Acute liver failure is a life-threatening clinical
syndrome with a high mortality rate. Currently, the research on Astragaloside
IV in liver diseases primarily focuses on liver cancer, and there is limited
understanding of its mechanism in acute liver failure’s innate immunity.
Therefore, this study aims to investigate
the potential protective effect of Astragaloside IV on acute liver failure and its impact on innate immune cells. The study employed D-GalN/LPS-induced acute
liver failure mouse models and employed various techniques such as a range of
molecular and analytical techniques. The experimental results demonstrated that
treatment with Astragaloside IV significantly reduced the inflammatory
response, alleviated liver injury, and improved the survival rate of mice with
acute liver failure induced by D-GalN/LPS. Further investigations revealed that
AS-IV played a beneficial role by regulating the proportion of CD11b+Ly6Chi monocytes and the secretion of inflammatory cytokines and anti-inflammatory
metabolites. These findings suggest that the pharmacological mechanism of AS-IV
may involve targeted regulation of CD11b+Ly6Chi monocytes
in both peripheral blood and liver. The implications of this study’s results
are twofold. Firstly, they provide a basis for the clinical application of
AS-IV in treating liver failure, offering potential therapeutic benefits.
Secondly, they serve as a reference for further development of safer and more
effective modified compounds.
References
[1]
Moreau, R., Jalan, R., Gines, P., Pavesi, M., Angeli, P., Cordoba, J., et al. (2013) Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients with Acute Decompensation of Cirrhosis. Gastroenterology, 144, 1426-1437.e1. https://doi.org/10.1053/j.gastro.2013.02.042
[2]
Peng, C.H., Shi, L.B., Zhang, H.W., Peng, S.Y., Zhou, G.W. and Li, H.W. (2005) Establishment of a New Pig Model for Auxiliary Partial Orthotopic Liver Transplantation. World Journal of Gastroenterology, 11, 917-921. https://doi.org/10.3748/wjg.v11.i6.917
[3]
Huang, K., Ji, F., Xie, Z., Wu, D., Xu, X., Gao, H., et al. (2019) Artificial Liver Support System Therapy in Acute-on-Chronic Hepatitis B Liver Failure: Classification and Regression Tree Analysis. Scientific Reports, 9, Article No. 16462. https://doi.org/10.1038/s41598-019-53029-0
[4]
McPhail, M.J., Kriese, S. and Heneghan, M.A. (2015) Current Management of Acute Liver Failure. Current Opinion in Gastroenterology, 31, 209-214. https://doi.org/10.1097/MOG.0000000000000174
[5]
Forbes, S.J., Gupta, S. and Dhawan, A. (2015) Cell Therapy for Liver Disease: From Liver Transplantation to Cell Factory. Journal of Hepatology, 62, S157-S169. https://doi.org/10.1016/j.jhep.2015.02.040
[6]
Kwon, Y.J., Lee, K.G. and Choi, D. (2015) Clinical Implications of Advances in Liver Regeneration. Clinical and Molecular Hepatology, 21, 7-13. https://doi.org/10.3350/cmh.2015.21.1.7
[7]
Yang, S., Kuang, G., Zhang, L., Wu, S., Zhao, Z., Wang, B., et al. (2020) Mangiferin Attenuates LPS/D-GalN-Induced Acute Liver Injury by Promoting HO-1 in Kupffer Cells. Frontiers in Immunology, 11, Article No. 285. https://doi.org/10.3389/fimmu.2020.00285
[8]
Zhang, H.W., Lin, Z.X., Xu, C., Leung, C. and Chan, L.S. (2014) Astragalus (a Traditional Chinese Medicine) for Treating Chronic Kidney Disease. Cochrane Database of Systematic Reviews, No. 10, CD008369. https://doi.org/10.1002/14651858.CD008369.pub2
[9]
Ren, S., Zhang, H., Mu, Y., Sun, M. and Liu, P. (2013) Pharmacological Effects of Astragaloside IV: A Literature Review. Journal of Traditional Chinese Medicine, 33, 413-416. https://doi.org/10.1016/S0254-6272(13)60189-2
[10]
Zhu, Y., Chai, Y., Xiao, G., Liu, Y., Xie, X., Xiao, W., et al. (2022) Astragalus and Its Formulas as a Therapeutic Option for Fibrotic Diseases: Pharmacology and Mechanisms. Frontiers in Pharmacology, 13, Article ID: 1040350. https://doi.org/10.3389/fphar.2022.1040350
[11]
Luo, Y., Zou, S.X. and Huang, Y.H. (2008) Evaluation of Safety and Efficacy of Astragali Glycoside Sodium Chloride Injection on Treating Heart Stroke of Coronary Heart Disease. Journal of Tianjin University of Traditional Chinese Medicine, No. 1, 11-14.
[12]
Dong, Z., Zhao, P., Xu, M., Zhang, C., Guo, W., Chen, H., et al. (2017) Astragaloside IV Alleviates Heart Failure via Activating PPARalpha to Switch Glycolysis to Fatty Acid Beta-Oxidation. Scientific Reports, 7, Article No. 2691. https://doi.org/10.1038/s41598-017-02360-5
[13]
Min, L., Wang, H. and Qi, H. (2022) Astragaloside IV Inhibits the Progression of Liver Cancer by Modulating Macrophage Polarization through the TLR4/NF-kappaB/ STAT3 Signaling Pathway. The American Journal of Translational Research, 14, 1551-1566.
[14]
Zhang, J., Wu, C., Gao, L., Du, G. and Qin, X. (2020) Astragaloside IV Derived from Astragalus membranaceus: A Research Review on the Pharmacological Effects. Advances in Pharmacology, 87, 89-112. https://doi.org/10.1016/bs.apha.2019.08.002
[15]
Wang, J.B., Wang, D.L., Wang, H.T., Wang, Z.H., Wen, Y., Sun, C.M., et al. (2014) Tumor Necrosis Factor-Alpha-Induced Reduction of Glomerular Filtration Rate in Rats with Fulminant Hepatic Failure. Laboratory Investigation, 94, 740-751. https://doi.org/10.1038/labinvest.2014.71
[16]
Plociennikowska, A., Hromada-Judycka, A., Borzecka, K. and Kwiatkowska, K. (2015) Co-Operation of TLR4 and Raft Proteins in LPS-Induced Pro-Inflammatory Signaling. Cellular and Molecular Life Sciences, 72, 557-581. https://doi.org/10.1007/s00018-014-1762-5
[17]
Galanos, C., Freudenberg, M.A. and Reutter, W. (1979) Galactosamine-Induced Sensitization to the Lethal Effects of Endotoxin. Proceedings of the National Academy of Sciences of the United States of America, 76, 5939-5943. https://doi.org/10.1073/pnas.76.11.5939
[18]
Tsutsui, H. and Nishiguchi, S. (2014) Importance of Kupffer Cells in the Development of Acute Liver Injuries in Mice. International Journal of Molecular Sciences, 15, 7711-7730. https://doi.org/10.3390/ijms15057711
[19]
Ju, C. and Tacke, F. (2016) Hepatic Macrophages in Homeostasis and Liver Diseases: from Pathogenesis to Novel Therapeutic Strategies. Cellular & Molecular Immunology, 13, 316-327. https://doi.org/10.1038/cmi.2015.104
[20]
Feng, M., Wang, Q., Zhang, F. and Lu, L. (2012) Ex Vivo Induced Regulatory T Cells Regulate Inflammatory Response of Kupffer Cells by TGF-beta and Attenuate Liver Ischemia Reperfusion Injury. International Immunopharmacology, 12, 189-196. https://doi.org/10.1016/j.intimp.2011.11.010
[21]
Tian, L., Zhao, J.L., Kang, J.Q., Guo, S.B., Zhang, N., Shang, L., et al. (2021) Astragaloside IV Alleviates the Experimental DSS-Induced Colitis by Remodeling Macrophage Polarization through STAT Signaling. Frontiers in Immunology, 12, Article ID: 740565. https://doi.org/10.3389/fimmu.2021.740565
[22]
Wang, Y.P., Li, X.Y., Song, C.Q. and Hu, Z.B. (2002) Effect of Astragaloside IV on T, B Lymphocyte Proliferation and Peritoneal Macrophage Function in Mice. Acta Pharmacologica Sinica, 23, 263-266.
[23]
Hoeffel, G. and Ginhoux, F. (2018) Fetal Monocytes and the Origins of Tissue-Resident Macrophages. Cellular Immunology, 330, 5-15. https://doi.org/10.1016/j.cellimm.2018.01.001
[24]
Amorim, A., De Feo, D., Friebel, E., Ingelfinger, F. anderfuhren, C.D., Krishnarajah, S., et al. (2022) IFNgamma and GM-CSF Control Complementary Differentiation Programs in the Monocyte-to-Phagocyte Transition during Neuroinflammation. Nature Immunology, 23, 217-228. https://doi.org/10.1038/s41590-021-01117-7
[25]
Han, J., Bae, J., Choi, C.Y., Choi, S.P., Kang, H.S., Jo, E.K., et al. (2016) Autophagy Induced by AXL Receptor Tyrosine Kinase Alleviates Acute Liver Injury via Inhibition of NLRP3 Inflammasome Activation in Mice. Autophagy, 12, 2326-2343. https://doi.org/10.1080/15548627.2016.1235124
[26]
Song, S., Tan, J., Miao, Y., Li, M. and Zhang, Q. (2017) Crosstalk of Autophagy and Apoptosis: Involvement of the Dual Role of Autophagy under ER Stress. Journal of Cellular Physiology, 232, 2977-2984. https://doi.org/10.1002/jcp.25785
[27]
Hu, J.M., Hsu, C.H., Lin, Y.C., Kung, C.W., Chen, S.Y., Lin, W.T., et al. (2021) Ethyl Pyruvate Ameliorates Heat Stroke-Induced Multiple Organ Dysfunction and Inflammatory Responses by Induction of Stress Proteins and Activation of Autophagy in Rats. International Journal of Hyperthermia, 38, 862-874. https://doi.org/10.1080/02656736.2021.1931479
[28]
Kma, L. and Baruah, T.J. (2022) The Interplay of ROS and the PI3K/Akt Pathway in Autophagy Regulation. Biotechnology and Applied Biochemistry, 69, 248-264. https://doi.org/10.1002/bab.2104
[29]
Lenart, J., Zieminska, E., Diamandakis, D. and Lazarewicz, J.W. (2017) Altered Expression of Genes Involved in Programmed Cell Death in Primary Cultured Rat Cerebellar Granule Cells Acutely Challenged with Tetrabromobisphenol A. Neurotoxicology, 63, 126-136. https://doi.org/10.1016/j.neuro.2017.09.014
[30]
Chang, C.C., Lin, T.C., Ho, H.L., Kuo, C.Y., Li, H.H., Korolenko, T.A., et al. (2018) GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling. International Journal of Molecular Sciences, 19, Article No. 2505. https://doi.org/10.3390/ijms19092505
[31]
Wang, Z., Wang, X., Cheng, F., Wen, X., Feng, S., Yu, F., et al. (2021) Rapamycin Inhibits Glioma Cells Growth and Promotes Autophagy by miR-26a-5p/DAPK1 Axis. Cancer Management and Research, 13, 2691-2700. https://doi.org/10.2147/CMAR.S298468
[32]
Fan, P., Wang, N., Wang, L. and Xie, X.Q. (2019) Autophagy and Apoptosis Specific Knowledgebases-Guided Systems Pharmacology Drug Research. Current Cancer Drug Targets, 19, 716-728. https://doi.org/10.2174/1568009619666190206122149
[33]
Ma, Z., Wang, D., Weng, J., Zhang, S. and Zhang, Y. (2020) BNIP3 Decreases the LPS-Induced Inflammation and Apoptosis of Chondrocytes by Promoting the Development of Autophagy. Journal of Orthopaedic Surgery and Research, 15, Article No. 284. https://doi.org/10.1186/s13018-020-01791-7
[34]
Yin, F., Kosewski, B. and Baer, M.R. (2021) Novel BRCA2 c.8434_8435insTT (p. Gly2812Valfs*10) Mutation in a Family with Multiple Hematologic Malignancies and Solid Tumors. Leukemia & Lymphoma, 62, 1275-1277. https://doi.org/10.1080/10428194.2020.1861269
[35]
Chang, J., Hong, L., Liu, Y., Pan, Y., Yang, H., Ye, W., et al. (2020) Targeting PIK3CG in Combination with Paclitaxel as a Potential Therapeutic Regimen in Claudin-Low Breast Cancer. Cancer Management and Research, 12, 2641-2651. https://doi.org/10.2147/CMAR.S250171
[36]
Nowosad, A. and Besson, A. (2020) CDKN1B/p27 Regulates Autophagy via the Control of Ragulator and MTOR Activity in Amino Acid-Deprived Cells. Autophagy, 16, 2297-2298. https://doi.org/10.1080/15548627.2020.1831217
[37]
Lee, M.S. (2016) Role of Mitochondrial Function in Cell Death and Body Metabolism. Frontiers in Bioscience (Landmark Ed), 21, 1233-1244. https://doi.org/10.2741/4453
[38]
Dong, H., Tian, L., Li, R., Pei, C., Fu, Y., Dong, X., et al. (2015) IFNg-Induced Irgm1 Promotes Tumorigenesis of Melanoma via Dual Regulation of Apoptosis and Bif-1-Dependent Autophagy. Oncogene, 34, 5363-5371. w https://doi.org/10.1038/onc.2014.459
[39]
Chang, S.N., Kim, S.H., Dey, D.K., Park, S.M., Nasif, O., Bajpai, V.K., et al. (2021) 5-O-Demethylnobiletin Alleviates CCl(4)-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction. International Journal of Molecular Sciences, 22, Article No. 1083. https://doi.org/10.3390/ijms22031083
[40]
Gajewska, M., Gajkowska, B. and Motyl, T. (2005) Apoptosis and Autophagy Induced by TGF-B1 in Bovine Mammary Epithelial BME-UV1 Cells. Journal of Physiology and Pharmacology, 56, 143-157.
[41]
Hsuan, S.W., Chyau, C.C., Hung, H.Y., Chen, J.H. and Chou, F.P. (2016) The Induction of Apoptosis and Autophagy by Wasabia japonica Extract in Colon Cancer. European Journal of Nutrition, 55, 491-503. https://doi.org/10.1007/s00394-015-0866-5
[42]
Gastol, J., Polus, A., Biela, M., Razny, U., Pawlinski, L., Solnica, B., et al. (2020) Specific Gene Expression in Type 1 Diabetic Patients with and without Cardiac Autonomic Neuropathy. Scientific Reports, 10, Article No. 5554. https://doi.org/10.1038/s41598-020-62498-7
[43]
Alqarni, A.M., Ferro, V.A., Parkinson, J.A., et al. (2018) Effect of Melittin on Metabolomic Profile and Cytokine Production in PMA-Differentiated THP-1 Cells. Vaccines (Basel), 6, Article No. 72. https://doi.org/10.3390/vaccines6040072
[44]
Song, Y.Q., Hu, T.T., Gao, H., et al. (2021) Altered Metabolic Profiles and Biomarkers Associated with Astragaloside IV-Mediated Protection against Cisplatin-Induced Acute Kidney Injury in Rats: An HPLC-TOF/MS-Based Untargeted Metabolomics Study. Biochemical Pharmacology, 183, Article ID: 114299. https://doi.org/10.1016/j.bcp.2020.114299
[45]
Navik, U., Sheth, V.G., Sharma, N., et al. (2022) L-Methionine Supplementation Attenuates High-Fat Fructose Diet-Induced Non-Alcoholic Steatohepatitis by Modulating Lipid Metabolism, Fibrosis, and Inflammation in Rats. Food & Function, 13, 4941-4953. https://doi.org/10.1039/D1FO03403K
[46]
Zeitz, J.O., Kaltenböck, S., Most, E., et al. (2019) Effects of L-Methionine on Performance, Gut Morphology and Antioxidant Status in Gut and Liver of Piglets in Relation to DL-Methionine. Journal of Animal Physiology and Animal Nutrition (Berl), 103, 242-250. https://doi.org/10.1111/jpn.13000
