CN114272231A - Application of physcion in medicine for relieving drug-induced liver injury - Google Patents
Application of physcion in medicine for relieving drug-induced liver injury Download PDFInfo
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- CN114272231A CN114272231A CN202210099850.6A CN202210099850A CN114272231A CN 114272231 A CN114272231 A CN 114272231A CN 202210099850 A CN202210099850 A CN 202210099850A CN 114272231 A CN114272231 A CN 114272231A
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Abstract
The invention belongs to the technical field of application of physcion and discloses application of physcion in a drug for relieving drug-induced liver injury. The application of physcion in relieving the drug-induced liver injury comprises the application of physcion in inhibiting HMGB1-NLRP3 signal channels so as to relieve the drug-induced liver injury, the invention provides a new application field for physcion, and physcion plays an important role in relieving the drug-induced liver injury by inhibiting HMGB1-NLRP3 inflammatory corpuscle signal channels to play an anti-inflammatory effect and inhibit inflammatory reaction.
Description
Technical Field
The invention belongs to the technical field of application of physcion, and particularly relates to application of physcion in a drug for relieving drug-induced liver injury.
Background
Drug-induced liver injury (DILI) refers to liver injury of various degrees induced by various prescription or non-prescription chemical drugs, traditional Chinese medicines, natural medicines, health products, biological agents, dietary supplements, metabolites thereof and adjuvants. According to statistics, more than 1100 marketed drugs in the world have potential hepatotoxicity, and the common drugs comprise non-steroidal anti-inflammatory drugs, anti-infective drugs, anti-tumor drugs, central nervous system drugs, cardiovascular system drugs, metabolic disease drugs, hormone drugs, certain biological agents and the like. In addition, DILI caused by Chinese herbal medicines is also being increasingly emphasized as a traditional Chinese herbal medicine used in the world.
Acetaminophen (also known as Acetaminophen, APAP) is a common cause of DILI. APAP is a common clinical antipyretic analgesic and is widely applied to the adjuvant therapy of common cold or influenza. Although APAP is safe and effective for use within therapeutic doses, excessive ingestion can cause severe liver damage and may even progress to liver failure and be life threatening. When APAP is excessive, the APAP is metabolized into N-acetyl-P-benzoquinone imine (NAPQI) by cytochrome P450 (CYP 450) oxidase (cytochrome 2E1, CYP2E1), superoxide anion is generated in the process, and under the participation of various anions, cations and enzymes, Reactive Oxygen Species (ROS)/Reactive Nitrogen Species (RNS) are increased and exceed the scavenging capacity of an antioxidant system, so that the organism is in an oxidative stress state, DNA oxidative damage and protein expression abnormality are caused, and finally liver cell necrosis is caused.
In recent years, it has been found that nucleotide binding oligomerization domain-like receptor family pyrin domain protein 3 (NLRP 3) is a multi-domain protein complex derived from NLR, and is an important component of innate immunity, and can recognize molecular patterns of different pathogens, and then through linker molecules, namely apoptosis-related plaque-like proteins (ASC) having cysteine aspartate-specific protease (caspase) activation and recruitment domains, activation effector molecules promote inflammatory factor maturation and participate in cellular inflammatory responses. Activation of NLRP3 inflammasome is a key molecular mechanism of liver injury and is thought to be a potential mediator in the mouse model after APAP overdose. When released from dead or damaged hepatocytes, local immune cells are activated and inflammatory responses are initiated, which include the actions of molecules and receptors, such as high mobility group protein B1 (HMGB 1), ATP, nuclear DNA fragments, bile acids, etc. HMGB1 is an intracellular binding protein, a known molecular pattern associated with danger signaling or injury, and plays a key role in inflammation, including in relation to sterile inflammation, immune and neurodegenerative diseases, making it an attractive emerging target for therapeutic intervention.
Physcion (PHY), also known as cinnabarinin B and fescue, is a widely distributed anthraquinone substance and widely distributed in Chinese herbal medicines such as rhubarb, giant knotweed rhizome, tuber fleeceflower root, cassia seed and the like. Modern pharmacological research shows that physcion has a plurality of pharmacological activities of resisting inflammation, oxidation, cancer, leukemia and the like. Previous studies of this group indicate that physcion can improve alcoholic steatosis injury and inflammation level through a signal path of silence information regulator protein 1 (SIRT 1) -adenylate-activated protein kinase (AMPK), and has a certain protective effect on liver, but the effect of physcion on drug-induced liver injury needs to be further studied.
Disclosure of Invention
In order to overcome the defects of the application of the existing physcion, the invention provides the application of physcion in the medicine for relieving the drug-induced liver injury, which makes full use of the physicochemical properties of physcion, is applied in the medicine for relieving the drug-induced liver injury, and relieves the drug-induced liver injury induced by acetaminophen through an HMGB1-NLRP3 signal channel.
The above purpose of the invention is realized by the following technical scheme: the application of physcion in the medicine for relieving the drug-induced liver injury, wherein the molecular structural formula of the physcion is as follows:
in the application of the physcion in relieving the drug-induced liver injury, the drug for relieving the drug-induced liver injury is applied to the drug-induced liver injury induced by acetaminophen.
The physcion is applied to relieving the drug-induced liver injury, and the drug for relieving the drug-induced liver injury is a human drug.
In the application of the physcion in relieving the drug-induced liver injury, the drug for relieving the drug-induced liver injury is an animal drug.
The application of physcion in relieving drug-induced liver injury comprises the application of physcion in inhibiting HMGB1-NLRP3 signal channel so as to relieve drug-induced liver injury.
The invention also provides a drug containing physcion for relieving drug-induced liver injury.
Furthermore, the drug for relieving the drug-induced liver injury comprises 20mg to 40mg of physcion per kilogram of organisms.
Compared with the prior art, the invention has the beneficial effects that: the invention provides a new application field for physcion, physcion plays an anti-inflammatory effect by inhibiting HMGB1-NLRP3 inflammatory corpuscle signal channel, inhibits inflammatory reaction and plays an important role in relieving drug-induced liver injury.
Drawings
The invention will be further explained with reference to the drawings and the detailed description
FIG. 1 is a schematic diagram of pathological tissue morphology observation of mouse liver (HE X200).
FIG. 2 is a schematic and bar graph (X200) of the effect of physcion on the expression of liver HMGB1 in APAP model mice.
FIG. 3 is a graph and bar graph (X200) showing the effect of physcion on expression of hepatic NLRP3 in APAP model mice.
FIG. 4 is a schematic and bar chart of the effect of physcion on the expression of HMGB1, NLRP3, caspase-1 protein and mRNA of APAP model mouse liver.
FIG. 5 is a bar chart showing the effect of physcion on the expression of IL-1 β and IL-18mRNA in liver of APAP model mouse.
Detailed Description
The invention is described in more detail below with reference to specific examples, without limiting the scope of the invention. Unless otherwise specified, the experimental methods adopted by the invention are all conventional methods, and experimental equipment, materials, reagents and the like used in the experimental method can be obtained from commercial sources.
Example 1
1 Material
1.1 SPF-level male C57BL/6 mice of 40, 8-10 weeks old, with a body mass of 20 + -2 g, purchased from SCXK 2020 0001. The experimental mice are placed in a standardized animal feeding room of the university of Dalian university medical school, the relative humidity is 40% -60%, the temperature is 23 +/-2 ℃, and the experimental mice can freely eat and drink water in a 12h light/12 h dark period. Animal experiments were approved by the ethical committee of the affiliated Zhongshan hospital of university of Dalian university (approval number DWLL2019060)
1.2 medicine and reagent physcion (batch No. HY-N0108), N-acetylcysteine (NAC, batch No. HY-B0215) purchased from MCE Shanghai Haoyuan biological medicine science and technology Limited; aspartate Aminotransferase (AST) kit (batch number C010-2-1), alanine Aminotransferase (ALT) kit (batch number C009-2-1), reduced Glutathione (GSH) assay kit (batch number A006-2-1), and Malondialdehyde (MDA) assay kit (batch number A003-1-2) were purchased from Nanjing institute of bioengineering; HMGB1 antibody (lot No. 6893), GAPDH antibody (lot No. 2118), HRP-labeled goat anti-rabbit secondary antibody (lot No. 7074), HRP-labeled goat anti-mouse secondary antibody (lot No. 7076) were purchased from Cell Signaling Technology, usa; NLRP3 antibody (lot No. 214185) was purchased from Abcam, uk; caspase-1 antibody (batch No. 392736) was purchased from Santa Cruz, USA; TRNzol Universal Total RNA extraction reagent (batch No. DP424) was purchased from Tiangen Biochemical technology Ltd.
1.3 Instrument high speed refrigerated centrifuge, MultiskanFC microplate reader (Thermo Fisher, USA); protein electrophoresis transfer system (Bio Rad, USA); fluorescent quantitative PCR instrument (Eppendorf, Germany).
2 method
2.1 animals were grouped and bred adaptively for 1 week in C57BL/6 model-making mice, and completely randomly divided into 5 groups by using random number table, i.e. Control group (Control), model group (APAP), positive Control group (NAC), physcion low and high dose groups (PHY 20mg/kg, 40mg/kg), each group containing 8 animals. Normal control group and model group ig are given physiological saline with equal amount, positive control group ip is given NAC with 300mg/kg, and low-physcion and high-dose group is given 1 time per day for ig and 5 days continuously. And (3) feeding the mice at 6d, fasting the mice for 12h without water prohibition, feeding APAP (300mg/kg) to the other 4 groups of mice in ip except the control group, anesthetizing the mice by using ether after 6h, collecting blood from eyeballs, taking out the left front leaves of the liver after dislocation and death of cervical vertebrae, fixing the left front leaves of the liver by using paraformaldehyde, and freezing and storing the rest at-80 ℃ for later use.
2.2 measuring the biochemical index and the oxidative stress index of the serum to take blood from the eyeballs of the mice, collecting the plasma, centrifuging the blood sample at 4 ℃ and 3000r/min for 30min, and then collecting the serum. And (3) measuring the AST and ALT contents in serum and the GSH and MDA contents in liver tissues by using a detection kit.
2.3 pathological observation of liver tissue fixed in paraformaldehyde, taking out the liver tissue, embedding the section with normal paraffin (thickness of 5 μm), HE staining, and observing and analyzing pathological change of liver tissue under 200 times optical microscope.
2.4 immunohistochemical staining, taking a paraffin section of liver tissue, dewaxing to water, repairing antigen, blocking by 5% BSA, adding antibodies HMGB1(1: 100) and NLRP3(1: 100), incubating overnight at 4 ℃, incubating for the next day, incubating for 1h at room temperature by using a secondary antibody, developing DAB, adding hematoxylin flowing water to turn blue, dehydrating, transparentizing, sealing, and observing the expression conditions of HMGB1 and NLRP3 under a 200-time optical microscope.
2.5 Western blot protein expression level taking each group of mouse tissues, adding a tissue lysate to homogenate and grind, fully cracking on ice for 30min, and then centrifuging at 4 ℃ (1000r/min, 15min), wherein the supernatant is the total liver protein. Determining the mass concentration of the protein by using a BCA method, carrying out electrophoresis on a protein sample by using 10% SDS-PAGE gel, and carrying out wet membrane transfer; 5% skim milk was blocked at room temperature for 1h, and then HMGB1(1:1000), NLRP3(1:1000), caspase-1(1:1000), and GAPDH (1:1000) antibodies were added, respectively, and incubated overnight at 4 ℃. On the next day, a corresponding secondary antibody labeled with HRP is added, incubated at room temperature for 1h and developed, and the gray value of the target strip is analyzed by using Quantity One software.
2.6 PCR detection of mouse liver mRNA expression levels Total RNA of mouse liver tissues of each group was extracted according to the kit instructions and cDNA was synthesized for RT-PCR analysis. Internal reference sequences of related protein genes used in the experiment, such as HMGB1, NLRP3, caspase-1, IL-1 beta, IL-18, GAPDH and the like, are designed and synthesized by Shanghai biological engineering GmbH instead of the primer sequence shown in Table 1.
TABLE 1 primer sequences
2.7 statistical analysis was performed using the GraphPad Prism 6.0 program, data to
Indicates that differences between groups were analyzed by one-way anova and Tukey's multifactorial t-test.
3 results
3.1 the influence of physcion on the content of AST and ALT in the blood serum of a mouse is shown in the results of Table 2, compared with a normal control group, the content of AST and ALT in the blood serum of the mouse of an APAP model group is obviously increased (P is less than 0.01), compared with the APAP model group, the physcion group can obviously inhibit the increase of the level of AST and ALT in the blood serum of the mouse (P is less than 0.01), and the physcion group is lower than an NAC positive control group, which indicates that the physcion has better effect of protecting liver injury.
TABLE 2 comparison of the serum AST and ALT levels in the groups of mice
Comparison with the control group:##P<0.01; comparison with model groups:**P<0.01
3.2 Effect of Physcion on pathological changes of mouse liver tissue As can be seen from the staining results of HE in FIG. 1, the hepatic lobules of the control group mouse are intact, the central veins around the hepatic cells are arranged radially, the hepatic tissue of the APAP model group mouse can show large area necrosis, and the portal area is accompanied by inflammatory cell infiltration. The cell necrosis degree of the low-dose and high-dose physcion groups and the NAC positive control group is obviously reduced, and the arrangement of hepatic cells is more regular, so that the physcion group can reduce inflammatory cell infiltration and relieve hepatic tissue injury to a certain extent.
3.3 Effect of physcion on GSH and MDA levels in liver tissues of mice As shown in the results of Table 3, GSH levels in liver tissues of mice in APAP model group are obviously lower than that of normal control group (P <0.01), and physcion low and high dose groups and NAC positive control group can obviously inhibit the reduction of GSH levels. Compared with a normal control group, the MDA level of the APAP model group is obviously increased (P is less than 0.01), and the low-physcion and high-dose group and the NAC positive control group obviously inhibit the MDA level of the liver tissue from increasing. The physcion is proved to enhance the oxidation resistance of the liver tissue and slow down the lipid peroxidation of the APAP on the liver cells.
TABLE 3 comparison of GSH, MDA levels in the livers of groups of mice
Comparison with the control group:##P<0.01; comparison with model groups:**P<0.01
3.4 Effect of physcion on HMGB1 and NLRP3 protein expression in mouse liver tissue As shown in the immunohistochemical staining result of FIG 2, the HMGB1 cells of mouse liver in APAP model group are stained with a large amount of brown yellow positive expression, and HMGB1 positive expression of physcion low and high dose groups and NAC positive control group is significantly reduced. As shown in fig. 3, compared with the control group, a large amount of NLRP3 was positively expressed in brown-yellow or brown-brown color in the APAP model group, the protein level was significantly increased, and the protein expression level of NLRP3 was significantly decreased in the low-physcion, high-dose group and NAC positive control group.
3.5 Effect of physcion on HMGB1-NLRP3 Signal channel in mouse liver tissue the above results show that physcion can down-regulate the increased protein expression levels of HMGB1 and NLRP3 in APAP-induced liver injury mice, and in order to further reveal the liver protection effect of physcion, a western bolt and PCR experiment is adopted to detect related proteins and mRNA of HMGB1-NLRP3 Signal channel, as shown in FIG. 4. The results show that compared with the control group, protein expression and mRNA level of HMGB1, NLRP3 and caspase-1 in liver tissues of the APAP model group are remarkably increased (P is less than 0.01), and compared with the APAP model group, protein expression and mRNA level of HMGB1, NLRP3 and caspase-1 can be remarkably reduced in the low-dose group, the high-dose group and the NAC positive control group of physcion.
3.6 the effect of physcion on the mRNA expression of IL-1 beta and IL-18 in mouse liver is the important mechanism of APAP induced acute liver injury, wherein the rapid increase of proinflammatory cytokines IL-1 beta and IL-18 is the main characteristic. As shown in FIG. 5, the expression levels of IL-1. beta. and IL-18mRNA in the APAP model group were significantly increased (P <0.01) compared to the control group; compared with the APAP model group, the low-dose and high-dose physcion and NAC positive control group has obviously reduced IL-1 beta and IL-18mRNA expression levels (P < 0.01).
Discussion 4
APAP is the most common medicine for researching drug-induced liver injury and is also a classical drug-induced liver injury animal model[12]. Liver damage caused by APAP has long been a hazard to humans, but the only drug currently on the market for treating liver damage caused by excessive APAP is NAC. The research result shows that after 300mg/kgAPAP is injected into the abdominal cavity, the serum AST and ALT levels of the mice are obviously increased, and the successful establishment of an APAP-induced liver injury model of the mice is prompted. The pre-administration of physcion and NAC significantly reduced the activity of these transaminases in serum, indicating that physcion can alleviate APAP-induced liver injury. Oxidative stress caused by APAP is mainly associated with massive release of mitochondrial-derived ROS and free radicalsOf concern is stress injury caused by ROS production exceeding the ability of the cell to clear itself. ROS, which are intracellular second messengers, are involved in the activation of NLRP3 and are important upstream signals that regulate the activation of the inflammatory-corpuscle NLRP 3. Research shows that after mitochondrial source ROS is eliminated, NLRP3, caspase1 protein and gene expression are obviously reduced, so that the antioxidant and anti-inflammatory effects are exerted. GSH can show the body's ability to resist oxidative stress at the in vivo level, and plays an important role in the body's aspect of resisting oxidative stress. MDA is an important index of lipid peroxidation, excessive APAP can consume GSH, intracellular lipid peroxidation is caused, and the content of MDA is increased. Compared with the APAP model group, the mouse GSH activity of each dose group of physcion is increased, the MDA content is obviously reduced, and the physcion can enhance the resistance of liver injury induced by APAP to oxidative stress and has potential oxidation resistance.
In APAP liver injury, HMGB1 may be an important activator of inflammatory cells. When APAP is taken in excessively, the cytochrome CYP2E1 is converted into its reactive toxic metabolites, the toxic metabolites can be covalently bound with HMGB1, and necrotic and apoptotic hepatocytes release a plurality of endogenous extracellular damage-related molecular pattern molecules (DAMPs) during liver damage caused by APAP, and participate in the pathogenesis of various autoimmune and inflammatory diseases. NLRP3 is a pattern recognition receptor present in the cytoplasm for sensing tissue damage and danger signals, and is involved in innate immune response with a polyprotein complex composed of adaptor protein ASC and caspase-1 (NLRP3 inflammasome). Studies have shown that HMGB1, an important inflammatory substance, is involved in the pathogenesis of NLRP3 inflammasome pathway in conjunction with downstream substances from caspase-1. Over-activation of the NLRP3 inflammasome cleaves caspase-1 activation, caspase-1 proproteins IL-1 β and IL-18 to mature IL-1 β and IL-18, which in turn activates downstream pro-inflammatory signaling pathways, causing a variety of inflammatory pathologies. Furthermore, studies have shown that treatment with HMGB 1-specific antagonists is very successful in APAP-overaged mice and provides a longer therapeutic time window compared to standard therapy, and more natural products have been shown to exhibit beneficial regulatory effects on a variety of chemical liver injuries such as APAP by modulating the NLRP3 inflammasome pathway. These results are consistent with the results shown in this study, which shows that physcion significantly reduces HMGB1 expression in a dose-dependent manner, and that the high dose group is superior to the positive control group. In order to further explore a possible mechanism of physcion for inhibiting inflammatory response, the study detects the expression of physcion on to NLRP3 inflammasome-related protein, and the result proves that physcion can inhibit APAP-induced expression of NLRP3 and caspase-1, and the mRNA levels of IL-1 beta and IL-18 in a high-dose group are superior to those of a positive control group, which indicates that physcion can play an anti-inflammatory effect by inhibiting HMGB1-NLRP3 inflammasome signal pathways. In addition, the HE staining result shows that the APAP model group has hepatocyte necrosis and inflammatory infiltration, the necrosis degree of each dose group and the positive control group of physcion is reduced, and the inflammatory cell infiltration is reduced, which indicates that physcion can inhibit inflammatory reaction. In conclusion, the research results suggest that physcion plays an important role in relieving drug-induced liver injury by inhibiting HMGB1-NLRP3 inflammatory body signal pathway, resisting oxidative stress and relieving inflammatory reaction.
In conclusion, physcion can relieve inflammatory injury caused by acetaminophen and has a protective effect on liver, and the mechanism of physcion is related to HMGB1-NLRP3 inflammatory corpuscle signaling pathway.
The embodiments described above are merely preferred embodiments of the invention, rather than all possible embodiments of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.
Claims (7)
1. The application of physcion in the medicine for relieving drug induced liver injury is provided.
2. The use of physcion in the medicament for relieving the drug-induced liver injury according to claim 1, wherein the medicament for relieving the drug-induced liver injury is applied to acetaminophen-induced drug-induced liver injury.
3. The use of physcion in a medicament for relieving drug induced liver injury according to claim 1, wherein the medicament for relieving drug induced liver injury is a human medicament.
4. The use of physcion in a medicament for relieving drug-induced liver injury according to claim 1, wherein the medicament for relieving drug-induced liver injury is an animal medicament.
5. The application of physcion in the medicine for relieving the drug-induced liver injury according to claim 1, which is characterized by comprising the application of physcion in inhibiting HMGB1-NLRP3 signal channel so as to relieve the drug-induced liver injury.
6. A medicine for relieving drug induced hepatic injury is provided.
7. The drug for relieving drug-induced liver injury according to claim 6, which comprises 20mg to 40mg of physcion per kilogram of organism.
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| CN101961326A (en) * | 2010-10-29 | 2011-02-02 | 西南交通大学 | Application of physcion in preparing medicines for treating depression |
| CN107213144A (en) * | 2017-05-31 | 2017-09-29 | 潘小平 | The purposes of Physcion and its derivative in antineoplastic is prepared |
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| CN101961326A (en) * | 2010-10-29 | 2011-02-02 | 西南交通大学 | Application of physcion in preparing medicines for treating depression |
| CN107213144A (en) * | 2017-05-31 | 2017-09-29 | 潘小平 | The purposes of Physcion and its derivative in antineoplastic is prepared |
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