Type 2 diabetes mellitus (T2DM) is the most widespread form of diabetes, characterized by chronic hyperglycaemia, insulin resistance, and inefficient insulin secretion and action. Primary care in T2DM is pharmacological, using drugs of several groups that include insulin sensitisers (e.g., biguanides, thiazolidinediones), insulin secretagogues (e.g., sulphonylureas, meglinides), alpha-glucosidase inhibitors, and the newest incretin-based therapies and sodium-glucose co-transporter 2 inhibitors. However, their long-term application can cause many harmful side effects, emphasising the importance of the using natural therapeutic products. Natural health substances including non-flavonoid polyphenols (e.g., resveratrol, curcumin, tannins, and lignans), flavonoids (e.g., anthocyanins, epigallocatechin gallate, quercetin, naringin, rutin, and kaempferol), plant fruits, vegetables and other products (e.g., garlic, green tea, blackcurrant, rowanberry, bilberry, strawberry, cornelian cherry, olive oil, sesame oil, and carrot) may be a safer alternative to primary pharmacological therapy. They are recommended as food supplements to prevent and/or ameliorate T2DM-related complications. In the advanced stage of T2DM, the combination therapy of synthetic agents and natural compounds with synergistic interactions makes the treatment more efficient. In this review, both pharmaceutical drugs and selected natural products, as well as combination therapies, are characterized. Mechanisms of their action and possible negative side effects are also provided.

Pharmaceutical Drugs and Natural Therapeutic Products for the Treatment of Type 2 Diabetes Mellitus.

Chemotherapy has opened a new window in cancer therapy. However, the resistance of cancer cells has dramatically reduced the efficacy of chemotherapy. Cisplatin is a chemotherapeutic agent and its potential in cancer therapy has been restricted by resistance of cancer cells. As a consequence, the scientists have attempted to find new strategies in elevating chemotherapy efficacy. Due to great anti-tumour activity, naturally occurring compounds are of interest in polychemotherapy. Quercetin is a flavonoid with high anti-tumour activity against different cancers that can be used with cisplatin to enhance its efficacy and also are seen to sensitise cancer cells into chemotherapy. Furthermore, cisplatin has side effects such as nephrotoxicity and ototoxicity. Administration of quercetin is advantageous in reducing the adverse effects of cisplatin without compromising its anti-tumour activity. In this review, we investigate the dual role of quercetin in enhancing anti-tumour activity of cisplatin and simultaneous reduction in its adverse effects.

Dual role of quercetin in enhancing the efficacy of cisplatin in chemotherapy and protection against its side effects: a review

Type 2 diabetes (T2D) is a fast-increasing health problem globally, and it results from insulin resistance and pancreatic β-cell dysfunction. The gastrointestinal (GI) tract is recognized as one of the major regulatory organs of glucose homeostasis that involves multiple gut hormones and microbiota. Notably, the incretin hormone glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells plays a pivotal role in maintaining glucose homeostasis via eliciting pleiotropic effects, which are largely mediated via its receptor. Thus, targeting the GLP-1 signaling system is a highly attractive therapeutic strategy to treatment T2D. Polyphenols, the secondary metabolites from plants, have drawn considerable attention because of their numerous health benefits, including potential anti-diabetic effects. Although the major targets and locations for the polyphenolic compounds to exert the anti-diabetic action are still unclear, the first organ that is exposed to these compounds is the GI tract in which polyphenols could modulate enzymes and hormones. Indeed, emerging evidence has shown that polyphenols can stimulate GLP-1 secretion, indicating that these natural compounds might exert metabolic action at least partially mediated by GLP-1. This review provides an overview of nutritional regulation of GLP-1 secretion and summarizes recent studies on the roles of polyphenols in GLP-1 secretion and degradation as it relates to metabolic homeostasis. In addition, the effects of polyphenols on microbiota and microbial metabolites that could indirectly modulate GLP-1 secretion are also discussed.

https://www.mdpi.com/1420-3049/26/3/703/pdf

The Emerging Role of Polyphenols in the Management of Type 2 Diabetes

Diabetes mellitus (DM) is a chronic metabolic disease, the third killer of mankind. The finding of potent drugs against diabetes remains challenging. In the present study, coumarin derivatives with known biological activity against diabetic protein have been used to predict functional groups' positions on coumarin derivatives. α-Glucosidase is a brush border membrane-bound lysosomal enzyme from the hydrolase enzyme family. It plays an important role in the metabolism of glycoproteins. Inhibitors of lysosomal α-glucosidase can reduce postprandial hyperglycemia. Due to this, lysosomal α-glucosidase is a good therapeutic target for drugs. A total of 116 coumarin derivatives with IC50 values against lysosomal α-glucosidase were selected for a CADD (computer-aided drug design) approach to identify more potent drugs. Pharmacophore modeling and atom-based 3-QSAR of 116 active compounds against lysosomal α-glucosidase were performed and identified positions and types of groups to increase activity. We performed molecular docking of 116 coumarin derivatives against the lysosomal α-glucosidase enzyme, and three compounds (isorutarine, 10_, and 36) resulted in a docking score of -7.64, -7.12, and -6.86 kcal/mol. The molecular dynamics simulation of the above three molecules and protein complex performed for 100 ns supported the interaction stability of isorutarine, 10_, and 36 with the lysosomal binding site α-glucosidase.

Discovery of Novel Coumarin Analogs against the α-Glucosidase Protein Target of Diabetes Mellitus: Pharmacophore-Based QSAR, Docking, and Molecular Dynamics Simulation Studies.

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia that is predominantly caused by insulin resistance or impaired insulin secretion, along with disturbances in carbohydrate, fat and protein metabolism. Various therapeutic approaches have been used to treat diabetes, including improvement of insulin sensitivity, inhibition of gluconeogenesis, and decreasing glucose absorption from the intestines. Recently, a novel approach has emerged using dipeptidyl peptidase-IV (DPP-IV) inhibitors as a possible agent for the treatment of T2DM without producing any side effects, such as hypoglycemia and exhaustion of pancreatic β-cells. DPP-IV inhibitors improve hyperglycemic conditions by stabilizing the postprandial level of gut hormones such as glucagon-like peptide-1, and glucose-dependent insulinotropic polypeptides, which function as incretins to help upregulate insulin secretion and β-cell mass. In this review, we summarized DPP-IV inhibitors and their mechanism of inhibition, activities of those isolated from various natural sources, and their capacity to overcome oxidative stress in disease conditions.

Dipeptidyl Peptidase (DPP)-IV Inhibitors with Antioxidant Potential Isolated from Natural Sources: A Novel Approach for the Management of Diabetes

Quercetin and coumarin, two naturally occurring phytochemicals of plant origin, are known to regulate hyperglycemia and oxidative stress. The present study was designed to evaluate the inhibitory activity of quercetin and coumarin on dipeptidyl peptidase-IV (DPP-IV) and their antioxidant potential. DPP-IV inhibition assays were performed, and evaluated IC50 values of diprotin A, quercetin, coumarin, and sitagliptin were found to be 0.653, 4.02, 54.83, and 5.49 nmol/mL, respectively. Furthermore, in silico studies such as the drug-likeliness and docking efficiency of quercetin and coumarin to the DPP-IV protein were performed; the ex vivo antiperoxidative potential of quercetin and coumarin were also evaluated. The results of the present study showed that the DPP-IV inhibitory potential of quercetin was slightly higher than that of sitagliptin. Virtual docking revealed the tight binding of quercetin with DPP-IV protein. Quercetin and coumarin reduced oxidative stress in vitro and ex vivo systems. We report for the first time that both compounds inhibited the DPP-IV along with antioxidant activity and thus may be use as function food ingredients in the prevention of diabetes.

Anand-Krishna Singh

Papers

Quercetin and Coumarin Inhibit Dipeptidyl Peptidase-IV and Exhibits Antioxidant Properties: In Silico, In Vitro, Ex Vivo

Dipeptidyl Peptidase (DPP)-IV Inhibitors with Antioxidant Potential Isolated from Natural Sources: A Novel Approach for the Management of Diabetes