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Discovery and Development of Antidiabetic Agents from Natural Products

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 38914

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Prof. Dr. Guglielmina Froldi

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Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
Interests: natural compounds; anti-senescence activities; new drugs; aging; diabetes mellitus; atherosclerosis; gender differences; advanced glycation end products; ROS
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Dear Colleagues,

Type 2 diabetes mellitus (T2DM) is a multifactorial chronic disease, characterized by a prolonged increase in blood glucose levels, which causes macrovascular and microvascular complications. T2DM is characterized by beta-cell dysfunction, insulin resistance, and chronic inflammation, which also cause accelerated age-related damage. To explain how hyperglycemia can induce diabetic complications, a key mechanism is the accumulation of non-enzymatic glycosylation (or glycation) products of proteins and lipids, with the formation of advanced glycation end products (AGEs). These are triggered by endogenous processes related to hyperglycemia and oxidative stress. In relation to these observations, the recognition of natural products, isolated compounds, or new synthetic compounds capable to reduce glycaemia and AGEs formation represents a great challenge in medicine.

Prof. Dr. Guglielmina Froldi
Guest Editor

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Keywords

Hypoglycemic agents
Medicinal plants
Plant biologically active compounds
Dietary phytochemicals
Advanced glycation end products (AGEs)
Free radical scavengers
Cell proliferation

Published Papers (6 papers)

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Research

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17 pages, 4540 KiB

Open AccessArticle

Baicalein Alleviates Liver Oxidative Stress and Apoptosis Induced by High-Level Glucose through the Activation of the PERK/Nrf2 Signaling Pathway

by Yuesheng Dong, Yan Xing, Jin Sun, Wenlong Sun, Yongbin Xu and Chunshan Quan

Molecules 2020, 25(3), 599; https://doi.org/10.3390/molecules25030599 - 30 Jan 2020

Cited by 35 | Viewed by 3194

Abstract

Baicalein, a widely-distributed natural flavonoid, exhibits antioxidative activity in mice with type-2 diabetes. However, the underlying mechanisms remain partially elucidated. In this study, we investigated the effect of baicalein on protein kinase R-like ER kinase (PERK)/nuclear factor erythroid-2-related factor 2 (Nrf2) pathway for the alleviation of oxidative stress and apoptosis. Human liver HL-7702 cells were stimulated with 60.5 mM of glucose to induce oxidative stress and treated with baicalein. The apoptosis was determined by fluorescence microscopy and flow cytometry. The regulation of the PERK/Nrf2 pathway by baicalein was determined by immunoblotting in both HL-7702 cells and liver tissues from diabetic mice. We found that baicalein significantly alleviated the oxidative stress and apoptosis in HL-7702 cells stimulated with glucose. Mechanistic studies showed that baicalein downregulated PERK and upregulated Nrf2, two key proteins involved in endoplasmic reticulum stress, in both HL-7702 cells and liver tissues from diabetic mice receiving baicalein treatment. Furthermore, the subcellular localization of Nrf2 and the regulation of downstream proteins including heme oxygenase-1 and CCAAT-enhancer-binding protein homologous protein (CHOP) by baicalein were also investigated. Our results suggest that the regulation of the PERK/Nrf2 pathway is one of the mechanisms contributing to the bioactivities of baicalein to improve diabetes-associated complications. Full article

(This article belongs to the Special Issue Discovery and Development of Antidiabetic Agents from Natural Products)

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42 pages, 10200 KiB

Open AccessArticle

Evaluation of the Anti-Diabetic Activity of Some Common Herbs and Spices: Providing New Insights with Inverse Virtual Screening

by Andreia S.P. Pereira, Antonio J. Banegas-Luna, Jorge Peña-García, Horacio Pérez-Sánchez and Zeno Apostolides

Molecules 2019, 24(22), 4030; https://doi.org/10.3390/molecules24224030 - 07 Nov 2019

Cited by 63 | Viewed by 11423

Abstract

Culinary herbs and spices are widely used as a traditional medicine in the treatment of diabetes and its complications, and there are several scientific studies in the literature supporting the use of these medicinal plants. However, there is often a lack of knowledge on the bioactive compounds of these herbs and spices and their mechanisms of action. The aim of this study was to use inverse virtual screening to provide insights into the bioactive compounds of common herbs and spices, and their potential molecular mechanisms of action in the treatment of diabetes. In this study, a library of over 2300 compounds derived from 30 common herbs and spices were screened in silico with the DIA-DB web server against 18 known diabetes drug targets. Over 900 compounds from the herbs and spices library were observed to have potential anti-diabetic activity and liquorice, hops, fennel, rosemary, and fenugreek were observed to be particularly enriched with potential anti-diabetic compounds. A large percentage of the compounds were observed to be potential polypharmacological agents regulating three or more anti-diabetic drug targets and included compounds such as achillin B from yarrow, asparasaponin I from fenugreek, bisdemethoxycurcumin from turmeric, carlinoside from lemongrass, cinnamtannin B1 from cinnamon, crocin from saffron and glabridin from liquorice. The major targets identified for the herbs and spices compounds were dipeptidyl peptidase-4 (DPP4), intestinal maltase-glucoamylase (MGAM), liver receptor homolog-1 (NR5A2), pancreatic alpha-amylase (AM2A), peroxisome proliferator-activated receptor alpha (PPARA), protein tyrosine phosphatase non-receptor type 9 (PTPN9), and retinol binding protein-4 (RBP4) with over 250 compounds observed to be potential inhibitors of these particular protein targets. Only bay leaves, liquorice and thyme were found to contain compounds that could potentially regulate all 18 protein targets followed by black pepper, cumin, dill, hops and marjoram with 17 protein targets. In most cases more than one compound within a given plant could potentially regulate a particular protein target. It was observed that through this multi-compound-multi target regulation of these specific protein targets that the major anti-diabetic effects of reduced hyperglycemia and hyperlipidemia of the herbs and spices could be explained. The results of this study, taken together with the known scientific literature, indicated that the anti-diabetic potential of common culinary herbs and spices was the result of the collective action of more than one bioactive compound regulating and restoring several dysregulated and interconnected diabetic biological processes. Full article

(This article belongs to the Special Issue Discovery and Development of Antidiabetic Agents from Natural Products)

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12 pages, 907 KiB

Open AccessArticle

Formulation of a Mixture of Plant Extracts for Attenuating Postprandial Glycemia and Diet-Induced Disorders in Rats

by Adam Jurgoński, Katarzyna Billing-Marczak, Jerzy Juśkiewicz and Marcin Krotkiewski

Molecules 2019, 24(20), 3669; https://doi.org/10.3390/molecules24203669 - 11 Oct 2019

Cited by 2 | Viewed by 2447

Abstract

The aim of this study was to design a mixture consisting of plant-derived preparations containing inhibitors of carbohydrate digestion and/or glucose absorption that could lower postprandial glycemia and attenuate dietary-induced disorders. The following standardized preparations were tested: white mulberry leaf extract, green coffee bean extract, white kidney bean extract, pomelo fruit extract, bitter melon fruit extract, and purified l-arabinose. The study design was composed of oral sucrose and starch tolerance tests in Wistar rats preceded by a single ingestion of the preparations or their mixtures. Then, a 20 week-long experiment was conducted on rats that were fed a high-fat diet and supplemented with the most effective mixture. Based on the results of the oral sucrose and starch tolerance tests, the mulberry leaf extract, l-arabinose, kidney bean extract, and coffee bean extract were selected for composing three mixtures. The most effective inhibition of postprandial glycemia in the oral tolerance tests was observed after the ingestion of a mixture of mulberry leaf, kidney bean, and coffee bean extract. The glucose-lowering effect of the mixture and its effective dosage was confirmed in the feeding experiment. Full article

(This article belongs to the Special Issue Discovery and Development of Antidiabetic Agents from Natural Products)

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22 pages, 11597 KiB

Open AccessArticle

Optimization of Hyperglycemic Induction in Zebrafish and Evaluation of Its Blood Glucose Level and Metabolite Fingerprint Treated with Psychotria malayana Jack Leaf Extract

by Khaled Benchoula, Alfi Khatib, Fairuz M. C. Quzwain, Che Anuar Che Mohamad, Wan Mohd Azizi Wan Sulaiman, Ridhwan Abdul Wahab, Qamar Uddin Ahmed, Majid Abdul Ghaffar, Mohd Zuwairi Saiman, Mohamed F. Alajmi and Hesham El-Seedi

Molecules 2019, 24(8), 1506; https://doi.org/10.3390/molecules24081506 - 17 Apr 2019

Cited by 27 | Viewed by 5749

Abstract

A standard protocol to develop type 1 diabetes in zebrafish is still uncertain due to unpredictable factors. In this study, an optimized protocol was developed and used to evaluate the anti-diabetic activity of Psychotria malayana leaf. The aims of this study were to develop a type 1 diabetic adult zebrafish model and to evaluate the anti-diabetic activity of the plant extract on the developed model. The ability of streptozotocin and alloxan at a different dose to elevate the blood glucose levels in zebrafish was evaluated. While the anti-diabetic activity of P. malayana aqueous extract was evaluated through analysis of blood glucose and LC-MS analysis fingerprinting. The results indicated that a single intraperitoneal injection of 300 mg/kg alloxan was the optimal dose to elevate the fasting blood glucose in zebrafish. Furthermore, the plant extract at 1, 2, and 3 g/kg significantly reduced blood glucose levels in the diabetic zebrafish. In addition, LC-MS-based fingerprinting indicated that 3 g/kg plant extract more effective than other doses. Phytosterols, sugar alcohols, sugar acid, free fatty acids, cyclitols, phenolics, and alkaloid were detected in the extract using GC-MS. In conclusion, P. malayana leaf aqueous extract showed anti-diabetic activity on the developed type 1 diabetic zebrafish model. Full article

(This article belongs to the Special Issue Discovery and Development of Antidiabetic Agents from Natural Products)

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Review

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19 pages, 2449 KiB

Open AccessFeature PaperReview

Catalpol in Diabetes and its Complications: A Review of Pharmacology, Pharmacokinetics, and Safety

by Ying Bai, Ruyuan Zhu, Yimiao Tian, Rui Li, Beibei Chen, Hao Zhang, Bingke Xia, Dandan Zhao, Fangfang Mo, Dongwei Zhang and Sihua Gao

Molecules 2019, 24(18), 3302; https://doi.org/10.3390/molecules24183302 - 11 Sep 2019

Cited by 50 | Viewed by 6266

Abstract

This review aimed to provide a general view of catalpol in protection against diabetes and diabetic complications, as well as its pharmacokinetics and safety concerns. The following databases were consulted with the retrieval of more than 100 publications through June 2019: PubMed, Chinese National Knowledge Infrastructure, WanFang Data, and web of science. Catalpol exerts an anti-diabetic effect in different animal models with an oral dosage ranging from 2.5 to 200 mg/kg in rats and 10 to 200 mg/kg in mice. Besides, catalpol may prevent the development of diabetic complications in kidney, heart, central nervous system, and bone. The underlying mechanism may be associated with an inhibition of inflammation, oxidative stress, and apoptosis through modulation of various cellular signaling, such as AMPK/PI3K/Akt, PPAR/ACC, JNK/NF-κB, and AGE/RAGE/NOX4 signaling pathways, as well as PKCγ and Cav-1 expression. The pharmacokinetic profile reveals that catalpol could pass the blood-brain barrier and has a potential to be orally administrated. Taken together, catalpol is a well-tolerated natural compound with promising pharmacological actions in protection against diabetes and diabetic complications via multi-targets, offering a novel scaffold for the development of anti-diabetic drug candidate. Further prospective and well-designed clinical trials will shed light on the potential of clinical usage of catalpol. Full article

(This article belongs to the Special Issue Discovery and Development of Antidiabetic Agents from Natural Products)

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28 pages, 1488 KiB

Open AccessReview

Anti-Diabetic Effects and Mechanisms of Dietary Polysaccharides

by Kumar Ganesan and Baojun Xu

Molecules 2019, 24(14), 2556; https://doi.org/10.3390/molecules24142556 - 13 Jul 2019

Cited by 112 | Viewed by 9256

Abstract

Diabetes mellitus is a multifactorial, heterogeneous metabolic disorder, causing various health complications and economic issues, which apparently impacts the human’s life. Currently, commercial diabetic drugs are clinically managed for diabetic treatment that has definite side effects. Dietary polysaccharides mainly derive from natural sources, including medicinal plants, grains, fruits, vegetables, edible mushroom, and medicinal foods, and possess anti-diabetic potential. Hence, this review summarizes the effects of dietary polysaccharides on diabetes and underlying molecular mechanisms related to inflammatory factors, oxidative stress, and diabetes in various animal models. The analysis of literature and appropriate data on anti-diabetic polysaccharide from electronic databases was conducted. In vivo and in vitro trials have revealed that treatment of these polysaccharides has hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory effects, which enhance pancreatic β-cell mass and alleviates β-cell dysfunction. It enhances insulin signaling pathways through insulin receptors and activates the PI3K/Akt pathway, and eventually modulates ERK/JNK/MAPK pathway. In conclusion, dietary polysaccharides can effectively ameliorate hyperglycemia, hyperlipidemia, low-grade inflammation, and oxidative stress in type 2 diabetes mellitus (T2DM), and, thus, consumption of polysaccharides can be a valuable choice for diabetic control. Full article

(This article belongs to the Special Issue Discovery and Development of Antidiabetic Agents from Natural Products)

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