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Discovery of therap...
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Zhang, ChengKTH,Science for Life Laboratory, SciLifeLab,Systembiologi,Zhengzhou Univ, Minist Educ, Sch Pharmaceut Sci, Zhengzhou 450001, Henan, Peoples R China.;Zhengzhou Univ, Minist Educ, Key Lab Adv Drug Preparat Technol, Zhengzhou 450001, Henan, Peoples R China.
(författare)
Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning
- Artikel/kapitelEngelska2022
Förlag, utgivningsår, omfång ...
Nummerbeteckningar
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LIBRIS-ID:oai:gup.ub.gu.se/319540
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https://gup.ub.gu.se/publication/319540URI
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https://doi.org/10.1016/j.ebiom.2022.104214DOI
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https://research.chalmers.se/publication/531813URI
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https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-320246URI
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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QC 20221019
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Background Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver pathologies. However, no medical treatment has been approved for the treatment of NAFLD. In our previous study, we found that PKLR could be a potential target for treatment of NALFD. Here, we investigated the effect of PKLR in in vivo model and performed drug repositioning to identify a drug candidate for treatment of NAFLD. Methods Tissue samples from liver, muscle, white adipose and heart were obtained from control and PKLR knock-out mice fed with chow and high sucrose diets. Lipidomics as well as transcriptomics analyses were conducted using these tissue samples. In addition, a computational drug repositioning analysis was performed and drug candidates were identified. The drug candidates were both tested in in vitro and in vivo models to evaluate their toxicity and efficacy. Findings The Pklr KO reversed the increased hepatic triglyceride level in mice fed with high sucrose diet and partly recovered the transcriptomic changes in the liver as well as in other three tissues. Both liver and white adipose tissues exhibited dysregulated circadian transcriptomic profiles, and these dysregulations were reversed by hepatic knockout of Pklr. In addition, 10 small molecule drug candidates were identified as potential inhibitor of PKLR using our drug repositioning pipeline, and two of them significantly inhibited both the PKLR expression and triglyceride level in in vitro model. Finally, the two selected small molecule drugs were evaluated in in vivo rat models and we found that these drugs attenuate the hepatic steatosis without side effect on other tissues. Interpretation In conclusion, our study provided biological insights about the critical role of PKLR in NAFLD progression and proposed a treatment strategy for NAFLD patients, which has been validated in preclinical studies. Copyright (C) 2022 The Authors. Published by Elsevier B.V.
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Shi, MengnanKTH,Science for Life Laboratory, SciLifeLab(Swepub:kth)u1vcf12k
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Kim, WoongheeKTH,Systembiologi,Science for Life Laboratory, SciLifeLab(Swepub:kth)u1nic2pk
(författare)
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Arif, MuhammadKTH,Systembiologi,Science for Life Laboratory, SciLifeLab(Swepub:kth)u1vvaean
(författare)
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Klevstig, MartinaGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine,Sahlgrenska universitetssjukhuset,Sahlgrenska University Hospital,Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Mol & Clin Med, Gothenburg, Sweden.(Swepub:gu)xklevs
(författare)
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Li, XiangyuKTH,Systembiologi,Science for Life Laboratory, SciLifeLab(Swepub:kth)u1h6x89c
(författare)
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Yang, HongKTH,Science for Life Laboratory, SciLifeLab,Systembiologi(Swepub:kth)u150v7zg
(författare)
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Bayram, C.Atatürk Üniversitesi,Atatürk University,Ataturk Univ, Fac Med, Dept Med Pharmacol, TR-25240 Erzurum, Turkey.
(författare)
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Bolat, I.Atatürk Üniversitesi,Atatürk University,Ataturk Univ, Vet Fac, Dept Pathol, TR-25240 Erzurum, Turkey.
(författare)
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Tozlu, O. O.Erzurum Teknik Üniversitesi,Erzurum Technical University,Erzurum Tech Univ, Fac Sci, Dept Mol Biol & Genet, TR-25200 Erzurum, Turkey.
(författare)
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Sebhaoui, J.Drug Res & Dev Ctr, Trustlife Labs, Istanbul, Turkey.
(författare)
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Iqbal, S.Drug Res & Dev Ctr, Trustlife Labs, Istanbul, Turkey.
(författare)
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Wei, Y. J.Zhengzhou University,Zhengzhou Univ, Minist Educ, Sch Pharmaceut Sci, Zhengzhou 450001, Henan, Peoples R China.;Zhengzhou Univ, Minist Educ, Key Lab Adv Drug Preparat Technol, Zhengzhou 450001, Henan, Peoples R China.
(författare)
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Shi, X. J.Zhengzhou University,Zhengzhou Univ, Minist Educ, Sch Pharmaceut Sci, Zhengzhou 450001, Henan, Peoples R China.;Zhengzhou Univ, Minist Educ, Key Lab Adv Drug Preparat Technol, Zhengzhou 450001, Henan, Peoples R China.
(författare)
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Nielsen, Jens B,1962Chalmers tekniska högskola,Chalmers University of Technology,Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden.(Swepub:cth)nielsenj
(författare)
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Turkez, H.Atatürk Üniversitesi,Atatürk University,Ataturk Univ, Fac Med, Dept Med Biol, Erzurum, Turkey.
(författare)
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Uhlén, MathiasKTH,Science for Life Laboratory, SciLifeLab,Systembiologi(Swepub:kth)u1dulvmw
(författare)
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Borén, Jan,1963Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine,Sahlgrenska universitetssjukhuset,Sahlgrenska University Hospital,Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Mol & Clin Med, Gothenburg, Sweden.(Swepub:gu)xborej
(författare)
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Mardinoglu, Adil,1982KTH,Science for Life Laboratory, SciLifeLab,Systembiologi,Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England.(Swepub:kth)u1t8kmr6
(författare)
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Haamuftuoglu, A.Atatürk Üniversitesi,Atatürk University,Ataturk Univ, Fac Med, Dept Med Pharmacol, TR-25240 Erzurum, Turkey.
(författare)
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Yildtrim, S.Atatürk Üniversitesi,Atatürk University,Ataturk Univ, Vet Fac, Dept Pathol, TR-25240 Erzurum, Turkey.
(författare)
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KTHScience for Life Laboratory, SciLifeLab
(creator_code:org_t)
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Ingår i:eBioMedicine: Elsevier BV832352-3964
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Zhang, Cheng
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Shi, Mengnan
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Kim, Woonghee
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Arif, Muhammad
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Klevstig, Martin ...
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Li, Xiangyu
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visa fler...
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Yang, Hong
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Bayram, C.
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Bolat, I.
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Tozlu, O. O.
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Sebhaoui, J.
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Iqbal, S.
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Wei, Y. J.
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Shi, X. J.
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Nielsen, Jens B, ...
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Turkez, H.
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Uhlén, Mathias
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Borén, Jan, 1963
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Mardinoglu, Adil ...
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Haamuftuoglu, A.
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Yildtrim, S.
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