In vitroPreprint
This preprint describes a computational study aimed at designing improved semaglutide analogues — variants of the GLP-1 receptor agonist used in weight-loss and diabetes treatment — in the context of the underperforming CagriSema Phase III trial. The researchers used an automated "natural amino acid scanning" approach, systematically introducing single amino acid mutations across the semaglutide peptide backbone. Using the crystal structure of the GLP-1–GLP-1R complex (PDB: 4ZGM) as a structural template, they performed high-throughput computational modeling with Modeller and estimated binding affinities (Kd) using the Prodigy tool. From this pipeline, the study identified 564 computationally designed semaglutide analogues predicted to show improved binding affinity to the extracellular domain (ECD) of GLP-1R. The authors propose a conceptual "interfacial electrostatic scaffold" consisting of four salt bridges at the peptide–receptor interface as a framework for next-generation GLP-1R agonist development, drawing an analogy to the century-long iterative optimization of insulin. Key limitations include the fully computational nature of the study — no experimental validation (biochemical, cellular, or in vivo) is presented — and reliance on a single structural template and computational binding affinity estimators, which may not fully capture dynamic receptor behavior.
Unknown journal · Apr 2025DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (recruiting). The OraGrowtH Phase 3 Trial is a multi-national trial. The goals of the trial are to study LUM-201 as a treatment for Pediatric Growth Hormone Deficiency (PGHD) in naive to treatment children and validate the LUM-201 predictive enrichment marker (LUM-201 PEM) strategy to select subjects likely to respond to therapy with daily oral LUM-201.
ClinicalTrials.gov · Apr 2025View trial ↗ Animal only
This study investigated whether Thymosin β4 (Tβ4), a bioactive polypeptide, could regulate liver inflammation in nonalcoholic fatty liver disease (NAFLD) by influencing macrophage polarization. Researchers used a mouse model of NAFLD induced by a methionine and choline-deficient (MCD) diet in C57 mice, with liver Tβ4 knocked down via tail-vein-injected siRNA. Macrophage involvement was assessed using clodronate liposome depletion. Additionally, in vitro experiments co-cultured THP-1 macrophage cells with oleic acid-treated LO2 hepatocytes at varying Tβ4 concentrations. The study found that Tβ4 treatment was associated with reduced liver inflammation and steatosis in mice, while Tβ4 knockdown worsened steatosis. Tβ4 appeared to shift macrophages toward an M2 (anti-inflammatory) phenotype, reduce M1 marker expression, decrease hepatocyte apoptosis, downregulate STAT1 phosphorylation, and increase SOCS1/3 expression. A publicly available dataset was also used to assess Tβ4 expression in hepatocellular carcinoma-adjacent fatty tissue. Limitations include reliance primarily on animal and in vitro models, a relatively small experimental scope, and no direct human clinical data, leaving the translational relevance of these findings uncertain.
Journal of inflammation research · Apr 2025DOI ↗ Limited · human
This retrospective, non-interventional drug utilization cohort study examined real-world prescribing patterns of two liraglutide formulations in the United Kingdom: Saxenda® (3.0 mg, approved for weight management) and Victoza® (1.2/1.8 mg, approved for type 2 diabetes). Using anonymized primary care data from the Clinical Practice Research Datalink (CPRD Aurum and GOLD databases), researchers identified 604 Saxenda® initiators and 4,853 Victoza® initiators who had no prior liraglutide prescription in the preceding 12 months. Descriptive statistics characterized demographics and drug utilization patterns. The study found that, where body weight data were available, 96.4% of Saxenda® initiators met the weight loss indication criteria. Saxenda® users were predominantly female (86.4%), younger (mean age ~46.5 years), and had shorter follow-up periods compared to Victoza® users. The authors concluded that both formulations were mostly prescribed in line with their approved indications and that real-world use raised no new safety signals. Key limitations include incomplete weight data for approximately half of Saxenda® initiators, the observational nature of the study, and reliance on administrative/primary care records, which may not capture all clinical details or secondary care prescribing.
Diabetes, obesity & metabolism · Apr 2025DOI ↗ Animal onlyPreprint
This preclinical study examined whether three incretin-based receptor agonists — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP receptor agonist), and retatrutide (triple GIP/GLP-1/glucagon receptor agonist) — could alter the interoceptive (subjective) effects of alcohol in rats using an operant drug discrimination paradigm. Male and female rats were trained to discriminate alcohol from saline, then tested after acute or repeated drug administration. The study found that acute administration of all three compounds reduced alcohol's discriminative stimulus effects, suggesting each compound modulated how the animals internally perceived alcohol. Repeated semaglutide treatment sustained this effect across a 15-day period, though discrimination returned to baseline levels within three days of stopping treatment. The authors interpret these findings as potentially relevant to understanding why GLP-1 receptor agonists reduce drinking behavior in humans, hypothesizing that blunting alcohol's subjective effects may be a contributing mechanism. Key limitations include the exclusive use of an animal model, meaning translation to human subjective experience remains uncertain, and the study does not establish clinical efficacy or safety in people with alcohol use disorder.
Unknown journal · Apr 2025DOI ↗ Review
This narrative review examines emerging therapeutic strategies for four major pediatric gastroenterological conditions: celiac disease (CeD), eosinophilic esophagitis (EoE), inflammatory bowel disease (IBD), and autoimmune hepatitis (AIH). For CeD, the authors discuss gluten-degrading enzymes (latiglutenase, Kuma030), the zonulin inhibitor larazotide acetate, transglutaminase 2 inhibitors (ZED-1227), and monoclonal antibodies such as AMG 714, noting inconsistent clinical outcomes and limited pediatric data. For EoE, biologics including dupilumab, cendakimab, dectrekumab (IL-13 inhibitors), mepolizumab, reslizumab, benralizumab (IL-5/IL-5R inhibitors), and the TSLP inhibitor tezepelumab are reviewed with varying reported efficacy. IBD coverage includes biologics (vedolizumab, ustekinumab, risankizumab) and small molecules (tofacitinib, etrasimod, upadacitinib), alongside personalized approaches integrating therapeutic drug monitoring. Emerging AIH therapies for refractory or steroid-dependent cases are also explored. The authors highlight proteomics and precision medicine as growing tools to individualize care. A key limitation is the narrative design, which is subject to selection bias, and the scarcity of pediatric-specific trial data across all discussed treatments.
Healthcare (Basel, Switzerland) · Apr 2025DOI ↗ Limited · human
This paper reports the case of a 22-year-old female who developed a mucosal malignant melanoma of the anterior maxilla following use of Melanotan II, an unlicensed synthetic analogue of melanocyte-stimulating hormone (α-MSH) administered as a nasal spray for cosmetic tanning purposes. Histological analysis confirmed the malignant melanoma diagnosis, and the patient was subsequently treated with surgical resection followed by immunotherapy. The authors conducted a supporting literature review examining the potential association between Melanotan II use and malignant melanoma development. They note that Melanotan II is illegal to sell in the United Kingdom and many other countries due to its unlicensed status and safety concerns. The paper highlights awareness of serious potential adverse effects linked to Melanotan II use. As a single case report, it cannot establish causation between Melanotan II use and oral mucosal melanoma; the temporal association is notable but confounding factors and the rarity of the event limit broader conclusions. The authors call for greater public and clinical awareness of risks associated with unregulated tanning peptides.
International journal of oral and maxillofacial surgery · Apr 2025DOI ↗ Animal only
This study investigated whether inhaled recombinant human thymosin beta 4 (rhTβ4), delivered via nebulization, could reduce pulmonary fibrosis in a mouse model. Researchers induced pulmonary fibrosis in mice using bleomycin and then administered rhTβ4 aerosols at three different time points: early, mid-term, and late stages of fibrosis development. Efficacy was assessed through hydroxyproline content (a marker of collagen deposition), lung function measurements, and histopathological examination of lung tissue. The study found that nebulized rhTβ4 was associated with reduced fibrosis markers across all three dosing strategies. In parallel cell-based experiments, rhTβ4 appeared to suppress lung fibroblast proliferation, migration, and activation, and to inhibit epithelial-mesenchymal transition (EMT) in pulmonary epithelial cells, with both effects linked to modulation of the TGF-β1 signalling pathway. Limitations include the exclusive use of a mouse bleomycin model (which incompletely recapitulates human IPF), the absence of human clinical data, and the lack of direct mechanistic confirmation in vivo. The authors conclude that nebulized rhTβ4 warrants further investigation as a potential therapy for idiopathic pulmonary fibrosis.
The Journal of pharmacy and pharmacology · Apr 2025DOI ↗ Strong · human
This network meta-analysis synthesized evidence from 39 randomized clinical trials (99,599 patients) to compare the efficacy and safety of three drug classes — SGLT-2 inhibitors, GLP-1 receptor agonists, and the non-steroidal mineralocorticoid receptor antagonist Finerenone — in adults with type 2 diabetes mellitus (T2DM) and non-dialysis chronic kidney disease (CKD). Databases were searched through November 2023, and methodological quality was assessed using the Cochrane RoB 2.0 tool. The study found that, compared to placebo, SGLT-2 inhibitors were most effective at reducing HbA1c, systolic and diastolic blood pressure, and body weight. Among GLP-1 receptor agonists, Liraglutide showed the greatest LDL-C reduction. Finerenone significantly reduced systolic blood pressure versus placebo. SUCRA rankings highlighted Empagliflozin for HbA1c and DBP reduction, Semaglutide for eGFR preservation, and Canagliflozin for blood pressure and weight loss. Safety profiles were generally favorable, with notable differences across agents in rates of urinary tract infection, hypoglycemia, and acute kidney injury. Limitations include indirect comparisons inherent to network meta-analysis, potential heterogeneity across trials, and the restriction to non-dialysis CKD populations, limiting broader generalizability.
Frontiers in pharmacology · Mar 2025DOI ↗ 🧪 TrialInsufficient
Registered Phase 2 interventional trial (completed). This study is designed to test how well once-weekly MET097 (an ultra-long-acting GLP-1 receptor agonist) works to treat adults with obesity or overweight and type 2 diabetes mellitus (T2DM) compared to placebo. MET097 or placebo will be administered to individuals via subcutaneous injection once weekly for 28 weeks. If an individual is randomly assigned to MET097 they will receive one of four different dose regimens.
ClinicalTrials.gov · Mar 2025View trial ↗ In vitro
This study investigated the synthesis and biological activity of novel conjugates combining hyaluronic acid (HA) with the copper-binding tripeptide glycyl-l-histidyl-l-lysine (GHK) at varying loading ratios, forming GHK-HA conjugates. The conjugates were designed to address the individual limitations of HA and GHK, including susceptibility to hydrolytic degradation and oxidative stress. In vitro assays demonstrated that GHK-HA bound copper(II) ions effectively and showed enhanced antioxidant properties compared to the individual components alone. When complexed with copper, the conjugates promoted the expression and release of several growth and trophic factors, including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and bone morphogenetic protein-2 (BMP-2), suggesting synergistic osteogenic and angiogenic potential. The study also explored a proposed mechanistic pathway, finding that copper's intracellular chaperones — CCS and Atox1 — translocated to the nucleus and appeared to function as transcription factors. Limitations include the exclusively in vitro nature of the experiments, meaning results cannot yet be extrapolated to animal models or human clinical outcomes. No in vivo validation was performed.
Bioconjugate chemistry · Mar 2025DOI ↗ Preclinical
This study investigated the biological activities of Ac-Tβ1-17, a novel acetylated peptide metabolite derived from the first 17 amino acids of thymosin β4 (Tβ4), with applications in regenerative biomaterials. Researchers first assessed its antiviral potential, finding that Ac-Tβ1-17 demonstrated protease inhibition activity against SARS-CoV-2 that reportedly exceeded that of its parent protein. In human umbilical vein endothelial cells (HUVECs), the peptide was associated with enhanced cell proliferation, wound healing, and reactive oxygen species (ROS) scavenging. The study also incorporated Ac-Tβ1-17 into a peptide-based scaffold, where it appeared to support cell growth and angiogenesis both within the scaffold and through gradual release. Mechanistically, treatment upregulated gene expression of Akt, ERK, PI3K, MEK, and Bcl-2, along with proangiogenic proteins. Ex vivo experiments in mouse fetal metatarsal tissue further suggested enhanced tissue growth and angiogenesis. Limitations include the predominantly in vitro and ex vivo design with no human clinical data, a small-animal ex vivo model, and the absence of controlled in vivo studies. The findings are exploratory and suggest Ac-Tβ1-17 as a candidate biomaterial-active peptide warranting further investigation.
Bioactive materials · Mar 2025DOI ↗ Review
This review paper synthesizes approximately 25 years of research on Epitalon (also called Epithalon or Epithalone), a synthetic tetrapeptide (Ala-Glu-Asp-Gly, or AEDG) derived from the amino acid composition of Epithalamin, a bovine pineal gland extract. The authors compile findings from in vitro, in vivo, and in silico studies examining Epitalon's biological and pharmacodynamic properties. According to the review, the compound has been associated with geroprotective and neuroendocrine effects, attributed in part to antioxidant, neuroprotective, and antimutagenic mechanisms. Specific findings cited include a reported direct influence on melatonin synthesis, alterations in interleukin-2 mRNA levels, modulation of murine thymocyte mitogenic activity, and enhancement of enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and telomerase. The authors acknowledge that whether these represent the complete mechanisms of action remains uncertain. Notably, the review also highlights that physicochemical and structural investigations of the peptide remain limited relative to the volume of biological research. Key limitations include the predominance of preclinical data and the absence of robust human clinical trial evidence, leaving the translation of these findings to human health outcomes unclear.
International journal of molecular sciences · Mar 2025DOI ↗ Review
This narrative review examines intravenous (IV) peptide and amino acid therapies as potential treatments for erectile dysfunction (ED), a condition involving interrelated vasculogenic, hormonal, and neurological mechanisms in which endothelial dysfunction and oxidative stress are central contributors. The authors conducted a PubMed literature search of English-language publications through October 2024, focusing primarily on studies from the past decade. Four compounds were highlighted: PT-141 (bremelanotide), a melanocortin receptor agonist proposed to act via central nervous system pathways; PnPP-19, a spider venom-derived peptide suggested to work through nitric oxide regulation; and the amino acids L-arginine and L-citrulline, both linked to enhanced endothelial function and nitric oxide synthesis. The review notes that these agents operate through mechanisms distinct from phosphodiesterase type 5 (PDE5) inhibitors, potentially offering alternatives or adjuncts for patients unresponsive to standard therapy. The authors conclude that while early evidence is promising, large-scale clinical trials are needed to establish safety profiles, optimal treatment parameters, and potential synergistic effects with existing ED treatments. As a narrative review, it is subject to selection bias and does not pool quantitative data.
Expert opinion on pharmacotherapy · Mar 2025DOI ↗ Animal only
This pre-clinical study investigated whether retatrutide (RETA, LY3437943) — a triple incretin agonist targeting GIP, GLP-1, and glucagon receptors — could reduce obesity-associated cancer progression beyond its known weight-loss effects. Using mouse models, researchers found that RETA-induced weight loss was associated with reduced pancreatic cancer engraftment, delayed tumor onset, and a 14-fold reduction in tumor volume compared to controls, outperforming single-agonist semaglutide (which achieved a 4-fold reduction). In a lung cancer model, RETA was associated with 50% reduced tumor engraftment and a 17-fold reduction in tumor volume. Notably, anti-tumor benefits persisted even after RETA withdrawal and subsequent weight regain, suggesting potential durable immune effects. Proposed mechanisms included systemic immune reprogramming: elevated circulating IL-6, increased antigen-presenting cells, reduced immunosuppressive cells, and activation of pro-inflammatory pathways within the tumor microenvironment. Key limitations include the exclusive use of pre-clinical (mouse) models, meaning findings may not translate directly to humans, and the mechanistic basis of durable immunity requires further investigation. The authors suggest these results warrant clinical exploration of RETA's potential to reduce cancer risk and improve outcomes in patients with obesity.
npj metabolic health and disease · Mar 2025DOI ↗ 🧪 TrialInsufficient
Registered Phase 4 interventional trial (recruiting). The main purpose of this study is to assess the effectiveness of adding tirzepatide to ixekizumab therapy in standard clinical practice in participants with active PsA and obesity or overweight with at least 1 weight-related comorbidity. The study will last up to 12 months.
ClinicalTrials.gov · Mar 2025View trial ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (active not recruiting). This is a study of retatrutide in participants with obesity. The main purpose is to learn more about how retatrutide maintains body weight loss. The study will have two treatment phases: an 80 week lead-in phase in which all participants will take retatrutide dose 1 and a 36 week randomized, double-blinded phase in which participants will either take retatrutide dose 1, retatrutide dose 2, or switch to placebo. Participation in the study will last around 125 weeks.
ClinicalTrials.gov · Mar 2025View trial ↗ Limited · human
This German post-authorisation safety study (PASS; EUPAS13004) evaluated the real-world safety and clinical effectiveness of afamelanotide 16 mg (SCENESSE) in 200 patients with erythropoietic protoporphyria (EPP), a rare inherited disorder causing severe acute phototoxicity upon light exposure. As an ongoing observational study linked to the European EPP Disease Registry, it collected treatment-emergent adverse events as the primary safety variable and used the validated EPP-Quality of Life (EPP-QoL) tool alongside treatment continuity as effectiveness measures. The study found that afamelanotide's real-world safety and benefit-risk profile was consistent with that observed in prior clinical trials. Patients reported a statistically significant improvement in quality of life compared to baseline (p-value not fully quoted in the abstract). High treatment continuity was also noted, suggesting ongoing clinical benefit. Key limitations include the absence of an untreated comparator group within this cohort, the observational (non-randomised) design, and potential for selection bias inherent in registry-based studies. The authors concluded that afamelanotide demonstrated a positive safety profile and was associated with improved quality of life in EPP patients under real-world conditions.
Photodermatology, photoimmunology & photomedicine · Mar 2025DOI ↗ Preclinical
This study investigated the role of plasmacytoid dendritic cells (pDCs) during the active effector phase of allergic asthma, moving beyond their previously known role in immune tolerance. Using BDCA2-DTR transgenic mice in which pDCs can be selectively depleted with diphtheria toxin, researchers sensitized and challenged animals with house dust mite allergen. They found that pDC depletion worsened asthmatic inflammation by increasing CCR2-dependent recruitment of inflammatory monocyte-derived cells. RNA sequencing of lung pDCs revealed that the small anti-inflammatory peptide thymosin β4 (Tβ4) was among the most upregulated genes in asthmatic conditions. IL-33 released by airway epithelial cells was found to drive Tβ4 expression in pDCs, which represented the dominant pulmonary source of Tβ4. Mechanistically, Tβ4 suppressed IL-4/IL-13-induced JAK1/STAT6/EGR2 signaling in alveolar macrophages, reducing CCL2 production and monocyte recruitment. Tβ4 supplementation reversed disease exacerbation in pDC-depleted mice. Notably, reduced serum Tβ4 levels were observed in both asthmatic mice and a human cohort with active allergic asthma. Limitations include the predominantly murine mechanistic data and a small, cross-sectional human serum dataset that limits causal interpretation in humans.
The Journal of allergy and clinical immunology · Feb 2025DOI ↗ Review
This review paper provides a broad overview of glucagon-like peptide-1 (GLP-1), an incretin hormone secreted primarily by intestinal L-cells, pancreatic α-cells, and the central nervous system, and its therapeutic relevance in type 2 diabetes mellitus (T2DM). The authors describe how GLP-1 promotes glucose homeostasis by stimulating insulin secretion, slowing gastric emptying, reducing food intake, and supporting β-cell proliferation. The paper surveys existing GLP-1-based pharmacological strategies, including GLP-1 receptor agonists (single, dual, and triple agonists) and dipeptidyl peptidase-4 (DPP-4) inhibitors, noting that both preclinical and clinical evidence supports their role in improving glycemic control. The review then shifts focus to emerging, non-pharmacological-style strategies: enhancing endogenous GLP-1 production through various physiological and molecular stimuli, and promoting intestinal L-cell differentiation as a means to expand the body's own GLP-1-secreting capacity. The authors frame L-cell differentiation as a particularly promising future therapeutic avenue. As a narrative review, the paper synthesizes existing literature rather than generating new primary data, and its conclusions are limited by the scope and quality of the studies it cites.
Diabetology & metabolic syndrome · Feb 2025DOI ↗