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OBJECTIVE: To evaluate the effectiveness and safety of Chinese medicine (CM) in the treatment of coronavirus disease 2019 (COVID-19) in China. METHODS: A multi-center retrospective cohort study was carried out, with cumulative CM treatment period of ⩾3 days during hospitalization as exposure. Data came from consecutive inpatients from December 19, 2019 to May 16, 2020 in 4 medical centers in Wuhan, China. After data extraction, verification and cleaning, confounding factors were adjusted by inverse probability of treatment weighting (IPTW), and the Cox proportional hazards regression model was used for statistical analysis. RESULTS: A total of 2,272 COVID-19 patients were included. There were 1,684 patients in the CM group and 588 patients in the control group. Compared with the control group, the hazard ratio (HR) for the deterioration rate in the CM group was 0.52 [95% confidence interval (CI): 0.41 to 0.64, P<0.001]. The results were consistent across patients of varying severity at admission, and the robustness of the results were confirmed by 3 sensitivity analyses. In addition, the HR for all-cause mortality in the CM group was 0.29 (95% CI: 0.19 to 0.44, P<0.001). Regarding of safety, the proportion of patients with abnormal liver function or renal function in the CM group was smaller. CONCLUSION: This real-world study indicates that the combination of a full-course CM therapy on the basic conventional treatment, may safely reduce the deterioration rate and all-cause mortality of COVID-19 patients. This result can provide the new evidence to support the current treatment of COVID-19. Additional prospective clinical trial is needed to evaluate the efficacy and safety of specific CM interventions. (Registration No. ChiCTR2200062917).
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In 2019, the US EPA Administrator issued a directive directing the agency away from reliance on vertebrate tests by 2035, whilst maintaining high-quality human health and environmental risk assessments. There is no accepted approach to achieve this. The decade-long duration of the crop protection (CP) chemical R&D process therefore requires both the invention and application of a modernized approach to those CP chemical projects entering corporate research portfolios by the mid-2020s. We conducted problem formulation discussions with regulatory agency scientists which created the problem statement: "Develop, demonstrate, and implement a modern scientifically sound and robust strategy that applies appropriate and flexible exposure and effects characterization without chemical specific vertebrate tests to reliably address risk, uncertainties, and deficiencies in data and its interpretation with equivalent confidence as do the currently accepted test guidelines and meet the regulatory needs of the agencies". The solution must provide the knowledge needed to confidently conclude human health and environmental protective risk assessments. Exploring this led to a conceptual model involving the creation and parallel submission of a new approach without reliance on chemical-specific vertebrate tests. Assessment in parallel to a traditional package will determine whether it supports some, or all, of the necessary risk management actions. Analysis of any deficiencies will provide valuable feedback to focus development of tools or approaches for subsequent iterations. When found to provide sufficient information, it will form the technical foundation of stakeholder engagement to explore acceptance of a new approach to CP chemical risk assessment.
The US EPA, and other regulatory agencies, aim to reduce the use of vertebrate animal tests for assessing risks of crop protection chemicals. There is currently no accepted way to do this. We outline a proposal to perform both the assessment using traditional vertebrate testing and a set of new non-animal methods. These data sets must each be combined with a calculated estimate of user exposure to the pesticide based on its intended use. Comparing the outcome of these two assessments will show whether the set of non-animal methods needs to be improved further. When the new approach appears to reliably predict the risks, the different stakeholders must be brought together to assess whether the non-animal methods package is acceptable and can replace the tests on vertebrate animals while maintaining the same level of protection of human health and the environment.
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Seguridad Química , Humanos , Protección de Cultivos , Medición de RiesgoRESUMEN
With the aid of the newly developed 'Sunway' heterogeneous-architecture supercomputer, which has world-leading HPC (high-performance computer) capability, a series of high-resolution coupled Earth system models (SW-HRESMs) with up to 5 km of atmosphere and 3 km of ocean have been developed. These models can meet the needs of multiscale interaction studies with different computational costs. Here we describe the progress of SW-HRESMs development, with an overview of the major advancements made by the international Earth science community in HR-ESMs. We also show the preliminary results of SW-HRESMs with regard to capturing major weather-climate extremes in the atmosphere and ocean, stressing the importance of permitted clouds and ocean submesoscale eddies in modeling tropical cyclones and eddy-mean flow interactions, and paving the way for further model development to resolve finer scales with even higher resolution and more realistic physics. Finally, in addition to increasing model resolution, the development procedure for a non-hydrostatic cloud and ocean submesoscale resolved ESM is discussed, laying out the major scientific directions of such a huge modeling advancement.
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In observational studies, herbal prescriptions are usually studied in the form of "similar prescriptions". At present, the classification of prescriptions is mainly based on clinical experience judgment, but there are some problems in manual judgment, such as lack of unified criteria, labor consumption, and difficulty in verification. In the construction of a database of integrated traditional Chinese and western medicine for the treatment of coronavirus disease 2019(COVID-19), our research group tried to classify real-world herbal prescriptions using a similarity matching algorithm. The main steps include 78 target prescriptions are determined in advance; four levels of importance labeling shall be carried out for the drugs of each target prescription; the combination, format conversion, and standardization of drug names of the prescriptions to be identified in the herbal medicine database; calculate the similarity between the prescriptions to be identified and each target prescription one by one; prescription discrimination is performed based on the preset criteria; remove the name of the prescriptions with "large prescriptions cover the small". Through the similarity matching algorithm, 87.49% of the real prescriptions in the herbal medicine database of this study can be identified, which preliminarily proves that this method can complete the classification of herbal prescriptions. However, this method does not consider the influence of herbal dosage on the results, and there is no recognized standard for the weight of drug importance and criteria, so there are some limitations, which need to be further explored and improved in future research.
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COVID-19 , Humanos , Algoritmos , Bases de Datos Factuales , Prescripciones , Extractos VegetalesRESUMEN
Global warming and climate change are gaining traction in recent years. As a major cause of global warming, carbon emissions were centered to China's climate change policy initiatives. Nevertheless, the existing policy discourse has yet reached a consensus on the optimal modeling method for carbon emissions prediction that is well-informed of both policy goals and the time-series pattern of carbon emissions. This paper fills the gap by promoting a novel data-driven decision model for carbon emissions prediction that is based on the extended belief rule base (EBRB) inference model. The new decision model consists of three components: 1) an indicator integration method, which aims to generate a few group indicators from a large number of statistical indicators; 2) a new EBRB construction method, which aims to consider the management policy goals for constructing EBRB; 3) a new ER-based inference method, which aims to predict carbon emissions based on time series change of relevant factors. The effectiveness of the proposed decision model has been tested against carbon emissions management data from 30 provinces in China. Experimental results demonstrate that the model will offer powerful reference value in the policy decision-making process, which will help to meet policy requirements for carbon emissions.
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Dióxido de Carbono , Carbono , Carbono/análisis , Dióxido de Carbono/análisis , China , Cambio Climático , Calentamiento GlobalRESUMEN
Conduct of a T-cell-dependent antibody response (TDAR) assay in rodents according to Environmental Protection Agency (EPA) Test Guideline OPPTS 870.7800 is now required for chemical pesticide active ingredients registered in the United States. To assess potential regulatory impact, a retrospective analysis was developed using TDAR tests conducted on 78 pesticide chemicals from 46 separate chemical classes. The objective of the retrospective analysis was to examine the frequency of positive responses and determine the potential for the TDAR to yield lower endpoints than those utilized to calculate reference doses (RfDs). A reduction in the TDAR response was observed at only the high-dose level in five studies, while it was unaltered in the remaining studies. Importantly, for all 78 pesticide chemicals, the TDAR no-observed-adverse-effect levels (TDAR NOAELs) were greater than the NOAELS currently in use as risk assessment endpoints. The TDAR NOAELs were higher than the current EPA-selected endpoints for the chronic RfD, short-term, intermediate and long-term exposure scenarios by 3-27,000, 3-1,688, 3-1,688 and 4.9-1,688 times, respectively. Based on this analysis, conduct of the TDAR assay had minimal impact on hazard identification and did not impact human health risk assessments for the pesticides included in this evaluation. These data strongly support employment of alternative approaches including initial weight-of-evidence analysis for immunotoxic potential prior to conducting functional immunotoxicity testing for pesticide active ingredients.
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Formación de Anticuerpos/efectos de los fármacos , Plaguicidas/toxicidad , Linfocitos T/efectos de los fármacos , Pruebas de Toxicidad/normas , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Nivel sin Efectos Adversos Observados , Ratas , Medición de Riesgo , Estados Unidos , United States Environmental Protection AgencyRESUMEN
As experience is gained with toxicology testing and as new assays and technologies are developed, it is critical for stakeholders to discuss opportunities to advance our overall testing strategies. To facilitate these discussions, a workshop on practices for assessing immunotoxicity for environmental chemicals was held with the goal of sharing perspectives on immunotoxicity testing strategies and experiences, developmental immunotoxicity (DIT), and integrated and alternative approaches to immunotoxicity testing. Experiences across the chemical and pharmaceutical industries suggested that standard toxicity studies, combined with triggered-based testing approaches, represent an effective and efficient approach to evaluate immunotoxic potential. Additionally, discussions on study design, critical windows, and new guideline approaches and experiences identified important factors to consider before initiating DIT evaluations including assay choice and timing and the impact of existing adult data. Participants agreed that integrating endpoints into standard repeat-dose studies should be considered for fulfilling any immunotoxicity testing requirements, while also maximizing information and reducing animal use. Participants also acknowledged that in vitro evaluation of immunosuppression is complex and may require the use of multiple assays that are still being developed. These workshop discussions should contribute to developing an effective but more resource and animal efficient approach for evaluating chemical immunotoxicity.
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Contaminantes Ambientales/toxicidad , Sistema Inmunológico/efectos de los fármacos , Animales , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Humanos , Embarazo , Efectos Tardíos de la Exposición Prenatal , Medición de Riesgo , Pruebas de ToxicidadRESUMEN
Chlorpyrifos was selected for EPA's Endocrine Disruptor Screening Program (EDSP) based on widespread use and potential for human and environmental exposures. The purpose of the program is to screen chemicals for their potential to interact with the estrogen, androgen, or thyroid pathways. A battery of 11 assays was completed for chlorpyrifos in accordance with test guidelines developed for EDSP Tier 1 screening. To determine potential endocrine activity, a weight-of-evidence (WoE) evaluation was completed for chlorpyrifos, which included the integration of EDSP assay results with data from regulatory guideline studies and the published literature. This WoE approach was based on the OECD conceptual framework for testing and assessment of potential endocrine-disrupting chemicals and consisted of a systematic evaluation of data, progressing from simple to complex across multiple levels of biological organization. The conclusion of the WoE evaluation is that chlorpyrifos demonstrates no potential to interact with the estrogen, androgen, or thyroid pathways at doses below the dose levels that inhibit cholinesterase. Therefore, regulatory exposure limits for chlorpyrifos, which are based on cholinesterase inhibition, are sufficient to protect against potential endocrine alterations. Based on the results of this WoE evaluation, there is no scientific justification for pursuing additional endocrine testing for chlorpyrifos.
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Bioensayo/métodos , Cloropirifos/toxicidad , Disruptores Endocrinos/toxicidad , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/metabolismo , Hormonas Tiroideas/metabolismo , Animales , Bioensayo/normas , Guías como Asunto , Humanos , Pruebas de Toxicidad/métodos , Pruebas de Toxicidad/normas , Estados Unidos , United States Environmental Protection AgencyRESUMEN
Suppression of the primary antibody response is particularly sensitive to suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice; however, surprisingly little is known concerning the effects of TCDD on humoral immunity or B cell function in humans. Results from a limited number of previous studies, primarily employing in vitro activation models, suggested that human B cell effector function is suppressed by TCDD. The present study sought to extend these findings by investigating, in primary human B cells, the effects of TCDD on several critical stages leading to antibody secretion including activation and plasmacytic differentiation using an in vitro CD40 ligand activation model. These studies revealed important differences in the response of human and mouse B cells to TCDD, the most striking being altered expression of plasmacytic differentiation regulators, B lymphocyte-induced maturation protein 1 and paired box protein 5, in mouse but not human B cells. The activation of human B cells was profoundly impaired by TCDD, as evidenced by decreased expression of activation markers CD80, CD86, and CD69. The impaired activation correlated with decreased cell viability, which prevented the progression of human B cells toward plasmacytic differentiation. TCDD treatment also attenuated the early activation of mitogen-activated protein kinases (MAPK) and Akt signaling in human B cells. Collectively, the present study provided experimental evidence for novel mechanisms by which TCDD impairs the effector function of primary human B cells.
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Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Ligando de CD40/fisiología , Dibenzodioxinas Policloradas/toxicidad , Animales , Ligando de CD40/antagonistas & inhibidores , Ligando de CD40/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Distribución AleatoriaRESUMEN
Past studies in rodent models identified the suppression of primary humoral immune responses as one of the most sensitive sequela associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Yet, the sensitivity of humoral immunity to TCDD in humans represents an important toxicological data gap. Therefore, the objectives of this investigation were two-fold. The first was to assess the induction of known aryl hydrocarbon receptor (AHR)-responsive genes in primary human B cells as a measure of early biological responses to TCDD. The second was to evaluate the direct effect of TCDD on CD40 ligand-induced immunoglobulin M (IgM) secretion by human primary B cells. The effects of TCDD on induction of AHR-responsive genes and suppression of the IgM response were also compared with B cells from a TCDD-responsive mouse strain, C57BL/6. AHR-responsive genes in human B cells exhibited slower kinetics and reduced magnitude of induction by TCDD when compared with mouse B cells. Evaluation of B-cell function from 12 donors identified two general phenotypes; the majority of donors exhibited similar sensitivity to suppression by TCDD of the IgM response as mouse B cells, which was not attributable to decreased B-cell proliferation. In a minority of donors, no suppression of the IgM response by TCDD was observed. Although donor-to-donor variation in sensitivity to TCDD was observed, human B cells from the majority of donors evaluated showed impairment of effector function by TCDD. Collectively, data presented in this series of studies demonstrate that TCDD impairs the humoral immunity of humans by directly targeting B cells.
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Linfocitos B/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Inmunoglobulina M/metabolismo , Dibenzodioxinas Policloradas/toxicidad , Receptores de Hidrocarburo de Aril/genética , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Antígenos CD40/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunomodulación/efectos de los fármacos , Inmunomodulación/genética , Inmunomodulación/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de Hidrocarburo de Aril/biosíntesis , Factores de TiempoRESUMEN
2,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD) is a potent suppressor of humoral immunity, disrupting antibody production in response to both T cell-dependent and T cell-independent antigens. Among the cell types required for humoral responses, the B cell is highly, and directly, sensitive to TCDD. B cells become antibody-secreting cells via plasmacytic differentiation, a process regulated by several transcription factors, including activator protein-1, B-cell CLL/lymphoma 6 (BCL-6), and B lymphocyte-induced maturation protein 1 (Blimp-1). The overarching conceptual framework guiding experimentation is that TCDD disrupts plasmacytic differentiation by altering the expression or activity for upstream regulators of Blimp-1. Multiparametric flow cytometry was used to investigate TCDD-induced alterations in both activation marker and transcription factor expression following lipopolysaccharide (LPS) activation of purified B cells. TCDD significantly impaired LPS-activated expression of major histocompatibility complex class II, cluster of differentiation (CD)69, CD80, and CD86. Immunosuppressive concentrations of TCDD also suppressed LPS-activated Blimp-1 and phosphorylated c-Jun expression, whereas elevating BCL-6 expression. Because BCL-6 and c-Jun are directly and indirectly regulated by the kinases AKT, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK), it was hypothesized that TCDD alters toll-like receptor-activated kinase phosphorylation. TCDD at 0.03 and 0.3 nM significantly impaired phosphorylation of AKT, ERK, and JNK in CH12.LX B cells activated with LPS, CpG oligonucleotides, or resiquimod (R848). In primary B cells, R848-activated phosphorylation of AKT, ERK, and JNK was also impaired by TCDD at 30 nM. These results suggest that impairment of plasmacytic differentiation by TCDD involves altered transcription factor expression, in part, by suppressed kinase phosphorylation.
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Linfocitos B/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Receptores Toll-Like/fisiología , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Secuencia de Bases , Línea Celular , Ensayo de Inmunoadsorción Enzimática , Femenino , Ratones , Ratones Endogámicos C57BL , Oligonucleótidos , Fosforilación , Factores de Transcripción/metabolismoRESUMEN
Rodent models have been extensively utilized to identify putative human immunotoxicants; however, even when immunotoxicity is established, uncertainty remains whether the effects are predictive of human risk. Therefore, the objective of this study was to establish a polyclonal immunoglobulin M (IgM) antibody-forming cell (AFC) response model to directly characterize immunotoxicity in primary mouse or human B cells. CD40 ligand (CD40L) was selected to activate B cells because it effectively drives both primary human and mouse B cells in vitro to AFC in a physiologically relevant manner to mimic T-cell-dependent antibody responses in vivo. In this model, the IgM AFC response is induced by cell surface-expressed CD40L and promoted by recombinant cytokines. Reported here are the conditions required to induce IgM AFC responses using mouse splenic B cells or human peripheral blood B cells, allowing for species comparisons. Moreover, less than one order of magnitude difference was observed in the CD40L-induced B-cell AFC responses based on data from multiple donors. In addition to antibody production, proliferation and phenotypic changes characteristic of B-cell activation as well as the plasma cell phenotype were also significantly induced. Finally, two well-characterized immunotoxicants, arsenic and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide, using the CD40L-induced IgM AFC response were compared in both mouse and human B cells. Collectively, an IgM AFC response model is described that can be applied to assess the sensitivity of antibody responses to modulation by xenobiotics using mouse as well as human primary B cells.
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Formación de Anticuerpos , Linfocitos B/inmunología , Inmunoglobulina M/inmunología , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/toxicidad , Animales , Antígenos CD/inmunología , Arsénico/toxicidad , Linfocitos B/citología , Linfocitos B/efectos de los fármacos , Proliferación Celular , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Inmunofenotipificación , Ratones , Ratones Endogámicos C57BLRESUMEN
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent suppressor of humoral immunity but the specific molecular mechanisms responsible for immunosuppression by TCDD are poorly understood. In vivo and in vitro studies of the primary humoral IgM response demonstrated that the B cell is a sensitive cell type to modulation by TCDD. We hypothesized that in vivo administration of TCDD disrupts expression of transcription factors controlling B cell to plasma cell differentiation. Female C57BL6 mice were treated with a single dose of TCDD (3, 10, or 30 microg/kg) and/or vehicle (sesame oil). On day 4 post-TCDD administration mice were sensitized with 25 microg lipopolysacchride (LPS) by intraperitioneal injection to stimulate an immune response. Splenocytes were isolated on subsequent days following LPS, up to 3 days post-LPS, and the expression of IgM, XBP-1, PAX5, BCL-6, and Blimp-1 was assessed. TCDD treatment dose-dependently suppressed LPS-induced IgM antibody-forming cell number, which was correlated with decreased frequency of CD19+ CD138+ cells. Gene expression analysis revealed that TCDD caused a dose-dependent suppression of Igmicro chain, Igkappa chain, IgJ chain, XBP-1, and Blimp-1. TCDD also dose-dependently suppressed LPS-stimulated increases in Blimp-1 protein expression in CD19+ B cells. The deregulation of Blimp-1 expression by TCDD provides a partial explanation for the concomitant suppression of the IgM response and confirms previous observations established in vitro.
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Inmunoglobulina M/metabolismo , Lipopolisacáridos/farmacología , Dibenzodioxinas Policloradas/toxicidad , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Factor de Transcripción PAX5/genética , Factor de Transcripción PAX5/metabolismo , Dibenzodioxinas Policloradas/administración & dosificación , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Factores de Transcripción del Factor Regulador X , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína 1 de Unión a la X-BoxRESUMEN
Inducible costimulator (ICOS), a prototypic T cell costimulator, is induced on activated T cells. ICOS regulates T cell activation and Th cell differentiation and is principally involved in humoral immune responses. Previous work showed that T cell accessory function is modulated by the plant-derived cannabinoid, delta-9-tetrahydrocannabinol (Delta(9)-THC). In light of an emerging role by ICOS in T cell-mediated immunity, the objective of this study was to investigate the effect of Delta(9)-THC on ICOS in activated mouse T cells. Induction of ICOS mRNA levels by phorbol ester (PMA) plus ionomycin (Io) activation in mouse splenocytes was attenuated by Delta(9)-THC in a concentration-related manner. Similar results were obtained in the mouse T cell line, EL4.IL-2. Anti-CD3/CD28 induced ICOS expression on CD4(+) splenic T cells, which was suppressed by Delta(9)-THC in a time- and concentration-related manner. The PMA/Io-induced icos promoter luciferase reporter activity was also down-regulated by Delta(9)-THC, suggesting that the suppression of ICOS expression by Delta(9)-THC occurs at the transcriptional level. Moreover, transcriptional activation of the NFAT was also down-regulated by Delta(9)-THC as shown by a NFAT luciferase reporter assay, which is consistent with a putative role of NFAT in regulating ICOS expression. Collectively, Delta(9)-THC suppresses ICOS expression in activated T cells, and this suppression may be related, in part, to its modulation of NFAT signaling. The emerging role of ICOS in a wide range of immune-related diseases also suggests that it may represent a potential therapeutic target, which could be modulated by cannabinoid compounds.
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Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/metabolismo , Dronabinol/farmacología , Animales , Formación de Anticuerpos/efectos de los fármacos , Antígenos/inmunología , Antígenos CD28/metabolismo , Complejo CD3/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Coestimuladora de Linfocitos T Inducibles , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ovinos , Bazo/citología , Bazo/efectos de los fármacos , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Transcripción Genética/efectos de los fármacosRESUMEN
The nuclear factor of activated T cells (NFAT) family proteins are transcription factors that regulate the expression of a variety of target genes with or without forming complexes with other transcription factors. Although NFAT proteins have been extensively investigated and characterized in immune systems, their role in carcinogenesis are far from being understood. We, to our knowledge, are first to determine the potential involvement of the NFAT pathway in cell responses to carcinogen exposure. Experimental evidence accumulated from our studies indicate the critical role of NFAT3 in some carcinogen-induced cell transformation and tumorigenicity. Moreover, NFAT proteins have been found to be involved in cell cycle regulation, cell differentiation, cell survival, angiogenesis, and tumor cell invasion and metastasis. In the meantime, NFAT inhibitors are being developed with the ultimate aim to specifically switch off NFAT signaling without side effects. This review comprehensively reviews the results from the most recent studies, and also discusses some difficulties in current studies. To validate whether NFAT can be a promising target for chemoprevention, more research has to be done to further detail the roles of NFAT and to differentiate the functions of different members of this protein family in future studies.
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Quimioprevención , Factores de Transcripción NFATC/fisiología , Neoplasias/fisiopatología , Animales , Carcinógenos/toxicidad , Humanos , Neoplasias/prevención & controlRESUMEN
It is widely accepted that the consumption of alcohol may lead to hepatic injuries such as hepatic fibrosis and cirrhosis. However, consumption of Maotai, one of the famous liquors in China, is found to have no obvious relevance with hepatic injury as ordinary white wine does in both epidemiological and histopathological studies. Present study used human hepatoma cell line Hep3B to address the mechanisms involved in the resistance of alcohol-induced hepatic injury by Maotai liquor. We found that exposure of Hep3B cells to Maotai residue without ethanol (MRWE) resulted in the increased GST A1 anti-oxidant responsive element (ARE) transcriptional expression, while MRWE treatment did not affect Nrf-2-dependent transcriptional activity. Those findings were further confirmed at all time points and doses tested, suggesting that GST A1 transcription was regulated by MRWE via an Nrf-2-independent pathway. Consistent with GST A1 induction, the phosphorylation of c-Jun, extracellular signal-regulated kinases (ERKs) and p38 kinase (p38 K), were also observed in MRWE-treated Hep3B cells. Furthermore, pretreatment of cells with either PD98059 (an inhibitor specific for MEK1/2-ERKs pathway) or SB202190 (an inhibitor specific for p38 K) led to a significant decrease in the induction of GST A1 transcriptional expression by MRWE treatment. Our results indicate that certain content in MRWE is able to induce GST A1 ARE transcriptional expression, which may provide protective effects for hepatic cells by antagonizing the oxidative stress derived from ethanol via an ERKs- and p38 K-dependent pathway.
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Bebidas Alcohólicas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Glutatión Transferasa/genética , Hígado/enzimología , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Carcinoma Hepatocelular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Glutatión Transferasa/metabolismo , Humanos , Neoplasias Hepáticas , Modelos Biológicos , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Factores de Tiempo , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Transcripción Genética , Quinasa de Factor Nuclear kappa BRESUMEN
Berries have attracted attention for their chemopreventive activities in last a few years. Dietary freeze-dried blackberries have been shown to reduce esophagus and colon cancer development induced by chemical carcinogen in rodents. To elucidate molecular mechanisms involved in chemoprevention by berry extracts, we employed mouse epidermal Cl 41 cell line, a well-characterized in vitro model in tumor promotion studies. Pretreatment of Cl 41 cells with methanol-extracted blackberry fraction RO-ME resulted in a dramatical inhibition of B(a)PDE-induced activation of AP-1 and NFkB, and expression of VEGF and COX-2. The inhibitory effects of RO-ME on B(a)PDE-induced activation of AP-1 and NFkappaB appear to be mediated via inhibition of MAPKs and IkappaBalpha phosphorylation, respectively. In view of the important roles of AP-1, NFkappaB, VEGF and COX-2 in tumor promotion/progression, and VEGF and COX-2 are target of AP-1 and NFkappaB, we anticipate that the ability of black raspberries to inhibit tumor development may be mediated by impairing signal transduction pathways leading to activation of AP-1 and NFkappaB, subsequently resulting in down-regulation of VEGF and COX-2 expression. The RO-ME fraction appears to be the major fraction responsible for the inhibitory activity of black raspberries.
Asunto(s)
Anticarcinógenos/farmacología , Frutas/química , Expresión Génica/efectos de los fármacos , Extractos Vegetales/farmacología , Rosaceae/química , Factores de Transcripción/antagonistas & inhibidores , Animales , Benzopiranos/farmacología , Línea Celular , Ciclooxigenasa 2/genética , Compuestos Epoxi/farmacología , Metanol , Ratones , FN-kappa B/antagonistas & inhibidores , Fitoterapia , Transducción de Señal/efectos de los fármacos , Factor de Transcripción AP-1/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Epidermal growth factor (EGF) has been reported to act as a tumor promoter in several tissues, such as skin, in association with the induction of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). However, molecular mechanisms involved in these regulations are not well defined. This study addressed a potential role of nuclear factor of activated T cells 3 (NFAT3) in EGF-induced COX-2 and iNOS transcription and cell transformation in mouse epidermal Cl 41 cells. We found that EGF markedly induced anchorage-independent growth (cell transformation) of Cl 41 cells, as well as COX-2 (> 6-fold) and iNOS (> 5-fold) promoter-dependent transcription. The EGF-induced COX-2 transcription was blocked by knockdown of NFAT3 with NFAT3 siRNA, whereas the transcription of iNOS and cell transformation induced by EGF were not affected. Although our recent studies supported that NFAT3 plays an essential role in chemical carcinogen benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE)-induced cell transformation, the data presented here demonstrated that NFAT3 is required for EGF-induced COX-2 transcription, but neither iNOS transcription nor cell transformation, indicating that the role of NFAT3 in regulating cell transformation is carcinogen-specific.
Asunto(s)
Ciclooxigenasa 2/genética , Células Epidérmicas , Factor de Crecimiento Epidérmico/farmacología , Epidermis/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Transcripción Genética/efectos de los fármacos , Animales , Línea Celular Transformada , Células Cultivadas , Ciclooxigenasa 2/biosíntesis , Inducción Enzimática/efectos de los fármacos , Humanos , Ratones , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Regiones Promotoras Genéticas/efectos de los fármacos , Regiones Promotoras Genéticas/genética , ARN Interferente Pequeño/metabolismo , Activación Transcripcional/efectos de los fármacos , TransfecciónRESUMEN
Several recent studies have identified nuclear factor-kappaB as a key modulator in driving inflammation to cancers. Besides this transcription factor, essential in regulating inflammation and cancer development, an inflammatory microenvironment inhabiting various inflammatory cells and a network of signaling molecules are also indispensable for the malignant progression of transformed cells, which is attributed to the mutagenic predisposition of persistent infection-fighting agents at sites of chronic inflammation. As a subverted host response to inflammation-induced tumors, the inflammatory cells and regulators may facilitate angiogenesis and promote the growth, invasion, and metastasis of tumor cells. Thus far, research regarding inflammation-associated cancer development has focused on cytokines and chemokines as well as their downstream targets in linking inflammation and cancer. Moreover, other proteins with extensive roles in inflammation and cancer, such as signal transducers and activators of transcription, Nrf2, and nuclear factor of activated T cells, are also proposed to be promising targets for future studies. The elucidation of their specific effects and interactions will accelerate the development of novel therapeutic interventions against cancer development triggered by inflammation.
Asunto(s)
Inflamación/complicaciones , Neoplasias/inmunología , Animales , Humanos , Inflamación/metabolismo , Neoplasias/epidemiología , Neoplasias/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismoRESUMEN
Nickel is a widely distributed metal that is industrially applied in many forms. Accumulated epidemiological evidence confirms that exposures to nickel compounds are associated with increased nasal and lung cancer incidence, both in mostly occupational exposures. Although the molecular mechanisms by which nickel compounds cause cancer are still under intense investigation, the carcinogenic actions of nickel compounds are thought to involve oxidative stress, genomic DNA damage, epigenetic effects, and the regulation of gene expression by activation of certain transcription factors related to corresponding signal transduction pathways. The present review summarizes our current knowledge on the molecular mechanisms of nickel carcinogenesis, with special emphasis on the role of nickel induced reactive oxygen species (ROS) and signal transduction pathways.