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Background: Among the three most used anticancer drugs, cyclophosphamide, Adriamycin, and 5-Fluorouracil (CAF), the most significant outcome is chemobrain, caused by increased oxidative stress, inflammatory insult, and mitochondrial dysfunction., Objective: In this study, endogenous antioxidant coenzyme Q10 (CoQ10) was evaluated for its neuroprotective effects in CICI., Materials and Methods: The chemobrain was induced in Swiss albino female mice by administering CAF (40 + 4 + 25 mg/kg) intraperitoneal (i.p.) in three cycles (single injection per week) followed by treatment with CoQ10 (40 mg/kg; p.o.) for up to 3 weeks followed by behavioral, biochemical, molecular and histopathological analysis., Results: Treatment with CoQ10 significantly improved cognition by improving exploring time in novel objects recognition test followed by increasing the time spent in the target quadrant in MWM test as compared to CAF-treated animals. Moreover, CoQ10 demonstrated antioxidant properties by reducing the expression of LPO while increasing levels of GSH, SOD, and catalase as compared to CAF-treated animals. While the levels of AChEs were significantly reduced after CoQ10 treatment in CAF-treated animals. In terms of its mechanism, it effectively counteracted the pro-inflammatory substances (TNF-α and IL-1β) triggered by CAF while also enhancing the levels of anti-inflammatory markers (IL-10 and Nrf2). Moreover, CoQ10 showed mitochondrial enhancers and it improved the level of Complex (I, II, and IV). Besides that, mitochondrial morphological analysis was done by TEM, and neuronal morphology along with quantification analysis was performed by H&E staining using Image J software to confirm the neuroprotective effect of CoQ10 over CAF-induced cognitive impairment., Conclusion: This study suggests CoQ10 can protect the mitochondria by imposing antioxidant, and anti-inflammatory properties, which could be a potential therapy for CICI., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Intermittent fasting (IF) has been shown to induce a well-organized adaptive defense against stress inside the cells, which increases the production of anti-oxidant defenses, repair of DNA, biogenesis of mitochondria, and genes that combat inflammation. So, the goal of the current investigation was to identify the effects of IF on rats with adriamycin (ADR)-induced nephropathy and any potential underlying mechanisms., Methods: Four groups of 40 mature Sprague-Dawley male rats were allocated as follow; control, fasting, ADR, and ADR plus fasting. After 8 weeks of ADR administration urine, blood samples and kidneys were taken for assessment of serum creatinine (Cr), BUN, urinary proteins, indicators of oxidative damage (malondialdehyde (MDA), reduced glutathione (GSH) and Catalase (CAT) levels), histopathological examinations, immunohistochemical examinations for caspase-3, Sirt1, aquaporin2 (AQP2) and real time PCR for antioxidant genes; Nrf2, HO-1 in kidney tissues., Results: IF significantly improved serum creatinine, BUN and urinary protein excretion, oxidative stress (low MDA with high CAT and GSH), in addition to morphological damage to the renal tubules and glomeruli as well as caspase-3 production during apoptosis. Moreover, IF stimulates significantly the expression of Sirt1 and Nrf2/HO-1 and AQP2., Conclusion: AQP2, Sirt1, Nrf2/HO-1 signaling may be upregulated and activated by IF, which alleviates ADR nephropathy. Enhancing endogenous antioxidants, reducing apoptosis and tubulointerstitial damage, and maintaining the glomerular membrane's integrity are other goals., 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 Ltd. All rights reserved.)

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague-Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5-ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences.

We investigated the rosiglitazone (RSG) effect on adriamycin (ADM)-induced cardio toxicity in experimental animals. Forty adult Wistar male rats were separated into four groups as follows: normal control; RSG (10 mg/kg)-treated; ADM (10 mg/kg)-administered; and ADM (10 mg/kg) + RSG (10 mg/kg)-treated. Serum lipid level, different biochemical biomarkers, histological analysis, and nuclear factor erythroid 2-related factor/heme oxygenase-1 (Nrf2/HO-1), Caspase 3, B-cell lymphoma 2 (Bcl-2), and Bax gene expression were assessed in serum and cardiac tissue samples. Our results show that RSG treatment in ADM-administered animals significantly diminished low-density lipoprotein cholesterol, triglyceride, and total cholesterol, and increases high-density lipoprotein cholesterol (HDL-c) in comparison with the ADM group. RSG treatment reduced the effect of ADM administration on cardiac dysfunction markers such as cardiac troponin T Creatine Kinase-MB, aspartate aminotransferase, and lactate dehydrogenase, showing the amelioration of cardio toxicity in ADM-administered rats. Additionally, RSG treatment significantly decreased the level of malondialdehyde and nitric oxide in cardiovascular tissue. RSG-treated rats in combination with ADM likewise showed a significant increase in reduced glutathione, superoxide dismutase, catalase content, and the activity of glutathione peroxidase (GPx) as compared with ADM group. Moreover, RSG treatment in ADM rats significantly increased an Nrf2 and HO-1 expression in comparison with ADM group. While in apoptosis parameters, RSG treatment in ADM rats significantly diminished a cleaved caspase-3 and Bax expression as well as expanded Bcl-2 expression when contrasted with ADM group of rats. In conclusion, RSG is capable of protecting heart toxicity in ADM-treated animals through defensive effects on oxidative stress and biochemical markers., (© 2019 International Union of Biochemistry and Molecular Biology.)

Doxorubicin (DOX) is a highly effective antineoplastic agent used in cancer treatment. Unfortunately, clinical use of DOX is limited due to the development of dose-dependent toxicity to cardiac and respiratory (i.e., diaphragm) muscles. After administration, DOX preferentially localizes to the inner mitochondrial membrane, where it promotes cellular toxicity via enhanced mitochondrial reactive oxygen species (ROS) production. Although recent evidence suggests that amelioration of mitochondrial ROS emission preserves cardiorespiratory muscle function following DOX treatment, the mechanisms responsible for this protection remain unknown. Therefore, we tested the hypothesis that DOX-induced mitochondrial ROS production is required to stimulate pathological signaling by the autophagy/lysosomal system (ALS), the ubiquitin-proteasome pathway (UPP), and the unfolded protein response (UPR). Cause and effect were determined by administration of the mitochondria-targeted peptide SS-31 to DOX-treated animals. Interestingly, while SS-31 abrogated aberrant ROS emission in cardiorespiratory muscles of DOX-treated animals, our results revealed muscle-specific regulation of effector pathways. In the heart, SS-31 prevented DOX-induced proteolytic signaling through the ALS and UPP. In contrast, ALS signaling was inhibited by SS-31 in the diaphragm, but the UPP was not affected. UPR signaling was activated in both muscles at eukaryotic translation initiation factor 2α (eIF2α) S51 in the heart and diaphragm of DOX-treated animals and was attenuated with SS-31 treatment in both tissues. However, downstream signaling of eIF2α (activating transcription factor 4 and CCAAT/enhancer-binding protein homologous protein) was diminished in the heart but upregulated in the diaphragm with DOX. Collectively, these results show that DOX-induced ROS production plays distinct roles in the regulation of cardiac and diaphragm muscle proteolysis.

Cardiotoxicity and nephrotoxicity due to the abnormal production of free radicals have been observed in patients treated with the anticancer antibiotic adriamycin (ADR). The aim of the present study was to evaluate the role of the heart of palm extract in preventing oxidative stress, cardiotoxicity and nephrotoxicity induced by ADR. In this work, an aqueous ethanolic extract of the heart of the Phoenix dactylifera tree (HP) was investigated. The polyphenol content was evaluated by gas chromatography-mass spectrometry (GC-MS) and High-performance liquid chromatography (HPLC). The protective effect of the HP-extract (250 and 500 mg/kg, p.o.) was evaluated along with ADR administration (cumulative dose 15 mg/kg, IP) in rats. The HP-extract (500 mg/kg) treated group showed significant reductions in cardiotoxicity and nephrotoxicity serum markers, apoptotic percentage, and caspase-3 and cyclooxygenase-2 level, with an improvement in antioxidant enzymes in both heart and kidney homogenate, compared with the ADR-induction group. The cardiac and kidney programmed cell death protein-1 (PD-1) was increased in high dose HP-extract treated rats after being inhibited by ADR administration. In conclusion, the HP-extract might be a promising food supplement for preventing the cardiotoxicity and nephrotoxicity induced by ADR administration., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Adriamycin (ADR) is an effective antineoplastic drug; the clinical application of ADR is limited due to fatal heart dysfunction. Exenatide has antioxidant, anti-apoptotic and anti-inflammatory properties. It can alleviate heart damage induced by ischaemia-reperfusion injury. Thus, we assumed that exenatide would produce protective effects on ADR-induced heart dysfunction., Method: Mice were treated with exenatide 1 h prior to every ADR treatment for 20 days. Left ventricular function and performance were assessed by echocardiography. Additionally, H9c2 cells were pretreated with exenatide followed by ADR, and intracellular reactive oxygen species (ROS) and cell viability, as well as the lactate dehydrogenase (LDH) and the creatine kinase MB (CK-MB), were subsequently measured. Flow cytometry and TUNEL staining were applied to assess the effect of exenatide on cardiac damage caused by ADR. Western blot and RT-PCR were performed to detect the effect of exenatide on apoptosis-related genes (Bcl-2 and Bax) and inflammation-related genes and/or proteins (tumour necrosis factor-α, interleukin-6, nuclear factor-κB, and p53)., Result: Echocardiography showed that cardiac dysfunction caused by ADR was significantly improved by treatment with exenatide. ADR mice had harmful changes in the levels of ROS and CK-MB/LDH production, as well as the targeted apoptotic and inflammatory molecules, and these effects were also reversed by exenatide. In vitro, exenatide mitigated ADR-induced oxidative stress and CK-MB/LDH production, as well as Annexin V + /PI + and TUNEL + apoptosis in H9c2 cells., Conclusion: In conclusion, our research demonstrated the potential protective effects of exenatide on ADR-induced heart dysfunction through suppressing oxidative stress, apoptosis and inflammation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background Because of the antioxidant effects of Zataria multiflora (ZM) and carvacrol (CAR) and also the role of oxidative stress in the induction of cardiotoxicity induced by Adriamycin (ADR), the aim of this study was to investigate the improvement effects of ZM extract and CAR on cardiotoxicity induced by ADR in rats. Methods Twenty-eight male rats were randomly assigned to four groups including (1) the control group; (2) the ADR group, which received ADR intravenously at the beginning of the study and the (3) ZM+ADR and (4) CAR+ADR groups, which received ZM and CAR by gavage for 28 consecutive days and ADR as single dose. Blood samples were collected on days 0 and 28 to determine serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and lactate dehydrogenase (LDH). Also, cardiac tissue was removed for redox marker evaluation. Results In the ADR group, malondialdehyde (MDA) significantly increased and superoxide dismutase (SOD) activity and total thiol contents significantly reduced, as compared with the control group, while CAR administration significantly improved this condition. Treatment with ZM significantly increased the SOD activity and total thiol content, as compared with the ADR group. The level of LDH significantly increased on day 28 in the ADR group compared to the control group, and administration of ZM and CAR significantly decreased it. The SGPT and SGOT levels in the ADR group significantly increased, and CAR administration significantly reduced them. Conclusion The results indicate that the administration of ZM hydroalcoholic extracts and its active ingredient, CAR, could reduce the oxidative stress damage through promotion of the cardiac and systemic antioxidant system. Also, CAR administration demonstrated better improvement in cardiotoxicity with ADR in rats.

Aim: This study aimed to evaluate the molecular mechanism mitigating progress of chronic nephropathy by mesenchymal stem cells (MSCs)., Methods: Rats were divided into normal control (Normal), adriamycin (ADR)+vehicle (CON), and ADR+MSC (MSC) groups. Nephropathy was induced by ADR (4 mg/kg) and MSCs (2 × 10 6 ) were injected. Rats were euthanized 1 or 6 weeks after ADR injection. NF-kB, MAPKs, inflammation, oxidative stress, profibrotic molecules, and nephrin expression were evaluated. Electron and light microscopy were used for structural analysis. MSCs were co-cultured with renal tubular epithelial cells or splenocytes to evaluate relation with oxidative stress and inflammatory molecules RESULTS: Adriamycin treatment upregulated inflammation, oxidative stress, and profibrotic molecules; this was mitigated by MSCs. Glomerulosclerosis and interstitial fibrosis were observed in ADR-treated groups, and were more prominent in the CON group than in the MSC group. Fusion of foot processes and loss of slit diaphragms were also more prominent in the CON group than in the MSC group. In vitro, MSCs reduced oxidative stress related molecules, inflammatory cytokines, and NF-kB transcription. MSC- or ADR-induced regulation of NF-kB transcriptional activity was confirmed by a luciferase reporter assay., Conclusions: Mesenchymal stem cells attenuate ADR-induced nephropathy by diminishing oxidative stress and inflammation via downregulation of NF-kB., (© 2017 Asian Pacific Society of Nephrology.)

The primary aim of this study was to find the potential modulatory roles of quercetin (QUE) against Adriamycin (ADR)-induced cardiotoxicity. A total of 50 rats were assigned to five groups: a control group, an ADR-treated group, a QUE-treated group, a prophylaxis-cotreated group, and a therapeutic-cotreated group, respectively. QUE exhibited a significant cardioprotective effect, particularly, when it was administered prior to and concurrently with ADR treatment (prophylaxis-cotreated group). This effect was biochemically evident by the significant decreases in the serum levels of myocardial injury biomarkers such as troponin, creatine kinase-myocardium bound, and creatine phosphokinase. In addition, significant elevations in myocardial antioxidant indices coupled with significant reductions in myocardial malondialdehyde contents and DNA damage, elicited by ADR injection, were observed. All these biochemical improvements were accompanied by a significant histopathological recovery and obvious modulation of the AMP-activated protein kinase (AMPK) signaling pathway by promoting the expression of the AMPKα2, PPARα, and PCG-1α genes. Taken together, these findings conclusively showed that QUE administration through its antioxidant capacity and myocardial energy metabolism restoration provides a prophylactic effect in response to ADR-induced deleterious effects, in the rat heart.

The infusion tea extracted from the leaves of the plant Camellia sinensis can be used in the prevention of cancer, cardiovascular and neurodegenerative diseases, and aging, while adriamycin (ADR) is an anticancer drug that increases oxidative stress in cells. The present study evaluated the protective effect of the long-term consumption of white tea used at two different doses against the oxidative stress produced by aging and acute oxidation caused ADR treatment. At wearing, rats received distilled water (control), or 0.15 (dose 1) or 0.45 mg (dose 2) of solid tea extract/kilogram body weight in their drink. At 12 months, about half of the rats of each group were injected with a bolus of ADR, and six rats of the control group with an injection of saline solution and sacrificed. The rest of the animals continued in their cages until 24 months of age, when they were sacrificed. Lipid and protein oxidation of liver and brain microsomes was analyzed by measuring hydroperoxide and carbonyl levels. White tea consumption for 12 months at a non-pharmacological dose was seen to reverse the oxidative damage caused by ADR in both liver and brain, while the consumption of white tea for 20 months at a non-pharmacological dose had no effect on carbonyl or hydroperoxides in these tissues. The long-term ingestion of white tea protected tissues from acute oxidative stress but did not affect chronic oxidative agents such aging.

To evaluate the cytoprotective effects of rutin, ozone and their combination on adriamycin (ADR)-induced testicular toxicity, 50 male albino rats were classified into five groups of ten animals each as follows: placebo group; ADR group; ADR + rutin group; ADR + ozone group and ADR + rutin + ozone group. Sperm functions, testosterone (T), luteinising hormone (LH), follicle stimulating hormone (FSH), testicular enzymes, oxidant/antioxidant status, C-reactive protein, monocyte chemoattractant proteins-1 and leukotriene B4 were determined. After ADR injection, a decline in sperm functions was observed. FSH and LH levels were increased, T level and testicular enzymes were decreased, significant enhancement in oxidative stress with subsequent depletion in antioxidants was detected and inflammatory markers were significantly elevated. Treatment with rutin and/or ozone, however, improved the aforementioned parameters. Ozone therapy alone almost completely reversed the toxic effects of ADR and restored all parameters to normal levels., (© 2016 Blackwell Verlag GmbH.)

Background: White tea infusion (Camelia sinensis) has antioxidants properties. The infusion contains polyphenols that have been proposed to induce antioxidant response element (ARE) response via nuclear factor E2-related factor 2 (NRF2). Adriamycin (ADR) has antitumour properties and oxidative effects. Oxidative stress is related to a variety of kidney diseases. Prevention of the oxidative stress through long-term intake of white tea and the study of the molecular mechanisms involved in protection could be of great interest. Rats were given distilled water, 0.015 or 0.045 g of solid white tea extract kg(-1) body weight for 12 months. Animals received an injection of ADR. In kidney, oxidative stress parameters were measured, the expressions of nuclear factor E2-related factor 2 gene (Nrf2), and detoxifying and antioxidants genes were analysed, and the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR) were measured., Results: ADR administration increased oxidative parameters and decreased the antioxidant activity; significantly increased the expression of analysed genes and the activity of CAT and SOD and decreased GR activity. The highest white tea dose protected redox status and inhibited ARE response., Conclusion: Long-term intake of white tea protected kidney against the oxidative stress. ADR activated the ARE response but in animals treated with the highest dose of white tea, this response was inhibited, probably for antioxidant protection. © 2015 Society of Chemical Industry., (© 2015 Society of Chemical Industry.)

Doxorubicin (DOX) is an anti-cancer agent whose clinical usage results in a cumulative and dose-dependent cardiotoxicity. We have previously shown that exercise performed prior to DOX treatment reduces the resulting cardiac(mito) toxicity. We sought to determine the effects on cardiac mitochondrial toxicity of two distinct chronic exercise models (endurance treadmill training-TM and voluntary free-wheel activity-FW) when used prior and during DOX treatment. Male-young Sprague-Dawley rats were divided into six groups (n=6 per group): SAL+SED (saline sedentary), SAL+TM (12-weeks TM), SAL+FW (12-weeks FW), DOX+SED (7-weeks of chronic DOX treatment 2mg/kg per week), DOX+TM and DOX+FW. DOX administration started 5weeks after the beginning of the exercise protocol. Heart mitochondrial ultrastructural alterations, mitochondrial function (oxygen consumption and membrane potential), semi-quantification of oxidative phosphorylation (OXPHOS) proteins and their in-gel activity, as well as proteins involved in mitochondrial oxidative stress (SIRT3, p66shc and UCP2), biogenesis (PGC1α and TFAM), acetylation and markers for oxidative damage (carbonyl groups, MDA,SH, aconitase, Mn-SOD activity) were evaluated. DOX treatment resulted in ultrastructural and functional alterations and decreased OXPHOS. Moreover, DOX decreased complex I activity and content, mitochondrial biogenesis (TFAM), increased acetylation and oxidative stress. TM and FW prevented DOX-induced alteration in OXPHOS, the increase in oxidative stress, the decrease in complex V activity and in complex I activity and content. DOX-induced decreases in TFAM and SIRT3 content were prevented by TM only. Both chronic models of physical exercise performed before and during the course of sub-chronic DOX treatment translated into an improved mitochondrial bioenergetic fitness, which may result in part from the prevention of mitochondrial oxidative stress and damage., (Copyright © 2014 © Elsevier B.V. and Mitochondria Research Society. Published by Elsevier B.V. All rights reserved.)

Adriamycin is an anticancer anthracycline drug that inhibits the progression of topoisomerase II activity and causes apoptosis. The effective clinical application of the drug is very much limited by its adverse drug reactions on various tissues. Most importantly, Adriamycin causes cardiomyopathy, one of the life‐threatening complications of the drug. Altered expression of PPARγ in adipocytes inhibited the glucose and fatty acids uptake by down regulating GLUT4 and CD36 expression and causes cardiotoxicity. Therefore, the influence of Adriamycin in cardiac ailments was investigated in vivo and in vitro. Adriamycin treated rats showed altered ECG profile, arrhythmic heartbeat with the elevated levels of CRP and LDH. Dysregulated lipid profiles with elevated levels of cholesterol and triglycerides were also observed. Possibilities of cardiac problems due to cardiomyopathy were analyzed through histopathology. Adriamycin treated rats showed no signs for atheromatous plaque formation in aorta but disorganized cardiomyocytes with myofibrillar loss and inflammation in heart tissue, indicative of cardiomyopathy. Reduced levels of antioxidant enzymes confirmed the incidence of oxidative stress. Adriamycin treatment significantly reduced glucose and insulin levels, creating energy demand due to decreased glucose and insulin levels with increased fatty acid accumulation, ultimately resulting in oxidative stress mediated cardiomyopathy. Since PPARs play a vital role in regulating oxidative stress, the effect of Adriamycin on PPARγ was analyzed by western blot. Adriamycin downregulated PPARγ in a dose‐dependent manner in H9C2 cells in vitro. Overall, our study suggests that Adriamycin alters glucose and lipid metabolism via PPARγ inhibition that leads to oxidative stress and cardiomyopathy that necessitates a different therapeutic approach. [ABSTRACT FROM AUTHOR]

Aims: Obese patients are highly sensitive to adriamycin (ADR)-induced cardiotoxicity. However, the potential mechanism of superimposed toxicity remains to be elucidated. Sestrin 2 (SESN2), a potential antioxidant, could attenuate stress-induced cardiomyopathy; therefore, this study aims to explore whether SESN2 enhances cardiac resistance to ADR-induced oxidative damage in high-fat diet (HFD)–induced obese mice. Results: The results revealed that obesity decreased SESN2 expression in ADR-exposed heart. And, HFD mice may predispose to ADR-induced cardiotoxicity, which was probably associated with inhibiting protein kinase B (AKT), glycogen synthase kinase-3 beta (GSK-3β) phosphorylation and subsequently blocking nuclear localization of nuclear factor erythroid-2 related factor 2 (NRF2), ultimately resulting in cardiac oxidative damage. However, these destructive cascades and cardiac oxidative damage effects induced by HFD/sodium palmitate combined with ADR were blocked by overexpression of SESN2. Moreover, the antioxidant effect of SESN2 could be largely abolished by sh-Nrf2 or wortmannin. And sulforaphane, an NRF2 agonist, could remarkably reverse cardiac pathological and functional abnormalities caused by ADR in obese mice. Innovation and Conclusion: This study demonstrated that SESN2 might be a promising therapeutic target for improving anthracycline-related cardiotoxicity in obesity by upregulating activity of NRF2 via AKT/GSK-3β/Src family tyrosine kinase signaling pathway. Antioxid. Redox Signal. 40, 598–615. [ABSTRACT FROM AUTHOR]

Adriamycin (ADR), one of the most effective broad-spectrum antitumor chemotherapeutic agents in clinical practice, is used to treat solid tumors as well as hematological malignancies in adults and children. However, long-term ADR use causes several adverse reactions, including time- and dose-dependent cardiotoxicity, which limit its clinical application. In addition, the mechanism by which ADR induces cardiotoxicity remains unclear. Therefore, we used zebrafish as animal models to evaluate ADR toxicity during embryonic heart development owing to the similarity of this process in zebrafish to that in humans. Exposure of zebrafish embryos to 1.25, 2.5, and 5 mg/L ADR induced abnormal embryonic development, with the occurrence of cardiac malformations, pericardial edema, decreased movement speed and activity, and increased distance between the venous sinus and the arterial bulb (SV-BA). ADR exposure induced dysregulated cardiogenesis during the precardiac mesoderm formation period. We also observed irregular expression of cardiac-related genes, an upregulation of apoptotic gene expression, and a dose-dependent increase in oxidative stress levels. Furthermore, oxidative stress-induced apoptosis exerted deleterious effects on cardiac development in zebrafish embryos, and treatment with astaxanthin (ATX) alleviated these heart defects. ADR- and Wnt pathway-related genes exhibited good energy and spatial matching, and ADR upregulated the Wnt signaling pathway in zebrafish. Moreover, IWR-1 effectively alleviated ADR-induced heart defects. In conclusion, we demonstrated that the toxic effects of ADR on cardiac development in zebrafish embryos could provide a theoretical basis for explaining the pathogenesis of ADR-induced cardiotoxicity, which occurs through the upregulation of oxidative stress and Wnt signaling pathway, as well as its prevention and treatment in humans. These findings will help develop effective treatment strategies to combat ADR-induced cardiotoxicity and broaden the application of ADR for clinical practice.

Proposed scheme depicting the mechanisms by which PSO protects against ADR-induced cardiotoxicity by activating the SIRT1/PPARγ signaling pathway. [Display omitted] • The beneficial effect of PSO on Adriamycin (ADR)-induced cardiotoxicity, which is manifested in amelioration of mitochondrial dysfunction, myocardial fibrosis, oxidative stress, and apoptosis • PSO protects ADR-induced cardiotoxicity via regulating SIRT1/PPARγ signaling pathway • PSO is proved to be a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in clinical and amplify the application of ADR in oncotherapy. Adriamycin (ADR) is an efficient and common broad-spectrum anticancer drug. However, the cumulative and dose-dependent toxicity induced by ADR severely limits its application in the clinic. Previous studies found that psoralidin (PSO) exhibits remarkable therapeutic effects against multiple cancers. The aim of this study was to determine if PSO has beneficial effects on ADR-induced cardiotoxicity and to investigate the underlying mechanisms. ADR-induced cardiotoxicity models were established in BALB/c mice and HL-1 cardiomyocytes. A series of experimental methods were used to evaluate the effects of PSO on cardiac function indicators, blood biochemical parameters, histopathology, oxidative stress, apoptosis, mitochondrial function, fibrosis, and SIRT1/PPARγ signaling. PSO significantly improved cardiac function indicators, blood biochemical parameters, and mitochondrial function and reduced the degree of myocardial fibrosis, oxidative stress, and apoptosis in ADR-injured mice. PSO significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in ADR-injured HL-1 cells. Moreover, we also demonstrated there was cross-talk between SIRT1 and PPARγ, as shown by SIRT1 siRNA significantly decreasing the expression of PPARγ and GW9662 (a PPARγ antagonist), which remarkably reduced the expression of SIRT1. In summary, this study proved for the first time the beneficial effect of PSO on ADR-induced cardiotoxicity through activation of the SIRT1/PPARγ signaling pathway. Therefore, these findings may favor PSO as a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in the clinic and improve the application of ADR in oncotherapy. [ABSTRACT FROM AUTHOR]

A cumulative and progressively developing cardiomyopathy induced by adriamycin (ADR)-based chemotherapy is a major obstacle for its clinical application. However, there is a lack of safe and effective method to protect against ADR-induced cardiotoxicity. Here, we found that mRNA and protein levels of FGF1 were decreased in ADR-treated mice, primary cardiomyocytes and H9c2 cells, suggesting the potential effect of FGF1 to protect against ADR-induced cardiotoxicity. Then, we showed that treatment with a FGF1 variant (FGF1ΔHBS) with reduced proliferative potency significantly prevented ADR-induced cardiac dysfunction as well as ADR-associated cardiac inflammation, fibrosis, and hypertrophy. The mechanistic study revealed that apoptosis and oxidative stress, the two vital pathological factors in ADR-induced cardiotoxicity, were largely alleviated by FGF1ΔHBS treatment. Furthermore, the inhibitory effects of FGF1ΔHBS on ADR-induced apoptosis and oxidative stress were regulated by decreasing p53 activity through upregulation of Sirt1-mediated p53 deacetylation and enhancement of murine double minute 2 (MDM2)-mediated p53 ubiquitination. Upregulation of p53 expression or cardiac specific-Sirt1 knockout (Sirt1-CKO) almost completely abolished FGF1ΔHBS-induced protective effects in cardiomyocytes. Based on these findings, we suggest that FGF1ΔHBS may be a potential therapeutic agent against ADR-induced cardiotoxicity.

Oxidative stress has a major role in the nephrosis. In the present study, the effects of hydroalcoholic extract of Zataria multiflora (ZM) and carvacrol (CAR) were evaluated on the renal damage induced by adriamycin (ADR). The animals accidentally divided into four groups including: Control, ADR, ZM + ADR and CAR + ADR. The renal tissue, urine, and blood samples subjected to biochemical markers and histopathological evaluation. ADR significantly decreased glomerular filtration rate (GFR) while escalated urine protein excretion as well as protein clearance (p <.01 to p <.001). Also, ADR significantly reduced the antioxidants and boosted the malondialdehyde (MDA) compared to the control (p <.05 to p <.01). In groups treated by ZM and CAR, GFR, and antioxidants significantly increased, whereas urine protein excretion and MDA decreased (p <.05 to p <.001). ZM and CAR induced an improvement in ADR-induced renal damage by improving renal function as well as antioxidant activity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Doxorubicin (DOX) is one of most used chemotherapeutic drugs, but it has important adverse effects. Nutrition has a critical role to prevent or minimize chemotherapy side effects. Caloric and nutrient restriction has been widely studied in different health fields showing extensive beneficial effects. Given the importance of these interventions, it is expected that some of them have benefits in patients under DOX chemotherapy. OBJECTIVE: This review aimed to compile published studies evaluating the effects of different dietary intetrventions based on restriction of calories or certain nutrients against DOX-induced damage and toxicity. RESULTS: Caloric restriction and partial reduction of fat have shown to reduce DOX cardiotoxicity correlating with a reduction of oxidative stress. Reduction of dietary fat was proved to act in the same sense at liver and kidney. Studies in relation to protein reduction is more elevated has focused only on kidneys and bone, and under certain circumstances, these interventions could increase susceptibility to DOX toxicity. CONCLUSIONS: The promising effects of restriction of dietary fat, protein and sodium on differerent organs have been supported by a greater number of studies among all the dietary interventions evaluated. Still, clinical studies are necessary to confirm the potential usefulness of these interventions. [ABSTRACT FROM AUTHOR]

Astragaloside IV (ASIV) is the main active component of Astragalus, and can ameliorate cardiomyocyte hypertrophy, apoptosis and fibrosis. In this experiment, we studied how ASIV reduces the cardiotoxicity caused by adriamycin and protects the heart. To this end, rats were randomly divided into the control, ADR, ADR + ASIV and ASIV groups (n = 6). Echocardiography was used to observe cardiac function, HE staining was used to observe myocardial injury, TUNEL staining was used to observe myocardial cell apoptosis, and immunofluorescence and Western blotting was used to observe relevant proteins expression. Experiments have shown that adriamycin can damage heart function in rats, and increase the cell apoptosis index, autophagy level and oxidative stress level. Further results showed that ADR can inhibit the PI3K/Akt pathway. ASIV treatment can significantly improve the cardiac function of rats treated with ADR and regulate autophagy, oxidative stress and apoptosis. Our findings indicate that ASIV may reduce the heart damage caused by adriamycin by activating the PI3K/Akt pathway.

Few studies have reported a prophylactic effect of the anti‐ischemic trimetazidine (TRI) against cardiac toxicity caused by adriamycin (ADR). However, the mechanism of action of TRI remained incomplete. The cardioprotective mechanism(s) of TRI against ADR‐induced cardiotoxicity was investigated in this study. Cardiotoxicity was induced in three groups of Wistar rats by injecting a single dose of ADR (10 mg/kg, i.p.). TRI was administered in two doses regimen, low (L) (2.5 mg/kg, i.p.) and high (H) (10 mg/kg, i.p.). The results of the study showed that both TRI L and H doses improved cardiac enzymes and pathology, while only the TRI H dose improved the electrocardiogram. Both TRI L and H doses decreased malondialdehyde and increased reduced glutathione and superoxide dismutase. Only TRI H dose increased glutathione peroxidase and catalase. Both TRI L and H doses decreased interleukin‐1 beta and tumor necrosis factor‐alpha (TNF‐α). Both TRI L and H doses downregulated TNF‐α, BAX, and vascular endothelial growth factor cardiac protein expression. The data obtained in this study provided evidence that TRI opposed ADR‐induced cardiotoxicity. The mechanism could be due to improved antioxidant levels as well as inhibition of inflammation and programmed cell death. [ABSTRACT FROM AUTHOR]

Astragaloside IV (ASIV) is the main active component of Astragalus , and can ameliorate cardiomyocyte hypertrophy, apoptosis and fibrosis. In this experiment, we studied how ASIV reduces the cardiotoxicity caused by adriamycin and protects the heart. To this end, rats were randomly divided into the control, ADR, ADR + ASIV and ASIV groups (n = 6). Echocardiography was used to observe cardiac function, HE staining was used to observe myocardial injury, TUNEL staining was used to observe myocardial cell apoptosis, and immunofluorescence and Western blotting was used to observe relevant proteins expression. Experiments have shown that adriamycin can damage heart function in rats, and increase the cell apoptosis index, autophagy level and oxidative stress level. Further results showed that ADR can inhibit the PI3K/Akt pathway. ASIV treatment can significantly improve the cardiac function of rats treated with ADR and regulate autophagy, oxidative stress and apoptosis. Our findings indicate that ASIV may reduce the heart damage caused by adriamycin by activating the PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

In this study, because of the anti‐inflammatory and antioxidant effect of the Ziziphus jujuba (ZJ), we assessed the protective properties of the ZJ extract against testis toxicity caused by Adriamycin in the rat. Twenty rats were grouped into (a) control, (b) Adriamycin, (c) ZJ group and (d) treatment group in which Adriamycin was administrated and the ZJ hydroalcoholic extract was used for three weeks. On the 21st day, two testes were removed to determine the oxidation markers and pathological evaluation. The levels of sex hormones were determined. Epididymis also was crushed, and its spermatozoa were evaluated as concentration, motility and normality. Adriamycin increased oxidative stress markers as well as Luteinising hormone, and follicle‐stimulating hormone and decreased testosterone levels compared to control. In the treated group, the levels of the above markers improved. The decreased number and motility of spermatozoa in treatment group increased, and the increased rate of abnormal spermatozoa in this group decreased. Pathological evaluations also show the healing process of damaged testicular tissue in the group receiving the ZJ extract. The ZJ extract relatively improves oxidative stress, sperm characteristics, hormonal alternation and pathological changes. These findings reveal the probable role of ZJ effective compounds in repairing tissue damage. [ABSTRACT FROM AUTHOR]

Due to the antioxidant effects of the Ziziphus jujuba Mill (Z. jujuba), we investigated the liver, heart, and brain-protective effects of this herb against toxicity induced by adriamycin (ADR). In this study, Wistar rats were divided into 1) control, 2) ADR and 3, 4, and 5) treated groups orally administrated three doses of Z. jujuba hydroalcoholic extract for 1 month. The liver, heart, and brain were removed for evaluation of the oxidative markers. Blood samples were evaluated to determine the levels of Lactate dehydrogenase, total and direct bilirubin, alkaline phosphatase, Aspartate transaminase, and Alanine aminotransferase. Administration of Z. jujuba significantly decreased the biochemical enzymes compared to the ADR. Oxidative condition in treated rats with different doses of Z. jujuba was improved compared to the ADR group. Z. jujuba could decrease the oxidative injury through invigoration of the tissues antioxidant system. The mentioned hepatic and cardiac parameters levels improved during extract administration. Practical applications: In the first stage, our findings and other supplementary works have shown that administration of jujube extract has prevented the effects of histotoxicity caused by adriamycin, so it seems that in the next stage, the effects of this herbal plant on patients with tissue toxicity caused by adriamycin should be evaluated and if the results are positive in pharmacological studies, it should be used as a complementary drug in the treatment of these patients. [ABSTRACT FROM AUTHOR]

Adriamycin (ADR)-induced chronic heart injury (CHI) is a serious complication of chemotherapy. The present study was designed to assess the ability of fasudil, a Rho kinase inhibitor, to prevent ADR-induced CHI. Forty male 6-week-old C57BL6 mice were randomly divided into the following four groups: (1) control group, (2) CHI induced by adriamycin (ADR group), (3) CHI plus low dose fasudil (ADR + L group), and (4) CHI plus high dose fasudil (ADR + H group). Animals from groups 2–4 received ADR (2.5 mg/kg, i.p.) once a week for 8 weeks, and the control group received saline. Meanwhile, the animals in groups 3–4 received 2 mg/kg/day or 10 mg/kg/day fasudil, respectively. After measurement of cardiac functions, blood samples were collected for biochemical assays. The hearts were excised for histological, immunohistochemistry and western blot study, respectively. Adriamycin produced evident cardiac damage revealed by cardiac functions changes: decreased left ventricular fractional shortening (FS), left ventricular ejection fraction (EF), increased left ventricular volume, cardiac injury marker changes (increased creatine kinase, lactate dehydrogenase), antioxidant enzymes activity changes (decreased superoxide dismutase), and lipid peroxidation (elevated malondialdehyde) to the control group. Fasudil treatment notably ameliorated ADR-induced cardiac damage, restored heart function, suppressed cell apoptosis and senescence, ameliorated redox imbalance, and DNA damage. Fasudil has a protective effect on ADR-induced chronic heart injury, which partially attributed to its antioxidant, anti-apoptotic effects of inhibiting the RhoA/Rho kinase (ROCK) signaling pathway. [ABSTRACT FROM AUTHOR]

Introduction: Adriamycin (ADR) is an antineoplastic antibiotic against many cancers, including bladder, kidney, and cervix malignancies. Plantago major is a herbaceous plant with many pharmacologic effects, including antioxidant, anti-inflammatory, hepatoprotective, and antiapoptotic actions. This study was done to assess the possible protective effects of hydroalcoholic extract of Plantago major in renal toxicity caused by Adriamycin. Methods and Materials: 40 rats divided into 4 groups: 1- control, 2- Adriamycin (5mg/kg), 3- Plantago major extract (600mg/kg) +ADR, 4- Plantago major extract (1200mg/kg) +ADR. The animals received the extract orally for 35 days, and an intravenous injection of Adriamycin was done through the tail vein on the seventh day of the study. At the end of the study, animals were humanely killed, and kidneys were removed to assess oxidative stress and histopathology. Result: The results of this study showed that Adriamycin significantly decreases renal SOD and CAT activities when compared to the control group. However, Plantago major extract, especially at the dose of 1200 mg/kg, significantly increased the activity of these antioxidant enzymes. The percent of kidney tissue damage in the ADR group was also significantly higher than that of the control group, and the extract could significantly improve these morphological changes compared to the ADR group. Conclusion: The results of the present study showed that the hydro-alcoholic extracts of Plantago Major at doses used in the study could reduce oxidative stress and renal tissue damage caused by Adriamycin. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the effect of combined treatment with quercetin and Adriamycin (doxorubicin) on the development of refractory acute leukemia. Primary leukemic cells were isolated from patients with refractory drug-resistant acute leukemia. The Cell Counting Kit-8 assay was used to detect the proliferation of cells treated with a range of doses of Adriamycin, quercetin and a combination of the two drugs. Non-irradiated mice were used to establish a T cell acute lymphoblastic leukemia (T-ALL) model, which was subsequently treated with Adriamycin, quercetin and a combination of the two drugs. The survival time was recorded, and white and red blood cells and platelets in mouse peripheral blood were counted. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content of cardiac tissues were measured as indicators of oxidative stress and damage. Proliferation of primary leukemic cells was reduced by Adriamycin depending on the dose (0.06, 0.6 or 6 µg/ml) and treatment duration (24, 48 or 72 h) compared with the vehicle treated group. Co-treatment with quercetin achieved a similar suppression of leukemic cell proliferation when a lower dose of Adriamycin (0.03, 0.3 or 3 µg/ml) was administered for the same duration. The survival of non-irradiated mice with T-ALL was improved by co-treatment with a high dose of Adriamycin and quercetin compared with either treatment alone. Compared with treatment with Adriamycin alone, the combined treatment with Adriamycin and quercetin significantly enhanced the SOD activity and reduced the MDA content in the heart. Therefore, quercetin may enhance the effects of Adriamycin on refractory acute leukemia. [ABSTRACT FROM AUTHOR]

Objective: Inflammation and oxidative stress is considered to have a crucial role in induction of nephropathy. Curcuma longa (C. longa) and Nigella sativa (N. sativa) have anti-inflammatory and antioxidant effects. This study was designed to investigate the effect of mixed hydro-alcoholic extract of N.sativa and C. longa on the oxidative stress induced by Adriamycin (ADR) in rat kidney. Material and Method: The animals were divided into 6 groups: control (CO), ADR, Adriamycin+ Vitamin C (ADR+VIT C), C. longa extract+ Adriamycin (C.LE+ADR), N. sativa extract+ Adriamycin (N.SE+ADR) and C. longa extract+ N. sativa extract + Adriamycin (N.S+C.L+ADR). ADR (5mg/kg) was injected intravenously, whereas VITC (100mg/kg) and extract of C. longa (1000mg/kg) and N. sativa (200mg/kg) were administrated orally. Finally, the renal tissue, urine and blood samples were collected and submitted to measure of redox markers, osmolarity and renal index. Results: The renal content of total thiol and superoxide dismutase (SOD) activity significantly decreased and Malondialdehyde (MDA) concentration increased in Adriamycin group compared to control group. The renal content of total thiol and SOD activity significantly enhanced and MDA concentration reduced in treated-mixed extract of C. longa and N. sativa along with ADR group compared to ADR group. The mixed extract did not restore increased renal index percentage induced by ADR. There also was no significant difference in urine and serum osmolarity between the groups. Conclusion: hydro-alcoholic extracts of N.sativa and C.longa led to an improvement in ADR-induced oxidative stress and mixed administration of the extracts enhanced the aforementioned therapeutic effect.

Background: Because of the antioxidant effects of Zataria multiflora (ZM) and carvacrol (CAR) and also the role of oxidative stress in the induction of cardiotoxicity induced by Adriamycin (ADR), the aim of this study was to investigate the improvement effects of ZM extract and CAR on cardiotoxicity induced by ADR in rats. Methods: Twenty-eight male rats were randomly assigned to four groups including (1) the control group; (2) the ADR group, which received ADR intravenously at the beginning of the study and the (3) ZM+ADR and (4) CAR+ADR groups, which received ZM and CAR by gavage for 28 consecutive days and ADR as single dose. Blood samples were collected on days 0 and 28 to determine serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and lactate dehydrogenase (LDH). Also, cardiac tissue was removed for redox marker evaluation. Results: In the ADR group, malondialdehyde (MDA) significantly increased and superoxide dismutase (SOD) activity and total thiol contents significantly reduced, as compared with the control group, while CAR administration significantly improved this condition. Treatment with ZM significantly increased the SOD activity and total thiol content, as compared with the ADR group. The level of LDH significantly increased on day 28 in the ADR group compared to the control group, and administration of ZM and CAR significantly decreased it. The SGPT and SGOT levels in the ADR group significantly increased, and CAR administration significantly reduced them. Conclusion: The results indicate that the administration of ZM hydroalcoholic extracts and its active ingredient, CAR, could reduce the oxidative stress damage through promotion of the cardiac and systemic antioxidant system. Also, CAR administration demonstrated better improvement in cardiotoxicity with ADR in rats. [ABSTRACT FROM AUTHOR]

Highlights • CMCOS with higher antioxidant activity was prepared and characterized. • CMCOS had therapeutic effects on renal function impairment and parenchymal injury. • CMCOS inhibited inflammation and fibrosis by regulating IL-1β, TNF-ɑ and TGF-β1. • CMCOS reduced oxidative stress by improving SOD and GSH-Px activities. Abstract Carboxymethyl chitosan oligosaccharide (CMCOS), the hydrolytic product of carboxymethyl chitosan, is nontoxic, easily absorbable and good antioxidant. In this study, CMCOS was prepared and its properties in adriamycin nephropathy therapy were investigated. Our results showed that CMCOS had good curative effects on renal function and parenchymal injury induced by adriamycin. CMCOS administration significantly relieved symptoms of proteinuria, hypoalbuminemia, hyperlipidemia, renal hyperplasia and histological lesions in rats (P < 0.01). Further exploration for the underlying mechanisms indicated that CMCOS treatment reduced macrophage accumulation, myofibroblast transdifferentiation and podocyte apoptosis. CMCOS treatment could regulate secretions of cytokines (IL-1β, TNF-ɑ and TGF-β1) and improve activities of antioxidative enzymes (SOD, GSH-Px) (P < 0.01). In conclusion, therapeutic effects of CMCOS on renal injury mediated by inflammation, fibrosis and oxidative stress made it a good kidney health product and a promising candidate in clinical treatment of human chronic kidney disease. [ABSTRACT FROM AUTHOR]

Leonurine, a major bioactive component from Herba Leonuri, shows therapeutic potential in several diseases, including diabetes, cardiovascular disease, bovine mastitis and depression. In kidney, it was reported that leonurine was performing a protective effect in both acute kidney injury and renal fibrosis mice models. The aim of this study is to investigate the effect of leonurine in podocyte injury. In the mice model of adriamycin (ADR) -induced nephropathy, the application of leonurine significantly prevented early kidney damage, macrophage infiltration and proteinuria. Meanwhile, leonurine suppressed ADR-induced podocyte injury and reactive oxygen species (ROS) production. Consistent to in vivo results, leonurine prevented ADR-induced podocyte injury and ROS production in cultured human podocytes. All these results suggested that leonurine might suppress ADR-induced podocyte injury via inhibiting oxidative stress. Leonurine might be a novel therapeutic drug for prevention of glomerular diseases. [ABSTRACT FROM AUTHOR]

Nephrotic syndrome (NS) is the most common kidney disease in clinical practice and may lead to end-stage renal failure. Astragalosides (AST) have been clinically tested for the treatment of NS, but their mechanism of action has remained to be elucidated. The aim of the present study was to investigate the effect of AST on the structure and function of podocytes with adriamycin (ADR)-induced damage and to elucidate the underlying molecular mechanisms. The mouse podocyte clone 5 (MPC5) immortalized mouse podocyte cell line was treated with 0.5 µmol/l ADR to establish a podocyte injury model. The MPC5 podocytes were divided into a control group, a podocyte injury group and a low-, medium- and high-concentration AST treatment group. The results indicated that the survival rate of the podocyte injury group was significantly decreased compared with that in the control group and each AST-treated group had an increased survival rate compared with that in the podocyte injury group. Furthermore, each dose of AST significantly inhibited the ADR-associated increases the levels of lactate dehydrogenase and malondialdehyde and the decrease in the activity of superoxide dismutase in MPC5 podocytes. In addition, AST improved the migration ability of MPC5 podocytes and suppressed the cytoskeletal rearrangement associated with ADR-induced damage. Furthermore, matrix metalloproteinase (MMP)-2 and −9 were decreased in the podocyte injury group, which was inhibited by different concentrations of AST. Thus, AST was able to maintain the balance of oxidative stress in podocytes cultured with ADR and protect them from ADR-induced injury. The mechanism may be associated with the upregulation of MMPs. [ABSTRACT FROM AUTHOR]

Adriamycin (ADR) is a chemotherapeutic drug used to treat tumors in a clinical setting. However, its use is limited by a side effect of cardiotoxicity. Glibenclamide (Gli), an inhibitor of mitochondrial ATP‑dependent potassium (K‑ATP) channels, blocks the cardioprotective effects of mitochondrial K‑ATP channel openers and induces apoptosis in rodent pancreatic islet β‑cell lines. However, little is known about the role of Gli in ADR‑induced cardiotoxicity. The present study was designed to investigate the impact of Gli on ADR‑induced cardiotoxicity in rats. A total of 60 male Sprague‑Dawley rats were divided into the following 4 groups: i) Control; ii) Gli; iii) ADR; and iv) Gli+ADR (n=15 in each). The rats in the ADR and Gli+ADR groups were treated with ADR (intraperitoneal, 2.5 mg/kg/week) for 6 weeks. The rats in the Gli and Gli+ADR groups received Gli at a dose of 12 mg/kg/day via gastric lavage for 30 days from the eighth week of the study. Following the completion of Gli treatment, cardiac function was assessed by echocardiography, and the rats were sacrificed. The hearts were subsequently harvested for analysis. The rats in the ADR group demonstrated significantly impaired cardiac function and increased levels of oxidative stress, endoplasmic reticulum stress (ERS) and apoptosis in the heart compared with rats in the control and Gli groups (without ADR treatment). These abnormalities were exacerbated by Gli in the Gli+ADR group. Gli treatment decreased cardiac function and significantly increased oxidative stress, ERS and apoptosis levels in myocardial tissues in rats treated with ADR. The findings indicated that Gli triggers oxidative stress‑induced ERS, and thus exacerbates ADR‑induced cardiotoxicity in rats. [ABSTRACT FROM AUTHOR]

Doxorubicin is utilized for anti-neoplastic treatment for several decades. The utility of this drug is limited due to its side effects. Generally, doxorubicin toxicity is originated from the myocardium and then other organs are also ruined. The mechanism of doxorubicin is intercalated with the DNA and inhibits topoisomerase 2. There are various signalling mechanisms involved in doxorubicin cardiotoxicity. First and foremost, the doxorubicin-induced cardiotoxicity is due to oxidative stress. Cardiac mitochondrial damage is supposed after few hours following the revelation of doxorubicin. This has led important new uses for the mechanism of doxorubicin-induced cardiotoxicity and novel avenues of investigation to determine better pharmacotherapies and interventions for the impediment of cardiotoxicity. The idea of this review is to bring up to date the recent findings of the mechanism of doxorubicin cardiomyopathies such as calcium dysregulation, endoplasmic reticulum stress, impairment of progenitor cells, activation of immune, ubiquitous system and some other parameters. [ABSTRACT FROM AUTHOR]

Purpose: Doxorubicin (DOX) is a highly active antineoplastic agent; however, its clinical use is limited due to associated cardiotoxicity. This study was performed to evaluate the beneficial effects of allicin, a dietary garlic active constituent against DOX-induced cardiotoxicity.Methods: Forty male Swiss albino mice were divided into five groups, which received normal saline, oral allicin (20 mg kg-1 once daily), intraperitoneal DOX (on the 7, 9 and 11th day of the experiment), or DOX plus once daily allicin at 10 or 20 mg kg-1. Sera were collected for evaluation of cardiac injury markers and proinflammatory cytokines. Additionally, heart tissue spacemen were harvested for determination of oxidative stress markers, as well as for histopathological examination and immunohistochemical analysis.Results: DOX administration induced significant (p < 0.05) reductions in cardiac tissue level of reduced glutathione and activities of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase). Moreover, it induced significant (p < 0.05) elevations in cardiac tissue concentrations of nitric oxide and malondialdehyde as well as serum levels of cardiac injury biomarkers (lactate dehydrogenase, creatine kinase, and creatine kinase-MB) and proinflammatory cytokines (interleukin-1β, and tumor necrosis factor-alpha). The histopathological examination showed necrotic and degenerative changes in the cardiac tissue, while immunohistochemical analysis revealed marked myocardial expression of activated caspase-3 and cyclooxygenase-2, following DOX adminstration. Allicin pretreatment significantly improved (p < 0.05) all examined parameters, and restored the cardiac architecture.Conclusion: The current study demonstrated that allicin effectively mitigates cardiac oxidative damage, apoptosis and inflammation, induced by acute DOX intoxication. Therefore, allicin could be a promising cytoprotective agent against DOX cardiotoxicity. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of Draba nemorosa extract (DNE) on oxidative stress and hemodynamics in rats with chronic congestive heart failure (CHF). Methods: Adriamycin was used to establish CHF in Sprague Dawley (SD) rat model. Six groups of SD rats were used in this study: control group, CHF group, captopril group (0.1 g/kg), as well as high-, medium- and low-dose DNE groups (5.2, 2.6 and 1.3 g/kg, respectively). Treatment for all groups lasted 4 weeks. Blood pressure and heart index were measured. In addition, serum creatine kinase (CK), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and nitric oxide synthase (NOS) were determined with enzyme-linked immunosorbent assay (ELISA) kits. Results: In the CHF group, arterial systolic pressure (SBP, 84.22 ± 16.23 mmHg); diastolic pressure (DBP, 77.36 ± 20.29 mmHg); mean arterial pressure (MAP, 78.45 ± 10.56 mmHg); heart rate (HR, 357.18 ± 37.34 beats/min) and left ventricular systolic peak (LVSP, 102.34 ± 16.37 mmHg) were significantly decreased (p < 0.05) when compared with the control group. However, left ventricular end diastolic pressure (LVEDP, 23.38 ± 1.78 mmHg); heart index (2.74 ± 0.16 mg/g); serum CK (0.87 ± 0.15 U/mL); MDA (19.34 ± 2.57 nmol/mL), NO (38.43 ± 3.32 umol/L) and NOS (42.65 ± 3.32 U/mL) were increased. Treatment with high-dose DNE significantly ameliorated hemodynamic function, and reduced MDA (9.13 ± 2.12 nmol/mL) and NO (22.37 ± 3.16 umol/L) levels (p < 0.05). High-dose DNE also led to significant decreases in CK (0.53 ± 0.35 U/mL) and NOS (24.27 ± 3.55U/mL) in the CHF rats (p < 0.05). Conclusion: DNE significantly improves hemodynamic function in CHF rats. Thus, it has a potential for development into a new drug for clinical treatment of CHF. [ABSTRACT FROM AUTHOR]

Sildenafil and febuxostat protect against doxorubicin-induced nephrotoxicity; however the exact mechanism remains to be elucidated. The effect of sildenafil and febuxostat on doxorubicin-induced nephrotoxicity in rats was studied. Male rats were subdivided into nine groups. The 1st group served as normal control, the 2nd group received dimethylsulfoxide 50% (DMSO), the 3rd group received doxorubicin (3.5 mg/kg, i.p.), twice weekly for 3 weeks. The next 3 groups received sildenafil (5 mg/kg; p.o.), febuxostat (10 mg/kg; p.o.) and their combination, respectively daily for 21 days. The last 3 groups received doxorubicin in combination with sildenafil, febuxostat or their combination. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically through measuring the following parameters, Kidney function biomarkers [serum levels of urea, creatinine and uric acid], oxidative stress biomarkers [kidney contents of glutathione reduced (GSH) and malondialdehyde (MDA)], The apoptotic marker namely; caspase-3 in kidney tissue and the inflammatory mediator tumor necrosis factor alpha (TNF-α). doxorubicin-induced a significant elevation in nephrotoxicity markers, expression of caspase-3 and caused induction of inflammation and oxidative stress. Histological changes in the kidney was tubular necrosis. Sildenafil and/or febuxostat administration with doxorubicin caused a significant decrease in nephrotoxicity markers and inflammatory mediators, restoration of normal values of oxidative stress biomarkers and hampering the expression of renal caspase-3. They also ameliorate histological changes induced by doxorubicin. sildenafil and febuxostat are promising protective agents against doxorubicin-nephrotoxicity through improving biochemical, inflammatory, histopathological and immunohistochemical alterations induced by doxorubicin. [ABSTRACT FROM AUTHOR]

Adriamycin (ADR), an antineoplastic drug, is widely used to treat different types of cancers. Yet, the usage is limited because of its severe side effects on testis. On the other hand, gemfibrozil (GEM), as an anti-hyperlipidemic drug, has other pharmacological effects independent of lipid- lowering activity including anti-inflammatory and antioxidant properties. The present experiment was designed to investigate the effect of GEM on ADR-induced testicular injury in male rats. A total of 28 male Wistar rats were divided into 4 equal groups: Control; ADR; ADR + GEM; GEM. Serum level of testosterone, luteinizing hormone and follicle stimulating hormone were assessed. Also, testicular tissue oxidant/antioxidant markers (malondialdehyde, total antioxidant capacity, nitric oxide, superoxide dismutase, catalase, glutathione peroxidase and glutathione) and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) were measured. Histopathological studies were conducted on testes. GEM improved hormonal profile and antioxidant defenses in comparison with ADR-treated animals. GEM, significantly reduced the production of proinflammatory cytokines compared with ADR-treated animals. Hormonal and biochemical results were further supported by testicular histopathological findings. Thus, GEM might represent a promising therapeutic modality for the attenuation of testicular injury induced by ADR in clinic. • ADR induces oxidative and inflammatory damages in testes. • ADR induces hormonal disturbances as well as histopathological lesions in testes. • GEM, as an anti-hyperlipidemic drug, has anti-inflammatory and antioxidant effects. • GEM improves ADR-induced alternations in oxidative and inflammatory parameters. • GEM attenuated the histopathological lesions which induced by ADR in testes. [ABSTRACT FROM AUTHOR]

Adriamycin (ADR), one of the most effective broad-spectrum antitumor chemotherapeutic agents in clinical practice, is used to treat solid tumors as well as hematological malignancies in adults and children. However, long-term ADR use causes several adverse reactions, including time- and dose-dependent cardiotoxicity, which limit its clinical application. In addition, the mechanism by which ADR induces cardiotoxicity remains unclear. Therefore, we used zebrafish as animal models to evaluate ADR toxicity during embryonic heart development owing to the similarity of this process in zebrafish to that in humans. Exposure of zebrafish embryos to 1.25, 2.5, and 5 mg/L ADR induced abnormal embryonic development, with the occurrence of cardiac malformations, pericardial edema, decreased movement speed and activity, and increased distance between the venous sinus and the arterial bulb (SV-BA). ADR exposure induced dysregulated cardiogenesis during the precardiac mesoderm formation period. We also observed irregular expression of cardiac-related genes, an upregulation of apoptotic gene expression, and a dose-dependent increase in oxidative stress levels. Furthermore, oxidative stress-induced apoptosis exerted deleterious effects on cardiac development in zebrafish embryos, and treatment with astaxanthin (ATX) alleviated these heart defects. ADR- and Wnt pathway-related genes exhibited good energy and spatial matching, and ADR upregulated the Wnt signaling pathway in zebrafish. Moreover, IWR-1 effectively alleviated ADR-induced heart defects. In conclusion, we demonstrated that the toxic effects of ADR on cardiac development in zebrafish embryos could provide a theoretical basis for explaining the pathogenesis of ADR-induced cardiotoxicity, which occurs through the upregulation of oxidative stress and Wnt signaling pathway, as well as its prevention and treatment in humans. These findings will help develop effective treatment strategies to combat ADR-induced cardiotoxicity and broaden the application of ADR for clinical practice. [Display omitted] • Adriamycin (ADR) induced dysregulated cardiogenesis in zebrafish. • ADR enhanced oxidative stress in zebrafish. • ADR upregulated Wnt signaling pathway in zebrafish. • Astaxanthin, an antioxidant, alleviated ADR-induced cardiotoxicity in zebrafish. • IWR-1, a Wnt signaling pathway inhibitor, alleviated ADR-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Ethyl pyruvate (EP), a derivative of pyruvic acid, is known to have protective effects against ischemic cardiomyopathy and other disorders. However, little is known about its role in Adriamycin (ADR)-induced cardiomyopathy. The present study was designed to investigate the impact of EP on ADR-induced cardiomyopathy in an animal model. Sixty male Sprague-Dawley (SD) rats were divided into four groups: Normal control, EP, ADR and ADR + EP groups (n=15/group). Rats in the ADR and ADR + EP groups were treated with ADR (2.5 mg/kg/week intraperitoneally) for 6 weeks. From the eighth week, rats in the EP and ADR + EP groups received EP via gastric lavage at a dose of 50 mg/kg/day for 30 days. After completing the EP treatment, cardiac function was assessed by echocardiography and then rats were sacrificed. Hearts were harvested for subsequent analysis. Compared with rats in the normal control and EP groups (without ADR treatment), rats in the ADR and ADR + EP groups showed significant impairments in terms of cardiac function, apoptosis, severe oxidative stress and fibrosis in the heart. However, these impairments were alleviated by EP treatment in the ADR + EP group. Upon EP treatment, cardiac function was significantly improved. The levels of oxidative stress, fibrosis and apoptosis in the myocardial tissues were also significantly reduced. These findings indicated that EP treatment attenuated, at least partially, ADR-induced cardiomyopathy in rats. [ABSTRACT FROM AUTHOR]

Introduction: The aim of the study was to investigate the effects of Curcuma longa (C. longa) extract on Adriamycin-induced hepatotoxicity in rat. Methods: Animals were divided in six groups: Control (CO), Adriamycin (ADR), Adriamycin with Vitamin C (ADR+VitC), Vitamin C (Vit C), C. longa with Adriamycin (CL+ADR) and without Adriamycin (CL-ADR). Hepatotoxicity was induced by Adriamycin 5mg/kg and rats were treated with C. longa 1000 mg/kg and Vitamin C 100 mg/kg , per day, orally for 4 weeks. Results: In the liver tissue of ADR group, Malonyldialdehyde (MDA) level was increased significantly compared to CO group, (p < 0.05). MDA level in the treatment groups, Vit C, CL+ADR and CL-ADR were increased significantly compared to ADR group (p < 0.05, for all three groups), and compared to ADR+VitC group (p < 0.01). Thiol level in ADR, ADR+VitC and CL+ADR groups were decreased compared to CO group (p < 0.001), and also thiol level in CL-ADR and Vit C were increased significantly compared to ADR group (p < 0.01 and p < 0.001 respectively). The activity of catalase in liver tissue in ADR group was lower compared to CO group (p < 0.01), though was increased in CL-ADR, ADR+VitC and Vit C groups in comparison with ADR group (p<0.05, p < 0.01 and p < 0.001, respectively). Conclusion: The results showed that chronic administration of C. longa hydroalcoholic extract in Adriamycin-induced hepatotoxic rats could decrease the oxidative stress injuries in the liver tissue. [ABSTRACT FROM AUTHOR]

Objective: Inflammation and oxidative stress is considered to have a crucial role in induction of nephropathy. Curcuma longa (C. longa) and Nigella sativa (N. sativa) have anti-inflammatory and antioxidant effects. This study was designed to investigate the effect of mixed hydro-alcoholic extract of N.sativa and C. longa on the oxidative stress induced by Adriamycin (ADR) in rat kidney. Materials and Methods: The animals were divided into 6 groups: control (CO), ADR, Adriamycin+ Vitamin C (ADR+VIT C), C. longa extract+ Adriamycin (C.LE+ADR), N. sativa extract+ Adriamycin (N.SE+ADR) and C. longa extract+ N. sativa extract + Adriamycin (N.S+C.L+ADR). ADR (5mg/kg) was injected intravenously, whereas VITC (100mg/kg) and extract of C. longa (1000mg/kg) and N. sativa (200mg/kg) were administrated orally. Finally, the renal tissue, urine and blood samples were collected and submitted to measure of redox markers, osmolarity and renal index. Results: The renal content of total thiol and superoxide dismutase (SOD) activity significantly decreased and Malondialdehyde (MDA) concentration increased in Adriamycin group compared to control group. The renal content of total thiol and SOD activity significantly enhanced and MDA concentration reduced in treated-mixed extract of C. longa and N. sativa along with ADR group compared to ADR group. The mixed extract did not restore increased renal index percentage induced by ADR. There also was no significant difference in urine and serum osmolarity between the groups. Conclusion: hydro-alcoholic extracts of N.sativa and C.longa led to an improvement in ADR-induced oxidative stress and mixed administration of the extracts enhanced the aforementioned therapeutic effect. [ABSTRACT FROM AUTHOR]

Background Adriamycin (ADM) is an antineoplastic agent that is effective against a wide range of cancers, but cardiac toxicity limits its clinical application. Ginsenoside Rg3 (Rg3), an anti-cancer active ingredient of Panax ginseng, was reported to have anti-oxidative, anti-apoptotic, and cardioprotective properties. Purpose The current study aimed to investigate the possible protective effect of Rg3 against ADM-induced cardiotoxicity. Study design The activity of Rg3 to improve endothelial dysfunction was processed both in vivo and in vitro . Methods We investigated the cardioprotective effect of Rg3 on ADM treated rats by echocardiography. The endothelial dysfunction was assessed using an aortic ring assay. Cardiac microvascular endothelial cells were cultured to investigate the effects of Rg3 on ADM-treated cells. Results Results showed that Rg3 could ameliorate the decrease in the ejection fraction and fractional shortening that was induced by ADM, and improve the left ventricular outflow. The aortic ring assay showed that Rg3 could partially recover the abnormal vascular function. In vitro studies showed that Rg3 could promote cell viability to attenuate ADM induced oxidative damage and apoptosis. This counteraction was achieved partially via activation of the Nrf2-ARE pathway through the activation of Akt. Conclusion These findings elucidated the potential of Rg3 as a promising reagent for treating ADM-induced cardiotoxicity in clinic. [ABSTRACT FROM AUTHOR]

Introduction: the well known antioxidant properties of white tea include the prevention of cancer, neurodegenerative diseases and oxidative stress. Adriamycin can generate an amount of oxidative stress in vivo.Objective: evaluate long term intake of white tea on plasma antioxidant capacity and on the fatty acid profile of liver and heart microsomes in animals subjected to acute oxidative stress.Methods: rats were given distilled water (controls), 15 mg/d (dose 1) or 45 mg/d (dose 2) of solid white tea extract/per kilogram of body weight for 12 months. After this time, all the animals received an injection of adriamycin (ADR) (10 mg/kg body weight), except half of the control group, which were given an injection of saline solution. Samples of plasma and liver and heart were taken. The antioxidant activity, the carbonyl groups and hydroperoxide concentration were analyzed in plasma, and the fatty acid profiles of liver and heart microsomes were obtained.Results& Discussion: only the hydroperoxides showed significant changes, while slight tendencies were observed in antioxidant activity and the carbonyl groups. Although the long term intake of white tea and the administration of adriamycin did not change the fatty acid profile, slight tendencies existed for the SFAs, MUFAs and PUFAs. [ABSTRACT FROM AUTHOR]

The flavonoid content of tea ( Camellia sinensis) has beneficial properties in the prevention of diseases. However, the mechanisms by which white tea can protect against oxidative stress remain unclear. To shed light on this issue, rats were given distilled water (controls), 0.15 mg/day (dose 1) or 0.45 mg/day (dose 2) of solid tea extract/kg body weight for 12 months. All the animals received an injection of adriamycin (ADR; 10 mg/kg body weight), except half of the control group, which were given an injection of saline solution. The expression of the nuclear factor, E2-related factor 2 ( Nrf2), NAD(P)H:quinone oxidoreductase 1 ( Nqo1), glutathione S-transferase ( Gst), haem oxygenase-1 ( Ho1), catalase ( Cat), superoxide dismutase ( Sod) and glutathione reductase ( Gr) in liver was analysed by real-time PCR, and the activity of catalase (CAT), superoxide dismutase (SOD) and glutathione reductase (GR) was measured spectrophotometrically. ADR significantly increased the expression of Nrf2, Gst, Nqo1, Ho1, Cat, Sod and Gr with respect to the control levels and also increased the activity of CAT, SOD and GR. The intake of white tea increased in a higher degree the expression of Nrf2, Gst, Nqo1 and Ho1 in the tea + ADR group compared with the control group and C + ADR group. In addition, tea + ADR groups decreased the expression and activity of CAT, SOD and GR in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

This study was designed to evaluate the effect of quercetin, a natural flavonoid, on behavioral alterations, brain oxidative stress, and immune dysregulation caused by a chemotherapeutic agent, Adriamycin (ADR; 7 mg/kg of body weight). Different subsets of male Wistar rats were used to determine the benefit of quercetin on ADR-related depression-like and anxiety-like behaviors in the forced swim test, open field, and elevated plus maze, respectively. Quercetin (60 mg/kg of body weight) was administered 24, 5, and 1 h before the test session of forced swim test (FST) or at the same time points before the elevated plus maze/open field (EPM/OF) tests. Other subsets of rats were sacrificed after quercetin injections to assess the plasma corticosterone level, the brain oxidative status, and the immune cell count. Our results indicate that quercetin alleviated the anxio-depressive-like behavior, attenuated the brain oxidative stress, and suppressed the corticosterone excess that appeared following ADR treatment. The ADR-induced immune disturbance was slightly diminished after quercetin administration, especially for the lymphocyte count. This study suggests that quercetin can mitigate the neurobehavioral and immunological impairments that manifest in ADR-treated rats. Therefore, the combination of quercetin treatment with the chemotherapeutic regimen seems to be beneficial against chemotherapy-related complications. [ABSTRACT FROM AUTHOR]