Design and Discovery of Novel 1,3,5-Triazines as Dipeptidyl Peptidase-4 Inhibitor against Diabetes

Pharmacology ◽  
2019 ◽  
Vol 103 (5-6) ◽  
pp. 273-281 ◽  
Author(s):  
Yu Wang ◽  
Xialian Tang ◽  
Lianghong Yi
Keyword(s):  
Glucose Tolerance ◽  
Wistar Rats ◽  
Defense Mechanism ◽  
Density Lipoprotein ◽  
Dipeptidyl Peptidase ◽  
Antidiabetic Activity ◽  
Control Group ◽  
Oral Glucose ◽  
Dipeptidyl Peptidase 4

This study aims at synthesizing novel di-morpholine 1,3,5-triazine derivatives as antidiabetic agent via inhibition of dipeptidyl peptidase-4 (DPP-4). The molecules were developed via sequential nucleophilic reaction to afford target derivatives 5(a–f) and subsequently tested for inhibitory potency against DPP iso-enzymes, such as DPP-4, DPP-8, and DPP-9. The in vitro inhibition assay suggested that these derivatives prominently and selectively inhibit DPP-4 over ­DPP-8 and DPP-9. These molecules also showed no presence of cardiotoxicity, as confirmed by no activity against human Ether-à-go-go related gene channel. The study disclosed compound 5c as the most potent inhibitor of DPP-4 with IC50 of 1.10 nmol/L as compared to the standard. Compound 5c was further evaluated for oral glucose tolerance test (OGTT) and antidiabetic activity in ICR mice and Wistar rats, respectively. In OGTT, compound 5c showed dose-dependent ­improvement of glucose tolerance with a maximum at 30 mg/kg. It also showed reduction in area under the curve from 0 to 120 min, similar to alogliptin (standard). In Wistar rats, compound 5c causes reduction in the blood glucose level, total cholesterol, triglyceride, low density lipoprotein (LDL) and very LDL level as compared to the diabetic control group, whereas the level of high-density lipoprotein was found to be increased. Compound 5c causes improvement in antioxidant defense mechanism, as confirmed via improving superoxide dismutase, catalase, glutathione peroxidase and reducing the malondialdehyde level as compared to normal control group rats.

Antidiabetic Effects of Ethanolic Extract of Ficus glomerata (L.) Roots

2020 ◽  
Vol 16 (1) ◽  
pp. 33-41
Author(s):  
Mohini C. Upadhye ◽  
Uday Deokate ◽  
Rohini Pujari ◽  
Vishnu Thakare
Keyword(s):  
Body Weight ◽  
Glucose Tolerance ◽  
Density Lipoprotein ◽  
Ethanolic Extract ◽  
Tolerance Test ◽  
Diabetic Rats ◽  
Antidiabetic Activity ◽  
Control Group ◽  
Oral Glucose ◽  
Ficus Glomerata

Background: Ficus glomerata (F. glomerata) Linn. Family Moraceace is a large tree found all over India including outer Himalayan ranges, Punjab, Chota Nagpur, Bihar, Orissa, West Bengal, Rajasthan, Deccan and also as a common plant in South India. It is planted around the home and temples. It is cultivated throughout the year, distributed in evergreen forests and moist localities. Objective: The Ethanolic Extract of roots of F. Glomerata (EEFG) belonging to the family Moraceace, was investigated for its antidiabetic activity using alloxan induced diabetic rats. Methods: Thirty rats were divided into 5 groups having 6 rats in each group. The alloxan was administered to the rats of all groups except normal control group through intraperitoneal route at a concentration of 140mg/kg body weight. A dose of 100mg/kg and 200 mg/kg body weight of EEFG was administered to alloxan induced diabetic rats. The administration of the extract was lasted for 11 days. Effectiveness of the extract on glucose, cholesterol, triglycerides, and high density lipoprotein and protein concentrations was analyzed. Results: Significant (p<0.05) reduction in the levels of glucose, cholesterol, triglyceride of the diabetic rats was observed after treatment with ethanolic extract. After subjecting to oral glucose tolerance test EEFG also showed significant improvement in glucose tolerance. Conclusion: F. glomerata root ethanolic extract showed that it possesses antidiabetic effect and can be found useful for the management of diabetes mellitus.

scholarly journals Polyalthia Clerodane Diterpene Potentiates Hypoglycemia via Inhibition of Dipeptidyl Peptidase 4

2019 ◽  
Vol 20 (3) ◽  
pp. 530 ◽  
Author(s):  
Po-Kai Huang ◽  
Shian-Ren Lin ◽  
Jirawat Riyaphan ◽  
Yaw-Syan Fu ◽  
Ching-Feng Weng
Keyword(s):  
Single Dose ◽  
Natural Compounds ◽  
Dipeptidyl Peptidase ◽  
Antidiabetic Activity ◽  
Drug Candidate ◽  
Diabetic Patients ◽  
Dose Administration ◽  
Dipeptidyl Peptidase 4

Serine protease dipeptidyl peptidase 4 (DPP-4) is involved in self/non-self-recognition and insulin sensitivity. DPP-4 inhibitors are conventional choices for diabetic treatment; however, side effects such as headache, bronchus infection, and nasopharyngitis might affect the daily lives of diabetic patients. Notably, natural compounds are believed to have a similar efficacy with lower adverse effects. This study aimed to validate the DPP-4 inhibitory activity of clerodane diterpene 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) from Polyalthia longifolia, rutin, quercetin, and berberine, previously selected through molecular docking. The inhibitory potency of natural DPP-4 candidates was further determined by enzymatic, in vitro Caco-2, and ERK/PKA activation in myocyte and pancreatic cells. The hypoglycemic efficacy of the natural compounds was consecutively analyzed by single-dose and multiple-dose administration in diet-induced obese diabetic mice. All the natural-compounds could directly inhibit DPP-4 activity in enzymatic assay and Caco-2 inhibition assay, and HCD showed the highest inhibition of the compounds. HCD down-regulated LPS-induced ERK phosphorylation in myocyte but blocked GLP-1 induced PKA expression. For in vivo tests, HCD showed hypoglycemic efficacy only in single-dose administration. After 28-days administration, HCD exhibited hypolipidemic and hepatoprotective efficacy. These results revealed that HCD performed potential antidiabetic activity via inhibition of single-dose and long-term administrations, and could be a new prospective anti-diabetic drug candidate.

scholarly journals The Dipeptidyl Peptidase-4 Inhibitor Teneligliptin Reduces Aortic Damage from Hypercholesterolaemia in Apolipoprotein E-Deficient Mice

2017 ◽  
Vol 2 (2) ◽  
pp. 1-9
Author(s):  
Ying Zhang ◽  
Nan Wang ◽  
Liyue Zhu ◽  
Yingshu Liu ◽  
Zuowei Pei ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Dipeptidyl Peptidase ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Low Density ◽  
Dipeptidyl Peptidase 4 ◽  
Gene And Protein Expression ◽  
Dipeptidyl Peptidase 4 Inhibitors

Objective: Hypercholesterolaemia is a well-established risk factor for blood vessel damage, which can lead to cardiovascular diseases. An abundance of clinical data show that dipeptidyl peptidase-4 inhibitors protect against aortic damage in patients with diabetes. The goal of this study was to investigate the possible protective effects of teneligliptin against aortic damage in apolipoprotein E knockout (ApoE-/-) mice. Methods: Eight-week-old male ApoE-/- mice were randomly divided into 3 groups: a control group fed a normal diet, a high-cholesterol diet (HD group), and an HD diet mixed with teneligliptin (HD + Tene group), and all the groups were fed with the different treatments for 6 weeks. Results and Conclusion: The metabolic characteristics of total cholesterol, low-density lipoprotein-cholesterol, and high-sensitivity C-reactive protein were lower in ApoE-/- HD + Tene mice than in ApoE-/- HD mice. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) gene and protein expression were lower in the aortic tissue of ApoE-/- HD + Tene mice than in ApoE-/- HD mice. IL-6 and TNF-α gene expression were lower in ApoE-/- HD + Tene mice than in ApoE-/- HD mice. These results indicate that teneligliptin may provide a potential therapeutic target for the aortic damage from hypercholesterolaemia.

Comparative Glycaemic Indices of a Four Herbal Combinatorial Formulation Administered On Wistar Rats

2019 ◽  
Vol 19 (7) ◽  
pp. 991-1004
Author(s):  
Inya Joseph ◽  
Ojiako Okey ◽  
Emejulu Angela
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Wistar Rats ◽  
Research Work ◽  
Control Group ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Oral Glucose Load ◽  
Glucose Load

Objective: The effect of dietary incorporation of ethanolic extracts of single and combinatorial formulations of Acanthus montanus (ACMO), Asystaciagangetica (ASGA), Gongronemalatifolium (GOLA) and Solanummelongena (SOME) on glucose tolerance was studied in normoglycaemicWistar rats. Methods: A total of 128 Wistar rats were used for the research work. The rats were divided into 32 groups of 4 rats each. One group was the normal control group and 15 groups were orally administered 200mg/kg body weight extract(s) for the single and combinatorial formulations. Another group (negative control) was given oral glucose load (4g/100ml) of 200mg/kg body weight alone and the remaining 15 groups were given oral glucose load (4g/100ml) of 200mg/kg body weight before giving the test extract(s) of 200mg/kg body weight. Results: Post-prandial serum glucose response at 30 minutes interval was plotted and the area under the curve (AUC) used to determine glycaemic index (GI) of each herbs. The herbs (ACMO, ASGA, GOLA and SOME) resulted in a marked improvement in oral glucose tolerance in rats after 10 days of treatment at an interval of 2 days. Blood glucose concentration (mmol/l) of rats administered with the combinations; ACMO+GOLA, ACMO+SOME, SOME+GOLA, ACMO+SOME+GOLA+GLU, ACMO+ASGA+GOLA, ACMO+SOME+GOLA and ACMO+ASGA+GOLA+SOME was found to belowered, with ACMO+ASGA+GOLA combination having the best result. This might be a result of hypoglycaemic synergy promoted by the various bioactive principles present in the combined extracts thereby lowering the GI. These findings revealed that the listed combinations have hypoglycaemic potentials and habitual consumption could positively modulate oral glucose tolerance. Conclusion: The herbs could be useful in the dietary management of diabetes as they could help regulate blood glucose level when consumed with normal meals and could also be incorporated into meals to prevent or delay the onset of diabetes or reverse the same in its early stages.

scholarly journals Effects of Moringa oleifera leaf powder on metabolic syndrome induced in male Wistar rats: a preliminary study

2018 ◽  
Vol 46 (8) ◽  
pp. 3327-3336 ◽  
Author(s):  
Marisa López ◽  
Mónica Ríos-Silva ◽  
Miguel Huerta ◽  
Yolitzy Cárdenas ◽  
Jaime Alberto Bricio-Barrios ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Wistar Rats ◽  
Moringa Oleifera ◽  
Fasting Glucose ◽  
Abdominal Circumference ◽  
Control Group ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Insulin Tolerance ◽  
Male Wistar Rats

Objective To evaluate the preventive effects of Moringa oleifera on metabolic syndrome (MS) in male Wistar rats. Methods MS was induced by feeding rats a high-fat diet and drinking water containing 10% fructose for 6 weeks. In the preventive group, M. oleifera was orally administered for 3 weeks prior to the induction of MS, while in the treatment group, M. oleifera was administered for 3 weeks after the onset of MS. The treatment groups were compared with a control group of untreated rats with induced MS. Fasting glucose, oral glucose tolerance, insulin tolerance, total cholesterol, triglycerides, abdominal circumference, and systolic and diastolic blood pressure were measured before and after MS induction and/or M. oleifera treatment. Results After the induction of MS, the control group had higher fasting glucose levels than the preventive group. No significant differences were observed in insulin tolerance, oral glucose tolerance, cholesterol, triglycerides, abdominal circumference, or systolic or diastolic blood pressure. Compared with untreated controls, rats in the treatment group had significantly improved glucose tolerance, triglycerides, and abdominal circumference. Conclusions M. oleifera treatment attenuates MS in Wistar rats.

Flavonoids Extracted from Asteriscus graveolens Improve Glucose Metabo-lism and Lipid Profile in Diabetic Rats

2020 ◽  
Vol 20 ◽  
Author(s):  
Fadwa El-ouady ◽  
Fatima Bachir ◽  
Mohamed Eddouks
Keyword(s):  
Glucose Tolerance ◽  
Lipid Profile ◽  
Histopathological Examination ◽  
Oral Treatment ◽  
Hdl Cholesterol ◽  
Diabetic Rats ◽  
Oral Glucose ◽  
Traditional Use ◽  
Soxhlet Apparatus

Aim: This study aimed to evaluate the antidiabetic and antihyperlipidemic effects of Asteriscus graveolens. Background: Asteriscus graveolens (Asteraceae) is a medicinal plant widely used by the Moroccan population to treat various diseases including diabetes. Objective: This work aimed to assess the capacity of flavonoids extracted from Asteriscus graveolens (FEE) to improve diabetes mellitus and dyslipidemia in normal and STZ-induced diabetic rats. Methods: Flavonoids were extracted from A. graveolens using the Soxhlet apparatus and using different organic solvents. Normal and streptozotocin-induced diabetic rats were treated orally by the extract of A. graveolens at a dose of 10 mg/kg. The oral treatment during 15 days was used to evaluate the effect of the flavonoids extracted from A. graveolens on blood glucose level and lipid profile in normal and diabetic rats. The oral glucose tolerance test as well as the analysis of histopathological examination of liver was performed. The antioxidant activity of FEE was also assessed by the method of trapping of free radical 2,2-diphenyl-1 picrylhydrazyl (DPPH), in order to estimate the mechanisms of action involved by FEE to improve hyperglycemia and lipid profile in normal and diabetic rats. Results: FEE reduced serum glucose concentrations in both normal and diabetic rats and exhibited in the last group lowering total cholesterol and triglycerides effects as well as improvement of the HDL-cholesterol serum level. In addition, a remarkable influence on glucose tolerance was also noticed after FEE treatment. Moreover, FEE was able to improve histopathological status of liver and possess a potential antioxidant effect in vitro. Conclusion: In conclusion, this study demonstrates the hypoglycemic and antihyperlipidemic effects of FEE in rats supporting then its traditional use for the management of diabetes.

scholarly journals Pharmacoinformatics and UPLC-QTOF/ESI-MS-Based Phytochemical Screening of Combretum indicum against Oxidative Stress and Alloxan-Induced Diabetes in Long–Evans Rats

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4634
Author(s):  
Md. Shaekh Forid ◽  
Md. Atiar Rahman ◽  
Mohd Fadhlizil Fasihi Mohd Aluwi ◽  
Md. Nazim Uddin ◽  
Tapashi Ghosh Roy ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Immune Modulation ◽  
Computational Study ◽  
Density Lipoprotein ◽  
Control Group ◽  
Esi Ms ◽  
Long Evans ◽  
Antidiabetic Effects

This research investigated a UPLC-QTOF/ESI-MS-based phytochemical profiling of Combretum indicum leaf extract (CILEx), and explored its in vitro antioxidant and in vivo antidiabetic effects in a Long–Evans rat model. After a one-week intervention, the animals’ blood glucose, lipid profile, and pancreatic architectures were evaluated. UPLC-QTOF/ESI-MS fragmentation of CILEx and its eight docking-guided compounds were further dissected to evaluate their roles using bioinformatics-based network pharmacological tools. Results showed a very promising antioxidative effect of CILEx. Both doses of CILEx were found to significantly (p < 0.05) reduce blood glucose, low-density lipoprotein (LDL), and total cholesterol (TC), and increase high-density lipoprotein (HDL). Pancreatic tissue architectures were much improved compared to the diabetic control group. A computational approach revealed that schizonepetoside E, melianol, leucodelphinidin, and arbutin were highly suitable for further therapeutic assessment. Arbutin, in a Gene Ontology and PPI network study, evolved as the most prospective constituent for 203 target proteins of 48 KEGG pathways regulating immune modulation and insulin secretion to control diabetes. The fragmentation mechanisms of the compounds are consistent with the obtained effects for CILEx. Results show that the natural compounds from CILEx could exert potential antidiabetic effects through in vivo and computational study.

scholarly journals Anti-Obesity and Anti-Adipogenic Effects of Chitosan Oligosaccharide (GO2KA1) in SD Rats and in 3T3-L1 Preadipocytes Models

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 331
Author(s):  
Jung-Yun Lee ◽  
Tae Yang Kim ◽  
Hanna Kang ◽  
Jungbae Oh ◽  
Joo Woong Park ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Density Lipoprotein ◽  
Treated Group ◽  
Control Group ◽  
Chitosan Oligosaccharide ◽  
Sd Rats ◽  
Adipogenic Gene

Excess body weight is a major risk factor for type 2 diabetes (T2D) and associated metabolic complications, and weight loss has been shown to improve glycemic control and decrease morbidity and mortality in T2D patients. Weight-loss strategies using dietary interventions produce a significant decrease in diabetes-related metabolic disturbance. We have previously reported that the supplementation of low molecular chitosan oligosaccharide (GO2KA1) significantly inhibited blood glucose levels in both animals and humans. However, the effect of GO2KA1 on obesity still remains unclear. The aim of the study was to evaluate the anti-obesity effect of GO2KA1 on lipid accumulation and adipogenic gene expression using 3T3-L1 adipocytes in vitro and plasma lipid profiles using a Sprague-Dawley (SD) rat model. Murine 3T3-L1 preadipocytes were stimulated to differentiate under the adipogenic stimulation in the presence and absence of varying concentrations of GO2KA1. Adipocyte differentiation was confirmed by Oil Red O staining of lipids and the expression of adipogenic gene expression. Compared to control group, the cells treated with GO2KA1 significantly decreased in intracellular lipid accumulation with concomitant decreases in the expression of key transcription factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (CEBP/α). Consistently, the mRNA expression of downstream adipogenic target genes such as fatty acid binding protein 4 (FABP4), fatty acid synthase (FAS), were significantly lower in the GO2KA1-treated group than in the control group. In vivo, male SD rats were fed a high fat diet (HFD) for 6 weeks to induced obesity, followed by oral administration of GO2KA1 at 0.1 g/kg/body weight or vehicle control in HFD. We assessed body weight, food intake, plasma lipids, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) for liver function, and serum level of adiponectin, a marker for obesity-mediated metabolic syndrome. Compared to control group GO2KA1 significantly suppressed body weight gain (185.8 ± 8.8 g vs. 211.6 ± 20.1 g, p < 0.05) with no significant difference in food intake. The serum total cholesterol, triglyceride, and low-density lipoprotein (LDL) levels were significantly lower in the GO2KA1-treated group than in the control group, whereas the high-density lipoprotein (HDL) level was higher in the GO2KA1 group. The GO2KA1-treated group also showed a significant reduction in ALT and AST levels compared to the control. Moreover, serum adiponectin levels were significantly 1.5-folder higher than the control group. These in vivo and in vitro findings suggest that dietary supplementation of GO2KA1 may prevent diet-induced weight gain and the anti-obesity effect is mediated in part by inhibiting adipogenesis and increasing adiponectin level.

scholarly journals Flaxseed, olive and fish oil influence plasmatic lipids, lymphocyte migration and morphometry of the intestinal of Wistar rats

2010 ◽  
Vol 25 (3) ◽  
pp. 275-280 ◽  
Author(s):  
Damiana Diniz Rosa ◽  
Regiane Lopes de Sales ◽  
Luis Fernando de Sousa Moraes ◽  
Fabíola Cesário Lourenço ◽  
Clóvis Andrade Neves ◽  
...  
Keyword(s):  
Fish Oil ◽  
Intestinal Mucosa ◽  
Wistar Rats ◽  
Density Lipoprotein ◽  
Parameter Analysis ◽  
Male Rats ◽  
Histological Evaluation ◽  
Control Group ◽  
Soy Oil ◽  
Lymphocyte Migration

PURPOSE: Evaluate the effect of flaxseed, olive and fish oil on the lipid profile, preservation of villosities and lymphocyte migration in the intestinal mucosa of Wistar rats. METHODS: Thirty Wistar male rats were divided into four groups, which received the AIN-93M diet, with changes only to their lipid source: flaxseed, olive, fish, and soy oil (control group). The serum was separated for the biochemical parameter analysis. A histological evaluation was performed in the ileal portion. RESULTS: The group which was fed fish oil presented lower values when compared to the other treatments for Total Cholesterol, High-density Lipoprotein Cholesterol and Triacylglycerol (p<0.05). The animals treated with fish and olive oils presented better intestinal villosities preservation. Less deposition of lymphocytes was observed in the flaxseed group (p<0.001). CONCLUSIONS: This study demonstrated that flaxseed, olive and fish oils present different responses than soy oil for the intestinal mucosa preservation and lymphocyte proliferation in Wistar rats.

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