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peptide science.

Glucagon, the Alpha Cell, and Potential Targets for Diabetes Treatment.

Endocrinology

Savita Dhanvantari, E Danielle Dean

Glucagon is a 29-amino acid hormone synthesized and secreted by the pancreatic alpha cell in the islets of Langerhans. It is the primary glucose counter-regulatory hormone, secreted by the alpha cell to maintain euglycemia by stimulating hepatic gluconeogenesis and glycogenolysis. In addition to glucose, the alpha cell senses and responds to a number of inputs, such as paracrine factors, neurotransmitters, and other nutrients, including amino acids, to regulate the secretion of glucagon. Disruption of this fine regulation results in excessive glucagon secretion (hyperglucagonemia) and contributes to the pathogenesis of diabetes. In this mini-review, we summarize the current understanding of glucagon biosynthesis and intracellular trafficking, and we discuss emerging concepts in amino acid sensing and signaling that underpin the biology of the alpha cell and that may provide clues to the control of the hyperglucagonemia of diabetes.

Real-world disease burden and health care resource utilization for patients with Barth syndrome.

J Med Econ

Lindsay Marjoram, Yonglin Huang, Mary Kay Koenig +2 more

Barth syndrome (BTHS) is an ultra-rare, X-linked genetic disorder for which there is limited economic data. Because compiling such data that target rare indications is difficult, we assessed real-world data to increase understanding of the cost of BTHS based on disease burden and health care resource utilization (HCRU).

Can diets alleviate constipation and promote bowel movement? Exploring the underlying mechanisms of effects.

Food Res Int

Xi Gui, Lan Wu, Kaijun Huang +7 more

Constipation is a common gastrointestinal disorder with a significant impact on quality of life. Diets play an important role as a modifiable lifestyle factor that can affect the onset and progression of constipation. This review examines the effects and mechanisms of multiple dietary patterns, including a high-fat diet, Mediterranean diet, fiber-rich diet, and plant-based diet, on constipation, microecological agents (probiotics, prebiotics, and synbiotics), and bioactive compounds (polysaccharides and polyphenols). In summary, the Mediterranean and plant-based diets can reduce the risk of constipation with favorable changes in gut microbiota, increase contents of short-chain fatty acids (SCFAs), and reduce the inflammatory markers. A fiber-rich diet increases stool bulk, retains water due to its high water-binding capacity, and serves as a substrate for gut microbiota. Additionally, microbiota can ferment fiber-rich diet to produce gases and SCFAs, which create an osmotic load and accelerate intestinal transit. Conversely, a high-fat diet correlates with an increased incidence of constipation with unfavorable changes in gut microbiota and reduces 5-hydroxytryptamine (5-HT) availability and mucin secretion. Meanwhile, probiotics, prebiotics, and synbiotics relieve constipation by restoring the imbalance of gut microbiota and increasing the contents of SCFAs and neurotransmitters. Also, polyphenols alleviate constipation by enhancing intestinal barrier, balancing neurotransmitters, and suppressing gut inflammation. Polysaccharides upregulate the expression of gastrointestinal transport proteins and genes (such as transient receptor potential vanilloid 1 [TRPV1], aquaporin 3 [AQP3], vasoactive intestinal peptide receptor 1 [VIPR1]) to maintain intestinal peristalsis. Furthermore, given the inter-individual in metabolic responses to dietary intake, we propose a framework for developing personalized diets for individuals with constipation, tailored to their specific compositions of gut microbiota.

The Role of Growth Hormone-Releasing Hormone and the Hypothalamic-Pituitary-Somatotropic Axis in Aging: Potential Therapeutic Applications and Risks.

Horm Metab Res

Ioannis Oikonomakos, Richard Siow, Stefan R Bornstein +1 more

Aging is marked by a gradual decline in multiple physiological functions, increasing the risk of age-related disorders. Multiple factors have been identified as contributors to aging, many of which are regulated by the hypothalamus. Growth hormone-releasing hormone (GHRH) produced in the hypothalamus is a key regulator of growth hormone (GH) secretion. With aging, both GHRH and GH levels decline, leading to muscle loss, increased fat accumulation, metabolic dysregulation, and cognitive impairments. GH replacement therapy has been explored as a potential intervention to counteract these effects; however, its long-term use is associated with significant risks, including metabolic disturbances, cardiovascular complications, and potential cancer promotion. In contrast, studies suggest that GHRH-based therapies can improve body composition, muscle strength, cognitive function, and cardiovascular health while avoiding the risks linked to direct GH administration. Additionally, preclinical findings indicate that GHRH agonists may offer cardioprotective and immunomodulatory benefits. In this review, we summarize current knowledge on the roles of GHRH and GH in aging, highlight the limitations of GH-based therapies, and discuss the potential of GHRH-based approaches in mitigating age-related decline and improving health span.

Analysis of growth hormone releasing hormone and its analogs in urine using nano liquid chromatography coupled with quadrupole/orbitrap mass spectrometry.

J Pharm Biomed Anal

Ebru Uçaktürk, Emirhan Nemutlu

Growth hormone-releasing hormone (GHRH) and its synthetic analogs are considered performance-enhancing substances and are therefore prohibited by the World Anti-Doping Agency (WADA). The analysis of GHRH and its analogs in urine presents significant analytical challenges due to their inherent in vivo instability, rapid renal clearance, and low urinary concentrations. The present study aimed to develop a robust nano-LC quadrupole/orbitrap mass spectrometry (nano-LC-Q/Orbitrap MS) method for both screening and confirmation analyses of GHRH and its synthetic analogs (sermorelin/CJC-1293, tesamorelin, and CJC-1295) and the primary metabolite of sermorelin in urine, in accordance with WADA requirements. The sample preparation workflow was systematically investigated. Existing solid-phase extraction (SPE) protocols were compared, and two additional commercially available SPE cartridges were evaluated. Within the SPE step, the influence of various washing and elution solvent strengths on peptide recovery was also systematically examined. The effectiveness of different cleanup solvents during the ultrafiltration step was further assessed. Based on these evaluations, a refined approach was developed, incorporating an initial ultrafiltration step followed by SPE. The proposed method was fully validated according to WADA guidelines, assessing key parameters such as selectivity, reliability, limits of detection (LOD), carryover, limits of identification (LOI), robustness, autosampler stability, and matrix effects. The validation results confirmed the method's suitability and robustness for anti-doping testing. Achieved LODs (≤ 0.5 ng/mL) and LOIs (0.5-0.75 ng/mL) demonstrated sufficient sensitivity for effective detection and confirmation analysis of the target peptides in urine.

Impact of glucocorticoid therapy on hypothalamic-pituitary-adrenal axis function in pediatric nephrotic syndrome: A narrative review.

World J Clin Pediatr

Subhankar Sarkar, Asiri Samantha Abeyagunawardena, Rajiv Sinha

Glucocorticoids (GCs) such as prednisolone are widely used in conditions like nephrotic syndrome, asthma, and autoimmune diseases. However, prolonged or high-dose use may suppress the hypothalamic-pituitary-adrenal (HPA) axis, leading to secondary adrenal insufficiency (AI). This condition occurs when the adrenal glands fail to produce adequate cortisol, which is essential for regulating metabolism, immune response, and stress adaptation. Corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the pituitary to release adrenocorticotropic hormone (ACTH), which then triggers cortisol production in the adrenal glands. Prolonged GC use disrupts this system by inhibiting CRH and ACTH secretion, leading to adrenal atrophy and reduced cortisol production. HPA axis suppression is primarily diagnosed through dynamic tests. Early morning cortisol levels above > 18 ng/mL typically indicate normal function, while levels < 3 ng/mL suggest AI. Intermediate values require additional testing, such as the insulin tolerance test, ACTH stimulation test, and metyrapone test. Prednisolone in nephrotic syndrome suppresses the HPA axis, heightening AI risk, influenced by dose, duration, and timing of administration. Careful GC management is essential to balance disease control with risks of HPA axis suppression. Early recognition and timely intervention can prevent adrenal crises and improve outcomes in pediatric patients.

PFKFB3 Promotes Myofibroblast Differentiation and Cardiac Fibrosis Through its Intra- and Extra- Cellular Roles.

J Cardiovasc Transl Res

Bing Han, Zhaowei Zhu, Yongxiang Wang +4 more

Cardiac fibrosis remains a major clinical challenge with limited therapeutic options, and the role of PFKFB3 in its pathogenesis remains unclear. Single-cell RNA sequencing analysis was applied and the results demonstrated that glycolysis was most prominently enhanced in activated cardiac myofibroblasts (myoCFs) in cardiomyopathy. Western blot analysis revealed that PFKFB3 expression was significantly increased in fibrotic hearts and TGF-β1-stimulated myoCFs. Genetic (Pfkfb3+/-) and pharmacological (3PO) inhibition of PFKFB3 attenuated myoCF activation, proliferation, and migration, while also reducing cardiac fibrosis in isoproterenol- and coronary ligation- induced mouse models. Mechanistically, TGF-β1 upregulated PFKFB3 in a HIF-1α-dependent manner, and extracellular PFKFB3 further promoted fibroblast activation and inflammatory responses. Clinically, elevated plasma PFKFB3 levels, as measured by ELISA, were significantly associated with fibrosis severity in patients with cardiomyopathy. These findings reveal for the first time that PFKFB3 drives cardiac fibrosis dually through intracellular glycolytic regulation and extracellular signaling, highlighting its translational potential.

Medical treatment in acromegaly: a network meta-analysis.

Eur J Endocrinol

Chrysi Kaparounaki, Mirela-Diana Ilie, Dario De Alcubierre +6 more

Acromegaly is a rare disorder caused by a growth hormone-secreting pituitary adenoma. Clinical trial evidence for its management is limited. This study compared medical treatments for acromegaly through a network meta-analysis, assessing biochemical and radiological responses.

Prevalence of heart failure stages in elderly population: from a community-dwelling elderly people survey.

BMC Geriatr

Manyun Huang, Min Wang, Xin Gong +7 more

Heart failure (HF) is a major public health concern in China, but there is a lack of epidemiological data on the prevalence of early-stage HF in the elderly.

Cerebrospinal Fluid Human Neutrophil Peptides 1-3: A Potential Prognostic Marker in Intracerebral Hemorrhage.

Genet Test Mol Biomarkers

Zhi He, Jun Xie, Fu-Ling Yan +4 more

Background: This study aims to investigate whether elevated human neutrophil peptides 1-3 (HNP 1-3) levels in cerebrospinal fluid (CSF) are associated with disease severity and clinical outcomes in patients with intracerebral hemorrhage (ICH). Materials and Methods: HNP 1-3 levels were measured in CSF samples collected within 3 days after hemorrhage onset in ICH patients and control subjects. Results: HNP 1-3 levels were significantly higher in ICH patients with moderate-severe coma and hematoma volume >30 mL group. Univariate and multivariate logistic regression analyses demonstrated that CSF HNP 1-3 levels were associated with unfavorable outcomes. Receiver operating characteristic analysis revealed that CSF HNP 1-3 concentrations >466.95 ng/mL could distinguish ICH patients at risk for an unfavorable prognosis. Conclusions: HNP 1-3 exhibit satisfactory diagnostic efficiency for predicting the prognosis of ICH patients.

High Rate Triggers Increased Atrial Release of BMP10, A Biomarker for Atrial Fibrillation and Stroke, and BMP10 Affects Ventricular Cardiomyocytes.

Circ Arrhythm Electrophysiol

Laura C Sommerfeld, Jessica Schrapers, Karl-Felix Müller +19 more

BMP10 (bone morphogenetic protein 10) is a ligand of the TGF (transforming growth factor) β superfamily secreted mainly by atrial cardiomyocytes. Elevated BMP10 blood concentrations predict atrial fibrillation (AF), AF recurrence after ablation, and AF-related cardiovascular complications like stroke. The conditions increasing BMP10 secretion and the downstream effects of BMP10 in cardiomyocytes are poorly understood. We assessed BMP10 secretion dynamics and BMP10 effects in a human 3-dimensional model of atrial and ventricular engineered heart tissue (EHT).

Chinese medicine formulation Mailuoning attenuates high-fat diet-induced obesity by regulating thermogenesis through activating the peroxisome proliferator-activated receptor α/fibroblast growth factor 21 axis.

Phytomedicine

Wangya Jia, Sijia Wu, Keke Wang +4 more

Mailuoning is a Chinese medicine formulation known for its efficacy in clearing heat, nourishing yin, activating blood circulation, and resolving blood stasis. In traditional Chinese medicine, Mailuoning is considered to have potential benefits in improving obesity. Our previous research has demonstrated that Mailuoning could effectively alleviate non-alcoholic fatty liver disease (NAFLD), a metabolic disorder with pathophysiological similarities to obesity. However, the alleviating effects of Mailuoning on obesity have yet to be fully elucidated, and further investigation is required to confirm its therapeutic effect.

Redox-sensitive miRNAs and Humanin could mediate effects of exercise and astaxanthin on oxidative stress and inflammation in type 2 diabetes.

Sci Rep

Aref Basereh, Karen Khoramipour, Najmeh Hosseini +4 more

Type 2 diabetes mellitus (T2DM) is driven by oxidative stress (OS) and inflammation (IF), accelerating disease progression. This study examined whether combined aerobic and resistance training (CT) and astaxanthin (AST) supplementation synergistically improve oxidant and inflammatory status as well as metabolic indices in T2DM, focusing on the mediatory role of Humanin (HN) and microRNAs (miRNA-122, miRNA-126-3p, and miRNA-146a). Ninety women with T2DM were randomly assigned to six groups (n = 15 each): control (C), placebo (P), AST supplementation (S), combined training (CT), CT + placebo (CT + P), and CT + AST supplementation (CT + S). CT, CT + P and CT + S groups underwent an 8-week training program (eight exercises, three sessions per week). Groups and CT + S groups received 8 mg/day of AST. OS markers, inflammatory cytokines, HN levels, miRNAs expression, fasting blood glucose (FBG), insulin resistance (HOMA-IR), lipid profile, and hemoglobin A1c (HbA1c) were assessed. Both CT and AST enhanced antioxidant defenses and reduced IF, with CT + S showing the best effects. HN levels increased significantly in CT and CT + S (p < 0.05). MiRNA-126-3p and miRNA-146a were upregulated, while miRNA-122 was downregulated in CT + S compared to other groups. Lipid profile improved with both interventions, with CT + S yielding the highest increases in HDL and triglycerides. FBG, IR, and HbA1c improved significantly in CT groups but remained unchanged with S group. The metabolic and anti-inflammatory benefits of CT and AST in T2DM may mediated by the effects of HN on mitochondrial function and insulin signaling, together with miRNA-mediated regulation of lipid metabolism, endothelial health, and innate immunity. Targeting these molecular pathways may improve therapeutic strategies for diabetes management.

Microglial Polarization and Therapeutic Strategies in Post-stroke Neuroinflammation.

Neurol Ther

Travis Yui Hei Chan, Brian De Yu Ma, Timothy Keith Hung +2 more

Stroke remains a leading cause of global disability, perpetuated by maladaptive neuroinflammation that drives secondary injury and impairs recovery. An early reparative (M2) state rapidly transitions into a dominant destructive (M1) phenotype within days, worsening tissue damage through the release of cytokines [tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6)], blood-brain barrier disruption, and amplified peripheral immune cell infiltration. Emerging pharmacological interventions, such as the free radical scavenger edaravone, the neurotrophic factor cerebrolysin, and the excitotoxicity modulator citicoline, demonstrate promising neuroprotective potential when strategically timed. Additionally, novel non-pharmacological approaches, including repetitive transcranial magnetic stimulation, stem cell therapy, and nanoparticle-based drug delivery, offer innovative pathways for targeting neuroinflammation. However, translational challenges persist, including narrow therapeutic windows, biomarker heterogeneity, and preclinical-to-clinical gaps. Future progress necessitates precision medicine paradigms integrating spatiotemporal drug delivery, biomarker-guided intervention timing, and synergistic combinatorial regimens targeting acute injury and chronic repair phases. By bridging mechanistic insights with clinical applications, this review delineates neuroinflammatory modulation as a pivotal frontier for redefining stroke recovery while outlining essential research trajectories to overcome existing barriers. Systematic search of electronic databases including PubMed, Web of Science, Embase, and Cochrane (1996-2025) was performed, with eligible studies assessed using PRISMA guidelines. Findings on neuroinflammation, mechanism, or interventions in ischemic stroke were narratively synthesized through thematic analysis. This review summarizes current insights into post-stroke neuroinflammatory mechanisms, with a focus on the dual role of microglial polarization.

Growth hormone - releasing hormone antagonists induce autophagy in cancer cells.

Growth Horm IGF Res

Madan Sigdel, Saikat Fakir, Md Matiur Rahman Sarker +1 more

GHRH antagonists (GHRHAnt) were developed to suppress cancers and have been associated with robust anti-inflammatory and anti-oxidative activities. The mechanisms involved in those effects are not completely understood. MDA-MB-468 and A549 cancer cells, which express GHRH receptors, were treated with GHRHAnt JV-1-36, to evaluate the effects of that compound in autophagy. JV-1-36 induces autophagy in MDA-MB-468 and A549 cells since exposure to the aforementioned peptide elevated the expression levels of the autophagy-related protein (ATG) - 5, ATG - 3, ATG - 7, and ATG-16L1. In contrast, MCF-7 cells - which do not express GHRH receptors - did not respond to GHRHAnt. Our findings suggest that the beneficial effects of GHRHAnt in cancers may involve autophagy. Further studies will attempt to delineate the underlying mechanisms.

Paltusotine: The first selective nonpeptide agonist of somatostatin receptor 2 (SSTR2) for the treatment of acromegaly.

Drug Discov Ther

Yueyi Sun, Daoran Lu, Jianjun Gao

Acromegaly is an endocrine disorder characterized by abnormal enlargement of the extremities and internal organs resulting from excessive secretion of growth hormone (GH) by the pituitary gland, which in turn leads to elevated levels of insulin-like growth factor 1 (IGF-1). Approximately 45% of patients remain biochemically uncontrolled after surgery and require long-term treatment with injectable somatostatin analogs such as octreotide or lanreotide. These polypeptide drugs generally require monthly administration to maintain disease control; however, many patients experience recurrence of symptoms towards the end of the dosing interval. Moreover, injection-site pain and local reactions are common, significantly impacting patients' quality of life. On September 25, 2025, the U.S. Food and Drug Administration (FDA) approved paltusotine, the first once-daily oral, nonpeptide somatostatin receptor 2 (SSTR2) agonist for the treatment of acromegaly. By enabling oral rather than injectable therapy, paltusotine reduces the treatment burden and enhances patient adherence. With its rapid onset and durable biochemical control, this novel agent has the potential to reshape the current paradigm of acromegaly pharmacotherapy and offer patients a more convenient and effective treatment option. Nevertheless, its long-term safety and efficacy warrant further evaluation in real-world clinical settings.

The Effect of Peptide Semax, an ACTH(4-10) Analogue, on Intracellular Calcium Dynamics in Rat Brain Neurons.

Bull Exp Biol Med

S N Kolbaev, I N Sharonova, V G Skrebitsky

We studied the effects of Semax on spontaneous fluctuations of intracellular calcium ion concentration [Ca2+]i in pyramidal neurons on hippocampal slices and on proton-induced increase in [Ca2+]i in cerebellar granule cells in cerebellar slices. Application of Semax (1 μM), significantly increased the frequency of spontaneous [Ca2+]i fluctuations in the pyramidal layer cells of the hippocampal CA1 field, but had no significant effect on proton-stimulated increase in [Ca2+]i in cerebellar granule cells. These data provide insight into the localization of cellular targets and elucidate the dynamics of the initial stages of interaction between the peptide and the hippocampal neuronal network. The primary mechanism of the neuroprotective effect of Semax appears to be unrelated to attenuation of calcium entry through acid-sensing ion channels in cerebellar granule cells.

Engineered Tandem Thymosin Peptide Promotes Corneal Wound Healing.

Invest Ophthalmol Vis Sci

Joseph Nguyen, Sudhir Verma, Vivian T Vuong +3 more

Thymosin beta-4 (TB4) is a small peptide upregulated in injured tissues, playing roles in cell migration, angiogenesis, inflammation, and oxidative stress. Studies show TB4 significantly promotes corneal wound healing after injury, leading to a clinical trial (RGN-259), with full US Food and Drug Administration approval still pending. Current limitations to TB4-based therapies are a short half-life and high peptide synthesis costs, limiting large-scale applications. Here, we engineered a tandem thymosin beta-4 (tTB4) peptide with improved therapeutic potential and scalability for corneal wound repair.

Contextual modulation of endogenous oxytocin signaling and its influence on exogenous oxytocin effects: A conceptual framework.

Neurosci Biobehav Rev

Kaat Alaerts, Eimi Van Weert, Lotte Theunissen +2 more

Posology for 177Lu-DOTATATE Therapy in Neuroendocrine Tumor: Effectiveness of Dose Reduction and Cycle Delay for Improving Therapy Tolerability.

Clin Nucl Med

Ivan E Wang, Jasmine Patterson, Azadeh Akhavanallaf +8 more

Approval of 177Lu-DOTATATE for the treatment of neuroendocrine tumors (NETs) requires monitoring for therapeutic efficacy and safety. A retrospective review was conducted on 173 patients who received 177Lu-DOTATATE at the University of Michigan to identify if posology changes would improve therapy tolerance and completion. Patients were followed up to 3 years following their last cycle of treatment to determine long-term adverse events. Dose reduction (from 7.4 GBq to 3.7 GBq) was used in 13 patients, and cycle delay (8±1 wk to >16-week gap) was used in 36 patients, leading to 82% completion of 4 cycles of therapy. Dose reduction led to higher rates for completing all 4 cycles of therapy, whereas cycle delay led to worsened outcomes. Amino acid infusions led to limited adverse events with nausea, vomiting, and fatigue, even with antiemetic prophylaxis. Carcinoid crisis was observed in 1.2% of patients, which was similar to the findings in the NETTER-1 trial. Acute decline in neutrophils and platelets was observed; however, these blood values rebounded. A decline in renal function (4.3 mL/min/1.73 m2 over 4 years compared with untreated patients) suggests a potential long-term risk for renal toxicity; however, it could also be associated with changes in therapy. When adverse events were severe due to underlying disease, dose reduction, or cycle delay did not adequately impact therapy completion, and required further therapy monitoring. Long-term occurrence of myelodysplasia syndrome was 1.8%, comparable to reported occurrences requiring further monitoring. Our analysis reinforces that 177Lu-DOTATATE is an effective, well-tolerated treatment for NETs with low incidences of long-term adverse events.