BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy

Molecular Metabolism, Год журнала: 2022, Номер 66, С. 101633 - 101633

Опубликована: Ноя. 7, 2022

Obesity and its associated comorbidities represent a global health challenge with need for well-tolerated, effective, mechanistically diverse pharmaceutical interventions. Oxyntomodulin is gut peptide that activates the glucagon receptor (GCGR) glucagon-like peptide-1 (GLP-1R) reduces bodyweight by increasing energy expenditure reducing intake in humans. Here we describe pharmacological profile of novel (GCGR)/GLP-1 dual agonist BI 456906.BI 456906 was characterized using cell-based vitro assays to determine functional agonism. In vivo studies were performed acute subchronic dosing regimens demonstrate target engagement GCGR GLP-1R, weight lowering efficacy.BI potent, acylated containing C18 fatty acid as half-life extending principle support once-weekly Pharmacological doses provided greater reductions mice compared maximally effective GLP-1R semaglutide. 456906's superior efficacy consequence increased reduced food intake. Engagement both receptors demonstrated via glucose tolerance, intake, gastric emptying tests liver nicotinamide N-methyltransferase mRNA expression circulating biomarkers (amino acids, fibroblast growth factor-21) GCGR. The activity at supported knockout transgenic reporter mice, an ex bioactivity assay.BI potent GCGR/GLP-1R robust anti-obesity achieved decreasing

Язык: Английский

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Microalgae—Sustainable Source for Alternative Proteins and Functional Ingredients Promoting Gut and Liver Health

Global Challenges, Год журнала: 2023, Номер 7(5)

Опубликована: Апрель 25, 2023

Dietary proteins derived from animal sources, although containing well-balanced profiles of essential amino acids, have considerable environmental and adverse health effects associated with the intake some protein-based products. Consuming foods based on carries a higher risk developing non-communicable diseases such as cancer, heart disease, non-alcoholic fatty liver disease (NAFLD), inflammatory bowel (IBD). Moreover, dietary protein consumption is increasing due to population growth, posing supply challenge. There is, therefore, growing interest in discovering novel alternative sources. In this context, microalgae been recognized strategic crops that can provide sustainable source protein. Compared conventional high-protein crops, using microalgal biomass for production presents several advantages food feed terms productivity, sustainability, nutritional value. positively impact environment by not exploiting land or causing water pollution. Many studies revealed potential an added value positive human their anti-inflammatory, antioxidant, anti-cancer properties. The main emphasis review health-promoting applications microalgae-based proteins, peptides, bioactive substances IBD NAFLD.

Язык: Английский

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The Metabolic Syndrome, a Human Disease

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(4), С. 2251 - 2251

Опубликована: Фев. 13, 2024

This review focuses on the question of metabolic syndrome (MS) being a complex, but essentially monophyletic, galaxy associated diseases/disorders, or just related rather independent pathologies. The human nature MS (its exceptionality in Nature and its close interdependence with action evolution) is presented discussed. text also describes components, special emphasis description their interrelations (including syndromic development recruitment), as well consequences upon energy handling partition. main theories MS’s origin are relation to hepatic steatosis, type 2 diabetes, obesity, encompass most components described so far. differential effects sex biological considered under light social needs evolution, which directly epidemiology, severity, relations senescence. triggering maintenance factors discussed, especial inflammation, complex process affecting different levels organization critical element for development. Inflammation operation connective tissue adipose organ) widely studied acknowledged influence diet. role diet composition, including transcendence anaplerotic Krebs cycle from dietary amino acid supply (and timing), developed context testosterone β-estradiol control insulin-glycaemia core system carbohydrate-triacylglycerol handling. high probability acting unique (essentially monophyletic) presented, together additional perspectives/considerations treatment this ‘very’ disease.

Язык: Английский

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Amino Acid Profiles and Nutritional Evaluation of Fresh Sweet–Waxy Corn from Three Different Regions of China

Nutrients, Год журнала: 2022, Номер 14(19), С. 3887 - 3887

Опубликована: Сен. 20, 2022

This study conducted a comparative analysis of the amino acid compositions Chinese Huangnuo 9 fresh sweet–waxy corn from three different provinces in China—Inner Mongolia, Jilin, and Heilongjiang Province. Moreover, we established nutritive evaluation system based on profiles to evaluate, compare, rank planted regions. A total 17 acids were quantified, composition was analyzed evaluated. The quality determined by pattern spectrum, chemical evaluations (including CS, AAS, EAAI, BV, U(a,u), NI, F, predict PER, PDCAAS), flavor evaluation, matching degree results factor analysis. showed that protein content 1–1 Inner Mongolia highest (40.26 ± 0.35 mg/g), but results, digestion, absorption efficiency 1–2 best. profile closest each evaluation’s model spectrum. diversity 3–2 best, 3–3 had most essential content. divided into principal component analyses: functional components (Leu, Pro, Glu, His, Ile, Ser, Met, Val, Tyr, Thr), regulatory (Lys, Gly, Ala, Asp, Arg, Trp), protection (Phe). scores comprehensive score all highest, followed 1–1. nutritional values 12 samples.

Язык: Английский

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Essential Amino Acid Metabolites as Chemical Mediators of Host-Microbe Interaction in the Gut

Annual Review of Microbiology, Год журнала: 2023, Номер 77(1), С. 479 - 497

Опубликована: Июнь 20, 2023

Amino acids are indispensable substrates for protein synthesis in all organisms and incorporated into diverse aspects of metabolic physiology signaling. However, animals lack the ability to synthesize several them must acquire these essential amino from their diet or perhaps associated microbial communities. The therefore occupy a unique position health relationships with microbes. Here we review recent work connecting production metabolism host biology, reciprocal impacts on We focus roles branched-chain (valine, leucine, isoleucine) tryptophan host-microbe communication intestine humans other vertebrates. then conclude by highlighting research questions surrounding less-understood acid animal hosts.

Язык: Английский

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Biomolecule-Grafted GO Enhanced the Mechanical and Biological Properties of 3D Printed PLA Scaffolds with TPMS porous structure

Journal of the mechanical behavior of biomedical materials/Journal of mechanical behavior of biomedical materials, Год журнала: 2024, Номер 157, С. 106646 - 106646

Опубликована: Сен. 1, 2024

Язык: Английский

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Nanomedicines Targeting Metabolic Pathways in the Tumor Microenvironment: Future Perspectives and the Role of AI

Metabolites, Год журнала: 2025, Номер 15(3), С. 201 - 201

Опубликована: Март 13, 2025

Background: Tumor cells engage in continuous self-replication by utilizing a large number of resources and capabilities, typically within an aberrant metabolic regulatory network to meet their own demands. This dysregulation leads the formation tumor microenvironment (TME) most solid tumors. Nanomedicines, due unique physicochemical properties, can achieve passive targeting certain tumors through enhanced permeability retention (EPR) effect, or active deliberate design optimization, resulting accumulation TME. The use nanomedicines target critical pathways holds significant promise. However, requires careful selection relevant drugs materials, taking into account multiple factors. traditional trial-and-error process is relatively inefficient. Artificial intelligence (AI) integrate big data evaluate delivery efficiency nanomedicines, thereby assisting nanodrugs. Methods: We have conducted detailed review key papers from databases, such as ScienceDirect, Scopus, Wiley, Web Science, PubMed, focusing on reprogramming, mechanisms action development metabolism, application AI empowering nanomedicines. integrated content present current status research metabolism potential future directions this field. Results: Nanomedicines possess excellent TME which be utilized disrupt cells, including glycolysis, lipid amino acid nucleotide metabolism. disruption selective killing disturbance Extensive has demonstrated that AI-driven methodologies revolutionized nanomedicine development, while concurrently enabling precise identification molecular regulators involved oncogenic reprogramming pathways, catalyzing transformative innovations targeted cancer therapeutics. Conclusions: great Additionally, will accelerate discovery metabolism-related targets, empower optimization help minimize toxicity, providing new paradigm for development.

Язык: Английский

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Unravelling cysteine-deficiency-associated rapid weight loss

Nature, Год журнала: 2025, Номер unknown

Опубликована: Май 21, 2025

Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, been explored to combat this epidemic3-6. Here we investigated impact removing individual acids on weight profiles mice. We show that conditional cysteine restriction resulted most substantial loss when compared essential amounting 30% within week, which was readily reversed. found deficiency activated integrated stress response oxidative response, amplify each other, leading induction GDF15 FGF21, partly explaining phenotype7-9. Notably, observed lower levels tissue coenzyme A (CoA), has considered be extremely stable10, resulting reduced mitochondrial functionality metabolic rewiring. This results energetically inefficient anaerobic glycolysis defective tricarboxylic cycle, sustained urinary excretion pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds acids. In summary, our investigation reveals by depleting GSH CoA, exerts a maximal loss, metabolism signalling other restrictions. These findings suggest strategies for addressing range diseases growing obesity crisis.

Язык: Английский

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Effect of fishmeal replacement with dried red wigglers (Eisenia fetida) worm meal on growth and feed utilization, production efficiency, and serum biochemistry in Nile tilapia (Oreochromis niloticus) fingerlings

Aquaculture Reports, Год журнала: 2023, Номер 29, С. 101518 - 101518

Опубликована: Март 1, 2023

This study investigated the effect of replacing fishmeal with red wigglers (Eisenia fetida) worm meal (RWWM) in diet Nile tilapia (Oreochromis niloticus) fingerlings. Red worms (RWW) were culture on a vegetable by-product medium, harvested and dried to obtain meal. The fish (average weight ± SE: 7.70 0.06 g) fed seven diets (30% crude protein 7.5% lipid), which was replaced 0%, 5%, 10%, 15%, 20%, 25%, 30% RWWM. reared 1000 L fiberglass tanks recirculating aquaculture system hand-fed twice daily for 90 days. At end experiment, growth, feed conversion ratio, energy utilization improved when feeding 15% 20% RWWM compared control (P < 0.05). Using broken line regression between growth efficiency utilization, showed optimum level FM fingerlings around 21 – 22% diet. whole-body ash content elevated 10–25% RWWM, while lipid contents 5–25% group essential non-essential amino acids profiles by plasma glucose decreased 15–20% significantly enhanced 25–30% total protein, albumin globulin increased Therefore, this demonstrates that could replace without negatively affecting physiological performance.

Язык: Английский

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Phytochemical and medicinal profiling of Russula vinosa Lindbl (RVL) using multiomics techniques

LWT, Год журнала: 2024, Номер 192, С. 115723 - 115723

Опубликована: Янв. 1, 2024

Russula vinosa Lindbl (RVL) is a multifunctional edible fungus that has recently gained widespread attention due to its numerous nutritious, delicious, and medicinal properties. However, little been directed toward analyzing comprehensive phytochemical profiling bioactivity in RVL. This study aimed evaluate the of RVL systematically. Herein, we characterized global using LC/GC-MS-based multiomics strategy through initial methodological optimization. A total 633 metabolites were identified untargeted multiomics, with fatty acids, amino polyphenols, terpenoids, organic sugars, phospholipids as primary metabolites. Polyphenols served main active components by quantitative analysis antioxidant evaluation, impling they may be related antitumor effects. Moreover, based on profiling, potential gene targets mechanisms anticancer properties explored network pharmacology. The significance this lies expanding our understanding bioactive providing references for further utilization exploitation. Therefore, could an excellent raw material food, nutraceutical, pharmaceutical industries richness nutrients ingredients.

Язык: Английский

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