Astragaloside IV plays a role in reducing radiation-induced liver inflammation in mice by inhibiting thioredoxin-interacting protein/nod-like receptor protein 3 signaling pathway

doi:10.19852/j.cnki.jtcm.2023.01.008

Abstract

Abstract:

OBJECTIVE: To investigate the efficacy of Astragaloside IV (AS-IV) on radiation-induced liver inflammation in mice.
METHODS: The mice were divided into normal group, dimethyl sulfoxide solvent group, irradiation group (IR), irradiation + AS-IV (20 mg/kg) group (IR+AS-20) and irradiation + AS-IV (40 mg/kg) group (IR+AS-40). One month after intraperitoneal injection of AS-IV, the mice were irradiated with 8Gry Co60γ, the blood was collected for biochemical analysis, and the liver was collected for hematoxylin-eosin staining, immunofluorescence and electron microscopic observation, oxidative stress, and Western blot analysis.
RESULTS: The AS-IV treatment significantly ameliorated the pathological morphology of liver and reduced the alanine aminotransferase and aspertate amino-transferase levels in serum induced by radiation; AS-IV treatment also significantly reduced the expression of inflammatory factors tumor necrosis factor alpha and interleukin 6 and antagonized malonaldehyde content and superoxide dismutase activity in liver caused by radiation; in addition, AS-IV treatment can significantly inhibited the positive expression of thioredoxin-interacting protein (TXNIP) and nod-like receptor protein 3 (NLRP3) inflammasome in liver tissue after radiation; The expression of TXNIP, NLRP3 inflammasome, apoptosis-associated speck-like protein containing a CARD, cysteinyl aspartate-specific proteinase 1 and interleukin 1beta in the AS-IV prevention group decreased significantly compared to the radiation group.
CONCLUSIONS: These findings suggested that Co60γ radiation can cause structural and functional damage to the liver, which may be related to the NLRP3 mediated inflammatory pathway; AS-IV may play a protective role by inhibiting the TXNIP/NLRP3 inflammasome signaling pathway in the radiation-induced liver injury model.

Key words: radiation, ionizing, astragaloside IV, liver inflammation, NLR family, pyrin domain-containing 3 protein, thioredoxin-interacting protein

DING Yanping, DONG Xiaoqing, MA Yifan, CHEN Lili, ZHOU Jie, LI Xinyan, SHAO Baoping. Astragaloside IV plays a role in reducing radiation-induced liver inflammation in mice by inhibiting thioredoxin-interacting protein/nod-like receptor protein 3 signaling pathway[J]. Journal of Traditional Chinese Medicine, 2023, 43(1): 87-94.

Figures/Tables 3

Figure 1 AS-IV alleviates radiation-induced liver injury A1: ALT levels in mice serum; A2: AST levels in mice serum; B: HE staining of liver with different amplification (B1-B5 is ×200, B6-B10 is ×400 ), B1, B5: control group; B2, B6: DMSO group; B3, B7: IR group; B4, B8: IR+AS-IV-20 group; B5, B10: IR+AS-IV-40 group; the arrow points to the hepatic sinus and the triangle points to the changes of liver structure after radiation; C: transmission electron microscopy of liver (C1-B5 is ×1000, C6-B10 is ×2500), C1, C5: Control group; C2, C6: DMSO group; C3, C7: IR group; C4, C8: IR+AS-IV-20 group; C5, C10: IR+AS-IV-40 group. DMSO: dimethyl sulfoxide; IR: irradiation; IR+AS-20: irradiation +AS-IV (20 mg/kg); IR+AS-40: irradiation +AS-IV (40 mg/kg); AS-IV: astragaloside IV; ALT: alanine aminotransferase; AST: aspertate aminotransferase; HE: hematoxylin-eosin. aP < 0.001 vs Control group; bP < 0.001 vs IR group.

Figure 2 AS-IV alleviates the oxidative damage and the expression of inflammatory factors in radiation-induced liver injury mice A1: levels of SOD; A2: content of MDA; B1: Western blot detection of the expression levels of IL-6 and TNF-α in mice liver; B2: relative density of IL-6; B3: relative density of TNF-α. DMSO: dimethyl sulfoxide; IR: irradiation; IR+AS-20: irradiation +AS-IV (20 mg/kg); IR+AS-40: irradiation +AS-IV (40 mg/kg); AS-IV: astragaloside IV; MDA: malonaldehyde; SOD: superoxide dismutase; IL-6: interleukin 6; TNF-α: tumor necrosis factor alpha. aP < 0.001 vs Control group; bP < 0.05 vs IR group; cP < 0.05 vs IR+AS-20 group; dP < 0.01 vs IR group; eP < 0.01 vs IR+AS-20 group; fP < 0.001 vs IR group.

Figure 3 AS-IV blocks radiation-induced activation in TXNIP/NLRP3 inflammasome pathway A: immunofluorescence expression of NLRP3 inflammasome in each group. A1: Control group; A2: DMSO group; A3: IR group; A4: IR+AS-IV-20 group; A5: IR+AS-IV-40 group; B1: the expressions of TXNIP, NLRP3, ASC, Caspase-1 and IL-1β in liver were measured by Western blot; B2: relative density of TXNIP; B3: relative density of NLRP3; B4: relative density of ASC. B5: relative density of Caspase-1; B6: relative density of IL-1β. DMSO: dimethyl sulfoxide; IR: irradiation; IR+AS-20: irradiation+AS-IV (20 mg/kg); IR + AS-40: irradiation +AS-IV (40 mg/kg); AS-IV: astragaloside IV; TXNIP: Thioredoxin-interacting protein; NLRP3: nod-like receptor protein 3; ASC: apoptosis-associated speck-like protein containing a CARD; Caspase-1: cysteinyl aspartate-specific proteinase 1; IL-1β: interleukin 1beta. aP < 0.001 vs Control group; bP < 0.001 vs IR group; cP < 0.05 vs IR + AS-20 group; dP < 0.01 vs IR group; eP < 0.01 vs IR + AS-20 group.

References 39

1	Najafi M, Shirazi A, Motevaseli E, Rezaeyan AH, Salajegheh A, Rezapoor S. The melatonin immunomodulatory actions in radiotherapy. Biophys rev 2017; 9: 139-48. DOI PMID
2	Stoecklein VM, Osuka A, Ishikawa S, Lederer MR, Wanke-Jellinek L, Lederer JA. Radiation exposure induces inflammasome pathway activation in immune cells. J immunol 2015; 194: 178-89.
3	Zhou R, Yazdi A, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011; 469: 221-5.
4	Liang H, Liu K, Zhuang Z, et al. Potential of Forsythoside I as a therapeutic approach for acute lung injury: involvement of TXNIP/NLRP3 inflammasome. Mol Immunol 2021; 134: 192-201.
5	Zhang H, Zahid A, Ismail H, Tang Y, Jin T, Tao J. An overview of disease models for NLRP3 inflammasome over-activation. Expert Opin Drug Discov 2021; 16: 429-46.
6	Wei J, Wang H, Wang H, et al. The role of NLRP 3 inflammasome activation in radiation damage. Biomed Pharmacother 2019; 118: 109217.
7	Cao Z, Fang Y, Lu Y, et al. Melatonin alleviates cadmium-induced liver injury by inhibiting the TXNIP-NLRP3 inflammasome. J Pineal Res 2017; 62: e12389.
8	Lin J, Fang L, Li H, et al. Astragaloside IV alleviates doxorubicin induced cardiomyopathy by inhibiting NADPH oxidase derived oxidative stress. Eur J Pharmacol 2019; 859: 172490.
9	Ren S, Zhang H, Mu Y, Sun M, Liu P. Pharmacological effects of Astragaloside IV: a literature review. J Tradit Chin Med 2013; 33: 413-6. DOI PMID
10	Qu X, Gao H, Tao L, et al. Astragaloside IV protects against cisplatin-induced liver and kidney injury via autophagy-mediated inhibition of NLRP3 in rats. J Toxicol Sci 2019; 44: 167-75.
11	Wei R, Liu H, Chen R, Sheng Y, Liu T. Astragaloside IV combating liver cirrhosis through the PI3K/Akt/mTOR signaling pathway. Exp Ther Med 2019; 17: 393-7. DOI PMID
12	Li L, Huang W, Wang S, et al. Astragaloside IV attenuates acetaminophen-induced liver injuries in mice by activating the Nrf 2 signaling pathway. Molecules 2018; 23: 2032.
13	Zhou B, Zhou D, Wei XH, Zhong RY, Xu J, Sun L. Astragaloside IV attenuates free fatty acid-induced ER stress and lipid accumulation in hepatocytes via AMPK activation. Acta Pharmacol Sin 2017; 38: 998-1008.
14	Leng B, Zhang Y, Liu X, et al. Astragaloside IV suppresses high glucose-induced NLRP 3 inflammasome activation by inhibiting TLR4/NF- κ B and CaSR. Mediators Inflamm 2019; 2019: 1-16.
15	Jin YR. Astragaloside IV inhibits radiation-induced brain injury through NLRP3 and TLR4 signaling pathway. Lanzhou: Northwest Normal University, 2019: 23-40.
16	Liu X, Shang S, Chu W, et al. Astragaloside IV ameliorates radiation-induced senescence via antioxidative mechanism. J Pharm Pharmacol 2020; 72: 1110-8.
17	Su CM, Wang HC, Hsu FT, et al. Astragaloside IV induces aoptosis, G-Phase arrest and inhibits anti-apoptotic signaling in hepatocellular carcinoma. In Vivo 2020, 34: 631-8.
18	Liu X, Chu W, Shang S, et al. Preliminary study on the anti-apoptotic mechanism of Astragaloside IV on radiation-induced brain cells. Int J Immunopathol Pharmacol 2020; 34: 1-12.
19	Postaci I, Coskun O, Senol N, Aslankoc R, Comlekci S.The physiopathological effects of quercetin on oxidative stress in radiation of 4.5 g mobile phone exposed liver tissue of rat. Bratisl Lek Listy 2018, 119: 481-9.
20	Holovská K, Almášiová V, Cigánková V, Beňová K, Račeková E, Martončíková M. Structural and ultrastructural study of rat liver influenced by electromagnetic radiation. J Toxicol Environ Health A 2015; 78: 353-6.
21	Lysek-Gladysinska M, Wieczorek A, Walaszczyk A, et al. Long-term effects of low-dose mouse liver irradiation involve ultrastructural and biochemical changes in hepatocytes that depend on lipid metabolism. Radiat Environ Biophys 2018; 57: 123-32. DOI PMID
22	Tekın S, Türker H, Güven T, Yel M. The effects of ultraviolet C radiation on the ultrastructure of the liver cells of mole rats. Ultrastruct Pathol 2016; 40: 51-6.
23	Ragy MM. Effect of exposure and withdrawal of 900-MHz-electromagnetic waves on brain, kidney and liver oxidative stress and some biochemical parameters in male rats. Electromagn Biol Med 2015, 34: 279-84. DOI PMID
24	Najafi M, Motevaseli E, Shirazi A, et al. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: clinical implications. Int J Radiat Biol 2018; 94: 335-56. DOI PMID
25	Lyu Z, Ji X, Chen G, An B. Atractylodin ameliorates lipopolysaccharide and d-galactosamine-induced acute liver failure via the suppression of inflammation and oxidative stress. Int Immunopharmacol 2019; 72: 348-57. DOI PMID
26	Han M, Li S, Li L. Verapamil inhibits early acute liver failure through suppressing the NLRP3 inflammasome pathway. J Cell Mol Med 2021; 25: 5963-75.
27	Zhou X, Sun X, Gong X, et al. Astragaloside IV from Astragalus membranaceus ameliorates renal interstitial fibrosis by inhibiting inflammation via TLR4/NF-кB in vivo and in vitro. Int Immunopharmacol 2017; 42: 18-24.
28	Guarda G, Zenger M, Yazdi AS, et al. Differential expression of NLRP3 among hematopoietic cells. J Immunol 2011; 186: 2529-34. DOI PMID
29	Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 2011; 29: 707-35. DOI PMID
30	De ND, Latz Eicke. NLRP 3 inflammasomes link inflammation and metabolic disease. Trends Immunol 2011; 32: 373-9. DOI PMID
31	Qian W, Cai X, Qian Q, et al. Astragaloside IV protects endothelial progenitor cells from the damage of ox-LDL via the LOX-1/NLRP3 inflammasome pathway. Drug Des Devel Ther 2019; 13: 2579-89.
32	Song MT, Ruan J, Zhang RY, Deng J, Ma ZQ, Ma SP.Astragaloside IV ameliorates neuroinflammation-induced depressive-like behaviors in mice via the PPARγ/NF-κB/NLRP3 inflammasome axis. Acta Pharmacol Sin 2018; 39: 1559-70.
33	Nasoohi S, Ismael S, Ishrat T. Thioredoxin-interacting protein (TXNIP) in cerebrovascular and neurodegenerative diseases: regulation and implication. Mol Neurobiol 2018; 55: 7900-20. DOI PMID
34	Chen Y, Ning J, Cao W, et al. Research progress of TXNIP as a tumor suppressor gene participating in the metabolic reprogramming and oxidative stress of cancer cells in various cancers. Front Oncol 2020, 10: 568574.
35	Tsubaki H, Tooyama I, Walker DG. Thioredoxin-interacting protein (TXNIP) with focus on brain and neurodegenerative diseases. Int J Mol Sci 2020; 21: 9357.
36	Yodoi J, Matsuo Y, Tian H, Masutani H, Inamoto T. Anti-inflammatory thioredoxin family proteins for medicare, healthcare and aging care. Nutrients 2017; 9: 1081.
37	Fang YL. The role of TXNIP-NLRP3 inflammasome activation in cadmium exposure induced liver injury and the antagonistic effect of melatonin. Chongqin: Third Military Medical University, 2017: 32-65.
38	Kumar A, Mittal R. Mapping Txnip: Key connexions in progression of diabetic nephropathy. Pharmacol Rep 2018; 70: 614-22. DOI PMID
39	Zhao Y, Li Q, Zhao W, et al. Astragaloside IV and cycloastragenol are equally effective in inhibition of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in the endothelium. J Ethnopharmacol 2015, 169: 210-8. DOI PMID

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