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Li Q, Yang Z, Lu H, Liu F, Zhou D, Zou Y. Astragalin Exerted Hypoglycemic Effect by Both Inhibiting α-Glucosidase and Modulating AMPK Signaling Pathway. Nutrients 2025; 17:406. [PMID: 39940264 PMCID: PMC11820219 DOI: 10.3390/nu17030406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND The hypoglycemic activity of mulberry leaf polyphenols has been widely studied, while its mechanism of action needs further elucidation. METHODS The inhibitory activity mechanism of astragalin on α-glucosidase was investigated with a combination of multispectroscopic techniques and molecular docking. The hypoglycemic pathway was further revealed with a high-glucose human hepatocellular carcinomas (HepG2) cell model. RESULTS The results indicated that astragalin inhibited α-glucosidase with IC50 of 154.5 µM, which was the highest in potency among the main polyphenols from mulberry leaves. Astragalin could bind to α-glucosidase with a single inhibition site and quench its endofluorescence with a static quenching mechanism. Astragalin changed the secondary structure of α-glucosidase, and the decreased α-helix content, representing the un-folding conformation, resulted in the decreased activity. The molecular docking further indicated that two sustainable hydrogen bonds were generated between astragalin and α-glucosidase residue Ser-88 and Tyr-133. The main driving forces to form the astragalin-α-glucosidase complex were the van der Waals force and hydrogen bond. Astragalin at a concentration of 80 µg/mL obtained the best hypoglycemic effect by activating the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. CONCLUSIONS This study provides new insights into the potential utilization of astragalin-rich foods in the improvement of diabetes mellitus.
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Affiliation(s)
- Qian Li
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs, Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China; (Q.L.); (Z.Y.); (F.L.); (D.Z.)
- Guangdong Laboratory for Lingnan Modern Agriculture, Maoming 525000, China
| | - Zhangchang Yang
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs, Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China; (Q.L.); (Z.Y.); (F.L.); (D.Z.)
- College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Huijie Lu
- Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China;
| | - Fan Liu
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs, Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China; (Q.L.); (Z.Y.); (F.L.); (D.Z.)
| | - Donglai Zhou
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs, Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China; (Q.L.); (Z.Y.); (F.L.); (D.Z.)
| | - Yuxiao Zou
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs, Guangdong Key Laboratory of Agricultural Products Processing, Guangzhou 510610, China; (Q.L.); (Z.Y.); (F.L.); (D.Z.)
- Guangdong Laboratory for Lingnan Modern Agriculture, Maoming 525000, China
- College of Food Science, South China Agricultural University, Guangzhou 510642, China
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Liu T, Ge X, Song L, Wu H, Qian X, Jia B, Zhao C, Zhuang Y. Zingiber striolatum phytochemicals ameliorated hyperglycemia symptoms by modulating gut microbial communities in mice with type 2 diabetes mellitus. Front Nutr 2025; 12:1537932. [PMID: 39911803 PMCID: PMC11794074 DOI: 10.3389/fnut.2025.1537932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 01/02/2025] [Indexed: 02/07/2025] Open
Abstract
Introduction Prolonged hyperglycemia caused by type 2 diabetes mellitus (T2DM) can lead to liver injury and disrupt the community of the gut microbiota that pose significant risks to human health. As a food rich in a variety of active ingredients, Zingiber striolatum (Z. striolatum) exhibits hypoglycemic and hypolipidemic effects. However, the regulatory influence of Z. striolatum ethanol extract (ZSE) on the gut microbiota of T2DM mice or its potential relationship with T2DM pathology remains unexplored. Methods After a one-week acclimation period, 12 mice were randomly selected as the normal group. The remaining 48 mice were employed T2DM model, and then randomly assigned to four groups: the model group, a low-dose ZSE group (ZSE-L, 100 mg/kg/day), a high-dose ZSE group (ZSE-H, 300 mg/kg/day), and a positive control group treated with metformin hydrochloride (MET, 100 mg/kg/day). Results After a 4-week intervention, the results revealed that ZSE significantly ameliorated fasting blood glucose (FBG), area under the curve of oral glucose tolerance test (AUC of OGTT) and glycated serum protein (GSP) in T2DM mice. Moreover, the high-dose (ZSE-H) treatment increased the relative abundance of beneficial bacteria such as Faecalibaculum, while reducing harmful bacteria such as Bilophila, thereby alleviating insulin resistance. Additionally, ZSE-H demonstrated superior efficacy over low-dose (ZSE-L) in improving FBG, AUC of OGTT, and other hypoglycemic parameters. Predictive analysis of the correlation between gut microbiota and hypoglycemic parameters identified Dubosiella, Bacillus, and Mailhella as potential microbial biomarkers for further investigation into the pathogenesis of T2DM. Conclusion ZSE plays a pivotal role in mitigating hyperglycemia in T2DM mice through the modulation of intestinal microbiota communities.
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Affiliation(s)
- Tingting Liu
- Department of Clinical Pharmacy, The Second People’s Hospital of Yancheng, Yancheng, China
| | - Xiaodong Ge
- College of Marine and Bioengineering, Yancheng Institute of Technology, Yancheng, China
| | - Lu Song
- Department of Clinical Pharmacy, The First People’s Hospital of Yancheng, Yancheng, China
| | - Huanhuan Wu
- Department of Clinical Pharmacy, Suqian Hospital Affiliated to Xuzhou Medical University, Suqian, China
| | - Xue Qian
- Department of Clinical Pharmacy, The Second People’s Hospital of Yancheng, Yancheng, China
| | - Bowen Jia
- Department of Clinical Pharmacy, The Second People’s Hospital of Yancheng, Yancheng, China
| | - Chao Zhao
- College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Yi Zhuang
- Department of Clinical Pharmacy, The Second People’s Hospital of Yancheng, Yancheng, China
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Melo BP, Zacarias AC, Oliveira JCC, de Souza Cordeiro LM, Horta NAC, Poletini MO, Tonoli C, Dos Santos ML, Wanner SP, Meeusen R, Heyman E, Avelar GF, Soares DD. Enhancing metabolic and inflammatory status in insulin-resistant rats: Acute intervention with cocoa flavanols and submaximal aerobic exercise activates intracellular signaling pathways for glucose metabolism. Clin Nutr 2025; 44:166-177. [PMID: 39675158 DOI: 10.1016/j.clnu.2024.11.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 11/26/2024] [Accepted: 11/29/2024] [Indexed: 12/17/2024]
Abstract
INTRODUCTION Type 2 diabetes, characterized by hyperglycemia, is closely linked to obesity and low-grade inflammation. Acute cocoa flavanols (CF) intake has demonstrated benefits in vasoreactivity, cognitive functions, and antioxidant enzyme activity. However, the physiological mechanisms of CF concerning glucose uptake, inflammatory mediators, and their interplay with aerobic exercise remain unclear in populations with metabolic diseases. OBJECTIVE This study aims to investigate the acute effects of CF, alone or combined with acute aerobic exercise on mechanisms involved in glucose uptake and inflammatory mediators in the liver, skeletal muscle, pancreas, and adipose tissue in insulin-resistant (IR) rats. METHODS Sixty-four Wistar rats (250 ± 10g; 15 weeks age) were subjected to a regular chow (CON) or an obesity-associated insulin-resistant (IR) state induced by a high-fat diet and fructose-rich beverage for 30 days. Seventy-two hours after an incremental maximal treadmill running test, rats received a placebo solution or CF supplementation (45 mg·kg-1 of body weight). One hour later, they either rested or ran on a treadmill at 60 % of peak oxygen uptake (VO2peak) for 30 min. Euthanasia occurred 30 min post-experimental sessions. Inflammatory and anti-inflammatory cytokines were assayed using ELISA in the liver, pancreas, gastrocnemius muscle, and epididymal adipose tissues. TRB3 and CPT1 mRNA were assessed by q-RTPCR in the liver and gastrocnemius muscle while Akt and AMPK phosphorylation were examined by immunohistochemistry. RESULTS CF attenuated hyperglycemia observed after submaximal aerobic exercise in IR rats (p < 0.001). In the liver, CF exhibited additive effects to aerobic exercise, enhancing Akt protein phosphorylation, potentially contributing to improved glucose uptake in IR rats. Submaximal aerobic exercise and CF increased AMPK protein phosphorylation in the liver (p < 0.001) and skeletal muscle (p < 0.001), reduced TRB3 gene expression (p < 0.01), elevated CPT-1a gene expression (p < 0.001), and ameliorated the inflammatory milieu in the pancreas, adipose tissue, liver, and gastrocnemius muscle. CONCLUSION Acute intake, of CF combined with submaximal aerobic exercise activates key proteins and genes involved in glucose uptake and lipid metabolism, improving the inflammatory milieu. This synergistic effect may contribute to mitigating metabolic complications associated with insulin resistance.
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Affiliation(s)
- B P Melo
- Federal University of Minas Gerais, Department of Physical Education, Exercise Physiology Laboratory, Av. Pres. Antônio Carlos, 6627 Campus-Pampulha, Belo Horizonte, Brazil.
| | - A C Zacarias
- Federal University of Minas Gerais, Department of Physical Education, Exercise Physiology Laboratory, Av. Pres. Antônio Carlos, 6627 Campus-Pampulha, Belo Horizonte, Brazil
| | - J C C Oliveira
- Federal University of Minas Gerais, Department of Physical Education, Exercise Physiology Laboratory, Av. Pres. Antônio Carlos, 6627 Campus-Pampulha, Belo Horizonte, Brazil
| | - L M de Souza Cordeiro
- Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Box 693 Rochester, NY 14642, Rochester, USA
| | - N A C Horta
- Federal University of Minas Gerais, Institute of Biological Sciences, Physiology and Biophysics Department, Av. Pres. Antônio Carlos, 6627 Campus-Pampulha, Belo Horizonte, Brazil
| | - M O Poletini
- Federal University of Minas Gerais, Institute of Biological Sciences, Physiology and Biophysics Department, Av. Pres. Antônio Carlos, 6627 Campus-Pampulha, Belo Horizonte, Brazil
| | - C Tonoli
- Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Universiteit Gent, Campus Heymans (UZ Gent), Building B3-De Pintelaan 185, 9000, Ghent, Belgium
| | - M L Dos Santos
- Federal University of Minas Gerais, Department of Morphology, Cellular Biology Laboratory, Av. Pres. Antônio Carlos, 6627 Campus-Pampulha, Belo Horizonte, Brazil
| | - S P Wanner
- Federal University of Minas Gerais, Department of Physical Education, Exercise Physiology Laboratory, Av. Pres. Antônio Carlos, 6627 Campus-Pampulha, Belo Horizonte, Brazil
| | - R Meeusen
- Human Physiology Research Group, Faculty of Physical Education and Physical Therapy, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium
| | - E Heyman
- Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, ULR 7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, F-59000 Lille, France; Institut Universitaire de France, Paris, France
| | - G F Avelar
- Federal University of Minas Gerais, Department of Morphology, Cellular Biology Laboratory, Av. Pres. Antônio Carlos, 6627 Campus-Pampulha, Belo Horizonte, Brazil
| | - D D Soares
- Federal University of Minas Gerais, Department of Physical Education, Exercise Physiology Laboratory, Av. Pres. Antônio Carlos, 6627 Campus-Pampulha, Belo Horizonte, Brazil.
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Golovinskaia O, Wang CK. The hypoglycemic potential of phenolics from functional foods and their mechanisms. FOOD SCIENCE AND HUMAN WELLNESS 2023. [DOI: 10.1016/j.fshw.2022.10.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Shakoor H, Hussein H, Al-Hassan N, Alketbi M, Kizhakkayil J, Platat C. The Muscle-Conditioned Medium Containing Protocatechuic Acid Improves Insulin Resistance by Modulating Muscle Communication with Liver and Adipose Tissue. Int J Mol Sci 2023; 24:9490. [PMID: 37298440 PMCID: PMC10253324 DOI: 10.3390/ijms24119490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/07/2023] [Accepted: 05/12/2023] [Indexed: 06/12/2023] Open
Abstract
Diabetes mellitus is a public health concern, affecting 10.5% of the population. Protocatechuic acid (PCA), a polyphenol, exerts beneficial effects on insulin resistance and diabetes. This study investigated the role of PCA in improving insulin resistance and the crosstalk between muscle with liver and adipose tissue. C2C12 myotubes received four treatments: Control, PCA, insulin resistance (IR), and IR-PCA. Conditioned media from C2C12 was used to incubate HepG2 and 3T3-L1 adipocytes. The impact of PCA was analyzed on glucose uptake and signaling pathways. PCA (80 µM) significantly enhanced glucose uptake in C2C12, HepG2, and 3T3-L1 adipocytes (p < 0.05). In C2C12, PCA significantly elevated GLUT-4, IRS-1, IRS-2, PPAR-γ, P-AMPK, and P-Akt vs. Control (p ≤ 0.05), and modulated pathways in IR-PCA. In HepG2, PPAR-γ and P-Akt increased significantly in Control (CM) vs. No CM, and PCA dose upregulated PPAR-γ, P-AMPK, and P-AKT (p < 0.05). In the 3T3-L1 adipocytes, PI3K and GLUT-4 expression was elevated in PCA (CM) vs. No CM. A significant elevation of IRS-1, GLUT-4, and P-AMPK was observed in IR-PCA vs. IR (p ≤ 0.001). Herein, PCA strengthens insulin signaling by activating key proteins of that pathway and regulating glucose uptake. Further, conditioned media modulated crosstalk between muscle with liver and adipose tissue, thus regulating glucose metabolism.
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Affiliation(s)
| | | | | | | | | | - Carine Platat
- Department of Nutrition and Health, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 15551, United Arab Emirates; (H.S.)
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Sharma N, Kar A, Panda S, Yadav D. Co-administration of Pterocarpus marsupium Extract and Glibenclamide Exhibits Better Effects in Regulating Hyperglycemia and Associated Changes in Alloxan-induced Diabetic Mice. Curr Top Med Chem 2022; 22:2617-2628. [PMID: 36366849 DOI: 10.2174/1568026623666221108125036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/21/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND Diabetes mellitus (DM) is a well-known global metabolic disorder. For its treatment, glibenclamide (GLB) is very often prescribed. However, herbal drugs are considered effective and better alternatives due to their low risk of side effects. This study was conducted to determine the combined effects of GLB and Pterocarpus marsupium (PM, a commonly available Indian herb) extract for the effective and safe treatment of hyperglycemia in the mouse model. METHODS Healthy adult male mice were distributed into five groups (n=7 in each group). Group I acted as the control, whereas groups II, III, IV, and V were considered experimental groups which received a single dosage (150 mg/kg body weight) of alloxan (ALX) intraperitoneally (i.p.). In addition, groups III, IV, and V received a pre-standardized dose of GLB (500 μg/kg body weight), PM extract (150 mg/kg body weight), and GLB+PM, respectively, at the same doses as used in individual treatment, after the seventh day of ALX administration for 15 days and the alterations in different DM related parameters were evaluated. RESULTS ALX-induced hyperglycemia and other adverse effects were nearly normalized by GLB and PM co-treatment as evidenced by marked suppression in glucose, triglyceride, total-cholesterol, lipid-peroxidation, and lipid-hydroperoxides with an increase in antioxidants status and liver glycogen content. The positive effects were more pronounced when both GLB and PM were given, as compared to that of either of the drugs, administered alone. Liver ultra-structure, analyzed through histology and transmission electron microscopy revealed normalization of the ALX-induced damaged hepatocytes. The presence of epicatechin, the major phytoconstituent of the PM extract, as confirmed by high-performance liquid chromatography (HPLC), is responsible for its antioxidative and glucose-lowering activities. CONCLUSION These findings reveal that PM, along with GLB, exhibits synergistic and better effects than the individual drug in regulating hyperglycemia and associated changes in alloxan-induced mice.
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Affiliation(s)
- Neha Sharma
- School of Life Sciences, Devi Ahilya University, Khandwa Road, Indore, 452017, India
| | - Anand Kar
- School of Life Sciences, Devi Ahilya University, Khandwa Road, Indore, 452017, India
| | - Sunanda Panda
- School of Life Sciences, Devi Ahilya University, Khandwa Road, Indore, 452017, India
| | - Dhananjay Yadav
- Department of Life Sciences, Yeungnam University, Gyeongsan, 38541, South Korea
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From Cocoa to Chocolate: Effect of Processing on Flavanols and Methylxanthines and Their Mechanisms of Action. Int J Mol Sci 2022; 23:ijms232214365. [PMID: 36430843 PMCID: PMC9698929 DOI: 10.3390/ijms232214365] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/14/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
Despite the health benefits associated with the ingestion of the bioactive compounds in cocoa, the high concentrations of polyphenols and methylxanthines in the raw cocoa beans negatively influence the taste, confer the astringency and bitterness, and affect the stability and digestibility of the cocoa products. It is, therefore, necessary to process cocoa beans to develop the characteristic color, taste, and flavor, and reduce the astringency and bitterness, which are desirable in cocoa products. Processing, however, affects the composition and quantities of the bioactive compounds, resulting in the modification of the health-promoting properties of cocoa beans and chocolate. In this advanced review, we sought to better understand the effect of cocoa's transformational process into chocolate on polyphenols and methylxanthine and the mechanism of action of the original flavanols and methylxanthines. More data on the cocoa processing effect on cocoa bioactives are still needed for better understanding the effect of each processing step on the final polyphenolic and methylxanthine composition of chocolate and other cocoa products. Regarding the mechanisms of action, theobromine acts through the modulation of the fatty acid metabolism, mitochondrial function, and energy metabolism pathways, while flavanols mainly act though the protein kinases and antioxidant pathways. Both flavanols and theobromine seem to be involved in the nitric oxide and neurotrophin regulation.
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García-Díez E, López-Oliva ME, Pérez-Jiménez J, Martín MA, Ramos S. Metabolic regulation of (-)-epicatechin and the colonic metabolite 2,3-dihydroxybenzoic acid on the glucose uptake, lipid accumulation and insulin signalling in cardiac H9c2 cells. Food Funct 2022; 13:5602-5615. [PMID: 35502961 DOI: 10.1039/d2fo00182a] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epicatechin (EC) and main colonic phenolic acids derived from flavonoid intake have been suggested to exert healthful effects, although their mechanism of action remains unknown. Heart damage is highly prevalent in metabolic diseases, and the failure of this organ is a major cause of death worldwide. In this study, the modulation of the energy metabolism and insulin signalling by the mentioned compounds in cardiac H9c2 cells was evaluated. Incubation of cells with EC (1-20 μM) and 2,3-dihydroxybenzoic acid (DHBA, 10 μM) reduced glucose uptake, and both compounds decreased lipid accumulation at concentrations higher than 0.5 μM. EC and DHBA also increased the tyrosine phosphorylated and total insulin receptor (IR) levels, and activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway in cardiac H9c2 cells. Interestingly, EC and DHBA did not modify glucose transporters (SGLT-1 and GLUT-1) levels, and increased GLUT-4 values. In addition, EC and DHBA decreased cluster of differentiation 36 (CD36) and fatty acid synthase (FAS) values, and enhanced carnitine palmitoyl transferase 1 (CPT1) and proliferator activated receptor α (PPARα) levels. By using specific inhibitors of AKT and 5'-AMP-activated protein kinase (AMPK), the participation of both proteins in EC- and DHBA-mediated regulation on glucose uptake and lipid accumulation was shown. Taken together, EC and DHBA modulate glucose uptake and lipid accumulation via AKT and AMPK, and reinforce the insulin signalling by activating key proteins of this pathway in H9c2 cells.
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Affiliation(s)
- Esther García-Díez
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040 Madrid, Spain.
| | - María Elvira López-Oliva
- Sección Departamental de Fisiología. Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Spain
| | - Jara Pérez-Jiménez
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040 Madrid, Spain.
| | - María Angeles Martín
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040 Madrid, Spain. .,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain
| | - Sonia Ramos
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040 Madrid, Spain.
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Krikorian R, Skelton MR, Summer SS, Shidler MD, Sullivan PG. Blueberry Supplementation in Midlife for Dementia Risk Reduction. Nutrients 2022; 14:1619. [PMID: 35458181 PMCID: PMC9031005 DOI: 10.3390/nu14081619] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/08/2022] [Accepted: 04/10/2022] [Indexed: 02/04/2023] Open
Abstract
Late-life dementia typically develops over a period of many years beginning in midlife. Prevalence of metabolic disturbance also accelerates in middle age and is a prominent risk factor for dementia. Preliminary studies indicate that blueberry supplementation can improve cognitive performance and influence metabolism and brain function and therefore may have a role in early intervention to prevent neurodegeneration. In a randomized controlled trial, we investigated the effects of daily blueberry supplementation in a middle-aged sample of insulin-resistant participants with elevated risk for future dementia. We enrolled overweight men and women, aged 50 to 65 years, with subjective cognitive decline (SCD) and performed pre- and post-intervention assessments of cognition and metabolism and exploratory measures of peripheral mitochondrial function. We observed improved performances for the blueberry group on measures of lexical access, p = 0.003, and memory interference, p = 0.04, and blueberry-treated participants reported reduced memory encoding difficulty in daily life activities, p = 0.03. The blueberry-treated group also exhibited correction of peripheral hyperinsulinemia, p = 0.04, and a modest trend for increased mitochondrial uncoupling, p = 0.11. The cognitive findings indicated improved executive ability in this middle-aged sample. In addition, the changes in metabolic and bioenergetic measures imply potential mechanistic factors associated with anthocyanin and proanthocyanidin actions. The demonstration of these benefits in middle-aged individuals with insulin resistance and SCD suggests that ongoing blueberry supplementation may contribute to protection against cognitive decline when implemented early in at-risk individuals.
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Affiliation(s)
- Robert Krikorian
- Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati Academic Health Center, Cincinnati, OH 45267, USA;
| | - Matthew R. Skelton
- Division of Neurology, Cincinnati Children’s Research Foundation, Cincinnati, OH 45229, USA;
| | - Suzanne S. Summer
- Bionutrition Core, Clinical Translational Research Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
| | - Marcelle D. Shidler
- Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati Academic Health Center, Cincinnati, OH 45267, USA;
| | - Patrick G. Sullivan
- Spinal Cord & Brain Injury Research Center, Chandler College of Medicine, University of Kentucky, Lexington, KY 40506, USA;
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Rebollo-Hernanz M, Aguilera Y, Martin-Cabrejas MA, Gonzalez de Mejia E. Phytochemicals from the Cocoa Shell Modulate Mitochondrial Function, Lipid and Glucose Metabolism in Hepatocytes via Activation of FGF21/ERK, AKT, and mTOR Pathways. Antioxidants (Basel) 2022; 11:antiox11010136. [PMID: 35052640 PMCID: PMC8772970 DOI: 10.3390/antiox11010136] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 12/31/2021] [Accepted: 01/05/2022] [Indexed: 02/04/2023] Open
Abstract
The cocoa shell is a by-product that may be revalorized as a source of bioactive compounds to prevent chronic cardiometabolic diseases. This study aimed to investigate the phytochemicals from the cocoa shell as targeted compounds for activating fibroblast growth factor 21 (FGF21) signaling and regulating non-alcoholic fatty liver disease (NAFLD)-related biomarkers linked to oxidative stress, mitochondrial function, and metabolism in hepatocytes. HepG2 cells treated with palmitic acid (PA, 500 µmol L−1) were used in an NAFLD cell model. Phytochemicals from the cocoa shell (50 µmol L−1) and an aqueous extract (CAE, 100 µg mL−1) enhanced ERK1/2 phosphorylation (1.7- to 3.3-fold) and FGF21 release (1.4- to 3.4-fold) via PPARα activation. Oxidative stress markers were reduced though Nrf-2 regulation. Mitochondrial function (mitochondrial respiration and ATP production) was protected by the PGC-1α pathway modulation. Cocoa shell phytochemicals reduced lipid accumulation (53–115%) and fatty acid synthase activity (59–93%) and prompted CPT-1 activity. Glucose uptake and glucokinase activity were enhanced, whereas glucose production and phosphoenolpyruvate carboxykinase activity were diminished. The increase in the phosphorylation of the insulin receptor, AKT, AMPKα, mTOR, and ERK1/2 conduced to the regulation of hepatic mitochondrial function and energy metabolism. For the first time, the cocoa shell phytochemicals are proved to modulate FGF21 signaling. Results demonstrate the in vitro preventive effect of the phytochemicals from the cocoa shell on NAFLD.
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Affiliation(s)
- Miguel Rebollo-Hernanz
- Department of Agricultural Chemistry and Food Science, Universidad Autónoma de Madrid, 28049 Madrid, Spain; (M.R.-H.); (Y.A.); (M.A.M.-C.)
- Institute of Food Science Research, CIAL (UAM-CSIC), 28049 Madrid, Spain
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Yolanda Aguilera
- Department of Agricultural Chemistry and Food Science, Universidad Autónoma de Madrid, 28049 Madrid, Spain; (M.R.-H.); (Y.A.); (M.A.M.-C.)
- Institute of Food Science Research, CIAL (UAM-CSIC), 28049 Madrid, Spain
| | - Maria A. Martin-Cabrejas
- Department of Agricultural Chemistry and Food Science, Universidad Autónoma de Madrid, 28049 Madrid, Spain; (M.R.-H.); (Y.A.); (M.A.M.-C.)
- Institute of Food Science Research, CIAL (UAM-CSIC), 28049 Madrid, Spain
| | - Elvira Gonzalez de Mejia
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Correspondence: ; Tel.: +1-217-244-3196
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Guisantes-Batan E, Mazuecos L, Rubio B, Pereira-Caro G, Moreno-Rojas JM, Andrés A, Gómez-Alonso S, Gallardo N. Grape seed extract supplementation modulates hepatic lipid metabolism in rats. Implication of PPARβ/δ. Food Funct 2022; 13:11353-11368. [DOI: 10.1039/d2fo02199d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Grape seed extract supplementationat low doses (25 mg per kg BW per day) modulates the transcriptional programs that controls the hepatic lipid metabolism in lean normolipidemic Wistar rats through PPARβ/δ activation.
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Affiliation(s)
- Eduardo Guisantes-Batan
- Regional Institute for Applied Scientific Research, University of Castilla-La Mancha, Avenida Camilo José Cela 1B, 13071 Ciudad Real, Spain
- Department of Analytical Chemistry and Food Technology, Faculty of Chemical Sciences and Technologies, University of Castilla-La Mancha, Avenida Camilo José Cela 10, 13071 Ciudad Real, Spain
| | - Lorena Mazuecos
- Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha, 13071 Ciudad Real, Spain
- Biochemistry Section, Faculty of Chemical Sciences and Technologies, University of Castilla-La Mancha, Avenida Camilo José Cela 10, 13071 Ciudad Real, Spain
| | - Blanca Rubio
- Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha, 13071 Ciudad Real, Spain
- Biochemistry Section, Faculty of Chemical Sciences and Technologies, University of Castilla-La Mancha, Avenida Camilo José Cela 10, 13071 Ciudad Real, Spain
| | - Gema Pereira-Caro
- Department of Agroindustry and Food Quality, Andalusian Institute of Agricultural and Fisheries Research and Training (IFAPA), Avenida Menendez-Pidal, SN, 14004 Córdoba, Spain
- Foods for Health Group, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - José Manuel Moreno-Rojas
- Department of Agroindustry and Food Quality, Andalusian Institute of Agricultural and Fisheries Research and Training (IFAPA), Avenida Menendez-Pidal, SN, 14004 Córdoba, Spain
- Foods for Health Group, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Antonio Andrés
- Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha, 13071 Ciudad Real, Spain
- Biochemistry Section, Faculty of Chemical Sciences and Technologies, University of Castilla-La Mancha, Avenida Camilo José Cela 10, 13071 Ciudad Real, Spain
| | - Sergio Gómez-Alonso
- Regional Institute for Applied Scientific Research, University of Castilla-La Mancha, Avenida Camilo José Cela 1B, 13071 Ciudad Real, Spain
- Department of Analytical Chemistry and Food Technology, Faculty of Chemical Sciences and Technologies, University of Castilla-La Mancha, Avenida Camilo José Cela 10, 13071 Ciudad Real, Spain
| | - Nilda Gallardo
- Regional Centre for Biomedical Research (CRIB), University of Castilla-La Mancha, 13071 Ciudad Real, Spain
- Biochemistry Section, Faculty of Chemical Sciences and Technologies, University of Castilla-La Mancha, Avenida Camilo José Cela 10, 13071 Ciudad Real, Spain
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12
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Sarma P, Bharadwaj S, Swargiary D, Ahmed SA, Sheikh Y, Barge SR, Manna P, Talukdar NC, Bora J, Borah JC. Iridoid glycoside isolated from Wendlandia glabrata and the role of its enriched fraction in regulating AMPK/PEPCK/G6Pase signaling pathway of hepatic gluconeogenesis. NEW J CHEM 2022. [DOI: 10.1039/d1nj05856h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Phytochemical investigation of W. glabrata and antihyperglycemic potential of isolated novel iridoid glycoside enriched fraction in CC1 hepatocytes and STZ-induced diabetic mice.
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Affiliation(s)
- Pranamika Sarma
- Laboratory of Chemical Biology, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Guwahati 781035, Assam, India
- Department of Chemistry, Gauhati University, Gopinath Bordoloi Nagar, Jalukbari, Guwahati, 781014, Assam, India
| | - Simanta Bharadwaj
- Laboratory of Chemical Biology, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Guwahati 781035, Assam, India
| | - Deepsikha Swargiary
- Laboratory of Chemical Biology, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Guwahati 781035, Assam, India
- Academy of Scientific and Innovative Research, Ghaziabad, 201002, Uttar Pradesh, India
| | - Semim Akhtar Ahmed
- Laboratory of Chemical Biology, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Guwahati 781035, Assam, India
- Academy of Scientific and Innovative Research, Ghaziabad, 201002, Uttar Pradesh, India
| | - Yunus Sheikh
- Laboratory of Chemical Biology, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Guwahati 781035, Assam, India
| | - Sagar Ramrao Barge
- Laboratory of Chemical Biology, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Guwahati 781035, Assam, India
| | - Prasenjit Manna
- Academy of Scientific and Innovative Research, Ghaziabad, 201002, Uttar Pradesh, India
- Biotechnology Group, Biological Science and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India
| | - Narayan Chandra Talukdar
- Laboratory of Chemical Biology, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Guwahati 781035, Assam, India
- Currently, Assam Down Town University, Sankar Madhab Path Gandhi Nagar, Panikhaiti, Guwahati, Assam 781026, India
| | - Jayanta Bora
- CSIR-North East Institute of Science and Technology Branch Itanagar, Itanagar, 791110, Arunachal Pradesh, India
| | - Jagat Chandra Borah
- Laboratory of Chemical Biology, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Guwahati 781035, Assam, India
- Academy of Scientific and Innovative Research, Ghaziabad, 201002, Uttar Pradesh, India
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13
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Deng Q, Du L, Zhang Y, Liu G. NEFAs Influence the Inflammatory and Insulin Signaling Pathways Through TLR4 in Primary Calf Hepatocytes in vitro. Front Vet Sci 2021; 8:755505. [PMID: 34966805 PMCID: PMC8710596 DOI: 10.3389/fvets.2021.755505] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/23/2021] [Indexed: 12/21/2022] Open
Abstract
Transition dairy cows are often in a state of negative energy balance because of decreased dry matter intake and increased energy requirements, initiating lipid mobilization and leading to high serum β-hydroxybutyrate (BHBA) and non-esterified fatty acid (NEFAs) levels, which can induce ketosis and fatty liver in dairy cows. Inflammation and insulin resistance are also common diseases in the perinatal period of dairy cows. What is the relationship between negative energy balance, insulin resistance and inflammation in dairy cows? To study the role of non-esterified fatty acids in the nuclear factor kappa beta (NF-κB) inflammatory and insulin signaling pathways through Toll-like receptor 4 (TLR4), we cultured primary calf hepatocytes and added different concentrations of NEFAs to assess the mRNA and protein levels of inflammatory and insulin signaling pathways. Our experiments indicated that NEFAs could activate the NF-κB inflammatory signaling pathway and influence insulin resistance through TLR4. However, an inhibitor of TLR4 alleviated the inhibitory effects of NEFAs on the insulin pathway. In conclusion, all of these results indicate that high-dose NEFAs (2.4 mM) can activate the TLR4/NF-κB inflammatory signaling pathway and reduce the sensitivity of the insulin pathway through the TLR4/PI3K/AKT metabolic axis.
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Affiliation(s)
- Qinghua Deng
- College of Animal Science and Technology, Inner Mongolia Minzu University, Tongliao, China.,Inner Mongolia Minzu University Key Laboratory for Prevention and Control of Herbivorous Livestock Perinatal Diseases, Tongliao, China
| | - Liyin Du
- College of Animal Science and Technology, Inner Mongolia Minzu University, Tongliao, China.,Inner Mongolia Minzu University Key Laboratory for Prevention and Control of Herbivorous Livestock Perinatal Diseases, Tongliao, China
| | - Yuming Zhang
- College of Animal Science and Technology, Inner Mongolia Minzu University, Tongliao, China.,Inner Mongolia Minzu University Key Laboratory for Prevention and Control of Herbivorous Livestock Perinatal Diseases, Tongliao, China
| | - Guowen Liu
- College of Animal Science and Technology, Inner Mongolia Minzu University, Tongliao, China.,College of Veterinary Medicine, Jilin University, Changchun, China
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14
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Wang ZJ, Bai Z, Yan JH, Liu TT, Li YM, Xu JH, Meng XQ, Bi YF. Anti-diabetic effects of linarin from Chrysanthemi Indici Flos via AMPK activation. CHINESE HERBAL MEDICINES 2021; 14:97-103. [PMID: 36120128 PMCID: PMC9476778 DOI: 10.1016/j.chmed.2021.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 04/08/2021] [Accepted: 08/05/2021] [Indexed: 11/08/2022] Open
Abstract
Objective The purpose of this study is to investigate the anti-diabetic effects of linarin, a flavonoid extracted from Chrysanthemi Indici Flos (CIF), and its potential mechanisms. Methods The effects of linarin on cell viability and glucose consumption in HepG2 cells were measured. Meanwhile, monosodium glutamate (MSG) mouse model was constructed to monitor the changes of insulin tolerance, glucose tolerance, triglyceride and cholesterol. The protein expression levels of p-AMPK, p-ACC, PEPCK and p-GS were detected by Western blot. Results Linarin could increase the relative glucose consumption of HepG2 cells, improve insulin tolerance and glucose tolerance, and decrease the levels of triglyceride and cholesterol of MSG mice. Simultaneously, the expression levels of p-AMPK and p-ACC in HepG2 cells and the liver tissue of MSG mice were increased, while the expression levels of PEPCK and p-GS were decreased after treatment with linarin. Conclusion Insulin resistance could be ameliorated by linarin in type 2 diabetes, and its mechanism may be related to AMPK signaling pathway.
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15
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( -)-Epicatechin and cardiometabolic risk factors: a focus on potential mechanisms of action. Pflugers Arch 2021; 474:99-115. [PMID: 34812946 DOI: 10.1007/s00424-021-02640-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 10/14/2021] [Accepted: 11/03/2021] [Indexed: 01/27/2023]
Abstract
This review summarizes experimental evidence on the beneficial effects of ( -)-epicatechin (EC) attenuating major cardiometabolic risk factors, i.e., dyslipidemias, obesity (adipose tissue dysfunction), hyperglycemia (insulin resistance), and hypertension (endothelial dysfunction). Studies in humans are revised and complemented with experiments in animal models, and cultured cells, aiming to understand the molecular mechanisms involved in EC-mediated effects. Firstly, an assessment of EC metabolism gives relevance to both conjugated-EC metabolites product of host metabolism and microbiota-derived species. Integration and analysis of results stress the maintenance of redox homeostasis and mitigation of inflammation as relevant processes associated with cardiometabolic diseases. In these processes, EC appears having significant effects regulating NADPH oxidase (NOX)-dependent oxidant production, nitric oxide (NO) production, and energy homeostasis (mitochondrial biogenesis and function). The potential participation of cell membranes and membrane-bound receptors is also discussed in terms of direct molecular action of EC and EC metabolites reaching cells and tissues.
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16
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Gardener SL, Rainey-Smith SR, Weinborn M, Bondonno CP, Martins RN. Intake of Products Containing Anthocyanins, Flavanols, and Flavanones, and Cognitive Function: A Narrative Review. Front Aging Neurosci 2021; 13:640381. [PMID: 34539375 PMCID: PMC8446387 DOI: 10.3389/fnagi.2021.640381] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 07/21/2021] [Indexed: 11/13/2022] Open
Abstract
The purpose of this review is to examine human research studies published within the past 6 years which evaluate the role of anthocyanin, flavanol, and flavanone consumption in cognitive function, and to discuss potential mechanisms of action underlying any observed benefits. Evidence to date suggests the consumption of flavonoid-rich foods, such as berries and cocoa, may have the potential to limit, or even reverse, age-related declines in cognition. Over the last 6 years, the flavonoid subgroups of anthocyanins, flavanols, and flavanones have been shown to be beneficial in terms of conferring neuroprotection. The mechanisms by which flavonoids positively modulate cognitive function are yet to be fully elucidated. Postulated mechanisms include both direct actions such as receptor activation, neurotrophin release and intracellular signaling pathway modulation, and indirect actions such as enhancement of cerebral blood flow. Further intervention studies conducted in diverse populations with sufficient sample sizes and long durations are required to examine the effect of consumption of flavonoid groups on clinically relevant cognitive outcomes. As populations continue to focus on adopting healthy aging strategies, dietary interventions with flavonoids remains a promising avenue for future research. However, many questions are still to be answered, including identifying appropriate dosage, timeframes for intake, as well as the best form of flavonoids, before definitive conclusions can be drawn about the extent to which their consumption can protect the aging brain.
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Affiliation(s)
- Samantha L Gardener
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.,Australian Alzheimer's Research Foundation, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia
| | - Stephanie R Rainey-Smith
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.,Australian Alzheimer's Research Foundation, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia.,Centre for Healthy Ageing, Health Futures Institute, Murdoch University, Murdoch, WA, Australia.,School of Psychological Science, The University of Western Australia, Crawley, WA, Australia
| | - Michael Weinborn
- School of Psychological Science, The University of Western Australia, Crawley, WA, Australia
| | - Catherine P Bondonno
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.,Medical School, Royal Perth Hospital, The University of Western Australia, Perth, WA, Australia
| | - Ralph N Martins
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.,Australian Alzheimer's Research Foundation, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA, Australia.,Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
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17
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Jean-Marie E, Bereau D, Robinson JC. Benefits of Polyphenols and Methylxanthines from Cocoa Beans on Dietary Metabolic Disorders. Foods 2021; 10:2049. [PMID: 34574159 PMCID: PMC8470844 DOI: 10.3390/foods10092049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/23/2021] [Accepted: 08/27/2021] [Indexed: 02/08/2023] Open
Abstract
Theobroma cacao L. is an ancestral cultivated plant which has been consumed by various populations throughout history. Cocoa beans are the basic material occurring in the most consumed product in the world, namely chocolate. Their composition includes polyphenols, methylxanthines, lipids and other compounds that may vary qualitatively and quantitatively according to criteria such as variety or culture area. Polyphenols and methylxanthines are known as being responsible for many health benefits, particularly by preventing cardiovascular and neurodegenerative diseases. Recent studies emphasized their positive role in dietary metabolic disorders, such as diabetes and weight gain. After a brief presentation of cocoa bean, this review provides an overview of recent research activities highlighting promising strategies which modulated and prevented gastro-intestinal metabolism dysfunctions.
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Affiliation(s)
| | | | - Jean-Charles Robinson
- Laboratoire COVAPAM, UMR Qualisud, Université de Guyane, 97300 Cayenne, France; (E.J.-M.); (D.B.)
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18
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de Godoi RS, Almerão MP, da Silva FR. In silico evaluation of the antidiabetic activity of natural compounds from Hovenia dulcis Thunberg. J Herb Med 2021. [DOI: 10.1016/j.hermed.2020.100349] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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19
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Miranda-Nuñez JE, Zamilpa-Alvarez A, Fortis-Barrera A, Alarcon-Aguilar FJ, Loza-Rodriguez H, Gomez-Quiroz LE, Salas-Silva S, Flores-Cruz M, Zavala-Sanchez MA, Blancas-Flores G. GLUT4 translocation in C2C12 myoblasts and primary mouse hepatocytes by an antihyperglycemic flavone from Tillandsia usneoides. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 89:153622. [PMID: 34161895 DOI: 10.1016/j.phymed.2021.153622] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/23/2021] [Accepted: 05/30/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Type 2 Diabetes (T2D) is characterized by deregulation in carbohydrate and lipid metabolism, with a very high mortality rate. Glucose Transporter type 4 (GLUT4) plays a crucial role in T2D and represents a therapeutic target of interest. Tillandsia usneoides (T. usneoides) is a plant used as a remedy for diabetes. T. usneoides decreased blood glucose in different experimental models. However, the involvement of GLUT4 in this effect has not yet been explored. PURPOSE This study aimed to investigate whether any component in T. usneoides might participate in the effect on blood glucose through a bioassay-guided fractionation, testing its potential antihyperglycemic effect in mice, as well as its influence on GLUT4 translocation in C2C12 myoblasts and primary hepatocytes. METHODS The aqueous extract and the Ethyl Acetate fraction (TU-AcOEt) of T. usneoides were evaluated in a hypoglycemic activity bioassay and in the glucose tolerance test in CD-1 mice. TU-AcOEt was fractionated, obtaining five fractions that were studied in an additional glucose tolerance test. C1F3 was fractioned again, and its fractions (C2F9-12, C2F22-25, and C2F38-44) were examined by HPLC. The C2F38-44 fraction was analyzed by Mass Spectrometry (MS) and subjected to additional fractionation. The fraction C3F6-9 was explored by Nuclear Magnetic Resonance (NMR), resulting in 5,7,4´-trihydroxy-3,6,3´,5´-tetramethoxyflavone (Flav1). Subsequently, a viability test was performed to evaluate the cytotoxic effect of Flav1 and fractions C2F9-12, C2F22-25. C2F38-44, and C3F30-41 in C2C12 myoblasts and primary mouse hepatocytes. Confocal microscopy was also performed to assess the effect of Flav1 and fractions on GLUT4 translocation. RESULTS The TU-AcOEt fraction exhibited a hypoglycemic and antihyperglycemic effect in mice, and its fractionation resulted in five fractions, among which fraction C1F3 decreased blood glucose. MS and NMR analysis revealed the presence of Flav1. Finally, Flav1 significantly promoted the translocation of GLUT4 in C2C12 myoblasts and primary hepatocytes. CONCLUSION To date, Flav1 has not been reported to have activity in GLUT4; this study provides evidence that T. usneoides is a plant with the potential to develop novel therapeutic agents for the control of T2D.
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Affiliation(s)
| | - Alejandro Zamilpa-Alvarez
- Departamento de Fitoquímica Farmacológica, Centro de Investigación Biomédica del Sur, Instituto Mexicano del Seguro Social, Xochitepec, Morelos, México
| | - Angeles Fortis-Barrera
- Laboratorio de Farmacología, Departamento de Ciencias de la Salud, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Ciudad de México, México
| | - Francisco Javier Alarcon-Aguilar
- Laboratorio de Farmacología, Departamento de Ciencias de la Salud, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Ciudad de México, México
| | - Hilda Loza-Rodriguez
- Laboratorio de Farmacología, Departamento de Ciencias de la Salud, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Ciudad de México, México
| | - Luis E Gomez-Quiroz
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Ciudad de México, México
| | - Soraya Salas-Silva
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Ciudad de México, México
| | - Maria Flores-Cruz
- Departamento el Hombre y su Ambiente, DCBS, Universidad Autónoma Metropolitana-Xochimilco, Calzada del Hueso 1100, Ciudad de México, México
| | - Miguel Angel Zavala-Sanchez
- Departamento de Sistemas Biológicos, DCBS, Universidad Autónoma Metropolitana-Xochimilco, Calzada del Hueso 1100, Ciudad de México, México
| | - Gerardo Blancas-Flores
- Laboratorio de Farmacología, Departamento de Ciencias de la Salud, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Ciudad de México, México.
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Proanthocyanidins and Where to Find Them: A Meta-Analytic Approach to Investigate Their Chemistry, Biosynthesis, Distribution, and Effect on Human Health. Antioxidants (Basel) 2021; 10:antiox10081229. [PMID: 34439477 PMCID: PMC8389005 DOI: 10.3390/antiox10081229] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/22/2022] Open
Abstract
Proanthocyanidins (PACs) are a class of polyphenolic compounds that are attracting considerable interest in the nutraceutical field due to their potential health benefits. However, knowledge about the chemistry, biosynthesis, and distribution of PACs is limited. This review summarizes the main chemical characteristics and biosynthetic pathways and the main analytical methods aimed at their identification and quantification in raw plant matrices. Furthermore, meta-analytic approaches were used to identify the main plant sources in which PACs were contained and to investigate their potential effect on human health. In particular, a cluster analysis identified PACs in 35 different plant families and 60 different plant parts normally consumed in the human diet. On the other hand, a literature search, coupled with forest plot analyses, highlighted how PACs can be actively involved in both local and systemic effects. Finally, the potential mechanisms of action through which PACs may impact human health were investigated, focusing on their systemic hypoglycemic and lipid-lowering effects and their local anti-inflammatory actions on the intestinal epithelium. Overall, this review may be considered a complete report in which chemical, biosynthetic, ecological, and pharmacological aspects of PACs are discussed.
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Guevara-Vásquez AM, Campos-Florián JV, Dávila-Castillo JH. Annona muricata L. extract decreases intestinal glucose absorption and improves glucose tolerance in normal and diabetic rats. JOURNAL OF HERBMED PHARMACOLOGY 2021. [DOI: 10.34172/jhp.2021.42] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Introduction: Poorly controlled hyperglycemia causes numerous health complications. Postprandial hyperglycemia is an important indicator of diabetic status. The aim of this research was to evaluate the effect of Annona muricata L. extract on the in vitro intestinal glucose absorption in diabetic rats and in vivo antihyperglycemic activity in both normal and diabetic rats. Methods: Phytochemical screening of the aqueous extract from the leaves of A. muricata was carried out. Albino rats were randomly assigned into normal and diabetic groups. Each group was divided into three subgroups: control (vehicle), experimental (A. muricata), and standard (Metformin) groups, to determine antihyperglycemic activity at different times after glucose overload. The everted intestinal sac technique was used to study intestinal glucose absorption in diabetic rats. Results: Aqueous leaf extract of Peruvian A. muricata exhibited statistically significant (P < 0.05) in vivo antihyperglycemic activity in both normal and diabetic rats when compared to the control group. The magnitude of the effect was similar to metformin treatment. Moreover, the aqueous leaf extract of A. muricata significantly diminished in vitro intestinal glucose absorption, with a magnitude similar to metformin treatment. Phytochemical analysis of the aqueous extract revealed the presence of tannins, flavonoids, alkaloids, and leucoanthocyanidins, among others. Conclusion: This study reveals that A. muricata aqueous extract is able to reduce in vitro intestinal glucose absorption and improve oral glucose tolerance in rats.
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Affiliation(s)
- Ana María Guevara-Vásquez
- Department of Pharmacology, School of Pharmacy and Biochemistry, Universidad Nacional de Trujillo, Av. Juan Pablo II s/n, Trujillo, Peru
| | - Julio Víctor Campos-Florián
- Department of Pharmacology, School of Pharmacy and Biochemistry, Universidad Nacional de Trujillo, Av. Juan Pablo II s/n, Trujillo, Peru
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Dietary Flavonoids and Insulin Signaling in Diabetes and Obesity. Cells 2021; 10:cells10061474. [PMID: 34208379 PMCID: PMC8231211 DOI: 10.3390/cells10061474] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes (T2D) and obesity are relevant worldwide chronic diseases. A common complication in both pathologies is the dysregulation of the insulin-signaling pathway that is crucial to maintain an accurate glucose homeostasis. Flavonoids are naturally occurring phenolic compounds abundant in fruits, vegetables and seeds. Rising evidence supports a role for the flavonoids against T2D and obesity, and at present, these compounds are considered as important potential chemopreventive agents. This review summarizes in vitro and in vivo studies providing data related to the effects of flavonoids and flavonoid-rich foods on the modulation of the insulin route during T2D and obesity. Notably, few human studies have evaluated the regulatory effect of these phenolic compounds at molecular level on the insulin pathway. In this context, it is also important to note that the mechanism of action for the flavonoids is not fully characterized and that a proper dosage to obtain a beneficial effect on health has not been defined yet. Further investigations will contribute to solve all these critical challenges and will enable the use of flavonoids to prevent, delay or support the treatment of T2D and obesity.
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23
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Zhao H, Wu H, Duan M, Liu R, Zhu Q, Zhang K, Wang L. Cinnamaldehyde Improves Metabolic Functions in Streptozotocin-Induced Diabetic Mice by Regulating Gut Microbiota. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:2339-2355. [PMID: 34103897 PMCID: PMC8179756 DOI: 10.2147/dddt.s288011] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
Purpose The aim of the present study was to examine the protective effects of cinnamaldehyde (CA) on type 1 diabetes mellitus (T1DM) and explore the underlying molecular mechanisms by using multiple omics technology. Methods T1DM was induced by streptozotocin in the mice. Immunostaining was performed to evaluate glycogen synthesis in the liver and morphological changes in the heart. Gut microbiota was analyzed using 16S rRNA gene amplification sequencing. The serum metabolomics were determined by liquid chromatography-mass spectrometry. The relevant gene expression levels were determined by quantitative real-time PCR. Results CA treatment significantly improved the glucose metabolism and insulin sensitivity in T1DM mice. CA increased glycogen synthesis in the liver and protected myocardial injury in T1DM mice. CA affected the gut microbiota particularly by increasing the relative abundance of Lactobacillus johnsonii and decreasing the relative abundance of Lactobacillus murinus in T1DM mice. The glucose level was positively correlated with 88 functional pathways of gut microbiota and negatively correlated with 2 functional pathways of gut microbiota. Insulin resistance was positively correlated with 11 functional pathways. The analysis of serum metabolomics showed that CA treatment significantly increased the levels of taurochenodeoxycholic acid, tauroursodeoxycholic acid, tauro-α-muricholic acid and tauro-β-muricholic acid, taurodeoxycholic acid, taurocholic acid and taurohyodeoxycholic acid in T1DM mice. Taurohyodeoxycholic acid level was highly correlated with the blood glucose levels. Furthermore, the abundance of Faecalibacterium prausnitzii was positively correlated with AKT2, insulin like growth factor 1 receptor, E2F1 and insulin receptor substrate 1 mRNA expression levels, while taurohyodeoxycholic acid level was negatively correlated with IRS1 mRNA expression level. Conclusion Our results indicated that CA may interfere with gut microbiota to affect host metabolomics, especially the bile acids, so as to directly or indirectly modulate the expression levels of glucose metabolism-related genes, thus subsequently reducing the blood glucose level in the T1DM mice.
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Affiliation(s)
- Honglei Zhao
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, People's Republic of China
| | - Hongyan Wu
- Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Meitao Duan
- Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Ruixuan Liu
- Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Quanhong Zhu
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, People's Republic of China
| | - Kai Zhang
- Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Lili Wang
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, People's Republic of China
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Heeba GH, Rabie EM, Abuzeid MM, Bekhit AA, Khalifa MM. Morin alleviates fructose-induced metabolic syndrome in rats via ameliorating oxidative stress, inflammatory and fibrotic markers. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2021; 25:177-187. [PMID: 33859058 PMCID: PMC8050609 DOI: 10.4196/kjpp.2021.25.3.177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 08/26/2020] [Accepted: 09/10/2020] [Indexed: 11/15/2022]
Abstract
Metabolic syndrome (MBS) is a widespread disease that has strongly related to unhealthy diet and low physical activity, which initiate more serious conditions such as obesity, cardiovascular diseases and type 2 diabetes mellitus. This study aimed to examine the therapeutic effects of morin, as one of the flavonoids constituents, which widely exists in many herbs and fruits, against some metabolic and hepatic manifestations observed in MBS rats and the feasible related mechanisms. MBS was induced in rats by high fructose diet feeding for 12 weeks. Morin (30 mg/kg) was administered orally to both normal and MBS rats for 4 weeks. Liver tissues were used for determination of liver index, hepatic expression of glucose transporter 2 (GLUT2) as well as both inflammatory and fibrotic markers. The fat/muscle ratio, metabolic parameters, systolic blood pressure, and oxidative stress markers were also determined. Our data confirmed that the administration of morin in fructose diet rats significantly reduced the elevated systolic blood pressure. The altered levels of metabolic parameters such as blood glucose, serum insulin, serum lipid profile, and oxidative stress markers were also reversed approximately to the normal values. In addition, morin treatment decreased liver index, serum liver enzyme activities, and fat/muscle ratio. Furthermore, morin relatively up-regulated GLUT2 expression, however, down-regulated NF-κB, TNF-α, and TGF-β expressions in the hepatic tissues. Here, we revealed that morin has an exquisite effect against metabolic disorders in the experimental model through, at least in part, antioxidant, anti-inflammatory, and anti-fibrotic mechanisms.
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Affiliation(s)
- Gehan Hussein Heeba
- Departments of Pharmacology and Toxicology, Minia University, El-Minia 61111, Egypt
| | - Esraa Mohamed Rabie
- Departments of Pharmacology and Toxicology, Minia University, El-Minia 61111, Egypt
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25
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Carrizzo A, Izzo C, Forte M, Sommella E, Di Pietro P, Venturini E, Ciccarelli M, Galasso G, Rubattu S, Campiglia P, Sciarretta S, Frati G, Vecchione C. A Novel Promising Frontier for Human Health: The Beneficial Effects of Nutraceuticals in Cardiovascular Diseases. Int J Mol Sci 2020; 21:E8706. [PMID: 33218062 PMCID: PMC7698807 DOI: 10.3390/ijms21228706] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/03/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs) such as hypertension, atherosclerosis, myocardial infarction, and diabetes are a significant public health problem worldwide. Although several novel pharmacological treatments to reduce the progression of CVDs have been discovered during the last 20 years, the better way to contain the onset of CVDs remains prevention. In this regard, nutraceuticals seem to own a great potential in maintaining human health, exerting important protective cardiovascular effects. In the last years, there has been increased focus on identifying natural compounds with cardiovascular health-promoting effects and also to characterize the molecular mechanisms involved. Although many review articles have focused on the individual natural compound impact on cardiovascular diseases, the aim of this manuscript was to examine the role of the most studied nutraceuticals, such as resveratrol, cocoa, quercetin, curcumin, brassica, berberine and Spirulina platensis, on different CVDs.
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Affiliation(s)
- Albino Carrizzo
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Carmine Izzo
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Maurizio Forte
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
| | - Eduardo Sommella
- Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy;
| | - Paola Di Pietro
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Eleonora Venturini
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
| | - Michele Ciccarelli
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Gennaro Galasso
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Speranza Rubattu
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
- Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S.Andrea, Via di Grottarossa 1035, 00189 Rome, Italy
| | - Petro Campiglia
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
| | - Sebastiano Sciarretta
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 74, 04100 Latina, Italy
| | - Giacomo Frati
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 74, 04100 Latina, Italy
| | - Carmine Vecchione
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, 86077 Pozzilli, Italy; (A.C.); (M.F.); (E.V.); (S.R.); (S.S.); (G.F.)
- Department of Medicine and Surgery, University of Salerno, 84081 Baronissi, Italy; (C.I.); (P.D.P.); (M.C.); (G.G.); (P.C.)
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Gao L, Yuan P, Zhang Q, Fu Y, Hou Y, Wei Y, Zheng X, Feng W. Taxifolin improves disorders of glucose metabolism and water-salt metabolism in kidney via PI3K/AKT signaling pathway in metabolic syndrome rats. Life Sci 2020; 263:118713. [PMID: 33157091 DOI: 10.1016/j.lfs.2020.118713] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/23/2020] [Accepted: 11/02/2020] [Indexed: 12/16/2022]
Abstract
AIMS Our study was designed to explore the function and mechanism of taxifolin on glucose metabolism and water-salt metabolism in kidney with metabolic syndrome (MS) rats. MAIN METHODS Spontaneous hypertensive rats were induced by fructose to establish MS model. Systolic blood pressure (SBP) and homeostasis model assessment of insulin resistance (HOMA-IR) were measured after 7 weeks of continuous administration with taxifolin. Kidney injury indices and histopathological evaluation were done. The apoptosis rate of primary kidney cells was detected by flow cytometry. Insulin signaling pathway related proteins and renal glucose transport-related proteins were detected by western blotting. We assessed the effects of taxifolin on sodium water retention and renin-angiotensin-aldosterone system (RAAS) in MS rats. We examined not only changes in urine volume, osmotic pressure, urinary sodium and urinary chloride excretion, but also the effects on NA+/K+-ATPase and RAAS indicators. We also detected changes in inflammatory factors by immunohistochemical staining and immunofluorescence. In vitro experiment, high glucose and salt stimulated NRK-52E cells. By adding the PI3K inhibitor (wortmannin) to inhibit the PI3K, the effects of inhibiting the PI3K/AKT signaling pathway on glucose metabolism, water-sodium retention and inflammatory response were discussed. KEY FINDINGS Taxifolin effectively reversed SBP, HOMA-IR, the kidney indices and abnormal histopathological changes induced by MS. Besides, taxifolin called back the protein associated with the downstream glucose metabolism pathway of PI3K/AKT. It also inhibited overactivation of RAAS and inflammatory response. In vitro experiments have demonstrated that the PI3K/AKT signaling pathway plays an important role in this process. SIGNIFICANCE Taxifolin can improve homeostasis of glucose, inhibit overactivation of RAAS and reduce inflammatory response by PI3K/AKT signaling pathway.
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Affiliation(s)
- Liyuan Gao
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Peipei Yuan
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Qi Zhang
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yang Fu
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Ying Hou
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yaxin Wei
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Xiaoke Zheng
- Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China.
| | - Weisheng Feng
- Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China.
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Li T, Chang R, Zhang H, Du M, Mao X. Water Extract of Potentilla discolor Bunge Improves Hepatic Glucose Homeostasis by Regulating Gluconeogenesis and Glycogen Synthesis in High-Fat Diet and Streptozotocin-Induced Type 2 Diabetic Mice. Front Nutr 2020; 7:161. [PMID: 33043040 PMCID: PMC7522508 DOI: 10.3389/fnut.2020.00161] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 08/10/2020] [Indexed: 12/12/2022] Open
Abstract
Potentilla discolor Bunge, as a traditional Chinese medicine, exhibits many phytochemical activities. The aim of the present study was to investigate the effects of Potentilla discolor Bunge water extract (PDBW) and its underlying mechanisms on gluconeogenesis and glycogen synthesis in high-fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic mice. LC-MS/MS analyses of PDBW identified 6 major compounds including apigenin-7-O-β-D-glucoside, epicatechin, quercetin 3-O-β-D-glucuronide, kaempferol-3-O-β-D-glucopyranoside, scutellarin, and quercitrin. In the study, a mouse model of type 2 diabetes was induced by 4-week HFD combined with STZ (40 mg/kg body weight) for 5 days. After oral administration of PDBW at 400 mg/kg body weight daily for 8 weeks, the mice with type 2 diabetes showed significant decrease in the levels of fasting blood glucose and glycated hemoglobin A1c (HbA1c), and increase in the insulin level. PDBW improved the glucose tolerance, insulin sensitivity and lipid profiles. Furthermore, PDBW inhibited the mRNA levels of key gluconeogenic enzymes [phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase)] in liver. PDBW also promoted glycogen synthesis by raising the liver glycogen content, decreasing the phosphorylation of glycogen synthase (GS) and increasing the phosphorylation of glycogen synthase kinase3β (GSK3β). Besides, PDBW induced the activation of protein kinase B (Akt) and AMP-activated protein kinase (AMPK), which might explain changes in the phosphorylation of above enzymes. In summary, PDBW supplementation ameliorates metabolic disorders in a HFD/STZ diabetic mouse model, suggesting the potential application of PDBW in prevention and amelioration of type 2 diabetes.
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Affiliation(s)
- Tiange Li
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Rui Chang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Huijuan Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Min Du
- Department of Animal Sciences, Washington State University, Pullman, WA, United States
| | - Xueying Mao
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
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28
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Cremonini E, Iglesias DE, Kang J, Lombardo GE, Mostofinejad Z, Wang Z, Zhu W, Oteiza PI. (-)-Epicatechin and the comorbidities of obesity. Arch Biochem Biophys 2020; 690:108505. [PMID: 32679195 DOI: 10.1016/j.abb.2020.108505] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/10/2020] [Indexed: 02/07/2023]
Abstract
Obesity has major adverse consequences on human health contributing to the development of, among others, insulin resistance and type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, altered behavior and cognition, and cancer. Changes in dietary habits and lifestyle could contribute to mitigate the development and/or progression of these pathologies. This review will discuss current evidence on the beneficial actions of the flavan-3-ol (-)-epicatechin (EC) on obesity-associated comorbidities. These benefits can be in part explained through EC's capacity to mitigate several common events underlying the development of these pathologies, including: i) high circulating levels of glucose, lipids and endotoxins; ii) chronic systemic inflammation; iii) tissue endoplasmic reticulum and oxidative stress; iv) insulin resistance; v) mitochondria dysfunction and vi) dysbiosis. The currently known underlying mechanisms and cellular targets of EC's beneficial effects are discussed. While, there is limited evidence from human studies supplementing with pure EC, other studies involving cocoa supplementation in humans, pure EC in rodents and in vitro studies, support a potential beneficial action of EC on obesity-associated comorbidities. This evidence also stresses the need of further research in the field, which would contribute to the development of human dietary strategies to mitigate the adverse consequences of obesity.
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Affiliation(s)
- Eleonora Cremonini
- Departments of Nutrition and Environmental Toxicology, University of California, Davis, CA, USA
| | - Dario E Iglesias
- Departments of Nutrition and Environmental Toxicology, University of California, Davis, CA, USA
| | - Jiye Kang
- Departments of Nutrition and Environmental Toxicology, University of California, Davis, CA, USA
| | - Giovanni E Lombardo
- Departments of Nutrition and Environmental Toxicology, University of California, Davis, CA, USA; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
| | - Zahra Mostofinejad
- Departments of Nutrition and Environmental Toxicology, University of California, Davis, CA, USA
| | - Ziwei Wang
- Departments of Nutrition and Environmental Toxicology, University of California, Davis, CA, USA
| | - Wei Zhu
- Departments of Nutrition and Environmental Toxicology, University of California, Davis, CA, USA
| | - Patricia I Oteiza
- Departments of Nutrition and Environmental Toxicology, University of California, Davis, CA, USA.
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Aloud AA, Chinnadurai V, Chandramohan G, Alsaif MA, Al-Numair KS. Galangin controls streptozotocin-caused glucose homeostasis and reverses glycolytic and gluconeogenic enzyme changes in rats. Arch Physiol Biochem 2020; 126:101-106. [PMID: 30269607 DOI: 10.1080/13813455.2018.1498521] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Galangin is a natural compound with anticancer, anti-inflammatory, and antioxidant properties. However, the ameliorating effect of streptozotocin (STZ)-induced glucose homeostasis has not yet been evaluated. Hence, this study was aimed at exploring the role of galangin in STZ-induced glucose homeostasis, glycolytic and gluconeogenic enzyme changes in rats. STZ-treated rats were characterised by increased plasma glucose and glycosylated haemoglobin and decreased plasma insulin and haemoglobin compared with the normal cage. Administration of galangin to STZ-treated rats effectively reversed the adverse biochemical and haematological changes. Significant alterations in glycogen levels as well as glycolytic and gluconeogenic enzyme activities were witnessed in STZ-treated rats, and these changes were reversed upon treatment with galangin. The compound exerts potent anti-hyperglycemic effects by regulating the glucose homeostasis and reversing the glycolytic and gluconeogenic enzyme changes in rats. However, the exact mechanism through which galangin prevents diabetic complications needs to be studied in detail.
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Affiliation(s)
- Amal A Aloud
- Department of Food Sciences and Nutrition, College of Food and Agriculture Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Veeramani Chinnadurai
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Govindasamy Chandramohan
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed A Alsaif
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Khalid S Al-Numair
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
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Long XS, Liao ST, Wen P, Zou YX, Liu F, Shen WZ, Hu TG. Superior hypoglycemic activity of mulberry lacking monosaccharides is accompanied by better activation of the PI3K/Akt and AMPK signaling pathways. Food Funct 2020; 11:4249-4258. [PMID: 32356550 DOI: 10.1039/d0fo00427h] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Mulberry has been used as a functional food to treat type 2 diabetes mellitus (T2DM). However, it contains relatively high levels of fructose and glucose, which are not suitable for excess consumption by diabetic patients. In this study we used microbial fermentation to remove fructose and glucose from mulberry fruit, and then determined the effects on glycemia, the phosphatidylinositol 3-hydroxykinase/Akt (PI3K/Akt) and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways and their downstream effectors in T2DM mice. After 5 weeks of administration, fermented mulberry (FM) significantly reduced fasting blood glucose, and also improved insulin sensitivity and glucose tolerance, more effectively than unfermented mulberry (MP). Moreover, compared with MP, FM had a more marked effect on the protein expression of intermediates in the PI3K/Akt and AMPK signaling pathways and their effectors: insulin receptor, phosphorylated Akt (Ser 308), phosphorylated glycogen synthase kinase-3β (Ser 9), glycogen synthetase, phosphorylated forkhead transcription factor 1 (Ser 256), pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-bisphosphatase, glucose-6-phosphatase, lipoprotein lipase, and phosphorylated AMPK (Thr 172), glucose transporter 4 and pyruvate kinase. These findings indicate that mulberry fruit modified to remove fructose and glucose may be more promising than whole mulberry as a treatment for diabetes.
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Affiliation(s)
- Xiao-Shan Long
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, No. 133 Yiheng St., Dongguanzhuang Rd, Tianhe District, Guangzhou 510610, P.R. China.
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Caponio GR, Lorusso MP, Sorrenti GT, Marcotrigiano V, Difonzo G, De Angelis E, Guagnano R, Ciaula AD, Diella G, Logrieco AF, Montagna MT, Monaci L, De Angelis M, Portincasa P. Chemical Characterization, Gastrointestinal Motility and Sensory Evaluation of Dark Chocolate: A Nutraceutical Boosting Consumers' Health. Nutrients 2020; 12:939. [PMID: 32231009 PMCID: PMC7230710 DOI: 10.3390/nu12040939] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/25/2020] [Accepted: 03/26/2020] [Indexed: 02/07/2023] Open
Abstract
We performed a comprehensive study encompassing chemical characterization and sensory evaluation of two types of dark chocolate, i.e., artisanal (Choco-A) and industrial (Choco-I), as well as an evaluation of onset of gastrointestinal symptoms and gastrointestinal motility in healthy subjects fed with dark chocolate. Proteomic, lipid and metabolite analysis were performed by LC-MS/MS analysis and the total phenol content and antioxidant activity were estimated in both types of chocolate. Fifty healthy volunteers joined the study of the sensory characteristics of both types of chocolate; another 16 subjects underwent the study of gallbladder and gastric emptying by functional ultrasonography and orocecal transit time by lactulose H2-breath test after ingestion of dark chocolate. Identification of polyphenols, amino acids and fatty acids was carried out in both types of chocolate analysed, and results confirmed their richness in polyphenols, amino acid derivatives and fatty acids (FAs) either saturated (stearic, myristic, palmitic, ecosanoic) or unsaturated (oleic and linolenic). For agreeability, Choco-A scored higher than Choco-I for smell, texture, and taste and they did not show significant differences in the gastrointestinal motility. In conclusion as for gastrointestinal motility studies, we report that the ingestion of a small amount of chocolate induced a mild gallbladder, gastric contraction and a fast transit time compared to the test meal in healthy subjects.
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Affiliation(s)
- Giusy Rita Caponio
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, via Amendola 165/a, 70126 Bari, Italy; (G.R.C.); (M.D.A.)
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Michele Pio Lorusso
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Giovanni Trifone Sorrenti
- Food Hygiene and Nutrition Service, Department of Prevention, Local Health Unit BT, 76125 Barletta-Andria-Trani, Italy; (G.T.S.); (V.M.)
| | - Vincenzo Marcotrigiano
- Food Hygiene and Nutrition Service, Department of Prevention, Local Health Unit BT, 76125 Barletta-Andria-Trani, Italy; (G.T.S.); (V.M.)
| | - Graziana Difonzo
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, via Amendola 165/a, 70126 Bari, Italy; (G.R.C.); (M.D.A.)
| | - Elisabetta De Angelis
- Institute of Sciences of Food Production, National Research Council of Italy (ISPA-CNR), Via Amendola 122/o, 70126 Bari, Italy; (E.D.A.); (A.F.L.)
| | - Rocco Guagnano
- Institute of Sciences of Food Production, National Research Council of Italy (ISPA-CNR), Via Amendola 122/o, 70126 Bari, Italy; (E.D.A.); (A.F.L.)
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Giusy Diella
- Department of Biomedical Sciences and Human Oncology, Section of Hygiene, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy (M.T.M.)
| | - Antonio Francesco Logrieco
- Institute of Sciences of Food Production, National Research Council of Italy (ISPA-CNR), Via Amendola 122/o, 70126 Bari, Italy; (E.D.A.); (A.F.L.)
| | - Maria Teresa Montagna
- Department of Biomedical Sciences and Human Oncology, Section of Hygiene, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy (M.T.M.)
| | - Linda Monaci
- Institute of Sciences of Food Production, National Research Council of Italy (ISPA-CNR), Via Amendola 122/o, 70126 Bari, Italy; (E.D.A.); (A.F.L.)
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, via Amendola 165/a, 70126 Bari, Italy; (G.R.C.); (M.D.A.)
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Piazza G. Cesare 11, 70124 Bari, Italy
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Sun C, Zhao C, Guven EC, Paoli P, Simal‐Gandara J, Ramkumar KM, Wang S, Buleu F, Pah A, Turi V, Damian G, Dragan S, Tomas M, Khan W, Wang M, Delmas D, Portillo MP, Dar P, Chen L, Xiao J. Dietary polyphenols as antidiabetic agents: Advances and opportunities. FOOD FRONTIERS 2020; 1:18-44. [DOI: 10.1002/fft2.15] [Citation(s) in RCA: 162] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
AbstractDietary polyphenols have been widely investigated as antidiabetic agents in cell, animals, human study, and clinical trial. The number of publication (Indexed by Web of Science) on “polyphenols and diabetes” significantly increased since 2010. This review highlights the advances and opportunities of dietary polyphenols as antidiabetic agents. Dietary polyphenols prevent and manage Type 2 diabetes mellitus via the insulin‐dependent approaches, for instance, protection of pancreatic islet β‐cell, reduction of β‐cell apoptosis, promotion of β‐cell proliferation, attenuation of oxidative stress, activation of insulin signaling, and stimulation of pancreas to secrete insulin, as well as the insulin‐independent approaches including inhibition of glucose absorption, inhibition of digestive enzymes, regulation of intestinal microbiota, modification of inflammation response, and inhibition of the formation of advanced glycation end products. Moreover, dietary polyphenols ameliorate diabetic complications, such as vascular dysfunction, nephropathy, retinopathy, neuropathy, cardiomyopathy, coronary diseases, renal failure, and so on. The structure–activity relationship of polyphenols as antidiabetic agents is still not clear. The individual flavonoid or isoflavone has no therapeutic effect on diabetic patients, although the clinical data are very limited. Resveratrol, curcumin, and anthocyanins showed antidiabetic activity in human study. How hyperglycemia influences the bioavailability and bioactivity of dietary polyphenols is not well understood. An understanding of how diabetes alters the bioavailability and bioactivity of dietary polyphenols will lead to an improvement in their benefits and clinical outcomes.
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Affiliation(s)
- Chongde Sun
- Zhejiang Provincial Key Laboratory of Horticultural Plant Integrative Biology Zhejiang University Hangzhou China
| | - Chao Zhao
- College of Food Science Fujian Agriculture and Forestry University Fuzhou China
- State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau Macau China
| | - Esra Capanoglu Guven
- Department of Food Engineering Faculty of Chemical and Metallurgical Engineering İstanbul Technical University Istanbul Turkey
| | - Paolo Paoli
- Department of Biomedical, Experimental, and Clinical Sciences University of Florence Florence Italy
| | - Jesus Simal‐Gandara
- Nutrition and Bromatology Group Department of Analytical Chemistry and Food Science Faculty of Food Science and Technology University of Vigo ‐ Ourense Campus Ourense Spain
| | - Kunka Mohanram Ramkumar
- Life Science Division SRM Research Institute SRM University Kattankulathur India
- Department of Biotechnology School of Bio‐engineering SRM University Kattankulathur India
| | - Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau Macau China
| | - Florina Buleu
- Centre for Interdisciplinary Research & Department of Cardiology University of Medicine and Pharmacy Victor Babes Timisoara Romania
| | - Ana Pah
- Centre for Interdisciplinary Research & Department of Cardiology University of Medicine and Pharmacy Victor Babes Timisoara Romania
| | - Vladiana Turi
- Centre for Interdisciplinary Research & Department of Cardiology University of Medicine and Pharmacy Victor Babes Timisoara Romania
| | - Georgiana Damian
- Centre for Interdisciplinary Research & Department of Cardiology University of Medicine and Pharmacy Victor Babes Timisoara Romania
| | - Simona Dragan
- Centre for Interdisciplinary Research & Department of Cardiology University of Medicine and Pharmacy Victor Babes Timisoara Romania
| | - Merve Tomas
- Faculty of Engineering and Natural Sciences Food Engineering Department Istanbul Sabahattin Zaim University Istanbul Turkey
| | - Washim Khan
- National Center for Natural Products Research School of Pharmacy The University of Mississippi, University Mississippi
| | - Mingfu Wang
- School of Biological Sciences The University of Hong Kong Pokfulam Hong Kong
| | - Dominique Delmas
- INSERM U866 Research Center Université de Bourgogne Franche‐Comté Dijon France
- INSERM Research Center U1231 – Cancer and Adaptive Immune Response Team Bioactive Molecules and Health Research Group Dijon France
- Centre Anticancéreux Georges François Leclerc Center Dijon France
| | - Maria Puy Portillo
- Nutrition and Obesity Group Department of Nutrition and Food Science Faculty of Pharmacy and Lucio Lascaray Research Institute University of País Vasco (UPV/EHU) Vitoria‐Gasteiz Spain
- CIBEROBN Physiopathology of Obesity and Nutrition Institute of Health Carlos III (ISCIII) Vitoria‐Gasteiz Spain
| | - Parsa Dar
- State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau Macau China
| | - Lei Chen
- College of Food Science Fujian Agriculture and Forestry University Fuzhou China
| | - Jianbo Xiao
- State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau Macau China
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Karaman EF, Zeybel M, Ozden S. Evaluation of the epigenetic alterations and gene expression levels of HepG2 cells exposed to zearalenone and α-zearalenol. Toxicol Lett 2020; 326:52-60. [PMID: 32119988 DOI: 10.1016/j.toxlet.2020.02.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 02/14/2020] [Accepted: 02/27/2020] [Indexed: 01/30/2023]
Abstract
Zearalenone, produced by various Fusarium species, is a non-steroidal estrogenic mycotoxin that contaminates cereals, resulting in adverse effects on human health. We investigated the effects of zearalenone and its metabolite alpha zearalenol on epigenetic modifications and its relationship with metabolic pathways in human hepatocellular carcinoma cells following 24 h of exposure. Zearalenone and alpha zearalenol at the concentrations of 1, 10 and 50 μM significantly increased global levels of DNA methylation and global histone modifications (H3K27me3, H3K9me3, H3K9ac). Expression levels of the chromatin modifying enzymes EHMT2, ESCO1, HAT1, KAT2B, PRMT6 and SETD8 were upregulated by 50 μM of zearalenone exposure using PCR arrays, consistent with the results of global histone modifications. Zearalenone and alpha zearalenol also changed expression levels of the AhR, LXRα, PPARα, PPARɣ, L-fabp, LDLR, Glut2, Akt1 and HK2 genes, which are related to nuclear receptors and metabolic pathways. PPARɣ, a key regulator of lipid metabolism, was selected from among these genes for further analysis. The PPARɣ promoter reduced methylation significantly following zearalenone exposure. Taken together, the epigenetic mechanisms of DNA methylation and histone modifications may be key mechanisms in zearalenone toxicity. Furthermore, effects of zearalenone in metabolic pathways could be mediated by epigenetic modifications.
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Affiliation(s)
- Ecem Fatma Karaman
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, 34116, Beyazit, Istanbul, Turkey
| | - Müjdat Zeybel
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, 34010, Topkapi, Istanbul, Turkey
| | - Sibel Ozden
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, 34116, Beyazit, Istanbul, Turkey.
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The Effects and Mechanism of Quercetin Dietary Supplementation in Streptozotocin-Induced Hyperglycemic Arbor Acre Broilers. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9585047. [PMID: 32104545 PMCID: PMC7035566 DOI: 10.1155/2020/9585047] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 12/28/2019] [Accepted: 01/24/2020] [Indexed: 12/19/2022]
Abstract
Quercetin, a flavonoid found in fruits and vegetables, is widely distributed as a secondary metabolite in the plant kingdom. Oxidative stress plays a role in the pathogenesis of diabetes mellitus (DM). The present study investigated the effects of quercetin dietary supplementation on streptozotocin- (STZ-) induced hyperglycemic Arbor Acre (AA) broilers by determining the levels of fasting blood glucose (FBG), fasting insulin (FINS), biochemical indicators, oxidative stress markers, inflammatory cytokines content, antioxidant enzymes activities in tissues, and mRNA expression of genes relating to the insulin signaling pathway. Three hundred one-day-old healthy AA broilers were randomly assigned into 5 treatments; A, control healthy broilers; B, STZ-induced broilers; C, STZ-induced broiler dietary supplemented with 0.02% quercetin; D, STZ-induced broiler dietary supplemented with 0.04% quercetin; and E, STZ-induced broiler dietary supplemented with 0.06% quercetin. The results showed that quercetin supplementation relieved the side effects of STZ-induced oxidative stress by changing activities of antioxidant enzymes, decreasing malondialdehyde (MDA) and nitric oxide (NO) levels, activating expression of genes relating to PI3K/PKB signaling pathway that modulate glucose metabolism and reduce oxidative damage, thereby decreasing FBG and increasing FINS levels. These findings suggest that quercetin exhibits a protective effect in STZ-induced hyperglycemic AA broilers via decreasing oxidative stress.
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Flavonoids and type 2 diabetes: Evidence of efficacy in clinical and animal studies and delivery strategies to enhance their therapeutic efficacy. Pharmacol Res 2020; 152:104629. [PMID: 31918019 DOI: 10.1016/j.phrs.2020.104629] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/23/2019] [Accepted: 01/02/2020] [Indexed: 12/26/2022]
Abstract
Diabetes mellitus type 2 (T2DM) is a metabolic disorder develops due to the overproduction of free radicals where oxidative stress could contribute it. Possible factors are defective insulin signals, glucose oxidation, and degradation of glycated proteins as well as alteration in glutathione metabolism which induced hyperglycemia. Previous studies revealed a link between T2DM with oxidative stress, inflammation and insulin resistance which are assumed to be regulated by numerous cellular networks such as NF-κB, PI3K/Akt, MAPK, GSK3 and PPARγ. Flavonoids are ubiquitously present in the nature and classified according to their chemical structures for example, flavonols, flavones, flavan-3-ols, anthocyanidins, flavanones, and isoflavones. Flavonoids indicate poor bioavailability which could be improved by employing various nano-delivery systems against the occurrences of T2DM. These bioactive compounds exert versatile anti-diabetic activities via modulating targeted cellular signaling networks, thereby, improving glucose metabolism, α -glycosidase, and glucose transport or aldose reductase by carbohydrate metabolic pathway in pancreatic β-cells, hepatocytes, adipocytes and skeletal myofibres. Moreover, anti-diabetic properties of flavonoids also encounter diabetic related complications. This review article has designed to shed light on the anti-diabetic potential of flavonoids, contribution of oxidative stress, evidence of efficacy in clinical, cellular and animal studies and nano-delivery approaches to enhance their therapeutic efficacy. This article might give some new insights for therapeutic intervention against T2DM in near future.
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Chen L, Lin X, Teng H. Emulsions loaded with dihydromyricetin enhance its transport through Caco-2 monolayer and improve anti-diabetic effect in insulin resistant HepG2 cell. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103672] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Park SJ, Lee D, Kim D, Lee M, In G, Han ST, Kim SW, Lee MH, Kim OK, Lee J. The non-saponin fraction of Korean Red Ginseng (KGC05P0) decreases glucose uptake and transport in vitro and modulates glucose production via down-regulation of the PI3K/AKT pathway in vivo. J Ginseng Res 2019; 44:362-372. [PMID: 32148419 PMCID: PMC7031776 DOI: 10.1016/j.jgr.2019.12.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 11/08/2019] [Accepted: 12/10/2019] [Indexed: 01/26/2023] Open
Abstract
Background The non-saponin fraction of Korean Red Ginseng has been reported to have many biological activities. However, the effect of this fraction on anti-diabetic activity has not been elucidated in detail. In this study, we investigated the effects of KGC05P0, a non-saponin fraction of Korean Red Ginseng, on anti-diabetic activity in vitro and in vivo. Methods We measured the inhibition of commercially obtained α-glucosidase and α-amylase activities in vitro and measured the glucose uptake and transport rate in Caco-2 cells. C57BL/6J mice and C57BLKS/Jdb/db (diabetic) mice were fed diets with or without KGC05P0 for eight weeks. To perform the experiments, the groups were divided as follows: normal control (C57BL/6J mice), db/db control (C57BLKS/Jdb/db mice), positive control (inulin 400 mg/kg b.w.), low (KGC05P0 100 mg/kg b.w.), medium (KGC05P0 200 mg/kg b.w.), and high (KGC05P0 400 mg/kg b.w.). Results KGC05P0 inhibited α-glucosidase and α-amylase activities in vitro, and decreased glucose uptake and transport rate in Caco-2 cells. In addition, KGC05P0 regulated fasting glucose level, glucose tolerance, insulin, HbA1c, carbonyl contents, and proinflammatory cytokines in blood from diabetic mice and significantly reduced urinary glucose excretion levels. Moreover, we found that KGC05P0 regulated glucose production by down-regulation of the PI3K/AKT pathway, which inhibited gluconeogenesis. Conclusion Our study thereby demonstrated that KGC05P0 exerted anti-diabetic effects through inhibition of glucose absorption and the PI3K/AKT pathway in in vitro and in vivo models of diabetes. Our results suggest that KGC05P0 could be developed as a complementary food to help prevent T2DM and its complications.
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Affiliation(s)
- Soo-Jeung Park
- Department of Medical Nutrition, Kyung Hee University, Yongin, Gwangju, Republic of Korea
| | - Dasom Lee
- Department of Medical Nutrition, Kyung Hee University, Yongin, Gwangju, Republic of Korea
| | - Dakyung Kim
- Department of Medical Nutrition, Kyung Hee University, Yongin, Gwangju, Republic of Korea
| | - Minhee Lee
- Department of Medical Nutrition, Kyung Hee University, Yongin, Gwangju, Republic of Korea
| | - Gyo In
- Korea Ginseng Corporation Research Institute, Korea Ginseng Corporation, Daejeon, Gwangju, Republic of Korea
| | - Sung-Tai Han
- Korea Ginseng Corporation Research Institute, Korea Ginseng Corporation, Daejeon, Gwangju, Republic of Korea
| | - Sung Won Kim
- Korea Ginseng Corporation Research Institute, Korea Ginseng Corporation, Daejeon, Gwangju, Republic of Korea
| | - Mi-Hyang Lee
- Korea Ginseng Corporation Research Institute, Korea Ginseng Corporation, Daejeon, Gwangju, Republic of Korea
| | - Ok-Kyung Kim
- Division of Food and Nutrition and Research Institute for Human Ecology, Chonnam National University, Gwangju, Republic of Korea
| | - Jeongmin Lee
- Department of Medical Nutrition, Kyung Hee University, Yongin, Gwangju, Republic of Korea
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Momtaz S, Salek-Maghsoudi A, Abdolghaffari AH, Jasemi E, Rezazadeh S, Hassani S, Ziaee M, Abdollahi M, Behzad S, Nabavi SM. Polyphenols targeting diabetes via the AMP-activated protein kinase pathway; future approach to drug discovery. Crit Rev Clin Lab Sci 2019; 56:472-492. [PMID: 31418340 DOI: 10.1080/10408363.2019.1648376] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 06/06/2019] [Accepted: 07/23/2019] [Indexed: 01/02/2023]
Abstract
Regarding the widespread progression of diabetes, its related complications and detrimental effects on human health, investigations on this subject seems compulsory. AMP-activated protein kinase (AMPK) is a serine/threonine kinase and a key player in energy metabolism regulation. AMPK is also considered as a prime target for pharmaceutical and therapeutic studies on disorders such as diabetes, metabolic syndrome and obesity, where the body energy homeostasis is imbalanced. Following the activation of AMPK (physiological or pharmacological), a cascade of metabolic events that improve metabolic health is triggered. While there are several publications on this subject, this is the first report that has focused solely on polyphenols targeting diabetes via AMPK pathway. The multiple characteristics of polyphenolic compounds and their favorable influence on diabetes pathogenesis, as well as their intersections with the AMPK signaling pathway, indicate that these compounds have a beneficial effect on the regulation of glucose homeostasis. PPs could potentially occupy a significant position in the future anti-diabetic drug market.
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Affiliation(s)
- Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR , Karaj , Iran
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences , Tehran , Iran
| | - Armin Salek-Maghsoudi
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences , Tehran , Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences , Tehran , Iran
| | - Amir Hossein Abdolghaffari
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR , Karaj , Iran
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences , Tehran , Iran
- Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN) , Tehran , Iran
- Department of Pharmacology, Pharmaceutical Sciences Branch, Islamic Azad University , Tehran , Iran
| | - Eghbal Jasemi
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR , Karaj , Iran
| | - Shamsali Rezazadeh
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR , Karaj , Iran
| | - Shokoufeh Hassani
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences , Tehran , Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences , Tehran , Iran
| | - Mojtaba Ziaee
- Cardiovascular Research Center, Tabriz University of Medical Sciences , Tabriz , Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences , Tehran , Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences , Tehran , Iran
| | - Sahar Behzad
- Evidence-Based Phytotherapy and Complementary Medicine Research Center, Alborz University of Medical Sciences , Karaj , Iran
- Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences , Tehran , Iran
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Jia Y, Ma Y, Cheng G, Zhang Y, Cai S. Comparative Study of Dietary Flavonoids with Different Structures as α-Glucosidase Inhibitors and Insulin Sensitizers. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:10521-10533. [PMID: 31461284 DOI: 10.1021/acs.jafc.9b04943] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
This work was designed to comparatively investigate 27 dietary flavonoids that act as α-glucosidase inhibitors and insulin sensitizers. On the basis of the results of an in vitro experiment of α-glucosidase inhibition, myricetin (IC50 = 11.63 ± 0.36 μM) possessed the strongest inhibitory effect, followed by apigenin-7-O-glucoside (IC50 = 22.80 ± 0.24 μM) and fisetin (IC50 = 46.39 ± 0.34 μM). A three-dimensional quantitative structure-activity relationship model of α-glucosidase inhibitors with good predictive capability [comparative molecular field analysis, q2 = 0.529, optimum number of components (ONC) = 10, R2 = 0.996, F = 250.843, standard error of estimation (SEE) = 0.064, and two descriptors; comparative similarity index analysis, q2 = 0.515, ONC = 10, R2 = 0.997, F = 348.301, SEE = 0.054, and four descriptors] was established and indicated that meta positions of ring B favored bulky and minor, electron-withdrawing, and hydrogen bond donor groups. The presence of electron-donating and hydrogen bond acceptor groups at position 4' of ring B could improve α-glucosidase activity. Position 3 of ring C favored minor, electron-donating, and hydrogen bond donor groups, whereas position 7 of ring A favored bulky and hydrogen bond acceptor groups. Molecular docking screened five flavonoids (baicalein, isorhamnetin-3-O-rutinoside, apigenin-7-O-glucoside, kaempferol-7-O-β-glucoside, and cyanidin-3-O-glucoside) that can act as insulin sensitizers and form strong combinations with four key protein targets involved in the insulin signaling pathway. Apigenin-7-O-glucoside (60 μM) can effectively improve insulin resistance, and glucose uptake increased by approximately 73.06% relative to the model group of insulin-resistant HepG2 cells. Therefore, apigenin-7-O-glucoside might serve as the most effective α-glucosidase inhibitor and insulin sensitizer. This work may guide diabetes patients to improve their condition through dietary therapy.
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Affiliation(s)
- Yijia Jia
- Yunnan Institute of Food Safety , Kunming University of Science and Technology , Kunming , Yunnan 650500 , People's Republic of China
| | - Yanli Ma
- College of Food Science and Technology , Hebei Agricultural University , Baoding , Hebei 071001 , People's Republic of China
| | - Guiguang Cheng
- Yunnan Institute of Food Safety , Kunming University of Science and Technology , Kunming , Yunnan 650500 , People's Republic of China
| | - Yuanyue Zhang
- Yunnan Institute of Food Safety , Kunming University of Science and Technology , Kunming , Yunnan 650500 , People's Republic of China
| | - Shengbao Cai
- Yunnan Institute of Food Safety , Kunming University of Science and Technology , Kunming , Yunnan 650500 , People's Republic of China
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Francini F, Schinella GR, Ríos JL. Activation of AMPK by Medicinal Plants and Natural Products: Its Role in Type 2 Diabetes Mellitus. Mini Rev Med Chem 2019; 19:880-901. [PMID: 30484403 DOI: 10.2174/1389557519666181128120726] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/04/2018] [Accepted: 11/22/2018] [Indexed: 12/26/2022]
Abstract
Type-2 Diabetes (T2D) is a metabolic disease characterized by permanent hyperglycemia, whose development can be prevented or delayed by using therapeutic agents and implementing lifestyle changes. Some therapeutic alternatives include regulation of glycemia through modulation of different mediators and enzymes, such as AMP-activated protein kinase (AMPK), a highly relevant cellular energy sensor for metabolic homeostasis regulation, with particular relevance in the modulation of liver and muscle insulin sensitivity. This makes it a potential therapeutic target for antidiabetic drugs. In fact, some of them are standard drugs used for treatment of T2D, such as biguanides and thiazolidindiones. In this review, we compile the principal natural products that are activators of AMPK and their effect on glucose metabolism, which could make them candidates as future antidiabetic agents. Phenolics such as flavonoids and resveratrol, alkaloids such as berberine, and some saponins are potential natural activators of AMPK with a potential future as antidiabetic drugs.
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Affiliation(s)
- Flavio Francini
- Centro de Endocrinologia Experimental y Aplicada, (CONICET-CCT La Plata-UNLP FCM, CEAS CICPBA), Argentina
| | - Guillermo R Schinella
- Cátedra de Farmacología Básica, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Argentina.,Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, La Plata, Argentina
| | - José-Luis Ríos
- Departament de Farmacologia, Facultat de Farmacia, Universitat de Valencia, Valencia, Spain
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Lee D, Hwang BS, Choi P, Kim T, Kim Y, Song BG, Yamabe N, Hwang GS, Kang KS, Ham J. Hypoxylonol F Isolated from Annulohypoxylon annulatum Improves Insulin Secretion by Regulating Pancreatic β-cell Metabolism. Biomolecules 2019; 9:biom9080335. [PMID: 31382473 PMCID: PMC6723394 DOI: 10.3390/biom9080335] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 07/24/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023] Open
Abstract
Insulin plays a key role in glucose homeostasis and is hence used to treat hyperglycemia, the main characteristic of diabetes mellitus. Annulohypoxylon annulatum is an inedible ball-shaped wood-rotting fungus, and hypoxylon F is one of the major compounds of A. annulatum. The aim of this study is to evaluate the effects of hypoxylonol F isolated from A. annulatum on insulin secretion in INS-1 pancreatic β-cells and demonstrate the molecular mechanisms involved. Glucose-stimulated insulin secretion (GSIS) values were evaluated using a rat insulin ELISA kit. Moreover, the expression of proteins related to pancreatic β-cell metabolism and insulin secretion was evaluated using Western blotting. Hypoxylonol F isolated from A. annulatum was found to significantly enhance glucose-stimulated insulin secretion without inducing cytotoxicity. Additionally, hypoxylonol F enhanced insulin receptor substrate-2 (IRS-2) levels and activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. Interestingly, it also modulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and pancreatic and duodenal homeobox 1 (PDX-1). Our findings showed that A. annulatum and its bioactive compounds are capable of improving insulin secretion by pancreatic β-cells. This suggests that A. annulatum can be used as a therapeutic agent to treat diabetes.
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Affiliation(s)
- Dahae Lee
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea
- College of Korean Medicine, Gachon University, Seongnam 13120, Korea
| | - Buyng Su Hwang
- Freshwater Bioresources Utilization Bureau, Nakdonggang National Institute of Biological Resources, Sangju 37242, Korea
| | - Pilju Choi
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung 25451, Korea
| | - Taejung Kim
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung 25451, Korea
| | - Youngseok Kim
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung 25451, Korea
| | - Bong Geun Song
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung 25451, Korea
| | - Noriko Yamabe
- College of Korean Medicine, Gachon University, Seongnam 13120, Korea
| | - Gwi Seo Hwang
- College of Korean Medicine, Gachon University, Seongnam 13120, Korea
| | - Ki Sung Kang
- College of Korean Medicine, Gachon University, Seongnam 13120, Korea.
| | - Jungyeob Ham
- Freshwater Bioresources Utilization Bureau, Nakdonggang National Institute of Biological Resources, Sangju 37242, Korea.
- Division of Bio-Medical Science and Technology, University of Science and Technology, Daejeon 34114, Korea.
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Li D, Sun L, Yang Y, Wang Z, Yang X, Zhao T, Gong T, Zou L, Guo Y. Young apple polyphenols postpone starch digestion in vitro and in vivo. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.03.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
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Rynarzewski J, Dicks L, Zimmermann BF, Stoffel-Wagner B, Ludwig N, Helfrich HP, Ellinger S. Impact of a Usual Serving Size of Flavanol-Rich Cocoa Powder Ingested with a Diabetic-Suitable Meal on Postprandial Cardiometabolic Parameters in Type 2 Diabetics-A Randomized, Placebo-Controlled, Double-Blind Crossover Study. Nutrients 2019; 11:E417. [PMID: 30781485 PMCID: PMC6412367 DOI: 10.3390/nu11020417] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 02/06/2019] [Accepted: 02/07/2019] [Indexed: 12/22/2022] Open
Abstract
Randomized controlled trials indicate that flavanol-rich cocoa intake may improve postprandial glucose and lipid metabolism in patients with type 2 diabetes (T2D), based on studies with meals that impose a strong metabolic load. Hence, the aim of the present study was to investigate whether flavanol-rich cocoa powder ingested as part of a diabetic-suitable meal may beneficially affect glucose, lipid metabolism, and blood pressure (BP) in patients with T2D. Twelve adults with T2D, overweight/obesity, and hypertension ingested capsules with 2.5 g of flavanol-rich cocoa or microcrystalline cellulose with a diabetic-suitable breakfast in a randomized, placebo-controlled, double-blind crossover study. BP was measured and blood samples were taken before, 2 and 4 h after breakfast and capsule intake. Cocoa treatment did not affect glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-IR), triglycerides, total cholesterol, low density lipoprotein-cholesterol, high density lipoprotein-cholesterol, and BP. For glucose, insulin and HOMA-IR, only effects by time were observed after both treatments. Thus, 2.5 g of flavanol-rich cocoa powder ingested as part of a diabetic-suitable meal does not seem to affect postprandial glucose and lipid metabolism and BP in stably-treated diabetics. Nevertheless, future studies with close-meshed investigations are desirable, providing realistic amounts of cocoa together with realistic meals rich in carbohydrates to subjects with T2D or metabolic syndrome, which do not afford pharmacological treatment.
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Affiliation(s)
- Janina Rynarzewski
- Faculty of Food, Nutrition and Hospitality Sciences, Hochschule Niederrhein, University of Applied Sciences, Rheydter Str. 277, 41065 Mönchengladbach, Germany.
| | - Lisa Dicks
- Faculty of Food, Nutrition and Hospitality Sciences, Hochschule Niederrhein, University of Applied Sciences, Rheydter Str. 277, 41065 Mönchengladbach, Germany.
| | - Benno F Zimmermann
- Department of Nutrition and Food Sciences, University of Bonn, Endenicher Allee 11-13, 53115 Bonn, Germany.
| | - Birgit Stoffel-Wagner
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
| | - Norbert Ludwig
- Faculty of Food, Nutrition and Hospitality Sciences, Hochschule Niederrhein, University of Applied Sciences, Rheydter Str. 277, 41065 Mönchengladbach, Germany.
- Praxis Anrath, Pastoratstr. 9-11, 47877 Willich, Germany.
| | - Hans-Peter Helfrich
- Institute of Numerical Simulation, University of Bonn, Endenicher Allee 60, 53115 Bonn, Germany.
| | - Sabine Ellinger
- Faculty of Food, Nutrition and Hospitality Sciences, Hochschule Niederrhein, University of Applied Sciences, Rheydter Str. 277, 41065 Mönchengladbach, Germany.
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Mazibuko-Mbeje SE, Dludla PV, Roux C, Johnson R, Ghoor S, Joubert E, Louw J, Opoku AR, Muller CJF. Aspalathin-Enriched Green Rooibos Extract Reduces Hepatic Insulin Resistance by Modulating PI3K/AKT and AMPK Pathways. Int J Mol Sci 2019; 20:ijms20030633. [PMID: 30717198 PMCID: PMC6387445 DOI: 10.3390/ijms20030633] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 01/26/2019] [Indexed: 12/18/2022] Open
Abstract
We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor (Insr) and insulin receptor substrate 1 and 2 (Irs1 and Irs2), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways.
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Affiliation(s)
- Sithandiwe E Mazibuko-Mbeje
- Biomedical Research and Innovation Platform, South African Medical Research Council, P.O. Box 19070, Tygerberg 7505, South Africa.
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Private Bag X1, Tygerberg 7505, South Africa.
| | - Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, P.O. Box 19070, Tygerberg 7505, South Africa.
| | - Candice Roux
- Biomedical Research and Innovation Platform, South African Medical Research Council, P.O. Box 19070, Tygerberg 7505, South Africa.
| | - Rabia Johnson
- Biomedical Research and Innovation Platform, South African Medical Research Council, P.O. Box 19070, Tygerberg 7505, South Africa.
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Private Bag X1, Tygerberg 7505, South Africa.
| | - Samira Ghoor
- Biomedical Research and Innovation Platform, South African Medical Research Council, P.O. Box 19070, Tygerberg 7505, South Africa.
| | - Elizabeth Joubert
- Plant Bioactives Group, Post-Harvest and Agro-Processing Technologies, Agricultural Research Council (ARC), Infruitec-Nietvoorbij, Private Bag X5026, Stellenbosch 7599, South Africa.
- Department of Food Science, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
| | - Johan Louw
- Biomedical Research and Innovation Platform, South African Medical Research Council, P.O. Box 19070, Tygerberg 7505, South Africa.
- Department of Biochemistry and Microbiology, University of Zululand, Private Bag X1001, KwaDlangezwa 3886, South Africa.
| | - Andy R Opoku
- Department of Biochemistry and Microbiology, University of Zululand, Private Bag X1001, KwaDlangezwa 3886, South Africa.
| | - Christo J F Muller
- Biomedical Research and Innovation Platform, South African Medical Research Council, P.O. Box 19070, Tygerberg 7505, South Africa.
- Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Private Bag X1, Tygerberg 7505, South Africa.
- Department of Biochemistry and Microbiology, University of Zululand, Private Bag X1001, KwaDlangezwa 3886, South Africa.
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Orhan C, Kucuk O, Tuzcu M, Sahin N, Komorowski JR, Sahin K. Effect of supplementing chromium histidinate and picolinate complexes along with biotin on insulin sensitivity and related metabolic indices in rats fed a high-fat diet. Food Sci Nutr 2019; 7:183-194. [PMID: 30680172 PMCID: PMC6341138 DOI: 10.1002/fsn3.851] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 09/20/2018] [Accepted: 09/26/2018] [Indexed: 12/13/2022] Open
Abstract
SCOPE To investigate the effects of chromium histidinate (CrHis) and chromium picolinate (CrPic) complex along with biotin to a high-fat diet (HFD) fed to rats on the insulin sensitivity and the anti-obesity properties. METHODS Forty-two Sprague-Dawley male rats were divided into six groups. The rats were fed either (a): a standard diet (Control) or (b): a HFD or (c): a HFD with biotin (HFD+B) or (d): a combination of HFD and biotin along with CrPic (HFD + B + CrPic) or (e): a combination of HFD and biotin along with CrHis (HFD + B + CrHis) or (f): a combination of HFD and biotin along with CrHis and CrPic (HFD + B + CrHis + CrPic). RESULTS Adding biotin with chromium to HFD improved the glucose, insulin, HOMA-IR, leptin, lipid profile, with HFD+B+CrHis treatment being the most effective (p = 0.0001). Serum, liver, and brain tissue Cr concentrations increased upon Cr supplementations (p = 0.0001). Supplementing CrHis along with biotin to a HFD (HFD + B + CrHis) provided the greatest levels of GLUT-1, GLUT-3, PPAR-γ, and IRS-1, but the lowest level of NF-κB in the brain and liver tissues. CONCLUSION Biotin supplementation with chromium complexes, CrHis in particular, to a HFD pose to be a potential therapeutic feature for the treatment of insulin resistance.
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Affiliation(s)
- Cemal Orhan
- Department of Animal NutritionFaculty of Veterinary ScienceFirat UniversityElazigTurkey
| | - Osman Kucuk
- Department of Animal NutritionFaculty of Veterinary ScienceErciyes UniversityKayseriTurkey
| | - Mehmet Tuzcu
- Division of BiologyFaculty of ScienceFirat UniversityElazigTurkey
| | - Nurhan Sahin
- Department of Animal NutritionFaculty of Veterinary ScienceFirat UniversityElazigTurkey
| | | | - Kazim Sahin
- Department of Animal NutritionFaculty of Veterinary ScienceFirat UniversityElazigTurkey
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Cremonini E, Fraga CG, Oteiza PI. (-)-Epicatechin in the control of glucose homeostasis: Involvement of redox-regulated mechanisms. Free Radic Biol Med 2019; 130:478-488. [PMID: 30447350 DOI: 10.1016/j.freeradbiomed.2018.11.010] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 11/05/2018] [Accepted: 11/10/2018] [Indexed: 01/07/2023]
Abstract
Emerging evidence supports a beneficial action of the flavan-3-ol (-)-epicatechin (EC) on insulin sensitivity and potential impact on the development/progression of type 2 diabetes (T2D). In humans, supplementation with EC-rich foods, extracts, and pure EC improves insulin sensitivity and glucose tolerance in normal weight, overweight, obese and T2D individuals. These effects of EC are also observed in rodent models of diet-induced obesity and T2D. The events involved in the development of insulin resistance and T2D are multiple and interrelated. EC has been shown to inhibit inflammation, oxidative and endoplasmic reticulum stress, to modulate mitochondrial biogenesis and function, and to regulate events in the gastrointestinal tract and the pancreas that impact glucose homeostasis. A downregulation of oxidant production, particularly through direct inhibition or suppression of NADPH oxidase expression, and of redox sensitive signals (NF-κB, JNK1/2) that inhibit the insulin pathway, appear to be central to the beneficial actions of EC on insulin sensitivity. Overall, EC seems to have a positive role in the regulation of glucose homeostasis, however definitive answers on its importance for the management of T2D will depend on further clinical and mechanistic studies.
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Affiliation(s)
- Eleonora Cremonini
- Department of Nutrition, University of California, Davis, USA; Department of Environmental Toxicology, University of California, Davis, USA
| | - Cesar G Fraga
- Department of Nutrition, University of California, Davis, USA; Fisicoquímica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina; Instituto de Bioquímica y Medicina Molecular (IBIMOL), UBA-CONICET, Buenos Aires, Argentina
| | - Patricia I Oteiza
- Department of Nutrition, University of California, Davis, USA; Department of Environmental Toxicology, University of California, Davis, USA.
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Role of Green Macroalgae Enteromorpha Prolifera Polyphenols in the Modulation of Gene Expression and Intestinal Microflora Profiles in Type 2 Diabetic Mice. Int J Mol Sci 2018; 20:ijms20010025. [PMID: 30577594 PMCID: PMC6337142 DOI: 10.3390/ijms20010025] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/09/2018] [Accepted: 12/18/2018] [Indexed: 11/17/2022] Open
Abstract
Effects of green macroalgae 55% ethanolic extract Enteromorpha prolifera through an ultrafiltration membrane of 3 kDa (EPE3k) on antidiabetic activity, gut microbiota, and regulation mechanism were investigated in high-fat/high-sucrose diet and streptozocin-induced diabetic mice. The structural characterizations of its major compounds in EPE3k were determined by ultra-performance liquid chromatography-quadrupole/time of flight mass spectrometry. Furthermore, the intestinal microflora modulation in diabetic mice was also investigated with high-throughput 16S rRNA gene sequencing. The proposed presence of polyphenols in EPE3k was confirmed. EPE3k could significantly decrease the fasting blood glucose and improve fasting glucose tolerance. The hypoglycemic effect of EPE3k was via activation of phosphatidylinositol 3-kinase and suppression of c-Jun N-terminal kinase in liver. EPE3k treatment significantly increased the relative abundance of Akkermansia and decreased the proportion of Alistipes and Turicibacter. The above results indicated that EPE3k could be provided as a new potential therapy for the treatment of type 2 diabetic mellitus.
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Theaflavins Improve Insulin Sensitivity through Regulating Mitochondrial Biosynthesis in Palmitic Acid-Induced HepG2 Cells. Molecules 2018; 23:molecules23123382. [PMID: 30572687 PMCID: PMC6320999 DOI: 10.3390/molecules23123382] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 12/16/2018] [Accepted: 12/17/2018] [Indexed: 12/31/2022] Open
Abstract
Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improving effects on insulin resistance-associated metabolic abnormalities, including obesity and type 2 diabetes mellitus. However, the related molecular mechanisms are still unclear. In this research, we investigated the protective effects of theaflavins against insulin resistance in HepG2 cells induced by palmitic acid. Theaflavins significantly increased glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the total and membrane bound glucose transporter 4 protein expressions, increasing the phosphor-Akt (Ser473) level, and decreasing the phosphorylation of IRS-1 at Ser307. Moreover, theaflavins were found to enhance the mitochondrial DNA copy number, down-regulate the PGC-1β mRNA level and increase the PRC mRNA expression. Mdivi-1, a selective mitochondrial division inhibitor, could attenuate TFs-induced promotion of glucose uptake in insulin-resistant HepG2 cells. Taken together, these results suggested that theaflavins could improve hepatocellular insulin resistance induced by free fatty acids, at least partly through promoting mitochondrial biogenesis. Theaflavins are promising functional food ingredients and medicines for improving insulin resistance-related disorders.
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Abima Shazhni J, Renu A, Vijayaraghavan P. Insights of antidiabetic, anti-inflammatory and hepatoprotective properties of antimicrobial secondary metabolites of corm extract from Caladium x hortulanum. Saudi J Biol Sci 2018; 25:1755-1761. [PMID: 30591796 PMCID: PMC6303170 DOI: 10.1016/j.sjbs.2018.03.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 03/14/2018] [Accepted: 03/25/2018] [Indexed: 01/11/2023] Open
Abstract
Medicinal plants have therapeutic potential and are used worldwide to treat various diseases. In this study, the corm of Caladium x hortulanum was extracted with various solvents and implied the availability of phytochemicals such as flavonoids, alkaloids, tannins, steroids, phenols, glycosides, saponins and terpenoids. The solvent extracts of the corm showed antibacterial and antifungal activity with the growth inhibition zone ranged 0-24 mm. The isolation of phytochemicals was carried out using gel column chromatography, Thin Layer Chromatography followed by High Performance Liquid Chromatography. Gas Chromatography and Mass Spectrophotometry analysis was used to determine the phytochemicals. The corm extract showed potent antidiabetic activity on Hep G2 cell lines and CCl4 induced toxicity was elucidated. This possessed antiinflammatory property on murine monocyclic macrophage cell line RAW 264.7 showed 45.85 ± 1.8% inhibition of cyclooxygenase activity. The corm extract showed hepatoprotective activity. The CCl4 incorporated Hep G2 cells showed 19.629 ± 1.5% viability, whereas viability increased as 78.82 ± 1.9% at 100 µg/ml of extract.
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Affiliation(s)
- J.R. Abima Shazhni
- Sathyabama University, Jeppiaar Nagar, Chennai 600 119, Tamil Nadu, India
| | - A. Renu
- Department of Biotechnology, Udhaya School of Engineering, Vellamodi 629 104, Tamil Nadu, India
| | - P. Vijayaraghavan
- Centre for Marine Science and Technology, Manonmaniam Sundaranar University, Rajakkamangalam, India
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Cinnamaldehyde ameliorates STZ-induced rat diabetes through modulation of IRS1/PI3K/AKT2 pathway and AGEs/RAGE interaction. Naunyn Schmiedebergs Arch Pharmacol 2018; 392:243-258. [DOI: 10.1007/s00210-018-1583-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 11/12/2018] [Indexed: 12/30/2022]
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