CN116139117A - Application of itaconic acid and derivative thereof in preventing and treating cardiotoxicity induced by doxorubicin - Google Patents

Application of itaconic acid and derivative thereof in preventing and treating cardiotoxicity induced by doxorubicin Download PDF

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CN116139117A
CN116139117A CN202210611534.2A CN202210611534A CN116139117A CN 116139117 A CN116139117 A CN 116139117A CN 202210611534 A CN202210611534 A CN 202210611534A CN 116139117 A CN116139117 A CN 116139117A
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doxorubicin
myocardial
cell
itaconic acid
cardiotoxicity
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代颜
王敏
欧阳沛沛
何婷婷
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Affiliated Hospital of Southwest Medical University
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Abstract

The invention relates to the technical field of application of doxorubicin, and discloses application of itaconic acid and derivatives thereof in preventing and treating doxorubicin-induced cardiotoxicity, which comprises the steps of constructing an doxorubicin in-vitro myocardial meat cell injury model, constructing an doxorubicin in-vivo myocardial meat cell injury model, carrying out myocardial zymogram analysis on myocardial meat cells, researching the problem of existence of a cardiotoxicity drug for preventing the doxorubicin, carrying out experiments and obtaining experimental data. Itaconic acid is used as a key immune metabolite for regulating innate immunity and inflammation, has few researches on improving the toxicity of doxorubicin heart through targeting NLRP3 and other ways, provides a certain theoretical basis and clinical basis for the composition and process modification of the existing doxorubicin injection, and can solve the partial limitation of the old, heart disease patients, teenagers, and patients with childbearing cancers when receiving anthracycline treatment, expand applicable population and greatly improve the life quality of patients.

Description

Application of itaconic acid and derivative thereof in preventing and treating cardiotoxicity induced by doxorubicin
Technical Field
The invention relates to the technical field of application of doxorubicin, in particular to application of itaconic acid and derivatives thereof in preventing and treating cardiotoxicity induced by doxorubicin.
Background
According to the global latest cancer burden data issued by the international cancer research Institute (IARC) of the world health organization, global new breast cancer reaches 226 tens of thousands in 2020, and the first time more than lung cancer (221 tens of thousands) becomes the global first-largest cancer, and it is counted that female breast cancer has become the most common cancer worldwide (accounting for 11.7% of new cases), in females, breast cancer is the most frequently diagnosed cancer and is also the main cause of cancer death, doxorubicin has antibiotic characteristics and has proved to be one of the most effective chemotherapies discovered so far; anthracyclines are currently one of the most effective drugs for treating 100 tens of thousands of cancer patients, especially leukemia and breast cancer patients, doxorubicin is still one of the most effective drugs for treating various adult and childhood cancers (breast cancer, hodgkin's disease, lymphocytic leukemia) every year, however, after cancer survivors stop chemotherapy for many years, one major side effect of continued use of doxorubicin is dose-dependent, long-term, possibly fatal cardiovascular toxicity (heart failure and cardiomyopathy), furthermore, susceptibility to cardiac toxicity varies greatly among individuals, the long-term opinion is that cardiac toxicity is caused by active oxygen formed by redox cycles of redox half-life, but there is no strict evidence for administering active oxygen antidotes in chronic animal models, cardiovascular dysfunction is one of the most common complications of long-term cancer treatment, more and more evidence suggests that antitumor drugs increase cardiovascular risk during cancer treatment, serious effect of doxorubicin severely affects survival rate of patients, cardiac toxicity side effects of doxorubicin limits their use, in fact, anthracycline-induced myocardial toxicity is a significant problem of being a drug-induced by a profound side effect, and that the systemic side effect of doxorubicin is not completely understood to be a clear, and that the three-dimensional side effect of the drug is a life-cycle is reduced, and that the systemic side effect of the drug is still has been completely understood to be a clear, and that the three-dimensional side effects of the drug can be reduced by the current pattern of toxicity, such drug-induced by the drug is well-known to be well-understood, and the three-known side effects of the drug can be reduced, such side effect, and the life-cycle can be completely-induced by the drug can be considered to have the drug-life and can be completely-life-related to have the side toxic side effect and can be further has a life-related toxicity and can be considered to cause toxicity, slow release at low concentrations, but does not solve the problem of cardiotoxicity, which is an unavoidable risk of patients during chemotherapy, nor does clinical trials using antioxidants to protect cardiomyocytes have achieved good results; anthracycline-based chemotherapy can lead to the development of cumulative and progressive cardiomyopathy, and doxorubicin is one of the highest prescribed anthracyclines in the united states because of its broad therapeutic effects, a critical role in doxorubicin-induced cardiomyopathy, critical for reducing this disorder that greatly limits the clinical success of such necessary anticancer chemotherapies, doxorubicin-induced mitochondrial toxicity including mitochondrial oxidative stress, interruption of mitochondrial oxidative phosphorylation and permeability switching, which alters the metabolic and redox loops of cardiomyocytes, ultimately leading to the disturbance of autophagy/phagocytic flow and the increase of apoptosis, and anthracycline-induced cardiotoxicity is generally categorized as a type i chemotherapy-related cardiac dysfunction, as opposed to type ii, characterized by the presence of defined but non-specific ultrastructural abnormalities in cardiomyocytes (myofibrillar disorders and deletions, sarcoplasmic reticulum distension, mitochondrial swelling, nuclear chromatin disorders), which gradually become irreversible for the purpose of deepening the study of doxorubicin and improving the resistance to doxorubicin and its use in the cardiotoxicity-induced application of doxorubicin and its derivatives.
Disclosure of Invention
In order to achieve the above purpose, the present invention provides the following technical solutions: the application of itaconic acid and derivatives thereof in preventing and treating cardiotoxicity induced by doxorubicin comprises constructing an in-vitro myocardial meat cell injury model of doxorubicin, constructing an in-vivo myocardial meat cell injury model of doxorubicin, performing myocardial zymogram analysis on myocardial meat cells, researching the problem of existence of cardiotoxicity drugs for preventing doxorubicin, and carrying out experiments and obtaining experimental data.
Preferably, the method constructs an doxorubicin in vitro myocardial meat cell injury model, and detects myocardial cell mitochondrial injury and inflammation markers TLR4, NLRP3, pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10);
the method specifically comprises the following steps:
s101, detecting myocardial zymogram including myocardial troponin T/I (cTn T/I), creatine kinase isozyme (CK-MB), lactate Dehydrogenase (LDH), B-type natriuretic peptide (BNP), N-terminal B-type pro-natriuretic peptide (NT-proBNP), soluble growth stimulation expression gene 2 protein (sST 2) and the like;
s102, determining glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activity and Malondialdehyde (MDA) level in rat myocardial tissue and myocardial cell mitochondria by using a myocardial cell mitochondrial injury biochemical method;
s103, ELISA kit for detecting inflammatory markers TLR4 and NLRP3 and pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10)
S104, detecting the apoptosis of the cell coke.
Preferably, the detection of the apoptosis in the step S104 comprises observing the cell morphology by a scanning electron microscope and detecting the expression level of the apoptosis-related gene or protein by a q-PCR/Western Blot method (Caspase-1; GSDMD; cleavedCAPP-3, etc.)
Preferably, the in vivo doxorubicin myocardial meat cell injury model is constructed by myocardial zymogram electrocardiogram, echocardiogram, cardiac Magnetic Resonance (CMR), myocardial tissue fibrosis degree related genes, myocardial cell mitochondrial injury, myocardial tissue inflammation markers TLR4 and NLRP3 and pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10), cell apoptosis and detection of spleen immunorestoration capability and level in rats;
the method specifically comprises the following steps:
s201, a myocardial zymogram comprises serological detection of myocardial troponin T/I (cTn T/I), creatine kinase isozyme (CK-MB), lactate Dehydrogenase (LDH), B-type natriuretic peptide (BNP), N-terminal B-type pro-natriuretic peptide (NT-proBNP), soluble growth stimulation expressed gene 2 protein (sST 2) and the like;
s202, electrocardiographic detection, including ST-T segment change, QTc interval prolongation, sinus tachycardia, ventricular premature beat, transient atrial contraction and the like;
s203, echocardiography, left ventricular global longitudinal strain (global longitudinal strain, GLS), LVEF, and echocardiography STE (speckle tracking technique) and TVI (tissue velocity doppler imaging) detection;
s204, cardiac Magnetic Resonance (CMR) is a gold standard for evaluating left ventricular volume and function, and can also evaluate myocardial strain, early microstructure and microvascular changes, and pericardial disease, comprehensively evaluating to detect CTRCD (cancer therapy-related cardiac dysfunction);
s205, observing myocardial tissue pathological changes by HE staining of heart tissue;
s206, detecting the myocardial tissue fibrosis degree by Masson staining;
s207, T-qPCR detection of fibrosis related genes Col1 alpha, col3 alpha, TGF-beta 1mRNA expression level;
s208, immunoblotting hair to detect p53 gene and Death Receptor (DR) expression levels, wherein the distribution of the expression levels is a key regulator of doxorubicin cardiotoxicity and an early transcription index of cardiotoxicity;
s209, determining glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activity and Malondialdehyde (MDA) level in rat myocardial tissue and myocardial cell mitochondria by using a myocardial cell mitochondrial injury biochemical method;
s210, detecting rat myocardial tissue inflammation markers TLR4 and NLRP3 and pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10) by ELISA kit;
s211, detecting cell apoptosis.
Preferably, the detection of cell apoptosis in the step S211 comprises observing cell morphology by a scanning electron microscope and detecting expression levels of gene or protein related to apoptosis (Caspase-1; GSDMD; cleavedCAPP-3, etc.) by a q-PCR/Western Blot method for detecting levels of lipoxygenase, cyclooxygenase and tumor necrosis factor-alpha in rat spleen; immune cell repair marker MRC-1 (also referred to as CD 206) levels in the heart.
Preferably, the cardiotoxicity preventive drug for doxorubicin comprises dexrazoxane, beta receptor blocker or ACE inhibitor, magnolol, dextroglutamine, trimetazidine, doxorubicin cardiotoxicity and inflammation and NLRP3 inflammation corpuscles, anti-inflammatory metabolite itaconic acid and NLRP3 inflammation corpuscles.
Preferably, the experiment comprises a rat doxorubicin acute toxicity experiment, and the rat doxorubicin acute toxicity experiment comprises the steps of changing the weight of the rat before and after the experiment, clinically observing the acute toxicity symptom of the rat doxorubicin, measuring the serum myocardial zymogram and detecting myocardial tissue pathology.
Compared with the prior art, the invention provides the application of itaconic acid and the derivative thereof in preventing and treating cardiotoxicity induced by doxorubicin, and has the following beneficial effects:
1. the use of itaconic acid and derivatives thereof for the prevention and treatment of doxorubicin-induced cardiotoxicity, itaconic acid being an immune metabolite (immutable) having a remarkable anti-inflammatory effect but for which the mechanism is not yet fully understood, itaconic acid being an endogenous metabolic regulator of NLRP3 inflammation, being capable of modifying specific cysteines (C548) on NLRP3 and inhibiting activation of NLRP3 by interfering with the interaction between NLRP3 and NEK7 and being useful in the treatment of inflammation alleviating the small body of NLRP3 inflammation, itaconic acid being an anti-inflammatory metabolite acting in a manner similar to that of immunosuppressive cytokine IL-10, itaconic acid being a five-carbon dicarboxylic acid formed by decarboxylation of tricarboxylic acid intermediate cis-aconitic acid under the catalysis of cis-aconitic acid decarboxylase, containing alpha, beta-unsaturated carboxylic acid structures, many endogenous metabolites containing this fragment being capable of alkylating the cysteine residues of proteins through Michael addition reaction, e.g. fumarate being capable of alkylating KEAP1 and GAPDH, thus exerting an anti-glycolytic effect
2. The application of the itaconic acid and the derivative thereof in preventing and controlling the cardiotoxicity induced by doxorubicin, the itaconic acid is taken as an immunoregulatory metabolite of macrophages, and in recent years, the itaconic acid has great therapeutic potential in the fields of Nature, nat Commun, nat. Rev. Cardiol. Cell Metabolism, nat Rev Immunol and the like, and the itaconic acid targeting NLRP3 has expanded the effect of itaconic acid salt as a key immunometabolite for regulating innate immunity and inflammation.
3. The itaconic acid and the derivative thereof are applied to preventing and treating the cardiotoxicity induced by the doxorubicin, the itaconic acid is used as a key immune metabolite for regulating innate immunity and inflammation, little research is carried out on the research on improving the cardiotoxicity of the doxorubicin by targeting NLRP3 and the like, a certain theoretical basis and clinical basis are provided for the composition and process modification of the existing doxorubicin injection, the clinical transformation can solve the partial limitation of the old, heart disease patients, teenagers, and patients with childbearing cancers and the like when receiving anthracycline treatment, reduce the cardiac function damage caused by chemotherapy side effects, treat the occurrence of related cancers and reproductive damage, ensure the anthracycline curative effect, expand applicable population and greatly improve the life quality of patients.
Drawings
FIG. 1 is a schematic flow chart of constructing an in vivo myocardial meat cell injury model of doxorubicin according to the invention;
FIG. 2 is a schematic flow chart of constructing an doxorubicin in vitro myocardial meat cell injury model in the present invention;
FIG. 3 is a schematic diagram showing the change of the body weight of a rat in the acute toxicity test of the doxorubicin of the present invention;
FIG. 4 is a schematic representation of the present invention itaconic acid group alleviating the acute toxicity symptoms of doxorubicin in rats;
FIG. 5 is a schematic diagram showing that itaconic acid groups in serum myocardial zymograms of the invention obviously reduce various indexes;
FIG. 6 is a schematic diagram showing the anti-inflammatory markers and anti-inflammatory cytokines shown in WB experiments of the present invention;
FIG. 7 is a schematic representation of ELISA experiments of the invention showing anti-inflammatory markers and anti-inflammatory cytokine expression.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Referring to fig. 1-7, an application of itaconic acid and its derivatives in preventing and treating cardiotoxicity induced by doxorubicin comprises constructing an in vitro myocardial meat cell injury model of doxorubicin, constructing an in vivo myocardial meat cell injury model of doxorubicin, performing myocardial zymogram analysis on myocardial meat cells, researching the problem of existence of cardiotoxicity drugs for preventing doxorubicin, and performing experiments and obtaining experimental data.
Further, the in vitro myocardial meat cell injury model of doxorubicin is constructed, and the mitochondrial injury and inflammation markers TLR4, NLRP3, pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10) of the myocardial cells are detected;
the method specifically comprises the following steps:
s101, detecting myocardial zymogram including myocardial troponin T/I (cTn T/I), creatine kinase isozyme (CK-MB), lactate Dehydrogenase (LDH), B-type natriuretic peptide (BNP), N-terminal B-type pro-natriuretic peptide (NT-proBNP), soluble growth stimulation expression gene 2 protein (sST 2) and the like;
s102, determining glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activity and Malondialdehyde (MDA) level in rat myocardial tissue and myocardial cell mitochondria by using a myocardial cell mitochondrial injury biochemical method;
s103, ELISA kit for detecting inflammatory markers TLR4 and NLRP3 and pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10)
S104, detecting the apoptosis of the cell coke.
Further, the detection of the apoptosis in the step S104 comprises observing the cell morphology by a scanning electron microscope and detecting the expression level of the apoptosis-related gene or protein by a q-PCR/Western Blot method (Caspase-1; GSDMD; cleavedCAPP-3, etc.)
Further, the in vivo myocardial meat cell injury model of doxorubicin is constructed, and the immune repair capacity and the level in spleen immunity and heart of rats are detected through myocardial zymogram, echocardiogram, cardiac Magnetic Resonance (CMR), myocardial tissue fibrosis degree related genes, myocardial cell mitochondrial injury, myocardial tissue inflammation markers TLR4 and NLRP3 and pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10), cell apoptosis and detection of the immune repair capacity and the level in the spleen of rats;
the method specifically comprises the following steps:
s201, a myocardial zymogram comprises serological detection of myocardial troponin T/I (cTn T/I), creatine kinase isozyme (CK-MB), lactate Dehydrogenase (LDH), B-type natriuretic peptide (BNP), N-terminal B-type pro-natriuretic peptide (NT-proBNP), soluble growth stimulation expressed gene 2 protein (sST 2) and the like;
s202, electrocardiographic detection, including ST-T segment change, QTc interval prolongation, sinus tachycardia, ventricular premature beat, transient atrial contraction and the like;
s203, echocardiography, left ventricular global longitudinal strain (global longitudinal strain, GLS), LVEF, and echocardiography STE (speckle tracking technique) and TVI (tissue velocity doppler imaging) detection;
s204, cardiac Magnetic Resonance (CMR) is a gold standard for evaluating left ventricular volume and function, and can also evaluate myocardial strain, early microstructure and microvascular changes, and pericardial disease, comprehensively evaluating to detect CTRCD (cancer therapy-related cardiac dysfunction);
s205, observing myocardial tissue pathological changes by HE staining of heart tissue;
s206, detecting the myocardial tissue fibrosis degree by Masson staining;
s207, T-qPCR detection of fibrosis related genes Col1 alpha, col3 alpha, TGF-beta 1mRNA expression level;
s208, immunoblotting hair to detect p53 gene and Death Receptor (DR) expression levels, wherein the distribution of the expression levels is a key regulator of doxorubicin cardiotoxicity and an early transcription index of cardiotoxicity;
s209, determining glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activity and Malondialdehyde (MDA) level in rat myocardial tissue and myocardial cell mitochondria by using a myocardial cell mitochondrial injury biochemical method;
s210, detecting rat myocardial tissue inflammation markers TLR4 and NLRP3 and pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10) by ELISA kit;
s211, detecting cell apoptosis.
Further, the detection of the apoptosis in the step S211 comprises observing the cell morphology by a scanning electron microscope and detecting the expression level of the gene or protein related to the apoptosis (Caspase-1; GSDMD; cleavedCAPP-3, etc.) by a q-PCR/Western Blot method, wherein the q-PCR/Western Blot method detects the levels of lipoxygenase, cyclooxygenase and tumor necrosis factor-alpha in the spleen of the rat; immune cell repair marker MRC-1 (also referred to as CD 206) levels in the heart.
Further, the cardiotoxicity preventive drug for doxorubicin comprises dexrazoxane, beta receptor blocker or ACE inhibitor, magnolol, dextroglutamine, trimetazidine and other drugs, doxorubicin cardiotoxicity and inflammation and NLRP3 inflammation corpuscles, anti-inflammatory metabolite itaconic acid and NLRP3 inflammation corpuscles.
Furthermore, the experiment comprises a rat doxorubicin acute toxicity experiment, and the rat doxorubicin acute toxicity experiment comprises the steps of changing the weight of the rat before and after the experiment, clinically observing the acute toxicity symptom of the rat doxorubicin, measuring the serum myocardial zymogram and detecting myocardial tissue pathology.
Working principle: itaconic acid is an immune metabolite (immattabolite) with remarkable anti-inflammatory effects, but the mechanism thereof is not fully understood, itaconic acid is an endogenous metabolic regulator of NLRP3 inflammation, specific cysteine (C548) on NLRP3 can be modified and can be used for inhibiting activation of NLRP3 by interfering with interaction between NLRP3 and NEK7 and can be used for treating inflammation for relieving NLRP3 inflammation in a small body, itaconic acid is an anti-inflammatory metabolite which acts in a similar way to immunosuppression cytokine IL-10, itaconic acid is a five-carbon dicarboxylic acid formed by decarboxylation of tricarboxylic acid intermediate cis-aconitic acid under catalysis of cis-aconitic acid decarboxylase, contains alpha, beta-unsaturated carboxylic acid structure, and many endogenous metabolites containing this fragment can exert anti-inflammatory effects through alkylation of cysteine residues of proteins through Michael addition reaction, for example fumarate can alkylate AP1 and GAPDH, and inhibit glycolysis.
Itaconic acid as an immunoregulatory metabolite of macrophages has been frequently published in recent years in journals of Nature, nature Commun, nature.rev. Cardiol. Cell Metabolism, nature Rev Immunol, etc., and itaconic acid targeting NLRP3 has a great therapeutic potential and expands the role of itaconic acid salts as key immunometabolites for regulating innate immunity and inflammation.
As key immune metabolites for regulating innate immunity and inflammation, itaconic acid has little research on improving the toxicity of doxorubicin heart through targeting NLRP3 and other approaches, provides a certain theoretical basis and clinical basis for the composition and process modification of the existing doxorubicin injection, and can solve the partial limitation of the old, heart disease patients, teenagers, and patients with childbearing cancers when receiving anthracyclines, reduce the damage of heart function caused by chemotherapy side effects, treat the occurrence of related cancers and reproductive damage, expand applicable crowds and greatly improve the life quality of patients while guaranteeing the anthracycline curative effect.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (7)

1. An application of itaconic acid and derivatives thereof in preventing and treating cardiotoxicity induced by doxorubicin is characterized in that: the method comprises the steps of constructing an in-vitro myocardial meat cell injury model of the doxorubicin, constructing an in-vivo myocardial meat cell injury model of the doxorubicin, carrying out myocardial zymography analysis on the myocardial meat cells, researching the problem of the existence of a cardiotoxicity drug for preventing the doxorubicin, and carrying out experiments and obtaining experimental data.
2. Use of itaconic acid and derivatives thereof in the prevention and treatment of doxorubicin-induced cardiotoxicity according to claim 1, characterized in that: constructing an doxorubicin in-vitro myocardial meat cell injury model, and detecting myocardial cell mitochondrial injury and inflammation markers TLR4, NLRP3, pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10);
the method specifically comprises the following steps:
s101, detecting myocardial zymogram including myocardial troponin T/I (cTn T/I), creatine kinase isozyme (CK-MB), lactate Dehydrogenase (LDH), B-type natriuretic peptide (BNP), N-terminal B-type pro-natriuretic peptide (NT-proBNP), soluble growth stimulation expression gene 2 protein (sST 2) and the like;
s102, determining glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activity and Malondialdehyde (MDA) level in rat myocardial tissue and myocardial cell mitochondria by using a myocardial cell mitochondrial injury biochemical method;
s103, ELISA kit for detecting inflammatory markers TLR4 and NLRP3 and pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10)
S104, detecting the apoptosis of the cell coke.
3. Use of itaconic acid and derivatives thereof in the prevention and treatment of doxorubicin-induced cardiotoxicity according to claim 2, characterized in that: the detection of the cell apoptosis in the step S104 comprises the steps of observing the cell morphology by a scanning electron microscope and detecting the expression level of a gene or protein related to the apoptosis (Caspase-1; GSDMD; cleavedCAPP-3, etc.) by a q-PCR/Western Blot method.
4. Use of itaconic acid and derivatives thereof in the prevention and treatment of doxorubicin-induced cardiotoxicity according to claim 1, characterized in that: constructing an in-vivo doxorubicin myocardial meat cell injury model, and detecting the immunoreparative capacity and the level of myocardial tissue injury, myocardial tissue inflammation markers TLR4 and NLRP3 and pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10), cell apoptosis and the immunocompetence of a rat spleen and heart through myocardial zymogram, echocardiogram, cardiac Magnetic Resonance (CMR), myocardial tissue fibrosis degree related genes;
the method specifically comprises the following steps:
s201, a myocardial zymogram comprises serological detection of myocardial troponin T/I (cTn T/I), creatine kinase isozyme (CK-MB), lactate Dehydrogenase (LDH), B-type natriuretic peptide (BNP), N-terminal B-type pro-natriuretic peptide (NT-proBNP), soluble growth stimulation expressed gene 2 protein (sST 2) and the like;
s202, electrocardiographic detection, including ST-T segment change, QTc interval prolongation, sinus tachycardia, ventricular premature beat, transient atrial contraction and the like;
s203, echocardiography, left ventricular global longitudinal strain (global longitudinal strain, GLS), LVEF, and echocardiography STE (speckle tracking technique) and TVI (tissue velocity doppler imaging) detection;
s204, cardiac Magnetic Resonance (CMR) is a gold standard for evaluating left ventricular volume and function, and can also evaluate myocardial strain, early microstructure and microvascular changes, and pericardial disease, comprehensively evaluating to detect CTRCD (cancer therapy-related cardiac dysfunction);
s205, observing myocardial tissue pathological changes by HE staining of heart tissue;
s206, detecting the myocardial tissue fibrosis degree by Masson staining;
s207, T-qPCR detection of fibrosis related genes Col1 alpha, col3 alpha, TGF-beta 1mRNA expression level;
s208, immunoblotting hair to detect p53 gene and Death Receptor (DR) expression levels, wherein the distribution of the expression levels is a key regulator of doxorubicin cardiotoxicity and an early transcription index of cardiotoxicity;
s209, determining glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activity and Malondialdehyde (MDA) level in rat myocardial tissue and myocardial cell mitochondria by using a myocardial cell mitochondrial injury biochemical method;
s210, detecting rat myocardial tissue inflammation markers TLR4 and NLRP3 and pro-inflammatory factors (TNF-alpha, IL-1 beta and IL-6) and anti-inflammatory factors (IL-10) by ELISA kit;
s211, detecting cell apoptosis.
5. Use of itaconic acid and derivatives thereof in the prevention and treatment of doxorubicin-induced cardiotoxicity according to claim 1, characterized in that: the detection of the cell apoptosis in the step S211 comprises observing the cell morphology by a scanning electron microscope and detecting the expression level of a gene or protein related to the apoptosis (Caspase-1; GSDMD; cleavedCASP-3, etc.) by a q-PCR/Western Blot method, wherein the q-PCR/Western Blot method detects the levels of lipoxygenase, cyclooxygenase and tumor necrosis factor-alpha in the spleen of the rat; immune cell repair marker MRC-1 (also referred to as CD 206) levels in the heart.
6. Use of itaconic acid and derivatives thereof in the prevention and treatment of doxorubicin-induced cardiotoxicity according to claim 1, characterized in that: the cardiotoxicity medicine for preventing the doxorubicin comprises dexrazoxane, beta receptor blocker or ACE inhibitor, magnolol, dextro-glutamine, trimetazidine and other medicines, doxorubicin cardiotoxicity and inflammation and NLRP3 inflammation corpuscles, and anti-inflammatory metabolite itaconic acid and NLRP3 inflammation corpuscles.
7. Use of itaconic acid and derivatives thereof in the prevention and treatment of doxorubicin-induced cardiotoxicity according to claim 1, characterized in that: the experiment comprises a rat doxorubicin acute toxicity experiment, wherein the rat doxorubicin acute toxicity experiment comprises the steps of rat weight change before and after the experiment, clinical observation of the rat doxorubicin acute toxicity symptom, measurement of serum myocardial zymogram and myocardial tissue pathology detection.
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