Comparison of the chemical constituents of Saposhnikoviae Radix associated with three different growth patterns and its therapeutic effect against atopic dermatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Saposhnikoviae Radix (SR) was initially documented in Shennong Bencao Jing classics for its properties in dispelling wind, dissolving surface, relieving pain, and alleviating spasms. This herb is commonly used in traditional Chinese medicine to address conditions that affect the body's surface, by aiding in the expulsion of pathogens from the surface and alleviating pain associated with the immune response. Atopic dermatitis (AD) is a prevalent allergic skin disorder, and the therapeutic effects of SR in dispelling wind and relieving the body's surface are consistent with the clinical symptoms commonly observed in AD. AIM OF THE STUDY: The anti-AD effects of SR were examined under three different growth patterns to identify active pharmacodynamic compounds. The results provide insight into the clinical efficacy of wild and cultivated SR. MATERIALS AND METHODS: The efficacy of wild, wild-simulated, and cultivated SR was assessed in a mouse model of AD. In addition, the effects of wild and varying doses of cultivated SR were evaluated in mice with short-term AD symptoms. GC-MS and UPLC-MS/MS were used to analyze the chemical components of the three SR treatments and molecular docking was used to identify active components. RESULTS: A mouse model of AD was used to assess the pharmacodynamic effects of SR prepared by three different cultivation methods. The study found that all three SR preparations improved phenotypic markers and histopathological features in the AD mouse model. The efficacy of wild SR and wild-simulated SR was similar, although there was a significant difference between wild and cultivated SR. Both wild SR and various doses of cultivated SR ameliorated skin injuries and reduced inflammation in serum and skin tissues. Furthermore, skin thickness, inflammatory cells, mast cell infiltration, and IL-33 expression improved following treatment. Notably, wild SR, double-cultivated SR, and triple-cultivated SR demonstrated significant therapeutic effects. An analysis using GC-MS revealed the presence of 55, 52, and 43 volatile oils in the three SR preparations, with more common components observed between wild and wild-simulated SR. Fewer common components were evident between cultivated and wild SR. UPLC-MS/MS analysis identified a total of 37 compounds, with larger relative peak areas observed for the chromogenic ketones. Molecular docking studies revealed that certain compounds, such as n-propyl 9,12-octadecadienoate, (E)-9-octadecenoic acid ethyl ester, and various chromogenic ketones, such as cimifugin, 5-O-methyIvisamminol, hamaudol, 3'-O-acetylhamaudol, 3'-O-angeloyhamandol, adenosine and farnesylaceton, may be the major substances that distinguish the activities of SR with three different growth patterns. CONCLUSION: Variations in the anti-AD efficacy of SR with three growth patterns were identified, and their chemical composition differences were determined. These findings suggest that increasing the dosage of cultivated SR could potentially be a viable clinical alternative for atopic dermatitis treatment.

Multi-DNA-Modified Double-Network Hydrogel with Customized Microstructure: A Novel System for Living Circulating Tumor Cells Capture and Real-Time Detection.

The precise and effective isolation of living circulating tumor cells (CTCs) from peripheral blood, followed by their real-time monitoring, is crucial for diagnosing cancer patients. In this study, a cell-imprinted double-network (DN) hydrogel modified with circular multi-DNA (CMD), coined the CMD-imprinted hydrogel with fixed cells as templates (CMD-CIDH), was developed. The hydrogel featured a customized surface for proficient capture of viable CTCs and in situ real-time fluorescent detection without subsequent release. The customized surface, constructed using polyacrylamide/chitosan DN hydrogel as the matrix on the cell template, had a dense network structure, thereby ensuring excellent stability and a low degradation rate. Optimal capture efficiencies, recorded at 93 ± 3% for MCF-7 cells and 90 ± 2% for Hela cells, were achieved by grafting the CMD and adjusting the nodule size on the customized surface. The capture efficiency remained significantly high at 67 ± 11% in simulated breast cancer patient experiments even at a minimal concentration of 5 cells mL-1. Furthermore, CMD grafted onto the surface produced a potent fluorescence signature, enabling in situ real-time fluorescent detection of the target cell's growth state even in complex environments. The customized surface is highly efficient for screening CTCs in peripheral blood and has promising potential for setting up the CTCs culture.

Inhibiting MEK1 R189 citrullination enhances the chemosensitivity of docetaxel to multiple tumour cells.

Drug resistance is still a big challenge for cancer patients. We previously demonstrated that inhibiting peptidylarginine deiminase 2 (PADI2) enzyme activity with Cl-amine increases the efficacy of docetaxel (Doc) on tamoxifen-resistant breast cancer cells with PADI2 expression. However, it is not clear whether this effect applies to other tumour cells. Here, we collected four types of tumour cells with different PADIs expression and fully evaluated the inhibitory effect of the combination of PADIs inhibitor (BB-Cla) and Doc in vitro and in vivo on tumour cell growth. Results show that inhibiting PADIs combined with Doc additively inhibits tumour cell growth across the four tumour cells. PADI2-catalysed citrullination of MEK1 Arg 189 exists in the four tumour cells, and blocking the function of MEK1 Cit189 promotes the anti-tumour effect of Doc in these tumour cells. Further analysis shows that inhibiting MEK1 Cit189 decreases the expression of cancer cell stemness factors and helps prevent cancer cell stemness maintenance. Importantly, this combined treatment can partially restore the sensitivity of chemotherapy-resistant cells to docetaxel or cisplatin in tumour cells. Thus, our study provides an experimental basis for the combined therapeutic approaches using docetaxel- and PADIs inhibitors-based strategies in tumour treatment. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.

The attenuation effect of licorice on the hepatotoxicity of Euodiae Fructus by inhibiting the formation of protein conjugates and GSH depletion.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine and food, Euodiae Fructus (EF) is widely used in clinics to relieve pain and prevent vomiting and for making tea for more than a thousand years. In recent years, hepatotoxic reactions to EF have been reported. The intermediates produced by evodiamine and rutaecarpine metabolism in vitro were captured by glutathione (GSH), suggesting that the toxicity of EF may be related to metabolic activation. Whether licorice can inhibit the metabolic activation of EF has not been reported, which needed an effective strategy to clarify the correlation between protein conjugates and hepatotoxicity and the attenuation mechanism of licorice processing. AIM OF THE STUDY: This study aimed to explore the toxic components and mechanisms of EF based on metabolic activation and the detoxification of licorice. MATERIALS AND METHODS: The content and toxicity index of protein conjugates in the liver were determined by orally administering mice and rats with EF. The attenuation mechanism of licorice was examined in cell and enzymology experiments. RESULTS: The change in evodiamine-cysteinylglycine (EVO-Cys-Gly) and evodiamine-cysteine (EVO-Cys) levels was consistent with the change in hepatotoxicity. Licorice inhibited the formation of the protein conjugates of EF and increased the content of GSH in L02 cells. CONCLUSION: EF mediated by P450 enzymes produced toxic intermediates, which combined with cysteine residues in animal liver and inactivate them, leading to hepatotoxicity. Interestingly, licorice can alleviate the GSH depletion caused by EF and inhibit the production of protein conjugates by inhibiting P450 enzymes.

[Research Progress on the Pathogenesis of Lung Cancer Associated with 
Idiopathic Pulmonary Fibrosis].

Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease (ILD) of unknown causes, which is characterized by pulmonary fibrosis. The median survival period after diagnosis is about 2-4 years. In recent years, the incidence rate of lung cancer associated with IPF (IPF-LC) is increasing, and the prognosis is worse than that of IPF alone. Pulmonary fibrosis may be closely associated with the occurrence and development of lung cancer. Although the pathogenesis of IPF-LC is still unclear, the current research shows that there are similarities between the pathogenesis of these two diseases at molecular and cellular levels. At present, the research on the cellular and molecular mechanism of lung cancer related to pulmonary fibrosis has become the focus of researchers' attention. This article reviews the related literature, focusing on the latest status of the cellular and molecular mechanisms and treatment of IPF-LC, hoping to help clinicians understand IPF-LC.
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Intestinal Flora Changes Induced by a High-Fat Diet Promote Activation of Primordial Follicles through Macrophage Infiltration and Inflammatory Factor Secretion in Mouse Ovaries.

Obesity induced by a high-fat diet (HFD) leads to the excessive consumption of primordial follicles (PFs) in the ovaries. There is systemic chronic inflammation under HFD conditions, but no previous studies have explored whether there is a certain causal relationship between HFD-induced chronic inflammation and the overactivation of PFs. Here, we showed that HFD causes disorders of intestinal microflora in mice, with five Gram-negative bacteria showing the most profound increase at the genus level compared to the normal diet (ND) groups and contributes to the production of endotoxin. Endotoxin promotes M1 macrophage infiltration in the ovaries, where they exhibit proinflammatory actions by secreting cytokines IL-6, IL-8, and TNFα. These cytokines then boost the activation of PFs by activating Signal Transducer and Activator of Transcription 3 (STAT3) signaling in follicles. Interestingly, transplantation of the HFD intestinal microflora to the ND mice partly replicates ovarian macrophage infiltration, proinflammation, and the overactivation of PFs. Conversely, transplanting the ND fecal microbiota to the HFD mice can alleviate ovarian inflammation and rescue the excessive consumption of PFs. Our findings uncover a novel and critical function of gut microbes in the process of PF overactivation under HFD conditions, and may provide a new theoretical basis for the microbial treatment of patients with premature ovarian insufficiency caused by HFD.

Preparation and evaluation of novel bio-based Bis-GMA-free dental composites with low estrogenic activity.

OBJECTIVE: Although bisphenol Aglycidyl methacrylate (Bis-GMA) are widely used in the dental composite, its raw materials include the petroleum-based product bisphenol A (BPA) with high estrogenic activity (EA). In this study, two new BPA-free dimethacrylate monomers from bio-based material creosol were synthesized and evaluated. METHODS: The renewable bisphenol monomer 5, 5'-methylenedicreosol (BCF) was prepared from bio-based material creosol. By the human breast cancer cells (MCF-7 cells) proliferation assay, a risk assessment of BCF was performed to determine if BCF possessed reduced EA in comparison to BPA. Then, the novel monomers 5, 5'-methylenedicreosol diglycidyl ether diacrylate (BCF-EA) and 5, 5'-methylenedicreosol diglycidyl ether dimethacrylate (BCF-GMA) were synthesized from BCF with epichlorohydrin and (meth)acrylate. All products were investigated by 1H NMR and FT-IR spectra. The control resin was a mixture based on Bis-GMA and tri(ethyleneglycol) dimethacrylate (TEGDMA) with a weight ratio of 5:5 (5B5T). Similarly, experimental resin matrix was a mixture based on BCF-EA/TEGDMA (5E5T) and BCF-GMA/TEGDMA (5G5T). And their corresponding composites were then prepared with corresponding resin matrices and hybrid SiO2 (5E5TC, 5G5TC and 5B5TC). The properties of these composites were investigated according to the standard or referenced methods. Each sample was evaluated for double bond conversion (DC), shrinkage stress (SS) and volumetric polymerization shrinkage (VS). Water sorption (WS), water solubility (SL), mechanical properties and cytotoxicity were also measured. RESULTS: 1H NMR and FT-IR spectra confirmed the chemical structure of each monomer. EA test revealed that bio-based bisphenol monomer BCF as the precursor of BCF-EA and BCF-GMA showed lower EA than BPA. Cured resin matrix: Both 5E5T and 5G5T had nearly the same DC (p < 0.05), which was higher than 5B5T (p < 0.05); 5E5T and 5G5T had lower VS, SL and cytotoxicity than 5B5T (p < 0.05); mechanical properties of 5E5T and 5G5T were all better than those of 5B5T (p < 0.05). Cured composite: There was no significant difference in conversion (p < 0.05); 5E5TC and 5G5TC had significantly lower VS (p < 0.05); WS of 5E5TC and 5G5TC were similar (p < 0.05), but higher compared to 5B5TC (p < 0.05); 5E5TC and 5G5TC had the deeper depth of cure (p > 0.05); before water immersion, there was no significant difference in flexural strength between 5E5TC and 5G5TC (p > 0.05), and higher than 5B5TC (p < 0.05); 5E5TC and 5G5TC showed less cytotoxicity than 5B5TC (p < 0.05). SIGNIFICANCE: The new BPA-free di(meth)acrylates are promising photocurable dental monomers owning to bio-based raw material, high degree of conversion coupled with low curing shrinkage and good mechanical properties. Therefore, BCF-EA and BCF-GMA has a potential to be used as the substitution for Bis-GMA to prepare Bis-GMA-free dental composite.

Systematic characterization of the metabolites of defatted walnut powder extract in vivo and screening of the mechanisms against NAFLD by UPLC-Q-Exactive Orbitrap MS combined with network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Walnut kernel, a well-known TCM, is often used after being defatted in tradition. And defatted walnut powder extract (DWPE) has the actions of tonifying the liver and kidney, dissipating stagnation and removing blood stasis, which has the effect on non-alcoholic fatty liver disease (NAFLD). However, the effective components of DWPE in vivo were unclear and the multiple mechanisms of DWPE against NAFLD have not been explored. AIM OF THE STUDY: The studies were performed to screen the effective substances in vivo by identification of the metabolites of DWPE in rats and to seek the potential mechanisms of DWPE on NAFLD by construction of the network pharmacology based on metabolites and verification of the highly correlated pathway. MATERIALS AND METHODS: To explore the effective substances in vivo, the metabolites of DWPE were identified in SD rats' bio-samples through UPLC-Q-Exactive Orbitrap MS. To analyze the mechanisms of DWPE on NAFLD, a Metabolite-Target-Disease network was established and the potential mechanisms were predicted. Then, highly correlated pathway was verified in animal and cells studies. RESULTS: A total of 52 metabolites of DWPE were identified in vivo, which were derived from gallic acid, ellagic acid (EA) and glansreginin A (Gla A). The possible metabolic pathways were phase Ⅰ (hydroxylation, hydrolyzation, etc) and phase Ⅱ metabolic reactions (methylation, sulfation and glucuronidation). Furthermore, in the network pharmacology, 54 core targets were enriched into pathways in cancer, nitrogen metabolism and other 9 pathways, which were essential pathways of DWPE against NAFLD. And the mechanism of nitrogen metabolism was verified in both of animal and cells studies. The results showed that DWPE could decline the concentration of ammonia and increase the expressions of carbonic anhydrase 2 (CA2) and carbamoylphosphate synthetase (CPS1) in nitrogen metabolism. CONCLUSION: Taken together, the study revealed the absorption components and their metabolic pathways and demonstrated the mechanism of nitrogen metabolism of DWPE on anti-NAFLD.

Capsella bursa-pastoris (L.) Medic. extract alleviate cataract development by regulating the mitochondrial apoptotic pathway of the lens epithelial cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Capsella bursa-pastoris (L.) Medic. (CBP) is a cruciferous plant valuable in reducing fever, improving eyesight and calming the liver. This herb was recorded in the Compendium of Materia Medica for cataract treatment. AIM OF THE STUDY: To determine the effects and mechanism of CBP on cataract prevention and treatment using a selenite cataract model. MATERIALS AND METHODS: The main compounds in CBP extract were analyzed by UPLC, 1H-NMR and 13C-NMR spectroscopic techniques. Flavonoids formed a significant proportion of its compounds, thus necessitating an evaluation of their inhibitory effects on the development of cataract using a selenite cataract model. The protective effects of CBP flavonoids (CBPF) against oxidative damage and the modulation of mitochondrial apoptotic pathway were subsequently verified on H2O2-treated SRA01/04 lens epithelial cells. RESULTS: CBPF significantly alleviated the development of cataract by decreasing the MDA level and increasing the GSH-Px and SOD levels in the lens. It also inhibited H2O2-induced apoptosis in SRA01/04 cells, increased the expression of Bcl-2 protein and decreased the expressions of Caspase-3 and Bax proteins. CONCLUSION: CBPF exerts a significant preventive effect on cataract development by regulating the mitochondrial apoptotic pathway of the lens epithelial cells. It is thus a potent traditional Chinese medicine (TCM) whose application should be further developed for the clinical treatment of cataract.

Use and Awareness of Heated Tobacco Products in Europe.

BACKGROUND: Heated tobacco products (HTP) are new forms of tobacco consumption with limited information available on their use among the general population. Our objective was to analyze the prevalence and associations of use of HTP across 11 countries in Europe. METHODS: Within the TackSHS Project, in 2017-2018 we conducted a cross-sectional study with information on HTP use in the following countries: Bulgaria, England, France, Germany, Greece, Italy, Latvia, Poland, Portugal, Romania and Spain. In each country, face-to-face interviews were performed on a representative sample of around 1,000 subjects aged ≥15 years, for a total of 10,839 subjects. RESULTS: Overall, 27.8% of study participants were aware of HTPs, 1.8% were ever HTP users (ranging from 0.6% in Spain to 8.3% in Greece), and 0.1% were current users. Men were more frequently HTP ever users than women (adjusted odds ratio [aOR] 1.47; 95% confidence interval [CI], 1.11-1.95). Ever HTP use was inversely related to age (P for trend <0.001) and more frequent in ex-smokers (compared with never smokers, aOR 4.32; 95% CI, 2.69-6.95) and current smokers (aOR 8.35; 95% CI, 5.67-12.28), and in electronic cigarette past users (compared with never users, aOR 5.48; 95% CI, 3.46-8.68) and current users (aOR 5.92; 95% CI, 3.73-9.40). CONCLUSIONS: In 2017-2018, HTP use was still limited in Europe among the general population; however, the dual use of these products, their high use among younger generations, and the interest of non-smokers in these products are worrying and indicate the need for close monitoring in terms of prevalence and the characteristics of users.

Cytotoxicity evaluation and metabolism of hepatotoxicity components of Euodiae Fructus in L02 cells.

Euodiae Fructus (EF), the dried unripe scented fruit of Euodia rutaecarpa (Juss.) Benth., was reported to show anti-hypertensive, antitumor, and anti-obesity effects. The main alkaloids of EF were reported as the reason for toxicity of EF by metabolic activation majority through CYP3A. Up till the present moment, the cytotoxicity mechanisms of EF have not yet to be fully clarified. For the purposes of this article, the influence of CYP3A inducer and inhibitor on cytotoxicity of EF and metabolism in L02 cells of five alkaloids related to toxicity of EF were evaluated. The results indicated that CYP3A inducer aggravated the toxicity and CYP3A inhibitor alleviated the toxicity. UPLC-Q-Exactive-MS was used for the identification of five alkaloids of EF in L02 cells. A total of 13 metabolites were detected in L02 cells. In general, five alkaloids were widely metabolized in L02 cells such as oxygenation, demethylation, dehydrogenation, and etc. In addition, oxygenation was the main metabolic pathway. It was inferred that the toxicity of EF was closely related to the CYP3A and the metabolic intermediate might be one of the reasons for the toxicity of EF. Hence, the choice of optimal dose might be critical to avoid the adverse reactions owing to combination of EF and CYP3A inducer.

Modifiable lifestyle-related risk factors for tinnitus in the general population: An overview of smoking, alcohol, body mass index and caffeine intake.

INTRODUCTION: Tinnitus is a symptom and not a disease in its own right. A number of medical conditions are known to increase the risk of developing tinnitus. Most known risk factors are otological or neurological, but general health and lifestyle can also precipitate the condition. Understanding these modifiable risk factors can help to identify vulnerable groups and can inform preventive actions to reduce likelihood of developing tinnitus. Smoking, alcohol consumption, body mass index (BMI) and caffeine intake are all lifestyle risk factors hypothesized to be related to tinnitus. Nonetheless, research findings in support of those relationships are somewhat mixed. METHODS: A systematic review was conducted to identify all relevant studies on the specific risk factors. Findings were summarized using a narrative synthesis and meta-analysis, where possible. RESULTS: Overall 384 studies were included, mostly using cross-sectional designs. Findings indicated significantly increased risk of tinnitus among current (based on 26 studies) and ever smokers (based on 16 studies) and among obese people (based on seven studies), but no effect of alcohol consumption (based on 11 studies). With respect to caffeine intake or coffee drinking, only three studies examined this risk factor and so we were unable to draw conclusions. CONCLUSION: Our results contribute to quantifying the relationship between tinnitus and specific lifestyle-related risk factors, and we highlight some of the gaps and inconsistencies across published studies.

Intestinal microbiota: A potential target for enhancing the antitumor efficacy and reducing the toxicity of immune checkpoint inhibitors.

Accumulating evidence suggests that the intestinal microbiota is associated with the antitumor efficacy of immune checkpoint inhibitors (ICIs) and the occurrence of immune-related adverse events (irAEs) following ICI treatment. However, the mechanisms underlying these interactions remain unclear. Recent technological advances have allowed more extensive investigation into the interplay between the intestinal microbiota and the tumor immune microenvironment. Breakthroughs by two research groups revealed that Bifidobacterium enhanced the efficacy of ICIs via the stimulator of interferon genes (STING) and adenosine 2A receptor (A2AR) signaling pathways, highlighting the molecular mechanisms through which the intestinal microbiota modulates immunotherapy. In this review, we summarize recent findings related to the potential role and mechanisms of the gut microbiota in ICI therapy, available microbiota-targeting strategies, and ongoing clinical trials. Further we discuss the associated challenges that remain in this field of research. The current review aims to evaluate the potential of the intestinal microbiota in maximizing the antitumor efficacy of ICIs while minimizing their toxic effects and guiding the development of more specific treatment regimens.

PADI2-Catalyzed MEK1 Citrullination Activates ERK1/2 and Promotes IGF2BP1-Mediated SOX2 mRNA Stability in Endometrial Cancer.

Peptidylarginine deiminase II (PADI2) converts positively charged arginine residues to neutrally charged citrulline, and this activity has been associated with the onset and progression of multiple cancers. However, a role for PADI2 in endometrial cancer (EC) has not been previously explored. This study demonstrates that PADI2 is positively associated with EC proregression. Mechanistically, PADI2 interacting and catalyzing MEK1 citrullination at arginine 113/189 facilitates MEK1 on extracellular signal-regulated protein kinases 1/2 (ERK1/2) phosphorylation, which activates insulin-like growth factor-II binding protein 1 (IGF2BP1) expression. Furthermore, RNA immunoprecipitation (RIP) and RNA stability analyses reveal that IGF2BP1 binds to the m6A sites in SOX2-3'UTR to prevent SOX2 mRNA degradation. Dysregulation of IGF2BP1 by PADI2/MEK1/ERK signaling results in abnormal accumulation of oncogenic SOX2 expression, therefore supporting the malignant state of EC. Finally, PADI2 gene silencing, inhibiting MEK1 citrullination by PADI2 inhibitor, or mutation of MEK1 R113/189 equally inhibits EC progression. These data demonstrate that PADI2-catalyzed MEK1 R113/189 citrullination is a critical diver for EC malignancies and suggest that targeting PADI2/MEK1 can be a potential therapeutic approach in patients with EC.

Secondhand smoke presence in outdoor areas in 12 European countries.

INTRODUCTION: Secondhand smoke (SHS) causes morbidity and mortality among non-smokers. OBJECTIVES: To investigate SHS presence in outdoor areas from 12 European countries and its association with country-level characteristics. METHODS: Cross-sectional study performed in 2017-2018 within the TackSHS project. We conducted a face-to-face survey on a representative sample of the population aged 15 years and older from 12 European countries: Bulgaria, England, France, Germany, Greece, Ireland, Italy, Latvia, Poland, Portugal, Romania, and Spain. Out of 11,902 participants, 8,562 were non-smokers. SHS presence was assessed in selected outdoor areas and defined as respondents viewing someone smoking the last time they visited each setting within the last 6 months. A ranking score for outdoor SHS presence was assigned to each country based on the SHS presence in each setting. We used Spearman's correlation (r) and the Chi-squared tests to assess the relationship between SHS presence and country-level characteristics. RESULTS: Except for children's playgrounds (39.5%; 95% confidence interval, CI: 37.6%-41.3%), more than half of non-smokers reported SHS presence in outdoor areas: schools (52.0%; 95%CI: 50.2%-53.7%), stadia (57.4%; 95%CI: 55.4%-59.4%), parks (67.3%; 95%CI: 66.0%-68.5%), hospitals (67.3%; 95%CI: 65.8%-68.7%), public transport stops (69.9%; 95%CI: 68.6%-71.2%), bar/restaurant terraces (71.4%; 95%CI: 70.2%-72.6%), and beaches (72.8%; 95%CI: 71.4%-74.1%). Residents in Latvia showed the highest overall outdoor SHS presence rank, followed by Greece, and Portugal. Outdoor SHS presence was directly correlated to the country's smoking prevalence (r = 0.64), and inversely correlated to the Tobacco Control Scale 2016 overall score (r = -0.62), the socio-demographic index 2017 (r = -0.56), and Gross Domestic Product per capita 2018 (r = -0.47) (p < 0.001). CONCLUSIONS: SHS presence is high in most outdoor areas in Europe, especially in countries with higher smoking prevalence and lower tobacco control performance. To address outdoor SHS exposure, our findings require considering smoking bans along with other strategies to reduce smoking prevalence.

Exposure to secondhand aerosol of electronic cigarettes in indoor settings in 12 European countries: data from the TackSHS survey.

INTRODUCTION: Exposure to secondhand aerosol from e-cigarette (SHA) may pose harmful effects to bystanders. This study aims to investigate the prevalence, duration and determinants of SHA exposure in various indoor settings in 12 European countries. METHODS: In 2017-2018, we conducted a cross-sectional study, the TackSHS survey, on a representative sample of the population aged ≥15 years in 12 European countries (Bulgaria, England, France, Germany, Greece, Ireland, Italy, Latvia, Poland, Portugal, Romania and Spain). We described the prevalence and duration of exposure to SHA in several indoor settings among 11 604 e-cigarette non-users. Individual-level and country-level characteristics associated with SHA exposure were also explored using multilevel logistic regression analyses. RESULTS: Overall, 16.0% of e-cigarette non-users were exposed to SHA in any indoor setting at least weekly, ranging from 4.3% in Spain to 29.6% in England. The median duration of SHA exposure among those who were exposed was 43 min/day. 'Other indoor settings' (eg, bar and restaurant) was reported as the place where most of e-cigarette non-users were exposed (8.3%), followed by workplace/educational venues (6.4%), home (5.8%), public transportation (3.5%) and private transportation (2.7%). SHA exposure was more likely to occur in certain groups of non-users: men, younger age groups, those with higher level of education, e-cigarette past users, current smokers, those perceiving SHA harmless and living in countries with a higher e-cigarette use prevalence. CONCLUSIONS: We found inequalities of SHA exposure across and within European countries. Governments should consider extending their tobacco smoke-free legislation to e-cigarettes to protect bystanders, particularly vulnerable populations such as young people. TRIAL REGISTRATION NUMBER: NCT02928536.

Who Smokes in Europe? Data From 12 European Countries in the TackSHS Survey (2017-2018).

BACKGROUND: Population data on tobacco use and its determinants require continuous monitoring and careful inter-country comparison. We aimed to provide the most up-to-date estimates on tobacco smoking from a large cross-sectional survey, conducted in selected European countries. METHODS: Within the TackSHS Project, a face-to-face survey on smoking was conducted in 2017-2018 in 12 countries: Bulgaria, England, France, Germany, Greece, Ireland, Italy, Latvia, Poland, Portugal, Romania, and Spain, representing around 80% of the 432 million European Union (EU) adult population. In each country, a representative sample of around 1,000 subjects aged 15 years and older was interviewed, for a total of 11,902 participants. RESULTS: Overall, 25.9% of participants were current smokers (31.0% of men and 21.2% of women, P < 0.001), while 16.5% were former smokers. Smoking prevalence ranged from 18.9% in Italy to 37.0% in Bulgaria. It decreased with increasing age (compared to <45, multivariable odds ratio [OR] for ≥65 year, 0.31; 95% confidence interval [CI], 0.27-0.36), level of education (OR for low vs high, 1.32; 95% CI, 1.17-1.48) and self-rated household economic level (OR for low vs high, 2.05; 95% CI, 1.74-2.42). The same patterns were found in both sexes. CONCLUSIONS: These smoking prevalence estimates represent the most up-to-date evidence in Europe. From them, it can be derived that there are more than 112 million current smokers in the EU-28. Lower socio-economic status is a major determinant of smoking habit in both sexes.

CYP3A4 inducer aggravates big flower Evodiae Fructus-induced hepatotoxicity whereas limonin attenuates its hepatotoxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Evodiae Fructus (EF), the traditional Chinese medicine, has been typically used to treat headache, abdominal pain, hernias, and menorrhagia for thousands of years. It is a mild toxicity herb-medicine listed in Sheng Nong's Herbal Classic. Recently, EF was reported to have toxicity or no toxicity in some investigations. Toxicity and approaches to reducing toxicity of EF are of great interest. Limonin (LIM), a major triterpenoid component of EF, also had various pharmacological activities such as anti-inflammatory, anticancer, and antioxidant effects. However, little attention was paid to the role of LIM in EF-induced hepatotoxicity. AIM OF STUDY: The study aimed to address the problem of controversial hepatotoxicity of EF, evaluate the role of CYP3A4 inducer/inhibitor in EF-induced hepatotoxicity and disclose the effect of LIM in EF-induced hepatotoxicity. MATERIALS AND METHODS: The chemical compositions and hepatotoxicity of small flower EF (SEF), medium flower EF (MEF), big flower EF (BEF) and the "organ knock-out" samples (the shell and seed part of BEF) were investigated. Simultaneously, C57BL-6 mice were randomly divided into four groups, which were given orally administered BEF, BEF in combination with dexamethasone (DEX), BEF in combination with ketoconazole (KTC), and BEF in combination with LIM, respectively. RESULTS: In this study, more alkaloids and less LIM were detected in BEF compared with the compounds in SEF and MEF. Furthermore, we found that BEF group induced hepatotoxicity whereas no hepatotoxicity was observed in SEF and MEF groups. In addition, no LIM was detected in the shell part of BEF and five alkaloids were not detected in the seed part of BEF. Correspondingly, the shell part of BEF group induced hepatotoxicity whereas no hepatotoxicity was observed in the seed part of BEF group. It was also found that the BEF-induced hepatotoxicity was remarkably exacerbated when the mice were pretreated with DEX whereas the BEF-induced hepatotoxicity could be reversed by pretreatment with KTC or LIM. CONCLUSIONS: Based on the results in this study, the misuse of BEF but not SEF and MEF could produce hepatotoxicity. The hepatotoxicity difference of different categories of EF might be associated with the relative contents of alkaloids and LIM. In addition, the results demonstrated that CYP3A4 inducer aggravated BEF-induced hepatotoxicity and LIM attenuated its hepatotoxicity.

Wilms' tumor 1 (WT1) promotes ovarian cancer progression by regulating E-cadherin and ERK1/2 signaling.

Wilms' tumor 1 (WT1) is reported to play an important role in tumor invasion and metastasis, two hallmarks of ovarian cancer (OC) that influence treatment efficacy and prognosis. However, the specific roles and underlying mechanisms of WT1 in OC have not been fully understood. Here, we investigated the potential function and signaling pathways of WT1 in OC cells. We showed that WT1 was significantly upregulated in human OC tissues and closely associated with OC type, grade and FIGO stage. In cultured cells and xenograft mouse models, WT1 depletion significantly inhibited cell migration and invasion, reversed epithelial-mesenchymal transition (EMT), and prevented metastasis of OC cells. We further demonstrated that WT1 inhibited E-cadherin expression via targeting E-cadherin gene promoter by chromatin immunoprecipitation and luciferase reporter assay. Moreover, ERK1/2 activation was suppressed upon WT1 silencing. Inhibiting ERK1/2 phosphorylation increased E-cadherin expression and suppressed WT1-induced OC cell migration and invasion. Taken together, our study reveals WT1 exerts a tumor-promoting role in OC, enhancing EMT through negative modulation of E-cadherin expression via ERK1/2 signaling. WT1 may represent a novel therapeutic target that may improve the prognosis of OC.