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Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in cell communication and microenvironmental signaling. Overexpression of CCN2 has been documented in various cardiovascular pathologies, wherein it may exert either deleterious or protective effects depending on the pathological context, thereby suggesting that its role in the cardiovascular system is not yet fully elucidated. In this study, we aimed to investigate the effects of Ccn2 gene deletion on the progression of acute cardiac injury induced by doxorubicin (DOX), a widely utilized chemotherapeutic agent. To this end, we employed conditional knockout (KO) mice for the Ccn2 gene (CCN2-KO), which were administered DOX and compared to DOX-treated wild-type (WT) control mice. Our findings demonstrated that the ablation of CCN2 ameliorated DOX-induced cardiac dysfunction, as evidenced by improvements in ejection fraction (EF) and fractional shortening (FS) of the left ventricle. Furthermore, DOX-treated CCN2-KO mice exhibited a significant reduction in the gene expression and activation of oxidative stress markers (Hmox1 and Nfe2l2/NRF2) relative to DOX-treated WT controls. Additionally, the deletion of Ccn2 markedly attenuated DOX-induced cardiac fibrosis. Collectively, these results suggest that CCN2 plays a pivotal role in the pathogenesis of DOX-mediated cardiotoxicity by modulating oxidative stress and fibrotic pathways. These findings provide a novel avenue for future investigations to explore the therapeutic potential of targeting CCN2 in the prevention of DOX-induced cardiac dysfunction.

Oxidative stress contributes greatly to doxorubicin (DOX)-induced cardiotoxicity. Down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor in DOX-induced myocardial oxidative injury. Recently, we found that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)-dependent k48-linked ubiquitination was responsible for down-regulation of myocardial Nrf2 in DOX-treated mice. Micafungin, an antifungal drug, was identified as a potential MALT1 inhibitor. This study aims to explore whether micafungin can reduce DOX-induced myocardial oxidative injury and if its anti-oxidative effect involves a suppression of MALT1-dependent k48-linked ubiquitination of Nrf2. To establish the cardiotoxicity models in vivo and in vitro, mice were treated with a single dose of DOX (15 mg/kg, i.p.) and cardiomyocytes were incubated with DOX (1 μM) for 24 h, respectively. Using mouse model of DOX-induced cardiotoxicity, micafungin (10 or 20 mg/kg) was shown to improve cardiac function, concomitant with suppression of oxidative stress, mitochondrial dysfunction, and cell death in a dose-dependent manner. Similar protective roles of micafungin (1 or 5 μM) were observed in DOX-treated cardiomyocytes. Mechanistically, micafungin weakened the interaction between MALT1 and Nrf2, decreased the k48-linked ubiquitination of Nrf2 while elevated the protein levels of Nrf2 in both DOX-treated mice and cardiomyocytes. Furthermore, MALT1 overexpression counteracted the cardioprotective effects of micafungin. In conclusion, micafungin reduces DOX-induced myocardial oxidative injury via suppression of MALT1, which decreases the k48-linked ubiquitination of Nrf2 and elevates Nrf2 protein levels. Thus, micafungin may be repurposed for treating DOX-induced cardiotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Doxorubicin (Dox) use is limited by Dox-induced cardiotoxicity. TANK-blinding kinase 1 (TBK1) is an important kinase involved in the regulation of mitophagy, but the role of TBK1 in cardiomyocytes in chronic Dox-induced cardiomyopathy remains unclear. Cardiomyocyte-specific Tbk1 knockout (Tbk1 CKO ) mice received Dox (6 mg/kg, injected intraperitoneally) once a week for 4 times, and cardiac assessment was performed 4 weeks after the final Dox injection. Adenoviruses encoding Tbk1 or containing shRNA targeting Tbk1, or a TBK1 phosphorylation inhibitor were used for overexpression or knockdown of Tbk1, or inhibit phosphorylation of TBK1 in isolated primary cardiomyocytes. Our results revealed that moderate Dox challenge decreased TBK1 phosphorylation (with no effect on TBK1 protein levels), resulting in compromised myocardial function, obvious mortality and overt interstitial fibrosis, and the effects were accentuated by Tbk1 deletion. Dox provoked mitochondrial membrane potential collapse and oxidative stress, the effects of which were exacerbated and mitigated by Tbk1 knockdown, specific inhibition of phosphorylation and overexpression, respectively. However, Tbk1 （Ser172A） overexpression did not alleviate these effects. Further scrutiny revealed that TBK1 exerted protective effects on mitochondria via SQSTM1/P62-mediated mitophagy. Tbk1 overexpression mediated cardioprotective effects on Dox-induced cardiotoxicity were cancelled off by Sqstm1/P62 knockdown. Moreover, TBK1-mitophagy-mitochondria cascade was confirmed in heart tissues from dilated cardiomyopathy patients. Taken together, our findings denoted a pivotal role of TBK1 in Dox-induced mitochondrial injury and cardiotoxicity possibly through its phosphorylation and SQSTM1/P62-mediated mitophagy., Competing Interests: Declaration of competing interest The authors confirm that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent evidence suggests the mechanistic role of mitochondria and oxidative stress in the development of celecoxib-induced cardiotoxicity. On the other, it has reported the positive effects of vitamin D on oxidative stress and the maintenance of mitochondrial functions. This current study examined the cardiac effects of celecoxib, doxorubicin, vitamin D, and a combination of them in rats. The effect of 10 days of celecoxib (100 mg/kg/day), doxorubicin (2.5 mg/kg), vitamin D (60,000 U/kg), and their combination was studied on cardiac function according to serum lactate dehydrogenase (LDH), creatine kinase (CK), glutathione (GSH), and malondialdehyde (MDA) levels as well as mitochondrial succinate dehydrogenases (SDH) activity, reactive oxygen species (ROS) production, mitochondrial swelling, and mitochondrial membrane potential (MMP). Results showed that celecoxib and its combination with doxorubicin led to abnormality in paws and limbs, increased pressure in the eyes, blindness and animal death (in about 75% of the animals under study). Moreover, celecoxib and its combination with doxorubicin significantly increased cardiotoxicity biomarkers, oxidative stress markers (GSH and MDA), and mitochondrial toxicity parameters (SDH, ROS formation, MMP collapse, mitochondrial swelling). However, the combination of vitamin D with celecoxib and celecoxib + doxorubicin caused a significant reversal of deformity in paws and limbs, increased pressure in the eye, blindness, and animal death, as well as cardiotoxicity, oxidative stress, and mitochondrial parameters. This study proved for the first time the beneficial effect of vitamin D on celecoxib-induced cardiotoxicity, which is aggravated in the presence of doxorubicin through the maintenance of mitochondrial functions and its antioxidant potential., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Doxorubicin (DOX) is a highly effective and widely used cytotoxic agent with application for various malignancies, but it's clinically limited due to its cardiotoxicity Oxidative stress and inflammation were reported to take part in DOX-induced cardiotoxicity. Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist has been approved to treat type 2 diabetes. However, its role in DOX-induced cardiotoxicity and the underlying mechanisms has not been explored., Methods: The cardioprotective properties of Tirzepatide against DOX-induced cardiotoxicity are examined in this work both in vivo and in vitro. For four weeks, an intraperitoneal injection of 4 mg/kg DOX was used to cause cardiotoxicity in C57BL/6 mice. To ascertain the cardioprotective function and underlying mechanisms of Tirzepatide against DOX-induced cardiotoxicity, mice and H9c2 cells were treated with and without Tirzepatide., Results: Tirzepatide treatment significantly inhibited DOX-induced oxidative stress, inflammation and cardiac injury. Mechanistically, PI3K/Akt signaling pathway contributes to the protective effect of Tirzepatide against DOX-induced cardiotoxicity and inhibited PI3K/Akt signaling pathway with LY294002 almost blocked its therapeutic effect., Conclusions: Collectively, Tirzepatide could alleviate DOX-induced oxidative stress, inflammation and cardiac injury via activating PI3K/Akt signaling pathway and Tirzepatide may be a novel therapeutic target for DOX-induced cardiotoxicity., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Doxorubicin (DOX) is a potent chemotherapy widely used in treating various neoplastic diseases. However, the clinical use of DOX is limited due to its potential toxic effect on the cardiovascular system. Thus, identifying the pathway involved in this toxicity may help minimize chemotherapy risk and improve cancer patients' quality of life. Recent studies suggest that Endothelial-to-Mesenchymal transition (EndMT) and endothelial toxicity contribute to the pathogenesis of DOX-induced cardiovascular toxicity. However, the molecular mechanism is yet unknown. Given that arachidonic acid and associated cytochrome P450 (CYP) epoxygenase have been involved in endothelial and cardiovascular function, we aimed to examine the effect of suppressing CYP epoxygenases on DOX-induced EndMT and cardiovascular toxicity in vitro and in vivo., Methods and Results: To test this, human endothelial cells were treated with DOX, with or without CYP epoxygenase inhibitor, MSPPOH. We also investigated the effect of MSPPOH on the cardiovascular system in our zebrafish model of DOX-induced cardiotoxicity. Our results showed that MSPPOH exacerbated DOX-induced EndMT, inflammation, oxidative stress, and apoptosis in our endothelial cells. Furthermore, we also show that MSPPOH increased cardiac edema, lowered vascular blood flow velocity, and worsened the expression of EndMT and cardiac injury markers in our zebrafish model of DOX-induced cardiotoxicity., Conclusion: Our data indicate that a selective CYP epoxygenase inhibitor, MSPPOH, induces EndMT and endothelial toxicity to contribute to DOX-induced cardiovascular toxicity., (© 2024. The Author(s).)

Cardiotoxicity is the main side effect of several chemotherapeutic drugs. Doxorubicin (Doxo) is one of the most used anthracyclines in the treatment of many tumors, but the development of acute and chronic cardiotoxicity limits its clinical usefulness. Different studies focused only on the effects of long-term Doxo administration, but recent data show that cardiomyocyte damage is an early event induced by Doxo after a single administration that can be followed by progressive functional decline, leading to overt heart failure. The knowledge of molecular mechanisms involved in the early stage of Doxo-induced cardiotoxicity is of paramount importance to treating and/or preventing it. This review aims to illustrate several mechanisms thought to underlie Doxo-induced cardiotoxicity, such as oxidative and nitrosative stress, inflammation, and mitochondrial dysfunction. Moreover, here we report data from both in vitro and in vivo studies indicating new therapeutic strategies to prevent Doxo-induced cardiotoxicity.

Coenzyme Q10 (CoQ10) occurs naturally in the body and possesses antioxidant and cardioprotective effects. Cardiotoxicity has emerged as a serious effect of the exposure to cadmium (Cd). This study investigated the curative potential of CoQ10 on Cd cardiotoxicity in mice, emphasizing the involvement of oxidative stress (OS) and NF-κB/NLRP3 inflammasome axis. Mice received a single intraperitoneal dose of CdCl 2 (6.5 mg/kg) and a week after, CoQ10 (100 mg/kg) was supplemented daily for 14 days. Mice that received Cd exhibited cardiac injury manifested by the elevated circulating cardiac troponin T (cTnT), CK-MB, LDH and AST. The histopathological and ultrastructural investigations supported the biochemical findings of cardiotoxicity in Cd-exposed mice. Cd administration increased cardiac MDA, NO and 8-oxodG while suppressed GSH and antioxidant enzymes. CoQ10 decreased serum CK-MB, LDH, AST and cTnT, ameliorated histopathological and ultrastructural changes in the heart of mice, decreased cardiac MDA, NO, and 8-OHdG and improved antioxidants. CoQ10 downregulated NF-κB p65, NLRP3 inflammasome, IL-1β, MCP-1, JNK1, and TGF-β in the heart of Cd-administered mice. Moreover, in silico molecular docking revealed the binding potential between CoQ10 and NF-κB, ASC1 PYD domain, NLRP3 PYD domain, MCP-1, and JNK. In conclusion, CoQ10 ameliorated Cd cardiotoxicity by preventing OS and inflammation and modulating NF-κB/NLRP3 inflammasome axis in mice. Therefore, CoQ10 exhibits potent therapeutic benefits in safeguarding cardiac tissue from the harmful consequences of exposure to Cd., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Huangqi Guizhi Wuwu Decoction (HQGZWWD) has shown promising potential in treating various cardiovascular diseases. This study aimed to elucidate the molecular basis and therapeutic role of HQGZWWD in the treatment of doxorubicin (DOX)-induced myocardial injury. The HPLC fingerprint of HQGZWWD was used to analyze the active components. A DOX-induced myocardial damage rat model was developed, and the therapeutic effects of HQGZWWD were evaluated using echocardiography, myocardial enzyme levels, and hematoxylin and eosin staining. Network pharmacology was used to screen treatment targets, and western blotting and immunohistochemistry were performed to assess cellular pyroptosis levels. Oxidative stress levels were measured using assay kits, and mitochondrial damage was examined using transmission electron microscopy. An in vitro model of DOX-induced cell damage was established, and treatment was administered using serum containing HQGZWWD and N-acetylcysteine (NAC). Oxidative stress levels were detected using assay kits and DCFH-DA, whereas cellular pyroptosis levels were assessed through WB, immunofluorescence, and ELISA assays. HQGZWWD ameliorated DOX-induced myocardial injury. Network pharmacology identified IL-1β and IL-18 as crucial targets. HQGZWWD downregulated the protein levels of the inflammatory factors IL-1β and IL-18, inhibited the expression of GSDMD-NT, and simultaneously suppressed the synthesis of Caspase-1, ASC, NLRP3, and Caspase-11. Additionally, HQGZWWD inhibited oxidative stress, and the use of NAC as an oxidative stress inhibitor resulted in significant inhibition of the GSDMD-NT protein in H9C2 cells. These findings highlight the myocardial protective effects of HQGZWWD by inhibiting oxidative stress and suppressing both canonical and non-canonical pyroptotic pathways., Competing Interests: Declaration of Competing Interest The authors declare no competing interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: Doxorubicin (DOX) is a highly effective chemotherapeutic used to treat many adult and pediatric cancers, such as solid tumors, leukemia, lymphomas and breast cancer. It can also cause injuries to multiple organs, including the heart, liver, and brain or kidney, although cardiotoxicity is the most prominent side effect of DOX. In this study, we examined the potential effects of DOX on autophagy activity in two different mouse fibroblasts. Methods: Mouse embryonic fibroblasts (NIH3T3) and mouse primary cardiac fibroblasts (CFs) were treated with DOX to assess changes in the expression of two commonly used autophagy protein markers, LC3II and p62. We also examined the effects of DOX the on expression of key genes that encode components of the molecular machinery and regulators modulating autophagy in response to both extracellular and intracellular signals. Results: We observed that LC3II levels increased and p62 levels decreased following the DOX treatment in NIH3T3 cells. However, similar effects were not observed in primary cardiac fibroblasts. In addition, DOX treatment induced the upregulation of a significant number of genes involved in autophagy in NIH3T3 cells, but not in primary cardiac fibroblasts. Conclusions: Taken together, these results indicate that DOX upregulates autophagy in fibroblasts in a cell-specific manner., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cardiotoxicity is a frequent and often lethal complication of doxorubicin (DOX)-based chemotherapy. Here, we report that hydropersulfides (RSSH) are the most effective reactive sulfur species in conferring protection against DOX-induced toxicity in H9c2 cardiac cells. Mechanistically, RSSH supplementation alleviates the DOX-evoked surge in reactive oxygen species (ROS), activating nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways, thus boosting endogenous antioxidant defenses. Simultaneously, RSSH turns on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a master regulator of mitochondrial function, while decreasing caspase-3 activity to inhibit apoptosis. Of note, we find that RSSH potentiate anticancer DOX effects in three different cancer cell lines, with evidence that suggests this occurs via induction of reductive stress. Indeed, cancer cells already exhibit much higher basal hydrogen sulfide (H 2 S), sulfane sulfur, and reducing equivalents compared to cardiac cells. Thus, RSSH may represent a new promising avenue to fend off DOX-induced cardiotoxicity while boosting its anticancer effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The medical usage of Doxorubicin (DOX) as a chemotherapeutic agent is restricted owing to its cardiotoxic properties. This study was designed to explore the effect and underlying mechanisms of Citronellal (CT) on DOX-related cardiotoxicity in rats. Rats were divided into six groups: control, DOX, CT, Lithium chloride (LiCl) (a Na+/H+exchanger-1 [NHE1] activator), DOX + CT, and DOX + CT + LiCl. To induce cardiotoxicity, a cumulative dose of 15 mg/kg DOX was intraperitoneally injected into rats. CT (150 mg/kg) and LiCl (1 mg/kg) were given daily by oral gavage for 6 weeks. CT improved cardiac functional parameters and attenuated the cardiac pathological changes induced by DOX. Further study indicated that CT administration regulated the levels of oxidative stress and apoptosis-related factors and in myocardial tissues, reducing cell per-oxidative damage and apoptosis. Besides this, CT attenuated DOX-induced NHE1 upregulation, and the preventive effects of CT against DOX-induced cardiotoxicity were abrogated by the concurrent administration of LiCl. These results demonstrate that CT could ameliorate DOX-induced cardiotoxicity by inhibiting the NHE1-mediated oxidative stress, apoptosis in rats., (© 2021 Wiley Periodicals LLC.)

In spite of the cardiotoxic effect of selective cyclooxygenase-2 inhibitors, they are most widely used as anti-inflammatory and analgesic drugs. Today, valdecoxib and rofecoxib have been withdrawn in the market but celecoxib remains. In this study, we focused on an analysis of celecoxib toxic effects on isolated mitochondria. Isolated rat heart mitochondria were obtained using differential centrifugation. Using flow cytometry and biochemical assays, we searched succinate dehydrogenases, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) formation, mitochondrial swelling, ATP/ADP ratio, lipid peroxidation, and mitochondrial complexes activity in rat heart isolated mitochondria. Herein, our results indicated a significant decrease in the activity of complex IV after exposure with celecoxib (16 µg/ml). This decrease in the activity of complex IV is paralleled by the MMP collapse, ROS formation, mitochondrial swelling, depletion of ATP, and lipid peroxidation. For the first time, this introductory study has shown a significant decrease in the activity of complex IV and mitochondrial dysfunction after exposure with celecoxib in rat heart isolated mitochondria., (© 2021 Wiley Periodicals LLC.)

Clinically, the use of doxorubicin (DOX) is limited due to DOX-induced cardiotoxicity (DIC). The current study aimed to evaluate the cardioprotective effect of trehalose (TRE) against DIC in a female Swiss albino mouse model. Mice were divided into five experimental groups: Gp. I: saline control group (200 μl/mouse saline three times per week for 3 weeks day after day), Gp. II: DOX-treated group (2 mg/kg body weight three times per week for 3 weeks day after day), Gp. III: TRE group (200 μg/mouse three times per week for 3 weeks day after day), Gp. IV: DOX + TRE cotreatment group (animals were coadministered with DOX and TRE as in Gp. II and III, respectively), and Gp. V: DOX + TRE posttreatment group (animals were treated with DOX as in Gp. II followed by treatment with TRE as in Gp. III). DOX-treated mice showed significant elevation in cardiac injury biomarkers (lactate dehydrogenase, creatine kinase isoenzyme-MB, and cardiac troponin I), cardiac oxidative stress (OS) markers (malondialdehyde and myeloperoxidase), and cardiac levels of autophagy-related protein 5. Moreover, DOX significantly reduced the levels of total antioxidant capacity and activities of catalase and glutathione S-transferase. In contrast, TRE treatment of DOX-administered mice significantly improved almost all of the above-mentioned assessed parameters. Furthermore, histopathological changes of cardiac tissues observed in mice treated with TRE in combination with DOX were significantly improved as compared to DOX-treated animals. Taken together, the present study provides evidence that TRE has cardioprotective effects against DIC, which is likely mediated via suppression of OS and autophagy., (© 2021 Wiley Periodicals LLC.)

Cardiotoxicity is a major adverse effect that can be induced by both therapeutic agents and industrial chemicals. The pathogenesis of such cardiac damage is multifactorial, often injuring the cardiac tissue by generating free radicals, oxidative stress, and/or inflammation. Curcumin (CUR) is a bright yellow chemical produced by Curcuma longa plants. It is the principal curcuminoid of turmeric (Curcuma longa), a member of the ginger family, Zingiberaceae. Administration of CUR has been reported to ameliorate the chemical and drug-induced cardiac injury in several studies. CUR has been suggested to act as an effective candidate against oxidative stress and inflammation in heart tissue via regulation of Nrf2 and suppression of p38 MAPK/NF-κB and NLRP3 inflammasomes. The anti-apoptotic properties of CUR have also been reported to modulate the AMPK, Akt, JNK, and ERK signaling pathways. This review explores the potential protective effects of CUR regarding the detrimental effects often observed in cardiac tissue following exposure to several chemicals including drugs.

Doxorubicin (DOX) is a widely used anticancer drug. However, its clinical use is severely limited due to drug-induced cumulative cardiotoxicity, which leads to progressive cardiomyocyte dysfunction and heart failure. Enormous efforts have been made to identify potential strategies to alleviate DOX-induced cardiotoxicity; however, to date, no universal and highly effective therapy has been introduced. Here we reported that cinnamic acid (CA) derivatives exert a multitarget protective effect against DOX-induced cardiotoxicity. The experiments were performed on rat cardiomyocytes (H9c2) and human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) as a well-established model for cardiac toxicity assessment. CA derivatives protected cardiomyocytes by ameliorating DOX-induced oxidative stress and viability reduction. Our data indicated that they attenuated the chemotherapeutic's toxicity by downregulating levels of caspase-3 and -7. Pre-incubation of cardiomyocytes with CA derivatives prevented DOX-induced motility inhibition in a wound-healing assay and limited cytoskeleton rearrangement. Detailed safety analyses-including hepatotoxicity, mutagenic potential, and interaction with the hERG channel-were performed for the most promising compounds. We concluded that CA derivatives show a multidirectional protective effect against DOX-induced cardiotoxicity. The results should encourage further research to elucidate the exact molecular mechanism of the compounds' activity. The lead structure of the analyzed CA derivatives may serve as a starting point for the development of novel therapeutics to support patients undergoing DOX therapy.

Background: Doxorubicin (DOX) is a widely used cancer chemotherapeutic drug with cardiotoxicity effect limiting its clinical use. DOX induced cardiotoxicity is mediated by oxidative stress and mitochondrial damage. Kininogen-1(KNG1) is an important pro-inflammatory and pro-oxidant factor, and studies have found that it can aggravate lung and brain damage. However, it has not been known in terms of cardiotoxicity. Therefore, the purpose of this study is to understand the mechanism of KNG1 in DOX-induced heart injury., Methods: C57 mice were selected for intraperitoneal injection of DOX. The model was successfully established, and fresh ventricular tissues were isolated from the ctrl group and the DOX group for mass spectrometry analysis to screen for differentially expressed proteins. Nuclear Factor-Like 2 (Nrf2), Heme Oxygenase 1 (HO-1), 4-Hydroxynonenal (4-HNE) were used to evaluate oxidative stress level, Cytochrome C Oxidase Subunit 4 (COX4) was used to evaluate mitochondria function. Mitochondrial inner membrane potential (ΔΨm) was monitored with JC-1 fluorescence., Results: KNG1 was identified as a core gene which was highly expressed in the DOX myocardial injury model. Following this, an overexpression adenovirus was constructed, and KNG1 was overexpressed in vivo (mice) and in vitro (neonatal mouse cardiomyocytes (NMCMs)). It was found that overexpression of KNG1 can aggravate heart oxidative stress and mitochondrial damage. Besides, a knockdown KNG1 model was constructed, and the low expression of KNG1 was performed in cytology. It was found that knockdown of KNG1 can improve cardiomyocyte oxidative stress and mitochondrial damage caused by DOX. Nrf2 is an important antioxidant factor. Further, following KNG1 knock down, Nrf2 was also knocked down, and found that its cardiomyocyte protective effect was weakened., Conclusion: The overexpression of KNG1 aggravates the oxidative stress and mitochondrial damage of the heart in vivo and in vitro, which might play a role by regulating Nrf2, providing a therapeutic target for DOX-induced cardiotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study was undertaken to evaluate the therapeutic potential effect of pentoxifylline (PTX) against arsenic trioxide (ATO)-induced cardiac oxidative damage in mice. Thirty-six male albino mice were divided into six groups and treated intraperitoneally with normal saline (group 1), ATO (5 mg/kg; group 2), PTX (100 mg/kg; group 3), and different doses of PTX (25, 50, and 100 mg/kg; groups 4, 5, and 6, respectively) with ATO. After four weeks, the blood sample was collected for biochemical experiments. In addition, cardiac tissue was removed for assessment of oxidative stress markers and histopathological changes (such as hemorrhage, necrosis, infiltration of inflammatory cells, and myocardial degeneration). The findings showed that ATO caused a significant raise in serum biochemical markers such as lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and troponin-I (cTnI), glucose, total cholesterol (TC), and triglyceride (TG) levels. In addition to histopathological changes in cardiac tissue, ATO led to the significant increase in cardiac lipid peroxidation (LPO) and nitric oxide (NO); remarkable decrease in the activity of cardiac antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx); and the depletion of the total antioxidant capacity (TAC) and total thiol groups (TTGs). PTX was able to reduce the increased levels of serum cardiac markers (LDH, CPK, cTnI, TC, and TG), cardiac LPO, and improve antioxidant markers (TAC, TTGs, CAT, SOD, and GPx) alongside histopathologic changes. However, no significant changes were observed in elevated serum glucose and cardiac NO levels. In conclusion, the current study showed the potential therapeutic effect of PTX in the prevention of ATO-induced cardiotoxicity via reversing the oxidative stress., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2021 Atefeh Gholami et al.)

Doxorubicin (DOX) is an effective anticancer drug, but its therapeutic use is limited by its cardiotoxicity. The principal mechanisms of DOX-induced cardiotoxicity are oxidative stress and apoptosis in cardiomyocytes. Orosomucoid 1 (ORM1), an acute-phase protein, plays important roles in inflammation and ischemic stroke; however, the roles and mechanisms of ORM1 in DOX-induced cardiotoxicity remain unknown. Therefore, in the present study, we aimed to investigate the function of ORM1 in cardiomyocytes experiencing DOX-induced oxidative stress and apoptosis. A DOX-induced cardiotoxicity animal model was established in C57BL/6 mice by administering an intraperitoneal injection of DOX (20 mg/kg), and the control group was intraperitoneally injected with the same volume of sterilized saline. The effects were assessed after 7 d. Additionally, H9c2 cells were stimulated with DOX (10  μ M) for 24 h. The results showed decreased ORM1 and increased oxidative stress and apoptosis after DOX stimulation in vivo and in vitro. ORM1 overexpression significantly reduced DOX-induced oxidative stress and apoptosis in H9c2 cells. ORM1 significantly increased the expression of nuclear factor-like 2 (Nrf2) and its downstream protein heme oxygenase 1 (HO-1) and reduced the expression of the lipid peroxidation end product 4-hydroxynonenal (4-HNE) and the level of cleaved caspase-3. In addition, Nrf2 silencing reversed the effects of ORM1 on DOX-induced oxidative stress and apoptosis in cardiomyocytes. In conclusion, ORM1 inhibited DOX-induced oxidative stress and apoptosis in cardiomyocytes by regulating the Nrf2/HO-1 pathway, which might provide a new treatment strategy for DOX-induced cardiotoxicity., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Xiaoli Cheng et al.)

Purpose: Aloin, an anthraquinone present in the aloe species, possesses antiangiogenic, chemopreventive and antioxidant properties. It exerts cytotoxicity against breast cancer and ovarian cancer cell lines. These properties of aloin project it as a chemopreventive adjuvant to anticancer chemotherapy., Methods: We evaluated the effect of concurrent oral administration of aloin against doxorubicin (DOX)-induced cardiotoxicity in rats. The protective effects of aloin against DOX-induced toxicity were evident as a statistically significant inhibition of a rise in the biochemical markers of myocardial damage including lactate dehydrogenase (LDH), creatinine kinase-myocardial band (CK-MB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)., Results: Aloin dose dependently inhibited the DOX-induced changes in ECG like increased ST-height and prolonged QT interval. It protected heart against the lipid peroxidation and restored the levels of antioxidative defenses: reduced glutathione, catalase and superoxide dismutase. Aloin prominently reduced the levels of proinflammatory cytokines- TNF-α, IL-1β and IL-6. Notably, the significant protective effects of aloin were evident even at the strikingly lower doses of 1 and 5 mg/kg per day., Conclusion: Our results highlight the necessity to further investigate the chemopreventive effects of aloin against other chemotherapeutic agents.

Oxidative stress is widely accepted as a key factor of doxorubicin (Doxo)‑induced cardiotoxicity. There is evidence to indicate that nitrosative stress is involved in this process, and that Doxo interacts by amplifying cell damage. Mitochondrial connexin 43 (mitoCx43) can confer cardioprotective effects through the reduction of mitochondrial reactive oxygen species production during Doxo‑induced cardiotoxicity. The present study aimed to evaluate the involvement of mitoCx43 in Doxo‑induced nitrosative stress. Rat H9c2 cardiomyoblasts were treated with Doxo in the absence or presence of radicicol, an inhibitor of Hsp90, the molecular chaperone involved in Cx43 translocation to the mitochondria that underlies its role in cardioprotection. FACS analysis and RT‑qPCR revealed that Doxo increased superoxide dismutase, and catalase gene and protein expression. As shown by hypodiploid nuclei and confirmed by western blot analysis, Doxo increased caspase 9 expression and reduced procaspase 3 levels, which induced cell death. Moreover, a significant increase in the activation of the NF‑κB signaling pathway was observed. It is well known that the increased expression of inducible nitric oxide synthase results in nitric oxide overproduction, which then rapidly reacts with hydrogen peroxide or superoxide generated by the mitochondria, to form highly reactive and harmful peroxynitrite, which ultimately induces nitrotyrosine formation. Herein, these interactions were confirmed and increased effects were observed in the presence of radicicol. On the whole, the data of the present study indicate that an interplay between oxidative and nitrosative stress is involved in Doxo‑induced cardiotoxicity, and that both aspects are responsible for the induction of apoptosis. Furthermore, it is demonstrated that the mechanisms that further increase mitochondrial superoxide generation (e.g., the inhibition of Cx43 translocation into the mitochondria) significantly accelerate the occurrence of cell death.

There is a distinct increase in the risk of heart disease in people exposed to ionizing radiation (IR). Radiation-induced heart disease (RIHD) is one of the adverse side effects when people are exposed to ionizing radiation. IR may come from various forms, such as diagnostic imaging, radiotherapy for cancer treatment, nuclear disasters, and accidents. However, RIHD was mainly observed after radiotherapy for chest malignant tumors, especially left breast cancer. Radiation therapy (RT) has become one of the main ways to treat all kinds of cancer, which is used to reduce the recurrence of cancer and improve the survival rate of patients. The potential cause of radiation-induced cardiotoxicity is unclear, but it may be relevant to oxidative stress. Oxidative stress, an accumulation of reactive oxygen species (ROS), disrupts intracellular homeostasis through chemical modification and damages proteins, lipids, and DNA; therefore, it results in a series of related pathophysiological changes. The purpose of this review was to summarise the studies of oxidative stress in radiotherapy-induced cardiotoxicity and provide prevention and treatment methods to reduce cardiac damage., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2020 Zhang Ping et al.)

Hydrogen sulfide (H 2 S), as an environmental gas pollutant, has harmful effects on many tissues and organs, including myocardium. However, the underlying mechanisms of H2S-induced myocardia toxicity remain poorly understood. The present study was designed to investigate the effect of H 2 S on myocardia injury in broilers from the perspective of apoptosis. 30 ppm H2S was administered in the broiler chamber for 2, 4 and 6 week, respectively, and the myocardial samples in control groups and H2S groups were collected immediately after euthanized broilers. Transmission electron microscope, test kits, qRT-PCR and western blot were performed. Results showed that H 2 S exposure decreased the activities of catalase (CAT) and total antioxidant capability (T-AOC), whereas the content of hydrogen peroxide (H 2 O 2 ) and the activity of inducible nitric oxide synthase (iNOS) enhanced. Besides, we found the excessive expression of mitochondrial fission genes (Drp1 and Mff) by H 2 S, the dynamic balance of mitochondrial fission and fusion is destroyed. Furthermore, the levels of pro-apoptotic gene (including CytC, Cas3, Cas8, Cas9, TNF-α and Bax) increased after H 2 S exposure, as well as the expression level of anti-apoptotic gene bcl-2 decreased. At the same time, the activities of ATPase (including Na + -K + -ATPase, Ca 2+ -ATPase, Mg 2+ -ATPase and Ca 2+ -Mg 2+ -ATPase) weakened under H 2 S exposure. Therefore, we conclude that H 2 S induced oxidative stress and then leaded to excessive mitochondrial fission, which involved in apoptosis and damage broiler myocardia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Doxorubicin (DOX) is a classic anti-tumor chemotherapeutic used to treat a wide range of tumors. One major downfall of DOX treatment is it can induce fatal cardiotoxicity. Astragaloside IV (AS-IV) is one of the primary active ingredients that can be isolated from the traditional Chinese herbal medicine, Astragalus membranaceus. This study uses both in vitro and in vivo tools to investigate whether AS-IV alleviates DOX induced cardiomyopathy. We found that AS-IV supplementation alleviates body weight loss, myocardial injury, apoptosis of cardiomyocytes, cardiac fibrosis and cardiac dysfunction in DOX-treated mice. Also, DOX-induced cardiomyocyte injury and apoptosis were effectively improved by AS-IV treatment in vitro. NADPH oxidase (NOX) plays an important role in the progress of the oxidative signal transduction and DOX-induced cardiomyopathy. In this study, we found that AS-IV treatment relieves DOX-induced NOX2 and NOX4 expression and oxidative stress in cardiomyocytes. In conclusion, AS-IV, an antioxidant, attenuates DOX-induced cardiomyopathy through the suppression of NOX2 and NOX4., (Copyright © 2019. Published by Elsevier B.V.)

Doxorubicin (DOX) is a potent anti-neoplastic agent with cumulative cardiotoxicity. DOX-induced cardiotoxicity has been shown to depend on the different dosing times. However, the basis for determining the dosing time to minimize DOX-induced cardiotoxicity and the underlying mechanisms remain incompletely understood. Here we first showed that SIRT3, the major mitochondrial deacetylase, is negatively correlated to DOX-induced cardiotoxicity through the regulation of ATP production, mitochondrial membrane potential (MMP) level and ROS level in human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Then, we used in vivo experiments to demonstrate that DOX significantly reduced the SIRT3 expression and the SIRT3 activity as reflected by the increased Ac K68 MnSOD/MnSOD ratio in rats after six weeks of treatment. Notably, the activity of SIRT3 had an obvious diurnal rhythm pattern in the myocardium of healthy rats. More importantly, an obvious lower Ac K68 MnSOD/MnSOD ratio was observed in rat hearts with DOX administrated at Zeitgeber time (ZT) 9 (ZT 0 was the time lights were turned on) than ZT1, which represent the peak and trough of SIRT3 activity. Moreover, DOX ZT9 reduced the body weight loss, extended the survival period, improved the heart function and alleviated the myocardial lesions compared to DOX ZT1. Mechanistic investigations demonstrated that DOX ZT1 significantly reduced ATP production, oxygen consumption rate (OCR) at various respiration states, MMP level and MnSOD activity and enhanced the H 2 O 2 level compared with CON ZT1, whereas there was no significant effect for DOX ZT9 compared with CON ZT9. Taken together, dosing at the peak time of SIRT3 activity reduced DOX-induced cardiotoxicity, which may be related to the increased endogenous tolerance against the mitochondrial dysfunction and oxidative stress caused by DOX., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Tumors and heart disease are two of the leading causes of human death. With the development of anti-cancer therapy, the survival rate of cancer patients has been significantly improved. But at the same time, the incidence of cardiovascular adverse events caused by cancer treatment has also been considerably increased, such as arrhythmia, left ventricular (LV) systolic and diastolic dysfunction, and even heart failure (HF), etc., which seriously affects the quality of life of cancer patients. More importantly, the occurrence of adverse events may lead to the adjustment or the cessation of anti-cancer treatment, which affects the survival rate of patients. Understanding the mechanism of cardiotoxicity (CTX) induced by antineoplastic drugs is the basis of adequate protection of the heart without impairing the efficacy of antineoplastic therapy. Based on current research, a large amount of evidence has shown that oxidative stress (OS) plays an essential role in CTX induced by antineoplastic drugs and participates in its toxic reaction directly and indirectly. Here, we will review the mechanism of action of OS in cardiac toxicity of antineoplastic drugs, to provide new ideas for researchers, and provide further guidance for clinical prevention and treatment of cardiac toxicity of anti-tumor drugs in the future., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine-butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function., Methods and Results: In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co-administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase-2 mRNAs, which were not elevated on co-treatment with FBA. DOXO, but not FBA + DOXO mice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre-treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H 2 O 2 , which were blunted by FBA pre-treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour-killing action of DOXO., Conclusions: Phenylalanine-butyramide protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by reduction in oxidative stress and amelioration of mitochondrial function., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Doxorubicin (Dox) induces cardiotoxicity, thereby limiting its clinical application for chemotherapy of cancer. The mechanism of cardiotoxicity includes the production of excess intracellular ROS. 14-3-3s have been found to protect the myocardium against various types of injury. Curcumin (Cur) is a polyphenolic compound that is derived from turmeric and has multiple bioactivities, including anti-oxidative and radical-scavenging activities that exert cytoprotection. We hypothesize that the cardioprotective effects of Cur are exerted by regulating 14-3-3γ. To test the hypothesis, Dox-induced cardiotoxicity was used to establish an in vivo myocardial injury model in mice (in vivo) and primary cardiomyocytes (in intro). The effects of Cur were assessed by determining the heart rate and ECG's ST segments, as well as lactate dehydrogenase (LDH) and creatine kinase (CK) activities in the serum, caspase-3 activity, apoptosis rate, and histopathological changes of the myocardium (in vivo). In addition, cell viability, LDH, SOD, CAT, GPx, and caspase-3 activities, levels of ROS, MDA, and MMP, mPTP opening, and the apoptosis rate (in vitro) were evaluated. The expression of 14-3-3γ and Bcl-2 as well as the phosphorylation levels of Bad (S112) were determined by western blot analysis. Our results showed that Dox-induced injury to the myocardium was decreased by Cur treatment via upregulating the protein expression of 14-3-3γ in total protein and Bcl-2 expression on mitochondria, activating Bad (S112) phosphorylation, reducing the heart rate and ST segment, and reducing LDH and CK activities in the serum, thereby causing a reduction in caspase-3 activity, the apoptosis rate, and histopathological changes of the myocardium (in vivo). Furthermore, Dox treatment increased cell viability and MMP levels, decreased LDH and caspase-3 activity, ROS levels, mPTP opening, and the apoptosis rate (in vitro). However, the cardioprotective effects of Cur were attenuated by pAD/14-3-3γ-shRNA, an adenovirus that caused a knock-down of intracellular 14-3-3γ expression. In conclusion, this is the first study to demonstrate that Cur protected the myocardium against Dox-induced injury via upregulating 14-3-3γ expression, thereby promoting the translocation of Bcl-2 to mitochondria, suppressing oxidative stress, and improving mitochondrial function.

Clinical application of doxorubicin (DOX) is limited because of its cardiotoxicity. Thus, exploration of effective lead compounds against DOX-induced cardiotoxicity is necessary. The aim of the present study was to investigate the effects and possible mechanisms of dioscin against DOX-induced cardiotoxicity. The in vitro model of DOX- treated H9C2 cells and the in vivo models of DOX-treated rats and mice were used in this study. The results showed that discoin markedly increased H9C2 cell viability, decreased the levels of CK, LDH, and improved histopathological and electrocardio- gram changes in rats and mice to protect DOX-induced cardiotoxicity. Furthermore, dioscin significantly inhibited myocardial oxidative insult through adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px in vitro and in vivo. Our data also indicated that dioscin activated Nrf2 and Sirt2 signaling pathways, and thereby affected the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a through decreasing miR-140-5p expression level. In addition, the level of intracellular ROS was significantly increased in H9C2 cells treated by DOX after miR-140-5p mimic transfection, as well as the down-regulated expression levels of Nrf2 and Sirt2, which were markedly reversed by dioscin. In conclusion, our data suggested that dioscin alleviated DOX-induced cardiotoxicity through modulating miR-140-5p-mediated myocardial oxidative stress. This natural product should be developed as a new candidate to alleviate cardiotoxicity caused by DOX in the future., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Although chemotherapeutics can be highly effective at targeting malignancies, their ability to trigger cardiovascular morbidity is clinically significant. Chemotherapy can adversely affect cardiovascular physiology, resulting in the development of cardiomyopathy, heart failure and microvascular defects. Specifically, anthracyclines are known to cause an excessive buildup of free radical species and mitochondrial DNA damage ( mt DNA) that can lead to oxidative stress-induced cardiovascular apoptosis. Therefore, oncologists and cardiologists maintain a network of communication when dealing with patients during treatment in order to treat and prevent chemotherapy-induced cardiovascular damage; however, there is a need to discover more accurate biomarkers and therapeutics to combat and predict the onset of cardiovascular side effects. Telomerase, originally discovered to promote cellular proliferation, has recently emerged as a potential mechanism to counteract mitochondrial defects and restore healthy mitochondrial vascular phenotypes. This review details mechanisms currently used to assess cardiovascular damage, such as C-reactive protein (CRP) and troponin levels, while also unearthing recently researched biomarkers, including circulating mt DNA, telomere length and telomerase activity. Further, we explore a potential role of telomerase in the mitigation of mitochondrial reactive oxygen species and maintenance of mt DNA integrity. Telomerase activity presents a promising indicator for the early detection and treatment of chemotherapy-derived cardiac damage., Competing Interests: The authors declare no conflict of interest.

Doxorubicin (DXR) is a highly effective drug for chemotherapy. However, cardiotoxicity reduces its clinical utility in humans. The present study aimed to assess the ameliorative effect of curcumin against DXR-induced cardiotoxicity in rats. Rats were subjected to oral treatment of curcumin (100 and 200 mg/kg body weight) for 7 days. Cardiotoxicity was induced by single intraperitoneal injection of DXR (40 mg/kg body weight) on the 5th day and the rats sacrificed on 8th day. Curcumin ameliorated DXR-induced lipid peroxidation, glutathione depletion, decrease in antioxidant (superoxide dismutase, catalase, and glutathione peroxidase) enzyme activities, and cardiac toxicity markers (CK-MB, LDH, and cTn-I). Curcumin also attenuated activities of Caspase-3, cyclooxygenase-2, inducible nitric oxide synthase, and levels of nuclear factor kappa-B, tumor necrosis factor-α, and interleukin-1β, and cardiac tissue damages that were induced by DXR. Moreover, curcumin decreased the expression of 8-OHdG and 3,3'-dityrosine. This study demonstrated that curcumin has a multi-cardioprotective effect due to its antioxidant, anti-inflammatory, and antiapoptotic properties., (© 2018 Wiley Periodicals, Inc.)

The present study aimed to investigate the potential protective effect of all-trans-retinoic acid (ATRA, a natural derivative of vitamin A) against doxorubicin (DOX)-induced in vivo cardiac toxicity and its underlying mechanisms. Forty male albino rats were allocated into control, ATRA (0.5 mg/kg bwt, intraperitoneally daily), DOX (2.5 mg/kg bwt, intraperitoneally twice weekly for 3 weeks), and DOX + ATRA groups. Serum lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase-cardiac type (CK-MB), troponin I, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) were measured. In addition, cardiac glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT), and malondialdehyde (MDA) were determined. Cardiac tissues were examined for histopathologic changes and immunoexpression of pro-apoptotic caspase 3 and tumor-suppressor p53 proteins. DOX caused severe myocardial damage; degenerative and necrotic changes and worsened cardiac function biomarkers; and elevated serum LDH, CK, CK-MB, and troponin I. In addition, DOX inhibited cardiac antioxidative enzymes (GSH, GSH-Px, SOD, CAT) activities and enhanced MDA level. DOX increased serum proinflammatory cytokines (TNF-α, IL-6) and area percent of caspase 3 and p53 immunoexpression in heart tissues. Pretreatment with ATRA maintained cardiac function biomarkers, and reduced proinflammatory cytokines, lipid peroxidation, and immunoexpression of caspase 3 and p53. Moreover, ATRA improved cardiac histoarchitecture, as well as the activities of antioxidative enzymes. Collectively, ATRA can counteract DOX-induced cardiomyopathy through antioxidative and anti-inflammatory properties, besides suppression of the activation of the mitochondrial apoptotic pathway.

Doxorubicin (DOX) is a highly effective drug, but its cardiotoxicity restricts its therapeutic index. Oxidative stress is the major etiopathological factor in DOX-induced cardiotoxicity. Tannic acid (TA) has various anti-cancer, antioxidant, and anti-inflammatory activities. The purpose of the study was to survey the possible effects of TA against acute DOX-induced cardiotoxicity. Male Sprague-Dawleyrats were randomly divided into five groups: control, DOX (10mg/kg) alone, DOX with TA (20 and 40mg/kg), or DOX withcaptopril (30mg/kg) treatments. TA or captopril was administered once daily for six days, and DOX was injected intraperitoneally on the fourth day. TA significantlyattenuated DOX myocardial effects. Pretreatment with TA caused a decrease in levels of the serum enzymes lactate dehydrogenase, creatine kinase, and creatine kinase isoenzyme-MB to normal values. As indicators of oxidative stress, the levels of glutathione peroxidasesuperoxide dismutase and catalasesignificantly increased while the levels of malondialdehyde decreased after TA treatment. Additionally, DOX provoked inflammatory responses by causing anincrease in levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), endothelin (ET)-1 levels, and nuclear factor kappa-B (NF-κB) expression while TA pretreatment significantly inhibited TNF-α, IL-1β, ET-1, and NF-κB. Furthermore, DOX induced apoptosis by increasing bcl-2like protein and caspase-3 activities and c-fos and c-jun levels while causing a decrease in B-cell lymphoma-2 levels. Overall, there was evidence that TA could inhibit DOX-induced cardiotoxicity by inhibiting oxidative stress, inflammation and apoptotic damage., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The aim of this study was to assess the possible modulatory effects of rosuvastatin and/or ubiquinone on trastuzumab (TRZ)-induced cardiotoxicity in mice. One hundred and twenty mice were divided into six equal groups as follows: control group; TRZ group; TRZ+carboxymethyl cellulose group; TRZ+rosuvastatin group; TRZ+Ubiquinone group and TRZ+rosuvastatin+Ubiquinone group. Serum creatine kinase (CK-MB), lactate dehydrogenase (LDH), troponin I and N-terminal pro-B-type natriuretic peptide (NT-pro BNP) were measured. Also, tissue malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPx), interleukin 6 (IL-6), transforming growth factor beta 1 (TGF-β1) and signal transducers and activators of transcription-3 (STAT-3) were determined. Also, echocardiography was performed. Parts of the heart were subjected to histopathological, immunohistochemical and electron microscopic examination. Administration of rosuvastatin and/or ubiquinone to TRZ-treated mice induced significant increase in tissue GPx, CAT and STAT-3 with significant decrease in serum CK-MB, LDH, troponin I, NT-pro BNP, tissue MDA, TGF-β1 and IL-6 and improved the histopathological, immunohistochemical, echocardiographic and electron microscopic changes compared to the group that received TRZ alone. These changes were significant in rosuvastatin/ubiquinone combination group compared to the use of each of these drugs alone. In conclusion, rosuvastatin/ubiquinone combination may represent a new therapeutic modality to ameliorate TRZ-induced cardiotoxicity., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: The principal aim of this study was to investigate the oxidative effects of acute alcohol consumption on the functions of the heart and the liver and the possible modification of this effect by phenolic compounds from n-butanol extract of Camellia sinensis supplementation., Method: Three experimental groups of rats were used: control, ethanol-exposed (40% v/v, 5 g/kg per oral every 12 hours for 3 doses, binge model), and ethanol-exposed plus n-butanol extract of Camellia sinensis (100 mg/kg once a day for three days before and simultaneously with ethanol administration). Serum transaminases, cholesterol, triglycerides, lipid peroxidation (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx) were estimated to assess organs damage., Results: n-butanol extract of Camellia sinensis at a dose of 100 mg/kg body weight exhibited a significant reversal effect in all biochemical parameters measured such as extent of lipid peroxidation, GSH, lipid profile, and serum aminotransferase activities., Conclusion: These results suggest that n-butanol extract of Camellia sinensis protected the heart and the liver from binge ethanol induced injury through attenuating oxidative stress., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Doxorubicin (DOX) is a chemotherapeutic agent used for treatment of different cancers and its clinical usage is hindered by the oxidative injury-related cardiotoxicity. This work aims to declare if the harmful effects of DOX on heart can be alleviated with the use of Coenzyme Q10 (CoQ10) or L-carnitine. The study was performed on seventy two female Wistar albino rats divided into six groups, 12 animals each: Control group; DOX group (10mg/kg); CoQ10 group (200mg/kg); L-carnitine group (100mg/kg); DOX+CoQ10 group; DOX+L-carnitine group. CoQ10 and L-carnitine treatment orally started 5days before a single dose of 10mg/kg DOX that injected intraperitoneally (IP) then the treatment continued for 10days. At the end of the study, serum biochemical parameters of cardiac damage, oxidative stress indices, and histopathological changes were investigated. CoQ10 or L-carnitine showed a noticeable effects in improving cardiac functions evidenced reducing serum enzymes as serum interleukin-1 beta (IL-1 β), tumor necrosis factor alpha (TNF-α), leptin, lactate dehydrogenase (LDH), Cardiotrophin-1, Troponin-I and Troponin-T. Also, alleviate oxidative stress, decrease of cardiac Malondialdehyde (MDA), Nitric oxide (NO) and restoring cardiac reduced glutathione levels to normal levels. Both corrected the cardiac alterations histologically and ultrastructurally. With a visible improvements in α-SMA, vimentin and eNOS immunohistochemical markers. CoQ10 or L-carnitine supplementation improves the functional and structural integrity of the myocardium., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: Exenatide is a glucagon-like peptide-1 analogue that mitigates myocardial injury caused by ischemia-reperfusion injury via the survival signaling pathway. We hypothesized that exenatide would provide a protective effect in doxorubicin-induced cardiotoxicity., Methods: H9c2 cardiomyocytes were pre-treated with exenatide followed by doxorubicin (DOX), and cell viability and intracellular reactive oxygen species (ROS) were subsequently measured. In order to determine the role of autophagy, we performed western blot as well as TUNEL and autophagosome staining. Additionally, rats were treated with exenatide 1h prior to every DOX treatment. Left ventricular (LV) function and performance were then assessed by echocardiography. Myocardial and serum ROS was measured with DHE fluorescence and ROS/RNS assay., Results: DOX-induced caspase-3 activation decreased after pre-treatment with exenatide both in vivo and in vitro. Oxidative stress was attenuated by exenatide in H9c2 cells, as well as in cardiac tissue and serum. The number of autophagosomes and autophagic markers were further increased by exenatide in the DOX-treated H9c2 cells, which mediated AMPK activation. Suppression of the autophagosome abolished exenatide-induced anti-apoptotic effect. Echocardiography showed that pre-treatment with exenatide significantly improved LV dysfunction that is induced by DOX treatment. Exenatide inhibits the DOX-induced production of intracellular ROS and apoptosis in the myocardium. The autophagic markers increased in exenatide pre-treated cardiac tissue., Conclusion: Exenatide reduces DOX-induced apoptosis of cardiomyocytes by upregulating autophagy and improving cardiac dysfunction. These novel results highlight the therapeutic potential of exenatide to prevent doxorubicin cardiotoxicity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Doxorubicin (DOX) is an effective anticancer drug; however, its clinical use is limited by its cardiotoxic effect. Adenosine was proved to mediate anti-inflammatory effects and protected from myocardial ischemia/reperfusion injury. So the present work was designed to examine the effectiveness of a selective A3 adenosine receptor agonist (Cl-IB-MECA) in DOX-induced cardiotoxicity and to elucidate the underlying mechanisms via studying its effect on different oxidative stress, inflammatory and apoptotic markers., Methods: Firstly the potential cardioprotective dose of Cl-IB-MECA was screened in male Wistar rats at different doses (20, 40 and 80 µg/kg; i.v) against a single dose of DOX (15 mg/kg; i.p). Secondly, the dose of 40 µg/kg Cl-IB-MECA was selected for further assessment of the cardioprotective mechanisms., Results: Cl-IB-MECA at a dose 40 µg/kg (i.v) protects against DOX-induced bradycardia, elevated creatine kinase isoenzyme-MB and histopathological changes. Also, it significantly ameliorates oxidative stress injury evoked by DOX as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme activities. Additionally, DOX provoked inflammatory responses by increasing the expressions of nuclear factor kappa B and the levels of tumor necrosis factor alpha. Cl-IB-MECA pretreatment significantly inhibited these inflammatory responses. Furthermore, DOX induced apoptotic tissue damage by increasing cytochrome c expressions which was suppressed by Cl-IB-MECA pretreatment., Conclusion: Cl-IB-MECA protects against DOX-induced cardiotoxicity through restoration of the oxidant/antioxidant status and consequential suppression of DOX-induced inflammatory responses and abrogation of the resultant apoptotic signals.

Cyclophosphamide (CP) is an oxazaphosphorine nitrogen mustard alkylating drug used for the treatment of chronic and acute leukemias, lymphoma, myeloma, and cancers of the breast and ovary. It is known to cause severe cardiac toxicity. This study investigated the protective effect of N-Acetylcysteine (NAC) on CP-induced cardiotoxicity in rats. CP resulted in a significant increase in serum aminotransferases, creatine kinase (CK), lactate dehydrogenase(LDH) enzymes, asymmetric dimethylarginine and tumor necrosis factor-α and significant decrease in total nitrate/nitrite(NOx). In cardiac tissues, a single dose of CP (200mg/kg, i.p.) resulted in significant increase in malondialdehyde and NOx and a significant decrease in reduced glutathione content, glutathione peroxidase, catalase, and superoxide dismutase activities. Interestingly, Administration of NAC (200mg/kg, i.p.) for 5 days prior to CP attenuates all the biochemical changes induced by CP. These results revealed that NAC attenuates CP-induced cardiotoxicity by inhibiting oxidative and nitrosative stress and preserving the activity of antioxidant enzymes., (Copyright © 2015 Elsevier B.V. All rights reserved.)