|
|
黄藤素对CCl4致大鼠急性肝损伤的防治作用研究
|
Abstract:
目的：评价黄藤素(palmatine, Pal)对四氯化碳(CCl4)诱导的大鼠急性肝损伤(ALI)的保护作用，初步探究其潜在靶点。方法：将48只大鼠随机分为正常对照组(NS)、模型组(CCl4)、低剂量Pal组(Pal-L, 5 mg/kg)、中剂量Pal组(Pal-M, 10 mg/kg)、高剂量Pal组(Pal-H, 20 mg/kg)和地塞米松组(DEX, 10 mg/kg)腹腔注射5，10，20 mg/kg的Pal，每天一次，连续三天，NS组和CCl4组的大鼠腹腔注射给予等体积的生理盐水。Pal处理组的大鼠最后一次给药1小时后，CCl4组和Pal处理组的大鼠腹腔注射25%的CCl4花生油溶液(3 ml/kg)，NS组的大鼠腹腔注射相同体积的溶剂。各组造模后开始计时，给予CCl4 24小时后处理所有大鼠，收集血清和肝组织，检测肺组织病理形态变化，评估肝损伤指标ALT和氧化应激指标MDA含量。网络药理学方法初步探究黄藤素抗急性肝损伤的潜在靶点。结果：Pal预处理剂量依赖性减轻CCl4诱导的急性肝损伤，表现为降低血清天冬氨酸转氨酶(AST)活性，抑制肝脏病理损伤。此外，Pal通过恢复丙二醛(MDA)水平来缓解CCl4引发的氧化应激和炎症反应。结论：黄藤素能够通过抑制炎症反应和氧化应激发减轻急性肝损伤，STAT3可能是黄藤素发挥肝脏保护作用最具潜力的靶点。
Objective: To evaluate the protective effect of palmatine (Pal) against carbon tetrachloride (CCl4)-induced acute liver injury (ALI) in rats, and preliminarily explore the potential targets of palmatine. Methods: 48 rats were randomly divided into a normal control group (NS), a model group (CCl4), a low dose Pal group (Pal-L, 5 mg/kg), a medium dose Pal group (Pal-M, 10 mg/kg), a high dose Pal group (Pal-H, 20 mg/kg), and a dexamethasone group (DEX, 10 mg/kg). Rats in the NS and CCl4 groups were intraperitoneally injected with 5, 10, and 20 mg/kg of Pal once a day for three consecutive days. Rats in the NS and CCl4 groups were given equal volumes of physiological saline by intraperitoneal injection. After the last administration of 1 hour, rats in the Pal-treated groups were intraperitoneally injected with 25% CCl4 peanut oil solution (3 ml/kg), while rats in the NS group were intraperitoneally injected with the same volume of solvent. After modeling, each group began timing, and all rats were treated with CCl4 24 hours later. Serum and liver tissue were collected to observe the pathological and morphological changes in lung tissue and evaluate the liver injury index ALT and oxidative stress index MDA content. Network pharmacology methods were used to preliminarily explore the potential targets of palmatine in treating acute liver injury. Results: Pal pretreatment attenuated CCl4-induced acute liver injury in a dose-dependent manner, manifested by a decrease in serum aspartate aminotransferase (AST) activity and inhibition of liver pathological damage. In addition, Pal alleviates oxidative stress and inflammatory responses induced by CCl4 by restoring malondialdehyde (MDA) levels. Conclusion: Palmatine can alleviate acute liver injury by inhibiting inflammatory reactions and oxidative stress. STAT3 may be the most potential target for Palmatine to
| [1] | Oh, I.S. and Park, S.H. (2015) Immune-Mediated Liver Injury in Hepatitis B Virus Infection. Immune Network, 15, 191-198. https://doi.org/10.4110/in.2015.15.4.191 |
| [2] | Allard, J., Le Guillou, D., Begriche, K. and Fromenty, B. (2019) Drug-Induced Liver Injury in Obesity and Nonalcoholic Fatty Liver Disease. Advances in Pharmacology, 85, 75-107. https://doi.org/10.1016/bs.apha.2019.01.003 |
| [3] | Long, X., Wang, P., Zhou, Y., et al. (2022) Preventive Effect of Lactobacillus plantarum HFY15 on Carbon Tetrachloride (CCl4)-Induced Acute Liver Injury in Mice. Journal of Food Science, 87, 2626-2639.
https://doi.org/10.1111/1750-3841.16171 |
| [4] | Niu, B., Lei, X., Xu, Q., et al. (2022) Protecting Mitochondria via Inhibiting VDAC1 Oligomerization Alleviates Ferroptosis in Acetaminophen-Induced Acute Liver Injury. Cell Biology and Toxicology, 38, 505-530.
https://doi.org/10.1007/s10565-021-09624-x |
| [5] | Liu, R., Hao, Y.T., Zhu, N., et al. (2023) Walnut (Juglans regia L.) Oligopeptides Alleviate Alcohol-Induced Acute Liver Injury through the Inhibition of Inflammation and Oxidative Stress in Rats. Nutrients, 15, Article 2210.
https://doi.org/10.3390/nu15092210 |
| [6] | Cai, J., Wu, J., Fang, S., et al. (2022) Cultured Bear Bile Powder Ameliorates Acute Liver Injury in Cholestatic Mice via Inhibition of Hepatic Inflammation and Apoptosis. Journal of Ethnopharmacology, 284, Article ID: 114829.
https://doi.org/10.1016/j.jep.2021.114829 |
| [7] | Yang, Z., Zhang, J., Wang, Y., et al. (2021) Caveolin-1 Deficiency Protects Mice against Carbon Tetrachloride-Induced Acute Liver Injury through Regulating Polarization of Hepatic Macrophages. Frontiers in Immunology, 12, Article 713808.
https://doi.org/10.3389/fimmu.2021.713808 |
| [8] | Zhang, X., Kuang, G., Wan, J., et al. (2020) Salidroside Protects Mice against CCl4-Induced Acute Liver Injury via Down-Regulating CYP2E1 Expression and Inhibiting NLRP3 Inflammasome Activation. International Immunopharmacology, 85, Article ID: 106662. https://doi.org/10.1016/j.intimp.2020.106662 |
| [9] | Feng, Y., Wang, N., Ye, X., et al. (2011) Hepatoprotective Effect and Its Possible Mechanism of Coptidis rhizoma Aqueous Extract on Carbon Tetrachloride-Induced Chronic Liver Hepatotoxicity in Rats. Journal of Ethnopharmacology, 138, 683-690. https://doi.org/10.1016/j.jep.2011.09.032 |
| [10] | Xiang, W., Wei, J., Lv, L., et al. (2023) Arctium lappa L. Root Polysaccharides Ameliorate CCl4-Induced Acute Liver Injury by Suppressing Oxidative Stress, Inflammation and Apoptosis. Natural Product Research.
https://doi.org/10.1080/14786419.2023.2272287 |
| [11] | Huang, J., Bai, Y., Xie, W., et al. (2023) Lycium barbarum Polysaccharides Ameliorate Canine Acute Liver Injury by Reducing Oxidative Stress, Protecting Mitochondrial Function, and Regulating Metabolic Pathways. Journal of Zhejiang University-SCIENCE B, 24, 157-171. https://doi.org/10.1631/jzus.B2200213 |
| [12] | Zhang, X., Su, K., Liu, Y., et al. (2021) Small Molecule Palmatine Targeting Musashi-2 in Colorectal Cancer. Frontiers in Pharmacology, 12, Article 793449. https://doi.org/10.3389/fphar.2021.793449 |
| [13] | Cheng, J.J., Ma, X.D., Ai, G.X., et al. (2022) Palmatine Protects against MSU-Induced Gouty Arthritis via Regulating the NF-κB/NLRP3 and Nrf2 Pathways. Drug Design, Development and Therapy, 16, 2119-2132.
https://doi.org/10.2147/DDDT.S356307 |
| [14] | Ho, Y.J., Lu, J.W., Huang, Y.L. and Lai, Z.Z. (2019) Palmatine Inhibits Zika Virus Infection by Disrupting Virus Binding, Entry, and Stability. Biochemical and Biophysical Research Communications, 518, 732-738.
https://doi.org/10.1016/j.bbrc.2019.08.120 |
| [15] | Okechukwu, P.N., Ekeuku, S.O., Chan, H.K., Eluri, K. and Froemming, G.R.A. (2021) Palmatine Inhibits Up-Regulation of GRP78 and CALR Protein in an STZ-Induced Diabetic Rat Model. Current Pharmaceutical Biotechnology, 22, 288-298. https://doi.org/10.2174/1389201021666200730124208 |
| [16] | Grabarska, A., Wroblewska-Luczka, P., Kukula-Koch, W., et al. (2021) Palmatine, a Bioactive Protoberberine Alkaloid Isolated from Berberis cretica, Inhibits the Growth of Human Estrogen Receptor-Positive Breast Cancer Cells and Acts Synergistically and Additively with Doxorubicin. Molecules, 26, Article 6253.
https://doi.org/10.3390/molecules26206253 |
| [17] | Liu, X., Zhang, Y., Wu, S., et al. (2020) Palmatine Induces G2/M Phase Arrest and Mitochondrial-Associated Pathway Apoptosis in Colon Cancer Cells by Targeting AURKA. Biochemical Pharmacology, 175, Article ID: 113933.
https://doi.org/10.1016/j.bcp.2020.113933 |
| [18] | Yuan, Y., Peng, W., Liu, Y., et al. (2017) Palmatine Attenuates Isoproterenol-Induced Pathological Hypertrophy via Selectively Inhibiting HDAC2 in Rats. International Journal of Immunopathology and Pharmacology, 30, 406-412.
https://doi.org/10.1177/0394632017742225 |
| [19] | Jie, L., Ma, Z., Gao, Y., et al. (2023) The Mechanism of Palmatine-Mediated Intestinal Flora and Host Metabolism Intervention in OA-OP Comorbidity Rats. Frontiers in Medicine, 10, Article 1153360.
https://doi.org/10.3389/fmed.2023.1153360 |
| [20] | Ekeuku, S.O., Pang, K.L. and Chin, K.Y. (2020) Palmatine as an Agent against Metabolic Syndrome and Its Related Complications: A Review. Drug Design, Development and Therapy, 14, 4963-4974.
https://doi.org/10.2147/DDDT.S280520 |
| [21] | Nwabueze, O.P., Sharma, M., Balachandran, A., et al. (2022) Comparative Studies of Palmatine with Metformin and Glimepiride on the Modulation of Insulin Dependent Signaling Pathway in Vitro, in Vivo & ex Vivo. Pharmaceuticals, 15, Article 1317. https://doi.org/10.3390/ph15111317 |
| [22] | Hopkins, A.L. (2008) Network Pharmacology: The Next Paradigm in Drug Discovery. Nature Chemical Biology, 4, 682-690. https://doi.org/10.1038/nchembio.118 |
| [23] | Mokdad, A.A., Lopez, A.D., Shahraz, S., et al. (2014) Liver Cirrhosis Mortality in 187 Countries between 1980 and 2010: A Systematic Analysis. BMC Medicine, 12, Article No. 145. https://doi.org/10.1186/s12916-014-0145-y |
| [24] | Pereira, J.F., De Sousa Neves, J.C., Fonteles, A.A., et al. (2023) Palmatine, a Natural Alkaloid, Attenuates Memory Deficits and Neuroinflammation in Mice Submitted to Permanent Focal Cerebral Ischemia. Journal of Neuroimmunology, 381, Article ID: 578131. https://doi.org/10.1016/j.jneuroim.2023.578131 |
| [25] | Tarabasz, D. and Kukula-Koch, W. (2020) Palmatine: A Review of Pharmacological Properties and Pharmacokinetics. Phytotherapy Research, 34, 33-50. https://doi.org/10.1002/ptr.6504 |
| [26] | Lee, W.C., Kim, J.K., Kang, J.W., et al. (2010) Palmatine Attenuates D-Galactosamine/Lipopolysaccharide-Induced Fulminant Hepatic Failure in Mice. Food and Chemical Toxicology, 48, 222-228.
https://doi.org/10.1016/j.fct.2009.10.004 |
| [27] | Qin, J., Luo, Z., Wang, Q., et al. (2023) Integrating Metabonomics and Metagenomics Sequencing to Study the Anti-Liver Fibrosis Effects of Palmatine in Corydalis saxicola Bunting. Journal of Ethnopharmacology, 315, Article ID: 116666. https://doi.org/10.1016/j.jep.2023.116666 |
| [28] | Zhong, Z., Wen, Z. and Darnell Jr., J.E. (1994) Stat3: A STAT Family Member Activated by Tyrosine Phosphorylation in Response to Epidermal Growth Factor and Interleukin-6. Science, 264, 95-98.
https://doi.org/10.1126/science.8140422 |
| [29] | Hillmer, E.J., Zhang, H., Li, H.S. and Watowich, S.S. (2016) STAT3 Signaling in Immunity. Cytokine & Growth Factor Reviews, 31, 1-15. https://doi.org/10.1016/j.cytogfr.2016.05.001 |
| [30] | Yao, W., Li, H., Luo, G., et al. (2017) SERPINB1 Ameliorates Acute Lung Injury in Liver Transplantation through ERK1/2-Mediated STAT3-Dependent HO-1 Induction. Free Radical Biology and Medicine, 108, 542-553.
https://doi.org/10.1016/j.freeradbiomed.2017.04.011 |
| [31] | Li, M., Zhang, X., Wang, B., et al. (2018) Effect of JAK2/STAT3 Signaling Pathway on Liver Injury Associated with Severe Acute Pancreatitis in Rats. Experimental and Therapeutic Medicine, 16, 2013-2021.
https://doi.org/10.3892/etm.2018.6433 |
| [32] | He, X., Kang, K., Pan, D., Sun, Y. and Chang, B. (2022) FTY720 Attenuates APAP-Induced Liver Injury via the JAK2/STAT3 Signaling Pathway. International Journal of Molecular Medicine, 49, Article No. 67.
https://doi.org/10.3892/ijmm.2022.5123 |
| [33] | Ruart, M., Chavarria, L., Camprecios, G., et al. (2019) Impaired Endothelial Autophagy Promotes Liver Fibrosis by Aggravating the Oxidative Stress Response during Acute Liver Injury. Journal of Hepatology, 70, 458-469.
https://doi.org/10.1016/j.jhep.2018.10.015 |
| [34] | Yuan, R., Tao, X., Liang, S., et al. (2018) Protective Effect of Acidic Polysaccharide from Schisandra chinensis on Acute Ethanol-Induced Liver Injury through Reducing CYP2E1-Dependent Oxidative Stress. Biomedicine & Pharmacotherapy, 99, 537-542. https://doi.org/10.1016/j.biopha.2018.01.079 |
| [35] | Cao, P., Sun, J., Sullivan, M.A., et al. (2018) Angelica sinensis Polysaccharide Protects against Acetaminophen-Induced Acute Liver Injury and Cell Death by Suppressing Oxidative Stress and Hepatic Apoptosis in Vivo and in Vitro. International Journal of Biological Macromolecules, 111, 1133-1139.
https://doi.org/10.1016/j.ijbiomac.2018.01.139 |
