Animal only
This study developed a multifunctional injectable hydrogel platform — called Exo@Tβ4/HAMA — designed to accelerate bone repair by simultaneously promoting stem cell recruitment, angiogenesis, neurogenesis, and osteogenesis. The hydrogel was fabricated by grafting Thymosin β4 (Tβ4), a short tissue-repair peptide, onto methylmalonic anhydride-modified hyaluronic acid (HAMA) via photo-cross-linking, then loading it with bone marrow mesenchymal stem cell (BMSC)-derived exosomes. In vitro experiments showed the hydrogel had favorable mechanical properties, good biocompatibility, and could recruit BMSCs, enhance tube formation in human umbilical vein endothelial cells (HUVECs), and promote osteogenic differentiation. In vivo rat cranial defect models demonstrated that the hydrogel promoted new bone formation, vascularization, and nerve ingrowth. The study identified the ERK1/2-dependent RUNX2 signaling pathway as a likely mechanistic contributor to osteogenesis. Key limitations include exclusive use of rat models with no human data, a relatively short observation window, and lack of comparison to current clinical gold-standard grafts. The findings suggest promise as a cell-free, injectable bone regeneration scaffold, but clinical translation requires further validation.
Animal only
This study introduces a biodegradable buccal suction patch designed to improve the systemic delivery of therapeutic peptides by bypassing gastrointestinal degradation. The researchers replaced previously used non-degradable silicone materials with biodegradable copolyesters, which were thermally crosslinked via a scalable mold-casting process. Mechanical testing identified the best-performing polymer formulation, and degradation was confirmed in both aqueous media and simulated waste environments. An ex vivo model using porcine buccal tissue demonstrated enhanced permeation of a poorly permeable dye when a chemical permeation enhancer was co-applied. In a beagle dog in vivo model, the biodegradable patch substantially improved the bioavailability of semaglutide (4.11 kDa) compared to a commercially available oral tablet within a 10-minute application window. The patch also achieved a relative bioavailability of approximately 26% for bremelanotide (1.03 kDa) versus subcutaneous injection. Key limitations include the use of an animal model rather than human subjects, a relatively small study scope, and the need for further safety and efficacy validation before clinical translation. The work highlights a promising, more sustainable alternative to silicone-based buccal delivery devices for peptide therapeutics.
Journal of controlled release : official journal of the Controlled Release Society · Jun 2025DOI ↗ Animal only
This review paper examines pharmacotherapies for abdominal compartment syndrome (ACS) and intra-abdominal hypertension (IAH) through the lens of cytoprotection theory, framing these conditions as failures of cytoprotective mechanisms. The authors survey existing pharmacological agents used in ACS/IAH management, noting that most currently reported treatments are limited in scope—typically effective in only one organ, tested only in mild-to-moderate IAH, applied prophylactically rather than therapeutically, and lacking confirmed broad effectiveness. The review then focuses on stable gastric pentadecapeptide BPC 157 as a proposed cytoprotective agent with claimed pleiotropic effects. The authors argue that BPC 157 may address multiple simultaneous targets in ACS/IAH, including compression/ischemia and decompression/reperfusion injury across several organs (brain, heart, lung, liver, kidney, gastrointestinal tract). A proposed mechanism involving activation of collateral "bypassing" vascular pathways—particularly azygos vein blood flow—is described as a potential key to counteracting multiorgan failure, vascular dysfunction, thrombosis, and free radical damage. The paper is a narrative review drawing primarily on animal study data; it does not present original clinical trial data or human evidence. Conclusions about BPC 157 efficacy are therefore speculative in a human clinical context.
Pharmaceuticals (Basel, Switzerland) · Jun 2025DOI ↗ Animal only
This preclinical study investigated whether mazdutide — a dual glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonist — could improve cognition in a mouse model of type 2 diabetes mellitus (T2DM). Male db/db mice (a well-established T2DM model characterized by obesity and hyperglycemia) were treated with mazdutide and compared against dulaglutide, a GLP-1R-only agonist. Researchers assessed cognitive function via behavioral tests and examined brain pathology for neurodegenerative markers. They also applied transcriptomic, proteomic, and metabolomic (multi-omics) analyses to explore underlying molecular mechanisms. The study found that mazdutide-treated mice showed greater improvements in cognitive performance compared to dulaglutide-treated mice, along with better neuronal structure and brain tissue integrity. Multi-omics data implicated molecular pathways related to neuroprotection, energy metabolism, and synaptic plasticity as potential contributors to these effects. Key limitations include exclusive use of male mice, meaning results cannot be generalized to females, and the entirely preclinical nature of the study. No human data were collected, so whether these findings translate to people with T2DM remains unknown. The authors suggest mazdutide may warrant further investigation as a treatment for metabolic disorder-associated cognitive decline.
EBioMedicine · Jun 2025DOI ↗ Animal only
This study investigated whether the synthetic hexapeptide Growth Hormone-Releasing Peptide-6 (GHRP-6), a ghrelin analog with known growth-promoting and immunomodulatory properties in fish, could protect against Nervous Necrosis Virus (NNV) — a pathogen that damages the central nervous system of many commercially farmed fish species. The researchers used two complementary approaches. In vitro, E11 fish cell lines were treated with GHRP-6 before and/or during NNV infection; treated cells showed higher survival rates, reduced viral genome replication, and lower production of infective viral particles compared to untreated controls. In vivo, European seabass (Dicentrarchus labrax) were given intraperitoneal injections of GHRP-6, which led to significant upregulation of immune-related genes — including TNF-α, RTP3, and IgM — in the head kidney and intestine. NNV replication in the brain was also lower in GHRP-6-treated fish than in controls, and the brain's antiviral immune response was modulated. The authors conclude that GHRP-6 shows potential as an antiviral agent for aquaculture disease prevention. Key limitations include that all experiments were conducted in fish (not humans) and the in vivo work lacked a full challenge trial design.
Aquaculture international · Jun 2025
Animal only
This study investigated whether Thymosin β4 (Tβ4), a bioactive polypeptide, could regulate liver inflammation in nonalcoholic fatty liver disease (NAFLD) by influencing macrophage polarization. Researchers used a mouse model of NAFLD induced by a methionine and choline-deficient (MCD) diet in C57 mice, with liver Tβ4 knocked down via tail-vein-injected siRNA. Macrophage involvement was assessed using clodronate liposome depletion. Additionally, in vitro experiments co-cultured THP-1 macrophage cells with oleic acid-treated LO2 hepatocytes at varying Tβ4 concentrations. The study found that Tβ4 treatment was associated with reduced liver inflammation and steatosis in mice, while Tβ4 knockdown worsened steatosis. Tβ4 appeared to shift macrophages toward an M2 (anti-inflammatory) phenotype, reduce M1 marker expression, decrease hepatocyte apoptosis, downregulate STAT1 phosphorylation, and increase SOCS1/3 expression. A publicly available dataset was also used to assess Tβ4 expression in hepatocellular carcinoma-adjacent fatty tissue. Limitations include reliance primarily on animal and in vitro models, a relatively small experimental scope, and no direct human clinical data, leaving the translational relevance of these findings uncertain.
Journal of inflammation research · Apr 2025DOI ↗ Animal onlyPreprint
This preclinical study examined whether three incretin-based receptor agonists — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP receptor agonist), and retatrutide (triple GIP/GLP-1/glucagon receptor agonist) — could alter the interoceptive (subjective) effects of alcohol in rats using an operant drug discrimination paradigm. Male and female rats were trained to discriminate alcohol from saline, then tested after acute or repeated drug administration. The study found that acute administration of all three compounds reduced alcohol's discriminative stimulus effects, suggesting each compound modulated how the animals internally perceived alcohol. Repeated semaglutide treatment sustained this effect across a 15-day period, though discrimination returned to baseline levels within three days of stopping treatment. The authors interpret these findings as potentially relevant to understanding why GLP-1 receptor agonists reduce drinking behavior in humans, hypothesizing that blunting alcohol's subjective effects may be a contributing mechanism. Key limitations include the exclusive use of an animal model, meaning translation to human subjective experience remains uncertain, and the study does not establish clinical efficacy or safety in people with alcohol use disorder.
Unknown journal · Apr 2025DOI ↗ Animal only
This study investigated whether inhaled recombinant human thymosin beta 4 (rhTβ4), delivered via nebulization, could reduce pulmonary fibrosis in a mouse model. Researchers induced pulmonary fibrosis in mice using bleomycin and then administered rhTβ4 aerosols at three different time points: early, mid-term, and late stages of fibrosis development. Efficacy was assessed through hydroxyproline content (a marker of collagen deposition), lung function measurements, and histopathological examination of lung tissue. The study found that nebulized rhTβ4 was associated with reduced fibrosis markers across all three dosing strategies. In parallel cell-based experiments, rhTβ4 appeared to suppress lung fibroblast proliferation, migration, and activation, and to inhibit epithelial-mesenchymal transition (EMT) in pulmonary epithelial cells, with both effects linked to modulation of the TGF-β1 signalling pathway. Limitations include the exclusive use of a mouse bleomycin model (which incompletely recapitulates human IPF), the absence of human clinical data, and the lack of direct mechanistic confirmation in vivo. The authors conclude that nebulized rhTβ4 warrants further investigation as a potential therapy for idiopathic pulmonary fibrosis.
The Journal of pharmacy and pharmacology · Apr 2025DOI ↗ Animal only
This pre-clinical study investigated whether retatrutide (RETA, LY3437943) — a triple incretin agonist targeting GIP, GLP-1, and glucagon receptors — could reduce obesity-associated cancer progression beyond its known weight-loss effects. Using mouse models, researchers found that RETA-induced weight loss was associated with reduced pancreatic cancer engraftment, delayed tumor onset, and a 14-fold reduction in tumor volume compared to controls, outperforming single-agonist semaglutide (which achieved a 4-fold reduction). In a lung cancer model, RETA was associated with 50% reduced tumor engraftment and a 17-fold reduction in tumor volume. Notably, anti-tumor benefits persisted even after RETA withdrawal and subsequent weight regain, suggesting potential durable immune effects. Proposed mechanisms included systemic immune reprogramming: elevated circulating IL-6, increased antigen-presenting cells, reduced immunosuppressive cells, and activation of pro-inflammatory pathways within the tumor microenvironment. Key limitations include the exclusive use of pre-clinical (mouse) models, meaning findings may not translate directly to humans, and the mechanistic basis of durable immunity requires further investigation. The authors suggest these results warrant clinical exploration of RETA's potential to reduce cancer risk and improve outcomes in patients with obesity.
npj metabolic health and disease · Mar 2025DOI ↗ Animal only
This mouse study investigated whether intranasal administration of ghrelin, GHRP-6, or MK-0677 could activate the brain's ghrelin signaling system. Researchers first screened compounds and doses by measuring food intake after intranasal application. Of the three compounds tested, only GHRP-6 at a specific dose increased food intake without adverse effects and was selected for detailed analysis. Investigators then examined meal patterns, neuronal activation in the arcuate nucleus of the hypothalamus using Fos mapping, and neurochemical identity of activated neurons using RNAscope in situ hybridization. They also measured serum growth hormone (GH) levels. The study found that intranasal GHRP-6 increased food intake by raising both meal frequency and meal size. Fos expression in the arcuate nucleus was significantly elevated compared to saline controls, and activated neurons showed co-expression with GHSR, AgRP, and GHRH mRNA markers, implicating circuits involved in feeding and GH regulation. Serum GH levels were also elevated following intranasal GHRP-6. Limitations include exclusive use of a mouse model, a single species and sex are not specified, and the absence of human or pharmacokinetic data, meaning translation to clinical settings remains uncertain.
Endocrinology · Feb 2025DOI ↗ Animal only
This rat study investigated whether the stable gastric pentadecapeptide BPC 157, administered orally, could promote reattachment of the quadriceps muscle to bone following surgical detachment in rats. The model involved both complete detachment of the rectus femoris muscle and partial detachment of the vastus muscles. Untreated control animals exhibited persistent healing failure, including impaired walking and permanent knee flexure across all observation time points (1 day through 90 days post-injury). In contrast, animals receiving oral BPC 157 (at two dose levels) showed consistent improvement across macro- and microscopic analysis, ultrasound, MRI, biomechanical testing, and functional walking assessments. The authors report that treated animals showed early muscle-to-bone approximation, elimination of leg contracture, and progressive tissue reorganization, including periosteal reactivation and mesenchymal cell proliferation by day 3, and well-organized cortical bone with mature, parallel-oriented muscle fibers by 3 months. Key limitations include exclusive use of an animal model with no human data, lack of blinding details, and relatively small group sizes typical of preclinical peptide research. The findings are attributed solely to the study authors and do not establish clinical efficacy or safety in humans.
Pharmaceutics · Jan 2025DOI ↗ Animal only
This study used female Syrian hamsters as an animal model to investigate how bremelanotide (Vyleesi), an FDA-approved drug for hypoactive sexual desire disorder (HSDD), affects the brain's reward system. Researchers examined melanocortin receptor (MC3R and MC4R) expression in the mesolimbic dopamine system — specifically the ventral tegmental area (VTA) and nucleus accumbens (NAc) — and assessed whether the drug enhanced sexual reward using a conditioned place preference (CPP) paradigm. Key findings attributed to the study include: MC4R mRNA was predominantly expressed in dopamine neurons in the VTA, while in the NAc and dorsal striatum, MC4R was rarely co-expressed with dopamine D1 or D2 receptor neurons, appearing instead in interneurons. Neither dose of bremelanotide tested altered melanocortin receptor mRNA expression in the mesolimbic system. Although sexual experience itself produced a CPP in female hamsters, bremelanotide did not enhance this sexual reward response. The authors conclude that bremelanotide does not appear to act through the VTA-NAc reward circuit in this model. A key limitation is that findings are derived entirely from an animal model and may not directly translate to human neurobiology or clinical outcomes.
Neuropharmacology · Jan 2025DOI ↗ Animal only
This animal study investigated whether two synthetic analogs of the ACTH(4-10) peptide fragment — Semax (ACTH(4-7)-Pro-Gly-Pro) and Melanotan II (MTII), a melanocortin receptor agonist — possess antidepressant-like and antistress properties in a chronic unpredictable stress (CUS) rat model of depression. Male adult Sprague-Dawley rats were subjected to CUS and received daily intraperitoneal injections of either saline or a low dose of Semax or MTII. Outcomes assessed included body weight, hedonic status via the sucrose preference test, adrenal gland weight, hippocampal BDNF levels, and immobility in the forced swim test. The study found that both Semax and MTII reversed or substantially reduced CUS-induced anhedonia, suppressed body weight gain, adrenal hypertrophy, and decreased hippocampal BDNF levels. Neither the CUS procedure nor the peptide treatments produced significant effects on immobility in the forced swim test. The authors concluded that systemically administered ACTH(4-10) analogs may have therapeutic potential for depression and stress-related conditions. Key limitations include the exclusive use of male rats, an animal-only design with no human data, and restriction to a single dose level.
European journal of pharmacology · Oct 2024DOI ↗ Animal only
This study investigated whether the naturally occurring copper-binding peptide GHK-Cu (glycyl-L-histidyl-L-lysine copper complex) could reduce Alzheimer's disease (AD)-related pathology in a transgenic mouse model. Male and female 5xFAD mice — a well-established preclinical model of AD — were treated with intranasal GHK-Cu three times per week from 4 to 7 months of age, with a C57BL/6J background strain as context. The researchers assessed behavioral outcomes, amyloid plaque burden, and neuroinflammation markers. The study found that treated mice showed delayed cognitive impairment compared to untreated controls, along with reductions in amyloid plaques and lower levels of MCP1-associated inflammation in the frontal cortex and hippocampus. The authors suggest these findings justify further investigation of GHK-Cu as a potential AD therapeutic. Key limitations include the exclusively preclinical (animal) nature of the work — results in transgenic mouse models do not reliably predict outcomes in humans — and the fact that 5xFAD mice represent an aggressive, artificially accelerated form of amyloid pathology that may not fully reflect the complexity of human AD.
Aging pathobiology and therapeutics · Sep 2024DOI ↗ Animal only
This review paper examines the published preclinical evidence on stable gastric pentadecapeptide BPC 157 as a potential therapeutic agent for intestinal anastomoses and related gastrointestinal conditions in rat models. The authors summarize findings across a range of anastomosis types — including esophagogastric, colocolonic, jejunoileal, and ileoileal — and report that BPC 157 therapy was associated with improved healing outcomes in these animal studies. The review also covers concomitant gastrointestinal disturbances such as esophagitis, sphincter dysfunction, colitis, short bowel syndrome, and major vessel occlusion, as well as dysfunction of the nitric oxide and prostaglandin systems. Additionally, the authors discuss fistula healing (e.g., colocutaneous, gastrocutaneous, vesicovaginal, rectovaginal) as a related phenomenon, framing fistulas as abnormal anastomoses between tissues. The review concludes that both anastomoses and fistulas showed healing responses attributed to BPC 157 in rat models. Limitations include the exclusive reliance on animal data, absence of human clinical trials, and the inherent interpretive limitations of a narrative review format. No controlled human evidence is presented or discussed.
Pharmaceuticals (Basel, Switzerland) · Aug 2024DOI ↗ Animal only
This preclinical study examined whether two ghrelin mimetics (growth hormone secretagogue receptor 1a agonists), anamorelin and ipamorelin, could reduce cisplatin-induced weight loss, appetite suppression, and vomiting in ferrets — an established animal model of chemotherapy-induced nausea and emesis. In isolated ferret ileum tissue, both compounds inhibited electrically-stimulated gut contractions, with anamorelin showing a greater maximum inhibitory effect. When administered intraperitoneally before and after cisplatin, neither compound reduced acute or delayed vomiting episodes, but both reduced associated weight loss by approximately 24% during the late delayed phase (48–72 hours). Strikingly, when anamorelin was delivered directly into the brain (intracerebroventricularly), it reduced acute emesis by approximately 60%, improved food and water intake during the acute phase by roughly 20–40%, and reduced delayed-phase weight loss by approximately 23%. These findings suggest that anamorelin's anti-emetic effects depend on central nervous system penetration rather than peripheral action. Limitations include the use of a single non-human animal species, small group sizes typical of ferret studies, and the invasive intracerebroventricular route, which is not clinically practical. No human data were generated.
Physiology & behavior · Jul 2024DOI ↗ Animal only
This study investigated the effects of ipamorelin acetate (IPA), a synthetic ghrelin agonist, on the reproductive axis of male Mozambique tilapia (Oreochromis mossambicus), a cichlid fish. Fish received either 5 µg or 30 µg of IPA over 21 days and were compared to untreated controls. The study found that IPA administration produced a dose-dependent increase in food intake. Histological analysis revealed significant increases in primary spermatocytes, secondary spermatocytes, and early spermatids in both treatment groups, while the higher dose also increased late spermatids, lobule area, and lumen area. Serum concentrations of luteinizing hormone (LH) and the fish androgen 11-ketotestosterone (11-KT) were significantly elevated in both IPA groups. Androgen receptor protein expression was significantly upregulated in the high-dose group. No significant differences in hypothalamic or pituitary GnRH-immunoreactive fiber density were observed across groups. The authors conclude that ghrelin signaling may promote meiosis-I stage germ cell development through LH stimulation at the pituitary level and 11-KT and androgen receptor activity at the testicular level. Limitations include the use of a single non-mammalian species, a short treatment duration, and the absence of mechanistic pathway confirmation.
Animal reproduction science · Jul 2024DOI ↗ Animal only
This mouse study investigated therapeutic strategies for hyperphagia, hyperglycemia, and obesity caused by a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y), which encodes the serotonin 2C receptor (5-HT2CR). Researchers tested three main approaches in male mice fed a high-fat diet. First, they used viral re-expression of functional 5-HT2CR specifically in hypothalamic POMC neurons, finding this was sufficient to reduce food intake and body weight, and restored neuronal responsiveness to lorcaserin (a selective 5-HT2CR agonist). Second, they administered melanotan II, an MC4R agonist, which effectively suppressed feeding and weight gain. Third, they promoted voluntary wheel-running exercise, which reduced high-fat diet consumption and improved glucose homeostasis. The study highlights the importance of the 5-HT2CR–melanocortin pathway in energy balance regulation and suggests MC4R agonists and physical activity may be relevant strategies for individuals carrying rare Htr2c variants. Key limitations include exclusive use of a single male mouse model, a specific engineered mutation, and the gap between rodent models and human metabolic disease.
Endocrinology · May 2024DOI ↗ Animal only
This animal study investigated whether AMP-activated protein kinase (AMPK) in the central nucleus of the amygdala (CeA) serves as an intracellular signaling mediator linking metabolic cues—ghrelin, fasting, and glucoprivation—to food intake regulation. Male Wistar rats were surgically implanted with cannulas in the CeA and received intra-CeA injections of various modulators, including glucose, 2-deoxy-D-glucose (2DG), ghrelin, and Melanotan II (MTII). The study measured AMPK phosphorylation at Thr172 (AMPKThr172) alongside food intake and body weight. Key findings attributed to the study include: fasting increased and refeeding reduced CeA AMPKThr172; intra-CeA glucose reduced food intake while 2DG (a glucoprivation inducer) increased food intake and blood glucose with modest AMPKThr172 elevation; intra-CeA ghrelin increased both food intake and AMPKThr172; and chronic intra-CeA MTII injection reduced body mass and food intake over seven days alongside a slight reduction in AMPKThr172. Limitations include use of a single rodent model, small and unspecified sample sizes per group, and the inability to establish direct causality between AMPK activation and feeding behavior. No human data were collected.
Molecular and cellular endocrinology · Apr 2024DOI ↗ Animal only
This review paper examines the proposed mechanisms underlying the wide-ranging (pleiotropic) biological effects of BPC 157, a synthetic 15-amino-acid peptide described as stable in human gastric juice. The authors attempt to frame BPC 157's observed effects within classical neurotransmitter criteria — including production, release, receptor interaction, and clearance — while acknowledging that direct conclusive evidence meeting these criteria is lacking. Instead, the paper compiles a network of interconnected preclinical evidence suggesting that BPC 157 may counteract disturbances across multiple neurotransmitter systems, including dopamine, serotonin, glutamate, GABA, adrenaline/noradrenaline, acetylcholine, and the nitric oxide (NO) system. The paper also discusses potential receptor interactions (e.g., VEGF and growth hormone receptors) and observations related to nerve-muscle and nerve-nerve relationships in various experimental models. The authors draw parallels between BPC 157's activity and gasotransmitter behavior. A key limitation explicitly noted by the authors is the absence of direct human clinical trial data; the evidence base relies predominantly on animal and in vitro studies. This paper does not establish clinical efficacy or safety in humans.
Pharmaceuticals (Basel, Switzerland) · Apr 2024DOI ↗