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Journal ArticleDOI

A dipyrrole derivative from Aloe vera inhibits an anti-diabetic drug target Dipeptidyl Peptidase (DPP)-IV in vitro.

08 Jan 2020-Preparative Biochemistry & Biotechnology (Taylor & Francis)-Vol. 50, Iss: 5, pp 511-520

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.
Citations
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Journal ArticleDOI
21 Mar 2021-Molecules
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.

8 citations


Journal ArticleDOI
Abstract: Ethno-pharmacological relevance The genus Aloe has a long history of usage in medicine. Aloe barbadensis Miller, commonly known as Aloe vera, is said to possess anti-diabetic, anti-inflammatory, anti-cancer, anti-microbial, immunomodulation, wound healing properties. Aim of the study In diabetes mellitus, loss in intestinal permeability is observed with high levels of zonulin and low levels of glucagon-like peptide-1 (GLP-1) leading to hyperglycemia. The aim of the study was to understand the role of peptide/polypeptide fraction (PPF) of Aloe vera in the alleviation of diabetes through maintaining the intestinal permeability by regulating the zonulin and GLP-1 levels. Materials and methods The PPF of Aloe vera was obtained through trichloroacetic acid precipitation. The anti-diabetic potential of the PPF was tested through DPP-IV inhibition, glucose diffusion assay, and by using Rin-m5F cells. The anti-diabetic potential of the PPF was tested at a dose of 0.450 mg/kg bw in vivo using streptozotocin-induced diabetic Wistar rats. The effect of PPF on fasting plasma glucose, insulin, glucagon, Zonulin, GLP-1, DPP-IV, levels were studied in diabetic rats. The histopathological studies of the pancreas, small intestine, and liver were carried out for organ-specific effects. Results PPF has the ability to reduce fasting plasma glucose levels with concomitant increase in insulin levels in streptozotocin-induced diabetic rats. It was also observed that increase in GLP-1 levels with a decrease in DPP-IV and zonulin levels thereby mitigating the loss of intestinal permeability. These findings correlate with the small intestine's histopathological observation where the excessive proliferation of epithelium in the small intestine of diabetic rats was reduced after PPF treatment. Conclusion These results suggest that the PPF of Aloe vera alleviates diabetes through islet cell rejuvenation via GLP-1/DPP-IV pathway and thereby suggesting the usage of PPF as an alternate medicine for diabetes mellitus with the possibility to reduce the intestinal permeability and zonulin levels.

3 citations


Journal ArticleDOI
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.

2 citations


Journal ArticleDOI
Suresh Kumar1, Suman Chowdhury1, Ajay Razdan1, Deepa Kumari1  +5 moreInstitutions (4)
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.

1 citations


Journal ArticleDOI
Neha Deora1, M.M. Sunitha2, M. Satyavani2, N. Harishankar2  +3 moreInstitutions (2)
Abstract: Ethnopharmacological relevance Aloe vera (L.) Burm. f. extract has been medicinally used for over 5000 years in different cultures for its curative and therapeutic properties ranging from dermatitis to diabetes. It has been demonstrated to alleviate diabetes through its protective effects on pancreatic islets and by improving insulin secretion. Aim of the study To investigate the simultaneous effect of ethanolic A. vera gel extract on diabetes and obesogenic milieu in Streptozotocin-induced WNIN/GR-Ob mutant obese rats. Materials and methods A total of 30 rats were grouped equally into WNIN/GR-Ob control (received water as a vehicle), WNIN/GR-Ob Diabetic rats (Streptozotocin-35 mg/kg bw), WNIN/GR-Ob Diabetic rats + Sitagliptin (10 mg/kg bw), WNIN/GR-Ob Diabetic rats + A. vera (300 mg/kg bw) and GR-Ob control + A. vera (300 mg/kg bw). After 4 weeks of treatment, fasting blood glucose, serum insulin, Homeostatic Model Assessment - Insulin Resistance and β-cell function, glucose-stimulated insulin secretion, Dipeptidyl peptidase-IV activity, and lipid profiles were studied. In addition, ultrastructural analysis of isolated islets and dual-energy X-ray absorptiometry analysis for body composition were also carried out. Results The A. vera treated group showed a significant reduction (p Conclusion The beneficial effects of A. vera in WNIN/GR-Ob strain may be attributed to its ability to lower lipid profile thus improve insulin sensitivity and/or modulating β-cell function. Thus, it has great therapeutic potential as an herbal remedy for the treatment of diabetes and associated adverse effects such as obesity. The exact mechanism underlying the observation needs to be investigated further to explore the anti-obesity and anti-diabetic properties of A. vera and advocate its potential application as alternative medicine.

1 citations


References
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Journal ArticleDOI
Laurie L. Baggio1, Daniel J. Drucker1Institutions (1)
01 May 2007-Gastroenterology
TL;DR: This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1).
Abstract: This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet β-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of β-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1–receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1–receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes.

2,807 citations


"A dipyrrole derivative from Aloe ve..." refers background in this paper

  • ...GLP-1, is a glucose-dependent insulinotropic gut hormone, secreted by the intestinal L-cells that stimulate insulin secretion.([6]) However, it is rapidly degraded by the ubiquitous proteolytic enzyme DPP-IV....

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Journal ArticleDOI
Josias H. Hamman1Institutions (1)
08 Aug 2008-Molecules
TL;DR: The aim of this review is to further highlight recently discovered effects and applications of the leaf gel of A. vera to enhance the intestinal absorption and bioavailability of co-administered compounds as well as enhancement of skin permeation.
Abstract: Many of the health benefits associated with Aloe vera have been attributed to the polysaccharides contained in the gel of the leaves. These biological activities include promotion of wound healing, antifungal activity, hypoglycemic or antidiabetic effects antiinflammatory, anticancer, immunomodulatory and gastroprotective properties. While the known biological activities of A. vera will be briefly discussed, it is the aim of this review to further highlight recently discovered effects and applications of the leaf gel. These effects include the potential of whole leaf or inner fillet gel liquid preparations of A. vera to enhance the intestinal absorption and bioavailability of co-administered compounds as well as enhancement of skin permeation. In addition, important pharmaceutical applications such as the use of the dried A. vera gel powder as an excipient in sustained release pharmaceutical dosage forms will be outlined.

755 citations


"A dipyrrole derivative from Aloe ve..." refers background in this paper

  • ...Aloe vera, a succulent herb that belongs to the Liliaceae family has been used for many centuries for its curative and therapeutic properties.([4,17,18]) It is a commonly used ingredient in...

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Journal ArticleDOI
Anthony H. Barnett1Institutions (1)
TL;DR: The leading DPP‐4 inhibitors have shown clinically significant HbA1c reductions up to 1 year of treatment and offer many potential advantages over existing diabetes therapies including a low risk of hypoglycaemia, no effect on body weight, and the potential for the regeneration and differentiation of pancreatic β‐cells.
Abstract: Summary The dipeptidyl peptidase 4 (DPP-4) inhibitors enhance the body's own ability to control blood glucose by increasing the active levels of incretin hormones in the body. Their mechanism of action is distinct from any existing class of oral glucose-lowering agents. They control elevated blood glucose by triggering pancreatic insulin secretion, suppressing pancreatic glucagon secretion, and signalling the liver to reduce glucose production. The leading DPP-4 inhibitors have shown clinically significant HbA1c reductions up to 1 year of treatment and offer many potential advantages over existing diabetes therapies including a low risk of hypoglycaemia, no effect on body weight, and the potential, based on animal and in vitro studies, for the regeneration and differentiation of pancreatic β-cells. They are efficacious as monotherapy and also in combination with commonly prescribed antidiabetic agents and are suitable for once-daily oral dosing. Consequently, many DPP-4 inhibitors such as vildagliptin (Galvus; LAF-237), sitagliptin (Januvia; MK-0431), and saxagliptin (BMS-477118) have advanced into late-stage human clinical trials. Search strategy and selection criteria This review was built on a systematic MEDLINE search for publications on the subject with the key words: DPP-4 inhibitor; vildagliptin (LAF-237); sitagliptin (MK-0431); saxagliptin (BMS-477118); and type 2 diabetes; up to August 2006. Meeting abstracts were also searched, as much of the data currently only exists in abstract form. Take home message for clinician The DPP-4 inhibitors appear to have great potential for the treatment of type 2 diabetes, but time will tell if this will be realized. While they do not lower glucose to a greater extent than existing therapies, they offer many potential advantages, including the ability to achieve sustainable reductions in HbA1c with a well-tolerated agent that has a low risk of hypoglycaemia and no weight gain, and which can be administered as a once-daily oral dose.

330 citations


"A dipyrrole derivative from Aloe ve..." refers result in this paper

  • ...In vivo and in vitro studies suggest that DPP-IV inhibitors enhance the regeneration and differentiation of pancreatic beta-cells, based on the observation that GLP-1 is able to stimulate the proliferation and inhibits the apoptosis of beta-cells and promotes the differentiation of beta-cells from precursor cells.([23]) The earlier research from our laboratory demonstrated that Aloe vera extract contains potential molecule(s) involved in the inhibition of human DPP-IV....

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Journal ArticleDOI
Alper Okyar1, Ayse Can1, Nuriye Akev1, Gül Baktir1  +1 moreInstitutions (1)
TL;DR: The pulps of Aloe vera leaves devoid of the gel could be useful in the treatment of non‐insulin dependent diabetes mellitus.
Abstract: Aloe vera (L.) Burm. fil. (= A. barbadensis Miller) (Liliaceae) is native to North Africa and also cultivated in Turkey. Aloes have long been used all over the world for their various medicinal properties. In the past 15 years, there have been controversial reports on the hypoglycaemic activity of Aloe species, probably due to differences in the parts of the plant used or to the model of diabetes chosen. In this study, separate experiments on three main groups of rats, namely, non-diabetic (ND), type I (IDDM) and type II (NIDDM) diabetic rats were carried out. A. vera leaf pulp and gel extracts were ineffective on lowering the blood sugar level of ND rats. A. vera leaf pulp extract showed hypoglycaemic activity on IDDM and NIDDM rats, the effectiveness being enhanced for type II diabetes in comparison with glibenclamide. On the contrary, A. vera leaf gel extract showed hyperglycaemic activity on NIDDM rats. It may therefore be concluded that the pulps of Aloe vera leaves devoid of the gel could be useful in the treatment of non-insulin dependent diabetes mellitus

203 citations


Journal ArticleDOI
TL;DR: Blood glucose-lowering medicinal herbs that have the ability to modulate one or more of the pathways that regulate insulin resistance, β-cell function, GLP-1 homeostasis, and glucose (re)absorption are selected and discussed.
Abstract: Diabetes mellitus has been recognized since antiquity. It currently affects as many as 285 million people worldwide and results in heavy personal and national economic burdens. Considerable progress has been made in orthodox antidiabetic drugs. However, new remedies are still in great demand because of the limited efficacy and undesirable side effects of current orthodox drugs. Nature is an extraordinary source of antidiabetic medicines. To date, more than 1200 flowering plants have been claimed to have antidiabetic properties. Among them, one-third have been scientifically studied and documented in around 460 publications. In this review, we select and discuss blood glucose-lowering medicinal herbs that have the ability to modulate one or more of the pathways that regulate insulin resistance, β-cell function, GLP-1 homeostasis, and glucose (re)absorption. Emphasis is placed on phytochemistry, anti-diabetic bioactivities, and likely mechanism(s). Recent progress in the understanding of the biological actions, mechanisms, and therapeutic potential of compounds and extracts of plant origin in type 2 diabetes is summarized. This review provides a source of up-to-date information for further basic and clinical research into herbal therapy for type 2 diabetes. Emerging views on therapeutic strategies for type 2 diabetes are also discussed.

200 citations


"A dipyrrole derivative from Aloe ve..." refers background in this paper

  • ...as insulin sensitizers, insulin secretagogues, DPP-IV and alpha-glucosidase inhibitor.([26]) Traditionally, Aloe vera was used topically to treat external wounds and internally to treat constipation, ulcer, headaches, and arthritis....

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