cytochrome-c-t and Cardiotoxicity

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Beclin-1; Cardiotoxicity; Caspase 3; Caspase 9; Cyclooxygenase 2; Cytochromes c; Inflammation; Interleukin-2; Male; Mice; Mice, Inbred C57BL; Nickel; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Thioredoxin-Disulfide Reductase; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Canagliflozin; Cardiotoxicity; Cisplatin; Cytochromes c; Heart Injuries; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats

Medical therapies can cause cardiotoxicity. Chloroquine (QC) and hydroxychloroquine (HQC) are drugs used in the treatment of malaria and skin and rheumatic disorders. These drugs were considered to help treatment of coronavirus disease (COVID-19) in 2019. Despite the low cost and availability of QC and HQC, reports indicate that this class of drugs can cause cardiotoxicity. The mechanism of this event is not well known, but evidence shows that QC and HQC can cause cardiotoxicity by affecting mitochondria and lysosomes.. Therefore, our study was designed to investigate the effects of QC and HQC on heart mitochondria. In order to achieve this aim, mitochondrial function, reactive oxygen species (ROS) level, mitochondrial membrane disruption, and cytochrome c release in heart mitochondria were evaluated. Statistical significance was determined using the one-way and two-way analysis of variance (ANOVA) followed by post hoc Tukey to evaluate mitochondrial succinate dehydrogenase (SDH) activity and cytochrome c release, and Bonferroni test to evaluate the ROS level, mitochondrial membrane potential (MMP) collapse, and mitochondrial swelling.. Based on ANOVA analysis (one-way), the results of mitochondrial SDH activity showed that the IC. The results suggest that QC and HQC can cause cardiotoxicity which can lead to heart disorders through oxidative stress and disfunction of heart mitochondria.

Topics: Cardiotoxicity; Chloroquine; COVID-19; COVID-19 Drug Treatment; Cytochromes c; Humans; Hydroxychloroquine; Mitochondria; Reactive Oxygen Species

To investigate whether hesperetin (Hes) alleviates doxorubicin (DOX)-induced cardiomyocytotoxicity by reducing oxidative stress via regulating silent information regulator 1 (SIRT1)/nuclear transcription factor E2-related factor 2 (NRF2) signaling in H9c2 cells.. H9c2 cells were treated with DOX to establish the cardiotoxicity model and were randomly assigned to four groups, a control group (Control) and three treatment groups, receiving respectively DOX (the DOX group), Hes+DOX (the DOX+Hes group), and Hes+SIRT1 inhibitor EX527+DOX (the DOX+Hes+EX527 group). Cellular morphology was observed by the light microscope. Cell viability was evaluated by CCK-8. DOX-induced apoptosis in H9c2 cells was examined by flow cytometry. The levels of reactive oxygen species (ROS) in the H9c2 cells of the four groups were determied with 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. The activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase (CAT), and SIRT1 as well as the malondialdehyde (MDA) content were measured using ELISA kits. The expressions of cleaved caspase-3, cytochrome c, SIRT1, Ac-FOXO1, NRF2, and heme oxygenase 1 (HO-1) were determined by Western blot.. Hes inhibits oxidative stress and apoptosis via regulating SIRT1/NRF2 signaling, thereby reducing DOX-induced cardiotoxicity in H9c2 cells.

Topics: Apoptosis; Cardiotoxicity; Caspase 3; Cytochromes c; Doxorubicin; Humans; Myocytes, Cardiac; NF-E2-Related Factor 2; Oxidative Stress; Reactive Oxygen Species; Sirtuin 1; Superoxide Dismutase

Decabromodiphenyl ethane (DBDPE) is a major alternative to BDE-209 owing to its lower toxicity. However, the mass production and increased consumption of DBDPE in recent years have raised concerns related to its adverse health effects. However, the effect and mechanism of DBDPE on cardiotoxicity have rarely been studied. In the present study, we investigated the impacts of DBDPE on the cardiovascular system in male SD rats and then explored the underlying mechanisms to explain the cardiotoxicity of DBDPE using AC16 cells. Under in vivo conditions, male rats were administered with an oral dosage of DBDPE at 0, 5, 50, and 500 mg/kg/day for 28 days, respectively. Histopathological analysis demonstrated that DBDPE induced cardiomyocyte injury and fibrosis, and ultrastructural observation revealed that DBDPE could induce mitochondria damage and dissolution. DBDPE could thus decrease the level of MYH6 and increase the level of SERCA2, which are the two key proteins involved in the maintenance of homeostasis during myocardial contractile and diastolic processes. Furthermore, DBDPE could increase the serum levels of glucose and low-density lipoprotein but decrease the content of high-density lipoprotein. In addition, DBDPE could activate the PI3K/AKT/GLUT2 and PPARγ/RXRα signaling pathways in AC16 cells. In addition, DBDPE decreased the UCP2 level and ATP synthesis in mitochondria both under in vitro and in vivo conditions, consequently leading to apoptosis via the Cytochrome C/Caspase-9/Caspase-3 pathway. Bisulfite sequencing PCR (BSP) identified the hypermethylation status of fat mass and obesity-associated gene (FTO). 5-aza exerted the opposite effects on the PI3K/AKT/GLUT2, PPARγ/RXRα, and Cytochrome C/Caspase-9/Caspase-3 signaling pathways induced by DBDPE in AC16 cells. In addition, the DBDPE-treated altered levels of UCP2, ATP, and apoptosis were also found to be significantly reversed by 5-aza in AC16 cells. These results suggested that FTO hypermethylation played a regulative role in the pathological process of DBDPE-induced glycolipid metabolism disorder, thereby contributing to the dysfunction of myocardial contraction and relaxation through cardiomyocytes fibrosis and apoptosis via the mitochondrial-mediated apoptotic pathway resulting from mitochondrial dysfunction.

Topics: Adenosine Triphosphate; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Apoptosis; Bromobenzenes; Cardiotoxicity; Caspase 3; Caspase 9; Cytochromes c; Fibrosis; Heart Diseases; Male; Obesity; Phosphatidylinositol 3-Kinases; PPAR gamma; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley

Excessive fluoride intake has been reported to cause toxicities to brain, thyroid, kidney, liver and testis tissues. Hesperidin (HSP) is an antioxidant that possesses anti-allergenic, anti-carcinogenic, anti-oxidant and anti-inflammatory activities. Presently, the studies focusing on the toxic effects of sodium fluoride (NaF) on heart tissue at biochemical and molecular level are limited. This study was designed to evaluate the ameliorative effects of HSP on toxicity of NaF on the heart of rats in vivo by observing the alterations in oxidative injury markers (MDA, SOD, CAT, GPX and GSH), pro-inflammatory markers (NF-κB, IL-1β, TNF-α), expressions of apoptotic genes (caspase-3, -6, -9, Bax, Bcl-2, p53, cytochrome c), levels of autophagic markers (Beclin 1, LC3A, LC3B), expression levels of PI3K/Akt/mTOR and cardiac markers. HSP treatment attenuated the NaF-induced heart tissue injury by increasing activities of SOD, CAT and GPx and levels of GSH, and suppressing lipid peroxidation. In addition, HSP reversed the changes in expression of apoptotic (caspase-3, -6, -9, Bax, Bcl-2, p53, cytochrome c), levels of autophagic and inflammatory parameters (Beclin 1, LC3A, LC3B, NF-κB, IL-1β, TNF-α), in the NaF-induced cardiotoxicity. HSP also modulated the gene expression levels of PI3K/Akt/mTOR signaling pathway and levels of cardiac markers (LDH, CK-MB). Overall, these findings reveal that HSP treatment can be used for the treatment of NaF-induced cardiotoxicity.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Beclin-1; Cardiotoxicity; Caspase 3; Cytochromes c; Heart Diseases; Hesperidin; Inflammation; NF-kappa B; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Sodium Fluoride; Superoxide Dismutase; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

To investigate the effect of honokiol (HKL) for reducing doxorubicin (DOX)-induced cardiotoxicity in H9c2 cells and the underlying mechanisms.. H9c2 cells were divided into control group, DOX group, HKL + DOX group, and HKL+compound C+DOX group. After 24 h of corresponding treatment, the cells were examined for morphological changes and cell viability using CCK-8 assay. The mRNA expressions of the inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were detected by RT-PCR, and the protein levels of cleaved caspase-3, cytochrome c, NOD-like receptor pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), p-AMPK and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) were detected with Western blotting; the expressions of NLRP3 and p-AMPK also detected with immunofluorescence staining.. DOX treatment caused swelling and significantly lowered the viability of H9c2 cells (. HKL can alleviate DOX-induced cardiotoxicity by inhibiting pyroptosis in H9c2 cells, and this effect is mediated by activation of AMPK to regulate Nrf2 signaling.

Topics: Allyl Compounds; AMP-Activated Protein Kinases; Biphenyl Compounds; Cardiotoxicity; Caspase 3; Cytochromes c; Doxorubicin; Humans; Interleukin-6; Myocytes, Cardiac; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Phenols; Pyroptosis; RNA, Messenger; Tumor Necrosis Factor-alpha

Tebuconazole is an effective systemic fungicide that belongs to the triazoles family. It has been widely used in both agricultural and medical sectors for the control of fungal diseases. Although TEB poses serious threats to mammals health, studies regarding its cardiotoxicity are very limited. Thus, we aimed to evaluate the effects of TEB on some biochemical parameters, the induction of apoptosis and DNA damage in the heart tissue. Male Wistar rats were treated with TEB at varied oral doses for 28 consecutive days. This study demonstrates that TEB decreased cardiac acetylcholinesterase, increased serum marker enzymes such as creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH), and altered the lipid profile by increasing serum levels of total cholesterol (T-CHOL), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C) levels. Furthermore, TEB increased levels of p53 and Bax/Bcl2 ratio, released the cytochrome c into the cytosol and activated caspase-9 and caspase-3. Besides, our results showed that TEB induced genotoxic effects. TEB induced DNA fragmentation and increased the frequency of micronucleated bone marrow cells. Moreover, TEB treatment developed fibrosis in the myocardium. Our results suggest that TEB exposure may affect myocardial cells normal functioning and triggers apoptosis.

Topics: Animals; Apoptosis; Cardiotoxicity; Cholesterol, LDL; Cytochromes c; DNA Fragmentation; Fungicides, Industrial; Humans; Male; Rats; Rats, Wistar; Triazoles; Triglycerides

Doxorubicin (Dox)-induced cardiotoxicity limits its clinical use. A number of microRNAs (miRs) have been found essential in Dox-induced cardiotoxicity. The aim of the present study was to elucidate the effects of miR-23a on Dox-induced cardiomyocyte apoptosis and underlying mechanisms.. Dox-induced cardiotoxicity model was established in primary neonatal rat ventricular myocytes (NRVMs). MTT assay, Live/Dead staining was employed to examine the viability and cell death of NRVMs. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were measured. Protein levels of mitochondria biogenesis and fission/fusion associated factors including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), dynamin-related protein-1 (Drp1) and mitofusin 2 (Mfn2) were detected. Meanwhile, apoptosis-related cytochrome c (Cyt c) and caspase-3 expression were examined by western blot. PGC-1α siRNA was employed to validate the role of miR-23a in Dox-induced cardiotoxicity.. MiR-23a expression was significantly increased by Dox concentration-dependently. Inhibition of miR-23a markedly increased viability and MMP, reduced cell death and ROS production of NRVMs. MiR-23a mimic significantly inhibited expression of its target PGC-1α. MiR-23a inhibitor significantly diminished phosphorylation of Drp1 without affecting Mfn2 expression. Protein expression of Cyt c and cleaved caspase-3 were markedly inhibited by miR-23a inhibitor. The protective effects of miR-23a inhibitor were reversed by PGC-1α siRNA.. Increased miR-23a promoted mitochondrial injury in the Dox-induced cellular model. Inhibition of miR-23a attenuated cardiomyocyte damage by directly targeting PGC-1α/p-Drp1, thereby inhibiting mitochondria-dependent apoptosis. These findings may provide a new potential target for the treatment of Dox-induced cardiotoxicity.

Topics: Animals; Animals, Newborn; Apoptosis; Cardiotoxicity; Caspase 3; Cells, Cultured; Cytochromes c; Doxorubicin; Dynamins; Membrane Potential, Mitochondrial; MicroRNAs; Mitochondria, Heart; Myocytes, Cardiac; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering; Signal Transduction

Quince (Cydonia oblonga Mill.) and fig (Ficus carica L.) exhibit a broad spectrum of pharmacological activities. Regarding the cardiotoxic effect of doxorubicin (DOX) is mediated mainly through mitochondrial oxidative stress and dysfunction; the present study evaluated the cardioprotective effects of the aqueous extracts of Cydonia oblonga Mill. fruit (ACO) and Ficus carica L. fruit (AFC) against DOX-induced cardiotoxicity. Cardiomyocytes toxicity was induced in male Sprague Dawley rats by intraperitoneal (ip) injections of 2.5 mg/kg DOX 3 times per week for a period of 2 weeks. After heart failure was induced in the rats, the animals were decapitated and their hearts were immediately removed. Then, the cardiac mitochondria were isolated by differential ultracentrifugation, and the protective effects of each particular extract on mitochondrial oxidative stress and dysfunction were determined. ACO and AFC ameliorated mitochondrial dysfunction in the isolated mitochondria and prevented mitochondrial reactive oxygen species formation, membrane lipid peroxidation, mitochondrial swelling, mitochondrial membrane potential collapse (%ΔΨm), and cytochrome c release. Also, the extracts significantly increased reduced glutathione levels and succinate dehydrogenase activity. These results indicated that ACO and AFC have beneficial effects against DOX cardiotoxicity which mediated by attenuating mitochondrial dysfunction. Therefore, it can be suggested that quince and fig may increase the therapeutic index of DOX.

Topics: Animals; Antibiotics, Antineoplastic; Cardiotonic Agents; Cardiotoxicity; Cytochromes c; Doxorubicin; Ficus; Fruit; Glutathione; Male; Membrane Potential, Mitochondrial; Mitochondria; Myocytes, Cardiac; Oxidative Stress; Plant Extracts; Rats; Rats, Sprague-Dawley; Rosaceae

Doxorubicin (DOX) is the mainstay chemotherapeutic agent against a variety of human neoplasmas. However, its clinical utility is limited by its marked cardiotoxicity. Chrysin, is a natural flavone which possesses antioxidant, anti-inflammatory and anti-cancer properties. The current study aimed to investigate the potential protective effect of chrysin against DOX-induced chronic cardiotoxicity and the underlying molecular mechanisms. Male Sprague-Dawley rats were treated with either DOX (5 mg/kg, once a week) and/or chrysin (50 mg/kg, four times a week) for four weeks. Chrysin prevented DOX-induced cardiomyopathy which was evident by conduction abnormalities, elevated serum CKMB and LDH and histopathological changes. Chrysin also ameliorated DOX-induced oxidative stress by decreasing lipid peroxidation and upregulating the antioxidant enzymes. Moreover, chrysin attenuated DOX-induced apoptosis via decreasing expression of p53, Bax, Puma, Noxa, cytochrome c and caspase-3 while increasing expression of Bcl-2. DOX induced activation of MAPK; p38 and JNK and increased expression of NF-κB. Meanwhile, DOX suppressed AKT pathway via decreasing expression of its upstream activator VEGF and increasing expression of PTEN. Conversely, chrysin effectively neutralised all these effects. Collectively, these findings indicate that chrysin effectively protected against DOX-induced cardiomyopathy via suppressing oxidative stress, p53-dependent apoptotic pathway, MAPK and NF-κB pathways while augmenting the VEGF/AKT pathway.

Topics: Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Cardiomyopathies; Cardiotonic Agents; Cardiotoxicity; Caspase 3; Cytochromes c; Doxorubicin; Drug Administration Schedule; Flavonoids; Gene Expression Regulation; Male; Myocytes, Cardiac; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Signal Transduction; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A

To explore the effect of Osthole on protecting myocardial cell apoptosis induced by doxorubicin during cardiac failure in rats.. Myocardial cells isolated from the newborn SD rats were separated into three groups: cells treated with 1 μmol doxorubicin, cells treated with Osthole at three concentrations of 10, 20, and 40 μmol, cells treated neither with Osthole nor with doxorubicin were the control groups. Consequently, cell apoptosis of myocardial cells in each group was analyzed using TUNEL assay. Also, expressions of oxidase, NADPH, and ROS in myocardial cells were analyzed using different biological methods. Moreover, expressions of cell apoptosis associated proteins were analyzed using Western blotting.. Compared with the controls, the results showed that cells received Osthole and doxorubicin treatments performed high percentage of cell apoptosis, suggesting that Osthole could anesis myocardial cell apoptosis induced by doxorubicin (P<0.05). Osthole of 10 μmol depressed the expressions of cell apoptosis associated proteins including Caspase-3 and Cytc, and enhancing expression of Bcl-XL expression (P<0.05). Osthole of 20 μmol significantly decreased the generation of intracellar superoxidase, NADPH, and NADPH activity in myocardial cells treated with doxorubicin (P<0.05). Moreover, Osthole of 20 μmol could significantly increase phosphorylated elF2α level in cells.. Our study suggested that Osthole may play a protective role in suppressing myocardial apoptosis induced by doxorubicin through inhibiting NADPH and superoxidase production and downstream phosphorylated elF2α.

Topics: Animals; Animals, Newborn; Antibiotics, Antineoplastic; Antioxidants; Apoptosis; bcl-X Protein; Cardiotoxicity; Caspase 3; Cells, Cultured; Coumarins; Cytochromes c; Cytoprotection; Dose-Response Relationship, Drug; Doxorubicin; Eukaryotic Initiation Factor-2; Myocytes, Cardiac; NADP; NADPH Oxidases; Oxidative Stress; Phosphorylation; Rats, Sprague-Dawley; Superoxides