Review
This review synthesizes evidence from approximately 108 priority studies—including RCTs, prospective cohorts, and mechanistic reports—identified through a systematic search of PubMed, Scopus, and Web of Science (2000–2025) to reframe heart failure with preserved ejection fraction (HFpEF) as a systemic cardio-metabolic syndrome rather than a purely cardiac condition. The authors argue that visceral adiposity, insulin resistance, chronic inflammation, and mitochondrial dysfunction collectively impair cardiac energetics and drive HFpEF pathophysiology. The review notes that conventional neurohormonal therapies (RAAS inhibitors, beta-blockers) showed neutral outcomes in heterogeneous HFpEF populations, whereas the landmark EMPEROR-Preserved and DELIVER RCTs demonstrated that SGLT-2 inhibitors reduced hospitalizations and cardiovascular events. GLP-1 receptor agonists were also reported to improve symptoms, exercise tolerance, and body weight, further supporting a metabolic-inflammation framework. The authors call for biomarker-driven patient phenotyping, advanced imaging, and adaptive trial designs to enable precision care. Limitations include the inherent heterogeneity of HFpEF populations and the reliance on synthesized rather than primary data, with mechanistic claims drawn partly from preclinical and observational sources.
Review
This narrative review synthesizes existing literature on obesity management strategies, drawing from PubMed, Scopus, ScienceDirect, and Google Scholar. It evaluates the comparative effectiveness, safety, sustainability, and real-world applicability of five broad intervention categories: lifestyle modifications, dietary approaches, behavioral therapy, pharmacotherapy, and bariatric or endoscopic procedures. Key findings reported by the authors include that lifestyle interventions, while foundational, are frequently undermined by physiological adaptations, behavioral challenges, and socioeconomic barriers. Dietary strategies tend to converge in weight-loss outcomes over time, with adherence emerging as the primary differentiator. Pharmacotherapy—particularly incretin-based agents such as GLP-1 receptor agonists and dual GIP/GLP-1 agonists—is highlighted as producing meaningful weight loss and cardiometabolic improvements, though the authors note concerns around cost, tolerability, and the need for continued use. Bariatric surgery is characterized as the most effective long-term option for severe obesity, with endoscopic procedures noted as an expanding alternative. Behavioral and psychological support is identified as a cross-cutting enabler of adherence. The authors conclude that personalized, multidisciplinary care is essential. As a narrative review, this paper does not conduct original data collection or meta-analysis, and findings are subject to selection bias inherent in non-systematic review methodology.
Journal of obesity · Jan 2026DOI ↗ Review
This review examines the evolving landscape of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapies and their role in cardiorenal protection in metabolic diseases, particularly type 2 diabetes (T2D) and obesity. The authors synthesize evidence from clinical and real-world studies demonstrating that GLP-1RAs consistently reduce HbA1c and body weight, and that mounting data support cardiovascular and kidney benefits beyond glycaemic control in high-risk populations. The review highlights that in T2D, GLP-1RAs have been shown to improve hard cardiovascular outcomes and, more recently, kidney outcomes. In individuals with obesity without T2D, semaglutide at a higher dose was reported to reduce body weight by up to 15% and lower major adverse cardiovascular events by approximately 20%. The review also covers next-generation "multi-agonist" molecules combining GLP-1 receptor agonism with activity at GIP, glucagon, and amylin receptors, aiming for complementary or synergistic metabolic effects. Tirzepatide, a dual GLP-1/GIP receptor agonist approved for T2D and obesity, is highlighted as achieving up to 22.5% weight loss in phase 3 trials. Limitations include the inherent constraints of a narrative review: no new primary data are generated, and conclusions depend on the scope and quality of included studies.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · Jan 2026DOI ↗ Review
This narrative review, aimed at orthopaedic and sports medicine physicians, synthesizes the existing biochemical and clinical literature on six commonly marketed injectable therapeutic peptides: BPC-157, TB-4, TB-500, CJC-1295 + ipamorelin, tesamorelin, and GHK-Cu. The authors conducted a PubMed literature search and evaluated evidence across preclinical and clinical settings. Key findings attributed to the reviewed studies include: BPC-157 showed potential in tendon and muscle repair in preclinical models, with one human case series reporting pain reduction after intra-articular knee injection, though that study had significant methodological limitations and no control group. TB-4 and TB-500 demonstrated angiogenesis and tissue repair effects in animal models, but no human orthopaedic data were identified, and both are banned in sport. CJC-1295 combined with ipamorelin improved muscle tension in a murine glucocorticoid-induced muscle loss model only. Tesamorelin holds FDA approval for HIV-associated lipodystrophy but lacks orthopaedic evidence. GHK-Cu showed wound healing and anti-inflammatory properties preclinically, with no clinical musculoskeletal data. The authors conclude that indications, safety profiles, and dosing for all these peptides remain undefined for orthopaedic use, and robust human trials are needed before clinical recommendations can be made.
The American journal of sports medicine · Jan 2026DOI ↗ Limited · human
This observational study investigated circulating levels of MOTS-c — a mitochondrial-derived peptide involved in metabolic regulation — in adults with and without obesity, and examined whether levels changed after bariatric surgery. Researchers compared 22 lean controls with 32 obese participants scheduled for bariatric surgery, measuring MOTS-c concentrations alongside metabolic and inflammatory markers. A subset of 10 obese patients was followed longitudinally before and 6 months after surgery. Adipose tissue MOTS-c expression was also assessed via immunofluorescence in lean (n=6) and obese (n=14) subjects. The study found that circulating MOTS-c was significantly higher in obese versus lean individuals (273 vs. 223 pg/mL), and positively correlated with BMI and HOMA-IR. A notable biphasic relationship emerged between MOTS-c and HOMA-IR, with a sharp rise above a threshold of ~6.6 mmol/L×µU/mL. Despite significant weight and BMI reductions following bariatric surgery, MOTS-c levels did not change significantly post-operatively. Adipose tissue expression did not differ between groups. The authors suggest MOTS-c may reflect a compensatory metabolic response in obesity and insulin resistance. Key limitations include the small sample size, particularly in the longitudinal substudy, and the lack of an independent validation cohort.
Journal of clinical & translational endocrinology · Dec 2025DOI ↗ Animal only
This study developed a novel low-temperature fabrication method for soluble microneedles (MNs) loaded with thymosin β4 (Tβ4), a peptide with known wound-healing and immunomodulatory properties. Traditional MN production methods involve conditions that can denature sensitive peptides, so the researchers used chitosan and sucrose to create stable, biocompatible MNs at lower temperatures. The resulting patches demonstrated uniform morphology, a high drug-loading capacity (~248 µg/patch), and rapid dissolution within one hour. In a mouse wound model, Tβ4-loaded MNs significantly enhanced wound healing compared to controls. To investigate the underlying mechanism, the study employed RNA sequencing and differentially expressed gene (DEG) analysis, identifying downregulated immune regulators Spp1, Vsig4, and IL22rα2 as potentially relevant targets. Subsequent in vitro experiments — including qPCR, western blot, and surface plasmon resonance (SPR) — demonstrated that Tβ4 specifically binds to Vsig4 (KD = 3.56 × 10⁻⁶ M) and IL22rα2 (KD = 9.69 × 10⁻⁶ M). A key limitation is that efficacy and mechanistic data are primarily derived from mouse models and cell-based assays, with no human clinical data reported. The findings offer insights into Tβ4's immunomodulatory targets and potential avenues for drug development.
Advanced healthcare materials · Dec 2025DOI ↗ Preclinical
This study investigated whether two peptides derived from Thymosin β4 (Tβ4) — TB500 and Ac-SDKP — could reduce Alzheimer's disease (AD)-related pathology using both cell-based and animal models. In vitro, the peptides were tested in Aβ25-35-treated HT22 neuronal cells and primary cortical neurons, where they were found to reduce neurite atrophy, restore cell viability, and modulate apoptosis-related gene expression. In BV2 microglia, the peptides suppressed LPS-induced nitric oxide production, reduced pro-inflammatory cytokines, and inhibited M1 microglial polarization. In the 5×FAD transgenic mouse model of AD, treated animals showed improved performance on the Morris water maze and novel object recognition tests compared to untreated counterparts. Immunohistochemical analyses indicated reduced glial activation and neuronal apoptosis in treated mice, along with restored axonal density in the perirhinal cortex. However, hippocampal amyloid-β plaque burden was not significantly changed. Transcriptomic profiling highlighted genes such as Foxb2 and Or2k2 as potentially relevant to the observed neuroprotective effects. Key limitations include the exclusive use of preclinical models (no human data), reliance on a single transgenic mouse strain, and the need for further mechanistic validation. No human trials were conducted.
International immunopharmacology · Dec 2025DOI ↗ Review
This review examines the potential neuroprotective role of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) — a drug class established for managing type 2 diabetes and obesity — in the context of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The authors propose that neurodegeneration is driven by a self-reinforcing cycle of chronic neuroinflammation and central metabolic dysfunction, worsened by impaired insulin/IGF-1 signalling, mitochondrial dysfunction, and pro-inflammatory microglial activation triggered by misfolded protein aggregates. The review synthesizes preclinical and clinical trial data to argue that GLP-1RAs may disrupt this cycle via a dual mechanism: reducing central insulin resistance and directly suppressing neuroinflammatory cascades by modulating glial responses, inhibiting pro-inflammatory cytokines, and reducing oxidative stress in the CNS. The authors conclude that GLP-1RAs represent a promising, translatable therapeutic strategy for neurodegeneration and call for large-scale human trials. Limitations include the review's reliance on synthesizing heterogeneous preclinical and early clinical data, without original data collection, and the mechanistic conclusions remain to be validated in robust, adequately powered human studies.
Diabetes, obesity & metabolism · Dec 2025DOI ↗ Review
This review examines sexual dysfunction as a sequela of breast and gynecologic cancer treatment, with a focus on genitourinary syndrome of menopause (GSM). The authors conducted a comprehensive literature search across PubMed, Google Scholar, and Scopus, covering peer-reviewed studies from the past 30 years. Findings were synthesized thematically, grouping studies by cancer type, treatment modality, and impact on sexual function. The review found that common symptoms—including vaginal dryness, dyspareunia, and diminished sexual desire—are frequently underrecognized. Nonhormonal management strategies identified included minimizing irritants, vaginal moisturizers, lubricants, dilators, and pelvic floor therapy. Local hormonal therapies were noted as potentially appropriate for select patients depending on cancer hormone-sensitivity status. For low sexual desire, pharmacological agents such as bremelanotide and flibanserin were reported to have demonstrated efficacy in the literature reviewed. The authors advise against vaginal laser treatments and compounded hormones in these populations due to safety concerns. A multidisciplinary approach involving gynecologic, psychological, and oncologic expertise was emphasized. Limitations include the absence of a formal quality assessment tool and reliance on narrative thematic synthesis rather than meta-analytic methods.
Journal of minimally invasive gynecology · Dec 2025DOI ↗ In vitro
This review/research paper examines two naturally occurring peptides — carnosine (β-alanyl-L-histidine) and GHK (glycyl-L-histidyl-L-lysine) — and explores strategies to improve their stability and bioavailability through glycoconjugation. A key challenge addressed is the rapid degradation of carnosine by the enzyme carnosinase and the inherent low stability of GHK. The authors report that conjugating these peptides to either trehalose (a disaccharide) or hyaluronan (a polysaccharide) inhibits carnosinase activity and increases tripeptide stability, while also protecting the saccharide components from degradation. The study further investigates copper-binding properties of these glycoconjugates, finding that the saccharide components potentiate the Cu,Zn-superoxide dismutase-like (antioxidant) activity of the resulting copper(II) complexes. The glycoconjugates are reported to act as copper ionophores in cell culture, increasing intracellular copper levels and stimulating copper-driven signaling pathways, leading to enhanced expression of trophic and angiogenic proteins including BDNF, BMP-2, and VEGF. Copper chaperones CCS and Atox-1 are implicated as transcription factors in these pathways. Limitations include reliance on in vitro cell culture models and biochemical assays, with no human clinical data presented.
Antioxidants (Basel, Switzerland) · Dec 2025DOI ↗ Moderate · human
This Phase 3 randomized controlled trial evaluated mazdutide, a dual glucagon receptor (GCGR) and GLP-1 receptor (GLP-1R) agonist, as monotherapy versus placebo in 320 Chinese adults with type 2 diabetes (T2D) inadequately controlled by diet and exercise. Participants had a mean HbA1c of 8.24% and BMI of 28.2 kg/m². They were randomized 1:1:1 to weekly subcutaneous injections of mazdutide (4 mg or 6 mg) or placebo for 24 weeks, followed by a 24-week mazdutide extension phase. At week 24, the study found that both mazdutide doses significantly reduced HbA1c versus placebo (−1.57% and −2.15% for 4 mg and 6 mg, respectively, vs. −0.14% for placebo). Both doses also produced significantly greater body weight reductions and improved rates of composite endpoints (HbA1c <7.0% with ≥5% weight loss) compared to placebo. The most common adverse events—diarrhea, decreased appetite, and nausea—were consistent with the GLP-1R agonist class. Limitations include the single-ethnicity population (Chinese adults), the relatively short 24-week primary endpoint period, and the lack of an active comparator arm, which limits generalizability and comparative effectiveness conclusions.
Moderate · human
This Phase III randomized controlled trial evaluated mazdutide, a novel once-weekly dual glucagon and GLP-1 receptor agonist, compared to dulaglutide in 731 Chinese adults with type 2 diabetes (T2D) on background oral anti-diabetic therapy. Participants were randomized 1:1:1 to one of two mazdutide doses or dulaglutide (1.5 mg) for 28 weeks. The study found that both mazdutide doses demonstrated non-inferiority and superiority to dulaglutide in reducing HbA1c from baseline, with least-squares mean treatment differences of -0.24% and -0.30% for the lower and higher doses, respectively. Mazdutide also produced significantly greater reductions in body weight than dulaglutide, with differences of -3.78% and -5.76% for the two doses. The safety profile was generally acceptable, though gastrointestinal adverse events occurred more frequently with mazdutide than dulaglutide. Limitations include the relatively short 28-week duration, restriction to a Chinese population, and the lack of a placebo arm, which may limit generalizability of findings.
In vitro
This study describes the development of a high-yield Chinese hamster ovary (CHO) cell manufacturing platform for a biosimilar of dulaglutide, a GLP-1/IgG4-Fc fusion protein approved for type 2 diabetes. Researchers used apoptosis-resistant CHO 4BGD cells and sequentially transfected two expression plasmids encoding dulaglutide, employing a two-step transgene amplification strategy using methotrexate (MTX) followed by methionine sulfoximine (MSX) selection. The dual-selection approach resulted in approximately 30% higher titers in polyclonal populations compared to MTX amplification alone. Through a clonal cell line selection pipeline, the top clone (4BGD/Dul #73) achieved a product titer of 1.05 g/L in a 3-week fed-batch process, with a specific productivity of up to 22 pg·cell⁻¹·day⁻¹ and stable expression over 69 days without selective pressure. Purity assessed by size-exclusion HPLC showed ≥95% monomer content. Biological activity testing in a GLP-1 receptor/CRE-luciferase reporter assay yielded an EC₅₀ of 52 pM for the biosimilar candidate versus 76 pM for the reference drug. Limitations include the absence of in vivo or clinical data, with all findings limited to cell culture and in vitro bioassay systems.
Pharmaceuticals (Basel, Switzerland) · Dec 2025DOI ↗ ReviewPreprint
This review paper examines the pharmacological mechanisms, safety profiles, and regulatory status of both approved and unapproved peptide therapies relevant to sports medicine, musculoskeletal injury recovery, and athletic performance enhancement. The compounds reviewed span a wide spectrum — from FDA-approved agents such as tesamorelin and sermorelin, to gray-market compounds including BPC-157, TB-500, CJC-1295, Ipamorelin, AOD-9604, FS-344, GHK-Cu, MOTS-C, and SS-31. The authors note that while many unapproved peptides show promising results in preclinical and animal models — including favorable tissue repair and metabolic effects — rigorous human safety and efficacy data remain scarce. The review highlights a growing direct-to-consumer gray market operating outside regulatory oversight and discusses how social media may amplify perceived benefits through placebo-related mechanisms. The paper also offers a clinical framework to guide patient conversations and support evidence-based decision-making. Key limitations include the inherent constraints of a narrative review design, reliance on heterogeneous preclinical data for unapproved compounds, and the absence of controlled human trials for most of the highlighted peptides.
Unknown journal · Dec 2025DOI ↗ Limited · human
This case report describes a 61-year-old woman with type 2 diabetes and morbid obesity who developed severe small bowel obstruction after more than a year of tirzepatide therapy. The patient experienced progressive constipation following initiation of tirzepatide, eventually presenting with acute diffuse abdominal pain and dry heaving. CT imaging revealed multiple dilated, fluid-filled small bowel loops with a transition point in the lower pelvis, moderate gastric distention, and free pelvic fluid. Initial conservative management with nasogastric decompression, bowel rest, intravenous fluids, and analgesia was insufficient, and the patient ultimately required laparoscopic adhesiolysis converted to exploratory laparotomy. Intraoperatively, a closed-loop obstruction caused by adhesive disease and an internal hernia was identified, necessitating resection of 25 cm of necrotic bowel. Pathology confirmed ischemic changes. Notably, tirzepatide had produced meaningful metabolic benefits, including hemoglobin A1c reduction and weight loss. The authors propose that tirzepatide's known effects on gastrointestinal motility may have worsened pre-existing constipation and contributed to the obstructive event in this predisposed patient. Key limitations include the single-patient design, the presence of confounding adhesive disease, and the inability to establish direct causation.
Limited · human
This study describes the development and validation of a urine-based liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for detecting semaglutide use in humans. Semaglutide is a GLP-1 receptor agonist originally approved for type 2 diabetes that has gained widespread use as a weight-loss aid. The authors note that semaglutide may confer a competitive advantage in weight-class sports (e.g., wrestling, boxing) by facilitating weight management, raising anti-doping concerns. The proposed method targets two unique urinary metabolites of semaglutide—designated U6 and U7—as biomarkers of exposure. Using only 2 mL of urine, the method achieved a reported limit of detection (LOD) of 50 pg/mL. The authors positioned this approach as a simpler alternative to existing blood-based testing regimens, given urine's relative ease of collection. Limitations include the absence of reported clinical validation data (e.g., pharmacokinetic profiling in dosed volunteers), no information on inter-individual variability, and no discussion of detection windows post-dose. The study is primarily an analytical methods paper rather than a clinical or pharmacological investigation.
Analytical and bioanalytical chemistry · Dec 2025DOI ↗ Animal only
This study introduced a Golgi-targeted copper delivery system (LNP-ATOX1/GHK-Cu@PCL-GelMA) designed to enhance the activity of copper-dependent proteins—particularly lysyl oxidase (LOX)—to promote fascia regeneration. The system combined GHK-Cu (a copper-peptide complex) as a sustained-release copper source with lipid nanoparticles (LNPs) delivering mRNA encoding ATOX1, a copper chaperone that shuttles copper into the Golgi apparatus via ATP7A/B transporters. In vitro experiments showed the system significantly increased Golgi copper accumulation, raised LOX activity to approximately 1.78 times that of controls, and enhanced angiogenic capacity. The researchers also reported that ATOX1 upregulation promoted copper-dependent translocation of ATP7A and Rac1 to the plasma membrane, potentially supporting neovascularization. In a rabbit fascia defect animal model, the strategy improved collagen alignment, neovascularization, and extracellular matrix reconstruction. Limitations include the absence of human or large-animal data, reliance on a single animal model, and the translational gap between rabbit fascia repair and human clinical outcomes. No human trials were conducted.
Journal of controlled release : official journal of the Controlled Release Society · Dec 2025DOI ↗ Animal only
This study investigated the central effects of Liver-Expressed Antimicrobial Peptide 2 (LEAP-2) on food intake in broiler chickens, and explored its potential interactions with the ghrelin and cannabinoid systems. Four separate experiments were conducted, each with four groups of neonatal broiler chickens receiving intracerebroventricular (ICV) injections. Experiment 1 tested LEAP-2 alone at three doses; Experiments 2–4 tested LEAP-2 in combination with a ghrelin receptor antagonist (D-Lys-3)-GHRP-6, a CB1 receptor antagonist (SR141716A), and a CB2 receptor antagonist (AM630), respectively. Food consumption was measured at 30, 60, and 120 minutes post-injection. The study reported that ICV LEAP-2 at the two higher doses significantly reduced cumulative food intake compared to saline controls. The interaction experiments suggested that LEAP-2's appetite-suppressing effects may involve both CB1 and CB2 cannabinoid receptors as well as the ghrelin receptor system. Key limitations include the exclusive use of an avian (broiler chicken) model, small experimental group sizes, a single-species focus, and the lack of direct mechanistic or molecular data. Findings cannot be directly extrapolated to humans or mammals without further research.
Poultry science · Dec 2025DOI ↗ In vitroPreprint
This paper proposes a molecular mechanism for BPC-157, a synthetic 15-amino-acid peptide previously studied in preclinical models for regenerative and cytoprotective effects. The authors hypothesize — based on computational structural modeling and in silico docking — that BPC-157 adopts a polyproline II (PPII) helix conformation and engages the SH3 domains of Src family kinases (c-Src, Yes, Fyn). The proposed interaction is suggested to relieve autoinhibition of these kinases, potentially activating downstream FAK-ERK and PI3K-Akt signaling pathways. To build a tool for future experimental testing, the authors engineered an mCherry-BPC157₂ fusion protein, encoded it in a baculovirus vector, and expressed it in insect (Sf9) cells. Expression was confirmed by fluorescence imaging and western blot at the expected ~31 kDa size. Importantly, this study does not include human subjects, animal experiments, or in vitro binding assays — the core mechanistic claims rest entirely on computational modeling. The fusion protein work is a proof-of-concept for a future experimental reagent. Findings should be interpreted as hypothesis-generating only.
Unknown journal · Dec 2025DOI ↗ Limited · human
This case report describes a 65-year-old woman who developed pyoderma gangrenosum (PG) — a rare, rapidly progressing neutrophilic skin ulceration — at abdominal injection sites following use of the synthetic peptide melanotan. Four ulcerated wounds with erythematous borders were observed, clinically correlating with the injection sites. A diagnosis of PG was established based on wound appearance and progression, failure to respond to multiple antibiotic courses, and negative bacteriology (including negative Panton-Valentine leukocidin Staphylococcus aureus testing). The patient was treated with topical betamethasone, steroid occlusion tape, and oral prednisolone, with the prednisolone subsequently tapered and topical Dermovate initiated. The wounds healed over several months, leaving characteristic cribriform scarring. The authors acknowledge that while drug-induced PG has rarely been documented, this appears to be the first reported case of melanotan-induced PG in the literature. Key limitations include the inherent constraints of a single case report: no causal mechanism is established, there is no control or comparator, and generalizability is very limited. The report serves primarily to raise clinical awareness of a potentially serious and previously unreported adverse effect of melanotan use.