Natural Coumarin Shows Toxicity to Spodoptera litura by Inhibiting Detoxification Enzymes and Glycometabolism.

Coumarin and its derivatives are plant-derived compounds that exhibit potent insecticidal properties. In this study, we found that natural coumarin significantly inhibited the growth and development of Spodoptera litura larvae through toxicological assay. By transcriptomic sequencing, 80 and 45 differentially expressed genes (DEGs) related to detoxification were identified from 0 to 24 h and 24 to 48 h in S. litura after coumarin treatment, respectively. Enzyme activity analysis showed that CYP450 and acetylcholinesterase (AChE) activities significantly decreased at 48 h after coumarin treatment, while glutathione S-transferases (GST) activity increased at 24 h. Silencing of SlCYP324A16 gene by RNA interference significantly increased S. litura larval mortality and decreased individual weight after treatment with coumarin. Additionally, the expression levels of DEGs involved in glycolysis and tricarboxylic acid (TCA) cycle were inhibited at 24 h after coumarin treatment, while their expression levels were upregulated at 48 h. Furthermore, metabonomics analysis identified 391 differential metabolites involved in purine metabolism, amino acid metabolism, and TCA cycle from 0 to 24 h after treated with coumarin and 352 differential metabolites associated with ATP-binding cassette (ABC) transporters and amino acid metabolism. These results provide an in-depth understanding of the toxicological mechanism of coumarin on S. litura.

Evaluation of in vitro cytotoxic and genotoxic effects of the 3-(3,4-dihydroxyphenyl)-8-hydroxycoumarin.

A wide variety of natural and synthetic coumarins present therapeutic potential. Therefore, the assessment of their safety for humans is essential. 3-(3,4-Dihydroxyphenyl)-8-hydroxycoumarin is a coumarin derivative with antioxidant properties, among other biological activities. The aim of this study is to evaluate the cytotoxic and genotoxic potential of this molecule on peripheral blood mononuclear cells (PBMC) and human hepatocellular carcinoma cells (HepG2/C3A). The results obtained for the cytotoxicity assays, evaluated by the trypan blue staining assay, using concentrations between 0.1 and 20 µg/mL, showed that there is no decrease in cell viability for both cell lines. The MTT assay showed a significant decrease in the viability of HepG2/C3A cells at the highest concentrations tested, after 48 h, for all the tested concentrations, after 72 h of exposure. Regarding the genotoxic assays, the data obtained by the comet assay and the micronucleus test, up to the tested concentration of 10 µg/mL, do not show significant DNA damage and/or chromosomal mutations, for both cell lines. However, at the highest tested concentration of 20 µg/mL, a small but significant genotoxic effect was observed in PBMC. In view of the observed results, it can be concluded that the 3-(3,4-dihydroxyphenyl)-8-hydroxycoumarin, up to a concentration of 10 µg/mL, does not present genotoxic effects in human cells with and without liver enzymes metabolism. Additional studies with higher concentrations of this molecule need to be performed to address its complete biosafety.

Intestinal epithelial damage due to herbal compounds - an in vitro study.

Intestinal epithelial injury from herbal products has rarely been reported, despite the gut being the first point of contact for oral preparations. These products often consist of multiple herbs, thereby potentially exposing consumers to higher levels of reactive phytochemicals than predicted due to pharmacokinetic interactions. The phytochemical coumarin, found in many herbal products, may be taken in combination with herbal medicines containing astragalosides and atractylenolides, purported cytochrome P450 (CYP) modulators. As herbal use increases, the need to predict interactions in multiple at-risk organ systems is becoming critical. Hence, to determine whether certain herbal preparations containing coumarin may cause damage to the intestinal epithelium, Caco2 cells were exposed to common phytochemicals. Coumarin, astragaloside IV (AST-IV) or atractylenolide I (ATR-I) solutions were exposed to Caco2 cultures in increasing concentrations, individually or combined. Coumarin produced a significant concentration-dependant fall in cell viability that was potentiated when CYP enzymes were induced with rifampicin and incubated with CYP3A4 inhibitor econazole, suggesting a role for other CYP enzymes generating toxic metabolites. ATR-I alone produced no toxicity in uninduced cells but showed significant toxicity in rifampicin-induced cells. ATR-I had no effect on coumarin-induced toxicity. AST-IV was nontoxic alone but produced significant toxicity when combined with nontoxic concentrations of coumarin. The combination of coumarin, ATR-I and AST-IV was significantly toxic, but no synergistic interaction was seen. This investigation was conducted to determine the likelihood for intestinal-based interactions, with the results demonstrating coumarin is potentially toxic to intestinal epithelium, and combinations with other phytochemicals can potentiate this toxicity.

Two smart coumarin-based fluorescent probes with AIE effect for sensing ClO- and imaging in living cells.

It's worth noting that detect effective methods for tracking ClO- could help us uncover the function of ClO- in living systems. Here, two coumarin-based probes, named (E)-3-(1-hydrazonoethyl)-2H-chromen-2-one (1A) and 3-((E)-1-(((E)-(2,3-dihydro-1H-imidazol-4-yl)methylene)-hydrazono)ethyl)- 2H-chromen-2-one (1B) with aggregation-induced emission (AIE) effect in Tris-HCl (pH = 7.2) buffer solution were synthesized and used for sensing ClO- selectivity. 1A and 1B responded to ClO- through the oxidation hydrolysis effect. The mechanism was further verified by HR-MS and DFT calculation. Cell imaging indicated that 1A and 1B were good membrane permeability with low toxicity to HEK293T, and expected to be used to detect ClO- in cells.

Time-resolved quantitative phosphoproteomics reveals cellular responses induced by caffeine and coumarin.

Protein phosphorylation is a critical way that cells respond to external signals and environmental stresses. However, the patterns of cellular response to chemicals at different times were largely unknown. Here, we used quantitative phosphoproteomics to analyze the cellular response of kinases and signaling pathways, as well as pattern change of phosphorylated substrates in HepG2 cells that were exposed to caffeine and coumarin for 10 min and 24 h. Comparing the 10 min and 24 h groups, 33 kinases were co-responded and 32 signaling pathways were co-enriched in caffeine treated samples, while 48 kinases and 34 signaling pathways were co-identified in coumarin treated samples. Instead, the percentage of co-identified phosphorylated substrates only accounted for 4.31% and 9.57% between 10 min and 24 h in caffeine and coumarin treated samples, respectively. The results showed that specific chemical exposure led to a bunch of the same kinases and signaling pathways changed in HepG2 cells, while the phosphorylated substrates were different. In addition, it was found that insulin signaling pathway was significantly enriched by both the caffeine and coumarin treatment. The pattern changes in phosphorylation of protein substrates, kinases and signaling pathways with varied chemicals and different time course shed light on the potential mechanism of cellular responses to endless chemical stimulation.

Implications for herbal polypharmacy: coumarin-induced hepatotoxicity increased through common herbal phytochemicals astragaloside IV and atractylenolide I.

Hepatotoxicity is a well-known adverse effect of many substances, with toxicity often resulting from interactions of drugs with other drug-like substances. With the increased availability of complementary and alternative medicines, including herbal medicines, the likelihood of adverse interactions between drugs and drug-like substances in herbs increases. However, the impact of potential herb-herb interactions is little understood. To assess the potential of two cytochrome P450 enzyme modulating phytochemicals common to many herbal medicines, atractylenolide I (ATR-I) and astragaloside IV (AST-IV), to interact with coumarin, another phytochemical common in many foods, a hepatocyte function model with a liver carcinoma cell line, HepG2, was exposed to these agents. To determine the effects of cytochrome P450 modulation by these phytochemicals certain cells were induced with rifampicin to induce cytochrome P450. Increasing concentrations of ATR-I combined with a fixed, nontoxic concentration of coumarin (200 µM), demonstrated significant additive interactions. 300 µM ATR-I produced a 31% reduction in cell viability (p < 0.01) with coumarin in rifampicin uninduced cells. In rifampicin-induced cells, ATR-I (100-300 µM) produced a significant reduction in cell viability (p < 0.01) with coumarin (200 µM). AST-IV with fixed coumarin (200 µM) showed 27% toxicity at 300 µM AST-IV in rifampicin uninduced cells (p < 0.05) and 30% toxicity in rifampicin induced cells (p < 0.05). However, when fixed coumarin and AST-IV were combined with increasing concentrations of ATR-I no further significant increase in toxicity was observed (p > 0.05). These results demonstrate the potential toxic interactive capabilities of common traditional Chinese herbal medicine phytochemicals and underline the potential importance of coumarin-mediated toxicity.

Comparing toxicity of galbanic acid, auraptene and umbelliprenin on adult T-cell leukaemia-lymphoma in normoxia and hypoxia.

Natural coumarins are valuable agents that induce anticancer effects and/or enhance sensitivity to therapeutic modalities. Galbanic acid (GBA), auraptene (AUR) and umbelliprenin (UMB) are coumarins derived from Ferula species with various pharmaceutical activities. The aim of the current research was to compare toxic effects of GBA, AUR, and UMB on human lymphoma cells in normoxia and hypoxia. In this regard, GBA and AUR were extracted from the roots of F. szowitsiana and UMB was derived from the roots of F. persica, all by thin-layer chromatography. MT-2 cells were treated with each agent for 3 consequent periods, while exposed to different O2 contents (21% and 2%). By the end of each treatment, the viability of MT-2 cells was determined by resazurin dye-based colorimetric assay. Obtained results revealed that low doses of GBA (10 and 20 µM) induced significant (p < 0.0001) toxic effects in hypoxia. However, similar toxicity was observed when cells were treated with 40 µM AUR in normoxia and hypoxia. Notably, UMB was the only coumarin that exerted cytotoxic effects in all time points (48, 72 and 96 h) in normoxia and hypoxia, although its concentration was highest (80 µM). In conclusion, this is the first report indicating GBA was the most toxic coumarin against ATL cells in hypoxia, AUR induced similar effects in normoxia and hypoxia, and low toxicity of UMB was stable during the time and different O2 contents. Future studies on other ATL cell lines are recommended to better evaluate the toxic effects of GBA, AUR and UMB in vitro.

Natural Dibenzo-α-Pyrones: Friends or Foes?

Natural dibenzo-α-pyrones (DAPs) can be viewed from two opposite angles. From one angle, the gastrointestinal metabolites urolithins are regarded as beneficial, while from the other, the emerging mycotoxin alternariol and related fungal metabolites are evaluated critically with regards to potential hazardous effects. Thus, the important question is: can the structural characteristics of DAP subgroups be held responsible for distinct bioactivity patterns? If not, certain toxicological and/or pharmacological aspects of natural DAPs might yet await elucidation. Thus, this review focuses on comparing published data on the two groups of natural DAPs regarding both adverse and beneficial effects on human health. Literature on genotoxic, estrogenic, endocrine-disruptive effects, as well as on the induction of the cellular anti-oxidative defense system, anti-inflammatory properties, the inhibition of kinases, the activation of mitophagy and the induction of autophagy, is gathered and critically reviewed. Indeed, comparing published data suggests similar bioactivity profiles of alternariol and urolithin A. Thus, the current stratification into hazardous Alternaria toxins and healthy urolithins seems debatable. An extrapolation of bioactivities to the other DAP sub-class could serve as a promising base for further research. Conclusively, urolithins should be further evaluated toward high-dose toxicity, while alternariol derivatives could be promising chemicals for the development of therapeutics.

A hypothetical skin sensitisation next generation risk assessment for coumarin in cosmetic products.

Next generation Risk Assessment (NGRA) is an exposure-led, hypothesis-driven approach which integrates new approach methodologies (NAMs) to assure safety without generating animal data. This hypothetical skin allergy risk assessment of two consumer products - face cream containing 0.1% coumarin and deodorant containing 1% coumarin - demonstrates the application of our skin allergy NGRA framework which incorporates our Skin Allergy Risk Assessment (SARA) Model. SARA uses Bayesian statistics to provide a human relevant point of departure and risk metric for a given chemical exposure based upon input data that can include both NAMs and historical in vivo studies. Regardless of whether NAM or in vivo inputs were used, the model predicted that the face cream and deodorant exposures were low and high risk respectively. Using only NAM data resulted in a minor underestimation of risk relative to in vivo. Coumarin is a predicted pro-hapten and consequently, when applying this mechanistic understanding to the selection of NAMs the discordance in relative risk could be minimized. This case study demonstrates how integrating a computational model and generating bespoke NAM data in a weight of evidence framework can build confidence in safety decision making.

Roles of human cytochrome P450 1A2 in coumarin 3,4-epoxidation mediated by untreated hepatocytes and by those metabolically inactivated with furafylline in previously transplanted chimeric mice.

Coumarin is a naturally occurring component of food products but is of clinical interest for its potential hepatotoxicity in humans. In the current study, the pharmacokinetics of coumarin in humanized-liver mice after oral and intravenous administrations (30 mg/kg) were investigated for its transformations to metabolically active coumarin 3,4-epoxide (as estimated by the levels of o-hydroxyphenylacetic acid) and to excretable 7-hydroxycoumarin. After oral administration, control mice metabolized coumarin to o-hydroxyphenylacetic acid at roughly the same rate as that to 7-hydroxycoumarin (total of unconjugated and conjugated forms). In contrast, the in vivo biotransformation of coumarin to o-hydroxyphenylacetic acid by humanized-liver mice was around two orders of magnitude less than that to conjugated and unconjugated 7-hydroxycoumarin. After intravenous administrations of coumarin, differences were observed in the plasma concentrations of o-hydroxyphenylacetic acid between humanized-liver mice treated with furafylline (daily oral doses of 13 mg/kg for 3 days) and untreated humanized-liver mice. The mean values of the areas under the plasma concentration versus time curves and the maximum concentrations for o-hydroxyphenylacetic acid were significantly lower in the group treated with furafylline (45% and 57% of the untreated values, respectively). These results suggested that the metabolic activation of coumarin in humans was mediated mainly by P450 1A2, which was suppressed by furafylline, and that humanized-liver mice orally treated with furafylline might constitute an in vivo model for metabolically inactivated P450 1A2 in human hepatocytes transplanted into chimeric mice.

Cytotoxicity of some choline-based deep eutectic solvents and their effect on solubility of coumarin drug.

The effect of some deep eutectic solvents (DESs) on the coumarin solubility has been investigated using Hansen solubility parameters (HSP). The solubility of coumarin was measured in aqueous systems containing some DESs based on choline chloride (ChCl) as hydrogen bond acceptor (HBA) with urea (U), ethylene glycol (EG), and glycerol (GLY) as hydrogen bond donors (HBD) by widely applied shake-flask method at T = (298.15 to 313.15) K. The results indicate that coumarin solubility enhances with the concentration of DESs and temperature. Also, coumarin was dissolved more than 80 times compared with pure water in the presence of ChCl/EG. Then experimental data were fitted to Wilson, electrolyte Non-Random Tow-Liquid (e-NRTL), and UNIQUAC activity coefficient models. Furthermore, the dissolution thermodynamic properties including enthalpy, Gibbs free energy, and entropy have been calculated based on Gibbs and van't Hoff equations. Due to these results, it is indicated that coumarin dissolution in the studied systems is an endothermic process. Moreover, to investigate the biological properties of DESs, MTT assay have been applied to determinate cytotoxicity of the DESs. In the melanoma skin cell line, cell culture tests revealed that these solvents had very low toxicity and high biocompatibility.

Dihydroisocoumarins and Dihydroisoflavones from the Rhizomes of Dioscorea collettii with Cytotoxic Activity and Structural Revision of 2,2'-Oxybis(1,4-di-tert-butylbenzene).

The investigation of the constituents of the rhizomes of Dioscorea collettii afforded one new dihydroisocoumarin, named (-)-montroumarin (1a), along with five known compounds-montroumarin (1b), 1,1'-oxybis(2,4-di-tert-butylbenzene) (2), (3R)-3'-O-methylviolanone (3a), (3S)-3'-O-methylviolanone (3b), and (RS)-sativanone (4). Their structures were elucidated using extensive spectroscopic methods. To the best of our knowledge, compound 1a is a new enantiomer of compound 1b. The NMR data of compound 2 had been reported but its structure was erroneous. The structure of compound 2 was revised on the basis of a reinterpretation of its NMR data (1D and 2D) and the assignment of the 1H and 13C NMR data was given rightly for the first time. Compounds 3a-4, three dihydroisoflavones, were reported from the Dioscoreaceae family for the first time. The cytotoxic activities of all the compounds were tested against the NCI-H460 cell line. Two dihydroisocoumarins, compounds 1a and 1b, displayed moderate cytotoxic activities, while the other compounds showed no cytotoxicity.

Metabolic activation and deactivation of dietary-derived coumarin mediated by cytochrome P450 enzymes in rat and human liver preparations.

Dietary-derived coumarin is of clinical interest for its potential hepatotoxicity in humans because such toxicity is especially evident in rats. In this study, the oxidative metabolism of coumarin to active coumarin 3,4-epoxide (as judged by the formation rates of o-hydroxyphenylacetic acid) and excretable 7-hydroxycoumarin was investigated in liver fractions from rats and humans. In rat liver microsomes, the formation rate of o-hydroxyphenylacetic acid (~6 pmol/min/mg microsomal protein) from coumarin at 10 µM was dependent on the presence of liver cytosolic fractions. Rat hepatocytes mediated similar formation rates of o-hydroxyphenylacetic acid and 7-hydroxycoumarin (~0.1 nmol/hr/106 cells) at 0.20-20 µM coumarin. Human hepatocytes mediated the biotransformation of coumarin to o-hydroxyphenylacetic acid at roughly similar rates to those of rat hepatocytes. In contrast, the formation rates of 7-hydroxycoumarin by human hepatocytes were around 10-fold higher at ~1 nmol/hr/106 cells. In the presence of human liver cytosolic fractions, the oxidative formation rate of o-hydroxyphenylacetic acid was relatively high in cytochrome P450 (P450) 1A2-rich human liver microsomes. The inhibitory effects of furafylline/α-naphthoflavone and 8-methoxypsoralen, P450 1A2 and 2A6 inhibitors, respectively, were seen on the rates of o-hydroxyphenylacetic and 7-hydroxylation formations, respectively, in pooled human liver microsomes. Human liver microsomes selectively inactivated for P450 1A2 and 2A6 showed low rates of o-hydroxyphenylacetic acid and 7-hydroxylation formation (~20-30% of control), respectively. Among the P450 isoforms tested, recombinant human P450 1A2 predominantly mediated o-hydroxyphenylacetic formation. These results suggested that the metabolic activation and deactivation of coumarin were mediated mainly by P450 1A2 and 2A6 enzymes, respectively. The metabolic oxidation of coumarin via 3,4-epoxidation forming o-hydroxyphenylacetic acid could inform individual human risk assessments of dietary-derived coumarin, for which hepatotoxicity is especially evident in rats.

Permeation, stability and acute dermal irritation of miroestrol and deoxymiroestrol from Pueraria candollei var. mirifica crude extract loaded transdermal gels.

In this study, permeation behaviors and chemical stability of miroestrol and deoxymiroestrol from Pueraria candollei var. mirifica (PM), Thai traditional medicine, crude extract containing transdermal gels were firstly evaluated. Three different PM extract containing gels were formulated, including hydroalcoholic and microemulsion gels using carbomer, and silicone gel using silicone elastomer. In vitro permeation through porcine ear skin demonstrated that the flux and 24 h cumulative permeation of miroestrol and deoxymiroestrol were in the order of hydroalcoholic > silicone > microemulsion gels. Hydroalcoholic gel provided the highest partition coefficient from gel onto skin, and thus the skin permeability coefficient. After 24 h permeation, no miroestrol and deoxymiroestrol remained deposited in the skin. Accelerated study using heating-cooling revealed insignificant difference between the remaining percentages of miroestrol and deoxymiroestrol in aqueous and non-aqueous based gels. Long-term stability study showed that miroestrol contents remained constant for 90 d and 30 d under 5 ± 3 °C and 30 ± 2 °C, 75 ± 5%RH, respectively; whereas the percentage of deoxymiroestrol decreased significantly after 30 d storage, irrespective of storage conditions. Acute dermal irritation test on New Zealand White rabbits showed that PM hydroalcoholic gels were non-irritant, with no signs of erythema or oedema.[Figure: see text].

Simple Osthole/Nanocarrier Pesticide Efficiently Controls Both Pests and Diseases Fulfilling the Need of Green Production of Strawberry.

The application of botanical pesticides is a good choice in organic agriculture. However, most botanical pesticides have limitations of slow action and short persistence for pest and disease management, which constrain their further application. With the objective of exploring a green pesticide for controlling strawberry pests and diseases simultaneously, a star polymer (SPc) with a low production cost was synthesized as a pesticide nanocarrier through simple reactions. The SPc complexed with osthole quickly through electrostatic interaction and hydrophobic association, which decreased the particle size of osthole down to the nanoscale (17.66 nm). With the help of SPc, more nano-sized osthole was delivered into cytoplasm through endocytosis, leading to the enhanced cytotoxicity against insect cells. As a green botanical pesticide, the control efficacy of the osthole/SPc complex was improved against main strawberry pests (green peach aphid and two-spotted spider mite) and disease (powdery mildew), which fulfilled the need of both pest and disease management in sustainable production of strawberry. Meanwhile, the introduction of SPc not only improved plant-uptake but also decreased the residue of osthole due to the higher degradation rate. Furthermore, the application of the osthole/SPc complex exhibited no influence on the strawberry fruit quality and nontarget predators. To our knowledge, it is the first success to control plant pests and diseases simultaneously for sustainable agriculture by only one pesticidal formulation based on nanoparticle-delivered botanical pesticides.

Preclinical safety assessment of the crude extract from Sida rhombifolia L. aerial parts in experimental models of acute and repeated-dose 28 days toxicity in rats.

Sida rhombifolia (Malvaceae) is popularly used as a treatment for several pathological conditions; however, there is a lack of studies that identify its compounds and that evaluate comprehensively the safety of its consumption. Therefore, the aim of this study was to determinate the phytochemical constitution of the crude extract of Sida rhombifolia (CESR), and its safety in models of acute and repeated doses (28 days) toxicity. The tested dose for the model of acute toxicity was 2000 mg/kg doses for the repeated dose model were 150, 300 e 600 mg/kg. Hematological, biochemical, histopathological and oxidative markers were investigated. HPLC-DAD-MS analysis evidenced the presence of caffeic acid, coumarin, and rutin. In the acute toxicity model the only altered parameters were tissue ROS, and AST and BUN in serum. As for the repeated dose experiment both hematological and biochemical markers remained within the values of reference for the species. Obtained results demonstrate that the CESR did not present significant toxic effects when administrated orally to male and female rats in acute and repeated doses.

Subtle Structural Changes of Dyes Lead to Distinctly Different Fluorescent Behaviors in Cellular Context: The Role of G-Quadruplex DNA Interaction Using Coumarin-Quinazolinone Conjugates as a Case Study.

Fluorogenic organic materials have gained tremendous attention due to their unique properties. However, only a few of them are suitable for bioimaging. Their different behaviors in organic and cellular environments hinder their application in bioimaging. Thus understanding the photoluminescent behaviors of organic materials in a cellular context is particularly important for their rational design. Herein, we describe two coumarin-quinazolinone conjugates: CQ and MeCQ. The high structure similarity makes them possess similar physical and photophysical properties, including bright fluorescence ascribed to the monomer forms in organic solvents and aggregation-caused quenching (ACQ) effect due to self-assembly aggregation in aqueous solution. However, they behave quite differently in cellular context: that is, CQ exhibits bright fluorescence in living cells, while the fluorescence of MeCQ is almost undetectable. The different performance between CQ and MeCQ in living cells is attributed to their different scenario in G-quadruplex (G4) DNA interaction. CQ selectively binds with G4 DNA to recover its fluorescence via aggregation-disaggregation switching in living cells, while MeCQ remained in the aggregate form due to its poor interplay with G4 DNA. Furthermore, CQ is applied as a two-photon fluorescent dye, and its photoswitchable fluorescence capability is exploited for super-resolution imaging of the specific mitochondrial structure in living cells via the STORM technique.

Psoralidin, a major component of Psoraleae Fructus, induces inflammasome activation and idiosyncratic liver injury.

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 1ß (IL-1ß) 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-1ß 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-1ß 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.

Coumarin (2H-1-benzopyran-2-one): a novel and eco-friendly aphicide.

Coumarin (2H-1-benzopyran-2-one) is a phenolic compound derived from the shikimate pathway and synthesized by various medicinal and aromatic plants as parent molecule of a large group of secondary metabolites, namely coumarins. Its main utilization is as fixative in perfumes and flavour enhancer. Given its role as phytoalexin and phagodepression activity, herein we evaluated for the first time its efficacy against several insect species: the green peach aphid, Myzus persicae, the moth Spodoptera littoralis, the housefly, Musca domestica and the filariasis vector Culex quinquefasciatus. Two non-target species were also included in our toxicity evaluation experiments: the ladybug Harmonia axyridis and the earthworm Eisenia fetida. Results highlighted remarkable selectivity of coumarin, being highly toxic to M. persicae aphids (LC50(90) values of 1.3(1.9) mg L-1) and friendly to natural enemies of aphids as well as soil invertebrates.