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Erzhi pills: a potential aging-modulating agent targeting immunosenescence in mice.
Biogerontology
Zhirui Fang, Wei Sun, Na Li +9 more
Erzhi Pills (EZP), a traditional Chinese herbal formula, has demonstrated potential aging-modulating properties, while its mechanisms in modulating immunosenescence remain incompletely understood. Two complementary aging murine models were employed to investigate the anti-immunosenescence efficacy of EZP, providing experimental validation for its translational application in delaying age-related immune decline. Morphological and physiological parameters were monitored and thymic/splenic organ coefficients were calculated. Histopathological evaluation of thymic involution was performed via hematoxylin-eosin (H&E) staining. Flow cytometry quantified splenic T cell subsets (naïve/memory CD4+ and CD8+ T cells). Reverse transcription quantitative PCR (RT-qPCR) analyzed mRNA expression of key immunosenescence markers (Lin28a, GDF-11, Sirt1, IL-2, IL-17), while enzyme-linked immunosorbent assay (ELISA) measured serum levels of pro-inflammatory cytokines (TNF-α, IFN-γ). Metabolomic profiling further elucidated EZP's bioactive pathways. EZP administration significantly attenuated age-related degeneration in both murine models by restoring thymic and splenic architecture, as evidenced by increased organ coefficients and reduced histopathological damage. EZP rebalanced T cell homeostasis through selective expansion of naïve T cells and contraction of memory T cell subsets, with a pronounced increase in CD8+ T cell populations. At the molecular level, EZP upregulated Lin28a, Sirt1, and IL-2 expression while modulating systemic cytokine profiles-reducing TNF-α and augmenting IFN-γ in the natural aging cohort. These findings suggest EZP mitigates chronic inflammatory aging and enhances immune responsiveness of effector T cells. EZP's anti-aging mechanism was mediated by fatty acid metabolism modulation. This study provides evidence supporting EZP's potential as a novel therapeutic strategy for immunosenescence and warrants further investigation into its clinical translation for geriatric populations.
Association of Glucagon-Like Peptide-1 Receptor Agonists and Suicidality: A Systematic Review.
Obes Rev
Hezekiah C T Au, Yang Jing Zheng, Gia Han Le +7 more
Increased risk of suicidality has been reported in association with glucagon-like peptide receptor agonist (GLP-1 RA) prescription. Herein, we conducted a comprehensive review evaluating reports of GLP-1 RA prescription and suicidality.
Semaglutide use in a patient with a long-term ileostomy: A case report highlighting clinical risks and evidence gaps.
J Am Pharm Assoc (2003)
Gabriela Gaytan, Andrea Pabon, Natalie Rosario
GLP-1 receptor agonists (GLP-1 RAs), such as semaglutide, dulaglutide, liraglutide, and exenatide, are increasingly used to treat type 2 diabetes and support weight loss. These agents function by enhancing glucose-dependent insulin secretion, suppressing inappropriate glucagon secretion, slowing gastric emptying, and regulating appetite through central nervous system pathways. Since semaglutide's approval in 2017 and U.S. market availability in 2018, its use has expanded significantly. However, there remains limited literature evaluating its safety and efficacy in patients with altered gastrointestinal anatomy, particularly those with ostomies.
Comparative Efficacy and Safety of Glucagon Receptor Agonists on Metabolic Outcomes: A Network Meta-Analysis of Randomised Controlled Trials.
Endocrinol Diabetes Metab
Ayah Abulehia, Hazem Ayesh, Omar Ayesh +7 more
Glucagon receptor agonists (GRAs) are an emerging class of therapies for obesity and type 2 diabetes, demonstrating encouraging metabolic and weight-reducing effects. Several investigational GRA-based agents, including retatrutide, cotadutide, mazdutide, and survodutide, have reported promising results across early and mid-phase clinical trials. This comprehensive meta-analysis evaluates the efficacy and safety of these agents in individuals with type 2 diabetes, overweight, or obesity.
Afamelanotide improves quality of life and light tolerance in Austrian erythropoietic protoporphyria patients.
J Dtsch Dermatol Ges
Magdalena Seidl-Philipp, Hanna Schratter, Johanna Auer +7 more
Erythropoietic protoporphyria (EPP) is a rare genetic disorder characterized by severe phototoxic reactions that occur within minutes of light exposure. In clinical studies, afamelanotide has been shown to prolong pain-free sun exposure, improve quality of life, and reduce the frequency and severity of phototoxic reactions.
Mas Knockout Mice Present Altered Behavioral and Neuroendocrine Coping Responses to Chronic Unpredictable Stress.
Mol Neurobiol
Sthéfanie C A Gonçalves, Andressa da Silveira Silva, Bruna Karen Oliveira Nogueira +6 more
Stress is defined as a disruption of homeostasis that elicits adaptive responses aimed at restoring physiological balance. However, when stress becomes chronic or overwhelming, maladaptive changes may occur, contributing to endocrine, behavioral, and neuropsychiatric dysfunctions. Beyond the classical neuroendocrine axes, such as the sympatho-adrenomedullary and hypothalamic-pituitary-adrenal (HPA) axes, the renin-angiotensin system has also being implicated in stress modulation. Previous studies have shown that angiotensin-(1-7), acting through its receptor Mas, exerts a modulatory effect on the stress response, attenuating anxiety- and depression-like behaviors induced by various stressors. Here we investigated the impact of genetic deletion of Mas on the consequences of chronic unpredictable stress (CUS) exposure. Over 21 consecutive days, mice were subjected to random stressors, after which endocrine, behavioral and neurochemical assessments were performed. Mas knockout (KO) mice exposed to CUS exhibited significantly elevated corticosterone and blood glucose levels compared to stressed wild-type mice. In behavioral tests, stressed Mas KO mice displayed the highest immobility times in the forced swimming test, indicating enhanced depressive-like behavior. Anxiety-like behavior was also heightened in Mas KO mice, as evidenced by a significant reduction in the percentage of time spent in the open arms of the elevated plus maze test. Neurochemical analysis revealed a marked reduction in brain-derived neurotrophic factor (BDNF) levels in key brain regions of stressed Mas KO animals. Together, these findings suggest that Mas plays a critical role in the neurobiology of stress, since its absence exacerbates HPA axis hyperactivity, depression- and anxiety-like behaviors, as well as BDNF reduction. Overall, these results highlight the potential neuroprotective role of Mas in stress-related disorders.
Oxytocin beyond social bonding: Advancing neuromodulation, synaptic plasticity, and epigenetic precision in CNS disorders.
Neuropeptides
Supratim Paul, Janvi Verma, Sidharth Mehan
Oxytocin, a neuropeptide predominantly produced in the hypothalamus, has garnered significant attention for its multifaceted roles extending beyond social bonding and reproduction to therapeutic applications in neurodegenerative and neuropsychiatric disorders. This review explores oxytocin's neuroprotective properties, including anti-inflammatory, antioxidant and anti-apoptotic effects, which counteract pathological mechanisms underlying diseases like Alzheimer's, Parkinson's and Epilepsy. Oxytocin's ability to modulate key neurotransmitter systems GABAergic, dopaminergic, and serotonergic pathways enhances synaptic plasticity, neurogenesis, and emotional regulation. These mechanisms have positioned oxytocin as a promising intervention for neuropsychiatric conditions such as autism, schizophrenia, depression, and anxiety. Preclinical and clinical studies have shown that intranasal administration of oxytocin improves social cognition, reduces symptom severity, and is well-tolerated, though challenges remain in standardizing dosages and measuring oxytocin levels due to individual variability. Emerging technologies, such as nanoparticle-based drug delivery systems, offer solutions to enhance oxytocin's bioavailability and brain penetration, making targeted, patient-specific therapies feasible. Epigenetic modifications of the oxytocin receptor gene including DNA methylation have been associated with variability in social and stress-related behaviors. While these findings offer insight into inter-individual differences, their application to precision medicine remains speculative and will require rigorous clinical validation. Combination therapies, integrating oxytocin with agents targeting neuroinflammation and synaptic plasticity, hold potential for synergistic effects. Despite methodological and translational challenges, oxytocin represents a transformative therapeutic agent with broad applications across neurological, psychiatric, and systemic disorders. Future research focusing on nanotechnology, epigenetics, and long-term clinical trials will be pivotal in realizing the full potential of oxytocin-based interventions for complex, multifactorial diseases.
Processing-induced structural remodeling enhances the hypoglycemic activity of Polygonatum cyrtonema Hua polysaccharides via gut microbiota-SCFA-GPR41/43 pathway.
Food Res Int
Chuyao Deng, Jiaxin Zheng, Fei Xu +9 more
Type 2 diabetes mellitus (T2DM) poses a major health and socioeconomic challenge, and long-term use of conventional hypoglycemic agents often causes adverse effects such as impaired gastrointestinal function. Natural polysaccharides have emerged as promising alternatives due to their safety and bioactivity. In this study, polysaccharides from raw Polygonatum cyrtonema Hua (RPCP) and processed Polygonatum cyrtonema Hua (PPCP) were successfully extracted using enzyme-assisted hot water extraction. The purified fractions of RPCP (RPCP-P) and PPCP (PPCP-P) were structurally characterized by molecular weight determination, monosaccharide composition, FT-IR, methylation, and NMR analyses. Their hypoglycemic effects and underlying mechanisms were evaluated in high-fat diet and streptozotocin-induced T2DM mice. Both RPCP and PPCP significantly reduced fasting blood glucose, improved insulin sensitivity, and ameliorated lipid metabolism disorders. Mechanistically, the polysaccharides modulated gut microbiota composition, promoted short-chain fatty acid (SCFA) production, upregulated colonic GPR41/43 expression, and increased glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion, thereby improving glucose homeostasis. Notably, PPCP exhibited superior antidiabetic effects to those of RPCP, which we attribute to its greater molecular heterogeneity and galactan-rich structure, suggesting that traditional steaming enhances polysaccharide bioactivity. These findings demonstrate that traditional processing enhances the functionality of Polygonatum cyrtonema polysaccharides through structure-dependent modulation of the gut microbiota-SCFA-host metabolic axis, providing a scientific basis for their development as functional food ingredients for glycemic regulation.
A DYRK inhibitor ameliorates glucose homeostasis and increases incretin-producing cells in diabetic mice.
J Mol Endocrinol
Michishige Terasaki, Qiao Zhou, Olov Andersson +1 more
Incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have been shown to improve hyperglycemia in patients with type 2 diabetes, suggesting that an enhanced capacity of GIP and GLP-1 production could be beneficial in type 2 diabetes. We have recently found that dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitors reduce glucose levels and increase the number of intestinal gip-expressing K-cells and glp-1-expressing L-cells in zebrafish. However, their effects on mammals require exploration in greater detail. In this study, we examined whether oral administration of a DYRK inhibitor, ID-8, to diabetic db/db mice affects glucose homeostasis, plasma levels of insulin, incretins, number of intestinal K-cells and L-cells and pancreatic cell volume in vivo. ID-8-treated mice showed a significant reduction in HbA1c levels and decreased blood glucose levels after oral glucose tolerance test along with enhanced plasma levels of insulin, total-GIP and total-GLP-1. The number of K-cells and L-cells in the intestines of ID-8-treated mice was increased, and a subset of these cells were co-stained with a DYRK-regulated transcriptional factor, nuclear factor of activated T cells 4 (NFATc4), but not co-localized with the proliferation marker EdU. There were no significant differences of pancreatic β- and α-cell mass between the ID-8- and vehicle-treated mice. Moreover, mRNA levels of incretins were significantly increased in ID-8-treated human intestinal organoids. Our present study demonstrated that ID-8 improved hyperglycemia in association with enhanced plasma levels of insulin and incretins as well as an increased number of K-cells and L-cells in diabetic mice; therefore, it may be a novel therapeutic agent for diabetes.
Aberrant hypothalamic neuronal activity blunts glucocorticoid diurnal rhythms in murine breast cancer.
Neuron
Adrian M Gomez, Yue Wu, Chao Zhang +6 more
Breast cancer patients often exhibit disrupted diurnal rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality; however, the exact cause of this phenomenon remains unclear. Here, we demonstrate that breast tumor-bearing mice exhibit blunted GC rhythms and a loss of diurnal rhythms in the activity of paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (PVNCRH). This change in neuronal activity is mediated by disinhibition from upstream GABAergic neurons. Using chemogenetics to stimulate PVNCRH neurons at different times of day, we show that stimulation just before the light-to-dark transition restores normal GC rhythms, reduces tumor progression, and increases intra-tumor effector T cells (CD8+). Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control the output of the hypothalamic-pituitary-adrenal (HPA) axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression via enhancing anti-tumor immunity.
Sex-based differences in the enteroendocrine system and food intake regulation due to dietary protein replacement by Alphitobius Diaperinus in rats.
Food Res Int
Oria Soler, Mònica Lores, Esther Rodríguez-Gallego +6 more
The rising global demand for animal protein, coupled with the environmental impact of conventional livestock, has sparked interest in sustainable alternatives. Insect-derived proteins, particularly from Alphitobius diaperinus (lesser mealworm), offer high nutritional value, good digestibility, and a minimal ecological footprint. Enteroendocrine hormones such as ghrelin, peptide YY (PYY), cholecystokinin (CCK), and glucagon-like peptide-1 (GLP-1) are key regulators of appetite, satiety, and energy homeostasis, responding dynamically to the composition and quality of ingested nutrients. Given the increasing prevalence of protein malnutrition in aging population and the metabolic challenges posed by obesogenic diets, this study aimed to investigate whether the enteroendocrine-modulating effects previously observed with acute A. diaperinus administration are sustained when utilized as the sole dietary protein source. Furthermore, we evaluated sex-specific responses under both standard and high-fat diet conditions in rats. Our findings demonstrate that A. diaperinus-based diets can alter caloric intake and elicit differential enteroendocrine secretion patterns depending on the sex and metabolic status of the animal, suggesting context-specific regulatory effects on energy balance and gut hormone responses. Together, these results enhance our understanding of how insect-based proteins interact with nutrient-sensing pathways and may inform the development of targeted nutritional strategies to support healthy aging, metabolic health, and environmental sustainability.
Effects of Traumatic Brain Injury on the Orexin/Hypocretin System.
Neurotrauma Rep
Rebecca T Somach, Miranda M Lim, Akiva S Cohen
Traumatic Brain Injuries (TBIs) are known to cause a myriad of symptoms in patients. One common symptom after injury is sleep disruptions. One neuropeptide system has been studied repeatedly as a potential cause of sleep disruptions after TBI- the orexin/hypocretin system. Orexin promotes wakefulness and arousal while disrupting the orexin system causes increased sleepiness and narcolepsy. Studies of TBI in human and animal subjects have shown that TBI affects the orexin system. This review serves as an overview of how TBI affects the orexin/hypocretin system, including structural and functional changes to the neurons after injury. This review is the first to include studies that examine how TBI affects orexin/hypocretin receptors. This review also examines how sex is accounted for in the studies of the orexin system after TBI.
Mitochondrial-Derived Peptides as Therapeutics and Biomarkers for Combating Vascular Aging and Associated Cardiovascular Diseases.
Curr Cardiol Rev
Rooban Sivakumar, Arul Senghor Kadalangudi Aravaanan, Vinodhini Vellore Mohanakrishnan +1 more
Vascular aging profoundly affects the onset of cardiovascular diseases in the elderly, mostly as a result of mitochondrial dysfunction. This review examines the protective roles of mitochondrial- derived peptides such as humanin, MOTS-c, and small humanin-like peptides in mitigating vascular aging. These peptides, encoded by mitochondrial DNA, are crucial for regulating apoptosis, inflammation, and oxidative stress, which have a major role in vascular health. MDPs have significant prospects as therapeutic and biomarker possibilities for the early diagnosis and intervention of vascular aging. MDPs influence the functions of endothelial and vascular smooth muscle cells by modulating critical signaling pathways, including AMPK, mTOR, and sirtuins. These pathways are essential for facilitating cellular metabolism, enhancing stress resilience, and prolonging longevity. Moreover, MDPs are essential in mitochondrial bioenergetics and dynamics, vital for mitigating endothelial dysfunction and enhancing vascular resilience. Furthermore, MDPs contribute to immunological modulation and the regulation of inflammatory responses, underscoring their potential therapeutic applications in the treatment of age-related vascular disorders. This review analyzes the various functions of MDPs in vascular health and their therapeutic importance, advocating for more studies to optimize their clinical benefits. By understanding the comprehensive roles and mechanisms of these multifunctional peptides, we can better appreciate their capacity to prevent and treat vascular aging and associated cardiovascular disorders. Future research should aim to further elucidate their therapeutic effects and optimize their clinical applications.
MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.
Free Radic Biol Med
Anders Gudiksen, Camilla Collin Hansen, Thibaux van der Stede +12 more
Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTS-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.
Redefining evidence for teprotumumab in thyroid eye disease: an updated meta-analysis of efficacy and safety.
Front Endocrinol (Lausanne)
Rongjing Song, Wei Zhao, Shasha Li +5 more
Thyroid eye disease (TED) is a sight-threatening autoimmune disorder with limited effective therapies. Teprotumumab, an insulin-like growth factor-1 receptor inhibitor, has emerged as a promising treatment. However, a comprehensive synthesis of its efficacy and safety across randomized trials remains limited.
Neoadjuvant immunochemotherapy plus thymalfasin in locally advanced gastric cancer: a prospective clinical trial.
BMC Med
Hao Xu, Fengyuan Li, Bowen Li +8 more
Neoadjuvant immunochemotherapy has emerged as a promising strategy for locally advanced gastric and gastroesophageal junction (G/EGJ) adenocarcinoma, but a substantial proportion of patients derive limited benefit. Thymalfasin is an immunomodulatory peptide that may amplify antitumor immunity while attenuating toxicity. We conducted a phase II trial to evaluate anti-PD-1 plus SOX (S-1 and oxaliplatin) immunochemotherapy combined with thymalfasin as neoadjuvant treatment for G/EGJ adenocarcinoma.
A hedgehog cathelicidin-derived peptide exhibits antiviral activity against herpes simplex virus type 1 infection.
Front Microbiol
Enjie Deng, Yaping Pei, Kun Yuan +7 more
Herpes simplex virus type 1 (HSV-1) is a widespread infectious virus that poses a substantial public health burden. With no specific curative therapy available and current antivirals providing only symptomatic relief, the development of new effective antiviral agents remains imperative. Antimicrobial peptides, particularly cathelicidins, are key immune effector molecules with antiviral and immunomodulatory properties. In this study, we found that European hedgehog skin extract (HSE) exhibited potent anti-HSV-1 activity, prompting us to investigate the contribution of the cathelicidin peptide CathEE. Based on this observation, three CathEE-derived antiviral peptides (CathEE-1, CathEE-2, and CathEE-3) were designed and further optimized to yield CathEE-2a and CathEE-2b. Notably, CathEE-2a displayed pronounced antiviral activity in vitro and significantly reduced brain viral loads in an HSV-1 mouse infection model. Histopathological analyses further revealed that CathEE-2a attenuated HSV-1-induced brain damage. Mechanistically, CathEE-2a suppressed HSV-1 infection by upregulating type I interferons and downstream antiviral genes. Collectively, these findings identify CathEE-2a as an immunomodulatory antiviral peptide and a promising lead candidate for the development of novel therapeutics against HSV-1 infection, highlighting the therapeutic potential of hedgehog-derived antimicrobial peptides in antiviral drug discovery.
Effects of Glucagon-Like Peptide-1 Receptor Agonist on Bone Metabolism and the Expression of Insulin Receptor Substrate 1 in an Osteoporotic Rat Model.
Int J Endocrinol
Yao Ye, Yu-Ling He, Jie He +2 more
This study aimed to investigate the effects of the GLP-1R agonist Exendin 4 on bone metabolism and insulin receptor Substrate 1 (IRS-1) expression in an osteoporotic (OP) rat model.
[The effect of neuroprotectors on the level of BDNF, tumor necrosis factor alpha and apoptosis markers, and in acute cerebrovascular accidents].
Zh Nevrol Psikhiatr Im S S Korsakova
A V Shchulkin, I V Chernykh, Y V Abalenikhina +5 more
To compare the effects of Mexidol, Cerebrolysin, and Cortexin on the levels of brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNFα), and apoptosis markers in the rat brain following middle cerebral artery (MCA) occlusion-reperfusion.
Med14 phosphorylation shapes genomic response to GLP-1 agonists.
Proc Natl Acad Sci U S A
Sam Van de Velde, Jungting Yu, K Garrett Evensen +4 more
Binding of GLP-1 to its receptor in pancreatic beta cells triggers activation of the cAMP pathway and phosphorylation of CREB, leading to induction of cellular target genes containing CREB binding sites. By contrast with their acute effects on beta cell gene expression, chronic exposure of beta cells to stable GLP-1 analogs like Exendin-4 stimulates sustained expression of beta cell-specific genes, leading to increases in beta cell viability and insulin secretion. In a proteomic screen for transcriptional coregulators that contribute to the transcriptional effects of GLP-1, we identified Med14, the scaffolding subunit of the conserved 30 subunit Mediator complex. Exposure to Exendin-4 and other GLP-1 receptor agonists stimulates sustained phosphorylation of Med14 at Ser983, which corresponds to a conserved PKA recognition site. Mutation of Med14 at Ser983 blocked Exendin-4 effects on cellular gene expression by interfering with CREB-mediated activation of beta cell-specific enhancers. Med14 mutation results in higher alpha-to-beta cell ratios and blunted gene regulation in response to Exendin-4 in Ser983-mutant primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.