Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity.

BACKGROUND: Mitochondrial dysfunction is a primary driver of cardiac contractile failure; yet, the cross talk between mitochondrial energetics and signaling regulation remains obscure. Ponatinib, a tyrosine kinase inhibitor used to treat chronic myeloid leukemia, is among the most cardiotoxic tyrosine kinase inhibitors and causes mitochondrial dysfunction. Whether ponatinib-induced mitochondrial dysfunction triggers the integrated stress response (ISR) to induce ponatinib-induced cardiotoxicity remains to be determined. METHODS: Using human induced pluripotent stem cells-derived cardiomyocytes and a recently developed mouse model of ponatinib-induced cardiotoxicity, we performed proteomic analysis, molecular and biochemical assays to investigate the relationship between ponatinib-induced mitochondrial stress and ISR and their role in promoting ponatinib-induced cardiotoxicity. RESULTS: Proteomic analysis revealed that ponatinib activated the ISR in cardiac cells. We identified GCN2 (general control nonderepressible 2) as the eIF2α (eukaryotic translation initiation factor 2α) kinase responsible for relaying mitochondrial stress signals to trigger the primary ISR effector-ATF4 (activating transcription factor 4), upon ponatinib exposure. Mechanistically, ponatinib treatment exerted inhibitory effects on ATP synthase activity and reduced its expression levels resulting in ATP deficits. Perturbed mitochondrial function resulting in ATP deficits then acts as a trigger of GCN2-mediated ISR activation, effects that were negated by nicotinamide mononucleotide, an NAD+ precursor, supplementation. Genetic inhibition of ATP synthase also activated GCN2. Interestingly, we showed that the decreased abundance of ATP also facilitated direct binding of ponatinib to GCN2, unexpectedly causing its activation most likely because of a conformational change in its structure. Importantly, administering an ISR inhibitor protected human induced pluripotent stem cell-derived cardiomyocytes against ponatinib. Ponatinib-treated mice also exhibited reduced cardiac function, effects that were attenuated upon systemic ISRIB administration. Importantly, ISRIB does not affect the antitumor effects of ponatinib in vitro. CONCLUSIONS: Neutralizing ISR hyperactivation could prevent or reverse ponatinib-induced cardiotoxicity. The findings that compromised ATP production potentiates GCN2-mediated ISR activation have broad implications across various cardiac diseases. Our results also highlight an unanticipated role of ponatinib in causing direct activation of a kinase target despite its role as an ATP-competitive kinase inhibitor.

Impact of Saussurea lappa root extract against copper oxide nanoparticles induced oxidative stress and toxicity in rat cardiac tissues.

Copper oxide nanoparticles (CuO NPs) have developed as a significant class of nanomaterial with potential dangers to organisms and the environment in a variety of applications. This study aimed to investigate the impact of costus root extract against CuO NPs induced oxidative stress, alterations in heart structure and functions. 40 adult male rats were assigned randomly to four groups: first; control, second; costus (300 mg/kg body weight/day) orally for 2 weeks, third; CuO NPs (100 mg/kg body weight/day) intraperitoneally for 4 weeks and fourth; CuO NPs + costus. Current results revealed, significant increases in serum levels of creatine kinase-MB, creatine kinase enzyme, lactate dehydrogenase, myoglobin, aspartate aminotransferase, alkaline phosphatase, cardiac TBIRS, total thiol, nitric oxide, and cardiac proliferating cell nuclear antigen after CuO NPs administration when compared with control group. Conversely, statistical significant decreases were detected in cardiac reduced glutathione, catalase, and superoxide dismutase in CuO NPs group as compared with control group. Interestingly, treatment of CuO NPs with costus root extract was associated with significant improvements of the studied parameters, heart structure and functions. CuO NPs-induced toxicity, injury and oxidative stress in rat heart and treatment with Costus root extract could scavenge free radicals producing beneficial effects against CuO NPs.

Protective Effects of Sauropus Androgynus Leaf Extract against Isoproterenol Induced Cardiotoxicity.

The current research work focuses on the identification of cardioprotective effect of the ethanolic extract of Sauropus androgynus (EESA) leaves. Sauropus androgynus leaves are being utilized in folk and ayurvedic medicines in India to treat cardiovascular diseases like myocardial infraction, atherosclerosis, and venous thrombosis. However, the cardioprotective effects associated with the leaf extract of this plant has not yet been established. METHODS: The identification of cardioprotective effects of the ethanolic extract of Sauropus androgynus (EESA) leaves was performed using in vitro and in vivo models. The cell culture studies were performed using cardio myoblast cells (H9C2) and in vivo cardioprotective effects of EESA was assessed in albino wistar rats employing isoproterenol (ISO) as cardiotoxic agent. The animals were divided into six treatment groups and myocardial infraction was induced at 14th day followed by the treatment with therapeutic doses of EESA (100, 200 and 400 mg/kg) for next two days. Various biochemical and histopathological parameters were evaluated in animals kept under control and treatment groups. RESULTS: The in vitro cell line studies revealed a positive impact on H9C2 cells. The ethanolic extract of Sauropus androgynus depicted low toxicity on cardiomyoblast cells and significant proliferation was observed after treatment. The results from animal studies have shown 1.7 times reduction in serum LDH (151.9 ± 1.302) and CPK (237.6 ± 5.781) levels with EESA treated groups compared to toxic control. EESA also significantly increased the antioxidant enzyme levels, which are responsible for cardioprotective effects in animals. CONCLUSION: This research study reveals that EESA possess antioxidant activity and also provides a protective role against myocardial infarction induced by ISO. We conclude that EESA could be a potential candidate to prevent and treat cardiotoxic consequences of high catecholamine levels.

Cytoprotective Effect of Vitamin D on Doxorubicin-Induced Cardiac Toxicity in Triple Negative Breast Cancer.

BACKGROUND: Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model. METHODS: Female Balb/c mice received rodent chow with vitamin D3 (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D3 (total, 11,500 IU/kg). the mice were inoculated with TNBC tumors and treated with intraperitoneal Dox (6 or 10 mg/kg). Cardiac function was evaluated with transthoracic echocardiography. The cardiac tissue was evaluated with immunohistochemistry and immunoblot for levels of 4-hydroxynonenal, NAD(P)H quinone oxidoreductase (NQO1), C-MYC, and dynamin-related protein 1 (DRP1) phosphorylation. RESULTS: At 15 to 18 days, the mean ejection fraction, stroke volume, and fractional shortening were similar between the mice treated with vitamin D + Dox (10 mg/kg) vs. vehicle but significantly greater in mice treated with vitamin D + Dox (10 mg/kg) vs. Dox (10 mg/kg). Dox (10 mg/kg) increased the cardiac tissue levels of 4-hydroxynonenal, NQO1, C-MYC, and DRP1 phosphorylation at serine 616, but these increases were not observed with vitamin D + Dox (10 mg/kg). A decreased tumor volume was observed with Dox (10 mg/kg) and vitamin D + Dox (10 mg/kg). CONCLUSIONS: Vitamin D supplementation decreased Dox-induced cardiotoxicity by decreasing the reactive oxygen species and mitochondrial damage, and did not decrease the anticancer efficacy of Dox against TNBC.

Low-level embryonic crude oil exposure disrupts ventricular ballooning and subsequent trabeculation in Pacific herring.

There is a growing awareness that transient, sublethal embryonic exposure to crude oils cause subtle but important forms of delayed toxicity in fish. While the precise mechanisms for this loss of individual fitness are not well understood, they involve the disruption of early cardiogenesis and a subsequent pathological remodeling of the heart much later in juveniles. This developmental cardiotoxicity is attributable, in turn, to the inhibitory actions of crude oil-derived mixtures of polycyclic aromatic compounds (PACs) on specific ion channels and other proteins that collectively drive the rhythmic contractions of heart muscle cells via excitation-contraction coupling. Here we exposed Pacific herring (Clupea pallasi) embryos to oiled gravel effluent yielding ΣPAC concentrations as low as ~ 1 µg/L (64 ng/g in tissues). Upon hatching in clean seawater, and following the depuration of tissue PACs (as evidenced by basal levels of cyp1a gene expression), the ventricles of larval herring hearts showed a concentration-dependent reduction in posterior growth (ballooning). This was followed weeks later in feeding larvae by abnormal trabeculation, or formation of the finger-like projections of interior spongy myocardium, and months later with hypertrophy (overgrowth) of the spongy myocardium in early juveniles. Given that heart muscle cell differentiation and migration are driven by Ca2+-dependent intracellular signaling, the observed disruption of ventricular morphogenesis was likely a secondary (downstream) consequence of reduced calcium cycling and contractility in embryonic cardiomyocytes. We propose defective trabeculation as a promising phenotypic anchor for novel morphometric indicators of latent cardiac injury in oil-exposed herring, including an abnormal persistence of cardiac jelly in the ventricle wall and cardiomyocyte hyperproliferation. At a corresponding molecular level, quantitative expression assays in the present study also support biomarker roles for genes known to be involved in muscle contractility (atp2a2, myl7, myh7), cardiomyocyte precursor fate (nkx2.5) and ventricular trabeculation (nrg2, and hbegfa). Overall, our findings reinforce both proximal and indirect roles for dysregulated intracellular calcium cycling in the canonical fish early life stage crude oil toxicity syndrome. More work on Ca2+-mediated cellular dynamics and transcription in developing cardiomyocytes is needed. Nevertheless, the highly specific actions of ΣPAC mixtures on the heart at low, parts-per-billion tissue concentrations directly contravene classical assumptions of baseline (i.e., non-specific) crude oil toxicity.

The Beneficial Effects of Saffron Extract on Potential Oxidative Stress in Cardiovascular Diseases.

Saffron is commonly used in traditional medicines and precious perfumes. It contains pharmacologically active compounds with notably potent antioxidant activity. Saffron has a variety of active components, including crocin, crocetin, and safranal. Oxidative stress plays an important role in many cardiovascular diseases, and its uncontrolled chain reaction is related to myocardial injury. Numerous studies have confirmed that saffron exact exhibits protective effects on the myocardium and might be beneficial in the treatment of cardiovascular disease. In view of the role of oxidative stress in cardiovascular disease, people have shown considerable interest in the potential role of saffron extract as a treatment for a range of cardiovascular diseases. This review analyzed the use of saffron in the treatment of cardiovascular diseases through antioxidant stress from four aspects: antiatherosclerosis, antimyocardial ischemia, anti-ischemia reperfusion injury, and improvement in drug-induced cardiotoxicity, particularly anthracycline-induced. Although data is limited in humans with only two clinically relevant studies, the results of preclinical studies regarding the antioxidant stress effects of saffron are promising and warrant further research in clinical trials. This review summarized the protective effect of saffron in cardiovascular diseases and drug-induced cardiotoxicity. It will facilitate pharmacological research and development and promote utilization of saffron.

Cardioprotective Activities of Ethanolic Extract Root of Ageratum conyzoides on Alloxan-Induced Cardiotoxicity in Diabetic Rats.

Diabetes mellitus has developed into one of the debilitating diseases disturbing the health of many people living with cardiovascular diseases in modern times. The root of Ageratum conyzoides was investigated for its effects on alloxan-induced diabetic Wistar rats' cardiac tissues. Thirty-two (32) Wistar rats weighing between 180 and 190 g were randomly divided into four groups. The animals in groups B-D were induced with a single dose of 150 mg/kg body weight of alloxan (ALX) intraperitoneally. They were confirmed hyperglycemic after 72 hours of induction and then sustained in hyperglycemic condition for 2 weeks. Animals in groups C and D received AC intervention, as stated above, for four weeks. The body weight of the experimental animals and blood collection for glucose estimation were taken weekly for six weeks using appropriate instruments. Biochemical assays for lipid profile, antioxidant enzymatic, and nonenzymatic markers were carried out. Histopathological changes in the cardiac tissues were also studied. Administration of 150 mg/kg of ALX to experimental rats induced diabetes and significantly reduced the body weights, significantly (p < 0.05) increased the glucose level, triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL) levels, and decreased the levels of high-density lipoprotein (HDL) and antioxidant enzymatic markers such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) while the antioxidant nonenzymatic marker such as malondialdehyde (MDA) level was significantly increased. By contrast, rats given the ethanolic extract root of A. conyzoides had significantly (p < 0.05) increased the body weight gain, whereas the glucose levels significantly (p < 0.05) improved in treated diabetic rats. This extract also improved the cardiovascular system of the diabetic rats by significantly decreasing TG and LDL levels, significantly (p < 0.05) increasing the HDL level, significantly reducing the cardiac contents of CAT, SOD, and GPx, and significantly (p < 0.05) decreasing MDA. Ethanolic extract root of A. conyzoides exhibited antihyperglycemic and antihyperlipidemic activities and mitigates damage to the heart from the ALX-induced myocardial toxicity associated with type-1 diabetes.

African Vegetables (Clerodendrum volibile Leaf and Irvingia gabonensis Seed Extracts) Effectively Mitigate Trastuzumab-Induced Cardiotoxicity in Wistar Rats.

Trastuzumab (TZM) is a humanized monoclonal antibody that has been approved for the clinical management of HER2-positive metastatic breast and gastric cancers but its use is limited by its cumulative dose and off-target cardiotoxicity. Unfortunately, till date, there is no approved antidote to this off-target toxicity. Therefore, an acute study was designed at investigating the protective potential and mechanism(s) of CVE and IGE in TZM-induced cardiotoxicity utilizing cardiac enzyme and oxidative stress markers and histopathological endpoints. 400 mg/kg/day CVE and IGE dissolved in 5% DMSO in sterile water were investigated in Wistar rats injected with 2.25 mg/kg/day/i.p. route of TZM for 7 days, using serum cTnI and LDH, complete lipid profile, cardiac tissue oxidative stress markers assays, and histopathological examination of TZM-intoxicated heart tissue. Results showed that 400 mg/kg/day CVE and IGE profoundly attenuated increases in the serum cTnI and LDH levels but caused no significant alterations in the serum lipids and weight gain pattern in the treated rats. CVE and IGE profoundly attenuated alterations in the cardiac tissue oxidative stress markers' activities while improving TZM-associated cardiac histological lesions. These results suggest that CVE and IGE could be mediating its cardioprotection via antioxidant, free radical scavenging, and antithrombotic mechanisms, thus, highlighting the therapeutic potentials of CVE and IGE in the management of TZM-mediated cardiotoxicity.

The protective effect of L-glutamine against acute Cantharidin-induced Cardiotoxicity in the mice.

BACKGROUND: Cantharidin (CTD) is a compound which have the potential to be exploited as an antitumor drug, and it has been demonstrated antitumor effects in a variety of cancers. However, the use is limited due to its severe toxicity. It has reported that it can induce fatal cardiac arrhythmias. Fortunately, we found that L-glutamine can alleviate cardiac toxicity caused by cantharidin in mice. METHODS: To investigate the protective effect of L-glutamine, we used a high dose of cantharidin in mice to create a model of cardiotoxicity. In the experimental mice, glutamine was given orally half an hour before they were administrated with cantharidin. The mice of control group were intraperitoneally injected with DMSO solution. The general state of all mice, cardiac mass index, electrocardiogram change and biological markers were determined. Hematoxylin-eosin staining (HE staining) of heart tissue was carried out in each group to reflect the protective effect of glutamine. To investigate the mechanisms underlying the injury and cardio-protection, multiple oxidative stress indexes were determined and succinate dehydrogenase activity was evaluated. RESULT: The results showed that L-glutamine (Gln) pretreatment reduced weight loss and mortality. It also decreased the biological markers (p < 0.05), improved electrocardiogram and histological changes that CTD induced cardiotoxicity in mice. Subsequently, the group pretreated with L-glutamine before CTD treatment increases in MDA but decreases in SOD and GSH, in comparison to the group treated with CTD alone. Besides, succinate dehydrogenase activity also was improved when L-glutamine was administrated before cantharidin compared to cantharidin. CONCLUSIONS: This study provided evidence that L-glutamine could protect cardiac cells against the acute cantharidin-induced cardiotoxicity and the protective mechanism of glutamine may be related to the myocardial cell membrane or the tricarboxylic acid cycle in the mitochondria.

Coumestrol ameliorates doxorubicin-induced cardiotoxicity via activating AMPKα.

Doxorubicin (DOX) acts as the cornerstone in multiple tumour chemotherapy regimens, however, its clinical application is often impeded due to the induction of a severe cardiotoxicity that eventually provokes left ventricular dysfunction and congestive heart failure. Coumestrol (CMT) is a common dietary phytoestrogen with pleiotropic pharmacological effects. The present study aims to investigate the role and mechanism of CMT on DOX-induced cardiotoxicity. Mice were intragastrically administrated with CMT (5 mg/kg/day) for consecutive 2 weeks and then received a single intraperitoneal injection of DOX (15 mg/kg) to mimic the clinical toxic effects after 8-day additional feeding. To verify the role of 5' AMP-activated protein kinase alpha (AMPKα), AMPKα2 global knockout mice were used. H9C2 cells were cultured to further validate the beneficial role of CMT in vitro. CMT administration notably ameliorated oxidative damage, cell apoptosis and cardiac dysfunction in DOX-treated mice. Besides, we observed that DOX-induced reactive oxygen species overproduction and cardiomyocyte apoptosis were also reduced by CMT incubation in H9C2 cells. Mechanistically, CMT activated AMPKα and Ampkα deficiency abolished the beneficial effects of CMT in vivo and in vitro. Finally, we proved that protein kinase A (PKA) was required for CMT-mediated AMPKα activation and cardioprotective effects. CMT activated PKA/AMPKα pathway to alleviate DOX-induced oxidative damage, cell apoptosis and cardiac dysfunction. Our findings provide a promising therapeutic agent for cancer patients receiving anthracycline chemotherapy.

Protective Effect of Methylxanthine Fractions Isolated from Bancha Tea Leaves against Doxorubicin-Induced Cardio- and Nephrotoxicities in Rats.

Doxorubicin is an anthracycline antibiotic that is used for the treatment of various types of cancer. However, its clinical usage is limited due to its potential life-threatening adverse effects, such as cardio- and nephrotoxicities. Nonetheless, simultaneous administration of doxorubicin and antioxidants, such as those found in green tea leaves, could reduce cardiac and renal tissue damage caused by oxidative stress. The methylxanthine fraction isolated from Bancha tea leaves were tested in vitro for its antioxidant activity and in vivo for its organoprotective properties against doxorubicin-induced cardio- and nephrotoxicities in a rat model. The in vivo study was conducted on male Wistar rats divided into 6 groups. Methylxanthines were administered at high (5 mg/kg body weight) and low (1 mg/kg body weight) doses, while doxorubicin was administered at a cumulative dose of 20 mg/kg body weight. Serum creatinine, uric acid, and urea concentrations, as well as serum enzyme levels (creatinine kinase (CK), creatinine kinase MB fraction (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH)) and electrolytes (Na+, K+, and Cl-), were analysed. In addition, histological analysis was performed to assess cardiac and renal tissue damage. The concomitant administration of Bancha methylxanthines and doxorubicin showed a dose-dependent reduction in the serum biochemical parameters, indicating a decrease in the cardiac and renal tissue damage caused by the antibiotic. Histological analysis showed that pretreatment with methylxanthines at the dose of 5 mg/kg resulted in an almost normal myocardial structure and a significant decrease in the morphological kidney changes caused by doxorubicin exposure compared with the group that received doxorubicin alone. The putative mechanism is most likely related to a reduction in the oxidative stress caused by doxorubicin.

Alangium longiflorum Merr. Leaf Extract Induces Apoptosis in A549 Lung Cancer Cells with Minimal NFκB Transcriptional Activation.

The chemotherapy drug doxorubicin (DOX) is effective in treating many types of cancers. However, due to its pro-inflammatory and cardiotoxic side effects, other remedies have also been explored as alternative treatments. The plant Alangium longiflorum was reported to contain cytotoxic activity against cancer cells, but it is unclear whether this plant would also yield side effects similar to doxorubicin. Hence,  this study investigated cytotoxic activity of A. longiflorum leaf extract against lung cancer cells and compared its pro-inflammatory and cardiotoxic side effects with those of DOX. METHODS: Cytotoxic activity of A. longiflorum in human lung (A549) and breast (MCF-7) cancer cells was initially assessed by MTT assay and then was compared with doxorubicin. Presence of secondary metabolites in the leaf extract was examined by phytochemical screening. The ability of the plant extract to induce apoptosis was determined by measuring caspase-3/7 activity and apoptosis-related gene expression. Pro-inflammatory response was assessed by quantifying NFκB transcriptional activity and nuclear translocation with dual luciferase reporter and immunofluorescence assays, respectively. Cardiotoxicity was measured using zebrafish as a model organism. RESULTS: A. longiflorum leaf extract displayed high cytotoxic activity against A549 versus MCF-7, which led this study to focus further on A549. Phytochemical screening showed that the extract contained terpenoids, alkaloids, phenols, cardiac glycosides, and tannins. The extract induced apoptosis through activation of caspase-3/7 and upregulation of pro-apoptotic genes without causing NFκB transcriptional activation and nuclear localization. The extract also did not significantly reduce heart function in zebrafish. CONCLUSION: Overall, our data suggested that extract from leaves of A. longiflorum can have the potential to serve as apoptotic agent towards lung cancer without inducing significant cardiotoxicity.

The protective effect of losartan against sorafenib induced cardiotoxicity: Ex-vivo isolated heart and metabolites profiling studies in rat.

Sorafenib, a tyrosine kinase inhibitor that is used in the treatment of hepatocellular and renal cell carcinoma, was reported to induce cardiotoxicity. This study aimed to investigate the potential cardioprotective effect of losartan against sorafenib-induced cardiotoxicity in rat. Sorafenib significantly reduced the left ventricular pressure, heart rate dp/dt max & dp/dt min (indexes of myocardial contractility and relaxation; respectively), and prolonged both the systolic and diastolic periods. Coadminstration of losartan significantly reversed the effects of sorafenib on heart rate, dp/dt max and dp/dt min. In addition, there was a tendency for losartan to reverse sorafenib reduction in left ventricular pressure and perfusion pressure but it did not reach statistical significance. A GC-MS non-targeted based metabolites profiling of rat plasma revealed elevated metaboites, including urea and fatty acids levels, associated with sorafenib induced cardiotoxicity. However, only glycine and lactic acid were statistically significant. Interestingly, losartan co-administration with sorafenib restored these changes, and resulted in a significantly reduced glycine, urea and some fatty acids levels namely; Cis-vaccenic acid, oleic acid, stearic acid and undecanoic acid. In addition, based on histology results, losartan coadminitration almost obviated sorafenib-induced changes in cardiac tissues. The study suggests that losartan has the potential to exert a protective effect against sorafenib-induced cardiotoxicity.

TFEB-NF-κB inflammatory signaling axis: a novel therapeutic pathway of Dihydrotanshinone I in doxorubicin-induced cardiotoxicity.

BACKGROUND: Doxorubicin is effective in a variety of solid and hematological malignancies. Unfortunately, clinical application of doxorubicin is limited due to a cumulative dose-dependent cardiotoxicity. Dihydrotanshinone I (DHT) is a natural product from Salvia miltiorrhiza Bunge with multiple anti-tumor activity and anti-inflammation effects. However, its anti-doxorubicin-induced cardiotoxicity (DIC) effect, either in vivo or in vitro, has not been elucidated yet. This study aims to explore the anti-inflammation effects of DHT against DIC, and to elucidate the potential regulatory mechanism. METHODS: Effects of DHT on DIC were assessed in zebrafish, C57BL/6 mice and H9C2 cardiomyocytes. Echocardiography, histological examination, flow cytometry, immunochemistry and immunofluorescence were utilized to evaluate cardio-protective effects and anti-inflammation effects. mTOR agonist and lentivirus vector carrying GFP-TFEB were applied to explore the regulatory signaling pathway. RESULTS: DHT improved cardiac function via inhibiting the activation of M1 macrophages and the excessive release of pro-inflammatory cytokines both in vivo and in vitro. The activation and nuclear localization of NF-κB were suppressed by DHT, and the effect was abolished by mTOR agonist with concomitant reduced expression of nuclear TFEB. Furthermore, reduced expression of nuclear TFEB is accompanied by up-regulated phosphorylation of IKKα/ß and NF-κB, while TFEB overexpression reversed these changes. Intriguingly, DHT could upregulate nuclear expression of TFEB and reduce expressions of p-IKKα/ß and p-NF-κB. CONCLUSIONS: Our results demonstrated that DHT can be applied as a novel cardioprotective compound in the anti-inflammation management of DIC via mTOR-TFEB-NF-κB signaling pathway. The current study implicates TFEB-IKK-NF-κB signaling axis as a previously undescribed, druggable pathway for DIC.

Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity.

Environmental factors are the largest contributors to cardiovascular disease. Here we show that cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones), and recapitulate hallmarks of myocardial infarction (in particular, pathological metabolic shifts, fibrosis and calcium handling) at the transcriptomic, structural and functional levels. We also show that the organoids can model hypoxia-enhanced doxorubicin cardiotoxicity. Human organoids that model diseases with non-genetic pathological factors could help with drug screening and development.

Human Induced Pluripotent Stem-Cardiac-Endothelial-Tumor-on-a-Chip to Assess Anticancer Efficacy and Cardiotoxicity.

Cancer remains a leading health threat in the United States, and cardiovascular drug toxicity is a primary cause to eliminate a drug from FDA approval. As a result, the demand to develop new anticancer drugs without cardiovascular toxicity is high. Human induced pluripotent stem (iPS) cell-derived tissue chips provide potentially a cost-effective preclinical drug testing platform, including potential avenues for personalized medicine. We have developed a three-dimensional microfluidic device that simultaneously cultures tumor cell spheroids with iPS-derived cardiomyocytes (iPS-CMs) and iPS-derived endothelial cells (iPS-EC). The iPS-derived cells include a GCaMP6 fluorescence reporter to allow real-time imaging to monitor intracellular calcium transients. The multiple-chambered tissue chip features electrodes for pacing of the cardiac tissue to assess cardiomyocyte function such as the maximum capture rate and conduction velocity. We measured the inhibition concentration (IC50) of the anticancer drugs, Doxorubicin (0.1 µM) and Oxaliplatin (4.2 µM), on the tissue chip loaded with colon cancer cells (SW620). We simultaneously evaluated the cardiotoxicity of these anticancer drugs by assessing the drug effect on the spontaneous beat frequency and conduction velocity of iPS-derived cardiac tissue. Consistent with in vivo observations, Doxorubicin reduced the spontaneous beating rate and maximum capture rate at or near the IC50 (0.04 and 0.22 µM, respectively), whereas the toxicity of Oxaliplatin was only observed at concentrations beyond the IC50 (33 and 9.9 µM, respectively). Our platform demonstrates the feasibility to simultaneously assess cardiac toxicity and antitumor effects of drugs and could be used to enhance personalized drug testing safety and efficacy. Impact statement Drug development using murine models for preclinical testing is no longer adequate nor acceptable both financially for the pharmaceutical industry as well as for generalized or personalized assessment of safety and efficacy. Innovative solutions using human cells and tissues provide exciting new opportunities. In this study, we report on the creation of a 3D microfluidic device that simultaneously cultures human tumor cell spheroids with cardiomyocytes and endothelial cells derived from the same induced pluripotent stem cell line. The platform provides the opportunity to assess efficacy of anticancer agents while simultaneously screening for potential cardiovascular toxicity in a format conducive for personalized medicine.

Doxorubicin-Induced Cardiac Abnormalities in Rats: Attenuation via Sandalwood Oil.

INTRODUCTION: The clinical use of doxorubicin (DOX) is challenged by its incremental dose-related cardiotoxicity. OBJECTIVE: The aim of the hereby study was to investigate sandalwood essential oil (SEO) against DOX-induced cardiac toxicity. METHODS: Male Sprague-Dawley rats were allocated into 4 groups. Groups 1 signified the control, whereas group 2 administered 100 mg/kg/day SEO, both act as control. In group 3, DOX was given intraperitoneal in a dose of 3 mg/kg/ every other day for 2 weeks to induced cardiotoxicity. While group 4 received a combination of SEO and DOX for 2 weeks. DOX prompted variations were assessed by measuring cardiac injury biomarkers, including creatine phosphokinase, cardiac troponin T, and lactate dehydrogenase (LDH), electrocardiogram (ECG) fluctuations, heart rate (HR), and blood pressure (BP) indices. The effect of both DOX and SEO on various antioxidants such as glutathione, superoxide dismutase, and catalase and inflammatory mediators including interleukin-1ß, tumor necrosis factor-alpha, and NF-κB was quantified. RESULTS: DOX augmented cardiac injury biomarkers, altered ECG, deceased HR and antioxidants, and finally increased BP indices. Treatment with SEO significantly (p < 0.05) decreased cardiac biomarkers and reversing ECG changes and BP. Moreover, treatment with SEO enhanced HR anomalies and antioxidant activity reduction and precluded the intensive inflammatory response induced by DOX. CONCLUSION: SEO may have the potential of mitigating cardiac rhythm and BP indices changes induced with DOX. SEO modifications may be due to antioxidant capacity improvement and inflammatory response prohibition of the heart muscle.

Resveratrol solid lipid nanoparticles to trigger credible inhibition of doxorubicin cardiotoxicity.

Background: Doxorubicin (DOX), a broad-spectrum chemotherapy drug, is clinically employed to treat cancers especially for breast cancer and lung cancer. But its clinical applications are limited by the dose-dependent cardiac toxicity. Resveratrol (Res), a polyphenolic antitoxin, has been proved to be capable of improving the cardiomyocyte calcium cycling by up-regulating SIRT-1-mediated deacetylation to inhibit DOX-induced cardiotoxicity. Purpose: The objective of this study was to develop a solid lipid nanoparticle (SLN) loaded with Res to trigger inhibition of DOX-induced cardiotoxicity. Methods: Res-SLN was prepared by emulsification-diffusion method followed by sonication and optimized using central composite design/response surface method. The Res-SLN was further evaluated by dynamic light scattering, transmission electron microscopy for morphology and high performance liquid chromatography for drug loading and release profile. And the Res distribution in vivo was determined on rats while the effect of inhibit DOX-induced cardiotoxicity was investigated on mice. Results: Res-SLN with homogeneous particle size of 271.13 nm was successfully formulated and optimized. The prepared Res-SLN showed stable under storage and sustained release profile, improving the poor solubility of Res. Heart rate, ejection fractions and fractional shortening of Res-SLN treating mice were found higher than those on mice with cardiac toxicity induced by single high-dose intraperitoneal injection of DOX. And the degree of myocardial ultrastructural lesions on mice was also observed. Conclusion: Res-SLN has a certain therapeutic effect for protecting the myocardium and reducing DOX-induced cardiotoxicity in mice.

Use of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Preclinical Cancer Drug Cardiotoxicity Testing: A Scientific Statement From the American Heart Association.

It is now well recognized that many lifesaving oncology drugs may adversely affect the heart and cardiovascular system, including causing irreversible cardiac injury that can result in reduced quality of life. These effects, which may manifest in the short term or long term, are mechanistically not well understood. Research is hampered by the reliance on whole-animal models of cardiotoxicity that may fail to reflect the fundamental biology or cardiotoxic responses of the human myocardium. The emergence of human induced pluripotent stem cell-derived cardiomyocytes as an in vitro research tool holds great promise for understanding drug-induced cardiotoxicity of oncological drugs that may manifest as contractile and electrophysiological dysfunction, as well as structural abnormalities, making it possible to deliver novel drugs free from cardiac liabilities and guide personalized therapy. This article briefly reviews the challenges of cardio-oncology, the strengths and limitations of using human induced pluripotent stem cell-derived cardiomyocytes to represent clinical findings in the nonclinical research space, and future directions for their further use.

Curcumin loaded mesoporous silica nanoparticles: assessment of bioavailability and cardioprotective effect.

Rhizomes of the plant Curcuma longa has been traditionally used in medicine and culinary practices in India. It possesses various pharmacological effect, namely, antioxidant, hepatoprotective, anti-inflammatory, anti-thrombosis, and anti-apoptotic. The study was undertaken to assess the effect of curcumin and curcumin loaded mesoporous silica nanoparticles (MSNs) against doxorubicin (DOX)-induced myocardial toxicity in rats. Furthermore, the study also included the bioavailability estimation of curcumin delivered alone and delivered via mesoporous technology. Cardiotoxicity was produced by cumulative administration of DOX (2.5 mg/kg for two weeks). Curcumin and curcumin loaded mesoporous nanoparticles (MSNs) each 200 mg/kg, po was administered as pretreatment for two weeks and then for two alternate weeks with DOX. The repeated administration of DOX induced cardiomyopathy associated with an antioxidant deficit and increased level of cardiotoxic biomarkers. Pretreatment with curcumin (alone and via MSNs) significantly protected myocardium from the toxic effects of DOX by significantly decreased the elevated level of malondialdehyde and increased the reduced level of reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in cardiac tissue. MSNs based delivery was found superior compared to curcumin delivered alone. Moreover, the results of bioavailability assessment in rats clearly indicated higher Cmax and AUC values in rats when curcumin was administered via MSNs indicating superior bioavailability. The bioavailability of curcumin loaded MSNs, biochemical and histopathology reports support the good cardioprotective effect of curcumin which could be attributed to its increased bioavaibility lead to good antioxidant and anti-inflammatory activity.