CN116139116A - Application of niclosamide in inhibiting acute liver failure - Google Patents
Application of niclosamide in inhibiting acute liver failure Download PDFInfo
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- CN116139116A CN116139116A CN202310328580.6A CN202310328580A CN116139116A CN 116139116 A CN116139116 A CN 116139116A CN 202310328580 A CN202310328580 A CN 202310328580A CN 116139116 A CN116139116 A CN 116139116A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention belongs to the technical field of new application of medicines, and particularly relates to application of niclosamide in protecting Acute Liver Failure (ALF). The ALF model is lipopolysaccharide/D-galactosamine induced ALF. The niclosamide is administered in the animal by intraperitoneal injection. Niclosamide was administered at a dose of 40mg/kg in the LPS/D-GalN induced ALF model. The niclosamide has the characteristic of extremely low water solubility, and the dissolution mode in an animal model is DMSO primary dissolution, PBS dilution and Tween80 auxiliary dissolution. Niclosamide solvent DMSO, tween80, PBS in a ratio of 2:1:37. according to the invention, by constructing a classical mouse ALF model, the niclosamide can obviously improve the survival rate of an ALF mouse, reduce liver hemorrhagic necrosis and reduce liver inflammation. Inhibition of macrophage proliferation, control of iron death, and modulation of its pathway by binding to signal transduction and transcriptional activator protein 3 may be the mechanism by which niclosamide produces liver protection. The invention demonstrates that niclosamide is a potential therapeutic agent for ALF and reveals the relevant mechanism.
Description
Technical Field
The invention belongs to the technical field of new application of medicines, and particularly relates to application of niclosamide in inhibiting acute liver failure.
Background
Acute liver failure (acute liver failure, ALF) is a severe liver disease that lacks the basis for chronic liver disease, resulting from the induction of massive death of hepatocytes by a variety of etiologies. The main clinical manifestations of ALF include liver dysfunction and coagulation dysfunction. Some patients may develop hepatic encephalopathy and as many as half of cases may develop multiple organ failure and death. ALF has high treatment cost and causes great threat to life and health of people. The pathogenesis of ALF is currently still unclear, and the lack of specific therapeutic means, liver transplantation, is still the most effective therapeutic means for the induction of ALF by various factors. However, liver transplantation has many problems such as scarcity of liver donors, high cost, and postoperative complications (such as postoperative infection and graft rejection). Therefore, there is an urgent need to intensively study the molecular mechanism of ALF and develop a drug with high specificity and good therapeutic effect against ALF.
Niclosamide is a traditional oral antiparasitic drug used to treat parasitic infections in millions of people worldwide. Recent studies have shown that niclosamide may have wide clinical application in the treatment of diseases other than those caused by parasites. These diseases and conditions may include cancer, bacterial and viral infections, metabolic diseases, and the like. However, its role in ALF has not been reported.
Disclosure of Invention
To solve the defects and the shortages of the prior art; according to the invention, by constructing a classical mouse ALF model, the niclosamide can obviously improve the survival rate of an ALF mouse, reduce liver hemorrhagic necrosis and reduce liver inflammation. Inhibition of macrophage proliferation, control of iron death, and modulation of its pathway in combination with signal transduction and transcriptional activator protein 3 (signal transducer and activator of transcription, stat 3) may be the mechanism by which niclosamide produces liver protection. The object of the present invention is to demonstrate that niclosamide is a potential therapeutic agent for ALF and to reveal the relevant mechanisms.
In order to achieve the above purpose, the invention adopts the following technical scheme:
use of niclosamide in the manufacture of a medicament for the prevention and treatment of acute liver failure (acute liver failure, ALF).
Preferably, the acute liver failure model is LPS/D-GalN-induced acute liver failure.
Preferably, the niclosamide is administered in the animal by intraperitoneal injection.
Preferably, the niclosamide is administered at a dose of 40mg/kg in a LPS/D-GalN-induced acute liver failure model.
Preferably, the niclosamide has the characteristic of extremely low water solubility, and the dissolution mode in the animal model is DMSO initial dissolution, PBS dilution and Tween80 dissolution assistance.
Preferably, the ratio of the niclosamide solvent DMSO to the Tween80 to the PBS is 2:1:37.
preferably, the niclosamide is applied to increasing survival rate, reducing serum transaminase level, reducing liver inflammation and reducing liver hemorrhagic necrosis in an LPS/D-GalN induced acute liver failure model.
Preferably, the niclosamide is used for inhibiting macrophage proliferation activity.
Preferably, the niclosamide is used for reducing the iron content of liver tissues and reducing iron death markers NOX1 and PTGS2 mRNA.
Preferably, the use of niclosamide to inhibit iron death.
Preferably, the niclosamide is used for regulating the pathway of STAT3 in combination.
According to the invention, by constructing a classical mouse ALF model, the niclosamide can obviously improve the survival rate of an ALF mouse, reduce liver hemorrhagic necrosis and reduce liver inflammation; further mechanical analysis proves that inhibiting macrophage proliferation, controlling iron death, and regulating the pathway in combination with STAT3 may be the mechanism by which niclosamide produces liver protection.
The present invention demonstrates that niclosamide is a potential therapeutic agent for ALF and reveals the relevant mechanisms.
Drawings
For a clearer description of embodiments of the present invention or technical solutions in the prior art, the present invention is described in detail by the following detailed description and the accompanying drawings.
FIG. 1 is the effect of niclosamide on LPS/D-GalN-induced survival of ALF. Control group, n=4; LPS/D-GalN group, n=9; niclosamide treated groups, n=11.
FIG. 2 is the effect of niclosamide on serum ALT levels of LPS/D-GalN-induced ALF. Control group, n=3; LPS/D-GalN group, n=7; niclosamide treated group, n=8.
FIG. 3 is the effect of niclosamide on LPS/D-GalN induced liver histopathology of ALF, liver paraffin sections stained with H & E. Control group, n=3; LPS/D-GalN group, n=3; niclosamide treated groups, n=5.
FIG. 4 is the effect of niclosamide on the liver tissue inflammatory factor transcriptome of LPS/D-GalN-induced ALF. Each group n=3-4.
Fig. 5A is a toxicity test of niclosamide on mouse mononuclear macrophages, and fig. 5B is an effect of niclosamide on LPS-induced mouse mononuclear macrophage proliferation activity. Each group n=3.
FIG. 6 is the effect of niclosamide administration on LPS/D-GalN induced ALF liver tissue iron levels. Control group, n=3; LPS/D-GalN group, n=3; niclosamide treated groups, n=5.
FIG. 7 is the effect of niclosamide administration on the expression of the hepatic tissue iron death marker gene of LPS/D-GalN-induced ALF. Each group n=3.
Fig. 8 is a molecular docking diagram of niclosamide and STAT 3.
Fig. 9 is a flow chart of an experimental example of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the present invention more apparent, the present invention is described below by means of specific embodiments shown in the accompanying drawings. It should be understood that the description is only illustrative and is not intended to limit the scope of the invention. In addition, in the following description, descriptions of well-known structures and techniques are omitted so as not to unnecessarily obscure the present invention.
It should be noted here that, in order to avoid obscuring the present invention due to unnecessary details, only structures and/or processing steps closely related to the solution according to the present invention are shown in the drawings, while other details not greatly related to the present invention are omitted.
Experimental example 1
1. Experimental protocol
1.1 subjects 7-9 week old male C57BL/6J mice. Mice were fed in separate cages, fed freely, fed water, and fed in a 12 hour environment each in dark and bright. Experimental mice were randomly divided into three groups: blank control group (i.e. niclosamide solvent+i.p. PBS solution), LPS/D-GalN experimental group (i.e. niclosamide solvent+i.p. LPS/D-GalN), niclosamide treatment group (i.e. niclosamide+i.p. LPS/D-GalN).
1.2 model pre-administration 1 hour prior to modeling a single intraperitoneal injection of niclosamide (40 mg/kg).
1.3A model of ALF was established by single dose LPS (10 ug/kg)/D-GalN (450 mg/kg) intraperitoneal injection in mice. Mice were sacrificed 5 hours after LPS/D-GalN administration, serum from mice was collected for detection of ALT changes in blood, and livers were collected and snap frozen in liquid nitrogen and stored in a-80℃refrigerator for subsequent experiments. Other mice were closely observed and survival at the 16 hour endpoint was recorded.
1.4 serum alanine Aminotransferase (ALT) was measured by a fully automated biochemical analyzer. H & E staining was used to observe liver tissue morphology and pathological changes.
1.5 detection of inflammatory factor transcriptional expression
(1) Trizol method is used for extracting total RNA of liver tissue of mice, and dissolving the RNA in 40ul DEPC H 2 In O, RNA concentration was measured with NanoDrop.
(2) The gene DNA was removed and the reverse transcription reaction was performed according to the instructions of the reverse transcription kit to obtain 20. Mu.l of cDNA.
(3) And (3) detecting relative expression amounts of TNF alpha, IL-1 beta, IL-6 and TGF-beta mRNA by using GAPDH as an internal reference standard in a Real-time quantitative polymerase chain reaction (Real time-quantitative polymerase chain reaction, RT-qPCR) experiment.
(4) Tnfα forward primer sequence:
CATCTTCTCAAAATTCGAGTGACAA
tnfα reverse primer sequence:
TGGGAGTAGACAAGGTACAACCC
IL-1. Beta. Forward primer sequence:
GCCTTGGGCCTCAAAGGAAAGAATC
IL-1 beta reverse primer sequence:
GGAAGACACAGATTCCATGGTGAAG
IL-6 forward primer sequence: AGCCAGAGTCCTTCAGA
IL-6 reverse primer sequence: GGTCCTTAGCCACTCCT
TGF- β forward primer sequence: CTCCCGTGGCTTCTAGTGC
TGF-beta reverse primer sequence: GCCTTAGTTTGGACAGGATCTGGAPDH forward primer sequence: AGGTCGGTGTGAACGGATTTGGAPDH reverse primer sequence:
TGTAGACCATGTAGTTGAGGTCA
1.6 the study involved animal experiments meeting relevant ethical regulations and were conducted in accordance with the protocol approved by the ethical committee of animals at the university of south China. The C57BL/6J mice are ideal animal models recognized in the experiment, and the experiment scheme adopts the minimum animal number to obtain reliable experiment results. In order to reduce the pain of experimental animals, the experimental method uses the modes of intraperitoneal injection administration and head and neck separation to rapidly kill the mice, and the experimental process accords with the animal life standard of humanization ending.
1.7 statistical analysis: data are expressed as mean ± standard error. Statistical differences were analyzed by a two-tailed unpaired Student t-test (when two groups compare differences) or analysis of variance (ANOVA)/Bonferroni posttest method (when two groups compare differences) using GraphPad Prism 8 medical mapping analysis software. P values <0.05 are considered statistically significant, with smaller P values being more pronounced. In the figure, p <0.05 represents p <0.01, p <0.001, and p <0.0001.
2. Experimental results
2.1 effect of niclosamide on survival of LPS/D-GalN induced ALF: FIG. 1 shows the survival curve analysis, and it is understood that almost all mice not treated with niclosamide die within 7 hours after LPS/D-GalN induction. Most mice treated with niclosamide survived the observation period with statistical differences compared to the ALF group (p=0.0004, fig. 1).
2.2 effects of niclosamide on ALT levels in LPS/D-GalN-induced acute liver failure: FIG. 2 shows ALT levels in mice of each group at 5 hours post LPS/D-GalN administration. ALF group showed significantly increased ALT levels (p <0.01, FIG. 2) compared to control group, and the mice in niclosamide treated group showed significantly decreased ALT levels (p <0.0001, FIG. 2) compared to experimental group.
2.3 effects of niclosamide on liver histopathology of LPS/D-GalN induced ALF: as is evident from fig. 3, the liver of the mice in ALF group showed massive hemorrhagic necrosis, a large amount of inflammatory cells infiltrated, and the liver hemorrhagic necrosis area of the mice treated with niclosamide was significantly reduced, and the inflammatory cells infiltrated was not apparent.
2.4 effects of niclosamide on liver tissue inflammatory factor transcriptome of LPS/D-GalN induced ALF: the inflammatory factors tnfα, IL-1 β, IL-6, TGF- β transcriptome expression of ALF were significantly up-regulated compared to the control group (p <0.0001, p <0.01, and p <0.01, respectively, fig. 4). The levels of pro-inflammatory mRNA expression were significantly reduced in the niclosamide treated group compared to the LPS/D-GalN induced ALF group (p <0.01, p <0.05 and p <0.001, respectively, fig. 4).
In conclusion, the results suggest that the LPS/D-GalN induced ALF mouse model is successfully constructed, and that niclosamide has a remarkable protective effect on LPS/D-GalN induced ALF.
Experimental example 2
1. Experimental protocol
1.1 cell culture: mouse mononuclear macrophage RAW264.7 was grown in DMEM medium supplemented with 10% FBS, in which 100 units mL-1 penicillin and 100. Mu.g mL-1 streptomycin were mixed. The above cells were placed in a 37℃humidified incubator containing 5% CO2 for growth.
1.2 cell seed plates: after repeated pipetting and centrifugation of RAW264.7 with ice-cold PBS, cell concentration was detected with a cell counter, RAW264.7 was diluted with complete medium according to cell concentration and plated in 96-well plates at 1×10 per well 4 Individual cells.
1.3 cell experiment group:
(1) Niclosamide toxicity test: blank (without any drug treatment), niclosamide concentration test groups (four different concentrations of niclosamide).
(2) Effect of niclosamide on LPS-induced mouse mononuclear macrophage proliferation activity: blank control group (without any drug treatment), LPS model group (with LPS), niclosamide treatment group (lps+four different concentrations of niclosamide).
1.4LPS induces macrophage inflammatory response: after 24 hours of the seed plates, LPS is used
50 ng/ml) induces macrophage inflammatory response with the administration of niclosamide treatment.
1.5 cell viability assay: after 24 hours of cell treatment, CCK8 working solution (a quantity of complete medium+10% of medium volume of CCK8 reagent) was prepared, the working solution was added to 96-well plates, 100ul per well was measured on a microplate reader after 1 hour and 20 minutes, and OD at 450nm absorbance was measured.
1.6 statistical analysis: data are expressed as mean ± standard error. Statistical differences were analyzed by analysis of variance (ANOVA)/Bonferroni posttest method using GraphPad Prism 8 medical mapping analysis software. P <0.05 is considered statistically significant, the smaller the P value, the more significant the difference. * Represents p <0.05, and p <0.01.
2. Experimental results
The cytotoxicity test results showed that 50-500nM niclosamide was not significantly toxic to RAW264.7 cells (FIG. 5A). Compared with cells without LPS, LPS can obviously induce the proliferation of mouse macrophages, 100-500nM niclosamide obviously inhibits the proliferation of RAW264.7 cells (p <0.05, figure 5B), and the dose dependence is that the higher the concentration of niclosamide is, the more obvious the inhibition effect is.
Experimental example 3
1. Experimental protocol
1.1 liver tissue iron detection
(1) Pretreatment of mouse liver tissue sample
The liver tissue weights of the mice in each group of experimental example 1 were accurately weighed, 9 volumes of physiological saline were added in a ratio of weight (mg): volume (ul) =1:9, and the mixture was placed in a homogenizer for mechanical homogenization 4 times (60 hz for 10 seconds), centrifuged at 2500rpm for 10 minutes, and 500ul of supernatant was collected for measurement.
(2) Tissue iron detection
According to the specification, a blank tube (double distilled water), a standard tube (2 mg/L iron standard application liquid) and a measuring tube (sample to be measured) are arranged, 1.5ml of iron color developing agent is added into each 500ul tube, the mixture is uniformly mixed, incubated for 5 minutes at 100 ℃, cooled by running water, centrifuged for 10 minutes at 3500rpm, and 200ul of supernatant is taken to measure OD value of each tube under the absorbance of 520nm on an enzyme-labeling instrument.
(3) Tissue iron content calculation
Tissue iron content (mg/gprot) = (a) Measurement -A Blank space /A Standard of -A Blank space )*C Standard of /C pro
C Standard of ＝2mg/L,C pro Tissue homogenate protein concentration, gprot/L.
1.2 detection of iron death marker Gene expression
(1) Trizol method is used for extracting total RNA of liver tissue of mice, and dissolving the RNA in 40ul DEPC H 2 In O, RNA concentration was measured with NanoDrop.
(2) The gene DNA was removed and the reverse transcription reaction was performed according to the instructions of the reverse transcription kit to obtain 20. Mu.l of cDNA.
(3) RT-qPCR experiments, using GAPDH as an internal standard, detect the relative expression levels of the iron death markers prostaglandin endoperoxide synthase 2 (prostaglandin-endoperoxide synthase, PTGS2) and NADPH oxidase 1 (NADPH oxidase 1, NOX 1) mRNA.
(4) PTGS2 forward primer sequence: GTCATTGGTGGAGAGGTGTATCPTGS2 reverse primer sequence: caggagatggagtgttgtaganox 1 forward primer sequence: tcacaacctctcttccataagnox 1 reverse primer sequence: CTTCTGCTGGGAGCGATAAA
GAPDH forward primer sequence: AGGTCGGTGTGAACGGATTTGGAPDH reverse primer sequence:
TGTAGACCATGTAGTTGAGGTCA
1.3 statistical analysis as in experimental example 1, p <0.05 and p <0.01 and p <0.0001.
2. Experimental results
2.1 effects of niclosamide administration on LPS/D-GalN induced liver tissue iron levels of ALF mice in the ALF group had significantly elevated liver tissue iron levels compared to the normal control group (p <0.05, FIG. 6). The levels of iron in the liver tissue of mice were significantly reduced in the niclosamide treated group compared to the LPS/D-GalN induced ALF group (p <0.0001, fig. 6).
2.2 effects of niclosamide administration on hepatic tissue iron death-related gene expression of LPS/D-GalN induced ALF iron death marker genes NOX1 and PTGS2 of ALF were significantly up-regulated compared to control (p <0.01 and p <0.0001, FIG. 7). The levels of NOX1 and PTGS2mRNA expression were significantly reduced in the niclosamide treated group compared to the LPS/D-GalN induced ALF group (p <0.05 and p <0.0001, FIG. 7).
In conclusion, LPS/D-GalN induced ALF may promote activation of iron death, whereas administration of niclosamide significantly inhibited iron death caused by ALF.
Experimental example 4
1. Experimental protocol
1.1 Small molecule design and treatment
Downloading the 3D structure of the SDF format of niclosamide from PubChem data, importing the structure into ChemBio3D Ultra 14.0 for energy minimization, setting Minimum RMS Gradient to: 0.001, the small molecule is stored in the mol2 format. And (3) introducing the optimized small molecules into Autodock tools-1.5.6 for hydrogenation, calculating charges, distributing the charges, setting rotatable bonds, and storing the small molecules in a 'pdbqt' format.
1.2 preparation and treatment of proteins
STAT3 (PDB ID:6 NJS) was downloaded from the PDB database, protein crystal water, original ligand, etc., were removed using Pymol2.3.0, and the protein structure was imported into AutoDocktools for hydrogenation, charge calculation, charge distribution, specifying atom type, and saved as "pdbqt" format.
1.3 preparation of parameter files
Protein binding sites were predicted using POCASA 1.1, docking was performed with autodock vina1.1.2, STAT 3-related parameters were set as: center_x=12.4, center_y=55.9, center_z= -1.3; search space: size_x:60, size_y:60, size_z:60 (pitch of each lattice is
) 10, and the rest parameters are default settings.
1.4 analysis of results
Interaction pattern analysis was performed on the docking results using pymol2.3.0 and liglot v 2.2.5.
2. Experimental results
The binding energy of niclosamide and STAT3 is-7.0 kcal/mol, which proves that the niclosamide has better binding effect. Niclosamide interacts with STAT3 mainly through hydrogen bond formation and hydrophobic acting force, and hydrogen bonds with Asp566 and Asn567, wherein the lengths of the hydrogen bonds are respectively
Has hydrophobic effect with Pro471, asp570, ile569 (FIG. 8).
In summary, niclosamide can effectively improve the survival rate of liver failure induced by LPS/D-GalN of a domestic and foreign classical ALF mouse model, and remarkably inhibit liver necrosis and inflammatory cell infiltration, which is possibly related to the fact that niclosamide reduces inflammatory response induced by macrophages by inhibiting macrophage proliferation, niclosamide inhibits iron death, and STAT3 is combined to regulate and control the pathway (figure 9). The application of the niclosamide in ALF has great prospect and is a potential therapeutic drug for ALF.
The reagents/consumables used in the above experimental examples are shown in the following table:
the instruments/manufacturers involved in the above experimental examples are as follows:
| instrument type | Manufacturer (S) |
| Centrifugal machine | Eppendorf |
| Constant temperature water bath box | ThermoFisherScientific |
| -20 ℃ experimental refrigerator | ThermoFisherScientific |
| -80 ℃ ultralow temperature experiment refrigerator | ThermoFisherScientific |
| Pipetting gun | Eppendorf |
| Refrigerator for 4 ℃ experiment | ThermoFisherScientific |
| Fume hood | ThermoFisherScientific |
| Centrifugal machine | Eppendorf |
| Constant temperature humidifying incubator for cells | ThermoFisherScientific |
| Multifunctional microplate detector | PerkinElmer |
| 7500 real-time fluorescent quantitative PCR instrument | ThermoFisherScientific |
The reagents of the above experimental examples were formulated as follows:
(1) the niclosamide working solution is prepared (in-situ) by the following steps: and weighing a certain amount of niclosamide, and calculating the final volume of the prepared solution according to the experimental dosage. Niclosamide suspension is prepared by dissolving niclosamide in 5% final volume DMSO, adding 92.5% PBS, and adding 2.5% Tween 80.
(2) Preparing a niclosamide cell experiment storage solution: niclosamide is added with a proper amount of DMSO to prepare 10mM storage solution, and the storage solution is placed in a refrigerator at the temperature of minus 80 ℃ for freezing.
(3) LPS/D-GalN injection preparation: 5mg/ml and 225mg/ml stock solutions are prepared respectively by PBS, frozen at-20 ℃, and the stock solutions are diluted into working solutions by PBS when in use (at room temperature).
According to the invention, by constructing a classical mouse ALF model, the niclosamide can obviously improve the survival rate of an ALF mouse, reduce liver hemorrhagic necrosis and reduce liver inflammation; inhibition of macrophage proliferation, control of iron death, and modulation of its pathway in combination with STAT3 may be one of the mechanisms by which niclosamide produces liver protection; the experimental examples comprehensively prove that the niclosamide is a potential therapeutic drug of ALF.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (10)
1. Use of niclosamide in inhibiting acute liver failure.
2. Use of niclosamide according to claim 1 for inhibiting acute liver failure, characterized in that: application of niclosamide as a medicament for preventing and treating acute liver failure; the acute liver failure model is LPS/D-GalN induced acute liver failure.
3. Use of niclosamide according to claim 1 for inhibiting acute liver failure, characterized in that: the niclosamide is administered in the animal body by intraperitoneal injection.
4. Use of niclosamide according to claim 2 for inhibiting acute liver failure, characterized in that: the niclosamide is administered at a dose of 40mg/kg in an LPS/D-GalN induced acute liver failure model.
5. Use of niclosamide according to claim 1 for inhibiting acute liver failure, characterized in that: the niclosamide has the characteristic of extremely low water solubility, and the dissolution mode in an animal model is DMSO primary dissolution, PBS dilution and Tween80 auxiliary dissolution.
6. Use of niclosamide according to claim 5 for inhibiting acute liver failure, characterized in that: the ratio of the niclosamide solvent DMSO to the Tween80 to the PBS is 2:1:37.
7. use of niclosamide according to claim 2 for inhibiting acute liver failure, characterized in that: the niclosamide can be applied to increasing survival rate, reducing serum transaminase level, reducing liver inflammation and reducing liver hemorrhagic necrosis in LPS/D-GalN induced acute liver failure model.
8. Use of niclosamide according to claim 1 for inhibiting acute liver failure, characterized in that: the application of the niclosamide in inhibiting macrophage proliferation activity.
9. Use of niclosamide according to claim 1 for inhibiting acute liver failure, characterized in that: application of niclosamide in reducing iron content of liver tissues and reducing iron death markers NOX1 and PTGS2 mRNA.
10. Use of niclosamide according to claim 1 for inhibiting acute liver failure, characterized in that: the application of the niclosamide in the combination with STAT3 to regulate and control the pathway of the niclosamide is provided.
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| CN104602682A (en) * | 2012-05-08 | 2015-05-06 | 埃罗米克斯有限公司 | New methods |
| US20170056347A1 (en) * | 2015-09-01 | 2017-03-02 | First Wave Biopharma | Methods and compositions for treating conditions associated with an abnormal inflammatory responses |
| CN112741826A (en) * | 2021-02-25 | 2021-05-04 | 澳门大学 | New application of niclosamide |
| US20230009145A1 (en) * | 2019-12-18 | 2023-01-12 | Universität Regensburg | Inhibition of tmem16a by benzbromarone or niclosamide for treating polycystic kidney disease and/or polycystic liver disease |
| US20230049822A1 (en) * | 2020-01-10 | 2023-02-16 | First Wave Bio, Inc. | Compositions comprising niclosamide for use in treating conditions associated with an abnormal inflammatory response |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104602682A (en) * | 2012-05-08 | 2015-05-06 | 埃罗米克斯有限公司 | New methods |
| US20170056347A1 (en) * | 2015-09-01 | 2017-03-02 | First Wave Biopharma | Methods and compositions for treating conditions associated with an abnormal inflammatory responses |
| US20230009145A1 (en) * | 2019-12-18 | 2023-01-12 | Universität Regensburg | Inhibition of tmem16a by benzbromarone or niclosamide for treating polycystic kidney disease and/or polycystic liver disease |
| US20230049822A1 (en) * | 2020-01-10 | 2023-02-16 | First Wave Bio, Inc. | Compositions comprising niclosamide for use in treating conditions associated with an abnormal inflammatory response |
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