PMID- 37952733 OWN - NLM STAT- MEDLINE DCOM- 20240101 LR - 20240101 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 321 DP - 2024 Mar 1 TI - Liuweiwuling Tablet relieves the inflammatory transformation of hepatocellular carcinoma by inhibiting the PI3K/AKT/NF-kappaB signaling pathway. PG - 117406 LID - S0378-8741(23)01276-X [pii] LID - 10.1016/j.jep.2023.117406 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Liuweiwuling Tablet (LWWL) is a patented Chinese medicine approved by the Chinese National Medical Products Administration (NMPA). Clinically, it is used to treat a range of liver diseases that precede hepatocellular carcinoma (HCC), including hepatitis, liver fibrosis and cirrhosis. LWWL is hypothesized to inhibit the inflammatory transformation of HCC, which may have a positive impact on the prevention and treatment of HCC. However, its exact mechanism of action remains unknown. AIM OF THE STUDY: To investigate how LWWL is effective in the treatment of HCC and to validate the pathways involved in this process. MATERIALS AND METHODS: An in vivo model of HCC induced by diethylnitrosamine (DEN) was established to study the effect of LWWL on the development of HCC. The rat serum was analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (gamma-GT). The rat liver tissues were stained with hematoxylin and eosin (HE) and Masson's trichrome for pathological analysis. Rat liver tissue was subjected to transcriptome sequencing. Expression of inflammatory and liver fibrosis-related factors in bone marrow-derived macrophages (BMDMs) and LX-2 cells was detected by QRT-PCR, ELISA and Western blot (WB). The expression of apoptosis and stemness genes in HepG2 and Huh7 cells was assessed through flow cytometry and QRT-PCR. Transcriptomics, network pharmacology, WB, and QRT-PCR were employed to validate the mechanisms associated with the amelioration of HCC development by LWWL. RESULTS: LWWL significantly reduced the severity of hepatitis and liver fibrosis, the expression of tumor stemness genes, and the incidence of HCC. In addition, LWWL inhibited the release of inflammatory substances and nuclear accumulation of P65 protein in BMDMs as well as the conversion of LX-2 cells to fibroblasts. LWWL inhibited the proliferation of HepG2 and Huh7 cells, including the initiation of apoptosis and the reduction of stemness gene expression. Importantly, LWWL regulates the PI3K/AKT/NF-kappaB pathway, which affects hepatic inflammation and cancer progression. CONCLUSION: LWWL inhibited the occurrence and development of HCC by modulating the severity of hepatitis and liver fibrosis, indicating the potential clinical relevance of LWWL in preventing and treating HCC. CI - Copyright (c) 2023. Published by Elsevier B.V. FAU - Chen, Yuanyuan AU - Chen Y AD - College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611100, China; Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Song, Zheng AU - Song Z AD - Peking University 302 Clinical Medical School, Beijing, 100191, China. FAU - Hou, Xiaorong AU - Hou X AD - College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611100, China; Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Liu, Jia AU - Liu J AD - College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611100, China. FAU - Zheng, Congyang AU - Zheng C AD - Digestive Department of the Second Medical Center, Chinese PLA General Hospital, Beijing, 100853, China. FAU - Zhao, Xiaomei AU - Zhao X AD - College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611100, China; Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Lv, Guiji AU - Lv G AD - Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Li, Junjie AU - Li J AD - Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Xiu, Ye AU - Xiu Y AD - Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Shi, Wei AU - Shi W AD - Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Zhao, Jia AU - Zhao J AD - Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Yang, Huijie AU - Yang H AD - Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Wang, Yan AU - Wang Y AD - Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Zhao, Jun AU - Zhao J AD - Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Zhan, Xiaoyan AU - Zhan X AD - Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China; National Key Laboratory of Kidney Diseases, Beijing, 100039, China. FAU - Niu, Ming AU - Niu M AD - Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. FAU - Zou, Wenjun AU - Zou W AD - College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611100, China. Electronic address: zouwenjun@163.com. FAU - Bai, Zhaofang AU - Bai Z AD - College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611100, China; Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China; National Key Laboratory of Kidney Diseases, Beijing, 100039, China. Electronic address: baizf2008@hotmail.com. FAU - Xiao, Xiaohe AU - Xiao X AD - College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611100, China; Department of Hepatology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China; National Key Laboratory of Kidney Diseases, Beijing, 100039, China. Electronic address: pharmacy_302@126.com. LA - eng PT - Journal Article DEP - 20231111 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (NF-kappa B) RN - 0 (liuweiwuling) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - 0 (Tablets) SB - IM MH - Rats MH - Animals MH - *Carcinoma, Hepatocellular/metabolism MH - NF-kappa B/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - *Liver Neoplasms/metabolism MH - Signal Transduction MH - Liver Cirrhosis/metabolism MH - *Hepatitis MH - Tablets OTO - NOTNLM OT - Hepatocellular carcinoma OT - Inflammation-fibrosis-cancer transformation axis OT - Liuweiwuling tablet OT - PI3K/AKT/NF-kappaB pathway COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/11/13 00:42 MHDA- 2024/01/02 11:43 CRDT- 2023/11/12 19:16 PHST- 2023/09/22 00:00 [received] PHST- 2023/10/30 00:00 [revised] PHST- 2023/11/07 00:00 [accepted] PHST- 2024/01/02 11:43 [medline] PHST- 2023/11/13 00:42 [pubmed] PHST- 2023/11/12 19:16 [entrez] AID - S0378-8741(23)01276-X [pii] AID - 10.1016/j.jep.2023.117406 [doi] PST - ppublish SO - J Ethnopharmacol. 2024 Mar 1;321:117406. doi: 10.1016/j.jep.2023.117406. Epub 2023 Nov 11.