Animal only
This animal study compared the anti-atherosclerotic effects of tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a selective GLP-1 receptor agonist) in ApoE knockout mice. Mice were treated with streptozotocin to induce diabetes and divided into early diabetes, late diabetes, and non-diabetic groups, each receiving either agent or saline for 12 weeks. The study found that in the early diabetes group, both tirzepatide and semaglutide significantly reduced aortic plaque formation compared to controls, with modest improvements in blood glucose and lipid levels. No significant vascular effects were observed in the late diabetes or non-diabetic groups in terms of plaque reduction. Tirzepatide more broadly reduced inflammatory markers—including Mcp-1, Il-6, I-cam, and Cd68—compared to semaglutide. Anti-inflammatory effects were also detected in non-diabetic mice, suggesting possible vascular protective mechanisms independent of metabolic control. The authors conclude that dual incretin receptor agonism may offer cardiovascular benefits, though the specific contribution of GIP signaling requires further investigation. Key limitations include the use of an animal model, which may not translate directly to human cardiovascular disease.
Scientific reports · Apr 2026DOI ↗ Animal only
This preclinical study investigated whether combining interleukin-15 (IL-15) with thymosin alpha 1 (Tα1) could reverse CD8+ T cell immunosenescence and enhance antitumor immunity in hepatocellular carcinoma (HCC). Using an orthotopic HCC model in aged C57BL/6 mice (22–26 months old), animals were randomized to saline, IL-15 alone, Tα1 alone, or combination therapy. The study found that the combination treatment significantly suppressed tumor growth and prolonged survival compared to either agent alone or control. Mechanistically, combination therapy reduced the proportion of senescent CD8+ T cells, expanded activated effector populations, and upregulated cytotoxic markers such as granzyme B, perforin, and interferon-gamma. Transcriptomic and Western blot analyses indicated that the combination suppressed chronically overactivated PI3K/AKT signaling in hepatic CD8+ T cells — an effect confirmed by in vitro experiments using primary human CD8+ T cells co-cultured with Huh7 hepatoma cells, where the AKT agonist SC79 reversed the therapeutic benefit. Key limitations include the exclusively preclinical design (no human clinical data), use of a single mouse HCC model, and the need for further validation of the proposed mechanism in clinical settings.
Journal of gastroenterology and hepatology · Mar 2026DOI ↗ Animal only
This review paper examines the preclinical and limited clinical evidence surrounding Body Protective Compound-157 (BPC-157), a synthetic pentadecapeptide derived from gastric proteins. The authors summarize experimental findings across a range of tissue types, noting that BPC-157 appears to support angiogenesis, collagen synthesis, fibroblast activity, and nitric oxide pathway modulation in animal models, with reported benefits to muscle, tendon, ligament, bone, and gastrointestinal healing. Anti-inflammatory effects, including reduced cytokine activity and improved microvascular integrity, as well as pain modulation via peripheral and dopaminergic mechanisms, are also described. The review notes that human research is limited to small pilot studies in musculoskeletal pain, interstitial cystitis, and intravenous administration contexts, with no major adverse effects reported. The authors acknowledge significant limitations: inconsistent preparation standards, lack of rigorous controlled trials, limited clinical validation, and ongoing regulatory restrictions. The paper concludes that BPC-157 represents a promising candidate for regenerative medicine but that robust clinical evidence is needed before therapeutic use can be recommended. As a narrative review drawing primarily on animal data, it does not establish efficacy in humans.
International journal of molecular sciences · Mar 2026DOI ↗ Animal only
This review paper examines the potential therapeutic role of BPC 157 (a synthetic 15-amino-acid peptide derived from a gastric protein) in treating severe electrolyte disturbances, drawing on a collection of animal and in-vitro experiments. The paper covers four electrolyte scenarios: (1) hyperkalemia — where BPC 157 was reported to counteract KCl overdose effects including arrhythmias, hypertension, sphincter dysfunction, and mortality in rat models; (2) hypokalemia — where BPC 157 administration (both prophylactically and therapeutically) was reported to prevent fatal outcomes, ECG abnormalities, AV block, and skeletal muscle myoclonus in furosemide-treated rats; (3) hypermagnesemia — where BPC 157 appeared to alleviate muscle weakness, brain lesions, and secondary hyperkalemia in rats; and (4) lithium intoxication — where BPC 157 was reported to promote collateral vascular pathways and resolve multiorgan failure features. In-vitro experiments using HEK293 cells suggested BPC 157 can modulate membrane potential changes induced by electrolyte imbalances. Key limitations include reliance on animal and cell-based data with no human clinical trials reported, and the review format limits independent assessment of individual study methodologies.
Current neuropharmacology · Mar 2026DOI ↗ Animal only
This review paper proposes cytoprotection as a unifying therapeutic framework to address what the authors call the "hemorrhage-thrombosis paradox" — the clinical challenge that hemorrhage and thrombosis can coexist as phase-dependent manifestations of vascular dysregulation. The paper centers on BPC 157, a stable synthetic gastric pentadecapeptide, which the authors argue can simultaneously counteract both hemorrhage and thrombosis in rodent models without directly interfering with the coagulation cascade (as assessed by aggregometry and thromboelastometry). The review synthesizes preclinical and conceptual evidence to argue that BPC 157 achieves this bidirectional vascular regulation through preservation of endothelial integrity, normalization of microcirculation, modulation of the nitric oxide system, and recruitment of collateral adaptive pathways. The authors contrast this proposed "full cytoprotection" with the "partial cytoprotection" of conventional agents such as anticoagulants, antiplatelet drugs, fibrinolytics, beta blockers, calcium channel blockers, and statins, which they contend act in isolated or unidirectional ways. The paper also discusses applications in wound healing, arrhythmia control, and normalization of Virchow's triad. Notably, the authors explicitly acknowledge that findings are predominantly preclinical and that clinical validation in humans remains necessary.
Pharmaceuticals (Basel, Switzerland) · Mar 2026DOI ↗ Animal only
This animal study investigated whether Growth Hormone-Releasing Peptide-6 (GHRP-6), a GH secretagogue hexapeptide, could reduce cardiac damage following myocardial infarction. Using a permanent left coronary artery ligation model in rats (a non-reperfusion model), researchers divided animals into three groups: sham-operated controls, infarcted rats treated with saline, and infarcted rats treated with GHRP-6. Treatment began post-surgery and continued for seven days. Outcomes were assessed via echocardiography and histology on day seven. A separate cohort of twelve healthy rats was used for mitochondrial proteomic analysis six hours after compound administration. The study found that, compared to the saline-treated infarcted group, GHRP-6-treated rats showed reduced myocardial tissue loss, less interstitial fibrosis and scarring, and improved left ventricular function. Proteomic data suggested that potential mechanisms may include upregulation of fatty acid beta-oxidation, apoptosis-prevention pathways, antioxidant defenses, and mitochondrial metabolic reprogramming. Key limitations include the exclusive use of an animal model, a short seven-day observation window, a small sample size, and the mechanistic proteomic findings being derived from healthy rather than infarcted animals. No human data were generated.
Pharmaceuticals (Basel, Switzerland) · Mar 2026DOI ↗ Animal only
This animal study investigated whether MOTS-c, a 16-amino acid mitochondrial-derived peptide, influences adrenal gland physiology in adult male Wistar rats. Sixteen rats received either continuous subcutaneous MOTS-c or saline for 24 hours via micro-osmotic pumps. The researchers used qRT-PCR, immunohistochemistry, ELISA, and RNA sequencing to assess adrenal tissue responses. The study first confirmed that endogenous MOTS-c expression was higher in the zona fasciculata/reticularis compared to the zona glomerulosa. MOTS-c treatment did not alter classical steroidogenic gene expression or circulating corticosterone and aldosterone levels. However, RNA sequencing identified 39 differentially expressed genes, most notably a 4.3-fold upregulation of the purinergic receptor P2ry4. The authors interpreted these findings as evidence that MOTS-c "primes" adrenocortical cells for steroidogenic responsiveness—via calcium signaling, lipid metabolism modulation, stress-response protein downregulation, and mitophagy inhibition—without directly stimulating basal hormone synthesis. Key limitations include the exclusive use of male rats, the short 24-hour treatment window, small sample size (n=16), and the absence of functional stimulation challenges (e.g., ACTH) to test the proposed "readiness" hypothesis.
Folia histochemica et cytobiologica · Mar 2026DOI ↗ Animal only
This study examined the effects of graviola (Annona muricata L.) oil extract (GOE) supplemented at three doses (200, 400, and 600 mg/kg feed) on growth performance and circadian rhythm profiles of several biomarkers in 48 male Anatolian Merino lambs over a 60-day feeding trial. Blood samples were collected at four time points across the day (07:00, 13:00, 19:00, and 01:00) on multiple study days to capture circadian variation. Measured biomarkers included Apelin (an adipokine), cardiac troponin I (cTnI), the circadian clock protein BMAL1, the mitochondria-derived peptide MOTS-c, and brown adipose mitochondrial carrier protein 1 (BMCP1), all assessed via ELISA. The 400 mg/kg dose was associated with the greatest linear improvement in live weight gain and with modulation of BMAL1, MOTS-c, and BMCP1 peaking at 19:00. The 600 mg/kg dose showed the most favorable results for Apelin and cTnI at certain time points. Limitations include the exclusive use of a single animal species, a relatively small sample size, lack of human relevance, and the observational nature of biomarker interpretation within a non-randomized animal production context.
BMC veterinary research · Mar 2026DOI ↗ Animal only
This animal study investigated the neuroprotective effects of hexarelin, a growth hormone secretagogue receptor type 1a (GHS-R1a) agonist, on retinal ganglion cell (RGC) survival following optic nerve transection (ONT) in golden hamsters. Researchers administered hexarelin at varying doses either once or twice daily for five days post-ONT and quantified RGC survival at seven days using Tuj1 immunostaining on retinal whole mounts. Single daily doses (25, 50, and 100 µg/kg) produced a dose-dependent increase in RGC survival compared to saline controls (62.4%, 68.5%, and 74.6% vs. 51.2%, respectively). Twice-daily dosing yielded further improvements, with the highest tested regimen (150 µg/kg twice daily) associated with a survival rate exceeding baseline (109.2% vs. 72.9% for twice-daily saline). The study suggests hexarelin may exert anti-apoptotic neuroprotective effects in the retina, attributed to its GHS-R1a agonism. Key limitations include the use of a single animal species (golden hamster), absence of mechanistic pathway data, and no translation to human subjects or disease models such as glaucoma.
Indian journal of pharmacology · Mar 2026DOI ↗ Animal only
This animal study investigated the anti-obesity effects of three GLP-1 receptor agonist peptides — semaglutide, tirzepatide, and retatrutide — in melanocortin 4 receptor knockout (MC4R KO) mice, a model of genetically driven obesity caused by disruption of the POMC-MC4R signaling pathway. All three compounds were administered for 21 days, after which body weight, body composition, metabolic markers, liver health, and gene expression were assessed. The study found that all three GLP-1 analogs produced statistically significant reductions in body weight, with tirzepatide showing the greatest effect (approximately 31.6%), followed by retatrutide (approximately 24.1%) and semaglutide (approximately 19.7%). All three agents reduced both fat and lean mass, improved plasma insulin levels and insulin resistance (HOMA-IR), lowered cholesterol, and reduced markers of liver damage (AST and ALT) as well as liver hypertrophy. Gene expression analysis showed suppression of fatty acid synthesis genes, but no significant effect on inflammatory gene expression. Energy expenditure was reduced by all agents; only tirzepatide significantly decreased the respiratory quotient. A key limitation is that this is a mouse model study, and findings may not directly translate to humans. The authors suggest MC4R KO mice are a valid model for studying obesity-related drug efficacy.
International journal of obesity (2005) · Feb 2026DOI ↗ Animal only
This systematic review examines the use of platelet-rich plasma (PRP), growth factors (PDGF, TGF-β1, IGF-1, FGF, VEGF, BMPs), and the stable gastric pentadecapeptide BPC 157 in the treatment of tendon, ligament, and muscle injuries, as well as osteotendinous, myotendinous, and muscle-to-bone junction injuries. The authors frame these interventions under the concept of "cytoprotection," emphasizing restoration of tissue integrity. The review concludes that while growth factors delivered locally via carriers show improvements in tendon, ligament, and muscle healing, some (PDGF, TGF-β1, IGF-1) appear to have limited benefit in muscle lesions, and all show limited or no efficacy at junctional healing sites. By contrast, the authors argue that BPC 157 — proposed as a cytoprotection mediator — demonstrated consistent efficacy across tendon, ligament, muscle, and junctional injuries in rat studies, via both systemic (intraperitoneal, intragastric, drinking water) and local (topical cream) administration, without requiring carriers or scaffolds. The authors suggest translational potential for clinical use and call for further clinical trials. Key limitations include that the supporting evidence for BPC 157 is derived almost exclusively from preclinical (rat) studies, with no human clinical trial data presented.
Pharmaceuticals (Basel, Switzerland) · Feb 2026DOI ↗ Animal only
This preclinical study examined how survodutide — a dual glucagon receptor (GCGR) and GLP-1 receptor (GLP-1R) agonist in clinical development for obesity and MASH — acts in the brain to reduce body weight. Researchers first mapped GCGR and GLP-1R expression in human and mouse circumventricular organs (CVOs), finding that GCGR is barely detectable in the area postrema (AP) and arcuate nucleus of the hypothalamus (ARH), whereas GLP-1R is expressed in both regions. Using a fluorophore-labeled version of survodutide in mice, the study found that the compound accesses CVOs and nearby hypothalamic and hindbrain nuclei directly, without evidence of broadly crossing the blood-brain barrier. C-Fos activation mapping showed that survodutide activated multiple brain nuclei associated with food intake control. A long-acting GCGR-selective agonist, by contrast, did not activate satiety-related brain regions or reduce food intake, though it did reduce body weight, suggesting the appetite-suppressing effects of survodutide are primarily GLP-1R dependent. Limitations include the exclusively preclinical (mouse) design and the use of a labeled surrogate compound. The authors conclude the findings support a dual mechanism for survodutide's weight-lowering effects.
Molecular metabolism · Feb 2026DOI ↗ Animal only
This systematic review examines the preclinical evidence for pharmacological activation of estrogen-related receptors (ERRα/β/γ) as a strategy to mimic the beneficial effects of exercise. The authors focused on synthetic pan-ERR agonists, particularly SLU-PP-332 and SLU-PP-915, reviewing experimental literature published between 2020 and 2024 from animal and cell-based models. The review found that these compounds appear to induce a gene expression program resembling that of acute aerobic exercise, dependent on ERRα, including activation of genes such as Ddit4 and Slc25a25. In preclinical obesity models, pan-ERR agonists were associated with enhanced fatty acid oxidation, increased oxidative-glycolytic (type IIa) muscle fiber composition, improved endurance capacity, reduced adiposity, better glycemic control, and increased basal energy expenditure, all without apparent toxicity signals. The compounds also showed potential to restore mitochondrial function and reduce inflammation in aging kidney models. The authors conclude that ERR activation is a promising exercise-mimetic strategy but explicitly acknowledge that no human clinical trials have been conducted, making translation to clinical practice premature. This represents a major limitation of the current evidence base.
Revista medica de Chile · Feb 2026DOI ↗ Animal only
This review paper proposes "cytoprotection" as a conceptual framework for evaluating antiarrhythmic drugs — defined as the ability to suppress arrhythmias while avoiding adverse electrophysiological or systemic effects. The authors systematically compare conventional antiarrhythmics (Classes I–IV) and newer agents (late INa inhibitors, IKs enhancers, RyR2 stabilizers, gap junction modulators, and atrial-selective antiarrhythmics), characterizing them as offering only partial cytoprotection over a narrow-to-moderate range. By contrast, the stable gastric pentadecapeptide BPC 157 is hypothesized to offer broader, "full-range" cytoprotective-antiarrhythmic effects. The authors cite preclinical rodent studies showing BPC 157 restoring sinus rhythm, normalizing ECG intervals, preventing AV block, suppressing ventricular tachycardia, and attenuating ST-segment changes across diverse arrhythmia models (hypo-/hyperkalemia, ischemia-reperfusion, drug-induced). In vitro HEK293 cell data reportedly show direct membrane-stabilizing actions. The authors acknowledge that human clinical data on BPC 157 remain limited and non-cardiac in nature, and explicitly call for translational clinical investigation. The paper's central claims about BPC 157 in arrhythmias rest almost entirely on preclinical and in vitro evidence, with no controlled human cardiac trials reported.
Pharmaceuticals (Basel, Switzerland) · Jan 2026DOI ↗ Animal only
This rat study used Fourier Transform Infrared (FTIR) spectroscopy to investigate how the stable gastric pentadecapeptide BPC 157 affects aortic wall composition following unilateral adrenalectomy. Abdominal aortas were collected from rats at three time points (15 minutes, 5 hours, and 24 hours) after surgery. BPC 157 was administered intragastrically immediately following the procedure. Spectral data were analyzed using principal component analysis (PCA) and support vector machine discriminant analysis (SVMDA). The study found that BPC 157-treated animals showed clear and reproducible spectral separation from controls at all time points, with the most notable differences in amide I and amide II bands (associated with protein secondary structure, including collagen and elastin) and lipid C-H stretching bands (associated with membrane integrity). The authors interpreted these signatures as consistent with early extracellular matrix reinforcement and membrane preservation in the vascular wall. Limitations include the exclusive use of an animal model, a small number of time points, and the indirect, spectroscopic nature of the outcome measures, which do not constitute direct functional or histological endpoints. No human data were reported.
Pharmaceuticals (Basel, Switzerland) · Jan 2026DOI ↗ Animal only
This study investigated a novel hydrogel-based therapy for intrauterine adhesions (IUA), a condition where uterine scarring causes infertility. The researchers engineered a hydrogel combining two components: a bioactive extracellular matrix derived from decidualized endometrium (DEndo-UdECM) and the anti-fibrotic peptide Thymosin β4 (Tβ4), designed for sustained local release. Using a mouse model of IUA, the study reported that a single administration of the hydrogel restored normal endometrial tissue architecture, reduced fibrosis, and resulted in near-complete fertility recovery in treated animals. Mechanistic investigations suggested the hydrogel worked by shifting macrophage polarization toward an anti-inflammatory M2 phenotype, suppressing pyroptosis-driven inflammation, and inhibiting the TGF-β/Smad3 signaling pathway, which drives fibrotic scarring. The study's primary limitation is that all experimental work was conducted in a murine model, meaning the findings have not yet been validated in humans or large-animal models. Whether the regenerative and anti-fibrotic effects, as well as the fertility outcomes, would translate to human patients remains unknown. Nonetheless, the study provides a mechanistically detailed preclinical proof-of-concept for a biomaterial strategy targeting the root pathology of IUA.
Nature communications · Jan 2026DOI ↗ Animal onlyPreprint
This preclinical study investigated whether mazdutide — a dual GLP-1/glucagon receptor agonist that has shown clinical promise for weight management and metabolic disorders — could alleviate non-alcoholic fatty liver disease (NAFLD) and explored its potential mechanism of action. Researchers induced NAFLD in mice via a 12-week high-fat diet, then treated animals with subcutaneous mazdutide for four weeks. Complementary in vitro experiments exposed hepatocytes to free fatty acids to model hepatic steatosis, followed by mazdutide co-treatment. The study measured serum and liver lipid profiles, liver injury markers, inflammatory cytokines, oxidative stress indicators, and key protein expression via Western blot and immunohistochemistry. Results indicated that mazdutide treatment was associated with reduced hepatic fat accumulation, lower liver injury markers, attenuated inflammation, and decreased oxidative stress in both models. Mechanistically, the authors attributed these effects to modulation of the PERK–eIF2α–ATF4–CHOP endoplasmic reticulum (ER) stress pathway, suppression of NF-κB-driven inflammation, and downregulation of lipogenic regulators (SREBP-1, C/EBPβ, PPARγ). Key limitations include the exclusive use of animal and cell-based models, lack of human data, and preprint status meaning findings have not yet undergone formal peer review.
Unknown journal · Jan 2026DOI ↗ Animal only
This 7-day rat study investigated the course of surgically created tracheocutaneous fistulas and whether the pentadecapeptide BPC 157 could promote healing, with a focus on the nitric oxide (NO) system's role. Rats with tracheocutaneous fistulas displayed severe respiratory distress, including open-mouth breathing, abdominal "heaving," cyanosis, abundant fistula secretion, weight loss, failed skin and tracheal wound healing, a well-formed fistulous tract, and tracheal shrinking below the fistula site. Tissue analyses showed decreased NO levels and increased malondialdehyde (MDA), a marker of oxidative stress. BPC 157, administered either intraperitoneally or in drinking water, was reported by the authors to accelerate fistula closure, improve macro- and microscopic healing of skin and tracheal defects, reduce respiratory distress signs, and counteract the NO and MDA changes observed in untreated controls. Using a "triple NO-agent" approach (L-NAME to block NO synthesis, L-arginine to enhance it, or both combined), the study further reported that BPC 157 could override L-NAME-induced worsening, enhance L-arginine-induced improvement, and restore healing even under combined NO immobilization. Key limitations include the exclusive use of an animal model, small experimental groups typical of rat studies, and the absence of human data.
Pharmaceuticals (Basel, Switzerland) · Jan 2026DOI ↗ Animal only
This mouse study investigated whether Growth Hormone Releasing Peptide-6 (GHRP-6) could protect against acute lung injury (ALI) and its progression to pulmonary fibrosis. Researchers used two established animal models: intratracheal lipopolysaccharide (LPS) instillation and a combined zymosan (ZYM) plus platelet-activating factor (PAF) injection. Both acute (24-hour to 15-day) and chronic (28-day) scenarios were examined. In the acute setting, GHRP-6 treatment was associated with reduced neutrophilic alveolitis, improved lung compliance, better alveolar-capillary permeability, and lower serum interleukin-1 beta levels compared to saline controls. In the chronic setting, GHRP-6-treated animals showed better preservation of lung parenchymal architecture and notably less collagen accumulation, suggesting reduced progression to fibrosis. The authors describe this as the first assessment of GHRP-6's protective potential in lung injury models. Key limitations include exclusive use of mouse models with no human data, multiple treatment variables across scenarios, and the lack of mechanistic depth regarding GHRP-6's specific molecular targets in lung tissue. The authors conclude that findings warrant future investigation into GHRP-6's pneumoprotective effects.
International immunopharmacology · Jan 2026DOI ↗ Animal only
This animal study investigated whether orally administered salmon acylated ghrelin (sAG) could stimulate food intake in common carp (Cyprinus carpio) and sought to identify the local mechanism behind any such effect. Carp were fed experimental diets containing a range of sAG concentrations in single-shot feeding trials, and additional voluntary feed intake was measured afterward. The study found that diets containing sAG at or above a certain threshold produced a significant, dose-dependent increase in feed intake that plateaued at higher concentrations. Notably, plasma ghrelin levels did not rise following oral administration, as confirmed by two separate radioimmunoassay methods, suggesting that sAG was not absorbed into the bloodstream. To probe the mechanism, researchers used a ghrelin receptor antagonist ([D-Lys3]-GHRP-6) and capsaicin — both abolished the orexigenic effect — pointing to a local signaling pathway involving growth hormone secretagogue receptors and peripheral sensory (likely vagal afferent) neurons. The authors propose this represents a non-circulatory gut-brain axis mechanism in fish. Limitations include that results are limited to a single fish species under controlled laboratory conditions, and translation to other vertebrates or aquaculture settings requires further research.