[논문]대황과 실리마린의 병용투여의 간섬유화 보호 효과

정일하; 지상우; 노성수

doi:10.22246/jikm.2023.44.3.402

대황과 실리마린의 병용투여의 간섬유화 보호 효과
Liver Protective Effect of the Co-treatment of Rhei Radix et Rhizoma and Silymarin on TAA-induced Liver Injury 원문보기

대한한방내과학회지 = The journal of internal Korean medicine, v.44 no.3, 2023년, pp.402 - 417

정일하 (대구한의대학교 한의과대학 본초약리학교실) , 지상우 (대구한의대학교 한의과대학 본초약리학교실) , 노성수 (대구한의대학교 한의과대학 본초약리학교실)

Abstract ▼ AI-Helper

Objective: Liver fibrosis is a highly conserved wound-healing response and the final common pathway of chronic inflammatory injury. This study aimed to evaluate the potential anti-fibrotic effect of the combination of Rhei Radix et Rhizoma water extract (RW) and silymarin in a thioacetamide (TAA)-induced liver fibrosis model. Methods: The liver fibrosis mouse model was established through the intraperitoneal injection of TAA (1 week 100 mg/kg, 2-3 weeks 200 mg/kg, 4-8 weeks 400 mg/kg) three times per week for eight weeks. Animal experiments were conducted in five groups; Normal, Control (TAA-induced liver fibrosis mice), Sily (silymarin 50 mg/kg), RSL (RW 50 mg/kg+silymarin 50 mg/kg), and RSH (RW 100 mg/kg+silymarin 50 mg/kg). Biochemical analyses were measured in serum, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA), and ammonia levels. Liver inflammatory cytokines and fibrous biomarkers were measured by Western blot analysis, and liver histopathology was evaluated through tissue staining. Results: A significant decrease in the liver function markers AST and ALT and a reduction in ammonia and total bilirubin were observed in the group treated with RSL and RSH. Measurement of reactive oxygen species and MDA revealed a significant decrease in the RSL and RSH administration group compared to the TAA induction group. The expression of extracellular matrix-related proteins, such as transforming growth factor β1, α-smooth muscle actin, and collagen type I alpha 1, was likewise significantly decreased. All drug-administered groups had increased matrix metalloproteinase-9 but a decreasing tissue inhibitor of matrix metalloproteinase-1. RSL and RSH exerted a significant upregulation of NADPH oxidase 2, p22phox, and p47phox, which are oxidative stress-related factors. Furthermore, pro-inflammatory proteins such as cyclooxygenase 2 and interleukin-1β were markedly suppressed through the inhibition of nuclear factor kappa B activation. Conclusions: The administration of RW and silymarin suppressed the NADPH oxidase factor protein level and showed a tendency to reduce inflammation-related enzymes. These results suggest that the combined administration of RW and silymarin improves acute liver injury induced by TAA.

주제어

표/그림 (8)

표 Table 1. Body Weight Change of Liver Fibrosis Model
그림 Fig. 1. The ALT, AST, and ammonia levels in serum.Normal : normal mice, Control : TAA-induced liver fibrosis mice, sliy : TAA-induced liver fibrosis with silymarin, RSL : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+Rhei Rhizoma (50 mg/kg), RSH : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+Rhizoma (100 mg/kg). All data are expressed means±SEM (n=7). Significance : ^###p<0.001 vs. Normal, *p<0.05, **p<0.01, and ***p<0.001 vs. Control.
그림 Fig. 2. ROS level and MDA concentration in serum and liver. Normal : normal mice, Control : TAA-induced liver fibrosis mice, sliy : TAA-induced liver fibrosis with silymarin; RSL : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (50 mg/kg), RSH : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (100 mg/kg). All data are expressed as means±SEM (n=7). Significance : ^##p<0.01 and ^###p<0.001 vs. Normal, *p<0.05, **p<0.01, and ***p<0.001 vs. Control.
그림 Fig. 3. MMP-9 and TIMP-1 activity in livers. Normal : normal mice, Control : TAA-induced liver fibrosis mice, sliy : TAA-induced liver fibrosis with silymarin, RSL : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (50 mg/kg), RSH : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (100 mg/kg). All data are expressed as means±SEM (n=7). Significance : ^###p<0.001 vs. Normal, *p<0.05, **p<0.01 vs. Control.
그림 Fig. 4. Expressions of TGF-β1, a-SMA, and COL1A1 protein in liver tissue. Normal : normal mice, Control : TAA-induced liver fibrosis mice, sliy : TAA-induced liver fibrosis with silymarin, RSL : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (50 mg/kg), RSH : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (100 mg/kg) body weight. All data are expressed as means±SEM (n=7). Significance : ^##p<0.01 and ^###p<0.001 vs. Normal, *p<0.05, **p<0.01, and ***p<0.001 vs. Control.
그림 Fig. 5. Expressions of NOX2, p22phox, and p47phox protein in liver tissue. Fig. 5. Expressions of NOX2, p22phox, and p47phox protein in liver tissue. Normal : normal mice, Control : TAA-induced liver fibrosis mice, sliy : TAA-induced liver fibrosis with silymarin, RSL : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (50 mg/kg), RSH : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (100 mg/kg) body weight. All data are expressed means±SEM (n=7). Significance : ^###p<0.001 vs. Normal, *p<0.05 and **p<0.01 vs. Control.
그림 Fig. 6. Expressions of NF-kB p65 and IkB-ɑ, COX-2, IL-1b protein in liver tissue. Normal : normal mice, Control : TAA-induced liver fibrosis mice, sliy : TAA-induced liver fibrosis with silymarin, RSL : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (50 mg/kg), RSH : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (100 mg/kg) body weight. All data are expressed as means±SEM (n=7). Significance : ^###p<0.001 vs. Normal, *p<0.05 and **p<0.01 vs. Control.
그림 Fig. 7. Histopathological analysis. hematoxylin-eosin : (H&E) staining, A : Masson's trichrome (MT), B : Sirius Red/Fast Green Stain, C in liver tissue. Normal : normal mice, Control : TAA-induced liver fibrosis mice, sliy : TAA-induced liver fibrosis with silymarin, RSL : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (50 mg/kg), RSH : TAA-induced liver fibrosis mice treated with silymarin (50 mg/kg)+RW (100 mg/kg) body weight. (x200, Scale bar 100 μm).

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