硒唑甲酰胺类Src激酶抑制剂对阿尔茨海默病中Aβ诱导的毒性作用

Selenazole Carboxamide Src Kinase Inhibitor Against Aβ-induced Toxicity in Alzheimer’s Disease

摘要

研究了Src酪氨酸蛋白激酶抑制剂(SAFA320)对转基因秀丽隐杆线虫CL4176的神经保护作用及其机制. 结果表明, 与空白对照相比, SAFA320处理显著减少了CL4176线虫中β淀粉样蛋白(Aβ)寡聚体的沉积, 降低了线虫的瘫痪率, 并能有效降低其体内活性氧(ROS)的产生, CL4176线虫组织内Src激酶活性也显著降低. 荧光实时定量聚合酶链式反应（PCR）结果显示, SAFA320处理会导致CL4176线虫体内skn-1基因及其下游靶基因gst-4的表达显著上调, 说明化合物SAFA320通过调节CL4176线虫中的SKN-1信号通路从而达到抑制Aβ毒性的效果. 综上所述, SAFA320在缓解CL4176线虫的Aβ毒性和改善认知功能方面具有显著效果, 是一种潜在的抗阿尔茨海默病(AD)候选药物.

Abstract

The study was designed to investigate the effects of Src tyrosine protein kinase inhibitor（SAFA320） on transgenic Caenorhabditis elegansstrain CL4176， along with its underlying mechanism. In the study， C. elegans CL4176 adminstrated with SAFA320 could reduce the deposition of Aβ oligomer to alleviate nematode paralysis， and decrease ROS production. Results of tissue Src kinase activity spectrophotometry analysis showed that SAFA320 could reduce the activities of Src in C. elegans. Meanwhile， the gene expression ofskn-1and its downstream target genegst-4 were significantly increased， suggesting that compound inhibited Aβ toxicity may involve in SKN-1 signaling pathway in CL4176. In conclusion， SAFA320 is effective in alleviating Aβ toxicity and improving cognitive functions in C. elegans CL4176， and it is a potent candidate agent against Alzheimer’s Disease（AD）.

关键词

阿尔茨海默病（AD） / Src激酶抑制剂(SAFA320) / β淀粉样蛋白 / 基因skn-1 / 秀丽隐杆线虫

Key words

Alzheimer’s disease（AD） / Src inhibitor（SAFA320） / Amyloid beta / Gene skn-1 / Caenorhabditis elegans

参考文献

[1] Baviskar P. S., Mahajan H. S., Ageing Res. Rev., 2026, 114, 102990

[2] Tiwari S., Atluri V., Kaushik A., Yndart A., Nair M., Int. J. Nanomedicine, 2019, 14, 5541-5554

[3] lo Vecchio F., la Torre A., Gravina C., D'onofrio G., Greco A., Int. J. Mol. Sci., 2026, 27(10), 4651

[4] Zheng Q., Wang X., Protein Cell, 2025, 16(2), 83-120

[5] Orobets K. S., Karamyshev A. L., Int. J. Mol. Sci., 2023, 24(19), 14794

[6] Zhang Y., Chen H., Li R., Sterling K., Song W., Signal Transduct. Target Ther., 2023, 8(1), 248

[7] Blennow K., Mattsson N., Schöll M., Hansson O., Zetterberg H., Trends Pharmacol. Sci., 2015, 36(5), 297-309

[8] Jin Y., Du Q., Song M., Kang R., Zhou J., Zhang H., Ding Y., J. Control Release, 2024, 375, 346-365

[9] Kim A. Y., Al Jerdi S., Macdonald R., Triggle C. R., Front. Pharmacol., 2024, 15, 1399121

[10] Passeri E., Elkhoury K., Morsink M., Broersen K., Linder M., Tamayol A., Malaplate C., Yen F. T., Arab—Tehrany E., Int. J. Mol. Sci., 2022, 23(22), 13954

[11] Shao W., Liu L., Zheng F., Ma Y., Zhang J., Biochem. Pharmacol., 2022, 206, 115333

[12] Su Y., Zhu K., Wang J., Liu B., Chang Y., Chang D., You Y., Eur. J. Med. Chem., 2025, 287, 117369

[13] Dhawan G., Combs C. K., J. Neuroinflammation, 2012, 9, 117

[14] Portugal C. C., Almeida T. O., Socodato R., Relvas J. B., Febs. J., 2022, 289(24), 7760-7775

[15] Ittner L. M., Ke Y. D., Delerue F., Bi M., Gladbach A., van Eersel J., Wölfing H., Chieng B. C., Christie M. J., Napier I. A., Eckert A., Staufenbiel M., Hardeman E., Götz J., Cell, 2010, 142(3), 387-397

[16] Jeayeng S., Thongsroy J., Chuaijit S., Biomolecules, 2024, 14(10), 1235

[17] Drake J., Link C. D., Butterfield D. A., Neurobiol. Aging, 2003, 24(3), 415-420

[18] Yu H. X. , The Design, Synthesis and Screening on Overriding Resistance of Bcr—Abl Selectivity Inhibitors, Guangxi University, Nanning, 2006

[19] (于海侠. 抗耐药作用的Bcr—Abl选择性抑制剂的设计、 合成与筛选, 南宁： 广西大学, 2006)

[20] Li W. L. , Design, Synthesis and Screening of Protein Tyrosine Kinase Inhibitors, Jilin University, Changchun, 2014

[21] (李文丽. 酪氨酸蛋白激酶抑制剂的设计、 合成和筛选, 长春： 吉林大学, 2014)

[22] Cabreiro F., Au C., Leung K. Y., Vergara—Irigaray N., Cochemé H. M., Noori T., Weinkove D., Schuster E., Greene N. D., Gems D., Cell, 2013, 153(1), 228-239

[23] Hahn A., Hung G. C. C., Ahier A., Dai C. Y., Kirmes I., Forde B. M., Campbell D., Lee R. S. Y., Sucic J., Onraet T., Zuryn S., Cell Metab., 2024, 36(12), 2528-2541

[24] Toledano M., Toledano—Osorio M., Navarro—Hortal M. D., Varela—López A., Osorio R., Quiles J. L., Antioxidants(Basel), 2019, 8(11), 550

[25] Chen Y., Onken B., Chen H., Xiao S., Liu X., Driscoll M., Cao Y., Huang Q., J. Agric. Food Chem., 2014, 62(15), 3422-3431

[26] Gruber J., Tang S. Y., Halliwell B., Ann NY Acad. Sci., 2007, 1100, 530-542

[27] Chen M. T., Zhou J. J., Han R. T., Ma Q. W., Wu Z. J., Fu P., Ma A. J., Feng N., Free Radic. Biol. Med., 2024, 223, 357-368

[28] Yu X., Tao J., Xiao T., Duan X., Front Aging Neurosci., 2024, 16, 1414956

[29] Lin C., Su Z., Luo J., Jiang L., Shen S., Zheng W., Gu W., Cao Y., Chen Y., Int. J. Biol. Macromol., 2020, 143, 243-254

[30] Zhi De J., Feng N., Liu D. L., Hou R. L., Wang M. Z., Ding X. X., Li H. Y., Arch. Pharm. Res., 2014, 37(3), 390-398

[31] Zhang H., Qin J., Lan X., Zeng W., Zhou J., Huang T. E., Xiao W. L., Wang Q. Q., Sun S., Su W., Nie W., Yang S., Yang J., Gao Q., Xiang Y., Biogerontology, 2022, 23(1), 115-128

[32] Liu H., Liu B., Zhang S., Fan M., Ji X., Zhang S., Wang Z., Qiao K., Ecotoxicol. Environ. Saf., 2023, 265, 115510

[33] Ishita Y., Chihara T., Okumura M., Neurosci. Res., 2020, 154, 9-19

[34] Chen C. H., Yang Y., Ke J. P., Yang Z., Li J. Y., Zhang Y. X., Liu G., Liu Z., Yao G., Bao G. H., J. Agric. Food Chem., 2024, 72(7), 3695-3706

[35] Zhang Z. P., Bai X., Cui W. B., Chen X. H., Liu X., Zhi D. J., Zhang Z. X., Fei D. Q., Wang D. S., Int. J. Mol. Sci., 2022, 23(12),

[36] Li N., Lin G., Zhang H., Sun J., Gui M., Liu Y., Li W., Liu J., Tang J., Biomolecules, 2022, 12(7), 984

[37] Bao J., Gur G., Yarden Y., Proc. Natl. Acad. Sci. USA, 2003, 100(5), 2438-2443

[38] Zhu F. D., Chen X., Yu L., Hu M. L., Pan Y. R., Qin D. L., Wu J. M., Li L., Law B. Y., Wong V. K., Zhou X. G., Wu A. G., Fan D. S., Phytomedicine, 2023, 117, 154916

[39] Yuan W., Wang S., Chen Y., Liang Y., Int. J. Biol. Macromol., 2026, 359, 151811

[40] Panagiotidou E., Gioran A., Bano D., Chondrogianni N., Redox. Biol., 2023, 65, 102817

[41] Zhou Q., Sun F., Zhang Y., Cao X., Li M., Yu H., Jiang T., Li S., Wang W., Xie J., He T., Liu Y., Ke D., Wang X. C., Xu P., Liu E., Chen H., Wang J. Z., Nat. Commun., 2026, 17(1), 7217

[42] Yong Y., Yan L., Wei J., Feng C., Yu L., Wu J., Guo M., Fan D., Yu C., Qin D., Zhou X., Wu A., Theranostics, 2024, 14(16), 6161-6184

[43] Bai R., Guo J., Ye X. Y., Xie Y., Xie T., Ageing Res. Rev., 2022, 77, 101619

[44] Poh A. R., Ernst M., Oncogene, 2023, 42(22), 1786-1801

[45] Mota S. I., Ferreira I. L., Valero J., Ferreiro E., Carvalho A. L., Oliveira C. R., Rego A. C., Exp. Neurol., 2014, 261, 698-709

[46] Roskoski R., Jr., Biochem. Biophys. Res. Commun., 2004, 324(4), 1155-1164

[47] Turner C. D., Ramos C. M., Curran S. P., Front. Aging, 2024, 5, 1369740

[48] Zečić A., Braeckman B. P., Cells, 2020, 9(1), 109

[49] Kyriakou E., Taouktsi E., Syntichaki P., Int. J. Mol. Sci., 2022, 23(23), 14907

[50] Li H., Su L., Su X., Liu X., Wang D., Li H., Ba X., Zhang Y., Lu J., Huang B., Li X., Redox. Biol., 2019, 21, 101111

[51] Kaspar J. W., Jaiswal A. K., The FASEB Journal, 2011, 25(3), 1076-1087

[52] Chu C. T., Uruno A., Suzuki T., Taguchi K., Baird L., Katsuoka F., Yamamoto M., Free Radical Bio. Med., 2026, 243, 318-337

[53] Lehrbach N. J., Ruvkun G., Elife, 2019, 8, e44425

基金资助

吉林省科技厅自然科学基金会(20220101268JC)