A dipyrrole derivative from Aloe vera inhibits an anti-diabetic drug target Dipeptidyl Peptidase (DPP)-IV in vitro.
TL;DR: The results of the studies suggested that the inhibition of the DPP-IV enzyme as one of the pathways by which the Aloe vera extract may restore the pancreatic islets cell mass in diabetic animal model.
Abstract: Aloe vera, a succulent herb, has a long history of use in traditional medicine, including diabetes. Earlier studies from our laboratory demonstrated that the Aloe vera extract has the ability to inhibit the diabetic drug target dipeptidyl peptidase (DPP) IV in vitro. This current study focuses on the isolation of small water soluble active molecule(s) involved in DPP-IV inhibition from Aloe vera extract, and further to characterize its structure and to elucidate the mode of inhibition of the DPP-IV enzyme. Aloe vera gel ethanolic extract was subjected to preparative reverse-phase high-pressure liquid chromatography (RP-HPLC), LH-20 Sephadex gel filtration chromatography, followed by analytical RP-HPLC, to isolate the active molecule involved in DPP-IV inhibition. Based on the spectroscopic studies, the structure of the isolated DPP-IV inhibitor was predicted to be 3, 6-dioxo-3, 3a, 6, 6 a-tetrahydropyrrolo [3, 4-c] pyrrole-1, 4-dicarboxamide with the chemical formula C8H6N4O4, having the molecular weight of 225.175 Da. This molecule inhibited the DPP-IV enzyme in a noncompetitive manner with an IC50 value of 8.59 ± 2.61 µM, with a Ki of 4.7 ± 0.038 µM. Thus, the mechanism of DPP-IV inhibition and the inhibitory constants were determined. The results of our studies suggested that the inhibition of the DPP-IV enzyme as one of the pathways by which the Aloe vera extract may restore the pancreatic islets cell mass in diabetic animal model.
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TL;DR: In this article, the authors employed an in-silico approach involving molecular docking, dynamics simulation, and binding free energy calculation using SARS-CoV-2 essential proteins as main protease and spike protein to identify lead compounds from Aloe that may help in novel drug discovery.
Abstract: Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease is a global rapidly spreading virus showing very high rates of complications and mortality. Till now, there is no effective specific treatment for the disease. Aloe is a rich source of isolated phytoconstituents that have an enormous range of biological activities. Since there are no available experimental techniques to examine these compounds for antiviral activity against SARS-CoV-2, we employed an in silico approach involving molecular docking, dynamics simulation, and binding free energy calculation using SARS-CoV-2 essential proteins as main protease and spike protein to identify lead compounds from Aloe that may help in novel drug discovery. Results retrieved from docking and molecular dynamics simulation suggested a number of promising inhibitors from Aloe. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) calculations indicated that compounds 132, 134, and 159 were the best scoring compounds against main protease, while compounds 115, 120, and 131 were the best scoring ones against spike glycoprotein. Compounds 120 and 131 were able to achieve significant stability and binding free energies during molecular dynamics simulation. In addition, the highest scoring compounds were investigated for their pharmacokinetic properties and drug-likeness. The Aloe compounds are promising active phytoconstituents for drug development for SARS-CoV-2.
23 citations
TL;DR: In this article, a review of 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 is presented.
Abstract: 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.
21 citations
TL;DR: In this article, the authors investigated the simultaneous effect of ethanolic A. vera gel extract on diabetes and obesogenic milieu in Streptozotocin-induced WNIN/GR-Ob mutant obese rats.
12 citations
TL;DR: The output of this research bestows support to utilize the SCKP stirred batch extract as a promising source of antioxidant and antidiabetic compounds in ayurvedic formulations.
Abstract: Syzygium cumini, owing to higher bioactive constituents, its parts principally kernels are used for the antidiabetic purpose since the olden days. The current manuscript illustrated batch extraction of phenolic compounds from S. cumini using a stirred extractor. The yields 0.61 mg/g, 35.9 mg/g, 79.89 mg GAE/g, and 7.29 mg CE/g of catechin, gallic acid, TPC and TFC, respectively, were obtained in 105 min. at 1:20 SCKP to water, 50 ± 2 °C temperature, 4 pH, at 250 rpm and 106 µm particle size of SCKP. In vitro evaluation of the antioxidant and antidiabetic potential of the obtained aqueous extract was carried out by DPPH, α-amylase, and α-glucosidase inhibitory assays. The IC50 values of SCKP aqueous extract obtained were 12.97, 9.03, and 7.13 µg/mL for DPPH scavenging, inhibition of α-amylase, and α-glucosidase, respectively. The cost required to extract 1 kg of catechin, gallic acid, TPC, and TFC was Rs 6691.6, 113.7, 51.1, and 559.93/-, respectively. Stirred batch extraction technique manifests traditional but simple, ecofriendly, and efficient compared to other traditional techniques. The output of this research bestows support to utilize the SCKP stirred batch extract as a promising source of antioxidant and antidiabetic compounds in ayurvedic formulations.
7 citations
TL;DR: In this paper, the authors evaluated the effect of piperine on Alzheimer's disease in diabetic rats and showed that piperines not only improved memory but also reduced the expression of specific AD-related genes.
Abstract: There is accumulating evidence showing that hyperglycemia conditions like diabetes possess a greater risk of impairment to the neuronal system because high glucose levels exacerbate oxidative stress, accumulation of amyloid-beta peptides, and mitochondrial dysfunction, and impair cognitive functions and cause neurodegeneration conditions like Alzheimer's diseases. Due to the extensive focus on pharmacological intervention to prevent neuronal cells' impairment induced by hyperglycemia, the underlying molecular mechanism that links between Diabetes and Alzheimer's is still lacking. Given this, the present study aimed to evaluate the protective effect of piperine on streptozotocin (STZ) induced hyperglycemia and candidate gene expression. In the present study, rats were divided into four groups: control (Vehicle only), diabetic control (STZ only), piperine treated (20 mg/kg day, i.p), and sitagliptin (Positive control) treated. The memory function was assessed by Morris water maze and probe test. After treatment, biochemical parameters such as HOMA index and lipid profile were estimated in the serum, whereas histopathology was evaluated in pancreatic and brain tissue samples. Gene expression studies were done by real-time PCR technique. Present data indicated that piperine caused significant memory improvement as compared to diabetic (STZ) control. The assessment of HOMA indices in serum samples showed that piperine and sitagliptin (positive control, PC) caused significant alterations of insulin resistance, β cell function, and insulin sensitivity. Assessment of brain and pancreas histopathology shows significant improvement in tissue architecture in piperine and sitagliptin treated groups compared to diabetic control. The gene expression profile in brain tissue shows significantly reduced BACE1, PSEN1, APAF1, CASPASE3, and CATALASE genes in the piperine and sitagliptin (PC) treated groups compared to Diabetic (STZ) control. The present study demonstrated that piperine not only improves memory in diabetic rats but also reduces the expression of specific AD-related genes that can help design a novel strategy for therapeutic intervention at the molecular level.
7 citations
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TL;DR: The results suggest that the inhibitory effect of aloe on BPDE-I-DNA adduct formation might have a chemopreventive effect by inhibition of B[a]P absorption.
Abstract: The antigenotoxic and chemopreventive effect of Aloe barbadensis Miller (polysaccharide fraction) on benzo[a]-pyrene (B[a]P-DNA adducts was investigated in vitro and in vivo. Aloe showed a time-course and dose-dependent inhibition of [ 3 H]B[a]P-DNA adduct formation in primary rat hepatocytes (1X10 6 cells/ml) treated with [ 3 H]B[a]P (4 nmol/ml). At concentrations of 0.4-250 μg/ml aloe, the binding of [ 3 H]B[a]P metabolites to rat hepatocyte DNA was inhibited by 9.1-47.9%. Also, in rat hepatocytes cultured for 3-48 h with aloe (250 μg/ml) and [ 3 H]B[a]P (4 nmol/ml), [ 3 H]B[a]P-DNA adducts were significantly reduced by 36% compared with [ 3 H]B[a]P alone. Aloe also inhibited cellular uptake of [ 3 H]B[a]P in a dose-dependent manner at a concentration of 0.4-250 Pg/ml by 6.3-34.1 %. After a single oral administration of B[a]P to male ICR mice (10 mg/mouse), benzo[a]pyrene diol epoxide I (BPDE-I)-DNA adduct formation and persistence for 16 days following daily treatment with aloe (50 mg/mouse) were quantitated by enzyme-linked immunosorbent assay using monoclonal antibody 8E11. In this animal model, BPDE-I-DNA adduct formation was significantly inhibited in various organs (liver, kidney, forestomach and lung) (P < 0.001). When mice were pretreated with aloe for 16 days before B[a]P treatment, inhibition of BPDE-I-DNA adduct formation and persistence was enhanced. Glutathione S-transferase activity was slightly increased in the liver but cytochrome P450 content was not affected by aloe. These results suggest that the inhibitory effect of aloe on BPDE-I-DNA adduct formation might have a chemopreventive effect by inhibition of B[a]P absorption.
93 citations
"A dipyrrole derivative from Aloe ve..." refers background in this paper
...Several studies have shown that the Aloe vera extract has anti-inflammatory,([28,29]) anti-cancer,([30]) and anti-fungal([31]) properties....
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TL;DR: The recently developed diabetes therapies, GLP-1 receptor agonists, appear to have beneficial effects on β-cell function and hence offer promise for durable glycemic control as well as potentially reducing the micro- and macrovascular complications associated with type 2 diabetes.
Abstract: There is a progressive deterioration in β-cell function in patients with type 2 diabetes. At diagnosis, islet function may be reduced by up to 50% compared with healthy control subjects, and there is also likely to be a reduction in β-cell mass of up to 60%. The reduction in β-cell mass is due to accelerated apoptosis. Currently, few pharmacological therapies address this reduction in β-cell mass and function. This means that patients are generally subjected to an increasing polypharmacy to control their diabetes, with most eventually being treated by insulin. Incretin hormones, which are released from the gastrointestinal tract after a meal, enhance glucose-dependent insulin secretion from the pancreas, aiding the overall regulation of glucose homeostasis in healthy subjects. In addition, these hormones, especially glucagon-like peptide (GLP)-1, have a number of protective effects on the β-cells, including a reduction in apoptosis and enhancement of β-cell proliferation and neogenesis. These benefits are lost to a significant extent in patients with diabetes. The recently developed diabetes therapies, GLP-1 receptor agonists, such as exenatide and liraglutide, appear to have beneficial effects on β-cell function and hence offer promise for durable glycemic control as well as potentially reducing the micro- and macrovascular complications associated with type 2 diabetes.
The clinical course of type 2 diabetes is characterized by a progressive decline in β-cell mass and function. Although the elevated levels of fasting glucose and impairment of insulin action in peripheral tissues may predate the diagnosis of type 2 diabetes, chronic hyperglycemia only results after a prolonged period of β-cell degeneration, a process that may begin as much as 12 years before diagnosis, involving a progressive reduction in functionality and mass (1,2). In the UK Prospective Diabetes Study, it was estimated that, at diagnosis, type 2 diabetic patients may have already lost up …
93 citations
TL;DR: It is suggested that Aloe vera-derived phytosterols could reduce visceral fat accumulation, and would be useful for the improvement of hyperlipidemia and hyperglycemia in obese animal model of type II diabetes, Zucker diabetic fatty rats.
88 citations
TL;DR: Aloe vera L. high molecular weight fractions, prepared by patented hyper-dry system in combination of freeze-dry technique with microwave and far infrared radiation, produced significant decrease in blood glucose level sustained for 6 weeks of the start of the study.
Abstract: Aloe vera L. high molecular weight fractions (AHM) containing less than 10 ppm of barbaloin and polysaccharide (MW: 1000 kDa) with glycoprotein, verectin (MW: 29 kDa), were prepared by patented hyper-dry system in combination of freeze–dry technique with microwave and far infrared radiation. AHM produced significant decrease in blood glucose level sustained for 6 weeks of the start of the study. Significant decrease in triglycerides was only observed 4 weeks after treatment and continued thereafter. No deterious effects on kidney and liver functions were apparent. Treatment of diabetic patients with AHM may relief vascular complications probably via activation of immunosystem.
86 citations
Journal Article•
TL;DR: The results suggest that a combination of low dose STZ and high-energy intake can effectively induce type 2 diabetes by altering the related gene expressions in major metabolic tissues.
Abstract: High energy-intake is a major factor revolved in type 2 diabetes. A number of animal models have been adopted for studying the type 2 diabetes, but they differ greatly from human type 2 diabetes. The objectives of the present study are to set up a suitable animal model, which is similar to the human type 2 diabetes, and then to understand possible molecular mechanisms underlying type 2 diabetes. Twenty five-week-old Wistar male rats were randomized into four groups. One group was fed with basal diet (BD) whereas the others consumed high-energy diet (HD) of 20% sucrose and 10% lard. Four weeks later, BD and one of HD were sampled. Other groups continued to consume HD, but one of them was treated by one injection of streptozotocin (STZ) (30 mg/kg body weight). After another four weeks, all were sacrificed. Changes in body weight were recorded, and levels of glucose, TG, TC, LDL in serum were analyzed by standard methods. Moreover, expressions of genes related to energy metabolism in liver, muscle and fat were measured by real-time RT-PCR. HD had no notable differentiation with BD on bodyweight and serum indices, but it altered gene expressions in a tissue-specific manner. Two receptors of adiponectin, leptin, PPARgamma, UCP2 mRNA levels in fat were up regulated, whereas most of them were down regulated in liver. STZ treatment induced symptoms of diabetes, and the gene expression mentioned above exhibited changes in both tissue- and gene-specific manners. The results suggest that a combination of low dose STZ and high-energy intake can effectively induce type 2 diabetes by altering the related gene expressions in major metabolic tissues.
81 citations
"A dipyrrole derivative from Aloe ve..." refers background in this paper
...The b-cells of the pancreas play a major role in maintaining the glucose homeostasis and defects in these cells, cannot properly secrete insulin in response to hyperglycemia, leading to diabetes mellitus.([2]) Current pharmacological agents such as sulfonylureas, biguanides, and so on are aimed at maintaining glucose homeostasis and these drugs cannot completely cure diabetes and they have various side effects such as hypoglycemia, weight gain, liver, and heart failure....
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