Luteolin improves heart preservation through inhibiting hypoxia‑dependent L‑type calcium channels in cardiomyocytes

Yan, Qingfeng; Liu, Yueping; Jia, Yan; Zhao, Ying; Liu, Yunzhong; Liu, Su

doi:10.3892/etm.2019.7214

Cited by 6 publications

(7 citation statements)

References 39 publications

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“…Li et al (2019) suggest that LUT protects heart tissues in STZinduced diabetic mice by modulating Nrf2-mediated oxidative stress and NF-κB-mediated inflammatory responses. In another study, Yan et al (2019) demonstrated LUT's protective effects during long-term heart preservation in a dose-dependent manner, which may be accomplished by inhibiting hypoxia-dependent L-type calcium channels. Yao et al (2016) also showed Luteolin-7-O-Glucoside cardioprotective effects by inhibiting the DOXinduced intracellular level of ROS and apoptosis, potentially acting as a therapeutic agent Figure 1 The experimental scheme and the effects of LUT on body weight and heart weight in DOX induced-cardiotoxicity model rats.…”

Section: Introductionmentioning

confidence: 95%

Luteolin attenuates doxorubicin-induced cardiotoxicity by modulating the PHLPP1/AKT/Bcl-2 signalling pathway

Zhang

Liu

et al. 2020

PeerJ

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Background Luteolin (LUT) is a flavonoid found in vegetables and fruits that has diverse functions. Doxorubicin (DOX) is an anthracycline antibiotic that is frequently used for the treatment of various cancers. Unfortunately, the clinical efficacy of DOX is limited by its dose-related cardiotoxicity. In this study, we aimed to investigate the potential mechanism through which LUT attenuates cardiotoxicity in vivo. Methods We evaluated the body weight, heart weight, electrocardiogram, and pathological changes before and after administration of LUT. Moreover, the effects of LUT (50 mg/kg in the low dose group, 100 mg/kg in the high dose group) on biochemical parameters (brain natriuretic peptide, creatine kinase MB, cardiac troponin T, and dehydrogenation of lactate enzyme) and oxidative stress parameters (malondialdehyde and superoxide dismutase) were studied in the sera of cardiotoxicity model rats. We also identified the apoptotic mediators whose expression was induced by LUT by quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR) evaluation. In addition, we used network analysis to predict DOX-induced cardiotoxicity and protection afforded by LUT. Western blotting was used to detect the expression of associated proteins. Results LUT significantly improved DOX-induced cardiotoxicity in a dose-dependent fashion. LUT ameliorated DOX-induced weight loss and heart weight changes, as well as changes in biochemical parameters and oxidative stress parameters in heart injury model rats. LUT’s protective effect was observed via regulation of the apoptotic markers Bcl-2, Bax, and caspase-3 mRNA and protein expression levels. Network analysis showed that the AKT/Bcl-2 signalling pathway was activated; specifically, the PH domain leucine-rich repeats protein phosphatase 1 (phlpp1) was involved in the AKT/Bcl-2 signal pathway. LUT inhibited the activity of phlpp1 leading to positive regulation of the AKT/Bcl-2 pathway, which attenuated doxorubicin-induced cardiotoxicity. Conclusions These results demonstrate that LUT exerted protective effects against DOX-induced cardiotoxicity in vivo by alleviating oxidative stress, suppressing phlpp1 activity, and activating the AKT/Bcl-2 signalling pathway.

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Section: Introductionmentioning

confidence: 95%

Luteolin attenuates doxorubicin-induced cardiotoxicity by modulating the PHLPP1/AKT/Bcl-2 signalling pathway

Zhang

Liu

et al. 2020

PeerJ

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“…Luteolin prevented bone loss in postmenopausal OP by reducing the differentiation ability of osteoclasts [95]. Also, luteolin inhibited L-type calcium currents in ventricular myocytes under hypoxia conditions and ameliorated calcium ion overload in rat cardiomyocytes [96]. By analyzing EXD targets, we hypothesize that EXD acts synergistically to mediate OP via calcium regulation and apoptosis, e.g., several studies have shown that ESR1 variants are related to postmenopausal OP [97][98][99], and ESR1 gene polymorphisms may be predictive of OP in female patients with Crohn's disease [65].…”

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Analysis of Molecular Mechanism of Erxian Decoction in Treating Osteoporosis Based on Formula Optimization Model

Yang

Fan

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Osteoporosis (OP) is a highly prevalent orthopedic condition in postmenopausal women and the elderly. Currently, OP treatments mainly include bisphosphonates, receptor activator of nuclear factor kappa-B ligand (RANKL) antibody therapy, selective estrogen receptor modulators, teriparatide (PTH1-34), and menopausal hormone therapy. However, increasing evidence has indicated these treatments may exert serious side effects. In recent years, Traditional Chinese Medicine (TCM) has become popular for treating orthopedic disorders. Erxian Decoction (EXD) is widely used for the clinical treatment of OP, but its underlying molecular mechanisms are unclear thanks to its multiple components and multiple target features. In this research, we designed a network pharmacology method, which used a novel node importance calculation model to identify critical response networks (CRNs) and effective proteins. Based on these proteins, a target coverage contribution (TCC) model was designed to infer a core active component group (CACG). This approach decoded the mechanisms underpinning EXD’s role in OP therapy. Our data indicated that the drug response network mediated by the CACG effectively retained information of the component-target (C-T) network of pathogenic genes. Functional pathway enrichment analysis showed that EXD exerted therapeutic effects toward OP by targeting PI3K-Akt signaling (hsa04151), calcium signaling (hsa04020), apoptosis (hsa04210), estrogen signaling (hsa04915), and osteoclast differentiation (hsa04380) via JNK, AKT, and ERK. Our method furnishes a feasible methodological strategy for formula optimization and mechanism analysis and also supplies a reference scheme for the secondary development of the TCM formula.

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“…Madhesh andVaiyapuri (2005 and found that luteolin (0.3 mg/kg/day) could protect cardiac function and prevent myocardial infarction by reducing mitochondrial lipid peroxidation (a route that produce ROS in vivo) and increasing the mitochondrial antioxidant levels as shown in isoproterenol induced myocardial infarction model in rats (Manju et al, 2005;Madhesh and Vaiyapuri, 2012). Luteolin appears to be an inhibitor of L-type calcium channels as confirmed by Yan et al (2018), Yan et al (2019). Luteolin (7.5, 15, or 30 μM) ameliorated calcium overload in freshly isolated cardiomyocytes, accompanied by suppressed Protein Kinase A (PKA) activity and enhanced Ca 2+ -Mg 2+ -ATPase activity (Yan et al, 2018).…”

Section: Natural Flavones Exhibit Potential In Treating Hf Via Dual Regulation Of Calcium and Rosmentioning

confidence: 90%

Navigating Calcium and Reactive Oxygen Species by Natural Flavones for the Treatment of Heart Failure

Huang

et al. 2021

Front. Pharmacol.

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Heart failure (HF), the leading cause of death among men and women world-wide, causes great health and economic burdens. HF can be triggered by many factors, such as coronary artery disease, heart attack, cardiomyopathy, hypertension, obesity, etc., all of which have close relations with calcium signal and the level of reactive oxygen species (ROS). Calcium is an essential second messenger in signaling pathways, playing a pivotal role in regulating the life and death of cardiomyocytes via the calcium-apoptosis link mediated by the cellular level of calcium. Meanwhile, calcium can also control the rate of energy production in mitochondria that are the major resources of ROS whose overproduction can lead to cell death. More importantly, there are bidirectional interactions between calcium and ROS, and such interactions may have therapeutic implications in treating HF through finely tuning the balance between these two by certain drugs. Many naturally derived products, e.g., flavones and isoflavones, have been shown to possess activities in regulating calcium and ROS simultaneously, thereby leading to a balanced microenvironment in heart tissues to exert therapeutic efficacies in HF. In this mini review, we aimed to provide an updated knowledge of the interplay between calcium and ROS in the development of HF. In addition, we summarized the recent studies (in vitro, in vivo and in clinical trials) using natural isolated flavones and isoflavones in treating HF. Critical challenges are also discussed. The information collected may help to evoke multidisciplinary efforts in developing novel agents for the potential prevention and treatment of HF.

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Luteolin improves heart preservation through inhibiting hypoxia‑dependent L‑type calcium channels in cardiomyocytes

Cited by 6 publications

References 39 publications

Luteolin attenuates doxorubicin-induced cardiotoxicity by modulating the PHLPP1/AKT/Bcl-2 signalling pathway

Luteolin attenuates doxorubicin-induced cardiotoxicity by modulating the PHLPP1/AKT/Bcl-2 signalling pathway

Analysis of Molecular Mechanism of Erxian Decoction in Treating Osteoporosis Based on Formula Optimization Model

Navigating Calcium and Reactive Oxygen Species by Natural Flavones for the Treatment of Heart Failure

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