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AIMS: To investigate the prevalence of anxiety and depression symptoms in intensive care unit (ICU) patients with cardiovascular disease (CVD) and to explore which elements are risk factors for the development of anxiety and depression symptoms. DESIGN: A cross-sectional study. METHODS: A total of 1028 ICU patients with CVD were enrolled in this cross-sectional study. Logistic regression was used to assess risk factors and associations between anxiety and depression symptoms, and mediation analysis was used to explore the effect of risk factors on the association between anxiety and depression symptoms. Reporting of the study followed the STROBE checklist. RESULTS: The results showed that among ICU patients with CVD, 38.1% had anxiety symptoms, 28.7% had depression symptoms and 19.3% had both anxiety and depression symptoms, and there was a significant association between anxiety and depression symptoms. We also identified female gender, hypertension, hyperlipidemia and cardiac function class IV as independent risk factors for anxiety and depression symptoms. Importantly, these factors also mediated the association between anxiety and depression symptoms, emphasising their role in the psychological well-being of this patient group. CONCLUSION: ICU patients with CVD were prone to anxiety and depression symptoms. Female gender, hypertension, hyperlipidemia and cardiac function class IV were identified as independent risk factors that also served as mediators in the relationship between anxiety and depression symptoms. Especially, cardiac function class IV emerged as a critical factor in this association. RELEVANCE TO CLINICAL PRACTICE: It is imperative for critical care professionals to recognize the elevated risk of depression and anxiety among ICU patients with severe CVD, especially those with cardiac function class IV, hypertension, hyperlipidemia and females. Proactive and supportive measures are essential for this vulnerable group during their ICU stay to safeguard their mental health and prevent negative outcomes. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.
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Hepatitis B virus (HBV) specific T cell immune response plays a vital role in viral clearance. Dendritic cell derived exosomes (Dexs) can activate T cell immunity effectively. Tapasin (TPN) is involved in antigen processing and specific immune recognition. In the present study, we elucidated that Dexs loading TPN (TPN-Dexs) could enhance CD8+ T cell immune response and inhibit virus replication in HBV transgenic mice. T cell immune response and the ability of inhibiting HBV replication were measured in HBV transgenic mice immunized with TPN-Dexs. Meanwhile, CD8+ T cell autophagy and specific T cell immune responses were measured in vitro and vivo, and the mechanisms probably involved in were explored. Purified TPN-Dexs could be taken up into the cytoplasm of DCs and upregulate CD8+ T cell autophagy to enhance specific T cell immune response. In addition, TPN-Dexs could increase the expression of AKT and decrease the expression of mTOR in CD8+ T cells. Further research confirmed that TPN-Dexs could inhibit virus replication and decrease the expression of HBsAg in the liver of HBV transgenic mice. Nevertheless, those also could elicit mice hepatocytes damage. In conclusion, TPN-Dexs could enhance specific CD8+ T cell immune responses via the AKT/mTOR pathway to regulate the autophagy and exert the antiviral effect in HBV transgenic mice.
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Exosomas , Virus de la Hepatitis B , Ratones , Animales , Linfocitos T CD8-positivos , Proteínas Proto-Oncogénicas c-akt , Ratones Transgénicos , Serina-Treonina Quinasas TOR , Presentación de Antígeno , Autofagia , Ratones Endogámicos C57BLRESUMEN
The disaccharide Suc cannot be utilized directly; rather, it is irreversibly hydrolyzed by invertase to the hexoses Glc and Fru to shape plant growth. In this context, Glc controls the stability of the transcription factor Ethylene-Insensitive3 (EIN3) via the function of Hexokinase1 (HXK1), a Glc sensor. Thus, invertase, especially the major neutral cytosolic invertase (CINV), constitutes a key point of control for plant growth. However, the cognate regulatory mechanisms that modulate CINV activity remain unclear. Here, we demonstrate that in Arabidopsis (Arabidopsis thaliana), EIN3 binds directly to both the promoters of Production of Anthocyanin Pigment1 (PAP1) and Phosphatidylinositol Monophosphate 5-Kinase 9 (PIP5K9), repressing and enhancing, respectively, their expression. Subsequently, PAP1 binds directly to and promotes transcription of the Cytosolic Invertase1 (CINV1) promoter, while PIP5K9 interacts with and negatively regulates CINV1. The accumulated CINV1 subsequently hydrolyzes Suc, releasing the sequestered signaling cue, Glc, which has been shown to negatively regulate the stability of EIN3 via HXK1. We conclude that a CINV1-Glc-HXK1-EIN3-PAP1/PIP5K9-CINV1 loop contributes to the modulation of CINV1 activity regulating root growth by Glc signaling.
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Arabidopsis/crecimiento & desarrollo , Arabidopsis/metabolismo , Citosol/metabolismo , Glucosa/metabolismo , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Transducción de Señal/fisiología , beta-Fructofuranosidasa/metabolismo , Variación Genética , Genotipo , Glucosa/genética , Mutación , Raíces de Plantas/genética , Transducción de Señal/genética , beta-Fructofuranosidasa/genéticaRESUMEN
The 3D cell culture model is an indispensable tool in the study of liver biology in the field of health and disease and the development of clinically relevant products for liver therapies. The 3D culture model captures critical factors of the microenvironmental niche required by hepatocytes for exhibiting optimal phenotypes, thus enabling the pursuit of a range of preclinical studies that are not entirely feasible in conventional 2D cell models. In this review, we highlight the major attributes associated with and the components needed for the development of a functional 3D liver culture model for a range of applications.
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Técnicas de Cultivo de Célula/métodos , Hepatocitos/metabolismo , Hígado/citología , Ingeniería de Tejidos/métodos , Bioimpresión/métodos , Matriz Extracelular/metabolismo , Humanos , Trasplante de Hígado , Fenotipo , Impresión Tridimensional , Andamios del TejidoRESUMEN
BACKGROUND: Patients coinfected with HBV and hepatitis D virus (HDV) have a greater risk of HCC and cirrhosis. The current study was undertaken to assess HDV genotype distribution and determine clinical characteristics of hepatitis delta virus (HDV) among HBsAg positive individuals in Shanghai. METHOD: This retrospective study involved 225 serum samples from HBsAg positive hospitalized patients from October 2010 to April 2013. HDV-specific RT-nested PCR was used to amplify HDV RNA. HDV genotypes were characterized by Next-generation sequencing (NGS), followed by phylogenetic analyses. HDV/HBV co-infected patients and HBV mono-infected patients were compared clinically and virologically. RESULTS: Out of the 225 HBsAg-positive serum samples with elevated transaminases, HDV-RNA was identified in 11 (4.9%) patients. The HBV loads in the HDV positive group were significantly lower than the HDV negative HBV-infected patients. The aminotransferase enzymes were significantly higher in HDV/HBV co-infected compared to HDV negative patients (P < 0.05). Phylogenetic analyses indicated that HDV-2 genotype being the predominant genotype, other HDV genotypes were not observed. HDV/HBV patients were significantly associated with a rather unfavourable clinical outcome. CONCLUSION: In summary, the prevalence of HDV infection in patients with elevated transaminases is not low and the predominance of HDV genotype 2 infection in Shanghai. This finding helps us to better understand the correlation of HDV/HBV co-infection. Moreover, Next-generation sequencing (NGS) technologies provide a rapid, precise method for generating HDV genomes to define infecting genotypes.
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Hepatitis D/diagnóstico , Virus de la Hepatitis Delta/genética , Adulto , Secuencia de Aminoácidos , China/epidemiología , Coinfección , Femenino , Genotipo , Hepatitis B/diagnóstico , Hepatitis B/virología , Antígenos de Superficie de la Hepatitis B/sangre , Hepatitis D/epidemiología , Hepatitis D/virología , Virus de la Hepatitis Delta/clasificación , Virus de la Hepatitis Delta/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Prevalencia , ARN Viral/química , ARN Viral/metabolismo , Estudios Retrospectivos , Factores de Riesgo , Carga Viral , Adulto JovenRESUMEN
Novel triphenylethylene-coumarin hybrids containing two amino side chains were designed and synthesized. Some of these 3,4-diphenyl coumarins, 7b-c (the double chains at 4-position on 3-,4-phenyl, respectively), and 13b-f (the double chains at 4-position on 3-phenyl and 7-position, respectively), showed a broad-spectrum and good anti-proliferative activity against five tumor cells and low cytotoxicity in osteoblast. UV-vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation exhibited that compounds 7b (R=piperidinyl), 7e (R=NEt2), and 7f (R=4-methylpiperazinyl) had significant interactions with Ct-DNA by the intercalative mode of binding. Structure activity relationships (SARs) analysis suggested that the location of the two amino alkyl chains would play an important role both in the compounds against tumor cells proliferation and their interactions with DNA.
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Cumarinas/síntesis química , Cumarinas/farmacología , ADN/química , Diseño de Fármacos , Estilbenos/síntesis química , Estilbenos/farmacología , Aminoácidos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dicroismo Circular , Cumarinas/química , Humanos , Estilbenos/química , Relación Estructura-ActividadRESUMEN
Novel dimers of triphenylethylene-coumarin hybrid containing one amino side chain were designed and synthesized by the condensation of four dicarboxylic acids with the amino monomeric hybrids catalyzed by HATU and DIPEA at room temperature. The adding order of the reactants had a significant effect on the condensation reaction when the malonic acid was used. The dimeric compounds 7a and 7b linked by the malonic acid, showed a broad-spectrum and good anti-proliferative activity against four tumor cells and low cytotoxicity in osteoblast. UV-vis, fluorescence, and circular dichroism (CD) spectroscopies and thermal denaturation exhibited that compounds 7b, 8b, 9b, and 10b had significant interactions with Ct-DNA by the intercalative mode of binding. Both the DNA binding properties and the anti-proliferative activities would be enhanced by dimerization of the monomeric hybrid with one amino side chain, and were significantly affected by the length of the linker (dicarboxylic acids).
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Aminas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Cumarinas/farmacología , ADN/química , Estilbenos/farmacología , Animales , Antineoplásicos/síntesis química , Sitios de Unión/efectos de los fármacos , Bovinos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cumarinas/química , Cumarinas/toxicidad , Dimerización , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Células K562 , Células MCF-7 , Estructura Molecular , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Estilbenos/química , Estilbenos/toxicidad , Relación Estructura-ActividadRESUMEN
We have reported a lentivector which could effectively induce HBV-specific cytotoxic T lymphocytes (CTLs). Avasimibe is an inhibitor of acetyl-CoA acetyltransferase-1 (ACAT1), and has been shown to enhance T lymphocyte cytotoxicity on tumor cells. However, the role of avasimibe in lentivector-induced HBV-specific T cytotoxic response remains unknown. Based on previous study, we constructed an integration-deficient lentivector LVDC-ID-HBV (harboring HBcAg expression), and the in vitro experiments showed that the combination of avasimibe exhibited better efficacy in inducing HBV-specific CTL responses including cell proliferation, production of cytokines, as well as CTL killing activities. Mechanism experiments showed that increasing cell membrane cholesterol levels by MßCD-coated cholesterol or ACAT1 inhibition efficiently promoted TCR clustering, signaling transduction and immunological synapse formation, thereby mediating augmented CTL responses. Nevertheless, the depletion of plasma membrane cholesterol with MßCD led to obviously decreased CTL responses. The avasimibe-mediated strengthened immune effects were also determined in animal experiments and the results were in agreement with those from the in vitro research. In particular, the in vivo CTL killing activities were identified by the CFSE or BV-labeled splenocyte lysis assay. Moreover, the experiments in HBV transgenic mice showed that the LVDC-ID-HBV plus avasimibe group demonstrated the lowest serum HBsAg and HBV DNA levels, as well as the lowest expression of HBsAg and HBcAg in liver tissues. We concluded that the HBV-specific CTL immune responses could be potentiated by avasimibe through regulating plasma membrane cholesterol levels. Avasimibe may be a potential adjuvant for lentivector vaccine against HBV infection.
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Antineoplásicos , Antígenos del Núcleo de la Hepatitis B , Ratones , Animales , Antígenos del Núcleo de la Hepatitis B/genética , Virus de la Hepatitis B/fisiología , Antígenos de Superficie de la Hepatitis B/genética , Ratones Transgénicos , Colesterol/metabolismoRESUMEN
BACKGROUND: Ambient air pollution caused by pesticide drift has received great attention. To accurately evaluate the health risk of inhaled pesticides, bioaccessibility should be considered. However, methods to reliably assess pesticide residues remain limited, hindering the precise estimation of exposure assessment. We aimed to optimize an in vitro method for the inhalation bioaccessibility (IBA) measurement of triazole fungicides and to incorporate this into inhalation exposure assessment during pesticide spraying. RESULTS: The IBA of triazole fungicides increased logarithmically with extraction duration, plateauing after 6 h. The frequency of agitation displayed a similar pattern, whereas the ratio of solid to liquid between 1/1500 and 1/250 was considerably negatively associated. The predicted values (35.9-53.5%) for IBA based on optimized methodological parameters determined using a response surface methodology showed an acceptable deviation from experimental values (30.7-50.8%), suggesting feasibility for in vitro IBA measurement. Incorporating IBA into calculations of inhalation exposure amount (IE) yielded a value of 8.5 × 10-7 -2.1 × 10-5 mg kg-1 day-1 , a 50-68% reduction compared to IE based on total amount. Additionally, the safety exposure threshold was determined for triazole fungicides using benchmark dose modelling of data from lung A549 cell proliferation toxicity assays, and in this context, margin of exposure (MOE) values were calculated to be within an acceptable level. CONCLUSION: This in vitro method supplements bioaccessibility evaluation based on pesticide inhalation exposure, along with the risk to human health. © 2023 Society of Chemical Industry.
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Fungicidas Industriales , Residuos de Plaguicidas , Plaguicidas , Humanos , Triazoles/toxicidad , Exposición por Inhalación/efectos adversos , Exposición por Inhalación/análisis , Medición de Riesgo/métodosRESUMEN
Although studies have shown severe Coronavirus disease 2019 (COVID-19) outcomes in patients with pre-existing coronary heart disease (CHD), the prognosis of COVID-19 patients with pre-existing CHD remains uncertain primarily due to the limited number of patients in existing studies. This study aimed to investigate the impacts of pre-existing CHD on the prognosis of COVID-19 patients. Five electronic databases were searched for eligible studies. This article focused on cohort and case-control studies involving the prognosis of COVID-19 patients with pre-existing CHD. The meta-analysis was performed using a random effects model. The odds ratios (ORs) and 95% confidence intervals (CIs) were used as valid indicators. The study was registered in PROSPERO with the identifier: CRD42022352853. A total of 81 studies, involving 157,439 COVID-19 patients, were included. The results showed that COVID-19 patients with pre-existing CHD exhibited an elevated risk of mortality (OR = 2.45; 95%CI: [2.04, 2.94], P < 0.001), severe/critical COVID-19 (OR = 2.57; 95%CI: [1.98, 3.33], P < 0.001), Intensive Care Unit or Coronary Care Unit (ICU/CCU) admission: (OR = 2.75, 95%CI: [1.61, 4.72], P = 0.002), and reduced odds of discharge/recovery (OR = 0.43, 95%CI: [0.28, 0.66], P < 0.001) compared to COVID-19 patients without pre-existing CHD. Subgroup analyses indicated that the prognosis of COVID-19 patients with pre-existing CHD was influenced by publication year, follow-up duration, gender, and hypertension. In conclusion, pre-existing CHD significantly increases the risk of poor prognosis in patients with COVID-19, particularly in those male or hypertensive patients.
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COVID-19 , Enfermedad Coronaria , Hipertensión , Humanos , Masculino , COVID-19/complicaciones , Enfermedad Coronaria/complicaciones , Pronóstico , HospitalizaciónRESUMEN
Hepatitis D is the most severe form of human viral hepatitis and currently lacks an efficient therapy. Dendritic cell-derived exosomes (Dexs) have been found to induce immune responses capable of eliminating viruses. However, the therapeutic potential of antigen-loaded exosomes in hepatitis D is still unknown. Recently, we designed exosomes loaded with ubiquitinated hepatitis delta virus (HDV) small delta antigen (Ub-S-HDAg) and then treated mice bearing replicating HDV with these exosomes to explore their antiviral effect and mechanism. Mature dendritic cell-derived exosomes (mDexs) were loaded with Ub-S-HDAg and their antivirus function was evaluated in mice with HDV viremia. Furthermore, the proportion of CD8+ cells, the ratio of Th1/Th2 cells, the postimmunization levels of cytokines were explored, and the Janus kinases (JAK)/signal transducer and activator of transcription (STAT) pathway was evaluated with a JAK2 inhibitor AG490. In Ub-S-HDAg-Dexs group, the HDV RNA viral load was significantly decreased compared with other groups by CD8+ cell enrichment and an increase Th1/Th2 cell ratio. Furthermore, lymphocyte infiltration was increased, while the HDAg level was decreased in mouse liver tissue. However, there were no significant differences in HBV surface antigen (HBsAg), alanine aminotransferase (ALT), or aspartate aminotransferase (AST) levels among the groups. Moreover, p-JAK2, p-STAT1, p-STAT4, STAT1, and STAT4 expression was increased in Ub-S-HDAg-Dexs group. In conclusion, Ub-S-HDAg-Dexs might be a potential immunotherapeutic agent for eradicating HDV by inducing specific cellular immune response via the JAK/STAT pathway. IMPORTANCE Hepatitis D is the most severe viral hepatitis with accelerating the process of liver cirrhosis and increasing the risk of hepatocellular carcinoma. However, there are no effective antiviral drugs. Exosomes derived from mature dendritic cells are used not only as immunomodulators, but also as biological carriers to deliver antigens to induce robust immune response. Based on these properties, exosomes could be used as a biological immunotherapy by enhancing adaptive immune response to inhibit hepatitis D virus replication. Our research may provide a new therapeutic strategy to eradicate HDV in the future.
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Linfocitos T CD8-positivos/inmunología , Micropartículas Derivadas de Células/inmunología , Exosomas/inmunología , Virus de la Hepatitis Delta/inmunología , Antígenos de Hepatitis delta/inmunología , Balance Th1 - Th2/fisiología , Alanina Transaminasa/análisis , Animales , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Aspartato Aminotransferasas/análisis , Micropartículas Derivadas de Células/virología , Células Cultivadas , Citocinas/sangre , Células Dendríticas/inmunología , Exosomas/virología , Femenino , Antígenos de Superficie de la Hepatitis B/análisis , Antígenos de Hepatitis delta/metabolismo , Factores Inmunológicos/farmacología , Inmunoterapia/métodos , Janus Quinasa 2/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Inhibidores de Proteínas Quinasas/farmacología , Tirfostinos/farmacología , Carga Viral , Replicación Viral/inmunologíaRESUMEN
In crop plants, the yield loss caused by drought exceeds the losses resulting from other adverse environment stresses. In numerous plant species, seedling establishment is positively correlated with the initial seed size under drought stress conditions. In intra- and interspecies, plants with large seeds can withstand water deficiency stresses, whereas those with small seeds are efficient colonizers as a result of their ability to produce more seeds. Therefore, larger initial seeds confer more drought resistance on germinating seedlings. Although this phenomenon has been observed by evolutionary biologists and ecologists, the correlation of initial seed size with the drought resistance of seedlings/plants is not well-reviewed and characterized. Furthermore, the related molecular mechanisms are unknown. Understanding these mechanisms will benefit future breeding or design strategies to increase crop yields. In the present review, we focus on recent research to analyze the genetic factors of plants/crops involved in the regulation of seed size and drought tolerance and their corresponding signal transduction pathways. Several signaling pathways that determine plant drought tolerance through influencing the initial seed size are identified. Such pathways include those that are involved in mitogen-activated protein kinase, abscisic acid, brassinosteroids, and several transcription factors and sugar signaling pathways.
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Productos Agrícolas/crecimiento & desarrollo , Semillas/química , Productos Agrícolas/clasificación , Productos Agrícolas/genética , Productos Agrícolas/metabolismo , Sequías , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Semillas/genética , Semillas/crecimiento & desarrollo , Semillas/metabolismo , Agua/análisis , Agua/metabolismoRESUMEN
In higher plants, seed size is an important parameter and agricultural trait in many aspects of evolutionary fitness. The loss of water-deficiency-induced crop yield is the largest among all natural hazards. Under water-deficient stress, the most prevalent response to terminal stress is to accelerate the early arrest of floral development and, thereby, to accelerate fruit/seed production, which consequently reduces seed size. This phenomenon is well-known, but its molecular mechanism is not well-reviewed and characterized. However, increasing evidence have indicated that water-deficient stress is always coordinated with three genetic signals (i.e., seed size regulators, initial seed size, and fruit number) that decide the final seed size. Here, our review presents new insights into the mechanism underlying cross-talk water-deficient stress signaling with three genetic signals controlling final seed size. These new insights may aid in preliminary screening, identifying novel genetic factors and future design strategies, or breeding to increase crop yield.
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Semillas/citología , Agua/metabolismo , Sequías , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Semillas/genética , Semillas/crecimiento & desarrollo , Semillas/metabolismo , Estrés Fisiológico , Agua/análisisRESUMEN
Purpose: Plumbagin is thought to be a bioactive phytochemical drug and exerts an antitumor effect on various cancers. However, few studies focus on the antitumor activity of plumbagin on liver cancer. This study first investigated the antitumor activity of plumbagin on liver cancer and further investigated the molecular mechanism of its antitumor activity against hepatocellular carcinoma, both in vitro and in vivo. Methods: The antiproliferative activity of plumbagin was evaluated through CCK-8, EdU, and colony forming test. The cell cycle and apoptosis were then analyzed by flow cytometer. Western blot was used to detect the expression of apoptosis related protein, SIVA, and mTOR pathway. RNA-seq was performed to determine the gene expression profiles and overexpressed or knocked down SIVA to validate its role in plumbagin's antitumor activity. Regarding animal experiment, a xenograft model in BALB/c nude mice was built using LM3-Luci cells. Then bioluminescence imaging and further immunohistochemistry were performed to study the antitumor activity and the expression of SIVA and mTOR in the plumbagin-treated group. Results: Plumbagin can inhibit proliferation and induce apoptosis of liver cancer cells in vitro. Further experiment demonstrated that plumbagin could inhibit the expression of SIVA and subsequently downregulate the mTOR signaling pathway, and upregulating the expression of SIVA will alleviate the antitumor activity of plumbagin on liver cancer, which confirmed the important role of the SIVA/mTOR signaling pathway in the antitumor activity of plumbagin. In vivo bioluminescence imaging showed a decreased signal in the plumbagin-treated group, and further immunohistochemistry demonstrated that plumbagin could inhibit the SIVA/mTOR signaling pathway in tumor tissues. Conclusion: Our promising results showed that plumbagin could inhibit proliferation and induce apoptosis of hepatic cancer through inhibiting the SIVA/mTOR signaling pathway for the first time, which indicated that plumbagin might be a good candidate against liver cancer.
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Antineoplásicos Fitogénicos/farmacología , Proteínas Reguladoras de la Apoptosis/genética , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Regulación hacia Abajo/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Naftoquinonas/farmacología , Animales , Proteínas Reguladoras de la Apoptosis/deficiencia , Proteínas Reguladoras de la Apoptosis/metabolismo , Carcinoma Hepatocelular/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Homeobox A10 (HOXA10) has been implicated in the development and progression of various human cancers. However, the precise biological functions of HOXA10 in hepatocellular carcinoma (HCC) have not been defined. METHODS: In this study, we examined mRNA expression by quantitative real-time PCR (qRT-PCR) of HOXA10 as well as histone deacetylase (HDAC) and protein levels by Western blot of HOXA10, HDAC1, Cyclin D1, proliferating cell nuclear antigen (PCNA), Survivin and p53 acetylation in HCC tissues and cell lines. We also assessed cell proliferation using Cell Counting Kit-8 (CCK-8) and analyzed cell cycle by flow cytometry. Furthermore, tumor growth of HCC cells in vivo was monitored using the nude mouse xenograft model. Finally, HDAC1 promoter activity and binding in HCC cell lines were detected by luciferase reporter assay and chromatin immunoprecipitation (ChIP), respectively. RESULTS: We uncovered the elevated expression of HOXA10 in HCC tissues compared to adjacent normal liver tissues. RNA interference-mediated knockdown of HOXA10 inhibited HCC cell proliferation both in vitro and in vivo. HOXA10 knockdown also induced cell cycle arrest at G0/G1 phase and apoptosis, which were accompanied with the reduced expression of Cyclin D1, PCNA and Survivin. Notably, HOXA10 knockdown enhanced p53 acetylation (Lys382), which is crucial to the activation of p53. Likewise, HOXA10 knockdown suppressed the transcription of HDAC1, a potential deacetylase for p53. In line with these observations, HDAC1 downregulation abrogated the effects of HOXA10 overexpression on proliferation, cell cycle progression, apoptosis and p53 acetylation, indicating the role of HDAC1 in mediating HOXA10 functions. CONCLUSION: Our results demonstrate that HOXA10 knockdown inhibits proliferation, induces cell cycle arrest and apoptosis in HCC cells by regulating HDAC1 transcription.
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Anthocyanin accumulation specifically depends on sucrose (Suc) signaling. However, the molecular basis of this process remains unknown. In this study, in vitro pull-down assays identified ETHYLENE-INSENSITIVE3 (EIN3), a component of both sugar signaling or/and metabolism. This protein interacted with YDA, and the physiological relevance of this interaction was confirmed by in planta co-immunoprecipitation, yeast two-hybrid (Y2H) assay, and bimolecular fluorescence complementation. Ethylene insensitive3-like 1 (eil1) ein3 double-mutant seedlings, but not ein3-1 seedlings, showed anthocyanin accumulation. Furthermore, ein3-1 suppressed anthocyanin accumulation in yda-1 plants. Thus, EMB71/YDA-EIN3-EIL1 may form a sugar-mediated gene cascade integral to the regulation of anthocyanin accumulation. Moreover, the EMB71/YDA-EIN3-EIL1 gene cascade module directly targeted the promoter of Transparent Testa 8 (TT8) by direct EIN3 binding. Collectively, our data inferred a molecular model where the signaling cascade of the YDA-EIN3-TT8 appeared to target TT8 via EIN3, thereby modulating Suc signaling-mediated anthocyanin accumulation.
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Antocianinas/biosíntesis , Arabidopsis/genética , Sistema de Señalización de MAP Quinasas , Sacarosa/metabolismo , Antocianinas/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Unión al ADN , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Unión Proteica , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
SUMMARY: The objective of this study was to investigate the mechanism of prenatal stress on the cognitive function of offspring, and clarify the change of histone deacetylase 2 (HDAC2) expression in hippocampal neurons of offspring. 16 pregnant SD rats were randomly divided into control group and stress group, with eight rats in each group. The stress group received restrained stress from 15 to 21 days of pregnancy, while the control group did not receive any treatment. Anxiety-like behavior and spatial memory, learning and memory ability were detected in open field, elevated plus maze, novel object recognition test, and Barnes maze. Nissl staining was used to detect the function of hippocampal neurons. Western blot was used to detect the expression of HDAC2 protein in hippocampal neurons of adult offspring. Immunofluorescence staining was used to detect the expression of HDAC2 protein and hippocampal neurogenesis. The learning and memory ability of adult offspring was decreased. The prenatal stress damaged the function of hippocampal neurons , the expression of HDAC2 was down-regulated, and the number of neurons was reduced. Maternal prenatal stress can down- regulate the expression of HDAC2 in the hippocampus of offspring, inhibits hippocampal neurogenesis and impairs the cognitive function.
El objetivo de este estudio fue investigar el mecanismo del estrés prenatal en la función cognitiva de la descendencia y aclarar el cambio de la expresión de la histona desacetilasa 2 (HDAC2) en las neuronas del hipocampo de la descendencia. 16 ratas SD preñadas se dividieron aleatoriamente en un grupo de control y un grupo de estrés, con ocho ratas en cada grupo. El grupo de estrés recibió estrés durante 15 a 21 días de pre, preñez, mientras que el grupo de control no recibió ningún tratamiento. El comportamiento similar a la ansiedad y la memoria espacial, el aprendizaje y la capacidad de memoria se detectaron en campo abierto, laberinto en cruz elevado, prueba de reconocimiento de objetos novedosos y laberinto de Barnes. La tinción de Nissl se utilizó para detectar la función de las neuronas del hipocampo. Se utilizó Western blot para detectar la expresión de la proteína HDAC2 en las neuronas del hipocampo de la descendencia adulta. La tinción de inmunofluorescencia se utilizó para detectar la expresión de la proteína HDAC2 y la neurogénesis del hipocampo. La capacidad de aprendizaje y memoria de la descendencia adulta se redujo. El estrés prenatal dañó la función de las neuronas del hipocampo, se reguló negativamente la expresión de HDAC2 y se redujo el número de neuronas. El estrés prenatal materno puede regular a la baja la expresión de HDAC2 en el hipocampo de la descendencia, inhibe la neurogénesis del hipocampo y deteriora la función cognitiva.