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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.
Mesenchymal stem cell-conditioned media alleviates diabetic cardiomyopathy by modulating glycemic control, oxidative stress-induced injury and inflammation regulation.
J Diabetes Metab Disord
Abeer M Abd El-Hameed, Fatimah A R AbdulAlim, Hebatullah A Abdulgawad
A major consequence of diabetes mellitus (DM) is a diabetic cardiomyopathy (DC). It is a clinical confusion that is identified when individuals with DM develop ventricular dysfunction without having coronary artery disease, heart disease or high blood pressure. It is marked by early diastolic dysfunction and late systolic heart failure. Although mesenchymal stem cell-conditioned media (MSC-CM) have demonstrated promise as therapies for a variety of illnesses, their therapeutic use is hampered by a lack of clinical studies and thorough knowledge of the underlying process. By focusing on oxidative stress, inflammation, and heart failure brought on by hyperglycaemia, this study investigates the positive effect and the possible mechanism by which MSCs-CM alleviate DC in a streptozotocin-induced diabetic rat model by two different delivery routes. 50 male albino rats were randomly assigned to 5 groups, each with 10 subjects, following the induction of diabetes. Amaryl was given to one group as part of their regular diabetes treatment. Every day, 0.5 mL of stem cell-conditioned media was given intravenously (IV) through the tail vein to a different group known as the DC group. Furthermore, 0.5 mL of stem cell-conditioned media was locally administered to a different DC group, going straight into the pancreas. For comparison, a typical control group was also included. All treatments continued for 28 days. Results showed significant alterations in serum glucose, insulin, HbA1c, lipid profile, and cardiac function parameters (atrial natriuretic peptide, troponin I, aspartate aminotransferase, creatine kinase MB) in DC group compare with controls. Treatment by Amaryl® and MSCs-CM demonstrated significant improvements in these parameters, indicating potential therapeutic benefits in diabetic cardiomyopathy. Furthermore, DC exhibited elevate levels of inflammatory markers (CRP, TNFα, IL-6 and Selectin), oxidative stress indicators (malondialdehyde, catalase, superoxide dismutase, and reduced glutathione), and cardiac injury biomarkers (erythropoietin, nuclear respiratory factor 2, vascular endothelial growth factor, and iNOS), which were attenuated by Amaryl® and MSCs-CM treatment (Fig. 3). These findings suggest the antioxidative, anti-inflammatory, and cardioprotective effects of MSCs-CM in diabetic cardiomyopathy highlighting their potential as a viable novel strategy for diabetic cardiovascular complications.
Emerging Roles, Mechanisms, and Therapeutic Potential of Thyroid Hormones in Neurodegenerative Diseases: A Review.
Brain Sci
Xin'ai Li, Zhe Li, Manna Sun +4 more
Thyroid hormones (THs) are master controllers in the endocrine system and have drawn considerable attention from the research community due to their associations with neurodegenerative diseases as well. In this review article, we present a comprehensive summary of the physiological functions and pathogenic mechanisms of THs in the regulation of several representative neurodegenerative diseases. Our study particularly focuses on Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). AD is the most common cause of dementia, primarily caused by tau protein tangles inside nerve cells and β-amyloid plaques outside, which lead to nerve cell death and brain atrophy. PD is primarily a movement disorder. The degeneration of dopaminergic neurons in the brain impairs the brain's control over muscle activity. MS is usually considered to be an autoimmune demyelinating disease, but it has been found that MS also presents with secondary neurodegenerative pathology, including axonal loss and neuronal damage. In this review, the effects of TH on the pathogeneses of AD, PD, and MS are discussed in detail, with a focus on the following potential mechanisms: neuroprotection, neurogenesis, oxidative stress, and inflammatory response. In addition, we conduct an in-depth review of the possible clinical applications of TH, TH analogs, and thyrotropin-releasing hormone (TRH) in the treatment of AD, PD, and MS based on recent preclinical and clinical studies. By integrating experimental, clinical, and epidemiological results on the effects of TH on neurodegeneration, the present review constructs a theoretical basis for the involvement of TH in the pathogeneses of these diseases in detail. We believe that this basis will be useful for clinical diagnosis and treatment.
Putative genes coding for pituitary adenylate cyclase-activating polypeptide and immunohistochemical localization of their mature peptides in the brain-pituitary axis of the inshore hagfish Eptatretus burgeri.
Gen Comp Endocrinol
Masafumi Amano, Shima Furuya, Naoyuki Yamamoto +3 more
Hagfish and lampreys, which are both members of the class Agnatha, are widely considered to represent one of the most basal evolutionary lineages of vertebrates. Pituitary adenylate cyclase-activating polypeptide (PACAP) and growth hormone-releasing hormone (GHRH) are both members of the secretin/PACAP family. We searched the Ensembl database for putative PACAP and GHRH sequences in the inshore hagfish, Eptatretus burgeri. We identified three putative GHRH/PACAP precursors (hagfish-1/2/3) whose expression in various tissues, including the brain, was confirmed using RNA sequencing. The hagfish-1 precursor encodes both GHRH/PRP (PACAP-related peptide) and PACAP, whereas the hagfish-2 and -3 precursors encod only PACAP. Of the three putative hagfish PACAPs, PACAP-2, encoded by hagfish-2, showed relatively high identity (77.8%) and similarity (85.2%) with PACAP from other species. In contrast, hagfish GHRH/PRP encoded by hagfish-1 showed low identity (27.3%) and similarity (50.3%) with other GHRHs, and low identity (26.7%) and similarity (46.7%) with other PRPs. Phylogenetic analysis confirmed that the hagfish-2 sequence clustered within the same clade as lamprey PACAP. PACAP-like-immunoreactive (ir) cell bodies and dense punctate fibers have been detected in several brain regions, including the preoptic area, infundibular nucleus of the hypothalamus, midbrain tegmentum, and medulla oblongata. In the pituitary gland, PACAP-like-ir fibers were observed in the dorsal wall of the neurohypophysis. GHRH/PRP immunoreactivity was also observed in the medulla oblongata. The present study demonstrated that PACAP-like- and GHRH/PRP-like peptides are expressed in the brain of the inshore hagfish E. burgeri.
Effect of GLP-1 Receptor Agonists in Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis.
J Cardiovasc Dev Dis
Benjamin J Behers, Christian Sanchez, Omar Hozayen +10 more
Heart failure with preserved ejection fraction (HFpEF) affects 32 million people worldwide and is responsible for tens of billions of dollars in healthcare expenditure annually, with costs primarily driven by hospitalizations. HFpEF is notoriously difficult to treat, but emerging studies suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may be effective therapies. We performed a systematic review and meta-analysis of six randomized controlled trials with 5564 total participants investigating GLP-1 RAs in patients with HFpEF. Overall, no significant effect was noted for GLP-1 RAs on our primary outcomes of cardiovascular mortality and worsening heart failure (HF) events, although they were associated with improvement in quality of life measures. Furthermore, safety data favored the GLP-1 RA group, although tolerability did not differ compared with placebo. While the pooled analysis of all GLP-1 RAs showed neutral effects versus hard endpoints, sensitivity analyses excluding older-generation agents (exenatide) revealed a significant 41% reduction in HF events, suggesting that newer, more potent agents (semaglutide, tirzepatide) may offer disease-modifying benefits in HFpEF. Although future studies are needed, GLP-1 RAs appear to be promising for the treatment of HFpEF.
Discovery and Preclinical Evaluation of TPM003: A Novel GLP-1/GIP/Glucagon Triple Hormone Receptor Agonist with Robust Efficacy in Obesity and NASH.
J Med Chem
Nan Zheng, Longfang Tu, Pu Xu +9 more
Harnessing the simultaneous activation of GLP-1R, GIPR, and GCGR has emerged as a highly promising therapeutic paradigm for obesity and related metabolic diseases, including nonalcoholic steatohepatitis (NASH). Here, we report the discovery of TPM003, a novel unimolecular GLP-1R/GIPR/GCGR triple agonist engineered by using a long-acting PEG-fatty acid (PEG-FA) stapling technology. TPM003 exhibits balanced triple receptor agonism and demonstrates an extended systemic half-life across multiple species. In obese mice, TPM003 induced robust and durable weight loss, accompanied by broad improvements in metabolic parameters, outperforming current GLP-1RA standards. Importantly, TPM003 also effectively reversed hepatic steatosis and improved markers of liver function in multiple NASH models. Furthermore, TPM003 is compatible with SNAC-based absorption enhancement, enabling oral delivery in a tablet formulation. Collectively, these findings highlight the therapeutic advantages of balanced GLP-1R/GIPR/GCGR agonism for obesity and NASH and support TPM003 as a promising preclinical candidate with translational potential.
[Mechanism of electroacupuncture on improving insulin resistance and intestinal mucosal barrier injury via the GLP-1R/PKA signaling pathway in type 2 diabetes mellitus rats].
Zhongguo Zhen Jiu
Jiayi Lin, Rui Li, Xiaolu Li +6 more
To observe the effect of electroacupuncture (EA) on the glucagon-like peptide-1 receptor (GLP-1R)/protein kinase A (PKA) signaling pathway in the colon tissue of type 2 diabetes mellitus (T2DM) rats and explore the mechanisms underlying EA's improvement of insulin resistance and intestinal mucosal barrier injury.
Retatrutide Shows Multiple Metabolic Benefits in Diet-Induced Obese MASH Mouse and Hamster Models.
Obesity (Silver Spring)
François Briand, Camille Le Cudennec, Estelle Grasset +4 more
Our aim was to evaluate the efficacy of the triple glucagon, GIP, and GLP-1 receptor agonist retatrutide in diet-induced obese MASH mouse and hamster models, two preclinical models that we routinely use for assessing new therapies targeting obesity.
The therapeutic revolution in thyroid eye disease: from orbital radiotherapy to teprotumumab and AI.
Front Med (Lausanne)
XiaoLi Yuan, Han Li, Feng Wang
Thyroid eye disease (TED) is a vision-threatening and quality-of-life-impairing manifestation of autoimmune thyroid disease, driven by orbital fibroblast activation, inflammation, and tissue remodeling. This review synthesizes current evidence on TED epidemiology and pathogenesis, with a particular focus on the pathogenic synergy between the thyrotropin receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1R). We discuss how this receptor complex propagates intracellular signaling that leads to disease hallmarks: fibroblast proliferation, glycosaminoglycan secretion, and adipogenesis. While we outline the established paradigm of management-encompassing glucocorticoids, orbital radiotherapy, and surgery-a key emphasis is placed on the recent therapeutic revolution ushered in by targeted biological agents, most notably IGF-1R inhibition. As well as research on new targets for immunotherapy such as Tregs and other aspects such as IL-6 or TNF-α. Finally, we explore the nascent role of artificial intelligence in refining diagnosis and prognostic assessment. This overview aims to equip clinicians and researchers with a forward-looking perspective on the evolving landscape of TED management.
The effects of early life pain and juvenile fear conditioning on CRF-receptor expression in the amygdala and hypothalamus of the juvenile rat.
PLoS One
Michael A Burman, Jared T Zuke
Early life pain and stress have lasting consequences on nervous system development that can interact with later stress or trauma to create a susceptibility to fear, anxiety, depression and chronic pain among other psychological disorders. Recent work has identified changes in corticotropin releasing factor signaling in limbic system structures, such as the amygdala and hypothalamus, as a key mechanism behind these changes - albeit in a sex-dependent manner. CRF has two major receptors, CRFR1 and CRFR2 which have also been shown to play key roles in fear and pain expression. The current work examines the effects of early life pain designed to mimic the neonatal medical trauma that occurs in the Neonatal Intensive Care Unit (NICU), paired with a juvenile trauma in the form of fear conditioning, on expression of crhr1 and crhr2 mRNA in the central nucleus (CeA) and basolateral nucleus (BLA) of the amygdala as well as the paraventricular nucleus (PVN) and ventromedial nucleus (VMH) hypothalamus of the juvenile rat. While prior work has demonstrated that early life pain significantly impacts expression of the CRF ligand mRNA, this study examines the effects of early life pain and stress, as well as adolescent fear conditioning, on CRF receptor expression. The data demonstrate that early life pain and fear conditioning have only modest effects on CRF receptor expression in the amygdala and hypothalamus in a sex dependent manner. In both sexes, fear conditioning increased crhr2 mRNA in the CeA only in neonatally undisturbed subjects. In addition, there was a trend towards altered crhr2 mRNA following neonatal manipulation in the PVN. In females specifically, we observed significant changes in crhr2 mRNA expression following fear conditioning in the right BLA. There were no female-specific changes following neonatal pain and stress. In males, we observed significant changes in crhr1 mRNA in the posterior PVN and trends toward changes in crhr2 mRNA in the CeA and VMH following neonatal manipulation. Together, these data confirm prior work that early life pain and stress alter the neural circuitry of pain and stress in a sex-specific manner. However, given the limited changes observed, in it unlikely that CRH receptor alterations are a major mechanism of action of early life pain.