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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.
Endothelin-1 in the failing Fontan: pathobiology, precision therapeutics, and future trial design.
Front Pediatr
Iman Maiza
The Fontan circulation, devised as definitive palliation for single-ventricle congenital heart disease, imposes systemic venous hypertension, loss of pulmonary arterial pulsatility, and restricted preload reserve. These hemodynamic trade-offs progressively injure the pulmonary vasculature, liver, and lymphatic system, producing late morbidities including elevated pulmonary vascular resistance, Fontan-associated liver disease (FALD), protein-losing enteropathy, and arrhythmias. Endothelin-1 (ET-1), a potent vasoconstrictor and profibrotic mediator, plausibly unifies these complications. Mechanistic studies demonstrate ET-1 upregulation in failed Fontan lungs, activating PLC-Ca2+, RhoA/ROCK, and MAPK/ERK cascades to drive vasoconstriction and remodeling. In cirrhotic livers, ET-1 localizes to stellate cells, promoting contraction and fibrogenesis, mechanisms biologically relevant to congestive FALD. Clinical cohorts consistently show elevated ET-1 correlating with hospitalization, exercise intolerance, and arrhythmias. Trials of endothelin-receptor antagonists (bosentan, ambrisentan, macitentan) demonstrate reassuring safety and suggest benefit when outcomes emphasize ventilatory efficiency or hepatic endpoints rather than peak oxygen consumption, which is physiologically constrained in Fontan physiology. Given the mixed results of existing trials, a framework is outlined that stratifies Fontan patients into pulmonary-inefficiency, congestive-hepatic, lymphatic, and arrhythmia-dominant phenotypes, using co-primary endpoints such as VE/VCO2 slope, elastography, and biomarker panels. By linking ET-1 biology to pragmatic trial design, this approach emphasizes targeted strategies that may stabilize the circulation, extend transplant candidacy, and improve long-term outcomes.
Longitudinal and cross-sectional associations of myocardial stress markers with kidney function and chronic kidney disease in the BiomarCaRE project.
Sci Rep
Jie-Sheng Lin, Tanja Zeller, Wolfgang Koenig +16 more
Given the complex relationship between cardiovascular disease (CVD) and chronic kidney disease (CKD), CVD-related markers may serve as CKD biomarkers. We examined associations of three major CVD-markers [mid-regional pro-adrenomedullin (MR-proADM), MR-pro-atrial natriuretic peptide (MR-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)] with CKD. Cross-sectional analyses included up to 61,830 participants, and longitudinal analyses (NT-proBNP only) 4205 individuals. Kidney function was assessed by estimated glomerular filtration rate (eGFR) using creatinine, cystatin C, or both (eGFRcr-cys). Markers were categorized into four groups. Cross-sectional analyses found that higher levels of all three markers were consistently associated with lower eGFR and higher CKD prevalence. For example, per 1 standard deviation (SD) increase in log-transformed NT-proBNP, corresponding to a 2.71-fold increase in the original concentration, was associated with -2.35 (-2.49, -2.21) ml/min/1.73m2 lower eGFRcr-cys, and the highest NT-proBNP group had a 5.72-fold higher odds of CKDcr-cys (eGFRcr-cys < 60 ml/min/1.73m2) compared with the lowest. Associations with eGFR were stronger among participants with CVD and diabetes. In longitudinal analyses, participants with higher baseline NT-proBNP had faster declines in eGFR, with a 10-year decline of -1.37 (-1.77, -0.98) ml/min/1.73m2 eGFRcr-cys per 1 SD increase, and higher CKD incidence. These findings suggest MR-proADM, MR-proANP, and NT-proBNP as CKD biomarkers.
Neurogenic Inflammation and Immune Dysregulation in Psoriasis: Mechanistic Pathways and Emerging Interventions.
Am J Pathol
Hemraj Singh, Rajeev Taliyan
Psoriasis is a chronic, immune-mediated inflammatory disorder characterized by keratinocyte hyperproliferation and systemic immune dysregulation. The neuroimmune axis, linking sensory nerve activity, neuropeptide signaling, and immune responses, is central to disease pathogenesis. Structural remodeling of sensory nerves enhances the release of neuropeptides such as Substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and neuropeptide Y, which activate dendritic cells, promote T-cell proliferation, and stimulate keratinocyte cytokine production, sustaining a neurogenic inflammatory loop. Psychological stress exacerbates inflammation through hypothalamic-pituitary-adrenal (HPA) axis dysregulation, altering cortisol signaling and systemic immune responses. Intracellular pathways, including mitogen-activated protein kinase, PI3KAktmTOR, JAKSTAT, and NF-κB, along with epigenetic modifications, integrate neural and immune signals, contributing to disease chronicity and heterogeneity. Targeting neuroimmune interactions through neuropeptide antagonists, neuromodulation, stress management, and precision immunotherapies reduces cutaneous inflammation and addresses systemic comorbidities. This review synthesizes molecular, cellular, and clinical insights into the neuroimmune-HPA axis network in psoriasis, highlighting its therapeutic potential for personalized and multidisciplinary management.
Perinatal High-Fat Diet Induces Vascular Hypercontractility via DNA Hypomethylation of Endothelin Receptors and PKC-LTCC Axis Activation in Male Offspring.
Mol Nutr Food Res
Qiutong Zheng, Huamei Jian, Qinyuan He +4 more
Excessive fat intake is a well-established risk for hypertension; perinatal nutritional imbalances could increase vascular risks, but underlying mechanisms remain unclear. Endothelin-1 (ET-1), a potent vasoconstrictor, is implicated in cardiovascular diseases. This study aimed to address this gap by investigating ET-1 receptor-mediated pathways with high-fat-diet (HFD) during pregnancy and lactation. Vascular function, Ca2 + signaling, molecular expression, and DNA methylation were assessed in mesenteric arteries (MA) of offspring. HFD offspring exhibited increased fetal/adult weight, thickened MA wall, and enhanced ET-1-mediated vasoconstriction. Mechanistically, perinatal HFD upregulated ET-1 receptors (ETAR/ETBR) via hypomethylation of their gene promoters (Ednra/Ednrb), which augmented ET-1-induced Ca2 + currents, fluorescence Ca2 + transients, and vascular tone. Which relied on the PKC-LTCC axis (strengthened by PKC activator and LTCC agonist) and altered intracellular Ca2 + handling (via ryanodine receptors and sarcoplasmic/endoplasmic reticulum Ca2 +-ATPase), but were independent of IP3 receptors. ETAR/ETBR blockers attenuated the hypercontractility, confirming receptor-mediated effects. This is the first study to reveal that perinatal HFD persistently enhances vascular re-activity via DNA hypomethylation of ET receptors and PKC-LTCC axis. These findings not only reveal a mechanism linking perinatal HFD to adult vascular hypercontractility but also highlight ET receptors and DNA methylation as potential targets for early intervention of developmental origins of cardiovascular disease.
Pentapeptide-18 as an anti-aging candidate: Spectroscopic characterization and molecular interaction analysis.
Comput Biol Chem
Dilan Akhan, Bilge Bicak, Elif Akalin +1 more
Skin aging is predominantly associated with the progressive breakdown of the dermal extracellular matrix (ECM), leading to visible manifestations such as wrinkle development caused by repetitive facial muscle movements and a gradual reduction in collagen and elastin synthesis. This degeneration is intensified by external factors including ultraviolet exposure, tobacco use, and nutritional imbalance, which interfere with major intracellular signaling pathways-namely TGF-β, TNF-α, MAPK, PI3K/AKT, and NF-κB-that collectively regulate inflammatory responses, oxidative stress, and ECM remodeling. Pentapeptide-18 (Leuphasyl®), a bioactive peptide known for its neuromodulatory properties, has demonstrated the ability to mitigate wrinkle formation by inhibiting neurotransmitter release, while simultaneously improving skin hydration, elasticity, and texture. In this study, the anti-aging activity of Pentapeptide-18 was comprehensively examined through a combination of experimental analyses and computational modeling. Structural optimization and electronic property evaluation were performed using density functional theory (DFT) calculations with the 6-31 + +G(d,p) basis set, complemented by frontier molecular orbital (HOMO-LUMO) and molecular electrostatic potential (MEP) analyses. Theoretical vibrational frequencies were assigned via potential energy distribution (PED) analysis and validated experimentally using FTIR, ATR-FTIR, and Raman spectroscopy. Additionally, molecular docking and molecular dynamics simulations were employed to investigate the binding behavior of Pentapeptide-18 with key molecular targets implicated in skin aging, including TGF-β, TNF-α, MAPK, PI3K/AKT, and NF-κB. Pharmacokinetic and drug-likeness properties were further assessed through ADMET (absorption, distribution, metabolism, excretion, and toxicity). The collective findings provide mechanistic insight into the molecular interactions and stability of Pentapeptide-18, reinforcing its potential as a safe, effective, and non-invasive candidate for advanced anti-aging skin care applications.
Beyond the membrane: Internalization and compartmentalization of insulin‑like growth factor 1 receptor signaling in cancer pathogenesis and treatment (Review).
Int J Oncol
Tiehong Zhang, Ling Li, Chunling Du
The insulin‑like growth factor 1 receptor (IGF‑1R) plays a central role in tumor initiation, progression and response to treatment. IGF‑1R internalization and compartmentalization have profound effects on tumor biology, extending beyond classical signaling associated with receptors at the cell membrane. Following internalization, IGF‑1R alters its intracellular localization and induces new signaling functions. These changes affect the duration and spatial dynamics of signal activation, thereby influencing tumor cell proliferation, migration and the development of drug resistance. However, the exact molecular mechanisms that mediate these processes remain elusive, and the inherent complexity of the downstream signaling network continues to limit the clinical translation of IGF‑1R‑targeted therapies. The present review systematically summarizes the current knowledge on the molecular mechanisms of IGF‑1R internalization and compartmentalization, highlighting their roles in tumor progression and treatment response. The recent advancements and persistent challenges in this field are also critically discussed, aiming to provide a theoretical foundation and new insights for the development of more efficient and effective therapeutic plans that specifically target IGF‑1R.
The Effect of GLP-1 Receptor Agonists on Alanine Aminotransferase and Other Metabolic Parameters in Youths with Obesity: A Systematic Review and Meta-Analysis.
Child Obes
Lauren A Hertzer, Robert M Siegel, Roohi Y Kharofa +2 more
While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) lower body mass index (BMI) in youths with obesity, less is known about their effect on metabolic parameters such as alanine aminotransferase (ALT), high-density lipoprotein, low-density lipoprotein, and hemoglobin A1c levels. We conducted a systematic review of the existing literature and a meta-analysis to determine the effect of GLP-1 RAs on metabolic parameters.