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peptide science.

MASH in Type 2 Diabetes: Pathophysiology, Diagnosis, and Therapeutic Management-A Narrative Review.

Medicina (Kaunas)

Adela Gabriela Ştefan, Adina Mitrea, Diana Clenciu +11 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as one of the greatest challenges for the modern public health system and serves as the foundation for the development of advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH), which may progress to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). MASLD and type 2 diabetes mellitus (T2DM) mutually exacerbate one another. MASLD increases the incidence of T2DM and the risk of complications in patients already affected. T2DM accelerates progression to MASH, which has become the second leading cause of liver transplantation and end-stage liver disease, and is associated with hepatic decompensation, cirrhosis, HCC, chronic kidney disease, and cardiovascular disease. MASLD and MASH are strongly linked to T2DM and obesity, pathogenesis including genetic polymorphisms, environmental factors, and multiple metabolic disturbances: insulin resistance (IR), gut dysbiosis, altered adipokine signaling, such as reduced adiponectin alongside increased pro-inflammatory cytokines. Inflammation plays a central role in the development of HCC in MASH, even in the absence of significant fibrosis. The Fibrosis-4 index (FIB-4) should be used as a first-line noninvasive tool to assess fibrosis risk. Additionally, ultrasound-based transient elastography (FibroScan) supports clinicians in assessing steatosis and fibrosis severity. Histologically, MASH is characterized by steatosis, lobular inflammatory changes, and ballooning degeneration of hepatocytes, with or without associated fibrosis. Accurately diagnosing and stratifying MASLD based on fibrosis risk is crucial to identify patients who may benefit from pharmacological treatment or can be managed only with lifestyle interventions. Patients should attain above 10% weight loss through lifestyle modifications. Resmetirom is recommended in F2/F3 fibrosis stages. For treating T2DM, glucagon-like peptide-1 receptor agonists and coagonists, sodium-glucose cotransporter-2 inhibitors, metformin (if glomerular filtration rate exceeds 30 mL/min), and insulin (in decompensated cirrhosis) are preferred. Clinical insights derived from trials are expected to optimize quality of life and long-term outcomes in patients with MASH.

Engineered nutrient-stimulated hormonal multi-agonists for precision targeting of obesity and metabolic disorders.

Clin Mol Hepatol

Yun Kyung Cho, Chang Hee Jung

Obesity and its related metabolic comorbidities, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease, are increasingly recognized as heterogeneous and multisystemic disorders. Despite the significant benefits in glycemic control and weight loss exhibited by GLP-1 receptor agonists (GLP-1RAs), their limitations have initiated the development of engineered multi-agonist therapies targeting additional nutrient-stimulated hormonal (NUSH) pathways. Dual and triple peptide-based co-agonists combining glucagon-like peptide-1 (GLP-1) with glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, or peptide YY have demonstrated superior metabolic efficacy in preclinical and clinical studies. Tirzepatide (GLP-1/GIP dual agonist), CagriSema (GLP-1/amylin dual agonist), and retatrutide (GLP-1/GIP/glucagon triple agonist) have achieved unprecedented levels of weight loss and glycemic improvement, with certain agents also demonstrating hepatic, cardiovascular, and inflammatory benefits. Non-peptidyl oral GLP-1RAs, such as orforglipron, offer novel formulation strategies to enhance treatment accessibility and adherence. Multi-agonist incretin-based therapies represent a paradigm shift in the management of obesity and metabolic diseases. These agents offer broad clinical utility beyond glucose lowering by mimicking the pleiotropic hormonal responses observed after bariatric surgery. These therapies are poised to emerge as key components of precision metabolic medicine. This review article explores the mechanistic basis, pharmacological characteristics, and clinical data supporting the use of engineered NUSH-based peptide therapies for obesity and its related metabolic disorders, with particular emphasis on recent progress in the development and clinical application of dual and triple agonists.

Evaluation of the Therapeutic Potential of Synthetic Growth Hormone-Releasing Hormone Antagonist MIA-690 as a Cognitive Modulator in a Mouse Model of Gulf War Illness.

Int J Mol Sci

Luis Manuel Salgueiro-Tosta, Arumugam Radhakrishnan Jayakumar, William Kochen +7 more

Gulf War illness (GWI) is a multi-symptom disorder affecting veterans of the Persian Gulf operations. Persistent neuroendocrine dysregulation contributes to impairing cognitive capacity and generates anxiety-like behavior. Effective treatments for this illness are challenging due to compromised metabolism, increased oxidative stress and neuroinflammation, perpetuated by chronic stress and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. This neuroinflammation can be alleviated with synthetic antagonistic analogs of the growth hormone-releasing hormone (GHRH) through modulation of the HPA axis. We evaluated the efficacy of the GHRH antagonist analog, MIA-690, against cognitive impairment and anxiety-like behavior in GWI. Mice exposed to an experimental GWI model involving corticosterone (CORT) and diisopropylfluorophosphate (DFP), followed by CORT and lipopolysaccharide (LPS), received a daily subcutaneous dose of 10 μg of MIA-690 for 10 days. Assessments of spatial memory, recognition capacity, somatic health, anxiety and innate survival were carried out, combining the Morris water maze (MWM), novel object recognition (NORT), grip strength (GST), and open field (OFT) tests. Learning efficiency was selectively enhanced in females using the MWM. There were no significant differences in the recall capacity and performance on the OFT, NOR, and GST tasks. Our findings suggest that the MIA-690 dosage is sufficient to improve learning deficits in experimental GWI exposures.

Sex Differences in [68Ga]Ga-NODAGA-Exendin-4 Uptake in the Pituitary of Individuals With Type 2 Diabetes.

Diabetes Obes Metab

Sevilay Tokgöz, Marti Boss, Rick I Meijer +5 more

Adjunctive use of Polypodium leucotomos extract in patients with erythropoietic protoporphyria: An exploratory study.

Photochem Photobiol

Nayha Shetty, Rebecca L Quiñonez, Marissa S Ceresnie +3 more

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) cause severe photosensitivity, resulting in significant quality of life (QoL) impairment. This study aims to evaluate the safety and efficacy of Polypodium leucotomos extract (PLE) as an adjunctive therapy in patients with persistent symptoms despite standard dosing of afamelanotide. In this prospective single-center cohort study, eight adults with confirmed EPP or XLP and ongoing symptoms despite regular afamelanotide implants every 2 months were enrolled. Participants received 480 mg oral PLE daily for 4 months. QoL and symptom severity were measured using questionnaires at baseline, Day 60, and Day 120. Six participants completed the study. Statistically significant improvements in QoL were observed on Day 60 (p = 0.014), but not at Day 120 (p = 0.152). Half of participants reported reduced reaction severity. No adverse events occurred. Adjunctive PLE improved short-term QoL in participants with incomplete symptom control on afamelanotide alone and was well tolerated. Larger studies are warranted.

Central Diabetes Insipidus as a Rare Cause of Polyuria.

Ann Afr Med

Stuti Bhandari, Samyama Sagare Venkatesh, L U Chirag +1 more

Central diabetes insipidus (CDI) is a rare condition characterized by arginine vasopressin deficiency, leading to persistent polyuria and polydipsia. Although it can present at any age, idiopathic CDI in young adults is uncommon and diagnostically challenging. Inflammatory conditions such as infundibuloneurohypophysitis must be considered, particularly when magnetic resonance imaging (MRI) reveals a thickened pituitary stalk and absence of the posterior pituitary bright spot. Early recognition and differentiation from diabetes mellitus, nephrogenic diabetes insipidus, and primary polydipsia are crucial for effective management. We report the case of a 20-year-old male who presented with excessive urination and thirst for 6 weeks. Physical examination was unremarkable, and the patient had no history of trauma or systemic illness. Urine osmolality was markedly low, and MRI of the brain showed absence of the posterior pituitary bright spot and thickening of the infundibulum, suggestive of infundibuloneurohypophysitis. The patient responded well to desmopressin therapy with symptomatic improvement, thus supporting the diagnosis of CDI. This case highlights the importance of considering idiopathic CDI in young adults presenting with unexplained polyuria and polydipsia. Infundibuloneurohypophysitis should be suspected in patients with characteristic MRI findings even in the absence of overt systemic autoimmune disease. A methodical diagnostic approach, including hormone assays, imaging, and therapeutic trials, can enable early diagnosis and effective long-term management.

Escitalopram Oxalate Improved Insomnia by Targeting SLC6A4 to Regulate the Hypothalamic-Pituitary-Adrenal Axis.

Pharmacology

Xin Gu, Jing An, Mingxue Zhang +3 more

Escitalopram oxalate (ESC) was extensively reported to improve insomnia in patients with depression/anxiety. The serotonin transporter gene (SLC6A4) was involved in regulating insomnia. However, it is still unclear whether ESC improves insomnia by regulating SLC6A4 expression. Therefore, this study aimed to investigate whether ESC improves insomnia by regulating SLC6A4 based on clinical and animal experiments.

Bioinspired cardiac-targeted metal-organic framework nanozyme for modulating inflammatory responses in heart failure with preserved ejection fraction.

Front Bioeng Biotechnol

Yuesheng Gui, Xiaowan Fan, Kairui Xiao +10 more

Heart failure with preserved ejection fraction (HFpEF) is a common heart failure type with poor prognosis. Its mechanisms are unclear, and specific diagnostic criteria and effective treatments are lacking. Recent studies have emphasized the impact of inflammation and oxidative stress on the occurrence and development of HFpEF. Anti-inflammatory interventions targeting oxidative stress show promise, but traditional antioxidants are insufficient.

Growth hormone-releasing hormone in retinal disorders and uveitis: an updated review.

Int J Ophthalmol

Sha-Lin Yi, Yu-Qiang Huang

Growth hormone-releasing hormone (GHRH) is a hypothalamic releasing hormone that plays a crucial physiological role in regulating the synthesis and release of anterior pituitary hormones. In recent years, studies have found that GHRH possesses functions like anti-inflammation, promoting cell proliferation, and facilitating cell migration. It participates in regulating the development of uveitis and diabetic retinopathy. Additionally, it also has an impact on the development of retinal ganglion cells by modulating the inflammatory response and mediating the immune response. Given the important roles of GHRH in ophthalmic diseases, elucidating the molecular regulation of the GHRH-GHRH receptor (GHRHR) signal and the innovative development of intervention pathways that directly or indirectly target GHRH serve as strong evidence of how basic research guides innovation and translation. In this review, research reports on GHRH in ophthalmic diseases including retinal diseases and uveitis were summarized and analyzed.

Treatment Patterns in Patients With Incident Pulmonary Hypertension: Real-World Data From the Pulmonary Hypertension Association Registry.

Chest

Sarah L Khan, Carly J Paoli, Noah Kime +6 more

Current evidence supports risk-based treatment for pulmonary arterial hypertension (PAH) with an endothelin receptor antagonist and phosphodiesterase type 5 inhibitor as initial therapy for patients with low- and intermediate-risk PAH, and triple therapy with the addition of a parenteral prostacyclin for patients with high-risk PAH.

Conventional Antiarrhythmics Class I-IV, Late INa Inhibitors, IKs Enhancers, RyR2 Stabilizers, Gap Junction Modulators, Atrial-Selective Antiarrhythmics, and Stable Gastric Pentadecapeptide BPC 157 as Useful Cytoprotective Therapy in Arrhythmias.

Pharmaceuticals (Basel)

Predrag Sikiric, Ivan Barisic, Mario Udovicic +20 more

This review examines and hypothesizes cytoprotection as a conceptual therapeutic criterion for antiarrhythmic drugs, referring to the possibility of suppressing arrhythmias while avoiding adverse electrophysiological or systemic effects. Toward a theoretically complete cytoprotective profile-preserving benefits and eliminating toxicity-the criterion was the degree of counteraction of arrhythmias (i.e., bradycardia, tachycardia, atrioventricular (AV) block, ventricular tachycardia (VT), ST-segment changes, prolonged P, PR, QRS, and QT/QTc intervals, and repolarization). Conventional and new antiarrhythmics share class I-IV ≈ partial cytoprotection/narrow range; late INa inhibitors, IKs enhancers, RyR2 stabilizers, gap junction modulators, and atrial-selective antiarrhythmics ≈ partial cytoprotection/more extended range. Still predominantly in preclinical models, stable gastric pentadecapeptide BPC 157, in the clinic, has not demonstrated adverse effects in available human trials (non-cardiac) to date. As a prominent cytoprotection mediator (LD1 not achieved in toxicology studies), it demonstrates well-matched cytoprotective-antiarrhythmic effects, BPC 157 ≈ full cytoprotection/wide-range homeostasis. In vivo, this was across models of hypo-/hyperkalemia, hypermagnesemia, ischemia-reperfusion, myocardial infarction, drug-induced arrhythmias (including local anesthetics), and vascular occlusion. BPC 157 restores sinus rhythm, normalizes P/QRS/QT intervals, prevents AV block, suppresses VT, attenuates ST-segment changes, and stabilizes heart rate, even when insults are advanced. In vitro, HEK293 studies confirm direct membrane-stabilizing actions: BPC 157 prevents hypokalemia-induced hyperpolarization, reduces hyperkalemia- and hypermagnesemia-induced depolarization, and mitigates local anesthetic-induced Na+/Ca2+ dysregulation, reflecting bidirectional homeostatic modulation of membrane potential. Thus, to confirm the hypothesis, these BPC 157 conditional, not constitutive effects, in rodent models or in vitro systems (HEK293 cells), mandate expansion of now limited clinical data and mechanisms in human investigated as a translational cytoprotective strategy for complex arrhythmias.

Tendon, Ligament, and Muscle Injury, Osteotendinous, Myotendinous, and Muscle-to-Bone Junction Therapy Perspectives with Growth Factors and Stable Gastric Pentadecapeptide BPC 157-A Review.

Pharmaceuticals (Basel)

Danijel Matek, Irena Matek, Mladen Japjec +18 more

As a novel theoretical and practical advantage, preclinical to clinical evidence, this systematic review of PRP, growth factors, and stable gastric pentadecapeptide BPC 157 efficacy in complex musculoskeletal and junctional injuries emphasizes the cytoprotection concept, healing to restore tissue integrity. Notably, the concept holds tendon, ligament, and muscle healing, in particular. Then, it holds their healing together as interconnected lesions. Consequently, this review presents the possibilities for cytoprotective therapies suited for tendon/ligament/muscle and recovery of osteotendinous, myotendinous, and the muscle-to-bone junction. The estimated key was the success of injury recovery amid each agent's direct exogenous administration, alone or with a carrier, locally or systemically, without reliance on complex scaffolds, carriers, or tissue-engineering constructs. As reviewed, while with commonly acknowledged physiological significance, and acting throughout cytoprotection principles, growth factors (PDGF, TGF-β1, IGF-1, FGF, VEGF, BMPs) delivered locally with various carriers improve tendon, ligament, and muscle healing; however, some (PDGF, TGF-β1, IGF-1) may fail in muscle lesions, and all show limited or no efficacy in junctional healing. Contrarily, proposed as a cytoprotection mediator, BPC 157 acts alone with a full cytoprotection range, given systemically or locally. Moreover, without any carrier, BPC 157 acts alone, combining beneficial effects on tendon, ligament, and muscle injuries with osteotendinous, myotendinous, and muscle-to-bone healing. In rat studies, across systemic (intraperitoneal, intragastric, or drinking water) and local (cream) administration, BPC 157 consistently demonstrated efficacy, indicating considerable translational potential. Further clinical studies will strengthen cytoprotective therapy and, particularly, BPC 157 in complex musculoskeletal and junctional injuries.

Comparative effectiveness of continuous positive airway pressure and glucagon-like peptide-1 receptor agonists in obstructive sleep apnea: A network meta-analysis of randomised trials.

Diabetes Obes Metab

Gaspar R Chiappa, Paula C N Santos, Deivyd Vieira Silva Cavalcante +5 more

To compare the effects of continuous positive airway pressure (CPAP), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), their combination, and no active intervention on respiratory, sleepiness, and metabolic outcomes in adults with obstructive sleep apnea (OSA). We searched PubMed, Embase, and CENTRAL through August 2025 for randomised trials of CPAP, exenatide, liraglutide, tirzepatide, or their combinations. The primary endpoint was apnea-hypopnea index (AHI). Secondary endpoints were Epworth Sleepiness Scale (ESS), body mass index (BMI), systolic and diastolic blood pressure (SBP, DBP), fasting glucose, and glycated haemoglobin (HbA1c). Random-effects network meta-analyses estimated mean differences (MDs) with 95% confidence intervals (CIs). Treatments were ranked using SUCRA, and certainty of evidence was assessed with GRADE. Thirty-four trials including 3964 participants were eligible. CPAP produced the largest reduction in AHI versus no active intervention (MD -22.17 events/h; 95% CI -38.01 to -6.33) and improved ESS (MD -2.75; 95% CI -3.71 to -1.79). Liraglutide reduced BMI (MD -1.60 kg/m2; 95% CI -2.04 to -1.16) and HbA1c (MD -0.19%; 95% CI -0.25 to -0.13), whereas CPAP showed no meaningful metabolic effect. Liraglutide plus CPAP achieved the greatest BMI reduction (MD -2.00 kg/m2; 95% CI -3.49 to -0.51). No intervention significantly changed SBP, DBP, or fasting glucose. According to GRADE, certainty of evidence was moderate for CPAP effects on respiratory and sleepiness outcomes and for GLP-1 receptor agonists on BMI and HbA1c, and low for blood pressure and fasting glucose. CPAP is the most effective therapy for respiratory control, while GLP-1 receptor agonists primarily improve weight and glycaemic indices, supporting an integrated airway-metabolic approach to OSA management.

Changes in Oral Mucosa Associated with Melanotan II Injections: A Case Report.

Life (Basel)

Alexander Bonchev

This case report presents a three-month follow-up of a patient who self-administered Melanotan II injections over a period of 64 days with the goal of achieving a deeper tanning effect. Melanotan II is an unlicensed synthetic peptide analog belonging to the melanocortin hormone family. It acts primarily by activating melanocortin 1 receptors on melanocytes, stimulating eumelanin production and resulting in skin pigmentation independent of sun exposure. Despite its popularity, particularly through promotion on social media, Melanotan II remains unregulated, and its use is associated with a range of potential adverse effects. During the initial intraoral examination, brown pigmentation was observed on the attached gingiva in both the maxillary and mandibular arches. The lesions were almost symmetrically distributed, with a more intense coloration in the anterior region of the lower jaw. Additional pigmented areas with irregular shapes and poorly defined borders were noted on the left and right buccal mucosa. At the one-month follow-up after discontinuation of the injections, the buccal mucosal pigmentation had nearly disappeared. However, at the three-month follow-up, gingival pigmentation persisted, though with visibly reduced intensity. To date, there is a lack of published data specifically addressing the timeline for resolution of oral pigmentation associated with Melanotan II use, making this case a valuable contribution to the limited existing literature on the subject.

The GLP-1-miRNA network: Epigenetic control of obesity and metabolic disorders.

Diabetes Obes Metab

Shihua Zhao, Ping Qin, Xin Wang +1 more

Glucagon-like peptide-1 (GLP-1) is a central incretin hormone with pleiotropic effects on glucose homeostasis, appetite regulation, and energy metabolism. Beyond its classical insulinotropic actions, GLP-1 enhances cardiovascular, renal, hepatic, and central nervous system (CNS) functions, thereby integrating multi-organ metabolic responses. Emerging evidence highlights the critical role of microRNAs (miRNAs) as epigenetic regulators of GLP-1 signalling, influencing receptor expression, β-cell survival, hypothalamic appetite circuits, and peripheral tissue metabolism. miRNAs act bidirectionally: they can attenuate GLP-1 receptor (GLP-1R) expression, contributing to 'incretin resistance' in obesity and type 2 diabetes (T2DM), or mediate GLP-1-induced transcriptional adaptations that enhance insulin secretion, lipid oxidation, and energy expenditure. This review synthesizes current knowledge of GLP-1 physiology, receptor signalling, and the miRNA-mediated regulatory network, with a focus on mechanisms underlying obesity and metabolic disorders. This review proposes an integrated GLP-1-miRNA framework that bridges molecular endocrinology with precision metabolic medicine.

Probable Tirzepatide-Induced Rhabdomyolysis in an HIV-Positive Patient.

Hosp Pharm

Drew A Wells, Kaulin Duncan, Sami Sakaan

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, has gained widespread use for the treatment of type 2 diabetes mellitus, obesity, and obstructive sleep apnea. This report presents the first probable case of tirzepatide-associated rhabdomyolysis in a human immunodeficiency virus (HIV)-positive patient.

Modulation of Corticotropin-Releasing Hormone Receptor Expression During In Vitro Keratinocyte Differentiation.

Curr Issues Mol Biol

Carole-Anne Martins, Sara Lesink, Angéline Roux +2 more

Corticotropin-releasing hormone (CRH) and its receptors CRHR1 and CRHR2 are major actors in the stress response and are well established as components of the hypothalamic-pituitary-adrenal (HPA) axis. Evidence also suggests they are expressed in peripheral tissues and, more interestingly, in the skin. While CRHR1 expression in keratinocytes is documented in terms of presence or absence, data on CRHR2 remain sparse. Moreover, there is no detailed description of the exact localization of CRHR1/2 receptors within the different layers of the epidermis, leaving this question fully unexplored. To better understand the link between stress and skin disorders, we aimed to investigate the differential expression of CRHR1 and CRHR2 in keratinocytes, depending on their level of differentiation. In vitro results demonstrated that CRHR1 appears to be more abundant at early stages of differentiation and CRHR2 at more advanced stages.

Peripartum Depression as a Heart-Brain-Endocrine-Immune Syndrome: Neuroendocrine, Cardiovascular, and Inflammatory Pathways Underlying Maternal Vulnerability.

Life (Basel)

Giuseppe Marano, Marianna Mazza

Peripartum depression (PPD) represents one of the most prevalent and disabling psychiatric conditions among women, yet its underlying biology remains poorly integrated across medical disciplines. Emerging evidence highlights PPD as a prototypical disorder of the heart-brain axis, where neuroendocrine changes, immune activation, and cardiovascular dysregulation converge to shape maternal vulnerability. During pregnancy and the postpartum period, abrupt fluctuations in estrogen, progesterone (P4), and placental corticotropin-releasing hormone (CRH) interact with a sensitized hypothalamic-pituitary-adrenal (HPA) axis, altering neural circuits involved in mood regulation, stress reactivity, and maternal behavior. Parallel cardiovascular adaptations, including endothelial dysfunction, altered blood pressure variability, and reduced heart rate variability (HRV), suggest a profound perturbation of autonomic balance with potential long-term implications for maternal cardiovascular health. Neuroinflammation, microglial activation, and systemic cytokine release further mediate the bidirectional communication between the heart and the brain, linking emotional dysregulation with vascular and autonomic instability. Evidence also indicates that conditions such as preeclampsia and peripartum cardiomyopathy share biological pathways with PPD, reinforcing the concept of a unified pathophysiological axis. This review synthesizes current knowledge on the neurobiological, cardiovascular, endocrine, and inflammatory mechanisms connecting PPD to maternal heart-brain health, while discussing emerging biomarkers and therapeutic strategies aimed at restoring integrative physiology. Understanding PPD as a multisystem heart-brain disorder offers a transformative perspective for early detection, risk stratification, and personalized intervention during one of the most biologically vulnerable periods of a woman's life.

Sexual aggression and prenatal stress lead to poor maternal care and aggressive behaviour in male Wistar rat offspring.

IBRO Neurosci Rep

Elvis Mbiydzenyuy Ngala, Sian Megan Joanna Hemmings, Jacqueline Samantha Womersley +2 more

Sexual aggression and prenatal stress can exert profound intergenerational effects, disrupting maternal care and enhancing aggression in offspring via alterations to the hypothalamic-pituitary-adrenal (HPA) axis and related neurochemical systems. This study in Wistar rats examined the combined impact of male sexual aggression and prenatal stress on maternal caregiving behaviours, and the neurobiological mechanisms underlying sexually aggressive behaviours in male offspring (F1). Following exposure to sexual aggression, females were mated with group-housed or isolated males and assigned to prenatal stress or control conditions. Maternal care was quantified from postnatal day (PND) 2-8, while F1 male aggression was assessed in resident-intruder and sexual aggression paradigms. Neurochemical analyses measured arginine vasopressin (AVP), corticotropin-releasing hormone (CRH), serotonin, oxytocin, corticosterone, and neurokinin B in the prefrontal cortex, hippocampus, amygdala, and hypothalamus, alongside gene expression profiling. Prenatal stress significantly reduced maternal care-particularly nursing and licking-across PND 2-8, with deficits most pronounced when paired with paternal isolation. High-quality maternal care was associated with reduced F1 aggression, longer attack latencies, and lower CRHR1 expression in the hippocampus, suggesting a neuroprotective role. Prenatal stress increased CRHR1 expression in the amygdala and amplified aggression, anxiety-like behaviours, and reduced sociability. Serotonin correlated negatively with aggression and positively with non-social exploration, while corticosterone correlated positively with aggression. Oxytocin was linked to social behaviours, and CRH to exploratory behaviours, indicating distinct neuromodulatory pathways. These findings highlight the interactive effects of maternal and paternal environments on intergenerational behavioural programming and identify key neurochemical targets for mitigating stress-related aggression.

Brain Kappa Opioid Receptor Availability Across Stress and Social Buffering Conditions: A Positron Emission Tomography Study in Coppery Titi Monkeys.

bioRxiv

Claudia Manca, John P Paulus, Alita J D Almeida +6 more

Social connectedness strongly influences health and longevity, and adult pair bonds provide psychological benefits distinct from other social relationships. Oxytocin (OT), corticotropin-releasing hormone (CRH), and opioids, play an important role in the formation and maintenance of pair bonds. Evidence suggests that OT modulates the stress response via the hypothalamic-pituitary-adrenal (HPA) axis, while the kappa (κ) opioid system interacts with and may modulate OT signaling in contexts of stress and separation. In this study 20 coppery titi monkeys were exposed to a physical stressor under three social conditions: baseline (no stressor, partner present), stress (stressor, no partner present) and buffering (stressor, partner present). We predicted stress-induced dynorphin release would reduce κ-opioid receptor availability measured via [¹¹C]GR103545 Positron Emission Tomography (PET) and lower cerebrospinal fluid (CSF) OT, whereas partner presence would mitigate dynorphin release and increase CSF OT, with reduced dynorphin inferred from higher κ-opioid receptor radioligand binding. Our results show condition-dependent differences in [¹¹C]GR103545 binding in several brain regions, including the amygdala and hippocampus, with altered binding in both the stress and social buffering conditions. Cortisol levels were elevated in the stress condition compared to baseline. Females exhibited lower CSF OT levels during stress than at baseline, whereas plasma OT levels did not differ across conditions or between sexes. Spearman correlations revealed no significant associations between plasma and CSF OT. Together, these findings highlight the complex interaction between κ-opioid signaling, OT, and HPA axis activity in the context of social relationships and highlight neuroendocrine mechanisms underlying stress regulation in pair-bonded species.