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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‐β, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-β 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The cGAS-STING signaling pathway is an essential section of the natural immune system. In recent years, an increasing number of studies have shown a strong link between abnormal activation of the cGAS-STING signaling pathway, a natural immune pathway mediated by the nucleic acid receptor cGAS, and the development and progression of autoimmune diseases. Therefore, it is important to identify an effective compound to specifically downregulate this pathway for disease. Methods: The effect of Glabridin (Glab) was investigated in BMDMs and Peripheral blood mononuclear cell (PBMC) by establishing an in vitro model of cGAS-STING signaling pathway activation. An activation model stimulated by DMXAA was also established in mice to study the effect of Glab. On the other hand, we investigated the possible mechanism of action of Glab and the effect of Glab on Trex1-deficient mice. Results: In this research, we report that Glab, a major component of licorice, specifically inhibits the cGAS-STING signaling pathway by inhibiting the level of type I interferon and inflammatory cytokines (IL-6 and TNF-α). In addition, Glab has a therapeutic effect on innate immune diseases caused by abnormal cytoplasmic DNA in Trex1-deficient mice. Mechanistically, Glab can specifically inhibit the interaction of STING with IRF3. Conclusion: Glab is a specific inhibitor of the cGAS-STING signaling pathway and may be used in the clinical therapy of cGAS-STING pathway-mediated autoimmune diseases. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B (CHB) remains a major world's most serious public health issues. Despite the remarkable effect of nucleos(t)ide analogues (NAs) in inhibiting hepatitis B virus (HBV) deoxyribonucleic acid (DNA) as the first-line drug, there are several limitations still, such as poor antigen inhibition, drug resistance, low-level viremia, restricting patients' functional cure. Due to the constraints of NAs, traditional medicines, such as traditional Chinese medicine (TCM), have become more prevalently used and researched in the clinical treatment of CHB as complementary alternative therapies. As a consequence, the review focuses on the background based on HBV's life cycle as well as the NAs' limitations, progress based on direct and indirect pathway of targeting HBV of TCM, and challenges of TCM. We found TCMs play an increasingly important role in anti-HBV. In a direct antiviral way, they regulate HBV infection, replication, assembly, and other aspects of the HBV life cycle. As for indirect way, TCMs can exert anti-HBV effects through targeting the host, including immune regulation, apoptosis, autophagy, oxidative stress, etc. Especially, TCMs have the advantages of strong antigenic inhibition compared to NAs. Specifically, we can combine the benefits of TCMs in strong HBV antigen inhibition with the benefits of NAs in targeted antiviral effects, in order to find a suitable combination of "TCM + NAs" to contribute to Chinese knowledge of the realisation of the "global elimination of HBV by 2030" goal of the World Health Organization. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic steatohepatitis (NASH) is a progressive and inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatocellular injury, inflammation, and fibrosis in various stages. More than 20% of patients with NASH will progress to cirrhosis. Currently, there is a lack of clinically effective drugs for treating NASH, as improving liver histology in NASH is difficult to achieve and maintain through weight loss alone. Hence, the present study aimed to investigate potential therapeutic drugs for NASH. Methods: BMDMs and THP1 cells were used to construct an inflammasome activation model, and then we evaluated the effect of epalrestat on the NLRP3 inflammasome activation. Western blot, real-time qPCR, flow cytometry, and ELISA were used to evaluate the mechanism of epalrestat on NLRP3 inflammasome activation. Next, MCD-induced NASH models were used to evaluate the therapeutic effects of epalrestat in vivo. In addition, to evaluate the safety of epalrestat in vivo, mice were gavaged with epalrestat daily for 14 days. Results: Epalrestat, a clinically effective and safe drug, inhibits NLRP3 inflammasome activation by acting upstream of caspase-1 and inducing ASC oligomerization. Importantly, epalrestat exerts its inhibitory effect on NLRP3 inflammasome activation by inhibiting the activation of aldose reductase. Further investigation revealed that the administration of epalrestat inhibited NLRP3 inflammasome activation in vivo, alleviating liver inflammation and improving NASH pathology. Conclusions: Our study indicated that epalrestat, an aldose reductase inhibitor, effectively suppressed NLRP3 inflammasome activation in vivo and in vitro and might be a new therapeutic approach for NASH. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic steatohepatitis (NASH) is a progressive and inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatocellular injury, inflammation, and fibrosis in various stages. More than 20% of patients with NASH will progress to cirrhosis. Currently, there is a lack of clinically effective drugs for treating NASH, as improving liver histology in NASH is difficult to achieve and maintain through weight loss alone. Hence, the present study aimed to investigate potential therapeutic drugs for NASH. Methods: BMDMs and THP1 cells were used to construct an inflammasome activation model, and then we evaluated the effect of epalrestat on the NLRP3 inflammasome activation. Western blot, real-time qPCR, flow cytometry, and ELISA were used to evaluate the mechanism of epalrestat on NLRP3 inflammasome activation. Next, MCD-induced NASH models were used to evaluate the therapeutic effects of epalrestat in vivo. In addition, to evaluate the safety of epalrestat in vivo, mice were gavaged with epalrestat daily for 14 days. Results: Epalrestat, a clinically effective and safe drug, inhibits NLRP3 inflammasome activation by acting upstream of caspase-1 and inducing ASC oligomerization. Importantly, epalrestat exerts its inhibitory effect on NLRP3 inflammasome activation by inhibiting the activation of aldose reductase. Further investigation revealed that the administration of epalrestat inhibited NLRP3 inflammasome activation in vivo, alleviating liver inflammation and improving NASH pathology. Conclusions: Our study indicated that epalrestat, an aldose reductase inhibitor, effectively suppressed NLRP3 inflammasome activation in vivo and in vitro and might be a new therapeutic approach for NASH. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Abnormal activation of NLRP3 inflammasome is related to a series of inflammatory diseases, including type 2 diabetes, gouty arthritis, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. Therefore, targeting NLRP3 inflammasome is regarded as a potential therapeutic strategy for many inflammatory diseases. A growing number of studies have identified tanshinone I (Tan I) as a potential anti-inflammatory agent because of its good anti-inflammatory activity. However, its specific anti-inflammatory mechanism and direct target are unclear and need further study. Methods: IL-1β and caspase-1 were detected by immunoblotting and ELISA, and mtROS levels were measured by flow cytometry. Immunoprecipitation was used to explore the interaction between NLRP3, NEK7 and ASC. In a mouse model of LPS-induced septic shock, IL-1β levels in peritoneal lavage fluid and serum were measured by ELISA. Liver inflammation and fibrosis in the NASH model were analyzed by HE staining and immunohistochemistry. Results: Tan I inhibited the activation of NLRP3 inflammasome in macrophages, but had no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, Tan I inhibited NLRP3 inflammasome assembly and activation by targeting NLRP3-ASC interaction. Furthermore, Tan I exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including septic shock and NASH. Conclusions: Tan I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC, and exhibits protective effects in mouse models of LPS-induced septic shock and NASH. These findings suggest that Tan I is a specific NLRP3 inhibitor and may be a promising candidate for treating NLRP3 inflammasome-related diseases. [ABSTRACT FROM AUTHOR]

Background: Idiosyncratic drug-induced liver injury (IDILI) is common in hepatology practices and, in some cases, lethal. Increasing evidence show that tricyclic antidepressants (TCAs) can induce IDILI in clinical applications but the underlying mechanisms are still poorly understood. Methods: We assessed the specificity of several TCAs for NLRP3 inflammasome via MCC950 (a selective NLRP3 inhibitor) pretreatment and Nlrp3 knockout (Nlrp3−/−) BMDMs. Meanwhile, the role of NLRP3 inflammasome in the TCA nortriptyline-induced hepatotoxicity was demonstrated in Nlrp3−/− mice. Results: We reported here that nortriptyline, a common TCA, induced idiosyncratic hepatotoxicity in a NLRP3 inflammasome-dependent manner in mildly inflammatory states. In parallel in vitro studies, nortriptyline triggered the inflammasome activation, which was completely blocked by Nlrp3 deficiency or MCC950 pretreatment. Furthermore, nortriptyline treatment led to mitochondrial damage and subsequent mitochondrial reactive oxygen species (mtROS) production resulting in aberrant activation of the NLRP3 inflammasome; a selective mitochondrial ROS inhibitor pretreatment dramatically abrogated nortriptyline-triggered the NLRP3 inflammasome activation. Notably, exposure to other TCAs also induced aberrant activation of the NLRP3 inflammasome by triggering upstream signaling events. Conclusion: Collectively, our findings revealed that the NLRP3 inflammasome may act as a crucial target for TCA agents and suggested that the core structures of TCAs may contribute to the aberrant activation of NLRP3 inflammasome induced by them, an important factor involved in the pathogenesis of TCA-induced liver injury. DBhggTBWtuReWsEtfqqAGm Video Abstract [ABSTRACT FROM AUTHOR]

Drug‐related adverse reactions are among the main reasons for harm to patients under care worldwide and even their deaths. The pharmacovigilance system has been proven to be an effective method of avoiding or alleviating such adverse events. In 2019, after two decades of implementation of the drug‐related adverse reaction reporting system, China formally implemented a pharmacovigilance system with the Pharmacovigilance Quality Management Standards and a series of supporting technical documents created to improve the safety of medication given to patients. China's pharmacovigilance system has faced many problems and challenges during its implementation. This spontaneous reporting system is the main source of data for China's medication vigilance activities, but it has not provided sufficiently powerful evidence for regulatory decision‐making. In conformity with the health‐centred drug regulatory concept, the Chinese government has accelerated the speed of examination and approval of urgently needed clinical drugs and orphan drugs along with the requirement to improve the safety supervision of these drugs after their listing. China's marketing authorization holders (MAHs) must strengthen their pharmacovigilance capabilities as the primary responsible departments for drug safety. Chinese medical schools generally lack professional courses on pharmacovigilance. The regulatory authorities have recognized such problems and have made efforts to improve the professional capacity of pharmacovigilance personnel and to strengthen cooperation with stakeholders through the implementation of an action plan of medication surveillance and the establishment of a patient‐based adverse events reporting system and active surveillance systems, which will help China bridge the gap to bring its pharmacovigilance practice up to standards. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

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

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 Aβ 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. [Display omitted] • G. lucidum exhibits therapeutic potential against Alzheimer's disease. • Polysaccharides and triterpenes represent main bioactive components of G. lucidum. • G. lucidum has a good safety profile within reasonable dosage ranges. • G. lucidum and its components can target multiple aspects of AD pathology. [ABSTRACT FROM AUTHOR]

• LicoB is a potential and effective cGAS-STING signaling pathway inhibitor. • LicoB affected the STING-TBK1-IRF3 signal axis. • LicoB effectively diminished systemic inflammation in Trex1-/- mice. 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. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is a common adverse drug reaction (ADR) and a serious threat to health that affects disease treatments. At present, no targeted clinical drugs are available for DILI. Traditional natural medicines have been widely used as health products. Some natural medicines exert specific hepatoprotective effects, with few side effects and significant clinical efficacy. Thus, natural medicines may be a promising direction for DILI treatment. In this review, we summarize the current knowledge, common drugs and mechanisms of DILI, as well as the clinical trials of natural drugs and their bioactive components in anticipation of the future development of potential hepatoprotective drugs. [ABSTRACT FROM AUTHOR]

Owing to the complexity of chemical ingredients in traditional Chinese medicine (TCM), it is difficult to maintain quality and efficacy by relying only on chemical markers. Lianhua Qingwen capsule (LHQW) was selected as an example to discuss the feasibility of a bioassay for quality control. Network pharmacology was used to screen potential targets in LHQW with respect to its anti-inflammatory effects. An in vitro cell model was used to validate the prediction. An anti-inflammatory bioassay was established for the quality evaluation of LHQW in 40 batches of marketed products and three batches of destructed samples. The tumor necrosis factor/interleukin-6 (TNF/IL-6) pathway via macrophage was selected as the potential target of LHQW. The IC50 value of LHQW on RAW 264.7 was 799.8 μg/mL. LHQW had significant inhibitory effects on the expression of IL-6 in a dose-dependent manner (p < 0.05). The anti-inflammatory biopotency of LHQW was calculated based on the inhibitory bioactivity on IL-6. The biopotency of 40 marketed samples ranged from 404 U/μg to 2171 U/μg, with a coefficient of variation (CV) of 37.91%. By contrast, the contents of forsythin indicated lower CV (28.05%) than the value of biopotency. Moreover, the biopotencies of destructed samples declined approximate 50%, while the contents of forsythin did not change. This newly established bioassay revealed a better ability to discriminate the quality variations of LHQW as compared to the routine chemical determination. A well-established bioassay may have promising ability to reveal the variance in quality of TCM. [ABSTRACT FROM AUTHOR]

• BA selectively inhibits NLRP3 inflammasome activation by acting on the upstream of ASC oligomerization. • BA attenuates NLRP3 inflammasome activation in LPS-mediated inflammation and MSU-induced peritonitis mouse model. • BA can serve as a drug candidate for NLRP3 inflammasome-driven diseases. Brevilin A (BA), is a natural biologically active ingredient derived from Centipeda minima with several reports of anti-cancer, while its anti-inflammatory activity is rarely reported. Current studies have found the dysregulated activation of NLRP3 inflammasome cause a variety of inflammatory diseases. Targeting the NLRP3 inflammasome contributes to the treatment of NLRP3-induced diseases. Here, we found that BA significantly attenuates the activation of caspase-1 and the subsequent secretion of the interleukin-1β (IL-1β) in mouse macrophages and human THP-1 cells, showing the inhibitory effect of BA on the NLRP3 inflammasome activation. Moreover, BA specifically inhibits NLRs inflammasomes activation triggered by multi-stimuli, but it has no effect on the AIM2 inflammasome activation, indicating that BA is a specific inhibitor of the NLRs inflammasomes. Research on the mechanism found BA inhibits NLRP3 inflammasome activation by blocking the upstream of ASC oligomerization. Importantly, in vivo experiments showed that BA markedly reduces the secretion of IL-1β to suppress NLRP3 inflammasome in the LPS-induced inflammation and MSU-challenged peritonitis model. In conclusion, our experiments show that BA is an effective NLRP3 inflammasome inhibitor and can be regarded as a drug candidate for NLRP3 inflammasome-driven diseases. [ABSTRACT FROM AUTHOR]

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

Reports on Chinese patent medicines preparations containing Epimedii Folium (EF) and Psoraleae Fructus (PF) resulting in idiosyncratic drug-induced liver injury (IDILI) have received widespread attention. Previous studies have shown that bavachin and epimedin B—two active ingredients derived from both EF and PF—are potential components associated with IDILI, but the underlying mechanism remains unclear. We evaluated bavachin and epimedin B-induced IDILI under TNF-α-mediated immunological stress conditions and generated liver lipid metabolism profiles using lipidomics and multivariate statistical analysis. We next applied transcriptomics to identify the differential gene expression on the transcription level. Our results showed that co-exposure to bavachin, epimedin B under immunological stress conditions resulted in obvious liver injury. The differential metabolites screened in our study were closely related to the immune homeostasis of the liver. Sixteen differentially expressed genes were found, Zc3h6 and R3hdml were upregulated, while Sumo2 , Cd74 , Banp , Oas3 , Oas2 , Gbp8 , Slfn8 , Gbp2b , Serpina3g , Zbtb40 , H2-Ab1 , Osgin1 , Tgtp1 and Hspa1b were all downregulated. These differentially expressed genes were associated with biological processes concerning metabolic process and immune system process. Further integrative analysis indicated that bavachin combined with epimedin B affected genes that were not only related to immune system processes, but also to lipid metabolism. Ultimately, this led to an imbalance in the immune microenvironment in the liver and may have contributed to the observed liver injury. [Display omitted] • Bavachin combined with epimedin B-induced IDILI was evaluated under immunological stress conditions. • Integrative lipidomics and transcriptomics approach was used to reveal differential genes and metabolites underlying IDILI. • This study provide fresh insights into unraveling the pathogenesis of IDILI associated with traditional Chinese medicine. [ABSTRACT FROM AUTHOR]

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

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. We sought to explore the therapeutic effect of the active components of Schisandra Chinensis on anti-viral immunity and further investigate the underlying mechanism. 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. SC promoted cGAS-STING pathway activation, accompanied by increased production of interferon β (IFN β) 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 β 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 β. 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. [Display omitted] • Schisandrin C (SC) promotes cGAS-STING pathway activation. • SC promotes cGAS-STING pathway activation by facilitating the interaction between TBK1 and STING. • SC markedly attenuates hepatitis B virus replication in vivo and promotes the expression of IFN β and ISGs. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Licorice flavonoids in licorice can specifically inhibit the cGAS-STING signaling pathway. • Licorice flavonoids inhibit the cGAS-STING pathway by reducing the synthesis of 2′3′-cGAMP. • Licorice flavonoids have ameliorative effects on acute lung injury in mice. [ABSTRACT FROM AUTHOR]

Lung cancer poses a serious threat to human health. Although targeted therapies have led to breakthroughs in the treatment of lung cancer, drug resistance and side effects limit their clinical applications. Xihuang pill (XHW), a classical anti-cancer traditional Chinese medicine formula, has been clinically proven to be an effective complementary therapy in the treatment of various of cancers. However, the underlying mechanism for its use in combination with anti-cancer drugs remains unclear. Here, we explored the anti-lung cancer effect of XHW combined with anlotinib in mice bearing Lewis lung cancer (LLC). We used gut microbiota and transcriptomics to elucidate the regulatory properties of XHW in improving anti-lung cancer effect of anlotinib. The results showed that combination treatment of XHW with Anlotinib significantly inhibited tumor growth in LLC-bearing mice. We found that XHW played a key role in the regulation of gut microbiota using 16 s rRNA sequencing analysis. Specifically, XHW increased the proportion of the beneficial bacteria Bacteroides and g_norank_f_Muribaculaceae. Based on transcriptomic analysis of tumor tissues, differentially expressed genes in the combination therapy group were related to biological processes concerning angiogenesis, such as regulation of blood vessel diameter, regulation of tube diameter, and regulation of tube size. Our data suggest that XWH enhances the anticancer effect of anlotinib by regulating gut microbiota composition and tumor angiogenesis pathway. Combination therapy with anlotinib and XHW may be a novel therapeutic strategy for lung cancer patients. [Display omitted] • XHW improved the effects of anlotinib in the Lewis lung cancer (LLC) -incubated mouse model. • XWH enhances the antitumor effect of Anlotinib by modulating gut microbiota composition. • XHW potentiates the antitumor effect of Anlotinib by regulating tumor angiogenesis. • Combination therapy with XHW and Anlotinib offers a new therapeutic strategy for lung cancer patients. [ABSTRACT FROM AUTHOR]

Keguan-1, a new traditional Chinese medicine (TCM) prescription contained seven Chinese herbs, is developed to treat coronavirus disease 19 (COVID-19). The first internationally registered COVID-19 randomised clinical trial on integrated therapy demonstrated that Keguan-1 significantly reduced the incidence of ARDS and inhibited the severe progression of COVID-19. To investigate the protective mechanism of Keguan-1 on ARDS, a lipopolysaccharide (LPS)-induced acute lung injury (ALI) model was used to simulate the pathological state of ARDS in patients with COVID-19, focusing on its effect and mechanism on ALI. Mice were challenged with LPS (2 mg/kg) by intratracheal instillation (i.t.) and were orally administered Keguan-1 (low dose, 1.25 g/kg; medium dose, 2.5 g/kg; high dose, 5 g/kg) after 2 h. Bronchoalveolar lavage fluid (BALF) and lung tissue were collected 6 h and 24 h after i.t. administration of LPS. The levels of inflammatory factors tumour necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, keratinocyte-derived chemokine (KC or mCXCL1), macrophage inflammatory protein 2 (MIP2 or mCXCL2), angiotensin II (Ang II), and endothelial cell junction-associated proteins were analysed using ELISA or western blotting. Keguan-1 improved the survival rate, respiratory condition, and pathological lung injury; decreased the production of proinflammatory factors (TNF-α, IL-6, IL-1β, KC, and MIP2) in BALF and the number of neutrophils in the lung tissues; and ameliorated inflammatory injury in the lung tissues of the mice with LPS-induced ALI. Keguan-1 also reduced the expression of Ang II and the adhesion molecule ICAM-1; increased tight junction proteins (JAM-1 and claudin-5) and VE-cadherin expression; and alleviated pulmonary vascular endothelial injury in LPS-induced ALI. These results demonstrate that Keguan-1 can improve LPS-induced ALI by reducing inflammation and pulmonary vascular endothelial injury, providing scientific support for the clinical treatment of patients with COVID-19. Moreover, it also provides a theoretical basis and technical support for the scientific use of TCMs in emerging infectious diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Sophora flavescens is a traditional Chinese medicine commonly used in clinical practice, which has the effects of clearing away heat and dampness. Unfortunately, it has been reported that Sophora flavescens and its preparation may cause liver damage to a certain extent, but the exact mechanism is not clear. To assess the safety and risk of Sophora flavescens and to elucidate the relationship between Idiosyncratic drug-induced liver injury (IDILI) and the NOD-like receptor family protein 3 (NLRP3) inflammasome. Western blot, Caspase-Glo® 1 Inflammasome Assay, ELISA kits, Flow cytometry and FLIPRT Tetra system were used to study the effect of isoxanthohumol (IXN) on the activation of NLRP3 inflammasome and its mechanism. Combined with the lipopolysaccharide-mediated susceptibility IDILI model in mice to evaluate the hepatotoxicity of IXN. IXN facilitates the activation of caspase-1 and secretion of interleukin (IL)-1β triggered by adenosine triphosphate (ATP), nigericin but not those induced by silicon dioxide and poly (I:C). Furthermore, the activation of NLR-family CARD-containing protein 4 (NLRC4) and the absent in melanoma 2 (AIM2) was not affected by IXN. Mechanistically, IXN promotes NLRP3-dependent apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) oligomerization and the generation of mitochondrial reactive oxygen species (mtROS) triggered by ATP. The in vivo data showed that non-hepatotoxic doses of IXN resulted in increased levels of glutamate-pyruvate transaminase, glutamate-oxaloacetate transaminase, tumor necrosis factor and IL-1β in the serum and showed increased liver inflammation in the susceptible IDILI model mediated by lipopolysaccharide. These results show that IXN enhances NLRP3 inflammasome activation by promoting the accumulation of ATP-induced mtROS and ASC oligomerization to cause IDILI, indicating that IXN may be a risk factor for liver injury caused by the clinical use of Sophora flavescens. [Display omitted] • Isoxanthohumol (IXN) can increase the activation of NLRP3 inflammasome. • IXN can induce hepatotoxicity in a LPS-mediated susceptibility mouse model of IDILI. • IXN enhanced the production of mtROS triggered by ATP in LPS-primed BMDMs. • The excessive activation of inflammasomes provides new insights into hepatotoxicity. [ABSTRACT FROM AUTHOR]