scholarly journals TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1153 ◽  
Author(s):  
Daisuke Kaya ◽  
Kosuke Kaji ◽  
Yuki Tsuji ◽  
Satoko Yamashita ◽  
Koh Kitagawa ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Proliferative Potential ◽  
Fecal Microbiome ◽  
Dipeptidyl Peptidase 4 ◽  
Porcine Serum ◽  
Novel Strategy ◽  
G Protein Coupled

Hyperglycemia and hyperinsulinemia activate the proliferative potential of hepatic stellate cells (HSCs) and promote hepatic fibrosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic agents, reportedly inhibit the HSC proliferation. Additionally, Takeda G protein-coupled receptor 5 (TGR5) agonists induce the systemic release of glucagon-like peptides from intestinal L cells, which maintains glycemic homeostasis. This study assessed the combined effect of TGR5 agonist and DPP-4 inhibitor on diabetes-based liver fibrosis development. Male diabetic rats received intraperitoneal injection of porcine serum (PS) to induce liver fibrosis, and they were orally administered the following agents: oleanolic acid (OA) as a TGR5 agonist, anagliptin (ANA) as a DPP-4 inhibitor, and a combination of both agents. Treatment with OA or ANA significantly improved glycemic status and attenuated intrahepatic steatosis and lipid peroxidation in diabetic rats. PS-induced liver fibrosis development was also drastically suppressed by treatment with either agent, and the combination of both reciprocally enhanced the antifibrotic effect. Fecal microbiome demonstrated that both agents inhibited the increase in the Firmicutes/Bacteroidetes ratio, an indicator of dysbiosis related to metabolic syndromes. Furthermore, ANA directly inhibited in vitro HSC proliferative and profibrogenic activities. Collectively, TGR5 agonist and DPP-4 inhibitor appears to be a novel strategy against liver fibrosis under diabetic conditions.

scholarly journals Rationally designed chemokine-based toxin targeting the viral G protein-coupled receptor US28 potently inhibits cytomegalovirus infection in vivo

2015 ◽  
Vol 112 (27) ◽  
pp. 8427-8432 ◽  
Author(s):  
Katja Spiess ◽  
Mads G. Jeppesen ◽  
Mikkel Malmgaard-Clausen ◽  
Karen Krzywkowski ◽  
Kalpana Dulal ◽  
...  
Keyword(s):  
G Protein ◽  
Pseudomonas Exotoxin ◽  
Viral Pathogen ◽  
Virus Origin ◽  
Ligand Interactions ◽  
Toxin Protein ◽  
Novel Strategy ◽  
G Protein Coupled

The use of receptor–ligand interactions to direct toxins to kill diseased cells selectively has shown considerable promise for treatment of a number of cancers and, more recently, autoimmune disease. Here we move the fusion toxin protein (FTP) technology beyond cancer/autoimmune therapeutics to target the human viral pathogen, human cytomegalovirus (HCMV), on the basis of its expression of the 7TM G protein-coupled chemokine receptor US28. The virus origin of US28 provides an exceptional chemokine-binding profile with high selectivity and improved binding for the CX3C chemokine, CX3CL1. Moreover, US28 is constitutively internalizing by nature, providing highly effective FTP delivery. We designed a synthetic CX3CL1 variant engineered to have ultra-high affinity for US28 and greater specificity for US28 than the natural sole receptor for CX3CL1, CX3CR1, and we fused the synthetic variant with the cytotoxic domain of Pseudomonas Exotoxin A. This novel strategy of a rationally designed FTP provided unparalleled anti-HCMV efficacy and potency in vitro and in vivo.

Phytochemical Screening and Anti-Diabetic Efficacy of O. Sanctum Seed Extract on Streptozotocin Induced Diabetic Rats

2017 ◽  
Vol 54 (3) ◽  
pp. 336
Author(s):  
Kavitha K. ◽  
Ponne S.
Keyword(s):  
Body Weight ◽  
Digestive Enzymes ◽  
Fasting Blood Glucose ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Seed Extract ◽  
Phytochemical Screening ◽  
Weight Changes

The present study was designed to assess the in vitro and in vivo anti-diabetic efficacy of <em>O. sanctum</em> seed and its phytochemical screening. In vitro inhibitory effect on carbohydrate digestive enzymes like α-amylase and α-glucosidase and in vivo parameters such as fasting blood glucose and body weight changes were studied, a potent inhibitory effect was observed on activities of digestive enzymes and a marked decrease in the glucose level in the <em>O. sanctum</em> seed extract treated streptozotocin induced diabetic rats was noted. Further a marked reduction in body weight was also observed.

scholarly journals α-Glucosidase Inhibitory, Anti-Oxidant, and Anti-Hyperglycemic Effects of Euphorbia nivulia–Ham. in STZ-Induced Diabetic Rats

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582093942
Author(s):  
Muhammad Younus ◽  
Muhammad Mohtasheem ul Hasan ◽  
Khalil Ahmad ◽  
Ali Sharif ◽  
Hafiz Muhammad Asif ◽  
...  
Keyword(s):  
High Performance ◽  
Wistar Rat ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
In Vivo Studies ◽  
Control Group ◽  
Control Drug ◽  
Antidiabetic Effects

In this study, we aimed to investigate the antidiabetic effects of Euphorbia nivulia (En), native to Cholistan Desert area of Bahawalpur, Pakistan. First, we performed high-performance liquid chromatography analysis and found that this plant contains ferulic acid, gallic acid, quercetin, benzoic acid, polyphenols, and flavonoids. Then, we performed in vitro and in vivo studies to assess its effects on diabetic Wistar rat model. The experiments were performed and compared with control drug glibenclamide. The 70% hydroalcoholic extract of En exhibited 97.8% in vitro α-glucosidase inhibitory effect at a dose of 1.0 mg/mL. We orally administered the extract of En and control drug to the streptozotocin (STZ)-induced diabetic rats and analyzed its antidiabetic effects. We found that the extract of En with a dose of 500 mg/kg/body weight exhibited significant effect to reduce blood glucose in STZ-induced rats as compared with the control group ( P < .001). Our histological data also showed that the extract significantly improved the histopathology of pancreas. Collectively, both in vitro and in vivo studies revealed that En possesses α-glucosidase inhibitory, antioxidant, and anti-hyperglycemic effect in STZ-induced diabetic rats.

scholarly journals GRK Inhibition Potentiates Glucagon-Like Peptide-1 Action

2021 ◽  
Vol 12 ◽  
Author(s):  
Seunghun P. Lee ◽  
Jenson Qi ◽  
Guozhang Xu ◽  
Matthew M. Rankin ◽  
James Littrell ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptor ◽  
Dipeptidyl Peptidase 4 ◽  
Receptor Kinases ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Receptor Interacting Proteins ◽  
G Protein Coupled

The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and β-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated β-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R function in vitro and in vivo. GRK inhibition is a potential therapeutic approach to enhance endogenous and pharmacologically stimulated GLP-1R signaling.

scholarly journals In vivo and in vitro antidiabetic properties of alkaloids extract from Salvia chudaei

2021 ◽  
pp. 45-53
Author(s):  
Mohammed Tlili ◽  
Roukia Hammoudi ◽  
Mahfoud Hadj-Mahammed
Keyword(s):  
Blood Glucose ◽  
Lipid Profile ◽  
Kidney Function ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Albino Rats ◽  
Liver And Kidney ◽  
Mean Blood Glucose

The aim of this study was to evaluate, for the first time, the antidiabetic effect of the alkaloids extract of Salvia chudaei Batt. & Trab. (Lamiaceae) on alloxan-induced diabetic rats. The alkaloids extract was prepared, and the in vitro inhibitory effect of key digesting enzymes related to postprandial hyperglycemia were determined. After acute toxicity test, the Swiss albino rats were induced with alloxan to get experimental diabetes animals. The fasting mean blood glucose, lipid profile, different liver and kidney function biomarkers and antioxidant biomarkers levels, after treatment for 30 days, diabetic untreated and diabetic rats treated with alkaloids extract were estimated. The alkaloids displayed remarkable in inhibiting ?-glucosidase (IC50 = 248.25?2.61 ?g/ml) than ?-amylase (IC50 = 262.96?9.64 ?g/ml) activities. In vivo, the results proved that alkaloids extract at dose of 500 mg/kg bw decreased significantly the blood glucose, lipid profile levels and improved the liver and kidney function biomarkers and increased the activities of antioxidant enzymes (superoxide dismutase and gluthatione reductase). This study demonstrates, that alkaloids are effective in inhibiting hyperglycemia and oxidative stress caused by diabetes.

scholarly journals Inhibitory Effect of the Leaf of Psidium guajava Grown in Vietnam on α-Glucosidase and Protein Tyrosine Phosphatase 1B in vitro

2019 ◽  
Vol 35 (1) ◽  
Author(s):  
Dang Kim Thu ◽  
Le Thi Thu Huong ◽  
Tran Trong Nghia ◽  
Bui Thanh Tung
Keyword(s):  
Type 2 Diabetes ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Psidium Guajava ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine

Type 2 diabetes is a fairly common chronic disease. α-glucosidase and protein tyrosine phosphatase, as enzymes, play an important role in type 2 diabetes. This study evaluates the inhibitory effect of the two enzymes in vitro of ethanol extract and fractions of Vietnam Psidium guajava’s leaves. The leaves were collected, dried and extracted with 96% ethanol and successively fractionated with n-hexane, ethyl acetate and butanol solvents. The results show that the EtOH extract, n-nexan, EtOAc and BuOH fractions had high α-glucosidase inhibitory effect with IC50 values ​​of 2.20; 2.53; 2.24 and 2.16 µg/mL, respectively. In addition, EtOAc and BuOH fractions also show strong inhibitory PTP1B effect with IC50 at 120.22 mg/mL and 97.72 mg/mL, respectively. The study results show that Psidium guajava leaves are a potential source of material to inhibit α-glucosidase and PTP1B in the treatment of diabetes. Keywords Psidium guajava, α-glucosidase, protein tyrosine phosphatase 1B, diabetes, extraction. References [1] A. Chaudhury, C. Duvoor, R. Dendi, V. Sena, S. Kraleti, A. Chada, et al. Clinical review of antidiabetic drugs: Implications for type 2 diabetes mellitus management, Frontiers in endocrinology. 8 (2017) 6.[2] F.A. Van de Laar, P.L. Lucassen, R.P. Akkermans, E. H. Van de Lisdonk, G.E. Rutten,C. Van, Alpha - glucosidase inhibitors for type 2 diabetes mellitus. The Cochrane Library (2005).[3] J. Montalibet, B.P. Kennedy. Therapeutic strategies for targeting PTP1B in diabetes. Drug Discovery Today: Therapeutic Strategies 2(2) (2005) 129.[4] S.M. Barbalho, Farinazzi-Machado, R. De Alvares Goulart, A.C.S. Brunnati, A. Otoboni, B. Ottoboni. Psidium guajava (Guava): A plant of multipurpose medicinal applications, Med Aromat Plants. 1(104) (2012) 2167.[5] R.M.P. Gutiérrez, S. Mitchell, Solis R. V. Psidium guajava: a review of its traditional uses, phytochemistry and pharmacology. Journal of ethnopharmacology 117(1) (2008) 1.[6] B. T. Tùng, Đ.K. Thu, P.T. Hải, N.T. Hải. Đánh giá tác dụng ức chế enzym α-glucosidase của các phân đoạn dịch chiết quả Lựu (Punica granatum Linn), Tạp chí Y Dược cổ truyền Việt Nam. 5(18) (2018) 59.[7] P.H. Nguyen, J.L. Yang, M.N. Uddin, S.L. Park, S.I. Lim, D.W. Jung, et al. Protein tyrosine phosphatase 1B (PTP1B) inhibitors from Morinda citrifolia (Noni) and their insulin mimetic activity, Journal of natural products. 76(11) (2013) 2080.[8] H.B.H. Khan, D. Rajendran, M.R. Bai, Sorimuthu S. Protective effect of Psidium guajava leaf extract on altered carbohydrate metabolism in streptozotocin-induced diabetic rats, Journal of dietary supplements. 10(4) (2013) 335.[9] H. Mukhtar, S. Ansari, M. Ali, T. Naved, Z. Bhat Effect of water extract of Psidium guajava leaves on alloxan-induced diabetic rats. Die Pharmazie-An International Journal of Pharmaceutical Sciences. 59(9) (2004) 734.[10] W. K. Oh, C. H. Lee, M. S. Lee, E. Y. Bae, C. B. Sohn, H. Oh, et al. Antidiabetic effects of extracts from Psidium guajava, Journal of ethnopharmacology. 96(3) (2005) 411.[11] B. Wang, H. Liu, J. Hong, H. Li, C. Huang, Effect of Psidium guajava leaf extract on alpha-glucosidase activity in small intestine of diabetic mouse. Sichuan da xue xue bao Yi xue ban, Journal of Sichuan University Medical science edition. 38(2) (2007) 298.[12] S. C. Shen, F. C. Cheng, N. J. Wu. Effect of guava (Psidium guajava Linn.) leaf soluble solids on glucose metabolism in type 2 diabetic rats, Phytotherapy Research. 22(11) (2008) 1458.      

In vitro effect of D-myo-inositol 1,2,6-trisphosphate (PP-56) on aggregation of platelets from normal and diabetic rats: relationship to malondialdehyde release and phosphoinositide pathway

1994 ◽  
Vol 72 (6) ◽  
pp. 644-649 ◽  
Author(s):  
J. C. Ruf ◽  
M. Ciavatti ◽  
T. Gustafsson ◽  
S. Renaud
Keyword(s):  
Platelet Aggregation ◽  
Inositol Phosphates ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Term Administration ◽  
In Vitro Effects ◽  
Vitro Effect ◽  
Induced Aggregation

In the present study, we investigated the in vitro effects of D-myo-inositol 1,2,6-trisphosphate (PP-56) on platelets from normal and streptozotocin-induced diabetic rats. PP-56 markedly inhibited aggregation, in a dose-related manner, when added in vitro, more efficiently with thrombin- than with ADP-induced aggregation and, after 90 min incubation, more in diabetic than in normal platelets. The PP-56 platelet inhibitory effect seems to be related to its phosphate content. PP-56 blocked the release of malondialdehyde from erythrocytes, but to the same extent in normal and diabetic rats. PP-56, after 20 min incubation, restored the platelet phosphoinositide turnover, which was significantly modified in diabetic rats. This last observation could explain at least part of the specificity of PP-56 for normalizing platelet aggregation in diabetic animals after long-term administration in vivo.Key words: inositol phosphates, platelet aggregation, streptozotocin-induced diabetic rats.

scholarly journals Phytochemical Screening and Antidiabetic, Antihyperlipidemic, and Antioxidant Properties ofAnthyllis henoniana(Coss.) Flowers Extracts in an Alloxan-Induced Rats Model of Diabetes

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Ameur Ben Younes ◽  
Maryem Ben Salem ◽  
Hanen El Abed ◽  
Raoudha Jarraya
Keyword(s):  
Antioxidant Activity ◽  
Ethyl Acetate ◽  
Ethyl Acetate Extract ◽  
Biological Activities ◽  
Antioxidant Properties ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Histological Results

Background. This study investigates the biological activities ofAnthyllis henonianaflowers extracts.Materials and Methods. Antioxidant activity and thein vitroinhibitory effect of key digesting enzymes related to postprandial hyperglycemia were determined. Diabetic rats were orally and daily given the best extract from flowers ofAnthyllis henonianaat a dose of acarbose for one month.Results. Among the extracts, the ethyl acetate one displayed remarkable antioxidant activity including DPPH (IC50= 2.34 mg/mL) and was more effective in inhibitingα-glucosidase (IC50= 17μg/mL) thanα-amylase (IC50= 920μg /mL) activities.In vivo, the results proved that ethyl acetate extract at doses of 400 mg/kg bw decreased significantly the blood glucose level and lipid profile levels and increased the activities of antioxidant enzymes. These protective impacts ofAnthyllis henonianaethyl acetate flowers extract were confirmed by histological results.Conclusion. This study demonstrates, for the first time, thatAnthyllis henonianaflowers ethyl acetate extract is effective in inhibiting hyperglycemia and oxidative stress caused by diabetes.

Pentoxifylline inhibits Ca2+-dependent and ATP proteasome-dependent proteolysis in skeletal muscle from acutely diabetic rats

2007 ◽  
Vol 292 (3) ◽  
pp. E702-E708 ◽  
Author(s):  
Amanda Martins Baviera ◽  
Neusa Maria Zanon ◽  
Luiz Carlos Carvalho Navegantes ◽  
Renato Hélios Migliorini ◽  
Isis do Carmo Kettelhut
Keyword(s):  
Protein Degradation ◽  
Muscle Protein ◽  
Phosphodiesterase Inhibitor ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Camp Phosphodiesterase ◽  
Camp Content ◽  
Muscle Protein Degradation ◽  
Vitro Effect

Previous studies from this laboratory have shown that catecholamines exert an inhibitory effect on muscle protein degradation through a pathway involving the cAMP cascade. The present work investigated the systemic effect of pentoxifylline (PTX; cAMP-phosphodiesterase inhibitor) treatment on the rate of overall proteolysis, the activity of proteolytic systems, and the process of protein synthesis in extensor digitorum longus muscles from normal and acutely diabetic rats. The direct in vitro effect of this drug on the rates of muscle protein degradation was also investigated. Muscles from diabetic rats treated with PTX showed an increase (22%) in the cAMP content and reduction in total rates of protein breakdown and in activity of Ca2+-dependent (47%) and ATP proteasome-dependent (23%) proteolytic pathways. The high content of m-calpain observed in muscles from diabetic rats was abolished by PTX treatment. The addition of PTX (10−3 M) to the incubation medium increased the cAMP content in muscles from normal (22%) and diabetic (51%) rats and induced a reduction in the rates of overall proteolysis that was accompanied by decreased activity of the Ca2+-dependent and ATP proteasome-dependent proteolytic systems, in both groups. The in vitro addition of H-89, an inhibitor of protein kinase A (PKA), completely blocked the effect of PTX on the reduction of proteolysis in muscles from normal and diabetic rats. The present data suggest that PTX exerts a direct inhibitory effect on protein degradative systems in muscles from acutely diabetic rats, probably involving the participation of cAMP intracellular pathways and activation of PKA, independently of tumor necrosis factor-α inhibition.

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