A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 7, 2021

Abstract Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design synthesis cyclometalated iridium(III) metal complex 1a as stabilizer hypoxia-inducible factor-1α (HIF-1α). vitro biophysical cellular analyses demonstrate that compound binds to Von Hippel-Lindau (VHL) inhibits VHL–HIF-1α interaction. Furthermore, accumulates HIF-1α levels cellulo activates mediated gene expression, including VEGF , GLUT1 EPO . vivo mouse models, significantly accelerates closure both normal mice, with greater effect being observed group. We also driven genes related (i.e. HSP-90 VEGFR-1 SDF-1 SCF Tie-2 ) increased tissue -treated mice (including, db / HFD/STZ STZ models). Our study demonstrates small molecule promising therapeutic agent for healing, and, more importantly, validates feasibility treating wounds by blocking VHL

Language: Английский

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Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist

Cell Metabolism, Journal Year: 2021, Volume and Issue: 34(1), P. 59 - 74.e10

Published: Dec. 20, 2021

Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight improved glucose control rodent models. We developed SAR441255, a synthetic peptide agonist GLP-1, GCG, GIP receptors, structurally based on exendin-4 sequence. SAR441255 displays high potency with balanced activation all three target receptors. In animal models, metabolic outcomes were superior to results dual GLP-1/GCG receptor agonist. Preclinical vivo positron emission tomography imaging binding GLP-1 GCG healthy subjects, glycemic during mixed-meal tolerance test impacted biomarkers for activation. Single doses well tolerated. The demonstrate that integrating into agonism provides effects loss while buffering diabetogenic risk chronic agonism.

Language: Английский

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The Importance of Animal Models in Biomedical Research: Current Insights and Applications

Animals, Journal Year: 2023, Volume and Issue: 13(7), P. 1223 - 1223

Published: March 31, 2023

Animal research is considered a key element in advance of biomedical science. Although its use controversial and raises ethical challenges, the contribution animal models medicine essential for understanding physiopathology novel treatment alternatives several human diseases. Current pandemics’ pathology, such as 2019 Coronavirus disease, has been studied primate, rodent, porcine to recognize infection routes develop therapeutic protocols. Worldwide issues diabetes, obesity, neurological disorders, pain, rehabilitation medicine, surgical techniques require studying process different species before testing them on humans. Due their relevance, this article aims discuss importance diverse lines by analyzing contributions various utilized science over past five years about topics concerning health.

Language: Английский

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The physiological control of eating: signals, neurons, and networks

Physiological Reviews, Journal Year: 2021, Volume and Issue: 102(2), P. 689 - 813

Published: Sept. 6, 2021

During the past 30 yr, investigating physiology of eating behaviors has generated a truly vast literature. This is fueled in part by dramatic increase obesity and its comorbidities that coincided with an ever increasing sophistication genetically based manipulations. These techniques have produced results remarkable degree cell specificity, particularly at signaling level, played lead role advancing field. However, putting these findings into brain-wide context connects physiological signals neurons to behavior somatic requires thorough consideration neuronal connections: field also seen extraordinary technological revolution. Our goal present comprehensive balanced assessment how associated energy homeostasis interact many brain levels control behaviors. A major theme engage sets interacting neural networks throughout are defined specific connections. We begin discussing some fundamental concepts, including ones still engender vigorous debate, provide necessary frameworks for understanding controls meal initiation termination. include key word definitions, ATP availability as pivotal regulated variable homeostasis, neuropeptide signaling, homeostatic hedonic eating, structure. Within this context, we discuss network models regions endbrain (or telencephalon), hypothalamus, hindbrain, medulla, vagus nerve, spinal cord work together gastrointestinal tract enable complex motor events permit animals eat diverse situations.

Language: Английский

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Activation of osteoblast ferroptosis via the METTL3/ASK1‐p38 signaling pathway in high glucose and high fat (HGHF)‐induced diabetic bone loss

The FASEB Journal, Journal Year: 2022, Volume and Issue: 36(3)

Published: Feb. 1, 2022

Diabetes mellitus (DM) and osteoporosis are two common diseases that may develop as a cause-and-effect relationship since the incidence of osteoporotic fractures is significantly increased in DM patients. However, pathophysiology diabetic yet to be clearly understood. Iron overload has been reported lead bone loss closely related osteoporosis. In this study, we hypothesized high glucose fat (HGHF) induce osteoblastic ferroptosis for pathogenesis explored possible molecular mechanisms behind. Using rat model established by HGHF feeding with subsequent intraperitoneal injection single low dose streptozocin, found serum ferritin level (a biomarker body iron store) was elevated HGHF-fed rats expression SLC7A11 GPX4 (inhibitory marker proteins ferroptosis) markedly attenuated tissue compared normal rats. an osteoblast cell model, treatment pre-osteoblastic MC3T3-E1 cells palmitic acid (HGPA) not only suppressed differentiation mineralization but also triggered ferroptosis-related death. m6A-seq revealed m6A methylation on ASK1 80.9-fold higher HGPA-treated cells. The p-ASK1 p-p38 Knockout METTL3 (methyltransferase-like 3), one major methyltransferases, abrogated HGPA-induced activation ASK1-p38 signaling pathway ferroptosis. Therefore, HGHF-induced osteoblasts main cause via METTL3/ASK1-p38 pathway, inhibition provide potential therapeutic strategy

Language: Английский

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Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency

Nature, Journal Year: 2022, Volume and Issue: 605(7911), P. 761 - 766

Published: May 18, 2022

Language: Английский

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Streptozotocin as a tool for induction of rat models of diabetes: a practical guide.

PubMed, Journal Year: 2023, Volume and Issue: 22, P. 274 - 294

Published: Jan. 1, 2023

Streptozotocin (STZ) is the most used diabetogenic chemical for creating rat models of type 1 and 2 diabetes. Despite ~60 years using STZ in animal diabetes research, some prevailing views about preparation use are not supported by evidence. Here, we provide practical guides to induce rats. Susceptibility effect inversely related age, males more susceptible than females. Wistar Sprague-Dawley rats, commonly-used strains, sensitive STZ, but strains (e.g., Wistar-Kyoto rats) less sensitive. mostly injected intravenously or intraperitoneally, its intravenous injection produces stable hyperglycemia. view, no fasting necessary before injection, anomer-equilibrated solutions (i.e., hours dissolving) recommended. Mortality following doses due severe hypoglycemia (during first 24 h) hyperglycemia (24 h after onwards). Some measures prevent hypoglycemia-related mortality rats include providing access food soon administration glucose/sucrose during 24-48 fed animals, STZ. Hyperglycemia-related high can be overcome with insulin administration. In conclusion, a valuable inducing should considered perform well-conducted ethical studies.

Language: Английский

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Potential Food and Nutraceutical Applications of Alginate: A Review

Marine Drugs, Journal Year: 2022, Volume and Issue: 20(9), P. 564 - 564

Published: Sept. 4, 2022

Alginate is an acidic polysaccharide mainly extracted from kelp or sargassum, which comprises 40% of the dry weight algae. It a linear polymer consisting β-D-mannuronic acid (M) and α-L-guluronic (G) with 1,4-glycosidic linkages, possessing various applications in food nutraceutical industries due to its unique physicochemical properties health benefits. Additionally, alginate able form gel matrix presence Ca2+ ions. also affect gelation, including structure experimental conditions such as pH, temperature, crosslinker concentration, residence time ionic strength. These features this have been widely used industry, gels, controlled-release systems film packaging. This review comprehensively covers analysis discussed potential industry nutraceuticals.

Language: Английский

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Bioinspired drug-delivery system emulating the natural bone healing cascade for diabetic periodontal bone regeneration

Bioactive Materials, Journal Year: 2022, Volume and Issue: 21, P. 324 - 339

Published: Sept. 14, 2022

Diabetes mellitus (DM) aggravates periodontitis, resulting in accelerated periodontal bone resorption. Disordered glucose metabolism DM causes reactive oxygen species (ROS) overproduction compromised healing, which makes diabetic regeneration a major challenge. Inspired by the natural healing cascade, mesoporous silica nanoparticle (MSN)-incorporated PDLLA (poly(dl-lactide))-PEG-PDLLA (PPP) thermosensitive hydrogel with stepwise cargo release is designed to emulate mesenchymal stem cell "recruitment-osteogenesis" cascade for regeneration. During therapy, SDF-1 quickly escapes from due diffusion early rat marrow (rBMSC) recruitment. Simultaneously, slow degradation of starts gradually expose MSNs sustained metformin, can scavenge overproduced ROS under high conditions reverse inhibited osteogenesis rBMSCs reactivating AMPK/β-catenin pathway, regulation microenvironment and facilitation osteogenesis. In vitro experiments indicate that markedly restores migration osteogenic capacities conditions. vivo results suggest it effectively recruit defect significantly promote type 2 DM. conclusion, our work provides novel therapeutic strategy bioinspired drug-delivery system emulating

Language: Английский

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Janus liposozyme for the modulation of redox and immune homeostasis in infected diabetic wounds

Nature Nanotechnology, Journal Year: 2024, Volume and Issue: 19(8), P. 1178 - 1189

Published: May 13, 2024

Language: Английский

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