scholarly journals Alpha-ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling

2020 ◽  
Author(s):  
Gang Shu ◽  
Yexian Yuan ◽  
Jia Sun ◽  
Canjun Zhu ◽  
Jinlong Feng ◽  
...  
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Mouse Model ◽  
Resistance Exercise ◽  
Glucose Homeostasis ◽  
Metabolic Function ◽  
Inhibitory Effects ◽  
Hepatic Gluconeogenesis ◽  
Beneficial Effects

Abstract While resistance exercise effectively improves overall health in diabetic patients, the underlying biological mechanism by which resistance exercise improves metabolic function and glucose homeostasis remain mostly unknown. Previously, we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial effects of resistance exercise on metabolic function. We found that resistance exercise-induced α-ketoglutaric acid (AKG) stimulates muscle hypertrophy and fat loss through 2-oxoglutarate receptor 1 (OXGR1)-dependent adrenal activation. Here, we provided evidence for the beneficial effects of AKG on glucose homeostasis in a diet-induced obesity (DIO) mouse model, which are independent of OXGR1. We showed that circulating AKG levels are negatively correlated with the fraction of blood glycated hemoglobin (HbA1c) in both humans and mice and significantly decreased in DIO mice. Consistently, pharmacological elevation of AKG effectively decreased body weight, blood glucose, and hepatic gluconeogenesis without changing insulin sensitivity and glucose tolerance in DIO mice. Notably, OXGR1KO blocked the inhibitory effects of AKG on body weight but failed to affect AKG’s suppression on blood glucose and hepatic gluconeogenesis, indicating distinct mechanisms for AKG’s regulation on energy balance and glucose homeostasis. In supporting this view, we showed that serpina1e, a member of protease inhibitor serpins superfamily, mediates the direct inhibitory effects of AKG on gluconeogenesis in both in vitro hepatocytes and liver slice. By using a liver-specific serpina1e deletion mouse model, we further demonstrated that liver serpina1e is required for the inhibitory effects of AKG on hepatic gluconeogenesis and hyperglycemia in DIO mice. Finally, we provided in vitro evidence to support a model in which AKG decreases hepatic gluconeogenesis by targeting trimethylation of lysine 27 on histone 3 (H3K27me3) in seprina1e promoter region. Our studies established an important role of AKG in glucose homeostasis, and identified the AKG-serpina1e pathway as potential therapeutic targets to attenuate hyperglycemia.

scholarly journals Sodium Meta-Arsenite Ameliorates Hyperglycemia in Obese Diabeticdb/dbMice by Inhibition of Hepatic Gluconeogenesis

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Young-Sun Lee ◽  
Eun-Kyu Lee ◽  
Hyun-Hee Oh ◽  
Cheol Soo Choi ◽  
Sujong Kim ◽  
...  
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Glucose Production ◽  
Diabetic Mouse ◽  
Hepatic Gluconeogenesis ◽  
Glucose Levels ◽  
Blood Glucose Levels

Sodium meta-arsenite (SA) is implicated in the regulation of hepatic gluconeogenesis-related genesin vitro; however, the effectsin vivohave not been studied. We investigated whether SA has antidiabetic effects in a type 2 diabetic mouse model. Diabeticdb/dbmice were orally intubated with SA (10 mg kg−1body weight/day) for 8 weeks. We examined hemoglobin A1c (HbA1c), blood glucose levels, food intake, and body weight. We performed glucose, insulin, and pyruvate tolerance tests and analyzed glucose production and the expression of gluconeogenesis-related genes in hepatocytes. We analyzed energy metabolism using a comprehensive animal metabolic monitoring system. SA-treated diabeticdb/dbmice had reduced concentrations of HbA1c and blood glucose levels. Exogenous glucose was quickly cleared in glucose tolerance tests. The mRNA expressions of genes for gluconeogenesis-related enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) were significantly reduced in the liver of SA-treated diabeticdb/dbmice. In primary hepatocytes, SA treatment decreased glucose production and the expression of G6Pase, PEPCK, and hepatocyte nuclear factor 4 alpha (HNF-4α) mRNA. Small heterodimer partner (SHP) mRNA expression was increased in hepatocytes dependent upon the SA concentration. The expression of Sirt1 mRNA and protein was reduced, and acetylated forkhead box protein O1 (FoxO1) was induced by SA treatment in hepatocytes. In addition, SA-treated diabeticdb/dbmice showed reduced energy expenditure. Oral intubation of SA ameliorates hyperglycemia indb/dbmice by reducing hepatic gluconeogenesis through the decrease of Sirt1 expression and increase in acetylated FoxO1.

scholarly journals Protective Effects of Polyphenol Enriched Complex Plants Extract on Metabolic Dysfunctions Associated with Obesity and Related Nonalcoholic Fatty Liver Diseases in High Fat Diet-Induced C57BL/6 Mice

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 302
Author(s):  
Ahtesham Hussain ◽  
Jin Sook Cho ◽  
Jong-Seok Kim ◽  
Young Ik Lee
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Mouse Model ◽  
High Fat Diet ◽  
Liver Diseases ◽  
Liver Weight ◽  
Control Group ◽  
High Fat ◽  
Herbal Formulation ◽  
Plants Extract

Background: Currently, obesity is a global health challenge due to its increasing prevalence and associated health risk. It is associated with various metabolic diseases, including diabetes, hypertension, cardiovascular disease, stroke, certain forms of cancer, and non-alcoholic liver diseases (NAFLD). Objective: The aim of this study to evaluate the effects of polyphenol enriched herbal complex (Rubus crataegifolius/ellagic acid, Crataegus pinnatifida Bunge/vitexin, chlorogenic acid, Cinnamomum cassiaa/cinnamic acid) on obesity and obesity induced NAFLD in the high-fat diet (HFD)-induced obese mouse model. Methods: Obesity was induced in male C57BL/6 mice using HFD. After 8 weeks, the mice were treated with HFD+ plants extract for 8 weeks. Body weight, food intake weekly, and blood sugar level were measured. After sacrifice, changes in the treated group’s liver weight, fat weight, serum biochemical parameters, hormone levels, and enzyme levels were measured. For histological analysis, tissues were stained with hematoxylin-eosin (H&E) and Oil Red-O. Results: Our results showed that the herbal complex ameliorated body weight and liver weight gain, and decreased total body fat in HFD-fed animals. Post prandial blood glucose (PBG) and fasting blood glucose (FBG) were lower in the herbal complex-treated group than in the HFD control group. Additionally, herbal formulation treatment significantly increased HDL levels in serum and decreased TC, TG, AST, ALT, deposition of fat droplets in the liver, and intima media thickness (IMT) in the aorta. Herbal complex increased serum adiponectin and decreased serum leptin. Herbal complex also increased carnitine palmityl transferase (CPT) activity and significantly decreased enzyme activity of beta-hydroxy beta methyl glutamyl-CoA (HMG-CoA) reductase, and fatty acid synthase (FAS). Conclusions: The results of this study demonstrated that the herbal complex is an effective herbal formulation in the attenuation of obesity and obesity-induced metabolic dysfunction including NAFLD in HFD-induced mouse model.

scholarly journals Triterpene Acid and Phenolics from Ancient Apples of Friuli Venezia Giulia as Nutraceutical Ingredients: LC-MS Study and In Vitro Activities

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1109 ◽  
Author(s):  
Stefania Sut ◽  
Gokhan Zengin ◽  
Filippo Maggi ◽  
Mario Malagoli ◽  
Stefano Dall’Acqua
Keyword(s):  
Radical Scavenging ◽  
Reducing Power ◽  
Total Phenolic ◽  
Inhibitory Effects ◽  
Triterpene Acid ◽  
Beneficial Effects ◽  
Triterpene Acids ◽  
Phenolic Constituents ◽  
Friuli Venezia Giulia

Triterpene acid and phenolic constituents from nine ancient varieties of apple (Malus domestica) fruits cultivated in Fanna, Friuli Venezia Giulia region, northeast Italy, were analyzed and compared with four commercial apples (‘Golden Delicious’, ‘Red Delicious’, ‘Granny Smith’ and ‘Royal Gala’). Total phenolic and flavonoid contents were measured by spectrophotometric assays. The quali-quantitative fingerprint of secondary metabolites including triterpene acid was obtained by LC-DAD-(ESI)-MS and LC-(APCI)-MS, respectively. Based on the two LC-MS datasets, multivariate analysis was used to compare the composition of ancient fruit varieties with those of four commercial apples. Significant differences related mainly to the pattern of triterpene acids were found. Pomolic, euscaphyc, maslinic and ursolic acids are the most abundant triterpene in ancient varieties pulps and peels, while ursolic and oleanolic acids were prevalent in the commercial fruits. Also, the content of the phenolic compounds phloretin-2-O-xyloglucoside and quercetin-3-O-arabinoside was greater in ancient apple varieties. The antioxidant (radical scavenging, reducing power, metal chelating and phosphomolybdenum assays) and enzyme inhibitory effects (against cholinesterase, tyrosinase, amylase and glucosidase) of the samples were investigated in vitro. Antioxidant assays showed that the peels were more active than pulps. However, all the samples exhibited similar enzyme inhibitory effects. Ancient Friuli Venezia Giulia apple cultivars can be a source of chlorogenic acid and various triterpene acids, which are known for their potential anti-inflammatory activity and beneficial effects on lipid and glucose metabolism. Our results make these ancient varieties suitable for the development of new nutraceutical ingredients.

scholarly journals Calcium Supplementation Enhanced Adipogenesis and Improved Glucose Homeostasis Through Activation of Camkii and PI3K/Akt Signaling Pathway in Porcine Bone Marrow Mesenchymal Stem Cells (pBMSCs) and Mice Fed High Fat Diet (HFD)

2018 ◽  
Vol 51 (1) ◽  
pp. 154-172 ◽  
Author(s):  
Fenglin Zhang ◽  
Jingjing Ye ◽  
Yingying Meng ◽  
Wei Ai ◽  
Han Su ◽  
...  
Keyword(s):  
Body Weight ◽  
Glucose Uptake ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Calcium Supplementation ◽  
Akt Signaling Pathway ◽  
Glut4 Expression ◽  
Marrow Mesenchymal Stem Cells

Background/Aims: It has been implicated that calcium supplementation is involved in reducing body weight/fat and improving glucose homeostasis. However, the underlying mechanisms are still not fully understood. Here, we investigated the effects of calcium supplementation on adipogenesis and glucose homeostasis in porcine bone marrow mesenchymal stem cells (pBMSCs) and high fat diet (HFD)-fed mice and explored the involved signaling pathways. Methods: In vitro, pBMSCs were treated with 4 mM extracellular calcium ([Ca2+]o) and/or 1 μM nifedipine, 0.1 μM BAPTA-AM, 1 μM KN-93, 50 nM wortmannin for 10 days. The intracellular calcium ([Ca2+]i) levels were measured using Fluo 3-AM by flow cytometry. The adipogenic differentiation of pBMSCs was determined by Oil Red-O staining and triglyceride assay. The expression of marker genes involved in adipogenesis (peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα)) and glucose uptake (glucose transporter 4 (GLUT4)), as well as the activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and PI3K/Akt-FoxO1/AS160 signaling pathways were determined by Western blotting. Glucose uptake and utilization were examined using 2-NBDG assay and glucose content assay, respectively. In vivo, C57BL/6J male mice were fed a HFD (containing 1.2% calcium) without or with 0.6% (w/w) calcium chloride in drinking water for 13 weeks. The adipogenesis, glucose homeostasis and the involvement of CaMKII and PI3K/Akt signaling pathway were also assessed. Results: In vitro, [Ca2+]o stimulated pBMSCs adipogenesis by increasing [Ca2+]i level and activating CaMKII and PI3K/Akt-FoxO1 pathways. In addition, [Ca2+]o promoted glucose uptake/utilization by enhancing AS160 phosphorylation, GLUT4 expression and translocation. However, the stimulating effects of [Ca2+]o on pBMSCs adipogenesis and glucose uptake/utilization were abolished by L-VGCC blocker Nifedipine, [Ca2+]i chelator BAPTA-AM, CaMKII inhibitor KN-93, or PI3K inhibitor Wortmannin. In vivo, calcium supplementation decreased body weight and fat content, increased adipocyte number, and improved glucose homeostasis, with elevated PPARγ and GLUT4 expression and PI3K/Akt activation in iWAT. Conclusion: calcium supplementation enhanced adipogenesis and glucose uptake in pBMSCs, which was coincident with the increased adipocyte number and improved glucose homeostasis in HFD-fed mice, and was associated with activation of CaMKII and PI3K/Akt-FoxO1/AS160 pathways. These data provided a broader understanding of the mechanisms underlying calcium-induced body weight/fat loss and glycemic control.

scholarly journals Swertiamarin Contributes to Glucose Homeostasis via Inhibition of Carbohydrate Metabolizing Enzymes

2017 ◽  
Vol 16 (4) ◽  
pp. 125 ◽  
Author(s):  
Javed Ahamad ◽  
Naila Hassan ◽  
Saima Amin ◽  
Showkat R. Mir
Keyword(s):  
Blood Glucose ◽  
Glucose Homeostasis ◽  
In Vivo Studies ◽  
Metabolizing Enzymes ◽  
Treatment Groups ◽  
Whole Plant ◽  
Peak Blood ◽  
Peak Blood Glucose

<strong>Objective:</strong> Swertiamarin is a common secoiridoid found among the members of Gentianaceae. The present study aimed to establish the effectiveness of swertiamarin in achieving glucose homeostasis via inhibition of carbohydrate metabolizing enzymes by in-vitro and in-vivo studies. <strong>Materials and methods:</strong> Swertiamarin was obtained from dried whole plant samples of <em>Enicostemma littorale</em> Blume chromatographic fractionation over the silica gel column. Its effect on carbohydrate metabolizing enzymes viz., α-amylase and α-glucosidase were evaluated at 0.15 to 10 mg/mL in-vitro. The results were supplemented by anti-hyperglycemic studies in carbohydrate challenged mice pretreated with swertiamarin at a dose of 20 mg/kg body weight orally. <strong>Results:</strong> Swertiamarin was effective in inhibiting α-amylase and α-glucosidase with IC<em>50</em> values of 1.29±0.25 mg/mL and 0.84±0.11 mg/mL, respectively. The studies in starch and sucrose challenged mice showed that swertiamarin effectively restricted the increase in the peak blood glucose level (BGL). The increase in peak BGL was 49 mg/dL and 57 mg/dL only in the treatment groups compared to 70 mg/dL and 80 mg/dL in untreated groups after 30 min in starch and sucrose-fed mice, respectively. Acarbose (10 mg/kg b.w.) also produced significant (p&lt;0.01) blood glucose lowering response in both the models. <strong>Conclusion:</strong> Swertiamarin was effective in the achieving stricter glycemic control in carbohydrate challenged mice through the inhibition of carbohydrate metabolizing enzymes.

scholarly journals Interactions of 7,8-Dihydroxyflavone with Serum Albumin as well as with CYP2C9, CYP2C19, CYP3A4, and Xanthine Oxidase Biotransformation Enzymes

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 655 ◽  
Author(s):  
Fliszár-Nyúl ◽  
Mohos ◽  
Bencsik ◽  
Lemli ◽  
Kunsági-Máté ◽  
...  
Keyword(s):  
Serum Albumin ◽  
Xanthine Oxidase ◽  
In Vitro Models ◽  
Stable Complex ◽  
Limited Information ◽  
Inhibitory Effects ◽  
Beneficial Effects ◽  
Biotransformation Enzymes ◽  
Pharmacokinetic Properties

7,8-dihydroxyflavone (DHF) is a flavone aglycone which has beneficial effects in several central nervous system diseases. Most of the pharmacokinetic properties of DHF have been characterized, while only limited information is available regarding its interactions with serum albumin and biotransformation enzymes. In this study, the interactions of DHF with albumin was examined employing fluorescence spectroscopy and ultrafiltration. Furthermore, the inhibitory effects of DHF on cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) and xanthine oxidase (XO) enzymes were also tested using in vitro models. Our results demonstrate that DHF forms a stable complex with albumin (K = 4.9 × 105 L/mol) and that it is able to displace both Site I and Site II ligands. Moreover, DHF proved to be a potent inhibitor of each enzyme tested, showing similar or slightly weaker effects than the positive controls used. Considering the above-listed observations, the coadministration of DHF with drugs may interfere with the drug therapy due to the development of pharmacokinetic interactions.

scholarly journals d-Fagomine lowers postprandial blood glucose and modulates bacterial adhesion

2011 ◽  
Vol 107 (12) ◽  
pp. 1739-1746 ◽  
Author(s):  
Livia Gómez ◽  
Eunice Molinar-Toribio ◽  
María Ángeles Calvo-Torras ◽  
Carles Adelantado ◽  
M. Emília Juan ◽  
...  
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Intestinal Mucosa ◽  
Bacterial Adhesion ◽  
Pathogenic Bacteria ◽  
Blood Glucose Concentration ◽  
Postprandial Blood Glucose ◽  
Dependent Manner ◽  
Food Component

d-Fagomine is an iminosugar originally isolated from seeds of buckwheat (Fagopyrum sculentumMoench), present in the human diet and now available as a pure crystalline product. We testedd-fagomine for activities connected to a reduction in the risk of developing insulin resistance, becoming overweight and suffering from an excess of potentially pathogenic bacteria. The activities were: intestinal sucrase inhibitionin vitro(rat mucosa and everted intestine sleeves), modulation of postprandial blood glucose in rats, bacterial agglutination and bacterial adhesion to pig intestinal mucosa. When ingested together with sucrose or starch,d-fagomine lowered blood glucose in a dose-dependent manner without stimulating insulin secretion.d-Fagomine reduced the area under the curve (0–120 min) by 20 % (P < 0·01) and shifted the time to maximum blood glucose concentration (Tmax) by 15 min at doses of 1–2 mg/kg body weight when administered together with 1 g sucrose/kg body weight. Moreover,d-fagomine (0·14 mm) agglutinated 60 % of Enterobacteriaceae (Escherichia coli,Salmonella entericaserovar Typhimurium) populations (P < 0·01), while it did not show this effect onBifidobacteriumspp. orLactobacillusspp. At the same concentration,d-fagomine significantly (P < 0·001) inhibited the adhesion of Enterobacteriaceae (95–99 % cells in the supernatant) and promoted the adhesion ofLactobacillus acidophilus(56 % cells in the supernatant) to intestinal mucosa.d-Fagomine did not show any effect on bacterial cell viability. Based on all this evidence,d-fagomine may be used as a dietary ingredient or functional food component to reduce the health risks associated with an excessive intake of fast-digestible carbohydrates, or an excess of potentially pathogenic bacteria.

scholarly journals In Vivo Activity of Posaconazole against Mucor spp. in an Immunosuppressed-Mouse Model

2002 ◽  
Vol 46 (7) ◽  
pp. 2310-2312 ◽  
Author(s):  
Qiu N. Sun ◽  
Laura K. Najvar ◽  
Rosie Bocanegra ◽  
David Loebenberg ◽  
John R. Graybill
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Amphotericin B ◽  
Immunosuppressed Mouse ◽  
Tissue Burden

ABSTRACT The in vivo activities of posaconazole, itraconazole, and amphotericin B in neutropenic mice with zygomycosis were compared. The in vitro MICs of posaconazole and itraconazole for the strains of Mucor spp. used in this study ranged from 0.125 to 8 μg/ml and 0.25 to 8 μg/ml, respectively. The in vitro MIC range for amphotericin B is 0.125 to 0.25 μg/ml. At twice-daily doses of ≥15 mg/kg of body weight, posaconazole prolonged the survival of the mice and reduced tissue burden.

scholarly journals Electrospun PCL/PLA Scaffolds Are More Suitable Carriers of Placental Mesenchymal Stromal Cells Than Collagen/Elastin Scaffolds and Prevent Wound Contraction in a Mouse Model of Wound Healing

2020 ◽  
Vol 8 ◽  
Author(s):  
Eva Vonbrunn ◽  
Marc Mueller ◽  
Melanie Pichlsberger ◽  
Monika Sundl ◽  
Alexander Helmer ◽  
...  
Keyword(s):  
Wound Healing ◽  
Mouse Model ◽  
Stromal Cells ◽  
Wound Care ◽  
Skin Wound ◽  
Beneficial Effects ◽  
New Therapeutic Approaches

Mesenchymal stem/stromal cells (MSCs) exert beneficial effects during wound healing, and cell-seeded scaffolds are a promising method of application. Here, we compared the suitability of a clinically used collagen/elastin scaffold (Matriderm) with an electrospun Poly(ε-caprolactone)/poly(l-lactide) (PCL/PLA) scaffold as carriers for human amnion-derived MSCs (hAMSCs). We created an epidermal-like PCL/PLA scaffold and evaluated its microstructural, mechanical, and functional properties. Sequential spinning of different PCL/PLA concentrations resulted in a wide-meshed layer designed for cell-seeding and a dense-meshed layer for apical protection. The Matriderm and PCL/PLA scaffolds then were seeded with hAMSCs, with or without Matrigel coating. The quantity and quality of the adherent cells were evaluated in vitro. The results showed that hAMSCs adhered to and infiltrated both scaffold types but on day 3, more cells were observed on PCL/PLA than on Matriderm. Apoptosis and proliferation rates were similar for all carriers except the coated Matriderm, where apoptotic cells were significantly enhanced. On day 8, the number of cells decreased on all carrier types except the coated Matriderm, which had consistently low cell numbers. Uncoated Matriderm had the highest percentage of proliferative cells and lowest apoptosis rate of all carrier types. Each carrier also was topically applied to skin wound sites in a mouse model and analyzed in vivo over 14 days via optical imaging and histological methods, which showed detectable hAMSCs on all carrier types on day 8. On day 14, all wounds exhibited newly formed epidermis, and all carriers were well-integrated into the underlying dermis and showing signs of degradation. However, only wounds treated with uncoated PCL/PLA maintained a round appearance with minimal contraction. Overall, the results support a 3-day in vitro culture of scaffolds with hAMSCs before wound application. The PCL/PLA scaffold showed higher cell adherence than Matriderm, and the effect of the Matrigel coating was negligible, as all carrier types maintained sufficient numbers of transplanted cells in the wound area. The anti-contractive effects of the PCL/PLA scaffold offer potential new therapeutic approaches to wound care.

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