Immunohistochemical, apoptotic and biochemical changes by dipeptidyl peptidase-4 inhibitor-sitagliptin in type-2 diabetic rats

Karabulut, Sezin; Coşkun, Zeynep Mine; Bolkent, Şehnaz

doi:10.1016/j.pharep.2015.01.010

Cited by 11 publications

(7 citation statements)

References 46 publications

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“…We showed that MDA formation was reduced after STG treatment also in livers subjected to IR. However, without pathology such as IR or diabetes, STG seems to have an opposite effect and increase the accumulation of TBARS, what was also noticed by other authors [29, 43].…”

Section: Discussionsupporting

confidence: 76%

“…These observations may imply that beneficial effects of drug are displayed solely in the presence of an additional factor increasing the oxidative stress. IR is another condition, in which STG treatment has been associated with improved antioxidant status both at systemic level [29] and locally in myocardium [24], kidney [28], and hippocampus [30]. In our work, carried out on rat livers, the protective effect of STG was visible only under IR conditions.…”

Section: Discussionmentioning

confidence: 66%

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Sitagliptin-Dependent Differences in the Intensity of Oxidative Stress in Rat Livers Subjected to Ischemia and Reperfusion

Trocha

Krzystek−Korpacka

Merwid-Ląd

et al. 2019

Oxidative Medicine and Cellular Longevity

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Purpose Ischemia/reperfusion (IR) is the main cause of liver damage after transplantation. We evaluated the effect of sitagliptin (STG) on oxidative stress parameters in the rat liver under IR. Methods Rats were treated with STG (5 mg/kg) (S and SIR) or saline solution (C and CIR). Livers from CIR and SIR were subjected to ischemia (60 min) and reperfusion (24 h). During reperfusion, aminotransferases (ALT and AST) were determined in blood samples. Thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), paraoxonase-1 (PON1), glutathione peroxidase (GPx), and the mRNA expression of SOD1 were determined in liver homogenates after reperfusion. Different regions of livers were also histologically evaluated. Results The PON1 activity was higher, and the TBARS level was lower in SIR than in CIR. There was an inverse relationship between TBARS and PON1 levels in the whole cohort. The GPx activity was lower in ischemic than in nonischemic groups regardless of the STG treatment. In SIR, the SOD1 activity was higher compared to that in CIR. In S, the expression of SOD1 mRNA was the highest of all examined groups and positively correlated with the SOD1 activity in the whole animal cohort. During IR aminotransferases, the activity in the drug-treated group was lower in all examined points of time. In drug-treated groups, the percentage of steatosis was higher than that in nontreated groups regardless of IR. Conclusions The protective effect of STG on the rat liver, especially its antioxidant properties, was revealed under IR conditions.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 66%

Sitagliptin-Dependent Differences in the Intensity of Oxidative Stress in Rat Livers Subjected to Ischemia and Reperfusion

Trocha

Krzystek−Korpacka

Merwid-Ląd

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…This finding is consistent with previous investigations that reported the antiapoptotic effects of sitagliptin. 10,51,52 Finally, sitagliptin is a new anti-diabetic agent that has many advantages over other hypoglycemic agents as weight neutral and a low risk of hypoglycemia as well as lack of drug interactions. Until now no limitation has been reported concerning the use of sitagliptin.…”

Section: Discussionmentioning

confidence: 99%

“…This finding is consistent with previous investigations that reported the antiapoptotic effects of sitagliptin. 10,51,52…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats

El‐Agamy

Abo‐Haded

Elkablawy

2016

Exp Biol Med (Maywood)

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There is a large body of evidence suggesting that inhibitors of dipeptidyl peptidase-4, such as sitagliptin, may exhibit beneficial effects against different inflammatory disorders. This investigation was conducted to elucidate the potential ability of sitagliptin to counteract the injurious effects of doxorubicin in cardiac tissue. Male Wistar rats were pretreated with sitagliptin for 10 days then treated with a single dose of doxorubicin (20 mg/kg, i.p). Electrocardiography, biochemical estimation of serum and tissue markers, and histo-and immunopathological examinations were done. Results have shown that supplementation with sitagliptin resulted in significant improvement of cardiac function with contaminant decrease in serum markers of doxorubicin-induced cardiotoxicity. These results were supported by the histopathological results. Furthermore, a marked protection against oxidative stress was evident through reduction of lipid peroxidation and prevention of reduced glutathione content depletion and superoxide dismutase activity reduction in cardiac tissue of rats pretreated with sitagliptin in combination with doxorubicin. Moreover, sitagliptin ameliorated the activation of nuclear factor kappa-B and the release of inflammatory cytokines, tumour necrosis factoralpha and nitric oxide. Finally, sitagliptin attenuated doxorubicin-induced increase in the expression of pro-apoptotic protein Bax and in the apoptotic marker, caspase-3. Collectively, these data indicate that sitagliptin pretreatment could alleviate doxorubicininduced cardiotoxicity via reducing oxidative damage and its subsequent inflammation and apoptosis.

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“…Serum glutathione levels did not change in either group. Glutathione conjugated metabolites were not detected in our study [20], however, the N-oxide metabolite needs further study to fully characterise its pharmacological/toxicological effects. …”

Section: Biotransformation Of Stg In Sprague-dawley Rat Hepatocytesmentioning

confidence: 55%

Identification of Novel Metabolic Pathways of Sitagliptin (STG) by LC/MS and LC/MS2 after Incubations with Rat Hepatocytes

Khreit¹,

Grant²,

Henderson³

et al. 2016

J Drug Metab Toxicol

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Sitagliptin (STG), a drug for treating Type Ii Diabetes Mellitus (T2DM), has been associated with severe joint pain in some patients. In this paper the metabolic profile of the drug has been investigated in order to determine metabolism and formation of reactive compounds which may contribute to this adverse effect. Metabolism of STG was investigated in vitro by incubation with freshly isolated Sprague-Dawley rat hepatocytes, to characterize Phase I and II metabolites, and the reaction mixture analysed on a zwitter ionic hydrophilic interaction (ZIC ® -HILIC) column using LC-MS and LC-MS 2 utilising electrospray ionization (ESI) in the positive ion mode.STG was metabolised to yield eleven metabolites, but in total only 3.1% of the parent drug was metabolised over 2 hrs incubation. These metabolites were structurally characterized on the basis of accurate mass analyses and the major metabolic routes for STG determined to be via aromatic oxidation (0.86%) and desaturation of N-C and C-C of the piperazine (0.44%).Novel metabolites of STG detected using these methods included STG N-glucuronide (M6) and a di-ketone metabolite (M4), hydroxylation of both the amine group and aromatic ring followed by formation of glucuronide metabolites (M5, M5'), oxidative desaturation of NH 2 and di-hydroxylation of metabolites followed by loss of HF.Also, observed was an N-sulfate metabolite (0.07%) and acetylation followed by glucuronide conjugation was also found in trace amounts (<0.01%). MS 2 fragment ions provide additional structural confirmation providing a possible structure for most metabolites such as by fragment ion loss of the glucuronide group (176 Da) from metabolite M5 and loss of the phenolic sulfate (80 Da) of N-Sulfate metabolite (M7).Reduction reaction of piperazine ring probably generates highly electrophilic metabolite of STG, which may be susceptible to produce adverse effects. Furthermore, N-oxidation reaction forming reactive intermediates metabolic to give a hydroxylamine metabolite that may undergo further reactions to yield electrophilic intermediate metabolites.

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Immunohistochemical, apoptotic and biochemical changes by dipeptidyl peptidase-4 inhibitor-sitagliptin in type-2 diabetic rats

Abstract: According to our findings, sitagliptin may be a useful therapeutic agent to a certain extent of type-2 diabetic condition.

Cited by 11 publications

References 46 publications

Sitagliptin-Dependent Differences in the Intensity of Oxidative Stress in Rat Livers Subjected to Ischemia and Reperfusion

Sitagliptin-Dependent Differences in the Intensity of Oxidative Stress in Rat Livers Subjected to Ischemia and Reperfusion

Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats

Identification of Novel Metabolic Pathways of Sitagliptin (STG) by LC/MS and LC/MS2 after Incubations with Rat Hepatocytes

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