Apremilast reversed carfilzomib-induced cardiotoxicity through inhibition of oxidative stress, NF-κB and MAPK signaling in rats

IF 2.8 4区 医学 Q2 TOXICOLOGY
F. Imam, N. Al-Harbi, M. M. Al-Harbi, M. Ansari, Mashal M. Almutairi, M. Alshammari, T. S. Almukhlafi, M. Ansari, K. Aljerian, S. Ahmad
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引用次数: 40

Abstract

Abstract Carfilzomib (CFZ), is a potent, selective second generation proteasome inhibitor, used for the treatment of multiple myeloma. The aim of the present study was to investigate the possible protective effect of apremilast (AP) on the CFZ -induced cardiotoxicity. Rats were randomly divided into four groups: Group 1, served as the control group, received normal saline. Group 2, served as the toxic group, received CFZ (4 mg/kg, intraperitoneally [i.p.]). Groups 3 and 4, served as treatment groups, and received CFZ with concomitant oral administration of AP in doses of 10 and 20 mg/kg/day, respectively. In the present study, administration of CFZ resulted in a significant increase in serum aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase-MB (CK-MB), which were reversed by treatment with AP. CFZ resulted in a significant increase in heart malondialdehyde (MDA) contents and decrease in cardiac glutathione (GSH) level and catalase (CAT) enzyme activity which were significantly reversed by treatment with AP. Induction of cardiotoxicity by CFZ significantly increased caspase-3 enzyme activity which were reversed by treatment with AP. RT-PCR analysis revealed an increased mRNA expression of NF-κB, ERK and JNK which were reversed by treatment with AP in cardiac tissues. Western blot analysis revealed an increased expression of caspase-3 and NF-κB p65 and a decrease expression of inhibitory kappa B-alpha (Iκbα) with CFZ, which were reversed by treatment with AP. In conclusion, apremilast showed protective effect against CFZ-induced cardiotoxicity.
阿普雷米司特通过抑制氧化应激、NF-κB和MAPK信号传导逆转卡非佐米诱导的大鼠心脏毒性
Carfilzomib (CFZ)是一种有效的选择性第二代蛋白酶体抑制剂,用于治疗多发性骨髓瘤。本研究的目的是探讨阿普雷米司特(AP)对CFZ诱导的心脏毒性可能的保护作用。将大鼠随机分为四组:第一组为对照组,给予生理盐水;2组为中毒组,给予CFZ (4 mg/kg,腹腔注射)。第3组和第4组作为治疗组,给予CFZ治疗同时口服AP,剂量分别为10和20 mg/kg/d。在本研究中,给药CFZ导致血清天冬氨酸转氨酶(AST)、乳酸脱氢酶(LDH)、肌酸激酶(CK)和肌酸激酶- mb (CK- mb)显著升高。CFZ诱导大鼠心肌中丙二醛(MDA)含量显著升高,谷胱甘肽(GSH)水平和过氧化氢酶(CAT)活性显著降低,而AP诱导大鼠心肌毒性升高的caspase-3酶活性则显著升高,而AP诱导的caspase-3酶活性则明显升高。ERK和JNK在心脏组织中被AP逆转。Western blot分析显示,caspase-3和NF-κB p65在CFZ中表达升高,抑制κbα (i -κB α)表达降低,AP可逆转这一现象。由此可见,阿普米司特对CFZ诱导的心脏毒性具有保护作用。
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来源期刊
自引率
3.10%
发文量
66
期刊介绍: Toxicology Mechanisms and Methods is a peer-reviewed journal whose aim is twofold. Firstly, the journal contains original research on subjects dealing with the mechanisms by which foreign chemicals cause toxic tissue injury. Chemical substances of interest include industrial compounds, environmental pollutants, hazardous wastes, drugs, pesticides, and chemical warfare agents. The scope of the journal spans from molecular and cellular mechanisms of action to the consideration of mechanistic evidence in establishing regulatory policy. Secondly, the journal addresses aspects of the development, validation, and application of new and existing laboratory methods, techniques, and equipment. A variety of research methods are discussed, including: In vivo studies with standard and alternative species In vitro studies and alternative methodologies Molecular, biochemical, and cellular techniques Pharmacokinetics and pharmacodynamics Mathematical modeling and computer programs Forensic analyses Risk assessment Data collection and analysis.
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