Activation of Nrf2 by miR-152 Inhibits Doxorubicin-Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis

Doxorubicin (DOX) could trigger congestive heart failure, which largely limited the clinical use of DOX. microRNAs (miRNAs) were closely involved in the pathogenesis of DOX-induced cardiomyopathy. Here, we aimed to investigate the effect of miR-152 on DOX-induced cardiotoxicity in mice. To study this, we used an adeno-associated viral vector to overexpress miR-152 in mice 6 weeks before DOX treatment, using a dose mimicking the concentrations used in the clinics. In response to DOX injection, miR-152 was significantly decreased in murine hearts and cardiomyocytes. After DOX treatment, mice with miR-152 overexpression in the hearts developed less cardiac dysfunction, oxidative stress, inflammation, and myocardial apoptosis. Furthermore, we found that miR-152 overexpression attenuated DOX-related oxidative stress, inflammation, and cell loss in cardiomyocytes, whereas miR-152 knockdown resulted in oxidative stress, inflammation, and cell loss in cardiomyocytes. Mechanistically, this effect of miR-152 was dependent on the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in response to DOX. Notably, Nrf2 deficiency blocked the protective effects of miR-152 against DOX-related cardiac injury in mice. In conclusion, miR-152 protected against DOX-induced cardiotoxicity via the activation of the Nrf2 signaling pathway. These results suggest that miR-152 may be a promising therapeutic target for the treatment of DOX-induced cardiotoxicity.

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Role of PI3K/AKT/mTOR Pathway Associated Oxidative Stress and Cardiac Dysfunction in Takotsubo Syndrome

Current Neurovascular Research ◽

10.2174/1567202617666191223144715 ◽

2020 ◽

Vol 17 (1) ◽

pp. 35-43

Author(s):

Shan Mao ◽

Xianghong Luo ◽

Yu Li ◽

Chaorong He ◽

Fuhua Huang ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Dysfunction ◽

Myocardial Dysfunction ◽

Cardiac Injury ◽

Protective Role ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Protective Effects ◽

Takotsubo Syndrome ◽

Akt Inhibitor

Introduction: Takotsubo syndrome (TTS) is a stress-induced cardiomyopathy, but the accurate cause of this syndrome is still unknown. Methods: β-adrenergic agonist isoproterenol (ISO) is used to establish the TTS rats model. TTS rats were treated with or without LY294002 or Rapamycin. The rat cardiomyoblast cell line H9C2 was subjected to infect with constitutively active Akt (myr-Akt) or dominant-negative mutant Akt (dn-Akt) and then, treated with ISO. Cell apoptosis was assessed using the Bax/ Bcl-2 ratio. In addition, reactive oxygen species (ROS) levels were measured using dihydroethidium (DHE). Mitochondrial superoxide generation and membrane potential were assayed by MitoSOX and JC-1 fluorescence intensity. Results: ISO might induce the erratic acute cardiac dysfunction and overexpression of PI3K/AKT/mTOR. Moreover, it also increased the oxidative stress and apoptosis in TTS rats. The Akt inhibitor significantly reversed the cardiac injury effect, which triggered by ISO treatment. In H9C2 cells, the inhibition of Akt provides a protective role against ISO-induced injury by reducing oxidative stress, apoptosis and mitochondrial dysfunction. Conclusion: This study provided new insight into the protective effects of myocardial dysfunction in TTS rats via chronic inhibition of the PI3K/AKT/mTOR expression, which could reduce mitochondrial ROS and oxidative stress-induced apoptosis. PI3K/AKT/mTOR inhibitor could be a therapeutic target to treat cardiovascular dysfunction induced by stress cardiomyopathy.

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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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Protection against Doxorubicin-Induced Cytotoxicity by Geniposide Involves AMPKα Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7901735 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Yan-Yan Meng ◽

Yu-Pei Yuan ◽

Xin Zhang ◽

Chun-Yan Kong ◽

Peng Song ◽

...

Keyword(s):

Oxidative Stress ◽

Therapeutic Potential ◽

Cell Loss ◽

Protective Role ◽

Protective Effects ◽

Morphological Examination ◽

Heart Injury ◽

Amp Activated Protein Kinase

Oxidative stress and cardiomyocyte apoptosis play critical roles in the development of doxorubicin- (DOX-) induced cardiotoxicity. Our previous study found that geniposide (GE) could inhibit cardiac oxidative stress and apoptosis of cardiomyocytes but its role in DOX-induced heart injury remains unknown. Our study is aimed at investigating whether GE could protect against DOX-induced heart injury. The mice were subjected to a single intraperitoneal injection of DOX (15 mg/kg) to induce cardiomyopathy model. To explore the protective effects, GE was orally given for 10 days. The morphological examination and biochemical analysis were used to evaluate the effects of GE. H9C2 cells were used to verify the protective role of GE in vitro. GE treatment alleviated heart dysfunction and attenuated cardiac oxidative stress and cell loss induced by DOX in vivo and in vitro. GE could activate AMP-activated protein kinase α (AMPKα) in vivo and in vitro. Moreover, inhibition of AMPKα could abolish the protective effects of GE against DOX-induced oxidative stress and apoptosis. GE could protect against DOX-induced heart injury via activation of AMPKα. GE has therapeutic potential for the treatment of DOX cardiotoxicity.

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Piperine Alleviates Doxorubicin-Induced Cardiotoxicity via Activating PPAR-γ in Mice

PPAR Research ◽

10.1155/2019/2601408 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Jie Yan ◽

Si-Chi Xu ◽

Chun-Yan Kong ◽

Xiao-Yang Zhou ◽

Zhou-Yan Bian ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Injury ◽

Inflammatory Factors ◽

Peroxisome Proliferator ◽

Protective Effects ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Myocardial Oxidative Stress

Background. Oxidative stress, inflammation and cardiac apoptosis were closely involved in doxorubicin (DOX)-induced cardiac injury. Piperine has been reported to suppress inflammatory response and pyroptosis in macrophages. However, whether piperine could protect the mice against DOX-related cardiac injury remain unclear. This study aimed to investigate whether piperine inhibited DOX-related cardiac injury in mice. Methods. To induce DOX-related acute cardiac injury, mice in DOX group were intraperitoneally injected with a single dose of DOX (15 mg/kg). To investigate the protective effects of piperine, mice were orally treated for 3 weeks with piperine (50 mg/kg, 18:00 every day) beginning two weeks before DOX injection. Results. Piperine treatment significantly alleviated DOX-induced cardiac injury, and improved cardiac function. Piperine also reduced myocardial oxidative stress, inflammation and apoptosis in mice with DOX injection. Piperine also improved cell viability, and reduced oxidative damage and inflammatory factors in cardiomyocytes. We also found that piperine activated peroxisome proliferator-activated receptor-γ (PPAR-γ), and the protective effects of piperine were abolished by the treatment of the PPAR-γ antagonist in vivo and in vitro. Conclusions. Piperine could suppress DOX-related cardiac injury via activation of PPAR-γ in mice.

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Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity

Clinical Science ◽

10.1042/cs20181022 ◽

2019 ◽

Vol 133 (13) ◽

pp. 1505-1521 ◽

Cited By ~ 2

Author(s):

Dong Zheng ◽

Yi Zhang ◽

Ming Zheng ◽

Ting Cao ◽

Grace Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Defense Mechanism ◽

Myocardial Dysfunction ◽

Cardiac Injury ◽

Autophagic Flux ◽

Protective Effects ◽

Nicotinamide Riboside ◽

And Oxidative Stress ◽

Cultured Cardiomyocytes ◽

Lysosomal Acidification

Abstract Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)+, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD+/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.

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Acute Blood Glucose Fluctuation Induces Myocardial Apoptosis through Oxidative Stress and Nuclear Factor-?B Activation

Cardiology ◽

10.1159/000345436 ◽

2013 ◽

Vol 124 (1) ◽

pp. 11-17 ◽

Cited By ~ 16

Author(s):

Wei Zhang ◽

Sheng Zhao ◽

Yan Li ◽

Guanjing Peng ◽

Ping Han

Keyword(s):

Oxidative Stress ◽

Blood Glucose ◽

Nuclear Factor ◽

Factor B ◽

Glucose Fluctuation ◽

Myocardial Apoptosis ◽

Blood Glucose Fluctuation

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Daphnetin Attenuated Cisplatin-Induced Acute Nephrotoxicity With Enhancing Antitumor Activity of Cisplatin by Upregulating SIRT1/SIRT6-Nrf2 Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2020.579178 ◽

2020 ◽

Vol 11 ◽

Author(s):

Xiaoye Fan ◽

Wei Wei ◽

Jingbo Huang ◽

Liping Peng ◽

Xinxin Ci

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Cell Damage ◽

Protective Effects ◽

Normal Tissues ◽

Nrf2 Signaling Pathway ◽

Apoptosis Pathways ◽

Underlying Mechanisms

Cisplatin (CDDP) is a widely used drug for cancer treatment that exhibits major side effects in normal tissues, such as nephrotoxicity in kidneys. The Nrf2 signaling pathway, a regulator of mitochondrial dysfunction, oxidative stress and inflammation, is a potential therapeutic target in CDDP-induced nephrotoxicity. We explored the underlying mechanisms in wild-type (WT) and Nrf2−/− mice on CDDP-induced renal dysfunction in vivo. We found that Nrf2 deficiency aggravated CDDP-induced nephrotoxicity, and Daph treatment significantly ameliorated the renal injury characterized by biochemical markers in WT mice and reduced the CDDP-induced cell damage. In terms of the mechanism, Daph upregulated the SIRT1 and SIRT6 expression in vivo and in vitro. Furthermore, Daph inhibited the expression level of NOX4, whereas it activated Nrf2 translocation and antioxidant enzymes HO-1 and NQO1, and alleviated oxidative stress and mitochondrial dysfunction. Moreover, Daph suppressed CDDP-induced NF-κB and MAPK inflammation pathways, as well as p53 and cleaved caspase-3 apoptosis pathways. Notably, the protective effects of Daph in WT mice were completely abrogated in Nrf2−/− mice. Moreover, Daph enhanced, rather than attenuated, the tumoricidal effect of CDDP.

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Protective effects of bisoprolol against cadmium-induced myocardial toxicity through inhibition of oxidative stress and NF-κΒ signalling in rats

Journal of Veterinary Research ◽

10.2478/jvetres-2021-0054 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Jinhua Liu ◽

Ying Xie ◽

Zhujun Han ◽

Hailong Wang ◽

Wenhu Xu

Keyword(s):

Oxidative Stress ◽

Cardiac Injury ◽

Therapeutic Drug ◽

Control Group ◽

Protective Effects ◽

Necrosis Factor Alpha ◽

Tissue Samples ◽

Gum Acacia ◽

Tnf Α ◽

Creatine Kinase Mb

Abstract Introduction The aim of the study was to investigate the mitigative effects of bisoprolol (BIS) in cadmium-induced myocardial toxicity on oxidative stress and its inhibitive effect on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signalling in rats. Material and Methods Male albino Wistar rats were assigned to control, Cd, BIS 2 (2 mg/kg b.w.) and BIS 8 (8 mg/kg b.w.) groups with nine rats in each. Over four weeks, the control group was administered 1% gum acacia, all other groups received 3mg/kg b.w. CdCl2 dissolved in distilled water, and the BIS groups were additionally given bisoprolol in gum acacia. Blood samples were collected for biochemical estimations. Blood pressure and serum biomarker (lactate dehydrogenase, aspirate transaminase, alanine transferase and creatine kinase-MB, enzyme (superoxide dismutase, lipid hydroxy peroxidase, catalase and malondialdehyde), and tumour necrosis factor alpha (TNF-α) concentrations were measured. Western blot analysis was conducted for NF-κB and glutathione S-transferase (GST). After sacrificing the rats, cardiac tissue samples were examined histopathologically. Results Our findings pointed to a significant decrease (P < 0.05) in the studied serum biomarkers and levels of the relevant enzymes in the BIS 8 group compared to the Cd group. A significant decrease (P < 0.05) in NF-kB p65 expression and TNF-α levels was noted in the BIS 8 group relative to the BIS 2 and Cd groups, indicating a reduction at a higher dose. In microscopy, histopathological changes in the cardiac muscles of the BIS 8 group were evident compared to those of the Cd group. Conclusion BIS seemed to have protective effects against cardiac injury induced by cadmium and could be considered a novel therapeutic drug and prognostic biomarker in the pathology of the many cardiovascular diseases caused by heavy metal intake.

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Luteolin Alleviates AflatoxinB1-Induced Apoptosis and Oxidative Stress in the Liver of Mice through Activation of Nrf2 Signaling Pathway

Antioxidants ◽

10.3390/antiox10081268 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1268

Author(s):

Shahid Ali Rajput ◽

Aftab Shaukat ◽

Kuntan Wu ◽

Imran Rashid Rajput ◽

Dost Muhammad Baloch ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Signaling Pathway ◽

Aflatoxin B1 ◽

Physiological Saline ◽

Protective Effects ◽

Biochemical Alterations ◽

Protein Levels ◽

Nrf2 Signaling Pathway ◽

Induced Apoptosis

Aflatoxin B1 (AFB1), a threatening mycotoxin, usually provokes oxidative stress and causes hepatotoxicity in animals and humans. Luteolin (LUTN), well-known as an active phytochemical agent, acts as a strong antioxidant. This research was designed to investigate whether LUTN exerts protective effects against AFB1-induced hepatotoxicity and explore the possible molecular mechanism in mice. A total of forty-eight mice were randomly allocated following four treatment groups (n = 12): Group 1, physiological saline (CON). Group 2, treated with 0.75 mg/kg BW aflatoxin B1 (AFB1). Group 3, treated with 50 mg/kg BW luteolin (LUTN), and Group 4, treated with 0.75 mg/kg BW aflatoxin B1 + 50 mg/kg BW luteolin (AFB1 + LUTN). Our findings revealed that LUTN treatment significantly alleviated growth retardation and rescued liver injury by relieving the pathological and serum biochemical alterations (ALT, AST, ALP, and GGT) under AFB1 exposure. LUTN ameliorated AFB1-induced oxidative stress by scavenging ROS and MDA accumulation and boosting the capacity of the antioxidant enzyme (CAT, T-SOD, GSH-Px and T-AOC). Moreover, LUTN treatment considerably attenuates the AFB1-induced apoptosis in mouse liver, as demonstrated by declined apoptotic cells percentage, decreased Bax, Cyt-c, caspase-3 and caspase-9 transcription and protein with increased Bcl-2 expression. Notably, administration of LUTN up-regulated the Nrf2 and its associated downstream molecules (HO-1, NQO1, GCLC, SOD1) at mRNA and protein levels under AFB1 exposure. Our results indicated that LUTN effectively alleviated AFB1-induced liver injury, and the underlying mechanisms were associated with the activation of the Nrf2 signaling pathway. Taken together, LUTN may serve as a potential mitigator against AFB1-induced liver injury and could be helpful for the development of novel treatment to combat liver diseases in humans and/or animals.

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