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In the realm of autoimmune and inflammatory diseases, the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) signaling pathway has been thoroughly investigated and established. Despite this, the clinical approval of drugs targeting the cGAS-STING pathway has been limited. The Total glucosides of paeony (TGP) is highly anti-inflammatory and is commonly used in the treatment of rheumatoid arthritis (RA), emerged as a subject of our study. We found that the TGP markedly reduced the activation of the cGAS-STING signaling pathway, triggered by various cGAS-STING agonists, in mouse bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) cells. This inhibition was noted alongside the suppression of interferon regulatory factor 3 (IRF3) phosphorylation and the expression of interferon-beta (IFN-β), C-X-C motif chemokine ligand 10 (CXCL10), and inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). The mechanism of action appeared to involve the TGP's attenuation of the STING-IRF3 interaction, without affecting STING oligomerization, thereby inhibiting the activation of downstream signaling pathways. In vivo , the TGP hindered the initiation of the cGAS-STING pathway by the STING agonist dimethylxanthenone-4-acetic acid (DMXAA) and exhibited promising therapeutic effects in a model of acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN). Our findings underscore the potential of the TGP as an effective inhibitor of the cGAS-STING pathway, offering a new treatment avenue for inflammatory and autoimmune diseases mediated by this pathway. [ABSTRACT FROM AUTHOR]

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. This study provides a whole epidemiological picture of L-ADR in mainland China, and concluded that L-ADR has a persistent increase. This work provides a powerful tool to mine the potential hepatotoxic drugs in the future. [Display omitted] [ABSTRACT FROM AUTHOR]

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (IFN) genes (STING) pathway is critical in the innate immune system and can be mobilized by cytosolic DNA. The various inflammatory and autoimmune diseases progression is highly correlated with aberrant cGAS-STING pathway activation. While some cGAS-STING pathway inhibitor were identified, there are no drugs that can be applied to the clinic. Compound Danshen Dripping Pill (CDDP) has been successfully used in clinic around the world, but the most common application is limited to cardiovascular disease. Therefore, the purpose of the present investigation was to examine whether CDDP inhibits the cGAS-STING pathway and could be used as a therapeutic agent for multiple cGAS-STING-triggered diseases. BMDMs, THP1 cells or Trex1−/− BMDMs were stimulated with various cGAS-STING-agonists after pretreatment with CDDP to detect the function of CDDP on IFN-β and ISGs productionn. Next, we detect the influence on IRF3 and P65 nuclear translocation, STING oligomerization and STING-TBK1-IRF3 complex formation of CDDP. Additionally, the DMXAA-mediated activation mice model of cGAS-STING pathway was used to study the effects of CDDP. Trex1−/− mice model and HFD-mediated obesity model were established to clarify the efficacy of CDDP on inflammatory and autoimmune diseases. CDDP efficacy suppressed the IRF3 phosphorylation or the generation of IFN-β, ISGs, IL-6 and TNF-α. Mechanistically, CDDP did not influence the STING oligomerization and IRF3-TBK1 and STING-IRF3 interaction, but remarkably eliminated the STING-TBK1 interaction, ultimately blocking the downstream responses. In addition, we also clarified that CDDP could suppress cGAS-STING pathway activation triggered by DMXAA, in vivo. Consistently, CDDP could alleviate multi-organ inflammatory responses in Trex1−/− mice model and attenuate the inflammatory disorders, incleding obesity-induced insulin resistance. CDDP is a specifically cGAS-STING pathway inhibitor. Furthermore, we provide novel mechanism for CDDP and discovered a clinical agent for the therapy of cGAS-STING-triggered inflammatory and autoimmune diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Aristolochic acids (AAs) have long been considered as a potent carcinogen due to its nephrotoxicity. Aristolochic acid I (AAI) reacts with DNA to form covalent aristolactam (AL)–DNA adducts, leading to subsequent A to T transversion mutation, commonly referred as AA mutational signature. Previous research inferred that AAs were widely implicated in liver cancer throughout Asia. In this study, we explored whether AAs exposure was the main cause of liver cancer in the context of HBV infection in mainland China. Totally 1256 liver cancer samples were randomly retrieved from 3 medical centers and a refined bioanalytical method was used to detect AAI–DNA adducts. 5.10% of these samples could be identified as AAI positive exposure. Whole genome sequencing suggested 8.41% of 107 liver cancer patients exhibited the dominant AA mutational signature, indicating a relatively low overall AAI exposure rate. In animal models, long-term administration of AAI barely increased liver tumorigenesis in adult mice, opposite from its tumor-inducing role when subjected to infant mice. Furthermore, AAI induced dose-dependent accumulation of AA–DNA adduct in target organs in adult mice, with the most detected in kidney instead of liver. Taken together, our data indicate that AA exposure was not the major threat of liver cancer in adulthood. [ABSTRACT FROM AUTHOR]

The adaptor protein apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain (CARD) can be activated through pyrin domain (PYD) interactions between sensors and ASC, and through CARD interactions between caspase-1 and ASC. Although the majority of ternary inflammasome complexes depend on ASC, drugs targeting ASC protein remain scarce. After screening natural compounds from Isatidis Radixin , we found that tryptanthrin (TPR) could inhibit NLRP3-induced IL-1β and caspase-1 production, but the underlying anti-inflammatory mechanisms remain to be elucidated. The purpose of this study was to determine the impact of TPR on the NLRP3, NLRC4, and AIM2 inflammasomes and the underlying mechanisms. Additionally, the efficacy of TPR was analysed in the further course of methionine- and choline-deficient (MCD)–induced NASH and lipopolysaccharide (LPS)–induced sepsis models of mice. In vitro studies used bone marrow-derived macrophages to assess the anti-inflammatory activity of TPR, and the techniques included western blot, testing of intracellular K+ and Ca2+, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), co-immunoprecipitation, ASC oligomerization assay, surface plasmon resonance (SPR), and molecular docking. We used LPS-induced sepsis models and MCD-induced NASH models in vivo to evaluate the effectiveness of TPR in inhibiting inflammatory diseases. Our observations suggested that TPR could inhibit NLRP3, NLRC4, and AIM2 inflammasome activation. As shown in a mouse model of inflammatory diseases caused by MCD-induced NASH and LPS-induced sepsis, TPR significantly alleviated the progression of diseases. TPR interrupted the interactions between ASC and NLRP3/NLRC4/AIM2 in the co-immunoprecipitation experiment, and stable binding of TPR to ASC was also evident in SPR experiments. The underlying mechanisms of anti-inflammatory activities of TPR might be associated with targeting ASC, in particular, PYD domain of ASC. In general, the requirement for ASC in multiple inflammasome complexes makes TPR, as a novel broad-spectrum inflammasome inhibitor, potentially useful for treating a wide range of multifactorial inflammasome-related diseases. [ABSTRACT FROM AUTHOR]

The involvement of NLRP3 inflammasome is associated with the progress of numerous inflammatory conditions. However, there is currently no single compound used in the clinic. Search for the inhibitor of NLRP3 inflammasome from natural products is an attractive direction. The compound Helenin (Hel), which is obtained from Inula helenium L., is reported to have anti-inflammatory activities. However, the underlying molecular mechanisms and specific inflammatory signal pathway remains not well understood. This research aims to determine the impacts of Hel on NLRP3 inflammasome and the underlying mechanism involved, meanwhile also assessing its potential as a therapeutic intervention for inflammatory diseases mediated by NLRP3 overactivation. Pretreated with Hel in BMDMs (bone marrow-derived macrophages), then stimulated with NLRP3 triggers and measured the expression of active caspase-1 and interleukin 1β (IL-1β). Determination of intracellular K+ and Ca2+, ASC oligomerization and mitochondrial reactive oxygen species (mtROS) production were employed to explore the preliminary mechanism of Hel on NLRP3 activation. Subsequently, Co-immunoprecipitation was used to investigate protein-protein interaction and reduction of covalent bonds of Hel was to explore the binding mode between drugs and proteins. Finally, in vivo experiments, we utilized mouse lethal sepsis and monosodium urate(MSU)-induced peritonitis models to evaluate the effectiveness of Hel in inhibiting inflammatory diseases. The findings revealed that Hel exhibited a specific blocking effect on NLRP3, with no impact on the assembly of NLRC4 and AIM2 inflammasome. Through the analysis of mechanisms targeting key upstream factors in NLRP3 activation, Hel inhibited NLRP3-dependent ASC oligomerization but did not regulating inflammasome priming, K+ efflux, Ca2+ influx, or mitochondrial damage and mtROS. Moreover, Hel effectively interrupted the binding of NEK7-NLRP3, which was dependent on the active double C=C of the α,β-unsaturated carbonyl units in Hel. In mouse models, Hel showed promising therapeutic effects in the treatment of NLRP3 overactivation-associated diseases, including the lethal sepsis and acute systemic inflammation induced by lipopolysaccharide (LPS) and peritonitis induced by MSU. Our results indicate that Hel dependent α,β-unsaturated carbonyl units interrupt the formation of the NLRP3-NEK7 interaction, thereby blocks the inflammasome assemblage and activation. These fundings would suggest that Hel is a promising inhibitor for treating diseases driven by NLRP3 overactivation. [Display omitted] [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (IDILI) is an infrequent but potentially serious disease that develops the main reason for post-marketing safety warnings and withdrawals of drugs. Epimedii Folium (EF), the widely used herbal medicine, has shown to cause idiosyncratic liver injury, but the underlying mechanisms are poorly understood. Increasing evidence has indicated that most cases of IDILI are immune mediated. Here, we report that icariside Ⅱ (ICS Ⅱ), the major active and metabolic constituent of EF, causes idiosyncratic liver injury by promoting NLRP3 inflammasome activation. ICS Ⅱ exacerbates NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) and nigericin, but not silicon dioxide (SiO 2), monosodium urate (MSU) crystal or cytosolic lipopolysaccharide (LPS). Additionally, the activation of NLRC4 and AIM2 inflammasomes is not affected by ICS Ⅱ. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial contributor to the enhancing effect of ICS Ⅱ on ATP- or nigericin-induced NLRP3 inflammasome activation. Importantly, in vivo data show that a combination of non-hepatotoxic doses of LPS and ICS Ⅱ causes the increase of aminotransferase activity, hepatic inflammation and pyroptosis, which is attenuated by Nlrp3 deficiency or pretreatment with MCC950 (a specific NLRP3 inflammasome inhibitor). In conclusion, these findings demonstrate that ICS Ⅱ causes idiosyncratic liver injury through enhancing NLRP3 inflammasome activation and suggest that ICS Ⅱ may be a risk factor and responsible for EF-induced liver injury. The activated NLRP3 inflammasome-mediated IL-1 β secretion and subsequently the production of TNF- α , pyroptosis and oxidative stress synergistically induced liver injury after the combination of non-hepatotoxic doses of LPS and ICS Ⅱ. ICS Ⅱ may be a risk factor and responsible for Epimedii Folium-induced idiosyncratic hepatotoxicity. Image 1 [ABSTRACT FROM AUTHOR]

Aberrant activation of NLRP3 inflammasome has been implicated in the pathogenesis of diverse inflammation-related diseases, and pharmacological molecules targeting NLRP3 inflammasome are of considerable value to identifying potential therapeutic interventions. Cardamonin (CDN), the major active ingredient of the traditional Chinese medicinal herb Alpinia katsumadai , has exerted an excellent anti-inflammatory activity, but the mechanism underlying this role is not fully understood. Here, we show that CDN blocks canonical and noncanonical NLRP3 inflammasome activation triggered by multiple stimuli. Moreover, the suppression of CDN on inflammasome activation is specific to NLRP3, not to NLRC4 or AIM2 inflammasome. Besides, the inhibitory effect is not dependent on the expression of NF- κ B-mediated inflammasome precursor proteins. We also demonstrate that CDN suppresses the NLRP3 inflammasome through blocking ASC oligomerization and speckle formation in a dose-dependent manner. Importantly, CDN improves the survival of mice suffering from lethal septic shock and attenuates IL-1 β production induced by LPS in vivo , which is shown to be NLRP3 dependent. In conclusion, our results identify CDN as a broad-spectrum and specific inhibitor of NLRP3 inflammasome and a candidate therapeutic drug for treating NLRP3 inflammasome-driven diseases. Cardamonin is a broad-spectrum inhibitor of NLRP3 inflammasome triggered by multiple stimuli. Moreover, the suppression of cardamonin on inflammasome activation is specific to NLRP3, not to NLRC4 or AIM2 inflammasome. Importantly, cardamonin improves the survival of mice suffering from LPS-induced lethal endotoxic shock, which is shown to be NLRP3 dependent. fx1 [ABSTRACT FROM AUTHOR]

Although oxymatrine (OMT) has been shown to directly inhibit the replication of hepatitis B virus (HBV) in vitro , limited research has been done with this drug in vivo . In the present study, the antiviral effect of OMT was investigated in an immunocompetent mouse model of chronic HBV infection. The infection was achieved by tail vein injection of a large volume of DNA solution. OMT (2.2, 6.7 and 20 mg/kg) was administered by daily intraperitoneal injection for 6 weeks. The efficacy of OMT was evaluated by the levels of HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B core antigen (HBcAg). The immunoregulatory activity of OMT was evaluated by serum ELISA and flow cytometry. Results shows that OMT at 20 mg/kg inhibited HBV replication, and it was more efficient than entecavir (ETV) in the elimination of serum HBsAg and intrahepatic HBcAg. In addition, OMT accelerated the production of interferon- γ (IFN- γ ) in a dose-dependent manner in CD4 + T cells. Our findings demonstrate the beneficial effects of OMT on the enhancement of immunological function and in the control of HBV antigens. The findings suggest this drug to be a good antiviral therapeutic candidate for the treatment of HBV infection. [ABSTRACT FROM AUTHOR]

[Display omitted] • GUP suppressed the activation of multiple inflammasomes. • GUP inhibits inflammasome activation by preventing ASC oligomerization. • GUP inhibits neutrophil release in the LPS-induced acute lung injury model. • GUP may be a candidate drug for the treatment of inflammasome-mediated diseases. Glycyrrhiza uralensis polysaccharides (GUP) has biological activities such as immune regulation, anti-tumor, and liver protection, and has good development prospects in the fields of medicines and health products, but its specific mechanism of action is not yet clear. In our study, we confirmed that GUP can effectively inhibit the activation of the NLRP3 inflammasome. Mechanistically, GUP blocked the activation of the inflammasome by significantly inhibiting the oligomerization and speckle aggregation of the apoptosis-related protein ASC. In addition, GUP effectively ameliorated LPS-induced acute lung injury in mice. Our findings indicate that the Traditional Chinese Medicine (TCM) GUP has broad-spectrum anti-inflammatory effects and is a potential drug candidate for the treatment of inflammasome-related diseases. [ABSTRACT FROM AUTHOR]

Product states are always considered as the states that do not contain quantum correlation. We discuss here when a quantum channel sends the product states to themselves. Exact forms of such channels are proposed. It is shown that such a quantum channel is a local quantum channel, a composition of a local quantum channel and a flip operation, or such that one of the local states is fixed. Both finite- and infinite-dimensional systems are considered. [ABSTRACT FROM AUTHOR]

Abstract: Let be a von Neumann algebra with no central summands of type I1. If is a nonlinear Lie derivation, then is of the form , where is an additive derivation of and is a mapping of into its center which maps commutators into zero. [Copyright &y& Elsevier]

• Parametric representation of strictly incoherent operations for one-qubit systems is offered. • Such representation is useful to coherence manipulation. • Such description can be applied to determine the relaxing of SIOs. Strictly incoherent operations (SIO) proposed in Winter and Yang (2016) [13] are promising to be a good candidate of free operations in the resource theory of quantum coherence, setting against the central role of local operations and classical communication in the resource theory of quantum entanglement. An important open problem for SIOs is to find minimal parametrization with operational efficiency. Such a description plays key role for axiomatic study of resource theory of quantum coherence. We are aimed to give a structural characterization of bistochastic SIOs in terms of Pauli operators and the Phase operator for one-qubit systems. Some applications of our results are also sketched in reconstructing quantum thermal averages via a quantum computer and in coherence manipulation. [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]

Abstract: Let X be a real or complex Banach space with dimension at least 3, be the family of all rank one nilpotent operators. We give the concrete form of every bijective map such that . Based on this result, we characterize the surjective map for all , where H is a Hilbert space (real or complex) with dimension at least 3. [Copyright &y& Elsevier]

• 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]

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]

Ethnopharmacological relevance Liuweiwuling (LWWL) tablets contain a six-herb Chinese formula and are commonly prescribed to facilitate nourishment of the liver and kidneys, clear away toxic materials and activate blood circulation. Administration of LWWL is well known for its protective effects on the liver and its capacity to confer long-term stability in patients exhibiting reduced transaminase levels. Clinical studies have reported that LWWL can also be used for the treatment of liver fibrosis with associated treatment regimens resulting in a concomitant reduction in transforming growth factor β1 (TGF-β1) levels in the serum of patients with hepatic fibrosis. TGF-β1 plays a prominent role in stimulating liver fibrogenesis and this effect is mediated by myofibroblasts (MFB) derived from hepatic stellate cells (HSCs). It is likely that this phenomenon underpins the antifibrotic effects associated with LWWL. Aim The purpose of this study was to investigate the antifibrotic effects and mechanisms pertaining to LWWL. Methods Hepatic fibrosis was induced in rats following bile duct ligation (BDL). Rats that underwent BDL received daily gavage administration of colchicine (0.2 mg/kg per day), LWWL (0.4, 1.6, 6.4 g/kg per day) or PBS (for the control group). Pathological changes in hepatic tissue were examined using hematoxylin and eosin (HE) and sirius red staining. Immunohistochemical analysis was performed to monitor α-SMA and type I collagen (Collagen I) protein expression. Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot analyses were used to monitor the expression of genes and proteins in the TGF-β/Smad signaling pathway, including TGF-β1, bone morphogenic protein and activin membrane-bound inhibitor (Bambi), Smad3, phosphorylated Smad3 (p-Smad3) and Smad7. We also monitored the expression of genes and proteins in the nuclear factor-κB (NF-κB) signaling pathway, including NF-κB p65, IκBα and phosphorylation of IκBα (p-IκBα), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1β (IL-1β). Results LWWL dose-dependently inhibited BDL-induced liver injury and hepatic fibrosis in rats. Furthermore, LWWL reduced liver tissue collagen deposition, hydroxyproline content, liver dysfunction and α-SMA expression in BDL-induced hepatic fibrosis rats. Moreover, LWWL markedly prevented activation of the TGF-β/Smad signaling pathway by inhibiting expression of Smad2/3 and phosphorylation of Smad3, and upregulating the expression of Bambi and Smad7. In addition, LWWL regulated the expression of the inflammatory cytokines IL-1β, TNF-α and IL-6 by inhibiting the activation of NF-κB p65 and the phosphorylation of IκBα, and increasing the expression of IκBα. Conclusions LWWL can attenuate BDL-induced hepatic fibrosis in rats, and this effect may be due to modulation of the NF-κB-dependent inflammatory response and activation of HSC and TGF-β/Smad-mediated synthesis and degradation of Collagen I. [ABSTRACT FROM AUTHOR]

• Psoralidin is an inflammasome agonist found in Chinese herbal medicine. • Psoralidin could induce the hepatotoxicity via activating inflammasomes. Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially fatal disease that is unpredictable and independent of the dose of the drug. Increasing evidence suggests that the majority of IDILI cases are immune-mediated, and the aberrant activation of inflammasome plays a vital role in progression. Psoraleae Fructus (PF), a tonic Chinese medicine, has been able to cause IDILI, but the precise mechanism of hepatotoxicity remains unclear. In this study, eight bioactive compounds involved in PF-induced inflammasome activation were investigated. The results demonstrated that psoralidin activated the inflammasomes followed by secreting caspase-1 and interleukin 1β (IL-1β) in a dose-dependent manner. Interestingly, MCC950, a potent inhibitor of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, could not entirely suppress the psoralidin-induced inflammasome activation. Moreover, psoralidin significantly induced IL-1β maturation and caspase-1 activation in NLRP3-knockout bone marrow-derived macrophages (BMDMs), suggesting that psoralidin not only activates the NLRP3 inflammasome but also activates other types of inflammasomes. The results also demonstrated that psoralidin activated the inflammasomes by promoting the C-terminal caspase recruitment domain (ASC) oligomerization, and the production of mitochondrial reactive oxygen species (mtROS) is a decisive factor in psoralidin-induced inflammasome activation. Importantly, in vivo data revealed that psoralidin induced hepatic inflammation, increased aminotransferase activity and increased the production of IL-1β and tumor necrosis factor (TNF-α) in a susceptible mouse model of lipopolysaccharide (LPS)-mediated IDILI. In summary, these results confirmed that psoralidin causes IDILI by inducing inflammasome activation. The study suggests that psoralidin is a possible risk factor and is responsible for PF-induced IDILI. [ABSTRACT FROM AUTHOR]

• Glaucocalyxin A alleviates septic shock via inhibiting NLRP3 inflammasome activation. Glaucocalyxin A (GLA) is a bioactive ent-kauranoid diterpenoid derived from the herbal medicine, Rabdosia japonica var. glaucocalyx, and it has been reported to possess marked anti-inflammatory properties. However, the underlying mechanisms are not fully understood. Here, we reported that GLA dramatically inhibited canonical and non-canonical NLRP3 inflammasome activation induced by multiple agonists. In addition, GLA also blocked NLRC4 inflammasome activation but had no effect on AIM2 inflammasome. Furthermore, we found that GLA inhibited NLRP3 or NLRC4 agonists-induced ASC oligomerization, which is an upstream event of the inflammasomes assembly. Most importantly, administration of GLA significantly reduced lipopolysaccharide (LPS)-induced mortality in septic-shock mouse model. Additionally, GLA dose-dependently inhibited the production of interleukin (IL)-1β, but had no effect on NLRP3-independent TNF-α production induced by LPS in vivo. In conclusion, our study suggests that GLA alleviates LPS-induced septic shock and inflammation via inhibiting NLRP3 inflammasome activation and provides a promising candidate drug for the treatment of NLRP3-driven diseases. [ABSTRACT FROM AUTHOR]