Doxorubicin (DOX) has a potent antineoplastic efficacy and is considered a cornerstone of chemotherapy. However, it causes several dose-dependent cardiotoxic results, which has substantially restricted its clinical application. This study was intended to explore the potential ameliorative effect of date palm pollen ethanolic extract (DPPE) against DOX-induced cardiotoxicity and the mechanisms underlying it. Forty male Wistar albino rats were equally allocated into Control (CTR), DPPE (500 mg/kg bw for 4 weeks), DOX (2.5 mg/kg bw, intraperitoneally six times over 2 weeks), and DPPE + DOX-treated groups. Pre-coadministration of DPPE with DOX partially ameliorated DOX-induced cardiotoxicity as DPPE improved DOX-induced body and heart weight changes and mitigated the elevated cardiac injury markers activities of serum aminotransferases, lactate dehydrogenase, creatine kinase, and creatine kinase-cardiac type isoenzyme. Additionally, the concentration of serum cardiac troponin I (cTnI), troponin T (cTnT), N-terminal pro-brain natriuretic peptide (NT-pro BNP), and cytosolic calcium (Ca+2) were amplified. DPPE also alleviated nitrosative status (nitric oxide) in DOX-treated animals, lipid peroxidation and antioxidant molecules as glutathione content, and glutathione peroxidase, catalase, and superoxide dismutase activities and inflammatory markers levels; NF-κB p65, TNF-α, IL-1β, and IL-6. As well, it ameliorated the severity of histopathological lesions, histomorphometric alteration and improved the immune-staining of the pro-fibrotic (TGF-β1), pro-apoptotic (caspase-3 and Bax), and anti-apoptotic (Bcl-2) proteins in cardiac tissues. Collectively, pre-coadministration of DPPE partially mitigated DOX-induced cardiac injuries via its antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic potential.

Date Palm Pollen Extract Avert Doxorubicin-Induced Cardiomyopathy Fibrosis and Associated Oxidative/Nitrosative Stress, Inflammatory Cascade, and Apoptosis-Targeting Bax/Bcl-2 and Caspase-3 Signaling Pathways.

The incidence of cardiovascular disorders is one of the most concerns among people who underwent cancer therapy. The heart side effects of cancer therapy may occur during treatment to some years after the end of treatment. Some epidemiological studies confirm that heart diseases are one of the most common reasons for mortality among patients that were received treatment for cancer. Experimental studies and also clinical investigations indicate that inflammatory changes such as pericarditis, myocarditis, and also fibrosis are key mechanisms of cardiac diseases following chemotherapy/radiotherapy. It seems that chronic oxidative stress, massive cell death, and chronic overproduction of pro-inflammatory and pro-fibrosis cytokines are the key mechanisms of cardiovascular diseases following cancer therapy. Furthermore, infiltration of inflammatory cells and upregulation of some enzymes such as NADPH Oxidases are a hallmark of heart diseases after cancer therapy. In the current review, we aim to explain how radiation or chemotherapy can induce inflammatory and fibrosis-related diseases in the heart. We will explain the cellular and molecular mechanisms of cardiac inflammation and fibrosis following chemo/radiation therapy, and then review some adjuvants to reduce the risk of inflammation and fibrosis in the heart.

Cardiac inflammation and fibrosis following chemo/radiation therapy: mechanisms and therapeutic agents.

Qindan capsule (QC), a traditional Chinese medicine compound, has been used to treat hypertension in the clinic for over 30 years. It is still not known about the effects of QC on pressure overload-induced cardiac remodeling. Hence, this study aims to investigate the effects of QC on pressure overload-induced cardiac hypertrophy, fibrosis, and heart failure in mice and to determine the possible mechanisms. Transverse aortic constriction (TAC) surgery was used to induce cardiac hypertrophy and heart failure in C57BL/6 mice. Mice were treated with QC or losartan for 8 weeks after TAC surgery. Cardiac function indexes were evaluated with transthoracic echocardiography. Cardiac pathology was detected using HE and Masson's trichrome staining. Cardiomyocyte ultrastructure was detected using transmission electron microscopy. Hypertrophy-related fetal gene expression was investigated using real-time RT-PCR. The expression of 8-OHdG and the concentration of MDA and Ang-II were assessed by immunohistochemistry stain and ELISA assay, respectively. The total and phosphorylated protein levels of mTOR, p70S6K, 4EBP1, Smad2, and Smad3 and the expression of TGF-β1 and collagen I were measured using western blot. The results showed that low- and high-dose QC improved pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. QC inhibited ANP, BNP, and β-MHC mRNA expression in failing hearts. QC improved myocardial ultrastructure after TAC surgery. Furthermore, QC downregulated the expression of 8-OHdG and the concentration of MDA, 15-F2t-IsoP, and Ang-II in heart tissues after TAC surgery. We also found that QC inhibited the phosphorylation of mTOR, p70S6K, and 4EBP1 and the expression of TGF-β1, p-Smad2, p-Smad3, and collagen I in pressure overload-induced failing hearts. These data indicate that QC has direct benefic effects on pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. The protective effects of QC involve prevention of increased oxidative stress injury and Ang-II levels and inhibition of mTOR and TGF-β1/Smad pathways in failing hearts.

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Qindan Capsule Attenuates Myocardial Hypertrophy and Fibrosis in Pressure Overload-Induced Mice Involving mTOR and TGF-β1/Smad Signaling Pathway Inhibition.

Application of the anticancer drug doxorubicin (DOX) is restricted due to its adverse, cardiotoxic side effects, which ultimately result in heart failure. Moreover, there are a limited number of chemical agents for the clinical prevention of DOX-induced cardiotoxicity. Based on the theories of traditional Chinese medicine (TCM) on chronic heart failure (CHF), Shenlijia (SLJ), a new TCM compound, has been developed to fulfill multiple functions, including improving cardiac function and inhibiting cardiac fibrosis. In the present study, the protective effects and molecular mechanisms of SLJ on DOX-induced CHF rats were investigated. The CHF rat model was induced by intraperitoneal injection of DOX for six weeks with the cumulative dose of 15 mg/kg. All rats were then randomly divided into the control, CHF, CHF + SLJ (3.0 g/kg per day), and CHF + captopril (3.8 mg/kg per day) groups and treated for further four weeks. Echocardiography and the assessment of hemodynamic parameters were performed to evaluate heart function. A protein chip was applied to identify proteins with diagnostic values that were differentially expressed following SLJ treatment. The data from these investigations showed that SLJ treatment significantly improved cardiac function by increasing the left ventricular ejection fraction, improving the hemodynamic index, and inhibiting interstitial fibrosis. Protein chip analysis revealed that SLJ upregulated MCP-1, MDC, neuropilin-2, TGF-β3, thrombospondin, TIE-2, EG-VEGF/PK1, and TIMP-1/2/3 expressions and downregulated that of MMP-13. In addition, immunohistochemistry and western blot results further confirmed that SLJ promoted TIMP-1/2/3 and inhibited MMP-13 expression. The results of the present study suggest that SLJ was effective against DOX-induced CHF rats and is related to the improvement of heart function and ultrastructure and the inhibition of myocardial fibrosis.

/pdf/shenlijia-attenuates-doxorubicin-induced-chronic-heart-45p7kj0xig.pdf

Shenlijia Attenuates Doxorubicin-Induced Chronic Heart Failure by Inhibiting Cardiac Fibrosis.

Heart failure (HF) is a clinical syndrome characterized by typical symptoms that usually occur at the end stage of various heart diseases and lead to death. Daidzein (DAI), an isoflavone found in soy foods, is widely used to treat menopausal syndrome, prostate cancer, breast cancer, heart disease, cardiovascular disease, and osteoporosis, and has anti-oxidant and anti-inflammatory properties. However, the effects of DAI in HF remain unknown. In this study, doxorubicin (DOX) was used to establish HF models of C57BL/6J mice and H9c2 cells with DAI treatment. Our results showed that DAI markedly improved the DOX-induced decline in cardiac function, and decreased the left ventricular ejection fraction, cardiac inflammation, oxidative stress, apoptosis, and fibrosis. Mechanistically, DAI affects cardiac energy metabolism by regulating SIRT3, and meets the ATP demand of the heart by improving glucose, lipid, and ketone body metabolism as well as restoring mitochondrial dysfunction in vivo and in vitro. Additionally, DAI can exert an antioxidant function and alleviate HF through the SIRT3/FOXO3a pathway. In conclusion, we demonstrate that DAI alleviates DOX-induced cardiotoxicity by regulating cardiac energy metabolism as well as reducing inflammation, oxidative stress, apoptosis and fibrosis, indicating its potential application for HF treatment.

Daidzein alleviates doxorubicin-induced heart failure via the SIRT3/FOXO3a signaling pathway.

Context: Therapeutic doxorubicin administration is restricted as this anticancer drug may be cardiotoxic. The traditional Chinese medicine qiliqiangxin has been approved for clinical treatment of c...

Qiliqiangxin improves cardiac function and attenuates cardiac remodelling in doxorubicin-induced heart failure rats.

Allergic asthma which is induced by ovalbumin (OVA) is a chronic airway inflammation disease. Isoorientin (Iso) is a natural C-glucosyl flavone with many biological properties. We aimed to evaluate the effectiveness of Iso on OVA-induced allergic asthma. A total of 30 C57BL/6 mice were randomly divided into five groups: control group, OVA group, Dex (dexamethasone, 10 mg/kg) group, low-dose Iso group (Iso-L, 25 mg/kg), and high-dose Iso group (Iso-H, 50 mg/kg). The serum and bronchoalveolar lavage fluid (BALF) were collected for biochemical parameters, the lung tissue was collected for hematoxylin-eosin (H&E) staining, immunohistochemistry (IHC), and western blot. The levels of IL-4, IL-5, IL-13, malondialdehyde (MDA), NO, and reactive oxygen species (ROS) in Iso-L and Iso-H groups were significantly lower than that in model group (p < 0.05). Simultaneously, the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity were higher than that in model group (p < 0.05). Iso significantly ameliorated airway hyperresponsiveness. Meanwhile, H&E staining revealed that mice treated with Iso resulted in the ameliorated inflammatory cell infiltration and a reduction in interstitial thickening. The nuclear factor erythroid 2-like 2 (Nrf2) and HO-1 protein expression in Iso-L and Iso-H groups were enhanced over that in model group, while p-NF-κB-p65 and p-IκB-α protein expression was decreased (p < 0.05). Our research indicated that Iso alleviated the OVA-induced allergic asthma, and this effect can be explained by the modulation of Nrf2/HO-1 and NF-κB signaling pathway; thus, the results providing a therapeutic rationale for the treatment of Iso on allergic asthma.

Guozhen Chen

Papers

Qiliqiangxin improves cardiac function and attenuates cardiac remodelling in doxorubicin-induced heart failure rats.

Isoorientin ameliorates OVA-induced asthma in a murine model of asthma