{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T20:13:01Z","timestamp":1788811981472,"version":"build-2803163510"},"reference-count":40,"publisher":"Institute of Physiology of the Czech Academy of Sciences","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiol Res"],"abstract":"<jats:p>Sepsis is a complicated disorder caused by infection, which may trigger various symptoms. Lipopolysaccharides (LPS) are among the primary pathogens which can stimulate host\u2019s immunoreaction. In the late stage of sepsis, the patients\u2019 immune system is significantly suppressed, thus the mortality increases. Notably, autophagy is pivotal during sepsis, in which autophagosome-lysosome fusion mediated by syntaxin 17 (STX17) is a key step. Previous studies have shown that histone deacetylase 2 (HDAC2) deacetylated STX17 to promote autophagosome-lysosome fusion. Trichostatin A (TSA) as a HDAC inhibitor (HDACi) has the capability of inhibiting histone deacetylase activity, while such an effect can be reversed by\nITSA-1. This time LPS was used to stimulate human monocyte-macrophages (THP-1 cells) to establish the inflammatory cell model. TSA and ITSA-1 were administrated. The cell proliferation was examined by WST-1. Cytokines such as TNF-\u03b1 and IL-6, as well as HDAC2 activity and deacetylated STX17 (DA-STX17) expression were detected by ELISA. Also, autophagy-related proteins such as P62 and microtubule-associated protein light chain 3 (LC3) were detected by Western Blotting (WB), and autophagosome-lysosome fusion was observed by fluorescence assay. Cell apoptosis was measured by flow cytometry. Besides, network pharmacology analysis was conducted. The data showed that TSA inhibited HDAC2 activity, and remarkably downregulated DA-STX17 expression, accompanied by the lower expression of P62 and LC3 \u2161\/I. Decreased DA-STX17 promoted autophagosome-lysosome fusion, and inhibited TNF-\u03b1 secretion. Furthermore, network pharmacology analysis revealed an inner relationship concerning HDAC2 between TSA and sepsis. Therefore, TSA can be considered a potential drug to cure sepsis-related diseases.<\/jats:p>","DOI":"10.33549\/physiolres.935799","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T19:53:29Z","timestamp":1788810809000},"page":"781","source":"Crossref","is-referenced-by-count":0,"title":["Trichostatin A Inhibits Cytokines Released in LPS-Induced THP-1 Cells via Downregulating Deacetylated-Syntaxin 17 and Promoting Autophagosome-Lysosome Fusion"],"prefix":"10.33549","volume":"75","author":[{"given":"Le","family":"Sang","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Shaoxing People\u2019s Hospital, Shaoxing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Zang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zewei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref0","doi-asserted-by":"crossref","unstructured":"1.\tWeng L, Zeng XY, Yin P, Wang LJ, Wang CY, Jiang W, et al. Sepsis-related mortality in China: a descriptive analysis. Intensive Care Medicine 2018;44:1071-1080. https:\/\/doi.org\/10.1007\/s00134-018-5203-z","DOI":"10.1007\/s00134-018-5203-z"},{"key":"ref1","doi-asserted-by":"crossref","unstructured":"2.\tTaniguchi LU, Bierrenbach AL, Toscano CM, Schettino GP, Azevedo LC. Sepsis-related deaths in Brazil: an analysis of the national mortality registry from 2002 to 2010. Crit Care 2014;18:608. https:\/\/doi.org\/10.1186\/s13054-014-0608-8","DOI":"10.1186\/s13054-014-0608-8"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"3.\tReinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing Sepsis as a Global Health Priority - A WHO Resolution. N Engl J Med 2017;377:414-417. https:\/\/doi.org\/10.1056\/NEJMp1707170","DOI":"10.1056\/NEJMp1707170"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"4.\tFleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, et al. Assessment of global incidence and mortality of hospital-treated sepsis. current estimates and limitations. Am J Respir Crit Care Med 2016;193:259-272. https:\/\/doi.org\/10.1164\/rccm.201504-0781OC","DOI":"10.1164\/rccm.201504-0781OC"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"5.\tZhou G, Xie D, Fan R, Yang Z, Du J, Mai S, et al. Comparison of pulmonary and extrapulmonary models of sepsis-associated acute lung injury. Physiol Res 2023;72:741-752. https:\/\/doi.org\/10.33549\/physiolres.935123","DOI":"10.33549\/physiolres.935123"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"6.\tQi Z, He Z, Chen J, Ma M, Deng M, Zhang Y, et al. Protection of toll-like receptor 9 against lipopolysaccharide-induced inflammation and oxidative stress of pulmonary epithelial cells via MyD88-mediated pathways. Physiol Res 2022;71:259-273. https:\/\/doi.org\/10.33549\/physiolres.934741","DOI":"10.33549\/physiolres.934741"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"7.\tTang Y, Li B, Wang N, Xie Y, Wang L, Yuan Q, et al. Fluorofenidone protects mice from lethal endotoxemia through the inhibition of TNF-alpha and IL-1beta release. Int Immunopharmacol 2010;10:580-583. https:\/\/doi.org\/10.1016\/j.intimp.2010.02.005","DOI":"10.1016\/j.intimp.2010.02.005"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"8.\tCadwell K. Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol 2016;16:661-675. https:\/\/doi.org\/10.1038\/nri.2016.100","DOI":"10.1038\/nri.2016.100"},{"key":"ref8","unstructured":"9.\tSun Jian, Qin E, Tang Jixian, Cao Miaoying, Shen Juxin. Doxycycline regulates lipopolysaccharide-induced inflammatory cytokine levels in THP-1 cells by upregulating autophagy. (In Chinese) Chinese J Pathophysiol. 2019;35:1489-1494."},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"10.\tZhang DM, Zhang T, Wang MM, Wang XX, Qin YY, Wu J, et al. TIGAR alleviates ischemia\/reperfusion-induced autophagy and ischemic brain injury. Free Radic Biol Med 2019;137:13-23. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2019.04.002","DOI":"10.1016\/j.freeradbiomed.2019.04.002"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"11.\tKitzmiller L, Ledford JR, Hake PW, O'connor M, Piraino G, Zingarelli B. Activation of AMP-Activated Protein Kinase by A769662 Ameliorates Sepsis-Induced Acute Lung Injury in Adult Mice. Shock 2019;52:540-549. https:\/\/doi.org\/10.1097\/SHK.0000000000001303","DOI":"10.1097\/SHK.0000000000001303"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"12.\tZois CE, Koukourakis MI. Radiation-induced autophagy in normal and cancer cells: towards novel cytoprotection and radio-sensitization policies? Autophagy 2009;5:442-450. https:\/\/doi.org\/10.4161\/auto.5.4.7667","DOI":"10.4161\/auto.5.4.7667"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"13.\tBoyle KB, Randow F. The role of 'eat-me' signals and autophagy cargo receptors in innate immunity. Curr Opin Microbiol 2013;16:339-348. https:\/\/doi.org\/10.1016\/j.mib.2013.03.010","DOI":"10.1016\/j.mib.2013.03.010"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"14.\tGao W, Chen Z, Wang W, Stang MT. E1-like activating enzyme Atg7 is preferentially sequestered into p62 aggregates via its interaction with LC3-I. PLoS One 2013;8:e73229. https:\/\/doi.org\/10.1371\/journal.pone.0073229","DOI":"10.1371\/journal.pone.0073229"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"15.\tShen Q, Shi Y, Liu J, Su H, Huang J, Zhang Y, et al. Acetylation of STX17 (syntaxin 17) controls autophagosome maturation. Autophagy 2021;17:1157-1169. https:\/\/doi.org\/10.1080\/15548627.2020.1752471","DOI":"10.1080\/15548627.2020.1752471"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"16.\tCui X, Wang B, Han D, Cheng M, Yuan P, Du P, et al. Exacerbation of atherosclerosis by STX17 knockdown: Unravelling the role of autophagy and inflammation. J Cell Mol Med 2024;28:e18402. https:\/\/doi.org\/10.1111\/jcmm.18402","DOI":"10.1111\/jcmm.18402"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"17.\tAzechi T, Kanehira D, Kobayashi T, Sudo R, Nishimura A, Sato F, et al. Trichostatin A, an HDAC class I\/II inhibitor, promotes Pi-induced vascular calcification via up-regulation of the expression of alkaline phosphatase. J Atheroscler Thromb 2013;20:538-547. https:\/\/doi.org\/10.5551\/jat.15826","DOI":"10.5551\/jat.15826"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"18.\tShen Z, Liao X, Shao Z, Feng M, Yuan J, Wang S, et al. Short-term stimulation with histone deacetylase inhibitor trichostatin a induces epithelial-mesenchymal transition in nasopharyngeal carcinoma cells without increasing cell invasion ability. BMC Cancer 2019;19:262. https:\/\/doi.org\/10.1186\/s12885-019-5482-y","DOI":"10.1186\/s12885-019-5482-y"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"19.\tZheng Y, Li G, Shi A, Guo J, Xu Y, Cai W. Role of miR-455-3p in the alleviation of LPS-induced acute lung injury by allicin. Heliyon 2024;10:e39338. https:\/\/doi.org\/10.1016\/j.heliyon.2024.e39338","DOI":"10.1016\/j.heliyon.2024.e39338"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"20.\tJiayi D, Chen YZ. LPS-induced decrease of specific binding of 3H-dexamethasone to peritoneal macrophages of C57BL\/6 mice. J Recept Res 1992;12:451-462. https:\/\/doi.org\/10.3109\/10799899209074806","DOI":"10.3109\/10799899209074806"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"21.\tBao W, Luo Y, Wang D, Li J, Wu X, Mei W. Sodium salicylate modulates inflammatory responses through AMP-activated protein kinase activation in LPS-stimulated THP-1 cells. J Cell Biochem 2018;119:850-860. https:\/\/doi.org\/10.1002\/jcb.26249","DOI":"10.1002\/jcb.26249"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"22.\tSun J, Shigemi H, Tanaka Y, Yamauchi T, Ueda T, Iwasaki H. Tetracyclines downregulate the production of LPS-induced cytokines and chemokines in THP-1 cells via ERK, p38, and nuclear factor-\u03baB signaling pathways. Biochem Biophys Rep 2015;4:397-404. https:\/\/doi.org\/10.1016\/j.bbrep.2015.11.003","DOI":"10.1016\/j.bbrep.2015.11.003"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"23.\tKoeller KM, Haggarty SJ, Perkins BD, Leykin I, Wong JC, Kao MC, et al. Chemical genetic modifier screens: small molecule trichostatin suppressors as probes of intracellular histone and tubulin acetylation. Chem Biol 2003;10:397-410. https:\/\/doi.org\/10.1016\/S1074-5521(03)00093-0","DOI":"10.1016\/S1074-5521(03)00093-0"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"24.\tCui SN, Chen ZY, Yang XB, Chen L, Yang YY, Pan SW, et al. Trichostatin A modulates the macrophage phenotype by enhancing autophagy to reduce inflammation during polymicrobial sepsis. Int Immunopharmacol 2019;77:105973. https:\/\/doi.org\/10.1016\/j.intimp.2019.105973","DOI":"10.1016\/j.intimp.2019.105973"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"25.\tShen MJ, Sun LC, Liu XY, Xiong MC, Li S, Tang AL, et al. Trichostatin A improves the inflammatory response and liver injury in septic mice through the FoxO3a\/autophagy signaling pathway. World J Emerg Med 2022;13:182-188. https:\/\/doi.org\/10.5847\/wjem.j.1920-8642.2022.056","DOI":"10.5847\/wjem.j.1920-8642.2022.056"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"26.\tZhao C, Liu J, Zhao S, Liu P, Li Z, Li Y, et al. Role of esketamine in attenuating neuroinflammation and improving postoperative cognitive function via autophagy activation through PARP1 targeting. Physiol Res 2025;74:871-884. https:\/\/doi.org\/10.33549\/physiolres.935577","DOI":"10.33549\/physiolres.935577"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"27.\tLiu J, Zhou H, Chen J, Zuo Q, Liu F. Baicalin ameliorates cartilage injury in rats with osteoarthritis via Modulating miR-766-3p\/AIFM1 axis. Physiol Res 2024;73:633-642. https:\/\/doi.org\/10.33549\/physiolres.935284","DOI":"10.33549\/physiolres.935284"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"28.\tLv J, Shan D, Jia H, Wang Z. The increase in autophagy induced by naringin alleviates Schwann cell apoptosis mediated by the AMPK\/mTOR signalling pathway. J Orthop Surg Res 2025;20:566. https:\/\/doi.org\/10.1186\/s13018-025-05969-9","DOI":"10.1186\/s13018-025-05969-9"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"29.\tLi Y, Ding X, Fan P, Guo J, Tian X, Feng X, et al. Inactivation of p27(kip1) promoted nonspecific inflammation by enhancing macrophage proliferation in islet transplantation. Endocrinology 2016;157:4121-4132. https:\/\/doi.org\/10.1210\/en.2016-1060","DOI":"10.1210\/en.2016-1060"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"30.\tLoppnow H, Libby P, Freudenberg M, Krauss JH, Weckesser J, Mayer H. Cytokine induction by lipopolysaccharide (LPS) corresponds to lethal toxicity and is inhibited by nontoxic Rhodobacter capsulatus LPS. Infect Immun 1990;58:3743-3750. https:\/\/doi.org\/10.1128\/iai.58.11.3743-3750.1990","DOI":"10.1128\/iai.58.11.3743-3750.1990"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"31.\tAl-Roub A, Al Madhoun A, Akhter N, Thomas R, Miranda L, Jacob T, et al. IL-1\u03b2 and TNF\u03b1 Cooperativity in Regulating IL-6 Expression in Adipocytes Depends on CREB Binding and H3K14 Acetylation. Cells 2021;10:3228. https:\/\/doi.org\/10.3390\/cells10113228","DOI":"10.3390\/cells10113228"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"32.\tBahman F, Al-Roub A, Akhter N, Al Madhoun A, Wilson A, Almansour N, et al. TNF-\u03b1\/stearate induced H3K9\/18 histone acetylation amplifies IL-6 expression in 3T3-L1 mouse adipocytes. Int J Mol Sci 2024;25:6776. https:\/\/doi.org\/10.3390\/ijms25126776","DOI":"10.3390\/ijms25126776"},{"key":"ref32","doi-asserted-by":"crossref","unstructured":"33.\tRaza A, Alvi S, Borok RZ, Span L, Parcharidou A, Alston D, et al. Excessive proliferation matched by excessive apoptosis in myelodysplastic syndromes: the cause-effect relationship. Leuk Lymphoma 1997;27:111-118. https:\/\/doi.org\/10.3109\/10428199709068277","DOI":"10.3109\/10428199709068277"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"34.\tLiu Y, Beyer A, Aebersold R. On the dependency of cellular protein levels on mRNA abundance. Cell 2016;165:535-550. https:\/\/doi.org\/10.1016\/j.cell.2016.03.014","DOI":"10.1016\/j.cell.2016.03.014"},{"key":"ref34","doi-asserted-by":"crossref","unstructured":"35.\tDas L. Epigenetic alterations impede epithelial-mesenchymal transition by modulating centrosome amplification and Myc\/RAS axis in triple negative breast cancer cells. Sci Rep 2023;13:2458. https:\/\/doi.org\/10.1038\/s41598-023-29712-8","DOI":"10.1038\/s41598-023-29712-8"},{"key":"ref35","doi-asserted-by":"crossref","unstructured":"36.\tLi J, Chen J, Ricupero CL, Hart RP, Schwartz MS, Kusnecov A, et al. Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia. Nat Med 2012;18:783-790. https:\/\/doi.org\/10.1038\/nm.2709","DOI":"10.1038\/nm.2709"},{"key":"ref36","doi-asserted-by":"crossref","unstructured":"37.\tFang J, Lian Y, Xie K, Cai S, Wen P. Epigenetic modulation of neuronal apoptosis and cognitive functions in sepsis-associated encephalopathy. Neurol Sci 2014;35:283-288. https:\/\/doi.org\/10.1007\/s10072-013-1508-4","DOI":"10.1007\/s10072-013-1508-4"},{"key":"ref37","doi-asserted-by":"crossref","unstructured":"38.\tHong GL, Kim KH, Karunasagara S, Jung JY. Characterization of LC3 and p62 on rat prostate lobe in benign prostate hyperplasia animal model. Anatomy & Biological Anthropology 2020;33:181-191. https:\/\/doi.org\/10.11637\/aba.2020.33.4.181","DOI":"10.11637\/aba.2020.33.4.181"},{"key":"ref38","doi-asserted-by":"crossref","unstructured":"39.\tGuo Y, Li Z, Shi C, Li J, Yao M, Chen X. Trichostatin A attenuates oxidative stress-mediated myocardial injury through the FoxO3a signaling pathway. Int J Mol Med 2017;40:999-1008. https:\/\/doi.org\/10.3892\/ijmm.2017.3101","DOI":"10.3892\/ijmm.2017.3101"},{"key":"ref39","doi-asserted-by":"crossref","unstructured":"40.\tWang P, Zhao C, Zhou H, Huang X, Ying H, Zhang S, et al. Dysregulation of histone deacetylases inhibits trophoblast growth during early placental development partially through TFEB-dependent autophagy-lysosomal pathway. Int J Mol Sci 2023;24:11899. https:\/\/doi.org\/10.3390\/ijms2415118992.","DOI":"10.3390\/ijms241511899"}],"container-title":["Physiological Research"],"original-title":[],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T19:53:35Z","timestamp":1788810815000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.biomed.cas.cz\/physiolres\/pdf\/2026\/75_781.pdf"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,8,31]]}},"URL":"https:\/\/doi.org\/10.33549\/physiolres.935799","relation":{},"ISSN":["1802-9973"],"issn-type":[{"value":"1802-9973","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]}}}