The living record of
peptide science.

Tirzepatide vs. semaglutide for obesity, glycemic control, and cardiovascular outcomes: a narrative review of clinical trials.

Front Med (Lausanne)

Maan H Harbi, Ahmad M Ashour, Nasser M Alorfi +3 more

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide, (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as an effective therapy for obesity and type 2 diabetes mellitus (T2DM). Its dual-incretin mechanism may offer enhanced metabolic benefits compared with selective GLP-1 receptor agonists such as semaglutide.

Use of Semaglutide and Tirzepatide in Rheumatic and Musculoskeletal Diseases: Insights on Initiation Patterns and Weight Loss From the Rheumatology Informatics System for Effectiveness Registry.

ACR Open Rheumatol

Nicholas P McCormick, Cristiano S Moura, Jingyi Zhang +5 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide (SEM) and tirzepatide (TZP) were initially approved for type 2 diabetes management but are increasingly used for weight loss. Limited data exist on real-world use among patients with rheumatic and musculoskeletal diseases (RMDs). This study aimed to describe characteristics and trends in SEM and TZP initiation among individuals with RMDs and to identify factors associated with weight loss.

MC4R-related monogenic obesity in children: insights from 2 cases.

Ann Pediatr Endocrinol Metab

Dhivya Shanmugam, Subbiah Sridhar, Nandini Kuppusamy +3 more

Childhood and adolescent obesity are growing global health concerns, with genetic factors playing an important role. Despite the increasing prevalence of obesity in India, monogenic obesity remains underdiagnosed. We report 2 cases of early-onset morbid obesity due to melanocortin-4 receptor (MC4R) gene mutation. Case 1 was a 5-year-old boy who presented with severe hyperphagia and rapid weight gain since infancy. Case 2 was a 12-year-old girl who presented with progressive obesity, hyperphagia, and bilateral genu varum. Both patients exhibited severe insulin resistance with no syndromic stigmata. Genetic analysis confirmed a homozygous MC4R mutation in both cases. They were managed with a multidisciplinary approach that included dietary modification, structured physical activity, and pharmacotherapy using the glucagon-like peptide-1 analog liraglutide and metformin. Both cases showed a satisfactory response to liraglutide. These case reports highlight the point at which monogenic obesity can be clinically suspected and distinguished from syndromic obesity. Moreover, they underscore the role of genetic testing for monogenic obesity and the targeted therapies in its management.

Obesity Management: Pharmacotherapy.

FP Essent

Morgan A Rhodes, A Miles Scott, Matthew Nodelman +1 more

Anti-obesity drugs should be offered as initial treatment of overweight and obesity for adults with weight-related comorbidities and for those at high risk of complications, and as a component of first-line treatment for patients with obesity and overweight without comorbidities. Currently, US Food and Drug Administration-approved drugs for obesity include centrally acting drugs, gastrointestinal lipase inhibitors, and incretin mimetics. Other drugs are used off-label to promote weight loss. The incretin mimetics, glucagon-like peptide-1 receptor agonists (eg, semaglutide, liraglutide) and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor ago- nist (ie, tirzepatide), demonstrate the greatest weight loss benefits, with tirzepatide achieving reductions exceeding 20% in some patients. Drug selection should be individualized based on comorbidities (eg, cardiovascular disease, obstructive sleep apnea), cost, and patient preference. Despite growing evidence of benefit, barriers (eg, prescriber hesitancy, high costs, limited insurance coverage) persist. With multiple drugs in development, continued innovation in pharmacotherapy management offers promise, but expanding education and access remains critical to improving obesity care.

Secretory form of viral protease NIa ameliorates amyloid-β pathology and cognitive deficits in a mouse model of Alzheimer's disease.

Front Aging Neurosci

Euy Jun Park, Bo-Ram Mun, Sung Yoon Kim +4 more

Alzheimer's disease (AD), the leading cause of dementia, is characterized by extracellular amyloid-β (Aβ) accumulation. Immunotherapies targeting Aβ clearance show promise, highlighting the therapeutic value of enhancing Aβ removal. We previously identified that nuclear inclusion a (NIa), a plant viral protease, fortuitously cleaves Aβ with strict sequence specificity. Here, we engineered a secretory form, SecNIa, to degrade extracellular Aβ. SecNIa was efficiently secreted from transfected cells while retaining potent Aβ-cleaving activity. Adeno-associated virus (AAV)-mediated delivery of SecNIa into 5xFAD mice resulted in robust hippocampal expression and cerebrospinal fluid secretion. SecNIa expression significantly reduced soluble and insoluble Aβ, decreased hippocampal plaques, and improved cognition, fully normalizing recognition memory and enhancing spatial learning. These findings establish SecNIa as a promising therapeutic strategy to directly target pathogenic extracellular Aβ in AD.

Using iPSC models to examine neuron-glia interactions in neurodegenerative diseases.

Biosci Rep

Dianne M Lopez, Lois K Keavey, Kathryn R Bowles

Neurodegenerative diseases remain without effective or accessible treatments and interventions, despite their increasing global burden. Clinically, these disorders are characterised by progressive cognitive decline, behavioural changes, and loss of motor function, all of which are associated with neuronal and synaptic loss or dysfunction. Although traditionally viewed as neuron-centric, it is becoming increasingly clear that glial cells play critical roles in maintaining and regulating neuronal and synaptic health. Mounting evidence implicates glial dysregulation in both the onset and progression of neurodegenerative diseases through mechanisms such as aberrant synaptic engulfment and protein clearance, impaired homeostatic support, metabolic dysfunction, chronic inflammation, transmission of pathogenic proteins, and cellular senescence. Elucidating how disruptions in neuron-glia interactions contribute to neuronal dysfunction is therefore essential for developing effective therapies. Induced pluripotent stem cell (iPSC)-based models provide a powerful platform to investigate these interactions in human-relevant systems. Here, we will discuss recent insights into the mechanisms contributing to neurodegenerative disease that have been gained specifically from modelling neuron-glia interactions in human iPSCs.

Tirzepatide and semaglutide: different twins?

Eur Heart J Suppl

Arturo Cesaro, Vincenzo Acerbo, Paolo Calabrò

Incretin-based therapies currently represent one of the cornerstones in the management of type 2 diabetes mellitus and obesity, owing to their ability to integratively modulate cardiometabolic risk. Semaglutide, a selective agonist of the glucagon-like peptide-1 (GLP-1) receptor, has consolidated its clinical role through an efficacy profile that combines marked improvement in glycaemic control, substantial body weight reduction, and well-established cardiovascular and renal benefits. Tirzepatide, the first dual agonist of the glucose-dependent insulinotropic polypeptide and GLP-1 receptors, has introduced a new generation of incretin-based agents, characterized by a superior impact on weight loss and insulin sensitivity, with a potential expansion of therapeutic indications. Although both molecules share a remarkable ability to reduce body weight and HbA1c levels, they differ in their mechanisms of action, current therapeutic indications, and the robustness of available evidence on cardiovascular outcomes. Their integration into clinical practice therefore requires a personalized approach that balances metabolic efficacy, safety, and individual patient risk profiles. Within this context, the incretin revolution offers new perspectives for cardio-reno-metabolic prevention.

Hypothalamic-superior frontal gyrus functional connectivity alterations and luteinizing hormone correlations in girls with central precocious puberty.

Ann Pediatr Endocrinol Metab

Hongqiang Cai, Lianzi Su, Xiyan Chen +7 more

In this study, the neural communication patterns between hypothalamic structures and cortical areas in girls diagnosed with central precocious puberty (CPP) were explored. Endocrine profiles were incorporated to clarify the pathophysiological interactions between cerebral networks and hormonal regulation. The hypothalamus was designated as the key focus area for connectivity analysis.

Mesenchymal Stem cell therapy with GHRH receptor analog resolves post-stroke vasogenic edema via modulating AQP4 and mitochondria-ER crosstalk.

J Transl Med

Aishika Datta, Bijoyani Ghosh, Anita Kumari +12 more

Post-stroke edema is one of the fatal consequences of ischemic stroke where increased intracranial pressure can exacerbate neurological dysfunction leading to mortality. To date, conventional post-stroke therapy has failed to manage cerebral edema and render neuroprotection. Earlier, our lab reported the benefits of intra-arterially administered mesenchymal stem cells (IA MSCs) in alleviating post-stroke vasogenic edema. Recently, post-stroke neuroendocrine regulation involving growth hormone releasing hormone receptor (GHRH-R) analog is gaining attention as one of the potential targets for stroke intervention, adjunctive to the existing conventional therapies. Therefore, the current study aims to explore the combined therapeutic potential of IA MSCs and GHRH-R analogs in resolution of cerebral vasogenic edema following ischemic stroke.

Tumor-specific lncRNA IGF1R-AS1 trans-regulates chromatin interactions associated with oncogenic MYC signaling.

Nat Commun

Yongyong Yang, Ting-You Wang, Joshua Fry +24 more

LncRNAs have emerged as pivotal regulators in the development and progression of various human cancers. However, understanding the precise mechanisms by which lncRNAs influence cancer progression remains a substantial challenge, largely due to their cell type- and tissue-specific expression patterns and the lack of well-defined functional domains or motifs. In this study, we investigate the complex interplay between super-enhancers and lncRNAs through a comprehensive analysis of lncRNA expression in a cohort of metastatic castration-resistant prostate cancer patients. Our analysis identifies 1344 lncRNAs, among which an antisense lncRNA in the IGF1R locus named IGF1R-AS1 displayed the strongest super-enhancer association. Through pan-cancer transcriptome analysis, we find that IGF1R-AS1 is specifically transcribed in tumor specimens and is overexpressed in prostate and lung cancers. Notably, we reveal a non-canonical trans-acting role for IGF1R-AS1 whereby it interacts with chromatin remodeling complexes and architectural proteins to facilitate long-range chromatin looping between distal MYC enhancers and its promoter, leading to MYC overexpression and enhanced tumorigenicity. Collectively, our findings elucidate a mechanism by which a tumor-specific trans-acting lncRNA modulates oncogenic MYC expression through long-range chromatin interactions, suggesting IGF1R-AS1 may play an important role in the pathogenesis of MYC-driven malignancies.

Curcumin attenuates uterine pain in mice through suppression of neuroinflammation in the DRG and spinal cord.

Int Immunopharmacol

Ya-Ru Yang, Ji-Tao Tang, Bing-Qiang He +4 more

Uterine pain associated with labor, dysmenorrhea, or endometriosis is often driven by inflammation, which enhances nociceptive signaling and contributes to hyperalgesia. Although nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are commonly prescribed, their clinical application is limited by side effects, and a subset of patients exhibit inadequate or no response to NSAID therapy. Curcumin, a natural polyphenol extracted from Curcuma longa, exhibits well-documented anti-inflammatory and analgesic properties. In this study, we investigated the analgesic efficacy and underlying mechanisms of curcumin in a mouse model of uterine pain. Both intraperitoneal and intrathecal administration of curcumin significantly reduced writhing responses and improved locomotor performance in open-field tests. Molecular analyses revealed that estrogen and oxytocin treatment induced activation of glial cells in the dorsal root ganglia (DRG) and spinal cord. Intrathecal curcumin attenuated the activation of satellite glial cells and macrophages in the DRG, suppressed MAPK signaling (ERK, JNK, and p38), and decreased the expression of proinflammatory mediators, including IL-6, TNF-α, IL-1β, CCL2, and CXCL1. Similarly, in the spinal cord, curcumin reduced astrocyte and microglia activation, MAPK phosphorylation, and inflammatory cytokine and chemokine levels. Moreover, curcumin diminished p-ERK expression in DRG neurons and reduced c-Fos expression in the spinal dorsal horn. Collectively, these findings demonstrate that curcumin alleviates uterine pain by suppressing glial activation, MAPK signaling, and inflammatory mediators' production, ultimately reduces markers of neuronal activation and plasticity in the DRG and spinal cord. This provides mechanistic support for curcumin's potential in managing uterine pain.

Beyond GLP-1 Monotherapy: Novel Multi-Agonists, Amylin Analogues, and Combination Strategies in Obesity and Type 2 Diabetes.

Diabetes Obes Metab

Mikhail Khachaturov, Dimitrios G Goulis

To provide a clinically oriented narrative review of recently reported human trial data on emerging pharmacotherapies for obesity and type 2 diabetes beyond glucagon-like peptide-1 receptor agonist (GLP-1RA) monotherapy.

Treatment of the disease of obesity in patients with type 1 diabetes with tirzepatide: a protocol for a randomised controlled trial in a single-centre setting.

BMJ Open

Ebaa Al Ozairi, Ameenah Al Awadhi, Etab Taghadom +5 more

Medication for the disease of obesity has improved, and clinical trials based on natural gut hormones such as tirzepatide, showed only mild side effects and ~22% weight loss maintenance. However, patients with type 2 diabetes only lose 15% bodyweight with tirzepatide while tolerating the medications very well, but little is known in patients with the disease of obesity who also have type 1 diabetes, especially regarding safety of the medications. Tirzepatide's licence in the Gulf countries and Europe for obesity does not exclude patients with obesity and type 1 diabetes, unlike the USA. In Kuwait, more than a quarter of patients with type 1 diabetes also have the disease of obesity. Tirzepatide is not approved for glycaemic control in patients with type 1 diabetes, because it is unlikely to make a difference. Because tirzepatide is approved for the treatment of obesity in patients who also have type 1 diabetes we can now test how effective treatments for obesity such as tirzepatide are for patients with obesity and type 1 diabetes. Concerns regarding the safety of the medication in type 1 diabetes can also be addressed thus addressing an important knowledge gap.

Paeonol mitigates age-related osteoporosis via mitophagy-mediated NLRP3 inflammasome inhibition.

Int Immunopharmacol

Jingliang Gu, Min Ma, Laiya Lu +4 more

Age-related osteoporosis, a progressive skeletal disorder inherent to aging, is pathologically defined by diminished bone mass and deteriorated bone microarchitecture, resulting in heightened skeletal fragility. Despite extensive research, effective therapeutic interventions for age-associated bone loss remain limited. Accumulating evidence indicates that aging-induced immune dysregulation contributes significantly to chronic low-grade inflammation, thereby exacerbating osteoporotic progression. In this study, we identify Paeonol (PAE) as a potent mitigator of senile osteoporosis, acting through the modulation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome/mitophagy axis. We demonstrate that PAE ameliorates aging-induced bone loss in the NLRP3 inflammasome-dependent manner by enhancing mitophagic flux. Specifically, PAE facilitates the clearance of dysfunctional mitochondria, thereby suppressing NLRP3 inflammasome activation and subsequent inflammatory responses. Notably, pharmacological or genetic inhibition of mitophagy abrogates the protective effects of PAE, as evidenced by the attenuated suppression of NLRP3 inflammasome activation and the diminished preservation of bone mass in aged murine models. These findings highlight the critical interplay between mitophagy and NLRP3 inflammasome in age-related bone loss and suggest that PAE-mediated enhancement of mitochondrial quality control represents a promising therapeutic strategy for osteoporosis management.

Hepatic expression of APOE3 Christchurch mitigates APOE4-related Alzheimer's disease pathologies in mice.

Neuron

Jin-Yi Tang, Qi Tan, Zhong-Yuan Yu +10 more

The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and exacerbates AD-related pathologies. Identifying strategies to mitigate the pathogenic effects of APOE4 remains a critical challenge in the field of AD research. The rare APOE3 Christchurch (APOE3Ch) variant has been suggested to be potentially protective against AD. Our study investigated whether hepatic expression of APOE3Ch could mitigate APOE4-associated AD pathologies. We successfully delivered APOE3Ch or APOE3 into the liver by adeno-associated virus in APP/PS1 mice expressing human APOE4. We observed that hepatic APOE3Ch delivery reduced amyloid-β (Aβ) burden in the brain. Hepatic APOE3Ch expression attenuated neuroinflammation, neurodegeneration, and cognitive impairments. Mechanistically, APOE3Ch expression increased the capacity of Aβ clearance by monocytes and hepatocytes. Our findings demonstrate that hepatic APOE3Ch expression attenuates AD-type pathologies in APOE4-expressing APP/PS1 mice, highlighting liver-directed APOE3Ch gene transfer as a promising therapeutic strategy for APOE4-associated AD.

Retraction notice to "Inhibition the ubiquitination of ENaC and Na,K-ATPase with erythropoietin promotes alveolar fluid clearance in sepsis-induced acute respiratory distress syndrome" [Biomedicine & Pharmacotherapy 174 (2024) 116447].

Biomed Pharmacother

Ye Gao, Fei Cao, Xinyi Tian +12 more

Prognostic significance of early ACTH levels on neurological recovery in patients with aneurysmal subarachnoid hemorrhage: a prospective cohort study.

BMC Neurol

Ghaith Saleh R Aljboor, Aoun Tulemat, Grace H E Tan +4 more

Aneurysmal subarachnoid hemorrhage (aSAH) triggers a marked systemic stress response and may be accompanied by hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Adrenocorticotropic hormone (ACTH) may reflect the acute neuroendocrine response to injury and could be associated with early functional status. This study aimed to describe the frequency of acute-phase ACTH abnormalities and evaluate the association between early ACTH levels and functional outcomes at hospital discharge in patients with aSAH.

Diagnostic value of unilateral adrenal vein sampling with simple and biochemical/imaging correction: a study on early screening and typing for primary aldosteronism.

BMC Endocr Disord

Yi Yan, Caie Li, Jianshu Chen +9 more

Adrenal vein sampling (AVS) is the gold standard for distinguishing subtypes for primary aldosteronism. However, its technical challenges and frequent intubation failures pose difficulties. Our study aimed to establish diagnostic models for unilateral primary aldosteronism (UPA) to guide appropriate treatment in early patients.

Single-cell transcriptional landscape of muscle-derived stem/progenitor cells reveals hallmarks of aging and rejuvenation.

bioRxiv

Kavitha Mukund, Seth David Thompson, Chelsea L Rugel +5 more

Muscle-derived stem/progenitor cells (MDSPCs) are an adult stem cell population with demonstrated regenerative and rejuvenative potential distinct from other muscle progenitor cells. However, their molecular identity and developmental status remain poorly defined. Using single-cell transcriptomics and proteomics, we comprehensively profiled murine MDSPCs across age groups. We show that MDSPCs exist along a transcriptional continuum of maturation-ranging from metabolically active, proliferative early-stage cells to late-stage, lineage-committed myogenic populations. While lacking canonical pluripotency markers, early-stage MDSPCs express gene programs associated with embryonic progenitor identity, suggesting a non-canonical, multipotent-like state. These features distinguish them from both satellite cells and committed myoblasts. Aging reshapes this continuum by reducing stemness-associated signatures while enhancing differentiation programs and oxidative stress. Our identification of distinct MDSPC states provide critical insights into mechanisms that underly tissue regeneration and aging. These findings offer a blueprint for development of future regenerative therapies to combat age-related functional decline.

LL-37: Biological Mechanisms and Emerging Therapeutic Applications in Intestinal Disease.

Immun Inflamm Dis

Qichao Liu, Peng Xu, Cheng Zhang

Human cathelicidin peptide LL-37 is encoded by the CAMP gene and plays a key role in innate immunity. It maintains intestinal homeostasis through antibacterial, immunomodulation, and tissue repair functions. This paper reviews the multiple functions of LL-37 in the intestinal-immune axis and its contribution to intestinal immune homeostasis. A large amount of evidence shows that the biological effect of LL-37 is highly dependent on the environmental background, and its effects vary with peptide concentration, receptor binding status, disease stage, and local microenvironment. This article reviews the latest findings of the dual role of LL-37 in inflammatory bowel disease (IBD) and colorectal cancer (CRC), and focuses on the conditional mechanism of the transformation of its activity from protective to pathogenic. We also discuss the interaction between LL-37 and intestinal microbiota, focusing on how microbial signals and host peptides can coordinate to regulate mucosal immunity. At the same time, this article examines the key obstacles to the therapeutic application of LL-37 and its clinical promotion: cytotoxicity, rapid degradation by proteases, and drug resistance. We have further explored new strategies to overcome these challenges in the near future, including peptide engineering, nanocarrier delivery systems, and combined therapy. These findings together position LL-37 at the intersection of intestinal immunity and microbial ecology, providing a theoretical basis for its therapeutic application in IBD, CRC and infectious colitis.