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Objective: To investigate the protective effects of stir-fried Semen Armeniacae Amarum (SAA) against aristolochic acid I (AAI)-induced nephrotoxicity and DNA adducts and elucidate the underlying mechanism involved for ensuring the safe use of Asari Radix et Rhizoma., Methods: In vitro, HEK293T cells overexpressing Flag-tagged multidrug resistance-associated protein 3 (MRP3) were constructed by Lentiviral transduction, and inhibitory effect of top 10 common pairs of medicinal herbs with Asari Radix et Rhizoma in clinic on MRP3 activity was verified using a self-constructed fluorescence screening system. The mRNA, protein expressions, and enzyme activity levels of NAD(P)H quinone dehydrogenase 1 (NQO1) and cytochrome P450 1A2 (CYP1A2) were measured in differentiated HepaRG cells. Hepatocyte toxicity after inhibition of AAI metabolite transport was detected using cell counting kit-8 assay. In vivo, C57BL/6 mice were randomly divided into 5 groups according to a random number table, including: control (1% sodium bicarbonate), AAI (10 mg/kg), stir-fried SAA (1.75 g/kg) and AAI + stir-fried SAA (1.75 and 8.75 g/kg) groups, 6 mice in each group. After 7 days of continuous gavage administration, liver and kidney damages were assessed, and the protein expressions and enzyme activity of liver metabolic enzymes NQO1 and CYP1A2 were determined simultaneously., Results: In vivo, combination of 1.75 g/kg SAA and 10 mg/kg AAI suppressed AAI-induced nephrotoxicity and reduced dA-ALI formation by 26.7%, and these detoxification effects in a dose-dependent manner (P<0.01). Mechanistically, SAA inhibited MRP3 transport in vitro, downregulated NQO1 expression in vivo, increased CYP1A2 expression and enzymatic activity in vitro and in vivo, respectively (P<0.05 or P<0.01). Notably, SAA also reduced AAI-induced hepatotoxicity throughout the detoxification process, as indicated by a 41.3% reduction in the number of liver adducts (P<0.01)., Conclusions: Stir-fried SAA is a novel drug candidate for the suppression of AAI-induced liver and kidney damages. The protective mechanism may be closely related to the regulation of transporters and metabolic enzymes., Competing Interests: Conflict of Interest. The authors declare no conflicts of interest. During the preparation of this work, we used [BioRender] to construct Figures 1 and 2A. Publication and licencing rights were obtained. The authors take full responsibility for the contents of this study., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

The evaluation of the effectiveness of traditional Chinese medicine(TCM) has long been a &quot;bottleneck&quot; issue that restricts the healthy development and internationalization of TCM. This article systematically analyzes the differences in diagnostic and treatment principles, material composition, new drug development pathways, efficacy cognition, and evaluation methodology between Chinese and Western medicine from the underlying logic of medical perspective. On this basis, it integrates the evidence elements of clinical experience, experimental research, and clinical trials, and for the first time proposes and establishes a new strategy and methodology for the evaluation of the effectiveness of TCM: the integrated evidence chain-based effectiveness evaluation of traditional Chinese medicine(iEC-Eff), forming an integrated evaluation and confirmation model of &quot;clinical experience-experimental research-clinical trial&quot; for the effectiveness of TCM. Preliminary application research shows that this method can scientifically enhance the evaluation level of the effectiveness of TCM, especially for classic prescriptions that have been passed down for thousands of years, have a good reputation, and are commonly used in clinical practice today, making the level of efficacy evidence more objectively reflect their clinical value and status. It breaks through the limitation of the current TCM efficacy evaluation that takes RCT as the only &quot;gold standard&quot;, providing a new strategy and method with originality, strategy, and leadership for solving the problem of TCM efficacy evaluation. It provides a new tool with operability for establishing a TCM registration review evidence system that combines TCM theory, human experience, and clinical trials. The iEC-Eff can be used for the efficacy evaluation of classic prescriptions in TCM, the development of new TCM drugs, and the re-evaluation of the effectiveness of TCM after listing, and can also be used as a reference for the selection of TCM varieties in the national medical insurance drug catalog and the national essential drug catalog.

This study deciphered the ameliorating effect and molecular mechanism of the total glucosides of White Paeony Capsules(TGP) in the treatment of mice model with acute lung injury(ALI) via NOD-like receptor thermal protein domain associated protein 3(NLRP3) signaling pathway of the inflammasome. The study established an inflammasome activation model of primed bone marrow-derived macrophages(BMDMs), and its molecular mechanism was investigated by Western blot(WB), immunofluorescence staining, enzyme-linked immunosorbent assay(ELISA), and flow cytometry. C57BL/6J mice were randomly divided into a blank control group, a TGP group, a model group(LPS group), LPS+low-and high-dose TGP groups, LPS+MCC950 group, and LPS+MCC950+TGP group, with eight mice per group. The ALI model was induced in mice. Finally, bronchoalveolar lavage fluid(BALF) and lung tissue were collected. Lung index and lung weight wet-to-dry ratio were determined for each group of mice. The pathological changes in lung tissue were observed through hematoxylin-eosin(HE) staining. The number of neutrophils in the BALF of each group was detected using flow cytometry. The levels of interleukin(IL)-1β, IL-6, and tumor necrosis factor(TNF)-α in the BALF were determined by ELISA. The expressions of IL-1β, IL-18, IL-6, and TNF-α in the lung tissue were determined by real-time quantitative PCR(RT-qPCR). This study demonstrated that TGP dramatically blocked the activation of the NLRP3 inflammasome by inhibiting the production of upstream mitochondrial reactive oxygen species(mtROS) and the subsequent oligomerization of apoptosis-associated specks(ASC). Additionally, in the ALI mice model, compared with the blank control group, the model group showed alveolar structure rupture, thic-kening of alveolar septa, and dramatically increased lung index, lung weight wet-to-dry ratio in lung tissue, neutrophil count, and inflammatory factor levels. Compared with the model group, the pathological morphology of lung tissue was significantly ameliorated in the TGP and MCC950 groups, and the lung index and lung weight wet-to-dry ratio were significantly reduced. Neutrophil counts were reduced, and levels of inflammatory factors were significantly downregulated. Notably, compared with the MCC950 group, there was no significant difference in effect in the MCC950+TGP group. Collectively, the study reveals that TGP may ameliorate ALI in mice by inhibiting the activation of NLRP3 inflammasome, providing a safe and effective drug candidate for the prevention or treatment of ALI/ARDS.

Background: Liuweiwuling Tablet (LWWL) is a Chinese patent medicine approved for the treatment of chronic inflammation caused by hepatitis B virus (HBV) infection. Previous studies have indicated an anti-HBV effect of LWWL, specifically in terms of antigen inhibition, but the underlying mechanism remains unclear., Aim: To investigate the potential mechanism of action of LWWL against HBV., Methods: In vitro experiments utilized three HBV-replicating and three non-HBV-replicating cell lines. The in vivo experiment involved a hydrodynamic injection-mediated mouse model with HBV replication. Transcriptomics and metabolomics were used to investigate the underlying mechanisms of action of LWWL., Results: In HepG2.1403F cells, LWWL (0.8 mg/mL) exhibited inhibitory effects on HBV DNA, hepatitis B surface antigen and pregenomic RNA (pgRNA) at rates of 51.36%, 24.74% and 50.74%, respectively. The inhibition rates of LWWL (0.8 mg/mL) on pgRNA/covalently closed circular DNA in HepG2.1403F, HepG2.2.15 and HepG2.A64 cells were 47.78%, 39.51% and 46.74%, respectively. Integration of transcriptomics and metabolomics showed that the anti-HBV effect of LWWL was primarily linked to pathways related to apoptosis (PI3K-AKT, CASP8-CASP3 and P53 pathways). Apoptosis flow analysis revealed that the apoptosis rate in the LWWL-treated group was significantly higher than in the control group (CG) among HBV-replicating cell lines, including HepG2.2.15 (2.92% ± 1.01% vs 6.68% ± 2.04%, P < 0.05), HepG2.A64 (4.89% ± 1.28% vs 8.52% ± 0.50%, P < 0.05) and HepG2.1403F (3.76% ± 1.40% vs 7.57% ± 1.35%, P < 0.05) (CG vs LWWL-treated group). However, there were no significant differences in apoptosis rates between the non-HBV-replicating HepG2 cells (5.04% ± 0.74% vs 5.51% ± 1.57%, P > 0.05), L02 cells (5.49% ± 0.80% vs 5.48% ± 1.01%, P > 0.05) and LX2 cells (6.29% ± 1.54% vs 6.29% ± 0.88%, P > 0.05). TUNEL staining revealed a significantly higher apoptosis rate in the LWWL-treated group than in the CG in the HBV-replicating mouse model, while no noticeable difference in apoptosis rates between the two groups was observed in the non-HBV-replicating mouse model., Conclusion: Preliminary results suggest that LWWL exerts a potent inhibitory effect on wild-type and drug-resistant HBV, potentially involving selective regulation of apoptosis. These findings offer novel insights into the anti-HBV activities of LWWL and present a novel mechanism for the development of anti-HBV medications., Competing Interests: Conflict-of-interest statement: The authors of this manuscript having no conflicts of interest to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To assess the risk of aristolochic acid (AA)-associated cancer in patients with AA nephropathy (AAN)., Methods: A retrospective study was conducted on patients diagnosed with AAN at Peking University First Hospital from January 1997 to December 2014. Long-term surveillance and follow-up data were analyzed to investigate the influence of different factors on the prevalence of cancer. The primary endpoint was the incidence of liver cancer, and the secondary endpoint was the incidence of urinary cancer during 1 year after taking AA-containing medication to 2014., Results: A total of 337 patients diagnosed with AAN were included in this study. From the initiation of taking AA to the termination of follow-up, 39 patients were diagnosed with cancer. No cases of liver cancer were observed throughout the entire follow-up period, with urinary cancer being the predominant type (34/39, 87.17%). Logistic regression analysis showed that age, follow-up period, and diabetes were potential risk factors, however, the dosage of the drug was not significantly associated with urinary cancer., Conclusions: No cases of liver cancer were observed at the end of follow-up. However, a high prevalence of urinary cancer was observed in AAN patients. Establishing a direct causality between AA and HCC is challenging., (© 2023. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Ethnopharmacological Relevance: Psoralea corylifolia Linn. (BGZ) is a commonly used traditional Chinese medicine (TCM) for the treatment of kidney-yang deficiency syndrome (Yang syn ) with good curative effect and security. However, BGZ was also reported to induce liver injury in recent years. According to TCM theory, taking BGZ may induce a series of adverse reactions in patients with kidney-yin deficiency syndrome (Yin syn ), which suggests that BGZ-induced liver damage may be related to its unreasonable clinical use., Aim of the Study: Liver injury caused by TCM is a rare but potentially serious adverse drug reaction, and the identification of predisposed individuals for drug-induced liver injury (DILI) remains challenging. The study aimed to investigate the differential responses to BGZ in Yang syn and Yin syn rat models and identify the corresponding characteristic biomarkers., Materials and Methods: The corresponding animal models of Yang syn and Yin syn were induced by hydrocortisone and thyroxine + reserpine respectively. Body weight, organ index, serum biochemistry, and Hematoxylin and Eosin (HE) staining were used to evaluate the liver toxicity effect of BGZ on rats with Yang syn and Yin syn . Transcriptomics and metabonomics were used to screen the representative biomarkers (including metabolites and differentially expressed genes (DEGs)) changed by BGZ in Yang syn and Yin syn rats, respectively., Results: The level changes of liver organ index, alanine aminotransferase (ALT), and aspartate aminotransferase (AST), suggested that BGZ has liver-protective and liver-damaging effects on Yang syn and Yin syn rats, respectively, and the results also were confirmed by the pathological changes of liver tissue. The results showed that 102 DEGs and 27 metabolites were significantly regulated related to BGZ's protective effect on Yang syn , which is mainly associated with the glycerophospholipid metabolism, arachidonic acid metabolism, pantothenate, and coenzyme A (CoA) biosynthesis pathways. While 28 DEGs and 31 metabolites, related to the pathway of pantothenate and CoA biosynthesis, were significantly regulated for the BGZ-induced liver injury in Yin syn . Furthermore, 4 DEGs (aldehyde dehydrogenase 1 family member B1 (Aldh1b1), solute carrier family 25 member 25 (Slc25a25), Pim-3 proto-oncogene, serine/threonine kinase (Pim3), out at first homolog (Oaf)) and 4 metabolites (phosphatidate, phosphatidylcholine, N-Acetylleucine, biliverdin) in the Yang syn group and 1 DEG [galectin 5 (Lgals5)] and 1 metabolite (5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate) in Yin syn group were significantly correlated to the ALT and AST levels of BGZ treated and untreated groups (receiver operating characteristic (ROC) ≥ 0.9)., Conclusions: Yin syn and Yang syn are the predisposed syndromes for BGZ to exert liver damage and liver protection respectively, which are mainly related to the regulation of amino acid metabolism, lipid metabolism, energy metabolism, and metabolism of cofactors and vitamins. The results further suggest that attention should be paid to the selection of predisposed populations when using drugs related to the regulation of energy metabolism, and the Yin syn /Yang syn animal models based on the theory of TCM syndromes may be a feasible method for identifying the susceptible population to receive TCM., (© 2023. International Society for Chinese Medicine and BioMed Central Ltd.)

With the increase in the medical level, the improvement of adverse drug reaction(ADR) monitoring systems, and the enhancement of public awareness of safe medication, drug safety incidents have been frequently reported. Drug-induced liver injury(DILI), especially liver injury attributed to herbal and dietary supplements(HDS), has globally attracted high attention, bringing great threats and severe challenges to the people for drug safety management such as clinical medication and medical supervision. Consensus on drug-induced liver injury had been published by the Council for International Organizations of Medical Sciences(CIOMS) in 2020. In this consensus, liver injury attributed to HDS was included in a special chapter for the first time. The hot topics, including the definition of HDS-induced liver injury, epidemiological history, potential risk factors, collection of related risk signals, causality assessment, risk prevention, control and management were discussed from a global perspective. Based on the previous works, some experts from China were invited by CIOMS to undertake the compilation of this chapter. Meanwhile, a new causality assessment in DILI based on the integrated evidence chain(iEC) method was widely recognized by experts in China and abroad, and was recommended by this consensus. This paper briefly introduced the main contents, background, and characteristics of the Consensus on drug-induced liver injury. Significantly, a brief interpretation was illustrated to analyze the special highlights of Chapter 8, &quot;Liver injury attributed to HDS&quot;, so as to provide practical references for the medical staff and the researchers who worked on either Chinese or Western medicine in China.

Profound changes have taken place in human disease spectrum, constitution spectrum, and drug use behavior, and the safety of traditional Chinese medicine(TCM) faces new trends and problems. In particular, serious adverse reactions/events such as liver injury and kidney injury caused by non-toxic TCM have been frequently reported, overturning people's understanding of TCM safety, and even shaking the public's confidence in the development of TCM. In the new era of globalization, correctly understanding the situation and problems of TCM safety and addressing the dilemmas in safety evaluation and risk prevention of TCM are the key missions to be undertaken by TCM practitioners. This paper suggests that the situation and problems of TCM safety should be viewed objectively and dialectically, and the use standard of TCM should be advanced with the times. Furthermore, this paper puts forward the new conception and methodology of TCM safety(including one innovative understanding, two types of evaluation modes, tri-elements injury hypothesis; four-quadrant risk decision processes, and five-grade safety evidence body) for the first time, hoping to provide new theories, new strategies, new methods and successful examples for solving the safety problems of TCM.

Since exploding rates of modern mental diseases, application of antidepressants has increased. Worryingly, the antidepressant-induced liver injury has gradually become a serious health burden. Furthermore, since most of the knowledge about antidepressant hepatotoxicity are from pharmacovigilance and clinical case reports and lack of observational studies, the underlying mechanisms are poorly understood and there is a lack of efficient treatment strategies. In this study, antidepressant paroxetine directly triggered inflammasome activation evidenced by caspase-1 activation and downstream effector cytokines interleukin(IL)-1β secretion. The pretreatment of echinatin, a bioactive component of licorice, completely blocked the activation. This study also found that echinatin effectively inhibited the production of inflammasome-independent tumor necrosis factor α(TNF)-α induced by paroxetine. Mechanistically, the accumulation of mitochondrial reactive oxygen species(mtROS) was a key upstream event of paroxetine-induced inflammasome activation, which was dramatically inhibited by echinatin. In the lipopolysaccharide(LPS)-mediated idiosyncratic drug-induced liver injury(IDILI) model, the combination of LPS and paroxetine triggered aberrant activation of the inflammasome to induce idiosyncratic hepatotoxicity, which was reversed by echinatin pretreatment. Notably, this study also found that various bioactive components of licorice had an inhibitory effect on paroxetine-triggered inflammasome activation. Meanwhile, multiple antidepressant-induced aberrant activation of the inflammasome could be completely blocked by echinatin pretreatment. In conclusion, this study provides a novel insight for mechanism of antidepressant-induced liver injury and a new strategy for the treatment of antidepressant-induced hepatotoxicity.

Traditional medicines have greatly contributed to people's health worldwide. However, in recent years, the frequent occurrence of herb-induced liver injury (HILI) has raised public concerns regarding the safety of herbs. HILI not only severely impacts public health, thus increasing its medical burden, but also consumes medical resources. However, the pharmacoepidemiology and risk factors of HILI are still unclear due to the complexity of herbs (medication theory, drug composition, dual properties of drugs and food, etc.). China is the country with the most extensive use of herbs and cases of HILI worldwide. The safety profile of herbs (especially with respect to HILI) has also affected the use of herbs internationally. Therefore, this review focuses on the epidemic situation of HILI in mainland China to compile its characteristics, while focusing on the three main aspects of patients, drugs, and unreasonable prescriptions to explore the potential risk factors. Our objective was to provide a reference for HILI pharmacovigilance and risk prevention and control and contribute to Chinese knowledge of the realisation of the "Medication without Harm" global safe medication strategic goal of the World Health Organization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Ge, Tang, Qin, Zeng, Yao, Xiao, Bai and Tang.)

Backgrounds: Drug induced liver injury (DILI) is sometimes similar to autoimmune hepatitis (AIH) in serology and histology. Clinicians empirically screened DILI with significant autoimmune characteristics to implement clinical intervention. We tried to characterize DILI with autoantibodies by metabolomics., Methods: Untargeted metabolomics coupled with pattern recognition approaches were performed on sera samples including AIH (n = 59), DILI with autoantibodies (DILI Ab+ , n = 68), and DILI without autoantibodies (DILI Ab- , n = 75). The differential metabolites and fingerprint metabolites between AIH and DILI Ab- were screened by orthogonal partial least squares-discriminant analysis and hierarchical clustering respectively., Results: Of the 388 annotated differential metabolites between AIH and DILI Ab- , 74 fingerprint metabolites were screened. The eigenmetabolite compressed from the fingerprint possessed high discrimination efficacy (AUC:0.891; 95 %CI, 0.838-0.944). In the fingerprint-based PCA model, AIH and DILI Ab- were separated into three regions: the "pure region" of AIH (Region 1), the "pure region" of DILI Ab- (Region 3), the mixture region of AIH and DILI Ab- (Region 2). After incorporated into the PCA model, DILI Ab+ samples were distributed into the three regions, indicating that DILI Ab+ samples had different etiological tendencies. Moreover, the fingerprint-based radar model verified the results of PCA model characterizing DILI Ab+ . Notably, the antibody titers of DILI Ab+ in the three regions did not differ significantly, while the response rates for glucocorticoids were obviously different. The metabolic difference among DILI Ab+ in different regions mainly lies in energy metabolism., Conclusions: In terms of metabolic signature, DILI Ab+ may not be a community of same pathogenesis, including AIH-inclined parts. Which deserves further study., Competing Interests: 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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Excess acetaminophen(APAP) can be converted by the cytochrome P450 system to the toxic metabolite N-acetyl-p-benzoquinoneimine(NAPQI), which consumes glutathione(GSH). When GSH is depleted, NAPQI covalently binds with proteins, inducing mitochondrial dysfunction and oxidative stress and thereby leading to hepatotoxicity. Schisandrin C(SinC) is a dibenzocyclooctadiene derivative isolated from Schisandra chinensis. Although there is some evidence showing that SinC has hepatoprotective activity, its protective effect and mechanism on APAP-induced liver injury remain unclear. In this paper, an acute liver injury mouse model was established by intraperitoneal injection of APAP at a dose of 400 mg·kg~(-1) to evaluate the effect of SinC administration on the APAP-induced liver injury and its mechanism through an animal experiment. At the same time, a potential candidate drug was provi-ded for traditional Chinese medicine(TCM) prevention and treatment of overdose APAP-induced liver injury. In the APAP-induced liver injury mouse model, we found that SinC can relieve hepatic histopathological lesions and significantly reduce the activities of alanine aminotransferase(ALT), aspartate aminotransferase(AST) and alkaline phosphatase(ALP). It was also capable of increasing the content of GSH and superoxide dismutase(SOD) and decreasing the levels of total bilirubin(TBIL), direct bilirubin(DBIL), malondialdehyde(MDA), interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α). Further analysis showed that SinC decreased the content of CYP2 E1 in liver tissues at protein and mRNA levels and increased nuclear factor erythroid 2-related factor 2(Nrf2) and the expression of its downstream targets(including HO-1, NQO1 and GCLC). Taken together, the above results indicate that SinC can alleviate APAP-induced liver injury by reducing the expression of CYP2 E1, suppressing apoptosis, improving inflammatory response and activating the Nrf2 signaling pathway to inhibit oxidative stress.

Objective: To investigate the protective effects of Schisandra chinensis oil (SCEO) against aristolochic acid I (AA I)-induced nephrotoxicity in vivo and in vitro and elucidate the underlying mechanism., Methods: C57BL/6 mice were randomly divided into 5 groups according to a random number table, including control group, AA I group, and AA I +SCEO (0.25, 0.5 and 1 g/kg) groups (n=5 per group). Pretreatment with SCEO was done for 2 days by oral administration, while the control and AA I groups were treated with sodium carboxymethyl cellulose. Mice of all groups except for the control group were injected intraperitoneally with AA I (5 mg/kg) from day 3 until day 7. Histopathological examination and apoptosis of kidney tissue were observed by hematoxylin and eosin and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatinine (SCr), as well as renal malondialdehyde (MDA), glutathione, r-glutamyl cysteingl+glycine (GSH), and superoxide dismutase (SOD) were analyzed using enzyme-linked immunosorbent assay (ELISA). Expressions of hepatic cytochrome P450 1A1 (CYP1A1), CYP1A2, and nad(p)hquinonedehydrogenase1 (NQO1) were analyzed using ELISA, quantitative real-time polymerase chain reaction (qPCR) and Western blot, respectively. In vitro, SCEO (40 µ g/mL) was added 12 h before treatment with AA I (40 µ mol/mL for 48 h) in human renal proximal tubule cell line (HK-2), then apoptosis and reactive oxygen species (ROS) were analyzed by flow cytometry., Results: SCEO 0.5 and 1 g/kg ameliorated histopathological changes and TUNEL + staining in the kidney tissues of mice with AA I-induced nephrotoxicity, and reduced serum levels of ALT, AST, BUN and SCr (P<0.01 or P<0.05). SCEO 0.5 and 1 g/kg alleviated the ROS generation in kidney, containing MDA, GSH and SOD (P<0.01 or P<0.05). SCEO 1 g/kg increased the expressions of CYP1A1 and CYP1A2 and decreased NQO1 level in the liver tissues (P<0.01 or P<0.05). Besides, in vitro studies also demonstrated that SCEO 40 µ g/mL inhibited apoptosis and ROS generation (P<0.05 or P<0.01)., Conclusions: SCEO can alleviate AA I-induced kidney damage both in vivo and in vitro. The protective mechanism may be closely related to the regulation of metabolic enzymes, thereby inhibiting apoptosis and ROS production., (© 2022. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and aims: Chronic drug-induced liver injury (DILI) is a rare but under-researched adverse drug reaction-related disease, which is highly likely to progress into liver fibrosis and even cirrhosis. In this study, metabolomics was used to screen out characteristic metabolites related to the histological progression of fibrosis in chronic DILI and analyze the metabolic changes during the development of fibrosis to explain the underlying mechanism. Methods: Chronic DILI patients who underwent liver biopsy were divided into different fibrosis grades. Serum was analyzed by untargeted metabolomics to find serological characteristic metabolite fingerprints. The screened fingerprints were validated by the validation group patients, and the identification ability of fingerprints was compared using FibroScan. Results: A total of 31 metabolites associated with fibrosis and 11 metabolites associated with advanced fibrosis were identified. The validation group confirmed the accuracy of the two metabolite fingerprints [area under the curve (AUC) value 0.753 and 0.944]. In addition, the fingerprints showed the ability to distinguish the grades of fibrosis by comparing using FibroScan. The metabolite fingerprint pathway showed that bile acid synthesis is disturbed while lipid metabolism is extremely active, resulting in an overload of lipid metabolites in the occurrence and development of chronic DILI-associated fibrosis. Conclusions: Our metabolomic analysis reveals the unique metabolomic fingerprints associated with chronic DILI fibrosis, which have potential clinical diagnostic and prognostic significances. The metabolomic fingerprints suggest the disturbance of the lipid metabolites as the most important factor in the development of DILI fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 He, Zhou, Cheng, Li, Gao, Ma, Song, Bai, Zou, Xiao, Wang and Lu.)

Traditional Chinese medicine(TCM) has made outstanding contributions to disease prevention and treatment, survival, and reproduction of the Chinese nation. Currently, the inheritance and innovative development of TCM have become a national strategy. However, in recent years, adverse reactions/events of Chinese medicine frequently occurred. In particular, in terms of the safety problem of newly discovered &quot;toxic&quot; Chinese medicine, it is often difficult to answer the question scientifically and develop effective solutions. When facing international public opinions and public questioning, they are often &quot;passively criticized&quot;. To solve the difficult problem about the safety of Chinese medicine, we urgently need to make breakthroughs in the cognition of toxicity of Chinese medicine and prevention and control of risks. This research team has been committed to the research on the safety of Chinese medicine for the long term. In particular, in terms of safety evaluation and risk prevention and control of newly discovered &quot;toxic&quot; Chinese medicine, they have made a series of original discoveries. On the basis of the discoveries, they innovated the cognition theory and methods of the toxicity of Chinese medicine, opened up a new field of research on the idiosyncratic toxicity and indirect toxicity of Chinese medicine, and proposed and established the disease-syndrome-based toxicology(DSBT), the model and method of safety evaluation of Chinese medicine related to diseases and syndromes. In light of the theory and methods of DSBT which have been applied to the objective eva-luation and analysis of the mechanism of the hepatotoxicity of Chinese medicine such as Polygoni Multiflori Radix, the mechanism hypothesis of &quot;toxicity due to three causes&quot; of idiosyncratic hepatotoxicity of Chinese medicine was proposed and confirmed. The findings revealed that the substances that induced idiosyncratic or indirect toxicity in Chinese medicine often did not possess definite direct toxi-city. Therefore, this research team proposed the concept of toxicity-related substances(TRS) in Chinese medicine. Based on the mo-dern scientific cognition of toxicity of Chinese medicine, the team proposed the strategy and method of Chinese medicine compatibility to reduce the toxicity based on the component-effect-target interaction to underpin the demonstration of the scientific connotation of toxicity and side effects of &quot;toxic&quot; Chinese medicine and establishment of scientific and effective risk prevention and control strategies. In light of the innovative development of toxicity cognition of Chinese medicine, this study is expected to provide important theoretical guidance and methodological support for scientific evaluation and precise prevention and control of the safety risk of &quot;toxic&quot; Chinese medicine.

Objective: Aging population is generally considered more sensitive to adverse drug reactions (ADRs). Yet, big data-based quantitative evidence currently does not exist to support this concept. This study aims to investigate age-associated risks of liver-related ADR (L-ADR)., Methods: Spontaneous reporting data from 2012 to 2016 were retrieved from the China National ADR Monitoring System. The risk ratio (RR) was used to quantify the relative risk of L-ADR of each age group. The reporting odds ratio (ROR) was used to quantify the correlation with the risk of L-ADR of each drug category or drug in older adults., Results: Totally, 64,702 L-ADR reports were retrieved, covering ages from 1 to 116, with a median age of 49. The RR values increased exponentially with the increase of age, which indicates that the relative risk of L-ADR increased by 33% for every 10-year increase in age. The age cutoff point for relative high risk of L-ADR was estimated at 52.0 years old (RR = 1). In 17 categories composed of 270 drugs, the top 3 drug categories with a high correlation to the risk of L-ADR in older adults were antiarrhythmic (ROR, 5.75; 95% CI: 4.45-7.42), antilipemic (ROR, 4.77; 95% CI: 4.53-5.02), and antihypertensive (ROR, 2.97; 95% CI: 2.59-3.41)., Conclusions: This research illustrates quantitatively that aging is a potential risk factor for L-ADR, with a 33% increase in relative risk for every 10-year increase in age. Risk management should be addressed for older adults when those drugs with a high correlation to the risk of L-ADR are used., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Han, Guo, Xiong, Ge, Jing, Niu, Zhao, Bai, Song, Xiao and Wang.)

Polygonum multiflorum (PM), a popular functional food, and a herbal and dietary supplement, is widely used as a tonic in China and East Asia. In recent years, it has attracted great concern for its ability to cause idiosyncratic drug-induced liver injury (IDILI). However, identifying individuals susceptible to IDILI remains challenging. This is a prospective study. For 6 patients whose serum alanine aminotransferase (ALT) levels after consuming PM were abnormally elevated (susceptible group), 15 patients with normal levels of liver injury markers were matched (tolerant group) based on similar baseline characteristics. ProcartaPlex immunoassays were adopted to quantitatively detect 33 serum cytokines in the two groups of patients before consuming PM, to characterize the cytokine profile and screen differential cytokines. Subsequently, the susceptibility of a potential biomarker to regulate PM-induced liver injury was validated in animal models. There were significant differences in the cytokine profiles between the susceptible and tolerant groups, wherein the susceptible patients showed immune perturbation characterized by high expression of multiple inflammatory cytokines, especially the proinflammatory cytokine TNF-α ( P = 0.006). Among them, the cytokine TNF-α had the strongest correlation with ALT, where the correlation coefficient was greater than 0.6, and the area under the receiver operating characteristic curve was more than 0.8. Animal experiments revealed that both PM water extract and its susceptibility component of liver injury, cis -stilbene glucoside, could cause liver injury in the mice pre-stimulated using TNF-α. Conversely, administration of the same dose of drugs on control mice did not show any hepatotoxicity. In conclusion, immune perturbation mainly mediated by TNF-α may regulate the susceptibility to PM-induced liver injury. This provides a new perspective for the study of susceptibility to IDILI.

The present study evaluated the clinical efficacy and safety of Liuwei Wuling Tablets combined with conventional drugs for the treatment of liver fibrosis and cirrhosis in chronic hepatitis B. CNKI, Wanfang, VIP, CBM, PubMed, EMbase and Cochrane Library were searched for the relevant randomized controlled trials(RCTs) published from database inception to February 2021. All the retrieved papers were independently screened, extracted and evaluated by two researchers, followed by Meta-analysis by Review Manager 5.4. Finally, 18 RCTs were included, involving 2 168 patients(1 106 in the treatment group and 1 062 in the control group). The Meta-analysis results showed that compared with conventional drugs alone, Liuwei Wuling Tablets combined with conventional drugs could increase the effective rate of clinical treatment by reducing serum hyaluronic acid(HA), laminin(LN), procollagen type Ⅲ(PCⅢ), and type Ⅳ collagen(Ⅳ-C) to improve liver function, decreasing the levels of total bilirubin(TBiL), alanine amino-transferase(ALT), and aspartate aminotransferase(AST), and improving the negative conversion ratio of hepatitis B virus(HBV) DNA. In terms of safety, there were no serious adverse reactions in the treatment group and the control group. The results showed that Liuwei Wuling Tablets combined with antiviral or other conventional liver-protecting drugs could improve liver function, treat liver cirrhosis, and reduce liver fibrosis with high safety. However, due to the influence of literature quality and quantity, multi-center and high-quality RCTs with large sample size are needed for verification.

The gene polymorphisms of ABCB1, EPHX1, and SCN1A were found to influence carbamazepine (CBZ) metabolism and resistance in epilepsy patients, but the relevance remains controversial. To reveal the relationships among the gene polymorphisms of ABCB1, EPHX1, SCN1A and the metabolism and resistance of CBZ, the databases of PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals, China Biology medicine disc and Wan Fang were retrieved for suitable studies up to April 2021. 18 studies containing 3293 epilepsy patients were included. The result revealed the gene polymorphism of ABCB1 c.3435C > T is significantly associated with altered concentration-dose ratios of CBZ (CDR CBZ ) (CC vs. CT, OR = 0.25 (95% CI: 0.08-0.42), P = 0.004), and EPHX c.416A > G gene polymorphism may also significantly adjusted the concentration-dose ratios of carbamazepine-10, 11-trans dihydrodiol (CDR CBZD ) (AA vs. GG, OR = 0.48 (95% CI: 0.01-0.96), P = 0.045; AG vs. GG, OR = 0.68 (95% CI: 0.16-1.20), P = 0.010, respectively) and the ratio of CBZD:carbamazepine-10,11-epoxide (CBZE) (CDR CBZD :CDR CBZE ) (AG vs GG, OR = 0.83 (95% CI: 0.31-1.36), P = 0.002). Furthermore, ABCB1 c.3435C > T polymorphism was also observed to be significantly influenced CBZ resistance (CC vs TT, OR = 1.78 (95% CI: 1.17-2.72), P = 0.008; CT vs TT, OR = 1.60 (95% CI: 1.12-2.30), P = 0.01; CC + CT vs TT, OR = 1.61 (95% CI: 1.15-2.26), P = 0.006, respectively). Therefore, CBZ metabolism and resistance in patients with epilepsy may be adjusted by the gene polymorphisms of ABCB1 c.3435C > T and EPHX1 c.416A > G which provides the further scientific basis for clinical individualized therapy of epilepsy. However, larger sample size studies are still needed to provide further conclusive evidence., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Long noncoding RNAs (lncRNAs) are known to be the important regulators in cancer progression. However, the role of lncRNA FAM66C (FAM66C) is yet to be investigated in intrahepatic cholangiocarcinoma (ICC). This study aimed to investigate the effects and related mechanisms of FAM66C in ICC. Human ICC tissues and cell lines were collected. The expression levels of FAM66C, hsa-miR-23b-3p (miR-23b-3p), and KCND2 were detected by qRT-RCR. The transfection experiments were employed to measure the effect of FAM66C on cell viabilities, migration, and invasion in ICC cells by CCK-8, transwell assays. Glycolysis was investigated by glucose consumption, lactate production and ATP levels. The dual-luciferase reporter and RNA pull down assays were conducted as a means of confirming the interactions between FAM66C, miR-23b-3p, and KCND2. Furthermore, the levels of the EMT-associated proteins (KCND2, GLUT1, PKM2, and LDHA) in ICC cells were detected by western blot. FAM66C was increased in ICC tissues and cells, increased cell viability, glycolysis, migration and invasion, and decreased apoptosis were shown in FAM66C overexpressing cells. Mechanistic analyses revealed that FAM66C regulated the downstream target gene KCND2 by sponging miR-23b-3p. FAM66C effect on ICC was further validated in murine xenograft assays. FAM66C knockdown cells gave rise to tumors that were smaller in size, consistent with the role of FAM66C as a promoter of in vivo tumor growth. These data revealed that FAM66C was able to drive ICC tumor progression and glycolytic activity via the miR-23b-3p/KCND2 axis, indicating FAM66C may be a viable target for treating ICC., (© 2021 Wiley Periodicals LLC.)

Objective: To analyze clinical feature and information of medication to explore the risk signals of preparations containing Psoraleae Fructus (BGZP) related with hepatobiliary adverse drug reactions (ADR), in order to reinforce pharmacovigilance., Methods: A retrospective study was conducted based on hepatobiliary ADR related with BGZP from the China Adverse Drug Reaction Monitoring System in years from January 2012 to December 2016. Serious and general ADRs were analyzed and assessed., Results: There were 355 cases of hepatobiliary ADR related to BGZP. Both the amount of cases and the proportion of serious ADR showed an increasing growth by years (P<0.05). It was found that 10.43% of 355 cases may be involved with irrational drug use, including overdose, repeated medication, and combination of multiple drugs. There were 190 cases which used BGZP (non-combination), and they were mainly for common in diseases caused by abnormal immune activation (accounting for 40.53% of the total cases). Especially at the age group with the most cases with age of 41-50 years, the cases associated with immunological diseases of female were obviously more than that of male (P<0.05). The latency of hepatobiliary ADR related to BGZP ranged from 1 to 386 days, and the median latency was 27.5 days, along with the range of cumulative dose (0.45-520.02 g) as well as the daily dose (0.09-2.64 g/d) after the conversion., Conclusions: Cases of hepatobiliary ADR related to BGZP showed significant individual differences, and there was no correlation between drug usage duration and dosage and the occurrence of hepatobiliary ADR. It may be similar with idiosyncratic drug-induced liver injury, and recommended that BGZP should be used with more caution under monitoring liver function, especially in female patients with immunological diseases., (© 2021. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Liuweiwuling Tablet (LWWL) is a licensed Chinese patent medicine (approval number: Z20060238) included in the national health insurance for anti-inflammation of chronic HBV infection, whereas its anti-HBV effect remains clarification. The study aimed to clarify its antiviral effect and related mechanisms. HepG2.2.15 cells (wild-type HBV-replicating cells) and HepG2. A64 cells (entecavir-resistant HBV-replicating cells) were used for in vitro test. Hydrodynamic injection-mediated HBV-replicating mouse model was used for in vivo test. Active compounds and related mechanisms for antiviral effect of LWWL were analyzed using network pharmacology and transcriptomics. The inhibition rates of LWWL (0.8 mg/ml) on HBV DNA, HBsAg, and pgRNA were 57.06, 38.55, and 62.49% in HepG2.2.15 cells, and 51.57, 17.57, and 53.88% in HepG2. A64 cells, respectively. LWWL (2 g kg -1 d -1 for 4 weeks)-treated mice had 1.16 log 10 IU/mL decrease of serum HBV DNA, and more than 50% decrease of serum HBsAg/HBeAg and hepatic HBsAg/HBcAg. Compared to tenofovir control, LWWL was less effective in suppressing HBV DNA but more effective in suppressing HBV antigens. Thirteen differentially-expressed genes were found in relation to HBV-host interaction and some of them were enriched in interferon (IFN)-β pathway in LWWL-treated HepG2.2.15 cells. CD3 + CD4 + T-cell frequency and serum IFN-γ were significantly increased in LWWL-treated mice compared to LWWL-untreated mice. Among 26 compounds with potential anti-HBV effects that were predicted by network pharmacology, four compounds (quercetin, luteolin, wogonin, and kaempferol) were experimentally confirmed to have antiviral potency. In conclusion, LWWL had potent inhibitory effect on both wild-type and entecavir-resistant HBV, which might be associated with increasing IFN-β and IFN-γ production., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ge, Si, Yang, Li, Lv, Liu, Liao, Wang, Zou, Li, Li, Zhang, Wang, Lu, Xu, Bai, Liu and Xiao.)

Ethnopharmacological Relevance: As a traditional Chinese medicinal, Bidens bipinnata L. has been used to treat many diseases with a long history in China. The anti-diabetic effects of extract from B. bipinnata have been demonstrated in the previous reports., Aim of the Study: The protective effects of flavonoids-rich extract from B. bipinnata (BBTF) on cell damage induced by H 2 O 2 in pancreatic β cell and its potential mechanisms were evaluated., Materials and Methods: MTT, ROS production, nuclear staining and flow cytometry assays were adopted to determine the effects of BBTF on cell viability, production of ROS and cell apoptosis in H 2 O 2 -treated INS-1 cell. Cell apoptosis-related proteins expressions were detected by Western blot assay., Results: Pre-treatment of BBTF could significantly increase INS-1 cell viability, inhibit the production of intracellular ROS and reduced the characteristic features of cell apoptosis induced by H 2 O 2 in INS-1 cells. The studies of the underlying mechanism showed that BBTF could regulate Bax and Bcl-2 proteins expressions, suppress the phosphorylation of JNK, ERK and p38, as well as down-regulate Fas and FasL proteins expressions induced by H 2 O 2 . The expressions of caspase-8, caspase-9 and caspase-3 were therefore decreased., Conclusion: The results indicated that flavonoids-rich extract from B. bipinnata could be a natural agent in diabetic prevention and therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To compare the risk of liver-related adverse drug reactions (ADRs) in children and adults., Study Design: A case/non-case analysis on spontaneous reports based on the China National Adverse Drug Reactions Monitoring System database were conducted, focusing on events of liver-related ADRs in children younger than 14 years of age. Both the relative risk of liver-related ADRs in children vs entire population and the risk stratification in children were expressed as a measure of disproportionality using the reporting odds ratio (ROR)., Results: There were 1206 cases of pediatric liver-related ADRs identified from 2012 to 2016, accounting for 2.82% of the entire population. The greatest ROR values in children from 0 to 14 years vs the entire population were observed for analgesics (3.97, 95% CI 3.27-4.81), respiratory (2.60, 95% CI 1.04-6.43), antineoplastic (2.29, 95% CI 2.02-2.58), immunomodulatory (1.91, 95% CI 1.44-2.53), and antimicrobial agents (1.47, 95% CI 1.33-1.63). Notably, infants aged 0-1 years showed significantly greater risk (3.14, 95% CI 2.85-3.48) of liver-related ADRs than the other age groups of children. For infants, analgesics (3.21, 95% CI 2.20-4.66) and antimicrobials (3.15, 95% CI 2.50-3.97) agents were found to have the greatest adjusted RORs than other drug categories. The highest RORs were found for meropenem, amoxicillin, fluconazole, vancomycin, cefaclor, and ceftazidime in the antimicrobial agents for infants., Conclusions: Children are sensitive to liver-related ADRs caused by several specific drug categories, and infants are the most sensitive., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) is a malignancy found globally. Accumulating studies have shown that long noncoding RNAs (lncRNAs) play critical roles in HCC. However, the function of lncRNA in HCC remains poorly understood., Aim: To understand the effect of lncRNA W42 on HCC and dissect the underlying molecular mechanisms., Methods: We measured the expression of lncRNA W42 in HCC tissues and cells (Huh7 and SMMC-7721) by quantitative reverse transcriptase polymerase chain reaction. Receiver operating characteristic curves were used to assess the sensitivity and specificity of lncRNA W42 expression. HCC cells were transfected with pcDNA3.1-lncRNA W42 or shRNA-lncRNA W42. Cell functions were detected by cell counting Kit-8 (CCK-8), colony formation, flow cytometry and Transwell assays. The interaction of lncRNA W42 and DBN1 was confirmed by RNA immunoprecipitation and RNA pull down assays. An HCC xenograft model was used to assess the role of lncRNA W42 on tumor growth in vivo . The Kaplan-Meier curve was used to evaluate the overall survival and recurrence-free survival after surgery in patients with HCC., Results: In this study, we identified a novel lncRNA (lncRNA W42), and investigated its biological functions and clinical significance in HCC. LncRNA W42 expression was upregulated in HCC tissues and cells. Overexpression of lncRNA W42 notably promoted the proliferative and invasion of HCC, and inhibited cell apoptosis. LncRNA W42 directly bound to DBN1 and activated the downstream pathway. LncRNA W42 knockdown suppressed HCC xenograft tumor growth in vivo . The clinical investigation revealed that HCC patients with high lncRNA W42 expression exhibited shorter survival times., Conclusion: In vitro and in vivo results suggested that the novel lncRNA W42, which is upregulated in HCC, may serve as a potential candidate prognostic biomarker and therapeutic target in HCC patients., Competing Interests: Conflict-of-interest statement: All authors have nothing to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Green tea extract (GTE) is popular in weight loss, and epigallocatechin gallate (EGCG) is considered as the main active component. However, GTE is the primary cause of herbal and dietary supplement-induced liver injury in the United States. Whether there is a greater risk of liver injury when EGCG is consumed during dieting for weight loss has not been previously reported. This study found for the first time that EGCG could induce enhanced lipid metabolism pathways, suggesting that EGCG had the so-called "fat burning" effect, although EGCG did not cause liver injury at doses of 400 or 800 mg/kg in normal mice. Intriguingly, we found that EGCG caused dose-dependent hepatotoxicity on mice under dietary restriction, suggesting the potential combination effects of dietary restriction and EGCG. The combination effect between EGCG and dietary restriction led to overactivation of linoleic acid and arachidonic acid oxidation pathways, significantly increasing the accumulation of pro-inflammatory lipid metabolites and thus mediating liver injury. We also found that the disruption of Lands' cycle and sphingomyelin-ceramides cycle and the high expression of taurine-conjugated bile acids were important metabolomic characteristics in EGCG-induced liver injury under dietary restriction. This original discovery suggests that people should not go on a diet while consuming EGCG for weight loss; otherwise the risk of liver injury will be significantly increased. This discovery provides new evidence for understanding the "drug-host" interaction hypothesis of drug hepatotoxicity and provides experimental reference for clinical safe use of green tea-related dietary supplements., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shi, Zhu, Guo, Niu, Zhang, Tu, Huang, Li, Zhao, Zhang, Bai, Zhang, Lu, Xiao and Wang.)

Aim: The diagnosis of drug-induced liver injury (DILI) remains a challenge and the cases of Polygonum multiflorum Thunb. (PM) induced DILI (PM-DILI) have received much attention This study aimed to identify a simple and high-efficiency approach to PM-DILI diagnosis via metabolomics analysis. Methods: Plasma metabolites in 13 PM-DILI patients were profiled by liquid chromatography along with high-resolution mass spectrometry. Meanwhile, the metabolic characteristics of the PM-DILI were compared with that of autoimmune hepatitis (AIH), hepatitis B (HBV), and healthy volunteers. Results: Twenty-four metabolites were identified to present significantly different levels in PM-DILI patients compared with HBV and AIH groups. These metabolites were enriched into glucose, amino acids, and sphingolipids metabolisms. Among these essential metabolites, the ratios of P-cresol sulfate vs. phenylalanine and inosine vs. bilirubin were further selected using a stepwise decision tree to construct a classification model in order to differentiate PM-DILI from HBV and AIH. The model was highly effective with sensitivity of 92.3% and specificity of 88.9%. Conclusions: This study presents an integrated view of the metabolic features of PM-DILI induced by herbal medicine, and the four-metabolite decision tree technique imparts a potent tool in clinical diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Huang, Zhao, Zhang, Chen, Li, Shi, Jing, Huang, Guo, Bai, Zou, Xiao, Wang and Niu.)

The extract of Bidens bipinnata L. exhibited wide spectrum of bioactivities owing to the presence of flavonoids. In this study, a purification process was developed to enrich the flavonoid-rich extract from B. bipinnata L. (BBTF). AB-8 resin was selected for the purification of total flavonoids. Response surface methodology coupled with Box-Behnken design was employed to optimize the purification condition; it was optimized as pH 5.1, volume of ethanol 80 ml, flow rate of ethanol 1.8 bed volume per hour (BV/h) and concentration of ethanol 76.0%. The total flavonoid content of BBTF was 56.48% under the optimal conditions. The identification of flavonoids in BBTF was conducted using UHPLC-ESI-Q-TOF MS. A total of 14 compounds, including 12 flavonoids, were identified in BBTF. Finally, the in vitro antioxidant activities, α-glucosidase and α-amylase inhibitory activities of BBTF were comprehensively analyzed by an analytical hierarchy process. The results indicated that it exhibited higher bioactivities than the crude extract. These findings suggested that the optimized process could significantly enhance the purity of flavonoids and their bioactivities. This study showed a comprehensive analysis of a total flavonoid extract of B. bipinnata L. for the first time, which could provide a useful approach for its purification process and quality control as well as bioactivities., (© 2020 John Wiley & Sons, Ltd.)

Objectives: To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients., Methods: A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed., Results: An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048)., Conclusions: Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).

In this paper, the correlation between the chemical constituents of Chinese herbal medicines Daphnes Cortex and the ecological factors and soil factors was studied, which provided a reference for the selection of suitable areas for artificial cultivation of Daphne giraldii and wild tending. The geographic information system(GIS) was applied to obtain the ecological factor information of 23 collection sites of Daphnes Cortex, and the soil factor information was determined by the standard procedure in the soil test standard manual. Combining the information of 93 chemical constituents of Daphnes Cortex in 23 collection sites the correlation between components and ecological factors and soil factors was analyzed by statistical methods. The correlation analysis showed that the longitude, annual average rainfall, annual sunshine intensity, annual average temperature in the ecological factors, soil type, effective copper and pH value were the dominant factors affecting the chemical composition of Daphnes Cortex.

The coronavirus disease 2019(COVID-19) is raging in China and more than 20 other countries and regions since the middle of December 2019. Currently, there is no specific drug or vaccine besides symptomatic supportive therapy. Taking full advantage of the clinical experience of traditional Chinese medicine(TCM) in preventing and controlling major epidemics such as SARS, it is an important mission for TCM to propose effective formula with immediate response and solid evidence by using modern biomedical knowledge and techniques(molecular docking assisted TCM formulation for short). In view of the high homology between the gene sequences of the novel coronavirus and SARS virus, and the similarities between the two in terms of pathogenic mechanism and clinical manifestations, our team established a rapid screening and optimization model for the prevention and treatment of the novel coronavirus based on clinical experience and molecular docking technology. Firstly, the clinical team and the research team pre-developed and screened TCM formula by using &quot;back-to-back&quot; manner. Then, the formula was optimized and determined by comparing and analyzing the results of the two groups. The results showed that the research team screened out 46 active ingredients from candidate TCMs that could act on the novel coronavirus S-protein-binding site of human ACE2 protein, which were mainly attributed to 7 herbs such as Lonicerae Japonicae Flos and Mori Folium. The result was largely consistent with the formula raised by the clinical group, verifying and supporting its rationality. This provides evidence for the scientific and potential efficacy of the TCM prescription from the perspective of treatment target analysis, and also suggests that the TCM prescription has the potential to directly inhibit viral infection in addition to improving clinical symptoms or syndromes. Based on this, our team optimized and formed a new anti-coronavirus TCM prescription &quot;Keguan Yihao&quot;, immediately providing the TCM prescription with certain clinical experience and objective evidence support for the prevention and treatment of new emergent infectious diseases in our hospital. The TCM prescription was combined with modern medicine symptomatic supportive treatment for clinical treatment, preliminary results showed better effect than symptomatic supportive therapy alone. This research has innovated the method mode in clinical practice and basic research integration of traditional Chinese medicine for the prevention and control of new emerging infectious diseases. It is of great significance to further improve the rapid response mechanism of TCM in face of major epidemics, and further improve the capability level of TCM to prevent and treat new emerging infectious diseases.

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction. To date, identifying individuals at risk for IDILI remains challenging. This is a prospective study, where a nested case-control (1:5) design was adopted. For six patients who had abnormalities in liver function test after Polygonum multiflorum Thunb. (PM) ingestion (susceptible group), 30 patients with normal liver function were matched (tolerant group). Based on liquid chromatography-mass spectrometry, metabolomics analysis was done on serum samples prior to PM ingestion, to screen the differential metabolites and characterize metabolomic profiles of patient serum in the two groups. Multivariate analysis showed that there were remarkable separations between susceptible and tolerant groups. A total of 25 major differential metabolites were screened out, involving glycerophospholipid metabolism, sphingolipid metabolism, fatty acid metabolism, histidine metabolism and aromatic amino acid metabolism. Wherein, the area under the curve of the receiver operating characteristic curves of metabolites PE 22:6, crotonoyl-CoA, 2E-tetradecenoyl-CoA, phenyllactic acid, indole-5,6-quinone, phosphoribosyl-ATP were all greater than 0.9. The overall serum metabolic profile comprising of 25 metabolites could clearly distinguish susceptible and tolerant groups. This proof-of-concept study used metabolomics to characterize the metabolic profile of IDILI risk individuals before drug ingestion for the first time. The metabolome characteristics in patient serum before PM ingestion may predict the risk of liver injury after PM ingestion.

Background: Depression is a prevalent disorder for patients with stroke. Clinical researches indicate that sertraline is utilized to treat post-stroke depression (PSD) effectively. However, no systematic review has investigated this issue yet presently. Thus, this study aims to systematically assess the efficacy and safety of sertraline for patients with PSD., Methods: Literature sources will be divided into 2 sections: electronic sources and manual sources. We will search electronic literature sources as follows: EMBASE, MEDICINE, Web of Science, Cochrane Library, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure from their inceptions to the February 28, 2019. Manual sources include dissertations, ongoing trials, and conference abstracts. Two reviewers will select the literatures, extract and collect data information, and evaluate the risk of bias independently. Statistical analysis will be carried out by using RevMan 5.3 software., Results: Primary outcome is depression. It can be measured by Hamilton depression scale, Beck Depression Inventory, or any other scales. Secondary outcome are anxiety (as assessed by Hamilton anxiety scale, or other tools) response rate, activities of daily living (as measured by Barthel Index, or other scales), quality of life (as measured by 36-Item Short Form Health Survey), and safety., Conclusions: The results of this systematic review may summarize the up-to-date evidence on the efficacy and safety of sertraline for patients with PSD., Ethics and Dissemination: This systematic review will not need any ethical approval, because it will not analyze any individual patient data. The findings of this study are expected to disseminate at peer-reviewed journals.

Background: This study aims to investigate the regulative role of microRNA-93 (miR-93) in mouse cardiac microvascular endothelial cells (CMECs) injury and inflammatory response by negatively targeting SPP1 gene via the NF-κB signaling pathway., Methods: Healthy Balb/c mice were recruited to establish a mouse model with myocarditis using the CVB3 virus. Mice were grouped into normal, blank, negative control (NC), miR-93 inhibitor, miR-93 mimic, SPP1 short hairpin RNA (shRNA), and miR-93 mimic+SPP1 shRNA groups. Reverse transcription quantitative polymerase chain reaction and Western blot analysis were applied to determine the expressions of miR-93, SPP1, VEGFA, p50, p65, Bax, and Bcl-2. MTT assay was conducted to evaluate cell viability, annexin V-fluorescein isothiocyanate/propidium iodide double staining was conducted to examine cell apoptosis, enzyme-linked immunosorbent assay was conducted to measure secretion of inflammatory factors, and chemical colorimetry was conducted to determine NO secretion., Results: SPP1 was a target gene of miR-93. Compared with the normal group, other six groups showed increased expressions of SPP1, p50, p65, VEGFA, and Bax, as well as cell apoptosis rate and secretion of cell inflammatory factors, and decreased expression of Bcl-2, cell viability, and NO secretion. Compared with the blank group, the miR-93 inhibitor group showed elevated expressions of SPP1, p50, p65, VEGFA, and Bax, as well as cell apoptosis rate and secretion of cell inflammatory factors, and reduced Bcl-2, cell viability, and NO secretion. While the miR-93 mimic and SPP1 shRNA groups displayed opposite results., Conclusion: Taking our results together, we conclude that upregulation of miR-93 reduces CMECs injury and inflammatory response by negatively targeting SPP1 via inactivating the NF-κB signaling pathway., (© 2018 Wiley Periodicals, Inc.)

The study was aimed to investigate the protective effect and pharmacodynamic difference of the ethanol extracts of Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus on the drug-induced liver injury induced by acetaminophen.The cell activations of LO2 cells treated by Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus ethanol extracts were tested by CCK-8 essay.The effects of ethanol extracts on cell survival rate,the activities of ALT and AST in culture medium were detected based on the injury model of LO2 cells induced by APAP.Further,in purpose to observe the protective effect of Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus ethanol extracts on a mouse model of liver injury induced by intraperitoneal injectionof acetaminophen was established.Mice were randomly divided into control group,model group,positive drug group and Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus ethanol extracts administration groups.The activities of ALT and AST in the serum and the levels of MDA,SOD,GSH and GSH-PX in the liver homogenate of the mice were detected by commercial kits.The HEstaining was used to observe the histopathological changes of liver tissue in each group and the TUNEL staining was used to observe the hepatocyte apoptosis.The results showed that the ethanol extracts at less than 1 g·L~(-1)did not affect the activity of LO2 cell.Compared with the model group,the cell survival rates of the Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus ethanol extract administration groups was significantly increased;the ALT and AST in the culture medium were distinct decreased(P<0.05 or P<0.01).The survival rate of Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus ethanol extract from different batches were similar,while that of the Schisandrea Sphenatherae Fructus ethanol extract from different batches were quite different(P<0.05or P<0.01).Further,animal experiments showed that Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus ethanol extract administration groups could markedly inhibit the increase of ALT and AST levels in serum(P<0.01),decrease MDA content significantly(P<0.01),and increase GSH,GSH-PX and SOD activity significantly(P<0.01).Among them,compared with other groups,Schisandrae Sphenantherae Fructus ethanol extract-2 group showed the best effect(P<0.05 or P<0.01)while Schisandrae Sphenantherae Fructus ethanol extract-1 showed a poor effect(P<0.05 or P<0.01).In conclusion,both Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus ethanol extracts have protective effect on APAP-induced drug-induced liver injury and there was a certain difference in the efficacy between Schisandrae Sphenantherae Fructus and Schisandrae Chinensis Fructus ethanol extracts from different habitats.

Context: Anti-inflammatory drugs are often used to treat chronic knee pain (CKP), but their long-term use is associated with decreased effectiveness and numerous side effects. Complementary and alternative medicine provides additional treatments for the condition, including percutaneous electrical nerve stimulation (PENS). However, the benefits of PENS for treatment of CKP are still controversial., Objective: The study intended to assess the effects and safety of PENS for treatment of CKP., Methods: This study was a 2-arm, randomized, sham-controlled trial., Setting: The study took place at the Fourth People's Hospital of Shaanxi (Xi'an, China)., Participants: Participants were 72 patients at the hospital being treated for CKP., Intervention: Participants were randomly divided into a real PENS group and a sham PENS group at a ratio of 1:1. All patients received etoricoxib and either real or sham PENS therapy, 3 ×/wk for 8 wk, at the same local acupoints around the knee., Outcome Measures: The primary outcome, pain, was measured on a numeric rating scale (NRS). Secondary outcomes, stiffness and physical function, were evaluated using the Western Ontario and McMaster Universities arthritis index (WOMAC) and the short-form 36-item health survey (SF-36) to obtain a score on the physical component scale (PCS) and the mental component scale (MCS). The NRS and the WOMAC were administered at initiation of treatment to establish a baseline and again after 8 wk of treatment. The SF-36 was administered postintervention., Results: At the end of 8 wk, the group receiving the real PENS exhibited statistically significant improvements in both primary and secondary outcomes compared with the group receiving the sham PENS treatment., Conclusions: The findings suggest that treatment with the real PENS with etoricoxib is effective for treatment of CKP.

Objectives: The present study aimed to evaluate the association between the concurrence of pre-existing chronic liver diseases (CLD) and worse prognosis in patients with HILI., Design: A case-control study., Setting: Tertiary hospital specialising in liver diseases in China., Participants: 145 hospitalised HILI patients were assessed with respect to prognosis by comparing HILI with or without pre-existing CLD from February 2007 to January 2017. Twenty-five HILI cases with pre-existing alcoholic liver disease (ALD) or non-alcoholic fatty liver disease (NAFLD) and 200 ALD or NAFLD controls matched 1:8 for sex, age (±4 years old), body mass index (±2 kg/m 2 ), the type of CLD, alcohol intake (±5 g/d) and the presence or absence of cirrhosis., Primary Outcome Measures: Mortality and chronicity in HILI patients with or without pre-existing CLD, and matched CLD patients., Results: Of the 193 714 hospitalised patients with liver diseases, 5703 patients met the diagnostic criteria for drug-induced liver injury (DILI), which was attributed to Polygonum multiflorum Thunb. (PMT) in 145 patients. Among these HILI patients, 22.8% (33 of 145) had pre-existing CLD, including 17 (51.5%) with ALD, 8 (24.2%) with NAFLD, 5 (15.2%) with chronic viral hepatitis and 3 (9.1%) with autoimmune liver disease. Compared with HILI patients without CLD, HILI patients with pre-existing CLD showed higher mortality (0.9% vs 9.1%, p=0.037) and higher chronicity (12.5% vs 30.3%, p=0.016). Compared with matched ALD (136 patients) or NAFLD (64 patients) patients, HILI patients with pre-existing ALD showed higher chronicity (35.3% vs 11.8%, p=0.019). Multivariate logistic regression analysis found that concurrence of pre-existing CLD was an independent risk factor for both of chronicity and mortality (OR 3.966, 95% CI 1.501 to 10.477, p=0.005), especially the chronicity (OR 3.035, 95% CI 1.115 to 8.259, p=0.030)., Conclusions: Concurrence of pre-existing CLD could be an independent risk factor for worse prognosis, especially chronicity, in PMT-related HILI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Herb-induced liver injury (HILI) is a type of adverse drug reactions related to using Chinese medicine (CM) or herbal medicine (HM), and is now a growing segment of drug-induced liver injury (DILI) worldwide. Owing to the complicated compositions and miscellaneous risk factors associated with the clinical usage of CM or HM, it is more challenging to diagnose and manage HILI than DILI. In the present guideline issued by the China Association of Chinese Medicine (CACM), the authors present an evidence chain-based workflow with 9 structured judgment criteria for diagnosing HILI. The 3 diagnostic ending points-suspected diagnosis, clinical diagnosis, and confirmed diagnosis-could be reached according to the length of the evidence chain acquired in the structured diagnostic workflow. Either identifying the species of CM or HM or excluding adulterations and toxin contaminants was strongly recommended to improve the level of evidence for a clinical diagnosis of HILI. In addition, the authors report that the improper use of CM, which violates the general law of CM theory, is one of the most important factors that contributes to HILI and should be avoided. By contrast, based on syndrome differentiation, some CM can also be used to treat HILI if used in accordance with the general law of CM theory. Therefore, 9 recommendations are put forward in this guideline.

Multiple components of traditional Chinese medicine (TCM) formulae determine their treatment targets for multiple diseases as opposed to a particular disease. However, discovering the unexplored therapeutic potential of a TCM formula remains challenging and costly. Inspired by the drug repositioning methodology, we propose an integrated strategy to feasibly identify new therapeutic uses for a formula composed of six herbs, Liuweiwuling. First, we developed a comprehensive systems approach to enrich drug compound-liver disease networks to analyse the major predicted diseases of Liuweiwuling and discover its potential effect on liver failure. The underlying mechanisms were subsequently predicted to mainly attribute to a blockade of hepatocyte apoptosis via a synergistic combination of multiple effects. Next, a classical pharmacology experiment was designed to validate the effects of Liuweiwuling on different models of fulminant liver failure induced by D-galactosamine/lipopolysaccharide (GalN/LPS) or thioacetamide (TAA). The results indicated that pretreatment with Liuweiwuling restored liver function and reduced lethality induced by GalN/LPS or TAA in a dose-dependent manner, which was partially attributable to the abrogation of hepatocyte apoptosis by multiple synergistic effects. In summary, the integrated strategy discussed in this paper may provide a new approach for the more efficient discovery of new therapeutic uses for TCM formulae.

In recent years, the issues related to herb-induced liver injury (HILI) have received much concern. Its clinical diagnosis is much difficult than that of Western medicine-induced liver injury due to its complicated drug combination and multiple constituents. Moreover, it is also correlated with physiques, inheritance and basic diseases. China Association of Chinese Medicine has released the first standards for HILI diagnosis and treatment technology in 2016, namely Guidelines for clinical diagnosis of herb-induced liver injury (hereinafter referred to as the Guidelines). The diagnostic processes with different diagnostic results were explained in this paper to help clinicians, particularly liver specialists, in diagnosing liver diseases by applying the operation of the Guidelines., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Many infections and stress signals can rapidly activate the NLRP3 inflammasome to elicit robust inflammatory responses. This activation requires a priming step, which is thought to be mainly for upregulating NLRP3 transcription. However, recent studies report that the NLRP3 inflammasome can be activated independently of transcription, suggesting that the priming process has unknown essential regulatory steps. Here, we report that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event and is essential for NLRP3 inflammasome activation. We show that NLRP3 inflammasome activation is disrupted in NLRP3-S194A knockin mice. JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. Importantly, we demonstrate that blocking S194 phosphorylation prevents NLRP3 inflammasome activation in cryopyrin-associated periodic syndromes (CAPS). Thus, our study reveals a key priming molecular event that is a prerequisite for NLRP3 inflammasome activation. Inhibiting NLRP3 phosphorylation could be an effective treatment for NLRP3-related diseases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The root of Polygonum multiflorum Thunb (PM) has been used in China to treat a variety of diseases, such as constipation, early graying of the hair and hyperlipemia. Recent evidence shows that PM causes idiosyncratic drug-induced liver injury (IDILI) in humans. In this study, we investigated the molecular basis of PM-induced liver injury in a rat model of IDILI based on a non-hepatotoxic dose of LPS. SD rats were orally administered 3 potentially hepatotoxic compounds of PM: cis-stilbene glucoside (cis-SG, 50 mg/kg), trans-SG (50 mg/kg) or emodin (5 mg/kg), followed by injection of LPS (2.8 mg/kg, iv). Serum and liver histology were evaluated 7 h after LPS injection. Among the 3 compounds tested, cis-SG, but not emodin or trans-SG, induced severe liver injury in rats when combined with LPS. The levels of AST and ALT in plasma and inflammatory cytokines in both plasma and liver tissues were markedly elevated. The liver tissues showed increased injury, hepatocyte apoptosis, and macrophage infiltration, and decreased cell proliferation. Microarray analysis revealed a negative correlation between peroxisome proliferator-activated receptor-γ (PPAR-γ) and LPS/cis-SG-induced liver injury. Immunohistochemical staining and RT-PCR results further confirmed that cis-SG significantly inhibited activation of the PPAR-γ pathway in the liver tissues of LPS/cis-SG-treated rats. Pre-treatment with a PPAR-γ agonist pioglitazone (500 g/kg, ig) reversed LPS/cis-SG-induced liver injury, which was associated with inhibiting the nuclear factor kappa B (NF-κB) pathway. These data demonstrate that cis-stilbene glucoside induces immunological idiosyncratic hepatotoxicity through suppressing PPAR-γ in a rat model of IDILI.

Sophocarpine is the major pharmacologically active compound of the traditional Chinese herbal medicine Radix Sophorae Subprostratae which has been used in treating hepatitis for years in China. It has been demonstrated that Sophocarpine exerts an activity in immune modulation and significantly decreases the production of inflammatory cytokines. However, the protective effects of Sophocarpine in T cell-dependent immune hepatitis remained unknown. The aim of this study was to determine the protective effects and pharmacological mechanisms of Sophocarpine on Concanavalin A (ConA)-induced hepatitis, an experimental model of T cell-mediated liver injury. BALB/C mice were pretreated with Sophocarpine or Bicyclol for five consecutive days. Thirty minutes after the final administration, the mice were injected with 15 mg⋅kg -1 of ConA intravenously. The results indicated that pretreatment with Sophocarpine significantly ameliorated liver inflammation and injury as evidenced by both biochemical and histopathological observations. Moreover, in Sophocarpine-pretreated mice, liver messenger RNA expression levels of chemokines and adhesion molecules, such as macrophage inflammatory protein-1α, CXC chemokine ligand 10, and Intercellular adhesion molecule-1, were markedly reduced. Further studies revealed that Sophocarpine significantly downregulated the expression of T-bet via inhibition of signal transducers and activators of transcription1 (STAT1) activation and overexpression of suppressor of cytokine signaling1, inhibiting the activation of Th1 cells and the expression of Interferon-γ (IFN-γ). Altogether, these results suggest new opportunities to use Sophocarpine in the treatment of T cell-mediated liver disease. In summary, Sophocarpine could attenuate ConA-induced liver injury, and the protective effect of Sophocarpine was associated with its inhibition effect of pro-inflammatory cytokines, chemokines, and the IFN- γ /STAT1 signaling pathway.

This study was conducted to investigate the inhibitory effect and the molecular mechanism of deoxyschizandrin on the activity of NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome. Bone marrow-derived macrophages were used to study the effects of deoxyschizandrin on inflammasome activation using inflammasome inducers (ATP and nigericin). Cytotoxic effect was evaluated with CCK-8. The expression of IL-1β, caspase-1 in the supernatant and the expression of pro-caspase-1, pro-IL-1β, ASC, NLRP3 in cell was detected by Western blot for the inhibitory effect of deoxyschizandrin (25, 50, 100 and 200 μmol·L(−1)) on the activity of NLRP3 inflammasome. Immunofluorescence was applied to investigate NF-κB (p65) transportation to the nucleus. The results of CCK-8 showed that the optimum concentration of deoxyschizandrin was 6.25–400 μmol·L(−1). Deoxyschizandrin (25, 50, 100, and 200 μmol·L(−1)) could inhibit the activation of NLRP3 inflammasome caused by nigericin and ATP, and inhibit the secretion of IL-1β, which was associated with inhibiting the cleavage of pro-caspase-1. The results of immunofluorescence and Western blot also suggest that the inhibitory activity of deoxyschizandrin on NLRP3 inflammasome was not dependent on NF-κB pathway and protein expression of NLRP3, ASC, pro-caspase-1 and pro-IL-1β mediated by NF-κB. Our results confirmed that deoxyschizandrin could suppress the cleavage of pro-caspase-1 and inhibit the activity of NLRP3 inflammasome at 25–200 μmol·L−1 to reduce the inflammation response.This study was conducted to investigate the inhibitory effect and the molecular mechanism of deoxyschizandrin on the activity of NLRP3 (NOD-like receptor family,pyrin domain containing 3) inflammasome.Bone marrow-derived macrophages were used to study the effects of deoxyschizandrin on inflammasome activation using inflammasome inducers (ATP and nigericin). Cytotoxic effect was evaluated with CCK-8.The expression of IL-1β,caspase-1 in the supernatant and the expression of pro-caspase-1,pro-IL-1β,ASC,NLRP3 in cell was detected by Western blot for the inhibitory effect of deoxyschizandrin (25, 50, 100 and 200 μmol·L(-1)) on the activity of NLRP3 inflammasome. Immunofluorescence was applied to investigate NF-κB (p65) transportation to the nucleus. The results of CCK-8 showed that the optimum concentration of deoxyschizandrin was 6.25-400 μmol·L(-1). Deoxyschizandrin (25, 50, 100,and 200 μmol·L(-1)) could inhibit the activation of NLRP3 inflammasome caused by nigericin and ATP, and inhibit the secretion of IL-1β, which was associated with inhibiting the cleavage of pro-caspase-1.The results of immunofluorescence and Western blot also suggest that the inhibitory activity of deoxyschizandrin on NLRP3 inflammasome was not dependent on NF-κB pathway and protein expression of NLRP3,ASC,pro-caspase-1 and pro-IL-1βmediated by NF-κB. Our results confirmed that deoxyschizandrin could suppress the cleavage of pro-caspase-1 and inhibit the activity of NLRP3 inflammasome at 25-200 μmol·L(-1) to reduce the inflammation response.

Drug toxicity is commonly divided into intrinsic and idiosyncratic types. The former can be generally uncovered in the preclinical safety evaluation stage by conventional toxicological experiments, while the latter is usually found only in the clinical evaluation stage, which is the main cause of severe adverse reactions and withdrawal of post-marketing drugs. Assessment and prediction of idiosyncratic toxicity is a challenging problem worldwide, and is an essential in the development of translational toxicology and precision medicine. Since traditional Chinese medicines (TCMs) have been applied for thousands of years with long experience in clinical efficacy and safety, idiosyncratic toxicity is regarded as an important factor for traditional "non-toxic" medicines and is associated with multiple individual states including different diseases, syndromes, habitus, etc. However, these individual conditions related to disease are often difficult to be resolved in conventional toxicological experiments, leading to insufficient translation of the experimental results into clinical application. We took an approach of systematic analysis of the differences and similarities in toxic property, medication rule and evaluating requirement between TCMs and chemical synthetic medicines. We present a novel and clinic-associated safety assessment strategy, namely as "disease-syndrome-based toxicology", for TCMs. The strategy is able to access the relativity, susceptibility and controllability of the toxicity of TCMs. The new strategy provides a theoretical and methodological guidance to practice and development of the TCM in favor of precision medicine.

This paper was aimed to investigate the protective effects of luteolin (Lut) against acetaminophen（APAP）-induced damage in L02 liver cells. CCK-8 was used to detect the cell activation of L02 cells treated by different Lut. The concentration and time of APAP induced L02 cell damage was screened. The effect of Lut on APAP induced apoptosis of L02 cells was detected by cell morphological observation, CCK-8 assay and flow cytometry. The contents of MDA, GSH and SOD activity in cell supernatant were detected by colorimetric assay. The expression of apoptosis-related genes Bax, Bcl-2 and caspase-3 was detected by RT-PCR. The results showed that Lut in 2.5-40 μmol•L⁻¹ range does not affect the activity of L02 cells; 12 mmol•L⁻¹ APAP incubated with L02 cell 12 h to establish damage model. Compared with the model group, the cell status of Lut group was significantly improved, the cell body was increased, the adherence ability was recovered, and the apoptosis rate was obviously decreased. MDA content decreased significantly (P<0.05, P<0.01), GSH and SOD activity significantly increased (P<0.05, P<0.01), at the same time, it could up-regulate expression of Bcl-2 mRNA and down-regulate the expression of Bax and caspase-3 mRNA. In conclusion,Lut has protective effect on APAP induced L02 cell injury, and its mechanism may be related to the reduction of oxidative stress and inhibition of apoptosis., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)