CN111068058A

CN111068058A - Application of PGC-1α activator in the preparation of drugs for the treatment of sepsis

Info

Publication number: CN111068058A
Application number: CN202010039489.9A
Authority: CN
Inventors: 李奇峰; 林青; 李明泓; 李秀芳; 代蓉; 杨云; 欧阳竞锋
Original assignee: Yunnan University of Traditional Chinese Medicine TCM
Current assignee: Yunnan University of Traditional Chinese Medicine TCM
Priority date: 2020-01-15
Filing date: 2020-01-15
Publication date: 2020-04-28

Abstract

The invention discloses an application of a PGC-1 α activator in preparing a medicament for treating sepsis, relates to the technical field of medicines, and solves the technical problems of lack of effective methods and medicaments for sepsis in the prior art.

Description

Application of PGC-1 α activator in preparation of medicament for treating sepsis

Technical Field

The invention relates to the technical field of medicines, and particularly relates to application of a PGC-1 α activator in preparation of a medicine for treating sepsis.

Background

The second Sepsis definition (Sepsis 2.0) was updated by The Society of Critical Care Medicine (SCCM) and The European Society of Critical Care Medicine (ESICM) at 2016, 2, 23, and The worldwide consensus of Sepsis and septic shock definition (Sepsis 3.0) was published by JAMA, which indicated that: sepsis is a life-threatening Multiple Organ Dysfunction Syndrome (MODS) that results from an excessive reaction of the body due to severe infection. This definition highlights MODS as the most important pathological feature of sepsis and also as a determinant of death from sepsis.

With the aging population and the increase of invasive medical means, the incidence of sepsis is increasing worldwide. Due to the lack of effective drugs for curing sepsis, severe sepsis only in China results in 33.5% -48.7% of fatality rate of inpatients, and the average inpatient cost of the inpatients in 2004 is as high as $ 11390, thereby causing heavy economic and social burden. With the failure of antioxidants and immunosuppressive drugs in clinical sepsis experiments, no new sepsis therapeutic drug has been successfully developed so far after the development of sepsis drugs for nearly 50 years. At present, the methods of mechanical oxygen therapy, tissue perfusion recovery and the like which are generally adopted clinically do not produce too many obvious practical effects.

Therefore, sepsis is always the main focus and difficulty of the current intensive medicine research, and the search for effective methods and drugs for treating sepsis becomes a technical problem to be solved urgently by those skilled in the art.

Disclosure of Invention

One of the purposes of the invention is to provide the application of a PGC-1 α activator in the preparation of a medicament for treating sepsis, and to solve the technical problem that the prior art lacks effective methods and medicaments for sepsis.

In order to achieve the purpose, the invention provides the following technical scheme:

the invention provides application of a PGC-1 α activator in preparing a medicament for treating sepsis.

Further, the PGC-1 α activator is a PGC-1 α direct activator and/or a PGC-1 α indirect activator.

Further, the PGC-1 α indirect activator is an Nrf-2 activator.

Further, the Nrf-2 activator is one or more of Octopz, resveratrol, Curcumin Curcumin, 4-OctylItacanate, Diethylmalenate, TBHQ and structural analogues and derivatives thereof.

Further, the PGC-1 α direct activator is one or more of AR β 2-PKA-PGC-1 α activator, SIRT1 activator and AMPK activator.

Further, the AR β 2-PKA-PGC-1 α activator is one or more of aconitine and structural analogues and derivatives thereof.

Further, the SIRT1 activator is one or more of SRT3025 HCl, CAY10602, SRT1720HCl, SRT2104, SRT2183 and structural analogues and derivatives thereof.

Further, the AMPK activator is one or more of AMPK activator1, A-769662, AICAR, PhenforminHCl, MK-3903, PF-06409577, ETC-1002, GSK621, Adenosine 5' -monophosphomontemonohydrate, ex229 and structural analogs and derivatives thereof.

The application of the PGC-1 α activator in preparing the medicament for treating sepsis provided by the invention at least has the following beneficial technical effects:

the PGC-1 α activator can enhance the activity of PGC-1 α through the PGC-1 α activator, the enhancement of the activity of PGC-1 α can directly start the generation of mitochondria, increase the number of mitochondria, simultaneously increase the utilization of oxygen, enhance the synthesis of ATP, enhance the energy metabolism and inhibit excessive inflammatory reaction, thereby having the effect of treating sepsis.

The medicament prepared from the PGC-1 α activator provided by the invention treats sepsis by the following modes:

classical theory of septic shock states that: hypometabolism and cell death due to hypo-oxygen supply to tissue cells caused by hemodynamic abnormalities caused by infection and inflammatory reactions are key causes of MODS. However, researches show that the fatality rate of patients with sepsis cannot be reduced even after the oxygen delivery index is reached by mechanical oxygen delivery; after the macro major cycle index is recovered, the tissue oxygen metabolism disorder with MODS still exists; the tissues in which MODS occurs are not anoxic due to microcirculation disturbance, the oxygen partial pressure of the tissues is even increased along with the deterioration of the disease, and the oxygen utilization of cells is disturbed; after the conventional hemodynamics is recovered, the lactic acid level which indirectly reflects the indexes of oxygen utilization obstacle and low energy metabolism is not reduced and even greatly increased; with the oxygen utilization disorder of MODS organs, ATP levels in tissues are significantly reduced, and energy metabolism is low. The above findings all indicate that: it is the MODS important feature that oxygen utilization of cells is impaired and energy metabolism is low. In addition, clinical autopsy results show that the proportion of cell death and apoptosis in heart and kidney tissues with MODS (moderate-resolution imaging system) accounts for less than or equal to 2-3% of the total number of cells, and the cell death and apoptosis are not the cause of MODS; surviving patients who have gone through the critical phase can be rapidly functionally resuscitated even in MODS organs with poor regenerative capacity (such as heart and kidney). Accordingly, the characteristics of MODS can be summarized as: sufficient oxygen supply to tissues, oxygen utilization obstacle, low energy metabolism and less cell death, and the organs of survivors can quickly recover the physiological and biochemical dysfunction of the process organs.

The sepsis on the one hand can directly and strongly damage mitochondria through inflammatory factors and inflammatory mediators generated by severe infection induction, but on the more critical other hand, the sepsis can severely inhibit hypothalamus-Pituitary-Adrenal Axis System (HPA), hypothalamus-Pituitary-thyroid Axis System (HPT) and sympathetic nerve-Adrenal medulla System (sympathiocardioideno-Medullalary System, SAMS) from activating PGC-1-mitogenic Axis (PGC-1 α -Mitochondrial Biogenesis, sepsis, PGC-1 α -MBA), and further induces the pathological conditions of oxidative inhibition of Mitochondrial function, the pathological conditions of metabolic damage, ATP metabolism, and ATP metabolism damage, the metabolic damage of mitochondria, ATP metabolism, and ATP metabolism, so that the pathological conditions of the metabolic damage, ATP metabolism, metabolic damage, ATP metabolism, and biochemical damage, the metabolic damage, ATP metabolism, and the metabolic damage, the metabolic damage of mitochondria, the ATP metabolism, the metabolic damage of mitochondria, the ATP metabolism, the metabolic damage of the ATP, the metabolic damage of the cell, the cell.

The activation of PHA, PHT and SAMS on PGC-1 α -MBA is severely inhibited by sepsis, so that an organism cannot rapidly update mitochondria damaged by inflammatory factors and inflammatory mediators by activating PGC-1 α -MBA under the condition of sepsis, therefore, the activation of PHA, PHT and SAMS on PGC-1 α -MBA is a decisive factor of mitochondrial damage caused by sepsis, and further typical pathological changes of sepsis such as oxygen utilization disorder, biochemical metabolic disorder, energy metabolism deficiency, oxidative stress, inflammatory storm, organ dysfunction and the like are further caused, otherwise, the activation of PGC-1 α -MBA can promote the updating of damaged mitochondria of sepsis, further improve the pathological changes such as oxygen utilization disorder, biochemical metabolic disorder, energy metabolism deficiency, oxidative stress, inflammatory storm, organ dysfunction and the like, and further save and treat sepsis MODS.

The sympathetic nervous system of the body is stimulated, released epinephrine binds to adrenergic β s receptor (AR β s), AC catalyzes ATP to generate cyclic adenosine monophosphate (cAMP), the intracellular concentration of cAMP is increased, cAMP allosteric activator Protein Kinase A (PKA) of G protein coupled with AR β s, activated PKA phosphorylates modified transcription factor cAMP response element binding protein (cAMP responsive-binding protein, CREB), and then CREB initiates peroxisome proliferator-activated receptor gamma coactivator-1 α (peroxisome proliferator-activated receptor-gamma-activator-alpha-activator 1-alpha, PGC-1 α) gene expression, acetylation of PGC-461 is directly initiated, the production of mitochondrial receptor acetylation is directly initiated, the production of mitochondrial receptor kinase is increased, the production of mitochondrial receptor kinase is also initiated by the phosphorylation of ATP kinase, the phosphorylation of ATP kinase is initiated, the production of mitochondrial receptor kinase is increased, the production of mitochondrial receptor kinase is also induced by ATP kinase, the number of ATP kinase, ATP kinase is increased, ATP kinase-activating, and the like, the number of mitochondrial receptor kinase is increased, the production of mitochondrial receptor kinase is increased, the number of mitochondrial receptor kinase is increased, the phosphorylation of mitochondrial receptor kinase is also called phosphorylation, the phosphorylation of mitochondrial receptor kinase, the mitochondrial receptor of mitochondrial receptor kinase, the phosphorylation of mitochondrial receptor of ATP-activating gene, the promoter-activating factor of mitochondrial receptor-activating gene of mitochondrial receptor-activating gene of ATP-activating gene of mitochondrial receptor-activating gene of ATP.

In clinical and sepsis animal models, PGC-1 α cooperates with Nrf2 to promote the expression of mitochondrial superoxide dismutase-2 (SOD-2), increase the GSH content and improve the survival rate of animals, so that PGC-1 α is activated under sepsis conditions, the mitochondrial generation can be promoted, the sepsis damaged mitochondria can be rapidly renewed, and the mitochondrial antioxidant capacity can be improved through the cooperation of PGC-1 α and N2, so that the oxidative damage of ROS and the like to the mitochondria DNA, protein, lipid and the like can be resisted, and the quality and the function of the mitochondria can be further improved.

In the development process of sepsis, although mitochondria are directly and strongly damaged by inflammatory factors and inflammatory mediators induced by severe infection, the mitochondria are organelles capable of being rapidly renewed, the generation of the mitochondria can be directly started by enhancing the activity of PGC-1 α, the number of the mitochondria is increased, meanwhile, the antioxidant capacity of the mitochondria can be enhanced through the cooperation of PGC-1 α and Nrf2, the number, the quality and the function of the mitochondria are improved, and excessive inflammatory response caused by sepsis can be remarkably inhibited.

Namely, the AR β 2-PKA-PGC-1 α activator, the SIRT1 activator, the AMPK activator and the Nrf-2 activator of the present invention activate PGC-1 α activity by directly and/or indirectly activating PGC-1 α gene expression, and/or by structural regulation, the PGC-1 α with enhanced total activity activates mitochondrial number by inducing nuclear respiratory factor 1 (NRF 1), nuclear respiratory factor 2(nuclear respiratory factors 2, NRF2, also known as GABP) gene expression, which in turn activates mitochondrial generation-related gene expression (mitochondrial and nuclear genes such as TFAM, etc.) through NRF1, NRF2, i.e., PGC-1 α activity enhancement directly activates mitochondrial generation, so that the mitochondrial number is increased, and simultaneously oxygen utilization is increased, ATP synthesis is enhanced, energy metabolism is enhanced, and inflammation response is suppressed, thus the inflammatory response is suppressed to sepsis treatment.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 is a graph showing a comparison of the change in body temperature of mice in the control group and in the AMPK activator1 group during the survival period;

FIG. 2 is a graph comparing the change in the number of mice surviving in the control group and the AMPK activator1 group;

FIG. 3 is a graph showing a comparison between the control group and the AMPK activator1 group in terms of the change in the amount of feed consumption of mice;

FIG. 4 is a graph comparing the inhibition of inflammatory factors in mice in the control group and in mice in the AMPK activator1 group;

FIG. 5 is a graph showing a comparison of liver slices of mice in a control group and in an AMPK activator1 group;

FIG. 6 is a comparison of kidney sections of mice in the control group and AMPK activator1 group.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.

The following describes in detail the application of the PGC-1 α activator in the preparation of a medicament for treating sepsis in combination with examples 1-4 and accompanying drawings 1-6.

Example 1

The embodiment provides a PGC-1 α direct activator, preferably, the PGC-1 α direct activator is a SIRT1 activator, more preferably, the SIRT1 activator is one or more of SRT3025 HCl, CAY10602, SRT1720HCl, SRT2104(GSK2245840), SRT2183 and structural analogues and derivatives thereof.

As previously described, SIRT1 is capable of catalyzing the deacetylation of PGC-1 α, thereby activating PGC-1 α, wherein SRT1720HCl is a SIRT1 specific activator.

The protective effect of the SRT1720HCl activator on sepsis CLP mice was examined by the following experimental procedure.

Before experimental operation, KM mice are circulated at the temperature of 22 ℃ and the humidity of 40% every day for 12h day/night, adaptive word culture is carried out for 3 days in the environment without special pathogenic bacteria, the KM mice are fed with standard pellet feed in the feeding process, and the KM mice can drink water and eat food freely. The groups were randomized into control and SRT1720HCl groups, 10 of which were included. The blank group was given daily intraperitoneal injections of 0.9 normal saline (containing normal saline + 2% dimethyl sulfoxide + 10% tween-80) at 15ul/g body weight for 4 consecutive days. The SRT1720HCl group was given daily injections of SRT1720HCl (SRT1720 HCl suspended in 2% dimethylsulfoxide, 10% tween-80 and 88% PBS) at a final concentration of 7mg/ml SRT1720HCl, 15ul/g body weight for 4 consecutive days.

4 days later, anesthetized mice were injected intraperitoneally with 7% chloral hydrate solution (0.5ml/100 g). After satisfactory anesthesia, the abdominal hair was shaved, the abdomen was sterilized with a 75% alcohol cotton swab, and the site to be surgically opened was covered with a sterile drape. A longitudinal incision of about 1cm length was made along the midline of the abdomen, and the abdominal cavity was probed with sterile forceps to find and expose the cecum. The mesentery and the cecum were separated and the cecum was pulled out of the abdominal cavity and ligated at the distal cecum end 1/4. A 21G needle was used to make a through puncture in a direction perpendicular to the cecal intestine and squeeze out a small amount of intestinal contents appropriately. The cecum was cleaned with an alcohol cotton swab to avoid contamination of the abdominal wound by intestinal contents, and then the cecum after the ligation puncture was carefully returned to the abdominal cavity and the abdominal cavity was closed by suturing layer by layer. Mice in each group were injected subcutaneously with normal saline (0.03ml/g) to replace lost body fluid after surgery. They were placed in cages until anesthesia was recovered.

The control group was given an intraperitoneal injection of 0.9 physiological saline (15ul/g body weight) every 8h after CLP surgery until the mice died. The SRT1720HCl group was given 1 intraperitoneal injection of 7mg/ml SRT1720HCl (15ul/g body weight) every 8h after CLP operation until the mice died. The survival of the control and SRT1720HCl mice was monitored and the results are shown in table 1 below.

TABLE 1 survival of mice in the control and SRT1720HCl groups

As can be seen from table 1, compared to the control group, the survival period of the mice in the SRT1720HCl group was prolonged, and the survival rate was higher, indicating that SRT1720HCl has a certain protective effect on sepsis mice.

SRT1720HCl activates SIRT1 and promotes PGC-1 α to deacetylate to further activate PGC-1 α, along with the activation of PGC-1 α and the cooperation with Nrf2, mitochondrial damage caused by sepsis is obviously relieved, inflammatory factor storm caused by sepsis is reduced, the final delay of death time is realized, and the survival rate is improved.

Example 2

Preferably, the PGC-1 α direct activator is an AR β 2-PKA-PGC-1 α activator, more preferably, the AR β 2-PKA-PGC-1 α activator is one or more of aconitine and structural analogs and derivatives thereof.

Aconitine is a natural AR β 2 receptor activator extracted from radix Aconiti lateralis, and can promote the expression of PGC-1 α via the AR β 2-PKA-PGC-1 α pathway.

The protective effect of the urothelial activator on sepsis CLP mice was examined by the following experimental procedure.

Before experimental operation, KM mice are circulated at the temperature of 22 ℃ and the humidity of 40% every day for 12h day/night, adaptive word culture is carried out for 3 days in the environment without special pathogenic bacteria, the KM mice are fed with standard pellet feed in the feeding process, and the KM mice can drink water and eat food freely. The test pieces were randomly divided into a control group and an aconitine group, each group containing 10 subjects. The control group was administered with 0.9 normal saline (containing normal saline + 2% dimethyl sulfoxide + 10% tween-80) per day by intraperitoneal injection for 4 consecutive days at a rate of 15ul/g body weight. Aconitine group was administered intraperitoneally daily with aconitine (aconitine suspended in 2% dimethyl sulfoxide, 10% tween-80 and 88% PBS) at a final concentration of 7mg/ml and 15ul/g body weight for 4 consecutive days.

The mice were anesthetized with a 7% chloral hydrate solution (0.5ml/100g) by intraperitoneal injection. After satisfactory anesthesia, the abdominal hair was shaved, the abdomen was sterilized with a 75% alcohol cotton swab, and the site to be surgically opened was covered with a sterile drape. A longitudinal incision of about 1cm length was made along the midline of the abdomen, and the abdominal cavity was probed with sterile forceps to find and expose the cecum. The mesentery and the cecum were separated and the cecum was pulled out of the abdominal cavity and ligated at the distal cecum end 1/4. A 21G needle was used to make a through puncture in a direction perpendicular to the cecal intestine and squeeze out a small amount of intestinal contents appropriately. The cecum was cleaned with an alcohol cotton swab to avoid contamination of the abdominal wound by intestinal contents, and then the cecum after the ligation puncture was carefully returned to the abdominal cavity and the abdominal cavity was closed by suturing layer by layer. Mice in each group were injected subcutaneously with normal saline (0.03ml/g) to replace lost body fluid after surgery. They were placed in cages until anesthesia was recovered.

The control group was given an intraperitoneal injection of 0.9 physiological saline (15ul/g body weight) every 8h after CLP operation until the mice died. The aconitine group was given an intraperitoneal injection of 7mg/ml aconitine (15ul/g body weight) every 8h after CLP operation until the mice died. The survival of the control and aconitine mice was monitored and the results are shown in table 2 below.

TABLE 2 survival of control and aconitine mice

As can be seen from Table 2, compared with the control group, the survival cycle of the aconitine group mice is prolonged, and the survival rate is higher, which indicates that aconitine has a certain protection effect on sepsis mice.

Example 3

The present example provides an indirect activator of PGC-1 α preferably, the indirect activator of PGC-1 α is an Nrf-2 activator more preferably, the Nrf-2 activator is one or more of Multipaz, resveratrol, Curcumin Curcumin, 4-Octyl Itaconate, Diethylmaleate, TBHQ and structural analogues and derivatives thereof.

Octopz activates Nrf-2, and Nrf-2, as described above, promotes PGC-1 α expression and, in turn, activates mitochondrial production.

The protective effect of the oligopaz activator on sepsis CLP mice was examined by the following experimental procedure.

Before experimental operation, KM mice are circulated at the temperature of 22 ℃ and the humidity of 40% every day for 12h day/night, adaptive word culture is carried out for 3 days in the environment without special pathogenic bacteria, the KM mice are fed with standard pellet feed in the feeding process, and the KM mice can drink water and eat food freely. The control group and the Otopaz group were randomly divided, and 10 were each group. The control group was administered with 0.9 normal saline (containing normal saline + 2% dimethyl sulfoxide + 10% tween-80) per day by intraperitoneal injection for 4 consecutive days at a rate of 15ul/g body weight. The Otopaz group was given daily intraperitoneal injections of Otopaz (Otopaz suspended in 2% dimethyl sulfoxide, 10% Tween-80 and 88% PBS) at a final concentration of 7mg/ml and 15ul/g body weight for 4 consecutive days.

The control group was given an intraperitoneal injection of 0.9 physiological saline (15ul/g body weight) every 8h after CLP surgery until the mice died. The Otopaz group was given 1 intraperitoneal injection of 7mg/ml Otopaz (15ul/g body weight) every 8h after line CLP surgery until the mice died. Survival of control and oligopaz mice was monitored and the experimental results are shown in table 3 below.

TABLE 3 survival of control and Otipaz mice

From Table 3, it can be seen that compared with the control group, the survival period of the mice in the Otopaz group is prolonged, and the survival rate is obviously higher, which indicates that the Otopaz has good protective effect on the sepsis mice, the Otopaz synergistically promotes the expression of PGC-1 α through activating Nrf-2 and further activates PGC-1 α through the Nrf-2, and from Table 3, the Otopaz has better protective effect on the mice particularly in the early stage of sepsis.

Example 4

More preferably, the AMPK activator is one or more of AMPK activator1, A-769662, AICAR, Phenformin HCl, MK-3903, PF-06409577, ETC-1002, GSK621, Adenosine 5' -monophosphonate, ex229(compound 991), and structural analogs and derivatives thereof.

AMPK is able to phosphorylate and activate PGC-1 α activator1 to activate AMPK, and in addition, structural analogs of AMP (adenosine monophosphate), such as AICAR and the like, are also able to activate AMPK.

The protective effect of AMPK activator1 activators on sepsis CLP mice was examined by the following experimental procedure.

Before experimental operation, KM mice are circulated at the temperature of 22 ℃ and the humidity of 40% every day for 12h day/night, adaptive word culture is carried out for 3 days in the environment without special pathogenic bacteria, the KM mice are fed with standard pellet feed in the feeding process, and the KM mice can drink water and eat food freely. The control group and the AMPK activator1 group were randomly divided into 20 individuals. The blank group was given daily intraperitoneal injections of 0.9 normal saline (containing normal saline + 2% dimethyl sulfoxide + 10% tween-80) at 15ul/g body weight for 4 consecutive days. The AMPK activator1 group was administered daily intraperitoneal injection of AMPK activator1(AMPK activator1 suspended in 2% dimethylsulfoxide, 10% tween-80, and 88% PBS) at a final concentration of 7mg/ml, 15ul/g body weight, AMPK activator1 for 4 consecutive days.

4 days later, anesthetized mice were injected intraperitoneally with 7% chloral hydrate solution (0.5ml/100 g). After satisfactory anesthesia, the abdominal hair was shaved, the abdomen was sterilized with a 75% alcohol cotton swab, and the site to be surgically opened was covered with a sterile drape. A longitudinal incision of about 1cm length was made along the midline of the abdomen, and the abdominal cavity was probed with sterile forceps to find and expose the cecum. The mesentery and the cecum were separated and the cecum was pulled out of the abdominal cavity and ligated at the distal cecum end 1/4. Puncture was performed 2 times (4 holes) with a 21G needle in the direction perpendicular to the cecal tube and a small amount of intestinal contents was squeezed out with appropriate squeezing. The cecum was cleaned with an alcohol cotton swab to avoid contamination of the abdominal wound by intestinal contents, and then the cecum after the ligation puncture was carefully returned to the abdominal cavity and the abdominal cavity was closed by suturing layer by layer. Mice in each group were injected subcutaneously with normal saline (0.03ml/g) to replace lost body fluid after surgery. They were placed in cages until anesthesia was recovered.

The control group was given an intraperitoneal injection of 0.9 physiological saline (15ul/g body weight) every 8h after CLP surgery until the mice died. The AMPK activator1 group was given 1 intraperitoneal injection of 7mg/ml AMPK activator1(15ul/g body weight) every 8h after CLP surgery until the mice died. Mice in the control and AMPK activator1 groups were monitored for survival and the results of the experiments are described below.

General observations in mice

The mice in the control group were anesthetized for about 4h after surgery and started to sleep, eat less, have poor mental state, less movement, slow movement, hair erection, inhabitation and colloidal and transparent secretion of canthus after about 6h, and the condition gradually worsens. After 15h, cold tremor, dyspnea and death began to appear. After the pleuroperitoneal cavity of a dead mouse is opened, turbid exudates in the abdominal cavity, air inflation of jejunum, even gangrene, cecum swelling, adhesion and partial rupture can be seen, and blood stasis in organs such as heart, liver, lung and the like can be seen. The CLP group mice are proved to have clinical general expression of sepsis and expression of tissue organ inflammatory edema and even necrosis, and the successful establishment of a mouse sepsis model is prompted.

AMPK activator1 mice exhibited similar control and after modeling, sepsis exhibited beginning 10h, was delayed and symptoms were reduced compared to the control. No obvious secretion is seen in the canthus of the eyes of the mice in the AMPK activator1 group, and no dyspnea is caused. The dead mice in the AMPK activator1 group have no turbid exudates in the thoracoabdominal cavity, and the caecum adhesion is obviously reduced compared with that in the control group.

Body temperature of mice in survival period

The changes in the body temperature of the mice of the control group and the AMPK activator1 at the survival stage are shown in fig. 1, and the lines with dots in fig. 1 represent the changes in the body temperature of the mice of the control group at the survival stage, and the lines with squares represent the changes in the body temperature of the mice of the AMPK activator1 group at the survival stage. Referring to fig. 1, it can be seen that: the AMPK activator1 can slow down temperature fluctuation of CLP sepsis mice, can inhibit temperature rise caused by abdominal cavity infection of the mice in the early stage for 8 hours, can enhance energy metabolism of the mice after 16 hours, and can inhibit temperature reduction of the mice.

Survival status of mice

The change of the survival number of mice in the control group and the AMPK activator1 is shown in figure 2, the lower line in figure 2 represents the change of the survival number of mice in the control group, and the upper line represents the change of the survival number of mice in the AMPK activator 1. referring to figure 2, the survival time of mice in the AMPK activator1 group is obviously prolonged, and the survival rate is greatly improved, which indicates that the PGC-1 α activator AMPK activator1 can actually improve the survival rate of the mice obviously.

Feed consumption in mice

The changes in the feed consumption of the control and AMPK activator1 group mice are shown in fig. 3, with the left bar in fig. 3 representing the changes in the feed consumption of the control group mice and the right bar representing the changes in the feed consumption of the AMPK activator1 group mice. Referring to fig. 3, it can be seen that: after CLP modeling, the food intake of KM mice is better than that of AMPK activator1 group, which indicates that AMPKactivator1 can improve sepsis of mice, thereby improving the survival condition of sepsis mice.

AMPK activator1 can improve excessive inflammatory response of sepsis

When mice die in the control group after CLP modeling, 10 mice are taken from the control group and the AMPK activator1 group respectively, blood is taken from the orbit, and IL-6, IL-1 β and TNF- α inflammatory factor indexes are detected, which indicates that the AMPK activator1 can activate PGC-1 α -MBA axis, improve the quality of mitochondria and inhibit excessive inflammatory response at the same time, and the experimental result is shown in figure 4.

Observation of paraffin sections of tissues

FIG. 5 shows liver slices of mice in the control group and the AMPK activator1 group, and from a comparison of FIG. 5, the liver of mice in the AMPKactivator1 group had significantly reduced interstitial lymphocyte infiltration and significantly improved tissue edema.

FIG. 6 shows the section of the kidney of the mice in the control group and the AMPK activator1 group, and from the comparison of FIG. 6, the liver of the mice in the AMPKactivator1 group has significantly reduced neutrophil infiltration and significantly improved tissue edema and degeneration.

Further, dissection of 6 mice in the AMPK activator1 group that remained alive after 5 days revealed that 4 of them had cecal ligation and the puncture site was tightly blocked by a large amount of adipose tissue within a short time. Even the fecal material (black) that had filled the cecum was found to disappear after the adipose tissue had been stripped off, and the cecum wall appeared as a shredded paper.

In particular, after AMPK activator1 activates AMPK, phosphorylation and activation of PGC-1 α are performed, and Nrf-2 expression is promoted through PGC-1 α, which proves that AMPK activator1 can activate PGC-1 α, alleviate mitochondrial damage caused by sepsis, and improve excessive inflammatory response caused by sepsis.

The AMPKactivator1 activates AMPK and PGC-1 α phosphorylation to further activate PGC-1 α, and Nrf-2 is synergistically activated along with PGC-1 α, so that mitochondrial damage caused by sepsis is remarkably relieved, death time is remarkably delayed, survival rate is improved, and inflammatory factor storm caused by sepsis is reduced.

The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.

Claims

1. The application of PGC-1α activator in the preparation of medicine for treating sepsis.

2. the application of PGC-1α activator according to claim 1 in the preparation of medicine for treating sepsis, it is characterized in that, described PGC-1α activator is PGC-1α direct activator and/or PGC-1α indirect activator.

3. The application of the PGC-1α activator according to claim 2 in the preparation of a medicine for treating sepsis, wherein the PGC-1α indirect activator is an Nrf-2 activator.

4. the application of PGC-1α activator according to claim 3 in the preparation of medicine for the treatment of sepsis, is characterized in that, described Nrf-2 activator is Oltipaz, Resveratrol, Curcumin, 4 - One or more of Octyl Itaconate, Diethylmaleate, TBHQ and structural analogs and derivatives thereof.

5. the application of PGC-1α activator according to claim 2 in the preparation of medicine for treating sepsis, it is characterized in that, described PGC-1α direct activator is ARβ2-PKA-PGC-1α activator, SIRT1 one or more of an activator and an AMPK activator.

6. the application of PGC-1α activator according to claim 5 in the preparation of medicine for treating sepsis, it is characterized in that, described ARβ2-PKA-PGC-1α activator is aconitine and its similar structure one or more of compounds and derivatives.

7. the application of PGC-1α activator according to claim 5 in the preparation of medicine for treating sepsis, it is characterized in that, described SIRT1 activator is SRT3025 HCl, CAY10602, SRT1720HCl, SRT2104, SRT2183 and its similar structure one or more of compounds and derivatives.

8. The application of the PGC-1α activator according to claim 5 in the preparation of a medicine for treating sepsis, wherein the AMPK activator is AMPK activator1, A-769662, AICAR, Phenformin HCl, MK- One or more of 3903, PF-06409577, ETC-1002, GSK621, Adenosine 5'-monophosphate monohydrate, ex229 and structural analogs and derivatives thereof.