WO2018188536A1 - Médicament pour le traitement de la fibrose hépatique et méthode de traitement - Google Patents
Médicament pour le traitement de la fibrose hépatique et méthode de traitement Download PDFInfo
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- WO2018188536A1 WO2018188536A1 PCT/CN2018/082188 CN2018082188W WO2018188536A1 WO 2018188536 A1 WO2018188536 A1 WO 2018188536A1 CN 2018082188 W CN2018082188 W CN 2018082188W WO 2018188536 A1 WO2018188536 A1 WO 2018188536A1
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Definitions
- the present invention belongs to the field of pharmacy, and in particular, the present invention relates to a method of targeting a NS5ATP9 gene for screening for a medicament for treating or preventing a tissue fibrotic disease, and a medicament obtained by screening by the above method.
- Fibrosis can occur in a variety of tissues and organs.
- the main pathological changes are the increase of fibrous connective tissue in organ tissues, and the decrease of parenchymal cells.
- the continuous progression can lead to organ structural damage and dysfunction, and even exhaustion, which seriously threatens human health and life.
- tissue fibrosis is the leading cause of disability and death in many diseases. According to statistics from the United States, nearly 45% of patients who die from various diseases in the United States can be attributed to tissue fibroproliferative diseases.
- Hepatic fibrosis is especially common in patients with tissue fibrosis. It is a reversible pathological phenomenon in which fibrous connective tissue is excessively deposited in liver tissue during liver repair. There are many causes of liver fibrosis, and all kinds of patients with chronic viral liver diseases are the most risky groups of liver fibrosis and cirrhosis; fatty liver in the early stage of alcoholism or long-term drinking, and liver fibrosis in the later stage.
- Liver cirrhosis other fatty livers caused by non-alcoholic factors such as obesity, can also develop liver fibrosis and cirrhosis; in addition, repeated infection with schistosomiasis can cause portal fibrosis; chronic cholestasis can produce biliary liver Fibrosis; hepatolenticular degeneration and hemoglobin deposition can produce metabolic liver fibrosis; various toxic substances can cause toxic liver fibrosis; people who prefer low-protein diets and prefer fat-fried foods can produce dystrophic liver Fibrosis; patients with chronic congestive heart failure can develop cardiogenic liver fibrosis.
- liver fibrosis The mechanism of occurrence and development of liver fibrosis is very complicated.
- the current research mainly focuses on the activation and transformation of hepatic stellate cells.
- the possible pathways are various chronic stimulation activation of transforming growth factor- ⁇ (TGF- ⁇ ) and vascular-derived growth factor (PDGF).
- TGF- ⁇ tumor necrosis factor alpha
- PDGF vascular-derived growth factor
- COX-2 prostaglandin oxidoreductase
- ECM diffuse extracellular matrix
- oxidative stress activate hepatic stellate cells It is transformed into myofibroblasts and fibroblasts, resulting in increased secretion or degradation of extracellular matrix, thereby forming liver fibrosis. Because the mechanism is not clear, there are certain restrictions on the treatment of drugs.
- liver fibrosis or cirrhosis caused by viral hepatitis (mainly hepatitis B or hepatitis C) is mainly treated with anti-viral treatment using nucleoside (acid) analogues or interferons, by inhibiting viral replication. Controls the response of inflammatory factors and slows the progression of liver fibrosis or cirrhosis.
- nucleoside (acid) analogues or interferons by inhibiting viral replication. Controls the response of inflammatory factors and slows the progression of liver fibrosis or cirrhosis.
- there is no effective treatment for liver fibrosis or cirrhosis caused by alcohol, metabolism, drug and other causes mainly with Chinese medicine or proprietary Chinese medicine.
- NS5ATP9 can inhibit cell proliferation, promote apoptosis, and regulate TGF- Various pathways such as ⁇ 1/Smad3 signaling pathway inhibit the activation and development of hepatic stellate cells and the development of fibrosis.
- An animal model of NS5ATP9 knockout mice and zebrafish was established. TDF screened on the basis of cell lines and animal models on / TAF NS5ATP9 significantly upregulated genes, and has significant therapeutic effect on the liver fibrosis model induced by CCl 4.
- the present invention provides a use of the NS5ATP9 gene or the NS5ATP9 protein as a drug target in screening and/or preparing a medicament for preventing and/or treating liver fibrosis diseases.
- the present invention provides the use of an NS5ATP9 agonist for the preparation of a medicament for preventing and/or treating liver fibrosis diseases.
- the present invention provides a derivative of tenofovir (TDF), tenofovir alafenamide fumaric acid (TAF) or both in the preparation of a medicament for preventing and/or treating liver fibrosis diseases. use.
- TDF tenofovir
- TAF tenofovir alafenamide fumaric acid
- the present invention provides a method for treating a liver fibrosis disease, which comprises administering to a patient a pharmaceutically effective amount of tenofovir (TDF), tenofovir alafenamide fumaric acid (TAF) or both. Things.
- TDF tenofovir
- TAF tenofovir alafenamide fumaric acid
- the main pathological change of fibrosis according to the present invention is an increase in fibrous connective tissue in organ tissues and a decrease in parenchymal cells.
- the liver fibrosis disease of the present invention is preferably cirrhosis.
- the liver fibrosis disease of the present invention may be caused by a viral disease, such as viral (HBV, HCV) hepatitis, or may be caused by a non-viral cause, such as alcohol, metabolism, dystrophicity, drugs. Sexual, toxic, and circulatory liver fibrosis.
- a viral disease such as viral (HBV, HCV) hepatitis
- a non-viral cause such as alcohol, metabolism, dystrophicity, drugs.
- sexual, toxic, and circulatory liver fibrosis such as sexual, toxic, and circulatory liver fibrosis.
- the present invention provides a method for promoting apoptosis of hepatic stellate cells and/or inhibiting proliferation of hepatic stellate cells, using an effective dose of tenofovir (TDF), tenofovir alafenamide fumaric acid ( Derivatives of TAF) and/or both are contacted with hepatic stellate cells.
- TDF tenofovir
- Derivatives of TAF tenofovir alafenamide fumaric acid
- the invention provides an animal model of NS5ATP9 gene knockout selected from the group consisting of a rat, a mouse or a zebrafish.
- the invention provides a preparation method of an animal model of NS5ATP9 gene knockout, comprising the following steps:
- Target gene localization the human gene NS5ATP9 is in the mouse species, the gene m2810417H13Rik (NM_026515.2; Ensembl: ENSMUSG00000040204), which is located on mouse chromosome 9;
- a homozygous mouse obtained by knocking out the NS5ATP9 gene F1 mice were selfed, and homozygous NS5ATP9 knockout mice were obtained.
- the present invention provides the use of an NS5ATP9 gene or a protein thereof as a diagnostic target for tissue fibrotic diseases.
- the liver fibrosis of the present invention refers to a pathophysiological process in which hepatic stellate cells are activated by various pathogenic factors, extracellular matrix synthesis is increased, degradation is reduced, and connective tissue in the liver is abnormally proliferated.
- the hepatitis refers to inflammation of liver cells and liver tissues. If the liver cells are repeatedly destroyed and regenerated by chronic hepatitis, the fibrous tissue and regenerative nodules in the liver are increased to evolve into cirrhosis or cirrhosis. . If the cirrhosis develops to a certain level or higher, complications such as Hepatic encephalopathy, Esophageal varicose, and ascites can be induced.
- prevention may refer to all the actions of an individual to administer an NS5ATP9 agonist of the invention (e.g., TDF/TAF) to inhibit or delay the onset of liver fibrotic disease.
- an NS5ATP9 agonist of the invention e.g., TDF/TAF
- treating may refer to all behaviors in which a suspected individual of a liver fibrotic disease is administered an NS5ATP9 agonist (e.g., TDF/TAF) to ameliorate the symptoms of the liver fibrotic disease or to facilitate symptomatic relief.
- an NS5ATP9 agonist e.g., TDF/TAF
- diagnosis may refer to all actions that assist in determining the degree of onset, stage of onset of liver fibrotic disease.
- the TDF, TAF or a derivative thereof of the present invention may be administered as a single therapeutic agent, or may be used in combination with other therapeutic agents, or may be administered sequentially or simultaneously with a conventional therapeutic agent.
- single administration or multiple administration may be employed. It is important to apply an amount that does not induce side effects and can achieve maximum effect in a minimum amount in consideration of the elements, which can be easily determined by those skilled in the art.
- administering means that the pharmaceutical composition of the present invention is introduced into a patient by some appropriate method, and the administration route of the composition of the present invention may be oral or non-oral, as long as the target tissue can be reached. kind of path.
- the mode of administration of the pharmaceutical composition of the present invention is not particularly limited, and a method generally used in the art can be employed. As a non-limiting manner of the mode of administration, the composition can be administered orally or parenterally.
- the pharmaceutical composition of the present invention can be prepared into various dosage forms in accordance with the mode of administration.
- the frequency of administration of the composition of the present invention is not particularly limited and may be administered once a day or in multiple portions.
- the present invention systematically screens a plurality of compound monomers on the basis of cell experiments and animal models, and firstly found that TDF, TAF or both derivatives thereof can significantly increase the expression level of NS5ATP9 gene and regulate the phosphorylation of Smad3 protein. Modification and intracellular translocation promote apoptosis of hepatic stellate cells, inhibit proliferation of hepatic stellate cells, and obtain significant effects in the treatment of hepatic fibrosis diseases in animal models. TDF or TAF have been approved by the FDA for the treatment of HIV and HCV, and can be directly used as a medicine. The discovery of this new indication expands the scope of treatment and use of TDF/TAF, and also brings good news to patients with liver fibrosis.
- Figure 1 H&E staining and horseshoe staining of liver perforating tissues at different stages of liver fibrosis: A.S1 phase; B.S2-3 phase; C.S4 phase.
- FIG. 1 Immunohistochemical staining method to detect the differential expression of NS5ATP9 in liver tissues of patients with different degrees of liver fibrosis.
- the expression level of NS5ATP9 was significantly down-regulated with the increase of liver fibrosis (S0 to S4).
- FIG. 4 CCl 4 induced fibrosis mouse liver tissue frozen section immunofluorescence double staining results: the left picture shows the control group mice; the right picture shows the experimental group CCl4 model 4w model mice.
- Figure 5b Successful establishment of a model of overexpression or silencing of the NS5ATP9 cell at the protein level in LX2 cells;
- Figure 5c Overexpression of NS5ATP9, down-regulation of mRNA expression of liver fibrosis-related genes; silencing of endogenous NS5ATP9, up-regulation of mRNA expression of liver fibrosis-related genes;
- FIG. 5d Overexpression of NS5ATP9, down-regulation of liver fibrosis-related gene protein levels, and interference with NS5ATP9, liver fibrosis-related gene protein levels are up-regulated.
- FIG. 6 Flow cytometry analysis of the effect of NS5ATP9 on HSC apoptosis: A. pcDNA3.1-NS5ATP9 transfection of LX-2 cells on apoptosis; B. siRNA-NS5ATP9 transfection of LX-2 cells The effect of apoptosis; C. Statistical results of the percentage of HSC apoptosis after overexpression or interference with NS5ATP9.
- FIG. 7 Cell count and CCK-8 kit assay analysis of the effect of NS5ATP9 on HSC proliferation: A. pcDNA3.1-NS5ATP9 transfected LX-2 cells after cell proliferation; B. siRNA-NS5ATP9 transfected LX-2 cells Changes in cell proliferation.
- Figure 8 Expression of NS5ATP9 and liver fibrosis-related factors in LX2 cells treated with different concentrations of TDF for 48 h: A. NS5ATP9 up-regulated at mRNA level; B. NS5ATP9 up-regulated at protein level; C. Liver fibrosis-associated factor Down-regulation of mRNA level expression; D. Down-regulation of protein expression level of liver fibrosis-related factors; E. Down-regulation of protein expression level of liver fibrosis-related factors.
- Figure 9 Expression of NS5ATP9 and liver fibrosis-related factors in LX2 cells treated with different concentrations of TAF for 48 h: A. NS5ATP9 up-regulated at mRNA level; B. NS5ATP9 up-regulated at protein level; C. Liver fibrosis-associated factor Down-regulation of mRNA level expression; D. Down-regulation of protein expression level of liver fibrosis-related factors; E. Down-regulation of protein expression level of liver fibrosis-related factors.
- TDF inhibits LX2 cell activation, promotes apoptosis of LX2 cells, and promotes the recovery of activated LX2 cells to a resting state:
- A.TGF ⁇ 1 activates LX2 cells, and then uses TDF to act on cells, and liver fibrosis-related factor protein levels are expressed.
- B.CCK-8 kit detects TDF promotes apoptosis of LX2 cells; C.
- TAF inhibits LX2 cell activation, promotes apoptosis of LX2 cells, and promotes the recovery of activated LX2 cells to a resting state:
- A B.
- TGF ⁇ 1 activates LX2 cells, and then uses TAF to act on cells, liver fibrosis-related factor protein levels. The expression level was down-regulated;
- C.CCK-8 kit detected TAF promoted apoptosis of LX2 cells; D.
- FIG. 12 Changes in two classical fibrosis-related signaling pathways of TGF ⁇ /smad3 and NF- ⁇ B after 48 hours of LX2 cells treated with different concentrations of TDF, and different time after TDF treatment of LX2 cells: A. After 48 hours of LX2 cells treated with different concentrations of TDF, Changes in TGF ⁇ /smad3 signaling pathway; changes in TGF ⁇ /smad3 signaling pathway after LX2 cells were treated with B.TDF; A. Changes in NF- ⁇ B signaling pathway after LX2 cells were treated with different concentrations of TDF for 48 h; B.TDF effect LX2 Changes in NF- ⁇ B signaling pathways after cells at different times.
- Figure 13 Changes of two classical fibrosis-related signaling pathways of TGF ⁇ /smad3 and NF- ⁇ B after 48 hours of LX2 cells treated with different concentrations of TAF and different time after TAF treatment of LX2 cells: A. After 48 hours of LX2 cells treated with different concentrations of TAF, Changes in TGF ⁇ /smad3 signaling pathway; B.TAF changes in TGF ⁇ /smad3 signaling pathway after LX2 cells at different time; A. Changes in NF- ⁇ B signaling pathway after LX2 cells treated with different concentrations of TAF for 48 h; B.TAF effect LX2 Changes in NF- ⁇ B signaling pathways after cells at different times.
- Figure 14a Mouse CCl 4 liver fibrosis model. After 1 month of modeling, low dose (5 mg/kg) and high dose (50 mg/kg) of TDF were used for treatment. After 1 month of drug intervention, Western blot was used to detect liver fibrosis. Related protein expression results;
- Figure 14b Mouse CCl 4 liver fibrosis model drug intervention 1 month, immunohistochemical staining to detect NS5ATP9 expression changes;
- Figure 14c Mouse CCl 4 liver fibrosis model After 1 month of drug intervention, Sirius red staining was used to detect collagen fiber content.
- FIG. 15 Mouse CCl 4 liver fibrosis model After 1 month of drug intervention, the expression of mRNA levels of liver fibrosis-related genes was down-regulated.
- FIG. 1 Mouse CCl 4 liver fibrosis model After 1 month of drug intervention, H&E staining was used to detect the pathological improvement of liver tissue in mice.
- Example 1 Differential expression of NS5ATP9 in different degrees of liver fibrosis
- liver biopsy specimens of 24 patients with HBV-related liver fibrosis were from the affiliated hospital of Putian College, Fujian province. After routine pathological H&E staining and Masson staining (shown as A-C in Figure 1), the degree of liver fibrosis was staged according to the Knodell HAI scoring system and divided into three groups: S0-S1, S2-S3, and S4. The expression levels of NS5ATP9 protein in the above three groups of liver perforating tissues were detected by immunohistochemical staining.
- NS5ATP9 regulates the expression of molecules related to liver fibrosis:
- LX-2 cells were transiently transfected with pcDNA3.1/myc-His9.
- (-)-NS5ATP9 overexpression plasmid pcDNA3.1/myc-His(-)-NC as a negative control
- establish a NS5ATP9 overexpressing cell model pcDNA3.1/myc-His(-)-NC as a negative control
- siRNA-NS5ATP9 siRNA-NC as a negative control
- NS5ATP9 mRNA and protein were used to detect the expression of NS5ATP9 mRNA and protein.
- the cell model was established and the genes related to liver fibrosis (TGF- ⁇ 1, ⁇ -SMA, collagen I, collagen III, Smad3 and p-Smad3) were detected. Protein expression levels vary. ⁇ -SMA is a marker of hepatic stellate cell activation, and collagen I and collagen III are the main extracellular matrix deposition components.
- liver fibrosis-related molecules TGF- ⁇ 1, ⁇ -SMA, collagenI, collagen III, Smad3 and p-Smad3 mRNA expression levels and protein expression levels were down-regulated to varying degrees (see Figures 5c, 5d); after silencing NS5ATP9, The mRNA expression and protein expression levels of liver fibrosis-related molecules were significantly up-regulated compared with the control group (see Figures 5c and 5d), and the difference was statistically significant (P ⁇ 0.05). It can be seen that NS5ATP9 inhibits the activation of hepatic stellate cells and inhibits Liver fibrosis.
- Example 3 Expression of NS5ATP9 gene induces apoptosis of hepatic stellate cells and inhibits proliferation of hepatic stellate cells
- HSC hepatic stellate cells
- Apoptosis of activated HSC is considered to be an important mechanism of liver fibrosis reversal and ECM degradation. Therefore, we used flow cytometry Annexin V-FITC/7-AAD apoptosis detection technology to analyze the apoptosis of HSC by NS5ATP9. The role. pcDNA3.1/myc-His9(-)-NS5ATP9 overexpression plasmid (pcDNA3.1/myc-His(-)-NC as negative control)/siRNA-NS5ATP9 (siRNA-NC as negative control) was transiently transfected into no Apoptotic changes were detected 48 hours after transfection in stimulated LX-2 cells.
- the CCK-8 cell proliferation and activity assay kit and cell count were used to analyze the effect of NS5ATP9 on HSC proliferation.
- LX-2 cells were transiently transfected with pcDNA3.1/myc-His9(-)-NS5ATP9 overexpression plasmid (pcDNA3.1/myc-His(-)-NC as negative control), or siRNA-NS5ATP9 (siRNA-NC as negative) Control), cells were collected 48 h after transfection, and cell proliferation was measured by cell counting. At the same time, the cell proliferation was detected by CCK-8 kit at 12h, 24h, 48h and 72h after transfection.
- the results of cell counting showed that the number of cells in the overexpressed group of NS5ATP9 gene was significantly decreased compared with the control group 48 h after transfection, and the number of cells in the interference group was significantly higher than that in the control group (see A in Figure 7).
- the results of CCK-8 showed that compared with the control group, the proliferation of LX-2 cells in the overexpressed NS5ATP9 group decreased significantly at 48h and 72h; the proliferation of the interference group increased significantly at 24h, 48h and 72h, and the difference was statistically significant (see figure 7 in B).
- NS5ATP9 inhibits the proliferation of hepatic stellate cells.
- TDF/TAF inhibits hepatic stellate cell activation
- LX2 cells are human semi-activated hepatic stellate cells, which are normally passaged. After 12 hours of adherent growth, different concentrations of TDF and TAF are added to stimulate. After 48 hours, cells are collected and total protein and RNA are extracted. Western blot and qRT-PRC were used to detect the expression of NS5ATP9 and liver fibrosis-related genes (collagen I and collagen III are the classic markers of extracellular matrix collagen deposition during liver fibrosis).
- NS5ATP9 was up-regulated at mRNA level (as shown in A in Figure 8); NS5ATP9 was up-regulated at protein level ( Figure 8) In B), other liver fibrosis-related factors such as collagen are down-regulated at both mRNA and protein levels (as shown in C, D, and E in Figure 8).
- TDF inhibits liver stellate cell activation and inhibits liver fibrosis by up-regulating NS5ATP9.
- NS5ATP9 was up-regulated at mRNA level (as shown in A in Figure 9); NS5ATP9 was up-regulated at protein level ( Figure 9) In B), other liver fibrosis-related factors such as collagen are down-regulated at both mRNA and protein levels (as shown in C, D, and E in Figure 9).
- TAF inhibits liver stellate cell activation and inhibits liver fibrosis by up-regulating NS5ATP9.
- TDF/TAF reverses the activation of hepatic stellate cells and promotes apoptosis of hepatic stellate cells
- LX2 cells were subcultured for 12 hours. After adherent growth for 12 hours, TGF ⁇ 1 was added to activate LX2 cells, TDF and TAF were added. After 24 hours, the cells were collected, total protein was extracted, and the expression of liver fibrosis-related genes was detected by Western blot.
- LX2 cells were subcultured for 12 hours. After adherent growth for 12 hours, cells were added with different concentrations of TDF, TAF for 48 hours or TDF and TAF for LX2 cells for different time. The cells were harvested and total protein was extracted. Western blot was used to detect apoptosis. Factor expression changes. Apoptosis was detected by CCK-8 kit and flow cytometry.
- TDF TDF is added to promote the recovery of activated LX2 cells to a resting state (as shown in A of Figure 10); after 48 hours of stimulation with different concentrations of TDF or after TDF treatment of LX2 cells for different time: promote LX2 Apoptosis (shown as B, C, D, E in Figure 10).
- TAF:TAF is added to promote the recovery of activated LX2 cells to rest (as shown in A and B in Figure 11); after 48 hours of stimulation with different concentrations of TAF or after different time of TAF treatment of LX2 cells: Promote apoptosis of LX2 cells (shown as C, D, E, F in Figure 11).
- TDF/TAF regulates liver fibrosis through TGF ⁇ /smad3 and NF- ⁇ B signaling pathways
- LX2 cells were subcultured for 12 hours. After adherent growth for 12 hours, LX2 cells were treated with different concentrations of TDF and TAF for 48 hours. After adding TDF and TAF to LX2 cells for different time, total protein was extracted and TGF ⁇ /smad3 and NF were detected by Western blot. - ⁇ B changes in two classical fibrosis-related signaling pathways.
- mice C57BL/6J male mice were intraperitoneally injected with CCl 4 to establish a model of liver fibrosis. After 1 month of modeling, low and high doses of TDF were administered for treatment. After 1 month of drug intervention, the mice were sacrificed. The expression of liver fibrosis-associated protein was detected by Western blot. The expression of collagen in CCl 4 model was increased. The expression of collagen in the TDF drug intervention group was significantly decreased (see Figure 14a).
- mice C57BL/6J male mice were injected intraperitoneally with CCl 4 to establish a model of liver fibrosis. After 1 month of modeling, low, medium and high doses of TAF were administered. After 1 month of drug intervention, the mice were sacrificed. The results of RT-PCR showed that the expression of fibrosis-related genes in the CCl 4 liver fibrosis model group was significantly higher than that in the normal control group, indicating that the mouse fibrosis model was successfully established.
- TDF low-dose group TDF high-dose group
- TAF low-dose group TAF low-dose group
- TAF middle-dose group TAF high-dose group
- TAF high-dose group were the best (clinical) The best dosage for treating HIV and HBV).
- the TDF and TAF groups were better than the positive control Anluo Huaxian Pills treatment group. This indicates that TDF and TAF inhibit liver stellate cell activation and inhibit liver fibrosis.
- the optimal dose is TDF high dose group (50mg/kg) and TAF medium dose group (4.5mg/kg) (see Figure 15).
- liver function showed that the levels of ALT and AST in the CCl 4 liver fibrosis model group were significantly higher than those in the normal control group, indicating that the liver function decreased after fibrosis in mice.
- the levels of ALT and AST in the TDF low-dose group, the TDF high-dose group, the TAF low-dose group, the TAF middle-dose group, and the TAF high-dose group were lower than those in the model group, and the curative effect was better than that of the positive control Anluohuaxian pill treatment group. This indicates that TDF and TAF can improve CCl 4 induced liver damage (see Figure 16).
- mice 80 NS5ATP9 knockout mice (KO-NS5ATP9) mice and 80 wild-type mice (WT) of the same age were divided into experimental group 40 and control group 40 .
- 10 rats were sacrificed at the 2nd week, 4th week, 6th week, and 8th week. The blood was collected from the eyeball and centrifuged. The liver was partially fixed with formalin and some liquid nitrogen was frozen.
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Abstract
L'invention concerne un procédé de criblage pour identifier un médicament destiné à prévenir ou à traiter de manière ciblée la fibrose tissulaire et le durcissement tissulaire, et un médicament acquis à l'aide dudit procédé de criblage. Une application de fumarate de ténofovir disoproxil (TDF), de ténofovir alafénamide (TAF), ou d'un dérivé de ceux-ci dans la préparation d'un médicament destiné à prévenir et/ou à traiter les de maladies fibrotiques hépatiques est en outre décrite.
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CN201710235242.2A CN108686211A (zh) | 2017-04-12 | 2017-04-12 | 一种治疗肝纤维化的药物和治疗方法 |
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CN109935281B (zh) * | 2018-12-28 | 2023-03-14 | 浙大城市学院 | 一种解析大黄酸对肾间质纤维化疗效的定量网络药理学模型构建方法 |
CN110646615B (zh) * | 2019-08-27 | 2021-07-13 | 南方医科大学 | 肝纤维化的生物学标志物、治疗靶点及其用途 |
CN112138162B (zh) * | 2020-09-29 | 2021-12-28 | 中国科学院动物研究所 | 降低kat7含量或活性的物质在预防衰老和治疗肝纤维化中的应用 |
CN113925856B (zh) * | 2021-10-13 | 2023-06-30 | 郑州大学 | 一种靶向肝星状细胞的仿生纳米药物的制备方法及其应用 |
CN114432334B (zh) * | 2022-03-29 | 2023-10-24 | 中山大学附属第三医院 | lnc-BIHAA1在制备预防和/或治疗肝纤维化药物中的应用 |
CN115925920B (zh) * | 2022-08-04 | 2023-07-25 | 瑞因细胞工程科技(广州)有限公司 | 一种基因增强型免疫细胞治疗肝硬化的方法 |
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WO2015032414A2 (fr) * | 2013-09-05 | 2015-03-12 | Aarhus Universitet | Procédé et outils pour prédire la fibrose hépatique |
CN104903334A (zh) * | 2012-08-30 | 2015-09-09 | 江苏豪森药业股份有限公司 | 一种替诺福韦前药及其在医药上的应用 |
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CN104903334A (zh) * | 2012-08-30 | 2015-09-09 | 江苏豪森药业股份有限公司 | 一种替诺福韦前药及其在医药上的应用 |
WO2015032414A2 (fr) * | 2013-09-05 | 2015-03-12 | Aarhus Universitet | Procédé et outils pour prédire la fibrose hépatique |
Non-Patent Citations (1)
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ZHANG M ET AL.: "NS5ATP9 Suppresses Activation of Human Hepatic Stellate Cells, Possibly via Inhibition of Smad3/Phosphorylated-Smad3 Expression", INFLAMMATION, vol. 38, no. 1, 28 February 2015 (2015-02-28), pages 278 - 289, XP035438957 * |
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