University of Groningen Pro- and anti-fibrotic agents in liver fibrosis Suriguga, S.

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University of Groningen

Pro- and anti-fibrotic agents in liver fibrosis Suriguga, S.

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Publication date: 2019

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Suriguga, S. (2019). Pro- and anti-fibrotic agents in liver fibrosis: Perspective from an ex vivo model of liver fibrosis.

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Abbreviations

Author affiliation

Acknowledgements

Curriculum vitae

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C

h

ap

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Abbreviations

ADP adenosine diphosphate ALD alcoholic liver disease ALK activin receptor-like kinase ALT alanine transaminase BDL bile duct-ligated

BMPs bone morphogenetic proteins

Ca2+ _calcium

CCl4 carbon tetrachloride

CoA coenzyme A

COL1 collagen type I

COL1A1 collagen type I-alpha 1 COL3A1 collagen type III-alpha1

CoQ10 coenzyme Q10

CYP cytochrome P450

CytC cytochrome C

DHA docosahexaenoic acid ECM extracellular matrix

eIF2α eukaryotic translation initiation factor 2 alpha EPA eicosapentaenoic acid

ER endoplasmic reticulum

Ero1a endoplasmic reticulum oxidoreductin 1 alpha FADH2 flavin adenine dinucleotide

FN2 fibronectin

GAPDH glyceraldehyde 3-phosphate dehydrogenase GDFs growth differentiation factors

GF germ-free

GSH glutathione

H2O2 hydrogen peroxide

HBV hepatitis B virus HCV hepatitis C virus

HMGB high-mobility group box

HNE 4-Hydroxynonenal

HO•

hydroxyl radical HSCs hepatic stellate cells HSP47 heat shock protein 47 ID1 inhibitor of DNA binding 1

IL interleukin

iNOS inducible nitric oxide synthase

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Abbreviations

IRAK-M interleukin-1 receptor-associated kinase type m JNK c-Jun N-terminal kinases

KC Kupffer cells

Lck lymphocyte-specific protein tyrosine kinases

LDA low-density array

Ldlr low density lipoprotein receptor

LPS lipopolysaccharide

MAPK mitogen-activated protein kinases MD-1 lymphocyte antigen 86

MD-2 lymphocyte antigen 96

MDA malondialdehyde

MKK mitogen-activated protein kinase kinases MMP matrix metalloproteinase

NADH nicotinamide adenine dinucleotide NAFLD non-alcoholic fatty liver disease NASH non-alcoholic steatohepatitis

NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells NFE2L2 nuclear factor (erythroid-derived 2)-like 2

NLRP3 nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3

NOX NADPH oxidase

O2 oxygen

O2•− superoxide anion

PAI-1 plasminogen activator inhibitor 1 PAMPs pathogen associated molecular patterns PCLS precision-cut liver slices

PDGF platelet-derived growth factor PDI protein disulfide isomerase

PERK protein kinase R (PKR)-like endoplasmic reticulum kinase PICP procollagen I C-peptide

ROS reactive oxygen species SMIs small molecule inhibitors

SOCS3 suppressor of cytokine signaling 3 SPF specific-pathogen-free

TGF-β1 transforming growth factor beta 1 TIMP1 tissue inhibitor of metalloproteinases 1 TLR toll like receptor

TNF-a tumor necrosis factor alpha

TbR TGF-b receptor

UPR unfolded protein response α-SMA alpha smooth muscle actin

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Author affiliation

Su Suriguga

(1) Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands

(2) Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Groningen, the Netherlands

Theerut Luangmonkong

(2) Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand

Henricus A.M. Mutsaers

(2) Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Luke M. Shelton

Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands

Geny M.M. Groothuis

Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Groningen, the Netherlands

Peter Olinga

Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands

Koert P. de Jong

Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, the Netherlands Miriam Boersema

Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, The Netherlands

Emilia Bigaeva

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Author affiliation

Dorenda Oosterhuis

Detlef Schuppan

(1) Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany

(2) Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, US.

Adhyatmika Adhyatmika

Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, the Netherlands

Amirah Adlia

Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, the Netherlands

Chuthamanee Suthisisang

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Acknowledgements

Time flies! On the 19th_{of September 2014, the China Southern Airline Flight No. CZ345}

landed exactly on time at 05:40 a.m. at the world-famous Schiphol Airport. There is where I was picked up by Peter and brought to Groningen. That was how a young-at-that-time and adventurous lady arrived in this low-sky-low-land country of the Netherlands to pursue her dream in science, thanks to Peter’s invitation and the China Scholarship Council. It was challenging to settle down in a foreign country and to get used to a new lab. Luckily, I met kind, funny and very brilliant people in Groningen that helped me go through this amazing four years.

Prof. dr. P. Olinga, dear Peter, thank you very much for inviting me to your lab and supervising me patiently each week through these years; without your help, I definitely could not finish this thesis and PhD study. I apologize for not following the “intestinal research” that you planned for me, because my favorite organ is indeed liver. It was very nice that you gave me the opportunities to go to the Annual Liver Meeting in the States for three times; through these meetings, I caught up with the frontiers of liver research, which is a very good starting point for a young researcher like me; also during these travels, I enjoyed the conversations we had and got to know you better. Thank you very much for kindly supporting my application as a registered toxicologist. I was very happy to meet you again in Shanghai last November, enjoyed walking together (30000 steps/half day) and discussing about life and work. I hope you will travel to China more often and we will have more collaborations in scientific research, and try out the Hot Pot and other food that you have not explored yet. Dank je wel again for everything. I wish you and your family: Judith, Sem and Mas, all the best.

Prof. dr. G.M.M. (Geny) Groothuis, dear Geny, I first met you during the skype interview with Peter, and you were kind and detail oriented during the interview. You later decided to give me the opportunity to come to the Netherlands and without this start the whole journey of my PhD would not be possible. You were always there through the key moments of these four years: thank you very much for the critical and sharp suggestions on the abstracts, manuscripts and publications; thank you for the advices on research development during the R&O meetings; thanks a lot for supporting my application for registered toxicologist. All in all, I am very lucky to have you as my supervisor; I wish you all the happiness and good health.

Rick, thank you very much for revising every abstracts and manuscripts of mine with your

scientifically-stylish words. I think we have to finish the beer competition when you visit China. All the best for you, Sanne and Colin. Miriam, you are the kindest colleague I have ever met, thank you very much, you are always there to help. All the best for you, Marten, Noah and Lynn.

I am very lucky to meet the Asian group in the slicing group, here I thank Jo, Nia and Radit for your friendship both at work and life. The first colleague I met after arriving in Groningen

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Acknowledgements

was Jo, who was wearing a lab coat early in the morning, apparently started the daily work very early. It turned out that you are the most hardworking and intelligent person, and not long ago you had successfully completed your PhD, congratulations again! I was lucky to work with you on the liver experiments and also publish together; without your help, this thesis would have definitely taken much more time. Besides the livers that always arrive during the weekend, we shared nice memories of travels and food. I appreciate your healthy eating style, long live Jo! I wish you and Gift all the best! See you in beautiful Thailand!

I was so happy when I heard Radit proposed to Nia in Groningen. Now you are married and have a beautiful son, Salman, who can already walk and dance. Radit, you are the coolest person in the lab. Sorry for rejecting your offer for doing intestinal experiments. Even though we had not worked together in the lab, we became good friends through those little arguments and fights during lunches. I appreciate your own style for fashion: dark red colored hair, Turkish perfume that gave Jo deep impressions and the cool motorcycle that you bought in Jakarta. Nia, I am so lucky to have you as my officemate and friend, you are the kindest and intelligent person, thank you so much 3 times (in your style) for helping me out when I was down, I really appreciate your philosophy on life and work. Good luck with your thesis and defense together with Radit, all the best for Salman. I will definitely visit you in Indonesia, see you there!

Emma, you lightened up the lab when you came back from Germany. I really enjoyed the time

together with you both at and after work, when you are present there is never boredom. I wish you good luck for finishing the thesis and all the best for your life, travels and adventures ahead. Gerian, you are a beautiful, intelligent, funny and hard-working girl. You always bring me joy. I enjoyed your jokes even though sometimes I have trouble getting them. Good luck with the livers that you will slice and I believe that in the near future you will be busy writing and defending your thesis. Isabel, you are the most efficient person at work, thank you for your nice suggestions at work and fun time after work. Emilia, thank you for helping me out when I had questions in the lab, best luck for finishing the thesis; best wishes. Mitchel, thank you very much for your scientific jokes that brought me a lot of laughter, all the best. Tobias, good luck with the thesis and medical career, all the best! BT and Jasper, thank you for your nice suggestions in the lab, wish you success.

Dear Dorenda, you always wondered what I would write in the acknowledgement, here it goes: in addition to numerous ordering for my reagents, thank you for witnessing my cloudy/rainy faces and comforting me with your warm hugs. I will miss your “fake ignorant face” when I am bored at work and try to disturb you while you are busy with the ordering/organizing. It was fun to work with you. All the best for you, Teun, Nila and Loïs. Dear Louise, the lab stuff became more organized after you came. Thank you very much for helping me out in the lab. All the best for you and Gerben.

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knowledge during my study. Yu, Annemarie, Philip, Imco, Max, Renee and Carin, wish you success. Herman, Ed, Sonja, Anko, Wouter, Marinella, Jan, Paul, Caroline, Doetie, Lida,

Duong and Anne De Boer, it was very pleasant to be in the same group with you, thank you

for your kindness, help and delicious cakes, all the best for you. I am also grateful for the students, Mies, Duligen, Arsalan and Amin for helping me for the lab work.

Leonie and Fransien, it was nice traveling together with you to the states, perhaps see you

soon in the Liver meeting; Leonie, thanks a lot for helping me out in the staining experiments; welcome you to the slicing group and wish you success; Fransien, best wishes for your family and career. Roberta, I enjoyed working with you in the slicing lab, wish you success.

Viktoriia, I am a fan of your paintings, don’t forget to share them via facebook, all the best. Adhy, thank you 3 times (in Nia’s style) for every moment that you helped me in the lab (most

of the time, for “emergency” moment), and thanks a lot for the Indonesian food and fun time that we had in your house, all the best for you, Nuri and Zidni. Special thanks to Marjolijn,

Marina, Catharina and Eduard, for numerous times you saved my experiments for slicing

the liver, offering reagents and fixing the machines; without your kind help, the data in this thesis will not be complete; thanks again for your super professional helps. Many thanks to other members of Department of Pharmacokinetics Toxicology and Targeting: Klaas, Barbro,

Inge, Jan, Sylvia, Amirah and Natalia.

Prof.dr. W.J. (Wim) Quax, dear Wim, thank you for your connection that gave me the opportunity to come to Groningen and be a member of Peter’s group. Jia Mei, I was so happy to meet you in Groningen as well as in Shanghai, wish you success and all the best for you family. Dear Dagula, Tegusi, Yiliqi and Byamba, I am very lucky to get to know you in the Netherlands, thank you so much for the delicious Mongolian dinners and happy times we spent together, wish you healthiness and happiness.

Special thanks to operation center, Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation and the liver donors, for offering the tissues that were used in this thesis for obtaining valuable human data. Many thanks to Dr. K.P. de Jong, for the valuable collaboration. I am also grateful and praying for the sacrificed mice and rats that increased our knowledge in science.

Sincere thanks to the assessment committee of this thesis, Prof. R.A. Bank, Prof. H.G.D.

Leuvenink and Prof. R. Safadi for careful reading, critical suggestions and evaluation on the

thesis.

Jielin and Hu Xu, I am so lucky to meet you two in Groningen and become close friends.

Jielin, you are calm, intelligent, hard-working and a true book worm. I learned a lot from you and enjoyed spending time with you. Hu Xu, your charm and big laughter (perhaps you only share it with certain people) brought me a lot of fun, remember that we laughed all the way on the train from Oslo to Bergen, in Norway? The movie and food nights, fun weekends and trips to many other countries together with you two will be a piece of beautiful memory that will

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Acknowledgements

never fade away. Thanks again for everything, hope to see you in Dubai or other places that we dreamed to go together. Baojie, you are the beautiful, smart and romantic lady among us, I was so joyful when you become a Mama; I will never forget the fun time we had and creative food that we tried to make in your lovely house, I wish you, Xiaodong and Louie all the best!

Li Jing, you are the cool girl who does what she wants; together, we visited a lot of museums

and shared the satisfying moments of enjoying the amazing master pieces of Dutch art; wish you live the life you dreamed of. Huala, you are the pretty, brave and artistic girl, wish you success and all the best. Yizhou and Shanshan, just love you girls, you are the best. I am truly thankful to my other bright and knowledgeable Chinese friends, Zhang Yang, Huatang, Tang

Zhenchen, Lu Liqiang & Yuan, Yu & Hao, Jingjing & Yuanze, Jiaying, Fangfang, Haigen, Zhang Ji, Keni and Guo Chao, it was always fun to gather with you.

Many thanks to Agaru & Jinzhu, for your friendship, you are the most hard-working and encouraging couple that I ever met. I am always relaxed being together with you guys, particularly grateful for picking me up from/to airport every time I travel to/back from China.

Meng Jie, you are the brave, hard-working and brilliant girl; I enjoy arguing with you over a

lot of things, before we know, these arguments made us get to know each other better and become close friends, good luck in Germany; love you, see you in April at my home. Xinjiltu, I was so happy to see you twice in France; you are the master of languages, wish you good luck and success.

I sincerely thank the schools and teachers for the excellent education since primary school, special thanks to my supervisor at master degree, Prof. Yi Zongchun, without your support and supervision, my studies abroad would not have been possible, thank you very much. Prof.

Wang Changshan, thank you so much for your support and care during my PhD study, looking

forward to working with you after my graduation.

My dear Naqin, like in the songs, you are the sunshine of my life. Your everyday big smile can drive away any cloud in the sky. Thank you for always being there for me, providing unconditional love, support and care. Love you! My dear Aba and Momo, I was so lucky to be born as your daughter. You are my role models; wish you happiness and healthiness. All the best for my dear brother Sudalafu, sister-in-law Sarina, and their lovely sons: Asafu and

Ayasi. I am so happy to be back and work in the same city as you are, so that we could spend

time together more often. Thanks a lot for my parents-in-law, for your kind support and warm regards during my stay in the Netherlands.

Heartily thanks- Hartelijk bedankt

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Curriculum vitae

Name Suriguga

Date of birth 22nd Nov. 1987

Hometown Nei Mongol, China

Education

• Doctor of Philosophy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, The Netherlands

• Master of Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, China

• Bachelor of Medicine, School of Nursing, Health Science Center, Peking University, China

Publications

• T. Luangmonkong*, S. Suriguga*, A. Adhyatmika, A. Adlia, D. Oosterhuis, C. Suthisisang, K. P. de Jong, H. A. M. Mutsaers and P. Olinga (2018). "In vitro and ex vivo anti-fibrotic effects of LY2109761, a small molecule inhibitor against TGF-beta." Toxicol Appl Pharmacol 355: 127-137.

*Authors contributed equally

• T. Luangmonkong*, S. Suriguga*, H. A. M. Mutsaers, G. M. M. Groothuis, P. Olinga and M. Boersema (2018). "Targeting Oxidative Stress for the Treatment of Liver Fibrosis." Rev Physiol Biochem Pharmacol 175: 71-102.

*Authors contributed equally

• T. Luangmonkong, S. Suriguga, E. Bigaeva, M. Boersema, D. Oosterhuis, K. P. de Jong, D. Schuppan, H. A. M. Mutsaers and P. Olinga (2017). "Evaluating the anti-fibrotic potency of galunisertib in a human ex vivo model of liver fibrosis." Br J Pharmacol 174(18): 3107-3117.

Manuscript in preparation

• S. Suriguga, T. Luangmonkong, H. A. M. Mutsaers, L. M. Shelton, G. M. M. Groothuis and P. Olinga. " Host microbiota dictates the proinflammatory impact of LPS in the murine liver."

• S. Suriguga, T. Luangmonkong, H. A. M. Mutsaers, K. P. de Jong, G. M. M. Groothuis, M. Boersema, L. M. Shelton and P. Olinga. " LPS aggravates fibrosis in early onset but not end stage human liver fibrosis.”

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Curriculum vitae

Publications outside the scope of this thesis

• Suriguga, X. F. Li, Y. Li, C. H. Yu, Y. R. Li and Z. C. Yi (2013). "The role of catechol-O-methyltransferase in catechol-enhanced erythroid differentiation of K562 cells." Toxicol Appl Pharmacol 273(3): 635-643.

• Yu, C. H., Suriguga, M. Gong, W. J. Liu, N. X. Cui, Y. Wang, X. Du and Z. C. Yi (2017). "High glucose induced endothelial to mesenchymal transition in human umbilical vein endothelial cell." Exp Mol Pathol 102(3): 377-383.

• Yu, C. H., Suriguga, Y. Li, Y. R. Li, K. Y. Tang, L. Jiang and Z. C. Yi (2014). "The role of ROS in hydroquinone-induced inhibition of K562 cell erythroid differentiation." Biomed Environ Sci 27(3): 212-214.

• Li, Y., X. R. Wu, X. F. Li, Suriguga, C. H. Yu, Y. R. Li and Z. C. Yi (2013). "Changes in DNA methylation of erythroid-specific genes in K562 cells exposed to phenol and hydroquinone." Toxicology 312: 108-114.

• Wang, Y., G. Y. Zhang, Q. L. Han, J. Wang, Suriguga, Y. Li, C. H. Yu, Y. R. Li and Z. C. Yi (2014). "Phenolic metabolites of benzene induced caspase-dependent cytotoxicities to K562 cells accompanied with decrease in cell surface sialic acids." Environ Toxicol 29(12): 1437-1451.

• Li, X. F., X. R. Wu, M. Xue, Y. Wang, J. Wang, Y. Li, Suriguga, G. Y. Zhang and Z. C. Yi (2012). "The role of DNA methylation in catechol-enhanced erythroid differentiation of K562 cells." Toxicol Appl Pharmacol 265(1): 43-50.