The NEDD8 activating enzyme inhibitor MLN4924 mitigates doxorubicin-induced cardiotoxicity in mice.

Doxorubicin (DOX) is a widely utilized chemotherapeutic agent in clinical oncology for treating various cancers. However, its clinical use is constrained by its significant side effects. Among these, the development of cardiomyopathy, characterized by cardiac remodeling and eventual heart failure, stands as a major concern following DOX chemotherapy. In our current investigation, we have showcased the efficacy of MLN4924 in mitigating doxorubicin-induced cardiotoxicity through direct inhibition of the NEDD8-activating enzyme, NAE. MLN4924 demonstrated the ability to stabilize mitochondrial function post-doxorubicin treatment, diminish cardiomyocyte apoptosis, alleviate oxidative stress-induced damage in the myocardium, enhance cardiac contractile function, mitigate cardiac fibrosis, and impede cardiac remodeling associated with heart failure. At the mechanistic level, MLN4924 intervened in the neddylation process by inhibiting the NEDD8 activating enzyme, NAE, within the murine cardiac tissue subsequent to doxorubicin treatment. This intervention resulted in the suppression of NEDD8 protein expression, reduction in neddylation activity, and consequential manifestation of cardioprotective effects. Collectively, our findings posit MLN4924 as a potential therapeutic avenue for mitigating doxorubicin-induced cardiotoxicity by attenuating heightened neddylation activity through NAE inhibition, thereby offering a viable and promising treatment modality for afflicted patients.

Protective effects of arbutin against doxorubicin-induced cardiac damage.

BACKGROUND: Doxorubicin is an effective antineoplastic agent but has limited clinical application because of its cumulative toxicities, including cardiotoxicity. Cardiotoxicity causes lipid peroxidation, genetic impairment, oxidative stress, inhibition of autophagy, and disruption of calcium homeostasis. Doxorubicin-induced cardiotoxicity is frequently tried to be mitigated by phytochemicals, which are derived from plants and possess antioxidant, anti-inflammatory, and anti-apoptotic properties. Arbutin, a natural antioxidant found in the leaves of the bearberry plant, has numerous pharmacological benefits, including antioxidant, anti-bacterial, anti-hyperglycemic, anti-inflammatory, and anti-tumor activity. METHODS AND RESULTS: The study involved male Wistar rats divided into three groups: a control group, a group treated with doxorubicin (20 mg/kg) to induce cardiac toxicity, a group treated with arbutin (100 mg/kg) daily for two weeks before doxorubicin administration. After treatment, plasma and heart tissue samples were collected for analysis. The samples were evaluated for oxidative stress parameters, including superoxide dismutase, malondialdehyde, and catalase, as well as for cardiac biomarkers, including CK, CK-MB, and LDH. The heart tissues were also analyzed using molecular (TNF-α, IL-1ß and Caspase 3), histopathological and immunohistochemical methods (8-OHDG, 4 Hydroxynonenal, and dityrosine). The results showed that arbutin treatment was protective against doxorubicin-induced oxidative damage by increasing SOD and CAT activity and decreasing MDA level. Arbutin treatment was similarly able to reverse the inflammatory response caused by doxorubicin by reducing TNF-α and IL-1ß levels and also reverse the apoptosis by decreasing caspase-3 levels. It was able to prevent doxorubicin-induced cardiac damage by reducing cardiac biomarkers CK, CK-MB and LDH levels. In addition to all these results, histopathological analyzes also show that arbutin may be beneficial against the damage caused by doxorubicin on heart tissue. CONCLUSION: The study suggests that arbutin has the potential to be used to mitigate doxorubicin-induced cardiotoxicity in cancer patients.

Electrocardiographic, biochemical, and scintigraphic evidence for the cardioprotective effect of paricalcitol and vitamin D3 on doxorubicin-induced acute cardiotoxicity in rats.

AIM: We aimed to investigate the possible cardioprotective effects of paricalcitol (PR), its vitamin D receptor agonist, and vitamin D3 (VIT-D3) on an experimental model of doxorubicin (DX) cardiotoxicity by 99mTc-PYP scintigraphy, electrocardiographic (ECG) and biochemical methods. METHOD: Forty-two male Wistar/Albino rats (250‒300 g; aged 10‒12 weeks) were randomly separated into six groups, namely into control (CN), doxorubicin (DX), paricalcitol (PR), vitamin D3 (VIT-D3), paricalcitol + doxorubicin (PR+DX), and vitamin D3 + doxorubicin (VIT-D3+DX) groups. Cardiotoxicity was induced by three doses of DX (18 mg/kg, i.p.) at 24-hour intervals on days 18, 19 and 20. PR (0.5 ug/ kg, i.p) and VIT-D3 (5,000 IU/kg, i.p) were injected for 20 days before and after the application of DX (18 mg/kg, i.p.). On day 21 of the experiment, biochemical parameters [tumor necrosis factor TNF-alpha (TNF-α); interleukin-6 (IL-6), nitric oxide (NO), and cardiac troponin T (cTnT)], as well as ECG and scintigraphic (99mTc-PYP) features were assessed. RESULTS: Compared to CN, DX significantly raised TNF-α, IL-6, and NO in heart tissue, cTnT in serum, 99mTc-PYP uptake in the myocardium, and ECG parameters, specifically QRS complex duration, QT interval duration, and ST-segment amplitude, while also reducing heart rate (p<0.001). Pretreatment with PR and VIT-D3 mitigated these abnormalities produced by DX in the heart (p<0.001). CONCLUSION: Results show that vitamin D receptor agonist paricalcitol and vitamin D protect against DX-induced cardiotoxicity through anti-inflammatory and antioxidant effects (Fig. 4, Ref. 59). Text in PDF www.elis.sk Keywords: paricalcitol, doxorubicin, vitamin D, ECG, 99mTc-PYP scintigraphy, cardiotoxicity, inflammation.

AP39, a novel mitochondria-targeted hydrogen sulfide donor ameliorates doxorubicin-induced cardiotoxicity by regulating the AMPK/UCP2 pathway.

Doxorubicin (DOX) is a broad-spectrum, highly effective antitumor agent; however, its cardiotoxicity has greatly limited its use. Hydrogen sulfide (H2S) is an endogenous gaseous transmitter that exerts cardioprotective effects via the regulation of oxidative stress and apoptosis and maintenance of mitochondrial function, among other mechanisms. AP39 is a novel mitochondria-targeted H2S donor that, at appropriate concentrations, attenuates intracellular oxidative stress damage, maintains mitochondrial function, and ameliorates cardiomyocyte injury. In this study, DOX-induced cardiotoxicity models were established using H9c2 cells and Sprague-Dawley rats to evaluate the protective effect of AP39 and its mechanisms of action. Both in vivo and in vitro experiments showed that DOX induces oxidative stress injury, apoptosis, and mitochondrial damage in cardiomyocytes and decreases the expression of p-AMPK/AMPK and UCP2. All DOX-induced changes were attenuated by AP39 treatment. Furthermore, the protective effect of AP39 was significantly attenuated by the inhibition of AMPK and UCP2. The results suggest that AP39 ameliorates DOX-induced cardiotoxicity by regulating the expression of AMPK/UCP2.

Protective Role of Dioscin against Doxorubicin-Induced Chronic Cardiotoxicity: Insights from Nrf2-GPX4 Axis-Mediated Cardiac Ferroptosis.

Recent evidence suggests that ferroptosis, an iron-facilitated cell death with excessive lipid peroxidation, is a critical mechanism underlying doxorubicin (DOX)-induced cardiotoxicity (DIC). Although dioscin has been reported to improve acute DIC, direct evidence is lacking to clarify the role of dioscin in chronic DIC and its potential mechanism in cardiac ferroptosis. In this study, we used chronic DIC rat models and H9c2 cells to investigate the potential of dioscin to mitigate DIC by inhibiting ferroptosis. Our results suggest that dioscin significantly improves chronic DIC-induced cardiac dysfunction. Meanwhile, it significantly inhibited DOX-induced ferroptosis by reducing Fe2+ and lipid peroxidation accumulation, maintaining mitochondrial integrity, increasing glutathione peroxidase 4 (GPX4) expression, and decreasing acyl-CoA synthetase long-chain family 4 (ACSL4) expression. Through transcriptomic analysis and subsequent validation, we found that the anti-ferroptotic effects of dioscin are achieved by regulating the nuclear factor-erythroid 2-related factor 2 (Nrf2)/GPX4 axis and Nrf2 downstream iron metabolism genes. Dioscin further downregulates nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and upregulates expression of frataxin (FXN) and ATP-binding cassette B8 (ABCB8) to limit mitochondrial Fe2+ and lipid peroxide accumulation. However, Nrf2 inhibition diminishes the anti-ferroptotic effects of dioscin, leading to decreased GPX4 expression and increased lipid peroxidation. This study is a compelling demonstration that dioscin can effectively reduce DIC by inhibiting ferroptosis, which is dependent on the Nrf2/GPX4 pathway modulation.

Ginsenoside Rb1 attenuates doxorubicin induced cardiotoxicity by suppressing autophagy and ferroptosis.

Ginsenoside Rb1 (Rb1), an active component isolated from traditional Chinese medicine Ginseng, is beneficial to many cardiovascular diseases. However, whether it can protect against doxorubicin induced cardiotoxicity (DIC) is not clear yet. In this study, we aimed to investigate the role of Rb1 in DIC. Mice were injected with a single dose of doxorubicin (20 mg/kg) to induce acute cardiotoxicity. Rb1 was given daily gavage to mice for 7 days. Changes in cardiac function, myocardium histopathology, oxidative stress, cardiomyocyte mitochondrion morphology were studied to evaluate Rb1's function on DIC. Meanwhile, RNA-seq analysis was performed to explore the potential underline molecular mechanism involved in Rb1's function on DIC. We found that Rb1 treatment can improve survival rate and body weight in Dox treated mice group. Rb1 can attenuate Dox induced cardiac dysfunction and myocardium hypertrophy and interstitial fibrosis. The oxidative stress increase and cardiomyocyte mitochondrion injury were improved by Rb1 treatment. Mechanism study found that Rb1's beneficial role in DIC is through suppressing of autophagy and ferroptosis. This study shown that Ginsenoside Rb1 can protect against DIC by regulating autophagy and ferroptosis.

Nanomedicine alleviates doxorubicin-induced cardiotoxicity and enhances chemotherapy synergistic chemodynamic therapy.

Doxorubicin (DOX) is widely used in clinic as a broad-spectrum chemotherapy drug, which can enhance the efficacy of chemodynamic therapy (CDT) by interfering tumor-related metabolize to increase H2O2 content. However, DOX can induce serious cardiomyopathy (DIC) due to its oxidative stress in cardiomyocytes. Eliminating oxidative stress would create a significant opportunity for the clinical application of DOX combined with CDT. To address this issue, we introduced sodium ascorbate (AscNa), the main reason is that AscNa can be catalyzed to produce H2O2 by the abundant Fe3+ in the tumor site, thereby enhancing CDT. While the content of Fe3+ in heart tissue is relatively low, so the oxidation of AscNa had tumor specificity. Meanwhile, due to its inherent reducing properties, AscNa could also eliminate the oxidative stress generated by DOX, preventing cardiotoxicity. Due to the differences between myocardial tissue and tumor microenvironment, a novel nanomedicine was designed. MoS2 was employed as a carrier and CDT catalyst, loaded with DOX and AscNa, coating with homologous tumor cell membrane to construct an acid-responsive nanomedicine MoS2-DOX/AscNa@M (MDA@M). In tumor cells, AscNa enhances the synergistic therapy of DOX and MoS2. In cardiomyocytes, AscNa could effectively reduce the cardiomyopathy induced by DOX. Overall, this study enhanced the clinical potential of chemotherapy synergistic CDT.

Doxorubicin­induced cardiomyopathy is mitigated by empagliflozin via the modulation of endoplasmic reticulum stress pathways.

Doxorubicin (Dox) exhibits a high efficacy in the treatment of numerous types of cancer. However, the beneficial cytotoxic effects of Dox are often accompanied by an increase in the risk of cardiotoxicity. Oxidative stress (OS) plays a key role in Dox­induced cardiomyopathy (DIC). OS in cardiomyocytes disrupts endoplasmic reticulum (ER) function, leading to the accumulation of misfolded/unfolded proteins known as ER stress. ER stress acts as an adaptive mechanism; however, prolonged ER stress together with OS may lead to the initiation of cardiomyocyte apoptosis. The present study aimed to explore the potential of an anti­diabetic drug, empagliflozin (EMPA), in mitigating Dox­induced ER stress and cardiomyocyte apoptosis. In the present study, the effects of 1 h pretreatment of EMPA on Dox­treated cardiomyocytes isolated from Sprague­Dawley rats were investigated. After 24 h, EMPA pre­treatment promoted cell survival in the EMPA + Dox group compared with the Dox group. Results of the present study also demonstrated that EMPA mitigated overall ER stress, as the increased expression of ER stress markers was reduced in the EMPA + Dox group. Additionally, OS, inflammation and expression of ER stress apoptotic proteins were also significantly reduced following EMPA pre­treatment in the EMPA + Dox group. Thus, EMPA may exert beneficial effects on Dox­induced ER stress and may exhibit potential changes that can be utilised to further evaluate the role of EMPA in mitigating DIC.

Heart failure related to contemporary breast cancer treatment.

ABSTRACT: This article addresses cardiotoxicity in patients with breast cancer who are treated with anthracyclines and/or anti-human epidermal growth factor 2 (HER2) therapy, namely doxorubicin and trastuzumab. Development of concise clinical guidelines for chemotherapy-induced heart failure is ongoing. Through identification of specific risk factors and clinical predictors of cardiotoxicity, clinicians are able to better understand and define effective monitoring strategies and optimize patient care. Close cardiac monitoring is recommended for patients throughout treatment with anthracyclines and anti-HER2 therapy. Pretreatment risk assessment with echocardiography and evaluation of cardiovascular risk factors aid in predicting the development of left ventricular (LV) dysfunction. Further clinical trials are needed to increase understanding and optimize treatment guidelines for LV dysfunction in patients taking anthracyclines or anti-HER2 therapy.

Cardioprotective role of royal jelly in the prevention of celecoxib-mediated cardiotoxicity in adult male albino rats.

BACKGROUND: Celecoxib, a cyclooxygenase-2 selective inhibitor non-steroidal anti-inflammatory drugs, is used for the management of short- and long-term pain as well as in other inflammatory conditions. Unfortunately, its chronic use is highly associated with serious abnormal cardiovascular events. The current study was designed to explore the effect of long-term administration of celecoxib on the cardiac tissues of male albino rats. The study also examined the alleged cardioprotective effect of royal jelly. METHODS: Thirty, male albino rats were randomly divided into 3 equal groups; 10 each: (1) rats served as the control group and received no drug; (2) rats received celecoxib (50 mg/kg/day, orally), for 30 consecutive days; (3) rats received celecoxib (50 mg/kg/day, orally) plus royal jelly (300 mg/kg/day, orally) for 30 consecutive days. Sera were collected to assay cardiac enzymes and oxidant/antioxidant status. Rats were euthanatized and cardiac tissues were dissected for quantitative estimation of apoptotic genes (Bax) and anti-apoptotic gene (Bcl-2). RESULTS: Long-term celecoxib administration caused cardiotoxicity in male albino rats as manifested by significant elevation of serum levels of creatine phosphokinase (CPK), creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH), with ameliorative effects of royal jelly against celecoxib-induced cardiotoxicity as manifested by significantly decrease in serum CPK, CK-MB, and LDH levels. It also showed a significant decrease in the oxidative stress indicator malondialdehyde (MDA) levels and the bax gene. Additionally, it demonstrated significant increases in the bcl-2 gene and superoxide dismutase (SOD) levels, which contribute to its therapeutic effects against celecoxib-induced cardiotoxicity. CONCLUSION: Long-term celecoxib administration caused cardiotoxicity in male albino rats with protective effect of royal jelly being given together. It could be concluded that royal jelly may prove a useful adjunct in patients being prescribed celecoxib. TRIAL REGISTRATION: Not applicable.

Astragaloside IV Alleviates Doxorubicin-Induced Cardiotoxicity by Inhibiting Cardiomyocyte Pyroptosis through the SIRT1/NLRP3 Pathway.

Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug used to treat a wide spectrum of tumors. However, its clinical application is limited due to cardiotoxic side effects. Astragaloside IV (AS IV), one of the major compounds present in aqueous extracts of Astragalus membranaceus, possesses potent cardiovascular protective properties, but the underlying molecular mechanisms are unclear. Thus, the aim of this study was to investigate the effect of AS IV on DOX-induced cardiotoxicity (DIC). Our findings revealed that DOX induced pyroptosis through the caspase-1/gasdermin D (GSDMD) and caspase-3/gasdermin E (GSDME) pathways. AS IV treatment significantly improved the cardiac function and alleviated myocardial injury in DOX-exposed mice by regulating intestinal flora and inhibiting pyroptosis; markedly suppressed the levels of cleaved caspase-1, N-GSDMD, cleaved caspase-3, and N-GSDME; and reversed DOX-induced downregulation of silent information regulator 1 (SIRT1) and activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in mice. The SIRT1 inhibitor EX527 significantly blocked the protective effects of AS IV. Collectively, our results suggest that AS IV protects against DIC by inhibiting pyroptosis through the SIRT1/NLRP3 pathway.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Ibogaine.

BACKGROUND: Ibogaine is a plant-derived alkaloid that has been used for thousands of years in rites of passage and spiritual ceremonies in West-Central Africa. In the West, it has primarily been used and studied for its anti-addictive properties and more recently for other neuropsychiatric indications, including post-traumatic stress disorder, depression, anxiety, and traumatic brain injury. AREAS OF UNCERTAINTY: Ibogaine requires careful patient screening and monitoring because of significant safety issues. There is potential for cardiotoxicity (prolonged QT interval); without rigorous screening, fatal arrhythmias may occur. However, preliminary research suggests that co-administration of ibogaine with magnesium may mitigate cardiotoxicity. Additionally, ibogaine may have dangerous interactions with opiates, so patients who receive ibogaine treatment for opioid use disorder must withdraw from long-acting opioids. Other potential concerning effects of ibogaine include rare incidences of mania or psychosis. Anticipated transient effects during ibogaine treatment can include ataxia, tremors, and gastrointestinal symptoms. THERAPEUTIC ADVANCES: Robust effects after a single treatment with ibogaine have been reported. In open-label and randomized controlled trials (RCTs), ibogaine reduces heroin and opioid cravings by upwards of 50%, up to 24 weeks after the treatment. An observational study of 30 Special Operations Forces veterans with mild traumatic brain injury reported that 86% were in remission from post-traumatic stress disorder, 83% from depression, and 83% from anxiety, one month after a single-dose ibogaine treatment. LIMITATIONS: Although there are several observational and open-label studies, there is only a single double-blind, placebo-controlled RCT on ibogaine. More RCTs with large sample sizes must be conducted to support ibogaine's safety and efficacy. CONCLUSIONS: Given the promising preliminary findings, ibogaine could potentially fill a much-needed gap in treatments for challenging conditions, including opioid dependence. Ibogaine's remarkable effects in traditionally treatment-resistant, combat-exposed individuals hints at its potential in broader populations with physical and psychological trauma.

Protective effect of thymoquinone nanoemulsion in reducing the cardiotoxic effect of 5-fluorouracil in rats.

5-Fluorouracil (5-FU), which is one of the most widely used chemotherapy drugs, has various side effects on the heart. Thymoquinone (TMQ), the main bioactive component of Nigella sativa, has antioxidant and protective effects against toxicity. In this study, we investigated the protective effect of thymoquinone against cardiotoxicity caused by 5-FU in vitro and in vivo models. H9C2 cells were exposed to 5-FU and TMQ, and cell viability was evaluated in their presence. Also, 25 male Wistar rats were divided into five control groups, 5-FU, 2.5, and 5 mg TMQ in nanoemulsion form (NTMQ) + 5-FU and 5 mg NTMQ. Cardiotoxicity was assessed through electrocardiography, cardiac enzymes, oxidative stress markers, and histopathology. 5-FU induced cytotoxicity in H9c2 cells, which improved dose-dependently with NTMQ cotreatment. 5-FU caused body weight loss, ECG changes (increased ST segment, prolonged QRS, and QTc), increased cardiac enzymes (aspartate aminotransferase [AST], creatine kinase-myocardial band [CK-MB], and lactate dehydrogenase [LDH]), oxidative stress (increased malondialdehyde, myeloperoxidase, nitric acid; decreased glutathione peroxidase enzyme activity), and histological damage such as necrosis, hyperemia, and tissue hyalinization in rats. NTMQ ameliorated these 5-FU-induced effects. Higher NTMQ dose showed greater protective effects. Thus, the results of our study indicate that NTMQ protects against 5-FU cardiotoxicity likely through antioxidant mechanisms. TMQ warrants further research as an adjuvant to alleviate 5-FU chemotherapy side effects.

A real-world analysis of FDA Adverse Event Reporting System (FAERS) events for liposomal and conventional doxorubicins.

The clinical application of conventional doxorubicin (CDOX) was constrained by its side effects. Liposomal doxorubicin was developed to mitigate these limitations, showing improved toxicity profiles. However, the adverse events associated with liposomal doxorubicin and CDOX have not yet been comprehensively evaluated in clinical settings. The FAERS data from January 2004 to December 2022 were collected to analyze the adverse events of liposomal doxorubicin and CDOX. Disproportionate analysis and Bayesian analysis were employed to quantify this association. Our analysis incorporated 68,803 adverse event reports related to Doxil/Caelyx, Myocet and CDOX. The relative odds ratios (RORs, 95%CI) for febrile neutropenia associated with CDOX, Doxil/Caelyx, and Myocet were 42.45 (41.44; 43.48), 17.53 (16.02; 19.20), and 34.68 (26.63; 45.15) respectively. For cardiotoxicity, they were 38.87(36.41;41.49), 17.96 (14.10; 22.86), and 37.36 (19.34; 72.17). For Palmar-Plantar Erythrodysesthesia (PPE), the RORs were 6.16 (5.69; 6.68), 36.13 (32.60; 40.06), and 19.69 (11.59; 33.44). Regarding onset time, significant differences adverse events including neutropenia, PPE, pneumonia and malignant neoplasm progression. This study indicates that clinical monitoring for symptoms of cardiotoxicity of CDOX and Myocet, and PPE and interstitial lung disease of Doxil should be performed. Additionally, the onset time of febrile neutropenia, malignant neoplasm progression, and pneumonia associated with Doxil and Myocet merits particular attention. Continuous surveillance, risk evaluations, and additional comparative studies between liposomal doxorubicin and CDOX were recommended.

Cationic Vitamin E-TPGS Mixed Micelles of Berberine to Neutralize Doxorubicin-Induced Cardiotoxicity via Amelioration of Mitochondrial Dysfunction and Impeding Apoptosis.

Anthracycline antibiotics, namely, doxorubicin (DOX) and daunorubicin, are among the most widely used anticancer therapies, yet are notoriously associated with severe myocardial damage due to oxidative stress and mitochondrial damage. Studies have indicated the strong pharmacological properties of Berberine (Brb) alkaloid, predominantly mediated via mitochondrial functions and nuclear networks. Despite the recent emphasis on Brb in clinical cardioprotective studies, pharmaceutical limitations hamper its clinical use. A nanoformulation for Brb was developed (mMic), incorporating a cationic lipid, oleylamine (OA), into the TPGS-mixed corona of PEGylated-phosphatidylethanolamine (PEG-PE) micelles. Cationic TPGS/PEG-PE mMic with superior Brb loading and stability markedly enhanced both intracellular and mitochondria-tropic Brb activities in cardiovascular muscle cells. Sub-lethal doses of Brb via cationic OA/TPGS mMic, as a DOX co-treatment, resulted in significant mitochondrial apoptosis suppression. In combination with an intense DOX challenge (up to ~50 µM), mitochondria-protective Brb-OA/TPGS mMic showed a significant 24 h recovery of cell viability (p ≤ 0.05-0.01). Mechanistically, the significant relative reduction in apoptotic caspase-9 and elevation of antiapoptotic Bcl-2 seem to mediate the cardioprotective role of Brb-OA/TPGS mMic against DOX. Our report aims to demonstrate the great potential of cationic OA/TPGS-mMic to selectively enhance the protective mitohormetic effect of Brb to mitigate DOX cardiotoxicity.

Toxicometabolomics-based cardiotoxicity evaluation of Thiazolidinedione exposure in human-derived cardiomyocytes.

INTRODUCTION: Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. OBJECTIVE: Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. METHODS: The present investigation included an untargeted liquid chromatography-mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. RESULTS: Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings - (i) valine and creatine, and (ii) L-tryptophan and L-methionine - that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. CONCLUSION: These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words).

Aucubin alleviates doxorubicin-induced cardiotoxicity through crosstalk between NRF2 and HIPK2 mediating autophagy and apoptosis.

BACKGROUND: Doxorubicin (DOX) is widely used for the treatment of a variety of cancers. However, its clinical application is limited by dose-dependent cardiotoxicity. Recent findings demonstrated that autophagy inhibition and apoptosis of cardiomyocytes induced by oxidative stress dominate the pathophysiology of DOX-induced cardiotoxicity (DIC), however, there are no potential molecules targeting on these. PURPOSE: This study aimed to explore whether aucubin (AU) acting on inimitable crosstalk between NRF2 and HIPK2 mediated the autophagy, oxidative stress, and apoptosis in DIC, and provide a new and alternative strategy for the treatment of DIC. METHODS AND RESULTS: We first demonstrated the protection of AU on cardiac structure and function in DIC mice manifested by increased EF and FS values, decreased serum CK-MB and LDH contents and well-aligned cardiac tissue in HE staining. Furthermore, AU alleviated DOX-induced myocardial oxidative stress, mitochondrial damage, apoptosis, and autophagy flux dysregulation in mice, as measured by decreased ROS, 8-OHdG, and TUNEL-positive cells in myocardial tissue, increased SOD and decreased MDA in serum, aligned mitochondria with reduced vacuoles, and increased autophagosomes. In vitro, AU alleviated DOX-induced oxidative stress, autophagy inhibition, and apoptosis by promoting NRF2 and HIPK2 expression. We also identified crosstalk between NRF2 and HIPK2 in DIC as documented by overexpression of NRF2 or HIPK2 reversed cellular oxidative stress, autophagy blocking, and apoptosis aggravated by HIPK2 or NRF2 siRNA, respectively. Simultaneously, AU promoted the expression and nuclear localization of NRF2 protein, which was reversed by HIPK2 siRNA, and AU raised the expression of HIPK2 protein as well, which was reversed by NRF2 siRNA. Crucially, AU did not affect the antitumor activity of DOX against MCF-7 and HepG2 cells, which made up for the shortcomings of previous anti-DIC drugs. CONCLUSION: These collective results innovatively documented that AU regulated the unique crosstalk between NRF2 and HIPK2 to coordinate oxidative stress, autophagy, and apoptosis against DIC without compromising the anti-tumor effect of DOX in vitro.

Surface entrenched ß-sitosterol niosomes for enhanced cardioprotective activity against isoproterenol induced cardiotoxicity in rats.

Cardiotoxicity (CT) is a severe condition that negatively impacts heart function. ß-sitosterol (BS) is a group of phytosterols and known for various pharmacological benefits, such as managing diabetes, cardiac protection, and neuroprotection. This study aims to develop niosomes (NS) containing BS, utilizing cholesterol as the lipid and Tween 80 as the stabilizer. The research focuses on designing and evaluating both conventional BS-NS and hyaluronic acid (HA) modified NS (BS-HA-NS) to enhance the specificity and efficacy of BS within cardiac tissue. The resulting niosomal formulation was spherical, with a size of about 158.51 ± 0.57 nm, an entrapment efficiency of 93.56 ± 1.48 %, and a drug loading of 8.07 ± 1.62 %. To evaluate cytotoxicity on H9c2 heart cells, the MTT assay was used. The cellular uptake of BS-NS and BS-HA-NS was confirmed by confocal microscopy on H9c2 cardiac cells. Administering BS-NS and BS-HA-NS intravenously at a dose of 10 mg/kg showed the ability to significantly decrease the levels of cardiac troponin-I (cTn-I), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and lipid peroxidation (MDA). Tissue histopathology indicated a substantial potential for repairing cardiac tissue after treatment with BS-NS and BS-HA-NS and strong cardioprotection against ISO induced myocardial tissue damages. Thus, enhancing BS's therapeutic effectiveness through niosome surface modification holds promise for mitigating cardiac damage resulting from CT.

Integrating serum pharmacochemistry and network pharmacology to explore the molecular mechanisms of Acanthopanax senticosus (Rupr. & Maxim.) Harms on attenuating doxorubicin-induced myocardial injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Acanthopanax senticosus (Rupr. & Maxim.) Harms (AS), also known as Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. or Siberian ginseng, has a rich history of use as an adaptogen, a substance believed to increase the body's resistance to stress, fatigue, and infectious diseases. As a traditional Chinese medicine, AS is popular for its cardioprotective effects which can protect the cardiovascular system from hazardous conditions. Doxorubicin (DOX), on the other hand, is a first-line chemotherapeutic agent against a variety of cancers, including breast cancer, lung cancer, gastric cancer, and leukemia, etc. Despite its effectiveness, the clinical use of DOX is limited by its side effects, the most serious of which is cardiotoxicity. Considering AS could be applied as an adjuvant to anticancer agents, the combination of AS and DOX might exert synergistic effects on certain malignancies with mitigated cardiotoxicity. Given this, it is necessary and meaningful to confirm whether AS would neutralize the DOX-induced cardiotoxicity and its underlying molecular mechanisms. AIM OF THE STUDY: This paper aims to validate the cardioprotective effects of AS against DOX-induced myocardial injury (MI) while deciphering the molecular mechanisms underlying such effects. MATERIALS AND METHODS: Firstly, the cardioprotective effects of AS against DOX-induced MI were confirmed both in vitro and in vivo. Secondly, serum pharmacochemistry and network pharmacology were orchestrated to explore the in vivo active compounds of AS and predict their ways of functioning in the treatment of DOX-induced MI. Finally, the predicted mechanisms were validated by Western blot analysis during in vivo experiments. RESULTS: The results demonstrated that AS possessed excellent antioxidative ability, and could alleviate the apoptosis of H9C2 cells and the damage to mitochondria induced by DOX. In vivo experiments indicated that AS could restore the conduction abnormalities and ameliorate histopathological changes according to the electrocardiogram and cardiac morphology. Meanwhile, it markedly downregulated the inflammatory factors (TNF-α, IL-6, and IL-1ß), decreased plasma ALT, AST, LDH, CK, CK-MB, and MDA levels, as well as increased SOD and GSH levels compared to the model group, which collectively substantiate the effectiveness of AS. Afterward, 14 compounds were identified from different batches of AS-dosed serum and selected for mechanism prediction through HPLC-HRMS analysis and network pharmacology. Consequently, the MAPKs and caspase cascade were confirmed as primary targets among which the interplay between the JNK/Caspase 3 feedback loop and the phosphorylation of ERK1/2 were highlighted. CONCLUSIONS: In conclusion, the integrated approach employed in this paper illuminated the molecular mechanism of AS against DOX-induced MI, whilst providing a valuable strategy to elucidate the therapeutic effects of complicated TCM systems more reliably and efficiently.

Exploring the mechanism of curcumin in the treatment of doxorubicin-induced cardiotoxicity based on network pharmacology and molecular docking technology.

Doxorubicin (DOX) is one of the most effective chemotherapeutic agents. However, the nonselective effect leads to serious cardiotoxicity risk in clinical use. Curcumin is a well-known dietary polyphenol that showed a protective effect against the cardiotoxic effect of DOX. This study aimed to assess the role of curcumin in protection against DOX-induced cardiotoxicity. Potential compound and disease targets were obtained from relevant databases, and common targets were screened. Protein-protein interaction (PPI) was used to predict the core targets. Gene ontology (GO) bioprocess analysis and Kyoto encyclopedia of genes and genome enrichment analysis enriched the possible biological processes (BP), cellular components, molecular function, and signaling pathways involved. Finally, the binding of curcumin to target proteins was evaluated through molecular docking. The docking score verified the reliability of the prediction results. In total, 205 curcumin and 700 disease targets were identified. A topological analysis of the PPI network revealed 10 core targets including TP53, tumor necrosis factor-alpha (TNF), AKT1, vascular endothelial growth factor A (VEGFA), prostaglandin-endoperoxide synthase 2 (PTGS2), signal transducer and activator of the transcription 3 (STAT3), HIF1A, MYC, epidermal growth factor receptor (EGFR), and CASP3 (Caspase-3). Furthermore, the enrichment analyses indicated that the effects of curcumin were mediated by genes related to oxidation, inflammation, toxification, cell proliferation, migration, apoptosis, wounding, metabolism, proteolysis, and the signaling pathway of calcium (Ca2+). Molecular docking showed that curcumin could bind with the target proteins with strong molecular force, exhibiting good docking activity. Curcumin has a multi-cardioprotective effect by modulating the core targets' expression in DOX-induced cardiotoxicity. This study elucidated the key target proteins and provided a theoretical basis for further exploring curcumin in the prevention and treatment of DOX-induced cardiotoxicity.