Marein, a novel natural product for restoring chemo-sensitivity to cancer cells through competitive inhibition of ABCG2 function.

The pivotal roles of ATP-binding cassette (ABC) transporters in drug resistance have been widely appreciated. Here we report that marein, a natural product from Coreopsis tinctoria Nutt, is a potent chemo-sensitizer in drug resistant cancer cells overexpressing ABCG2 transporter. We demonstrate that marein can competitively inhibit efflux activity of ABCG2 protein and increase the intracellular accumulation of the chemotherapeutic drugs that belong to substrate of this transporter. We further show that marein can bind to the conserved amino acid residue F439 of ABCG2, a critical site for drug-substrate interaction. Moreover, marein can significantly sensitize the ABCG2-expressing tumor cells to chemotherapeutic drugs such as topotecan, mitoxantrone, and olaparib. This study reveals a novel role and mechanism of marein in modulating drug resistance, and may have important implications in treatment of cancers that are resistant to chemotherapeutic drugs that belong to the substrates of ABCG2 transporters.

Dual-targeting inhibition of TNFR1 for alleviating rheumatoid arthritis by a novel composite nucleic acid nanodrug.

Selective suppression of tumor necrosis factor (TNF) α-TNF receptor 1 (TNFR1) signaling is a potent solution for rheumatoid arthritis (RA). Herein, novel composite nucleic acid nanodrugs that simultaneously restrain TNF α binding and TNFR1 multimerization were designed to reinforce inhibition of TNF α-TNFR1 signaling for RA therapy. Towards this end, a novel peptide Pep4-19 that suppresses TNFR1 clustering was extracted from TNFR1. The resulting peptide and a DNA aptamer Apt2-55, which inhibits TNF α binding, were integrally or separately anchored on DNA tetrahedron (TD) to obtain nanodrugs with different spatial distribution of Apt2-55 and Pep4-19 (TD-3A-3P and TD-3(A-P)). Our results showed that Pep4-19 enhanced the viability of inflammatory L929 cells. Both TD-3A-3P and TD-3(A-P) suppressed caspase 3, reduced cell apoptosis, and inhibited FLS-RA migration. Compared to TD-3(A-P), TD-3A-3P supplied sufficient flexibility for Apt2-55 and Pep4-19, and showed better anti-inflammation properties. Furthermore, TD-3A-3P significantly relieved symptoms in collagen-induced arthritis (CIA) mice, and the anti-RA efficacy through intravenous injection was comparable to transdermal administration via microneedles. Overall, the work provides an effective strategy for RA treatment by dual-targeting TNFR1, and demonstrates that microneedles are promising approach to drug administration in the treatment of RA.

Tenofovir alters the immune microenvironment of pregnant women with hepatitis B virus infection: Evidence from single-cell RNA sequencing.

BACKGROUND: Mother-to-child is the main route of the transmission of hepatitis B virus (HBV) infection. Tenofovir fumarate (TDF) antiviral treatment has become the most extensive choice worldwide. However, the effects of TDF treatment on the immune function of pregnant women remains unclear. Here we investigate the effect of TDF treatment on the immune microenvironment of pregnant women with HBV infection using single-cell RNA sequencing (scRNA-seq). METHODS: Three HBV-infected pregnant women were treated with TDF and six samples were collected before and after the treatment. In total, 68,200 peripheral blood mononuclear cells (PBMCs) were extracted for 10 × scRNA-seq. The cells were clustered using t-distributed stochastic neighbor embedding (t-SNE) and unbiased computational informatics analysis. RESULTS: The analysis identified four-cell subtypes, including T cells, monocytes, natural killer (NK) cells, and B cells, and unraveled the developmental trajectory and maturation of CD4+ T and CD8+ T cell subtypes. The cellular state and molecular features of the effector/memory T cells revealed a significant increase in the inflammatory state of CD4+ T cells and the cytotoxic characteristics of CD8+ T cells. Additionally, after TDF treatment, the monocytes showed a tendency for M1 polarization, and the cytotoxicity of NK cells was enhanced. Furthermore, the analysis of intercellular communication revealed the interaction of various subtypes of cells and the heterogeneous expression of key signal pathways. CONCLUSIONS: The findings of this study reveal significant differences in cellular subtypes and molecular characteristics of PBMCs of pregnant women with HBV infection before and after TDF treatment and demonstrate the recovery of immune response after treatment. These findings could help develop immune intervention measures to control HBV during pregnancy and the puerperium period.

Mechanistic insights of NAC1 nuclear export and its role in ovarian cancer resistance to docetaxel.

In this study, we uncovered the nuclear export of nucleus accumbens-associated protein-1 (NAC1) as a novel mechanism involved in ovarian cancer resistance to taxanes, the chemotherapeutic drugs commonly used in treatment of this malignancy. We showed that NAC1, a nuclear factor of the BTB/POZ gene family, has a nuclear export signal (NES) at the N terminus (aa 17-28), and this NES critically contributes to the NAC1 nuclear-cytoplasmic shuttling when tumor cells were treated with docetaxel. Mechanistically, the nuclear-exported NAC1 bound to cullin3 (Cul3) and Cyclin B1 via its BTB and BOZ domains respectively, and the cyto-NAC1-Cul3 E3 ubiquitin ligase complex promotes the ubiquitination and degradation of Cyclin B1, thereby facilitating mitotic exit and leading to cellular resistance to docetaxel. We also showed in in vitro and in vivo experiments that TP-CH-1178, a membrane-permeable polypeptide against the NAC1 NES motif, blocked the nuclear export of NAC1, interfered with the degradation of Cyclin B1 and sensitized ovarian cancer cells to docetaxel. This study not only reveals a novel mechanism by which the NAC1 nuclear export is regulated and Cyclin B1 degradation and mitotic exit are impacted by the NAC1-Cul3 complex, but also provides the nuclear-export pathway of NAC1 as a potential target for modulating taxanes resistance in ovarian cancer and other malignancies.

Single-cell RNA sequencing reveals transcriptional profiles of monocytes in HBV-infected pregnant women during mid-pregnancy.

There is a growing body of evidence that innate immunity also plays an important role in the progression of hepatitis B virus (HBV) infection. However, there is less study on systematically elucidating the characteristics of innate immunity in HBV-infected pregnant women. We compared the features of peripheral blood mononuclear cells in three healthy pregnant women and three HBV-infected pregnant women by single-cell RNA sequencing. 10 DEGs were detected between groups and monocytes were the main expression source of most of the DEGs, which involved in the inflammatory response, apoptosis and immune regulation. Meanwhile, qPCR and ELISA were performed to verify above genes. Monocytes displayed immune response defect, reflecting poor ability of response to IFN. In addition, eight clusters were identified in monocytes. We identified molecular drivers in monocytes subpopulations.TNFSF10+ monocytes, MT1G+ monocytes and TUBB1+ monocytes were featured with different gene expression pattern and biological function.TNFSF10+ monocytes and MT1G+ monocytes were characterized by high levels of inflammation response.TNFSF10+ monocytes, MT1G+ monocytes and TUBB1+ monocytes showed decreased response to IFN. Our results dissects alterations in monocytes related to the immune response of HBV-infected pregnant women and provides a rich resource for fully understanding immunopathogenesis and developing effective preventing HBV intrauterine infection strategies.

Electron transfer-based antioxidant nanozymes: Emerging therapeutics for inflammatory diseases.

Inflammatory diseases are usually featured with relatively high level of reactive oxygen species (ROS). The excess ROS facilitate the polarization of microphages into proinflammatory M1 phenotype, and cause DNA damage, protein carbonylation, and lipid peroxidation, resulting in further deterioration of inflammatory diseases. Therefore, alleviating oxidative stress by ROS scavenging has been an effective strategy for reversing inflammation. Inspired by the natural antioxidant enzymes, electron transfer-based artificial antioxidant nanozymes have been emerging therapeutics for the treatment of inflammatory diseases. The present review starts with the basic knowledge of ROS and diseases, followed by summarizing the possible active centers for the preparation of antioxidant nanozymes. The strategies for the design of antioxidant nanozymes on the purpose of higher catalytic activity are provided, and the applications of the developed antioxidant nanozymes on the therapy of inflammatory diseases are discussed. A perspective is included for the design and applications of artificial antioxidant nanozymes in biomedicine as well.

The core of maintaining neuropathic pain: Crosstalk between glial cells and neurons (neural cell crosstalk at spinal cord).

BACKGROUND: Neuropathic pain (NP) caused by the injury or dysfunction of the nervous system is a chronic pain state accompanied by hyperalgesia, and the available clinical treatment is relatively scarce. Hyperalgesia mediated by pro-inflammatory factors and chemokines plays an important role in the occurrence and maintenance of NP. DATA TREATMENT: Therefore, we conducted a systematic literature review of experimental NP (PubMed Medline), in order to find the mechanism of inducing central sensitization and explore the intervention methods of hyperalgesia caused by real or simulated injury. RESULT: In this review, we sorted out the activation pathways of microglia, astrocytes and neurons, and the process of crosstalk among them. It was found that in NP, the microglia P2X4 receptor is the key target, which can activate the mitogen-activated protein kinase pathway inward and then activate astrocytes and outwardly activate neuronal tropomyosin receptor kinase B receptor to activate neurons. At the same time, activated neurons continue to maintain the activation of astrocytes and microglia through chemokines on CXCL13/CXCR5 and CX3CL1/CX3CR1. This crosstalk process is the key to maintaining NP. CONCLUSION: We summarize the further research on crosstalk among neurons, microglia, and astrocytes in the central nervous system, elaborate the ways and connections of relevant crosstalk, and find potential crosstalk targets, which provides a reference for drug development and preclinical research.

Stimulus-responsive and dual-target DNA nanodrugs for rheumatoid arthritis treatment.

Tumor necrosis factor receptor-1 (TNFR1) and DEK are closely associated with the development of rheumatoid arthritis (RA). Taking advantage of the high adenosine triphosphate (ATP) in RA microenvironment and the interactions of DNA aptamers with their targets, an ATP-responsive DNA nanodrug was constructed that simultaneously targets TNFR1 and DEK for RA therapy. To this end, DEK target aptamer DTA and TNFR1 target aptamer Apt1-67 were equipped with sticky ends to hybridize with ATP aptamer (AptATP) and fabricated DNA nanodrug DAT. Our results showed that DAT was successfully prepared with good stability. In the presence of ATP, DAT was disassembled, resulting in the release of DTA and Apt1-67. In vitro studies demonstrated that DAT was superior to the non-responsive DNA nanodrug TD-3A3T in terms of anti-inflammation activity and ATP was inevitable to maximize the anti-inflammation ability of DAT. The superior efficacy of DAT is attributed to the more potent inhibition of caspase-3 and NETs formation. In vivo results further confirmed the anti-RA efficacy of DAT, whereas the administration routes (intravenous injection and transdermal administration via microneedles) did not cause significant differences. Overall, the present study supplies an intelligent strategy for RA therapy and explores a promising administration route for future clinical medication of RA patients.

Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer.

Accurate identification of molecular targets of disease plays an important role in diagnosis, prognosis, and therapies. Breast cancer (BC) is one of the most common malignant cancers in women worldwide. Thus, the objective of this study was to accurately identify a set of molecular targets and small molecular drugs that might be effective for BC diagnosis, prognosis, and therapies, by using existing bioinformatics and network-based approaches. Nine gene expression profiles (GSE54002, GSE29431, GSE124646, GSE42568, GSE45827, GSE10810, GSE65216, GSE36295, and GSE109169) collected from the Gene Expression Omnibus (GEO) database were used for bioinformatics analysis in this study. Two packages, LIMMA and clusterProfiler, in R were used to identify overlapping differential expressed genes (oDEGs) and significant GO and KEGG enrichment terms. We constructed a PPI (protein-protein interaction) network through the STRING database and identified eight key genes (KGs) EGFR, FN1, EZH2, MET, CDK1, AURKA, TOP2A, and BIRC5 by using six topological measures, betweenness, closeness, eccentricity, degree, MCC, and MNC, in the Analyze Network tool in Cytoscape. Three online databases GSCALite, Network Analyst, and GEPIA were used to analyze drug enrichment, regulatory interaction networks, and gene expression levels of KGs. We checked the prognostic power of KGs through the prediction model using the popular machine learning algorithm support vector machine (SVM). We suggested four TFs (TP63, MYC, SOX2, and KDM5B) and four miRNAs (hsa-mir-16-5p, hsa-mir-34a-5p, hsa-mir-1-3p, and hsa-mir-23b-3p) as key transcriptional and posttranscriptional regulators of KGs. Finally, we proposed 16 candidate repurposing drugs YM201636, masitinib, SB590885, GSK1070916, GSK2126458, ZSTK474, dasatinib, fedratinib, dabrafenib, methotrexate, trametinib, tubastatin A, BIX02189, CP466722, afatinib, and belinostat for BC through molecular docking analysis. Using BC cell lines, we validated that masitinib inhibits the mTOR signaling pathway and induces apoptotic cell death. Therefore, the proposed results might play an effective role in the treatment of BC patients.

A Machine Learning Approach Using XGBoost Predicts Lung Metastasis in Patients with Ovarian Cancer.

Background: Liver metastasis (LM) is an independent risk factor that affects the prognosis of patients with ovarian cancer; however, there is still a lack of prediction. This study developed a limit gradient enhancement (XGBoost) to predict the risk of lung metastasis in newly diagnosed patients with ovarian cancer, thereby improving prediction efficiency. Patients and Methods. Data of patients diagnosed with ovarian cancer in the Surveillance, Epidemiology, and Final Results (SEER) database from 2010 to 2015 were retrospectively collected. The XGBoost algorithm was used to establish a lung metastasis model for patients with ovarian cancer. The performance of the predictive model was tested by the area under the curve (AUC) of the receiver operating characteristic curve (ROC). Results: The results of the XGBoost algorithm showed that the top five important factors were age, laterality, histological type, grade, and marital status. XGBoost showed good discriminative ability, with an AUC of 0.843. Accuracy, sensitivity, and specificity were 0.982, 1.000, and 0.686, respectively. Conclusion: This study is the first to develop a machine-learning-based prediction model for lung metastasis in patients with ovarian cancer. The prediction model based on the XGBoost algorithm has a higher accuracy rate than traditional logistic regression and can be used to predict the risk of lung metastasis in newly diagnosed patients with ovarian cancer.

Downregulation of the long non-coding RNA MALAT1 in tenofovir-treated pregnant women with hepatitis B virus infection promotes immune recovery of natural killer cells via the has-miR-155-5p/HIF-1α axis.

BACKGROUND: Currently, tenofovir disoproxil fumarate (TDF) treatment in pregnant women with hepatitis B virus (HBV) infection in the second trimester of pregnancy to reduce the HBV DNA load and block the mother-to-child transmission of HBV has become a consensus. An increasing number of studies have shown that lncRNAs play an important role in immune regulation; however, there are only a few studies on how lncRNAs affect the immune function of TDF-treated pregnant women with HBV infection. METHODS: The peripheral blood of pregnant women with HBV infection was collected before and after TDF treatment for whole-transcriptome sequencing; the differential expression of lncRNA MALAT1 in PBMCs and natural killer (NK) cells was verified by qRT-PCR. ELISA and flow cytometry were used to detect the effect of MALAT1 on NK-92 cells on IFN-γ secretion. Dual-luciferase reporter, qRT-PCR, and western blot analyses were used to verify the relationship between the expression levels of MALAT1, has-miR-155-5p and HIF-1α. RESULTS: After TDF treatment, the MALAT1 expression in the PBMCs of pregnant women with HBV infection, especially in NK cells, was significantly reduced. MALAT1 overexpression decreased IFN-γ secretion in NK-92 cells, while IFN-γ secretion increased after MALAT1 knockdown. Mechanistically, we identified MALAT1 as a competitive endogenous RNA that regulates HIF-1α expression by sponging has-miR-155-5p. Low HIF-1α expression resulted in increased IFNG expression in, and IFN-γ secretion by, NK cells. CONCLUSIONS: Thus, MALAT1 may play an important role in NK cell-mediated immunity in TDF-treated pregnant women with HBV infection by regulating the has-miR-155-5p/HIF-1α axis.

Removal of Antimony in Wastewater by Antimony Tolerant Sulfate-Reducing Bacteria Isolated from Municipal Sludge.

Antimony (Sb), a global and priority controlled pollutant, causes severe environmental issues. Bioremediation by microbial communities containing sulfate-reducing bacteria (SRB) is considered to be among the safest, economical, and environmentally friendly methods to remove Sb from wastewater. However, the roles of SRB species in these communities remain uncertain, and pure cultures of bacteria that may be highly efficient have not yet been developed for Sb removal. In this study, an Sb tolerant community was enriched from municipal sludge, and molecular ecological analysis showed that Escherichia (40%) and Desulfovibrio (15%) were the dominant bacteria. Further isolation and identification showed that the enriched SRB strains were closely related to Cupidesulfovibrio oxamicus, based on the molecular analyses of 16S rRNA and dsrB genes. Among them, a strain named SRB49 exhibited the highest activity in removal of Sb(V). SRB49 was able to remove 95% of Sb(V) at a concentration of 100 mg/L within 48 h under optimum conditions: a temperature of 37-40 °C, an initial pH value of 8, 4 mM of sulfate, and an initial redox potential of 145-229 mV. SEM-EDX analysis showed that SRB49 did not adsorb Sb(V) but reduced and precipitated Sb(V) via the formation of Sb2S3. The results demonstrated the potential roles that pure cultures of SRB species may play in Sb removal and the use of Sb-tolerant SRB strains for Sb remediation.

Alteration of the Immune Microenvironment in HBsAg and HBeAg Dual-Positive Pregnant Women Presenting a High HBV Viral Load.

PURPOSE: The aim of this study was to compare the differences in the immune microenvironment between HBV-infected pregnant women with a high HBV viral load and healthy pregnant women, with an emphasis on T cell subset alteration. PATIENTS AND METHODS: We compared the differences of cellular and molecular signatures between HBV-infected and healthy pregnant women by performing single-cell RNA and T cell receptor sequencing of peripheral blood mononuclear cells from 51,836 women in the mid-trimester pregnancy stage. Specific trajectories of the different T clusters throughout the course of T cell differentiation were investigated. Flow cytometry was used to validate the proportion of different T cell subtypes. RESULTS: We identified nine cellular subtypes and found an increased proportion of effector/memory CD8+ T cells in HBV-infected pregnant women. Both CD4+ and CD8+ effector/memory T cells in HBV-related samples expressed higher levels of metallothionein (MT)-related genes (MT2A, MTIE, MTIF, MTIX), metal ion pathways, and multiple inflammatory responses. Among CD8+ T cell clusters, we identified a particular subset of effector/memory CD8+ T cells (CD8-cluster 2) with MTs as the top-ranking genes, which may be enriched in HBV-related samples. These cells showed an increased clonal expansion in HBV infection. Moreover, we found more active immune responses, according to cellular interaction patterns, between immune cell subsets in HBV-infected samples. CONCLUSION: This study shows significant differences between HBV-infected and healthy samples, including cell clusters, dominant gene sets, T cell function, clonal expansion, and V/J gene usage of T cell clonotypes, and identifies a distinct CD8+ T cell cluster with immune-active and antiviral properties. These findings pave the way for a deeper understanding of the impact of HBV infection on the immune microenvironment during pregnancy.

HBxAg promotes HBV replication and EGFR activation in human placental trophoblasts.

Hepatitis B virus (HBV) infection is a global epidemic. The main transmission route of chronic HBV infection is from mother to child, yet the mechanisms underlying HBV intrauterine infection remain unclear. In the present study, the effect and the mechanism underlying hepatitis B virus X antigen (HBxAg) on HBV replication and EGFR activation in trophoblasts was investigated. Serum samples from pregnant women with HBV infection were used to infect trophoblasts and HBxAg expression was detected using ELISA. HBV plasmids carrying either full length hepatitis B virus X (HBx) or HBx with a deletion mutation (ΔHBx) were transfected into trophoblasts and expression levels of HBV DNA, hepatitis B e-antigen and pregenomic (pg)RNA, and structural maintenance of chromosomes (Smc) 5/6 were assessed. The association between HBx and EGFR promoters was characterized using a luciferase reporter assay and EGFR/PI3K/phosphorylated (p)-AKT expression and apoptosis rate were also monitored. The results of the present study indicated that HBxAg expression increased with the increasing titre of HBV DNA (P<0.05). Compared with the wild-type group, the amount of HBV DNA in the supernatant and cells was significantly reduced (P<0.05) in the ΔHBx group and the intracellular HBeAg and pgRNA levels were also significantly decreased (P<0.05). In addition, Smc5/6 expression was also significantly decreased (P<0.05) when the intracellular HBx protein was expressed compared with mock-transfected cells. Co-transfection of HBx and EGFR promoter plasmids in JEG-3 and HTR-8 cells significantly elevated EGFR promoter driven luciferase expression relative to the control group (P<0.01). In EGFR overexpressing cells, the expression of PI3K/p-AKT was significantly increased, whereas the apoptosis rate was significantly decreased (P<0.05). These results were reversed in the EGFR-knockdown group. In conclusion, the present study demonstrated that HBx promotes HBV replication in trophoblasts via downregulation of Smc5/6, activates the EGFR promoter and inhibits trophoblast apoptosis via the PI3K/p-AKT downstream signalling pathway, thereby increasing the risk of HBV intrauterine infection.

Vitamin A, D, and E Levels and Reference Ranges for Pregnant Women: A Cross-Sectional Study 2017-2019.

Background: Pregnancy-specific vitamin reference ranges are currently not available for maternal vitamin management during pregnancy. This study aimed to propose pregnancy-specific vitamin reference ranges and to investigate the factors influencing vitamin levels during pregnancy. Methods: A cross-sectional study that included pregnant women from 17 cities in 4 provinces in western China was conducted from 2017 to 2019. A total of 119,286 subjects were enrolled in the study. Serum vitamin A, vitamin D, and vitamin E levels were measured. A multivariable linear regression model and restricted cubic spline function were used to analyze the factors related to vitamin levels. Results: The reference ranges for vitamin A, D, and E levels were 0.22-0.62 mg/L, 5-43 ng/mL, and 7.4-23.5 mg/L, respectively. A linear relationship was found between vitamin E level and age (ß = 0.004; 95% confidence interval [CI], 0.0037-0.0042; p < 0.001), and a nonlinear relationship was found between vitamin D (p nonlinear = 0.033) and vitamin A levels and age (p nonlinear < 0.001). Season, gestational trimester, and regions were related to the levels of the three vitamins in the multivariable models (p < 0.05). Conclusions: The lower limit of vitamin A during pregnancy was the same as the reference value currently used for the general population. The reference ranges of vitamins D and E during pregnancy were lower and higher, respectively, than the currently used criteria for the general population. Vitamin A, D, and E levels differed according to age, season, gestational trimester, and region.

Development and validation of a nomogram to predict synchronous lung metastases in patients with ovarian cancer: a large cohort study.

PURPOSE: Lung metastasis is an independent risk factor affecting the prognosis of ovarian cancer patients. We developed and validated a nomogram to predict the risk of synchronous lung metastases in newly diagnosed ovarian cancer patients. METHODS: Data of ovarian cancer patients from the Surveillance, Epidemiology, and Final Results (SEER) database between 2010 and 2015 were retrospectively collected. The model nomogram was built on the basis of logistic regression. The consistency index (C-index) was used to evaluate the discernment of the synchronous lung metastasis nomogram. Calibration plots were drawn to analyze the consistency between the observed probability and predicted probability of synchronous lung metastases. The Kaplan-Meier method was used to estimate overall survival rate, and influencing factors were included in multivariate Cox regression analysis (P<0.05) to determine the independent prognostic factors of synchronous lung metastases. RESULTS: Overall, 16059 eligible patients were randomly divided into training (n=11242) and validation cohorts (n=4817). AJCC T, N stage, bone metastases, brain metastases, and liver metastases were evaluated as predictors of synchronous lung metastases. Finally, a nomogram was constructed. The nomogram based on independent predictors was calibrated and showed good discriminative ability. Mixed histological types, chemotherapy, and primary site surgery were factors affecting the overall survival of patients with synchronous lung metastases. CONCLUSION: The clinical prediction model has high accuracy and can be used to predict lung metastasis risk in newly diagnosed ovarian cancer patients, which can guide the treatment of patients with synchronous lung metastases.

[Toxicological research and safety consideration of coumarins].

Coumarin is an important class of natural organic compounds, which widely exists in a variety of plants and microorganisms. Coumarins have many biological activities and wide clinical applications, such as anti-tumor, anti-HIV, anti-bacterial, anti-inflammatory, anti-oxidation, anti-coagulation, but they have obvious toxic effects in rodents. It was found that the toxicity of coumarins in different animals and organs was significantly different, and high dose oral administration was more likely to produce toxic reactions. Based on the research and analysis of domestic and foreign literatures in recent 60 years, this paper mainly summarized the hepatotoxicity and pulmonary toxicity induced by coumarins, and probed into their possible mechanisms. It was found that the toxicity of coumarins had metabolic differences and species differences. The liver of rats and lungs of mice were more susceptible to coumarins. Toxic reactions occurred mainly in the second metabolic pathway of coumarin metabolism in vivo. In order to put forward safety considerations and evaluate the impact of coumarin on human body, it was found that coumarin is unlikely to produce hepatotoxicity at normal exposure level. It was also suggested that species differences due to different metabolic patterns in model animals should be carefully considered when assessing coumarin toxicity, in order to provide reference for clinical research and rational use of coumarins and improve the rational use of coumarins.

A clinical model to predict the risk of liver metastases in newly diagnosed ovarian cancer: a population-based study.

BACKGROUND: Liver metastases are important in determining the prognosis of ovarian cancer. We aimed to develop and validate nomograms to predict the risk of liver metastases in patients with early-stage ovarian cancer. METHODS: A total of 13,487 patients were enrolled in the study based on their records in the Surveillance, Epidemiology, and End Results (SEER) database. Risk factors of liver metastases were assessed based on univariable and multivariable logistic regression. A nomogram was also formulated based on the results of multivariable logistic analysis. The area under the receiver-operating characteristic curve was calculated to evaluate the discrimination abilities of the metastasis-related factors and liver metastases nomogram. A calibration plot was generated to analyze the consistency between the observed probability and predicted probability of liver metastases in patients with ovarian cancer. RESULTS: Four related factors were determined based on univariable and multivariable logistic regression, including the T1 stage, N1 stage, and presence of lung and bone metastases. The liver metastases nomogram composed of four features could be used to determine the prediction effect. The calibration plot showed good consistency between the nomogram prediction and actual observation. The receiver-operating characteristic curve showed that the forecast nomogram exhibited a good forecast value. CONCLUSIONS: This clinical prediction model has high accuracy to identify patients with newly diagnosed ovarian cancer who carry a high risk of liver metastases and provide a personalized treatment plan for these patients.

Cichorium intybus L. Extract Suppresses Experimental Gout by Inhibiting the NF-κB and NLRP3 Signaling Pathways.

BACKGROUND: The production and maturation of interleukin (IL)-1ß, regulated by the NF-κB and NLRP3 signaling pathways, lie at the core of gout. This study aimed to evaluate the antigout effect of Cichorium intybus L. (also known as chicory) in vivo and in vitro. METHODS: A gout animal model was established with monosodium urate (MSU) crystal injections. Rats were orally administered with chicory extract or colchicine. Levels of ankle edema, inflammatory activity, and IL-1ß release were observed. Several essential targets of the NF-κB and NLRP3 signaling pathways were detected. Primary macrophages were isolated to verify the antigout mechanism of chicory extract as well as chicoric acid in vitro. RESULTS: Improvements of swelling degree, inflammatory activity, and histopathological lesion in MSU-injected ankles were observed in the treatment with chicory extract. Further, the chicory extract significantly decreased IL-1ß release by suppressing the NF-κB and NLRP3 signaling pathways in gout rats. Similar to the in vivo results, IL-1ß release was also inhibited by chicory extract and chicoric acid, a specific effective compound in chicory, through the NF-κB and NLRP3 signaling pathways. CONCLUSION: This study suggests that chicory extract and chicoric acid may be used as promising therapeutic agents against gout by inhibiting the NF-κB and NLRP3 signaling pathways.