PMID- 36028178 OWN - NLM STAT- MEDLINE DCOM- 20221004 LR - 20221026 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 191 DP - 2022 Oct TI - Pyrogallol enhances therapeutic effect of human umbilical cord mesenchymal stem cells against LPS-mediated inflammation and lung injury via activation of Nrf2/HO-1 signaling. PG - 66-81 LID - S0891-5849(22)00558-5 [pii] LID - 10.1016/j.freeradbiomed.2022.08.030 [doi] AB - The main challenges in clinical applications of mesenchymal stem cells (MSCs) are attributed to their heterogeneity. It is believed that preconditioning of MSCs with active compounds may enhance the expression of potentially therapeutic molecules and thus achieve stable and effective therapeutic outcomes. In the present study, we investigated the mechanism by which pyrogallol increased the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) against LPS-induced acute lung injury (ALI). hUCMSCs with pyrogallol treatment increased expression of HO-1 at both mRNA and protein levels, accompanied by Kelch-Like ECH-Associated Protein 1 (Keap1) degradation, and upregulation of the Nrf2 protein levels as well as nuclear translocation of Nrf2. Moreover, the modulation of Keap1 and Nrf2 as well as HO-1 upregulation by pyrogallol was reversed by pretreatment with N-acetylcysteine (NAC) and a P38 kinase inhibitor (SB203580). Whereas, NAC pretreatment abrogated pyrogallol-mediated activation of P38 kinase, indicating that pyrogallol-derived ROS led to P38 kinase activation, thus promoting Nrf2/HO-1 signaling. Additionally, we found that the induction of p62 by the pyrogallol-mediated ROS/P38/Nrf2 axis interacted with Keap1 and resulted in autophagic degradation of Keap1, which created a positive feedback loop to further release of Nrf2. Furthermore, the increased expression of HO-1 in pyrogallol-pretreated hUCMSCs led to enhanced inhibitory effects on LPS-mediated TLR4/P-P65 signaling in BEAS-2B cells, resulting in increasing suppression of LPS-indued expression of a series of pro-inflammatory mediators. Compared to untreated hUCMSCs, Sprague-Dawley (SD) rats with pyrogallol-primed hUCMSCs transplantation showed enhanced improvements in LPS-mediated lung pathological alterations, the increased lung index (lung/body ratio), apoptosis of epithelial cells, the activation of TLR4/NF-kappaB signaling as well as the release of pro-inflammatory mediators. Together, these results suggested that hUCMSCs with pyrogallol pretreatment enhanced the therapeutic efficacy of hUCMSCs, which may provide a promising therapeutic strategy to maximize the therapeutic efficacy of hUCMSC-based therapy for treating LPS-associated ALI. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Zhang, Yuehan AU - Zhang Y AD - Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China. FAU - Yang, Sushan AU - Yang S AD - Department of Clinical Laboratory, The People's Hospital of Gaozhou, Gaozhou, 525200, China. FAU - Qiu, Zhenhua AU - Qiu Z AD - Department of Clinical Laboratory, The People's Hospital of Gaozhou, Gaozhou, 525200, China. FAU - Huang, Li AU - Huang L AD - Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China. FAU - Huang, Linyan AU - Huang L AD - Department of Hematopathology, The People's Hospital of Gaozhou, Gaozhou, 525200, China. FAU - Liang, Yueyun AU - Liang Y AD - Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China. FAU - Liu, Xuanyu AU - Liu X AD - Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China. FAU - Wang, Maosheng AU - Wang M AD - Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China. Electronic address: mmwmsmd@126.com. FAU - Zhou, Beixian AU - Zhou B AD - Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, 525200, China; Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315, Guangzhou, China. Electronic address: zbeixian@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220824 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Inflammation Mediators) RN - 0 (Kelch-Like ECH-Associated Protein 1) RN - 0 (Lipopolysaccharides) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NF-kappa B) RN - 0 (RNA, Messenger) RN - 0 (Reactive Oxygen Species) RN - 0 (Toll-Like Receptor 4) RN - 01Y4A2QXY0 (Pyrogallol) RN - EC 1.14.14.18 (Heme Oxygenase-1) RN - WYQ7N0BPYC (Acetylcysteine) SB - IM MH - Acetylcysteine/metabolism MH - *Acute Lung Injury/drug therapy/therapy MH - Animals MH - Heme Oxygenase-1/genetics/metabolism MH - Humans MH - Inflammation/drug therapy/therapy MH - Inflammation Mediators/metabolism MH - Kelch-Like ECH-Associated Protein 1/genetics/metabolism MH - Lipopolysaccharides MH - *Mesenchymal Stem Cell Transplantation MH - Mesenchymal Stem Cells/cytology MH - NF-E2-Related Factor 2/genetics/metabolism MH - NF-kappa B/metabolism MH - *Pyrogallol/pharmacology MH - RNA, Messenger/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Reactive Oxygen Species/metabolism MH - Toll-Like Receptor 4/genetics/metabolism MH - Umbilical Cord/cytology OTO - NOTNLM OT - Acute lung injury OT - Autophagy OT - Inflammation OT - LPS OT - Nrf2/HO-1 OT - Pyrogallol OT - hUCMSC COIS- Declaration of competing interest All authors declare no competing interests. EDAT- 2022/08/27 06:00 MHDA- 2022/10/05 06:00 CRDT- 2022/08/26 19:27 PHST- 2022/06/13 00:00 [received] PHST- 2022/07/31 00:00 [revised] PHST- 2022/08/18 00:00 [accepted] PHST- 2022/08/27 06:00 [pubmed] PHST- 2022/10/05 06:00 [medline] PHST- 2022/08/26 19:27 [entrez] AID - S0891-5849(22)00558-5 [pii] AID - 10.1016/j.freeradbiomed.2022.08.030 [doi] PST - ppublish SO - Free Radic Biol Med. 2022 Oct;191:66-81. doi: 10.1016/j.freeradbiomed.2022.08.030. Epub 2022 Aug 24.