placental homeostasis of OXT, we compared OXT levels in neonatal cord blood among neonates (23–42 weeks gestation) whose mothers either received prenatal OXT or experienced spontaneous labor. Our previous research revealed that the oxytocin receptor (OXTR), essential in forming the blood–retina barrier, is expressed in the retinal pigment epithelium (RPE). We hypothesized that perinatal OXT administration might influence the development of the neural retina and its vasculature, offering therapeutic potential for retinal diseases such as retinopathy of prematurity (ROP). Plasma OXT levels were measured using a commercial OXT ELISA kit. Human fetal RPE (hfRPE) cells treated with OXT (10 µM) were assessed for gene expression via RNA sequencing, revealing 14 downregulated and 32 upregulated genes. To validate these differentially expressed genes (DEGs), hfRPE cells were exposed to OXT (0.01, 0.1, 1, or 10 µM) for 12 h, followed by RNA analysis via real-time PCR. Functional, enrichment, and network analyses (Gene Ontology term, FunRich, Cytoscape) were performed to predict the affected pathways. This translational study suggests that OXT likely crosses the placenta, altering fetal OXT concentrations. RNA sequencing identified 46 DEGs involved in vital metabolic and signaling pathways and critical cellular components. Our results indicate that the perinatal administration of OXT may affect neural retina and retinal vessel development, making OXT a potential therapeutic option for developmental eye diseases, including ROP. Full article

Background: Caregiver–infant reciprocity is related to infant/toddler development and health. However, there is a dearth of research on reciprocity variables like co-occupation and developmental variables such as infant/toddler sensory processing/preferences, and it is important to understand the biopsychosocial mediators of these relations. These include novel genetic markers like maternal oxytocin receptor single-nucleotide polymorphisms (OXTR SNPs). Therefore, this study examined whether mothers carrying risk alleles for three OXTR SNPs displayed different co-occupational behaviors with their infants and whether their infants/toddlers showed different sensory processing/preferences. Methods: Data from the Infant Development and Healthy Outcomes in Mothers Study included prenatal saliva samples assayed for OXTR SNPs, 6-month postnatal behavioral observations coded for maternal–infant co-occupations (reciprocal emotionality, physicality, and intentionality), and 10-, 14-, and 18-month postnatal, maternal-reported Infant/Toddler Sensory Profiles (classified as within or outside the majority range for low registration, sensory seeking, sensory sensitivity, and sensory avoiding). Results: Mothers with rs53576 risk allele A engaged in more frequent reciprocal emotionality, while those with rs2254298 risk allele A engaged in less frequent reciprocal emotionality but more frequent reciprocal intentionality. Mothers with rs53576 risk allele A had infants with 11 times greater odds of being outside of the majority range for sensation avoiding at 10 months old. Conclusions: The results converge with the literature supporting links between OXTR SNPs, caregiver reciprocity, and infant/toddler development but extend the findings to relatively novel constructs (caregiver–infant co-occupations and infant/toddler sensory processing/preferences). Full article

This study aimed to elucidate the morphophysiology and oxytocin receptor (OXTR) expression in the cervix of doe goats during various reproductive stages to enhance reproductive management strategies. A total of 40 cervical samples were categorized into follicular (n = 15), luteal (n = 10), and early pregnancy (n = 15) stages. Utilizing advanced imaging based on functional and morphological markers, the study employed computed tomography (CT) scans, histochemical staining (Masson trichrome and alcian blue), immunohistochemistry, Western blotting, and quantitative PCR (qPCR) to assess structural changes in the cervix and in OXTR expression during the estrous cycle and early pregnancy. CT scans revealed consistent cervical folds and a significant reduction in cervical width during pregnancy, suggesting structural adaptations for gestational integrity. Histochemical analyses indicated a well-organized collagen network and presence of mucins, essential for cervical function and integrity. Immunohistochemistry and Western blotting demonstrated elevated OXTR protein levels during the follicular stage, which were markedly reduced during pregnancy, indicating a role in facilitating cervical relaxation and sperm transport during estrus and maintaining cervical closure during gestation. qPCR analysis showed stable OXTR mRNA levels during follicular and luteal stages with a slight, non-significant increase during pregnancy, pointing towards posttranscriptional regulatory mechanisms. In conclusion, this study demonstrates that cervical morphology and OXTR expression in doe goats undergo significant changes across reproductive stages, with elevated OXTR protein levels during the follicular phase and notable reductions in cervical width and OXTR protein levels during pregnancy, indicating structural and functional adaptations for both reproductive processes and gestational integrity. Full article

Background: Neurodevelopmental disorders (NDDs) like intellectual disability (ID) are highly heritable, but the environment plays an important role. For example, endocrine disrupting chemicals (EDCs), including bisphenol A (BPA) and its analogues, have been termed neuroendocrine disruptors. This study aimed to evaluate the influence of different genetic polymorphisms (SNPs) on cognitive function in Spanish schoolchildren according to dietary bisphenol exposure. Methods: A total of 102 children aged 6–12 years old were included. Ten SNPs in genes involved in brain development, synaptic plasticity, and neurotransmission (BDNF, NTRK2, HTR2A, MTHFR, OXTR, SLC6A2, and SNAP25) were genotyped. Then, dietary exposure to bisphenols (BPA plus BPS) was estimated and cognitive functions were assessed using the WISC-V Spanish form. Results: BDNF rs11030101-T and SNAP25 rs363039-A allele carriers scored better on the fluid reasoning domain, except for those inheriting the BDNF rs6265-A allele, who had lower scores. Secondly, relevant SNP–bisphenol interactions existed in verbal comprehension (NTRK2 rs10868235 (p-int = 0.043)), working memory (HTR2A rs7997012 (p-int = 0.002), MTHFR rs1801133 (p-int = 0.026), and OXTR rs53576 (p-int = 0.030)) and fluid reasoning (SLC6A2 rs998424 (p-int = 0.004)). Conclusions: Our findings provide the first proof that exploring the synergistic or additive effects between genetic variability and bisphenol exposure on cognitive function could lead to a better understanding of the multifactorial and polygenic aetiology of NDDs. Full article

Background: Alexithymia is a trait involving difficulties in processing emotions. Genetic association studies have investigated candidate genes involved in alexithymia’s pathogenesis. Therefore, the aim of the present study was to perform a systematic review of the genetic background associated with alexithymia. Methods: A systematic review of genetic studies of people with alexithymia was conducted. Electronic databases including PubMed, Scopus, and Web of Science were searched for the study purpose. We used the words “Alexithymia”, “gene”, “genetics”, “variants”, and “biomarkers”. The present systematic review was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. We found only candidate gene studies. A total of seventeen studies met the eligibility criteria, which comprised 22,361 individuals. The candidate genes associated with alexithymia were the serotoninergic pathway genes solute carrier family 6 member 4 (SLC6A4), serotonin 1A receptor (HTR1A), and serotonin 1A receptor (HTR2A); the neurotransmitter metabolism genes dopamine receptor D2 (DRD2), ankyrin repeat and kinase domain containing 1 (ANKK1), catechol-o-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and oxytocin receptor (OXTR); and other pathway genes, vitamin D-binding protein (VDBP), tumor protein P53 regulated apoptosis inducing protein 1 (TP53AIP1), Rho GTPase Activating Protein 32 (ARHGAP32), and transmembrane protein 88B (TMEM88B). Conclusion: The results of this study showed that only case–control gene studies have been performed in alexithymia. On the basis of our findings, the majority of alexithymia genes and polymorphisms in this study belong to the serotoninergic pathway and neurotransmitter metabolism genes. These data suggest a role of serotoninergic neurotransmission in alexithymia. Nevertheless, more and future research is required to learn about the role of these genes in alexithymia. Full article