In vitro
This study investigated the cellular mechanisms by which larazotide acetate (LA), a synthetic octapeptide in clinical development for celiac disease, protects the intestinal epithelial barrier. Researchers pretreated two intestinal epithelial cell lines — C2BBe1 (human) and IPEC-J2 (a "leaky" porcine line) — with LA before exposing them to anoxia/reoxygenation (A/R) injury, a model of ischemia-reperfusion stress. LA pretreatment significantly increased transepithelial electrical resistance (TEER), a measure of barrier integrity, and preserved the normal localization of tight junction (TJ) proteins. RNA sequencing identified enriched gene sets related to barrier regulation, small GTPase signaling, protein phosphorylation, cell proliferation, and migration. Consistent with transcriptomic findings, LA markedly reduced phosphorylation of myosin light chain-2 (MLC-2), suggesting modulation of the ROCK signaling pathway, which is known to influence TJ dynamics. LA also enhanced epithelial cell proliferation. Limitations include exclusive reliance on in vitro cell culture models with no animal or human data, and the use of a single, fixed LA concentration. The authors conclude that LA stabilizes tight junctions, reduces MLC-2 phosphorylation, and promotes epithelial renewal, supporting its broader potential in gastrointestinal conditions involving mucosal barrier disruption.
Biomedicines · Oct 2025DOI ↗ Review
This comprehensive review synthesizes research published between 2016 and 2025 on the role of tripeptides in wound healing and skin regeneration. The authors examine how these short, three-amino-acid peptides regulate critical repair processes including cell migration, proliferation, and differentiation, as well as inflammation modulation, angiogenesis promotion, and extracellular matrix (ECM) remodeling. The review highlights several specific tripeptides: GHK-based formulations (including nanoparticle conjugates, hydrogels, and clinical derivatives TriHex and TriHex 2.0) were found in cited studies to enhance fibroblast migration, collagen and elastin synthesis, ECM remodeling, and wound closure with added antimicrobial activity. KdPT was reported to mitigate hyperglycemia-induced oxidative stress and restore keratinocyte function, while KPV-loaded hydrogels reduced inflammation and combated MRSA infections. Lipotripeptides (DICAMs) were noted to inhibit and disrupt bacterial biofilms, and GPE was associated with neuroprotection via ERK and PI3K/Akt signaling. The review also addresses physicochemical comparisons with larger peptides, biomaterial scaffold integration, and emerging applications in cancer and cosmetics. As a narrative review, it does not generate new experimental data. Key limitations include inherent selection bias and the predominance of preclinical evidence in the underlying literature. The authors call for further research into stability, bioavailability, and delivery optimization.
International journal of medical sciences · Oct 2025DOI ↗ Review
This updated narrative review examines the efficacy and safety of anti-obesity medications (AOMs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). The authors synthesize evidence on several pharmacologic classes, with particular focus on incretin-based therapies. GLP-1 receptor agonists, specifically liraglutide and semaglutide, are reported to reduce hepatic steatosis, improve liver enzyme profiles, and attenuate fibrosis progression. Tirzepatide, a dual GLP-1/GIP agonist, is noted to produce superior weight loss compared to GLP-1 monotherapy, though data on hepatic histological outcomes in MASLD/MASH remain limited. Retatrutide, a triple GLP-1/GIP/glucagon agonist, showed the most pronounced metabolic effects overall, but its liver-specific histological impact is described as underexplored. The review also flags safety concerns with other AOMs such as bupropion-naltrexone and phentermine-topiramate, citing potential hepatotoxicity risks. The authors note that advanced MASLD may alter drug pharmacokinetics, complicating treatment decisions. Key limitations include the review's narrative design, heterogeneity of cited primary studies, and a general lack of large-scale, liver-histology-focused trials for newer agents.
World journal of gastroenterology · Oct 2025DOI ↗ Limited · human
This experimental study investigated the potential of Growth Hormone Releasing Protein-6 (GHRP-6), a ghrelin hormone agonist, to improve in vitro maturation (IVM) of human oocytes. Researchers collected 240 human germinal vesicle (GV) oocytes and cultured them in varying concentrations of GHRP-6, comparing outcomes against a blastocyst single-step culture medium (control) and human tubal fluid (HTF) 10% (sham). Maturation rates were tracked over two days. A subset of 164 GV oocytes was then used to assess gene expression of CENP-E (associated with meiotic progression) and LINGO2 (a membrane protein gene) via real-time PCR after 24 hours of culture. The study found that a specific concentration of GHRP-6 produced the highest maturation rates on both day one and day two, outperforming both comparison media. However, real-time PCR analysis revealed that GHRP-6 did not significantly elevate expression of either CENP-E or LINGO2 in metaphase II oocytes, suggesting nuclear maturation was promoted without a corresponding improvement in cytoplasmic maturation markers. Key limitations include the absence of downstream developmental outcomes (e.g., fertilization or embryo quality data), a relatively small oocyte sample, and the lack of blinded assessment or patient-level randomization.
International journal of fertility & sterility · Sep 2025DOI ↗ Review
This article is a regulatory milestone review summarizing the development history of mazdutide (Xinermei®), a dual glucagon receptor (GcgR) and glucagon-like peptide-1 receptor (GLP-1R) agonist co-developed by Eli Lilly and Innovent Biologics. The review traces the compound's path to its first regulatory approval in China in June 2025 for long-term body weight management in adults with obesity (BMI ≥28 kg/m²) or overweight with comorbidities (BMI ≥24 kg/m²), alongside diet and physical activity. A subsequent Chinese approval for glycemic control in type 2 diabetes followed in September 2025. The article also notes ongoing clinical investigations into metabolic dysfunction-associated fatty liver disease, obstructive sleep apnea, and alcohol use disorder. As a "First Approval" narrative review, it consolidates developmental milestones rather than presenting original trial data. It does not independently report clinical outcomes, efficacy effect sizes, or safety data from primary studies, limiting the ability to assess the strength of underlying evidence directly from this article alone.
Animal only
This paper is a commentary responding to a previously published literature and patent review by Józwiak et al. (Pharmaceuticals 2025) that raised concerns about BPC 157, a stable synthetic gastric pentadecapeptide. The authors defend BPC 157's therapeutic profile, arguing that the reviewed concerns — specifically that it promotes pathological angiogenesis, elevates nitric oxide (NO) and eNOS toward damaging free radical formation, and may contribute to tumorigenesis or neurodegenerative diseases — are speculative and contradicted by existing preclinical evidence. The authors frame BPC 157 as a cytoprotective agent rooted in Robert's and Szabo's cytoprotection concept, emphasizing its alleged pleiotropic effects across organ systems. They argue that BPC 157 modulates rather than indiscriminately amplifies angiogenesis and the NO system, citing animal model studies on wound healing, corneal transparency, anti-tumor effects (per Folkman's concept), and counteraction of Parkinson's- and Alzheimer's-like disturbances in mice and rats. The paper reports a high safety profile (LD50 not achieved in animal studies). Key limitations include that this is a narrative commentary relying heavily on preclinical data, with no new human clinical trial data presented and no controlled experimental methodology introduced.
Pharmaceuticals (Basel, Switzerland) · Sep 2025DOI ↗ Insufficient
This paper is a published correspondence ("Reply") in the journal Pharmaceuticals, in which the original authors of a literature and patent review on the BPC 157 peptide respond to a commentary submitted by Sikiric et al. The reply addresses points raised in the comment regarding BPC 157's proposed mechanisms of action, specifically its purported roles in modulating angiogenesis and nitric oxide (NO) pathways. The responders engage with the argument that BPC 157 may selectively target the cytotoxic and damaging aspects of NO signaling while preserving or restoring its essential protective physiological functions. As a correspondence piece reacting to a comment on a review article, this paper does not present new experimental data, clinical trials, or original preclinical findings. Its contribution is interpretive and editorial in nature, clarifying the scope and conclusions of the original review in light of the mechanistic claims put forth by the commentators. Limitations include the absence of any new empirical evidence; all mechanistic claims discussed are derived from previously published literature cited by both parties.
Pharmaceuticals (Basel, Switzerland) · Sep 2025DOI ↗ Moderate · humanPreprint
This single-center randomized controlled trial enrolled 171 elderly patients with sepsis-associated acute respiratory distress syndrome (ARDS) to evaluate whether adding thymosin alpha 1 (Tα1) to a background regimen of sivelestat sodium and ambroxol improved outcomes. Participants were assigned to a control group (sivelestat + ambroxol, n=86) or an experimental group (same regimen plus Tα1, n=85) for 7 days; all patients also received high-flow nasal cannula oxygen therapy. The study found that the experimental group demonstrated a higher overall clinical response rate (85.9% vs. 72.1%, P<0.05), reduced mortality, improved survival, and better respiratory function parameters compared with controls. Safety profiles were reported as favorable in both groups. Limitations include the single-center design, which may reduce generalizability; the relatively short 7-day intervention window; and the fact that the paper is a preprint, meaning it has not yet undergone formal peer review. The combination of co-interventions (sivelestat and ambroxol alongside Tα1) also makes it difficult to isolate the independent contribution of Tα1 to the observed outcomes.
Unknown journal · Sep 2025DOI ↗ Review
This review examines the expanding cardiovascular applications of glucagon-like peptide-1 (GLP-1) receptor agonists, a class of peptide-based agents originally developed for type 2 diabetes management. The authors synthesize molecular mechanistic data alongside clinical evidence from major cardiovascular outcome trials (CVOTs) to characterize how GLP-1 agonists may reduce risk across conditions including atherosclerosis, heart failure, stroke, and vascular dementia. Proposed mechanisms discussed include anti-inflammatory, anti-atherogenic, endothelial-protective, and direct cardioprotective effects. The review highlights findings from multiple CVOTs reporting reductions in major adverse cardiovascular events (MACEs), myocardial infarction, stroke, and cardiovascular mortality. Notably, the SELECT trial is cited as evidence extending potential benefit to non-diabetic individuals with obesity and established CVD. The review also addresses emerging dual GLP-1/GIP agonists such as tirzepatide and its own CVOT data. The authors acknowledge important limitations, including high drug costs, unresolved long-term safety questions, and real-world implementation barriers. As a narrative review, this paper does not generate primary data and is subject to the inherent risk of selective literature synthesis. It provides a useful conceptual overview but does not independently establish causality or efficacy.
Journal of clinical medicine · Sep 2025DOI ↗ Review
This scoping review examined the potential role of incretin mimetics — specifically GLP-1 receptor agonists (e.g., semaglutide), dual GLP-1/GIP receptor agonists (e.g., tirzepatide), and the investigational triple agonist retatrutide — as treatments for polycystic ovarian syndrome (PCOS). Following PRISMA guidelines and drawing on literature from EBSCO Medline and PubMed, the authors explored how these agents compare to traditional PCOS pharmacotherapy such as metformin and estradiol-progesterone combination pills. The review found that all three classes of incretin mimetics were associated with meaningful improvements in weight loss and insulin sensitivity relative to conventional treatments. Dual- and triple-acting agonists, which additionally target the GIP receptor, appeared to produce greater reductions in weight and improvements in insulin sensitivity than GLP-1-only agents. Some included studies also reported PCOS-specific symptom improvements, such as reductions in dysmenorrhea and changes in ovarian morphology. The authors note that the precise mechanisms by which incretin mimetics may address the hormonal dysregulation of PCOS remain unclear, and they call for further research to optimize the integration of these agents with existing standard-of-care therapies. Key limitations include the scoping review design, heterogeneity of included studies, and limited long-term human trial data.
Moderate · human
This meta-analysis systematically reviewed the evidence on GLP-1 receptor agonists (e.g., semaglutide, liraglutide) in patients undergoing spinal fusion surgery. Following Cochrane guidelines, the authors searched five major databases and included 11 studies encompassing 14,344 participants, assessing outcomes such as pseudoarthrosis, readmission, acute kidney injury (AKI), cerebrovascular accidents, and deep vein thrombosis. Quality assessment used the Newcastle-Ottawa Scale, and statistical analysis was performed with RevMan 5.4 using risk ratios for dichotomous outcomes. The study found that GLP-1 receptor agonist use was associated with a statistically significant reduction in pseudoarthrosis at both six months (RR = 0.63) and 12 months (RR = 0.64), but this benefit was not sustained at 24 months (RR = 1.03). GLP-1 receptor agonists were also associated with a significantly increased risk of AKI (RR = 1.30). No significant differences were observed for readmission, stroke, deep vein thrombosis, or reoperation rates. Subgroup analysis by diabetic status provided additional insights. Key limitations include the absence of randomized controlled trials among included studies, significant heterogeneity in several outcomes, variability in outcome definitions, and relatively short follow-up periods. The authors call for larger, well-designed RCTs to confirm these findings.
In vitro
This study developed a dual-mode semi-preparative anion-exchange chromatography (AEX) method to fractionate and characterize charge variants of dulaglutide, a GLP-1 receptor agonist used in type 2 diabetes management. Because dulaglutide is an acidic Fc-fusion protein with complex charge heterogeneity, standard characterization methods are technically challenging. The researchers isolated acidic, main, and basic charge variant fractions and subjected them to comprehensive downstream analyses, including assessments of sialic acid content, post-translational modifications (phosphorylation, sialylation, deamidation, oxidation), size heterogeneity, aggregation, truncation, and biological activity. A key finding was that aggregates in basic variants are primarily held together by non-covalent interactions, while acidic variants contain covalently linked aggregates—a structurally meaningful distinction. Charge variants showed only slight differences in biological activity, potentially linked to aggregate presence. A comparative analysis between the innovator product Trulicity® and a biosimilar candidate revealed minor differences in acidic variants, likely attributable to variations in phosphorylation and sialylation profiles. Limitations include the in vitro nature of the biological activity assessments and the absence of in vivo or clinical data. The study provides a detailed analytical framework for characterizing charge heterogeneity in complex biopharmaceuticals.
International journal of biological macromolecules · Sep 2025DOI ↗ Review
This review paper examines survodutide, a dual glucagon and glucagon-like peptide-1 (GLP-1) receptor agonist, and its potential role in cardiometabolic disease management. The authors synthesize findings from Phase 2 clinical trials, which reported weight loss of up to 18.7% and HbA1c reductions of up to -1.71%, suggesting survodutide may outperform semaglutide on weight outcomes while achieving comparable glycemic control. The paper also discusses Phase 2 evidence showing improvements in liver fat content and fibrosis markers in patients with metabolic dysfunction-associated steatohepatitis (MASH), alongside proposed mechanisms for cardiovascular benefit, including reductions in visceral and epicardial adiposity, systemic inflammation, and fibrosis-related remodeling. Early signals of renal benefit are noted. Limitations acknowledged include higher rates of gastrointestinal adverse events and modest heart rate increases compared to some comparators, contributing to elevated discontinuation rates. The authors emphasize that definitive evidence from cardiovascular outcomes trials is still lacking, with the ongoing SYNCHRONIZE-CVOT trial expected to address this gap. As a narrative review relying primarily on Phase 2 data, the paper does not establish long-term cardiovascular efficacy or safety.
Cardiology in review · Sep 2025DOI ↗ Review
This review examines the current and emerging therapeutic landscape for celiac disease (CeD), an autoimmune enteropathy triggered by dietary gluten. The authors note that while a strict gluten-free diet (GFD) remains the only established treatment, its burdensome nature and incomplete efficacy in some patients have driven significant research into alternatives. The review systematically covers multiple therapeutic categories: gluten-degrading enzymes (e.g., AN-PEP, Latiglutenase, Zamaglutenase), gluten-sequestering agents (e.g., AGY-010, BL-7010), intestinal permeability modulators (e.g., Larazotide acetate, IMU-856), immune-modulating agents (e.g., ZED1227, AMG 714, EQ102), immune tolerization strategies (e.g., TAK-101, KAN-101, Nexvax2), probiotics, nutraceuticals, and food modification technologies. The authors conclude that despite encouraging preclinical and early clinical results across these approaches, no therapy has yet been conclusively proven as an effective GFD alternative. Key limitations of the review include its narrative rather than systematic design, potential selection bias in literature cited, and the absence of head-to-head comparisons between strategies. The authors emphasize the urgent need for further research to validate efficacy, optimize dosing, and establish safety in broader patient populations.
Nutrients · Sep 2025DOI ↗ Limited · human
This case report describes the use of Mazdutide, a dual glucagon-like peptide-1/glucagon receptor (GLP-1/GCGR) agonist, in a 15-year-old male presenting with obesity (BMI 30.64 kg/m²), type 2 diabetes (HbA1c 9.60%), and hyperuricemia (serum uric acid 511 µmol/L). The patient received a dose-escalation regimen of subcutaneous once-weekly Mazdutide alongside metformin and insulin over 36 weeks. The authors report substantial improvements across multiple metabolic parameters: body weight decreased by 16.8 kg (18.89% BMI reduction), HbA1c fell by 21.88%, and serum uric acid dropped by 37.00%. Lipid outcomes also improved, with triglycerides declining 69.02%, total cholesterol 13.65%, and LDL cholesterol 17.27%. Hepatic steatosis, confirmed by ultrasound, resolved by week 14. No hypoglycemic episodes or other adverse events were reported, and benefits were described as sustained after treatment ended. Key limitations include the single-patient design, the absence of a control condition, and the concurrent use of metformin and insulin, making it impossible to attribute outcomes specifically to Mazdutide. These preliminary observations may inform future controlled studies in adolescent populations.
Frontiers in endocrinology · Sep 2025DOI ↗ Preclinical
This study investigated how dysregulation of the NLRP3 inflammasome in melanocytes contributes to vitiligo pathogenesis. Using skin samples from vitiligo patients and a melanoma-Treg-induced vitiligo mouse model, the researchers found that NLRP3 expression is significantly elevated in vitiligo melanocytes. Mechanistically, they identified that decreased expression of the E3 ubiquitin ligase β-TrCP1 in vitiligo melanocytes reduces K27-linked ubiquitination of NLRP3, weakening its interaction with the autophagy receptor NDP52. This disrupts selective autophagic clearance of NLRP3, allowing it to hyperactivate inflammatory and pyroptotic pathways—including GSDMD pore formation and IL-1β release—ultimately destroying melanocytes. Genetic knockout of NLRP3 in mice alleviated vitiligo progression. As a potential therapeutic approach, the authors developed lysine-proline-valine (KPV)-modified deformable liposomes carrying Nlrp3 shRNA, which achieved melanocyte-targeted NLRP3 knockdown and reduced vitiligo development in mice. Key limitations include reliance primarily on a mouse model, limited human mechanistic validation, and the therapeutic intervention being tested only in animals, leaving clinical translation unestablished.
Cell death and differentiation · Sep 2025DOI ↗ Moderate · human
This systematic review and meta-analysis pooled data from six randomized controlled trials (RCTs) involving 1,272 adults to evaluate the efficacy and safety of survodutide, a glucagon/GLP-1 receptor co-agonist peptide, for glycemic control and weight loss. Compared with placebo, the study found that survodutide was associated with statistically significant reductions in HbA1c, fasting glucagon levels, body weight, and waist circumference. Subgroup analyses suggested that higher total weekly doses and longer treatment durations (greater than 16 weeks) were associated with more pronounced effects on body weight and waist circumference, while greater HbA1c reductions were linked to higher doses. Secondary outcomes including BMI, total cholesterol, triglycerides, and blood pressure also showed modest reductions. On the safety side, survodutide was associated with a significantly higher risk of treatment discontinuation due to adverse events, with gastrointestinal events being the most frequently reported, though serious adverse events did not increase significantly. Limitations include the small number of included trials (six), limited participant diversity, and varying treatment durations across studies. The authors call for larger, longer, multicenter RCTs to confirm these findings across broader populations.
Diabetes, obesity & metabolism · Sep 2025DOI ↗ Animal only
This preclinical study developed a dual-crosslinked injectable hydrogel (HSMP-LA) designed to mimic natural gut mucus for treating colitis. The hydrogel combined thiol/maleimide-modified hyaluronic acid with two active agents: antimicrobial ε-polylysine (ε-PL) and larazotide acetate (LA), a tight junction–regulating peptide. In laboratory (in vitro) experiments using LPS-injured Caco-2 intestinal cells, sustained release of LA was reported to selectively inhibit zonulin-mediated tight junction disruption by targeting the MLCK/p-MLC signaling pathway, thereby restoring epithelial barrier integrity. The hydrogel also demonstrated broad-spectrum antimicrobial activity and strong mucoadhesive properties with prolonged retention. In a dextran sodium sulfate (DSS)-induced mouse model of colitis, HSMP-LA significantly reduced disease activity indices, suppressed pro-inflammatory cytokines, upregulated anti-inflammatory IL-10, repaired tight junction proteins (ZO-1, occludin, claudin-5), restored mucus production (MUC2), and rebalanced gut microbiota composition. The study's primary limitations are that all findings are confined to cell culture and animal models, with no human data reported. The dual-action strategy—simultaneously targeting barrier dysfunction and microbial imbalance—represents the authors' proposed innovation, though clinical translation remains undemonstrated.
Journal of controlled release : official journal of the Controlled Release Society · Sep 2025DOI ↗ Moderate · human
This systematic review and meta-analysis evaluated the efficacy of thymosin α1 (Tα1), a synthetic immunomodulatory peptide, in treating sepsis. Researchers searched for prospective clinical studies measuring 28-day mortality in sepsis patients treated with Tα1 (excluding combination therapy studies), ultimately including 11 randomized controlled trials (RCTs) totaling 1,927 patients. The overall meta-analysis found a statistically significant reduction in 28-day mortality associated with Tα1 (OR 0.73, 95% CI: 0.59–0.90). However, when analysis was restricted to high-quality trials or multicenter trials — considered more rigorous subsets — the mortality benefit was no longer statistically significant (ORs 0.82 and 0.86, respectively). A heterogeneity of treatment effects analysis drawing on individual patient data from two large multicenter RCTs (representing ~75% of total patients) suggested potential benefits in subgroups with cancer (moderate credibility), diabetes, and coronary heart disease (both low credibility). Trial sequential analysis indicated the current evidence base is underpowered. The authors concluded that while Tα1 shows potential, its benefits appear to vary across patient subgroups, and personalized immunotherapy approaches warrant investigation in future, adequately powered trials.
Frontiers in cellular and infection microbiology · Sep 2025DOI ↗ Preclinical
This study investigated the role of Thymosin β4 (Tβ4) in breast cancer progression and its molecular mechanism. The researchers found that Tβ4 is significantly overexpressed in breast cancer tissues and cell lines, with high expression correlating with poorer clinical outcomes. Using functional experiments, the study showed that elevated Tβ4 promotes cancer cell proliferation, migration, epithelial-mesenchymal transition (EMT), and angiogenesis, while inhibiting apoptosis. Mechanistically, the study identified that Tβ4 directly regulates SLC7A11, a cystine/glutamate antiporter, which in turn enhances glutathione biosynthesis and suppresses lipid peroxidation — effectively inhibiting ferroptosis (an iron-dependent form of programmed cell death). Rescue experiments, conducted both in cell cultures (in vitro) and animal models (in vivo), demonstrated that silencing SLC7A11 reversed the cancer-promoting effects of Tβ4. The study concludes that a novel Tβ4/SLC7A11 signaling axis modulates ferroptosis resistance and contributes to breast cancer malignancy. Limitations include reliance on preclinical models, and no human clinical trials were conducted, leaving the translational relevance to patients yet to be established.
Cellular signalling · Sep 2025DOI ↗