DPP-4 Inhibitory Activity Research Articles

In Silico Analysis of novel Phytocompounds targetting Dipeptidyl peptidase 4 Enzyme: A New Link between Prediabetes and its cardio-metabolic complications

BackgroundDPP-4 inhibitors, are widely used clinically for treatment of Diabetes. Increase in circulating DPP4 levels have been well demonstrated in patients with Type 2 Diabetes mellitus. The present study assessed the contribution of DPP-4 axis to the pathophysiology of Prediabetes and its cardiometabolic complications. In addition, in silico analysis of phytocompounds that target DPP 4 enzyme was undertaken to identify novel Phytocompounds with therapeutic potential in Prediabetes. MethodologyA novel experimental model of Prediabetes coexisting with hypertension and dyslipidemia was developed in experimental rats to elucidate the pathophysiological role of DPP-4 in Prediabetes and its resultant cardio-metabolic sequale. In the Prediabetic rats, DPP-4 levels, lipid profile, blood pressure readings, fasting blood sugar values, insulin resistance, beta cell function were measured and compared to Normal Control group. In addition, the DPP-4 Inhibitory activity of Phytocompounds (Arjunetin, Guggulsterone) was studied by molecular docking studies including Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), DPP 4 binding affinity and Protein-ligand simulation between the DPP4 and the Phytocompounds was performed. Results were compared to Vildagliptin, the synthetic DPP-4 inhibitor and metformin (Glucophage), the standard antidiabetic drug used in clinical settings. ResultsA statistically significant increase (p < 0.001) in DPP-4 levels along with a decline in bea cell function with increase in Insulin resistance was observed in Prediabetic rats. A positive correlation (p < 0.001) between serum DPP-4 with HbA1c, lipids, and systolic blood pressure was found. The novel model of Prediabetes co-existing with hypertension and dyslipidemia was successfully developed and validated. The silico active site interaction data from simulation studies demonstrated that Arjunetin and Guggulsterone shows effective and stable binding with DPP-4. Arjunetin maintains its contact with Glu205, Glu206, and Asn710 and by interacting with Val207 and His740, it effectively occupies the flanking residues of the active site area. Based on their protein-ligand contact report, Vildagliptin maintains its connection through Tyr547 and during simulation, Guggulsterone interacts with Ser630. ConclusionThe current study offers experimental evidence of DPP-4′s causal role in the development of cardio-metabolic consequences (dyslipidemia and hypertension) of Prediabetes. Arjunetin and Guggulsterone are two Phytocompounds whose potential as promising DPP-4 inhibitors has been further documented using in silico molecular docking studies.

Exploring the Antidiabetic and Antihypertensive Potential of Peptides Derived from Bitter Melon Seed Hydrolysate

Background/Objectives: Type 2 diabetes (T2D) has become a critical global health issue, with an increasing prevalence that contributes to significant morbidity and mortality. Inhibiting dipeptidyl peptidase-IV (DPP4) is a promising strategy for managing T2D. This study aimed to explore the DPP4 inhibitory peptide derived from bitter melon seed protein (BMSP) hydrolysate. Methods: Reversed-phase high-performance liquid chromatography (RP-HPLC) was utilized to fractionate the hydrolysate. Peptide in the highest activity fraction was analyzed using liquid chromatography-mass spectrometry (LC-MS/MS). Peptide synthetic was used for further characterizations, such as bioactivity exploration, inhibition mechanism, molecular docking, and peptide stability against in vitro simulated gastrointestinal (SGI) digestion. Results: The BMSP hydrolysate was digested with gastrointestinal proteases (GP) and assessed for DPP4 inhibitory activity, yielding an IC50 of 1448 ± 105 μg/mL. Following RP-HPLC fractionation, MPHW (MW4) and VPSGAPF (VF7) were identified from fraction F8 with DPP4 IC50 values of 128.0 ± 1.3 µM and 150.6 ± 3.4 µM, respectively. Additionally, MW4 exhibited potential antihypertensive effects through ACE inhibition with an IC50 of 172.2 ± 10.6 µM. The inhibitory kinetics and molecular docking simulations indicated that both MW4 and VF7 were competitive inhibitors of DPP4, while MW4 was also a competitive inhibitor of ACE. Importantly, both peptides remained stable during simulated gastrointestinal digestion, suggesting their resistance to human digestive processes and their capacity to maintain biological activity. Conclusions: The findings suggest that BMSP-GP hydrolysate may have potential in terms of the development of health foods or therapeutic agents. However, in vivo studies are also essential for further confirmation of efficacy.

Integrative approach to assessing bioactivity from hempseed protein isolate extracted and dehydrated by different methods: Synergising in silico prediction and in vitro validation

This study demonstrated a comprehensive workflow combining in silico screening and prediction with in vitro validation to investigate the bioactivity of hempseed protein isolate (HPI) extracted and dehydrated using different methods. By adopting an in silico approach, 13 major proteins of HPI were hydrolysed by 20 selected enzymes, leading to the prediction of 20 potential bioactivities. With papain hydrolysis, dipeptidyl peptidase-IV (DPP4) and angiotensin-converting enzyme (ACE) inhibitory activities emerged as having the highest potential. In vitro experiments confirmed these predictions, with DPP4 and ACE inhibitory activities displaying IC50 values of 0.32–0.42 mg/mL and 6.8–9.17 μg/mL, respectively. A strong correlation (r2 = 0.96) was observed between in vitro protein inhibitory results and in silico predicted data. This study demonstrated an effective integrative approach for predicting bioactive peptides in food protein, providing valuable guidance on its processing to create value-added products.

Isospongian Diterpenoids from the Leaves of Amomum tsao-ko Promote GLP-1 Secretion via Ca2+/CaMKII and PKA Pathways and Inhibit DPP-4 Enzyme.

Three uncommon isospongian diterpenoids including a new one, 3-epi-kravanhin A (2), were isolated from the leaves of Amomum tsao-ko. Compounds 2 and 3 dose-dependently promoted GLP-1 secretion on STC-1 cells with promotion ratios of 109.7% and 186.1% (60 μM). Mechanism study demonstrated that the GLP-1 stimulative effects of 2 and 3 were closely related with Ca2+/CaMKII and PKA pathways, but irrelevant to GPBAR1 and GPR119 receptors. Moreover, compound 1 showed moderate DPP-4 inhibitory activity with an IC50 value of 311.0 μM. Molecular docking verified the binding affinity of 1 with DPP-4 by hydrogen bonds between the γ-lactone carbonyl (C-15) and Arg61 residue. Bioinformatics study indicated that compound 1 exerted antidiabetic effects by improving inflammation, oxidative stress and insulin resistance. This study first disclosed the presence of isospongian diterpenoids in A. tsao-ko, which showed antidiabetic potency by promoting GLP-1 secretion and inhibiting DPP-4 activity.

Steps in discovery of alogliptin

Alogliptin was initially approved to treat T2DM in Japan in 2010 and then approved by FDA and by EMA in 2013. Alogliptin, a highly potent and selective, noncovalent inhibitor of DPP-4. Inhibition of DPP-4 activity, alogliptin slows the inactivation of incretin hormones, glucagon-like peptide-1 (GLP-1). In terms of drug safety alogliptin is generally well-tolerated, with a low risk of hypoglycemia, weight gain, acute pancreatitis, and hepatotoxicity. Alogliptin has been effectively combined with Metformin or Pioglitazone to provide better glycaemic control. The drug can be used in mild hepatic or renal impairment with appropriate dosage adjustment. Treatment with alogliptin has shown less weight gain compared with sulfonylureas. Alogliptin and FDC of Alogliptin + Metformin approved and available in India with brand name Aloja &amp; Aloja M/Forte, with well documented safety and efficacy through phase IV study conducted in India.

IAVPGEVA: Orally Available DPP4-Targeting Soy Glycinin Derived Octapeptide with Therapeutic Potential in Nonalcoholic Steatohepatitis.

IAVPGEVA, an octapeptide derived from soybean 11S globulin hydrolysis, also known as SGP8, has exhibited regulatory effects on lipid metabolism, inflammation, and fibrosis in vitro. Studies using MCD and HFD-induced nonalcoholic steatohepatitis (NASH) models in mice show that SGP8 attenuates hepatic injury and metabolic disorders. Mechanistic studies suggest that SGP8 inhibits the JNK-c-Jun pathway in L02 cells and liver tissue under metabolic stress and targets DPP4 with DPP4 inhibitory activity. In conclusion, the results suggest that SGP8 is an orally available DPP4-targeting peptide with therapeutic potential in NASH.

Experimental and theoretical studies for I⋯F, I⋯I and I⋯N intermolecular interactions Analysis in 5, 7-diiodoquinoline derivatives and their In-vitro DPP-4 inhibitory activity

5, 7-diiodoquinoline derivatives have been synthesized and characterized to study quantitative intermolecular noncovalent interactions through theoretical and experimental investigations, particularly for interactions involving electronegative atoms like I⋯F, I⋯I, and I⋯N. X-ray crystallography and Hirshfeld surface analysis have been used to perform the quantitative assessments of non-covalent interactions. Using Crystal Explorer 17, the calculations for intermolecular interactions were completed. Further, antidiabetic in-silico and in-vitro DPP-4 inhibitory activity have been done. The silicon studies have been carried out by Schrodinger on 2OLE pdb id. The in-vitro inhibitory DPP- 4 activity was determined by observing the rate of hydrolysis of a substrate Gly-pro-p-nitroanilide taking sitagliptin as a standard drug. The molecular docking and in-vitro studies revealed that all molecules had shown significant DPP-4 inhibitory activity compared to standard drugs sitagliptin.

Identification, rapid screening, docking mechanism and in vitro digestion stability of novel DPP-4 inhibitory peptides from wheat gluten with ginger protease.

To better understand the hypoglycemic potential of wheat gluten (WG), we screened dipeptidyl peptidase IV (DPP-4) inhibitory active peptides from WG hydrolysates. WG hydrolysates prepared by ginger protease were found to have the highest DPP-4 inhibitory activity among the five enzymatic hydrolysates, from which a 1-3 kDa fraction was isolated by ultrafiltration. Further characterization of the fraction with nano-HPLC-MS/MS revealed 1133 peptides. Among them, peptides with P'2 (the second position of the N-terminal) and P2 (the second position of the C-terminal) as proline residues (Pro) accounted for 12.44% and 43.69%, respectively. The peptides including Pro-Pro-Phe-Ser (PPFS), Ala-Pro-Phe-Gly-Leu (APFGL), and Pro-Pro-Phe-Trp (PPFW) exhibited the most potent DPP-4 inhibitory activity with IC50 values of 56.63, 79.45, and 199.82 μM, respectively. The high inhibitory activity of PPFS, APFGL, and PPFW could be mainly attributed to their interaction with the S2 pocket (Glu205 and Glu206) and the catalytic triad (Ser630 and His740) of DPP-4, which adopted competitive, mixed, and mixed inhibitory modes, respectively. After comparative analysis of PPFS, PPFW, and PPF, Ser was found to be more conducive to enhancing the DPP-4 inhibitory activity. Interestingly, peptides with P2 as Pro also exhibited good DPP-4 inhibitory activity. Meanwhile, DPP-4 inhibitory peptides from WG showed excellent stability, suggesting a potential application in type 2 diabetes (T2DM) therapy or in the food industry as functional components.

Mining Bovine Milk Proteins for DPP-4 Inhibitory Peptides Using Machine Learning and Virtual Proteolysis.

Dipeptidyl peptidase-IV (DPP-4) enzyme inhibitors are a promising category of diabetes medications. Bioactive peptides, particularly those derived from bovine milk proteins, play crucial roles in inhibiting the DPP-4 enzyme. This study describes a comprehensive strategy for DPP-4 inhibitory peptide discovery and validation that combines machine learning and virtual proteolysis techniques. Five machine learning models, including GBDT, XGBoost, LightGBM, CatBoost, and RF, were trained. Notably, LightGBM demonstrated superior performance with an AUC value of 0.92 ± 0.01. Subsequently, LightGBM was employed to forecast the DPP-4 inhibitory potential of peptides generated through virtual proteolysis of milk proteins. Through a series of in silico screening process and in vitro experiments, GPVRGPF and HPHPHL were found to exhibit good DPP-4 inhibitory activity. Molecular docking and molecular dynamics simulations further confirmed the inhibitory mechanisms of these peptides. Through retracing the virtual proteolysis steps, it was found that GPVRGPF can be obtained from β-casein through enzymatic hydrolysis by chymotrypsin, while HPHPHL can be obtained from κ-casein through enzymatic hydrolysis by stem bromelain or papain. In summary, the integration of machine learning and virtual proteolysis techniques can aid in the preliminary determination of key hydrolysis parameters and facilitate the efficient screening of bioactive peptides.

Discovery and Characterization of a Dual-Function Peptide Derived from Bitter Gourd Seed Protein Using Two Orthogonal Bioassay-Guided Fractionations Coupled with In Silico Analysis.

The hydrolysate of bitter gourd seed protein, digested by the combined gastrointestinal proteases (BGSP-GPs), exhibited the most potent inhibition on angiotensin-I-converting enzyme (ACE) with an IC50 value of 48.1 ± 2.0 µg/mL. Using two independent bioassay-guided fractionations, fraction F5 from reversed-phase chromatography and fraction S1 from strong cation exchange chromatography exhibited the highest ACE inhibitory (ACEI) activity. Three identical peptides were simultaneously detected from both fractions and, based on the in silico appraisal, APLVSW (AW6) was predicted as a promising ACEI peptide. Their dipeptidyl peptidase-IV (DPP4) inhibitory (DPP4I) activity was also explored. The IC50 values of AW6 against ACE and DPP4 were calculated to be 9.6 ± 0.3 and 145.4 ± 4.4 µM, respectively. The inhibitory kinetics and intermolecular interaction studies suggested that AW6 is an ACE competitive inhibitor and a DPP4 non-competitive inhibitor. The quantities of AW6 in BGSP-GP hydrolysate, fractions F5 and S1, were also analyzed using liquid chromatography-tandem mass spectrometry. Notably, AW6 could resist hydrolysis in the human gastrointestinal tract according to the result of the simulated gastrointestinal digestion. To the best of our knowledge, this is the first discovery and characterization of a dual-function (ACEI and DPP4I activities) peptide derived from bitter gourd seed protein.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, and Dose-Increasing Study on the Safety, Tolerability and PK/PD of Multiple Doses of HSK7653 by Oral Administration in Patients with Type 2 Diabetes Mellitus in China.

This study assessed the safety, tolerability, and PK/PD of HSK7653 tablets in Chinese patients with type 2 diabetes mellitus (T2DM). This was a Phase IIa, multicenter, randomized, double-blind, placebo-controlled, and dose-increasing study with 48 Chinese diabetes patients. Subjects were randomly assigned to placebo and 10/25/50mg dose groups, and they received oral administration once every two weeks for a total of six times. Safety and tolerability were assessed throughout this study, and PK/PD parameters were analyzed using non-compartment model with WinNonlin. The three doses of HSK7653 were well tolerated, and the incidence of TEAE and ADR was not significantly increased compared with the placebo group. Cmax increased linearly with the increasing dose, and the mean t1/2 was 64.0-87.0h. The first dose and last dose PK parameters were similar. After oral administration of 10-50mg HSK7653 every two weeks, the average Rac_Cmax and Rac_AUC were 0.9-1.0 and 1.0-1.1 respectively; therefore, HSK7653 was not accumulated in vivo. All three doses significantly inhibited DPP-4 activity and increased plasma GLP-1 level and serum insulin levels. When the plasma concentration of HSK7653 was ≥ 20.0ng/mL, the DPP-4 inhibition rate in all subjects was maintained at > 80.0%. In 10 and 25mg dose groups, the HbA1c levels maintained a downward trend compared with the placebo group. HSK7653 showed desirable pharmacokinetic and pharmacodynamic properties with good safety and tolerability in Chinese T2DM patients. DPP-4 inhibition rate and plasma GLP-1 levels were higher in each dose group than in placebo group. CTR20182505 (Drug Clinical Trial Registration and Information Disclosure Platform, www.chinadrugtrials.org.cn ).

Transepithelial Transport of the Bifunctional Peptide IPYWTY Indirectly Induced Insulin Release Mediated by Active GLP-1.

There is currently no appropriate cell model suitable for evaluating the insulinotropic effects of DPP-4 inhibitory peptides (DPP-4IPs) mediated by active glucagon-like peptide-17-36 (active GLP-1). The study aims to evaluate the transepithelial transport of IPYWTY on its in situ insulinotropic effects by using a 2D and dual-layered coculture cell model that consists of Caco-2 and NCI-H716 cells on the apical (AP) side and β-TC-6 cells on the basolateral (BL) side. During transportation, IPYWTY was absorbed in its intact form through PepT1 and paracellular transport. Meanwhile, it was degraded to several peptide fragments, including PYWTY, YWTY, WTY, and IPY, which decreased its in situ DPP-4 inhibitory activity. IPYWTY does not directly stimulate insulin release in β-TC-6 cells, while it increased the active GLP-1 level from 76.57 ± 15.16 to 95.63 ± 1.99 pM (1.25 times) in NCI-H716 cells. Interestingly, IPYWTY indirectly increased insulin levels from 426.91 ± 6.07 to 573.94 ± 2.97 μIU/mL (1.34 times) in the 2D and dual-layered coculture cell model for its dual function of stimulating active GLP-1 secretion and DPP-4 inhibition. These results suggested that the 2D and dual-layered coculture cell model is an alternative strategy for effectively evaluating the insulinotropic effects of DPP-4IPs mediated by active GLP-1.

Identification of Dipeptidyl-Peptidase 4 (DPP-4) Inhibitors from Miracle Berry Fruit (Synsepalum dulcificum) Extract

Dipeptidyl-peptidase 4 is a novel targeted enzyme in type 2 diabetes mellitus (T2DM) therapy due to its regulatory effect on incretin; glucagon-like peptide 1 (GLP-1) that responsible for stimulating insulin and suppressing glucagon secretion. DPP-4 degrades GLP-1 to biologically inactive fragments. In incretin-based therapies, DPP-4 inhibitor helps to restrain the inactivation of GLP-1, which in turn prolonging GLP-1’s half-life in blood and subsequently reducing the blood sugar more effectively. Nowadays, researchers are focusing to replace the synthetic drugs with natural-based drugs since they exert less toxicity. In our attempt to discover the natural inhibitor for DPP-4, miracle berry fruit was sequentially extracted with different solvents such as hexane, dichloromethane, chloroform, ethyl acetate and methanol and screened for the DPP-4 inhibitory activity. The analyses on the extractions show dichloromethane yielded the highest number of phenolic compounds with 38.37 mg GAE/g, while the highest number of flavonoids was found in hexane extract with 142.269 mg QE/g. On the other hand, qualitative analyses showed that methanol was able to extract alkaloids, terpenoids, saponins, tannins, quinones and carbohydrate from miracle berry fruit. It was also found that ethyl acetate extract was able to completely inhibit the enzyme. For further identification of constituent responsible for DPP-4 inhibitory activity, ethyl acetate extract was then subjected to silica gel column chromatography and eluted with different solvents with increasing polarity. The active fraction was then subjected to LC-MS/MS analysis and the results show it contains astragalin, nialamide, n-acetyl-l-phenylalanine, (+)-6-gingerol, 9-nitro oleate and 4(3H)-quinazolinone. The study indicates that miracle berry fruit extract contains natural DPP-4 inhibitor that can potentially be used for treating T2DM.

Discovery of imeglimin-inspired novel 1,3,5-triazine derivatives as antidiabetic agents in streptozotocin-induced diabetes in Wistar rats via inhibition of DPP-4.

Novel 1,3,5-triazine derivatives bearing oxazine have been synthesized and tested for their ability to inhibit a panel of dipeptidyl peptidase (DPP)-4, 8, and 9 enzymes. In a comparative inhibitory assay, the molecules showed potent inhibition of DPP-4 ranging from IC50 of 4.2 ± 0.30-260.5 ± 0.42 nM, with no activity against DPP-8 and DPP-9. Among the tested series, compound 8c demonstrated the strongest DPP-4 inhibitory activity with an IC50 of 4.2 ± 0.30 nM. It also showed the greatest binding affinity during docking studies with DPP-4 with a docking score of -8.956 and a glide energy of -78.546 kcal mol-1 and was found oriented in the S1 and S2 pockets of the DPP-4 active site, which is composed of the catalytic triad Ser 630, Asp 710, and His 740. The in vivo pharmacological assay revealed that compound 8c in a dose-dependent manner improved the insulin level, body weight, antioxidants, and HDL, and reduced the levels of blood glucose, LDL, and VLDL in streptozotocin-induced diabetes in Wistar rats. Our study demonstrated the discovery and development of novel 1,3,5-triazine derivatives bearing oxazine as a novel class of anti-diabetic agents via inhibition of DPP-4.

Lead modification via computational studies: Synthesis of pyrazole-containing β-amino carbonyls for the treatment of type 2 diabetes.

This article describes studies on the design, synthesis, and biological evaluation of pyrazole-containing β-amino carbonyl compounds (5a-5q) as DPP-4 inhibitors and anti-diabetic agents. In contrast, mannich reactions went smoothly with bismuth nitrate (Bi (NO3 )3 ) catalyst in the presence of ethanol and produced pyrazole-containing β-amino carbonyl compounds in good yield. Molecular docking studies of designed derivatives with DPP-4 enzyme (PDB: 2OLE), compounds 5d, 5h, 5j, and 5k showed excellent interaction. 3D QSAR and pharmacophoric model studies were also carried out. ADMET parameters, pharmacokinetic properties, and in vivo toxicity studies further confirmed that all the designed compounds were found to have good bioavailability and were less toxic. Further, these compounds were evaluated as enzyme-based in vitro DPP-4 inhibitory activity, and 5d, 5h, 5i, 5j, and 5k exhibited IC50 toward DPP-4 enzyme of 10.52, 10.41, 5.55, 4.16, and 7.5nM, respectively. The most potent compound, 5j, was further selected for in vivo anti-diabetic activity using an STZ-induced diabetic mice model, and 5j showed a significant diabetic control effect.

In vitro evaluation of 2-pyrazoline derivatives as DPP-4 inhibitors

Abstract Objectives In this study, the synthesis of three pyrazoline derivatives and the evaluation of their inhibitory effects on dipeptidyl peptidase (DPP-4) were aimed. Methods Pyrazoline-based compounds (1–3) were obtained via the reaction of 1-(2-furyl)-3-(1,3-benzodioxol-5-yl)-2-propen-1-one with 4-substituted phenylhydrazine hydrochloride. The DPP-4 inhibitory effects of compounds 1–3 were determined with a fluorometric assay using Gly-Pro-aminomethylcoumarin as the fluorogenic substrate. The cytotoxicity of compounds 1–3 on L929 mouse fibroblast (healthy) cell line was evaluated using MTT assay. Results 1-(4-Methylsulfonylphenyl)-3-(2-furyl)-5-(1,3-benzodioxol-5-yl)-2-pyrazoline (2) exhibited the highest DPP-4 inhibitory activity (IC50=5.75 ± 0.35 µM). Moreover, compound 2 exerted no significant cytotoxicity against L929 cells (IC50=34.33 ± 7.09 µM). Conclusions Target compounds exhibited moderate DPP-4 inhibitory activity and compound 2 was identified as the most active compound.

Synthesis of Novel 1,2,3-Triazole Derivatives of Tolbutamide and Evaluation of Their Antibacterial, Antioxidant, and DPP-4 Inhibitory Activity

Synthesis of Novel 1,2,3-Triazole Derivatives of Tolbutamide and Evaluation of Their Antibacterial, Antioxidant, and DPP-4 Inhibitory Activity

Amelioration of intracerebroventricular streptozotocin-induced cognitive dysfunction by Ocimum sanctum L. through the modulation of inflammation and GLP-1 levels.

DPP-4 inhibitors have been shown to reverse amyloid deposition in Alzheimer's disease (AD) patients with cognitive impairment. Ocimum sanctum L. leaves reported the presence of important phytoconstituents which are reported to have DPP-4 inhibitory activity. To investigate the effects of petroleum ether extract of Ocimum sanctum L. (PEOS) in Intracerebroventricular streptozotocin (ICV-STZ) induced AD rats. ICV-STZ (3mg/kg) was injected bilaterally into male Wistar rats, while sham animals received the artificial CSF. The ICV-STZ-induced rats were administered with three doses of PEOS (100, 200, and 400mg/kg, p.o.) for thirty days. All experimental rats were subjected to behaviour parameters (radial arm maze task and novel object recognition test), neurochemical parameters such as GLP-1, Aβ42, and TNF-α levels, and histopathological examination (Congo red staining) of the left brain hemisphere. PEOS significantly reversed the spatial learning and memory deficit exhibited by ICV-STZ-induced rats. Furthermore, PEOS also shows promising results in retreating Aβ deposition, TNF α, and increasing GLP-1 levels. The histopathological study also showed a significant dose-dependent reduction in amyloid plaque formation and dense granule in PEOS -treated rats as compared to the ICV-STZ induced rats (Negative control). The results show that extract of Ocimum sanctum L. attenuated ICV-STZ-induced learning and memory deficits in rats and has the potential to be employed in the therapy of AD.

Click inspired novel pyrazole-triazole-persulfonimide & pyrazole-triazole-aryl derivatives; Design, synthesis, DPP-4 inhibitor with potential anti-diabetic agents

This work presented the first report on designing, synthesizing of novel pyrazole-triazole-persulfonimide (7a-i) and pyrazole-triazole-aryl derivatives (8a-j) via click reaction using CuI catalyst and evaluated for their anti-diabetic activity and DPP-4 inhibitory effect. Click reactions went smoothly with CuI catalyst in the presence of tridentate chelating ligands and produced copper-free target pyrazole-triazole-persulfonimide analogues in excellent yield at RT. The designed compounds were docked against DPP-4 enzyme and showed excellent interaction with active amino acids residue. Further, all novel pyrazole-triazole-persulfonimide and pyrazole-triazole derivatives were subjected to enzyme-based in vitro DPP-4 inhibitory activity. Based on the SAR study DPP-4 inhibitory capacity compounds 7f (9.52 nM) and 8h (4.54 nM) possessed the significant inhibition of DPP-4. Finally compounds 7f and 8h were evaluated for their in vivo anti-diabetic activity using STZ induced diabetic mice model, and 8h showed a significant diabetic control effect compared to the sitagliptin drug. These studies demonstrated that the novel pyrazole-triazole-persulfonimide and pyrazole-triazole-aryl derivatives might be used as the leading compounds to develop novel DPP-4 inhibitors as potential anti-diabetic agents.

Evaluation of Antidiabetic Activity of Rosmarinus officinalis var. prostratus Growing in Syria in Alloxan Diabetic Rats

Background: The genus of Rosmarinus officinalis (Rosemary) is found in many parts of the world. Traditionally, Rosemary has been used in traditional medicine due to its therapeutic virtues and its ability to treat some diseases. Rosmarinus officinalis var. prostrates grows in the Al Kalamoon region of Syria but only a limited amount of scientific research on the medicinal uses of this plant has been done. This study focused on the medicinally active substances found in ethanolic extract of the leaves and flowers of this plant and their antidiabetic effect in alloxan-induced diabetic rats. First, an acute toxicity study was carried out to detect the optimal dose of the Rosmarinus officinalis var. prostrates extract. Then, the effect of the optimal dose of 300mg/kg was measured over 36 days. Method: During the study, diabetic rats were treated with different doses of extract (100, 200, 300, 400, 500, and 600 mg/kg). The percentage of fasting blood glucose (FBG) was measured immediately after administration of the extract and at 2h, 4h and 8h after administration. The dose of 300mg/kg was then used in the second part of the study, which involved four groups of rats: a healthy group, a diabetic group without treatment (the control group), a diabetic group treated with 300mg/kg of extract, and a diabetic group treated by metformin (50mg/kg). The treatment continued for 36 days. Results: The results showed that the extract was rich with flavonoids, phenols and tannins. Levels of FBG and DPP-4 were significantly lower in the extract-treated group in comparison with the control group; however, the level of insulin was significantly elevated in the extract-treated group compared to the control group. This effect may be caused by two factors. First, the antioxidant effects of flavonoids which protect pancreatic beta cells from damage caused by alloxan, supports regeneration of pancreatic beta cells, and therefore insulin production. Second, the inhibition of DPP-4 activity, which in turn leads to increased secretion of insulin. Conclusion: The ethanolic extract of Rosmarinus officinalis var. prostrates has an antidiabetic effect.