Animal only
This study investigated whether activating estrogen-related receptors (ERRα and ERRγ) — key regulators of cardiac metabolism — could treat heart failure (HF). Researchers designed two novel pan-ERR agonist compounds, SLU-PP-332 and SLU-PP-915, using structure-based drug design, and tested them in a mouse model of pressure overload-induced HF. Both compounds significantly improved ejection fraction, reduced cardiac fibrosis, and increased survival in mice without causing additional cardiac hypertrophy. Multi-omics analyses (RNA sequencing and metabolomics) revealed that ERR agonists broadly activated metabolic gene programs — particularly those governing fatty acid oxidation and mitochondrial function — and substantially normalized disrupted metabolic profiles in failing hearts. In vitro and in vivo genetic dependency experiments identified ERRγ as the primary mediator of these cardioprotective effects and confirmed target specificity. The study also found that ERR agonism downregulated cell cycle and developmental pathways, partly via the transcription factor E2F1. Limitations include that all in vivo work was conducted in mice, and no human data were presented. The authors conclude that ERR agonists represent a promising pharmacologic strategy for HF, warranting further development.
Circulation · Nov 2023DOI ↗ In vitro
This study developed and validated a novel analytical strategy for characterizing how BPC-157 — a peptide classified as a doping agent — is metabolized in laboratory (in vitro) conditions. The researchers used stable isotope labeling (¹³C/¹⁵N-labeled BPC-157) combined with ultra-high-performance liquid chromatography–high-resolution mass spectrometry (UHPLC-HRMS) to systematically identify metabolites without needing prior knowledge of metabolic pathways. Using two in vitro incubation models, the study identified nine total metabolites: eight arising from conventional amide-bond cleavage and one from a previously unreported metabolic pathway. The team then developed and validated a detection method for BPC-157 and five key metabolites in human urine, achieving detection limits of 0.01–0.11 ng/mL and strong quantitative performance. Importantly, this was an entirely in vitro study; no human participants or animals were involved, meaning the metabolic profile observed may not fully reflect what occurs in the human body. The findings are primarily relevant to anti-doping laboratories seeking improved detection targets and analytical workflows, and do not speak to the biological effects or clinical utility of BPC-157.
Molecules (Basel, Switzerland) · Oct 2023DOI ↗ Insufficient
This study, conducted by a doping control laboratory, describes the development and analytical validation of a method for detecting growth hormone-releasing hormones (GHRHs) — specifically tesamorelin, CJC-1295, sermorelin (GRF 1-29), sermorelin (3-29)-NH₂, and somatorelin — in human urine samples. GHRHs are prohibited in sport under World Anti-Doping Agency (WADA) regulations. The method combines weak cation exchange solid-phase extraction (SPE) with ultra-high-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry (UHPLC-MS/MS). The researchers validated the method according to WADA technical documents, evaluating selectivity, limit of detection (LOD), carryover, reliability, stability, and recovery. The method achieved an LOD of 0.2 ng/mL, a limit of quantification (LOQ) of 0.6 ng/mL, and linearity from 0.1 to 1.2 ng/mL. The study reports adequate recovery and sensitivity for routine anti-doping screening. A key limitation is that this is purely an analytical/method-development study; it does not investigate pharmacological effects, clinical outcomes, or administer any compound to human or animal subjects.
Analytical biochemistry · Oct 2023DOI ↗ Animal only
This mouse study investigated the role of estrogen-related receptors (ERRs) in age-related kidney decline, focusing on mitochondrial dysfunction and inflammation as key mechanisms. The researchers first observed that ERR expression was reduced in both aging human and mouse kidneys, and that lifelong caloric restriction (CR) preserved ERR levels in mice. They then treated 21-month-old mice (equivalent to elderly) for 8 weeks with a pan-ERR agonist (SLU-PP-332) or for 3 weeks with a STING pathway inhibitor (C-176). The ERR agonist treatment reversed age-associated increases in albuminuria (a marker of kidney damage), podocyte loss, mitochondrial dysfunction, and inflammatory cytokines, acting through the cGAS-STING and STAT3 signaling pathways — effects resembling those of caloric restriction. STING inhibition reduced inflammatory cytokines and the senescence marker p21, but also unexpectedly restored mitochondrial pathway components (PGC-1α, ERRα, mitochondrial complexes, MCAD). The study identifies ERRs as potential CR mimetics and highlights the cGAS-STING pathway as a link between mitochondrial dysfunction and renal inflammation in aging. Key limitations include reliance on animal models, short treatment durations, and the absence of human interventional data.
The American journal of pathology · Sep 2023DOI ↗ Animal only
This study investigated whether the growth hormone-releasing peptide Hexarelin could protect against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) and explored its molecular mechanisms. Using a rat I/R model, animals were pretreated with Hexarelin for seven days before injury induction. Researchers assessed kidney function (serum creatinine), histology (tubular necrosis and dilation), and apoptosis markers. In vitro, a hypoxia/reoxygenation (H/R) model in human kidney tubular (HK-2) cells was used to complement findings. The study reports that Hexarelin pretreatment reduced pathological kidney changes, improved renal function, and suppressed apoptosis, as evidenced by downregulation of pro-apoptotic proteins (Caspase-3, Bax, Bad) and upregulation of anti-apoptotic Bcl-2. Gene Set Enrichment Analysis (GSEA) highlighted the apoptosis pathway's role in I/R-AKI. Molecular docking suggested Hexarelin binds MDM2, a negative regulator of p53, and both MDM2 and p53 expression were suppressed by Hexarelin in vivo and in vitro. Key limitations include exclusive use of animal and cell models with no human data, a relatively narrow mechanistic focus, and reliance on computational docking without direct protein-interaction validation.
European journal of medical research · Sep 2023DOI ↗ 🧪 TrialInsufficient
Registered observational trial (completed). It is a single-center, retrospective, controlled study to investigate the efficacy and safety of neoadjuvant chemoradiotherapy combined with PD-1 inhibitor and thymalfasin for locally advanced mid-low rectal cancer.
ClinicalTrials.gov · Sep 2023View trial ↗ 🧪 TrialInsufficient
Registered Phase 2 interventional trial (completed). A multicenter randomized double-blind placebo parallel control design was used in this study. The 90 participants were randomly assigned to placebo, 0.5μg/kg dose group, and 1.0μg/kg dose group in a ratio of 1:1:1. After randomization, subjects received the trial drug or placebo intravenously within 12 hours and on days 2 to 7 after PCI. The patients were observed 90 days after PCI.
ClinicalTrials.gov · Aug 2023View trial ↗ Animal only
This study investigated whether a short-term high-fat (HF) diet could impair neurobehavioral outcomes in zebrafish (Danio rerio) and whether treatment with Melanotan-II (MT-II), a melanotropin receptor agonist, could reverse those effects. Zebrafish were fed an HF diet for approximately three weeks — roughly 1% of their lifespan — and then assessed for recognition memory, anxiety levels, and exploratory behavior. The researchers found that zebrafish on the HF diet showed measurable impairments in recognition memory, elevated anxiety, and reduced exploratory behavior compared to control-diet animals. Notably, HF-diet zebrafish that also received MT-II treatment demonstrated memory, anxiety, and exploratory behavior comparable to the control group, suggesting a reversal of HF diet-induced changes. The authors describe this as the first study demonstrating MT-II's ability to reverse short-term HF diet-induced neurobehavioral abnormalities. Key limitations include the use of a non-mammalian animal model (zebrafish), which limits direct translation to human neurology, and the absence of mechanistic data clarifying how MT-II acts on the relevant brain pathways. No human or clinical data are presented.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · Jul 2023DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (active not recruiting). The purpose of this study is to is to evaluate the efficacy and safety of retatrutide in participants with type 2 diabetes in participants who have obesity or overweight (J1I-MC-GZBK master protocol) including a subset of participants who have obstructive sleep apnea (OSA) (J1I-MC-GSA2). The study will last about 89 weeks and will include up to 24 visits.
ClinicalTrials.gov · Jul 2023View trial ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (completed). The purpose of this study is to evaluate the efficacy and safety of retatrutide in participants who have obesity or overweight (J1I-MC-GZBJ master protocol) including subsets of participants who have knee osteoarthritis (OA) (J1I-MC-GOA1) or who have obstructive sleep apnea (OSA) (J1I-MC-GSA1). This study will last about 89 weeks and will include up to 24 visits. Addendum (2) is optional and available to approximately 500 participants to continue treatment with retatrutide for up to an additional 24 weeks.
ClinicalTrials.gov · Jul 2023View trial ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (active not recruiting). The main purpose of this study is to evaluate the efficacy and safety of retatrutide once weekly in participants with obesity and established cardiovascular disease (CVD). The study will last about 113 weeks.
ClinicalTrials.gov · May 2023View trial ↗ Review
This review examines the role of zonulin — a protein regulator of tight junctions in intestinal epithelial cells — in the context of the microbiota-gut-brain axis. The authors synthesize evidence from the past decade linking gut dysbiosis to increased intestinal permeability, whereby bacterial fragments and toxins enter systemic circulation, trigger local and systemic inflammation, and ultimately affect the brain. The review discusses how zonulin may also influence blood-brain barrier integrity, suggesting a dual role in both gut and neurological health. The authors survey potential pharmaceutical strategies targeting zonulin-associated pathways, including larazotide acetate and various zonulin receptor agonists and antagonists. Notably, the review also raises important methodological concerns, including inconsistent and potentially misleading nomenclature surrounding "zonulin" in the literature, as well as unresolved questions about the protein's exact molecular sequence. As a narrative review, it does not present new experimental data and is subject to selection bias. Its strength lies in synthesizing emerging findings and clearly identifying open scientific questions, making it a useful conceptual reference but not a source of direct clinical evidence.
International journal of molecular sciences · Apr 2023DOI ↗ Animal only
This study identified SLU-PP-332, a synthetic pan-agonist targeting all three estrogen receptor-related receptors (ERRα, ERRβ, and ERRγ), with the highest potency for ERRα. Researchers first characterized the compound's pharmacokinetic properties to confirm it could be used as an in vivo tool. In cultured skeletal muscle cells, SLU-PP-332 was shown to increase mitochondrial function and cellular respiration. In mouse experiments, administration of SLU-PP-332 increased type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. The study also demonstrated that the compound induced a genetic program closely resembling an acute aerobic exercise response, and that this effect was ERRα-dependent — mice lacking ERRα did not show the same enhancement in exercise endurance. The authors propose that targeting ERRα may be a viable strategy for developing exercise mimetics useful in treating metabolic disorders and age-related muscle decline. Key limitations include that all in vivo experiments were conducted in mice, no human data were generated, and the long-term safety and efficacy of SLU-PP-332 remain untested.
ACS chemical biology · Mar 2023DOI ↗ 🧪 TrialInsufficient
Registered Phase 3 interventional trial (active not recruiting). This study will look at how well semaglutide helps children and teenagers losing weight. This will be tested by comparing the effect on body weight in children and teenagers taking semaglutide in comparison to placebo, a "dummy" medicine. In addition to taking the medicine, the child's parent and the child will have talks with study staff about healthy food choices, how to be more physically active and what your child can do to try to lose weight. The child will either get semaglutide or a "dummy" medicine. Which treatment the ch
ClinicalTrials.gov · Feb 2023View trial ↗ 🧪 TrialInsufficient
Registered Phase 1/Phase 2 interventional trial (active not recruiting). This is a single site, double-blind, placebo-controlled, crossover trial to quantify the effects of combination adjunctive therapy on glycemic control, ketogenesis during insulinopenia, insulin resistance, and diabetes burden and quality of life.
ClinicalTrials.gov · Jan 2023View trial ↗ In vitro
This study investigated whether two growth hormone secretagogues (GHSs) — hexarelin and JMV2894 — could protect neural cells from oxidative stress in the context of amyotrophic lateral sclerosis (ALS). The researchers used human neuroblastoma cells (SH-SY5Y) engineered to express the SOD1-G93A mutant protein, a model relevant to familial ALS. Cells were exposed to hydrogen peroxide (H₂O₂) to simulate oxidative stress, with or without GHS co-treatment. The study found that both hexarelin and JMV2894 appeared to protect cells from H₂O₂-induced cytotoxicity by activating molecular pathways associated with the regulation of apoptosis and cell survival. The authors suggest these compounds may have antioxidant and neuroprotective properties worth exploring for ALS therapy. Key limitations include that this is a cell-based (in vitro) study only, using a cancer-derived cell line rather than primary motor neurons, and no animal or human data were generated. The authors themselves acknowledge the need for further work to clarify mechanisms and develop improved GHS candidates before any translational conclusions can be drawn.
International journal of molecular sciences · Jan 2023DOI ↗ Animal only
This animal study investigated how the central nervous system melanocortin (CNS-MC) system influences feed intake, metabolic hormones, and insulin sensitivity in sheep. Ewes were surgically fitted with intracerebroventricular (ICV) cannulas and infused with artificial cerebrospinal fluid (aCSF), the α-MSH analog melanotan-I (MTI), or agouti-related peptide (AGRP) directly into the third ventricle. The study found that ICV MTI infusion significantly reduced voluntary feed intake, while AGRP infusion modestly increased it. MTI also elevated plasma triiodothyronine and thyroxine independently of changes in food intake, suggesting a direct central effect on thyroid hormone regulation. Notably, MTI did not affect plasma glucose, insulin, or cortisol under normal feeding conditions. However, during hyperinsulinemic-euglycemic clamp experiments in energy-restricted ewes, MTI impaired insulin's ability to suppress endogenous glucose production, indicating reduced hepatic insulin sensitivity. MTI also tended to lower plasma leptin in a feeding-level-dependent manner, with no effect on adiponectin. AGRP infusion did not significantly alter any measured plasma metabolic variables. The authors concluded that the CNS-MC system plays a role in regulating metabolic efficiency and peripheral insulin action in ruminants. Limitations include small sample sizes, a single non-human species, and the invasive ICV delivery route.
Journal of animal science · Jan 2023DOI ↗ Limited · human
This prospective, open-label, randomized pilot trial (NCT04487444) evaluated the preliminary efficacy and safety of thymalfasin (synthetic Thymosin-α-1, or Tα1) compared with standard of care in 49 hospitalized COVID-19 patients presenting with both hypoxemia and lymphocytopenia. The primary clinical outcome—rate of clinical recovery—was numerically higher in treated patients receiving either low-flow or high-flow baseline oxygen support, but neither difference reached statistical significance (subdistribution hazard ratios of 1.48 and 1.28, respectively, with wide confidence intervals crossing 1.0). A notable immunological finding was that treated patients on baseline low-flow oxygen had, on average, 3.84 times more CD4+ T cells on day 5 compared with day 1, versus controls (P = .01), suggesting faster T-cell reconstitution. Nine serious adverse events occurred in the treatment group but were adjudicated as unrelated to Tα1. Key limitations include the small sample size (n=49), open-label design (no blinding), and lack of statistical power to draw definitive efficacy conclusions. The authors suggest Tα1 may have a role in managing COVID-19-related immunosuppression, but larger trials are needed to confirm these preliminary findings.
The Journal of infectious diseases · Jan 2023DOI ↗ Animal only
This preclinical study investigated the neurological mechanisms by which obesity medications suppress food intake, focusing on proglucagon (PPG)-expressing neurons in the nucleus of the solitary tract (PPG-NTS). Using single-nucleus RNA sequencing and histochemistry, researchers characterized gene expression profiles of PPG-NTS neurons in rodents, finding that serotonin 2C receptors (5-HT2CR) — the target of lorcaserin — were widely expressed in these neurons, while GLP-1 receptors and melanocortin-4 receptors were not. Lorcaserin was found to significantly activate PPG-NTS neurons. When PPG-NTS neurons were virally ablated, lorcaserin lost its ability to suppress food intake, whereas the MC4R agonist melanotan-II retained its effect, confirming the functional role of 5-HT2CR expression in these neurons. Additionally, combining lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction than either drug alone. The study concludes that PPG-NTS neurons are a necessary mechanistic link for lorcaserin's appetite-suppressing effects and suggests that combining 5-HT2CR and GLP-1R agonists may enhance therapeutic outcomes. Key limitations include that all experiments were conducted in animals, and translational relevance to humans remains to be established.
Molecular metabolism · Dec 2022DOI ↗ Animal only
This study investigated whether MK-0677 (ibutamoren), an orally active, non-peptide growth hormone secretagogue that activates the ghrelin receptor, could be detected in equine hair following oral administration to a single Thoroughbred racehorse. Researchers extracted MK-0677 and its O-dealkylated metabolite from mane and tail hair samples using an established method for prohibited substances, then analyzed them by liquid chromatography tandem mass spectrometry (LC-MS/MS). The study found that MK-0677 was detectable in all collected hair samples, with a detection window of up to 209 days in mane hair and 358 days in tail hair. A follow-up wash procedure confirmed true internal incorporation of the compound rather than mere surface contamination. Wash criteria analyses suggested that hair samples collected at later time points (≥52 days post-administration) reflected internal incorporation via the bloodstream, while the earliest sample (2 days) showed a combination of internal incorporation and external deposition via sweat and sebum. A key limitation is that the study involved only one horse, restricting generalizability. The findings are relevant to anti-doping efforts in equine sports, highlighting the long detection window MK-0677 may afford in hair matrices.
Drug testing and analysis · Dec 2022DOI ↗