Animal only
This systematic review (PRISMA-guided) examined whether GLP-1 receptor agonists (GLP-1 RAs) exert neuroprotective effects in preclinical models of stroke and Parkinson's disease (PD). Researchers searched four major databases (Cochrane CENTRAL, PubMed, Web of Science, Scopus), identifying 1,643 records and ultimately including 13 experimental animal studies published between 2013 and 2026. For stroke, studies primarily used middle cerebral artery occlusion (MCAO) models; the review found that agents such as liraglutide and linagliptin were associated with notable reductions in infarct volume and improved neurological deficit scores in treated animals. For PD models, the included studies reported improvements in motor function, preservation of dopaminergic neurons, and reduced α-synuclein aggregation. Across both disease models, GLP-1 RAs appeared to modulate neuroinflammatory markers (TNF-α, IL-1β, IL-6), oxidative stress indicators (ROS, 4-HNE), and apoptotic pathways (increased Bcl-2, decreased Bax). Risk of bias assessment using the SYRCLE tool rated overall quality as moderate, with four studies flagged as high risk due to small sample sizes and inadequate reporting of randomization and blinding procedures. The authors concluded that while preclinical evidence appears promising, standardized studies and clinical trials are needed before translational conclusions can be drawn.
Disease-a-month : DM · Jun 2026DOI ↗ Animal only
This study developed a targeted nanodelivery system — GLP-1@tMSN (glucagon-like peptide-1 loaded into matrix metalloproteinase-2-targeted mesoporous silica nanoparticles) — designed to mobilize endothelial progenitor cells (EPCs) and promote re-endothelialization following coil embolization of intracranial aneurysms (IAs). Using a rat coiled aneurysm model, the researchers evaluated whether the platform could recruit EPCs to the lesion site and accelerate vascular repair. The study found that GLP-1@tMSN significantly enhanced EPC recruitment and re-endothelialization compared to controls. After 28 days, histological analysis showed formation of mature endothelial-like tissue in treated animals, while controls exhibited fibrous tissue. Immunofluorescence confirmed preferential accumulation of CD34+VEGFR2+ EPCs at the lesion site, alongside activation of the Wnt/β-catenin signaling pathway, which the authors implicate as a key driver of vascular repair. Preliminary biocompatibility assessments suggested an acceptable safety profile. Limitations include the exclusive use of a rat model, a single 28-day follow-up endpoint, small experimental scale, and lack of human translational data. The authors conclude that this nanotherapeutic approach may hold promise for reducing long-term IA recurrence after embolization, though clinical validation is needed.
Journal of neurosurgery · Jun 2026DOI ↗ Animal only
This study investigated whether sustained GLP-1 gene delivery could stimulate β-cell regeneration in diabetic rats, and whether regenerative responses differ between neonatal and adult stages. Researchers engineered a third-generation HIV-based lentiviral vector encoding native GLP-1 (LentiGLP-1) under a CMV promoter. Two rat models of type 2 diabetes were used: neonatal rats treated with low-dose streptozotocin (STZ) to exploit developmental pancreatic plasticity, and adult rats subjected to a high-fat diet combined with low-dose STZ. In neonatal diabetic rats, LentiGLP-1 administration markedly promoted differentiation of ductal and progenitor cells into insulin-producing β-cells, accompanied by increased β-cell proliferation. In adult diabetic rats, LentiGLP-1 partially restored β-cell populations via activation of residual progenitors and stimulation of existing β-cell replication, with improvements in glycemic control and insulin sensitivity. Acinar cells were not observed to contribute to β-cell regeneration in either model. A key limitation is that findings are entirely in rodents, and the translational relevance to human β-cell biology remains unestablished. The study provides mechanistic insight into developmentally regulated GLP-1 effects but does not constitute evidence of efficacy in humans.
Journal of molecular medicine (Berlin, Germany) · Jun 2026DOI ↗ Animal only
This preclinical study designed and tested a novel unimolecular dual agonist that combines glucagon-like peptide-1 (GLP-1) and fibroblast growth factor-21 (FGF21) into a single molecule, connected by a thermally responsive elastin-like polypeptide linker intended to form a sustained-release subcutaneous depot. Receptor activity was first confirmed in cell-based assays. The molecule was then tested in male C57Bl/6J mice fed a diet designed to induce advanced metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis. The study found that treated mice showed improvements in body weight, liver mass, blood glucose, and cholesterol compared to controls. Histological and molecular analyses indicated reductions in liver fat accumulation, inflammation, and fibrosis, along with decreased expression of inflammatory and fibrotic marker genes and increased hepatocyte proliferation. Limitations include the exclusive use of a single male mouse strain, the absence of female animals, and the inherent translational gap between diet-induced rodent models and human MASH. No human data were generated. The authors conclude that this dual-agonist approach warrants further development as a potential chronic liver disease therapy.
Communications medicine · Jun 2026DOI ↗ Animal onlyPreprint
This mouse study investigated the effects of semaglutide, a GLP-1 receptor agonist (GLP-1 RA), administered from preconception through lactation in dams fed either a high-fat diet (HFD) or a standard diet. Researchers assessed metabolic outcomes in both the treated mothers and their offspring, who were weaned onto a standard diet. The study found that semaglutide improved body composition and glucose metabolism in HFD-fed dams during pregnancy, and these benefits persisted approximately 10 weeks after weaning even after treatment was discontinued. Offspring born to HFD-fed, untreated dams showed impaired glucose homeostasis and hepatic steatosis (fatty liver) at 18 weeks of age. These metabolic disturbances were attenuated in offspring whose mothers received semaglutide. Notably, semaglutide treatment did not adversely affect conception rates or fetal viability. The authors conclude that GLP-1 RA therapy during the perinatal period may improve both maternal and offspring metabolic health in an obesity mouse model, and they call for further investigation into GLP-1–based therapies in this context. Key limitations include the exclusive use of a mouse model, limiting direct translation to human pregnancy, and the fact that this appears to be a preprint not yet formally peer-reviewed.
Unknown journal · Jun 2026DOI ↗ Animal only
This mouse study investigated the molecular mechanisms by which tirzepatide (TZP), a dual GIP/GLP-1 receptor agonist, affects the liver in metabolic dysfunction-associated steatotic liver disease (MASLD). Male C57BL/6J mice (n=32) were fed a high-fat, high-fructose (HFHFr) diet to induce MASLD and then randomized to receive no treatment, semaglutide (Sema), or TZP. Researchers combined RNA sequencing and liquid chromatography-mass spectrometry (LC-MS) to generate hepatic transcriptomic and proteomic profiles, with key targets validated by PCR and immunoblotting. The study found that HFHFr feeding produced hyperglycemia, insulin resistance, elevated liver enzymes, and hepatic steatosis and inflammation. Both TZP and Sema were associated with improvements in these parameters; TZP was associated with reductions in pro-inflammatory markers (MCP-1, IL-1β, TNF-α, GSDMD) and partial restoration of IL-10. Integrated omics analysis implicated the CCL2/CCR2 chemokine axis and PI3K-AKT signaling pathway as key molecular signatures associated with TZP's hepatic effects. Key limitations include the exclusive use of an animal model, a small sample size, and the mechanistic (non-causal) nature of omics associations.
BMC gastroenterology · Jun 2026DOI ↗ Animal only
This study investigated whether MOTS-c, a small peptide encoded within mitochondrial DNA, could protect the heart from ischemia-reperfusion (IR) injury. Using the Langendorff isolated heart perfusion model in female Wistar rats (n=6 per group), researchers subjected hearts to 30 minutes of global ischemia followed by 60 minutes of reperfusion. MOTS-c was administered either before ischemia or at the start of reperfusion. The study evaluated cardiac mechanical function, oxidative stress, mitochondrial enzyme activities, membrane potential, mitochondrial DNA (mtDNA) copy number, and regulatory gene expression across two distinct mitochondrial subpopulations — subsarcolemmal and interfibrillar mitochondria. IR injury significantly impaired cardiac recovery, increased oxidative stress, reduced electron transport chain activity, and decreased mtDNA copy number and regulatory gene expression. MOTS-c treatment was associated with improved post-ischemic mechanical recovery, reduced oxidative stress, partial preservation of mitochondrial enzyme activity and membrane potential, and attenuation of mtDNA loss. Protective effects were seen in both mitochondrial subpopulations, though the magnitude varied. Key limitations include the exclusive use of an isolated ex vivo animal model, small group sizes, a single sex, and uncharacterized signaling mechanisms underlying the observed effects.
Molecular biology reports · Jun 2026DOI ↗ Animal only
This study investigated whether the mitochondrial-derived peptide MOTS-c could improve survival of ischemic tissue flaps used in reconstructive surgery — a context where distal necrosis due to poor blood flow remains a significant clinical challenge. Using a rat ischemic flap model, researchers employed a broad range of techniques including RNA sequencing, tissue clearing, laser speckle contrast imaging, laser Doppler blood flow analysis, histological staining, Western blotting, ELISA, immunofluorescence, and adeno-associated virus (AAV)-mediated gene overexpression. The study also used human umbilical vein endothelial cells (HUVECs) for in vitro experiments. The authors report that MOTS-c treatment was associated with improved blood perfusion, enhanced angiogenesis, and better collagen remodeling in ischemic flaps. Mechanistically, the study found that MOTS-c appeared to suppress phosphorylation of PLA2G4A (cytosolic phospholipase A2) via the MAPK1/ERK2–MAPK3/ERK1–NF-κB signaling cascade, thereby reducing lysosomal membrane permeabilization (LMP), decreasing endothelial pyroptosis, and enhancing autophagy. AAV-mediated PLA2G4A overexpression in vivo was used to confirm this pathway. Key limitations include the absence of human clinical data and the complexity of the multi-modal experimental design, which makes it difficult to isolate individual mechanistic contributions.
Autophagy · Jun 2026DOI ↗ Animal only
This mouse study investigated whether adjunctive thymosin beta-4 (Tβ4) combined with the antibiotic ciprofloxacin could restore corneal nerve integrity and visual function following Pseudomonas aeruginosa bacterial keratitis, a serious eye infection. Researchers induced keratitis in C57BL/6 mice by inoculating wounded corneas with P. aeruginosa, then administered one of four topical treatments three times daily beginning 24 hours post-infection: PBS (vehicle control), Tβ4 alone, ciprofloxacin alone, or Tβ4 combined with ciprofloxacin. Outcomes assessed included clinical disease severity, visual acuity, contrast sensitivity, corneal sensitivity (nerve function), and corneal nerve density/architecture via β-III tubulin immunofluorescence. The study found that the combination of Tβ4 and ciprofloxacin outperformed all monotherapy and control groups across every measured outcome, restoring nerve density and visual function to levels comparable to uninfected controls. Key limitations include the exclusive use of an animal model, meaning findings may not directly translate to humans, and the study does not address long-term safety, optimal treatment windows, or clinical feasibility. These results suggest Tβ4 may be a promising adjunctive therapy warranting further investigation.
Investigative ophthalmology & visual science · Jun 2026DOI ↗ Animal only
This rat study investigated whether BPC 157, a synthetic pentadecapeptide derived from a gastric protein, could protect skeletal muscle tissue from ischemia-reperfusion (I/R) injury. Twenty-four male Wistar rats were divided into four groups (n=6 each): sham surgery, BPC 157 alone, I/R injury alone, and I/R injury treated with BPC 157. I/R was induced by clamping the abdominal aorta for 45 minutes followed by 2 hours of reperfusion; BPC 157 was given intraperitoneally at the end of the ischemia period. The study measured oxidative stress markers (MDA, SOD, TAS, TOS) in serum, gene expression of inflammatory and apoptotic markers (IL-6, HIF-1α, p53, Bcl-2, Bax, Caspase-3) via qRT-PCR, and protein expression (VEGF, eNOS, IL-6, Caspase-3) via immunohistochemistry, alongside histopathological scoring. The authors report that I/R increased oxidative stress, inflammation, and apoptotic signaling, while BPC 157 treatment was associated with reduced oxidative markers, decreased inflammatory and pro-apoptotic gene expression, increased anti-apoptotic Bcl-2, partial restoration of VEGF, and improved muscle histology. Limitations include very small group sizes (n=6), use of a single dose, a single species, and no human data, restricting the generalizability of findings.
Scientific reports · May 2026DOI ↗ Animal onlyPreprint
This preclinical study investigated whether the endogenous copper-binding peptide GHK-Cu (glycyl-L-histidyl-L-lysine–copper complex) could mitigate age-related cognitive decline in middle-aged to old C57BL/6J mice (20–21 months). Two delivery routes were compared: short-term intraperitoneal (IP) administration over 5 days and longer-term intranasal (IN) administration over 8 weeks. Hippocampal-dependent spatial learning was assessed via an escape latency task; molecular changes were examined through hippocampal immunohistochemistry and bulk RNA sequencing, with differential gene expression analyzed using DESeq2 and gene set enrichment analysis (GSEA). Both delivery routes were associated with improved escape latency performance in treated mice of both sexes compared to controls, suggesting behavioral rescue of age-related learning deficits. However, the two routes produced divergent hippocampal transcriptomic profiles, implying that delivery method and exposure duration engage distinct molecular aging programs. Key limitations include the exclusive use of a mouse model, the absence of human data, variability in statistical power across outcome measures, and preprint status meaning the findings have not yet undergone formal peer review. The study does not establish causality in humans and is hypothesis-generating for future translational research.
Unknown journal · May 2026DOI ↗ Animal only
This study investigated whether MOTS-c, a mitochondrial-derived peptide with metabolic and exercise-mimicking properties, could attenuate skeletal muscle loss in cancer cachexia. In vitro, differentiated myotubes treated with MOTS-c showed increased PGC-1α mRNA expression (~85%) and enhanced AMPK phosphorylation (~103%), suggesting activation of mitochondrial biogenesis and energy-sensing pathways. In vivo, male mice implanted with Colon-26 (C26) carcinoma cells developed significant systemic wasting (~9% body weight loss). Daily MOTS-c treatment did not prevent total body weight loss or fat mass loss in these tumor-bearing mice, but it did significantly preserve skeletal muscle mass — notably rescuing quadriceps weight (~12% vs. C26 vehicle controls). Mechanistically, MOTS-c appeared to modulate FOXO signaling and reduce atrogene expression (MuRF1 and Atrogin-1), key mediators of muscle protein breakdown, while promoting mitochondrial biogenesis markers. The authors conclude that MOTS-c partially protects against cachexia-associated muscle deterioration. Key limitations include the exclusive use of male mice, an animal-only in vivo model, and the authors' own acknowledgment that human studies are needed to validate these findings.
Frontiers in medicine · May 2026DOI ↗ Animal only
This study investigated whether the mitochondrial-derived peptide MOTS-c could protect the neonatal heart from hyperoxia-induced injury. Using neonatal mice exposed to 85% oxygen as an in vivo model and the rat cardiomyocyte cell line H9C2 as an in vitro model, researchers found that hyperoxia caused cardiac hypertrophy, fibrosis, and dysfunction, alongside reduced circulating MOTS-c levels. Administration of MOTS-c was reported to markedly reduce these pathological changes and restore cardiac function in the mouse model. Mechanistically, the study found that hyperoxia activates a KEAP1–PGAM5–AIFM1 signaling axis, triggering a ROS-specific form of programmed cell death called oxeiptosis. MOTS-c appeared to interact directly with KEAP1, preserving its binding to PGAM5 and thereby preventing nuclear translocation of AIFM1, the downstream executioner of oxeiptosis. Overexpression of KEAP1 abolished MOTS-c's protective effects, supporting KEAP1 as a key target. Limitations include exclusive reliance on animal and cell-line models with no human data, a relatively narrow mechanistic focus, and the absence of long-term outcome measures. These findings are preclinical and require validation in human studies before clinical conclusions can be drawn.
Life sciences · May 2026DOI ↗ Animal only
This study investigated an engineered variant of the mitochondria-derived peptide MOTS-c, called R13A-MOTS-c, designed to overcome the poor cellular permeability of the wild-type peptide. The researchers substituted arginine at position 13 with alanine to increase hydrophobicity, then characterized the modified peptide's uptake mechanism, showing through competition assays and knockdown experiments that it enters cells via the LAT1 amino acid transporter. In vitro, R13A-MOTS-c was reported to reduce inflammatory markers, oxidative damage, and mitochondrial dysfunction in mouse lung epithelial (MLE-12) cells exposed to radiation. In vivo, C57BL/6 mice receiving thoracic irradiation (20 Gy) and treated with intraperitoneal R13A-MOTS-c showed attenuated pulmonary inflammation, oxidative stress, and mitochondrial impairment compared to controls. The proposed mechanism centers on Nrf2 pathway activation, supported by evidence of increased nuclear Nrf2 translocation and upregulation of downstream target genes; protective effects were lost when LAT1 or Nrf2 was inhibited or knocked out. Key limitations include exclusive use of animal and cell models with no human data, a single radiation dose and treatment regimen tested, and the need for further pharmacokinetic and safety characterization before clinical translation.
Redox biology · May 2026DOI ↗ Animal only
This study investigated whether GHK-Cu (the tripeptide Glycine-Histidine-Lysine complexed with copper, naturally found in human plasma and urine) could delay aging using the roundworm Caenorhabditis elegans as a model organism. The researchers measured lifespan, stress resistance (oxidative and thermal), physical function (motility, pharyngeal pumping, defecation rhythm), and markers of cellular aging such as lipofuscin and lipid accumulation. They also examined mitochondrial health and key longevity signaling pathways. The study found that GHK-Cu extended worm lifespan, improved multiple age-related functional measures, and reduced aging biomarkers. At the mechanistic level, GHK-Cu appeared to preserve mitochondrial function—maintaining membrane potential, reducing age-related mitochondrial fragmentation, promoting mitochondrial fusion (via regulation of drp-1 and fzo-1), and increasing ATP production. Additionally, GHK-Cu activated the DAF-16 and SKN-1 longevity pathways and upregulated downstream target genes including sod-3, gst-4, gcs-1, lys-7, and lys-8. A key limitation is that all experiments were conducted in C. elegans; whether these findings translate to mammals or humans remains unknown.
Biogerontology · May 2026DOI ↗ Animal only
This mouse study investigated whether potassium-competitive acid blockers (P-CABs), sometimes empirically used for eosinophilic gastrointestinal diseases, might worsen eosinophilic enteritis (EoN) under psychological stress conditions. Researchers established an EoN model in BALB/c mice using ovalbumin sensitization and challenge, then exposed animals to water avoidance stress (WAS) or sham stress, with or without P-CAB administration. Compared to the WAS-only group, WAS combined with P-CAB significantly worsened multiple disease markers, including diarrhea incidence, villus/crypt ratio, eosinophil and mast cell counts, Th2 cytokine expression (mRNA and protein), OVA-specific IgE levels, and ileal permeability measured via Ussing chamber. The study further found that larazotide acetate, a zonulin inhibitor targeting gut tight junctions, reduced ileal inflammation and permeability in WAS + P-CAB-treated EoN mice, suggesting a permeability-mediated mechanism. Key limitations include exclusive use of a mouse model, which may not fully replicate human eosinophilic gastrointestinal disease, and the artificial nature of the stress and sensitization protocols. These findings raise important cautions about P-CAB use in patients with EoN who may be under psychological stress, though human clinical evidence is still lacking.
Digestion · Apr 2026DOI ↗ Animal only
This study examined how combination antiretroviral therapy (cART) interacts with calorie-dense diets to affect heart function in a rat model. One hundred and twenty weanling Sprague Dawley rats were assigned to one of three diets (normal chow, calorie-dense low-protein, or calorie-dense normal-protein) for 15 weeks, then subdivided into four treatment groups for an additional 9 weeks: saline control, dolutegravir (DTG) plus tesamorelin, DTG alone, or a classical cART regimen. At week 24, electrocardiographic (ECG) recordings and myocardial tissue analysis were performed. The study found statistically significant differences across groups in multiple ECG parameters, including Q, R, S, and T wave amplitudes, PR interval, QRS duration, ST height, and corrected QT interval. Myocardial fibrosis was notably observed in animals receiving DTG alone or classical cART while on calorie-dense diets. The authors suggest these structural changes may disrupt electrical conduction and predispose to arrhythmias. Notably, tesamorelin appeared to attenuate these cardiac effects, leading the authors to implicate growth hormone pathway dysfunction in the pathology. Key limitations include the exclusive use of an animal model, meaning findings may not directly translate to humans.
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas · Apr 2026DOI ↗ Animal only
This study investigated the anti-inflammatory and antioxidant properties of the bioactive tripeptide complex GHK-Cu (Glycyl-L-histidyl-L-lysine-Cu²⁺) using zebrafish larvae as an in vivo model. Researchers induced acute inflammation in larvae using either copper sulfate (CuSO₄) or lipopolysaccharide (LPS) and then assessed the effects of GHK-Cu treatment. According to the study, GHK-Cu notably reduced the migration of neutrophils and macrophages to sites of inflammation. It also suppressed the gene expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) while upregulating the anti-inflammatory cytokine IL-10. The compound was further reported to reduce markers of oxidative stress, including nitric oxide (NO) and reactive oxygen species (ROS), and to improve superoxide dismutase (SOD) activity. Pathway analysis suggested that GHK-Cu's effects may be mediated in part through downregulation of the JAK1 signaling pathway. The authors propose that these findings provide a theoretical basis for the use of GHK-Cu as a functional cosmetic ingredient. Key limitations include the use of a non-mammalian animal model and the absence of human or cell-culture mechanistic data, meaning clinical translation remains unestablished.
European journal of pharmacology · Apr 2026DOI ↗ Animal only
This preclinical study investigated whether obesity could be reversed without activating the GLP-1 receptor (GLP-1R), which is commonly associated with adverse gastrointestinal side effects in current therapies. Using diet-induced obese (DIO) mice and rats, as well as GLP-1R knock-out (KO) mice, researchers tested selective, dual, and triple agonists targeting the GIP receptor (GIPR), glucagon receptor (GCGR), and GLP-1R in various combinations. Three independent experimental approaches — (1) administering the triagonist retatrutide to GLP-1R KO mice, (2) physically combining separate selective GIPR and GCGR agonists, and (3) testing a novel unimolecular GIPR:GCGR co-agonist called BWB3054 — all demonstrated meaningful reductions in body weight and improvements in blood glucose without meaningful GLP-1R engagement. BWB3054 showed potency at the mouse GIPR comparable to retatrutide, 4-fold reduced potency at the mouse GCGR, and more than 100-fold reduced potency at the mouse GLP-1R. Indirect calorimetry and pair-feeding studies were used to characterize mechanisms of weight loss. A key limitation is that all experiments were conducted in rodents, leaving the translatability of these findings to humans uncertain. The study raises the possibility that GLP-1R-independent obesity treatment strategies could avoid the GI tolerability issues seen with current agents.
Molecular metabolism · Apr 2026DOI ↗ Animal onlyPreprint
This mouse study investigated whether the endogenous copper-binding peptide GHK-Cu could improve age-related cognitive decline, and whether outcomes differed based on how the compound was delivered. Aged C57BL/6J mice (20–21 months old) received GHK-Cu either intraperitoneally (IP) for 5 days or intranasally (IN) for 8 weeks. Researchers assessed hippocampal-dependent spatial learning, along with hippocampal tissue markers and bulk RNA sequencing. Both delivery routes were associated with improvements in escape learning, though IN administration showed broader and more sustained benefits across both sexes, while IP dosing produced a more limited effect, primarily in males. Immunohistochemistry revealed route-dependent changes in markers of synaptic density (synaptophysin), neuroinflammation (GFAP, MCP-1, TGF-β), and cellular senescence (p21). Transcriptomic analysis showed striking divergence: IN treatment was associated with suppression of oxidative phosphorylation and MYC target pathways, while IP treatment activated stress-response, DNA repair, and mitochondrial metabolic pathways. The authors conclude that GHK-Cu can improve cognitive outcomes through mechanistically distinct biological programs depending on the route and duration of administration. Key limitations include use of a single rodent strain, lack of human data, and preprint status (not yet peer-reviewed).
Unknown journal · Apr 2026DOI ↗