Inhibition of hepatitis B virus via selective apoptosis modulation by Chinese patent medicine Liuweiwuling Tablet.

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.

The combination of Schisandrin C and Luteolin synergistically attenuates hepatitis B virus infection via repressing HBV replication and promoting cGAS-STING pathway activation in macrophages.

BACKGROUND: HBV infection can result in severe liver diseases and is one of the primary causes of liver cell carcinoma-related mortality. Liuwei Wuling tablet (LWWL) is a traditional Chinese medicine formula, with a protecting liver and decreasing enzyme activity, usually used to treat chronic hepatitis B with NAs in clinic. However, its main active ingredients and mechanism of action have not been fully investigated. Hence, we aimed to screen the active ingredient and effective ingredient combinations from Liuwei Wuling tablet to explore the anti-herpatitis B virus activity and mechanism. METHODS: Analysis and screening of effective antiviral components in LWWL by network pharmacology, luteolin (Lut) may be a compound with significant antiviral activity. The mechanism of antiviral action of Lut was also found by real-time PCR detection and western blotting. Meanwhile, we established a co-culture model to investigate the antiviral mechanism of Schisandrin C (SC), one of the main active components of Schisandra chinensis fructus (the sovereign drug of LWWL). Next, HBV-infected mice were established by tail vein injection of pAAV-HBV1.2 plasmid and administered continuously for 20 days. And their antiviral capacity was evaluated by checking serum levels of HBsAg, HBeAg, levels of HBV DNA, and liver levels of HBcAg. RESULTS: In this study, we conducted network pharmacology analysis on LWWL, and through in vitro experimental validation and data analysis, we found that luteolin (Lut) possessed obviously anti-HBV activity, inhibiting HBV replication by downregulating hepatocyte nuclear factor 4α (HNF4α) via the ERK pathway. Additionally, we established a co-culture system and proved that SC promoted activation of cGAS-STINIG pathway and IFN-ß production in THP-1 cells to inhibit HBV replication in HepG2.2.15 cells. Moreover, we found the combination of SC and Lut shows a greater effect in inhibiting HBV compared to SC or Lut alone in HBV-infected mice. CONCLUSION: Taken together, our study suggests that combination of SC and Lut may be potential candidate drug for the prevention and treatment of chronic hepatitis B.

A multi-omics study reveals the therapeutic effect of Linderae Radix water extract on irritable bowel syndrome (IBS-D).

ETHNOPHARMACOLOGICAL RELEVANCE: Linderae Radix (Lindera aggregata (Sims) Kosterm) is a traditional Chinese medicine known for its capability to regulate qi and relieve pain, particularly in the context of gastrointestinal disorders. AIM OF THE STUDY: While our previous research has demonstrated the efficacy of the Linderae Radix water extract (LRWE) in the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), the precise mechanisms remain elusive. This study aims to provide a comprehensive understanding of the therapeutic effects of LRWE on IBS-D through multi-omics techniques. MATERIALS AND METHODS: 16 S rRNA gene sequencing combined with LC-MS metabolomics was employed to investigate the effect of LRWE on the gut microbiota and metabolites of IBS-D rats. Spearman correlation analysis was performed on the gut microbiota and metabolites. RESULTS: LRWE administration significantly ameliorated IBS-D rats' symptoms, including diarrhea, visceral hypersensitivity, and low-grade intestinal inflammation. Gut microbiota analysis revealed that LRWE influenced the diversity of the gut microbiota in IBS-D rats by significantly reducing the relative abundance of Patescibacteria and Candidatus Saccharimonas, while increasing the relative abundance of Jeotgalicoccus. Serum metabolomic analysis identified 16 differential metabolites, associated with LRWE's positive effects on IBS-D symptoms, focusing on glyoxylate and dicarboxylic acid metabolism, and cysteine and methionine metabolism. Spearman analysis demonstrated a strong correlation between cecal microbiota composition and serum metabolite levels. CONCLUSIONS: This study elucidates that LRWE plays a crucial role in the comprehensive therapeutic approach to IBS-D by restoring the relative abundance of gut microbiota and addressing the disturbed metabolism of endogenous biomarkers. The identified bacteria and metabolites present potential therapeutic targets for IBS-D.

Marine-Derived Bisindoles for Potent Selective Cancer Drug Discovery and Development.

Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics.

Flavonoid extracted from Epimedium attenuate cGAS-STING-mediated diseases by targeting the formation of functional STING signalosome.

Hyperactivation of the cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway has been shown to be associated with the development of a variety of inflammatory diseases, and the discovery of an inhibitor of the cGAS-STING signalling pathway holds great promise in the therapeutic interventions. Epimedium flavonoid (EF), a major active ingredient isolated from the medicinal plant Epimedium, has been reported to have good anti-inflammatory activity, but its exact mechanism of action remains unclear. In the present study, we found that EF in mouse bone marrow-derived macrophages (BMDMs), THP-1 (Tohoku Hospital Pediatrics-1) as well as in human peripheral blood mononuclear cells (hPBMC) inhibited the activation of the cGAS-STING signalling pathway, which subsequently led to a decrease in the expression of type I interferon (IFN-ß, CXCL10 and ISG15) and pro-inflammatory cytokines (IL-6 and TNF-α). Mechanistically, EF does not affect STING oligomerization, but inhibits the formation of functional STING signalosome by attenuating the interaction of interferon regulatory factor 3 (IRF3) with STING and TANK-binding kinase 1 (TBK1). Importantly, in vivo experiments, EF has shown promising therapeutic effects on inflammatory diseases mediated by the cGAS-STING pathway, which include the agonist model induced by DMXAA stimulation, the autoimmune inflammatory disease model induced by three prime repair exonuclease 1 (Trex1) deficiency, and the non-alcoholic steatohepatitis (NASH) model induced by a pathogenic amino acid and choline deficiency diet (MCD). To summarize, our study suggests that EF is a potent potential inhibitor component of the cGAS-STING signalling pathway for the treatment of inflammatory diseases mediated by the cGAS-STING signalling pathway.

Therapeutic potential of the medicinal mushroom Ganoderma lucidum against Alzheimer's disease.

Alzheimer's disease (AD) is a high-incidence neurodegenerative disorder, characterized by cognitive impairment, memory loss, and psychiatric abnormalities. Ganoderma lucidum is a famous medicinal fungus with a long history of dietary intake, containing various bioactive components, and have been documented to exhibit antioxidant, anti-inflammatory, anti-tumor, anti-aging, and immunomodulatory effects, among others. Recent studies have shown that G. lucidum and its components have promising therapeutic potential against AD from various aspects, which can delay the progression of AD, improve cognitive function and quality of life. The underlying mechanisms mainly include inhibiting tau hyperphosphorylation, inhibiting Aß formation, affecting activated microglia, regulating NF-κB/MAPK signalling pathway, inhibiting neuronal apoptosis, modulating immune system, and inhibiting acetylcholinesterase, etc. This paper systematically reviewed the relevant studies on the therapeutic potential of G. lucidum and its active components for treatment of AD, key points related with the mechanism studies and clinical trials have been discussed, and further perspectives have been proposed. Totally, as a natural medicinal mushroom, G. lucidum has the potential to be developed as effective adjuvant for AD treatment owing to its therapeutic efficacy against multiple pathogenesis of AD. Further mechanical investigation and clinical trials can help unlock the complete potential of G. lucidum as a therapeutic option for AD.

[Pseudo-targeted metabolomics study of immune stress-mediated idiosyncratic liver injury induced by synergistic effects of bavachin and epimedin B].

Chinese patent medicine preparations containing Epimedii Folium and Psoraleae Fructus have been associated with the occurrence of idiosyncratic drug-induced liver injury(IDILI). However, the specific toxic biomarkers and mechanisms underlying these effects remain unclear. This study aimed to comprehensively assess the impact of bavachin and epimedin B, two principal consti-tuents found in Psoraleae Fructus and Epimedii Folium, on an IDILI model induced by tumor necrosis factor-α(TNF-α) treatment, both in vitro and in vivo. To evaluate the extent of liver injury, various parameters were assessed. Lactate dehydrogenase(LDH) release in the cell culture supernatant, as well as the levels of alanine aminotransferase(ALT) and aspartate transaminase(AST) in mouse plasma were measured. Additionally, histological analysis employing hematoxylin-eosin staining was performed to observe liver tissue changes indicative of the severity of liver injury. Furthermore, a pseudo-targeted metabolomics approach was employed, followed by multivariate analysis, to identify differential metabolites. These identified metabolites were subsequently subjected to Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis. The results showed that at the cellular level, after 2 hours of TNF-α stimulation, bavachin significantly increased the release of LDH in HepG2 cells compared to the normal group and the group treated alone; after the combination of bavachin and epimedin B, the release of LDH further significantly increased on the original basis. Similarly, although the individual or combination treatments of bavachin and epimedin B did not induce liver injury in normal mice, the combination of both drugs induced marked liver injury in TNF-α treated mice, leading to a significant elevation in plasma AST and ALT levels and substantial infiltration of inflammatory immune cells in the liver tissue. Pseudo-targeted metabolomics analysis identified seven common differential metabolites. Among these, D-glucosamine-6-phosphate, N1-methyl-2-pyridone-5-carboxamide, 17beta-nitro-5a-androstane, irisolidone-7-O-glucuronide, and N-(1-deoxy-1-fructosyl) valine emerged as potential biomarkers, with an area under the curve(AUC) exceeding 0.9. Furthermore, our results suggest that the metabolism of nicotinic acid and nicotinamide, as well as the linoleic acid metabolic pathway, may play pivotal roles in bavachin and epimedin B-induced IDILI. In conclusion, within an immune-stressed environment mediated by TNF-α, bavachin and epimedin B appear to induce IDILI through disruptions in metabolic processes.

LicochalconeB inhibits cGAS-STING signaling pathway and prevents autoimmunity diseases.

Cytosolic DNA activates the STING (stimulator of interferon genes) signaling pathway to trigger interferon and inflammatory responses that protect against microbial infections and cancer. However, Aicardi-Goutières syndrome (AGS) persistently activates the STING signaling pathway, which can lead to severe autoimmune diseases. We demonstrate herein that Licochalcone B (LicoB), the main component of traditional licorice, is an inhibitor of the STING signaling pathway. We observed that LicoB inhibited the activation of the STING signaling pathway in macrophages. Mechanically, LicoB affected the STING-TBK1-IRF3 signal axis and inhibited the activation of the STING downstream signaling pathway. Furthermore, LicoB inhibited the increase in type I interferon levels in mice induced by the STING agonist CMA. LicoB significantly reduced systemic inflammation in Trex1-/- mice. Our results show that LicoB, a STING signaling pathway inhibitor, is a promising candidate for the treatment of diseases related to STING signaling pathway activation.

Liuweiwuling Tablet relieves the inflammatory transformation of hepatocellular carcinoma by inhibiting the PI3K/AKT/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Liuweiwuling Tablet (LWWL) is a patented Chinese medicine approved by the Chinese National Medical Products Administration (NMPA). Clinically, it is used to treat a range of liver diseases that precede hepatocellular carcinoma (HCC), including hepatitis, liver fibrosis and cirrhosis. LWWL is hypothesized to inhibit the inflammatory transformation of HCC, which may have a positive impact on the prevention and treatment of HCC. However, its exact mechanism of action remains unknown. AIM OF THE STUDY: To investigate how LWWL is effective in the treatment of HCC and to validate the pathways involved in this process. MATERIALS AND METHODS: An in vivo model of HCC induced by diethylnitrosamine (DEN) was established to study the effect of LWWL on the development of HCC. The rat serum was analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (γ-GT). The rat liver tissues were stained with hematoxylin and eosin (HE) and Masson's trichrome for pathological analysis. Rat liver tissue was subjected to transcriptome sequencing. Expression of inflammatory and liver fibrosis-related factors in bone marrow-derived macrophages (BMDMs) and LX-2 cells was detected by QRT-PCR, ELISA and Western blot (WB). The expression of apoptosis and stemness genes in HepG2 and Huh7 cells was assessed through flow cytometry and QRT-PCR. Transcriptomics, network pharmacology, WB, and QRT-PCR were employed to validate the mechanisms associated with the amelioration of HCC development by LWWL. RESULTS: LWWL significantly reduced the severity of hepatitis and liver fibrosis, the expression of tumor stemness genes, and the incidence of HCC. In addition, LWWL inhibited the release of inflammatory substances and nuclear accumulation of P65 protein in BMDMs as well as the conversion of LX-2 cells to fibroblasts. LWWL inhibited the proliferation of HepG2 and Huh7 cells, including the initiation of apoptosis and the reduction of stemness gene expression. Importantly, LWWL regulates the PI3K/AKT/NF-κB pathway, which affects hepatic inflammation and cancer progression. CONCLUSION: LWWL inhibited the occurrence and development of HCC by modulating the severity of hepatitis and liver fibrosis, indicating the potential clinical relevance of LWWL in preventing and treating HCC.

No Incidence of Liver Cancer Was Observed in A Retrospective Study of Patients with Aristolochic Acid Nephropathy.

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.

Icariside I reduces breast cancer proliferation, apoptosis, invasion, and metastasis probably through inhibiting IL-6/STAT3 signaling pathway.

OBJECTIVES: Breast cancer is a common malignancy in women. More than 90% of breast cancer deaths are caused by metastasis. Epimedii Folium (EF) is a commonly used herb with anti-tumor benefits, but its underlying mechanisms and active components for breast cancer prevention are little understood. This study assessed the therapeutic role of Icariside I (ICS I) in Epimedium flavonoids (EF) on lung metastasis of breast cancer, including the underlying mechanism. METHODS: Western blot, RT-qPCR, wound healing assay, colony formation assay, and flow cytometry were used to investigate the inhibition of breast cancer cells growth and migration by EF and ICS I through disrupting the IL-6/STAT3 pathway. Combined with 4T1 breast cancer model in mice, Western blot, RT-qPCR, Hematoxylin and Eosin staining, immunohistochemistry were used to evaluate the therapeutic role of ICS I in proliferation, apoptosis, invasion, and metastasis of breast cancer. KEY FINDINGS: EF can inhibit STAT3 phosphorylation and reduce the colony formation and migration of breast cancer cells. Detecting the active ingredients in EF, we found ICS I can reduce the activation of STAT3 in 4T1 breast cancer cells, impair colony formation and migration. Moreover, ICS I induced cells G1 phase arrest and modulated Cyclin D1, CDK4, bcl-2, and bax to inhibit proliferation and survival of breast cancer cells. Similarly, the in vivo studies demonstrated that ICS I significantly suppressed tumor development and lung metastasis in the 4T1 mouse model. Tumor cells in vehicle group were arranged in a spoke-like pattern with obvious heterogeneity, and multinucleated tumor giant cells were seen. But, the tumor cells in the ICS I group were disorganized and necrotic lysis was seen in some areas. In ICS I-treated group, tumors' STAT3 phosphorylation level, IL-6, Cyclin D1, CDK4, bcl-2, and vimentin expression were downregulated, bax and cleaved caspase 3 expression were upregulated. In the lung tissue, we could find less metastasis of breast cancer cells and less lung injury in the ICS I group. Besides, the expression of metastasis-related genes MMP9 and vimentin was decreased in the lung tissue of ICS I group. CONCLUSIONS: These findings suggest that ICS I can inhibit breast cancer proliferation, apoptosis, invasion and metastasis probably via targeting IL-6/STAT3 pathway. Therefore, ICS I has the potential to become an innovative therapeutic candidate to breast cancer prevention and treatment.

Insights on Antitumor Activity and Mechanism of Natural Benzophenanthridine Alkaloids.

Benzophenanthridine alkaloids are a class of isoquinoline compounds, which are widely found in the plants of papaveraceae, corydalis, and rutaceae. Biological activities and clinical studies have shown that benzophenanthridine alkaloids have inhibitory effects on many cancers. Considering that the anticancer activities and mechanisms of many natural benzophenanthridine alkaloids have been discovered in succession, the purpose of this paper is to review the anticancer effects of benzophenanthridine alkaloids and explore the application potential of these natural products in the development of antitumor drugs. A literature survey was carried out using Scopus, Pubmed, Reaxys, and Google Scholar databases. This review summarizes and analyzes the current status of research on the antitumor activity and antitumor mechanism of natural products of benzophenanthridine from different sources. The research progress of the antitumor activity of natural products of benzophenanthridine from 1983 to 2023 was reviewed. The antitumor activities of 90 natural products of benzophenanthridine and their related analogues were summarized, and the results directly or indirectly showed that natural products of benzophenanthridine had the effects of antidrug-resistant tumor cell lines, antitumor stem cells, and inducing ferroptosis. In conclusion, benzophenanthridine alkaloids have inhibitory effects on a variety of cancers and have the potential to counteract tumor resistance, and they have great application potential in the development of antitumor drugs.

Yin/Yang associated differential responses to Psoralea corylifolia Linn. In rat models: an integrated metabolomics and transcriptomics study.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoralea corylifolia Linn. (BGZ) is a commonly used traditional Chinese medicine (TCM) for the treatment of kidney-yang deficiency syndrome (Yangsyn) 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 (Yinsyn), 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 Yangsyn and Yinsyn rat models and identify the corresponding characteristic biomarkers. MATERIALS AND METHODS: The corresponding animal models of Yangsyn and Yinsyn 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 Yangsyn and Yinsyn. Transcriptomics and metabonomics were used to screen the representative biomarkers (including metabolites and differentially expressed genes (DEGs)) changed by BGZ in Yangsyn and Yinsyn 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 Yangsyn and Yinsyn 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 Yangsyn, 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 Yinsyn. 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 Yangsyn group and 1 DEG [galectin 5 (Lgals5)] and 1 metabolite (5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate) in Yinsyn group were significantly correlated to the ALT and AST levels of BGZ treated and untreated groups (receiver operating characteristic (ROC) ≥ 0.9). CONCLUSIONS: Yinsyn and Yangsyn 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 Yinsyn/Yangsyn animal models based on the theory of TCM syndromes may be a feasible method for identifying the susceptible population to receive TCM.

Schisandrin C enhances cGAS-STING pathway activation and inhibits HBV replication.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra Chinensis (Turcz.) Baill. is a long-term used traditional Chinese medicine with the functions of tonifying the kidney and calming the heart, tonifying qi and engendering fluid. It can be used to treat insomnia and dreaminess, spermatorrhea, coughs, as well as liver and kidney deficiency of Yin or Yang Syndrome. Modern pharmacological studies have shown that Schisandra Chinensis regulates host immunity and exhibits anti-cancer, antiviral and liver-protecting effects. However, the specific mechanism by which Schisandra Chinensis modulates antiviral immunity is unknown. AIM OF THE STUDY: We sought to explore the therapeutic effect of the active components of Schisandra Chinensis on anti-viral immunity and further investigate the underlying mechanism. MATERIALS AND METHODS: Immunoblotting, quantitative real-time PCR, enzyme-linked immunosorbent assay, immunofluorescence, and immunoprecipitation were used to investigate the effect of schisandrin C (SC), one of the most abundant and biologically active components of Schisandra Chinensis, on the activation of cGAS-STING signaling pathway and the underlying mechanism. In addition, CMA-mediated STING activation and hydrodynamic injection-mediated HBV-replicating mouse model were used to investigate the effect of SC on the activation of STING signaling pathway and its antiviral effect in vivo. RESULTS: SC promoted cGAS-STING pathway activation, accompanied by increased production of interferon ß (IFN ß) and downstream gene expression. Moreover, SC also exerted anti-HBV effects, reducing HBeAg, HBcAg, HBsAg, and HBV DNA levels in hydrodynamic injection-mediated HBV-replicating mouse model and elevating the production of IFN ß and expression of interferon-stimulated genes (IFIT1, ISG15, and CXCL10). Mechanistically, SC could facilitate the interaction between TANK-binding kinase 1 (TBK1) and STING, which is important for IRF3 phosphorylation and production of IFN ß. CONCLUSIONS: Our study confirmed that SC enhances cGAS-STING pathway activation and inhibits HBV replication, as well as provides clues for chronic hepatitis B and other infectious diseases treated by SC.

Flavonoids derived from licorice suppress LPS-induced acute lung injury in mice by inhibiting the cGAS-STING signaling pathway.

In recent years, we have found that the dysregulation of the cyclic-GMP-AMP synthase (cGAS)‒stimulator of interferon genes (STING) pathway leads to the development of immune and inflammatory diseases, therefore, finding compounds that can specifically regulate this pathway is essential for effective regulation of the immune pathway for addressing inflammatory diseases. Licorice flavonoids (LFs), are active ingredients extracted from the Chinese herb licorice, which has been reported to have strong anti-inflammatory activity in previous studies. Here, we report that LFs inhibit the activation of the cGAS-STING pathway evidenced by the inhibition of the expression of type I interferons and related downstream genes such as interferon-stimulated gene 15 (ISG15) and C-X-C motif chemokine ligand 10 (CXCL10), as well as inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Notably, LFs markedly improve the LPS-induced acute lung injury by inhibiting the excessive activation of cGAS-STING signaling pathway. Mechanistically, LFs treatment leads to the blocking of 2'3'-cyclic GMP-AMP (cGAMP) synthesis resulting in an inhibition of the activation of the cGAS-STING pathway. Our results indicate that LFs is a specific inhibitor of the cGAS-STING pathway, which is suggested to be a potential candidate for the treatment of cGAS-STING pathway-mediated inflammatory diseases.

Landscape of DILI-related adverse drug reaction in China Mainland.

Drug-induced liver injury (DILI) is a type of bizarre adverse drug reaction (ADR) damaging liver (L-ADR) which may lead to substantial hospitalizations and mortality. Due to the general low incidence, detection of L-ADR remains an unsolved public health challenge. Therefore, we used the data of 6.673 million of ADR reports from January 1st, 2012 to December 31st, 2016 in China National ADR Monitoring System to establish a new database of L-ADR reports for future investigation. Results showed that totally 114,357 ADR reports were retrieved by keywords searching of liver-related injuries from the original heterogeneous system. By cleaning and standardizing the data fields by the dictionary of synonyms and English translation, we resulted 94,593 ADR records reported to liver injury and then created a new database ready for computer mining. The reporting status of L-ADR showed a persistent 1.62-fold change over the past five years. The national population-adjusted reporting numbers of L-ADR manifested an upward trend with age increasing and more evident in men. The annual reporting rate of L-ADR in age group over 80 years old strikingly exceeded the annual DILI incidence rate in general population, despite known underreporting situation in spontaneous ADR reporting system. The percentage of herbal and traditional medicines (H/TM) L-ADR reports in the whole number was 4.5%, while 80.60% of the H/TM reports were new findings. There was great geographical disparity of reported agents, i.e. more cardiovascular and antineoplastic agents were reported in higher socio-demographic index (SDI) regions and more antimicrobials, especially antitubercular agents, were reported in lower SDI regions. In conclusion, this study presented a large-scale, unbiased, unified, and computer-minable L-ADR database for further investigation. Age-, sex- and SDI-related risks of L-ADR incidence warrant to emphasize the precise pharmacovigilance policies within China or other regions in the world.

[Preventive and therapeutic effect of bioactive component of licorice on antidepressant-induced liver injury].

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)-1ß 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.

[Schisandrin C improves acetaminophen-induced liver injury in mice by regulating Nrf2 signaling pathway].

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.

Asari Radix et Rhizoma consumption lacks relevance for hepatocellular carcinoma in patients: A retrospective cohort study.

Objective: Although some studies have linked Asari Radix et Rhizoma (Asari Radix) administration to hepatocellular carcinoma (HCC), few studies have examined the association between the development of HCC and use of Asari Radix among patients in mainland China. This study aimed to evaluate the real-world association between Asari Radix and HCC in patients to strengthen the understanding of Asari Radix safety. Methods: A retrospective cohort study among hepatitis B virus (HBV)-monoinfected patients and non-HBV-monoinfected patients were performed. Patients over 18 years of age were eligible for inclusion. Prescription records of inpatients and outpatients were inquired to distinguish Asari Radix users and nonusers. The risk of developing HCC among Asari Radix users and nonusers in the HBV cohort and the non-HBV cohort was analyzed. Results: There were 49 500 HBV and 133 148 non-HBV patients involved in the two cohorts. Among HBV patients (2 901 users; 46 599 nonusers), the prevalence of HCC in Asari Radix users was lower than that in nonusers (145.70 vs. 265.43 per 105). Among non-HBV patients (5 042 users; 128 106 nonusers), the prevalence of HCC in Asari Radix users was lower than that in nonusers (81.62 vs. 134.11 per 105). None of the hazard ratios (HRs) of Asari Radix exposure ranging from 1 g to 200 g in the two cohorts showed correlation between Asari Radix exposure and hepatocarcinogenesis. Conclusion: An obvious irrelevancy was found between the consumption of Asari Radix and HCC development both in patients with and in those without HBV infection. Use of Asari Radix under 200 g appears safe in terms of HCC risk in the Chinese population; further prospective studies are needed to confirm our results.

Tetrahydroxy stilbene glucoside alters neurogenesis and neuroinflammation to ameliorate radiation-associated cognitive disability via AMPK/Tet2.

Along with the extensive application of radiation in medical, military and other fields, human beings carry a greater risk of exposure to radiation environment that causes a range of physical injure, particularly to the brain in cognition. However, the radiation-associated cognitive disability is poorly understood and there is no effective prevention or long-term treatment. Here, we demonstrate that neurogenesis and neuroinflammation disorder are primarily involved in the pathophysiological basis of irradiation-induced cognitive decline. Furthermore, we discovered that tetrahydroxy stilbene glucoside (TSG), a natural active ingredient from Heshouwu that has been well known for its unique anti-aging effect as the Chinese herb, can be a promising mitigator to improve learning-memory ability by facilitating the neurogenesis in the proliferation and differentiation of the surviving neural progenitor cells via AMPK/Tet2, and attenuating the neuroinflammation in the microglial NLRP3 inflammasomes activation via AMPK in vivo. Additionally, TSG was also revealed to activate AMPK by molecular docking and kinase enzyme system assay in vitro. Taken together, our findings identify TSG, as the AMPK activator, prevents radiation-induced cognitive dysfunction by regulating neurogenesis and neuroinflammation via AMPK/Tet2 in rodents, and represents a very promising candidate for developing drugs that can be used for radiation-associated brain injury.