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Moon DO. MetAP2 as a Therapeutic Target for Obesity and Type 2 Diabetes: Structural Insights, Mechanistic Roles, and Inhibitor Development. Biomolecules 2024; 14:1572. [PMID: 39766279 PMCID: PMC11673396 DOI: 10.3390/biom14121572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/07/2024] [Accepted: 12/08/2024] [Indexed: 01/11/2025] Open
Abstract
Type 2 Diabetes Mellitus (T2DM) and obesity are globally prevalent metabolic disorders characterized by insulin resistance, impaired glucose metabolism, and excessive adiposity. Methionine aminopeptidase 2 (MetAP2), an intracellular metalloprotease, has emerged as a promising therapeutic target due to its critical role in regulating lipid metabolism, energy balance, and protein synthesis. This review provides a comprehensive analysis of MetAP2, including its structural characteristics, catalytic mechanism, and functional roles in the pathophysiology of T2DM and obesity. The unique architecture of MetAP2's active site and its interactions with substrates are examined to elucidate its enzymatic function. The review also explores the development of MetAP2 inhibitors, focusing on their mechanisms of action, preclinical and clinical findings, and therapeutic potential. Special emphasis is placed on docking studies to analyze the binding interactions of six key inhibitors (fumagillin, TNP-470, beloranib, ZGN-1061, indazole, and pyrazolo[4,3-b]indole) with MetAP2, revealing their structural determinants for efficacy and specificity. These findings underscore the potential of MetAP2 as a therapeutic target and provide valuable insights for the rational design of next-generation inhibitors to address obesity and T2DM.
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Affiliation(s)
- Dong Oh Moon
- Department of Biology Education, Daegu University, 201, Daegudae-ro, Gyeongsan-si 38453, Gyeongsangbuk-do, Republic of Korea
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Jee W, Cho HS, Kim SW, Bae H, Chung WS, Cho JH, Kim H, Song MY, Jang HJ. Lycium chinense Mill Induces Anti-Obesity and Anti-Diabetic Effects In Vitro and In Vivo. Int J Mol Sci 2024; 25:8572. [PMID: 39201257 PMCID: PMC11354703 DOI: 10.3390/ijms25168572] [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: 07/02/2024] [Revised: 07/31/2024] [Accepted: 08/04/2024] [Indexed: 09/02/2024] Open
Abstract
This study investigated the effects of Lycium chinense Mill (LCM) extract on obesity and diabetes, using both in vitro and high-fat diet (HFD)-induced obesity mouse models. We found that LCM notably enhanced glucagon-like peptide-1 (GLP-1) secretion in NCI-h716 cells from 411.4 ± 10.75 pg/mL to 411.4 ± 10.75 pg/mL compared to NT (78.0 ± 0.67 pg/mL) without causing cytotoxicity, implying the involvement of Protein Kinase A C (PKA C) and AMP-activated protein kinase (AMPK) in its action mechanism. LCM also decreased lipid droplets and lowered the expression of adipogenic and lipogenic indicators, such as Fatty Acid Synthase (FAS), Fatty Acid-Binding Protein 4 (FABP4), and Sterol Regulatory Element-Binding Protein 1c (SREBP1c), indicating the suppression of adipocyte differentiation and lipid accumulation. LCM administration to HFD mice resulted in significant weight loss (41.5 ± 3.3 g) compared to the HFD group (45.1 ± 1.8 g). In addition, improved glucose tolerance and serum lipid profiles demonstrated the ability to counteract obesity-related metabolic issues. Additionally, LCM exhibited hepatoprotective properties by reducing hepatic lipid accumulation and diminishing white adipose tissue mass and adipocyte size, thereby demonstrating its effectiveness against hepatic steatosis and adipocyte hypertrophy. These findings show that LCM can be efficiently used as a natural material to treat obesity and diabetes, providing a new approach for remedial and therapeutic purposes.
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Affiliation(s)
- Wona Jee
- College of Korean Medicine, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (W.J.); (S.W.K.); (H.B.)
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hong-Seok Cho
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (H.-S.C.); (W.-S.C.); (J.-H.C.); (H.K.)
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Seok Woo Kim
- College of Korean Medicine, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (W.J.); (S.W.K.); (H.B.)
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hanbit Bae
- College of Korean Medicine, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (W.J.); (S.W.K.); (H.B.)
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Won-Seok Chung
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (H.-S.C.); (W.-S.C.); (J.-H.C.); (H.K.)
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jae-Heung Cho
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (H.-S.C.); (W.-S.C.); (J.-H.C.); (H.K.)
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hyungsuk Kim
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (H.-S.C.); (W.-S.C.); (J.-H.C.); (H.K.)
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Mi-Yeon Song
- Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (H.-S.C.); (W.-S.C.); (J.-H.C.); (H.K.)
- Department of Korean Rehabilitation Medicine, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hyeung-Jin Jang
- College of Korean Medicine, Kyung Hee University, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (W.J.); (S.W.K.); (H.B.)
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
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Xiang G, Guo S, Xing N, Du Q, Qin J, Gao H, Zhang Y, Wang S. Mangiferin, a Potential Supplement to Improve Metabolic Syndrome: Current Status and Future Opportunities. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:355-386. [PMID: 38533569 DOI: 10.1142/s0192415x24500150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
Metabolic syndrome (MetS) represents a considerable clinical and public health burden worldwide. Mangiferin (MF), a flavonoid compound present in diverse species such as mango (Mangifera indica L.), papaya (Pseudocydonia sinensis (Thouin) C. K. Schneid.), zhimu (Anemarrhena asphodeloides Bunge), and honeybush tea (Cyclopia genistoides), boasts a broad array of pharmacological effects. It holds promising uses in nutritionally and functionally targeted foods, particularly concerning MetS treatment. It is therefore pivotal to systematically investigate MF's therapeutic mechanism for MetS and its applications in food and pharmaceutical sectors. This review, with the aid of a network pharmacology approach complemented by this experimental studies, unravels possible mechanisms underlying MF's MetS treatment. Network pharmacology results suggest that MF treats MetS effectively through promoting insulin secretion, targeting obesity and inflammation, alleviating insulin resistance (IR), and mainly operating via the phosphatidylinositol 3 kinase (PI3K)/Akt, nuclear factor kappa-B (NF-[Formula: see text]B), microtubule-associated protein kinase (MAPK), and oxidative stress signaling pathways while repairing damaged insulin signaling. These insights provide a comprehensive framework to understand MF's potential mechanisms in treating MetS. These, however, warrant further experimental validation. Moreover, molecular docking techniques confirmed the plausibility of the predicted outcomes. Hereafter, these findings might form the theoretical bedrock for prospective research into MF's therapeutic potential in MetS therapy.
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Affiliation(s)
- Gelin Xiang
- State Key Laboratory of Southwestern, Chinese Medicine Resources, School of Ethnic Medicine, Chengdu, P. R. China
| | - Sa Guo
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Nan Xing
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Qinyun Du
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Jing Qin
- State Key Laboratory of Southwestern, Chinese Medicine Resources, School of Ethnic Medicine, Chengdu, P. R. China
| | - Huimin Gao
- Meishan Hospital of Chengdu University of Traditional Chinese Medicine, Meishan 620010, P. R. China
| | - Yi Zhang
- State Key Laboratory of Southwestern, Chinese Medicine Resources, School of Ethnic Medicine, Chengdu, P. R. China
| | - Shaohui Wang
- State Key Laboratory of Southwestern, Chinese Medicine Resources, School of Ethnic Medicine, Chengdu, P. R. China
- Meishan Hospital of Chengdu University of Traditional Chinese Medicine, Meishan 620010, P. R. China
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A multitarget angiogenesis inhibitor, CTT peptide-endostatin mimic-kringle 5, prevents diet-induced obesity. J Mol Med (Berl) 2020; 98:1753-1765. [PMID: 33141247 DOI: 10.1007/s00109-020-01993-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 09/28/2020] [Accepted: 10/13/2020] [Indexed: 12/14/2022]
Abstract
Adipose tissue vasculature has been considered an attractive target for prevention and treatment of obesity. AARP (CTT peptide-endostatin mimic-kringle 5) is a novel multitarget fusion protein against tumor angiogenesis. This study aimed to examine the effects of AARP on diet-induced obesity and its possible molecular mechanism. Treatment with AARP markedly prevented weight gains, improved metabolic disturbances, and decreased adipose tissue angiogenesis in diet-induced obese mice without noticeable toxicities. In addition to its potent antiangiogenic and MMP-2/9 inhibitory activities, AARP administration also significantly increased energy expenditure, influenced the metabolic and angiogenic gene expression profiles, and attenuated obesity-induced inflammation, demonstrating its systemic beneficial effects. Importantly, AARP exhibited no effect on mice fed with standard normal mouse diet. Furthermore, the AARP-treated HFD-fed mice experienced a significant increase in lifespan during the posttreatment observation period, compared with untreated HFD-fed mice. Our results suggest that AARP might be pharmacologically useful for treatment of obesity or obesity-related metabolic disorders in humans. KEY MESSAGES: What is already known • More effective and safe therapies for obesity are in urgent need. • AARP is a novel multitarget fusion protein against tumor angiogenesis. What this study adds • AARP prevents obesity, improves metabolic disorders in mice fed high-fat diet. • AARP increases energy expenditure, decreases adipose tissue angiogenesis, and increases lifespan. • AARP is well tolerated and exhibits no observable toxicity. Clinical significance • AARP may be a promising therapeutic agent against obesity or obesity-related metabolic disturbances.
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Moore MC, Coate KC, Scott M, Kraft G, Vath JE, Hughes TE, Farmer B, Cherrington AD. MetAP2 inhibitor treatment of high-fat and -fructose-fed dogs: impact on the response to oral glucose ingestion and a hyperinsulinemic hyperglycemic clamp. Am J Physiol Endocrinol Metab 2020; 318:E514-E524. [PMID: 31990576 PMCID: PMC7191409 DOI: 10.1152/ajpendo.00451.2019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We examined the methionine aminopeptidase 2 inhibitor fumagillin in dogs consuming a high-fat and -fructose diet (HFFD). In pilot studies (3 dogs that had consumed HFFD for 3 yr), 8 wk of daily treatment with fumagillin reduced food intake 29%, weight 6%, and the glycemic excursion during an oral glucose tolerance test (OGTT) 44%. A second group of dogs consumed the HFFD for 17 wk: pretreatment (weeks 0-4), treatment with fumagillin (FUM; n = 6), or no drug (Control, n = 8) (weeks 4-12), washout period (weeks 12-16), and fumagillin or no drug for 1 wk (week 17). OGTTs were performed at 0, 4, 11, and 16 wk. A hyperinsulinemic hyperglycemic clamp was performed in week 12; 4 chow-fed dogs underwent identical clamps. Kilocalories per day intake during the treatment period was 2,067 ± 50 (Control) versus 1,824 ± 202 (FUM). Body weights (kg) increased 1.9 ± 0.3 vs. 2.7 ± 0.8 (0-4 wk) and 1.2 ± 0.2 vs. -0.02 ± 0.9 (4-12 wk) in Control versus fumagillin. The OGTT glycemic response was 30% greater in Control versus fumagillin at 11 wk. Net hepatic glucose uptake (NHGU; mg·kg-1·min-1) in the Chow, Control, and fumagillin dogs was ~1.5 ± 0.6, -0.1 ± 0.1, and 0.3 ± 0.4 (with no portal glucose infusion) and 3.1 ± 0.6, 0.5 ± 0.3, and 1.5 ± 0.5 (portal glucose infusion at 4 mg·kg-1·min-1), respectively. Fumagillin improved glucose tolerance and NHGU in HFFD dogs, suggesting methionine aminopeptidase 2 (MetAP2) inhibitors have the potential for improving glycemic control in prediabetes and diabetes.
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Affiliation(s)
- Mary Courtney Moore
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Katie C Coate
- Diabetes Research and Training Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Melanie Scott
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Guillaume Kraft
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | | | - Thomas E Hughes
- Zafgen, Incorporated, Boston, Massachusetts
- Navitor Pharmaceuticals, Incorporated, Cambridge, Massachusetts
| | - Ben Farmer
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Alan D Cherrington
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
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Jensen CH, Kosmina R, Rydén M, Baun C, Hvidsten S, Andersen MS, Christensen LL, Gastaldelli A, Marraccini P, Arner P, Jørgensen CD, Laborda J, Holst JJ, Andersen DC. The imprinted gene Delta like non-canonical notch ligand 1 (Dlk1) associates with obesity and triggers insulin resistance through inhibition of skeletal muscle glucose uptake. EBioMedicine 2019; 46:368-380. [PMID: 31383551 PMCID: PMC6711890 DOI: 10.1016/j.ebiom.2019.07.070] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 07/29/2019] [Accepted: 07/29/2019] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is considered an inhibitor of adipogenesis, but its in vivo impact on fat mass indeed remains elusive and controversial. METHODS Fat deposits were assessed by MRI and DXA scanning in two cohorts of non-diabetic men, whereas glucose disposal rate (GDR) was determined during euglycemic hyperinsulinemic clamp. Blood analyte measurements were used for correlation and mediation analysis to investigate how age, BMI, and fat percentage affect the relation between DLK1 and GDR. Confirmatory animal studies performed in normal (NC) and high fat diet (HFD) fed Dlk1+/+ and Dlk1-/- mice included DXA scanning, glucose tolerance tests (GTTs), blood measurements, and skeletal muscle glucose uptake studies by positron emission tomography (PET), histology, qRT-PCR, and in vitro cell studies. FINDINGS Overall, DLK1 is positively correlated with fat amounts, which is consistent with a negative linear relationship between DLK1 and GDR. This relationship is not mediated by age, BMI, or fat percentage. In support, DLK1 also correlates positively with HOMA-IR and ADIPO-IR in these humans, but has no linear relationship with the early diabetic inflammation marker MCP-1. In Dlk1-/- mice, the increase in fat percentage and adipocyte size induced by HFD is attenuated, and these animals are protected against insulin resistance. These Dlk1 effects seem independent of gluconeogenesis, but at least partly relies on increased in vivo glucose uptake in skeletal muscles by Dlk1 regulating the major glucose transporter Glut4 in vivo as well as in two independent cell lines. INTERPRETATION Thus, instead of an adipogenic inhibitor, Dlk1 should be regarded as a factor causally linked to obesity and insulin resistance, and may be used to predict development of type 2 diabetes. FUND: The Danish Diabetes Academy supported by the Novo Nordisk Foundation, The Danish National Research Council (#09-073648), The Lundbeck Foundation, University of Southern Denmark, and Dep. Of Clinical Biochemistry and Pharmacology/Odense University Hospital, the Swedish Research Council, the Swedish Diabetes Foundation, the Strategic Research Program in Diabetes at Karolinska Institute and an EFSD/Lilly grant.
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Affiliation(s)
- Charlotte Harken Jensen
- Laboratory of Molecular and Cellular Cardiology, Dep. of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark; Danish Center for Regenerative Medicine (danishcrm.com), Odense University Hospital, Denmark
| | - Rok Kosmina
- Laboratory of Molecular and Cellular Cardiology, Dep. of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark; The Danish Diabetes Academy, Denmark; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Mikael Rydén
- Dep. of Medicine-H7, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Christina Baun
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark
| | - Svend Hvidsten
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark
| | | | | | | | | | - Peter Arner
- Dep. of Medicine-H7, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | | | - Jorge Laborda
- Department of Inorganic and Organic Chemistry and Biochemistry, University of Castilla-La Mancha, Pharmacy School, Albacete, Spain
| | - Jens Juul Holst
- Department of Endocrinology and Metabolism, Section for Translational Metabolic Physiology, University of Copenhagen, Denmark
| | - Ditte Caroline Andersen
- Laboratory of Molecular and Cellular Cardiology, Dep. of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark; Danish Center for Regenerative Medicine (danishcrm.com), Odense University Hospital, Denmark; Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; Clinical Institute, University of Southern Denmark, Odense, Denmark.
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Yaribeygi H, Zare V, Butler AE, Barreto GE, Sahebkar A. Antidiabetic potential of saffron and its active constituents. J Cell Physiol 2018; 234:8610-8617. [PMID: 30515777 DOI: 10.1002/jcp.27843] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 11/13/2018] [Indexed: 12/26/2022]
Abstract
The prevalence of diabetes mellitus is growing rapidly worldwide. This metabolic disorder affects many physiological pathways and is a key underlying cause of a multitude of debilitating complications. There is, therefore, a critical need for effective diabetes management. Although many synthetic therapeutic glucose-lowering agents have been developed to control glucose homeostasis, they may have unfavorable side effects or limited efficacy. Herbal-based hypoglycemic agents present an adjunct treatment option to mitigate insulin resistance, improve glycemic control and reduce the required dose of standard antidiabetic medications. Saffron (Crocus sativus L.), whilst widely used as a food additive, is a natural product with insulin-sensitizing and hypoglycemic effects. Saffron contains several bioactive β carotenes, which exert their pharmacological effects in various tissues without any obvious side effects. In this study, we discuss how saffron and its major components exert their hypoglycemic effects by induction of insulin sensitivity, improving insulin signaling and preventing β-cell failure, all mechanisms combining to achieve better glycemic control.
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Affiliation(s)
- Habib Yaribeygi
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Zare
- Applied Microbiology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Alexandra E Butler
- Diabetes Research Center, Qatar Biomedical Research Institute, Doha, Qatar
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia.,Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Naseri R, Farzaei F, Haratipour P, Nabavi SF, Habtemariam S, Farzaei MH, Khodarahmi R, Tewari D, Momtaz S. Anthocyanins in the Management of Metabolic Syndrome: A Pharmacological and Biopharmaceutical Review. Front Pharmacol 2018; 9:1310. [PMID: 30564116 PMCID: PMC6288909 DOI: 10.3389/fphar.2018.01310] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 10/26/2018] [Indexed: 12/14/2022] Open
Abstract
The term "metabolic syndrome" (MetS) refers to a combination of diabetes, high blood pressure, and obesity. The origin of MetS includes a combination of multiple factors, such as sedentary lifestyle, unhealthy diet choice, and genetic factors. MetS is highly prevalent and adversely affects the general population by elevating risk of cardiovascular complications, organ failure, and much other pathology associated with late-stage diabetes. Anthocyanins (ANTs) are health-promoting bioactive compounds belonging to the flavonoids subclass of polyphenols. Numerous studies have reported the potential therapeutic benefits on MetS syndrome and diabetes from fruits rich in ANTs. This review summarizes the role of several dietary ANTs on preventing and managing MetS as well as the pharmacological mechanisms and biopharmaceutical features of their action. We also discuss potential nanoformulation and encapsulation approaches that may enhance the bioefficacy of ANTs in MetS. Experiments have demonstrated that ANTs may attenuate the symptoms of MetS via improving insulin resistance, impaired glucose tolerance, dyslipidaemia, cholesterol levels, hypertension, blood glucose, protecting β cells, and preventing free radical production. In brief, the intake of ANT-rich supplements should be considered due to their plausible ability for prevention and management of MetS. Additionally, randomized double-blind clinical trials are obligatory for evaluating the bioefficacy and pharmacological mechanisms of ANTs and their pharmaceutical formulations in patients with MetS.
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Affiliation(s)
- Rozita Naseri
- Internal Medicine Department, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Farzaei
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Pouya Haratipour
- Department of Chemistry, Sharif University of Technology, Tehran, Iran
- Phyto Pharmacology Interest Group, Universal Scientific Education and Research Network, Los Angeles, CA, United States
| | - Seyed Fazel Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Solomon Habtemariam
- Pharmacognosy Research Laboratories, Medway School of Science, University of Greenwich, Kent, United Kingdom
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Khodarahmi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Devesh Tewari
- Department of Pharmaceutical Sciences, Faculty of Technology, Kumaun University, Nainital, India
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran
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Greydanus DE, Agana M, Kamboj MK, Shebrain S, Soares N, Eke R, Patel DR. Pediatric obesity: Current concepts. Dis Mon 2018; 64:98-156. [DOI: 10.1016/j.disamonth.2017.12.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus. Sci Rep 2017; 7:16072. [PMID: 29167582 PMCID: PMC5700121 DOI: 10.1038/s41598-017-16405-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 11/13/2017] [Indexed: 01/19/2023] Open
Abstract
Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are now considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. In this work, a series of novel symmetric molecular constructs, in which two pyridoxine moieties are connected via sulfur-containing linkers, have been synthesized and tested in vitro for glucokinase activation potential. The enzyme activation rates by two most active compounds at 100 μM (~150% and 130%) were comparable to that of the reference agent PF-04937319 (~154%). Both leading compounds demonstrated low cytotoxicity and excellent safety profile in acute toxicity experiment in rats after oral administration with LD50 exceeding 2000 mg/kg of body weight. Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellitus, as well as a promising starting point for the design of structural analogs with improved activity.
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Adipokines in hereditary breast cancer patients and healthy relatives. Oncotarget 2017; 8:101255-101261. [PMID: 29254161 PMCID: PMC5731871 DOI: 10.18632/oncotarget.21018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 08/26/2017] [Indexed: 11/25/2022] Open
Abstract
Background The role of adipocytokines and ghrelin in hereditary breast cancer syndrome (HBCS) has never been tested. Results No significant differences in leptin, adiponectin and ghrelin plasma levels between cancer patients and healthy subjects was observed. Conversely, an higher level of adiponectin was shown in healthy subjects with BRCA 1/2 gene mutation vs those without (p < 0.03). Logistic regression analysis demonstrated that Adiponectin plasma level (OR 0.26; 95% CI:0.007–0.81; p < 0.02) and age (OR 5.51; 95% CI:1.78–19.71; p < 0.004) were the only factors independently associated with BMI; furthermore, Leptin plasma level (OR 0.23; 95% CI:0.06–0.76; p < 0.01) and age (OR 0.05; 95% CI:0.05–0.61; p < 0.007) resulted the only factors significantly associated with breast cancer. Materials and Methods We analyzed blood plasma expression of leptin, adiponectin and ghrelin using Bio-Plex platform in 25 breast cancer patients with HBCS and in 38 healthy relatives. BRCA 1/2 gene status (presence of pathogenic mutations by direct molecular sequencing), clinical-pathological characteristics and Body Mass Index (BMI) of each subject were recorded. Conclusions Adiponectin confirms to be associated with BMI also in subjects with HBCS. Leptin plasma level seems a direct and independent biomarker of a breast cancer risk. A validation of Leptin as a circulating biomarker of breast cancer development in larger series of HBCS subjects is needed.
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Chang YH. Common therapeutic target for both cancer and obesity. World J Biol Chem 2017; 8:102-107. [PMID: 28588753 PMCID: PMC5439161 DOI: 10.4331/wjbc.v8.i2.102] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 02/08/2017] [Accepted: 03/13/2017] [Indexed: 02/05/2023] Open
Abstract
Obesity and cancer are two interrelated conditions of high epidemiological need, with studies showing that obesity is responsible for nearly 25% of the relative contribution to cancer incidence. Given the connection between these conditions, a drug that can operate on both obesity and cancer is highly desirable. Such a drug is accomplishable through the development of potent anti-angiogenesis agents due to the shared underlying role of angiogenesis in the development of both diseases. Prior research has demonstrated a key role of type-2 methionine aminopeptidase (MetAP2) for angiogenesis, which has led to the development of numerous of novel inhibitors. Several irreversible MetAP2 inhibitors have entered clinical trials without great success. Though this lack of success could be attributed to off-target adverse effects, the underlying causes remain unclear. More promising reversible inhibitors have been recently developed with excellent pre-clinical results. However, due to insufficient knowledge of the biological functions of N-terminal protein processing, it is hard to predict whether these novel inhibitors would successfully pass clinical trials and thereby benefit cancer and obesity patients. Significantly more efforts are needed to advance our understanding of the regulation of methionine aminopeptidases and the processes by which they govern the function of proteins.
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Elfers CT, Roth CL. Robust Reductions of Excess Weight and Hyperphagia by Beloranib in Rat Models of Genetic and Hypothalamic Obesity. Endocrinology 2017; 158:41-55. [PMID: 27849360 DOI: 10.1210/en.2016-1665] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 11/15/2016] [Indexed: 02/08/2023]
Abstract
Hypothalamic lesions or deficient melanocortin (MC) signaling via MC4 receptor (MC4r) mutations often lead to hyperphagia and severe treatment-resistant obesity. We tested the methionine aminopeptidase 2-inhibitor beloranib (ZGN-440) in 2 male rat models of obesity, one modeling hypothalamic obesity with a combined medial hypothalamic lesion (CMHL) and the other modeling a monogenic form of obesity with MC4r mutations (MC4r knockout [MC4rKO]). In CMHL rats (age 3 months), postsurgery excess weight gain was significantly inhibited (ZGN-440, 0.2 ± 0.7 g/d; vehicle, 3.8 ± 0.6 g/d; P < 0.001) during 12 days of ZGN-440 treatment (0.1 mg/kg daily subcutaneously) together with a 30% reduction of daily food intake vs vehicle injection. In addition, ZGN-440 treatment improved glucose tolerance and reduced plasma insulin, and circulating levels of α-melanocyte stimulating hormone were increased. Serum lipid levels did not differ significantly in ZGN-440-treated vs vehicle-treated rats. Similar results were found in MC4rKO rats: ZGN-440 treatment (14-21 d) was associated with significant reductions of body weight gain (MC4rKO, -1.7 ± 0.6 vs 2.8 ± 0.4 g/d; lean wild-type controls, -0.7 ± 0.2 vs 1.7 ± 0.7 g/d; ZGN-440 vs vehicle, respectively), reduction of food intake (MC4rKO, -28%; lean controls, -7.5%), and insulin resistance, whereas circulating levels of interleukin-1β did not change. In both obesity models, body temperature and locomotor activity were not affected by ZGN-440 treatment. In conclusion, the robust reduction of body weight in response to ZGN-440 observed in rats with severe obesity is related to a strong reduction of food intake that is likely related to changes in the central regulation of feeding.
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Affiliation(s)
- Clinton T Elfers
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101; and
| | - Christian L Roth
- Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101; and
- Division of Endocrinology, Department of Pediatrics, University of Washington, Seattle, Washington 98105
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Fomenko EV, Chi Y. Mangiferin modulation of metabolism and metabolic syndrome. Biofactors 2016; 42:492-503. [PMID: 27534809 PMCID: PMC5077701 DOI: 10.1002/biof.1309] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 05/21/2016] [Accepted: 06/05/2016] [Indexed: 12/17/2022]
Abstract
The recent emergence of a worldwide epidemic of metabolic disorders, such as obesity and diabetes, demands effective strategy to develop nutraceuticals or pharmaceuticals to halt this trend. Natural products have long been and continue to be an attractive source of nutritional and pharmacological therapeutics. One such natural product is mangiferin (MGF), the predominant constituent of extracts of the mango plant Mangifera indica L. Reports on biological and pharmacological effects of MGF increased exponentially in recent years. MGF has documented antioxidant and anti-inflammatory effects. Recent studies indicate that it modulates multiple biological processes involved in metabolism of carbohydrates and lipids. MGF has been shown to improve metabolic abnormalities and disorders in animal models and humans. This review focuses on the recently reported biological and pharmacological effects of MGF on metabolism and metabolic disorders. © 2016 BioFactors, 42(5):492-503, 2016.
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Affiliation(s)
| | - Yuling Chi
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
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15
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Conceição EPS, Moura EG, Manhães AC, Carvalho JC, Nobre JL, Oliveira E, Lisboa PC. Calcium reduces vitamin D and glucocorticoid receptors in the visceral fat of obese male rats. J Endocrinol 2016; 230:263-74. [PMID: 27325245 DOI: 10.1530/joe-16-0041] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 06/20/2016] [Indexed: 01/04/2023]
Abstract
Rats overfed during lactation show higher visceral adipose tissue (VAT) mass and metabolic dysfunctions at adulthood. As both vitamin D and glucocorticoids change adipogenesis, parameters related to metabolism and action of these hormones in the adipocyte can be altered in rats raised in small litters (SL). We also studied the antiobesity effects of high calcium diet since it decreases visceral fat in obesity models. On postnatal day (PN) 3, litter size was adjusted to 3pups/dam (SL) to induce overfeeding. Control litters (NL) remained with 10pups/dam until weaning. From PN120 to PN180, half of the SL rats were fed standard chow (SL) and the other half was fed a calcium-supplemented chow (SL-Ca, 10g CaCO3/kg). Both SL groups were heavier and hyperphagic when compared with the NL group; however, SL-Ca rats ate less than SL. SL-Ca rats had decreased VAT mass and adipocyte size, associated with lower hypothalamic NPY content, VAT fat acid synthase content and leptinemia. At PN120, SL rats had increased plasma 25(OH)D3, Cyp27b1 mRNA and glucocorticoid receptor (GR-α) in the VAT, but lower vitamin D receptor (Vdr) mRNA. At PN180, Cyp27b1 and GR-α remained higher, while Vdr normalized in SL rats. SL-Ca rats had normal VAT Cyp27b1 and GR-α, but lower Vdr Thus, higher body mass and glucocorticoid receptors in the VAT of SL rats are normalized by calcium-enriched diet, and Vdr expression in this tissue is reduced, suggesting a possible role of glucocorticoids and vitamin D in calcium action in the adipocyte.
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Affiliation(s)
- E P S Conceição
- Laboratory of Endocrine PhysiologyDepartment of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - E G Moura
- Laboratory of Endocrine PhysiologyDepartment of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - A C Manhães
- Laboratory of NeurophysiologyDepartment of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - J C Carvalho
- Laboratory of Endocrine PhysiologyDepartment of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - J L Nobre
- Laboratory of Endocrine PhysiologyDepartment of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - E Oliveira
- Laboratory of Endocrine PhysiologyDepartment of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - P C Lisboa
- Laboratory of Endocrine PhysiologyDepartment of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
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Anishchenko AP, Arkhangel’skaya AN, Pustovalov DA, Rogoznaya EV, Ignatov NG, Gurevich KG. The nutritional preferences in the college students and the risk of gaining excessive weight. ACTA ACUST UNITED AC 2015. [DOI: 10.17116/dokgastro201543-427-30] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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