CN116549435B - Endoplasmic reticulum stress inhibitor and application thereof - Google Patents
Endoplasmic reticulum stress inhibitor and application thereof Download PDFInfo
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- CN116549435B CN116549435B CN202310481485.XA CN202310481485A CN116549435B CN 116549435 B CN116549435 B CN 116549435B CN 202310481485 A CN202310481485 A CN 202310481485A CN 116549435 B CN116549435 B CN 116549435B
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- glabridin
- endoplasmic reticulum
- reticulum stress
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- Epidemiology (AREA)
Abstract
The application relates to the field of biotechnology, in particular to an endoplasmic reticulum stress inhibitor and application thereof. According to the application, natural product glabridin capable of remarkably inhibiting endoplasmic reticulum stress is screened through drug screening targeting IRE1 alpha-XBP 1s pathway for the first time; the application proves for the first time that the glabridin improves the non-alcoholic fatty liver disease of mice caused by high-fat diet, including endoplasmic reticulum stress, lipid deposition and organelle injury; and glabridin ameliorates tunicamycin-induced liver injury in mice, including endoplasmic reticulum stress, bubble-like changes, and lipid deposition.
Description
Technical Field
The application relates to the field of biotechnology, in particular to an endoplasmic reticulum stress inhibitor and application thereof.
Background
Endoplasmic reticulum is a dynamic membranous organelle, and its main functions include protein synthesis and folding, ca 2+ Storage, lipid metabolism, etc. The endoplasmic reticulum contributes to the production and folding of about one third of cellular proteins, and misfolding of proteins can directly lead to the occurrence of a variety of diseases, thus maintaining a delicate balance between homeostasis of the endoplasmic reticulum and disease. When the cells are stimulated by adverse conditions, ca is caused 2+ Disruption of homeostasis, or intracellular redox imbalance, etc., will lead to abnormal protein glycosylation or defective protein folding, accumulation of unfolded or misfolded proteins within the lumen of the endoplasmic reticulum, affecting the functioning of the normal function of the endoplasmic reticulum, a condition known as endoplasmic reticulum stress (ER stress). In order to defend against or respond to endoplasmic reticulum stress, cells have a complete set of signaling systems to restore endoplasmic reticulum homeostasis and normal endoplasmic reticulum function, including unfolded protein response (Unfolded protein response, UPR), endoplasmic reticulum-associated degradation (ERAD), and autophagy.
The first line of defense for the fastest response is the UPR when the cell is in the ER stress state. UPR consists of three endoplasmic reticulum membrane intercalating proteins, myo-inositol essential enzyme 1 (Inositol requiring Protein, IRE 1), double-stranded RNA-activated Protein kinase-like endoplasmic reticulum kinase (PERK) and activated transcription factor 6 (Activating transcription factor, ATF 6), where IRE1 and PERK pathways are most conserved in a variety of eukaryotes. Under ER stress conditions, IRE1 dissociates from chaperone immunoglobulin binding protein (Binding immunoglobulin protein, bip) on the endoplasmic reticulum to form a dimer which is autophosphorylated to have nuclease activity, catalyzing the splicing of the mRNA of X-box binding protein 1 (X-box binding protein 1, XBP 1) to delete a 26bp intron sequence to form transcriptionally active XBP1s (spiiced XBP 1), the XBP1s nuclear-entering activating downstream including chaperone protein, foldase and ERAD pathway-related gene expression to relieve endoplasmic reticulum stress and restore protein homeostasis; on the other hand, the nuclear entry of XBP1s can regulate non-UPR related genes associated with adipogenesis, lipid metabolism and inflammation.
The development and progression of many diseases of many livers are accompanied by the generation of ER stress, such as lipid deposition in the livers caused by high-fat diet, and the activation of ER stress and UPR is accompanied in the process of nonalcoholic fatty liver disease (Non-alcoholic fatty liver disease, NAFLD); and drug-induced liver damage such as Acetaminophen (APAP) and Tunicamycin (Tm) can also cause ER stress. Therefore, alleviating ER stress to improve and treat related liver diseases is a new therapeutic means and strategy, and screening drugs capable of inhibiting ER stress has important significance in treating liver related diseases.
Disclosure of Invention
The present application aims to overcome the above-mentioned shortcomings of the prior art and provide an endoplasmic reticulum stress inhibitor and application thereof.
In order to achieve the above purpose, the technical scheme adopted by the application is as follows:
in a first aspect, the present application provides the use of glabridin in the preparation of an endoplasmic reticulum stress inhibitor.
According to the application, natural product glabridin capable of remarkably inhibiting endoplasmic reticulum stress is screened through drug screening targeting IRE1 alpha-XBP 1s pathway for the first time.
A second object is to provide the use of glabridin for the manufacture of a medicament for the treatment of a disease caused by endoplasmic reticulum stress.
As a preferred embodiment of the use described herein, the disease comprises liver disease or obesity disease.
Glabridin can inhibit activation of endoplasmic reticulum stress, and glabridin can improve liver injury and lipid deposition.
After glabridin treatment, endoplasmic reticulum stress in the liver of DIO mice is remarkably relieved, and Western blot and RT-PCR detection show that the activation of IRE1 alpha-XBP 1s channels is remarkably inhibited, the number and the particle size of lipid drops are remarkably reduced, the form of mitochondria is more complete, the ridge is clear, the number and the area of mitochondria are remarkably increased, the endoplasmic reticulum form is complete, and the connection between the endoplasmic reticulum form and mitochondrial membranes and nuclear membranes is more tight.
In a third aspect, the present application provides an inhibitor for use in the preparation of a medicament for treating a disorder associated with the IRE1 alpha-XBP 1s pathway, wherein the functional component of the inhibitor is glabridin.
In a fourth aspect, the present application provides the use of glabridin as an endoplasmic reticulum stress inhibitor in the preparation of a medicament for treating liver diseases or obesity diseases.
As a preferred embodiment of the use described herein, the liver disease comprises non-alcoholic fatty liver disease or liver injury.
The present application demonstrates for the first time that glabridin improves high fat diet induced non-alcoholic fatty liver disease in mice, including endoplasmic reticulum stress, lipid deposition and organelle damage.
The present application demonstrates for the first time that glabridin ameliorates tunicamycin-induced liver injury in mice, including endoplasmic reticulum stress, bubble-like changes, and lipid deposition.
As a preferred embodiment of the application described herein, the glabridin inhibits at least one of the endoplasmic gateway bond chaperone Bip, PERK-ATF4-CHOP pathway and IRE 1. Alpha. -XBP1s pathway.
Through verification, glabridin has the effect of inhibiting IRE1α -XBP1s pathway activity, the key pathway of endoplasmic reticulum stress is obviously activated in cells treated by thapsigargin or tunicamycin, and when glabridin is used for pretreatment of the cells, activation of endoplasmic gateway bond chaperones Bip, PERK-ATF4-CHOP pathway and IRE1α -XBP1s pathway can be obviously inhibited.
Fifth, the present application provides a screening cell model for an endoplasmic reticulum stress inhibitor based on IRE1 alpha-XBP 1s pathway as a target, constructing a cell line for expressing IRE1 alpha-XBP 1s and a reporter gene with immune related signal pathway response elements, wherein mRNA encoded by the reporter gene contained in the cell line is identified and spliced by an RNase domain of activated IRE1 alpha, deleting an intron sequence containing 26nt, generating a frame shift to cause a stop codon UAA to move backwards, expressing fluorescent protein, detecting fluorescence intensity change, and screening to obtain the screening cell model for the endoplasmic reticulum stress inhibitor.
As a preferred embodiment of the endoplasmic reticulum stress inhibitor screening cell model described herein, the parent cells used in the cell line include HEK293T cells.
As a preferred embodiment of the endoplasmic reticulum stress inhibitor screening cell model described herein, the cell line is pLVX-XBP1mNeonGreen NLS HEK293T cells into which green fluorescent protein is introduced.
According to the application, the medicine which effectively influences the fluorescence level of the pLVX-XBP1mNeonGreen NLS HEK293T cells is selected through screening, and the natural product glabridin can obviously inhibit the fluorescence intensity of the cells and inhibit the endoplasmic reticulum stress through verification.
Compared with the prior art, the application has the following beneficial effects:
the application provides an endoplasmic reticulum stress inhibitor and application thereof, wherein the natural product glabridin capable of remarkably inhibiting endoplasmic reticulum stress is screened through drug screening of targeting IRE1 alpha-XBP 1s pathway for the first time; the application proves for the first time that the glabridin improves the non-alcoholic fatty liver disease of mice caused by high-fat diet, including endoplasmic reticulum stress, lipid deposition and organelle injury; and glabridin ameliorates tunicamycin-induced liver injury in mice, including endoplasmic reticulum stress, bubble-like changes, and lipid deposition.
Drawings
FIG. 1 is a graph of the results of drug screening targeting IRE1 a-XBP 1s pathway;
FIG. 2 is a graph showing the results of glabridin inhibiting IRE1 alpha-XBP 1s pathway activity;
FIG. 3 is a graph showing the results of in vivo verification of glabridin in mice;
FIG. 4 is a graph showing the effect of glabridin on obese (DIO) mouse model.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present application, the present application will be further described with reference to the accompanying drawings and specific embodiments.
In the following examples, the experimental methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used are commercially available.
Preparing a lentiviral vector containing a reporter gene:
(1) wild Type (WT) HEK293T cells were plated in 10cm cell culture dishes to reach a cell fusion of 50-70% after 16h with DMEM (Corning, # 10-013-CVRC) containing 1% penicillin/streptomycin (P/S, hyClone, # SV 30010) and 10% fetal bovine serum (FBS, multicell, # 086-150).
(2) After 16h, the medium was changed to pre-warmed Opti-MEM (thermo Fisher, # 31985070) at 37℃using Lipofectamine TM 2000 (ThermoFisher, # 11668019) transfection reagents lentiviral envelope protein plasmid (pCMV-VSV-G), packaging plasmid (psPAX 2) and reporter plasmid (pLVX-XBP 1 mNanGreen NLS) were co-transfected into HEK293T cells. After 16h of transfection the medium was replaced with complete medium.
(3) The supernatant containing lentiviral vector was collected 48h of transfection, centrifuged at 13000rpm at 4℃for 5min, the supernatant was collected in clean EP tubes, viral titer was calculated and frozen at-80℃for use.
Example 1 drug screening targeting IRE1 alpha-XBP 1s pathway
In order to target IRE1 alpha-XBP 1s channel for drug screening, the embodiment constructs a cell line for stably expressing pLVX-XBP1 mNaNON Green NLS by transfecting HEK293T cells with a second-generation lentivirus. The specific experimental steps are as follows:
lentivirus transfection HEK293T cells:
(1) HEK293T cells are paved in a 6-hole plate, and the cell fusion degree reaches 60-80% after 16 h.
(2) The lentiviral vector prepared above was taken out from the refrigerator at-80℃and thawed in an ice bath, and a suitable MOI value (e.g., MOI value of 10 9 ) The volume of lentiviral vector required was calculated and added to the cell culture medium and gently mixed in a "cross" fashion.
(3) After mixing, the cells were returned to the incubator overnight for 16 hours and replaced with fresh complete medium, and the cell status and fluorescence expression were observed under a microscope.
(4) The medium was changed to 2. Mu.g/mL Puromycin (Puromycin, solarbio, #P8230) medium once a day for 5 consecutive days to screen for pLVX-XBP1mNeonGreen NLS HEK293T cell lines stably expressing the reporter gene.
The mRNA encoded by the reporter gene contained in the above cells can be recognized and spliced by the RNase domain of activated IRE 1. Alpha. Deleting an intron sequence containing 26nt, resulting in a frame shift leading to the back shift of the stop codon UAA, thus allowing the expression of the green fluorescent protein mNaNON Green (FIG. 1-A).
In this embodiment, the cell line is treated with the drug to detect the change of fluorescence intensity of the cell, and the specific experimental steps are as follows:
(1) Drug-treated cells
And (3) paving a pLVX-XBP1mNeonGreen NLS HEK293T cell line in a 48-hole plate, wherein the cell fusion degree reaches 60-80% after 16 h. Subsequently, different drugs in the compound library, including a pool of homologous compounds for medicine and food (Medicine Food Homology Compound Library, MCE, #HY-L055) and a pool of monomeric compounds for traditional Chinese medicine (Traditional Chinese Medicine Monomer Library, MCE, #HY-L065), were added to the cells, respectively. 3 repeated holes are arranged on each medicine, the concentration is 10nM, the medicines are gently mixed in a cross-shaped mode, and the treatment time is 24 hours.
(2) Detection of drug effects on cells by flow cytometry
The treated pLVX-XBP1mNeonGreen NLS HEK293T cell line was aspirated, and after gentle washing with PBS for 3 times, 100. Mu.L of pancreatin was added, incubated at 37℃for 2min, 400. Mu.L of PBS solution containing 2% FBS was added for homogenization and resuspension, and then the change in fluorescence level of the cells was detected by flow cytometry.
(3) Analysis of results
The results of the above experiments were analyzed using FlowJo v.10.4 to screen for drugs that effectively affect the fluorescence levels of the pLVX-XBP1mNeonGreen NLS HEK293T cell line. Referring to FIG. 1, natural product Glycyrrhiza glabra can significantly inhibit cell fluorescence intensity (FIG. 1-C-1-D) and endoplasmic reticulum stress (FIG. 1-B).
Example 2 action of glabridin on inhibition of IRE 1. Alpha. -XBP1s pathway Activity
To further verify the effect of glabridin in inhibiting ire1α -XBP1s pathway activity, the present application next used endoplasmic reticulum stress agonists Thapsigargin (Tg) or Tunicamycin (Tm) to treat the human and murine hepatocyte lines HepG2 and AmL12, respectively.
The specific treatment comprises the following steps: the cell fusion degree reaches 60% -80% after the human liver cell line HepG2 and the mouse liver cell line AmL12 are paved in a six-hole plate for 16 h. After 10. Mu.M Glabridin was added to the cells to pretreat the cells for 16 hours, 100nM Tg or 2.5. Mu.g/mL Tm was added to the cells to treat the cells for 6 hours, and then cellular protein samples were collected and the expression levels of endoplasmic reticulum stress-related proteins such as PERK, IRE 1. Alpha., biP, XBP1s, ATF4, CHOP and the like in the cells were detected by protein gel electrophoresis.
Referring to fig. 2, it was found by Western blot detection of changes in the expression levels of endoplasmic reticulum stress-related proteins that key pathways of endoplasmic reticulum stress were significantly activated after either Tg or Tm treatment, including endoplasmic gateway key chaperones Bip, PERK-ATF4-CHOP pathway and ire1α -XBP1s pathway, and activation of these pathways was significantly inhibited when cells were pretreated with Glabridin.
Example 3 in vivo verification of glabridin Effect in mice
This example demonstrates the effect of glabridin in experimental animals and mice. Tm can specifically cause stress in the hepatic endoplasmic reticulum of mice, causing acute liver injury and lipid deposition, and is a good animal model for verifying the effects of glabridin in vivo.
Injecting 150mg/kg glabridin into the abdominal cavity of a mouse for pretreatment for 2 hours, injecting 1mg/kg Tm into the abdominal cavity for molding, injecting 150mg/kg glabridin into the abdominal cavity again for treatment after 4 hours, and euthanizing the mouse after molding for 6 hours.
Western blot detection is performed on liver tissues, and referring to FIG. 3, tm modeling causes remarkable activation of endoplasmic reticulum stress channels in livers, and glabridin treatment can inhibit the expression level of related proteins, which indicates that glabridin can protect livers of mice from endoplasmic reticulum stress caused by Tm (FIG. 3-A). Serum from mice was collected to detect levels of glutamic oxaloacetic transaminase (AST) and glutamic pyruvic transaminase (ALT), which are markers of liver injury, and it was found that glabridin did not cause elevated AST and ALT without significant hepatotoxicity when administered alone for a short period of time. After Tm modeling, serum AST levels were significantly elevated in mice, but ALT was not significantly altered, indicating that Tm caused some degree of liver injury in a short period of time. After glabridin pretreatment and treatment, the increase of AST caused by Tm is obviously inhibited, which indicates that the glabridin can protect the liver of the mice from liver injury caused by Tm (figures 3-B-3-C).
Histomorphometric examination of mouse livers by H & E staining and oil red staining revealed that glabridin alone did not cause significant liver denaturation and lipid deposition, whereas liver developed bubble-like changes and lipid deposition after Tm modeling, which disappeared after glabridin treatment, further indicating that glabridin could protect mouse livers from Tm-induced liver injury and lipid deposition (fig. 3-D).
Example 4 Effect of glabridin on obese (DIO) mouse model
Treatment was given with glabridin 150mg/kg/day orally 1 every 2 days for 8 weeks after significant differences in body weight after 4 weeks of HFD in a high fat diet (Research Diets, # D12492) resulting in obese (DIO) mice model (prior art).
Referring to fig. 4, high fat diet induced obesity resulted in chronic endoplasmic reticulum stress in the liver, which was significantly relieved in DIO mice after glabridin treatment, and activation of ire1α -XBP1s pathway was significantly inhibited as detected by Western blot and RT-PCR (fig. 4-a-4-B).
As a result of observing the change of subcellular structures of hepatic parenchymal cells by a transmission electron microscope, a large number of lipid droplets appear in the hepatic parenchymal cells of the HFD mice, and the number and the particle size of the lipid droplets are obviously reduced after the treatment of the glabridin; meanwhile, mitochondria in liver parenchyma cells of the DIO mice are fragmented, compared with normal diet (Chow diet) mice, the number and the surface area of the mitochondria are obviously reduced, the morphology of the mitochondria is more complete after glabridin treatment, the cristae is clear, and the number and the area of the mitochondria are obviously increased; in addition, the endoplasmic reticulum morphology was discontinuous in DIO mice hepatocytes compared to normal diet mice, whereas the endoplasmic reticulum morphology was intact after glabridin treatment, with a more intimate association with mitochondrial and nuclear membranes (fig. 4-C).
Finally, it should be noted that the above embodiments are only for illustrating the technical solutions of the present application and not for limiting the scope of protection of the present application, and although the present application has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solutions of the present application without departing from the spirit and scope of the technical solutions of the present application.
Claims (4)
1. The use of glabridin as an endoplasmic reticulum stress inhibitor in the preparation of a medicament for treating liver injury, characterized in that glabridin targets the IRE1α -XBP1s pathway, and the liver injury is caused by tunicamycin.
2. An application of an inhibitor in preparing a medicament for treating liver injury related to IRE1 alpha-XBP 1s pathway, wherein a functional component of the inhibitor is glabridin, the glabridin targets IRE1 alpha-XBP 1s pathway, and the liver injury is liver injury caused by tunicamycin.
3. The use of glabridin in the manufacture of a medicament for treating liver injury caused by endoplasmic reticulum stress, wherein glabridin targets the ire1α -XBP1s pathway, and the liver injury is caused by tunicamycin.
4. The use according to any one of claims 1 to 3, wherein glabridin inhibits at least one of the endoplasmic gateway key chaperone Bip, PERK-ATF4-CHOP pathway and IRE1 a-XBP 1s pathway.
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