CN115814087A - Application of mitochondrial oxidized cardiolipin as target in screening products for preventing and treating endotoxemia-related cardiac dysfunction - Google Patents
Application of mitochondrial oxidized cardiolipin as target in screening products for preventing and treating endotoxemia-related cardiac dysfunction Download PDFInfo
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Abstract
The invention provides application of mitochondrial oxidized cardiolipin as a target point in screening products for diagnosing, preventing and/or treating endotoxemia-related cardiac dysfunction, and the inventor discovers that the level of oxidized cardiolipin in animal cardiac mitochondria with endotoxemia-related cardiac dysfunction is increased by constructing a mouse model of endotoxemia-related cardiac dysfunction, and performs experiments by utilizing an internationally recognized anti-mitochondrial cardiolipin oxidant XJB-5-131 to prove that the mitochondrial oxidized cardiolipin can improve the endotoxemia-related cardiac dysfunction at the early stage, inhibit the occurrence and development of the endotoxemia-related cardiac dysfunction and improve the survival rate. The invention provides a product for screening, diagnosing, preventing and/or treating the heart dysfunction related to the endotoxemia by taking the mitochondrial oxidized cardiolipin as a target point, and provides a new idea for diagnosing, preventing and/or treating the heart dysfunction related to the endotoxemia.
Description
Technical Field
The invention relates to the technical field of pharmacology, in particular to application of mitochondrial oxidized cardiolipin serving as a target point in screening products for preventing and treating endotoxemia-related cardiac dysfunction.
Background
Sepsis and endotoxemia are multiple organ dysfunctions which are caused by maladjustment of body response to infection and endanger life, are one of global public health problems focused in recent years, have the characteristics of high mortality, poor prognosis and low quality of life, and have the fatality rate of 30-70%. In 2017, the WHO listed sepsis and endotoxemia as global health preferred items to better improve the prevention, diagnosis and management thereof. While cardiac dysfunction is one of the most common complications of endotoxemia, about 50% of patients with endotoxemia have combined cardiac dysfunction, which is a significant cause of initiating multiple organ failure and leading to death. The mortality rate of patients with endotoxemia-associated myocardial dysfunction (EIMD) is found to be approximately 70-90%, which is much higher than that of patients with endotoxemia with uncomplexed cardiac dysfunction (mortality rate is 20%).
In recent years, it has been found that myocardial dysfunction can occur in the early stages of endotoxemia (i.e., when there is no significant change in the hemodynamics of the circulation), and that this is closely related to prognosis. The theory of myocardial depressant factors is thought to be an early key mechanism involved in EIMD, but a number of previous prospective clinical studies associated with macrotoxicosis have shown that administration of treatment regimens that either inhibit or neutralize inflammatory cytokines to patients fail to improve their clinical prognosis. In addition, toll-like receptor4 (TLR 4) was identified as an endotoxin Lipopolysaccharide (LPS) membrane receptor in the last 90 s, and LPS induces transcription of cytokines and inflammatory factors after binding to TLR4, but LPS-induced shock and death cannot be completely improved by blocking the interaction between TLR4 and LPS. Therefore, the search for a new therapeutic target for early and effective improvement of myocardial dysfunction associated with endotoxemia and improvement of survival rate is imminent.
However, the mechanism of how endotoxemia directly leads to early myocardial function impairment is not clear, and thus there are few relevant intervention targets and drugs.
The pathophysiological mechanisms of endotoxemia-associated myocardial dysfunction are complex, including extracellular and intracellular mechanisms, wherein extracellular mechanisms include myocardial inhibitory factors, microvascular changes, endothelial dysfunction, and intracellular mechanisms include calcium regulation disorders, autophagy of the heart, and mitochondrial dysfunction. In recent years, mitochondrial dysfunction is considered as an early key pathophysiological mechanism of EIMD, and causes of myocardial mitochondrial dysfunction are many, including mitochondrial structural abnormality, oxidative stress, mitochondrial permeability change, mitochondrial uncoupling, mitochondrial quality control system and the like, and it is found that mitochondrial oxidative stress may be a key promoter.
The cell perforating protein GSDMD is used as a key molecule for mediating cell apoptosis, releases GSDMD-N terminal with cell perforating activity after inflammatory caspase-1 and caspase-11 (caspase-4 in human) are sheared, can be combined with special phospholipid on a membrane, and is oligomerized to play a perforating role, so that a cell structure is damaged, and inflammatory cytokines (such as IL-1 beta, IL-18, leukotriene and the like) are released.
In the body, 15% of Cardiolipin is located in cardiac muscle, and Cardiolipin (Cardiolipin) is widely distributed on bacterial membranes and inner membranes of eukaryotic mitochondria as a specific binding substrate at the N-terminal end of GSDMD-N, is asymmetrically distributed on the mitochondrial membranes, and plays an important role in maintaining normal physiological functions and morphology of the mitochondria. Under non-stress state, the N-terminal of GSDMD is not in direct contact with cardiolipin, and under the inflammation and infection state of a body, the ROS generation in mitochondria is increased, and the cardiolipin can be oxidized and transferred to the outer membrane of the mitochondria, thereby providing a binding target point for perforating the N-terminal of GSDMD on the mitochondrial membrane.
At present, no literature report on the aspect of detecting or preventing and treating endotoxemia-related cardiac dysfunction by taking mitochondrial oxidized cardiolipin as a target point exists at home and abroad.
Disclosure of Invention
Based on the above, the invention provides that the N-terminal of the activated GSDMD with membrane perforation activity is combined with oxidized cardiolipin on the outer mitochondrial membrane, and the perforation on the mitochondrial membrane is a key mechanism for starting the pathological process of early-stage endotoxemia-related myocardial damage.
Based on this, it is an object of the present invention to provide the use of mitochondrial oxidized cardiolipin as a target for screening for preparations for preventing endotoxemia-associated cardiac dysfunction.
In some embodiments, the article of manufacture prevents endotoxemia-related 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; the medicine 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 components having the same or similar activity as the present invention, or different activity from the present invention, which may enhance the activity described in the above embodiments of the present invention, or, in some cases, an adjuvant or other active ingredient may reduce the activity in any of the above embodiments of the present invention.
The invention also aims to provide application of the mitochondrial oxidized cardiolipin as a target in screening a medicinal product for treating endotoxemia-related cardiac dysfunction.
In some embodiments, the article of manufacture treats endotoxemia-related 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; the medicine 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 components having the same or similar activity as the present invention, or different activity from the present invention, which may enhance the activity described in the above embodiments of the present invention, or, in some cases, an adjuvant or other active ingredient may reduce the activity in any of the above embodiments of the present invention.
The invention also aims to provide application of the mitochondrial cardiolipin antioxidant XJB-5-131 in preparation of a product for preventing cardiodysfunction related to endotoxemia.
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; the medicine 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 components having the same or similar activity as the present invention, or different activity from the present invention, which may enhance the activity described in the above embodiments of the present invention, or, in some cases, an adjuvant or other active ingredient may reduce the activity in any of the above embodiments of the present invention.
The fourth purpose of the invention is to provide the application of the mitochondrial cardiolipin antioxidant XJB-5-131 in preparing 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; the medicine 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 components with the same or similar activity as the present invention, or with different activity from the present invention, which may enhance the activity as described in the above embodiments of the present invention, or, in some cases, an adjuvant or other active ingredient may reduce the activity in any of the above embodiments of the present invention.
The fifth purpose of the invention is to provide the application of the mitochondrial oxidized cardiolipin as a target point in screening products for detecting early 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; the medicine 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 components having the same or similar activity as the present invention, or different activity from the present invention, which may enhance the activity described in the above embodiments of the present invention, or, in some cases, an adjuvant or other active ingredient may reduce the activity in any of the above embodiments of the present invention.
It is a further object of the present invention to provide a kit, the active ingredients of which can be used to detect preparations of 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; the medicine 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 components having the same or similar activity as the present invention, or different activity from the present invention, which may enhance the activity described in the above embodiments of the present invention, or, in some cases, an adjuvant or other active ingredient may reduce the activity in any of the above embodiments of the present invention.
The applications in any of the above embodiments do not include methods for diagnosing and treating diseases.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers a target point, namely 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 heart dysfunction related to the endotoxemia, the invention discovers that the mitochondrial oxidized cardiolipin can be used as a biomarker for diagnosing the heart dysfunction related to the early endotoxemia, preventing and treating the occurrence and development of the heart dysfunction related to the endotoxemia in advance and improving the survival rate. The mitochondrial cardiolipin oxidation, mitochondrial membrane pore formation and/or GSDMDN-end contact with the mitochondrial cardiolipin can be inhibited by drugs, so that the endotoxemia-related cardiac dysfunction can be effectively prevented and treated, products which take the mitochondrial oxidized cardiolipin as a target point and are used for screening, diagnosing, preventing and/or treating endotoxemia-related cardiac dysfunction are provided, a new thought is provided for realizing the diagnosis, prevention and/or treatment of early endotoxemia-related cardiac dysfunction, and therefore, the endotoxemia-related cardiac dysfunction can be effectively prevented and/or treated.
Drawings
FIG. 1 is a typical mass spectrum of oxidized cardiolipin of mitochondria in mouse myocardium after LPS early stage dry prognosis;
FIG. 2 is a typical mass spectrum of mouse myocardial mitochondrion oxidized cardiolipin after early intervention of LPS by specific anti-mitochondrial cardiolipin oxidizing agent XJB-5-131;
FIG. 3 is a graph showing the effect of specific anti-mitochondrial cardiolipin oxidizing agent XJB-5-131 on the cardiac function of mice with endotoxemia-associated cardiac dysfunction;
FIG. 4 is a graph showing the effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on myocardial cell necrosis in mice with endotoxemia-associated cardiac dysfunction;
FIG. 5 is a graph showing the effect of specific anti-mitochondrial cardiolipin oxidizing agent XJB-5-131 on myocardial mitochondrial membrane pore formation in early endotoxemia-associated cardiac dysfunction mice;
FIG. 6 is a graph of the effect of specific Kangmitochondrial cardiolipin oxidant XJB-5-131 on myocardial mitochondrial GSDMDM-N oligomers in early endotoxemia associated cardiac dysfunction mice;
FIG. 7 is a graph showing the effect of XJB-5-131 on the survival rate of mice with heart dysfunction associated with endotoxemia.
Detailed Description
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather should be construed as broadly as the present invention is capable of modification in various respects, all without departing from the spirit and scope of the present invention.
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 in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Example 1 increased levels of mitochondrial oxidized cardiolipin in myocardial tissue in mice with early endotoxemia-associated cardiac dysfunction
In the experiment, an endotoxemia related myocardial dysfunction model is constructed on (Wild-type, WT) C57BL/6 (8-10 weeks, 22-27 g) mice, and specifically comprises the following steps:
intraperitoneal injection, 1mg/kg of ploy (I: C) (Invivogen company, cat # tlrl-picw) is given for pretreatment for 7 hours, then 10mg/kg of Escherichia coli LPS (O128: B12) (sigma company, cat # L2880) is added, after 4 hours of intervention, mice are killed under chloral hydrate anesthesia, myocardial tissues are rapidly taken out, an Abcam (# ab 110168) mitochondria extraction kit is adopted for carrying out extraction of cardiac tissue mitochondria, and the level of mitochondrial oxidized cardiolipin is detected by ultra high performance liquid chromatography-high resolution tandem mass spectrometry (UHPL-HRMS/MS). The results are detailed in table 1 and fig. 1.
As shown in table 1 and fig. 1, the levels of mitochondrial oxidized cardiolipin (oxCL) and each subtype were significantly increased in early endotoxemia-associated cardiac dysfunction.
TABLE 1 Change in mouse myocardial mitochondrial oxidized cardiolipin levels following LPS intervention
* Compared to the Control group: 0.01<P<0.05； ** Compared to the Control group: p<0.01；
Example 2 specific anti-mitochondrial cardiolipin oxidizing agent inhibition of myocardial mitochondrial oxidized cardiolipin levels in mice with early endotoxemia-associated cardiac dysfunction
In the experiment, WT C57BL/6 (22-27 g at 8-10 weeks) mice were subjected to intraperitoneal injection of 10mg/kg XJB-5-131 (Sigma, cat # SML 2982) by using a specific anti-mitochondrial cardiolipin oxidizing agent, control groups were pretreated with PBS at the same dose for 1 hour, 1mg/kg ploy (I: C) (Invivogen, cat # tlrl-picw) was administered for 7 hours, 10mg/kg Escherichia coli (O128: B12) LPS (sigma, cat # L2880) was administered after 7 hours, the mice were sacrificed by chloral hydrate anesthesia after 4 hours of intervention, myocardial tissues were rapidly removed, mitochondrial extraction was performed by using Abcam (# 110168) mitochondrial extraction kit, and the level of mitochondrial oxidized cardiolipin was detected by PL-HRMS/MS. The results are detailed in table 2 and fig. 2.
As shown in Table 2 and FIG. 2, the specific anti-mitochondrial cardiolipin oxidant XJB-5-131 can obviously inhibit the level of myocardial mitochondrial oxidized cardiolipin and its subtypes in mice with early-stage endotoxemia-related cardiac dysfunction.
TABLE 2 Effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on myocardial mitochondrial oxidized cardiolipin levels in mice with early endotoxemia associated cardiac dysfunction
# Compared to LPS 4h group: 0.01<P<0.05; # compared to LPS 4h group：P<0.01；
Example 3 Effect of specific anti-mitochondrial cardiolipin oxidizing Agents on improving Heart function in mice with endotoxemia-associated Heart dysfunction
In this experiment, WT C57BL/6 (22-27 g at 8-10 weeks) mice were treated with specific anti-mitochondrial cardiolipin oxidizing agent by intraperitoneal injection of 10mg/kg XJB-5-131 (Sigma, cat # SML 2982), the control group was pretreated with PBS at the same dose for 1 hour, 1mg/kg ploy (I: C) (Invivogen, cat # tlrl-picw) for 7 hours, and 10mg/kg Escherichia coli (O128: B12) LPS (sigma # L2880) after 7 hours, and after 4 and 14 hours of intervention, the mice were subjected to cardiac ultrasonography using a Vevo770 ultrasonography system from Visual Sonic, university of Central and south China, with an ultrasonic probe RMV707B at a frequency of 23MHz-30MHz and a depth probe of 10-15mm. Mice were placed supine under inhalation anesthesia with 2-3% isoflurane on a 37 ℃ constant temperature heating plate, and ultrasonic testing was performed after the precordial depilatory had depilated. Placing the probe in the chest of the left chest side of a mouse, performing 2D ultrasound to show a left ventricle short axis section, performing M-mode ultrasound recording on the motion condition of the left ventricle at the papillary muscle level, and measuring the Heart Rate (HR), the left ventricle end systolic internal diameter (LVESD), the left ventricle end diastolic internal diameter (LVEDD), the left ventricle anterior wall thickness (contraction/relaxation) (LVAWD/S) and the left ventricle posterior wall thickness (contraction/relaxation) (LVPWD/S) of the mouse; the short axis shortening rate (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, after 4 hours and 14 hours of LPS administration, the heart function of mice pretreated by XJB-5-131 was improved compared with that of mice pretreated by PBS control, and it can be seen that specific anti-mitochondrial cardiolipin oxidation can significantly improve the heart function of mice with cardiomyopathy related to early endotoxemia and inhibit the development of cardiomyopathy related to early endotoxemia.
TABLE 3 Effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on Heart function in mice with endotoxemia-related cardiac dysfunction
* With Control groupThe ratio is as follows: 0.01<P<0.05； ** Compared to the Control group: p<0.01；
# Compared to LPS 4h group: 0.01<P<0.05； ## Compared to LPS 4h group: p<0.01；
+ Compared to LPS 14h group: 0.01<P<0.05； ++ Compared to LPS 14h group: p<0.01。
Example 4 Effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on ameliorating myocardial necrosis in mice with endotoxemia-associated cardiac dysfunction
In this experiment, WT C57BL/6 (22-27 g at 8-10 weeks) mice were treated with specific anti-mitochondrial cardiolipin oxidizing agent by intraperitoneal injection of 10mg/kg XJB-5-131 (Sigma, cat # SML 2982), the control group was pretreated with PBS at the same dose for 1 hour, 1mg/kg ploy (I: C) (Invivogen, cat # tlrl-pic w) for 7 hours, and 10mg/kg Escherichia coli (O128: B12) LPS (sigma, cat # L2880) after 7 hours, the mice were sacrificed by anesthesia with chloral hydrate for 4 and 14 hours, the myocardial tissues were rapidly removed, the apical tissues were isolated, fixed in 4% paraformaldehyde overnight, dehydrated, embedded, and sectioned. Taking heart tissue slices, respectively carrying out immunofluorescence co-staining on terminal deoxyluteotidyl transferase-mediated dUTP-biotin-end labeling (TUNEL) -red and myocardial cells (alpha-actin) -green, and determining the death degree and the damage severity degree of the myocardial cells. The test results are detailed in table 4 and fig. 4.
As shown in Table 4 and FIG. 4, after 14 hours of LPS intervention, the number of cardiomyocytes (alpha-actin) co-infected with TUNEL-red cells began to increase significantly, and the number of myocardium in mice pretreated with XJB-5-131 was significantly reduced compared to that of TUNEL-positive cardiomyocytes in the myocardium of mice treated with PBS, indicating that specific anti-mitochondrial cardiolipin oxidation significantly reduced the cardiomyocyte death in mice with endotoxemia-related myocardial dysfunction.
TABLE 4 Effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on myocardial cell necrosis in mice with endotoxemia-associated cardiac dysfunction
* Compared to the Control group: 0.01<P<0.05； ** Compared to the Control group: p<0.01；
# Compared to LPS 4h group: 0.01<P<0.05； ## Compared to LPS 4h group: p<0.01；
+ Compared to LPS 14h group: 0.01<P<0.05； ++ Compared to LPS 14h group: p<0.01。
Example 5 Effect of specific anti-mitochondrial cardiolipin oxidizing Agents on improving myocardial mitochondrial Membrane pore formation in early endotoxemia-associated Heart dysfunction mice
In the experiment, 10mg/kg XJB-5-131 (Sigma, product number SML 2982) is intraperitoneally injected into WT C57BL/6 (22-27 g at 8-10 weeks) mice by using a specific anti-mitochondrial cardiolipin oxidizing agent, a control group is pretreated for 1 hour by using PBS with the same dosage, 1mg/kg ploy (I: C) (Invivogen, product number tlrl-pic w) is then administered for 7 hours, 10mg/kg Escherichia coli (O128: B12) LPS (Sigma, product number L2880) is then administered after 7 hours, the mice are killed by chloral hydrate anesthesia after 4 hours of intervention, myocardial tissues are rapidly taken out, and morphology changes such as myocardial mitochondrial swelling, membrane rupture, mitochondrial cristae change, mitochondrial contraction and the like and the formation of membrane pores are observed by using an ultramicro transmission electron microscope of the university of Minam. The test results are detailed in table 5 and fig. 5.
As shown in Table 5 and FIG. 5, the mitochondrial membrane pores of the myocardium in WT mice appeared after 4 hours of LPS intervention and were 10-21nm in diameter (as indicated by the arrows), while the mitochondrial membrane pores of the myocardium were significantly reduced after pretreatment with XJB-5-131, indicating that specific anti-mitochondrial cardiolipin oxidation significantly reduced the myocardial mitochondrial edema and decreased mitochondrial membrane pores in mice with myocardial dysfunction associated with endotoxemia.
TABLE 5 Effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on myocardial mitochondrial membrane pore formation in early endotoxemia associated cardiac dysfunction mice
* Compared to the Control group: 0.01<P<0.05； ** Compared to the Control group: p<0.01；
# Compared to LPS 4h group: 0.01<P<0.05； ## Compared to LPS 4h group: p<0.01。
Example 6 Effect of specific anti-mitochondrial cardiolipin Oxidation on inhibition of myocardial mitochondrial GSDMDM-N oligomer formation in mice with endotoxemia-associated cardiac dysfunction
In this experiment, WT C57BL/6 (22-27 g at 8-10 weeks) mice were subjected to intraperitoneal injection of 10mg/kg XJB-5-131 (Sigma, cat # SML 2982) using a specific anti-mitochondrial cardiolipin oxidizing agent, control groups were pretreated with PBS at the same dose for 1 hour, 1mg/kg ploy (I: C) (Invivogen, cat # tlrl-picw) for 7 hours, 10mg/kg Escherichia coli (O128: B12) LPS (sigma, cat # L2880) was administered after 7 hours, the mice were sacrificed by chloral hydrate anesthesia for 4 hours, myocardial tissues were rapidly removed, and mitochondrial extraction was performed using an Abcam (# ab 110168) mitochondrial extraction kit. Weighing 1-2mg of myocardial tissue, fully washing the myocardial tissue with 1.5ml of WashBuffer for 2 times, grinding the myocardial tissue on ice, adding 2ml of Isolation Buffer, transferring the sample into a centrifuge tube, adding 2.0ml of Isolation Buffer, centrifuging the sample at the temperature of 4 ℃ for 10min at 1000g, keeping supernatant, discarding precipitate, transferring the supernatant into two new centrifuge tubes, adding 2.0ml of Isolation Buffer to each centrifuge tube, centrifuging the centrifuge tube at the temperature of 4 ℃ for 15min at 12000g, collecting the precipitate as mitochondria, and collecting the supernatant as cytoplasm; the cells were washed with IsolationBuffer containing PMSF protein inhibitor (1. Precipitation mitochondria were lysed on ice for 15 minutes with 1 × naive buffer +1% DDM +1% PMSF protein inhibitor, centrifuged at 4 ℃ 20000g for 30min, the precipitate discarded, the supernatant dispensed, and each group of mitochondria GSDMD-N oligomer formation was determined by BN-PAGE. The test results are detailed in table 6 and fig. 6.
As shown in table 6 and fig. 6, after 4 hours of LPS intervention, the WT type mouse myocardial mitochondria GSDMD-N Oligomer (GSDMD-N Oligomer) was significantly increased, while the mouse myocardial mitochondria GSDMD-N Oligomer pretreated with XJB-5-131 was significantly decreased, indicating that specific anti-mitochondrial cardiolipin oxidation significantly inhibited the formation of the myocardial mitochondria GSDMD-N Oligomer in the endotoxemia-associated myocardial dysfunction mouse.
TABLE 6 Effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on myocardial mitochondrial GSDMDM-N oligomers in endotoxemia-associated cardiac dysfunction mice
* Compared to the Control group: 0.01<P<0.05； ** Compared to the Control group: p is<0.01；
# Compared to LPS 4h group: 0.01<P<0.05； ## Compared to LPS 4h group: p<0.01；
Example 7 Effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on survival in mice with endotoxemia-associated cardiac dysfunction
In this experiment, WT C57BL/6 (8-10 weeks, 22-27 g) mice were treated with specific kang mitochondrial cardiolipin oxidant i.p. injection of 10mg/kg XJB-5-131 (Sigma, cat # SML 2982), control groups were pretreated with the same amount of PBS for 1 hour, 1mg/kg ploy (I: C) (Invivogen, cat # tlrl-picw) for 7 hours, and then 10mg/kg Escherichia coli (O128: B12) LPS (sigma, cat # L2880) for 7 hours, and then continuously observed for 7 days to observe the survival rate of each group, as shown in Table 7 and FIG. 7.
As shown in Table 7 and FIG. 7, specific resistance to mitochondrial cardiolipin oxidation significantly prolonged survival in mice with endotoxemia-associated myocardial dysfunction.
TABLE 7 Effect of specific anti-mitochondrial cardiolipin oxidant XJB-5-131 on survival in mice with endotoxemia-associated cardiac dysfunction
* Compared to the Control group: 0.01<P<0.05； ** Compared to the Control group: p<0.01；
# Compared to LPS 4h group: 0.01<P<0.05； ## Compared to LPS 4h group: p<0.01。
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. Use of mitochondrial oxidized cardiolipin as a target for screening a product for treating endotoxemia-associated cardiac dysfunction.
2. The use according to claim 1, wherein the preparation is useful for treating endotoxemia-related cardiac dysfunction by inhibiting mitochondrial cardiolipin oxidation, mitochondrial membrane pore formation and/or GSDMD N-terminal contact with mitochondrial cardiolipin.
3. Application of mitochondrial oxidized cardiolipin as a target in screening products for preventing cardiodysfunction related to endotoxemia.
4. The use according to claim 3, wherein the preparation is useful for preventing endotoxemia-related cardiac dysfunction by inhibiting mitochondrial cardiolipin oxidation, mitochondrial membrane pore formation and/or GSDMDM N-terminal contact with mitochondrial cardiolipin.
5. Application of mitochondrial oxidized cardiolipin as a target in screening products for detecting early endotoxemia-associated cardiac dysfunction.
6. A kit comprising as active ingredients preparations which can be used to detect mitochondrial oxidized cardiolipin.
7. Application of antioxidant XJB-5-131 for resisting mitochondrial cardiolipin in preparing product for preventing endotoxemia and cardiac dysfunction is provided.
8. Application of antioxidant XJB-5-131 for resisting mitochondrial cardiolipin in preparing product for treating endotoxemia and cardiac dysfunction is provided.
9. Application of antioxidant XJB-5-131 for resisting mitochondrial cardiolipin in preventing endotoxemia cardiac dysfunction is provided.
10. Application of anti-mitochondrial oxidant XJB-5-131 in preparation for treating endotoxemia and cardiac dysfunction is provided.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090042808A1 (en) * | 2007-08-08 | 2009-02-12 | Fink Mitchell P | Use of mitochondria-targeted electron scavengers as anti-inflammatory agents |
| US7718603B1 (en) * | 2006-01-06 | 2010-05-18 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Selective targeting agents for mitochondria |
| CN106360723A (en) * | 2016-10-20 | 2017-02-01 | 常州迪纳托生物科技有限公司 | Industrial production method for lycopene microcapsule powder |
| CN106866784A (en) * | 2015-12-11 | 2017-06-20 | 凯瑞康宁生物工程（武汉）有限公司 | Targetted mitochondria antioxidant and its production and use |
| CN107981355A (en) * | 2017-11-28 | 2018-05-04 | 戴凤 | A kind of preparation method of lycopene microcapsule |
| CN114586977A (en) * | 2022-01-26 | 2022-06-07 | 深圳市绿航星际太空科技研究院 | Preparation method of antioxidant lycopene microcapsule for spaceflight |
-
2022
- 2022-09-26 CN CN202211175385.6A patent/CN115814087B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7718603B1 (en) * | 2006-01-06 | 2010-05-18 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Selective targeting agents for mitochondria |
| US20090042808A1 (en) * | 2007-08-08 | 2009-02-12 | Fink Mitchell P | Use of mitochondria-targeted electron scavengers as anti-inflammatory agents |
| CN106866784A (en) * | 2015-12-11 | 2017-06-20 | 凯瑞康宁生物工程（武汉）有限公司 | Targetted mitochondria antioxidant and its production and use |
| CN106360723A (en) * | 2016-10-20 | 2017-02-01 | 常州迪纳托生物科技有限公司 | Industrial production method for lycopene microcapsule powder |
| CN107981355A (en) * | 2017-11-28 | 2018-05-04 | 戴凤 | A kind of preparation method of lycopene microcapsule |
| CN114586977A (en) * | 2022-01-26 | 2022-06-07 | 深圳市绿航星际太空科技研究院 | Preparation method of antioxidant lycopene microcapsule for spaceflight |
Non-Patent Citations (5)
| Title |
|---|
| MIN WAN等: ""Oxidized but not native cardiolipin has pro-inflammatory effects, which are inhibited by Annexin A5"", 《ATHEROSCLEROSIS》, 31 December 2014 (2014-12-31), pages 592 - 598 * |
| SILVIA ALVAREZ等: ""Cardiac dysfunction, mitochondrial architecture, energy production, and inflammatory pathways: Interrelated aspects in endotoxemia andsepsis"", 《THE INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY》, 31 December 2016 (2016-12-31), pages 307 - 314 * |
| 刘涛等: ""线粒体损伤与糖尿病心肌病发病关系的研究进展"", 《中国药理学通报》, 31 December 2018 (2018-12-31), pages 456 - 458 * |
| 刘耕科: ""白藜芦醇对糖尿病大鼠心功能障碍及酸性鞘磷脂酶-神经酰胺通路的影响"", 《中国病理生理杂志》, 31 December 2018 (2018-12-31), pages 1206 - 1213 * |
| 符会妮等: ""脓毒症合并心肌损伤患者的炎症因子与心功能障碍的相关性分析"", 《齐齐哈尔医学院学报》, 31 December 2020 (2020-12-31), pages 2396 - 2398 * |
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