Application of malic acid in preparation of medicine for preventing and treating sepsis

Abstract

The invention discloses application of malic acid in preparation of a medicine for preventing and treating sepsis, and belongs to the technical field of biological medicine. Animal experiments find that after malic acid treatment, inflammation and damage of multiple organs (including but not limited to lung, intestinal tract, heart, liver, spleen, kidney and the like) of the whole body of a sepsis animal model can be remarkably relieved, and the survival rate after malic acid treatment is also remarkably higher than that of a control group. Therefore, the malic acid has a good effect of improving the functions and the death rate of multiple organs of the whole body with sepsis. In addition, the malic acid is a natural product and an endogenous metabolite, so that the malic acid has very high safety when being used as a medicine. In conclusion, the malic acid is used for preparing the medicine for preventing and treating sepsis and has a very good application prospect.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and particularly to the application of malic acid in the preparation of drugs for preventing and treating sepsis. Background Art

[0002] Sepsis refers to a dysregulated systemic inflammatory response syndrome caused by infection, accompanied by severe organ dysfunction, and is a global disease with a high mortality rate. Although good progress has been made in the understanding of sepsis in recent years, to date, the clinical medications for sepsis are still very limited. Currently, the treatment of sepsis mainly relies on antibiotics, immunomodulatory therapy, etc., but there are currently many problems and challenges, such as the antibiotic resistance, the increase in drug-resistant strains making the traditional antibiotics ineffective; the complexity of immunomodulation, resulting in the difficulty of a single immunomodulatory drug to comprehensively regulate, etc. Therefore, there is an urgent need to develop new drugs for effectively preventing and treating sepsis.

[0003] Malic acid is a naturally occurring organic acid, widely distributed in plant, animal and microbial cells. Malic acid is a four-carbon acid, and due to its chiral structure, there are three forms, namely D-malic acid, DL-malic acid and L-malic acid, and it exists in the form of L-malic acid in nature. As an important intermediate of the tricarboxylic acid cycle, malic acid has a variety of biological functions, such as antioxidant stress, improving energy metabolism, improving mitochondrial function, anti-inflammatory, regulating intestinal flora, etc. From the existing research, malic acid has powerful and pleiotropic functions and can improve a variety of acute and chronic diseases, and it has been widely used in many fields closely related to life and health, such as clinical, pharmaceutical engineering, food engineering, bioengineering, etc. However, the effect of malic acid on sepsis has not been reported yet. Summary of the Invention

[0004] The purpose of the present invention is to provide the application of malic acid in the preparation of drugs for preventing and treating sepsis, so as to solve the problems existing in the above-mentioned prior art. Develop new drugs and new treatment strategies for effectively preventing and treating sepsis.

[0005] To achieve the above purpose, the present invention provides the following solutions:

[0006] One of the technical solutions of the present invention is the application of malic acid in the preparation of drugs for preventing and treating sepsis.

[0007] Another technical solution of the present invention is a drug for preventing and treating sepsis, which is prepared from malic acid or a pharmaceutically acceptable salt thereof or a malic acid derivative as an active ingredient, plus a pharmaceutically acceptable excipient or auxiliary ingredient.

[0008] Based on the above technical solutions, the present invention has the following technical effects:

[0009] Through animal experiments, the present invention found that after treatment with malic acid, the inflammation and damage of multiple organs throughout the body (including but not limited to the lungs, intestines, heart, liver, spleen, kidneys, etc.) in a sepsis animal model can be significantly reduced, and the survival rate after treatment with malic acid is also significantly higher than that of the control group. Thus, it can be seen that malic acid has a good improvement effect on the functions of multiple organs throughout the body and the mortality rate in sepsis. In addition, since malic acid is a natural product and an endogenous metabolite, malic acid has high safety when used as a drug. In summary, malic acid has good application prospects for preparing drugs for preventing and treating sepsis. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required to be used in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0011] Figure 1 Experimental results of the changes of malic acid in the disease progression of sepsis patients in Example 1; among them, sepsis patients (n = 34), healthy volunteers (n = 55), the above data are expressed as mean ± standard deviation; the statistical method is one-way analysis of variance; *P < 0.05, **P < 0.01; ns: no significant difference.

[0012] Figure 2 Schematic diagram of the experimental process of Example 2.

[0013] Figure 3Experimental results of the role of malic acid in the disease progression of a sepsis animal model in Example 2; wherein, A is the sepsis score of septic mice at multiple time points (6 h, 12 h, 24 h, 48 h, and 72 h after cecal ligation and puncture (CLP)); B is the mouse pulse oxygen saturation (SpO2); C is the serum malic acid level; D is a typical diagram of the gross specimen of the mouse lung; E is a typical diagram of HE staining of lung tissue and the pathological score of lung injury; F is the protein concentration in bronchoalveolar lavage fluid (BALF); G is the total cell count in BALF; H is a typical diagram of HE staining of colon tissue; I is the pathological score of colon injury; J is the correlation analysis between the serum malic acid level and the time after CLP; K is the correlation analysis between the serum malic acid level and the lung injury score; L is the correlation analysis between the serum malic acid level and the colon injury score; the above data are expressed as mean ± standard deviation; Sham (sham operation group) n = 6 mice / group; CLP disease group n = 10 mice / group; the statistical method is one-way ANOVA; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001; ns: no significant difference; scale bar = 500 μm or 100 μm or 20 μm.

[0014] Figure 4 Experimental results of the effect of malic acid on improving the survival rate of a sepsis animal model in Example 3; wherein, A is the survival analysis after gavage treatment with different doses of malic acid (100 mg / kg, 200 mg / kg, 400 mg / kg of malic acid); B is the survival analysis after gavage treatment with different doses of sodium malate (100 mg / kg, 200 mg / kg, 400 mg / kg of sodium malate); C is the survival analysis of severely septic mice intervened with 200 mg / kg of sodium malate (6 h after surgery, gavage once a day); D is the survival analysis of septic mice induced by LPS (intraperitoneal injection, 10 mk / kg) intervened with 200 mg / kg of sodium malate (6 h after surgery, gavage once a day); Sham (sham operation group) n = 6 mice / group; CLP or LPS intraperitoneal injection disease group n = 15 - 18 mice / group; the statistical method is one-way ANOVA; *P < 0.05, ***P < 0.001, and ****P < 0.0001; ns: no significant difference.

[0015] Figure 5 Schematic diagram of the experimental procedure for Example 4.

[0016] Figure 6Experimental results of the efficacy evaluation of malic acid on a sepsis animal model in Example 4; among them, A shows the effect of supplementing 200 mg / kg of sodium malate on the malic acid level in the circulating blood of sepsis mice; B shows the change in the sepsis score of mice after treatment with 200 mg / kg of sodium malate; C shows the typical HE staining images of multiple organs (lung, colon, heart, liver, spleen, kidney) and the pathological scores of organ damage after treatment with 200 mg / kg of sodium malate; the above data are expressed as mean ± standard deviation; the Sham control group has n = 6 mice / group; the CLP disease group has n = 10 mice / group; the statistical method is two-way ANOVA; *P<0.05, ***P<0.001 and ****P<0.0001; the scale bar = 500 μm or 100 μm or 20 μm.

[0017] Figure 7 This is the scoring details for sepsis model mice in Example 2 of the present invention. Detailed implementation manners

[0018] Now, the various exemplary implementation manners of the present invention will be described in detail. This detailed description should not be considered as a limitation to the present invention, but rather as a more detailed description of certain aspects, characteristics, and implementation schemes of the present invention.

[0019] It should be understood that the terms used in the present invention are only for describing specific implementation manners and are not used to limit the present invention. Additionally, for the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded from the range.

[0020] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein can also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In case of conflict with any incorporated document, the content of this specification shall prevail.

[0021] Without departing from the scope or spirit of the present invention, various improvements and changes can be made to the specific implementation manners of the present invention's specification, which are obvious to those skilled in the art. Other implementation manners obtained from the specification of the present invention are obvious to those skilled in the art. The specification and examples of this application are only exemplary.

[0022] As used herein, terms such as "comprising", "including", "having", "containing", etc. are all open-ended terms, meaning including but not limited to.

[0023] Unless otherwise specified, the technical solutions described in the present invention are all conventional solutions in the art, and the reagents or raw materials used, unless otherwise specified, are all purchased from commercial channels or are publicly available.

[0024] The embodiments of the present invention provide the use of malic acid in the preparation of a drug for preventing and treating sepsis.

[0025] In some specific embodiments, the sepsis includes sepsis caused by cecal ligation and puncture, LPS intraperitoneal injection, and LPS tracheal instillation.

[0026] In some specific embodiments, the malic acid includes L-malic acid, D-malic acid, and DL-malic acid.

[0027] The embodiments of the present invention also provide a drug for preventing and treating sepsis, which is prepared from malic acid or a pharmaceutically acceptable salt or derivative thereof as an active ingredient, plus a pharmaceutically acceptable excipient or auxiliary ingredient.

[0028] In some specific embodiments, the dosage form of the drug is a solid preparation, semi-solid preparation, liquid preparation, or gas preparation.

[0029] "Pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or the salts formed thereby are generally chemically or physically compatible with the other components constituting a pharmaceutical dosage form and are physiologically compatible with the receptor.

[0030] The present invention also provides the use of malic acid in the preparation of a biomarker for detecting sepsis. The malic acid in the present invention is significantly reduced in sepsis serum samples and is related to the disease progression. Therefore, the malic acid can be used as a biomarker for evaluating the severity and prognosis of sepsis.

[0031] Example 1

[0032] Changes of malic acid in the disease progression of sepsis patients

[0033] 1.1 Establish a sepsis population cohort and collect serum specimens

[0034] Inclusion criteria for sepsis patients:

[0035] ① Age ≥ 18 years old, gender is not limited;

[0036] ② Have active infection, and the sequential organ failure assessment (SOFA) score caused by the infection ≥ 2 points;

[0037] ③ Meet the sepsis diagnostic criteria.

[0038] Exclusion criteria:

[0039] ① Previous diseases with a life expectancy of less than 6 months, etc.;

[0040] ② Incomplete data or lack of informed consent forms. The collection of clinical data mainly includes the following content: basic information (age, gender, BMI, blood pressure), SOFA score, and Acute Physiology and Chronic Health Evaluation II (APACHE II) score at the time of admission to the intensive care unit, etc.

[0041] Meanwhile, healthy volunteers matched in age, gender, etc. were recruited as the control group, and basic information was collected. Peripheral blood (5 mL each time) of septic patients at multiple time points (the 1st, 3rd, and 7th days after admission) was collected, and the supernatant was taken after centrifugation and immediately stored in a -80 °C refrigerator. All subjects obtained the approval of the hospital ethics committee, followed the Declaration of Helsinki, and signed a written informed consent form.

[0042] 1.2 Detection of malic acid in serum

[0043] The level of malic acid in serum was detected using a malic acid content detection kit. The specific operation steps are as follows:

[0044] (1) Sample treatment: Add 100 μL of serum to 1 mL of extraction solution I, centrifuge at 4 °C (12000 g) for 10 minutes, take 0.8 mL of the supernatant, then slowly add 0.15 mL of extraction solution II, and slowly pipette and mix until there are no bubbles. After centrifuging at 12000 g for 10 minutes, take the supernatant for measurement. (2) Measurement steps: Preheat the spectrophotometer for more than 30 minutes, adjust the wavelength to 450 nm, and zero with distilled water. After adding samples according to the requirements of the kit, mix well, accurately react in a 37 °C constant temperature incubator in the dark for 30 minutes, take 200 μL of the reaction solution into a cuvette, measure the absorbance at 450 nm, and calculate the malic acid content according to the given formula.

[0045] 1.3 Experimental results

[0046] As Figure 1 shown, a total of 34 septic patients (n = 34) and 55 healthy volunteers (n = 55) were included in this example. By measuring the level of malic acid in serum at multiple time points (the 1st, 3rd, and 7th days after admission) and comparing with healthy volunteers, it was found that with the progression of sepsis, the level of malic acid in serum showed a gradually decreasing trend. Thus, it was conjectured that malic acid might be related to the progression of sepsis in patients, and supplementing malic acid might improve the disease progression.

[0047] Example 2

[0048] The role of malic acid in the disease progression of a sepsis animal model

[0049] 2.1 Construction of a murine sepsis model at multiple time points induced by CLP

[0050] The method of CLP modeling is as Figure 2 shown. C57BL / 6J mice aged 8 - 10 weeks (body weight 18 - 25 g) were used and fed under constant laboratory conditions (12-hour / 12-hour light-dark cycle, room temperature 23 ± 2 °C, relative humidity 55 ± 10%). All animal treatments and experimental procedures were approved by the Ethics Committee.

[0051] The specific operation is as follows: After successful anesthesia, a 1 - 2 cm surgical incision was made below the midpoint of the linea alba under sterile conditions. The cecum was ligated 1 cm from the distal end, and punctured once with a 22G needle at the ligated end. Then, 1 ml of sterile saline was injected subcutaneously into the abdominal cavity. Finally, the abdominal cavity was sutured and closed; in the sham operation group, only the abdomen was opened to expose the cecum and then the abdominal cavity was closed.

[0052] At 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours after modeling, sepsis scores were measured, pulse oxygen saturation was measured. After collecting venous blood from the mice, the mice were sacrificed, and whole lung morphological evaluation was performed. Further, lung tissue, colon tissue, and bronchoalveolar lavage fluid (BALF) were obtained for further experimental analysis. The specific grouping is as follows: ① Sham operation group (Sham): n = 6 mice / group; ② After CLP (6 hours, 12 hours, 24 hours, 48 hours, and 72 hours): n = 10 mice / group.

[0053] 2.2 Murine sepsis scoring

[0054] For murine sepsis scoring, there are 7 observation indicators: appearance, consciousness, spontaneous activity, response to stimuli, presence of eye discharge, respiratory rate, and respiratory quality. Each indicator is divided into 5 grades (0 - 4 points). The total score of each mouse is the sum of the scores of the 7 indicators, with a maximum score of 28 points. Dead mice are recorded as the maximum score. The scoring details are shown in Figure 3 .

[0055] 2.3 Monitoring of small animal pulse oxygen saturation

[0056] The MouseOx Plus was used to detect the pulse oxygen saturation (SpO2) of mice. The specific steps are as follows: (1) The hair on the mouse's neck was removed using hair removal cream, and the mouse was allowed to adapt using an adaptor clip 15 - 30 minutes in advance to prevent low blood oxygen due to discomfort; (2) The MouseOx Plus was started, and after the signal was stable, the SpO2 data was recorded and the numerical changes were observed; (3) The data was exported for further statistical analysis.

[0057] 2.4 BALF lavage and total cell count

[0058] Fix the mouse in a supine position on the operating table, disinfect the skin of the neck, make an incision along the midline of the neck, bluntly separate the muscles, and clearly expose the trachea. Make a small incision above the trachea and insert the lavage tube. Slowly inject 1 mL of pre-cooled sterile PBS. Gently massage the mouse's chest to evenly distribute the PBS, slowly withdraw the lavage tube, and recover the lavage fluid. Repeat this step 3 times. Pre-cool the centrifuge in advance, centrifuge the lavage fluid at 4°C and 2000 rpm for 10 minutes, aspirate the supernatant for protein concentration detection, and at the same time aspirate sterile PBS to resuspend the cell pellet. Use an automatic cell counter to count the cells and record the data, so as to evaluate the degree of pulmonary inflammation and injury in septic mice.

[0059] 2.5 Histopathological examination with hematoxylin and eosin (HE) staining and pathological injury scoring

[0060] To evaluate the improvement effect of malic acid on multi-organ injury and inflammation in septic mice, HE staining and pathological injury scoring were performed in this example.

[0061] The specific operation steps are as follows: (1) Tissue fixation and paraffin sectioning: The tissue is fixed in 10% neutral formalin solution for more than 48 hours. After dehydration with an automatic tissue dehydrator, paraffin embedding is carried out in a paraffin embedding hot and cold table integrated machine. The thickness of the tissue paraffin section is 4-5 μm. Then the section is placed on a slide warming table at 65°C. After 10 minutes, it is transferred to an oven to melt the paraffin in the section to ensure that the tissue adheres tightly to the glass slide without detachment; (2) Drop hematoxylin staining for about 9 minutes and rinse with tap water for 5-10 minutes; (3) Drop eosin staining for about 11 minutes and rinse with tap water 2-3 times, 5 minutes each time; (4) Dehydration: 75% alcohol → 80% alcohol → 90% alcohol → 95% alcohol → 100% alcohol I and II) → xylene I → xylene II (3 minutes for each alcohol; 10 minutes for each xylene); (5) After transparency with xylene, quickly wipe off the excess liquid around the material, drop 1-2 drops of neutral resin for mounting, and make a permanent slide specimen after mounting, which can be used to observe the morphological structure of each tissue and organ under a microscope; (6) Tissue pathological injury scoring: Scoring is based on the number of thrombi, (micro)abscesses, the presence and degree of inflammation, and the presence and severity of necrosis. 10 high-power fields are evaluated for each tissue, and the score for each parameter ranges from 0 (absent) to 3 (severe). Calculate the sum and perform statistical analysis.

[0062] 2.6 Correlation analysis

[0063] Through Pearson analysis, the correlation between malic acid and the severity of the disease in septic mice (here, the correlation between the most common and earliest affected organs by sepsis (lungs and intestines) was mainly evaluated.

[0064] 2.7 Experimental results

[0065] As Figure 4As shown, a sepsis mouse model at multiple time points induced by CLP was constructed in this example. By evaluating the sepsis score and pulse oxygen saturation (SpO2) of the mice, detecting the serum malic acid level, collecting the lung and colon tissues and bronchoalveolar lavage fluid (BALF) of the mice, and further detecting the BALF protein concentration and analyzing the total cell count. Further, the correlation analysis was performed between the serum malic acid level and the indexes of lung injury and colon injury in sepsis mice. The results showed that during the disease progression of sepsis, the sepsis score, oxygen saturation, and serum malic acid level of sepsis mice were significantly decreased compared with those of the sham-operated mice ( Figure 4 A-C in); obvious lung injury was observed in the gross lung specimens of sepsis mice (swelling, bleeding, and even necrosis were visible in the lung tissue) ( Figure 4 D in); further, the lung HE pathological staining and lung injury score showed that with the prolongation of time after CLP modeling, the lung injury score was higher, indicating that the lung injury gradually worsened with the disease progression of sepsis mice ( Figure 4 E in); consistently, by detecting the BALF supernatant protein concentration and the total number of BALF cells, it was found that compared with the sham-operated mice, the BALF supernatant protein concentration and cell count in sepsis mice increased, especially 48-72 hours after CLP ( Figure 4 F, G in); at the same time, the colon HE pathological staining and colon injury score showed that obvious colon injury and inflammation existed in sepsis mice ( Figure 4 H, I in); importantly, through Pearson correlation analysis, it was found that the level of malic acid in the serum was negatively correlated with the CLP exposure time ( Figure 4 J in); the level of malic acid in the serum was negatively correlated with the degrees of lung injury and colon injury ( Figure 4 K, L in). The above results indicate that malic acid is involved in the disease progression of sepsis.

[0066] Example 3

[0067] Improvement effect of malic acid on the survival rate of sepsis animal models

[0068] 3.1 Construction of multiple sepsis mouse models for survival analysis

[0069] 8-10-week-old C57BL / 6J mice were used, and the feeding conditions and CLP modeling method were the same as those in Example 2. The intraperitoneal injection dose of LPS was 10 mg / kg (single injection). According to the sepsis manifestations (referring to the sepsis score, Figure 3) The model is considered successful when the animals show fever, significantly increased heart rate and respiratory rate, increased secretions from the oral and nasal cavities, listlessness, lethargy, huddling, piloerection, reduced movement, anorexia or hypophagia, secretion at the corners of the eyes, and positive blood culture (blood culture is the gold standard for diagnosing bacteremia and fungemia). At the same time, at least one organ dysfunction is the standard for establishing the model of severe sepsis.

[0070] After the model was established, the status of the mice was observed every 4 - 6 hours, and the specific death time of each mouse was recorded. The body weight of the mice was measured daily for a total of 10 days. The Kaplan - Meier method was used to plot the survival curve, and the Log - rank test was used to compare the survival differences between groups, so as to systematically evaluate the improvement effect of malic acid on the survival rate of septic mice.

[0071] The specific grouping is as follows: Sham sham - operation group, n = 6 mice / group; after CLP or intraperitoneal injection of LPS, n = 15 - 18 mice / group.

[0072] 3.2 Experimental results

[0073] As Figure 5 shown, to clarify the optimal treatment dose of malic acid in the septic mouse model and the efficacy of malic acid in septic animal models of different severities and other types, in this example, through survival analysis, it was found that intragastric administration of malic acid (dose 200 mg / kg, once a day for 3 consecutive days) could significantly improve the survival rate of septic mice ( Figure 5 in A). Further, in the survival analysis of sodium malate in this example, a similar therapeutic effect was also observed. Intragastric administration of sodium malate could significantly improve the survival rate of septic mice ( Figure 5 in B). At the same time, in CLP - induced severe septic mice, sodium malate could still significantly improve the survival rate of the mice ( Figure 5 in C). In addition, in the septic mouse model induced by intraperitoneal injection of LPS, sodium malate could also significantly improve its survival rate ( Figure 5 in D). In summary, the treatment with malic acid and its sodium salt can significantly improve the survival rate of various septic animal models. Even in severe septic animal models, malic acid has a good effect on improving their survival rate.

[0074] Example 4

[0075] Evaluation of the efficacy of malic acid on septic - related animal models

[0076] 4.1 Construction of CLP - induced septic mice for efficacy evaluation

[0077] As Figure 6 shown, 8 - 10 - week - old C57BL / 6J mice were used, and the feeding conditions and CLP modeling methods were the same as those in Example 2.

[0078] After treating mice with sodium malate by gavage at a dose of 200 mg / kg for 3 days, the effect of sodium malate on the circulating malic acid level in septic mice was evaluated. At the same time, the sepsis score of the mice after treatment with malic acid and the pathological scores of multi-organ (lung, colon, heart, liver, spleen, kidney) injury were evaluated. The specific grouping is as follows: Sham sham operation group: n = 6 mice / group; CLP-induced sepsis disease group: n = 10 mice / group.

[0079] 4.2 The evaluation methods of the sepsis score and the pathological scores of multi-organ injury are the same as those in Example 2.

[0080] 4.3 Experimental results

[0081] As Figure 7 shown, after treatment with sodium malate, the serum malic acid level in septic mice can be increased ( Figure 7 A in Figure 7 ) and the disease severity of septic mice can be improved ( Figure 7 B in Figure 7 ). Further, through HE pathological staining and tissue injury scoring, it is indicated that sodium malate can significantly improve the multi-organ (lung, colon, heart, liver, spleen, kidney) injury and inflammation in septic mice ( Figure 7 C in Figure 7 ). In summary, sodium malate can be used to treat sepsis, protect multi-organ functions, and significantly reduce the mortality of sepsis.

[0082] Obviously, the above-mentioned embodiments of the present invention are only examples for clearly explaining the present invention, and are not intended to limit the implementation manners of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation manners here. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention shall be included within the protection scope of the claims of the present invention.

Claims

1. Use of malic acid in the preparation of a drug for preventing and treating sepsis.

2. The application according to claim 1, wherein The sepsis includes sepsis caused by cecal ligation and puncture, LPS intraperitoneal injection, and LPS tracheal instillation.

3. The application according to claim 1, characterized in that, The malic acid includes L-malic acid, D-malic acid, and DL-malic acid.

4. A drug for preventing and treating sepsis, characterized in that, The drug is prepared with malic acid or a pharmaceutically acceptable salt or derivative of malic acid as the active ingredient, plus pharmaceutically acceptable excipients or auxiliary components.

5. The drug according to claim 4, characterized in that, The dosage form of the drug is a solid preparation, semi-solid preparation, liquid preparation, or gas preparation.

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