Ergosterol Attenuates LPS-Induced Myocardial Injury by Modulating Oxidative Stress and Apoptosis in Rats

Background/Aims: Ergosterol (ER) is the primary sterol found in fungi and is named after the ergot fungus. A variety of pharmacological activities have been reported for ER, including antioxidative, anti-proliferative, and anti-inflammatory effects, although its role in sepsis remains unclear. Methods: The protective effect of ER on lipopolysaccharide (LPS)-induced sepsis myocardial injury was evaluated both in vivo and in vitro. Rats were pretreated with ER and then with LPS. Histopathology of heart tissues was first performed. Subsequently, the levels of superoxide dismutase (SOD), malondialdehyde (MDA), creatine kinase MB fraction (CK-MB), and lactate dehydrogenase (LDH) in serum and heart tissues were assessed by enzyme-linked immunosorbent assay kits. Western blotting was further used to evaluate the expression of antioxidant proteins (HO-1 and cytochrome c) and apoptosis associated proteins (Bcl-2, Bax, cleaved-caspase-3, cleaved-caspase-9, and cleaved-PARP). In addition, the effects of ER on oxidative stress biomarkers and apoptosis proteins were also detected in LPS-treated H9C2 cells. Moreover, small interfering Nrf2 RNA was transfected to H9C2 cells to study the role of Nrf2 signaling in connection with the protective effects of ER. Results: Pretreatment with ER ameliorated the histopathological changes in heart tissue induced by LPS injection, increased SOD activity, and reduced MDA content, and CK-MB and LDH levels. Furthermore, ER restored the expression of Nrf-2 and HO-1 in rat hearts, attenuating apoptotic damage via up-regulation of Bcl-2 in combination with the inhibition of Bax, cytochrome c, cleaved-caspase-3 and 9, and PARP, as revealed by western blot. When Nrf2 was blocked by siRNA, the effects of ER on SOD and MDA activity, as well as the expression of the antioxidant proteins and apoptosis-associated proteins were abolished. Conclusions: We demonstrated that ER has a cardioprotective effect in LPS-induced sepsis model through modulation of the antioxidant activity and anti-apoptosis effects and this process might be regulated by Nrf2 signaling.

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The MicroRNA-210/Casp8ap2 Pathway Alleviates Hypoxia-Induced Injury in Myocardial Cells by Regulating Apoptosis and Autophagy

The Heart Surgery Forum ◽

10.1532/hsf.3173 ◽

2020 ◽

Vol 23 (6) ◽

pp. E797-E802

Author(s):

Kunsheng Li ◽

Jun Pan ◽

Qiuchang Li ◽

Shiliang Li ◽

Kai Li ◽

...

Keyword(s):

Myocardial Injury ◽

Caspase 3 ◽

Transfection Efficiency ◽

Beclin 1 ◽

Caspase 8 ◽

H9c2 Cells ◽

Myocardial Cells ◽

Western Blot Assay ◽

H9c2 Cardiomyocytes ◽

Associated Proteins

Aim: This study was conducted to investigate the role of the miR-210/Caspase8ap2 pathway in apoptosis and autophagy in hypoxic myocardial cells. Methods: The miR-control, miR-210 mimic, and miR-210 inhibitor were transfected into rat myocardial H9C2 cells. The transfection efficiency of exogenous miR-210 was determined by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). H9C2 cells were then treated with CoCl2 for 24, 48, and 72 h to generate a myocardial injury model. The apoptosis of H9C2 cells was assessed by flow cytometry. Additionally, a western blot assay was used to determine the expression of the autophagy-associated proteins light chain 3 (LC3), p62 and Beclin-1, and apoptosis-associated proteins Caspase8ap2, cleaved caspase 8, and cleaved caspase 3. Results: We determined that a 48 h hypoxia treatment duration in H9C2 cardiomyocytes induced myocardial injury. Additionally, the overexpression of miR-210 significantly inhibited cell apoptosis. MiR-210 suppressed autophagy by upregulating p62 and downregulating LC3II/I in hypoxic H9C2 cells. Caspase8ap2 was a putative target of miR-210, miR-210 mediated apoptosis, and autophagy of H9C2 cells via suppressing Caspase8ap2. Furthermore, the expression of caspase 8, caspase 3, and Beclin-1 were decreased in response to miR-210. Conclusion: miR-210 exhibits anti-apoptosis and anti-autophagy effects, which alleviate myocardial injury in response to hypoxia.

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Ginkgetin Alleviates Inflammation, Oxidative Stress, and Apoptosis Induced by Hypoxia/Reoxygenation in H9C2 Cells via Caspase-3 Dependent Pathway

BioMed Research International ◽

10.1155/2020/1928410 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Xin Liu ◽

Hong Bian ◽

Qing-Li Dou ◽

Xian-Wen Huang ◽

Wu-Yuan Tao ◽

...

Keyword(s):

Oxidative Stress ◽

Cytochrome C ◽

Cell Viability ◽

Caspase 3 ◽

Cell Counting ◽

Therapeutic Effects ◽

H9c2 Cells ◽

The Impact ◽

Dependent Pathway ◽

Hypoxia Reoxygenation

Ginkgetin, the extract of Ginkgo biloba leaves, has been reported to exert preventive and therapeutic effects on cardiovascular disease. However, little is known about its role in myocardial ischemia-reperfusion injury (MIRI). The present study aimed to unveil the function of ginkgetin in cardiomyocytes subjected to hypoxia/reoxygenation (H/R) injury. Cell Counting Kit-8 (CCK-8) was employed to evaluate the impact of ginkgetin on cell viability in the absence or presence of H/R. Proinflammatory cytokines and malondialdehyde (MDA), reactive oxygen species (SOD), and lactate dehydrogenase (LDH) were determined via corresponding kits. In addition, flow cytometry was performed to detect apoptotic level. Western blot analysis was utilized to estimate caspase-3 and cytochrome C. Ginkgetin had no significant effect on cell viability; however, it could enhance viability of H9C2 cells exposed to H/R. Inflammation and oxidative stress induced by H/R injury were relieved via pretreatment with ginkgetin. Preconditioning of ginkgetin also decreased apoptotic rate and the protein levels of caspase-3, cytochrome C under H/R condition. Furthermore, 2-HBA, an inducer of caspase-3, was used for the activation of caspase-3 signaling pathway. It was found that induction of caspase-3 eliminated the protective effect of ginkgetin on H9C2 cells exposed to H/R. These results indicated that ginkgetin attenuated inflammation, oxidative stress, and apoptosis. These protective roles of ginkgetin may attribute to caspase-3 dependent pathway.

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Direct Effect of Septic Plasma in Human Cell Lines Viability

Blood Purification ◽

10.1159/000494597 ◽

2018 ◽

Vol 47 (1-3) ◽

pp. 270-276

Author(s):

Grazia Maria Virzì ◽

Chiara Borga ◽

Chiara Pasqualin ◽

Silvia Pastori ◽

Alessandra Brocca ◽

...

Keyword(s):

Cytochrome C ◽

Cell Viability ◽

Cell Lines ◽

Caspase 3 ◽

Test Group ◽

Organ Injury ◽

Enzyme Linked Immunosorbent Assay ◽

Caspase 9 ◽

Renal Tubular Cells

Background: Sepsis is a life-threatening condition often associated with a high incidence of multiple organs injury. Several papers suggested the immune response by itself, with the production of humoral inflammatory mediators, is crucial in determining organ injury. However, little is known of how sepsis directly induces organ injury at the cellular levels. To assess this point, we set up an in vitro study to investigate the response of renal tubular cells (RTCs), monocytes (U937) and hepatocytes (HepG2) after 24 h-incubation with septic patients’ plasma. Methods: We enrolled 26 septic patients (“test” group). We evaluated cell viability, apoptosis and necrosis by flow cytometer. Caspase-3,-8,-9 and cytochrome-c concentrations have been analyzed using the Human enzyme-linked immunosorbent assay kit. Results: We found that a decrease of cell viability in all cell lines tested was associated to the increase of apoptosis in RTCs and U937 (p < 0.0001) and increase of necrosis in HepG2 (p < 0.5). The increase of apoptosis in RTCs and U937 cells was confirmed by higher levels of caspase-3 (p < 0.0001). We showed that apoptosis in both RTCs and U937 was triggered by the activation of the intrinsic pathway, as caspase-9 and cytochrome-c levels significantly increased (p < 0.0001), while caspase-8 did not change. This assumption was strengthened by the significant correlation of caspase-9 with both cytochrome-c (r = 0.73 for RTCs and r = 0.69 for U937) and caspase-3 (r = 0.69 for RTCs and r = 0.63 for U937). Conclusion: Humoral mediators in septic patients’ plasma induce apoptosis. This fact suggests that apoptosis inhibitors should be investigated as future strategy to reduce sepsis-induced organ damages.

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Salidroside pretreatment protects against myocardial injury induced by heat stroke in mice

Journal of International Medical Research ◽

10.1177/0300060519868645 ◽

2019 ◽

Vol 47 (10) ◽

pp. 5229-5238

Author(s):

Guo-dong Chen ◽

Heng Fan ◽

Jian-Hua Zhu

Keyword(s):

Oxidative Stress ◽

Myocardial Injury ◽

Troponin I ◽

Heat Stroke ◽

Cardiac Injury ◽

Myocardial Damage ◽

Thiobarbituric Acid ◽

Protective Effects ◽

Creatine Kinase Mb ◽

Factor Α

Objective To explore the protective effects and mechanisms of salidroside on myocardial injury induced by heat stroke (HS) in mice. Methods We pretreated mice with salidroside for 1 week and then established an HS model by exposure to 41.2°C for 1 hour. We then examined the effects of salidroside on survival. We also assessed the severity of cardiac injury by pathology, and analyzed changes in levels of myocardial injury markers, inflammatory cytokines, and oxidative stress. Results Salidroside pretreatment significantly reduced HS-induced mortality and improved thermoregulatory function. Salidroside also provided significant protection against HS-induced myocardial damage, and decreased the expression levels of cardiac troponin I, creatine kinase-MB, and lactate dehydrogenase. Moreover, salidroside attenuated HS-induced changes in the inflammation markers tumor necrosis factor-α, interleukin (IL)-6, and IL-10, and down-regulated the oxidative stress response indicated by thiobarbituric acid reactant substances, malondialdehyde, reduced glutathione, and superoxide dismutase. Conclusions Salidroside pretreatment protected against HS-induced myocardial damage, potentially via a mechanism involving anti-inflammatory and anti-oxidative effects.

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CARDIOPROTECTIVE POTENTIAL OF QUERCETIN AGAINST DIESEL OR PETROL EXHAUST NANOPARTICLE INDUCED TOXICITY: A PROSPECTIVE IN VITRO PHARMACOLOGICAL STUDY IN H9C2 CELLS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2021.v14i4.40858 ◽

2021 ◽

pp. 139-144

Author(s):

MOHAN DURGA ◽

THIYAGARAJAN DEVASENA

Keyword(s):

Oxidative Stress ◽

Diesel Exhaust ◽

Pharmacological Study ◽

Lethal Effect ◽

Protective Role ◽

Cardiac Cells ◽

H9c2 Cells ◽

Sod Activity ◽

Cardioprotective Effects

Objective: Phytochemicals are known to elicit potential antioxidant activity. This study examined the cardioprotective effects of quercetin against oxidative damage to rat cardiomyocyte cells (H9c2) after treatment with Diesel Exhaust Nanoparticles (DEPs) or Petrol Exhaust Nanoparticles (PEPs). Methods: Cardiomyocyte cells were exposed to DEPs or PEPs alone and in a combination with quercetin for 24 h. Results: Results showed that quercetin had no lethal effect on H9c2 cells up to a concentration of 1.0 μg/ml. Exposure to DEPs (4.0 μg/ml) or PEPs (10.0 μg/ml) induced cytotoxicity, oxidative stress, and inflammation (p<0.05). It also provoked lipid peroxidation by an increase in MDA and a decrease in SOD activity and glutathione activity (p<0.05). Simultaneous addition of quercetin restored these parameters to near normal. Conclusion: These results thus specify that quercetin plays a protective role in cardiac cells exposed to DEPs and PEPs.

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Ling-Gui-Zhu-Gan Decoction Protects H9c2 Cells against H2O2-Induced Oxidative Injury via Regulation of the Nrf2/Keap1/HO-1 Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/8860603 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Xiang Wang ◽

Tongjuan Tang ◽

Mengting Zhai ◽

Ruirui Ge ◽

Liang Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Stress Response ◽

Caspase 3 ◽

Underlying Mechanism ◽

Oxidative Stress Response ◽

Control Group ◽

H9c2 Cells ◽

Model Group ◽

Blank Control Group

Objectives. Ling-Gui-Zhu-Gan decoction (LGZGD) is a potentially effective treatment for heart failure, and it showed significant anti-inflammatory potential in our previous studies. However, its ability to ameliorate heart failure through regulation of oxidative stress response is still unknown. This study was aimed to investigate the protective effect of LGZGD-containing serum on H2O2-induced oxidative injury in H9c2 cells and explore the underlying mechanism. Methods. Eighteen rats were randomly divided into two groups: the blank control group and LGZGD group. The LGZGD group rats were administrated with 8.4 g/kg/d LGZGD for seven consecutive days through gavage, while the blank control group rats were given an equal volume of saline. The serum was extracted from all the rats. To investigate the efficacy and the underlying mechanism of LGZGD, we categorized the H9c2 cells into groups: the control group, model group, normal serum control (NSC) group, LGZGD group, LGZGD + all-trans-retinoic acid (ATRA) group, and ATRA group. Malonedialdehyde (MDA) and superoxide dismutase (SOD) were used as markers for oxidative stress. Dichlorodihydrofluorescin diacetate (DCFH-DA) staining was used to measure the levels of reactive oxygen species (ROS). The apoptosis rate was detected using flow cytometry. The expression levels of pro-caspase-3, cleaved-caspase-3, Bcl-2, Bax, Keap1, Nrf2, and HO-1 were measured using western blotting. The mRNA levels of Keap1, Nrf2, and HO-1 were measured using RT-qPCR. Results. The LGZGD attenuated injury to H9c2 cells and reduced the apoptosis rate. It was also found to upregulate the SOD activity and suppress the formation of MDA and ROS. The expression levels of pro-caspase-3 and Bcl-2 were significantly increased, while those of cleaved-caspase-3 and Bax were decreased in the LGZGD group compared with the model group. As compared with the model group, the LGZGD group demonstrated decreased Keap1 protein expression and significantly increased Nrf2 nuclear expression and Nrf2-mediated transcriptional activity. ATRA was found to reverse the LGZGD-mediated antioxidative and antiapoptotic effect on injured H9c2 cells induced by H2O2. Conclusion. Our results demonstrated that LGZGD attenuated the H2O2-induced injury to H9c2 cells by inhibiting oxidative stress and apoptosis via the Nrf2/Keap1/HO-1 pathway. These observations suggest that LGZGD might prevent and treat heart failure through regulation of the oxidative stress response.

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Mangiferin Attenuates Myocardial Ischemia-Reperfusion Injury via MAPK/Nrf-2/HO-1/NF-κB In Vitro and In Vivo

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7285434 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Kun Liu ◽

Fei Wang ◽

Shuo Wang ◽

Wei-Nan Li ◽

Qing Ye

Keyword(s):

Oxidative Stress ◽

Coronary Artery ◽

Myocardial Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

H9c2 Cells ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion

The aim of this study was to investigate the cardioprotective effect of mangiferin (MAF) in vitro and in vivo. Oxidative stress and inflammatory injury were detected in coronary artery ligation in rats and also in hypoxia-reoxygenation- (H/R-) induced H9c2 cells. MAF inhibited myocardial oxidative stress and proinflammatory cytokines in rats with coronary artery occlusion. The ST segment of MAF treatment groups also resumed. Triphenyltetrazolium chloride (TTC) staining and pathological analysis showed that MAF could significantly reduce myocardial injury. In vitro data showed that MAF could improve hypoxia/reoxygenation- (H/R-) induced H9c2 cell activity. In addition, MAF could significantly reduce oxidative stress and inflammatory pathway protein expression in H/R-induced H9c2 cells. This study has clarified the protective effects of MAF on myocardial injury and also confirmed that oxidative stress and inflammation were involved in the myocardial ischemia-reperfusion injury (I/R) model.

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A Novel Antioxidant Protects Against Contrast Medium-Induced Acute Kidney Injury in Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2020.599577 ◽

2020 ◽

Vol 11 ◽

Author(s):

Shuo Huang ◽

Yanyan Tang ◽

Tianjun Liu ◽

Ning Zhang ◽

Xueyan Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Superoxide Dismutase ◽

Renal Function ◽

Cytochrome C ◽

Caspase 3 ◽

Mitochondrial Protein ◽

Kidney Injury ◽

High Efficient ◽

Superoxide Dismutase 2

Many studies proposed that oxidative stress and apoptosis are key mechanisms in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). Xylose-pyrogallol conjugate (XP) is an original effective antioxidant that showed decent antioxidant and anti-apoptosis effect before. Thus the therapeutic effect and mechanism of XP in preventing CI-AKI in the short and long term were investigated in this research. Renal function and histological grade were evaluated to determine the severity of renal injury. Kidney samples were then collected for the measurement of oxidative stress markers and the detection of apoptosis. Transmission electron microscopy (TEM) and western blot of mitochondrial protein were utilized for the analysis of the mitochondrial conditions. The results demonstrated that the CI-AKI rats caused a significant decrease in renal function accompanied by a remarkable increase in Malondialdehyde (MDA), bax, caspase-3, cytochrome c (Cyt C) level, TdT-mediated dUTP nick end labeling (TUNEL) positive apoptotic cells, and damaged mitochondria, while a decline in antioxidase activities and mitochondrial superoxide dismutase 2 (SOD2) expression compared with the control rats. However, when XP (50 or 100 or 200 mg/kg/day) was given orally for consecutive 7 days before CI-AKI modeling, XP (200 mg/kg) showed a better capability to restore renal dysfunction, histopathological appearance, the level of apoptosis, mitochondrial damage, oxidative stress, and fibrosis generation without interference in computed tomographic imaging. Our study indicated that antioxidant XP played a nephroprotective role probably via antiapoptotic and antioxidant mechanisms. Besides, XP may regulate the mitochondria pathway via decreasing the ratio of bax/bcl-2, inhibiting caspase-3 expression, cytochrome c release, and superoxide dismutase 2 activity. Overall, XP as a high-efficient antioxidant may have the potentials to prevent CI-AKI.

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Geniposide Prevents Hypoxia/Reoxygenation-Induced Apoptosis in H9c2 Cells: Improvement of Mitochondrial Dysfunction and Activation of GLP-1R and the PI3K/AKT Signaling Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000445634 ◽

2016 ◽

Vol 39 (1) ◽

pp. 407-421 ◽

Cited By ~ 50

Author(s):

You-Qin Jiang ◽

Guang-lei Chang ◽

Ying Wang ◽

Dong-Ying Zhang ◽

Li Cao ◽

...

Keyword(s):

Cytochrome C ◽

Cell Viability ◽

Mitochondrial Dysfunction ◽

Mitochondrial Membrane ◽

Caspase 3 ◽

Akt Signaling ◽

Mitochondrial Morphology ◽

Mitochondrial Calcium ◽

H9c2 Cells ◽

Akt Signaling Pathway

Background/Aims: Myocardial ischemia/reperfusion injury is a major cause of morbidity and mortality associated with coronary heart disease. Many studies have demonstrated that natural products are promising chemotherapeutic drugs counteracting the loss of cardiomyocytes. Thus, the purpose of the present study was to investigate the effects of geniposide, a traditional Chinese herb extract from Gardenia jasminoides J. Ellis, on cardiomyocyte apoptosis induced by hypoxia/reoxygenation (H/R) in H9c2 cells, and their underlying mechanisms. Methods: Cell viability and apoptosis ratio were assessed using the cell counting kit-8 assay and Annexin V/propidium iodide (PI) staining. The concentrations of lactate dehydrogenase (LDH), intracellular total superoxide dismutase (T-SOD), and malondialdehyde (MDA) were detected by microplate reader. The production of reactive oxygen species/reactive nitrogen species (ROS/RNS), the level of mitochondrial calcium, and mitochondrial membrane potential depolarization were measured by confocal laser scanning microscopy. Mitochondrial morphology was visualized using transmission electron microscopy. The expressions of Bcl-2 mRNA and Caspase-3 mRNA were measured by reverse transcription-polymerase chain reaction (RT-PCR). The protein levels of cleaved caspase-3, Bcl-2, Bax, AKT, p-AKTserine473, cytochrome-c were detected by western bloting. Results: Geniposide pretreatment increased cell viability, decreased LDH levels in the supernatant, and inhibited cardiomyocyte apoptosis caused by H/R. Furthermore, geniposide reversed mitochondrial dysfunction by decreasing oxidative stress products (ROS/RNS and MDA), increasing anti-oxidative enzyme (T-SOD) level, improving mitochondrial morphology, attenuating mitochondrial calcium overload and blunting depolarization of mitochondrial membrane. Moreover, geniposide pretreatment increased Bcl-2 level and decreased Bax level, thus enhancing the Bcl-2/Bax ratio. Consistent with the above result, Bcl-2 mRNA expression was upregulated and caspase-3 mRNA expression was downregulated by geniposide. In addition, geniposide decreased the protein expression of cleaved caspase-3 and cytochrome-c and increased the level p-AKTserine473. The protective effects of geniposide were partially reversed by glucagon-like pepitide-1 receptor antagonist exendin-(9-39) and the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002. Conclusions: Our results suggest that geniposide pretreatment inhibits H/R-induced myocardial apoptosis by reversing mitochondrial dysfunction, an effect in part due to activation of GLP-1R and PI3K/AKT signaling pathway.

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Xinmailong Attenuates Doxorubicin-Induced Lysosomal Dysfunction and Oxidative Stress in H9c2 Cells via HO-1

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5896931 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Yu Jiang ◽

Yanjuan Liu ◽

Wen Xiao ◽

Dandan Zhang ◽

Xiehong Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Injury ◽

Specific Inhibitor ◽

Heme Oxygenase 1 ◽

H9c2 Cells ◽

Autophagy Flux ◽

Sod Activity ◽

Lysosomal Function ◽

Lysosomal Dysfunction ◽

And Oxidative Stress

The clinical use of doxorubicin (DOX) is limited by its cardiotoxicity, which is closely associated with oxidative stress. Xinmailong (XML) is a bioactive peptide extracted from American cockroaches, which has been mainly applied to treat chronic heart failure in China. Our previous study showed that XML attenuates DOX-induced oxidative stress. However, the mechanism of XML in DOX-induced cardiotoxicity remains unclear. Heme oxygenase-1 (HO-1), an enzyme that is ubiquitously expressed in all cell types, has been found to take antioxidant effects in many cardiovascular diseases, and its expression is protectively upregulated under DOX treatment. Lysosome and autophagy are closely involved in oxidative stress as well. It is still unknown whether XML could attenuate doxorubicin-induced lysosomal dysfunction and oxidative stress in H9c2 cells via HO-1. Thus, this study was aimed at investigating the involvement of HO-1-mediated lysosomal function and autophagy flux in DOX-induced oxidative stress and cardiotoxicity in H9c2 cells. Our results showed that XML treatment markedly increased cell proliferation and SOD activity, improved lysosomal function, and ameliorated autophagy flux block in DOX-treated H9c2 cells. Furthermore, XML significantly increased HO-1 expression following DOX treatment. Importantly, HO-1-specific inhibitor (Znpp) or HO-1 siRNA could significantly attenuate the protective effects of XML against DOX-induced cell injury, oxidative stress, lysosomal dysfunction, and autophagy flux block. These results suggest that XML protects against DOX-induced cardiotoxicity through HO-1-mediated recovery of lysosomal function and autophagy flux and decreases oxidative stress, providing a novel mechanism responsible for the protection of XML against DOX-induced cardiomyopathy.

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