A GLP‐1R/Y1 receptor/Y2 receptor triple agonist decreases fentanyl‐evoked dopamine release in the nucleus accumbens and attenuates fentanyl taking and seeking in rats DOI Creative Commons
Antonia Caffrey, Enzo Lavecchia,

Kylie S. Chichura

и другие.

British Journal of Pharmacology, Год журнала: 2025, Номер unknown

Опубликована: Июнь 2, 2025

Abstract Background and Purpose Emerging literature indicates that simultaneously targeting glucagon‐like peptide‐1 receptors (GLP‐1Rs) neuropeptide Y (Y 1 /Y 2 ) may represent a new pharmacotherapeutic approach to treating opioid use disorder (OUD). The overall goal of this study was screen the efficacy GEP12, novel GLP‐1R/Y receptor/Y receptor triple agonist, reduce voluntary fentanyl taking seeking. Experimental Approach Rats were allowed self‐administer (2.5 μg kg −1 , i.v.) for 21 days. then pretreated with vehicle or GEP12 (1.57 12.53 i.p.) prior self‐administration test sessions. Opioid extinguished rats subsequent reinstatement Key Results reduced in both male female shifted dose–response curve downward. Importantly, we identified behaviourally selective doses well‐tolerated fentanyl‐experienced rats. also seeking during abstinence at did not alter food intake produce adverse malaise‐like effects. To identify central mechanism underlying agonists, showed systemic penetrated brain distributed mesolimbic reward system. Using vivo fibre photometry, discovered self‐administration‐evoked dopamine release nucleus accumbens. Conclusions Implications Together, these findings support continued development agonists as class pharmacotherapies OUD.

Язык: Английский

Emerging Pharmacotherapies for Obesity: A Systematic Review DOI Creative Commons
Michail Kokkorakis, Marlene Chakhtoura, Caline Rhayem

и другие.

Pharmacological Reviews, Год журнала: 2024, Номер 77(1), С. 100002 - 100002

Опубликована: Сен. 20, 2024

The history of anti-obesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the conviction that excess body signifies a lack willpower. However, categories emerging generate hope to reduce obesity rates. This systematic review phase 2 3 trials in adults overweight/obesity investigates effect novel pharmacotherapies, compared placebo/control or Food Drug Administration-approved medication, through searching Medline, Embase, ClinicalTrials.gov (2012-2024). We identified 53 trials, 36 drugs combinations thereof four withdrawn terminated trials. Oral semaglutide 50 mg only medication has completed trial. There are 14 ongoing on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide, survodutide), GLP-1/glucose-dependent insulinotropic polypeptide glucagon RA (retatrutide), dapagliflozin, combination sibutramine/topiramate. Completed incretin-based therapies showed mean percent 7.4-24.2%. Almost half undergoing were incretin analogs. drug pipeline expanding rapidly, most promising results reported Data mortality obesity-related complications, such as cardio-renal-metabolic events, needed. Moreover, long-term follow-up data safety efficacy maintenance along studies focused under-represented populations, cost-effectiveness assessments, availability, needed bridge care gap for patients obesity. Significance Statement Obesity epidemic 21st century. Except newer injectable medications, suboptimal have been available clinician's armamentarium. alternatives agents populate therapeutic pipeline. identifies state mechanism action having clinical information provided herein furthers understanding management, implying direct implications stimulating research initiatives.

Язык: Английский

Процитировано

14
Overweight and obesity significantly increase colorectal cancer risk: a meta-analysis of 66 studies revealing a 25–57% elevation in risk DOI Creative Commons
Zoltán Ungvári, Mónika Fekete, Péter Varga

и другие.

GeroScience, Год журнала: 2024, Номер unknown

Опубликована: Окт. 8, 2024

Abstract The incidence of colorectal cancer (CRC) has been steadily rising, and obesity identified as a significant risk factor. Numerous studies suggest strong correlation between excess body weight increased CRC, but comprehensive quantification through pooled analysis remains limited. This study aims to systematically review meta-analyze the existing literature evaluate association CRC risk, considering variations across sex designs. A systematic search was conducted in PubMed, Cochrane Central Register Controlled Trials (CENTRAL), Web Science identify randomized controlled trials human clinical from 1992 2024. Statistical performed using https://metaanalysisonline.com web application random effects model estimate hazard rates (HR). Forest plots, funnel Z-score plots were utilized visualize results. We 52 14 case–control studies, encompassing total 83,251,050 236,877 subjects, respectively. indicated that significantly prevalence (HR = 1.36, 95% CI 1.24–1.48, p < 0.01). effect consistent sexes, with HRs 1.57 (95% 1.38–1.78, 0.01) for males 1.25 1.14–1.38, females. Case–control specifically showed an effect, marginal significance only 1.27, 0.98–1.65, 0.07). plot need additional group. heterogeneity observed all four settings. meta-analysis provides robust evidence is factor cancer, overall rate indicating 36% risk. pronounced both showing slightly higher compared Although weaker association, trend supports link CRC. These results underscore importance public health interventions aimed at reducing potentially lower cancer.

Язык: Английский

Процитировано

13
Triazination/IEDDA Cascade Modular Strategy Installing Pyridines/Pyrimidines onto Tyrosine Enables Peptide Screening and Optimization DOI
Quan Zuo,

Xinyi Song,

Jie Yan

и другие.

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Modular chemical postmodification of peptides is a promising strategy that supports the optimization and innovation hit peptide therapeutics by enabling rapid derivatization. However, current methods are primarily limited to traditional bio-orthogonal strategies ligation techniques, which require preintroduction non-natural amino acids impose fixed limit diversity. Here, we developed Tyrosine-1,2,3-Triazine Ligation (YTL) strategy, constructs novel linkages (pyridine pyrimidine) through "one-pot, two-step" process combining SNAr IEDDA reactions, promoting modular post modification Tyr-containing peptides. After optimizing YTL establishing standard procedures, successfully applied it solid-phase various biorelated peptides, such as synthesis dual-mode imaging probes long-acting GLP-1 analogs. As proof concept, library 384 amphipathic was constructed using based on 96-well microfiltration plates. modifications were then performed screened template tripeptide RYR, leading generation 20 derivatives. The antibacterial activity these derivatives systematically characterized, identifying Z8 potential candidate.

Язык: Английский

Процитировано

2
Gut hormones and bone homeostasis: potential therapeutic implications DOI
Béatrice Bouvard, Guillaume Mabilleau

Nature Reviews Endocrinology, Год журнала: 2024, Номер unknown

Опубликована: Июнь 10, 2024

Язык: Английский

Процитировано

9
Skeletal muscle loss and sarcopenia in obesity pharmacotherapy DOI
David C. D. Hope, Tricia Tan

Nature Reviews Endocrinology, Год журнала: 2024, Номер unknown

Опубликована: Сен. 18, 2024

Язык: Английский

Процитировано

7
SGLT2 inhibitors and dietary calorie restriction for type 2 diabetes remission DOI Open Access
David C. D. Hope, Jonathan Valabhji

BMJ, Год журнала: 2025, Номер unknown, С. r40 - r40

Опубликована: Янв. 22, 2025

Язык: Английский

Процитировано

1
Expanding applications of GLP-1 therapies: a careful view DOI
Domenico Azzolino, Tiziano Lucchi

International Journal of Obesity, Год журнала: 2025, Номер unknown

Опубликована: Апрель 16, 2025

Язык: Английский

Процитировано

1
Metabolic alliance: pharmacotherapy and exercise management of obesity DOI
Javier Butragueño, Jonatan R. Ruiz

Nature Reviews Endocrinology, Год журнала: 2024, Номер 20(9), С. 505 - 506

Опубликована: Июнь 5, 2024

Язык: Английский

Процитировано

6
Recent advances in incretin-based therapy for MASLD: from single to dual or triple incretin receptor agonists DOI
Giovanni Targher, Alessandro Mantovani, Christopher D. Byrne

и другие.

Gut, Год журнала: 2024, Номер unknown, С. gutjnl - 334023

Опубликована: Ноя. 26, 2024

Clinically effective pharmacological treatment(s) for metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form steatohepatitis (MASH) represent a largely unmet need in medicine. Since glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been licensed the treatment of type 2 diabetes mellitus obesity, they were one first drug classes to be examined individuals with MASLD/MASH. Successful phase randomised clinical trials these agents resulted progression 3 (principally testing long-term efficacy subcutaneous semaglutide). Over last few years, addition GLP-1RAs, newer glucose-dependent insulinotropic peptide and/or glucagon agonist functions tested, increasing evidence from histological improvements MASLD/MASH, as well benefits on MASLD-related extrahepatic complications. Based this background evidence, single, dual or triple incretin are becoming an attractive promising option MASLD MASH, particularly coexisting obesity mellitus. In narrative review, we examine rapidly expanding body supporting role incretin-based pharmacotherapies delaying reversing MASH progression. We also discuss biology incretins putative hepatoprotective mechanisms managing MASH.

Язык: Английский

Процитировано

5
A novel bifunctional peptide VAMP mined from hemp seed protein hydrolysates improves glucose homeostasis by inhibiting intestinal DPP-IV and increasing the abundance of Akkermansia muciniphila DOI
Haihong Chen, Wei Li, Weiguo Hu

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 23, 2024

Abstract Discovery of new dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from natural protein resources capable regulating glucose metabolism in type 2 diabetic populations has been a significant challenge. In this study, we constructed molecular docking- and machine learning-aided DPP-IV peptide library combined functional screening approach based on intestinal organoids to discover efficient DPP-IV-inhibiting hemp seed hydrolysates. A novel tetrapeptide, VAMP, was then identified strongly inhibit (IC 50 =1.00 μM vitro ), which competitively binds improves vivo with high safety by increasing active glucagon-like peptide-1 (GLP-1) levels obese mouse models. Interestingly, VAMP specifically promoted the growth abundance Akkermansia muciniphila , at same time, responsible for improved barrier function insulin resistance. Our study demonstrated that bifunctional can effectively target DPP-IV-GLP-1 axis simultaneously regulate gut microbial A. homeostasis, providing promising nutraceutical therapeutic tetrapeptide hyperglycaemia treatment targeting gut-microbiata axis. Teaser GLP-1 level promoting improve function.

Язык: Английский

Процитировано

3