Doxorubicin-induced Oxidative Stress Research Articles

Interleukin-1β triggers muscle-derived extracellular superoxide dismutase expression and protects muscles from doxorubicin-induced atrophy

Oxidative stress plays an important role in skeletal muscle atrophy. Doxorubicin, a conventional chemotherapeutic agent prescribed for cancer, causes skeletal muscle atrophy and adversely affects mobility and strength. Since doxorubicin-induced muscle atrophy is primarily attributable to oxidative stress, its effects could be mitigated by antioxidant-focused therapies; however, these protective therapeutic targets remain ambiguous. This study aimed at demonstrating that doxorubicin triggered severe muscle atrophy via upregulation of oxidative stress (4-Hydroxynonenal and Malondialdehyde) and atrogenes (Atrogin-1/MAFbx and Muscle RING Finger-1) in association with decreased expression of the antioxidant enzyme, extracellular superoxide dismutase (EcSOD), in cultured C2C12 myotubes and mouse skeletal muscle. EcSOD recombinant protein supplementation elevated EcSOD levels on the cellular membrane of cultured myotubes, consequently inhibiting doxorubicin-induced oxidative stress and myotube atrophy. Furthermore, doxorubicin treatment reduced interleukin-1β (IL-1β) mRNA expression in cultured myotubes and skeletal muscle, while transient IL-1β treatment increased EcSOD protein expression on the myotube membrane. Notably, transient IL-1β treatment of cultured myotubes and local administration in mouse skeletal muscle attenuated doxorubicin-induced muscle atrophy, which is associated with increased EcSOD expression. Collectively, these findings reveal that the regulation of skeletal muscle EcSOD via maintenance of IL-1β signaling is a potential therapeutic approach against doxorubicin-and oxidative stress-mediated muscle atrophy. This study was supported by Grant-in-Aid for Scientific Research (B) (15H03080, 18H03153, 21H03326), Grant-in-Aid for Exploratory Research (20K21766), Suzuken Memorial Foundation, Toyoaki Scholarship Foundation, The Nakatomi Foundation, and The Uehara Memorial Foundation (to M.O.). This research was also supported by Grant-in-Aid for JSPS Fellows (20J15551), Grant-in-Aid for Early-Career Scientists (22K17733), Suzuken Memorial Foundation, The Nakatomi Foundation, and The Uehara Memorial Foundation (to M.Y.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Magnetostriction enhanced self-powered nanofiber sheet as cardiac patch with magnetoelectric synergistic effect on actuating Na+ k+-ATPase

Cardiac tissue engineering has great promise in the treatment of heart disease. Aiming to develop the novel magnetoelectric cardiac patch for improving the non-conduction of injured myocardium after myocardial infarction, the self-powered nanofiber sheet was electro-spun by doping magnetostrictive CoFe2O4 in piezoelectric Poly (vinylidene fluoride) (PVDF). The piezoelectric ratios increased several folds with the doping of CoFe2O4 due to the increased β phase and crystallinity of CoFe2O4-PVDF confirmed by experimental data. Molecular Dynamics and Finite Element Simulation demonstrated that non-β phase transformed to β phase of PVDF with doping CoFe2O4 and the deformation of CoFe2O4 enhanced the piezoelectric effect of PVDF, respectively. The proliferation and spread area of Doxorubicin-induced oxidative stress injured cardiomyocytes, H9c2 cells, were significantly improved under magnetoelectric cue compared with those without magnetoelectric cue when co-cultured with CoFe2O4-PVDF. Importantly, a new mechanism pathway of magnetoelectric cue on cardiomyocytes has been found, including up-regulating of steroid hormone biosynthesis, enhancing of sodium–potassium enzyme, and increasing of intracellular Ca2+, which would trigger the cardiomyocyte contraction to overcome the non-conduction of injured cardiomyocytes by RNA-seq transcriptome sequencing, Polymerase Chain Reaction and downstream expression analysis. Hence, this CoFe2O4-PVDF composite nanofiber sheet would be potentially used as the magnetoelectric cardiac patch to treat injured myocardium after myocardial infarction clinical.

Interleukin-1β triggers muscle-derived extracellular superoxide dismutase expression and protects muscles from doxorubicin-induced atrophy.

Doxorubicin, a conventional chemotherapeutic agent prescribed for cancer, causes skeletal muscle atrophy and adversely affects mobility and strength. Given that doxorubicin-induced muscle atrophy is attributable primarily to oxidative stress, its effects could be mitigated by antioxidant-focused therapies; however, these protective therapeutic targets remain ambiguous. The aim of this study was to demonstrate that doxorubicin triggers severe muscle atrophy via upregulation of oxidative stress (4-hydroxynonenal and malondialdehyde) and atrogenes (atrogin-1/MAFbx and muscle RING finger-1) in association with decreased expression of the antioxidant enzyme extracellular superoxide dismutase (EcSOD), in cultured C2C12myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein elevated EcSOD levels on the cellular membrane of cultured myotubes, consequently inhibiting doxorubicin-induced oxidative stress and myotube atrophy. Furthermore, doxorubicin treatment reduced interleukin-1β (IL-1β) mRNA expression in cultured myotubes and skeletal muscle, whereas transient IL-1β treatment increased EcSOD protein expression on the myotube membrane. Notably, transient IL-1β treatment of cultured myotubes and local administration in mouse skeletal muscle attenuated doxorubicin-induced muscle atrophy, which was associated with increased EcSOD expression. Collectively, these findings reveal that the regulation of skeletal muscle EcSOD via maintenance of IL-1β signalling is a potential therapeutic approach to counteract the muscle atrophy mediated by doxorubicin and oxidative stress. KEY POINTS: Doxorubicin, a commonly prescribed chemotherapeutic agent for patients with cancer, induces severe muscle atrophy owing to increased expression of oxidative stress; however, protective therapeutic targets are poorly understood. Doxorubicin induced muscle atrophy owing to increased expression of oxidative stress and atrogenes in association with decreased protein expression of extracellular superoxide dismutase (EcSOD) in cultured C2C12myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein increased EcSOD levels on the cellular membrane of cultured myotubes, resulting in inhibition of doxorubicin-induced oxidative stress and myotube atrophy. Doxorubicin treatment decreased interleukin-1β (IL-1β) expression in cultured myotubes and skeletal muscle, whereas transient IL-1β treatment in vivo and in vitro increased EcSOD protein expression and attenuated doxorubicin-induced muscle atrophy. These findings reveal that regulation of skeletal muscle EcSOD via maintenance of IL-1β signalling is a possible therapeutic approach for muscle atrophy mediated by doxorubicin and oxidative stress.

FGF10 mitigates doxorubicin-induced myocardial toxicity in mice via activation of FGFR2b/PHLDA1/AKT axis.

Doxorubicin is a common chemotherapeutic agent in clinic, but myocardial toxicity limits its use. Fibroblast growth factor (FGF) 10, a multifunctional paracrine growth factor, plays diverse roles in embryonic and postnatal heart development as well as in cardiac regeneration and repair. In this study we investigated the role of FGF10 as a potential modulator of doxorubicin-induced cardiac cytotoxicity and the underlying molecular mechanisms. Fgf10+/- mice and an inducible dominant negative FGFR2b transgenic mouse model (Rosa26rtTA; tet(O)sFgfr2b) were used to determine the effect of Fgf10 hypomorph or blocking of endogenous FGFR2b ligands activity on doxorubicin-induced myocardial injury. Acute myocardial injury was induced by a single injection of doxorubicin (25 mg/kg, i.p.). Then cardiac function was evaluated using echocardiography, and DNA damage, oxidative stress and apoptosis in cardiac tissue were assessed. We showed that doxorubicin treatment markedly decreased the expression of FGFR2b ligands including FGF10 in cardiac tissue of wild type mice, whereas Fgf10+/- mice exhibited a greater degree of oxidative stress, DNA damage and apoptosis as compared with the Fgf10+/+ control. Pre-treatment with recombinant FGF10 protein significantly attenuated doxorubicin-induced oxidative stress, DNA damage and apoptosis both in doxorubicin-treated mice and in doxorubicin-treated HL-1 cells and NRCMs. We demonstrated that FGF10 protected against doxorubicin-induced myocardial toxicity via activation of FGFR2/Pleckstrin homology-like domain family A member 1 (PHLDA1)/Akt axis. Overall, our results unveil a potent protective effect of FGF10 against doxorubicin-induced myocardial injury and identify FGFR2b/PHLDA1/Akt axis as a potential therapeutic target for patients receiving doxorubicin treatment.

Chlorogenic Acid Attenuates Doxorubicin-Induced Oxidative Stress and Markers of Apoptosis in Cardiomyocytes via Nrf2/HO-1 and Dityrosine Signaling.

(1) Background: Doxorubicin (DOX) is extensively used for cancer treatments; however, its clinical application is limited because of its cardiotoxic adverse effects. A combination of DOX and agents with cardioprotective properties is an effective strategy to ameliorate DOX-related cardiotoxicity. Polyphenolic compounds are ideal for the investigation of novel cardioprotective agents. Chlorogenic acid (CGA), an essential dietary polyphenol found in plants, has been previously reported to exert antioxidant, cardioprotective, and antiapoptotic properties. The current research evaluated CGA's in vivo cardioprotective properties in DOX-induced cardiotoxicity and the probable mechanisms underlying this protection. (2) Methods: CGA's cardioprotective properties were investigated in rats that were treated with CGA (100 mg/kg, p.o.) for fourteen days. The experimental model of cardiotoxicity was induced with a single intraperitoneal (15 mg/kg i.p.) injection of DOX on the 10th day. (3) Results: Treatment with CGA significantly improved the DOX-caused altered cardiac damage markers (LDH, CK-MB, and cTn-T), and a marked improvement in cardiac histopathological features accompanied this. DOX downregulated the expression of Nrf2/HO-1 signaling pathways, and the CGA reversed this effect. Consistently, caspase-3, an apoptotic-related marker, and dityrosine expression were suppressed, while Nrf2 and HO-1 expressions were elevated in the cardiac tissues of DOX-treated rats after treatment with the CGA. Furthermore, the recovery was confirmed by the downregulation of 8-OHdG and dityrosine (DT) expressions in immunohistochemical findings. (4) Conclusions: CGA demonstrated a considerable cardioprotective effect against DOX-induced cardiotoxicity. One of the possible mechanisms for these protective properties was the upregulation of the Nrf2/HO-1-dependent pathway and the downregulation of DT, which may ameliorate oxidative stress and cardiomyocyte apoptosis. These findings suggest that CGA may be cardioprotective, particularly in patients receiving DOX-based chemotherapy.

Thioredoxin Reductase 2 Synergizes with Cytochrome c, Somatic to Alleviate Doxorubicin-Induced Oxidative Stress in Cardiomyocytes and Mouse Myocardium.

Doxorubicin (DOX) may cause multiple side effects, which include cardiotoxicity. Hence, to ascertain the impact of thioredoxin reductase 2 (TXNRD2) and cytochrome c, somatic (CYCS) on DOX-induced oxidative stress (OS) in cardiomyocytes and mouse myocardium, this study was implemented. DOX was utilized to treat cardiomyocytes and mice, and TXNRD2 and CYCS expression in cell supernatant and mouse myocardial tissues was detected. TXNRD2 and/or CYCS were overexpressed in DOX-induced cardiomyocytes and mice. In cardiomyocytes, cell viability and the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and glutathione (GSH) were measured. In mice, pathologic changes of the heart, ejection fraction (EF), fractional shortening (FS), and heart weight (HW) /tibial length (TL) ratio, and the contents of lactic dehydrogenase (LDH), creatine kinase-MB (CK-MB), and cardiac troponin I (cTnI) were analyzed. To assess the binding between TXNRD2 and CYCS, coimmunoprecipitation and glutathione S-transferase pull-down assays were performed. TXNRD2 and CYCS were downregulated in DOX-treated cardiomyocytes and mice. Mechanistically, TXNRD2 interacted with CYCS. Overexpression of TXNRD2 or CYCS augmented viability and SOD, CAT, and GSH levels but reduced ROS and MDA contents in DOX-induced cardiomyocytes, which was further facilitated by simultaneous overexpression of TXNRD2 or CYCS. Moreover, TXNRD2 or CYCS upregulation improved the pathologic changes in myocardial tissues, along with increases in EF, FS, and HW/TL ratio of the heart and SOD, CAT, and GSH levels and decreases in LDH, CK-MB, cTnI, ROS, and MDA levels. TXNRD2 coordinated with CYCS to alleviate DOX-induced OS in cardiomyocytes and mouse myocardium.

Role of Gender in the Protection Against Doxorubicin-Induced Oxidative Stress

Background: There are gender differences in the oxidation-reduction reactions. Doxorubicin (Dox) is a chemotherapeutic drug that can produce oxidative stress which may require prevention by antioxidants. Aim: The study aimed to investigate the gender-dependent changes in Dox-induced oxidative stress, and the protective effects of coenzyme Q10 (CoQ10). Materials and Methods: Rats were administered CoQ10 orally for 17 days. On day 13, some rats receiving CoQ10 received a single intraperitoneal dosage of Dox, whereas other rats received normal saline. Glutathione (GSH), malondialdehyde (MDA), and total anti-oxidant capacity (T-AOC) were measured in both genders of albino rats. Results: Dox significantly reduced both GSH and T-AOC levels and caused a significant increase in MDA. The administration of CoQ10 significantly prevented these changes. Dox caused a larger reduction in GSH in males than in females, while CoQ10 caused more protection in females. Dox caused a higher increase in MDA levels in males. Conclusion: Pre-treatments with CoQ10 may protect against Dox-induced oxidative stress, with gender-dependent variations in the extent of these Dox/CoQ10 effects.

Effect of selenium against doxorubicin-induced oxidative stress, inflammation, and apoptosis in the brain of rats: Role of TRPM2 channel

Doxorubicin (DOX) is widely used as an anticancer drug in humans' various solid and haematological tumours. Although many studies on the toxic effect of DOX are used in different organs, its impact on brain tissue has yet to be adequately studied. This study investigated the protective effect of selenium (Se) and the role of transient receptor potential melastatin‐2 (TRPM2) channel activation against brain damage caused by DOX administration. Sixty rats were randomly divided into the sham, dimethyl sulfoxide (DMSO), DOX, DOX + Se, DOX + N-(p-amylcinnamoyl) anthranilic acid (ACA), and DOX + Se + ACA groups. The reactive oxygen species (ROS), poly [ADP-ribose] polymerase 1 (PARP1), and TRPM2 channel levels in brain tissues were measured by ELISA. In addition, a histopathological examination was performed in the cerebral cortex and hippocampal areas, and the TRPM2 channel, NF-κB, and caspase-3 expression were determined immunohistochemically. The levels of ROS, PARP1 and TRPM2 channel in the DOX group were higher than in the sham and DMSO groups (P < 0.05). However, these parameters were decreased in the in DOX+Se and DOX+ACA groups by the treatments of Se and ACA (P < 0.05). Also, we determined that Se and ACA treatment decreased the NF-κB, caspase-3, and TRPM2 channel expression in the cerebral cortex and hippocampal areas in the DOX-induced rats. The data showed that Se and/or ACA administration together with DOX administration could be used as a protective agent against DOX-induced brain damage.

The Preclinical Study Exploring the Effects of Creatine Supplementation on Renal Antioxidant Enzymes Following Doxorubicin Treatment

Introduction: Doxorubicin is an effective chemotherapy drug, but its use is limited by its cytotoxicity. One of doxorubicin’s anticancer mechanisms is generation of reactive oxygen species which may lead to oxidative stress. The kidney, however, is very vulnerable to oxidative stress, and one way to manage oxidative stress is to scavenge reactive oxygen species via antioxidant enzymes. Although doxorubicin-induced oxidative stress has been extensively studied, a viable treatment to attenuate doxorubcin side effects has yet to be found. This study investigated the effect of creatine feeding on catalase, glutathione peroxide, and superoxide dismutase-1 expression in the kidney following doxorubicin treatment. Methods: Twenty-eight male Sprague-Dawley rats were randomly assigned to four groups, control saline (C+SAL, n=7), control doxorubicin (C+DOX, n=7), creatine saline (Cr+SAL, n=6) and creatine doxorubicin (Cr+DOX, n=8). Control groups were fed normal chow, and creatine groups were fed chow supplemented with 3% creatine. After two weeks of feeding, doxorubicin groups received15 mg/kg doxorubicin whereas saline groups received saline as a placebo. Western blotting was used to access antioxidant enzyme expression in renal tissue. Results: A significant between group difference was observed with catalase expression, but post hoc testing did not reveal where differences existed. A trend existed toward doxorubicin treatment increasing catalase expression and creatine attenuated this trend. Glutathione peroxidase and superoxide dismutase-1 presented a similar profile as catalase; however, no significant between group differences were observed. There was a trend, however, toward increased expression of glutathione peroxidase and superoxide dismutase-1 in doxorubicin-treated animals that seemed to be attenuated with creatine supplementation. Conclusion: To our knowledge there are no studies exploring the antioxidant properties of creatine supplementation in the kidney with doxorubicin, and it is possible that creatine may enhance antioxidant properties that can attenuate the negative effects doxorubicin in the kidney. A trend towards antioxidant enzyme normalization promoted by creatine with doxorubicin suggests that creatine might have similar effect to that observed in previous studies using antioxidant drugs.

Elabela blunts doxorubicin-induced oxidative stress and ferroptosis in rat aortic adventitial fibroblasts by activating the KLF15/GPX4 signaling.

Doxorubicin (DOX) is a chemotherapeutic drug for a variety of malignancies, while its application is restricted by the cardiovascular toxic effects characterized by oxidative stress. Ferroptosis is a novel iron-dependent regulated cell death driven by lipid peroxidation. Our study aimed to investigate the role of Elabela (ELA) in DOX-induced oxidative stress and ferroptosis. In cultured rat aortic adventitial fibroblasts (AFs), stimulation with DOX dramatically induced cytotoxicity with reduced cell viability and migration ability, and enhanced lactate dehydrogenase (LDH) activity. Importantly, ELA and ferrostatin-1 (Fer-1) mitigated DOX-mediated augmentation of reactive oxygen species (ROS) in rat aortic AFs, accompanied by upregulated levels of Nrf2, SLC7A11, GPX4, and GSH. In addition, ELA reversed DOX-induced dysregulation of apoptosis- and inflammation-related factors including Bax, Bcl2, interleukin (IL)-1β, IL6, IL-10, and CXCL1. Intriguingly, knockdown of Krüppel-like factor 15 (KLF15) by siRNA abolished ELA-mediated alleviation of ROS production and inflammatory responses. More importanly, KLF15 siRNA impeded the beneficial roles of ELA in DOX-pretreated rat aortic AFs by suppressing the Nrf2/SLC7A11/GPX4 signaling. In conclusion, ELA prevents DOX-triggered promotion of cytotoxicity, and exerts anti-oxidative and anti-ferroptotic effects in rat aortic AFs via activation of the KLF15/GPX4 signaling, indicating a promising therapeutic value of ELA in antagonizing DOX-mediated cardiovascular abnormality and disorders.

Monotropein attenuates doxorubicin-induced oxidative stress, inflammation, and arrhythmia via the AKT signal pathway

As a glycoside iridoid, monotropein (MON) has a wide range of pharmacological properties, including anti-inflammatory, antioxidant, and anti-apoptotic effects. However, few studies have investigated MON's cardiovascular protective effects. Therefore, this study aimed to explore the role of MON in doxorubicin (DOX)-induced cardiotoxicity. To establish the myocardial toxicity model, mice were intraperitoneally injected with DOX. After admimistration of DOX, myocardial injury markers were increased, cardiac function was reduced, and pathological changes were observed in the myocardium, indicating successful construction of the myocardial injury model. Our study showed that MON treatment mitigated DOX-induced myocardial damage and improved cardiac dysfunction. In addition, DOX-treated mice displayed higher levels of inflammation and oxidative stress, while MON treatment also reversed these pathological changes. Moreover, DOX-treated mice were more susceptible to ventricular fibrillation, whereas MON reduced ventricular fibrillation incidence. Further studies have shown that MON could reverse DOX-induced inhibition of the AKT signaling pathway. Besides, the application of AKT inhibitor could partially abolish MON's cardioprotective effects. To conclude, this study demonstrated the ability of MON to reduce DOX-induced myocardial damage, cardiac dysfunction, inflammation, and oxidative stress, as well as ventricular fibrillation risk. These may attributable to the activation of the AKT pathway.

Doxorubicin-induced oxidative stress injury: The protective effect of kumiss on cardiotoxicity

Bu çalışmanın amacı, doksorubisinin (DOX) neden olduğu kardiyotoksisite üzerine kımızın etkisini araştırmaktı. Yirmi sekiz Wistar-Albino erkek sıçan 4 gruba ayrıldı: Birinci gruba (kontrol) herhangi bir müdahale yapılmadı. İkinci gruba 7 gün gavaj yoluyla 2 ml/kg/gün, üçüncü gruba intraperitoneal DOX, dördüncü gruba kımız+DOX 20 mg/kg tek doz verildi. DOX uygulamasından 7 gün önce Kumiss uygulamasına başlandı ve 7 gün devam edildi. 7 On thkımız uygulamasının ilk gününde intraperitoneal olarak DOX uygulandı. Malondialdehit (MDA), indirgenmiş glutatyon (GSH) seviyeleri ve katalaz (CAT), glutatyon peroksidaz (GSH-Px), süperoksit dismutaz (SOD), glukoz-6-fosfat dehidrojenaz (G6PD) ve glutatyon-S- gibi antioksidan enzimler Kalp ve kan dokularında kardiyotoksisite patogenezindeki etkinliklerini belirlemek için transferaz (GST) aktiviteleri belirlendi. DOX grubu kontrol grubu ile karşılaştırıldığında MDA (p<0,001, p<0,001) ve GSH (p<0,001, p=0,002) düzeylerinde artış ve CAT'de azalma (p=0,001, p<0,001) , GSH-Px (p<0.001, p<0.001), G6PD (p<0.001, p=0.001) ve GST (p=0.003) aktiviteleri bulundu ve SOD aktivitesinde istatistiksel olarak anlamlı fark bulunmadı. Histopatolojik olarak dejenerasyon, nekroz, DOX uygulanan grupta kanama ve ödem gözlendi. DOX ile tedavi edilen grup ile karşılaştırıldığında, DOX ile kımız verilen grupta MDA, GSH düzeyleri ve antioksidan enzim aktivitelerinin kontrol grubu değerlerine ulaştığı görüldü. Sonuç olarak, lipid peroksidasyon ürünlerindeki artış ve antioksidan enzimlerdeki azalmanın, güçlü bir kemoterapötik ilaç olan DOX ile indüklenen kardiyotoksisitenin patogenezinde rol oynayabileceği belirlendi ve kırmızının DOX kaynaklı oksidatif hasara karşı koruduğu gösterildi.

MicroRNA-4732-3p Is Dysregulated in Breast Cancer Patients with Cardiotoxicity, and Its Therapeutic Delivery Protects the Heart from Doxorubicin-Induced Oxidative Stress in Rats.

Anthracycline-induced cardiotoxicity is the most severe collateral effect of chemotherapy originated by an excess of oxidative stress in cardiomyocytes that leads to cardiac dysfunction. We assessed clinical data from patients with breast cancer receiving anthracyclines and searched for discriminating microRNAs between patients that developed cardiotoxicity (cases) and those that did not (controls), using RNA sequencing and regression analysis. Serum levels of 25 microRNAs were differentially expressed in cases versus controls within the first year after anthracycline treatment, as assessed by three different regression models (elastic net, Robinson and Smyth exact negative binomial test and random forest). MiR-4732-3p was the only microRNA identified in all regression models and was downregulated in patients that experienced cardiotoxicity. MiR-4732-3p was also present in neonatal rat cardiomyocytes and cardiac fibroblasts and was modulated by anthracycline treatment. A miR-4732-3p mimic was cardioprotective in cardiac and fibroblast cultures, following doxorubicin challenge, in terms of cell viability and ROS levels. Notably, administration of the miR-4732-3p mimic in doxorubicin-treated rats preserved cardiac function, normalized weight loss, induced angiogenesis, and decreased apoptosis, interstitial fibrosis and cardiac myofibroblasts. At the molecular level, miR-4732-3p regulated genes of TGFβ and Hippo signaling pathways. Overall, the results indicate that miR-4732-3p is a novel biomarker of cardiotoxicity that has therapeutic potential against anthracycline-induced heart damage.

Allium vineale methanol extract attenuated oxidative stress and inflammation induced by doxorubicin in Sprague Dawley Rats

Doxorubicin-induced organ toxicities, through inflammation and oxidative stress, reduce its widespread use in the treatment of cancer. Thus, there is need for the development of less toxic and more effective plant-derived drugs and spice supplements to mitigate inflammation and oxidative stress induced by doxorubicin. The present study investigated the phyto-chemical profile and ameliorative potential of Allium vineale bulb methanol extract (AVBME) on doxorubicin-induced oxidative stress and inflammation in Sprague Dawley rats. Forty-nine (49) male Sprague Dawley rats were randomly stratified into 7 groups with 7 rats per group. Groups A and B received distilled water for 7 days. Groups C, D, and E were pretreated for 7 days with 200 mg/kg silymarin, 500 mg/kg, and 1000 mg/kg AVBME, respectively followed by intraperitoneal injection of 20 mg/kg doxorubicin (DOX) to groups B, C, D, and E on the 8th day. Groups F and G were orally administered 500 mg/kg and 1000 mg/kg AVBME respectively for 7 days with an intraperitoneal injection of distilled water on the 8th day. The AVBME GC–MS analysis revealed the presence of 21 phyto-compounds, rich in flavonoids and LD50 ˃ 2000 mg/kg. AVBME exhibited a very strong inhibitory activity against DPPH, ABTS+, OH., NO, and H2O2 with IC50 values of 0.09, 0.01, 0.036, 2.09, and 3.57 mg/ml respectively. Pre-treatment with AVBME and Silymarin for 7 days increased the PCV, RBC and lymphocytes with the highest WBC count recorded in DOX-administered rats compared to the healthy control. Also, pre-treatment with AVBME for 7 days significantly (p < 0.05) decreased the levels of AST, ALT and ALP in the serum while improving the levels of urea and electrolytes to near basal level in the serum and kidneys. However, doxorubicin administered on the 8th day significantly (p < 0.05) reduced the levels of GSH and antioxidant enzymes in the serum, liver, heart and kidneys while the levels of TNF-α and C-reactive protein increased. Interestingly, pre-treatment with AVBME for 7 days elevated IL-10 and reversed all the alterations induced by doxorubicin toxicity. Also, doxorubicin induced degenerative hepatic, nephrotic and cardiac biochemical and histological changes, while remarkable reversal of these pathological features was observed in groups pretreated with AVBME. AVBME protects the liver, heart and kidneys of Sprague Dawley rats through antioxidative and anti-inflammatory effects.

Hydroxytyrosol Prevents Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes.

Doxorubicin (Dox) is a highly effective chemotherapeutic agent employed in the handling of hematological and solid tumors. The effective use of Dox in cancer therapy has been seriously limited due to its well-known cardiotoxic side effects, mainly mediated by oxidative damage. Therefore, the identification of an effective and safe antagonist against Dox-induced cardiotoxicity remains a challenge. In this respect, as plant polyphenols have attracted considerable interest due to their antioxidant properties and good safety profile, hydroxytyrosol (HT), the major phenolic compound in olive oil, could be a potential candidate due to its remarkable antioxidant and anticancer powers. In this study, the effect of HT was tested on Dox-induced cardiotoxicity by using a combination of biochemical and cellular biology techniques. Interestingly, HT was able to counteract Dox-induced cytotoxicity in cardiomyocytes by acting on the SOD2 level and the oxidative response, as well as on apoptotic mechanisms mediated by Bcl-2/Bax. At the same time, HT did not to interfere with the antitumorigenic properties of Dox in osteosarcoma cells. This study identifies new, beneficial properties for HT and suggests that it might be a promising molecule for the development of additional therapeutic approaches aimed at preventing anthracycline-related cardiotoxicity and improving long-term outcomes in antineoplastic treatments.

Nauclea orientalis (L.) Bark Extract Protects Rat Cardiomyocytes from Doxorubicin-Induced Oxidative Stress, Inflammation, Apoptosis, and DNA Fragmentation.

The therapeutic efficacy of anthracycline antibiotic, doxorubicin (Dox), is hampered due to the dose-dependent cardiotoxicity. The objective of the study was to explore the counteraction of aqueous bark extract of Nauclea orientalis in Dox-induced cardiotoxicity in Wistar rats. The acute and subchronic toxicity study performed with 2.0 g/kg of the plant extract revealed biochemical and haematological parameters to be within the physiological range, and no histological alterations were observed in any organs isolated. Screening of plant extract for the protection of the myocardium from Dox-induced oxidative stress, inflammation, and apoptosis was performed on five groups of rats: control, plant extract control, Dox control (distilled water (D.H2O) 2 weeks + on the 11th day single injection of Dox, 18 mg/kg), plant + Dox (2.0 g/kg plant extract 2 weeks + on the 11th day Dox, 18 mg/kg), and positive control, dexrazoxane. A significant increase in cardiac biomarkers and lipid peroxidation (p < 0.001) and a significant decrease in antioxidant parameters (p < 0.001) were observed in the Dox control group. All these parameters were reversed significantly (p < 0.05) in the plant-pretreated group. The histopathological assessment of myocardial damage provided supportive evidence for the biochemical results obtained. Inflammatory markers, myeloperoxidase, expression of TNFα and caspase-3, and DNA fragmentation (TUNEL positive nuclei) were significantly elevated (p < 0.05), and expression of Bcl-2 was significantly decreased (p < 0.05) in the Dox control; however, all these parameters were significantly reversed in the plant extract-treated group. In conclusion, the aqueous bark extract of Nauclea orientalis (2.0 g/kg) has the ability to attenuate the Dox-induced oxidative stress, inflammation, apoptosis, and DNA fragmentation in Wistar rats.

Rutaecarpine Inhibits Doxorubicin-Induced Oxidative Stress and Apoptosis by Activating AKT Signaling Pathway.

Patients with cancer who receive doxorubicin (DOX) treatment can experience cardiac dysfunction, which can finally develop into heart failure. Oxidative stress is considered the most important mechanism for DOX-mediated cardiotoxicity. Rutaecarpine (Rut), a quinazolinocarboline alkaloid extracted from Evodia rutaecarpa was shown to have a protective effect on cardiac disease. The purpose of this study is to investigate the role of Rut in DOX-induced cardiotoxicity and explore the underlying mechanism. Intravenous injection of DOX (5 mg/kg, once a week) in mice for 4 weeks was used to establish the cardiotoxic model. Echocardiography and pathological staining analysis were used to detect the changes in structure and function in the heart. Western blot and real-time PCR analysis were used to detect the molecular changes. In this study, we found that DOX time-dependently decreased cardiac function with few systemic side effects. Rut inhibited DOX-induced cardiac fibrosis, reduction in heart size, and decrease in heart function. DOX-induced reduction in superoxide dismutase (SOD) and glutathione (GSH), enhancement of malondialdehyde (MDA) was inhibited by Rut administration. Meanwhile, Rut inhibited DOX-induced apoptosis in the heart. Importantly, we further found that Rut activated AKT or nuclear factor erythroid 2-related factor 2 (Nrf-2) which further upregulated the antioxidant enzymes such as heme oxygenase-1 (HO-1) and GSH cysteine ligase modulatory subunit (GCLM) expression. AKT inhibitor (AKTi) partially inhibited Nrf-2, HO-1, and GCLM expression and abolished the protective role of Rut in DOX-induced cardiotoxicity. In conclusion, this study identified Rut as a potential therapeutic agent for treating DOX-induced cardiotoxicity by activating AKT.

Polysaccharide-Protein Complex Isolated from Fruiting Bodies and Cultured Mycelia of Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), Attenuates Doxorubicin-Induced Oxidative Stress and Myocardial Injury in Rats.

This study aimed to evaluate the effect of the polysaccharide-protein complex isolated from the fruiting bodies (GLFPPC) and cultured mycelia (GLMPPC) of a highly valued medicinal mushroom, Ganoderma lucidum, to alleviate doxorubicin (DOX)-induced cardiotoxicity. GLFPPC and GLMPPC were isolated from aqueous-alcoholic extracts of fruiting bodies and cultured mycelia of G. lucidum by repeated ethanol precipitation, dialysis, treatment with Sevag reagent, and freeze drying. The polysaccharide component was confirmed by assays with anthrone and phenol-sulphuric acid regents and protein moiety with Bradford reagent. The amino acid profile of protein moiety was determined by high-performance liquid chromatography analysis. DOX-induced cardiotoxicity was determined using Swiss albino mice. DOX administration caused a marked increase of creatine kinase and lactate dehydrogenase enzyme activities, indicating injury to the myocardium. The polysaccharide-protein complex downregulated cardiac injury marker enzymes, enhanced activities of endogenous antioxidants (namely, superoxide dismutase, catalase, glutathione peroxidase, and reduced glutathione levels), and significantly attenuated lipid peroxidation. The results indicated that GLFPPC and GLMPPC imparted protection against DOX-induced oxidative stress. Biochemical assays coupled with histopathological observations supported this conclusion. These experimental findings suggest that the polysaccharide-protein complex isolated from G. lucidum might be a useful therapeutic agent to ameliorate DOX-induced cardiomyopathy.

Prevention of doxorubicin-induce renal function abnormalities by turmeric in Wistar rats

Doxorubicin is an anthracycline antibiotic with anti-neoplastic potentials mediated mainly by affecting the DNA synthetic machinery of the cell. It is found to be effective against a wide range of cancers including the ovary, uterus, lung, breast etc. Doxorubicin exerts its nephrotoxicity on the kidney by inducing inflammatory changes leading to increased capillary porousness and glomerular shrinking. This study investigated the effect of turmeric on the renal function biomarkers in doxorubicin-induced oxidative stress in Wistar rats. 54 adult Wistar rats were divided into 9 groups of six animals each. Group 1 animals served as control (normal saline), group 2 animals served as negative control, and received doxorubicin, group 3 animals were given doxorubicin and turmeric, group 4 animals received doxorubicin and vitamin C, group 5 animals received doxorubicin and vitamin E, group 6 animals received doxorubicin, vitamins C and turmeric, group 7 animals received doxorubicin, vitamin E and turmeric, while group 8 animals received doxorubicin, vitamin C and vitamin E and finally, group 9 animals receive doxorubicin, vitamin C, vitamin E and turmeric. The experiment lasted for 28 days and blood samples were collected from each animal from the various groups for renal function assay. Doxorubicin caused significant increase in the serum levels of urea, creatinine, sodium (Na+), calcium (Ca2+), and decrease serum levels of chloride (Cl-), magnesium (Mg2+) and potassium (K+). These abnormal electrolyte imbalances were prevented by administration of turmeric alone or in combination with vitamins C and or E along with doxorubicin concomitantly.

Prevention of doxorubicin-induced haematotoxicity by turmeric in Wistar rats

Doxorubicin is a known anticancer drug used in treatment of various cancers including leukemias, lymphomas, soft-tissue sarcomas and solid tumors. Doxorubicin exerts its toxicity on the blood by causing bone marrow suppression, myelosuppression, pronounced marrow depression and bone marrow depletion, and hypoplasia This study investigated the effect of turmeric on the haematological parameters in doxorubicin-induced oxidative stress in Wistar rats. 54 adult Wistar rats were divided into 9 groups of six animals each. Group 1 animals served as control (normal saline), group 2 animals served as negative control, and received doxorubicin, group 3 animals were given doxorubicin and turmeric, group 4 animals received doxorubicin and vitamin C, group 5 animals received doxorubicin and vitamin E, group 6 animals received doxorubicin, vitamins C and turmeric, group 7 animals received doxorubicin, vitamin E and turmeric, while group 8 animals received doxorubicin, vitamin C and vitamin E and finally, group 9 animals receive doxorubicin, vitamin C, vitamin E and turmeric. The experiment lasted for 28 days and blood samples were collected from each animal from the various groups for haematological assay. Doxorubicin caused a significant decrease in the serum levels of white blood cell count, neutrophil count, lymphocyte count, monocyte count, platelet count, red blood cell count, hemoglobin concentration, hematocrit and mean corpuscular volume. These changes were prevented by turmeric alone or in combined concomitant administration with vitamins C and or E and doxorubicin