{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:00:41Z","timestamp":1788969641181,"version":"build-2803163510"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,18]],"date-time":"2022-06-18T00:00:00Z","timestamp":1655510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2020A1515010370"],"award-info":[{"award-number":["2020A1515010370"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2021A1515012456"],"award-info":[{"award-number":["2021A1515012456"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["82171877"],"award-info":[{"award-number":["82171877"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["202002030043"],"award-info":[{"award-number":["202002030043"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2020A1515010370"],"award-info":[{"award-number":["2020A1515010370"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2021A1515012456"],"award-info":[{"award-number":["2021A1515012456"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171877"],"award-info":[{"award-number":["82171877"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["202002030043"],"award-info":[{"award-number":["202002030043"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Science and Technology of Guangzhou city","award":["2020A1515010370"],"award-info":[{"award-number":["2020A1515010370"]}]},{"name":"Department of Science and Technology of Guangzhou city","award":["2021A1515012456"],"award-info":[{"award-number":["2021A1515012456"]}]},{"name":"Department of Science and Technology of Guangzhou city","award":["82171877"],"award-info":[{"award-number":["82171877"]}]},{"name":"Department of Science and Technology of Guangzhou city","award":["202002030043"],"award-info":[{"award-number":["202002030043"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Methamphetamine (METH) is a stimulant drug. METH abuse induces hepatotoxicity, although the mechanisms are not well understood. METH-induced hepatotoxicity was regulated by TLR4-mediated inflammation in BALB\/c mice in our previous study. To further investigate the underlying mechanisms, the wild-type (C57BL\/6) and Tlr4\u2212\/\u2212 mice were treated with METH. Transcriptomics of the mouse liver was performed via RNA-sequencing. Histopathological changes, serum levels of metabolic enzymes and lipopolysaccharide (LPS), and expression of TLR4-mediated proinflammatory cytokines were assessed. Compared to the control, METH treatment induced obvious histopathological changes and significantly increased the levels of metabolic enzymes in wild-type mice. Furthermore, inflammatory pathways were enriched in the liver of METH-treated mice, as demonstrated by expression analysis of RNA-sequencing data. Consistently, the expression of TLR4 pathway members was significantly increased by METH treatment. In addition, increased serum LPS levels in METH-treated mice indicated overproduction of LPS and gut microbiota dysbiosis. However, antibiotic pretreatment or silencing Tlr4 significantly decreased METH-induced hepatic injury, serum LPS levels, and inflammation. In addition, the dampening effects of silencing Tlr4 on inflammatory pathways were verified by the enrichment analysis of RNA-sequencing data in METH-treated Tlr4\u2212\/\u2212 mice compared to METH-treated wild-type mice. Taken together, these findings implied that Tlr4 silencing, comparable to antibiotic pretreatment, effectively alleviated METH-induced hepatotoxicity by inhibiting LPS-TLR4-mediated inflammation in the liver.<\/jats:p>","DOI":"10.3390\/ijms23126810","type":"journal-article","created":{"date-parts":[[2022,6,19]],"date-time":"2022-06-19T10:14:52Z","timestamp":1655633692000},"page":"6810","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Silencing the Tlr4 Gene Alleviates Methamphetamine-Induced Hepatotoxicity by Inhibiting Lipopolysaccharide-Mediated Inflammation in Mice"],"prefix":"10.3390","volume":"23","author":[{"given":"Li-Bin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Toxicology, School of Public Health (Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, No. 1838 North Guangzhou Road, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Jian","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1556-2167","authenticated-orcid":false,"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Li","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Toxicology, School of Public Health (Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, No. 1838 North Guangzhou Road, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/d41586-019-02671-9","article-title":"Tackle the epidemic, not the opioids","volume":"573","author":"Feinberg","year":"2019","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.biopsych.2019.03.966","article-title":"Dopamine D1 and D2 Receptors Differentially Regulate Rac1 and Cdc42 Signaling in the Nucleus Accumbens to Modulate Behavioral and Structural Plasticity After Repeated Methamphetamine Treatment","volume":"86","author":"Tu","year":"2019","journal-title":"Biol. 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