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peptide science.
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Exenatide through PPARδ improved hepatic insulin resistance in patients of type 2 diabetes mellitus via suppressing pyroptosis.
Int Immunopharmacol
Xizhi Li, Tingting Zhou, Yixi Wu +8 more
Exenatide, the first glucagon-like peptide-1 receptor agonist (GLP-1RA), exerted multiple beneficial effects, including stimulating insulin secretion, slowing gastric emptying, and improving insulin resistance (IR). Our previous work demonstrated that the peroxisome proliferator-activated receptor delta (PPARδ) gene (PPARD) polymorphisms correlated with exenatide monotherapy efficacy, possibly due to the pivotal role of PPARδ in regulating IR. Specifically, PPARδ has been shown to modulate the nucleotide-binding domain and leucine-rich repeat pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of pyroptosis, thereby participating in the regulation of this inflammatory cell death pathway. However, the underlying mechanisms by which exenatide ameliorated hepatic IR in patients with type 2 Diabetes Mellitus (T2DM) remained incompletely understood. Herein, we found that exenatide suppressed pyroptosis and ameliorated hepatic IR; furthermore, it could bind to PPARδ and upregulate PPARδ protein expression both in vitro and in vivo. Notably, PPARδ knockdown abolished the protective effects of exenatide against pyroptosis and hepatic IR, whereas pharmacological activation of PPARδ enhanced these beneficial effects. Moreover, T2DM patients carrying the AA genotype at PPARD rs3777744 and exhibiting higher baseline homeostasis model assessment of insulin resistance (HOMA-IR) showed a superior response to exenatide. Collectively, our findings revealed that exenatide ameliorated hepatic IR by suppressing pyroptosis via PPARδ, underscoring the potential of PPARD rs3777744 as a biomarker for personalized exenatide therapy in T2DM.
CRISPR/Cas9-engineered Salmonella phage displaying antimicrobial peptide LL37 for enhanced antibacterial activity.
Int J Antimicrob Agents
Su Jin Jo, Se Chang Park, Sang Guen Kim
The increasing prevalence of antibiotic-resistant Salmonella Typhimurium has highlighted the urgent need for alternative therapeutic strategies. This study engineered a lytic S. Typhimurium bacteriophage to present the antimicrobial peptide LL-37 on the virion surface, followed by evaluation of its enhanced antibacterial efficacy.
Amoebicidal effect of Antimicrobial Peptides against Acanthamoeba castellanii: A study of cell death using Fluorescence imaging systems.
Acta Trop
Ines Sifaoui, Rubén L Rodríguez-Expósito, María Reyes-Batlle +6 more
Acanthamoeba infections are hindered by limitations including prolonged treatment duration, cytotoxicity, limited efficacy against the resistant cystic stage, and a high rate of recurrence. Antimicrobial peptides (AMPs) demonstrate broad-spectrum antimicrobial activity, rapid mechanism of action, low potential for inducing resistance, and efficacy against both trophozoite and cyst forms, highlighting their potential as promising alternatives in the treatment of these infections. Herein, we report the amoebicidal activity of various peptides derived from cathelicidins and piscidins against Acanthamoeba castellanii Neff. Afterwards, the impact of the most effective peptide on the clinical features of a clinical strain of Acanthamoeba castellanii was evaluated using a fluorescence imaging system. Peptide OH_KR34 was the most active against A. castellanii Neff with an IC₅₀ values of 2.00 ± 0.58 µM. OH_KR34 was able to inhibit the clinical strain of A. castellanii (L10) with an IC50 of 5.75 ± 0.30 μM. We demonstrated that the peptide OH_KR34 (related to OH-CATH) induces cytoskeletal damage and trigger apoptosis-like process by disrupting cell membrane permeability, mitochondrial dysfunction and DNA fragmentation. This antimicrobial peptide could therefore offer a potential target to develop new anti-parasitic drugs.
Growth hormone enhances mitochondria biogenesis and endows mitochondrial thermogenesis in murine adipocytes.
Mol Cell Endocrinol
Esha Sadiq, Yinghao Liu, Ni Li +9 more
Growth hormone (GH) can reduce the size of white adipocytes in vivo and in vitro. This catabolic effect was previously believed to be related to the breakdown of stored triglycerides into free fatty acids. However, little is known about its effects on mitochondria in adipose or adipocytes. We thus examined effects of GH on mitochondrial number change and metabolic changes in fat of diet induced obese mice as well as 3T3-L1 adipocytes. We first found in vitro GH increase the density of mitochondria in 3T3-L1 adipocytes. We figured out that GH enhanced the expression of mitochondria biogenesis related genes, such as peroxisome proliferative activated receptor gamma coactivator 1 alpha (Pgc1α), DNA polymerase gamma (Polg) and transcription factor A of mitochondria (Tfam) in vitro and in vivo. To explore the underlying mechanism, we further confirmed that the enhanced expression of these proteins was dependent on the three pathways of GH signaling transduction and that GH enhanced the promoter transactivation of Pgc1α or Polg. We also found that GH increased the cell death-inducing DNA fragmentation factor alpha subunit-like effector A (CIDEA) and uncoupling protein 1 (UCP1) expression by enhancing the promoter transactivation of Cidea. We further elucidated that GH induced UCP1 expression was dependent on CIDEA using CRISPR-Cas9 technique. We therefore conclude that GH has effects on reducing adipocyte size via promoting PGC1α and POLG mediated mitochondrial biogenesis, and also on increasing UCP1 expression via CIDEA. Making adipocytes browning by GH or its analogs may provide a therapeutic strategy for metabolic diseases.
From the pancreas to the amygdala: New brain area critical for ingestive and motivated behavior control exerted by amylin.
iScience
Suyeun Byun, Ivana Maric, Stina Börchers +4 more
Amylin, a pancreatic peptide, has a well-established role in feeding behavior control. Amylin analogues are clinically utilized in patients with diabetes and are under investigation as potential anti-obesity pharmacotherapies. The neural circuits underlying actions of amylin on behavior are not well understood. While amylin was found to bind to the central amygdala (CeA) of rodents and primates and we found that all components of amylin receptors are present in the CeA, their potential role in physiology or behavior remains unknown. Here, we investigated the impact of this potential pancreas - CeA amylin-mediated communication - on ingestive and motivated behaviors. Activation of CeA amylin receptors resulted in a robust hypophagia, reduced food-motivated behavior, and altered macronutrient preference in male and female rats. Clinically used amylin analogue, pramlintide, reduced meal size and frequency by acting on the CeA. Disruption of CeA amylin signaling led to hyperphagia and body weight gain in a sex divergent manner. Importantly, CeA amylin signaling was required for appetite suppression induced by peripherally applied amylin, highlighting translational relevance of this brain site. Our data indicate the CeA is a critical neural substrate for amylin signaling.
The Role of the Apelin Receptor in the Pathophysiology of Pulmonary Arterial Hypertension.
Cells
Karla M Rada, Alejandra M Zúniga-Muñoz, Yamnia Q Alvarez-Alvarez +8 more
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by endothelial dysfunction, vascular remodeling, and a sustained increase in pulmonary vascular resistance, causing cardiopulmonary damage. The apelin receptor (APJ), a member of the G protein-coupled receptor family, has emerged as an essential modulator of vascular homeostasis. Clinical and preclinical studies have demonstrated that its activation exerts beneficial effects on the progression of PAH. Its main actions include the restoration of endothelial function, reactivation of the BMPR2/SMAD axis, induction of nitric oxide-mediated vasodilation, inhibition of autophagy and the migration of the pulmonary artery smooth muscle cells (PASMCs). Furthermore, its expression and functionality are modulated by epitranscriptomic mechanisms, particularly by microRNAs involved in the post-transcriptional regulation of key genes for vascular homeostasis. These findings position the APJ as a relevant therapeutic target in PAH. However, the clinical application of its agonists still faces pharmacokinetic limitations that restrict their therapeutic use. Therefore, the aim of this review is to gather current information on APJ in the pathophysiology of PAH and focus attention on its potential as a therapeutic target.
NMDA Receptor in Vasopressin 1b Neurons Is Not Required for Short-Term Social Memory, Object Memory or Aggression.
Front Behav Neurosci
Sarah K Williams Avram, Heon-Jin Lee, Jarrett Fastman +10 more
The arginine vasopressin 1b receptor (Avpr1b) plays an important role in social behaviors including aggression, social learning and memory. Genetic removal of Avpr1b from mouse models results in deficits in aggression and short-term social recognition in adults. Avpr1b gene expression is highly enriched in the pyramidal neurons of the hippocampal cornu ammonis 2 (CA2) region. Activity of the hippocampal CA2 has been shown to be required for normal short-term social recognition and aggressive behaviors. Vasopressin acts to enhance synaptic responses of CA2 neurons through a NMDA-receptor dependent mechanism. Genetic removal of the obligatory subunit of the NMDA receptor (Grin1) within distinct hippocampal regions impairs non-social learning and memory. However, the question of a direct role for NMDA receptor activity in Avpr1b neurons to modulate social behavior remains unclear. To answer this question, we first created a novel transgenic mouse line with Cre recombinase knocked into the Avpr1b coding region to genetically target Avpr1b neurons. We confirmed this line has dense Cre expression throughout the dorsal and ventral CA2 regions of the hippocampus, along with scattered expression within the caudate-putamen and olfactory bulb (OB). Conditional removal of the NMDA receptor was achieved by crossing our line to an available floxed Grin1 line. The resulting mice were measured on a battery of social and memory behavioral tests. Surprisingly, we did not observe any differences between Avpr1b-Grin1 knockout mice and their wildtype siblings. We conclude that mice without typical NMDA receptor function in Avpr1b neurons can develop normal aggression as well as short-term social and object memory performance.
Dual receptor therapy with pituitrin for spinal cord injury-induced diabetes insipidus: A propensity-matched retrospective cohort study.
Chin J Traumatol
Lianhua Li, Jie Gao, Hao Wang +3 more
Spinal cord injury (SCI)-induced diabetes insipidus (DI) presents a unique therapeutic challenge due to concurrent autonomic hypotension unresponsive to conventional desmopressin. This study evaluates the clinical efficacy of Pituitrin, a synthetic vasopressin analog with dual V1a/V2 receptor agonism, designed to simultaneously address antidiuretic hormone deficiency and hemodynamic instability in acute SCI-related DI.
Heterogeneous effect of saxagliptin on glucose fluctuation and β-cell function in T1DM: a multicentre, randomised trial.
Nutr Diabetes
Yun Shi, Min Shen, Yong Gu +18 more
We aimed to explore whether saxagliptin, a dipeptidyl peptidase-IV inhibitor, could ameliorate glucose fluctuations and maintain β-cell function in T1DM.
Temporal variation in incretin and insulin secretion in ponies in association with dietary macronutrients.
Vet J
K E Andrews, P E M Sibthorpe, D M Fitzgerald +1 more
Equine insulin dysregulation (ID) is a common condition that predisposes to hyperinsulinaemia-associated laminitis. Improved pathophysiological understanding would enable better management of ID and reduce the risk of laminitis. The incretin peptides, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), augment the insulin response to dietary glucose and GLP-1 has been implicated in the pathophysiology of ID. However, their temporal variation in response to a low-energy diet has not been reported. This study determined the variation in GLP-1, GIP and insulin in eight healthy ponies, in relation to both the fed and unfed state, over a 24 h period. The ponies were fed a high-fibre ration plus two types of forage. Blood samples were analysed for blood glucose, total protein, serum triglycerides, which were used as proxy measures for the dietary macronutrients, as well as GLP-1, GIP and insulin concentrations. All analytes varied throughout the study (P < 0.05) with the principal pattern being a peak after eating compared to the fasted state. Blood glucose, GLP-1 and insulin were strongly positively (ρ close to 1) and synchronously (ρ peaked at time shift (τ) 0) correlated over time. Plasma GIP concentration also peaked in the unfed state (P = 0.01) and was potentially positively correlated (r = 0.39; P = 0.08) with triglyceride concentration. This relationship was confirmed in a larger cohort of 30 ponies using archived samples (P = 0.03). These data indicate that GIP likely has a physiological role in lipid clearance and/or fat metabolism in ponies, as shown in other species. As obesity is an important component of equine metabolic syndrome, further studies on the role of GIP in metabolic dysfunction are warranted.
Effects of Microplastics on the Central Reproductive Neuroendocrine System in a Sheep Model.
Int J Mol Sci
Patrycja Młotkowska, Bartosz Osuch, Elżbieta Marciniak +3 more
The present study investigated the impact of microplastics, specifically polystyrene microparticles (PS-MP), on the hypothalamic-pituitary-gonadal (HPG) neurohormonal axis, which regulates reproductive functions in animals and humans. The primary objective was to examine the effects of PS-MP on the expression of key genes and hormone concentrations within the gonadotropic system of sheep. Two doses of PS-MP-the lower dose (LD; 0.015 mg/kg) and the higher dose (HD; 0.15 mg/kg)-were administered intravenously every three days over two estrous cycles (34 days). Both doses significantly decreased the relative abundance of gonadotropin-releasing hormone (GnRH) transcripts in the mediobasal hypothalamus (MBH), whereas only the HD reduced GnRH mRNA levels in the preoptic area (POA). These transcript-level changes were not accompanied by detectable alterations in GnRH protein concentration. In the MBH, the expression of kisspeptin (KISS-1) and neurokinin B (NKB) genes decreased following exposure to the HD, whereas in the POA, significant decrease in expression were observed only after the LD administration. Changes in prodynorphin (PDYN) gene expression were confined to the MBH and were dose-dependent: the LD increased transcript levels, whereas the HD caused a decrease. The HD of PS-MP also significantly downregulated GnRH receptor (GnRHR) expression in the anterior pituitary (AP). Both PS-MP doses resulted in marked reductions in luteinizing hormone beta (LHβ) and follicle-stimulating hormone beta (FSHβ) subunit gene expression in the AP, without significant changes in hormone protein concentrations. Exposure to PS-MP reduced plasma LH and FSH concentrations: the lower dose reduced both hormones, while the higher dose significantly reduced mainly FSH, showing statistical differences between doses. To summarize, the present study demonstrates that PS-MP exerts a modulatory effect on the secretory activity of the central reproductive system in sheep, at both the hypothalamic and pituitary levels. Consequently, PS-MP has the potential to induce significant disruptions to the reproductive processes of large farm animals.
Reduced serum and skeletal muscle MOTS c levels in women with polycystic ovary syndrome are associated with mitochondrial dysfunction.
Sci Rep
Irem Sonmezoglu Kutuk, Senay Akin, Haydar Demirel +3 more
Polycystic ovary syndrome (PCOS) is characterized by insulin resistance and metabolic dysfunction. Mitochondrial-derived peptides (MDPs), including MOTS-c, regulate glucose homeostasis and skeletal muscle metabolism. Whether MOTS-c expression is altered in PCOS across different physiological compartments remains unknown. The aim was to assess circulating and skeletal muscle MOTS-c levels in women with PCOS and to examine their associations with metabolic and hormonal parameters. Forty women with PCOS and 40 age- and BMI-matched healthy controls underwent clinical, biochemical, and hormonal phenotyping. Serum MOTS-c concentrations were quantified by ELISA. In a representative subgroup, skeletal muscle MOTS-c expression was assessed in vastus lateralis biopsy specimens using Western blotting. Women with PCOS exhibited lower circulating MOTS-c concentrations compared with controls (220.2 ± 147.6 pg/mL vs. 498.3 ± 224.4 pg/mL, p < 0.001). Skeletal muscle MOTS-c expression was also reduced in the PCOS group (74.2 ± 15.2 vs. 100.0 ± 8.5 arbitrary units; p = 0.005). Serum MOTS-c levels were inversely associated with total testosterone (r = − 0.224, p = 0.046) and total cholesterol (r = − 0.228, p = 0.044). Women with PCOS display reduced MOTS-c expression in both the circulation and skeletal muscle, suggesting reduced availability of this mitochondrial-derived peptide. Associations with hyperandrogenism and lipid profiles suggest a potential link between altered mitochondrial peptide biology and the endocrine–metabolic phenotype of PCOS. These findings suggest that MOTS-c may represent a potential marker of tissue-specific mitochondrial involvement in PCOS and warrant further investigation.
Pyrroloquinoline quinone alleviates age-related osteoarthritis via nuclear factor erythroid 2-related factor 2-mediated stress response and insulin-like growth factor 1 receptor upregulation.
Phytomedicine
Qi Xue, Yueqiang Gu, Ran Qin +8 more
Age-related knee osteoarthritis (OA) arises from cumulative oxidative damage, chondrocyte senescence and extracellular matrix loss; yet safe and effective disease‑modifying interventions for aging‑associated OA are lacking. Pyrroloquinoline quinone (PQQ; molecular formula C14H6N2O8) is a naturally bioactive compound that has been reported to activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates antioxidant and cytoprotective gene expression. However, its effects on age-related OA and the underlying mechanisms remain unclear.
Sleep-disordered breathing in patients with heart failure with preserved left ventricular ejection fraction.
Sleep Breath
Cornelia Grimm, Christian Viniol, Mikail Degerli +5 more
Data on sleep-disordered breathing (SDB) in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) are sparse. Therefore, we aimed to determine the prevalence and characteristics of SDB in a large patient cohort with HFpEF.
The Benefits and Risks of Glucagon-Like Peptide-1 Receptor Agonists on Ocular Diseases: A Narrative Review.
Cureus
Jacky Xiao Feng Huang, Joshua Wu, Hunain Ahmad +5 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin-based agents used in the management of type 2 diabetes mellitus (T2DM) and obesity. This class of medications mimics the action of the endogenous GLP-1 hormone, enhances insulin secretion, delays gastric emptying, causes early satiety, lowers systemic glycemic levels, and results in weight loss. There are emerging concerns about the use of GLP-1RAs, which may be an observational association with ocular pathologies, including retinal vascular occlusion (RVO), vitreous hemorrhage (VH), diabetic retinopathy (DR), non-arteritic ischemic optic neuropathy (NAION), and diabetic macular edema (DME). In contrast, there are beneficial impacts of GLP-1RAs on various conditions, including glaucoma and idiopathic intracranial hypertension. This narrative review aims to analyze current findings on the beneficial and adverse ocular effects of GLP-1RAs use, highlighting studies that elucidate the harmful causes, such as retinal microvascular dysregulation, inflammatory modulation, oxidative stress, osmotic dysregulation from sorbitol accumulation, and metabolic shifts. The literature search was conducted using PubMed, Elsevier, Embase, Google Scholar, Scopus, and Science Direct to retrieve relevant literature published in peer-reviewed journals from 2014 to 2025. Understanding the benefits and risks of GLP-1RAs in ophthalmology is crucial for clinicians to manage ocular conditions safely while a patient is using GLP-1RAs, and enables personalized ophthalmological screenings to minimize the risk of disease exacerbation.
Incidentally Discovered Adrenal Mass With Mild Autonomous Cortisol Secretion and Pheochromocytoma.
Cureus
Padala Ravi Kumar, Sai Madhav Reddy Duggempudi, Deepak K Dash +2 more
Adrenal incidentalomas are adrenal masses detected on imaging performed for conditions unrelated to suspected adrenal disease. While pheochromocytomas and adrenal cortical adenomas are well-recognized entities, their coexistence with autonomous cortisol secretion (ACS) within a single lesion is rare and presents diagnostic and therapeutic challenges. A 53-year-old woman was incidentally found to have a left adrenal mass during imaging performed for evaluation of obstructive jaundice. She had hypertension but no classic symptoms of pheochromocytoma or overt Cushing's syndrome. Adrenal-protocol non-contrast CT showed an attenuation of -13 Hounsfield units (HU), suggestive of a benign adrenal adenoma. Biochemical evaluation revealed non-suppressible cortisol on the overnight dexamethasone suppression test (ONDST) and low-dose dexamethasone suppression test (LDDST), along with suppressed adrenocorticotropic hormone (ACTH), consistent with mild autonomous cortisol secretion (MACS). Additionally, 24-hour urinary fractionated normetanephrine levels were elevated, with normal fractionated metanephrine levels, confirming catecholamine excess. Preoperatively, she was managed with alpha- and beta-blockade, followed by open left adrenalectomy. Intraoperatively, she developed hypertension requiring nitroprusside infusion, and postoperatively she experienced transient hypotension, which was managed with intravenous fluids and hydrocortisone. Histopathology revealed a collision tumor with features of adrenal cortical adenoma and pheochromocytoma. Postoperatively, her requirement for antihypertensive drugs decreased from three to one. Repeat 24-hour urinary fractionated normetanephrine levels were normal at four weeks after surgery. This case highlights the importance of comprehensive biochemical and imaging assessment in adrenal incidentalomas. The tumor's dual-secretory nature necessitated meticulous perioperative management to prevent complications, and recognition of such rare entities is crucial for optimizing surgical and medical outcomes.
Reversible Cardiomyopathy Induced by Adrenal Insufficiency: A Case Report.
Cureus
Nehad M Makki, Amjad A Bugis, Amr E Waly +2 more
Adrenal insufficiency, though rare, can cause serious cardiovascular complications such as reversible cardiomyopathy. We present the case of a 56-year-old woman admitted to the intensive care unit with bradycardia, hypotension, and hypoglycemia, followed by hemodynamic instability and subsequent development of supraventricular tachycardia requiring stabilization. Endocrine assessment performed after stabilization demonstrated panhypopituitarism with radiological evidence of an empty sella, central hypothyroidism, and biochemical findings consistent with central adrenal insufficiency, confirmed by low morning cortisol with low adrenocorticotropic hormone levels. On admission, echocardiography showed biventricular dysfunction with a reduced ejection fraction and severe tricuspid regurgitation. Following initiation of intravenous hydrocortisone and supportive therapy, repeat echocardiography at one month demonstrated significant improvement, with recovery of systolic function and marked reduction in valvular regurgitation, consistent with reversible cardiomyopathy. This case highlights the importance of adrenal insufficiency as a potential cause of unexplained cardiomyopathy. The patient's cardiac function improved markedly following appropriate endocrine therapy, with normalization of ejection fraction and resolution of valvular abnormalities. These findings underscore the value of early endocrine evaluation and timely management in preventing irreversible cardiac damage and achieving complete functional recovery.
Effect of Normal Level Endocrine Hormones and Hypothalamic Neuropeptides on Obesity in Women of Childbearing Age.
J Obes
Yingying Tang, Xiukun Zhang, Lei Fan +4 more
To explore the association of endocrine hormones and hypothalamic neuropeptides fluctuations within normal level with obesity in women of childbearing age.
Physical activity promotes gut adaptation, nutrient responsiveness, and sensitivity to gut peptides in male mice.
EBioMedicine
Cecilie Bæch-Laursen, Jon Vergara Ucin, Katrine Douglas Galsgaard +6 more
Physical activity helps maintain a healthy stable body weight. One mechanism underlying this beneficial effect could be the improved coupling between energy intake and expenditure, since hunger and satiety are better regulated in active individuals. Whether this enhancement of appetite control by exercise is reflected in overall adaptations in the gut and gut-brain communication remains poorly defined.
Pathogenesis of Non-Familial Somatotroph Adenomas.
J Clin Endocrinol Metab
Anat Ben-Shlomo, Shlomo Melmed
Excess growth hormone (GH) production leading to acromegaly most commonly emanates from an adenomatous pituitary somatotroph. Understanding the pathogenesis of these adenomas will elucidate how biologic behavior affects acromegaly treatment outcomes.