Flufenamic acid protects against intestinal fluid secretion and barrier leakage in a mouse model of Vibrio cholerae infection through NF-κB inhibition and AMPK activation

被引:19
作者
Pongkorpsakol, Pawin [1 ]
Satitsri, Saravut [2 ]
Wongkrasant, Preedajit [2 ]
Chittavanich, Pamorn [3 ]
Kittayaruksakul, Suticha [4 ]
Srimanote, Potjanee [5 ]
Chatsudthipong, Varanuj [2 ]
Muanprasat, Chatchai [2 ,6 ]
机构
[1] Mahidol Univ, Ramathibodi Hosp, Fac Med, Res Ctr,Grad Program Translat Med, Rama 6 Rd, Bangkok 10400, Thailand
[2] Mahidol Univ, Fac Sci, Dept Physiol, Rama 6 Rd, Bangkok 10400, Thailand
[3] Mahidol Univ, Fac Sci, Dept Pharmacol, Rama 6 Rd, Bangkok 10400, Thailand
[4] Navamindradhiraj Univ, Vajira Hosp, Fac Med, Dept Basic Med Sci, Bangkok, Thailand
[5] Thammasat Univ, Fac Allied Hlth Sci, Grad Studies, Paholyothin Rd, Pathum Thani 12120, Thailand
[6] Mahidol Univ, Excellent Ctr Drug Discovery, Rama 6 Rd, Bangkok 10400, Thailand
关键词
Cholera; Vibrio cholerae; Flufenamic acid; AMP-activated protein kinase; Inflammation; EL-TOR VARIANT; EPITHELIAL-CELLS; KINASE; BANGLADESH; DIARRHEA; O1; FLOODS; DHAKA;
D O I
10.1016/j.ejphar.2017.01.026
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Nuclear factor kappa B (NF-kappa B)-mediated inflammatory responses play crucial roles in the pathogenesis of diarrhea caused by the Vibrio cholerae El Tor variant (EL), which is a major bacterial strain causing recent cholera outbreaks. Flufenamic acid (FFA) has previously been demonstrated to be a potent activator of AMP-activated protein ldnase (AMPK), which is a negative regulator of NF-kappa B signaling. This study aimed to investigate the anti-diarrheal efficacy of FFA in a mouse model of EL infection and to investigate the mechanisms by which FFA activates AMPK in intestinal epithelial cells (IEC). In a mouse closed loop model of EL infection, FFA treatment (20 mg/kg) significantly abrogated EL-induced intestinal fluid secretion and barrier disruption. In addition, FFA suppressed NF-kappa B nuclear translocation and expression of proinflammatory mediators and promoted AMPK phosphorylation in the EL-infected mouse intestine. In T84 cells, FFA induced AMPK activation. Furthermore, FFA promoted tight junction assembly and prevented interferon gamma (IFN-gamma)-induced barrier disruption in an AMPK-dependent manner. Biochemical and molecular docking analyses indicated that FFA activates AMPK via a direct stimulation of calcium/calmodulin-dependent protein kinase kinase beta (CaMICK beta) activity. Collectively, our data indicate that FFA represents a class of existing drugs that may be of potential utility in the treatment of cholera caused by EL infection via AMPK-mediated suppression of NF-kappa B signaling in IEC.
引用
收藏
页码:94 / 104
页数:11
相关论文
共 22 条
[1]   RETRACTED: Nonsteroidal Anti-Inflammatory Drug Flufenamic Acid Is a Potent Activator of AMP-Activated Protein Kinase (Retracted article. See vol. 295, pg. 670, 2020) [J].
Chi, Yuan ;
Li, Kai ;
Yan, Qiaojing ;
Koizumi, Schuichi ;
Shi, Liye ;
Takahashi, Shuhei ;
Zhu, Ying ;
Matsue, Hiroyuki ;
Takeda, Masayuki ;
Kitamura, Masanori ;
Yao, Jian .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2011, 339 (01) :257-266
[2]   A New Lamarckian Genetic Algorithm for Flexible Ligand-Receptor Docking [J].
Fuhrmann, Jan ;
Rurainski, Alexander ;
Lenhof, Hans-Peter ;
Neumann, Dirk .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 2010, 31 (09) :1911-1918
[3]   Flufenamic acid as an ion channel modulator [J].
Guinamard, Romain ;
Simard, Christophe ;
Del Negro, Christopher .
PHARMACOLOGY & THERAPEUTICS, 2013, 138 (02) :272-284
[4]  
GULLIKSON GW, 1982, J PHARMACOL EXP THER, V220, P236
[5]   AMPK: a nutrient and energy sensor that maintains energy homeostasis [J].
Hardie, D. Grahame ;
Ross, Fiona A. ;
Hawley, Simon A. .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2012, 13 (04) :251-262
[6]   Shifting Prevalence of Major Diarrheal Pathogens in Patients Seeking Hospital Care during Floods in 1998, 2004, and 2007 in Dhaka, Bangladesh [J].
Harris, Aaron M. ;
Chowdhury, Fahima ;
Begum, Yasmin Ara ;
Khan, Ashraful Islam ;
Faruque, Abu S. G. ;
Svennerholm, Ann-Mari ;
Harris, Jason B. ;
Ryan, Edward T. ;
Cravioto, Alejandro ;
Calderwood, Stephen B. ;
Qadri, Firdausi .
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 2008, 79 (05) :708-714
[7]   Cholera [J].
Harris, Jason B. ;
LaRocque, Regina C. ;
Qadri, Firdausi ;
Ryan, Edward T. ;
Calderwood, Stephen B. .
LANCET, 2012, 379 (9835) :2466-2476
[8]  
Hobbie S, 1997, J IMMUNOL, V159, P5550
[9]   Mechanistic Insight into Control of CFTR by AMPK [J].
Kongsuphol, Patthara ;
Cassidy, Diane ;
Hieke, Bernhard ;
Treharne, Kate J. ;
Schreiber, Rainer ;
Mehta, Anil ;
Kunzelmann, Karl .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (09) :5645-5653
[10]   Adenosine Monophosphate-Activated Kinase and Its Key Role in Catabolism: Structure, Regulation, Biological Activity, and Pharmacological Activation [J].
Krishan, Sukriti ;
Richardson, Des R. ;
Sahni, Sumit .
MOLECULAR PHARMACOLOGY, 2015, 87 (03) :363-377