Peptide Research Database

NAD+ depletion by catalytic TIR domains triggers a distinct form of regulated necrosis in mammalian cells.

This study found together, these findings implicate NAD+ depletion and the induction of host cell death as the main mechanism by which catalytic TIR domains suppress innate immunity.

Espinas NA, Lacante L, Hartenian E, Mack V, Niou ZX, Lu HC, Broz P

Proteins containing Toll/interleukin-1 receptor (TIR) domains with catalytic NADase activity have recently emerged as major regulators of innate immunity in both bacteria and plants. In humans, however, only a single protein-SARM1-exhibits TIR-dependent NADase activity. Initially reported to act as a negative regulator of Toll-like receptor (TLR) signaling, SARM1-mediated NAD+ hydrolysis is now recognized as the central driver of Wallerian degeneration, a regulated form of axonal cell death that occurs following injury. Here, we demonstrate that suppression of TLR signaling by SARM1 requires its NADase activity and correlates with the induction of host cell death. Furthermore, we show that immune suppression by the Staphylococcus aureus effector TirS similarly relies on its ability to hydrolyze NAD+ and induce host cell death. Further analysis of TIR-induced cell death shows that it constitutes a form of regulated necrosis that is independent of known programmed cell death pathways. Comparative analysis of a panel of animal, bacterial, and plant TIR domains reveals that, in mammalian cells, TIR-induced cell death primarily results from the depletion of cellular NAD+ levels, and not from the accumulation of specific NAD+ hydrolysis products. Together, these findings implicate NAD+ depletion and the induction of host cell death as the main mechanism by which catalytic TIR domains suppress innate immunity.

LL-37-based oral antimicrobial therapeutics: translational challenges and future directions-a narrative review.

In an animal study, LL-37 may have strong applications in oral diagnosis, prevention, and treatment of oral diseases, if the safety, efficacy, and delivery methods are effectively enhanced.

J M, Veeraraghavan VP, Govindarajan S

LL-37 is an antimicrobial peptide involved in antimicrobial defence, inflammatory regulation, tissue repair, and bone regeneration in the oral cavity. Salivary and gingival crevicular fluid LL-37 levels are associated with disease activity and treatment responses. Although there is solid mechanistic and preclinical data on LL-37, research on clinical applications of this remarkable peptide seem to be stalled due to a multitude of factors. The use of LL-37 in clinical practice is affected by proteolytic degradation, cytotoxicity at higher concentrations, microbial tolerance, biofilm protection, rapid salivary clearance, and high production costs. Our review provides a comprehensive update emphasizing the key gaps in LL-37 research and the translational challenges faced by researchers. We also suggest a three-pronged roadmap to future approaches comprising (i) rational peptide engineering and smart nanocarrier-based delivery, (ii) host-directed induction of endogenous LL-37 via vitamin D and short-chain fatty acid pathways, and (iii) standardisation of salivary/gingival crevicular fluid LL-37 as a non-invasive biomarker, aimed at developing LL-37 as a viable diagnostic and therapeutic agent in periodontal disease, dental caries, endodontic infections, oral mucosal disorders, and oral squamous cell carcinoma. Peptide derivatives, nanocarrier-based delivery systems, combination therapy, and vitamin D-mediated induction are being studied to improve its stability and therapeutic activity. LL-37 may have strong applications in oral diagnosis, prevention, and treatment of oral diseases, if the safety, efficacy, and delivery methods are effectively enhanced.

Glucagon-like receptor-1 agonists and impotence: A meta-analysis.

In a combined analysis of multiple studies, GLP-1 agonists notably improved ED, TT, SHBG, and FSH in males, no effects were observed on FT, and LH; larger randomized trials are needed.

Mirghani HO, AlQurashi AM

Glucagon-like peptide receptors-1 agonists (GLP-1 agonists) have revolutionized the treatment of obesity and diabetes due to their potent effects on weight and glycemic control, and cardiorenal protection. However, emerging reports and post-marketing surveillance have raised concerns regarding erectile dysfunction (ED) or impotence in a subset of male patients. To assess the association between GLP-1 agonists, ED, total (TT) and free testosterone (FT), sex hormone binding globulins (SHBG), luteinizing hormone (LH), and follicular stimulating hormone (FSH). We systematically searched PubMed, Google Scholar, and Web of Science in November and December 2026 for articles examining the association between GLP-1 agonists and ED, with no publication date restriction. However, only articles published in the English language were eligible. The terms used were GLP-1 agonists, ED, semaglutide, liraglutide, ozympic, tirzepatide, dulaglutide, and Impotence. One hundred seventy-two articles were found; after removing duplicates, 63 remained, of which 12 full texts were screened, and 7 studies were included in the final meta-analysis. Seven studies involving 237 males were included. GLP-1 agonist therapy improved ED score with a significant statistical difference, MD = 2.73, 95% confidence interval (CI): 1.64-3.83. A significant increase was found regarding TT, SHBG, and FSH, MD 73.04, 95%CI: 16.91-129.17, MD 7.00, 95%CI: 1.71-12.30, and MD 0.46, 95%CI: 0.01-0.91 respectively. No significant differences were evident regarding the FT, and LH. GLP-1 agonists significantly improved ED, TT, SHBG, and FSH in males, no effects were observed on FT, and LH; larger randomized trials are needed.

Pancreatic-liver crosstalk, novel molecular mediators, and 2025 therapeutic breakthroughs.

In a research review, this review synthesizes new interorgan signaling mechanisms and 2025 therapeutic breakthroughs, emphasizing the pancreas-liver axis as a critical target for obesity management.

Pan HY, Chen WW, Liang JX, Sheng YY, Zhang WJ, Zhu XW, Wang SY, Yang GH, Liu Y, Xu TC

Obesity, a global public health crisis driven by dysregulated systemic energy homeostasis, is increasingly recognized as a disorder of interorgan communication, with the pancreas and liver serving as central interconnected metabolic hubs. Their bidirectional crosstalk, mediated through neural and humoral pathways, is a key driver of disease progression. Recent breakthroughs have uncovered novel molecular mechanisms amplifying this pathogenic axis: Adipocyte-derived exosomes carrying miR-138-5p directly target pancreatic β-cell SOX4, suppressing insulin secretion and promoting apoptosis, while hepatic RNA demethylase ALKBH5 stabilizes glucagon receptor mRNA and activates lipogenic pathways, exacerbating hyperglycemia and steatosis. Further, colonic inflammation activates hepatic ERK signaling, which is converted into neural signals by the liver and precisely delivered to the pancreas through the liver-pancreas vagus nerve circuit, driving adaptive β-cell proliferation in early obesity by releasing neurotransmitters such as acetylcholine. Traditional pathogenic loops persist: Pancreatic exocrine insufficiency disrupts gut-liver homeostasis, inducing systemic inflammation, and hepatic free fatty acid flux exerts direct and immune-mediated lipotoxicity on pancreatic β-cells, forming a self-perpetuating vicious cycle. Emerging interventions target this axis: GLP-1/GIP dual agonists (e.g., tirzepatide) demonstrate remarkable efficacy in weight loss and non-alcoholic steatohepatitis remission, while time-restricted feeding (e.g., 16:8 regimen) reduces liver fat through circadian and metabolic pathway activation, independent of caloric restriction. This review synthesizes novel interorgan signaling mechanisms and 2025 therapeutic breakthroughs, emphasizing the pancreas-liver axis as a critical target for obesity management.

Reprogramming NAD+ homeostasis and FOXO3a-Nrf2 signaling mitigates bleomycin-driven pulmonary fibrosis.

In a rat study, these findings indicate that NA-driven NAD+ metabolic support can amplify the protective profile of SEMA in experimental lung tissue scarring. Here, we evaluated an adjunctive strategy in which nicotinic acid (NA), a NAD+-supporting supplement/adjuvant, was added to semaglutide (SEMA), a GLP-1 receptor agonist.

Mo'men M, Saber S, Amer AE, El-Kashef HA

Pulmonary fibrosis arises from intertwined oxidative, inflammatory, and profibrotic processes, whereas current therapies target only parts of this network. Here, we evaluated an adjunctive strategy in which nicotinic acid (NA), a NAD+-supporting supplement/adjuvant, was added to semaglutide (SEMA), a GLP-1 receptor agonist. The prespecified objective was to determine whether adding NA to SEMA provides greater protection than SEMA alone in bleomycin (BLM)-induced pulmonary fibrosis. Rats were challenged with BLM and treated with SEMA, NA, or SEMA+NA for 21 days. Biochemical, molecular, histological, and western blot endpoints were assessed, and the fixed-dose Highest Single Agent (HSA) and Bliss independence models were used as exploratory interaction metrics. BLM induced oxidative stress, inflammatory cytokine elevation, NAD+ and SIRT1 depletion, FOXO3a suppression, TGF-β/SMAD activation, and collagen deposition. Compared with SEMA alone, SEMA+NA produced broader protection, restoring NAD+/SIRT1-FOXO3a-Nrf2 pathway-associated readouts and suppressing NF-κB/TGF-β-linked inflammatory and fibrotic markers. Exploratory HSA and Bliss analyses suggested enhanced fixed-dose effects across several endpoints but were interpreted descriptively, not as definitive pharmacological synergy. These findings indicate that NA-driven NAD+ metabolic support can amplify the protective profile of SEMA in experimental pulmonary fibrosis. Dose-response matrices, pathway-inhibition studies, temporal profiling, and lung-function testing remain required to establish definitive synergy, mechanism, and translational relevance.

Oral semaglutide vs DPP-4 inhibitors in reducing risk of cognitive impairment in elderly patients with HFpEF and obesity: comment.

Odic P, Nardi O, Foucault-Fruchard L

Changes in Abdominal Adiposity and Associations With Metabolic Health Markers Following Tirzepatide in Japanese Participants With Obesity Disease: Results From the SURMOUNT-J Study.

In a randomized trial, strong associations between anthropometric measures and VAT support their use as surrogate markers of visceral body fat in Japanese patients with obesity disease.

Waki H, Kaneyuki E, Shingaki T, Oura T, Nagakubo T, Ishigaki Y

This analysis characterized obesity-related outcomes in SURMOUNT-J and explored relationships among weight loss, abdominal adiposity, and metabolic improvements. Japanese adults with obesity disease without diabetes were randomized (1:1:1) to tirzepatide (10 or 15 mg) or placebo plus lifestyle modification. Prespecified analyses evaluated changes from baseline to week 72 in obesity and glycemic parameters. Post hoc analyses assessed correlations among changes in weight, anthropometrics, abdominal adiposity (visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], hepatic fat fraction [HFF]), and glycemic outcomes. Among 225 participants (placebo n=75; tirzepatide 10 mg n=73; 15 mg n=77), tirzepatide significantly increased high molecular weight adiponectin (mean change: 78.9% and 88.4% vs 0.9%) and reduced leptin (-57.3% and -63.1% vs -8.4%), high-sensitivity C-reactive protein (-55.1% and -65.3% vs -17.7%), and liver-related markers, including procollagen III (-21.3% and -24.8% vs -3.8%) and cytokeratin-18 (-59.8% and -62.0% vs -32.8%) (all P<.001). Glucose, insulin, and C-peptide AUC during a 75-g oral glucose tolerance test were also significantly reduced. At week 72, weight loss correlated linearly with reductions in adiposity. Weight loss was strongly correlated with VAT reduction (r=0.722-0.837 across groups), and VAT reductions strongly correlated with waist measures (r=0.837). Weight and VAT reductions showed moderate correlations with reductions in glucose, insulin, and C-peptide AUC (r=0.378-0.656). Tirzepatide-induced reductions in body weight and VAT were associated with improvements in metabolic markers and glucose metabolism. Strong associations between anthropometric measures and VAT support their use as surrogate markers of visceral adiposity in Japanese patients with obesity disease.

Ethical considerations for semaglutide use in children.

This study found advocates highlight its potential to reduce cardiovascular risk and prevent obesity-related illness, while critics emphasise uncertainties about long-term safety, efficacy and impacts on child development.This paper examines the ethical challenges raised by prescribing semaglutide to children, focusing on access barriers, stigma and the neglect of structural determinants of obesity, and provides.

Ryan N, Wilkinson D, Savulescu J

Semaglutide, marketed as Ozempic, Wegovy and Rybelsus, has rapidly become one of the most prominent medications of recent years. Initially approved in 2021 for type 2 diabetes in adults, semaglutide is now authorised for obesity management in adults and children in several countries, including Germany, the UK, Denmark and the United Arab Emirates. Despite this broad regulatory approval, its paediatric use remains a subject of debate. Advocates highlight its potential to reduce cardiovascular risk and prevent obesity-related illness, while critics emphasise uncertainties about long-term safety, efficacy and impacts on child development.This paper examines the ethical challenges raised by prescribing semaglutide to children, focusing on access barriers, stigma and the neglect of structural determinants of obesity, and provides ethical recommendations for clinicians aimed at mitigating harm, supporting autonomy and promoting children's health.

Orforglipron: An Oral GLP-1 Receptor Agonist for Obesity Treatment.

In a research review, orforglipron is a potentially useful addition for the treatment of obesity, but it still requires additional data on efficacy in treatment of obesity-related related conditions for full comparison.

Wietholter JP, Terpening CM

To describe the properties of a newly approved oral glucagon-like peptide-1 receptor agonist for the treatment of obesity. A literature search of MEDLINE and SCOPUS was performed without date range exclusions using the search terms orforglipron and obesity. Additional articles were identified from review of clinical trial bibliographies and product monograph. Two phase 1 studies in healthy individuals and in patients with type 2 diabetes mellitus and 4 phase 2/3 clinical trials specifically evaluating orforglipron use for obesity were identified for analysis, using no date exclusion criteria. Orforglipron was evaluated in 4 phase 2/3 trials regarding its efficacy for weight loss. These trials showed a mean 7.1% to 10.6% placebo-adjusted weight reduction with orforglipron. Adverse events seen with its use were primarily gastrointestinal.Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs:Orforglipron provides an oral weight management option that is potentially more effective than liraglutide, similarly effective compared with semaglutide, and less effective than tirzepatide. As a non-injectable option that does not require strict oral administration parameters, orforglipron has advantages in certain patient populations. Orforglipron is a potentially useful addition for the treatment of obesity, but it still requires additional data on efficacy in treatment of obesity-related comorbidities for full comparison.

Unimolecular GLP-1/APJ receptor co-agonism improves metabolism and dyslipidaemia as well as normalising hepatic triglyceride and aminotransferase elevation in high-fat-fed mice.

In a mouse study, long-term administration of ELA, and especially ELA-Lys12(γGluPal), delivered pronounced metabolic improvements in HFF mice, with the clearest differences from liraglutide treatment evident in circulating lipids and hepatic biomarkers.

Sridhar A, Palmer ES, Craig SL, Tanday N, O'Harte FPM, Irwin N

The aim of this study was to determine the applicability of dual activation of glucagon-like peptide-1 (GLP-1) and apelin (APJ) receptors as a next-generation therapeutic option for obesity and diabetes. A fully characterised unimolecular dual GLP-1/APJ receptor agonist, namely exendin-linker-apelin (ELA), as well as its acylated long-acting equivalent, ELA-Lys12(γGluPal), were administered once daily to high-fat-fed (HFF) mice for 28 days, with liraglutide used as a positive control. Effects on appetite and body weight, as well as glucose, pyruvate and insulin tolerance, circulating lipids, liver transaminases and triglyceride content, indirect calorimetry measurements and pancreatic morphology were then examined. ELA, and particularly ELA-Lys12(γGluPal), reduced food intake, circulating glucose and HbA1c concentrations relative to saline-treated HFF control mice. ELA-Lys12(γGluPal) substantially reduced blood glucose concentrations during glucose and pyruvate tolerance tests. These positive effects were largely independent of alterations in circulating insulin. However, circulating triglyceride and LDL-cholesterol concentrations were lowered, accompanied by complete normalisation of hepatic triglyceride and aminotransferase levels in all GLP-1/apelin hybrid-treated HFF mice. Assessment of indirect calorimetry demonstrated restoration of metabolic flexibility in mice treated with ELA-Lys12(γGluPal), despite reductions in energy expenditure. Notably, GLP-1/apelin hybrid treatment did not affect locomotor activity, whereas liraglutide treatment was associated with marked reductions in physical activity. Histological assessment of pancreatic islets revealed that all treatment modalities induced a marked enhancement of beta cell proliferative frequency, and accompanying suppression of apoptotic rates, without major alterations in islet or beta cell areas. Chronic administration of ELA, and especially ELA-Lys12(γGluPal), delivered pronounced metabolic improvements in HFF mice, with the clearest differences from liraglutide treatment evident in circulating lipids and hepatic biomarkers.