PMID- 35212223 OWN - NLM STAT- MEDLINE DCOM- 20220310 LR - 20220531 IS - 1520-5118 (Electronic) IS - 0021-8561 (Linking) VI - 70 IP - 9 DP - 2022 Mar 9 TI - Inhibition of HMGB1/TLR4 Signaling Pathway by Digitoflavone: A Potential Therapeutic Role in Alcohol-Associated Liver Disease. PG - 2968-2983 LID - 10.1021/acs.jafc.2c00195 [doi] AB - Digitoflavone (DG) is a natural flavonoid abundant in many fruits, vegetables, and medicinal plants. We investigated whether DG inhibits lipid accumulation and inflammatory responses in alcoholic liver disease (ALD) in vivo and in vitro. The mouse ALD model was established by chronically feeding male C57BL/6 mice an ethanol-containing Lieber-DeCarli liquid diet. In vitro, mouse peritoneal macrophages (MPMs) and mouse bone marrow-derived macrophages (BMDMs) were stimulated with LPS/ATP, whereas HepG2 cells and mouse primary hepatocytes were treated with ethanol. DG reduced the serum levels of transaminase and serum and hepatic levels of triglycerides and malondialdehyde in ALD mice. DG downregulated SREBP1 and its target genes and upregulated PPARalpha and its target genes in the liver of mice with ALD. DG inhibited TLR4-mediated NLRP3 inflammasome activation, consequently reversing the inflammatory response, including the production of HMGB1, IL-1beta, and IL-36gamma, as well as the infiltration of macrophages and neutrophils. DG blocked NLRP3/ASC/caspase-1 inflammasome activation and HMGB1 release in LPS/ATP-stimulated MPMs. When Tlr4 was knocked in LPS/ATP-stimulated BMDMs, HMGB1 production and release were blocked, and NLRP3-mediated cleavage and release of IL-1beta was suppressed in Hmgb1-silenced BMDMs. DG amplified these inhibitory effects in Tlr4 or Hmgb1 knockdown BMDMs. In ethanol-exposed hepatocytes, DG reduced lipogenesis and promoted lipid oxidation by inhibiting the HMGB1-TLR4 signaling pathway while suppressing the inflammatory response induced by ethanol exposure. Our data demonstrated that DG inhibited the occurrence of lipid accumulation and the inflammatory response via the HMGB1-TLR4 axis, underscoring a promising approach and utility of DG for the treatment of ALD. FAU - Shang, Yue AU - Shang Y AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Jiang, Min AU - Jiang M AD - Department of Pharmacology, Binzhou Medical University, Yantai Campus, Yantai, Shandong 264000, China. FAU - Chen, Nan AU - Chen N AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Jiang, Xue-Li AU - Jiang XL AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Zhan, Zi-Ying AU - Zhan ZY AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Zhang, Zhi-Hong AU - Zhang ZH AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Zuo, Rong-Mei AU - Zuo RM AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Wang, Hui AU - Wang H AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Lan, Xiao-Qi AU - Lan XQ AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Ren, Jie AU - Ren J AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Wu, Yan-Ling AU - Wu YL AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Cui, Zhen-Yu AU - Cui ZY AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Nan, Ji-Xing AU - Nan JX AUID- ORCID: 0000-0002-6221-4309 AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin Province 133002, China. FAU - Lian, Li-Hua AU - Lian LH AD - Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. AD - Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin Province 133002, China. LA - eng PT - Journal Article DEP - 20220225 PL - United States TA - J Agric Food Chem JT - Journal of agricultural and food chemistry JID - 0374755 RN - 0 (Flavones) RN - 0 (HMGB1 Protein) RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) SB - IM MH - Animals MH - Flavones/*pharmacology MH - *HMGB1 Protein/metabolism MH - Hep G2 Cells MH - Humans MH - Inflammasomes MH - *Liver Diseases, Alcoholic/drug therapy/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - Signal Transduction/*drug effects MH - *Toll-Like Receptor 4/metabolism OTO - NOTNLM OT - HMGB1 OT - TLR4 OT - alcoholic liver disease OT - digitoflavone EDAT- 2022/02/26 06:00 MHDA- 2022/03/11 06:00 CRDT- 2022/02/25 08:37 PHST- 2022/02/26 06:00 [pubmed] PHST- 2022/03/11 06:00 [medline] PHST- 2022/02/25 08:37 [entrez] AID - 10.1021/acs.jafc.2c00195 [doi] PST - ppublish SO - J Agric Food Chem. 2022 Mar 9;70(9):2968-2983. doi: 10.1021/acs.jafc.2c00195. Epub 2022 Feb 25.