Animal only
This study introduced a Golgi-targeted copper delivery system (LNP-ATOX1/GHK-Cu@PCL-GelMA) designed to enhance the activity of copper-dependent proteins—particularly lysyl oxidase (LOX)—to promote fascia regeneration. The system combined GHK-Cu (a copper-peptide complex) as a sustained-release copper source with lipid nanoparticles (LNPs) delivering mRNA encoding ATOX1, a copper chaperone that shuttles copper into the Golgi apparatus via ATP7A/B transporters. In vitro experiments showed the system significantly increased Golgi copper accumulation, raised LOX activity to approximately 1.78 times that of controls, and enhanced angiogenic capacity. The researchers also reported that ATOX1 upregulation promoted copper-dependent translocation of ATP7A and Rac1 to the plasma membrane, potentially supporting neovascularization. In a rabbit fascia defect animal model, the strategy improved collagen alignment, neovascularization, and extracellular matrix reconstruction. Limitations include the absence of human or large-animal data, reliance on a single animal model, and the translational gap between rabbit fascia repair and human clinical outcomes. No human trials were conducted.
Journal of controlled release : official journal of the Controlled Release Society · Dec 2025DOI ↗ Animal only
This study investigated the central effects of Liver-Expressed Antimicrobial Peptide 2 (LEAP-2) on food intake in broiler chickens, and explored its potential interactions with the ghrelin and cannabinoid systems. Four separate experiments were conducted, each with four groups of neonatal broiler chickens receiving intracerebroventricular (ICV) injections. Experiment 1 tested LEAP-2 alone at three doses; Experiments 2–4 tested LEAP-2 in combination with a ghrelin receptor antagonist (D-Lys-3)-GHRP-6, a CB1 receptor antagonist (SR141716A), and a CB2 receptor antagonist (AM630), respectively. Food consumption was measured at 30, 60, and 120 minutes post-injection. The study reported that ICV LEAP-2 at the two higher doses significantly reduced cumulative food intake compared to saline controls. The interaction experiments suggested that LEAP-2's appetite-suppressing effects may involve both CB1 and CB2 cannabinoid receptors as well as the ghrelin receptor system. Key limitations include the exclusive use of an avian (broiler chicken) model, small experimental group sizes, a single-species focus, and the lack of direct mechanistic or molecular data. Findings cannot be directly extrapolated to humans or mammals without further research.
Poultry science · Dec 2025DOI ↗ In vitroPreprint
This paper proposes a molecular mechanism for BPC-157, a synthetic 15-amino-acid peptide previously studied in preclinical models for regenerative and cytoprotective effects. The authors hypothesize — based on computational structural modeling and in silico docking — that BPC-157 adopts a polyproline II (PPII) helix conformation and engages the SH3 domains of Src family kinases (c-Src, Yes, Fyn). The proposed interaction is suggested to relieve autoinhibition of these kinases, potentially activating downstream FAK-ERK and PI3K-Akt signaling pathways. To build a tool for future experimental testing, the authors engineered an mCherry-BPC157₂ fusion protein, encoded it in a baculovirus vector, and expressed it in insect (Sf9) cells. Expression was confirmed by fluorescence imaging and western blot at the expected ~31 kDa size. Importantly, this study does not include human subjects, animal experiments, or in vitro binding assays — the core mechanistic claims rest entirely on computational modeling. The fusion protein work is a proof-of-concept for a future experimental reagent. Findings should be interpreted as hypothesis-generating only.
Unknown journal · Dec 2025DOI ↗ ▶ Video
In this educational video, Canadian physicians Dr. Brad and Dr. Paul from the "Talking With Docs" YouTube channel offer their opinion on the peptide BPC-157 (Body Protective Compound-157), a 15-amino-acid fragment naturally found in the stomach. They explain that while BPC-157 has gained significant popularity through social media and biohacking communities, it is not FDA or Health Canada approved for human use, and is banned by WADA. The doctors acknowledge that in vitro and animal studies suggest potential benefits such as tissue repair, angiogenesis, and reduced inflammation, but emphasize there are no well-conducted human clinical trials demonstrating efficacy. The only human data includes a small Phase 1 safety trial and a limited 12-person knee injection study with weak methodology. The doctors raise concerns about unregulated sourcing, potential contamination, sterility risks from self-injection, and a theoretical link between the compound's tissue-growth properties and carcinogenesis. They advise against using BPC-157 and suggest proven alternatives for injury recovery. This video represents the hosts' informed opinions and is not a peer-reviewed study.
YouTube · Dec 2025Watch ↗ Limited · human
This case report describes a 65-year-old woman who developed pyoderma gangrenosum (PG) — a rare, rapidly progressing neutrophilic skin ulceration — at abdominal injection sites following use of the synthetic peptide melanotan. Four ulcerated wounds with erythematous borders were observed, clinically correlating with the injection sites. A diagnosis of PG was established based on wound appearance and progression, failure to respond to multiple antibiotic courses, and negative bacteriology (including negative Panton-Valentine leukocidin Staphylococcus aureus testing). The patient was treated with topical betamethasone, steroid occlusion tape, and oral prednisolone, with the prednisolone subsequently tapered and topical Dermovate initiated. The wounds healed over several months, leaving characteristic cribriform scarring. The authors acknowledge that while drug-induced PG has rarely been documented, this appears to be the first reported case of melanotan-induced PG in the literature. Key limitations include the inherent constraints of a single case report: no causal mechanism is established, there is no control or comparator, and generalizability is very limited. The report serves primarily to raise clinical awareness of a potentially serious and previously unreported adverse effect of melanotan use.
Moderate · human
The REDEFINE 1 trial was a phase 3a, 68-week randomized controlled trial that evaluated the blood pressure (BP) effects of CagriSema (a fixed-dose combination of semaglutide 2.4 mg and cagrilintide 2.4 mg) in 3,417 adults without diabetes who had overweight or obesity, with or without obesity-related complications. Participants were randomized to once-weekly CagriSema, semaglutide alone, cagrilintide alone, or placebo, alongside lifestyle intervention. Secondary and post hoc analyses focused on antihypertensive outcomes. The study found that CagriSema was associated with greater reductions in systolic BP (−10.9 vs. −2.8 mmHg) and diastolic BP (−5.4 vs. −1.7 mmHg) compared to placebo at week 68. A higher proportion of CagriSema participants reached BP targets (63.0% vs. 32.0%). Among those with resistant hypertension at baseline, BP target attainment was 42.0% vs. 29.3% (OR 1.7; 95% CI 0.7–4.4), though the confidence interval crossed 1. Notably, 39.6% of CagriSema participants on antihypertensive medications reduced or stopped treatment versus 18.8% with placebo. Limitations include that BP outcomes were secondary/post hoc endpoints, not primary, which limits causal inference strength for these specific findings.
Hypertension (Dallas, Tex. : 1979) · Dec 2025DOI ↗ 🧪 TrialInsufficient
Registered Phase 4 interventional trial (recruiting). This study will explore whether tirzepatide is a practical and acceptable treatment for postmenopausal females with a history of hormone receptor-positive breast cancer and obesity. The investigators aim to understand whether participants are willing and able to take this medication once weekly for 6 months and whether it may help improve weight and overall health. There will be monthly check-ins to monitor progress and safety. At the beginning and end of the study, participants will undergo body composition assessments, blood tests and a s
ClinicalTrials.gov · Dec 2025View trial ↗ In vitro
This study investigated how Thymosin β4 (Tβ4), a 43-amino-acid secreted peptide, may protect against hypoxia-induced blood-brain barrier (BBB) disruption using human brain microvascular endothelial cells (hBMVECs) as an in vitro model. The researchers exposed hBMVECs to hypoxic conditions to simulate aspects of ischemic injury and traumatic brain injury (TBI), then examined whether Tβ4 pretreatment could reverse resulting damage. They measured gene expression of tight junction proteins, Sphingosine 1-phosphate receptor 1 (S1PR1), endothelial cell permeability, and tight junction dynamics. The study found that Tβ4 pretreatment appeared to reverse hypoxia-induced impairment of BBB components, and identified S1PR1 as a potential mechanistic target. Notably, when S1PR1 was pharmacologically inhibited, Tβ4 lost its protective effect, suggesting S1PR1 signaling is required for Tβ4's action. The authors conclude that S1PR1 pathway modulation is central to hypoxia-induced BBB pathophysiology and propose Tβ4 as a candidate therapeutic agent warranting further investigation. Key limitations include the exclusive use of cell culture models, absence of animal or human data, and lack of in vivo validation of the proposed mechanism.
Scientific reports · Dec 2025DOI ↗ Animal only
This study investigated whether a self-assembling Growth Hormone-Releasing Peptide-6 (GHRP-6) peptide hydrogel could improve outcomes in acute kidney injury (AKI) by targeting metabolic reprogramming in renal tubular epithelial cells (TECs). Using a mouse model of AKI (likely ischemia-reperfusion injury), the researchers administered the GHRP-6 hydrogel and performed metabolomic sequencing analysis to characterize changes in cellular metabolism. The study found that treatment was associated with elevated levels of spermidine, L-glutamine, and acetyl-CoA — metabolites linked to amino acid and fatty acid metabolism — suggesting a favorable metabolic shift in TECs. Further mechanistic experiments indicated that the GHRP-6 hydrogel promoted TEC survival under ischemic conditions by activating the mTOR-P70 signaling pathway. The authors conclude that GHRP-6 hydrogel may protect TECs and reduce the risk of post-AKI fibrosis through metabolic reprogramming. Key limitations include that findings are restricted to a mouse model with no human data, the sample sizes and controls are not detailed in the abstract, and translation to clinical settings remains undemonstrated. The novel hydrogel formulation adds a materials-science dimension but also introduces additional variables requiring further study.
Journal of nanobiotechnology · Dec 2025DOI ↗ Moderate · human
This systematic review and meta-analysis evaluated the efficacy and safety of retatrutide — a novel triple agonist (GIP/GLP-1/glucagon receptor) — specifically in patients with type 2 diabetes and/or obesity comorbid with chronic kidney disease (CKD). Researchers conducted a comprehensive literature search and ultimately included eight randomized controlled trials. The study found that retatrutide was associated with a statistically significant mean reduction in HbA1c of -1.04% (95% CI: -1.42 to -0.67) and body weight reductions of up to -24.2%. A subgroup analysis suggested a dose-dependent pattern in glycemic outcomes, with lower doses appearing to produce greater HbA1c reductions than higher doses, though this finding warrants cautious interpretation. Secondary analyses indicated possible renoprotective effects, reflected by reductions in albuminuria. Gastrointestinal adverse events were the most commonly reported safety concern, consistent with the broader drug class. Key limitations include the small number of included studies (n=8), potential heterogeneity across trials, and the fact that CKD-specific data may have been drawn from subgroup analyses of broader trials rather than CKD-dedicated studies. The overall evidence base for retatrutide in CKD patients remains early-stage.
Limited · human
This retrospective observational study used the TriNetX electronic medical records database to examine cardiovascular outcomes and safety of semaglutide compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes (T2D) who had a body mass index (BMI) below 25 kg/m². From a large cohort of 340,721 patients identified between 2018 and 2020, the researchers compared all-cause mortality, cardiovascular outcomes, and adverse events between the two treatment groups. The study found that semaglutide was associated with a lower 3-year risk of all-cause mortality compared with DPP-4 inhibitors in this non-overweight population. These findings are notable because most landmark GLP-1 receptor agonist cardiovascular outcome trials have predominantly enrolled overweight or obese participants, leaving the effects in leaner individuals less well understood. Key limitations include the retrospective, non-randomized design, which introduces potential confounding by indication, residual confounding from unmeasured variables, and reliance on administrative/electronic health record data. Generalizability may also be limited by the database's geographic and demographic composition. The authors attribute differences in outcomes specifically to the semaglutide versus DPP-4 inhibitor comparison within this BMI subgroup.
European heart journal. Quality of care & clinical outcomes · Dec 2025DOI ↗ Animal only
This preclinical study characterizes SLU-PP-915, a novel orally bioavailable pan-agonist of estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ) — orphan nuclear receptors that regulate mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation, and the Krebs cycle. The researchers compared SLU-PP-915 to a previously developed ERR pan-agonist, SLU-PP-332, which lacks oral bioavailability. In mouse models, both compounds similarly enhanced aerobic exercise performance (measured by running distance and duration) when administered intraperitoneally, and SLU-PP-915 maintained comparable efficacy via oral administration when adjusted for systemic exposure. Both compounds strongly induced expression of Ddit4, a gene upregulated by acute aerobic exercise, at levels matching or exceeding those produced by treadmill running, depending on the muscle group examined. Notably, SLU-PP-915 appeared to synergize with exercise training to further enhance Ddit4 and mitochondrial gene expression. The authors propose that orally active ERR agonists could have therapeutic relevance for metabolic disorders, cardiovascular disease, and muscle pathologies. Key limitations include exclusive use of animal models, with no human data reported, and the need for long-term safety and efficacy evaluation.
The Journal of pharmacology and experimental therapeutics · Dec 2025DOI ↗ Animal only
This paper introduces a novel conceptual framework called the "triad" — linking corneal ulcer healing, corneal neovascularization, and intraocular pressure — and extends it to avascular tissue healing, using tendon as a parallel model. The authors propose cytoprotection as a unifying therapeutic principle and use the stable gastric pentadecapeptide BPC 157 as a primary illustrative agent. Drawing on preclinical studies, the paper describes findings in which BPC 157 reportedly normalized elevated intraocular pressure in glaucomatous rats, preserved retinal integrity, restored pupil function, maintained corneal transparency during ulcer or abrasion healing, and counteracted corneal neovascularization and dry eye. The paper also systematically maps a broad range of existing standard therapeutic agents — including ascorbate, fibronectin, EGF, anti-VEGF agents, corticosteroids, prostaglandin analogs, and Rho-kinase inhibitors — onto this triad to highlight shared pathways and inconsistencies across drug classes. The work is framed as a theoretical and narrative synthesis of preclinical data rather than a new clinical trial, and the authors explicitly call for further translational research before clinical application. Key limitations include the absence of human trial data and reliance on animal models.
Pharmaceuticals (Basel, Switzerland) · Nov 2025DOI ↗ Review
This review paper examines the relationship between aging and Thymosin Alpha-1 (Tα1), a peptide hormone naturally produced by the thymus gland. The authors describe how age-related thymic involution leads to reduced T-cell production, chronic low-grade inflammation (inflammaging), and heightened vulnerability to age-related diseases — a phenomenon collectively termed immunosenescence. The paper outlines Tα1's proposed mechanisms of action, including stimulation of T-cell differentiation, enhancement of thymic output, and modulation of dendritic cells and macrophages. It also highlights Tα1's immunomodulatory, anti-inflammatory, and antioxidant properties. The authors review preclinical and clinical evidence suggesting Tα1 may improve vaccine responses in elderly populations and help counteract immunosenescence. Additionally, the paper discusses Refnot, a hybrid fusion drug combining Tα1 with tumor necrosis factor alpha (TNFα), which reportedly retains antitumor activity while exhibiting reduced toxicity compared to TNFα alone. The authors conclude that Tα1 holds therapeutic promise for age-related immune dysfunction but emphasize that long-term efficacy and safety data in geriatric populations remain limited and that further research is warranted. As a review, this paper synthesizes existing literature rather than presenting original experimental data.
International journal of molecular sciences · Nov 2025DOI ↗ Review
This review article examines the evolving landscape of engineered nutrient-stimulated hormonal (NUSH) peptide therapies for obesity and related metabolic conditions, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease. The authors describe the mechanistic basis of GLP-1 receptor agonists (GLP-1RAs) and their limitations as monotherapies, then explore how dual and triple co-agonist strategies — combining GLP-1 with GIP, glucagon, amylin, or peptide YY — aim to overcome those gaps. The review highlights clinical and preclinical data for specific agents: tirzepatide (GLP-1/GIP), CagriSema (GLP-1/amylin), and retatrutide (GLP-1/GIP/glucagon), noting reported benefits in weight reduction, glycemic control, liver health, cardiovascular outcomes, and inflammation. The paper also discusses non-peptidyl oral GLP-1 RAs such as orforglipron as adherence-improving alternatives. The authors frame these multi-agonist therapies as a paradigm shift analogous to the pleiotropic hormonal effects of bariatric surgery, and as building blocks for precision metabolic medicine. As a narrative review, it does not generate new primary data, and conclusions depend on the quality and heterogeneity of the underlying cited studies.
Clinical and molecular hepatology · Nov 2025DOI ↗ In vitroPreprint
This paper proposes a molecular mechanism for BPC-157, a synthetic pentadecapeptide previously studied in preclinical settings for regenerative and cytoprotective properties. The authors use structural modeling and in silico docking to hypothesize that BPC-157 adopts a polyproline II (PPII) helix conformation that enables it to bind the SH3 domains of Src family kinases (SFKs), including c-Src, Yes, and Fyn. According to this model, such binding would relieve SH3-mediated autoinhibition of these kinases, triggering downstream FAK-ERK and PI3K-Akt signaling cascades associated with cell survival and repair. To build a tool for future experimental validation, the researchers engineered an mCherry-BPC157₂ fluorescent fusion protein, encoded it in a baculovirus vector, and expressed it in Sf9 insect cells. Expression was confirmed by fluorescent imaging and western blot at the predicted ~31 kDa molecular weight. Notably, no binding interaction or functional activity in mammalian systems was experimentally demonstrated; the SH3 engagement hypothesis remains computational. Limitations include the absence of human or animal data, reliance on in silico docking, and use of an insect cell expression system solely for protein production validation.
Unknown journal · Nov 2025DOI ↗ Insufficient
This exploratory simulation study compared the quality of responses generated by a large language model (GPT-4o) versus standard internet searches (Google) when answering 17 common patient-style questions about GLP-1 receptor agonist (GLP-1RA) therapy for obesity. Questions were selected based on Google Trends data and covered indications, expected treatment course, side effects, and specific risks. Two independent evaluators scored responses using a 5-point Likert scale across six domains: safety, guideline consensus, objectivity, reproducibility, relevance, and explainability. The study found that LLM responses scored significantly higher than internet search results in objectivity and reproducibility, while no significant differences were observed in the remaining four domains. Interrater agreement was high (Gwet AC ≈ 0.879). Qualitatively, LLM responses were noted to lack coverage of emerging clinical issues due to static training data, whereas internet results were more current but often commercially biased and inconsistent. The authors conclude that LLMs may offer a more reliable and objective source of health information for patients, though human oversight and real-time data integration remain important limitations to address. The study is limited by its small, simulated question set and lack of real patient interaction data.
JMIR formative research · Nov 2025DOI ↗ Review
This narrative review examines the current and emerging landscape of GLP-1 receptor agonists (GLP-1RAs) as treatments for obesity and related metabolic conditions. The authors survey the three FDA-approved agents for obesity—liraglutide, semaglutide, and tirzepatide—alongside off-label options, summarizing evidence for their efficacy in weight reduction and glycemic control. The review also discusses expanding indications, including potential benefits in neurodegenerative disorders, fatty liver disease, dyslipidemia, atherosclerosis, cardiovascular disease, chronic kidney disease, and heart failure. Emerging pipeline agents—such as CagriSema, orforglipron, mazdutide, retatrutide, and survodutide—are highlighted alongside innovations like ultralong-acting formulations, combination therapies, higher-dose oral delivery, and AI-integrated drug development. The authors note that generic liraglutide and evolving insurance coverage may reshape affordability and access. Key limitations acknowledged include adherence challenges, safety concerns, disparities in global access, and the need for long-term data on sustained weight loss and disease modification. As a narrative review, the paper synthesizes existing literature rather than generating new primary data, and conclusions are therefore subject to the quality and selection of included studies.
Journal of obesity · Nov 2025DOI ↗ Animal only
This study investigated whether milk-derived small extracellular vesicles (sEVs) could serve as oral delivery vehicles for two GLP-1 receptor agonists (GLP-1RAs): semaglutide and tirzepatide. Researchers loaded both peptides onto sEVs in vitro and administered them orally to diabetic db/db mice—a well-established mouse model of type 2 diabetes. The study found that both peptides were efficiently incorporated into the sEV carrier system and that oral administration of the loaded vesicles effectively reduced blood glucose levels in the diabetic mice. The authors compared this approach to the existing SNAC (sodium N-[8-(2-hydroxybenzoyl) amino] caprylate) technology used in the commercially approved oral semaglutide formulation (Rybelsus), arguing that sEVs offer broader applicability across multiple peptide drugs, not just semaglutide. Key limitations include the exclusive use of an animal model with no human pharmacokinetic or efficacy data, a relatively small and homogeneous study design, and the early-stage, preclinical nature of the platform. Translation to humans remains undemonstrated.
Journal of extracellular biology · Nov 2025DOI ↗ Review
This scoping review examines the biological rationale and existing evidence for using glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the management of psoriatic disease (PsD), a chronic systemic inflammatory condition frequently accompanied by cardiometabolic comorbidities such as obesity, type 2 diabetes mellitus, and cardiovascular disease. The authors explored three main areas: (1) how obesity, diabetes, and cardiovascular disease influence PsD severity and treatment resistance; (2) the established efficacy of GLP-1RAs in managing these comorbidities; and (3) early evidence from rheumatologic and dermatologic conditions including rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, and hidradenitis suppurativa. The review highlights shared immunopathogenic mechanisms — particularly Th1/Th17-driven cytokines such as TNF, IL-6, and IL-17 — as a rationale for GLP-1RA use beyond metabolic indications. The authors report that early clinical and preclinical data suggest GLP-1RAs may reduce systemic inflammation and PsD burden, but acknowledge this evidence is preliminary. Key limitations include the scoping review design (which maps available evidence rather than synthesizes effect sizes), reliance on preclinical and indirect data, and the absence of dedicated randomized controlled trials in PsD populations. The authors conclude that further clinical trials are needed to establish disease-modifying potential.
Inflammation research : official journal of the European Histamine Research Society ... [et al.] · Nov 2025DOI ↗