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Yesmin Sharna S, Hossain KMA, Kabir F, Hossain MZ, Jahan S, Rahman E, Agarwal S, Hossain MK, Sharmin F, Islam A, Hossain KMA. Multicentre randomised controlled trial protocol comparing structured physical exercise programme (SPEP) and medication versus conventional care for glycaemic control in type 2 diabetes mellitus. BMJ Open Sport Exerc Med 2025; 11:e002527. [PMID: 40124123 PMCID: PMC11927472 DOI: 10.1136/bmjsem-2025-002527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 02/18/2025] [Indexed: 03/25/2025] Open
Abstract
ABSTRACT Introduction One of the most widespread non-communicable diseases in the world is type 2 diabetes mellitus (T2DM) which increases the risk of cardiovascular mortality and morbidity, in addition to elevated blood pressure, and lipid disorders, for which physical activity and exercise programmes have shown a great impact on reducing cholesterol and glucose level. So, this study aims to generate a proper or Structured Physical Exercise Programme (SPEP) for the glycaemic control of people with T2DM. Methods and analysis The study will be a double-blinded, multicentre, randomised controlled trial where participants with T2DM will be enrolled from three Diabetic Centres in Bangladesh. All the participants will be allocated to experimental and control groups in a 1:1 ratio. Both groups will receive 18 sessions/6 weeks of intervention with an additional 24-week follow-up. Warm-up exercises, stretching and aerobic exercise will be provided along with medication for experimental and conventional approaches will be provided in the control group. A glucometer will measure the primary outcome (capillary blood glucose level). The secondary outcomes (cardiorespiratory fitness, T2DM-related comorbidities and quality of life) will be measured by a 6-min walk-test, self-structured questionnaire and SF-36. All outcomes will be measured at baseline, post-test after 6 weeks and follow-up after 24 weeks. Trial registration number CTRI/2023/08/057032.
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Affiliation(s)
- Suraiya Yesmin Sharna
- Department of Physiotherapy & Rehabilitation, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Kazi Md Azman Hossain
- Department of Physiotherapy & Rehabilitation, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Feroz Kabir
- Department of Physiotherapy & Rehabilitation, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Md. Zahid Hossain
- Department of Physiotherapy & Rehabilitation, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Sharmila Jahan
- Department of Physiotherapy & Rehabilitation, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Ehsanur Rahman
- Department of Physiotherapy & Rehabilitation, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Shagun Agarwal
- Allied and Health Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Md. Kabir Hossain
- Department of Physiotherapy & Rehabilitation, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Farzana Sharmin
- Department of Physiotherapy & Rehabilitation, Jashore University of Science and Technology, Jashore, Bangladesh
- Department of Physiotherapy, Centre for the Rehabilitation of the Paralysed (CRP), Savar, Bangladesh
| | - Azharul Islam
- Department of Physiotherapy & Rehabilitation, Jashore University of Science and Technology, Jashore, Bangladesh
| | - K M Amran Hossain
- Department of Physiotherapy & Rehabilitation, Jashore University of Science and Technology, Jashore, Bangladesh
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Sharma A, Narang A, Kumar N, Rana R, Megha, Pooja, Dhir M, Gulati HK, Jyoti, Khanna A, Singh JV, Kaur S, Bedi PMS. CADD based designing and biological evaluation of novel triazole based thiazolidinedione coumarin hybrids as antidiabetic agent. Sci Rep 2025; 15:4302. [PMID: 39905269 PMCID: PMC11794853 DOI: 10.1038/s41598-025-88944-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 01/31/2025] [Indexed: 02/06/2025] Open
Abstract
A series of 5-(substituted benzylidene) thiazolidine-2,4-dione and coumarin hybrids (I-1 to I-16) were designed and synthesized to explore key structural requirements for effective α-glucosidase inhibitors. Molecular docking studies were conducted to investigate their interactions with various targets, including DPP-4, α-glucosidase, α-amylase, and PPAR-γ. The docking scores and binding energies indicated that Compound I-1 emerged as the optimal scaffold for drug design, excluding α-amylase. Compound I-1 was synthesized based on the insights gained from molecular docking and simulations, which helped predict interactions and identify critical structural features. Pharmacokinetic properties were evaluated through drug-likeness and ADMET studies. Additionally, density functional theory (DFT) analyses were performed to assess the stability and reactivity of potential diabetes mellitus drug candidates. Dynamic simulation studies further elucidated the stability and interaction dynamics of the top-ranked compound I-1. In vitro evaluation against the α-glucosidase enzyme yielded an IC50 value of 1.49 µg/ml. In vivo studies demonstrated that Compound I-1 significantly reduced blood glucose levels, with values of 94.15 mg/dL and 74.60 mg/dL at doses of 10 mg/kg and 20 mg/kg, respectively. Furthermore, Compound I-1, like Acarbose, resulted in significant reductions in ALT, AST, ALP, urea, LDH, and creatinine levels, suggesting improved liver and kidney function.
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Affiliation(s)
- Anchal Sharma
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.
| | - Anmol Narang
- Department of Microbiology, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Nitish Kumar
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
- Sri Sai College of Pharmacy, Badhani, Pathankot, Punjab, 145001, India
| | - Rupali Rana
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Megha
- Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Pooja
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Muskan Dhir
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Harmandeep Kaur Gulati
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
- Dashmesh College of Pharmacy, Faridkot, Punjab, 151203, India
| | - Jyoti
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Aanchal Khanna
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Jatinder Vir Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
| | - Sukhraj Kaur
- Department of Microbiology, Guru Nanak Dev University, Amritsar, Punjab, 143005, India
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Khademian A, Halimi M, Azarbad R, Alaedini AH, Noori M, Dastyafteh N, Mojtabavi S, Faramarzi MA, Mohammadi-Khanaposhtani M, Mahdavi M. Quinoline-thiosemicarbazone-1,2,3-triazole-acetamide derivatives as new potent α-glucosidase inhibitors. Sci Rep 2024; 14:30876. [PMID: 39730503 DOI: 10.1038/s41598-024-81668-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 11/28/2024] [Indexed: 12/29/2024] Open
Abstract
In this work, a novel series of quinoline-thiosemicarbazone-1,2,3-triazole-aceamide derivatives 10a-n as new potent α-glucosidase inhibitors was designed, synthesized, and evaluated. All the synthesized derivatives 10a-n were more potent than acarbose (positive control). Representatively, (E)-2-(4-(((3-((2-Carbamothioylhydrazineylidene)methyl)quinolin-2-yl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-phenethylacetamide (10n), as the most potent entry, with IC50 = 48.4 µM was 15.5-times more potent than acarbose. According to kinetic study, compound 10n was a competitive inhibitor against α-glucosidase. This compound formed the desired interactions with important residues of the binding pocket of α-glucosidase with favorable binding energy in the molecular docking and molecular dynamics. Compounds 10n, 10e, and 10 g as the most potent compounds among the synthesized compounds were evaluated in term of pharmacokinetics and toxicity via online servers. These evaluations predicted that compounds 10n, 10e, and 10 g had good pharmacokinetic properties and toxicity profile.
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Affiliation(s)
- Aynaz Khademian
- Biomedical and Microbial Advanced Technologies (BMAT) Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Halimi
- Department of Biology, Islamic Azad University, Babol BranchBabol, Iran
| | - Reza Azarbad
- Biomedical and Microbial Advanced Technologies (BMAT) Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | | | - Milad Noori
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Navid Dastyafteh
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Mojtabavi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Faramarzi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mohammadi-Khanaposhtani
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
| | - Mohammad Mahdavi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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Roy S, Ghosh A, Majie A, Karmakar V, Das S, Dinda SC, Bose A, Gorain B. Terpenoids as potential phytoconstituent in the treatment of diabetes: From preclinical to clinical advancement. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155638. [PMID: 38728916 DOI: 10.1016/j.phymed.2024.155638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/21/2024] [Accepted: 04/13/2024] [Indexed: 05/12/2024]
Abstract
BACKGROUND Diabetes mellitus, a hyperglycemic condition associated with multitudinous organ dysfunction, is a hallmark of the metabolic disorder. This life-threatening condition affects millions of individuals globally, harming them financially, physically and psychologically in the course of therapy. PURPOSES The course therapy for illnesses has undergone ground-breaking transformations due to recent technical advances and insights. Alternatively, the administration of hyperglycemia-reducing agents results in several complications, including severe cardiovascular disease, kidney failure, hepatic problems, and several dermatological conditions. Consideration of alternate diabetic therapy having minimal side effects or no adverse reactions has been driven by such problems. STUDY DESIGN An extensive literature study was conducted in authoritative scientific databases such as PubMed, Scopus, and Web of Science to identify the studies elucidating the bioactivities of terpenoids in diabetic conditions. METHODS Keywords including 'terpenoids', 'monoterpenes', 'diterpenes', 'sesquiterpenes', 'diabetes', 'diabetes mellitus', 'clinical trials', 'preclinical studies', and 'increased blood glucose' were used to identify the relevant research articles. The exclusion criteria, such as English language, duplication, open access, abstract only, and studies not involving preclinical and clinical research, were set. Based on these criteria, 937 relevant articles were selected for further evaluation. RESULTS Triterpenes can serve as therapeutic agents for diabetic retinopathy, peripheral neuropathy, and kidney dysfunction by inhibiting several pathways linked to hyperglycemia and its complications. Therefore, it is essential to draw special attention to these compounds' therapeutic effectiveness and provide scientific professionals with novel data. CONCLUSION This study addressed recent progress in research focussing on mechanisms of terpenoid, its by-products, physiological actions, and therapeutic applications, particularly in diabetic and associated disorders.
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Affiliation(s)
- Sukanta Roy
- School of Pharmacy, The Neotia University, Diamond Harbour Rd, Sarisha, West Bengal, India
| | - Arya Ghosh
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Ankit Majie
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Varnita Karmakar
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Sourav Das
- School of Pharmacy, The Neotia University, Diamond Harbour Rd, Sarisha, West Bengal, India
| | - Subas Chandra Dinda
- School of Pharmacy, The Neotia University, Diamond Harbour Rd, Sarisha, West Bengal, India
| | - Anirbandeep Bose
- School of Medical Science, Adamas University, Barbaria, Jagannathpur, Kolkata, India.
| | - Bapi Gorain
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.
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Huang X, Lin K, Liu S, Yang J, Zhao H, Zheng XH, Tsai MJ, Chang CS, Huang L, Weng CF. Combination of plant metabolites hinders starch digestion and glucose absorption while facilitating insulin sensitivity to diabetes. Front Pharmacol 2024; 15:1362150. [PMID: 38903985 PMCID: PMC11188438 DOI: 10.3389/fphar.2024.1362150] [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: 12/27/2023] [Accepted: 04/29/2024] [Indexed: 06/22/2024] Open
Abstract
Introduction Diabetes mellitus (DM) is a common endocrine disease resulting from interactions between genetic and environmental factors. Type II DM (T2DM) accounts for approximately 90% of all DM cases. Current medicines used in the treatment of DM have some adverse or undesirable effects on patients, necessitating the use of alternative medications. Methods To overcome the low bioavailability of plant metabolites, all entities were first screened through pharmacokinetic, network pharmacology, and molecular docking predictions. Experiments were further conducted on a combination of antidiabetic phytoactive molecules (rosmarinic acid, RA; luteolin, Lut; resveratrol, RS), along with in vitro evaluation (α-amylase inhibition assay) and diabetic mice tests (oral glucose tolerance test, OGTT; oral starch tolerance test, OSTT) for maximal responses to validate starch digestion and glucose absorption while facilitating insulin sensitivity. Results The results revealed that the combination of metabolites achieved all required criteria, including ADMET, drug likeness, and Lipinski rule. To determine the mechanisms underlying diabetic hyperglycemia and T2DM treatments, network pharmacology was used for regulatory network, PPI network, GO, and KEGG enrichment analyses. Furthermore, the combined metabolites showed adequate in silico predictions (α-amylase, α-glucosidase, and pancreatic lipase for improving starch digestion; SGLT-2, AMPK, glucokinase, aldose reductase, acetylcholinesterase, and acetylcholine M2 receptor for mediating glucose absorption; GLP-1R, DPP-IV, and PPAR-γ for regulating insulin sensitivity), in vitro α-amylase inhibition, and in vivo efficacy (OSTT versus acarbose; OGTT versus metformin and insulin) as nutraceuticals against T2DM. Discussion The results demonstrate that the combination of RA, Lut, and RS could be exploited for multitarget therapy as prospective antihyperglycemic phytopharmaceuticals that hinder starch digestion and glucose absorption while facilitating insulin sensitivity.
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Affiliation(s)
- Xin Huang
- Functional Physiology Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
- Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
| | - Kaihuang Lin
- Functional Physiology Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
- Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
| | - Sinian Liu
- Functional Physiology Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
- Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
| | - Junxiong Yang
- Functional Physiology Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
- Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
| | - Haowei Zhao
- Functional Physiology Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
- Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
| | - Xiao-Hui Zheng
- Functional Physiology Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
- Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
| | - May-Jywan Tsai
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chun-Sheng Chang
- Department of Biotechnology and Food Technology, Southern Taiwan University of Science and Technology, Tainan, Taiwan
| | - Liyue Huang
- Functional Physiology Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
- Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
| | - Ching-Feng Weng
- Functional Physiology Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
- Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen, China
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Homolya L, Mathomes RT, Varga L, Docsa T, Juhász L, Hayes JM, Somsák L. Synthesis, In Silico and Kinetics Evaluation of N-(β-d-glucopyranosyl)-2-arylimidazole-4(5)-carboxamides and N-(β-d-glucopyranosyl)-4(5)-arylimidazole-2-carboxamides as Glycogen Phosphorylase Inhibitors. Int J Mol Sci 2024; 25:4591. [PMID: 38731811 PMCID: PMC11083775 DOI: 10.3390/ijms25094591] [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: 03/11/2024] [Revised: 04/05/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
Recently studied N-(β-d-glucopyranosyl)-3-aryl-1,2,4-triazole-5-carboxamides have proven to be low micromolar inhibitors of glycogen phosphorylase (GP), a validated target for the treatment of type 2 diabetes mellitus. Since in other settings, the bioisosteric replacement of the 1,2,4-triazole moiety with imidazole resulted in significantly more efficient GP inhibitors, in silico calculations using Glide molecular docking along with unbound state DFT calculations were performed on N-(β-d-glucopyranosyl)-arylimidazole-carboxamides, revealing their potential for strong GP inhibition. The syntheses of the target compounds involved the formation of an amide bond between per-O-acetylated β-d-glucopyranosylamine and the corresponding arylimidazole-carboxylic acids. Kinetics experiments on rabbit muscle GPb revealed low micromolar inhibitors, with the best inhibition constants (Kis) of ~3-4 µM obtained for 1- and 2-naphthyl-substituted N-(β-d-glucopyranosyl)-imidazolecarboxamides, 2b-c. The predicted protein-ligand interactions responsible for the observed potencies are discussed and will facilitate the structure-based design of other inhibitors targeting this important therapeutic target. Meanwhile, the importance of the careful consideration of ligand tautomeric states in binding calculations is highlighted, with the usefulness of DFT calculations in this regard proposed.
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Affiliation(s)
- Levente Homolya
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary; (L.H.); (L.S.)
| | - Rachel T. Mathomes
- School of Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK
| | - Luca Varga
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (L.V.); (T.D.)
| | - Tibor Docsa
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (L.V.); (T.D.)
| | - László Juhász
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary; (L.H.); (L.S.)
| | - Joseph M. Hayes
- School of Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK
| | - László Somsák
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary; (L.H.); (L.S.)
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Hou Y, Zhai X, Wang X, Wu Y, Wang H, Qin Y, Han J, Meng Y. Research progress on the relationship between bile acid metabolism and type 2 diabetes mellitus. Diabetol Metab Syndr 2023; 15:235. [PMID: 37978556 PMCID: PMC10656899 DOI: 10.1186/s13098-023-01207-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 11/02/2023] [Indexed: 11/19/2023] Open
Abstract
Bile acids, which are steroid molecules originating from cholesterol and synthesized in the liver, play a pivotal role in regulating glucose metabolism and maintaining energy balance. Upon release into the intestine alongside bile, they activate various nuclear and membrane receptors, influencing crucial processes. These bile acids have emerged as significant contributors to managing type 2 diabetes mellitus, a complex clinical syndrome primarily driven by insulin resistance. Bile acids substantially lower blood glucose levels through multiple pathways: BA-FXR-SHP, BA-FXR-FGFR15/19, BA-TGR5-GLP-1, and BA-TGR5-cAMP. They also impact blood glucose regulation by influencing intestinal flora, endoplasmic reticulum stress, and bitter taste receptors. Collectively, these regulatory mechanisms enhance insulin sensitivity, stimulate insulin secretion, and boost energy expenditure. This review aims to comprehensively explore the interplay between bile acid metabolism and T2DM, focusing on primary regulatory pathways. By examining the latest advancements in our understanding of these interactions, we aim to illuminate potential therapeutic strategies and identify areas for future research. Additionally, this review critically assesses current research limitations to contribute to the effective management of T2DM.
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Affiliation(s)
- Yisen Hou
- Department of Oncology Surgery, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 710018, Shanxi, People's Republic of China
| | - Xinzhe Zhai
- Department of General Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, People's Republic of China
| | - Xiaotao Wang
- Department of General Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, People's Republic of China
| | - Yi Wu
- Department of General Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, People's Republic of China
| | - Heyue Wang
- Department of General Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, People's Republic of China
| | - Yaxin Qin
- Department of General Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, People's Republic of China
| | - Jianli Han
- Department of General Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, People's Republic of China.
| | - Yong Meng
- Department of Oncology Surgery, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 710018, Shanxi, People's Republic of China.
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Sun Y, Mehmood A, Giampieri F, Battino MA, Chen X. Insights into the cellular, molecular, and epigenetic targets of gamma-aminobutyric acid against diabetes: a comprehensive review on its mechanisms. Crit Rev Food Sci Nutr 2023; 64:12620-12637. [PMID: 37694998 DOI: 10.1080/10408398.2023.2255666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Diabetes is a metabolic disease due to impaired or defective insulin secretion and is considered one of the most serious chronic diseases worldwide. Gamma-aminobutyric acid (GABA) is a naturally occurring non-protein amino acid commonly present in a wide range of foods. A number of studies documented that GABA has good anti-diabetic potential. This review summarized the available dietary sources of GABA as well as animal and human studies on the anti-diabetic properties of GABA, while also discussing the underlying mechanisms. GABA may modulate diabetes through various pathways such as inhibiting the activities of α-amylase and α-glucosidase, promoting β-cell proliferation, stimulating insulin secretion from β-cells, inhibiting glucagon secretion from α-cells, improving insulin resistance and glucose tolerance, and increasing antioxidant and anti-inflammatory activities. However, further mechanistic studies on animals and human are needed to confirm the therapeutic effects of GABA against diabetes.
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Affiliation(s)
- Yu Sun
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
- Institute of Food Physical Processing, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
| | - Arshad Mehmood
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
- Institute of Food Physical Processing, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
| | - Francesca Giampieri
- Research Group on Food, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Santander, Spain
| | - Maurizio Antonio Battino
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
- Research Group on Food, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Santander, Spain
- Department of Clinical Sciences, Università Politecnica delle Marche, Ancona, Italy
| | - Xiumin Chen
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
- Institute of Food Physical Processing, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
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Safapoor S, Halimi M, Ghomi MK, Noori M, Dastyafteh N, Javanshir S, Hosseini S, Mojtabavi S, Faramarzi MA, Nasli-Esfahani E, Larijani B, Fakhrioliaei A, Dekamin MG, Mohammadi-Khanaposhtani M, Mahdavi M. Synthesis, ADMT prediction, and in vitro and in silico α-glucosidase inhibition evaluations of new quinoline-quinazolinone-thioacetamides. RSC Adv 2023; 13:19243-19256. [PMID: 37377867 PMCID: PMC10291282 DOI: 10.1039/d3ra01790g] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 06/17/2023] [Indexed: 06/29/2023] Open
Abstract
In this work, a new series of quinoline-quinazolinone-thioacetamide derivatives 9a-p were designed using a combination of effective pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized by simple chemical reactions and evaluated for their anti-α-glucosidase activity. Among the tested compounds, compounds 9a, 9f, 9g, 9j, 9k, and 9m demonstrated significant inhibition effects in comparison to the positive control acarbose. Particularly, compound 9g with inhibitory activity around 83-fold more than acarbose exhibited the best anti-α-glucosidase activity. Compound 9g showed a competitive type of inhibition in the kinetic study, and the molecular simulation studies demonstrated that this compound with a favorable binding energy occupied the active site of α-glucosidase. Furthermore, in silico ADMET studies of the most potent compounds 9g, 9a, and 9f were performed to predict their drug-likeness, pharmacokinetic, and toxicity properties.
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Affiliation(s)
- Sajedeh Safapoor
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences Tehran Iran
| | - Mohammad Halimi
- Department of Biology, Islamic Azad University Babol Branch Babol Iran
| | - Minoo Khalili Ghomi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences Tehran Iran
| | - Milad Noori
- Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology Tehran 16846-13114 Iran
| | - Navid Dastyafteh
- Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology Tehran 16846-13114 Iran
| | - Shahrzad Javanshir
- Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology Tehran 16846-13114 Iran
| | | | - Somayeh Mojtabavi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences Tehran Iran
| | - Mohammad Ali Faramarzi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences Tehran Iran
| | - Ensieh Nasli-Esfahani
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences Tehran Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences Tehran Iran
| | - Azadeh Fakhrioliaei
- Faculty of Pharmacy, Islamic Azad University Pharmaceutical Sciences Branch Tehran Iran
| | - Mohammad G Dekamin
- Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology Tehran 16846-13114 Iran
| | - Maryam Mohammadi-Khanaposhtani
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences Babol Iran
| | - Mohammad Mahdavi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences Tehran Iran
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10
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Emadi M, Mosavizadeh-Marvest F, Asadipour A, Pourshojaei Y, Hosseini S, Mojtabavi S, Faramarzi MA, Larijani B, Mohammadi-Khanaposhtani M, Mahdavi M. Indole-carbohydrazide linked phenoxy-1,2,3-triazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors: design, synthesis, in vitro α-glucosidase inhibition, and computational studies. BMC Chem 2023; 17:56. [PMID: 37316931 DOI: 10.1186/s13065-023-00971-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 05/30/2023] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND A new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a-o was designed based on molecular hybridization of the active pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized and evaluated against α-glucosidase. METHODS The 15 various derivatives of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold were synthesized, purified, and fully characterized. These derivatives were evaluated against yeast α-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted. RESULTS All new derivatives 11a-o (IC50 values = 6.31 ± 0.03-49.89 ± 0.09 µM) are excellent α-glucosidase inhibitors in comparison to acarbose (IC50 value = 750.0 ± 10.0 µM) that was used as a positive control. Representatively, (E)-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl) phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide 11d with IC50 = 6.31 µM against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against α-glucosidase and showed the lowest binding energy at the active site of this enzyme in comparison to other potent compounds. Furthermore, computational calculations predicted that compound 11d can be an orally active compound. CONCLUSION According to obtained data, compound 11d can be a valuable lead compound for further structural development and assessments to obtain effective and potent new α-glucosidase inhibitors.
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Affiliation(s)
- Mehdi Emadi
- Electrical and Computer Engineering Department, Babol Noshirvani University of Technology, Babol, Iran
| | - Fahimeh Mosavizadeh-Marvest
- Department of Medicinal Chemistry, Faculty of Pharmacy & Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Ali Asadipour
- Department of Medicinal Chemistry, Faculty of Pharmacy & Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Yaghoub Pourshojaei
- Department of Medicinal Chemistry, Faculty of Pharmacy & Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
- Extremophile and Productive Microorganisms Research Center, Kerman University of Medical Sciences, Kerman, Iran.
| | | | - Somayeh Mojtabavi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Faramarzi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Mohammadi-Khanaposhtani
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Mahdavi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
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11
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Dwivedi PS, Rasal VP, Chavan RS, Khanal P, Gaonkar VP. Feronia elephantum reverses insulin resistance in fructose-induced hyper-insulinemic rats; an in-silico, in-vitro, and in-vivo approach. JOURNAL OF ETHNOPHARMACOLOGY 2023:116686. [PMID: 37279812 DOI: 10.1016/j.jep.2023.116686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/13/2023] [Accepted: 05/24/2023] [Indexed: 06/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Feronia elephantum corr. (synonym: Feronia limonia, Murraya odorata, Schinus Limonia, or Limonia acidissima; common names: Bela, Kath, Billin, and Kavitha), belonging to the family Rutaceae has been known for clinical conditions such as pruritus, diarrhea, impotence, dysentery, heart diseases, and is also used as a liver tonic. However, the effect of the fruit pulp of F. elephantum on insulin resistance has yet not been reported. AIM OF THE STUDY The present study aimed to assess the effect of hydroalcoholic extract/fraction of F. elephantum fruit pulp on fasting blood glucose, oral glucose tolerance test, and glucose uptake in fructose-induced insulin-resistant rats and predict the gene-set enrichment of lead hits of F. elephantum with targets related to insulin resistance. MATERIAL AND METHODS System biology tools were used to predict the best category of fraction and propose a possible mechanism. Docking was carried out with adiponectin and its receptor (hub gene). Further, fructose supplementation was used for the induction of insulin resistance. Later, three doses of extract (400, 200, and 100 mg/kg) and a flavonoid-rich fraction (63 mg/kg) were used for treatment along with metformin as standard. The physical parameters like body weight, food intake, and water intake were measured along with oral glucose tolerance test, insulin tolerance test, glycogen content in skeletal muscles and liver, glucose uptake by rat hemidiaphragm, lipid profiles, anti-oxidant biomarkers, and histology of the liver and adipose tissue. RESULTS Network pharmacology reflected the potency of F. elephantum to regulate adiponectin (ADIPOQ) which may promote the reversal of insulin resistance and inhibit α-amylase and α-glucosidase. Vitexin was predicted to modulate the most genes associated with diabetes mellitus. Further, F. elephantum ameliorated the exogenous glucose clearance, promoted insulin sensitivity, reduced oxidative stress, and improved glucose and lipid metabolism. HPLC profiling revealed the presence of apigenin and quercetin in the extract for the first time. CONCLUSION The fruit pulp of F. elephantum reverses insulin resistance by an increase in glucose uptake and a decrease in gluconeogenesis which may be due to the regulation of multiple proteins via multiple bio-actives.
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Affiliation(s)
- Prarambh Sr Dwivedi
- Department of Pharmacology and Toxicology, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research (KAHER), Belagavi, 590010, India.
| | - V P Rasal
- Department of Pharmacology, Rani Chennamma College of Pharmacy, Belagavi, 590010, India
| | - Rajashekar S Chavan
- Department of Pharmacology and Toxicology, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research (KAHER), Belagavi, 590010, India
| | - Pukar Khanal
- Department of Pharmacology and Toxicology, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research (KAHER), Belagavi, 590010, India.
| | - Vishakha Parab Gaonkar
- Department of Pharmaceutical Quality Assurance, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research (KAHER), Belagavi, 590010, India
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12
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Han Jeong G, Cho JH, Park KI, Kim K, Hoon Kim T. Enzymatic transformation of esculetin as a potent class of α-glucosidase inhibitors. Bioorg Med Chem Lett 2023; 88:129302. [PMID: 37088219 DOI: 10.1016/j.bmcl.2023.129302] [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: 03/14/2023] [Revised: 04/17/2023] [Accepted: 04/20/2023] [Indexed: 04/25/2023]
Abstract
A rapid and simple enzymatic transformation of the representative coumarin esculetin (1) with polyphenol oxidase originating from Agaricus bisporus afforded five new oxidized metabolites, esculetinins A (2), B (3), C (4), D (5), and E (6), together with the known compound isoeuphorbetin (7). The structures of the oligomerized transformation products were established on the basis of spectroscopic interpretations. The esculetin oligomers 2 and 3 revealed highly enhanced inhibitory activities against α-glucosidase, with IC50 values of 0.7 ± 0.1 and 2.3 ± 0.3μM, respectively, as compared to the original esculetin. Kinetic analysis also exhibited that the two new potent metabolites 2 and 3 have competitive modes of action.
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Affiliation(s)
- Gyeong Han Jeong
- Research Division for Biotechnology, Advanced Radiation Technology Institute (ARTI), Korea Atomic Energy Research Institute (KAERI), Jeongeup 56212, Republic of Korea
| | - Jae-Hyeon Cho
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Kwang-Il Park
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Kyungho Kim
- Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea
| | - Tae Hoon Kim
- Department of Food Science and Biotechnology, Daegu University, Gyeongsan 38453, Republic of Korea.
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13
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Korthikunta V, Singh R, Srivastava R, Pandey J, Srivastava A, Chaturvedi U, Mishra A, Srivastava AK, Tamrakar AK, Tadigoppula N. Design, synthesis, and evaluation of benzofuran-based chromenochalcones for antihyperglycemic and antidyslipidemic activities. RSC Med Chem 2023; 14:470-481. [PMID: 36970150 PMCID: PMC10033782 DOI: 10.1039/d2md00341d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 01/18/2023] [Indexed: 01/22/2023] Open
Abstract
A series of benzofuran-based chromenochalcones (16-35) were synthesized and evaluated for in vitro and in vivo antidiabetic activities in L-6 skeletal muscle cells and streptozotocin (STZ)-induced diabetic rat models, respectively, and further in vivo dyslipidemia activity of the compounds was evaluated in a Triton-induced hyperlipidemic hamster model. Among them, compounds 16, 18, 21, 22, 24, 31, and 35 showed significant glucose uptake stimulatory effects in skeletal muscle cells and were further evaluated for in vivo efficacy. Compounds 21, 22, and 24 showed a significant reduction in blood glucose levels in STZ-induced diabetic rats. Compounds 16, 20, 21, 24, 28, 29, 34, 35, and 36 were found active in antidyslipidemic studies. Furthermore, compound 24 effectively improved the postprandial and fasting blood glucose levels, oral glucose tolerance, serum lipid profile, serum insulin level, and the HOMA-index of db/db mice, following 15 days of successive treatment.
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Affiliation(s)
- Venkateswarlu Korthikunta
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute Lucknow (U.P.) - 226031 India
| | - Rohit Singh
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute Lucknow (U.P.) - 226031 India
- Academy of Scientific and Innovative Research (AcSIR) Sector 19 Kamla Nehru Nagar Ghaziabad-201002 India
- Department of Pharmaceutical Chemistry, College of Pharmacy, JSS Academy of Technical Education C-1/A, Sector-62 Noida Uttar Pradesh-201309 India
| | - Rohit Srivastava
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute Lucknow (U.P.) - 226031 India
| | - Jyotsana Pandey
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute Lucknow (U.P.) - 226031 India
- Academy of Scientific and Innovative Research (AcSIR) Sector 19 Kamla Nehru Nagar Ghaziabad-201002 India
| | - Atul Srivastava
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute Lucknow (U.P.) - 226031 India
| | - Upma Chaturvedi
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute Lucknow (U.P.) - 226031 India
| | - Akansha Mishra
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute Lucknow (U.P.) - 226031 India
| | - Arvind K Srivastava
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute Lucknow (U.P.) - 226031 India
| | - Akhilesh K Tamrakar
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute Lucknow (U.P.) - 226031 India
- Academy of Scientific and Innovative Research (AcSIR) Sector 19 Kamla Nehru Nagar Ghaziabad-201002 India
| | - Narender Tadigoppula
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute Lucknow (U.P.) - 226031 India
- Academy of Scientific and Innovative Research (AcSIR) Sector 19 Kamla Nehru Nagar Ghaziabad-201002 India
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14
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Ali MY, Park SE, Seong SH, Zamponi GW, Jung HA, Choi JS. Ursonic acid from Artemisia montana exerts anti-diabetic effects through anti-glycating properties, and by inhibiting PTP1B and activating the PI3K/Akt signaling pathway in insulin-resistant C2C12 cells. Chem Biol Interact 2023; 376:110452. [PMID: 36933777 DOI: 10.1016/j.cbi.2023.110452] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023]
Abstract
Artemisia is one of the largest genera in the plant family Asteraceae and has long been used in traditional medicine for its antitussive, analgesic, antihypertensive, antitoxic, antiviral, antimalarial, and anti-inflammatory properties. However, the anti-diabetic activity of Artemisia montana has not been broadly studied. The goal of this study was to determine whether extracts of the aerial parts of A. montana and its main constituents inhibit protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase activities. We isolated nine compounds from A. montana including ursonic acid (UNA) and ursolic acid (ULA), which significantly inhibited PTP1B with IC50 values of 11.68 and 8.73 μM, respectively. In addition, UNA showed potent inhibitory activity against α-glucosidase (IC50 = 61.85 μM). Kinetic analysis of PTP1B and α-glucosidase inhibition revealed that UNA was a non-competitive inhibitor of both enzymes. Docking simulations of UNA demonstrated negative binding energies and close proximity to residues in the binding pockets of PTP1B and α-glucosidase. Molecular docking simulations between UNA and human serum albumin (HSA) revealed that UNA binds tightly to all three domains of HSA. Furthermore, UNA significantly inhibited fluorescent AGE formation (IC50 = 4.16 μM) in a glucose-fructose-induced HSA glycation model over the course of four weeks. Additionally, we investigated the molecular mechanisms underlying the anti-diabetic effects of UNA in insulin-resistant C2C12 skeletal muscle cells and discovered that UNA significantly increased glucose uptake and decreased PTP1B expression. Further, UNA increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. These findings clearly demonstrate that UNA from A. montana shows great potential for treatment of diabetes and its complications.
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Affiliation(s)
- Md Yousof Ali
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Se Eun Park
- Department of Food and Life Science, Pukyong National University, Busan, 48513, Republic of Korea
| | - Su Hui Seong
- Department of Food and Life Science, Pukyong National University, Busan, 48513, Republic of Korea; Division of Natural Products Research, Honam National Institute of Biological Resource, Mokpo, 58762, Republic of Korea
| | - Gerald W Zamponi
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Hyun Ah Jung
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju, 54896, Republic of Korea.
| | - Jae Sue Choi
- Department of Food and Life Science, Pukyong National University, Busan, 48513, Republic of Korea.
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15
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Niri DR, Sayahi MH, Behrouz S, Moazzam A, Mojtabavi S, Faramarzi MA, Larijani B, Rastegar H, Mohammadi-Khanaposhtani M, Mahdavi M. Design, synthesis, in vitro, and in silico biological evaluations of coumarin-indole hybrids as new anti-α-glucosidase agents. BMC Chem 2022; 16:84. [PMID: 36329490 PMCID: PMC9635080 DOI: 10.1186/s13065-022-00882-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND A series of coumarin-indole hybrids was synthesized as the new α-glucosidase inhibitors. The title hybrids were considered as α-glucosidase inhibitors because had two active pharmacophores against α-glucosidase: coumarin and indole. METHODS The thirteen various derivatives 4a-m were synthesized, purified, and fully characterized. These compounds were evaluated against α-glucosidase in vitro and in silico. In silico pharmacokinetic studies of the most potent compounds were also performed. RESULTS Most of the title compounds exhibited high anti-α-glucosidase activity in comparison to standard drug acarbose. In particular, the phenoxy derivative 4d namely 3-((1H-indol-3-yl)(3-phenoxyphenyl)methyl)-4-hydroxy-2H-chromen-2-one showed promising activity. This compound is a competitive inhibitor against α-glucosidase and showed the lowest binding energy at the α-glucosidase active site in comparison to other potent synthesized compounds and acarbose. CONCLUSION Compound 4d can be a lead compound for further structural development to obtain effective and potent α-glucosidase inhibitors.
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Affiliation(s)
- Davood Rezapour Niri
- grid.444860.a0000 0004 0600 0546Medicinal Chemistry Research Laboratory, Department of Chemistry, Shiraz University of Technology, Shiraz, Iran
| | - Mohammad Hosein Sayahi
- grid.412462.70000 0000 8810 3346Department of Chemistry, Payame Noor University (PNU), Tehran, Iran
| | - Somayeh Behrouz
- grid.444860.a0000 0004 0600 0546Medicinal Chemistry Research Laboratory, Department of Chemistry, Shiraz University of Technology, Shiraz, Iran
| | - Ali Moazzam
- grid.411705.60000 0001 0166 0922Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Mojtabavi
- grid.411705.60000 0001 0166 0922Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Faramarzi
- grid.411705.60000 0001 0166 0922Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- grid.411705.60000 0001 0166 0922Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Rastegar
- Cosmetic Products Research Center, Iranian Food and Drug Administration, MOHE, Tehran, Iran
| | - Maryam Mohammadi-Khanaposhtani
- grid.411705.60000 0001 0166 0922Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran ,grid.411495.c0000 0004 0421 4102Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Mahdavi
- grid.411705.60000 0001 0166 0922Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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16
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Wei J, Zhao C, Ji G, Dong M, Lu R, Huang B, Bao G, Hu F. Two novel enantiomers from metarhizium flavoviride and their inhibitory activities against α-glucosidase. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.133322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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17
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Liang CC, Shaw SW, Huang YH, Lee TH. Human amniotic fluid stem cell therapy can help regain bladder function in type 2 diabetic rats. World J Stem Cells 2022; 14:330-346. [PMID: 35722197 PMCID: PMC9157602 DOI: 10.4252/wjsc.v14.i5.330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/03/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is a serious and growing global health burden. It is estimated that 80% of diabetic patients have micturition problems such as poor emptying, urinary incontinence, urgency, and urgency incontinence. Patients with diabetic bladder dysfunction are often resistant to currently available therapies. It is necessary to develop new and effective treatment methods. AIM To examine the therapeutic effect of human amniotic fluid stem cells (hAFSCs) therapy on bladder dysfunction in a type 2 diabetic rat model. METHODS Sixty female Sprague-Dawley rats were divided into five groups: Group 1, normal-diet control (control); group 2, high-fat diet (HFD); group 3, HFD plus streptozotocin-induced DM (DM); group 4, DM plus insulin treatment (DM + insulin); group 5, DM plus hAFSCs injection via tail vein (DM + hAFSCs). Conscious cystometric studies were done at 4 and 12 wk after insulin or hAFSCs treatment to measure peak voiding pressure, voided volume, intercontraction interval, bladder capacity, and residual volume. Immunoreactivities and/or mRNA expression of muscarinic receptors, nerve growth factor (NGF), and sensory nerve markers in the bladder and insulin, MafA, and pancreatic-duodenal homeobox-1 (PDX-1) in pancreatic beta cells were studied. RESULTS Compared with DM rats, insulin but not hAFSCs treatment could reduce the bladder weight and improve the voided volume, intercontraction interval, bladder capacity, and residual volume (P < 0.05). However, both insulin and hAFSCs treatment could help to regain the blood glucose and bladder functions to the levels near controls (P > 0.05). The immunoreactivities and mRNA expression of M2- and M3-muscarinic receptors (M2 and M3) were increased mainly at 4 wk (P < 0.05), while the number of beta cells in islets and the immunoreactivities and/or mRNA of NGF, calcitonin gene-related peptide (CGRP), substance P, insulin, MafA, and PDX-1 were decreased in DM rats (P < 0.05). However, insulin and hAFSCs treatment could help to regain the expression of M2, M3, NGF, CGRP, substance P, MafA, and PDX-1 to near the levels of controls at 4 and/or 12 wk (P > 0.05). CONCLUSION Insulin but not hAFSCs therapy can recover the bladder dysfunction caused by DM; however, hAFSCs and insulin therapy can help to regain bladder function to near the levels of control.
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Affiliation(s)
- Ching-Chung Liang
- Female Urology Section, Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Steven W Shaw
- Division of Obstetrics, Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 105, Taiwan
| | - Yung-Hsin Huang
- Female Urology Section, Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Tsong-Hai Lee
- Stroke Center and Department of Neurology, Linkou Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
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18
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Haque SM. Optimized Box-Behnken experimental design based response surface methodology and Youden's robustness test to develop and validate methods to determine nateglinide using kinetic spectrophotometry. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2022; 268:120712. [PMID: 34896681 DOI: 10.1016/j.saa.2021.120712] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 11/05/2021] [Accepted: 12/01/2021] [Indexed: 06/14/2023]
Abstract
Selective and straightforward kinetic spectrophotometric methods were developed to quantify nateglinide (NTG) in pharmaceutical dosage forms. Fixed time (ΔA) and the equilibrium methods utilized the reaction of NTG with 1-chloro-2,4-dinitrobenzene (CDNB) in dimethyl sulfoxide (DMSO) with heating at 80 °C for 25 min to form a stable yellow-coloured Meisenheimer complex, which absorbs maximally at 421 nm. The optimization was achieved by utilizing the Box-Behnken experimental design (BBD) combined with response surface methodology (RSM). In which three significant factors were studied, namely, CDNB volume (A), heating temperature (B) and heating time (C) against the absorbance as a response. Method validation presented the International Conference on Harmonisation (ICH) parameters such as specificity, selectivity, linearity, precision, accuracy, limit of detection (LOD), limit of quantitation (LOQ), robustness and solution stability. The LOD and LOQ values were 0.48, 1.46, and 0.21, 0.62 µg/ml, respectively, for a fixed time (ΔA) and equilibrium methods with the linear dynamic range of 1-15 µg/ml. Furthermore, Youden's robustness test using factorial combinations of the selected analytical parameters was performed and investigated its influence with alternative conditions. All results were reproducible and quickly adopted for routine analysis of NTG in pharmaceutical formulations and laboratory preparations.
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Affiliation(s)
- Sk Manirul Haque
- Department of Chemical & Process Engineering Technology, Jubail Industrial College, Jubail Industrial City 31961, Saudi Arabia.
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19
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Sharma S, Baral M, Kanungo BK. Recent advances in therapeutical applications of the versatile hydroxypyridinone chelators. J INCL PHENOM MACRO 2022. [DOI: 10.1007/s10847-021-01114-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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20
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Farwa U, Raza MA. Heterocyclic compounds as a magic bullet for diabetes mellitus: a review. RSC Adv 2022; 12:22951-22973. [PMID: 36105949 PMCID: PMC9379558 DOI: 10.1039/d2ra02697j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/01/2022] [Indexed: 11/26/2022] Open
Abstract
Diabetes mellitus (DM) is a major metabolic disorder due to hyperglycemia, which is increasing all over the world. From the last two decades, the use of synthetic agents has risen due to their major involvement in curing of chronic diseases including DM. The core skeleton of drugs has been studied such as thiazolidinone, azole, chalcone, pyrrole and pyrimidine along with their derivatives. Diabetics assays have been performed in consideration of different enzymes such as α-glycosidase, α-amylase, and α-galactosidase against acarbose standard drug. The studied moieties were depicted in both models: in vivo as well as in vitro. Molecular docking of the studied compounds as antidiabetic molecules was performed with the help of Auto Dock and molecular operating environment (MOE) software. Amino acid residues Asp349, Arg312, Arg439, Asn241, Val303, Glu304, Phe158, His103, Lys422 and Thr207 that are present on the active sites of diabetic related enzymes showed interactions with ligand molecules. In this review data were organized for the synthesis of heterocyclic compounds through various routes along with their antidiabetic potential, and further studies such as pharmacokinetic and toxicology studies should be executed before going for clinical trials. Diabetes mellitus (DM) is a major metabolic disorder due to hyperglycemia, which is increasing all over the world.![]()
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Affiliation(s)
- Umme Farwa
- Department of Chemistry, University of Gujrat, Gujrat 50700, Pakistan
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21
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Ardalani H, Hejazi Amiri F, Hadipanah A, Kongstad KT. Potential antidiabetic phytochemicals in plant roots: a review of in vivo studies. J Diabetes Metab Disord 2021; 20:1837-1854. [PMID: 34900828 PMCID: PMC8630315 DOI: 10.1007/s40200-021-00853-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 07/03/2021] [Indexed: 12/11/2022]
Abstract
Background Medicinal plants are used to treat various disorders, including diabetes, globally in a range of formulations. While attention has mainly been on the aerial plant parts, there are only a few review studies to date that are focused on the natural constituents present in the plant roots with health benefits. Thus, the present study was performed to review in vivo studies investigating the antidiabetic potential of the natural compounds in plant roots. Methods We sorted relevant data in 2001-2019 from scientific databases and search engines, including Web of Knowledge, PubMed, ScienceDirect, Medline, Reaxys, and Google Scholar. The class of phytochemicals, plant families, major compounds, active constituents, effective dosages, type of extracts, time of experiments, and type of diabetic induction were described. Results In our literature review, we found 104 plants with determined antidiabetic activity in their root extracts. The biosynthesis pathways and mechanism of actions of the most frequent class of compounds were also proposed. The results of this review indicated that flavonoids, phenolic compounds, alkaloids, and phytosteroids are the most abundant natural compounds in plant roots with antidiabetic activity. Phytochemicals in plant roots possess different mechanisms of action to control diabetes, including inhibition of α-amylase and α-glucosidase enzymes, oxidative stress reduction, secretion of insulin, improvement of diabetic retinopathy/nephropathy, slow the starch digestion, and contribution against hyperglycemia. Conclusion This review concludes that plant roots are a promising source of bioactive compounds which can be explored to develop against diabetes and diabetes-related complications. Graphical abstract
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Affiliation(s)
- Hamidreza Ardalani
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.,Department of Chemistry, Centre for Analysis and Synthesis, Lund University, Lund, Sweden
| | - Fatemeh Hejazi Amiri
- Department of Microbiology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Amin Hadipanah
- Department of Plant Biology, Faculty of Sciences, Shahrekord University, Shahrekord, Iran
| | - Kenneth T Kongstad
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
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22
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Suarez-Castellanos I, Singh T, Chatterjee Bhowmick D, Cohen J, Jeremic A, Zderic V. Effect of Therapeutic Ultrasound on the Release of Insulin, Glucagon, and Alpha-Amylase from Ex Vivo Pancreatic Models. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2021; 40:2709-2719. [PMID: 33595146 DOI: 10.1002/jum.15661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 01/22/2021] [Accepted: 01/29/2021] [Indexed: 06/12/2023]
Abstract
OBJECTIVES Our previously published studies showed the potential of therapeutic ultrasound (US) as a novel non-pharmacological alternative for the treatment of secretory deficiencies in type 2 diabetes. Despite showing enhanced insulin release from beta cells, these studies did not explore the potential effects of US treatment on other cells in the islets of Langerhans such as glucagon-secreting alpha cells or acinar cells of the exocrine pancreas. METHODS We applied US parameters found capable of safely stimulating insulin secretion from pancreatic beta cells (f = 800 kHz, ISPTA = 0.5-1 W/cm2 , 5 minutes) to a diced rabbit pancreas model in culture plates (n = 6 per group). Released quantities of insulin and glucagon in response to US treatment were measured by collecting aliquots of the extracellular medium prior to the start of the treatment (t = 0 minute), immediately after treatment (t = 5 minutes) and 30 minutes after the end of treatment (t = 35 minutes). Potential release of digestive enzyme alpha-amylase as a result of US treatment was evaluated in rabbit pancreas experiments. Preliminary studies were also performed in a small number of human pancreatic islets in culture plates (n = 3 per group). The general integrity of the US-treated rabbit pancreatic tissue and human pancreatic islets was evaluated through histological analysis. RESULTS While sham-treated rabbit pancreas samples showed decreased extracellular insulin content, there was an increase in insulin release at t = 5 minutes from samples treated with US at 800 kHz and 1 W/cm2 (P <.005). Furthermore, no further insulin release was detected at t = 35 minutes. No statistically significant difference in extracellular glucagon and alpha-amylase concentrations was observed between US-treated and sham rabbit pancreas groups. Preliminary studies in human islets appeared to follow trends observed in rabbit pancreas studies. Islet and other pancreatic tissue integrity did not appear to be affected by the US treatment. CONCLUSION A potential US-based strategy for enhanced insulin release would require optimization of insulin secretion from pancreatic beta cells while minimizing glucagon and pancreatic enzyme secretions.
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Affiliation(s)
- Ivan Suarez-Castellanos
- Department of Biomedical Engineering, The George Washington University, Washington, District of Columbia, USA
- LabTAU, INSERM, Centre Léon Bérard, Université Lyon 1, Université Lyon 1, Université Lyon, Lyon, France
| | - Tania Singh
- Department of Biomedical Engineering, The George Washington University, Washington, District of Columbia, USA
| | - Diti Chatterjee Bhowmick
- Department of Biological Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Joshua Cohen
- Department of Endocrinology, Medical Faculty Associates, The George Washington University, Washington, District of Columbia, USA
| | - Aleksandar Jeremic
- Department of Biological Sciences, The George Washington University, Washington, District of Columbia, USA
| | - Vesna Zderic
- Department of Biomedical Engineering, The George Washington University, Washington, District of Columbia, USA
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23
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Klochkov VG, Bezsonova EN, Dubar M, Melekhina DD, Temnov VV, Zaryanova EV, Lozinskaya NA, Babkov DA, Spasov AA. Towards multi-target antidiabetic agents: In vitro and in vivo evaluation of 3,5-disubstituted indolin-2-one derivatives as novel α-glucosidase inhibitors. Bioorg Med Chem Lett 2021; 55:128449. [PMID: 34780899 DOI: 10.1016/j.bmcl.2021.128449] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/29/2021] [Accepted: 11/06/2021] [Indexed: 11/18/2022]
Abstract
Type 2 diabetes mellitus is a chronic progressive disease that usually requires polypharmacological treatment approaches. Previously we have described a series of 2-oxindole derivatives as GSK3β inhibitors with in vivo antihyperglycemic activity. α-Glucosidase is another antidiabetic target that prevents postprandial hyperglycemia and corresponding hyperinsulinemic response. Herein we report a study of 3,5-disubstituted indolin-2-one derivatives as potent α-glucosidase inhibitors. These inhibitors were identified via efficient synthesis, in vitro screening, and biological evaluation. The most active compound 5f inhibits yeast α-glucosidase with IC50 of 6.78 µM and prevents postprandial hyperglycemia in rats after maltose and sucrose challenge at 5.0 mg/kg dose. Two lead glucosidase inhibitors, 5f and 5m, are also GSK3β inhibitors with submicromolar potency. Hence, structure-activity studies elucidate foundation for development of dual GSK3β/α-glucosidase inhibitors for treatment of type 2 diabetes.
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Affiliation(s)
- Vladlen G Klochkov
- Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Pavshikh Bortsov Sq. 1, Volgograd 400131, Russia
| | - Elena N Bezsonova
- Lomonosov Moscow State University, Department of Chemistry, Leninskie gory St., 1, Moscow 119234, Russia
| | - Meriam Dubar
- Lomonosov Moscow State University, Department of Chemistry, Leninskie gory St., 1, Moscow 119234, Russia
| | - Daria D Melekhina
- Lomonosov Moscow State University, Department of Chemistry, Leninskie gory St., 1, Moscow 119234, Russia
| | - Victor V Temnov
- Lomonosov Moscow State University, Department of Chemistry, Leninskie gory St., 1, Moscow 119234, Russia
| | - Ekaterina V Zaryanova
- Lomonosov Moscow State University, Department of Chemistry, Leninskie gory St., 1, Moscow 119234, Russia
| | - Natalia A Lozinskaya
- Lomonosov Moscow State University, Department of Chemistry, Leninskie gory St., 1, Moscow 119234, Russia.
| | - Denis A Babkov
- Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Pavshikh Bortsov Sq. 1, Volgograd 400131, Russia; Scientific Center for Innovative Drugs, Volgograd State Medical University, Novorossiyskaya St. 39, Volgograd 400087, Russia.
| | - Alexander A Spasov
- Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Pavshikh Bortsov Sq. 1, Volgograd 400131, Russia; Scientific Center for Innovative Drugs, Volgograd State Medical University, Novorossiyskaya St. 39, Volgograd 400087, Russia
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24
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Tolmie M, Bester MJ, Apostolides Z. Inhibition of α-glucosidase and α-amylase by herbal compounds for the treatment of type 2 diabetes: A validation of in silico reverse docking with in vitro enzyme assays. J Diabetes 2021; 13:779-791. [PMID: 33550683 DOI: 10.1111/1753-0407.13163] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 01/25/2021] [Accepted: 02/03/2021] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND α-Amylase and α-glucosidase are important therapeutic targets for the management of type 2 diabetes mellitus. The inhibition of these enzymes decreases postprandial hyperglycemia. In the present study, compounds found in commercially available herbs and spices were tested for their ability to inhibit α-amylase and α-glucosidase. These compounds were acetyleugenol, apigenin, cinnamic acid, eriodictyol, myrcene, piperine, and rosmarinic acid. METHODS The enzyme inhibitory nature of the compounds was evaluated using in silico docking analysis with Maestro software and was further confirmed by in vitro α-amylase and α-glucosidase biochemical assays. RESULTS The relationships between the in silico and in vitro results were well correlated; a more negative docking score was associated with a higher in vitro inhibitory activity. There was no significant (P > .05) difference between the inhibition constant (Ki ) value of acarbose, a widely prescribed α-glucosidase and α-amylase inhibitor, and those of apigenin, eriodictyol, and piperine. For α-amylase, there was no significant (P > .05) difference between the Ki value of acarbose and those of apigenin, cinnamic acid, and rosmarinic acid. The effect of the herbal compounds on cell viability was assessed with the sulforhodamine B (SRB) assay in C2C12 and HepG2 cells. Acetyleugenol, cinnamic acid, myrcene, piperine, and rosmarinic acid had similar (P > .05) IC50 values to acarbose. CONCLUSIONS Several of the herbal compounds studied could regulate postprandial hyperglycemia. Using herbal plants has several advantages including low cost, natural origin, and easy cultivation. These compounds can easily be consumed as teas or as herbs and spices to flavor food.
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Affiliation(s)
- Morné Tolmie
- Department of Biochemistry, Genetics, and Microbiology, University of Pretoria, Pretoria, South Africa
| | - Megan Jean Bester
- Department of Anatomy, University of Pretoria, Pretoria, South Africa
| | - Zeno Apostolides
- Department of Biochemistry, Genetics, and Microbiology, University of Pretoria, Pretoria, South Africa
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25
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Sipos Á, Szennyes E, Hajnal NÉ, Kun S, Szabó KE, Uray K, Somsák L, Docsa T, Bokor É. Dual-Target Compounds against Type 2 Diabetes Mellitus: Proof of Concept for Sodium Dependent Glucose Transporter (SGLT) and Glycogen Phosphorylase (GP) Inhibitors. Pharmaceuticals (Basel) 2021; 14:ph14040364. [PMID: 33920838 PMCID: PMC8071193 DOI: 10.3390/ph14040364] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/07/2021] [Accepted: 04/13/2021] [Indexed: 12/15/2022] Open
Abstract
A current trend in the quest for new therapies for complex, multifactorial diseases, such as diabetes mellitus (DM), is to find dual or even multi-target inhibitors. In DM, the sodium dependent glucose cotransporter 2 (SGLT2) in the kidneys and the glycogen phosphorylase (GP) in the liver are validated targets. Several (β-D-glucopyranosylaryl)methyl (het)arene type compounds, called gliflozins, are marketed drugs that target SGLT2. For GP, low nanomolar glucose analogue inhibitors exist. The purpose of this study was to identify dual acting compounds which inhibit both SGLTs and GP. To this end, we have extended the structure-activity relationships of SGLT2 and GP inhibitors to scarcely known (C-β-D-glucopyranosylhetaryl)methyl arene type compounds and studied several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitors against SGLT. New compounds, such as 5-arylmethyl-3-(β-D-glucopyranosyl)-1,2,4-oxadiazoles, 5-arylmethyl-2-(β-D-glucopyranosyl)-1,3,4-oxadiazoles, 4-arylmethyl-2-(β-D-glucopyranosyl)pyrimidines and 4(5)-benzyl-2-(β-D-glucopyranosyl)imidazole were prepared by adapting our previous synthetic methods. None of the studied compounds exhibited cytotoxicity and all of them were assayed for their SGLT1 and 2 inhibitory potentials in a SGLT-overexpressing TSA201 cell system. GP inhibition was also determined by known methods. Several newly synthesized (C-β-D-glucopyranosylhetaryl)methyl arene derivatives had low micromolar SGLT2 inhibitory activity; however, none of these compounds inhibited GP. On the other hand, several (C-β-D-glucopyranosylhetaryl)arene type GP inhibitor compounds with low micromolar efficacy against SGLT2 were identified. The best dual inhibitor, 2-(β-D-glucopyranosyl)-4(5)-(2-naphthyl)-imidazole, had a Ki of 31 nM for GP and IC50 of 3.5 μM for SGLT2. This first example of an SGLT-GP dual inhibitor can prospectively be developed into even more efficient dual-target compounds with potential applications in future antidiabetic therapy.
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Affiliation(s)
- Ádám Sipos
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (Á.S.); (K.U.)
- Doctoral School of Molecular Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
| | - Eszter Szennyes
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary; (E.S.); (N.É.H.); (S.K.); (K.E.S.)
| | - Nikolett Éva Hajnal
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary; (E.S.); (N.É.H.); (S.K.); (K.E.S.)
| | - Sándor Kun
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary; (E.S.); (N.É.H.); (S.K.); (K.E.S.)
| | - Katalin E. Szabó
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary; (E.S.); (N.É.H.); (S.K.); (K.E.S.)
| | - Karen Uray
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (Á.S.); (K.U.)
| | - László Somsák
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary; (E.S.); (N.É.H.); (S.K.); (K.E.S.)
- Correspondence: (L.S.); (T.D.); (É.B.); Tel.: +36-525-129-00 (ext. 22348) (L.S.); +36-525-186-00 (ext. 61192) (T.D.); +36-525-129-00 (ext. 22474) (É.B.)
| | - Tibor Docsa
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary; (Á.S.); (K.U.)
- Correspondence: (L.S.); (T.D.); (É.B.); Tel.: +36-525-129-00 (ext. 22348) (L.S.); +36-525-186-00 (ext. 61192) (T.D.); +36-525-129-00 (ext. 22474) (É.B.)
| | - Éva Bokor
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary; (E.S.); (N.É.H.); (S.K.); (K.E.S.)
- Correspondence: (L.S.); (T.D.); (É.B.); Tel.: +36-525-129-00 (ext. 22348) (L.S.); +36-525-186-00 (ext. 61192) (T.D.); +36-525-129-00 (ext. 22474) (É.B.)
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26
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Insulin-Mimetic Dihydroxanthyletin-Type Coumarins from Angelica decursiva with Protein Tyrosine Phosphatase 1B and α-Glucosidase Inhibitory Activities and Docking Studies of Their Molecular Mechanisms. Antioxidants (Basel) 2021; 10:antiox10020292. [PMID: 33672051 PMCID: PMC7919472 DOI: 10.3390/antiox10020292] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 01/04/2023] Open
Abstract
As a traditional medicine, Angelica decursiva has been used for the treatment of many diseases. The goal of this study was to evaluate the potential of four natural major dihydroxanthyletin-type coumarins—(+)-trans-decursidinol, Pd-C-I, Pd-C-II, and Pd-C-III—to inhibit the enzymes, protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase. In the kinetic study of the PTP1B enzyme’s inhibition, we found that (+)-trans-decursidinol, Pd-C-I, and Pd-C-II led to competitive inhibition, while Pd-C-III displayed mixed-type inhibition. Moreover, (+)-trans-decursidinol exhibited competitive-type, and Pd-C-I and Pd-C-II mixed-type, while Pd-C-III showed non-competitive type inhibition of α-glucosidase. Docking simulations of these coumarins showed negative binding energies and a similar proximity to residues in the PTP1B and α-glucosidase binding pocket, which means they are closely connected and strongly binding with the active enzyme site. In addition, dihydroxanthyletin-type coumarins are up to 40 µM non-toxic in HepG2 cells and have substantially increased glucose uptake and decreased expression of PTP1B in insulin-resistant HepG2 cells. Further, coumarins inhibited ONOO−-mediated albumin nitration and scavenged peroxynitrite (ONOO−), and reactive oxygen species (ROS). Our overall findings showed that dihydroxanthyletin-type coumarins derived from A. decursiva is used as a dual inhibitor for enzymes, such as PTP1B and α-glucosidase, as well as for insulin susceptibility.
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Rivera-Chávez J, Bustos-Brito C, Aguilar-Ramírez E, Martínez-Otero D, Rosales-Vázquez LD, Dorazco-González A, Cano-Sánchez P. Hydroxy- neo-Clerodanes and 5,10- seco- neo-Clerodanes from Salvia decora. JOURNAL OF NATURAL PRODUCTS 2020; 83:2212-2220. [PMID: 32597650 DOI: 10.1021/acs.jnatprod.0c00313] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Preliminary analysis of the mass spectrometric (MS) and NMR spectroscopic data of the primary fractions from the biologically active extract of Salvia decora revealed spectra that are characteristic for neo-clerodane-type diterpenoids. MS-guided isolation of the bioactive fractions led to the isolation of three new chemical entities, including two hydroxy-neo-clerodanes (1 and 2) and one acylated 5,10-seco-neo-clerodane (3), along with three known diterpenoids (4-6), ursolic acid (7), and eupatorin (8). The structures of the new compounds were established by analysis of the 1D and 2D NMR and MS data, whereas their absolute configuration was deduced using a combination of experimental and theoretical ECD data and confirmed by X-ray crystallography (1 and 4). Furthermore, compounds 1, 3, 4, and 6-8 were evaluated as hPTP1B1-400 (human protein tyrosine phosphatase) inhibitors, where 7 showed the best activity, with an IC50 value in the lower μM range. Additionally, compound 7 was evaluated as an α-glucosidase inhibitor. The affinity constant of the 7-hPTP1B1-400 complex was determined by quenching fluorescence experiments (ka = 1.3 × 104 M-1), while the stoichiometry ratio (1:1 protein-ligand) was determined by a continuous variation method.
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Affiliation(s)
- José Rivera-Chávez
- Departamento de Productos Naturales, Instituto de Quı́mica, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, Ciudad de México, Mexico
| | - Celia Bustos-Brito
- Departamento de Productos Naturales, Instituto de Quı́mica, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, Ciudad de México, Mexico
| | - Enrique Aguilar-Ramírez
- Departamento de Productos Naturales, Instituto de Quı́mica, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, Ciudad de México, Mexico
| | - Diego Martínez-Otero
- Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM, Carretera Toluca-Atlacomulco, Toluca, 50200, Mexico
| | - Luis D Rosales-Vázquez
- Departamento de Quı́mica Inorgánica, Instituto de Quı́mica, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, Ciudad de México, Mexico
| | - Alejandro Dorazco-González
- Departamento de Quı́mica Inorgánica, Instituto de Quı́mica, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, Ciudad de México, Mexico
| | - Patricia Cano-Sánchez
- Departamento de Quı́mica de Biomacromoléculas, Instituto de Quı́mica, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, Ciudad de México, Mexico
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Colorado D, Fernandez M, Orozco J, Lopera Y, Muñoz DL, Acín S, Balcazar N. Metabolic Activity of Anthocyanin Extracts Loaded into Non-ionic Niosomes in Diet-Induced Obese Mice. Pharm Res 2020; 37:152. [PMID: 32700034 DOI: 10.1007/s11095-020-02883-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Anthocyanins (ACNs) are polyphenols that might reduce pathological processes associated with type 2 diabetes mellitus and other chronic diseases, but their bioavailability is still controversial. In this study, the metabolic activity of oral delivery of ACN-loaded niosomes was investigated and evaluated in a diet-induced obesity (DIO) mice model. METHODS ACNs extracted from Vaccinium Meridionale by the supercritical fluid extraction method were loaded in niosomes. The niosomal formulation was physically characterized and further administrated in drinking water to obese, insulin resistant mouse. We evaluated the effect of ACN loaded niosomes on hyperglycemia, glucose and insulin intolerance and insulin blood levels in C57BL/6 J mice fed with a high-fat diet. RESULTS The ACN-loaded particles were moderately monodisperse, showed a negative surface charge and 57% encapsulation efficiency. The ACN-loaded niosomes ameliorated the insulin resistance and glucose intolerance in the DIO mice model. Additionally, they reduced animal weight and plasma insulin, glucose, leptin and total cholesterol levels in obese mice. CONCLUSION ACN-loaded niosomes administration, as a functional drink, had a beneficial effect on the reversal of metabolic abnormalities associated with obesity.
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Affiliation(s)
- Diana Colorado
- GENMOL Group, Universidad de Antioquia, Calle 62 # 52-59, Medellin, Colombia
| | - Maritza Fernandez
- Max Planck Tandem Group in Nanobioengineering, University of Antioquia, Complejo Ruta N, Calle 67 N° 52-20, Medellín, 050010, Colombia
| | - Jahir Orozco
- Max Planck Tandem Group in Nanobioengineering, University of Antioquia, Complejo Ruta N, Calle 67 N° 52-20, Medellín, 050010, Colombia
| | | | - Diana Lorena Muñoz
- Department of Physiology and Biochemistry, School of Medicine, Universidad de Antioquia, Carrera 51D N° 62-29, Medellin, Colombia
| | - Sergio Acín
- GENMOL Group, Universidad de Antioquia, Calle 62 # 52-59, Medellin, Colombia.,Department of Physiology and Biochemistry, School of Medicine, Universidad de Antioquia, Carrera 51D N° 62-29, Medellin, Colombia
| | - Norman Balcazar
- GENMOL Group, Universidad de Antioquia, Calle 62 # 52-59, Medellin, Colombia. .,Department of Physiology and Biochemistry, School of Medicine, Universidad de Antioquia, Carrera 51D N° 62-29, Medellin, Colombia.
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Goyard D, Kónya B, Czifrák K, Larini P, Demontrond F, Leroy J, Balzarin S, Tournier M, Tousch D, Petit P, Duret C, Maurel P, Docsa T, Gergely P, Somsák L, Praly JP, Azay-Milhau J, Vidal S. Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition. Org Biomol Chem 2020; 18:931-940. [PMID: 31922157 DOI: 10.1039/c9ob01190k] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks' protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (Ki = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ∼36% at 30 mg kg-1 and ∼43% at 60 mg kg-1. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.
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Affiliation(s)
- David Goyard
- Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR 5246, CNRS, Université Claude Bernard Lyon 1, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, France.
| | - Bálint Kónya
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary
| | - Katalin Czifrák
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary
| | - Paolo Larini
- Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR 5246, CNRS, Université Claude Bernard Lyon 1, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, France.
| | - Fanny Demontrond
- Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR 5246, CNRS, Université Claude Bernard Lyon 1, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, France.
| | - Jérémy Leroy
- Montpellier University, EA7288, Biocommunication in cardiometabolism (BC2M), Montpellier, France
| | - Sophie Balzarin
- Montpellier University, EA7288, Biocommunication in cardiometabolism (BC2M), Montpellier, France
| | - Michel Tournier
- Montpellier University, EA7288, Biocommunication in cardiometabolism (BC2M), Montpellier, France
| | - Didier Tousch
- Montpellier University, EA7288, Biocommunication in cardiometabolism (BC2M), Montpellier, France
| | - Pierre Petit
- Montpellier University, EA7288, Biocommunication in cardiometabolism (BC2M), Montpellier, France
| | - Cédric Duret
- INSERM U1040, Montpellier, France and Montpellier University, UMR-1040, Montpellier, France
| | - Patrick Maurel
- INSERM U1040, Montpellier, France and Montpellier University, UMR-1040, Montpellier, France
| | - Tibor Docsa
- Institute of Medical Chemistry, University of Debrecen, POB 7, Nagyerdei krt. 98, H-4012 Debrecen, Hungary
| | - Pál Gergely
- Institute of Medical Chemistry, University of Debrecen, POB 7, Nagyerdei krt. 98, H-4012 Debrecen, Hungary
| | - László Somsák
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary
| | - Jean-Pierre Praly
- Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR 5246, CNRS, Université Claude Bernard Lyon 1, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, France.
| | - Jacqueline Azay-Milhau
- Montpellier University, EA7288, Biocommunication in cardiometabolism (BC2M), Montpellier, France
| | - Sébastien Vidal
- Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR 5246, CNRS, Université Claude Bernard Lyon 1, Bâtiment Lederer, 1 Rue Victor Grignard, F-69622 Villeurbanne, France.
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Rammohan A, Bhaskar BV, Venkateswarlu N, Gu W, Zyryanov GV. Design, synthesis, docking and biological evaluation of chalcones as promising antidiabetic agents. Bioorg Chem 2020; 95:103527. [PMID: 31911298 DOI: 10.1016/j.bioorg.2019.103527] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 10/25/2019] [Accepted: 12/19/2019] [Indexed: 02/05/2023]
Abstract
Diabetes mellitus (DM) is a serious chronic metabolic disorder which occurs due to dysfunction of insulin and therapeutic approaches are poor. It is an under estimation that 387 million people currently suffering globally with diabetic and more than 592 million people may be affected by 2030. It makes an urgent necessity to discover novel drugs to control amplified diabetic populations. In this study, amino chalcones (3a-j) were synthesized and hydroxy chalcones (3g-j) were isolated from natural source such as Sophora interrupta, Clerodendrum phlomidis and Andrographis macrobotrys. Structural elucidation was carried out using Mass, 1H and 13C NMR Spectra. In vivo studies were carried out with alloxan induced diabetic rats (100 mg/kg) which reveals compounds 3c, 3a and 3h have significant antidiabetic efficacy with decreased blood glucose levels in the diabetic rats while compared with control rats. Besides, docking studies with aldose reductase, dipeptidyl peptidase, PPAR and glucosidase were monitored which accomplishes that the compounds 3c, 3i, 3a and 3d have eloquent binding affinity (kcal/mol) with aldose reductase, besides the chalcones 3c, 3b, 3d, 3e and 3i were also showed inhibition with DPP-IV, PPAR-α and α-glucosidase. Also, these compounds explicated distinct interactions i.e., π-π, π-cationic, polar, electrostatic and hydrophobic bonds were observed with key residues of binding pockets. Bioavailability is disclosed with Lipinski rule of five and the design pharmacokinetic as well as pharmacodynamic properties are reliable. Therefore, chalcones were implied as antidiabetic leads for in further studies and could be worthwhile for the development of new classes of effective antidiabetic agents.
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Affiliation(s)
- Aluru Rammohan
- Department of Organic and Biomolecular Chemistry, Ural Federal University, 19 Mira, Yekaterinburg 620002, Russian Federation; Natural Products Division, Department of Chemistry, Sri Venkateswara University, Tirupati, India.
| | - Baki Vijaya Bhaskar
- Department of Pathophysiology, The Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, Shantou, Guangdong 515031, China; Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, United States
| | - Nagam Venkateswarlu
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266200, China
| | - Wei Gu
- Department of Pathophysiology, The Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, Shantou, Guangdong 515031, China
| | - Grigory V Zyryanov
- Department of Organic and Biomolecular Chemistry, Ural Federal University, 19 Mira, Yekaterinburg 620002, Russian Federation; Ural Division of the Russian Academy of Sciences, I. Ya. Postovskiy Institute of Organic Synthesis, 22 S. Kovalevskoy Street, Yekaterinburg, Russian Federation
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31
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Zhu X, Qiu Z, Ouyang W, Miao J, Xiong P, Mao D, Feng K, Li M, Luo M, Xiao H, Cao Y. Hepatic transcriptome and proteome analyses provide new insights into the regulator mechanism of dietary avicularin in diabetic mice. Food Res Int 2019; 125:108570. [PMID: 31554135 DOI: 10.1016/j.foodres.2019.108570] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 07/10/2019] [Accepted: 07/18/2019] [Indexed: 11/23/2022]
Abstract
Many dietary flavonoids existing as glycosides in fruits and vegetables are considered bioactive food components with various potential health benefits. Type 2 diabetes mellitus (T2DM) is a complex and polygenic disease with increasing global prevalence and economic burden. In this study, the hypoglycemic effect of avicularin (quercetin-3-O-α-arabinofuranoside), a flavonoid glycoside commonly found in natural plants and fruits, was determined in a high fat diet/streptozotocin induced type 2 diabetes mouse model. Our results demonstrated that dietary avicularin treatment reduced levels of fasting blood glucose, serum TG and LDL-C, liver AST and ALT, and increased hepatic glycogen in T2DM mice. Furthermore, we used RNA-Seq and iTRAQ to compare the gene and protein expression in the livers of the normal control mice (NC), diabetic control mice (DC) and avicularin treated mice (DA100). The differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were analyzed based on gene annotations and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Integrated analysis of the RNA-Seq and iTRAQ data indicated that the fifteen DEGs/DEPs showed the same trend in mRNA and protein expression levels in comparisons of both NC vs DC and DC vs DA100. KEGG analysis revealed that four DEGs/DEPs (PKM, PEPCK, PYG, and PLA2) in the glycolysis, gluconeogenesis, and arachidonic acid pathway, and six DEPs (Ndufb4, Ndufa6, Cox5a, Cox5b, Cox6c, and ATPSβ) in the oxidative phosphorylation signaling pathway, play important roles in avicularin's hypoglycemic effect. We also found six other DEGs/DEPs related to T2DM (CA1, Serpinb6a, AK, Pcolce, Cand2, and Atp2a3), and five related to cancer (Phgdh, Tes, Papss1, Psat1, and Fam49b). We did further verify by qRT-PCR and explored the possible binding modes of avicularin with targeted proteins with molecular docking simulations. Taken together, our results demonstrated the protective effects of avicularin against diabetes and provided a global view about the system-level hypoglycemic mechanisms of avicularin by the comprehensive analysis of transcriptomic and proteomic data in T2DM mice.
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Affiliation(s)
- Xiaoai Zhu
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, PR China; Department of Food Science, University of Massachusetts, Amherst, MA 01003, United States
| | - Zhirou Qiu
- Zhaoqing University, Zhaoqing 526000, PR China
| | - Wen Ouyang
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410007, PR China
| | - Jianyin Miao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Ping Xiong
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Duobin Mao
- Collaborative Innovation Center of Food Production and Safety, Henan Key Laboratory of Cold Chain Food Quality and Safety Control, School of Food and Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou 450002, PR China
| | - Konglong Feng
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Minxiong Li
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Minna Luo
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, PR China
| | - Hang Xiao
- Department of Food Science, University of Massachusetts, Amherst, MA 01003, United States.
| | - Yong Cao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, PR China.
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Russart KLG, Chbeir SA, Nelson RJ, Magalang UJ. Light at night exacerbates metabolic dysfunction in a polygenic mouse model of type 2 diabetes mellitus. Life Sci 2019; 231:116574. [PMID: 31207311 PMCID: PMC6689263 DOI: 10.1016/j.lfs.2019.116574] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/10/2019] [Accepted: 06/13/2019] [Indexed: 01/21/2023]
Abstract
AIMS Electric lighting is beneficial to modern society; however, it is becoming apparent that light at night (LAN) is not without biological consequences. Several studies have reported negative effects of LAN on health and behavior in humans and nonhuman animals. Exposure of non-diabetic mice to dim LAN impairs glucose tolerance, whereas a return to dark nights (LD) reverses this impairment. We predicted that exposure to LAN would exacerbate the metabolic abnormalities in TALLYHO/JngJ (TH) mice, a polygenic model of type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS We exposed 7-week old male TH mice to either LD or LAN for 8-10 weeks in two separate experiments. After 8 weeks of light treatment, we conducted intraperitoneal glucose tolerance testing (ipGTT) followed by intraperitoneal insulin tolerance testing (ipITT). In Experiment 1, all mice were returned to LD for 4 weeks, and ipITT was repeated. KEY FINDINGS The major results of this study are i) LAN exposure for 8 weeks exacerbates glucose intolerance and insulin resistance ii) the effects of LAN on insulin resistance are reversed upon return to LD, iii) LAN exposure results in a greater increase in body weight compared to LD exposure, iv) LAN increases the incidence of mice developing overt T2DM, and v) LAN exposure decreases survival of mice with T2DM. SIGNIFICANCE In conclusion, LAN exacerbated metabolic abnormalities in a polygenic mouse model of T2DM, and these effects were reversed upon return to dark nights. The applicability of these findings to humans with T2DM needs to be determined.
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Affiliation(s)
- Kathryn L G Russart
- Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
| | - Souhad A Chbeir
- Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Randy J Nelson
- Department of Neuroscience, West Virginia University, Morgantown, WV 26505, USA
| | - Ulysses J Magalang
- Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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Barr D, Szennyes E, Bokor É, Al-Oanzi ZH, Moffatt C, Kun S, Docsa T, Sipos Á, Davies MP, Mathomes RT, Snape TJ, Agius L, Somsák L, Hayes JM. Identification of C-β-d-Glucopyranosyl Azole-Type Inhibitors of Glycogen Phosphorylase That Reduce Glycogenolysis in Hepatocytes: In Silico Design, Synthesis, in Vitro Kinetics, and ex Vivo Studies. ACS Chem Biol 2019; 14:1460-1470. [PMID: 31243960 DOI: 10.1021/acschembio.9b00172] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Several C-β-d-glucopyranosyl azoles have recently been uncovered as among the most potent glycogen phosphorylase (GP) catalytic site inhibitors discovered to date. Toward further exploring their translational potential, ex vivo experiments have been performed for their effectiveness in reduction of glycogenolysis in hepatocytes. New compounds for these experiments were predicted in silico where, for the first time, effective ranking of GP catalytic site inhibitor potencies using the molecular mechanics-generalized Born surface area (MM-GBSA) method has been demonstrated. For a congeneric training set of 27 ligands, excellent statistics in terms of Pearson (RP) and Spearman (RS) correlations (both 0.98), predictive index (PI = 0.99), and area under the receiver operating characteristic curve (AU-ROC = 0.99) for predicted versus experimental binding affinities were obtained, with ligand tautomeric/ionization states additionally considered using density functional theory (DFT). Seven 2-aryl-4(5)-(β-d-glucopyranosyl)-imidazoles and 2-aryl-4-(β-d-glucopyranosyl)-thiazoles were subsequently synthesized, and kinetics experiments against rabbit muscle GPb revealed new potent inhibitors with best Ki values in the low micromolar range (5c = 1.97 μM; 13b = 4.58 μM). Ten C-β-d-glucopyranosyl azoles were then tested ex vivo in mouse primary hepatocytes. Four of these (5a-c and 9d) demonstrated significant reduction of glucagon stimulated glycogenolysis (IC50 = 30-60 μM). Structural and predicted physicochemical properties associated with their effectiveness were analyzed with permeability related parameters identified as crucial factors. The most effective ligand series 5 contained an imidazole ring, and the calculated pKa (Epik: 6.2; Jaguar 5.5) for protonated imidazole suggests that cellular permeation through the neutral state is favored, while within the cell, there is predicted more favorable binding to GP in the protonated form.
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Affiliation(s)
- Daniel Barr
- School of Physical Sciences & Computing, University of Central Lancashire, Preston PR1 2HE, United Kingdom
| | - Eszter Szennyes
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary
| | - Éva Bokor
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary
| | - Ziad H. Al-Oanzi
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Colin Moffatt
- Health & Life Sciences, De Montfort University, Gateway House, Leicester LE1 9BH, United Kingdom
| | - Sándor Kun
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary
| | - Tibor Docsa
- Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
| | - Ádám Sipos
- Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
| | - Matthew P. Davies
- School of Physical Sciences & Computing, University of Central Lancashire, Preston PR1 2HE, United Kingdom
| | - Rachel T. Mathomes
- School of Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, United Kingdom
| | - Timothy J. Snape
- School of Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, United Kingdom
| | - Loranne Agius
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - László Somsák
- Department of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen, Hungary
| | - Joseph M. Hayes
- School of Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, United Kingdom
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Peter JS, Shalini M, Giridharan R, Basha KS, Lavinya UB, Evan Prince S. Administration of coenzyme Q10 to a diabetic rat model: changes in biochemical, antioxidant, and histopathological indicators. Int J Diabetes Dev Ctries 2019. [DOI: 10.1007/s13410-019-00752-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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35
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Diéguez-Santana K, Rivera-Borroto OM, Puris A, Pham-The H, Le-Thi-Thu H, Rasulev B, Casañola-Martin GM. Beyond model interpretability using LDA and decision trees for α-amylase and α-glucosidase inhibitor classification studies. Chem Biol Drug Des 2019; 94:1414-1421. [PMID: 30908888 DOI: 10.1111/cbdd.13518] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 02/17/2019] [Accepted: 03/03/2019] [Indexed: 12/17/2022]
Abstract
In this report are used two data sets involving the main antidiabetic enzyme targets α-amylase and α-glucosidase. The prediction of α-amylase and α-glucosidase inhibitory activity as antidiabetic is carried out using LDA and classification trees (CT). A large data set of 640 compounds for α-amylase and 1546 compounds in the case of α-glucosidase are selected to develop the tree model. In the case of CT-J48 have the better classification model performances for both targets with values above 80%-90% for the training and prediction sets, correspondingly. The best model shows an accuracy higher than 95% for training set; the model was also validated using 10-fold cross-validation procedure and through a test set achieving accuracy values of 85.32% and 86.80%, correspondingly. Additionally, the obtained model is compared with other approaches previously published in the international literature showing better results. Finally, we can say that the present results provided a double-target approach for increasing the estimation of antidiabetic chemicals identification aimed by double-way workflow in virtual screening pipelines.
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Affiliation(s)
| | - Oscar M Rivera-Borroto
- Departamento de Química Física Aplicada, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain
| | - Amilkar Puris
- Facultad de Ciencias de La Ingeniería, Universidad Técnica Estatal de Quevedo, Quevedo, Ecuador
| | | | - Huong Le-Thi-Thu
- School of Medicine and Pharmacy, Vietnam National University, Hanoi, Vietnam
| | - Bakhtiyor Rasulev
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, North Dakota
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Yang L, Yang YL, Dong WH, Li W, Wang P, Cao X, Yuan JZ, Chen HQ, Mei WL, Dai HF. Sesquiterpenoids and 2-(2-phenylethyl)chromones respectively acting as α-glucosidase and tyrosinase inhibitors from agarwood of an Aquilaria plant. J Enzyme Inhib Med Chem 2019; 34:853-862. [PMID: 31010356 PMCID: PMC6495113 DOI: 10.1080/14756366.2019.1576657] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The ethyl ether extract of agarwood from an Aquilaria plant afforded six new sesquiterpenoids, Agarozizanol A − F (1−6), together with four known sesquiterpenoids and six known 2-(2-phenylethyl)chromones. Their structures were elucidated via detailed spectroscopic analysis, X-ray diffraction, and comparisons with the published data. All the isolates were evaluated for the α-glucosidase and tyrosinase inhibitory activities in vitro. Compounds 5, 7, 8, and 10 showed significant inhibition of α-glucosidase with IC50 values ranging between 112.3 ± 4.5 and 524.5 ± 2.7 µM (acarbose, 743. 4 ± 3.3 µM). Compounds 13 and 14 exhibited tyrosinase inhibitory effect with IC50 values of 89.0 ± 1.7 and 51.5 ± 0.6 µM, respectively (kojic acid, 46.1 ± 1.3). In the kinetic studies, compounds 5 and 14 were found to be uncompetitive inhibitors for α-glucosidase and mixed type inhibitors for tyrosinase, respectively. Furthermore, molecular docking simulations revealed the binding sites and interactions of the most active compounds with α-glucosidase and tyrosinase.
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Affiliation(s)
- Li Yang
- a Key Laboratory of Biology and Genetic Resources of Tropical Crops, Ministry of Agriculture , Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences , Haikou , People's Republic of China.,b Hainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine , Haikou , People's Republic of China
| | - Yi-Ling Yang
- a Key Laboratory of Biology and Genetic Resources of Tropical Crops, Ministry of Agriculture , Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences , Haikou , People's Republic of China.,b Hainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine , Haikou , People's Republic of China
| | - Wen-Hua Dong
- a Key Laboratory of Biology and Genetic Resources of Tropical Crops, Ministry of Agriculture , Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences , Haikou , People's Republic of China.,b Hainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine , Haikou , People's Republic of China.,c Hainan Engineering Research Center of Agarwood , Haikou , People's Republic of China
| | - Wei Li
- a Key Laboratory of Biology and Genetic Resources of Tropical Crops, Ministry of Agriculture , Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences , Haikou , People's Republic of China.,b Hainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine , Haikou , People's Republic of China.,c Hainan Engineering Research Center of Agarwood , Haikou , People's Republic of China
| | - Pei Wang
- a Key Laboratory of Biology and Genetic Resources of Tropical Crops, Ministry of Agriculture , Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences , Haikou , People's Republic of China.,b Hainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine , Haikou , People's Republic of China.,c Hainan Engineering Research Center of Agarwood , Haikou , People's Republic of China
| | - Xue Cao
- a Key Laboratory of Biology and Genetic Resources of Tropical Crops, Ministry of Agriculture , Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences , Haikou , People's Republic of China.,b Hainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine , Haikou , People's Republic of China
| | - Jing-Zhe Yuan
- a Key Laboratory of Biology and Genetic Resources of Tropical Crops, Ministry of Agriculture , Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences , Haikou , People's Republic of China.,b Hainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine , Haikou , People's Republic of China.,c Hainan Engineering Research Center of Agarwood , Haikou , People's Republic of China
| | - Hui-Qin Chen
- a Key Laboratory of Biology and Genetic Resources of Tropical Crops, Ministry of Agriculture , Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences , Haikou , People's Republic of China.,b Hainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine , Haikou , People's Republic of China.,c Hainan Engineering Research Center of Agarwood , Haikou , People's Republic of China
| | - Wen-Li Mei
- a Key Laboratory of Biology and Genetic Resources of Tropical Crops, Ministry of Agriculture , Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences , Haikou , People's Republic of China.,b Hainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine , Haikou , People's Republic of China.,c Hainan Engineering Research Center of Agarwood , Haikou , People's Republic of China
| | - Hao-Fu Dai
- a Key Laboratory of Biology and Genetic Resources of Tropical Crops, Ministry of Agriculture , Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences , Haikou , People's Republic of China.,b Hainan Key Laboratory for Research and Development of Natural Products from Li Folk Medicine , Haikou , People's Republic of China.,c Hainan Engineering Research Center of Agarwood , Haikou , People's Republic of China
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Harun Al Rashid M, Majumder S, Mandal V, Mandal SC, Thandavarayan RA. In search of suitable extraction technique for large scale commercial production of bioactive fraction for the treatment of diabetes: The case Diospyros melanoxylon Roxb. J Tradit Complement Med 2019; 9:106-118. [PMID: 30963045 PMCID: PMC6435958 DOI: 10.1016/j.jtcme.2017.11.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 11/16/2017] [Accepted: 11/20/2017] [Indexed: 11/20/2022] Open
Abstract
Diospyros melanoxylon Roxb. (D. melanoxylon) belongs to the family Ebenaceae and its leaves are very well known for making beedi throughout the World. The current study estimated the comparative extraction technique and its in-vitro antidiabetic prospective of the leaves of D. melanoxylon. Qualitative phytochemicals analysis of the samples from D. melanoxylon was carried out for the detection of secondary metabolites. Total phenolics, flavonoids, triterpenoids and tannins content of D. melanoxylon were estimated using colorimetric assay. Microwave-assisted extraction (MAE) technique with a low carbon output was observed for the speedy extraction of bioactive compounds obtained from Diospyros melanoxylon leaf extract. MAE produced a maximum yield of bioactive compounds which was found to be more efficient than ultrasound, soxhlet and maceration extraction. Qualitative HPLC analysis was performed for bioactive compounds. The in-vitro antidiabetic assay was performed using α-amylase and α-glucosidase inhibitory activity. In conclusion, the fractions exhibited the concentration-dependent inhibitory effect with significant (P < 0.0001) result. So the above performance might be accountable for the antidiabetic activity of D. Melanoxylon leaf extract due to presence of bioactive compounds.
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Affiliation(s)
- Md. Harun Al Rashid
- Pharmacognosy and Phytotherapy Research Laboratory, Division of Pharmacognosy, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Sayani Majumder
- Pharmacognosy and Phytotherapy Research Laboratory, Division of Pharmacognosy, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
| | - Vivekananda Mandal
- Institute of Pharmacy, Guru Ghasidas Central University, Bilaspur 495009, India
| | - Subhash C. Mandal
- Pharmacognosy and Phytotherapy Research Laboratory, Division of Pharmacognosy, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
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MicroRNA-125b-5p improves pancreatic β-cell function through inhibiting JNK signaling pathway by targeting DACT1 in mice with type 2 diabetes mellitus. Life Sci 2019; 224:67-75. [PMID: 30684546 DOI: 10.1016/j.lfs.2019.01.031] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 01/08/2019] [Accepted: 01/18/2019] [Indexed: 11/23/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a progressive disease, accompanied by increased insulin resistance and deteriorating β-cell function. Previous studies have revealed that microRNA (miRNA) plays a crucial role in the treatment of T2DM. Hence, we aim to investigate the role of microRNA-125b-5p (miR-125b-5p) in pancreatic β-cell function and insulin sensitivity of mice with T2DM with the involvement of Dishevelled antagonist Dapper1 (DACT1) and the c-Jun NH2-terminal kinases (JNK) signaling pathway. Firstly, a mouse model of T2DM was established by administering a high-fat diet plus low dosage of streptozotocin, and function of pancreatic β-cell and insulin sensitivity in the normal and T2DM mice were detected. Then, the pancreatic β-cells were collected from pancreatic islet tissues and treated with different mimics, inhibitors and siRNAs. After that, the relationship among miR-125b-5p, DACT1, and the JNK signaling-related factors in T2DM mice was determined. Finally, cell proliferation and apoptosis were determined. Mice with T2DM had lower pancreatic β-cell function and insulin sensitivity, as well as diminished expression of miR-125b-5p but enhanced expressions of DACT1, JNK and c-Jun. miR-125b-5p inhibited DACT1 expression and the activation of the JNK signaling pathway, as well as restrained cell proliferation and promoted cell apoptosis. The current results suggest that up-regulated miR-125b-5p promotes insulin sensitivity and enhances pancreatic β-cell function through inhibiting the JNK signaling pathway by negatively mediating DACT1.
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Jeong GH, Park EK, Kim TH. Anti-diabetic effects of trans-resveratrol byproducts induced by plasma treatment. Food Res Int 2019; 119:119-125. [PMID: 30884639 DOI: 10.1016/j.foodres.2019.01.035] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 01/11/2019] [Accepted: 01/14/2019] [Indexed: 01/12/2023]
Abstract
Cold plasma processing has emerged a promising green technology with great potential to improve the quality and microbial safety of various minimally processed foods and materials. However, studies on non-thermal plasma-induced chemical interactions between major food ingredients that might change chemical structure and biological properties are very sparse. Thus, the objective of this study was to evaluate the influence of a dielectric barrier discharge (DBD) treatment on principal trans-resveratrol (TR) in several food stuffs by spectroscopic (HPLC, NMR, MS) and biological analyses. TR was dissolved in methanol and directly exposed to atmospheric non-thermal plasma field at 250 W for different durations (10, 20, 40, and 60 min), 40% relative humidity, and 25 °C. TR treated with plasma for 40 min showed greatly enhanced inhibitory activities for α-glucosidase and α-amylase than parent TR. Newly generated unusual compounds (1, 2) and known compounds (3-6) from plasma treated TR for 40 min were characterized using chromatographic and spectroscopic methods. The predominant reaction of TR induced by cold plasma followed by typical dimerization of products included methylene bridge formation and cyclization of TR. Among predominantly generated products, new compounds 1 and 2 showed more potent α-glucosidase and α-amylase inhibition capacities than parent TR. These results might be used to modify structures and enhance biological property of TR during food processing using DBD plasma treatment.
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Affiliation(s)
- Gyeong Han Jeong
- Department of Food Science and Biotechnology, Daegu University, Gyeongsan 38453, Republic of Korea
| | - Eui Kyun Park
- Department of Oral pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Republic of Korea
| | - Tae Hoon Kim
- Department of Food Science and Biotechnology, Daegu University, Gyeongsan 38453, Republic of Korea.
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Choi SH, Jeong GH, Lee KB, Jo C, Kim TH. A green chemical oligomerization of phloroglucinol induced by plasma as novel α-glucosidase inhibitors. Biosci Biotechnol Biochem 2018; 82:2059-2063. [PMID: 30200805 DOI: 10.1080/09168451.2018.1516544] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A new facile method was developed for simple green synthesis of methylene-bridged phloroglucinol oligomers using nonthermal dielectric barrier discharge (DBD) plasma in methanolic solution. The chemical structures of these newly generated oligomers 2-5 were determined by interpretation of the spectroscopic data, and the inhibitory activity toward α-glucosidase of all isolates was evaluated. The unusual phloroglcuinol pentamer 5 connected by four methylene linkages showed a much higher potential inhibitory effect against α-glucosidase than the other generated oligomers 2-4 and appeared to be a promising lead for development as a potential antidiabetic agent. Abbreviations: T2DM, type2 diabetes mellitus; DBD, dielectric barrier discharge; HPLC, high-performance liquid chromatography; IC50, 50% inhibition concentration; NMR, nuclear magnetic resonance; FABMS, fastatom bombardment mass spectrometry.
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Affiliation(s)
- Soon Ho Choi
- a Department of Crop Science and Biotechnology , Seoul National University , Seoul , Republic of Korea
| | - Gyeong Han Jeong
- b Department of Food Science and Biotechnology , Daegu University , Gyeongsan , Republic of Korea
| | - Kyung-Bon Lee
- c Department of Biology Education , Chonnam National University , Gwangju , Republic of Korea
| | - Cheorun Jo
- d Department of Agricultural Biotechnology, Center for Food and Bioconvergence, and Research Institute of Agriculture and Life Science , Seoul National University , Seoul , Republic of Korea
| | - Tae Hoon Kim
- b Department of Food Science and Biotechnology , Daegu University , Gyeongsan , Republic of Korea
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41
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Fu D, Rao X, Xu J, Tanabe G, Muraoka O, Wu X, Xie W. First total synthesis of cyclic pentadepsipeptides Hikiamides A–C. Tetrahedron Lett 2018. [DOI: 10.1016/j.tetlet.2018.01.096] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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42
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Hydrogen sulfide in the regulation of insulin secretion and insulin sensitivity: Implications for the pathogenesis and treatment of diabetes mellitus. Biochem Pharmacol 2018; 149:60-76. [DOI: 10.1016/j.bcp.2018.01.004] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 01/02/2018] [Indexed: 01/04/2023]
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43
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Liu QB, Cheng ZY, Yan ZY, Wang D, Bai M, Huang XX, Song SJ. Prunus tomentosa seed waste as a source of aromatic glycosides: Valuable phytochemicals with α-glucosidase inhibitory and hepatoprotective properties. INDUSTRIAL CROPS AND PRODUCTS 2018; 111:590-596. [DOI: 10.1016/j.indcrop.2017.11.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/07/2025]
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Sun Y, Liu J, Li L, Gong C, Wang S, Yang F, Hua H, Lin H. New butenolide derivatives from the marine sponge-derived fungus Aspergillus terreus. Bioorg Med Chem Lett 2017; 28:315-318. [PMID: 29295795 DOI: 10.1016/j.bmcl.2017.12.049] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 12/11/2017] [Accepted: 12/21/2017] [Indexed: 11/25/2022]
Abstract
Two new butenolide derivatives (±)-asperteretal D ((±)-1) and asperteretal E (2) containing rare 2-benzyl-3-phenyl substituted lactone core, together with nine known analogues (3-11) were obtained from a fungus Aspergillus terreus derived from the marine sponge Phakellia fusca. All the structures were elucidated on the basis of extensive NMR spectroscopic data. The chiral chromatography analyses allowed the separation of the (±)-asperteretal D, of which the absolute configurations were determined by comparing the experimental to calculated electronic circular dichroic (ECD) spectra. Compounds (±)-1, 2-5, and 7 exhibited potent inhibitory activities against α-glucosidase with IC50 values ranging from 8.65 to 20.3 µM (positive control acarbose with an IC50 value of 320 µM). In addition, derivatives 5-8 also showed moderate antioxidant activities.
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Affiliation(s)
- Yating Sun
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China
| | - Jingtang Liu
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Lei Li
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Chi Gong
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China
| | - Shuping Wang
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Fan Yang
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Huiming Hua
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China.
| | - Houwen Lin
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
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45
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Meena SN, Majik MS, Ghadi SC, Tilve SG. Quick Identification of Piperidine Alkaloid from Roots of Grewia nervosa
and Their Glucosidase Inhibitory Activity. Chem Biodivers 2017; 14. [DOI: 10.1002/cbdv.201700400] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 10/13/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Surya N. Meena
- Department of Biotechnology; Goa University; Taliegao Plateau Goa 403206 India
| | - Mahesh S. Majik
- Department of Chemistry; Goa University; Taliegao Plateau Goa 403206 India
| | - Sanjeev C. Ghadi
- Department of Biotechnology; Goa University; Taliegao Plateau Goa 403206 India
| | - Santosh G. Tilve
- Department of Chemistry; Goa University; Taliegao Plateau Goa 403206 India
- Organic Chemistry Department; RUDN University; 6 Miklukcho-Maklaya str. Moscow 117198 Russia
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46
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Suarez Castellanos I, Singh T, Balteanu B, Bhowmick DC, Jeremic A, Zderic V. Calcium-dependent ultrasound stimulation of secretory events from pancreatic beta cells. J Ther Ultrasound 2017; 5:30. [PMID: 29214024 PMCID: PMC5715497 DOI: 10.1186/s40349-017-0108-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 11/09/2017] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Our previous studies have indicated that ultrasound can stimulate the release of insulin from pancreatic beta cells, providing a potential novel treatment for type 2 diabetes. The purpose of this study was to explore the temporal dynamics and Ca2+-dependency of ultrasound-stimulated secretory events from dopamine-loaded pancreatic beta cells in an in vitro setup. METHODS Carbon fiber amperometry was used to detect secretion from INS-1832/13 beta cells in real time. The levels of released insulin were also measured in response to ultrasound treatment using insulin-specific ELISA kit. Beta cells were exposed to continuous wave 800 kHz ultrasound at intensities of 0.1 W/cm2, 0.5 W/cm2 and 1 W/cm2 for several seconds. Cell viability tests were done with trypan blue dye exclusion test and MTT analysis. RESULTS Carbon fiber amperometry experiments showed that application of 800 kHz ultrasound at intensities of 0.5 and 1 W/cm2 was capable of stimulating secretory events for durations lasting as long as the duration of the stimulus. Furthermore, the amplitude of the detected peaks was reduced by 64% (p < 0.01) when extracellular Ca2+ was chelated with 10 mM EGTA in cells exposed to ultrasound intensity of 0.5 W/cm2. Measurements of released insulin in response to ultrasound stimulation showed complete inhibition of insulin secretion by chelating extracellular Ca2+ with 10 mM EGTA (p < 0.01). Viability studies showed that 800 kHz, 0.5 W/cm2 ultrasound did not cause any significant effects on viability and metabolic activity in cells exposed to ultrasound as compared to sham-treated cells. CONCLUSIONS Our results demonstrated that application of ultrasound was capable of stimulating the release of insulin from pancreatic beta cells in a safe, controlled and Ca2+-dependent manner.
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Affiliation(s)
- Ivan Suarez Castellanos
- Department of Biomedical Engineering, The George Washington University, 800 22nd St. NW rm 5290, Washington, District of Columbia 20052 USA
| | - Tania Singh
- Department of Biomedical Engineering, The George Washington University, 800 22nd St. NW rm 5290, Washington, District of Columbia 20052 USA
| | - Bogdan Balteanu
- Department of Biomedical Engineering, The George Washington University, 800 22nd St. NW rm 5290, Washington, District of Columbia 20052 USA
| | - Diti Chatterjee Bhowmick
- Department of Biological Sciences, The George Washington University, Washington, District of Columbia USA
| | - Aleksandar Jeremic
- Department of Biological Sciences, The George Washington University, Washington, District of Columbia USA
| | - Vesna Zderic
- Department of Biomedical Engineering, The George Washington University, 800 22nd St. NW rm 5290, Washington, District of Columbia 20052 USA
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Najari Beidokhti M, Andersen MV, Eid HM, Sanchez Villavicencio ML, Staerk D, Haddad PS, Jäger AK. Investigation of antidiabetic potential of Phyllanthus niruri L. using assays for α-glucosidase, muscle glucose transport, liver glucose production, and adipogenesis. Biochem Biophys Res Commun 2017; 493:869-874. [PMID: 28928090 DOI: 10.1016/j.bbrc.2017.09.080] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 09/15/2017] [Indexed: 01/12/2023]
Abstract
Phyllanthus niruri is used in herbal medicine for treatment of diabetes. The objective of this study was to investigate the antidiabetic potential of P. niruri, using assays for α-glucosidase, muscle glucose transport, liver glucose production and adipogenesis. α-Glucosidase inhibitory activity was performed on aqueous and ethanolic extract of aerial parts of P. niruri. The aqueous and ethanolic extract of P. niruri showed α-glucosidase inhibitory activity with IC50 values of 3.7 ± 1.1 and 6.3 ± 4.8 μg/mL, respectively. HR-bioassay/HPLC-HRMS and NMR analysis was used for identification of compounds. Corilagin (1) and repandusinic acid A (2) were identified as α-glucosidase inhibitors in the water extract of P. niruri with IC50 values of 0.9 ± 0.1 and 1.9 ± 0.02 μM, respectively. In in vitro cell-based bioassays, cells were treated for 18 h with maximal non-toxic concentrations of the ethanolic extract of P. niruri, which were determined by the lactate dehydrogenase cytotoxicity assay. The ethanolic extract of P. niruri was not able to reduce glucose-6-phosphatase activity. However, the extract increased deoxyglucose uptake in C2C12 muscle cells and enhanced adipogenesis in 3T3-L1 fat cells which has been reported for the first time. The present study demonstrated that P. niruri may thus have potential application for treatment and/or management of type 2 diabetes.
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Affiliation(s)
- Maliheh Najari Beidokhti
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
| | - Mia Vesterholm Andersen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark
| | - Hoda M Eid
- Natural Health Products and Metabolic Diseases Laboratory, Department of Pharmacology, Université de Montréal, H3T 1J4, Montreal, QC, Canada; Department of Pharmacognosy, University of Beni-Suef, 62511, Beni-Suef, Egypt
| | - Mayra Luz Sanchez Villavicencio
- Natural Health Products and Metabolic Diseases Laboratory, Department of Pharmacology, Université de Montréal, H3T 1J4, Montreal, QC, Canada
| | - Dan Staerk
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark
| | - Pierre S Haddad
- Natural Health Products and Metabolic Diseases Laboratory, Department of Pharmacology, Université de Montréal, H3T 1J4, Montreal, QC, Canada
| | - Anna K Jäger
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark
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Kim TH, Lee J, Kim HJ, Jo C. Plasma-Induced Degradation of Quercetin Associated with the Enhancement of Biological Activities. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:6929-6935. [PMID: 28745879 DOI: 10.1021/acs.jafc.7b00987] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Nonthermal plasma is a promising technology to improve the safety and to extend the shelf-life of various minimally processed foods. However, research on plasma-induced systemic degradation related to changes in chemical structure and biological activity is still very limited. In this study, the enhancement of biological activity and the mechanism of degradation of the most common type of flavonol, quercetin, induced by a dielectric barrier discharge (DBD) plasma were investigated. Quercetin is dissolved in methanol and exposed to nonthermal DBD plasma for 5, 10, 20, and 30 min. The quercetin treated with the plasma for 20 min showed rapidly increased α-glucosidase inhibitory and radical scavenging activities compared to those of parent quercetin. The structures of the degradation products 1-3 from the quercetin treated with the plasma for 20 min were isolated and characterized by interpretation of their spectroscopic data. Among the generated products, (±)-alphitonin (1) exhibited significantly improved antidiabetic and antioxidant properties compared to those of the parent quercetin. The antidiabetic and antioxidant properties were measured by α-glucosidase inhibition and 1,1-diphenyl-2-picrylhydrazyl radical scavenging assays. These results suggested that structural changes in quercetin induced by DBD plasma might be attributable to improving the biological activity.
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Affiliation(s)
- Tae Hoon Kim
- Department of Food Science and Biotechnology, Daegu University , Gyeongsan 38453, Republic of Korea
| | - Jaemin Lee
- Department of Oral Pathology, School of Dentistry, Kyungpook National University , Daegu 41940, Republic of Korea
| | - Hyun-Joo Kim
- Crop Post-harvest Technology Division, Department of Central Area Crop Science, National Institute of Crop Science, RDA , Suwon 16613, Republic of Korea
| | - Cheorun Jo
- Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Science, Seoul National University , Seoul 08826, Republic of Korea
- Institute of Green Bio Science and Technology, Seoul National University , Pyeongchang 25354, Republic of Korea
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Arnold SV, Goyal A, Inzucchi SE, McGuire DK, Tang F, Mehta SN, Sperling LS, Maddox TM, Einhorn D, Wong ND, Hammar N, Fenici P, Khunti K, Lam CSP, Kosiborod M. Quality of Care of the Initial Patient Cohort of the Diabetes Collaborative Registry ®. J Am Heart Assoc 2017; 6:JAHA.117.005999. [PMID: 28862933 PMCID: PMC5586443 DOI: 10.1161/jaha.117.005999] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Although guidelines and performance measures exist for patients with diabetes mellitus, achievement of these metrics is not well known. The Diabetes Collaborative Registry® (DCR) was formed to understand the quality of diabetes mellitus care across the primary and specialty care continuum in the United States. METHODS AND RESULTS We assessed the frequency of achievement of 7 diabetes mellitus-related quality metrics and variability across the Diabetes Collaborative Registry® sites. Among 574 972 patients with diabetes mellitus from 259 US practices, median (interquartile range) achievement of the quality metrics across the practices was the following: (1) glycemic control: 19% (5-47); (2) blood pressure control: 80% (67-88); (3) angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in patients with coronary artery disease: 62% (51-69); (4) nephropathy screening: 62% (53-71); (5) eye examination: 0.7% (0.0-79); (6) foot examination: 0.0% (0.0-2.3); and (7) tobacco screening/cessation counseling: 86% (80-94). In hierarchical, modified Poisson regression models, there was substantial variability in meeting these metrics across sites, particularly with documentation of glycemic control and eye and foot examinations. There was also notable variation across specialties, with endocrinology practices performing better on glycemic control and diabetes mellitus foot examinations and cardiology practices succeeding more in blood pressure control and use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers. CONCLUSIONS The Diabetes Collaborative Registry® was established to document and improve the quality of outpatient diabetes mellitus care. While target achievement of some metrics of cardiovascular risk modification was high, achievement of others was suboptimal and highly variable. This may be attributable to fragmentation of care, lack of ownership among various specialists concerning certain domains of care, incomplete documentation, true gaps in care, or a combination of these factors.
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Affiliation(s)
- Suzanne V Arnold
- Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO
| | | | | | | | - Fengming Tang
- Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO
| | | | | | | | - Daniel Einhorn
- University of California, San Diego School of Medicine, San Diego, CA
| | - Nathan D Wong
- University of California, Irvine School of Medicine, Irvine, CA
| | | | | | | | - Carolyn S P Lam
- Duke-National University of Singapore and National Heart Centre, Singapore
| | - Mikhail Kosiborod
- Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO
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50
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Bioactive constituents from Vitex negundo var. heterophylla and their antioxidant and α-glucosidase inhibitory activities. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.05.047] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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