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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]

HIF-1α/mTOR signaling pathway is considered to play a crucial role in genesis and progress of tissue fibrosis. The elevation of HIF-1α and mTOR is relevant to CCl4 induced liver fibrotic rats. Paeoniflorin has been consistently shown to exhibit multiple pharmacological effects in liver disease. However, so far, no research demonstrates the relationship between paeoniflorin and HIF-1α/mTOR fibrogenesis pathway in liver fibrosis. In this study, the liver fibrosis was performed by CCl4 rats and HSC-T6 cell line. The data demonstrated that paeoniflorin treatment could attenuate liver fibrosis and inhibit the activation of HSC. Moreover, paeoniflorin significantly enhanced hepatic function by decreasing serum level of ALT, AST and ALP, and increasing level of ALB, TP. Meanwhile, ECM degradation was modulated by paeoniflorin treated rats with a remarkable reduce of α-SMA and collagen III mRNA expression. Moreover, the alleviation effect of liver fibrosis was relevant to inhibiting HIF-1α and phosphor-mTOR. Our data indicate that paeoniflorin alleviates liver fibrosis by inhibiting HIF-1α expression partly through mTOR pathway and paeoniflorin may be a potential therapeutic agent for liver fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: The crude secondary roots of Aconitum carmichaelii Debeaux (Fuzi), together with its processed products, including Yanfuzi, Heishunpian and Paofupian, are commonly applied in clinic using for thousands of years, such as collapse, syncope, rheumatic fever, painful joints and various tumors. Aim of the study: To explore the different effects of Fuzi and its processed products on energy metabolism, with mitochondria as the model with the aim of guiding the clinical use of Fuzi and its products. fingerprints of Fuzi, Yanfuzi, Heishunpian and Paofupian were established by Ultra-high Performance Liquid Chromatography (UPLC) and effects of Fuzi and its processed products on rat’s liver׳s mitochondrial metabolism were studied by microcalorimetry. Spectrum-effect relationships between UPLC fingerprints and energy metabolism of mitochondria were investigated using canonical correlation analysis (CCA). Results: Because of their inherent differences in chemical compositions, the main activities of energy metabolism of mitochondria were different among Fuzi and its processed products. The potential bioactivity sequence of the tested products was Fuzi>Heishunpian>Paofupian>Yanfuzi. Results of CCA showed that compounds mesaconitine, benzoylaconitine, and benzoylhypacoitine might be the principal active components. Conclusion: Altogether, this work provides a general model of combination of UPLC and microcalorimetry to study the spectrum-effect relationships of Fuzi and its processed products which can offer some references for detecting principal components of traditional Chinese medicine on bioactivity to mitochondrial growth. [Copyright &y& Elsevier]

Abstract: A comparative study was designed and conducted to compare the pharmacokinetic difference of paeoniflorin and albiflorin after oral administration of Radix Paeoniae Rubra to normal rats and the acute cholestasis hepatitis rats induced by alpha-naphthylisothiocyanate (ANIT). UPLC-ESI-MS/MS method was employed to determine the level of paeoniflorin and albiflorin in rat plasma using geniposide as the internal standard (IS). Unpaired Student''s t-test was used for the statistical comparison. The investigation showed that there were significant differences between the normal rats and the acute cholestasis hepatitis rat groups in calculated parameters, such as AUC0− t , AUC0−∞, T max and CLz/F. The results indicated that acute liver injury in rats could alter the pharmacokinetics of drug. Since patients are the final users of the drug, it is essential to investigate the pharmacokinetics of the drug in disease status. Therefore, we used normal rats and the acute cholestasis hepatitis rats to study pharmacokinetics of Radix Paeoniae Rubra with the purpose of examining the influence of disease on the metabolic course. [Copyright &y& Elsevier]