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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]

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]

Two new coordination polymers, namely poly[[hexathiocyanatotetrakis{μ3‐2,4,6‐trimethyl‐1,3,5‐tris[(triazol‐1‐yl)methyl]benzene}tricadmium(II)] 3.5‐hydrate], {[Cd3(SCN)6(C18H21N9)4]·3.5H2O}n (1), and poly[[hexathiocyanatotetrakis{μ3‐2,4,6‐trimethyl‐1,3,5‐tris[(triazol‐1‐yl)methyl]benzene}trizinc(II)] 3.5‐hydrate], {[Zn3(SCN)6(C18H21N9)4]·3.5H2O}n (2), have been synthesized under hydrothermal conditions and characterized by elemental analysis, IR spectroscopy and single‐crystal X‐ray diffraction analysis. From the X‐ray analysis, it is noteworthy that polymers 1 and 2 are isostructural, with their three‐dimensional structures composed of three kinds of four‐connection metal ions and two kinds of three‐connection 2,4,6‐trimethyl‐1,3,5‐tris[(triazol‐1‐yl)methyl]benzene (TTTMB) ligand nodes. Each metal ion is six‐coordinated in a slightly distorted octahedral geometry. The antioxidant activity against DPPH (2,2‐diphenyl‐1‐picrylhydrazyl) and the antidiabetic activity against α‐amylase of the synthesized compounds were evaluated in vitro. The results of the DPPH free‐radical scavenging assay showed that polymers 1 and 2 exhibited strong antioxidant effects, with IC50 values of 3.81 and 2.56 mg ml−1, respectively. The IC50 value in the antidiabetic studies of polymer 1 was 3.94 mg ml−1, while polymer 2 exhibited no antidiabetic activity. Polymers 1 and 2 revealed different inhibitory activities on DPPH and α‐amylase, which indicated that the metal ions play important roles in the biological activity of coordination polymers. In addition, the solid‐state photoluminescence properties and thermal stability of 1 and 2 have been investigated. [ABSTRACT FROM AUTHOR]

Cholestasis is a leading cause of hepatic accumulation of bile acids resulting in liver injury, fibrosis, and liver failure. Paeoniflorin displays bright prospects in liver protective effect. However, its molecular mechanism has not been well-explored. This study was designed to assess the effects and possible mechanisms of paeoniflorin against alpha-naphthylisothiocyanate-induced liver injury. Ultraperformance liquid chromatography coupled with quadrupole time-of-flight combined with principle component analysis and partial least squares discriminant analysis were integrated to obtain differentiating metabolites for the pathways and clarify mechanisms of disease. The results indicated that paeoniflorin could remarkably downregulate serum biochemical indexes and alleviate the histological damage of liver tissue. Different expression of 14 metabolites demonstrated that paeoniflorin mainly regulated the dysfunctions of glycerophospholipid metabolism and primary bile acid biosynthesis. Moreover, several pathways such as arginine and proline metabolism, ether lipid metabolism, and arachidonic acid metabolism were also related to the efficacy. In conclusion, paeoniflorin has indicated favorable pharmacological effect on serum biochemical indexes and pathological observation on cholestatic model. And metabolomics is a promising approach to unraveling hepatoprotective effects by partially regulating the perturbed pathways, which provide insights into mechanisms of cholestasis. [ABSTRACT FROM AUTHOR]

Cholestasis causes hepatic accumulation of bile acids leading to liver injury, fibrosis and liver failure. Paeoniflorin, the major active compound isolated from the roots of Paeonia lactiflora pall and Paeonia veitchii Lynch, is extensively used for liver diseases treatment in China. However, the mechanism of paeoniflorin's hepatoprotective effect on cholestasis has not been investigated yet. In this study, we administered paeoniflorin to rats for 3 days prior to alpha-naphthylisothiocyanate (ANIT) administration for once, then went on administering paeoniflorin to rats for 3 days. The data demonstrated that paeoniflorin significantly prevented ANIT-induced change in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphates (ALP), serum total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA) and gamma-glutamyl transpeptidase (γ-GT). Histology examination revealed that paeoniflorin treatment rats relieved more liver injury and bile duct proliferation than ANIT-administered rats. Moreover, our data indicated that paeoniflorin could restore glutathione (GSH) and its related synthase glutamate-cysteine ligase catalytic subunit (GCLc) and glutamate-cysteine ligase modifier subunit (GCLm) in ANIT-treated group. In addition, the RNA and protein expression of Akt and nuclear factor-E2-related factor-2 (Nrf2) were also activated by paeoniflorin in ANIT-induced rats. These findings indicated that paeoniflorin protected ANIT-induced cholestasis and increased GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway. Therefore, paeoniflorin might be a potential therapeutic agent for cholestasis. [ABSTRACT FROM AUTHOR]

A new reversed phase ultra performance liquid chromatography coupled with evaporative light scattering detection is developed for the fast and direct quantification of underivatized muscone in precious herbal medicine musk. Separation of muscone was achieved on a Waters Acquity BEH C18 (50 × 2.1 mm id, 1.7 μm) column. The runtime was as short as 5 min. The mode of evaporative light scattering detection was set at Impact On. The influence of evaporative light scattering detection condition on sensitivity was investigated. The optimized condition was: drift tube temperature at 30°C, gas flow rate 4.2 L/min. The method was validated with respect to the precision, sensitivity, accuracy, linearity, stability, and robustness were measured in this paper. The calibration curves showed good linear regression ( r = 0.9914) within the test range. The recovery rate was 98.6%. The limit of detection for muscone was 2.0 ng. The validated method was rapid, simple, reproducible, and convenient for the quantification of muscone in musk and the related products. [ABSTRACT FROM AUTHOR]

A rapid, simple and sensitive ultra high-performance liquid chromatography (UHPLC-MS/MS) method was established for determining the absorption amount of emodin in the five digestive segments of rat. Plasma samples were pre-purified by solid-phase extraction (SPE) with Oasis MAX cartridge. Separation of emodin and 1,8-dihydroxyanthraquinone (internal standard) was performed on an Acquity BEH UHPLC C column (100 mm×2.1 mm, 1.7 μm) with gradient elution of methanol and 0.1% formic acid aqueous solution. The LC/MS system was operated under multiple reaction monitoring mode using electrospray ionization (ESI) in negative ion mode. The results showed that this established method was valid and sensitive for emodin within 0.04-16.4 μg/mL, with low limits of detection and quantification of 0.6 ng/mL and 2.4 ng/mL, respectively and upper limit of quantification of 220.0 ng/mL. The intra- and interday variations were below 4.9% of RSD. The extraction recoveries were 98.9-106.1% with RSD of 1.9-3.2%. The plasma concentration-time relationship showed that the absorption of emodin in stomach was faster than in intestine segments. The sequence of absorption amount was: ileum>jejunum>colon≈duodenum>stomach. Most of emodin was absorbed in ileum, and the absorption amount was increased with prolonged retention of drug form in intestine, especially in ileum and jejunum. The developed UHPLC-ESI-MS/MS method was appropriate for determining the in vivo absorption of emodin in other herbal medicines or preparations containing this compound. [ABSTRACT FROM AUTHOR]