Combinatorial Chemistry & High Throughput ScreeningCombinatorial Chemistry & High Throughput ScreeningCombinatorial Chemistry & High Throughput Screening1386-20731875-5402Bentham Science64388210.2174/0113862073272407231201071629ChemistryResearch ArticleThe Different Therapeutic Effects of Traditional Chinese Medicine Shensong Yangxin Capsule and Salubrinal in High-intensity Exercise-induced Heart Failure in Rats with Acute Myocardial InfarctionZhaoJianinfo@benthamscience.netWangDongmeiinfo@benthamscience.netLuJunliinfo@benthamscience.netMaYanzhuoinfo@benthamscience.netLvHongzhiinfo@benthamscience.netLiCongxininfo@benthamscience.netRuLeishenginfo@benthamscience.netDepartment of Radiology, The Third Hospital of Hebei Medical UniversityInternal Medicine Teaching and Research Section, Hebei Medical Universitynternal Medicine Teaching and Research Section, Hebei Medical UniversityDepartment of Orthopedic Surgery, The Third Hospital of Hebei Medical UniversityDepartment of Pharmacy, The Third Hospital of Hebei Medical University0106202427111592160107012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjpbr.com/1386-2073/article/view/643882

Background:Currently, endoplasmic reticulum stress is studied utilizing a dephosphorylation inhibitor (Sal). The traditional Chinese patent medicine and simple formulation Shensong Yangxin Capsule is a commonly used medication for the treatment of arrhythmia. However, the efficacy and underlying mechanism of the capsule in treating post-ischemic heart failure in myocardial tissue have not yet been investigated.

Objective:The therapeutic effects and the underlying mechanism of the Shensong Yangxin Capsule (SSYX) and the dephosphorylation inhibitor Salubrinal (Sal) on heart failure (HF) induced by high-intensity exercise in rats with acute myocardial infarction (AMI) were investigated.

Methods:Male infants of 8 weeks Spragge-Dawley (SD) rats were randomly assigned to one of four groups: sham surgery group, AMI+placebo group, AMI+Shensong Yangxin Capsule group (AMI+SSYX), and AMI+Sal administration group. Rats' myocardial infarction was induced by left coronary artery ligation. Rats were subjected to a 3-week high-intensity exercise program to simulate heart failure after 7 days of postoperative rest. After the fourth postoperative week, echocardiography was applied to determine the left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and left ventricular systolic volume (LVESV) in each group. HE and TUNEL labeling were employed to examine the morphology of cardiac cells and measure the percentage of apoptosis in each group; Western blotting was applied to detect the cardiomyocyte apoptosis-related proteins p-JNK, p-P38, and NOX2, while ELISA was used to detect glutathione(GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) in serum.

Results:Following a 4-week drug intervention:(1)LVFS and LVEF in the AMI+placebo group were statistically significantly reduced, while LVESV were significantly higher, compared to those in the sham surgery group (P(<0.05); The AMI+SSYX group performed statistically significantly better than the AMI+placebo group(P(<0.05). (2) The myocardial cells in the AMI+placebo group exhibited significant swelling and inflammatory cell infiltration; the myocardial cells in the AMI+SSYX group and AMI+Sal group displayed mild swelling and minimal inflammatory cell infiltration; the AMI+SSYX group's myocardial cell morphology was superior to that of the AMI+Sal group; (3) The apoptosis rate of the AMI+placebo group was around 95%, greater than that of the sham surgery group (2.55%). The apoptosis rate of the AMI+SSYX group is approximately 21%, while the apoptosis rate of the AMI+Sal group is about 43%. (4) In the AMI+placebo group, p-JNK, p-P38, and NOX2 protein expression dramatically increased compared to the sham surgery group. The expression of p-P38, NOX2, and p-JNK/t-JNK was considerably reduced in the AMI+Shensong group and AMI+Sal group， compared to the AMI+placebo group. (P(<0.01)The AMI+SSYX group's result is superior to that of the AMI+Sal group. (5) Compared to the sham surgery group, the serum levels of SOD and GSH were significantly lower, and MDA was significantly higher in the AMI+placebo group. Compared to the AMI+placebo group, the serum levels of SOD and GSH were significantly higher, and MDA was significantly lower in the AMI+SSYX group and the AMI+Sal group. (P(<0.05)

Conclusion:In rats with acute myocardial infarction in high-intensity exercise-induced heart failure, Shensong Yangxin Capsule dramatically reduces myocardial cell death and cardiac dysfunction. SSYX has a shorter course of treatment and a better therapeutic effect than Sal.

Acute myocardial infarctionhigh-intensity exerciseheart failureshensong yangxin capsulemyocardial cell apoptosisdephosphorylation inhibitor salubrinal.Ambrosy, A.P.; Fonarow, G.C.; Butler, J.; Chioncel, O.; Greene, S.J.; Vaduganathan, M.; Nodari, S.; Lam, C.S.P.; Sato, N.; Shah, A.N.; Gheorghiade, M. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J. Am. Coll. Cardiol., 2014, 63(12), 1123-1133. doi: 10.1016/j.jacc.2013.11.053 PMID: 24491689Branch of cardiovascular physicians, chinese medical doctor association, chinese cardiovascular health alliance, the expert working group on the prevention and treatment of heart failure after myocardial infarction. 2020 Expert consensus on the prevention and treatment of heart failure after myocardial infarction. Chin. J. Circulation, 2020, 35(12), 1166-1180.Groenendyk, J.; Sreenivasaiah, P.K.; Kim, D.H.; Agellon, L.B.; Michalak, M. Biology of endoplasmic reticulum stress in the heart. Circ. Res., 2010, 107(10), 1185-1197. doi: 10.1161/CIRCRESAHA.110.227033 PMID: 21071716Huwait, E.; Mobashir, M. Potential and therapeutic roles of diosmin in human diseases. Biomedicines, 2022, 10(5), 1076. doi: 10.3390/biomedicines10051076 PMID: 35625813Lewinska, A.; Adamczyk-Grochala, J.; Kwasniewicz, E.; Deregowska, A.; Wnuk, M. Diosmin-induced senescence, apoptosis and autophagy in breast cancer cells of different p53 status and ERK activity. Toxicol. Lett., 2017, 265, 117-130. doi: 10.1016/j.toxlet.2016.11.018 PMID: 27890807Srinivasan, S.; Pari, L. Ameliorative effect of diosmin, a citrus flavonoid against streptozotocin-nicotinamide generated oxidative stress induced diabetic rats. Chem. Biol. Interact., 2012, 195(1), 43-51. doi: 10.1016/j.cbi.2011.10.003 PMID: 22056647Mobashir, M.; Helmi, N.; Alammari, D. Role of potential COVID-19 immune system associated genes and the potential pathways linkage with type-2 diabetes. Comb. Chem. High Throughput Screen., 2022, 25(14), 2452-2462. doi: 10.2174/1386207324666210804124416 PMID: 34348612Liu, Y.; Qi, S.Y.; Ru, L.S.; Ding, C.; Wang, H.J.; Li, A.Y.; Xu, B.Y.; Zhang, G.H.; Wang, D.M. Salubrinal improves cardiac function in rats with heart failure post myocardial infarction through reducing endoplasmic reticulum stress-associated apoptosis. Zhonghua Xin Xue Guan Bing Za Zhi, 2016, 44(6), 494-500. PMID: 27346262Hao, Panpan Traditional chinese medicine for cardiovascular disease evidence and potential mechanisms. J. amer college card., 2017, 69(24), 2952-2966. doi: 10.1016/j.jacc.201.04.041Jiang, Y.; Zhao, Q.; Li, L.; Huang, S.; Yi, S.; Hu, Z. Effect of traditional chinese medicine on the cardiovascular diseases. Front. Pharmacol., 2022, 13(13), 806300. doi: 10.3389/fphar.2022.806300 PMID: 35387325Yang, J.; Sun, W.; Sun, J.; Wang, F.; Hou, Y.; Guo, H.; Chen, H.; Fu, L. Guanxintai exerts protective effects on ischemic cardiomyocytes by mitigating oxidative stress. Evid. Based Complement. Alternat. Med., 2017, 2017, 1-10. doi: 10.1155/2017/4534387 PMID: 29075303Guan, F. Effects of astragalus injection on myocardial cell damages due to oxidative stress. Chin. J. Rehabil. Theor. Pract., 2010, 16(9), 830-832.Feng, L.; Gong, J.; Jin, Z.Y.; Li, N.; Sun, L.P.; Wu, Y.L.; Pu, J.L. Electrophysiological effects of Chinese medicine Shen song Yang xin (SSYX) on Chinese miniature swine heart and isolated guinea pig ventricular myocytes. Chin. Med. J., 2009, 122(13), 1539-1543. J. doi: 10.3760/cma.j.issn.0366-6999.2009.13.012 PMID: 19719944Cheng, W.; Wang, L.; Yang, T.; Wu, A.; Wang, B.; Li, T.; Lu, Z.; Yang, J.; Li, Y.; Jiang, Y.; Wu, X.; Meng, H.; Zhao, M. Qiliqiangxin capsules optimize cardiac metabolism flexibility in rats with heart failure after myocardial infarction. Front. Physiol., 2020, 11, 805. doi: 10.3389/fphys.2020.00805 PMID: 32848816Hao, S.; Sui, X.; Wang, J.; Zhang, J.; Pei, Y.; Guo, L.; Liang, Z. Secretory products from epicardial adipose tissue induce adverse myocardial remodeling after myocardial infarction by promoting reactive oxygen species accumulation. Cell Death Dis., 2021, 12(9), 848. doi: 10.1038/s41419-021-04111-x PMID: 34518516Albadrani, G.M.; Binmowyna, M.N.; Bin-Jumah, M.N.; El-Akabawy, G.; Aldera, H.; Al-Farga, A.M. Quercetin protects against experimentally-induced myocardial infarction in rats by an antioxidant potential and concomitant activation of signal transducer and activator of transcription 3. J. Physiol. Pharmacol., 2020, 71(6), 875-890. J. doi: 10.26402/jpp.2020.6.11 PMID: 33901998Sun, X.; Xue, H. JAK2 expression in myocardial tissue of rats after exercise preconditioning and exhaustive exercise injury. Chi. J. Tis. Eng. Res., 2015, 19(20), 3216-3220. doi: 10.3969/j.issn.2095-4344.2015.20.019Tran, K.V.; Tanriverdi, K.; Aurigemma, G.P.; Lessard, D.; Sardana, M.; Parker, M.; Shaikh, A.; Gottbrecht, M.; Milstone, Z.; Tanriverdi, S.; Vitseva, O.; Keaney, J.F.; Kiefe, C.I.; McManus, D.D.; Freedman, J.E. Circulating extracellular RNAs, myocardial remodeling, and heart failure in patients with acute coronary syndrome. J. Clin. Transl. Res., 2019, 5(1), 33-43. J. PMID: 31579840Zhu, H.; Tannous, P.; Johnstone, J.L.; Kong, Y.; Shelton, J.M.; Richardson, J.A.; Le, V.; Levine, B.; Rothermel, B.A.; Hill, J.A. Cardiac autophagy is a maladaptive response to hemodynamic stress. J. Clin. Invest., 2007, 117(7), 1782-1793. doi: 10.1172/JCI27523 PMID: 17607355Boyce, M.; Bryant, K.F.; Jousse, C.; Long, K.; Harding, H.P.; Scheuner, D.; Kaufman, R.J.; Ma, D.; Coen, D.M.; Ron, D.; Yuan, J. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science, 2005, 307(5711), 935-939. doi: 10.1126/science.1101902 PMID: 15705855Liu, C.L.; Li, X.; Hu, G.L.; Li, R.J.; He, Y.Y.; Zhong, W.; Li, S.; He, K.L.; Wang, L.L. Salubrinal protects against tunicamycin and hypoxia induced cardiomyocyte apoptosis via the PERK-eIF2α signaling pathway. J. Geriatr. Cardiol., 2012, 9(3), 258-268. PMID: 23097656Mehta, S.; Sharma, A.K.; Singh, R.K. Advances in ethnobotany, synthetic phytochemistry and pharmacology of endangered herb Picrorhiza kurroa (Kutki): A comprehensive review (2010-2020). Mini Rev. Med. Chem., 2021, 21(19), 2976-2995. doi: 10.2174/1389557521666210401090028 PMID: 33797375Mehta, S.; Sharma, A.K.; Singh, R.K. Therapeutic journey of Andrographis paniculata (Burm.f.) nees from natural to synthetic and nanoformulations. Mini Rev. Med. Chem., 2021, 21(12), 1556-1577. doi: 10.2174/1389557521666210315162354 PMID: 33719961Mehta, S.; Sharma, A.K.; Singh, R.K. Pharmacological activities and molecular mechanisms of pure and crude extract of Andrographis paniculata: An update. Phytomedicine Plus, 2021, 1(4), 100085. doi: 10.1016/j.phyplu.2021.100085Singh, R.K.; Mehta, S.; Sharma, A.K. Ethnobotany, pharmacological activities and bioavailability studies on "king of bitters" (Kalmegh): A Review (2010-2020). Comb. Chem. High Throughput Screen., 2022, 25(5), 788-807. doi: 10.2174/1386207324666210310140611 PMID: 33745423Nauseef, W.M. Biological roles for the NOX family NADPH oxidases. J. Biol. Chem., 2008, 283(25), 16961-16965. doi: 10.1074/jbc.R700045200 PMID: 18420576Vermot, A.; Petit-Härtlein, I.; Smith, S.M.E.; Fieschi, F. NADPH Oxidases (NOX): An overview from discovery, molecular mechanisms to physiology and pathology. Antioxidants, 2021, 10(6), 890. doi: 10.3390/antiox10060890 PMID: 34205998Checa, J.; Aran, J.M. Reactive oxygen species: Drivers of physiological and pathological processes. J. Inflamm. Res., 2020, 13, 1057-1073. doi: 10.2147/JIR.S275595 PMID: 33293849Leng, Li-li Tissue distribution and physiological function of NOX family NADPH oxidases. Intern. J. Patho. Clin. Med., 2008, 28(1), 19-23.Piccoli, C.; Ria, R.; Scrima, R.; Cela, O.; D’Aprile, A.; Boffoli, D.; Falzetti, F.; Tabilio, A.; Capitanio, N. Characterization of mitochondrial and extra-mitochondrial oxygen consuming reactions in human hematopoietic stem cells. Novel evidence of the occurrence of NAD(P)H oxidase activity. J. Biol. Chem., 2005, 280(28), 26467-26476. doi: 10.1074/jbc.M500047200 PMID: 15883163Montiel, V.; Bella, R.; Michel, L.Y.M.; Esfahani, H.; De Mulder, D.; Robinson, E.L.; Deglasse, J.P.; Tiburcy, M.; Chow, P.H.; Jonas, J.C.; Gilon, P.; Steinhorn, B.; Michel, T.; Beauloye, C.; Bertrand, L.; Farah, C.; Dei Zotti, F.; Debaix, H.; Bouzin, C.; Brusa, D.; Horman, S.; Vanoverschelde, J.L.; Bergmann, O.; Gilis, D.; Rooman, M.; Ghigo, A.; Geninatti-Crich, S.; Yool, A.; Zimmermann, W.H.; Roderick, H.L.; Devuyst, O.; Balligand, J.L. Inhibition of aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide. Sci. Transl. Med., 2020, 12(564), eaay2176. doi: 10.1126/scitranslmed.aay2176 PMID: 33028705Juan, C.A.; Pérez de la Lastra, J.M.; Plou, F.J.; Pérez-Lebeña, E. The chemistry of reactive oxygen species (ROS) revisited: Outlining their role in biological macromolecules (DNA, Lipids and Proteins) and induced pathologies. Int. J. Mol. Sci., 2021, 22(9), 4642. doi: 10.3390/ijms22094642 PMID: 33924958Protein kinases-promising targets for anticancer drug research; Singh, R.K.; Bhatia, R., Eds.; Intech Open, 2021. doi: 10.5772/intechopen.82939Yue, J; López, JM Understanding MAPK signaling pathways in apoptosis. Int J Mol Sci., 2020, 21(7), 2346. doi: 10.3390/ijms21072346Zhang, C.; Shen, M.; Chen, L. Research progress of oxidative stress MAPK signal pathway and treatment of osteoarthritis. Zhongguo Guzhi Shusong Zazhi, 2023, 29(4), 583-588. J.Seternes, O.M.; Kidger, A.M.; Keyse, S.M. Dual-specificity MAP kinase phosphatases in health and disease. Biochim. Biophys. Acta Mol. Cell Res., 2019, 1866(1), 124-143. doi: 10.1016/j.bbamcr.2018.09.002 PMID: 30401534Ferguson, B.S.; Nam, H.; Morrison, R.F. Dual-specificity phosphatases regulate mitogen-activated protein kinase signaling in adipocytes in response to inflammatory stress. Cell. Signal., 2019, 53, 234-245. doi: 10.1016/j.cellsig.2018.10.011 PMID: 30347224Morrison, DK MAP kinase pathways. Cold Spring Harb Perspect. Biol., 2012, 4(11), 011254. doi: 10.1101/cshperspect.a011254Kumari, A.; Silakari, O.; Singh, R. K. Recent advances in colony stimulating factor-1 receptor/c-FMS as an emerging target for various therapeutic implications. Biomed. Pharmacother., 2018, 103, 662-679. doi: 10.1016/j.biopha.2018.04.046Sun, H.Y.; Wang, N.P.; Halkos, M.; Kerendi, F.; Kin, H.; Guyton, R.A.; Vinten-Johansen, J.; Zhao, Z.Q. Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways. Apoptosis, 2006, 11(9), 1583-1593. doi: 10.1007/s10495-006-9037-8 PMID: 16820962Clerk, A.; Sugden, P.H. 10 Mitogen-activated protein kinases are activated by oxidative stress and cytokines in neonatal rat ventricular myocytes. Biochem. Soc. Trans., 1997, 25(4), S566. J. doi: 10.1042/bst025s566Kumari, A.; Singh, R.K. Synthesis, molecular docking and biological evaluation of N ‐substituted indole derivatives as potential anti‐inflammatory and antioxidant agents. Chem. Biodivers., 2022, 19(9), e202200290. doi: 10.1002/cbdv.202200290 PMID: 35818885Fujii, J; Homma, T; Osaki, T. Superoxide radicals in the execution of cell death. Antioxidants, 2022, 11(3), 501. doi: 10.3390/antiox11030501Singh, R.K.; Kumari, A. Synthesis, molecular docking and ADME prediction of 1H-indole/5- substituted indole derivatives as potential antioxidant and anti- inflammatory agents. Med. Chem., 2023, 19(2), 163-173. doi: 10.2174/1573406418666220812152950 PMID: 35959908Liu, H.; Zhong, G.; Li, Y. Effect of different proportion of Flos Puerariae and Semen Hoveniae extracted by alcohol or water on the livers’ antioxidant function of alcoholic liver injury rats. Chi. J. Trad. Chi. Med. Pharma., 2012, 27(4), 1181-1184.Mi, Y. Clinical research and application progress of reduced glutathione. J. Difficult Dis., 2007, 6(6), 375-373.Musthafa, Q.A.; Abdul Shukor, M.F.; Ismail, N.A.S.; Mohd Ghazi, A.; Mohd Ali, R.; M Nor, I.F.; Dimon, M.Z.; Wan Ngah, W.Z. Oxidative status and reduced glutathione levels in premature coronary artery disease and coronary artery disease. Free Radic. Res., 2017, 51(9-10), 787-798. doi: 10.1080/10715762.2017.1379602 PMID: 28899235Armstrong, J.S.; Steinauer, K.K.; Hornung, B.; Irish, J.M.; Lecane, P.; Birrell, G.W.; Peehl, D.M.; Knox, S.J. Role of glutathione depletion and reactive oxygen species generation in apoptotic signaling in a human B lymphoma cell line. Cell Death Differ., 2002, 9(3), 252-263. doi: 10.1038/sj.cdd.4400959 PMID: 11859408