CN115814087B - Application of mitochondrial oxidized cardiolipin as target in screening product for preventing and treating endotoxemia-related cardiac dysfunction - Google Patents
Application of mitochondrial oxidized cardiolipin as target in screening product for preventing and treating endotoxemia-related cardiac dysfunction Download PDFInfo
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Abstract
The invention provides an application of mitochondrial oxidized cardiolipin as a target in screening products for diagnosing, preventing and/or treating endotoxemia-related cardiac dysfunction, and the inventor discovers that the level of oxidized cardiolipin in the cardiac mitochondria of an animal with endotoxemia-related cardiac dysfunction is increased by constructing a mouse model of endotoxemia-related cardiac dysfunction, and experiments are carried out by utilizing internationally accepted anti-mitochondrial cardiolipin oxidant XJB-5-131, so that the occurrence and development of endotoxemia-related cardiac dysfunction can be improved in early stage, and the survival rate can be improved. The invention provides a product for screening, diagnosing, preventing and/or treating endotoxemia-related heart dysfunction by taking mitochondrial oxidized cardiolipin as a target spot, and provides a new thought for diagnosing, preventing and/or treating endotoxemia-related heart dysfunction.
Description
Technical Field
The invention relates to the technical field of pharmacology, in particular to application of mitochondrial oxidized cardiolipin serving as a target spot in screening products for preventing and treating endotoxemia-related cardiac dysfunction.
Background
Sepsis and endotoxemia are life-threatening multi-organ dysfunction caused by imbalance of organism reaction to infection, are one of global public health problems focused in recent years, and have the characteristics of high death rate, poor prognosis and low quality of life, and the death rate of the disease is as high as 30% -70%. WHO listed sepsis and endotoxemia as global health preference programs in 2017 to better improve their prevention, diagnosis and management. While heart dysfunction is one of the most common complications of endotoxemia, about 50% of endotoxemia patients have heart dysfunction in combination, and is an important cause of initiation of multiple organ failure and death. It was found that the mortality rate of patients with endotoxemia-associated myocardial dysfunction (endotoxin-induced myocardial dysfunction, EIMD) was nearly 70-90% higher than that of endotoxemia patients without heart dysfunction (mortality rate 20%).
In recent years, research has found that myocardial dysfunction can occur in early stages of endotoxemia (i.e. when there is no significant change in hemodynamics in the circulation), and is closely related to prognosis. Myocardial inhibition factor theory is thought to be a critical mechanism involved in early EIMD, but a number of prospective clinical studies related to large-scale endotoxin diseases have shown that none of the treatment regimens given to patients to inhibit or neutralize inflammatory cytokines improve their clinical prognosis. In addition, toll-like receptor4 (Toll like receptor, TLR 4) was identified as an endotoxin lipopolysaccharide Lipopolysaccharide (LPS) membrane receptor in the last 90 th century, and LPS induced cytokine and inflammatory factor transcription after binding to TLR4, but LPS-induced shock and death could not be completely ameliorated by blocking TLR4 interaction with LPS. Therefore, a new therapeutic target for early and effectively improving the myocardial dysfunction related to endotoxemia is sought, the survival rate is improved, and the need is felt.
However, the mechanism of how endotoxemia directly causes early myocardial function damage is not clear, so related intervention targets and medicines are few.
The pathophysiological mechanisms of endotoxemia-associated myocardial dysfunction are complex, including extracellular and intracellular mechanisms, where extracellular mechanisms include myocardial suppressors, microvascular changes, endothelial dysfunction, and intracellular mechanisms include calcium regulation disorders, autophagy, and mitochondrial dysfunction. In recent years, mitochondrial dysfunction is considered to be an early key pathophysiological mechanism of EIMD, and causes of myocardial mitochondrial dysfunction are numerous, including mitochondrial structural abnormality, oxidative stress, mitochondrial permeability change, mitochondrial uncoupling, mitochondrial quality control system and the like, and mitochondrial oxidative stress is found to be a possibly key promoter.
Cell-piercing protein GSDMD, which is a key molecule mediating cell apoptosis, releases GSDMD-N-terminal with cell-piercing activity after inflammatory caspase-1 and caspase-11 (in human being caspase-4) are sheared, can be combined with specific phospholipids on a membrane, and undergo oligomerization to perform the piercing action, so that cell structure is damaged, and inflammatory cytokines (such as IL-1 beta, IL-18, leukotriene and the like) are released.
In the organism, 15% of Cardiolipin is positioned in cardiac muscle, and the Cardiolipin (Cardiolipin) is used as a specific binding substrate of GSDMD-N end, is widely distributed on bacterial membranes and eukaryotic mitochondrial inner membranes, is asymmetrically distributed on the mitochondrial membranes, and plays an important role in maintaining normal physiological functions and morphology of mitochondria. In the non-stressed state, the N-terminal end of GSDMD is not in direct contact with cardiolipin, but in the inflammatory and infectious states of the body, the ROS production in mitochondria is increased, and cardiolipin can be oxidized and transferred to the outer mitochondrial membrane, which provides a binding target for perforating the mitochondrial membrane by the N-terminal end of GSDMD.
At present, no literature report on the aspect of detecting or preventing and treating endotoxemia related heart dysfunction by taking mitochondrial oxidized cardiolipin as a target point exists at home and abroad.
Disclosure of Invention
Based on this, the present invention proposes that the activated N-terminus of GSDMD with membrane-piercing activity binds to oxidized cardiolipin on the outer mitochondrial membrane, which is a key mechanism for initiating early endotoxemia-associated myocardial injury pathological processes.
Based on this, it is an object of the present invention to provide the use of mitochondrial oxidized cardiolipin as a target in the screening of a preparation for the prevention of endotoxemia-associated cardiac dysfunction.
In some embodiments, the preparation prevents endotoxemia-associated cardiac dysfunction by inhibiting mitochondrial cardiolipin oxidation, mitochondrial membrane pore formation, and/or contact of the GSDMD N-terminus with mitochondrial cardiolipin.
In some preferred embodiments, the article of manufacture includes, but is not limited to, a pharmaceutical or biochemical agent. When the product is a medicament, the medicament can contain one or more pharmaceutically acceptable carriers; and, the medicament can be further prepared into corresponding pharmaceutical preparations by conventional methods in the pharmaceutical field; and, the medicament may also contain one or more other ingredients having the same or similar activity as the present invention, or having different activities from the present invention, which may enhance the activity described in the various embodiments of the present invention, or, in some cases, adjuvants or other active ingredients may reduce the activity in any of the embodiments of the present invention.
It is a second object of the present invention to provide the use of mitochondrial oxidized cardiolipin as a target in the screening of pharmaceutical products for the treatment of endotoxemia-associated cardiac dysfunction.
In some embodiments, the preparation treats endotoxemia-associated cardiac dysfunction by inhibiting mitochondrial cardiolipin oxidation, mitochondrial membrane pore formation, and/or GSDMD N-terminal contact with mitochondrial cardiolipin.
In some preferred embodiments, the article of manufacture includes, but is not limited to, a pharmaceutical or biochemical agent. When the product is a medicament, the medicament can contain one or more pharmaceutically acceptable carriers; and, the medicament can be further prepared into corresponding pharmaceutical preparations by conventional methods in the pharmaceutical field; and, the medicament may also contain one or more other ingredients having the same or similar activity as the present invention, or having different activities from the present invention, which may enhance the activity described in the various embodiments of the present invention, or, in some cases, adjuvants or other active ingredients may reduce the activity in any of the embodiments of the present invention.
The invention also aims to provide the application of the anti-mitochondrial cardiolipin oxidant XJB-5-131 in preparing products for preventing endotoxemia-related cardiac dysfunction.
In some preferred embodiments, the article of manufacture includes, but is not limited to, a pharmaceutical or biochemical agent. When the product is a medicament, the medicament can contain one or more pharmaceutically acceptable carriers; and, the medicament can be further prepared into corresponding pharmaceutical preparations by conventional methods in the pharmaceutical field; and, the medicament may also contain one or more other ingredients having the same or similar activity as the present invention, or having different activities from the present invention, which may enhance the activity described in the various embodiments of the present invention, or, in some cases, adjuvants or other active ingredients may reduce the activity in any of the embodiments of the present invention.
The fourth object of the invention is to provide the application of the anti-mitochondrial cardiolipin oxidant XJB-5-131 in preparing the products for treating endotoxemia related cardiac dysfunction.
In some preferred embodiments, the article of manufacture includes, but is not limited to, a pharmaceutical or biochemical agent. When the product is a medicament, the medicament can contain one or more pharmaceutically acceptable carriers; and, the medicament can be further prepared into corresponding pharmaceutical preparations by conventional methods in the pharmaceutical field; and, the medicament may also contain one or more other ingredients having the same or similar activity as the present invention, or having different activities from the present invention, which may enhance the activity described in the various embodiments of the present invention, or, in some cases, adjuvants or other active ingredients may reduce the activity in any of the embodiments of the present invention.
The fifth object of the present invention is to provide the use of mitochondrial oxidized cardiolipin as a target in screening of products for the detection of early endotoxemia-associated cardiac dysfunction.
In some preferred embodiments, the article of manufacture includes, but is not limited to, a pharmaceutical or biochemical agent. When the product is a medicament, the medicament can contain one or more pharmaceutically acceptable carriers; and, the medicament can be further prepared into corresponding pharmaceutical preparations by conventional methods in the pharmaceutical field; and, the medicament may also contain one or more other ingredients having the same or similar activity as the present invention, or having different activities from the present invention, which may enhance the activity described in the various embodiments of the present invention, or, in some cases, adjuvants or other active ingredients may reduce the activity in any of the embodiments of the present invention.
It is a sixth object of the present invention to provide a kit, the active ingredients of which can be used in the preparation of a product for detecting mitochondrial oxidized cardiolipin.
In some preferred embodiments, the article of manufacture includes, but is not limited to, a pharmaceutical or biochemical agent. When the product is a medicament, the medicament can contain one or more pharmaceutically acceptable carriers; and, the medicament can be further prepared into corresponding pharmaceutical preparations by conventional methods in the pharmaceutical field; and, the medicament may also contain one or more other ingredients having the same or similar activity as the present invention, or having different activities from the present invention, which may enhance the activity described in the various embodiments of the present invention, or, in some cases, adjuvants or other active ingredients may reduce the activity in any of the embodiments of the present invention.
The application of any of the above embodiments does not include the diagnosis and treatment method of the disease.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers a target point-mitochondrial oxidized cardiolipin with potential diagnosis, prevention and/or treatment of endotoxemia-related cardiac dysfunction through research. Aiming at the research process related to the endotoxemia related cardiac dysfunction, the invention discovers that mitochondrial oxidized cardiolipin can be used as a biomarker for diagnosing early endotoxemia related cardiac dysfunction, preventing and treating occurrence and development of endotoxemia related cardiac dysfunction in advance and improving survival rate. And mitochondrial cardiolipin oxidation, mitochondrial membrane pore formation and/or contact of GSDMDN-terminal and mitochondrial cardiolipin can be inhibited by medicaments, and endotoxemia-related cardiac dysfunction can be effectively prevented and treated.
Drawings
FIG. 1 is a typical mass spectrum of mouse myocardial mitochondrial oxidized cardiolipin after LPS early-dry;
FIG. 2 is a typical mass spectrum of the specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on myocardial mitochondrial oxidized cardiolipin of mice after LPS early-stage drying;
FIG. 3 is the effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on heart function in endotoxemia-associated heart dysfunction mice;
FIG. 4 is the effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on myocardial cell necrosis in endotoxemia-associated heart dysfunction mice;
FIG. 5 is the effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on myocardial mitochondrial membrane pore formation in early endotoxemia-associated heart dysfunction mice;
FIG. 6 is the effect of specific kang mitochondrial cardiolipin oxidant XJB-5-131 on myocardial mitochondrial GSDMD-N oligomer in early endotoxemia-associated cardiac dysfunction mice;
FIG. 7 is the effect of XJB-5-131 on survival of mice with endotoxemia-associated cardiac dysfunction.
Detailed Description
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The invention may be embodied in many other forms than described herein and similarly modified by those skilled in the art without departing from the spirit or scope of the invention, which is therefore not limited to the specific embodiments disclosed below.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
EXAMPLE 1 mitochondrial oxidized cardiolipin levels elevated in myocardial tissue of early endotoxemia-associated heart dysfunction mice
The experiment constructs an endotoxemia-related myocardial dysfunction model on (Wild-type, WT) C57BL/6 (8-10 weeks, 22-27 g) mice, specifically:
abdominal injection was performed by first administering 1mg/kg ploy (I: C) (Invivogen, cat# tlrl-picw) for 7 hours, then adding 10mg/kg Escherichia coli LPS (O128: B12) (sigma, cat# L2880), after 4 hours of intervention, killing the mice by chloral anesthesia, rapidly taking out myocardial tissue, performing mitochondrial extraction of cardiac tissue using Abcam (#ab 110168) mitochondrial extraction kit, and detecting the level of mitochondrial oxidized cardiolipin by ultra high performance liquid chromatography-high resolution tandem mass spectrometry (UHPL-HRMS/MS). The detection results are shown in Table 1 and FIG. 1.
From table 1 and fig. 1, it can be seen that mitochondrial oxidized cardiolipin (oxidized cardiolipin, oxCL) levels and subtypes were significantly elevated in early endotoxemia-associated cardiac dysfunction.
TABLE 1 Change of cardiolipin levels in mouse myocardium mitochondrial Oxidation following LPS interference
* Compared with the Control group: 0.01<P<0.05； ** Compared with the Control group: p (P)<0.01；
EXAMPLE 2 specific anti-mitochondrial cardiolipin Oxidation Agents inhibit myocardial mitochondrial oxidized cardiolipin levels in early endotoxemia-associated cardiac dysfunction mice
This experiment was performed on WT C57BL/6 (22-27 g for 8-10 weeks) mice, 10mg/kg XJB-5-131 (sigma Co., cat# SML 2982) was intraperitoneally injected with a specific anti-mitochondrial cardiolipin oxidant, the control group was pretreated with the same dose of PBS for 1 hour, followed by 1mg/kg ploy (I: C) (Invivogen Co., cat# tlrl-picw) for 7 hours, 10mg/kg Escherichia coli (O128: B12) LPS (sigma Co., cat# L2880) for 7 hours, the mice were sacrificed after 4 hours of intervention, myocardial tissue was rapidly removed by anesthesia with chloral hydrate, and mitochondrial extraction was performed using the Abcam (# 110168) mitochondrial extraction kit, and mitochondrial cardiolipin levels were detected by PL-HRMS/MS. The detection results are shown in Table 2 and FIG. 2.
From Table 2 and FIG. 2, it is shown that the specific anti-mitochondrial cardiolipin oxidant XJB-5-131 can significantly inhibit the myocardial mitochondrial oxidized cardiolipin and its subtype levels in mice with early endotoxemia-associated cardiac dysfunction.
TABLE 2 Effect of specific anti-mitochondrial cardiolipin Oxidation Agents XJB-5-131 on mouse myocardial mitochondrial oxidized cardiolipin levels for early endotoxemia-associated cardiac dysfunction
# Compared with the LPS 4h group: 0.01<P<0.05; # # compared to LPS 4h group: p (P)<0.01；
EXAMPLE 3 Effect of specific anti-mitochondrial cardiolipin Oxidation Agents on improving cardiac function in mice with endotoxemia-associated cardiac dysfunction
In this experiment, 10mg/kg XJB-5-131 (sigma Co., cat# SML 2982) was intraperitoneally injected with a specific anti-mitochondrial cardiolipin oxidant on WT C57BL/6 (22-27 g) mice, and the control group was pretreated with PBS at the same dose for 1 hour, followed by 1mg/kg ploy (I: C) (Invivogen Co., cat# tlrl-picw) for 7 hours, followed by 10mg/kg Escherichia coli (O128: B12) LPS (sigma Co., cat# L2880) for 7 hours, and after 4 and 14 hours of intervention, a mouse heart ultrasound examination was performed using a Vevo770 ultrasound imaging system from Visual Sonic, university of China, with an ultrasound probe RMV707B at a frequency of 23MHz-30MHz and a detection depth of 10-15mm. The mice were given 2-3% isoflurane inhalation anesthesia and were supine fixed on a 37 ℃ constant temperature heating plate and subjected to ultrasound testing after dehairing of the chest depilatory. The probe is placed in front of the left chest side of the mouse, 2D ultrasound is used for showing the short axis surface of the left chamber, M-mode ultrasound is used for recording the movement condition of the left chamber at the papillary muscle level, and the Heart Rate (HR), the inner diameter of the left chamber at the end of systole (LVESD), the inner diameter of the left chamber at the end of diastole (LVEDD), the thickness of the front wall of the left chamber (systolic/diastolic) (LVAWD/S) and the thickness of the rear wall of the left chamber (systolic/diastolic) (LVPWD/S) of the mouse are measured; and the short axis shortening (FS%) and ejection fraction (EF%) were calculated, and the test results are shown in table 3 and fig. 3.
As shown in table 3 and fig. 3, the XJB-5-131 pretreated mice had improved cardiac function compared to PBS control pretreated mice after 4 hours and 14 hours of LPS administration, and it was seen that specific anti-mitochondrial cardiolipin oxidation significantly improved cardiac function and inhibited development in mice with early endotoxemia-associated cardiomyopathy.
TABLE 3 Effect of specific anti-mitochondrial cardiolipin Oxidation Agents XJB-5-131 on cardiac function in endotoxemia-associated cardiac dysfunction mice
* Compared with the Control group: 0.01<P<0.05； ** Compared with the Control group: p (P)<0.01；
# Compared with the LPS 4h group: 0.01<P<0.05； ## Compared with the LPS 4h group: p (P)<0.01；
+ Compared with the LPS 14h group: 0.01<P<0.05； ++ Compared with the LPS 14h group: p (P)<0.01。
Example 4 Effect of specific anti-mitochondrial cardiolipin Oxidation agent XJB-5-131 on improving myocardial necrosis in endotoxemia-associated cardiac dysfunction mice
In this experiment, 10mg/kg XJB-5-131 (sigma, cat# SML 2982) was intraperitoneally injected with a specific anti-mitochondrial cardiolipin oxidant on WT C57BL/6 (22-27 g) mice, the control group was pretreated with the same dose of PBS for 1 hour, followed by 1mg/kg ploy (I: C) (Invivogen, cat# tlrl-picw) for 7 hours, 10mg/kg Escherichia coli (O128: B12) LPS (sigma, cat# L2880) for 7 hours, the mice were sacrificed with chloral hydrate for 4 and 14 hours, respectively, myocardial tissue was rapidly removed, the apical tissue was isolated, fixed overnight in 4% paraformaldehyde, dehydrated, embedded, and sliced. Terminal deoxynucleotidyl transferase-mediated dUTP-biological nucleic-end labeling (TUNEL) -red and cardiomyocytes (alpha-actin) -green immunofluorescence were co-stained, respectively, in heart tissue sections to determine myocardial cell death and injury severity. The test results are shown in Table 4 and FIG. 4.
As shown in Table 4 and FIG. 4, after 14 hours of LPS intervention, cardiomyocytes (alpha-actin) co-stained with TUNEL-red began to significantly increase, and the XJB-5-131 pretreated mouse myocardium significantly decreased compared to TUNEL-positive cardiomyocytes in PBS treated mouse myocardium, demonstrating that specific anti-mitochondrial cardiolipin oxidation significantly reduced the death of cardiomyocytes in endotoxemia-associated cardiomyodysfunctional mice.
TABLE 4 Effect of specific anti-mitochondrial cardiolipin Oxidation Agents XJB-5-131 on myocardial cell necrosis in endotoxemia-associated cardiac dysfunction mice
* Compared with the Control group: 0.01<P<0.05； ** Compared with the Control group: p (P)<0.01；
# Compared with the LPS 4h group: 0.01<P<0.05； ## Compared with the LPS 4h group: p (P)<0.01；
+ Compared with the LPS 14h group: 0.01<P<0.05； ++ Compared with the LPS 14h group: p (P)<0.01。
EXAMPLE 5 Effect of specific anti-mitochondrial cardiolipin Oxidation Agents on improving myocardial mitochondrial Membrane pore formation in mice with early endotoxemia-associated cardiac dysfunction
In this experiment, 10mg/kg XJB-5-131 (sigma Co., cat# SML 2982) was intraperitoneally injected with a specific anti-mitochondrial cardiolipin oxidant on WT C57BL/6 (22-27 g) mice for 8-10 weeks, the control group was pretreated with the same dose of PBS for 1 hour, followed by 1mg/kg ploy (I: C) (Invivogen Co., cat# tlrl-picw) for 7 hours, 10mg/kg Escherichia coli (O128: B12) LPS (sigma Co., cat# L2880) for 7 hours, and after intervention for 4 hours, the mice were sacrificed with chloral hydrate, myocardial tissue was rapidly removed, and photographed using a Nanno university ultramicrotransmission electron microscope to observe morphological changes such as myocardial mitochondrial swelling, membrane rupture, ridge change and mitochondrial shrinkage of each group. The test results are shown in Table 5 and FIG. 5.
As shown in table 5 and fig. 5, after 4 hours of LPS intervention, WT mice exhibited mitochondrial oedema of myocardium with a mitochondrial membrane pore diameter of 10-21nm (as indicated by the arrow), whereas after XJB-5-131 pretreatment, the mitochondrial membrane pore was significantly reduced, indicating that specific anti-mitochondrial cardiolipin oxidation significantly reduced myocardial mitochondrial oedema in mice with endotoxemia-associated myocardial dysfunction and reduced mitochondrial membrane pore formation.
TABLE 5 Effect of specific anti-mitochondrial cardiolipin Oxidation Agents XJB-5-131 on myocardial mitochondrial Membrane pore formation in mice with early endotoxemia-associated cardiac dysfunction
* Compared with the Control group: 0.01<P<0.05； ** Compared with the Control group: p (P)<0.01；
# Compared with the LPS 4h group: 0.01<P<0.05； ## Compared with the LPS 4h group: p (P)<0.01。
EXAMPLE 6 Effect of specific anti-mitochondrial cardiolipin Oxidation on inhibition of myocardial mitochondrial GSDMD-N oligomer formation in endotoxemia-associated cardiac dysfunction mice
In this experiment, 10mg/kg XJB-5-131 (sigma, cat# SML 2982) was intraperitoneally injected with a specific anti-mitochondrial cardiolipin oxidant on WT C57BL/6 (22-27 g) mice, the control group was pretreated with the same dose of PBS for 1 hour, followed by 1mg/kg ploy (I: C) (Invivogen, cat# tlrl-picw) for 7 hours, 10mg/kg Escherichia coli (O128: B12) LPS (sigma, cat# L2880) for 7 hours, and after 4 hours of intervention, the mice were sacrificed by anesthesia with chloral hydrate, myocardial tissue was rapidly removed, and myocardial tissue was rapidly removed using the Abcam (# ab 110168) mitochondrial extraction kit for mitochondrial extraction of cardiac tissue. Weighing 1-2mg of myocardial tissue, washing with 1.5ml of WashBuffer for 2 times, grinding myocardial tissue on ice, adding 2. 2ml Isolation Buffer, transferring the sample into a centrifuge tube, adding 2.0ml Isolation Buffer, centrifuging at 4deg.C for 10min, retaining supernatant, discarding precipitate, transferring the supernatant into two new centrifuge tubes, adding Isolation Buffer to 2.0ml each, centrifuging at 12000g for 15min at 4deg.C, collecting precipitate as mitochondria, and collecting supernatant as cytoplasm; washing with an IsolationBuffer containing PMSF protein inhibitor (1:100), centrifuging at 12000g at 4deg.C for 15min, washing for 2 times, precipitating to mitochondria, and discarding supernatant. The pellet mitochondria were lysed on ice with 1 Xnaive buffer+1% DDM+1% PMSF protein inhibitor for 15min, centrifuged at 20000g at 4deg.C for 30min, the pellet was discarded and the supernatant was split and the mitochondrial GSDMD-N oligomer formation was determined for each group by BN-PAGE. The test results are shown in Table 6 and FIG. 6.
As shown in table 6, fig. 6, WT type mice myocardial mitochondrial GSDMD-N Oligomer (GSDMD-N Oligomer) increased significantly after 4 hours of LPS intervention, whereas XJB-5-131 pretreated mice had significantly reduced myocardial mitochondrial GSDMD-N Oligomer, demonstrating that specific anti-mitochondrial cardiolipin oxidation significantly inhibited myocardial mitochondrial GSDMD-N Oligomer formation in endotoxemia-associated myocardial dysfunction mice.
TABLE 6 Effect of specific anti-mitochondrial cardiolipin Oxidation Agents XJB-5-131 on myocardial mitochondrial GSDMD-N oligomer in endotoxemia-associated cardiac dysfunction mice
* Compared with the Control group: 0.01<P<0.05； ** Compared with the Control group: p (P)<0.01；
# Compared with the LPS 4h group: 0.01<P<0.05； ## Compared with the LPS 4h group: p (P)<0.01；
Example 7 Effect of specific anti-mitochondrial cardiolipin Oxidation agent XJB-5-131 on survival of endotoxemia-associated cardiac dysfunction mice
This experiment was performed on WT C57BL/6 (8-10 weeks, 22-27 g) mice, and 10mg/kg XJB-5-131 (sigma Co., ltd., cat# SML 2982) was intraperitoneally injected with a specific Kangchortsin oxidant, and the control group was pretreated with the same dose of PBS for 1 hour, followed by 1mg/kg ploy (I: C) (Invivogen Co., ltd., cat# tlrl-picw) for 7 hours, followed by 10mg/kg Escherichia coli (O128: B12) LPS (sigma Co., ltd., cat# L2880), and then observed for 7 days continuously, and the survival rates of the mice in each group were observed, and the results are shown in Table 7 and FIG. 7.
As shown in table 7 and fig. 7, specific anti-mitochondrial cardiolipin oxidation significantly prolonged survival in mice with endotoxemia-associated myocardial dysfunction.
TABLE 7 Effect of specific anti-mitochondrial cardiolipin Oxidation agent XJB-5-131 on survival of endotoxemia-associated cardiac dysfunction mice
* Compared with the Control group: 0.01<P<0.05； ** Compared with the Control group: p (P)<0.01；
# Compared with the LPS 4h group: 0.01<P<0.05； ## Compared with the LPS 4h group: p (P)<0.01。
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (2)
1. Application of anti-mitochondrial cardiolipin oxidant XJB-5-131 in preparing medicine for preventing endotoxemia heart dysfunction.
2. Application of anti-mitochondrial cardiolipin oxidant XJB-5-131 in preparing medicine for treating endotoxemia heart dysfunction.
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