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Document Type

Dissertation - University Access Only

Award Date

2015

Degree Name

Doctor of Philosophy (PhD)

Department / School

Pharmaceutical Sciences

Abstract

Thiols are an important component of the body’s antioxidant defense mechanism. Thiols are oxidized to disulfides when exposed to free radicals. Disulfides are subsequently reduced to their corresponding thiols by enzymes such as thioredoxin reductase (TrxR) and glutathione reductase (GR). Thiol redox state (TRS) is expressed as the ratio of thiols to disulfides within the cell. An imbalance in TRS results in a damaging condition known as thiol oxidative stress. Thiol oxidative stress has been implicated in a variety of cardiovascular diseases. Carvedilol is a β-blocker used in treatment of cardiovascular diseases such as heart failure. It possesses antioxidant properties; however, the exact mechanism of antioxidant effect is unknown. Berberine is a natural product established in traditional Chinese medicine. It has been reported to have multiple effects including antidiabetic and anticancer activities. In this study, H9c2 rat cardiomyocytes were used to study the protective effects of carvedilol and berberine against thiol oxidative stress. Thiol oxidative stress was induced using two models. First, 1,3-bis-(2-chloroethyl)-1- nitrosourea (BCNU) was used to induce thiol oxidative stress through GR and TrxR inhibition. Doxorubicin, an anticancer agent that produces cardiotoxicity as a result of reactive oxygen species production, was used as the second model. xx BCNU exposure significantly increased protein disulfide content signaling induction of thiol oxidative stress; however, a combination of carvedilol and BCNU was able to lower protein disulfide content to control levels. This was correlated with an increase in TrxR activity. No change in GR activity was observed with the addition of carvedilol to BCNU treatment. Therefore, carvedilol may protect against thiol oxidative stress via the thioredoxin pathway. Berberine also protected against BCNU-induced cytotoxicity. Berberine lowered protein disulfide and GSSG content while increasing GSH. This was correlated with an increase in TrxR and GR activities. Pre-treatments with carvedilol and/or berberine followed by exposure to doxorubicin provided protective effects against doxorubicin-induced cardiotoxicity. Shorter exposure time to doxorubicin produced a more significant impact on maintaining TRS compared to longer treatments. In conclusion, berberine and carvedilol were able to protect against loss of cell viability under conditions of thiol oxidative stress through stabilization of cellular TRS.

Library of Congress Subject Headings

Thiols
Berberine
Oxidative stress
Antioxidants
Cardiovascular system--Diseases--Prevention

Description

Includes bibliographical references (pages 141-160)

Format

application/pdf

Number of Pages

181

Publisher

South Dakota State University

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Rights Statement

In Copyright