Journal of Traditional Chinese Medicine ›› 2025, Vol. 45 ›› Issue (2): 385-398.DOI: 10.19852/j.cnki.jtcm.2025.02.004
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Integrating network pharmacology and experimental validation to uncover the synergistic effects of Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis) with 5-fluorouracil in colorectal cancer models
TAN Xiying1, GU Ruxin2,3, TAO Jing4, ZHANG Yu3, SUN RuiQian5, YIN Gang5, ZHANG Shuo6, TANG Decai5(
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- 1 Department of Pharmacy, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
2 Department of Pain Management, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
3 School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
4 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
5 School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
6 Department of Pharmacy, Nantong Hospital of Traditional Chinese Medicine, Nantong, 226001, China
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Received:2023-12-22Accepted:2024-05-15Online:2025-04-15Published:2025-03-10 -
Contact:TANG Decai, School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China. talknow@njucm.edu.cn, Telephone: +86-13813929742 -
About author:TAN Xiying and GU Ruxin are co-first authors and contributed equally to this work -
Supported by:National Natural Science Foundation of China Youth Found Project: Anti-Colorectal Cancer Metastasis Mechanism of Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis) According to the Hypoxia-Inducible Factor 2 Alpha/β-Catenin Cross-Talk Which Influence the Colon Tumor Stem Cells in Hypoxia Microenvironment(82003961);National Natural Science Foundation of China Youth Found Project: the Mechanism of the Compatibility of Huangqi (Radix Astragali Mongolici) and Ezhu (Rhizoma Curcumae Phaeocaulis) on the Early Metastasis of Hepatocellular Carcinoma Mediated by Cancer Associated Fibroblasts(82104408);Science Foundation of China Project: Involvement of Hypoxia Inducible Factor-1α Signal in Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis) Combination Induced Remolding of Tumor Hypoxic Microenvironment(82074035);Science and Technology Development Project of Traditional Chinese Medicine in Jiangsu Province: Mechanism of Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis) Herb Pair on the Inhibition of Colon Cancer Metastasis Through the Wnt/β-catenin Pathway(YB201921)
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TAN Xiying, GU Ruxin, TAO Jing, ZHANG Yu, SUN RuiQian, YIN Gang, ZHANG Shuo, TANG Decai. Integrating network pharmacology and experimental validation to uncover the synergistic effects of Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis) with 5-fluorouracil in colorectal cancer models[J]. Journal of Traditional Chinese Medicine, 2025, 45(2): 385-398.
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Figure 1 HQEZ significantly increased sensitivity of colorectal cancer to 5-FU in vivo and in vitro A: measure of tumor volume; B: increase of tumor volume (n = 5-7); C: at the end of the animal experiment, the tumors were collected for photograph. C1: tumors from mice of control group; C2: tumors from mice of 5-FU group; C3: tumors from HQEZ group, C4: tumors from combined group 5-FU combined with HQEZ group (n = 5-7). And the final weight of tumors from every group (C5). D: in EdU incorporation experiment, HQEZ significantly enhanced the inhibition of 5-FU on the growth of HCT116 by immunofluorescence staining. D1: EdU signaling from control group; D2: DAPI which stains the nucleus of control group; D3: merge image of D1 and D2; D4: EdU signaling from 5-FU (0.18 μg/mL, 48 h) treated group; D5: DAPI which stains the nucleus of 5-FU treated group; D6: merge image of D4 and D5, D7: EdU signaling from 5-FU (0.18 μg/mL, 48 h) combined with HQEZ (30 mg/mL, 48 h) group; D8: DAPI which stains the nucleus of 5-FU (0.18 μg/mL, 48 h) combined with HQEZ (30 mg/mL, 48 h) group; D9: merge image of D7 and D8 (n = 5, repeated 3 times); D10: the rate of EdU positive cells. HQEZ: Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis); 5-FU: 5-Fluorouracil; i.p.: intraperitoneal; p.o.: peros; EdU: 5-Ethynyl-2’- deoxyuridine. Control group (PBS, i.p. every two days and p.o. daily), 5-FU group (30 mg/kg every two days, i.p.), HQEZ group (10 g·kg-1·d-1, p.o.), combined group (5-FU, 30 mg/kg every two days, i.p.; HQEZ, 10 g·kg-1·d-1, p.o.). Data are presented as mean ± standard deviation. aP < 0.05 and bP < 0.001, compared with the Control group. cP < 0.001, compared with the 5-FU group, differences were evaluated by one-way analysis of variance, bar = 50 μm.
Figure 1 HQEZ significantly increased sensitivity of colorectal cancer to 5-FU in vivo and in vitro A: measure of tumor volume; B: increase of tumor volume (n = 5-7); C: at the end of the animal experiment, the tumors were collected for photograph. C1: tumors from mice of control group; C2: tumors from mice of 5-FU group; C3: tumors from HQEZ group, C4: tumors from combined group 5-FU combined with HQEZ group (n = 5-7). And the final weight of tumors from every group (C5). D: in EdU incorporation experiment, HQEZ significantly enhanced the inhibition of 5-FU on the growth of HCT116 by immunofluorescence staining. D1: EdU signaling from control group; D2: DAPI which stains the nucleus of control group; D3: merge image of D1 and D2; D4: EdU signaling from 5-FU (0.18 μg/mL, 48 h) treated group; D5: DAPI which stains the nucleus of 5-FU treated group; D6: merge image of D4 and D5, D7: EdU signaling from 5-FU (0.18 μg/mL, 48 h) combined with HQEZ (30 mg/mL, 48 h) group; D8: DAPI which stains the nucleus of 5-FU (0.18 μg/mL, 48 h) combined with HQEZ (30 mg/mL, 48 h) group; D9: merge image of D7 and D8 (n = 5, repeated 3 times); D10: the rate of EdU positive cells. HQEZ: Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis); 5-FU: 5-Fluorouracil; i.p.: intraperitoneal; p.o.: peros; EdU: 5-Ethynyl-2’- deoxyuridine. Control group (PBS, i.p. every two days and p.o. daily), 5-FU group (30 mg/kg every two days, i.p.), HQEZ group (10 g·kg-1·d-1, p.o.), combined group (5-FU, 30 mg/kg every two days, i.p.; HQEZ, 10 g·kg-1·d-1, p.o.). Data are presented as mean ± standard deviation. aP < 0.05 and bP < 0.001, compared with the Control group. cP < 0.001, compared with the 5-FU group, differences were evaluated by one-way analysis of variance, bar = 50 μm.
Table 1 Cluster information of the protein-protein interaction network
| Cluster | Score | Nodes | Edges | Gene Symbol |
|---|---|---|---|---|
| 1 | 5.429 | 8 | 19 | MMP9, MPO, TLR9, MMP2, KDR, IGF1R, TLR4, PPARG |
| 2 | 4.8 | 6 | 12 | TYMS, AKT1, ESR2, SRC, PTGS2, EP300 |
| 3 | 3.5 | 5 | 7 | TOP2A, DHFR, DPYD, ABCC1, TOP1 |
| 4 | 3.5 | 5 | 7 | ABCB1, MTHFR, SLC19A1, EGFR, ABCG2 |
Table 1 Cluster information of the protein-protein interaction network
| Cluster | Score | Nodes | Edges | Gene Symbol |
|---|---|---|---|---|
| 1 | 5.429 | 8 | 19 | MMP9, MPO, TLR9, MMP2, KDR, IGF1R, TLR4, PPARG |
| 2 | 4.8 | 6 | 12 | TYMS, AKT1, ESR2, SRC, PTGS2, EP300 |
| 3 | 3.5 | 5 | 7 | TOP2A, DHFR, DPYD, ABCC1, TOP1 |
| 4 | 3.5 | 5 | 7 | ABCB1, MTHFR, SLC19A1, EGFR, ABCG2 |
Table 2 Cluster information of the protein-protein interaction network
| Active ingredient | Target name | PDB ID | Binding energy (kcal/mol) |
|---|---|---|---|
| Curcumin | EGFR | 1M17 | －2.16 |
| Folate | TYMS | 1JU6 | －1.98 |
| PTGS2 | 5IKR | －1.1 | |
| Isorhamnetin | ABCB1 | 6QEX | －1.6 |
| AKT1 | 6HHI | －3.59 | |
| Kaempferol | EGFR | 1M17 | －2.06 |
| ABCB1 | 6QEX | －3.05 | |
| PTGS2 | 5IKR | －3.92 | |
| AKT1 | 6HHI | －5.01 | |
| Quercetin | EGFR | 1M17 | －2.44 |
| ABCB1 | 6QEX | －1.34 | |
| AKT1 | 6HHI | －3.72 |
Table 2 Cluster information of the protein-protein interaction network
| Active ingredient | Target name | PDB ID | Binding energy (kcal/mol) |
|---|---|---|---|
| Curcumin | EGFR | 1M17 | －2.16 |
| Folate | TYMS | 1JU6 | －1.98 |
| PTGS2 | 5IKR | －1.1 | |
| Isorhamnetin | ABCB1 | 6QEX | －1.6 |
| AKT1 | 6HHI | －3.59 | |
| Kaempferol | EGFR | 1M17 | －2.06 |
| ABCB1 | 6QEX | －3.05 | |
| PTGS2 | 5IKR | －3.92 | |
| AKT1 | 6HHI | －5.01 | |
| Quercetin | EGFR | 1M17 | －2.44 |
| ABCB1 | 6QEX | －1.34 | |
| AKT1 | 6HHI | －3.72 |
Figure 2 Administration of HQEZ inhibited hub targets and FOXO pathway in HCT116 in vitro A: in CCK8 assay, HQEZ only significantly inhibited the proliferation of HCT116 in a relatively high concentration (n = 3). B: after 48 h, the influence of different concentration of HQEZ on the mRNA levels of target genes according to network pharmacology were evaluated by qPCR assay. B1: the influence of TYMS; B2: the influence of MDR1; B3: the influence of Bcl-2; B4: the influence of EGFR. C: after 48 hours, the protein levels of Hub targets from network pharmacology were evaluated by Western-blot assay and the bands of were showed. (n = 3). D: after 48 h, the protein levels of Hub targets from network pharmacology were evaluated by western-blot assay which were administrated with HQEZ dose-dependently. D1: the protein levels of BNIP3 were downregulated; D2: the protein levels of PEPCK were not significantly influenced; D3: the protein levels of CCND1 were not significantly influenced; D4: the protein levels of Catalase were significantly downregulated (n = 3). HCT116 cells were treated with different concentrations of HQEZ including 0, 5, 10, 20 and 40 mg/mL for 48 h. TYMS: thymidylate synthetase; MDR1: multidrug resistance protein 1; Bcl-2: B-cell lymphoma-2; EGFR: epidermal growth factor receptor; BNIP3: BCL2/Adenovirus E1B 19 kDa Protein-Interacting Protein 3; PEPCK: phosphoenolpyruvate carboxykinase 2; CCND1: Cyclin D1. Data are presented as mean ± standard deviation. aP < 0.05, bP < 0.01 and cP < 0.001, compared with the control group, differences were evaluated by one-way analysis of variance.
Figure 2 Administration of HQEZ inhibited hub targets and FOXO pathway in HCT116 in vitro A: in CCK8 assay, HQEZ only significantly inhibited the proliferation of HCT116 in a relatively high concentration (n = 3). B: after 48 h, the influence of different concentration of HQEZ on the mRNA levels of target genes according to network pharmacology were evaluated by qPCR assay. B1: the influence of TYMS; B2: the influence of MDR1; B3: the influence of Bcl-2; B4: the influence of EGFR. C: after 48 hours, the protein levels of Hub targets from network pharmacology were evaluated by Western-blot assay and the bands of were showed. (n = 3). D: after 48 h, the protein levels of Hub targets from network pharmacology were evaluated by western-blot assay which were administrated with HQEZ dose-dependently. D1: the protein levels of BNIP3 were downregulated; D2: the protein levels of PEPCK were not significantly influenced; D3: the protein levels of CCND1 were not significantly influenced; D4: the protein levels of Catalase were significantly downregulated (n = 3). HCT116 cells were treated with different concentrations of HQEZ including 0, 5, 10, 20 and 40 mg/mL for 48 h. TYMS: thymidylate synthetase; MDR1: multidrug resistance protein 1; Bcl-2: B-cell lymphoma-2; EGFR: epidermal growth factor receptor; BNIP3: BCL2/Adenovirus E1B 19 kDa Protein-Interacting Protein 3; PEPCK: phosphoenolpyruvate carboxykinase 2; CCND1: Cyclin D1. Data are presented as mean ± standard deviation. aP < 0.05, bP < 0.01 and cP < 0.001, compared with the control group, differences were evaluated by one-way analysis of variance.
Figure 3 The combination therapy of HQEZ with 5-FU significantly down-regulated 5-FU resistance targets in HCT116 in vitro A: the influence of 5-FU (0.18 μg/mL) combined with different concentration of HQEZ on the transcription level of target genes in HCT116 cells after 48 h by qPCR assay. A1: BRCA1; A2: MDR1; A3: TYMS; A4: ERCC1; A5: RRM1; A6: POLH; A7: co MLH1; (n = 3). B: HQEZ decreased expression of protein from 5-FU resistance-related genes by western blot assay (n = 3). C: by immunofluorescence staining, combined treatment of 5-FU (0.18 μg/mL) and different concentration of HQEZ significantly increased the inhibition of p-AKT in HCT116 cells after 48 h. (n = 3). C1: p-AKT signaling from control group; C2: p-AKT merged with DAPI signaling from control group; C3: p-AKT signaling from 5-FU group; C4: p-AKT merged with DAPI signaling from 5-FU group; C5: p-AKT signaling from 5-FU combined HQEZ group; C6: p-AKT merged with DAPI signaling from 5-FU combined HQEZ (5 mg/mL) group; C7: p-AKT signaling from 5-FU combined HQEZ (10 mg/mL) group; C8: p-AKT merged with DAPI signaling from 5-FU combined HQEZ (10 mg/mL) group; C9: p-AKT signaling from 5-FU combined HQEZ (20 mg/mL) group; C10: p-AKT merged with DAPI signaling from 5-FU combined HQEZ (20 mg/mL) group; C11: p-AKT signaling from 5-FU combined HQEZ (40 mg/mL) group; C12: p-AKT merged with DAPI signaling from 5-FU combined HQEZ (40 mg/mL) group. D: the immunofluorescence density of p-AKT of C. E: the downregulation of p-AKT was also confirmed by western-blot. The concentration of 5-FU is 0.18 μg/mL and the cells were treated for 48 h. HCT116 cells were treated with 5-FU (0.18 μg/mL) and different concentrations of HQEZ, including 0 mg/mL, 5 mg/mL, 10 mg/mL, 20 mg/mL and 40 mg/mL for 48 h. HQEZ: Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis); 5-FU: 5-Fluorouracil; BRCA1: Breast and Ovarian Cancer Susceptibility Protein 1; MDR1: multidrug resistance protein 1; TYMS: thymidylate synthetase; ERCC1: Excision Repair Cross-Complementation Group 1; RRM1: ribonucleotide reductase catalytic subunit M1; POLH: DNA Polymerase Eta; MLH1: MutL Homolog 1; EGFR: epidermal growth factor receptor; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; TS: thymidylate synthetase; p-AKT: phospho- protein kinase B; DAPI: 4',6-Diamidino-2-phenylindole dilactate. Data are presented as mean ± standard deviation. aP < 0.05, bP < 0.01 and cP < 0.001, compared with the Control group, differences were evaluated by one-way analysis of variance, bar = 20 μm.
Figure 3 The combination therapy of HQEZ with 5-FU significantly down-regulated 5-FU resistance targets in HCT116 in vitro A: the influence of 5-FU (0.18 μg/mL) combined with different concentration of HQEZ on the transcription level of target genes in HCT116 cells after 48 h by qPCR assay. A1: BRCA1; A2: MDR1; A3: TYMS; A4: ERCC1; A5: RRM1; A6: POLH; A7: co MLH1; (n = 3). B: HQEZ decreased expression of protein from 5-FU resistance-related genes by western blot assay (n = 3). C: by immunofluorescence staining, combined treatment of 5-FU (0.18 μg/mL) and different concentration of HQEZ significantly increased the inhibition of p-AKT in HCT116 cells after 48 h. (n = 3). C1: p-AKT signaling from control group; C2: p-AKT merged with DAPI signaling from control group; C3: p-AKT signaling from 5-FU group; C4: p-AKT merged with DAPI signaling from 5-FU group; C5: p-AKT signaling from 5-FU combined HQEZ group; C6: p-AKT merged with DAPI signaling from 5-FU combined HQEZ (5 mg/mL) group; C7: p-AKT signaling from 5-FU combined HQEZ (10 mg/mL) group; C8: p-AKT merged with DAPI signaling from 5-FU combined HQEZ (10 mg/mL) group; C9: p-AKT signaling from 5-FU combined HQEZ (20 mg/mL) group; C10: p-AKT merged with DAPI signaling from 5-FU combined HQEZ (20 mg/mL) group; C11: p-AKT signaling from 5-FU combined HQEZ (40 mg/mL) group; C12: p-AKT merged with DAPI signaling from 5-FU combined HQEZ (40 mg/mL) group. D: the immunofluorescence density of p-AKT of C. E: the downregulation of p-AKT was also confirmed by western-blot. The concentration of 5-FU is 0.18 μg/mL and the cells were treated for 48 h. HCT116 cells were treated with 5-FU (0.18 μg/mL) and different concentrations of HQEZ, including 0 mg/mL, 5 mg/mL, 10 mg/mL, 20 mg/mL and 40 mg/mL for 48 h. HQEZ: Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis); 5-FU: 5-Fluorouracil; BRCA1: Breast and Ovarian Cancer Susceptibility Protein 1; MDR1: multidrug resistance protein 1; TYMS: thymidylate synthetase; ERCC1: Excision Repair Cross-Complementation Group 1; RRM1: ribonucleotide reductase catalytic subunit M1; POLH: DNA Polymerase Eta; MLH1: MutL Homolog 1; EGFR: epidermal growth factor receptor; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; TS: thymidylate synthetase; p-AKT: phospho- protein kinase B; DAPI: 4',6-Diamidino-2-phenylindole dilactate. Data are presented as mean ± standard deviation. aP < 0.05, bP < 0.01 and cP < 0.001, compared with the Control group, differences were evaluated by one-way analysis of variance, bar = 20 μm.
Figure 4 Combination administration of HQEZ inhibited drug resistance targets relating to 5-FU in vivo and important candidate targets are upregulated in colorectal cancer patients according to TCGA database A: western-blot analysis of expression of genes in tumors from tumor-bearing mice after treatments; B: results of western-blot analysis of expression of genes in tumors from tumor-bearing mice after treatments; B1: MDR1 was downregulated in the combined group; B2: MLH1 was downregulated in the combined group; B3: EGFR was downregulated in the combined group; B4: RRM1 was downregulated in the combined group; B5: POLH was downregulated in the combined group; B6: p-AKT was downregulated in the combined group; B7: p53 was downregulated in the combined group; B8: Bcl-2 was downregulated in the combined group; B9: TYMS was downregulated in the combined group (n = 3). C: qPCR analysis of expression of genes in tumors from tumor-bearing mice after treatments; C1: Bcl-2 was downregulated in the combined group; C2: MDR1 was downregulated in the combined group; C3: EGFR was downregulated in the combined group; C4: RRM1 was downregulated in the combined group; C5: MLH1 was downregulated in the combined group; C6: POLH was downregulated in the combined group; C7: TYMS was downregulated in the combined group (n = 3). D: gene expressions in colorectal cancer patients according to TCGA database; D1: upregulated expressions of MDR1; D2: upregulated expressions of POLH; D3: upregulated expressions of TYMS; D4: upregulated expressions of RRM1; D5: upregulated expressions of MLH1. Mice were treated with phosphate-buffered saline (PBS, i.p. every two days and p.o. daily), 5-FU alone (30 mg/kg every two days, i.p. HQEZ alone (10 g·kg-1·d-1, p.o.) and 5-FU (30 mg/kg every two days, i.p.) combined with HQEZ (10 g·kg-1·d-1, p.o.). HQEZ: Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis); 5-FU: 5-Fluorouracil; MDR1: multidrug resistance protein 1; TYMS: thymidylate synthetase; RRM1: ribonucleotide reductase catalytic subunit M1; POLH: DNA Polymerase Eta; MLH1: MutL Homolog 1; p-AKT: phospho- protein kinase B; Bcl-2: B-cell lymphoma-2; p53: Tumor Suppressor P53. Data are presented as mean ± standard deviation. aP < 0.05, dP < 0.01 and eP < 0.001, compared with the control group. cP < 0.05 and bP < 0.01, compared with the 5-FU group. fP < 0.01 and gP < 0.001, compared with the normal group, differences were evaluated by one-way analysis of variance.
Figure 4 Combination administration of HQEZ inhibited drug resistance targets relating to 5-FU in vivo and important candidate targets are upregulated in colorectal cancer patients according to TCGA database A: western-blot analysis of expression of genes in tumors from tumor-bearing mice after treatments; B: results of western-blot analysis of expression of genes in tumors from tumor-bearing mice after treatments; B1: MDR1 was downregulated in the combined group; B2: MLH1 was downregulated in the combined group; B3: EGFR was downregulated in the combined group; B4: RRM1 was downregulated in the combined group; B5: POLH was downregulated in the combined group; B6: p-AKT was downregulated in the combined group; B7: p53 was downregulated in the combined group; B8: Bcl-2 was downregulated in the combined group; B9: TYMS was downregulated in the combined group (n = 3). C: qPCR analysis of expression of genes in tumors from tumor-bearing mice after treatments; C1: Bcl-2 was downregulated in the combined group; C2: MDR1 was downregulated in the combined group; C3: EGFR was downregulated in the combined group; C4: RRM1 was downregulated in the combined group; C5: MLH1 was downregulated in the combined group; C6: POLH was downregulated in the combined group; C7: TYMS was downregulated in the combined group (n = 3). D: gene expressions in colorectal cancer patients according to TCGA database; D1: upregulated expressions of MDR1; D2: upregulated expressions of POLH; D3: upregulated expressions of TYMS; D4: upregulated expressions of RRM1; D5: upregulated expressions of MLH1. Mice were treated with phosphate-buffered saline (PBS, i.p. every two days and p.o. daily), 5-FU alone (30 mg/kg every two days, i.p. HQEZ alone (10 g·kg-1·d-1, p.o.) and 5-FU (30 mg/kg every two days, i.p.) combined with HQEZ (10 g·kg-1·d-1, p.o.). HQEZ: Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis); 5-FU: 5-Fluorouracil; MDR1: multidrug resistance protein 1; TYMS: thymidylate synthetase; RRM1: ribonucleotide reductase catalytic subunit M1; POLH: DNA Polymerase Eta; MLH1: MutL Homolog 1; p-AKT: phospho- protein kinase B; Bcl-2: B-cell lymphoma-2; p53: Tumor Suppressor P53. Data are presented as mean ± standard deviation. aP < 0.05, dP < 0.01 and eP < 0.001, compared with the control group. cP < 0.05 and bP < 0.01, compared with the 5-FU group. fP < 0.01 and gP < 0.001, compared with the normal group, differences were evaluated by one-way analysis of variance.
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