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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. To investigate how LWWL is effective in the treatment of HCC and to validate the pathways involved in this process. 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 (γ-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. 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-κB pathway, which affects hepatic inflammation and cancer progression. 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. [Display omitted] • Potential efficacy of LWWL in chemically related hepatocellular carcinoma. • LWWL inhibits the development of the hepatitis-fibrosis-HCC axis. • A key mechanism of LWWL is the PI3K/AKT/NF-κB signalling pathway. [ABSTRACT FROM AUTHOR]

Dictamnus dasycarpus Turcz. (Dictamni Cortex, DC), a Chinese herbal medicine, is commonly used for treating chronic dermatosis and rheumatism, but can also cause herb-induced liver injury (HILI). Our study has demonstrated that DC can induce idiosyncratic HILI, but the mechanism remains unknown. The NLRP3 inflammasome has become a major target for addressing many diseases. The activation of NLRP3 inflammasome is responsible for many liver-related inflammatory diseases, including idiosyncratic HILI. The objective of our study was to demonstrate the mechanism underlying the idiosyncratic HILI induced by DC and clarify the susceptible component in DC. Bone marrow-derived macrophages (BMDMs) and THP1 cells were selected to assess the effect of isomaculosidine (IMD) on NLRP3 inflammasome activation in vitro. Western blot, ELISA and Caspase-Glo® 1 Inflammasome Assay, flow cytometry and Immunofluorescence were employed to detect the mechanism of IMD on NLRP3 inflammasome activation. To assess the efficacy of IMD in vivo , mice were intravenously administrated with LPS and then IMD were injected intraperitoneally for 6 h. The results of our in vitro studies demonstrate that IMD, the major constituent of DC, specifically promoted ATP- and nigericin-induced activation of NLRP3 inflammasome, but not NLRC4 and AIM2 inflammasomes. Additionally, IMD promoted nigericin-induced ASC oligomerization. Notably, synergistic induction of mtROS played a key role on the activation of NLRP3 inflammasome. IMD increased the mtROS production in the activation of NLRP3 inflammasome induced by nigericin. In addition, the results of our in vivo study showed that the combination of nonhepatotoxic doses of LPS and IMD can increase the levels of ALT, AST, and DBIL, leading to liver injury. IMD specifically facilitated the activation of NLRP3 inflammasome induced by nigericin and ATP, which is responsible for DC-induced idiosyncratic HILI. [Display omitted] • IMD enhances NLRP3 inflammasome activation triggered by ATP or nigericin. • The production of mtROS was a key element to the promoting effect of IMD on NLRP3 inflammasome activation. • IMD induces idiosyncratic HILI by promoting NLRP3 inflammasome activation. • IMD is responsible for DC-induced idiosyncratic HILI. [ABSTRACT FROM AUTHOR]

Anethum graveolens L. (dill), which has been used as a medicine, spice and aromatic plant since ancient times, is not only a traditional Chinese medicines but also an important medicinal and functional food in Europe and Central and South Asia. In ethnomedicine, dill reportedly exerts a protective effect on the liver and has been widely used as a traditional medicine for the treatment of jaundice in the liver and spleen and inflammatory gout diseases in Saudi Arabia. Furthermore, studies have found that dill can regulate the NAT2 enzyme, and this plant was thus selected to study its alleviating effect on isoniazid liver injury. The purpose of this study was to explore the effect of dill on alleviating liver injury induced by hydrazine compounds represented by isoniazid through the use of network pharmacology combined with in vivo and in vitro experimental verifications. First, we screened the key targets of dill in the treatment of liver injury through the use of network pharmacology; we then performed GO and KEGG pathway enrichment analyses using the DAVID database. We also verified the alleviative and anti-inflammatory effects of dill on isoniazid liver injury in rats by animal experiments. We further investigated the modulating effect of dill on the enzymatic activity of NAT2, a common metabolizing enzyme of hydrazine compounds. A total of 111 key targets were screened through network pharmacology. In vivo experiments showed that dill reduced the amount of inflammatory factors produced by isoniazid, such as IL-10, IL-1β, TNF-α and IL-6, restored the levels of ALT, AST, r-GT, AKP and TBA in vivo, and attenuated isoniazid liver injury. Both in vivo and vitro results indicated that dill could regulate the expression of NAT2 enzymes. The results tentatively demonstrate that dill can alleviate isoniazid liver injury through multiple components, targets and pathways and exerts a regulatory effect on the NAT2 enzyme, and these findings thus provide new ideas for subsequent studies on hydrazide liver injury——reducing the risk of hydrazide-induced liver injury through anti-inflammation and regulation of NAT2 enzymes. [Display omitted] • Predicting potential targets and pathways of dill for the treatment of isoniazid liver injury. • Dill alleviated liver injury in rat. • Dill regulated inflammatory mediators levels in rat. • Dill improves cell survival in isoniazid-treated HepG2. • Dill regulates NAT2. [ABSTRACT FROM AUTHOR]