Preclinical
This study investigated the role of mast cell (MC)-derived thymosin β4 (Tβ4) in stress-induced intestinal barrier dysfunction in irritable bowel syndrome (IBS). Researchers measured Tβ4 levels in colonic mucus of IBS patients and used a combination of in vitro experiments, rodent models (including Tβ4-knockout rats and MC-deficient mice), and reconstitution experiments to examine mechanisms. The study found that Tβ4 levels were elevated in the colonic mucosa and intestinal MCs of IBS patients. In animal models, Tβ4 appeared to reduce tight junction proteins and the IL22RA1/Reg3γ cascade while increasing myosin light chain kinase activity, collectively impairing the epithelial barrier. Tβ4-deficient rats showed resistance to stress-induced barrier disruption, and reintroduction of Tβ4 or wild-type peritoneal MCs restored that disruption. Mechanistically, Tβ4 release from MCs was found to depend on corticotropin-releasing hormone receptor 1 signaling rather than classic degranulation, and its barrier-impairing effects were linked to inhibition of the IL22RA1/JAK1/STAT3 signaling pathway. Limitations include reliance on rodent models for mechanistic work, modest human clinical data, and the complexity of translating these findings to therapeutic applications.
World journal of gastroenterology · Nov 2025DOI ↗ Limited · human
This study used synthetic target trial emulation and computational predictive modeling to compare amylin-pathway therapies — specifically CagriSema, cagrilintide, and amycretin formulations — for obesity and type 2 diabetes. Following PRISMA 2020 and TARGET framework guidelines, the researchers pooled data from seven randomized controlled trials (N = 5,786 participants) published through September 2025. Rather than analyzing real individual patient data, they reconstructed high-precision synthetic individual patient datasets and applied network meta-analysis, dose-response modeling, virtual head-to-head comparisons, and machine learning. The study reported that synthetic data reconstruction achieved greater than 99% fidelity to source trials, and virtual modeling suggested CagriSema outperformed subcutaneous amycretin at matched timepoints (posterior probability >0.95). Dose-response modeling identified an estimated ED80 for amycretin and benefit-risk analysis suggested a potential therapeutic window in the 10–20 mg subcutaneous range. Machine learning models predicted treatment response with 82–87% accuracy from baseline characteristics. Key limitations include reliance on reconstructed — not real — individual patient data, indirect comparisons rather than direct head-to-head trial evidence, and calibration metrics indicating moderate model uncertainty. The authors suggest these findings may inform future confirmatory trial design.
Metabolism open · Oct 2025DOI ↗ Strong · human
This systematic review and network meta-analysis examined the renal effects of three classes of novel antidiabetic agents—DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors—in adults with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Researchers searched four major databases through July 2025 and identified 20 randomized controlled trials enrolling 80,670 participants, with a minimum follow-up of 24 weeks. Key outcomes assessed were composite renal outcomes, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR). The study found that several agents significantly reduced composite renal outcomes compared with placebo; dapagliflozin demonstrated the largest effect (high-certainty evidence), followed by canagliflozin, empagliflozin, and select GLP-1 agonists (efpeglenatide, sotagliflozin, semaglutide, dulaglutide). Canagliflozin most strongly reduced UACR, while dapagliflozin showed no significant effect on this measure. No agent significantly altered eGFR. DPP-4 inhibitors showed no renal benefit. Certainty of evidence, assessed via GRADE, was high for direct placebo-controlled comparisons but fell to low or very low for indirect network estimates. A key limitation is that conclusions about head-to-head drug comparisons rely on indirect evidence, which carries greater uncertainty.
Diabetes, obesity & metabolism · Oct 2025DOI ↗ Animal only
This study describes the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method for measuring tirzepatide — a dual GIP/GLP-1 receptor agonist — in rat plasma. Researchers used protein precipitation with methanol for sample preparation, a peptide C18 column for chromatographic separation, and positive electrospray ionization with multiple reaction monitoring for detection, using semaglutide as an internal standard. The method demonstrated good linearity (1–1000 ng/mL), with intra- and inter-day accuracy and precision meeting regulatory criteria. Stability under various storage and handling conditions was also confirmed. The validated method was then applied to a pharmacokinetic study in rats administered tirzepatide intravenously and subcutaneously at 0.3 mg/kg. The study reports terminal half-lives of approximately 10 hours via both routes and estimates subcutaneous bioavailability at roughly 62%. Key limitations include the exclusive use of a rat model, a single dose level, and a small number of animals typical of preclinical PK studies, meaning findings may not translate directly to humans. The authors suggest the method could be adapted for quantifying other structurally similar peptide therapeutics.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences · Oct 2025DOI ↗ Review
This narrative review examines pharmacologic management of vasomotor symptoms (VMS) and decreased libido in breast cancer patients receiving endocrine therapy — a population that commonly experiences new or worsened menopausal symptoms. The authors searched PubMed, Cochrane Library, and Web of Science to summarize established agents (SSRIs, SNRIs, gabapentin, clonidine) and highlight emerging therapies: fezolinetant and elinzanetant (neurokinin 3 receptor antagonists for VMS), and flibanserin and bremelanotide (serotonin/dopaminergic modulator and melanocortin receptor agonist, respectively, for low libido). The review notes that existing options provide inadequate symptom relief, representing a meaningful therapeutic gap. Crucially, the authors emphasize that clinical trials supporting these novel agents explicitly excluded breast cancer patients, meaning their safety and efficacy in this population remain unestablished. The paper aims to equip clinicians with practical considerations for weighing these therapies in breast cancer patients while awaiting dedicated research. Key limitations include the review format, reliance on trials conducted in the general population, and the absence of breast cancer-specific clinical data for the highlighted novel agents.
Expert review of clinical pharmacology · Oct 2025DOI ↗ Moderate · humanPreprint
This meta-analysis pooled data from four randomized controlled trials (n = 918) to evaluate the efficacy of mazdutide — a dual GLP-1 and glucagon receptor agonist — in nondiabetic adults with overweight or obesity. Researchers searched PubMed, Scopus, and Web of Science and applied a random-effects model to analyze primary outcomes including body weight, BMI, and waist circumference, along with secondary cardiometabolic markers. The pooled analysis found that, compared with placebo, mazdutide was associated with statistically significant reductions in body weight (mean difference: −7.72 kg), BMI (−2.84 units), waist circumference (−5.76 cm), HbA1c (−0.30%), LDL cholesterol (−10.59 mg/dL), total cholesterol (−18.61 mg/dL), and triglycerides (−49.87 mg/dL). The authors concluded that mazdutide shows promise as a pharmacotherapy option for this population. Key limitations include the small number of included trials (n = 4), the relatively modest total sample size, the lack of long-term follow-up data, and the preprint status of this analysis, meaning it has not yet undergone formal peer review. Findings should therefore be interpreted with caution pending publication.
Unknown journal · Oct 2025DOI ↗ Review
This review paper examines the potential role of nutrient-stimulated hormone-based therapies (NuSHs) — particularly GLP-1 receptor agonists — in the prevention and management of metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC). The authors contextualize MASH as the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), which is now the most prevalent chronic liver disease in Western populations. The review synthesizes emerging clinical and preclinical evidence suggesting that NuSHs can resolve MASH without worsening fibrosis, primarily through weight loss and improved insulin sensitivity. However, the authors note that benefits appear less pronounced in cirrhotic patients, implying greater utility in early disease stages. Preclinical models suggest NuSHs may reduce MASH-related HCC incidence and tumor burden through systemic metabolic improvements rather than direct anti-cancer mechanisms. Observational data from bariatric surgery populations further support a preventive role for weight loss. The authors also propose that integrating NuSHs into post-locoregional HCC treatment pathways could delay systemic therapy, improve immunotherapy synergy, and enhance transplant eligibility. Key limitations include the indirect nature of evidence, inconsistent fibrosis regression data, and an absence of trials with oncological primary endpoints.
Journal of clinical and translational hepatology · Oct 2025DOI ↗ 🧪 TrialInsufficient
Registered Phase 4 interventional trial (recruiting). The purpose of this study is to determine the effect of tirzepatide on vasomotor symptoms and on measures of biological aging.
ClinicalTrials.gov · Oct 2025View trial ↗ Insufficient
This study focused on the development and validation of an analytical detection method — not a clinical intervention — for identifying growth hormone-releasing hormone (GHRH) and its synthetic analogs (sermorelin/CJC-1293, tesamorelin, and CJC-1295) in human urine samples for anti-doping purposes. These peptides are banned by the World Anti-Doping Agency (WADA) due to their potential performance-enhancing effects. The researchers developed a nano liquid chromatography coupled with quadrupole/orbitrap mass spectrometry (nano-LC-Q/Orbitrap MS) approach, systematically optimizing sample preparation steps including solid-phase extraction (SPE) and ultrafiltration. The finalized workflow — ultrafiltration followed by SPE — was fully validated per WADA guidelines, assessing selectivity, reliability, limits of detection (LOD ≤ 0.5 ng/mL), limits of identification (LOI 0.5–0.75 ng/mL), carryover, robustness, autosampler stability, and matrix effects. The method demonstrated sufficient sensitivity for both screening and confirmation of target peptides in urine. A key limitation is that this is a purely analytical/methodological study; it provides no clinical, pharmacological, or physiological data about the effects of these peptides in humans, and its findings are confined to laboratory detection performance.
Journal of pharmaceutical and biomedical analysis · Oct 2025DOI ↗ Animal only
This study investigated the role of ferroptosis (a form of iron-dependent regulated cell death) in pulpitis and evaluated whether thymosin α1 (Tα1) could mitigate this process. Using single-cell RNA sequencing (scRNA-seq) of tissue from 3 pulpitis and 3 healthy pulp samples, researchers identified 12 distinct cell clusters and found that differentially expressed ferroptosis-related genes (DE-FRGs) were broadly present across clusters in pulpitis tissue. Elevated reactive oxygen species (ROS) and Fe²⁺ levels, alongside reduced GPX4 and elevated PTGS2 expression by immunohistochemistry, suggested active ferroptosis in inflamed pulp. In LPS-stimulated dental pulp cells (DPCs) in vitro, Tα1 treatment was associated with increased GPX4 and FTL expression and reduced inflammatory markers (TNF-α, IL-1β, IL-6) and Fe²⁺ levels. In rat pulpitis models, delivery of prothymosin α (PTMA, the Tα1 precursor) via gelatin sponge or direct injection reduced inflammatory cell infiltration, decreased PTGS2, and increased GPX4. RNA sequencing of LPS-stimulated DPCs confirmed reversal of DE-FRG expression with Tα1 treatment. Key limitations include small human tissue sample sizes (n=3 per group), reliance on animal and cell models for intervention data, and the lack of human clinical trials.
International journal of oral science · Oct 2025DOI ↗ In vitro
This study investigated PapB, a radical S-adenosyl-l-methionine (rSAM) enzyme involved in the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs). Classically, RiPP maturase enzymes require an N-terminal leader sequence on the precursor peptide to guide substrate recognition and modification. The researchers discovered that PapB can function in a "leader-independent" manner — meaning it can process peptide substrates that entirely lack canonical leader sequences. To demonstrate the practical utility of this finding, the team applied PapB to three analogues of glucagon-like peptide (GLP-1) pathway agonists — a therapeutically relevant class of peptides — and showed that the enzyme achieved complete conversion of each linear peptide into a thioether-macrocyclized (C-terminally cyclized) product. The study is primarily a biochemical and enzymological characterization conducted in vitro, with no human or animal subjects involved. Limitations include that all work was performed outside of a biological system, and the therapeutic relevance of the resulting macrocyclic GLP-1 analogues in vivo remains to be established. The findings position PapB as a potentially versatile biocatalytic tool for generating conformationally constrained peptide drug candidates.
ACS bio & med chem Au · Oct 2025DOI ↗ 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 ↗ 🧪 TrialInsufficient
Registered observational trial (terminated). This study is designed to compare weight loss outcomes and safety of ESG versus lifestyle modification in patients with obesity who discontinued GLP-1 therapy due to intolerance or suboptimal weight loss.
ClinicalTrials.gov · Sep 2025View trial ↗