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Application of rhIL-1Ra in preparing medicaments for treating acute liver failure

An acute liver failure and drug technology, applied in the field of medicine, can solve the problems of aggravating liver damage and limited efficacy, and achieve the effects of inhibiting liver cell apoptosis, promoting liver cell proliferation, and overcoming the limited source of liver donors.

Inactive Publication Date: 2020-02-11
SHANGHAI SIXTH PEOPLES HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2001, rhIL-1Ra was approved for clinical use in the treatment of refractory rheumatoid arthritis patients for whom traditional medicines had very limited efficacy
Fujioka et al. reported that sequential treatment with inactivated acnesPropioniobacteRaum and lipopolyside resulted in hepatic necrosis, increased expression of IL-1ra and IL-1 in the liver, and the use of neutralizing IL-1ra further aggravated liver damage

Method used

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  • Application of rhIL-1Ra in preparing medicaments for treating acute liver failure
  • Application of rhIL-1Ra in preparing medicaments for treating acute liver failure
  • Application of rhIL-1Ra in preparing medicaments for treating acute liver failure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] In this example, the effect of rhIL-1Ra on the survival rate of APAP-induced mice, the activities of ALT and AST in serum, and the apoptosis of hepatocytes was determined through animal experiments. The specific experimental steps include:

[0031] 1. In the first group of experiments, all mice were induced with acute liver failure by a single intraperitoneal injection of 650 or 550 mg / kg APAP. One hour later, the mice in the rhIL-1Ra group were subcutaneously injected with 1 mg / kg rhIL-1Ra every 12h to 168h, and the mice in the NS group were treated with NS as the control. The number of dead mice in each group was recorded after APAP injection.

[0032] 2. In the next set of experiments, all mice were injected intraperitoneally with 550 mg / kg APAP to create models, and then treated with the above rhIL-1Ra or NS. Whole blood samples were collected after APAP injection, and ALT and AST activities in serum were measured using a Fuji Chemical 3500V following the manufactur...

Embodiment 2

[0038] In this example, the effect of rhIL-1Ra on APAP-induced liver cell pathology was verified through liver histological experiments. The specific experimental steps include: the liver specimen is cut into small pieces (0.1cm 3 ), fixed in formaldehyde solution, dehydrated, embedded in paraffin, thickness 5mm. Sections were stained with hematoxylin-eosin. Tdt-mediated dUTP-x nick-endlabeling staining (TUNEL method) was performed using an in situ cell death detection kit. PCNA was determined by immunohistochemical method. Histological examination was done by NIS-Elements Basic Research (Nikon, Kanagawa, Japan). Two slices were taken from the left and right middle lobes of each liver, and 8 low-power mirrors were taken from each slice for calculation.

[0039] Depend on Figure 4 It can be seen that rhIL-1Ra significantly reduced the number of hepatocyte apoptosis at the time point of 3h and 6h after APAP induction in mice.

[0040] Depend on Figure 5 It can be seen t...

Embodiment 3

[0044] This example explores the cascade relationship between rhIL-1Ra and hepatocyte apoptosis pathway based on the above conclusions, and the specific steps are as follows:

[0045] 1. Determination of cytochrome c and Bax by Western Blotting: The liver samples were homogenized with PIPA buffer, and the protein concentration in each lysate was detected by BSA microbiuret method. Proteins were extracted using a mitochondrial / cytoplasmic fractionation kit. The cytoplasmic fraction (S100) and mitochondrial-rich fraction (HM) of liver extracts were determined by cytochrome c, and Bax and b-actin in liver lysates were determined by western blotting. Proteins were electrophoresed on SDS-PAGE gels (4% stacking gel and 15% flow gel) and then transferred to PVDF membranes (Pall, NY, USA). These membranes are then sequentially hybridized with primary and secondary antibodies. Signal detection was performed using enhanced chemiluminescent reagents (Thermo, IL, USA).

[0046] 2. Asse...

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Abstract

The invention provides application of rhIL-1Ra in preparing medicaments for treating acute liver failure. Compared with a control group, the rhIL-1Ra can obviously inhibit the activity of alanine aminotransferase and aspartate aminotransferase in serum, the death of liver cells is reduced, and the proliferation of the liver cells is promoted, so that the rhIL-1Ra has obvious therapeutic effects ofprotecting liver injury and promoting liver regeneration. In addition, the rhIL-1Ra inhibits apoptosis mediated by caspase-3, caspase-8 and caspase-9 activation in liver tissue by decreasing mitochondrial cytochrome c release. In summary, the rhIL-1Ra provides a strategy for the preparation of candidate drugs capable of reducing hepatocyte apoptosis for the treatment of APAP-induced acute liver failure and liver injury.

Description

technical field [0001] The invention relates to the field of medicine, in particular to the application of rhIL-1Ra in the preparation of medicines for treating acute liver failure. Background technique [0002] The liver is an important organ that undertakes various functions such as metabolic regulation and storage of sugar, protein, and lipid as the three major nutrients, as well as decomposing and detoxifying substances that the body does not need. Excessive intake of alcohol, viral infections, unbalanced eating habits, stress, and smoking can cause acute or chronic impairment of these functions, and when this impairment develops, for example, acute hepatitis, chronic hepatitis, cirrhosis, alcoholic fat Liver, hepatitis B virus, liver cancer, acute liver failure and other diseases. [0003] Acute liver failure is a life-threatening disease characterized by sudden loss of liver function, with no previous history of liver disease, massive death of liver cells, and only a ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P1/16
CPCA61K45/00A61P1/16
Inventor 胡建军
Owner SHANGHAI SIXTH PEOPLES HOSPITAL
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