Protective effect of Shenmai injection on doxorubicin-induced cardiotoxicity via regulation of inflammatory mediators

Abstract Background Doxorubicin (DOX) is a chemotherapy drug for malignant tumors. The clinical application of DOX is limited due to its dosage relative cardiotoxicity. Oxidative damage and cardiac inflammation appear to be involved in DOX-related cardiotoxicity. Shenmai injection (SMI), which mainly consists of Panax ginsengC.A.Mey.and Ophiopogon japonicus (Thunb.) Ker Gawl, is widely used for the treatment of atherosclerotic coronary heart disease and viral myocarditis in China. In this study, we investigated the protective effect of Shenmai injection on doxorubicin-induced acute cardiac injury via the regulation of inflammatory mediators. Methods Male ICR mice were randomly divided into seven groups: control, DOX (10 mg/kg), SMI (5 g/kg), DOX with pretreatment with SMI (0.5 g/kg, 1.5 g/kg or 5 g/kg) and DOX with post-treatment with SMI (5 g/kg). Forty-eight hours after the last DOX administration, all mice were anesthetized for ultrasound echocardiography. Then, serum was collected for biochemical and inflammatory cytokine detection, and heart tissue was collected for histological and Western blot detection. Results A cumulative dose of DOX (10 mg/kg) induced acute cardiotoxicity in mice manifested by altered echocardiographic outcome, and increased tumor necrosis factor, interleukin 6 (IL-6), monocyte chemotactic protein 1, interferon-γ, and serum AST and LDH levels, as well as cardiac cytoplasmic vacuolation and myofibrillar disarrangement. DOX also caused the increase in the expression of IKK-α and iNOS and produced a large amount of NO, resulting in the accumulation of nitrotyrosine in the heart tissue. Pretreatment with SMI elicited a dose-dependent cardioprotective effect in DOX-dosed mice as evidenced by the normalization of serum inflammatory mediators, as well as improve dcardiac function and myofibril disarrangement. Conclusions SMI could recover inflammatory cytokine levels and suppress the expression of IKK-α and iNOS in vivo, which was increased by DOX. Overall, there was evidence that SMI could ameliorate DOX-induced cardiotoxicity by inhibiting inflammation and recovering heart dysfunction.

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Acyl-CoA thioesterase 1 prevents cardiomyocytes from Doxorubicin-induced ferroptosis via shaping the lipid composition

Cell Death and Disease ◽

10.1038/s41419-020-02948-2 ◽

2020 ◽

Vol 11 (9) ◽

Author(s):

Yunchang Liu ◽

Liping Zeng ◽

Yong Yang ◽

Chen Chen ◽

Daowen Wang ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Composition ◽

Cardiac Injury ◽

Leading Edge ◽

Heart Tissue ◽

Protective Role ◽

Enzymatic Function

Abstract In this study, we first established the doxorubicin-induced cardiotoxicity (DIC) model with C57BL/6 mice and confirmed cardiac dysfunction with transthoracic echocardiography examination. RNA-sequencing was then performed to explore the potential mechanisms and transcriptional changes in the process. The metabolic pathway, biosynthesis of polyunsaturated fatty acid was significantly altered in DOX-treated murine heart, and Acot1 was one of the leading-edge core genes. We then investigated the role of Acot1 to ferroptosis that was reported recently to be related to DIC. The induction of ferroptosis in the DOX-treated heart was confirmed by transmission electron microscopy, and the inhibition of ferroptosis using Fer-1 effectively prevented the cardiac injury as well as the ultrastructure changes of cardiomyocyte mitochondrial. Both in vitro and in vivo experiments proved the downregulation of Acot1 in DIC, which can be partially prevented with Fer-1 treatment. Overexpression of Acot1 in cell lines showed noteworthy protection to ferroptosis, while the knock-down of Acot1 sensitized cardiomyocytes to ferroptosis by DIC. Finally, the heart tissue of αMHC-Acot1 transgenic mice presented altered free fatty acid composition, indicating that the benefit of Acot1 in the inhibition of ferroptosis lies biochemically and relates to its enzymatic function in lipid metabolism in DIC. The current study highlights the importance of ferroptosis in DIC and points out the potential protective role of Acot1 in the process. The beneficial role of Acot1 may be related to its biochemical function by shaping the lipid composition. In all, Acot1 may become a potential treating target in preventing DIC by anti-ferroptosis.

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Shenmai Injection Alleviates Cardiomyocyte Apoptosis Induced by Doxorubicin

10.21203/rs.3.rs-870812/v1 ◽

2021 ◽

Author(s):

Xiaonan Zhang ◽

Yanyang Li ◽

Wanqin Zhang ◽

Qiujin Jia ◽

Yaping Zhu ◽

...

Keyword(s):

Protective Effect ◽

Myocardial Injury ◽

Myocardial Damage ◽

Myocardial Cell ◽

Type Iii Collagen ◽

Type I ◽

Pathological Changes ◽

Sprague Dawley ◽

Shenmai Injection

Abstract Background: Shenmai Injection (SMI) is a patented Chinese medicine extract, has been widely used to treat myocardial damage caused by doxorubicin (DOX), but its underlying mechanisms remain elusive. The study aimed to explore the protective effect of SMI on myocardial injury caused by DOX in vivo.Methods: The male Sprague-Dawley (SD) rats received DOX (2mg/kg) tail vein injection every week for 4 weeks, with or without SMI and miR-30a agomir treatment for 2 weeks. The protective effect of SMI on myocardial injury caused by DOX has been determined by measuring rat body mass and general heart morphology, myocardial pathological changes, and serum markers. The myocardial pathological changes were observed by Van Gieson (VG) staining, the serum marker levels of myocardial injury were detected by ELISA, the myocardial cell apoptosis was observed by TUNEL assay and transmission electron microscope, and the expression of target protein was detected by Western Blot.Results: SMI treatment significantly reduced rat HMI and LVMI, reduced the levels of serum CK, LDH, cTnT, NT-proBNP, and also reduced the levels of serum sST2 and GDF-15, and reduced the expression of rat myocardial type I and type III collagen, which was effective reduce the fibrosis of myocardial collagen knot tissue and interstitial. The study further found that SMI can increase the expression of Bcl-2 protein, reduce the expression of Bax, Caspase-9, and Caspase-3 protein, and reduce the apoptotic index of cardiomyocytes. Conclusion: The potential mechanism of SMI on cardiomyocytes from apoptosis induced by the DOX may be attributed to the regulation of miR-30a/beclin 1.

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The M2 Gene Is a Determinant of Reovirus-Induced Myocarditis

10.1101/2021.07.16.452757 ◽

2021 ◽

Author(s):

Marcelle Dina Zita ◽

Matthew B Phillips ◽

Johnasha D. Stuart ◽

Asangi R Kumarapeli ◽

Vijayalakshmi Sridharan ◽

...

Keyword(s):

Cardiac Injury ◽

Viral Myocarditis ◽

Newborn Mice ◽

Viral Loads ◽

Lethal Infection ◽

Strain Type ◽

Rapid Kinetics ◽

Inflammatory Infiltrates ◽

Type 3

Although a broad range of viruses cause myocarditis, the mechanisms that underlie viral myocarditis are poorly understood. Here, we report that the M2 gene is a determinant of reovirus myocarditis. The reovirus M2 gene encodes outer capsid protein µ1, which influences both cell entry and cell death. We infected newborn mice with reovirus strain type 1 Lang (T1L) or a reassortant reovirus in which the M2 gene from strain type 3 Dearing (T3D) was substituted into the T1L background (T1L/T3DM2). T1L was non-lethal in wild-type mice, whereas ~ 90% of mice succumbed to T1L/T3DM2. T1L/T3DM2 produced higher viral loads than T1L at the site of inoculation. In secondary organs, T1L/T3DM2 was detected with more rapid kinetics and reached higher peak titers than T1L. We found that hearts from T1L/T3DM2-infected mice were grossly abnormal, with large lesions corresponding to substantial cardiac injury with inflammatory infiltrates. Lesions in T1L/T3DM2-infected mice contained aggregates of necrotic cardiomyocytes with pyknotic debris, and prominent lymphocyte and histiocyte infiltration. In contrast, T1L induced the formation of smaller lesions in a subset of animals, consistent with T1L being mildly myocarditic. Finally, more activated caspase-3-positive cells were observed in hearts from animals infected with T1L/T3DM2 compared to T1L. Together, our findings indicate that substitution of the T3D M2 allele into an otherwise T1L genetic background is sufficient to change a non-lethal infection into a lethal infection. Our results further indicate that T3D M2 enhances T1L replication and dissemination in vivo, which potentiates the capacity of reovirus to cause myocarditis.

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LPS-induced bronchial hyperreactivity: interference by mIL-10 differs according to site of delivery

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00053.2003 ◽

2004 ◽

Vol 286 (1) ◽

pp. L98-L105 ◽

Cited By ~ 13

Author(s):

Virginie Deleuze ◽

Jean Lefort ◽

Michel F. Bureau ◽

Daniel Scherman ◽

B. Boris Vargaftig

Keyword(s):

Protective Effect ◽

Lung Inflammation ◽

Inflammatory Cytokine ◽

Ex Vivo ◽

Blood Levels ◽

Tnf Α ◽

Circulating Levels ◽

Anti Inflammatory Cytokine ◽

Intranasal Instillation

When administered to mice systemically or via the airways, LPS induces bronchoconstriction (BC) and/or bronchopulmonary hyperreactivity (BHR), associated with inflammation. Accordingly, a relationship between inflammation and allergic and nonallergic BHR can be hypothesized. We therefore studied the interference of the anti-inflammatory cytokine murine IL-10 (mIL-10) with LPS-induced lung inflammation, BC, and BHR. mIL-10 was administered directly into the airways by intranasal instillation or generated in vivo after muscle electrotransfer of mIL-10-encoding plasmid. Electrotransfer led to high mIL-10 circulating levels for a longer time than after the injection of recombinant mIL-10 (rmIL-10). rmIL-10 administered intranasally reduced lung inflammation and BHR after LPS administration into airways. It also reduced the ex vivo production of TNF-α by LPS-stimulated lung tissue explants. Two days after electrotransfer, mIL-10 blood levels were elevated, but lung inflammation, BC, and BHR persisted unaffected. Blood mIL-10 reaches the airways poorly, which probably accounts for the ineffectiveness of mIL-10-encoding plasmid electrotransfer. When LPS was aerosolized 15 days after electrotransfer, lung inflammation persisted but BHR was significantly reduced, an effect that may be related to the longer exposure of the relevant cells to mIL-10. The dissociation between inflammation and BHR indicates that both are not directly correlated. In conclusion, this study shows that mIL-10 is efficient against BHR when present in the airway compartment. Despite this, the muscle electrotransfer with mIL-10-encoding plasmid showed a protective effect against BHR after a delay of 2 wk that should be further investigated.

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A new mixed-ligand coordination polymer: crystal structure and protective effect on viral myocarditis via regulating inflammatory response in vivo

Inorganic and Nano-Metal Chemistry ◽

10.1080/24701556.2020.1745834 ◽

2020 ◽

Vol 50 (12) ◽

pp. 1234-1238

Author(s):

Lei Wang ◽

Yang Liu ◽

Jiabing Zhang ◽

Yunfeng Xia

Keyword(s):

Crystal Structure ◽

Coordination Polymer ◽

Inflammatory Response ◽

Protective Effect ◽

Viral Myocarditis ◽

Mixed Ligand ◽

Polymer Crystal ◽

Ligand Coordination

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P1220 Phytoestrogens do not abolish the protective effect of preconditioning in vivo

European Heart Journal ◽

10.1016/s0195-668x(03)94512-x ◽

2003 ◽

Vol 24 (5) ◽

pp. 230

Author(s):

E SBAROUNI

Keyword(s):

Protective Effect

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Protective Effect of Boswellic Resin Against Memory Loss and Alzheimer’s Induced by Aluminum Tetrachloride and D-Galactose (Experimental study in Mice)

Phytothérapie ◽

10.3166/phyto-2020-0222 ◽

2020 ◽

Author(s):

K. Zerrouki ◽

N. Djebli ◽

L. Gadouche ◽

I. Erdogan Orhan ◽

F. SezerSenol Deniz ◽

...

Keyword(s):

Chemical Composition ◽

Protective Effect ◽

Cell Damage ◽

Memory Loss ◽

Control Group ◽

Total Extract ◽

Swiss Mice ◽

Octyl Acetate

Nowadays, because of the industrialization, a lot of contaminant were available ; the consequences of this availability are apparition of diseases including neurodegeneration. Neurodegenerative diseases of the human brain comprise a variety of disorders that affect an increasing percentage of the population. This study is based on the effect of the Boswellic resin, which is from a medicinal plant and known for its antioxidant effects on nerve cell damage. The objective of this work was to evaluate the in vitro and in vivo effects of the Boswellic resin on anticholinesterase activity and Alzheimer’s disease (AD) induced by D-galactose and aluminum tetrachloride in Swiss mice. Chemical composition of the resin essential oil was identified by the CG-MS analysis. The antioxidant activity was also assessed by the DMPD and metal chelation methods. In order to understand the mechanism of memory improvement, the acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, inhibitory assays were performed. In vivo part of the study was achieved on Swiss mice divided into four groups: control, AD model, treated AD, and treated control group. The identification of chemical composition by CG-MS reach the 89.67% of the total extract compounds presented some very important molecules (p-Cymene, n-Octyl acetate, α-Pinene…). The present study proves that Boswellic resin improves memory and learning in treated Alzheimer’s group, modulates the oxidative stress and be involved in the protective effect against amyloid deposition and neurodegeneration, and stimulates the immune system in mice’s brain.

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