CN103301097A - Application of disulfiram in preparing anti-liver cirrhosis or anti-liver fibrosis pharmaceuticals - Google Patents
Application of disulfiram in preparing anti-liver cirrhosis or anti-liver fibrosis pharmaceuticals Download PDFInfo
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Abstract
The invention relates to an application of disulfiram in preparing pharmaceuticals for relieving hepatic injury and further relates to an application of the disulfiram in preparing anti-liver fibrosis, anti-liver cirrhosis or liver fat reducing pharmaceuticals. The invention also discloses a heptatic stellate cell external proliferation inhabitation function of the disulfiram. A specific brand-new pharmaceutical is provided for treating anti-liver fibrosis and anti-liver cirrhosis.
Description
Technical field
The present invention relates to the pharmaceutical applications of disulfiram, the invention still further relates to the molecular biosciences mechanism of disulfiram.
Background technology
Liver cirrhosis is one of common chronic disease of serious harm human health.Hepatic fibrosis is the pathologic basis of liver cirrhosis, and Different types of etiopathogenises (such as viral hepatitis, alcoholic liver disease, non-alcoholic hepatopathy, medicine and chemical factor damage etc.) can cause liver injury and inflammation, causes hepatic fibrosis, finally develops into liver cirrhosis.Hepatic fibrosis is the result of extracellular matrix over-deposit, also is the main intermediate link that further develops to liver cirrhosis.The activation of hepatic stellate cell (Hepatic Stellate Cells, HSCs) and propagation are the key links that hepatic fibrosis forms.Under pathologic condition, HSCs is activated, lose original phenotype and function, the HSCs rapid conversion that is activated becomes the flesh fibroblast-like cells, the myofibroblast hyper-proliferative, the extracellular matrixs (Extracellular Matrix, ECM) such as a large amount of synthetic I, III Collagen Type VI finally cause hepatic fibrosis simultaneously.Think at present, hepatic fibrosis is a reversible process, and therefore, the fibrosis treatment can stop even reverse hepatic fibrosis, and then can prevent the generation of liver cirrhosis, therefore paid much attention to always.
The therapeutic strategy of present hepatic fibrosis comprises:
(1) treatment protopathy, the removal cause of disease: this is the method for the most effectively treating hepatic fibrosis at present.After numerous bibliographical informations the have been arranged removal cause of disease, the hepatic fibrosis due to a variety of causes hepatopathy is reversed.At patients with alcoholic liver disease, the alleviating alcohol addiction heptic fibrosis can obtain remarkable improvement.In the patients with liver fibrosis with HBV or HCV infection, when antiviral therapy is effective, also can observe the remarkable improvement of hepatic fibrosis.Other measures of removing the cause of disease comprise deposition of iron in the removal hemachromatosis patient body, remove the copper deposition in wilson ' the s patient body, kill schistosomicide, the inactive medicine that causes hepar damnification etc.
(2) weaken inflammation and immunoreation: in the process with IFN-a treatment HCV, even observe the patient virus is suppressed not reaction, the fibrosis effect that moderate strength also can be arranged, the antiinflammatory action of prompting IFN-a may have certain anti-fibrosis effect.Steroid hormone has been used several centuries in the hepatopath of some type for the treatment of, especially in the treatment of autoimmune liver disease.The medicine of new adjusting inflammatory reaction comprises that TNF-a antagonist, cox-2 inhibitors are still needed to want large-scale clinical trial prove its effectiveness;
(3) suppress the activation of hepatic stellate cell: because the Central Position of HSC in hepatic fibrosis occurs, reducing static HSC is a direction that has much captivation to the transformation of activated hepatic stellate cells.A possible approach is to reduce oxidative stress, because oxidative stress can activate HSC, especially infects and the deposition of iron disease at alcoholic liver disease, HCV.Antioxidant can reduce the activation of HCV infected patient HSC, can block the generation of hepatic fibrosis in experimental deposition of iron.Antioxidant comprises vitamin E, silibinin, sulfuradenosin methionine etc.Specifically, vitamin E can be protected the multivalence unsaturated acids, reduces the oxygen consumption of body tissue, can also protect impaired hepatocyte.Therefore, vitamin E can be used as the adjuvant drug of cirrhosis treatment.Sulfuradenosin methionine is a kind of biochemical drug that improves cellular metabolism; affect its flowability and microviscosity by methylating of plasma membrane phospholipid and protein; increase liver glutathion inside (gsh), sulfate radical and taurine levels by turning sulfation; effective to kwashiorkor, hepatotoxin and alcoholic fatty liver, can prevent hepatitis, fatty liver, hepatic fibrosis, liver cirrhosis and hepatocarcinoma that liver causes because of cholestasis etc.Silibinin has cytoprotective and suppresses the effect of Kupffer cytoactive, minimizing hepar damnification.
Other medicines that suppress the HSC activation have: IFN-r all can reduce HSC in HSC cultivation and Hepatic Fibrosis of Animal model activation; Leptin (Leptin) has expression on the HSC surface of activation, it can affect lipid metabolism and wound healing, and noticed very early the less generation hepar damnification of animal and the fibrosis that lacks Leptin, therefore understand the strategy that the effect of Leptin in HSC may produce new treatment hepatic fibrosis in depth.
(4) in and cell effect: the HSC feature of activation comprises that lipid loses, obtains contractility, breeds in a large number and produce collagen etc.These features are mainly caused by cytokine, such as platelet derived growth factor (PDGF) and Endothelin (ET).The antagonist of these factors, receptor or endocellular signal molecule all are pharmaceutically-active target spots.Some short multiplicaiton factor, such as fibroblast growth factor (FGF), PDGF and VEGF (VEGF) etc. all belong to receptor tyrosine kinases family.
Suppressing cytokine mediated substrate synthetic is the major measure for the treatment of hepatic fibrosis.TGF-β 1 is the topmost short fibrosis factor, and the TGF-beta 1 antagonists comprises that monoclonal antibody and protease inhibitor are carrying out widely clinical front experiment.Suppress the effect of TGF-β 1, not only can suppress substrate synthetic, can also accelerate the degraded of substrate, its curative effect is confirmed in the Liver Fibrosis Model that nitrosamine and bile duct obstruction cause.No matter be protease inhibitor or angiotensin converting enzyme inhibitor, all has the effect that reduces TGF-β 1 activity.Another method is 6-phosphomannose (M6P) competitiveness and film surface M6P receptors bind of using soluble, with the combination of blocking-up or minimizing TGF-β 1 and M6P receptor.Because TGF-β 1 can in conjunction with and activate the M6P receptor on HSC film surface, thereby the short HSC effect of performance.But owing to the effect of TGF at aspects such as antitumor, adjusting immunity and inflammation-inhibiting reactions, its safety is paid close attention to during prolonged application TGF antagonistic.
In animal model, hepatic fibrosis has obtained challenging result as the liver protecting Drug therapy to utilize liver somatomedin (hepatic growth factor, HGF).HGF can promote the hepatocyte mitosis, and the synthetic TGF of reaching of propagation, collagen that regulates hepatic stellate cell expresses.Directly use HGF or its gene therapy all can stop hepatic fibrosis in different animal models progress, but its mechanism of action and cell site it be unclear that.
Additive method comprises by suppressing collagen synthase class such as proline hydroxylase, perhaps suppresses direct the inhibition synthesizing of collagen such as translation of collagen mrna.
(5) induce apoptosis on hepatic stellate cells: promote that by inducing apoptosis on hepatic stellate cells the recovery of hepatic fibrosis is another Critical policies for the treatment of.In the Experimental Liver Fibrosis model, the apoptosis of hepatic stellate cell can make hepatic fibrosis reverse.On the contrary, can prolong the existence of the hepatic stellate cell of activation to the opposing of apoptosis, the progress of hepatic fibrosis is played an important role.Gluing toxin (Gliotoxin) can stimulate the apoptosis of activated hepatic stellate cells, thereby alleviates hepatic fibrosis.Confirmed to organize between the opposing of metalloprotein enzyme inhibitor (TIMP-1) and apoptosis and had obvious dependency.Therefore the activity that suppresses TIMP has dual function, both can promote the degraded of substrate, can induce again the apoptosis of hepatic stellate cell.
(6) degraded of increase substrate: the treatment hepatic fibrosis not only will reduce the deposition of extracellular matrix, also will make the substrate degradation that has deposited, and this helps the recovery of liver function.TGF-β 1 antagonistic is by suppressing the activity of TIMP, increases the activity of interstitial collagenase and promotes the degraded of substrate.Urokinase plasminogen activator can promote the multiple normal of the recovery of hepatic fibrosis, hepatocellular regeneration and liver function as the promoter of substrate degradation chain reaction.Although the method is because the restriction of at present gene therapy still can not be carried out clinical practice, it has indicated the direction for the treatment of liver fibrosis.
The treatment liver cirrhosis does not have specific medicament at present, but the blindness drug abuse, unrest is taken medicine, and can increase the weight of burden of liver, not only liver is recovered unfavorable, also can accelerate the appearance of cirrhotic complications, take medicine and also will carry out under doctor's guidance.Common hepatopathy can be taked Drug therapy, can not treat but liver cirrhosis has not been medicine, and Drug therapy reversing liver cirrhosis probability is very little, and easily leads to complications, and injures the function of other organ.This also is why the symptoms such as upper gastrointestinal hemorrhage, portal hypertension often appear in the patient.
Treating in the world at present liver cirrhosis therapy commonly used is to adopt the stem cell biological technology.Particularly American-European countries has obtained long-term clinical practice in this respect.Stem cell has the ability of self replication and directed differentiation hypertrophy, can be divided into hepatocyte in the liver environment, participates in reparation and the reconstruct of liver structure, improves liver function.The difference of it and Drug therapy is exactly that stem cell can generate new liver cell in the differentiation of liver the inside, replace necrosis and mutant, and medicine can not promote to generate liver cell.That one is to change liver by operation, has operation risk with the difference of liver transplantation, postoperative also will be used repelling substance, and stem cell is by interventional method, and stem cell is sent to the liver injury position, break up the liver cell that makes new advances, replace the cell of dying of illness, again revert to brand-new liver.
As mentioned above, this technical field is badly in need of the specific medicament of energy anti-hepatic fibrosis and anti-liver cirrhosis.
Disulfiram (Disulfiram, DSF) has the following formula structure:
Disulfiram
It is a kind of inhibitor of aldehyde dehydrogenase, at present clinically as Temperance medicine.Specifically, disulfiram suppresses the aldehyde dehydrogenase in the liver, make ethanol be oxidized to acetaldehyde in vivo after, can not continue again to decompose oxidation, cause in the body acetaldehyde to be accumulated and produce a series of uncomfortable reactions, the people is produced ethanol detests sense, thereby reach the alleviating alcohol addiction purpose.
The disulfide bond of disulfiram has weak oxidisability, and is all unstable under acidity, alkali condition, and comparatively stable when pH6-7, and reduction reaction easily occurs under reducing condition.Disulfiram can also form sequestration thing, proteasome enzyme inhibition cell death inducing with metal ions such as copper, zinc.Some results of study show that disulfiram can suppress the activity of dopamine-β hydroxylase (DBH), suppress the degraded of neurotransmitter dopamine, at the treatment cocaine addiction effect are arranged.In addition, disulfiram is found to suppress growth and the transfer of some malignant tumor, such as melanoma and hepatocarcinoma etc.At present, the clinical trial of disulfiram treatment cocaine addiction and solid tumor is all underway.
Do not disclose the effect that disulfiram has anti-liver cirrhosis and anti-fibrosis in the prior art.
Summary of the invention
An object of the present invention is to provide the new pharmaceutical applications of disulfiram,
Specifically, one aspect of the invention relates to disulfiram and alleviates application in the medicine of liver dysfunction in preparation.Preferably, described liver dysfunction is caused by chemical induction.
In one embodiment, described liver dysfunction is selected from liver fatization, liver proliferation of fibrous tissue, hepatic fibrosis or liver cirrhosis.
The invention still further relates to the application of disulfiram in the medicine of the anti-liver fatization of preparation.
Of the present invention relate in one aspect to again disulfiram the preparation anti-hepatic fibrosis medicine in application.
Another aspect of the present invention relates to the application of disulfiram in the medicine of the anti-liver cirrhosis of preparation.
A further object of the present invention provides a kind of biological method of vitro inhibition cell.Specifically, of the present inventionly relate in one aspect to again a kind of method that suppresses the hepatic stellate cell in-vitro multiplication, comprise the disulfiram that the culture that comprises hepatic stellate cell is given effective dose.Preferably, described method only suppresses the in-vitro multiplication of hepatic stellate cell and does not suppress hepatocellular in-vitro multiplication.
Description of drawings
Figure 1A shows matched group (CCl
4) and medicine group (CCl
4+ DSF) separately serum AST (AST) level, wherein symbol " * * " expression statistically has significant difference (p＜0.01).
Figure 1B shows matched group (CCl
4) and medicine group (CCl
4+ DSF) separately alanine aminotransferase (ALT) level, wherein symbol " * * " expression statistically has significant difference (p＜0.01).
Fig. 2 A is matched group (CCl
4) and medicine group (CCl
4+ DSF) H﹠amp; E dyeing and Picro-Sirius red dye test organize microgram.
Fig. 2 B is for matched group (CCl
4) and medicine group (CCl
4+ DSF) the statistical analysis figure of collagen fiber dyeing situation, wherein symbol " * " expression statistically has difference (p＜0.05).
Fig. 3 A shows that the disulfiram of certain concentration can significantly suppress the block diagram of sternzellen (LX-2) in-vitro multiplication, and wherein symbol " * * " expression statistically has significant difference (p＜0.01).
Fig. 3 B shows that the disulfiram of certain concentration does not suppress the block diagram of hepatocyte (THLE-2) in-vitro multiplication.
The specific embodiment
The below makes further detailed elaboration based on each specific embodiment to the present invention.
Embodiment 1: the foundation of Rat Liver Fibrosis Model
1) test material:
Disulfiram (DSF): available from Sigma-Aldrich company;
Carbon tetrachloride (CCL4) and olive oil: available from Chemical Reagent Co., Ltd., Sinopharm Group.
2) matched group: get 6 of 3-4 week male Sprague-Dawley (SD) rats, lumbar injection 50% carbon tetrachloride (olive oil), injection volume 2ml/kg body weight 2 times weekly, in totally 8 weeks, is set up the rat liver fibrosis animal model.
3) administration group: get 5 of 3-4 week male Sprague-Dawley (SD) rats, CCl
4Process giving simultaneously disulfiram, its amount is pressed 8mg/kg body weight lumbar injection, twice weekly.
Embodiment 2: the preparation of serum and liver specimens
1) serum preparation: after 8 weeks, put to death rat.Blood is positioned over 4 ℃ of refrigerator overnight, and it is centrifugal that second day is drawn supernatant, and 3000 rev/mins, 20 minutes, carefully draw supernatant ,-20 ℃ are frozen.
2) liver is processed: the clip left liver leaf is put into cryopreservation tube, places immediately liquid nitrogen, then is positioned over-80 ℃ and is used for extracting RNA and cytokine assay.The residue liver cleans twice in PBS after, put into the 50ml centrifuge tube fixing with the paraformaldehyde solution immersion, be used for paraffin section.
Embodiment 3: the detection of Serum ALT and AST
Alanine aminotransferase (ALT) test kit and AST (AST) test kit are available from Shanghai Shensuo Youfu Medical Diagnosis Products Co., Ltd..
A) get 96 orifice plates, add respectively 7.5 μ l rat blood serums, three multiple holes of each sample.Then in sample well, add R-1 solution in the 150 μ l test kits, mixing afterreaction 5 minutes;
B) add R-2 solution in the 50 μ l test kits, mix;
C) measure absorbance A 1 under the 340nm wavelength after 1 minute;
D) again measure absorbance A 2 under the 340nm wavelength after 4 minutes;
E) calculate rat blood serum ALT value:
ALT (U/L)=(A1-A2)/4 minute * 207.5 μ l * 1000/ (6.22 * 7.5 μ l * 1cm)
The results are shown in Figure 1A and Figure 1B, these accompanying drawings show, CCl
4Serum ALT and the AST level of+DSF processed group (being the administration group) will significantly be lower than CCl
4Processed group (being matched group) shows that disulfiram has the effect of the liver dysfunction that alleviates chemical induction.
Embodiment 4: paraffin section is made, section H﹠amp; E dyeing, Picro-Sirius red dyeing and α-SMA immunohistochemical staining
1) test reagent: hematoxylin, Yihong and Picro-Sirius red are available from Chemical Reagent Co., Ltd., Sinopharm Group, and saturated picric acid buffer is available from source leaf bio tech ltd, and α-SMA antibody is available from Sigma-Aldrich company.
2) paraffin section is made:
Rat liver piece of tissue after paraformaldehyde is fixing is carried out paraffin embedding with embedding machine behind dehydration, transparent, waxdip, wax stone solidifies rearmounted 4 ℃ of freezer storages.Subsequently paraffin embedded tissues is made into paraffin section and is used for H﹠amp; E dyeing, Picro-Sirius red dyeing and α-SMA immunohistochemical staining.
3) H﹠amp; E dyeing
A) dewaxing: dewaxed each 10 minutes through dimethylbenzene I, II and 1/2 dimethylbenzene;
B) aquation: will cut into slices and put into successively the alcoholic solutions at different levels such as 100%, 95%, 85%, 75% each 10 minutes, then place distilled water 5 minutes;
C) dyeing: hematoxylin was contaminated 2 minutes, tap water flushing 10 minutes, 1% acidic alcohol differentiation 5 seconds, tap water flushing 10 minutes, Yihong dyeing 2 minutes, tap water flushing 10 minutes.
D) dehydration, mounting: cut into slices in 75%, 85%, 95%, 100% alcoholic solutions at different levels each 5 minutes, 1/2 dimethylbenzene 5 minutes among dimethylbenzene I, the II each 5 minutes, is used gummy mounting at last.
Coloration result is seen Fig. 2 A, wherein, and H﹠amp; E dyeing shows that the matched group liver tissue injury is serious, and liver fatization is obvious, proliferation of fibrous tissue.Compare with matched group, administration group liver tissue injury, proliferation of fibrous tissue degree all significantly alleviate, and have obviously alleviated degree of hepatic fibrosis.
4) picric acid Picro-Sirius red dyeing:
A) dewaxing: dewaxed each 10 minutes through dimethylbenzene I, II and 1/2 dimethylbenzene;
B) aquation: will cut into slices and put into successively the alcoholic solutions at different levels such as 100%, 95%, 85%, 75% each 10 minutes, then place distilled water 5 minutes;
C) dyeing: hematoxylin was contaminated 2 minutes, tap water flushing 10 minutes, 1% acidic alcohol differentiation 5 seconds, tap water flushing 10 minutes, picric acid Picro-Sirius red dyeing 10 minutes, tap water flushing 10 minutes.
D) dehydration, mounting: cut into slices in 75%, 85%, 95%, 100% alcoholic solutions at different levels each 5 minutes, 1/2 dimethylbenzene 5 minutes among dimethylbenzene I, the II each 5 minutes, is used gummy mounting at last.
E) the collagen protein expression analysis of the Picro-Sirius red positive: matched group and administration group coloration result carry out 100 times of magnification fields of light field takes pictures, and every rat is 5 visuals field of random shooting at least, every group of dyeing slice, thin piece of taking at least 3 rats; With ImageTool software analysis positive staining result, the result who obtains represents two groups degree of hepatic fibrosis.
Coloration result is seen Fig. 2 A and Fig. 2 B.Picro-Sirius red collagen fiber dyeing demonstration among Fig. 2 A, the matched group collagen fiber extensively are present in the fibroplasia district, and the fibrous septum is thicker, holds the formation pseudolobuli.The visual field of amplifying 100 times of random shootings added up (every rat is 5 visuals field of random shooting at least, every group of dyeing slice, thin piece of taking at least 3 rats), the positive painted collagen fiber of the Picro-Sirius red of discovery medicine group significantly are less than matched group (P＜0.05) (seeing Fig. 2 B).
Embodiment 5: disulfiram is on the impact of people's hepatic stellate cell (LX-2) propagation
A) with trypsinization sternzellen and counting, cell concentration is diluted to 2 * 10
4Cell/ml.Inoculate sternzellen in 96 orifice plates, every hole 100 μ l place 37 ℃ to cultivate 12 hours.
B) discard in 96 orifice plates and train liquid, add the fresh training liquid that contains the variable concentrations disulfiram, 3 parallel multiple holes of each concentration.Continue to place 37 ℃ to cultivate 48 hours.
C) discard in 96 orifice plates and train liquid, add the training liquid that contains CCK-8 reagent.Place after 1 hour for 37 ℃, survey training liquid absorbance under the 450nm with microplate reader.
Measurement result is seen Fig. 3 A, and it shows that certain density disulfiram can significantly suppress rat sternzellen in-vitro multiplication.
Embodiment 6: disulfiram is on the impact of human liver cell propagation
A) with trypsinization hepatocyte and counting, cell concentration is diluted to 2 * 104 cells/ml.Inoculate hepatocyte in 96 orifice plates, every hole 100 μ l place 37 ℃ to cultivate 12 hours.
B) discard in 96 orifice plates and train liquid, add the fresh training liquid that contains the variable concentrations disulfiram, 3 parallel multiple holes of each concentration.Continue to place 37 ℃ to cultivate 48 hours.
C) discard in 96 orifice plates and train liquid, add the training liquid that contains CCK-8 reagent.Place after 1 hour for 37 ℃, survey training liquid absorbance under the 450nm with microplate reader.
Measurement result is shown in Fig. 3 B, and it shows that the disulfiram of being tested concentration does not suppress the hepatocyte in-vitro multiplication.
In sum, the present invention finds that first disulfiram can reduce collagen protein and express, and has the effect of obvious anti-hepatic fibrosis, anti-liver cirrhosis.
Different from antioxidants such as vitamin E, silibinin, sulfuradenosin methionines, disulfiram is not only weak oxidant, can also the sequestration metal ion, thus the proteasome enzyme inhibition cell death inducing.The present invention finds the survival ability of the special inhibition liver sternzellen of disulfiram energy, but hepatocyte is not had inhibitory action, and this may be because the effect of disulfiram cell death inducing.In addition, the inhibitor of disulfiram or dopamine-β hydroxylase (DBH) can suppress dopamine and be degraded to norepinephrine, reduces the generation of norepinephrine; And norepinephrine energy promotes cultured rat hepatic stellate cells propagation, and this may also be another mechanism that disulfiram suppresses liver cirrhosis in this research.Therefore, disulfiram can be used as the brand-new medicine of the treatment of hepatic fibrosis and liver cirrhosis.
Claims (7)
1. disulfiram alleviates application in the medicine of liver dysfunction in preparation.
2. application as claimed in claim 1 is characterized in that, described liver dysfunction is caused by chemical induction.
3. application as claimed in claim 1 or 2 is characterized in that, described liver dysfunction is selected from liver fatization, liver proliferation of fibrous tissue, hepatic fibrosis or liver cirrhosis.
4. the application of disulfiram in the medicine of preparation reduction liver fatization.
5. the application of disulfiram in the medicine of preparation fibrosis.
6. the application of disulfiram in the medicine of the anti-liver cirrhosis of preparation.
7. a method that suppresses the hepatic stellate cell in-vitro multiplication comprises the disulfiram that the culture that comprises hepatic stellate cell is given effective dose.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107737108A (en) * | 2017-12-17 | 2018-02-27 | 姚蕾 | A kind of combination of oral medication for treating Pathogenesis of Post-infarction Ventricular Remodeling |
| US9937133B2 (en) | 2014-05-02 | 2018-04-10 | Ucl Business Plc | Treatment of fibrosis |
| CN111803477A (en) * | 2020-08-11 | 2020-10-23 | 上海交通大学 | Application of abstinence sulfur in preparation of anti-head and neck cancer and anti-fibrosis drugs |
| CN112972446A (en) * | 2019-12-16 | 2021-06-18 | 中国科学院生物物理研究所 | Application of TRMT6/TRMT61A inhibitor in treatment of liver cancer |
| WO2021135654A1 (en) * | 2019-12-30 | 2021-07-08 | 广州医科大学 | Use of disulfiram in preparation of medicament for prevention and treatment of diseases related to nlrp3 inflammasome |
| WO2021170093A1 (en) * | 2020-02-26 | 2021-09-02 | 上海科技大学 | Application of disulfiram in coronavirus resistance |
-
2012
- 2012-03-14 CN CN2012100662648A patent/CN103301097A/en active Pending
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9937133B2 (en) | 2014-05-02 | 2018-04-10 | Ucl Business Plc | Treatment of fibrosis |
| EP3632420A1 (en) * | 2014-05-02 | 2020-04-08 | The University Of Birmingham | Treatment of fibrosis |
| CN107737108A (en) * | 2017-12-17 | 2018-02-27 | 姚蕾 | A kind of combination of oral medication for treating Pathogenesis of Post-infarction Ventricular Remodeling |
| CN112972446A (en) * | 2019-12-16 | 2021-06-18 | 中国科学院生物物理研究所 | Application of TRMT6/TRMT61A inhibitor in treatment of liver cancer |
| WO2021135654A1 (en) * | 2019-12-30 | 2021-07-08 | 广州医科大学 | Use of disulfiram in preparation of medicament for prevention and treatment of diseases related to nlrp3 inflammasome |
| WO2021170093A1 (en) * | 2020-02-26 | 2021-09-02 | 上海科技大学 | Application of disulfiram in coronavirus resistance |
| CN111803477A (en) * | 2020-08-11 | 2020-10-23 | 上海交通大学 | Application of abstinence sulfur in preparation of anti-head and neck cancer and anti-fibrosis drugs |
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