Ameliorative effects and mechanism of crocetin in arsenic trioxide‑induced cardiotoxicity in rats

Zhao, Zhifeng; Li, Jinghan; Zheng, Bin; Liang, Yingran; Shi, Jing; Zhang, Jianping; Han, Xue; Chu, Li; Chu, Xi; Gao, Yanni

doi:10.3892/mmr.2020.11587

Cited by 26 publications

(11 citation statements)

References 76 publications

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“…This study found that ATO-induced oxidative damage is embodied as the accumulation of ROS and MDA, the reduction of SOD, CAT and GSH in tissue (Figures 4,5). This finding is consistent with the results of previous studies (Liang et al, 2020;Zhao et al, 2020). However, HES treatment alleviated ATO-induced oxidative stress by attenuating ROS and MDA levels and stimulating the activity of enzymatic and nonenzymatic antioxidant systems.…”

Section: Discussionsupporting

confidence: 93%

“…Many studies have confirmed that inflammation has played a key role in the pathogenesis of ATO-induced cardiotoxicity (Liang et al, 2020;Zhao et al, 2020). ATO induces the overproduction of ROS, used as signal molecules to activate the intracellular inflammatory cascade and promote the expression of downstream inflammatory cytokines TNF-α and IL-6 (Kang et al, 2019).…”

Section: Discussionmentioning

confidence: 98%

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Based on Activation of p62-Keap1-Nrf2 Pathway, Hesperidin Protects Arsenic-Trioxide-Induced Cardiotoxicity in Mice

Jia

et al. 2021

Front. Pharmacol.

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Background: Hesperidin (HES) is a flavonoid glycoside found in the tangerine peel and has antioxidant properties. Arsenic trioxide (ATO) is an anti-tumour drug; however, its serious cardiotoxicity limits its clinical application. In addition, the protection of HES against ATO-induced cardiotoxicity has not been explored.Objective: The study aims to investigate and identify the underlying effect and mechanism of HES on ATO-induced cardiotoxicity.Methods: Fifty mice were randomly assigned to five groups. Mice were orally given HES:100 or 300 mg/kg/day concurrently and given ATO intraperitoneal injections: 7.5 mg/kg/day for 1 week. Blood and heart tissues were collected for examination. Evaluated in serum was the levels of creatine kinase (CK), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI). In addition, evaluated in heart tissues were the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, cleaved-Caspase-3, p62, Kelch-like ECH-associated protein 1 (Keap1), and nuclear factor erythroid 2-related factor 2 (Nrf2). The heart tissues were also examined for histopathology and mitochondrial ultrastructure.Results: Compared with the ATO group, the HES treatment groups reduced the levels of CK, LDH, cTnI, ROS, MDA, TNF-α, IL-6, Bax, Caspase-3, cleaved-Caspase-3 and Keap1 and enhanced the levels of SOD, GSH, CAT, Bcl-2, p62 and Nrf2.Conclusions: The results demonstrate that HES protects against ATO-induced cardiotoxicity, through inhibiting oxidative stress, and subsequent inflammation and apoptosis. The underlying results are closely related to the regulation of the p62-Keap1-Nrf2 signalling pathway.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Based on Activation of p62-Keap1-Nrf2 Pathway, Hesperidin Protects Arsenic-Trioxide-Induced Cardiotoxicity in Mice

Jia

et al. 2021

Front. Pharmacol.

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“…Treatment with crocetin did not alter the levels of ROS (Figure 3), but suppressed the As 2 O 3 -induced induction of ROS levels, and 20 μM was more effective than 10 μM of crocetin (Figure 3). In a rat model, crocetin has been reported to not only induce the activities of superoxide dismutase, glutathione-peroxidase, and catalase, but also decrease the levels of malondialdehyde and ROS (33).…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Crocetin on Arsenic Trioxide-induced Oxidative Stress in Human Umbilical Vein Endothelial Cells

Tsai

Chang

et al. 2021

In Vivo

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Background/Aim: The clinical use of arsenic trioxide (As 2 O 3 ) is hampered due to its cardiotoxicity. Therefore, it is critical to prevent As 2 O 3 -induced loss of endothelial integrity. The purpose of this study was to examine As 2 O 3 -induced endothelial dysfunction and evaluate the efficacy of crocetin on reversing As 2 O 3 -induced cardiotoxicity. Materials and Methods: Cultured human umbilical vein endothelial cells (HUVECs) were used to examine As 2 O 3 -induced oxidative stress, apoptosis, production of reactive oxygen species (ROS) and DNA adducts. In addition, the impact of crocetin on As 2 O 3induced cardiotoxicity was evaluated. Results: As 2 O 3 decreased the viability of HUVEC cells and led to apoptosis. Additionally, As 2 O 3 elevated NADPH oxidase activity, and the levels of intracellular ROS. Furthermore, the formamidopyrimidine DNA-glycosylase-and endonuclease III-digestible adducts were induced by As 2 O 3 . Crocetin treatment reversed the As 2 O 3induced reduction in cell viability, the induction of apoptosis, the activation of NADPH oxidase activity, ROS levels and DNA adducts. Conclusion: Crocetin protects from As 2 O 3 -induced cardio-toxicity.Arsenic trioxide (As 2 O 3 ) is a very toxic agent used in Chinese medicine, which has been used to successfully treat refractory acute promyelocytic leukemia (1). The efficacy of As 2 O 3 has been reported for its capacity to induce acute promyelocytic leukemia cells to undergo apoptosis, however, its cardio-toxicity has hindered its therapeutic application (2, 3). In addition, accumulated literature has pointed that chronic exposure to As 2 O 3 from drinking water is closely associated with various human diseases, including atherosclerosis (4), diabetes mellitus (5), hypertension (6), ischemic heart disease (7, 8), peripheral vascular disease (9), and cancer (10,11). Up to date, relatively few published articles are available on the influence of acute or chronic As 2 O 3 exposure on the vascular endothelial system. At the same time, the identification of potential traditional Chinese medicine for the prevention of the diseases associated with chronic exposure to As 2 O 3 is of great interest. Εndothelial cells, human umbilical vein endothelial cells (HUVEC) are frequently used as the cell model, are the main targets of vasculopathy caused by As 2 O 3 exposure. As 2 O 3 has been reported to cause oxidative stress, and induce endothelial cells to undergo programmed cell death (12). Oxidative stress and its intracellular consequences are believed to be the major cause of As 2 O 3 cytotoxicity (13).Crocetin (C 20 H 24 O 4 ; molecular weight 328.4g/mol) is a primary constituent of saffron (Crocus sativus L), which has been known to possess lots of beneficial pharmacological effects, such as anti-inflammatory ( 14) and anti-apoptotic (15, 16). Crocetin has also been reported to effectively eliminate ischemia-reperfusion-induced oxidative damage in rats and scavenge free radicals (17). More interesting, crocetin has beneficial cardiovascular effects, su...

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“…For TCM treatment of arsenic trioxide-induced cardiotoxicity, relatively few studies were found. One such studies indicated that crocin ameliorates arsenic trioxide-induced cardiotoxicity by reducing OS, inflammation, and apoptosis ( 170 , 171 ), magnesium isoglycyrrhizinate attenuates via Nrf2 and TLR4/NF-κB signaling pathways arsenic trioxide-induced cardiotoxicity ( 172 ). In addition, microRNAs and non-coding RNAs are also involved in the pathogenesis of radiotherapy-associated cardiotoxicity ( 173 – 175 ), mitochondrial fusion ( 176 ), and cellular scorching ( 177 ).…”

Section: Discussionmentioning

confidence: 99%

Role and molecular mechanism of traditional Chinese medicine in preventing cardiotoxicity associated with chemoradiotherapy

Wen

et al. 2022

Front. Cardiovasc. Med.

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Cardiotoxicity is a serious complication of cancer therapy. It is the second leading cause of morbidity and mortality in cancer survivors and is associated with a variety of factors, including oxidative stress, inflammation, apoptosis, autophagy, endoplasmic reticulum stress, and abnormal myocardial energy metabolism. A number of studies have shown that traditional Chinese medicine (TCM) can mitigate chemoradiotherapy-associated cardiotoxicity via these pathways. Therefore, this study reviews the effects and molecular mechanisms of TCM on chemoradiotherapy-related cardiotoxicity. In this study, we searched PubMed for basic studies on the anti-cardiotoxicity of TCM in the past 5 years and summarized their results. Angelica Sinensis, Astragalus membranaceus Bunge, Danshinone IIA sulfonate sodium (STS), Astragaloside (AS), Resveratrol, Ginsenoside, Quercetin, Danggui Buxue Decoction (DBD), Shengxian decoction (SXT), Compound Danshen Dripping Pill (CDDP), Qishen Huanwu Capsule (QSHWC), Angelica Sinensis and Astragalus membranaceus Bunge Ultrafiltration Extract (AS-AM),Shenmai injection (SMI), Xinmailong (XML), and nearly 60 other herbs, herbal monomers, herbal soups and herbal compound preparations were found to be effective as complementary or alternative treatments. These preparations reduced chemoradiotherapy-induced cardiotoxicity through various pathways such as anti-oxidative stress, anti-inflammation, alleviating endoplasmic reticulum stress, regulation of apoptosis and autophagy, and improvement of myocardial energy metabolism. However, few clinical trials have been conducted on these therapies, and these trials can provide stronger evidence-based support for TCM.

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Ameliorative effects and mechanism of crocetin in arsenic trioxide‑induced cardiotoxicity in rats

Cited by 26 publications

References 76 publications

Based on Activation of p62-Keap1-Nrf2 Pathway, Hesperidin Protects Arsenic-Trioxide-Induced Cardiotoxicity in Mice

Based on Activation of p62-Keap1-Nrf2 Pathway, Hesperidin Protects Arsenic-Trioxide-Induced Cardiotoxicity in Mice

Protective Effects of Crocetin on Arsenic Trioxide-induced Oxidative Stress in Human Umbilical Vein Endothelial Cells

Role and molecular mechanism of traditional Chinese medicine in preventing cardiotoxicity associated with chemoradiotherapy

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