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Carcinogens, such as arecoline, play a crucial role in cancer progression and continuous gene mutations by generating reactive oxygen species (ROS). Antioxidants can reduce ROS levels and potentially prevent cancer progression but may paradoxically enhance the survival of cancer cells. This study investigated whether epigallocatechin-3-gallate (EGCG), an antioxidant from green tea, could resolve this paradox. Prostate cancer cells (PC-3 cell line) were cultured and treated with arecoline combined with NAC (N-acetylcysteine) or EGCG; the combined effects on intracellular ROS levels and cell viability were examined using the MTT and DCFDA assays, respectively. In addition, apoptosis, cell cycle, and protein expression were investigated using flow cytometry and western blot analysis. Our results showed that EGCG, similar to NAC (N-acetylcysteine), reduced the intracellular ROS levels, which were elevated by arecoline. Moreover, EGCG not only caused cell cycle arrest but also facilitated cell apoptosis in arecoline-treated cells in a synergistic manner. These were evidenced by elevated levels of cyclin B1 and p27, and increased fragmentation of procaspase-3, PARP, and DNA. Our findings highlight the potential use of EGCG for cancer prevention and therapy.
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Trophoblast migration and invasion play crucial roles in placental development. However, the effects of (-)-epigallocatechin-3-gallate (EGCG) on trophoblast cell functions remain largely unexplored. In this study, we investigated the impact of EGCG on the survival of trophoblast cells and employed a proteomics analysis to evaluate its influence on trophoblast cell migration and invasion. Be-Wo trophoblast cells were treated with EGCG, and a zone closure assay was conducted to assess the cell migration and invasion. Subsequently, a proteomics analysis was performed on the treated and control groups, followed by a bioinformatics analysis to evaluate the affected biological pathways and protein networks. A quantitative real-time PCR and Western blot analysis were carried out to validate the proteomics findings. Our results showed that EGCG significantly suppressed the trophoblast migration and invasion at a concentration not affecting cell survival. The proteomics analysis revealed notable differences in the protein expression between the EGCG-treated and control groups. Specifically, EGCG downregulated the signaling pathways related to EIF2, mTOR, and estrogen response, as well as the processes associated with the cytoskeleton, extracellular matrix, and protein translation. Conversely, EGCG upregulated the pathways linked to lipid degradation and oxidative metabolism. The quantitative PCR showed that EGCG modulated protein expression by regulating gene transcription, and the Western blot analysis confirmed its impact on cytoskeleton and extracellular matrix reorganization. These findings suggest EGCG may inhibit trophoblast migration and invasion through multiple signaling pathways, highlighting the potential risks associated with consuming EGCG-containing products during pregnancy. Future research should investigate the impact of EGCG intake on maternal and fetal proteoforms.
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Both the annotation and identification of genes in pathogenic parasites are still challenging. Although, as a survival factor, nitric oxide (NO) has been proven to be synthesized in Trichomonas vaginalis (TV), nitric oxide synthase (NOS) has not yet been annotated in the TV genome. We developed a witness-to-suspect strategy to identify incorrectly annotated genes in TV via the Smith-Waterman and Needleman-Wunsch algorithms through in-depth and repeated alignment of whole coding sequences of TV against thousands of sequences of known proteins from other organisms. A novel NOS of TV (TV NOS), which was annotated as hydrogenase in the NCBI database, was successfully identified; this TV NOS had a high witness-to-suspect ratio and contained all the NOS cofactor-binding motifs (NADPH, tetrahydrobiopterin (BH4), heme and flavin adenine dinucleotide (FAD) motifs). To confirm this identification, we performed in silico modeling of the protein structure and cofactor docking, cloned the gene, expressed and purified the protein, performed mass spectrometry analysis, and ultimately performed an assay to measure enzymatic activity. Our data showed that although the predicted structure of the TV NOS protein was not similar to the structure of NOSs of other species, all cofactor-binding motifs could interact with their ligands with high affinities. We clearly showed that the purified protein had high enzymatic activity for generating NO in vitro. This study provides an innovative approach to identify incorrectly annotated genes in TV and highlights a novel NOS that might serve as a virulence factor of TV.
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Sepsis is a health issue that affects millions of people worldwide. It was assumed that erythrocytes were affected by sepsis. However, in recent years, a number of studies have shown that erythrocytes affect sepsis as well. When a pathogen invades the human body, it infects the blood and organs, causing infection and sepsis-related symptoms. Pathogens change the internal environment, increasing the levels of reactive oxygen species, influencing erythrocyte morphology, and causing erythrocyte death, i.e., eryptosis. Characteristics of eryptosis include cell shrinkage, membrane blebbing, and surface exposure of phosphatidylserine (PS). Eryptotic erythrocytes increase immune cell proliferation, and through PS, attract macrophages that remove the infected erythrocytes. Erythrocyte-degraded hemoglobin derivatives and heme deteriorate infection; however, they could also be metabolized to a series of derivatives. The result that erythrocytes play an anti-infection role during sepsis provides new perspectives for treatment. This review focuses on erythrocytes during pathogenic infection and sepsis.
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BACKGROUND: To investigate the cost-effectiveness of endovascular aortic repair (EVAR) versus open aortic repair (OAR) for abdominal aortic aneurysm (AAA) using incremental costs per decreased in-hospital mortality rate gained through our patients' cohort. METHODS: Medical records and healthcare costs of patients with AAA hospitalized between 2010 and 2015 were extracted from the National Health Insurance Research Database (NHIRD) of Taiwan. Multiple regression analysis was applied to adjust for confounding factors and to compare the differences in postoperative clinical outcomes between patients who received EVAR and OAR. The incremental cost-effectiveness ratio (ICER) of EVAR was determined based on the healthcare cost obtained from the analyzed data. RESULTS: A total of 2803 AAA patients were identified (n = 559 with ruptured AAA and n = 2244 unruptured AAA). Patients with ruptured AAA who underwent EVAR compared with OAR patients had shorter hospital and intensive care unit (ICU) stays (all p < 0.05). For patients with unruptured AAA, those who received EVAR compared with OAR, the adjusted odds ratio (aOR) of postoperative complications and in-hospital mortality were 0.371 and 0.447 (all p < 0.05). The total direct surgical costs and medical expenses during hospitalization in all AAA patients were higher for the EVAR group; however, ICER was <1 per capita gross domestic product. Stratification by age groups further suggested that ICER for patients with unruptured AAA who received EVAR, compared with OAR, decreased with age. CONCLUSION: Total direct medical costs were higher for AAA patients receiving EVAR regardless of rupture status; however, the cost is offset by lower odds of postoperative complications and in-hospital mortality. The observed decrease in ICER with age and EVAR use warrants further analysis. Our findings further validate the use of EVAR over OAR. These results provides supporting evidence for physicians and patients with AAA to inform shared decision making regarding endovascular or OAR options.
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Aneurisma de la Aorta Abdominal/cirugía , Procedimientos Endovasculares/economía , Mortalidad Hospitalaria , Anciano , Aneurisma de la Aorta Abdominal/fisiopatología , Análisis Costo-Beneficio , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Taiwán/epidemiologíaRESUMEN
OBJECTIVES: Pneumonia is the fourth leading cause of death globally, with rapid progression during sepsis. Multidrug-resistant organisms (MDROs) are becoming more common with some healthcare-associated pneumonia events. Early detection of MDRO risk improves the outcomes; however, MDROs risk in pneumonia with sepsis is unknown. This study investigated the disease outcomes of pneumonia with septic shock in patients admitted in the emergency department (ED) intensive care unit (ICU), a population with a high prevalence of MDROs, after early screening of MDROs risk. METHODS: In this retrospective cohort study, patients with pneumonia and early septic shock (nâ=â533) admitted to the ED at the Taipei Tzu Chi Hospital from 2013 to 2019 were selected. The study population was divided into four subgroups after the MDROs risk and screening procedure were completed within 1 or 6âh of admission. ICU mortality and multidrug antibiotic therapy were compared. RESULTS: The high-risk MDROs groups had higher percentage of P aeruginosa than the low-risk group. Furthermore, the appropriate ED first antibiotics were higher in the 1-h subgroup than in the 6-h subgroup of the high-risk MDROs group. In multivariate analysis, the 6-h high-risk MDROs group had an adjusted odds ratio of 7.191 (95% CI: 2.911-17.767, Pâ<â0.001) and 2.917 (95% CI: 1.456-5.847, Pâ=â0.003) for ICU mortality and multidrug therapy in the ICU, respectively, after adjusting for other confounding factors. CONCLUSIONS: MDRO screening within 1 h is recommended following admission of patients with pneumonia and early septic shock in the ED, especially in areas with a high prevalence of MDROs.
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Farmacorresistencia Bacteriana Múltiple , Neumonía Bacteriana/microbiología , Choque Séptico/microbiología , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Diagnóstico Precoz , Servicio de Urgencia en Hospital , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de RiesgoRESUMEN
Objective: In the present study, we investigated the effects of dextromethorphan (DM) and its metabolites, including dextrorphan (LK2), 3-methoxymorphinan (LK3), and 3-hydroxymorphinan (LK4), on platelet aggregation in vitro and the inflammatory pain caused by carrageenan in rats, and their underlying mechanisms. Materials and Methods: Rabbit platelets were pretreated with DM or its metabolites to assess their effects on platelet aggregation and related target mediators. In addition, the analgesic activity and the underlying mechanisms of DM and LK3 were investigated in a carrageenan-evoked thermal hyperalgesia rat model. Results: The inhibitory potency of DM and its metabolites on platelet aggregation induced by arachidonic acid or collagen was LK3> DM > LK4>> LK2 as demonstrated by the half-maximal inhibitory concentration values. Moreover, the mechanisms of the antiplatelet effect of DM and LK3 may involve the inhibition of intracellular calcium mobilization, expression of platelet surface glycoprotein IIb/IIIa, the formation of thromboxane B2, and elevation of platelet membrane fluidity. DM and LK3 also exhibited analgesic effects on carrageenan-evoked thermal hyperalgesia by suppressing the production of pro-inflammatory cytokines, nitric oxide, prostaglandin E2, and neutrophil infiltration in inflammatory sites. Conclusion: DM and its metabolites, especially LK3, exhibit both antiplatelet and analgesic effects, and may, therefore, potentially ameliorate platelet hyperactivity and inflammatory-related diseases.
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OBJECTIVES: Appropriate initial antibiotic therapy is critical for successfully treating sepsis. In the emergency department (ED), clinicians often rely on septic symptoms to guide empirical therapy. The aim of this study was to investigate whether history of contacting pre-ED healthcare setting is easy to be neglected and whether the patients received more inappropriate initial antibiotic therapy and developed poorer outcomes. METHODS: Septic patients (n = 453) admitted from ED to the intensive care unit (ICU) between 2014 and 2017 were retrospectively selected. Appropriate antibiotic treatment or not was determined by checking whether the selected antibiotics can effectively eradicate the bacteria identified. Various indexes were compared between patients with appropriate and inappropriate initial antibiotic treatments, including septic symptoms (qSOFA scores) in ED, septic-severity change in ICU (SOFA-score ratios), and septic outcomes (APACHE II scores, stay length, 30-day survival probability). These indexes were also compared between pre-ED healthcare and pre-ED community patients. RESULTS: In comparison with pre-ED community patients, pre-ED healthcare patients received more inappropriate initial antibiotic treatment in ED, showing poorer outcomes in ICU, including septic severity, stay-lengths in ICU and 30-day survival probabilities. Pre-ED settings is more significant than qSOFA scores to predict the inappropriate initial antibiotic treatment. CONCLUSIONS: Pre-ED healthcare settings, which are indexes for infection with antibiotic resistant pathogens, are easy to be neglected in the first hour in ED. We suggested that standard operating procedure for getting enough information of pre-ED settings should be incorporated to the 1 h bundle of sepsis guideline.
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Antibacterianos/uso terapéutico , Servicio de Urgencia en Hospital/normas , Prescripción Inadecuada/efectos adversos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Anciano , Comorbilidad , Diagnóstico Precoz , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Hospitalización , Humanos , Prescripción Inadecuada/estadística & datos numéricos , Tiempo de Internación , Masculino , Pronóstico , Estudios Retrospectivos , Sepsis/diagnósticoRESUMEN
Dysregulation of alveolar macrophage activation has been recognized as the major mechanism in the pathogenesis of acute lung injury. The aim of the present study was to investigate the role of NKCC1 regulating mechanism in modulating macrophage activation. Knockout (SPAK-/- and WNK4-/-) and knockin (WNK4D561A/+) mice were used in this study. LPS induced expression of p-NKCC1 and activation of NFκB in the primary culture of alveolar macrophages. WNK4 or SPAK knockout suppressed p-NKCC1 expression and inflammation cascade activation, whereas WNK4 knockin enhanced these responses. Intrapulmonary administration of LPS induced in vivo expression and phosphorylation of NKCC1 in alveolar inflammation cells and caused a shift in the cell population from macrophage to neutrophil predominance. WNK4 or SPAK knockout attenuated the LPS-induced alveolar cell-population shifting, macrophage NKCC1 phosphorylation, and acute lung injury, whereas WNK4 knockin augmented the inflammatory response. In summary, our results demonstrated the presence of NKCC1 in alveolar macrophage, which is inducible by lipopolysaccharide. Our results also showed showed that the WNK4-SPAK-NKCC1 cascade plays an important role in modulating macrophage activation to regulate LPS-induced lung inflammation and lung injury.
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FN-kappa B/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , Animales , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Lipopolisacáridos/farmacología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/genética , Lesión Pulmonar/metabolismo , Macrófagos Alveolares/citología , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , FN-kappa B/genética , Fosforilación/efectos de los fármacos , Neumonía/inducido químicamente , Neumonía/genética , Neumonía/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Miembro 2 de la Familia de Transportadores de Soluto 12/genéticaRESUMEN
Staphylococcus aureus is frequently isolated from patients with community-acquired pneumonia and acute respiratory distress syndrome (ARDS). ARDS is associated with staphylococcal phosphatidylinositol-specific phospholipase C (PI-PLC); however, the role of PI-PLC in the pathogenesis and progression of ARDS remains unknown. Here, we showed that recombinant staphylococcal PI-PLC possesses enzyme activity that causes shedding of glycosylphosphatidylinositol-anchored CD55 and CD59 from human umbilical vein endothelial cell surfaces and triggers cell lysis via complement activity. Intranasal infection with PI-PLC-positive S. aureus resulted in greater neutrophil infiltration and increased pulmonary oedema compared with a plc-isogenic mutant. Although indistinguishable proinflammatory genes were induced, the wild-type strain activated higher levels of C5a in lung tissue accompanied by elevated albumin instillation and increased lactate dehydrogenase release in bronchoalveolar lavage fluid compared with the plc- mutant. Following treatment with cobra venom factor to deplete complement, the wild-type strain with PI-PLC showed a reduced ability to trigger pulmonary permeability and tissue damage. PI-PLC-positive S. aureus induced the formation of membrane attack complex, mainly on type II pneumocytes, and reduced the level of CD55/CD59, indicating the importance of complement regulation in pulmonary injury. In conclusion, S. aureus PI-PLC sensitised tissue to complement activation leading to more severe tissue damage, increased pulmonary oedema, and ARDS progression.
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Proteínas Bacterianas/metabolismo , Proteínas del Sistema Complemento/metabolismo , Fosfoinositido Fosfolipasa C/metabolismo , Edema Pulmonar/inmunología , Edema Pulmonar/microbiología , Síndrome de Dificultad Respiratoria/microbiología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/enzimología , Células Epiteliales Alveolares/enzimología , Células Epiteliales Alveolares/inmunología , Células Epiteliales Alveolares/microbiología , Animales , Proteínas Bacterianas/genética , Antígenos CD55/inmunología , Antígenos CD59/inmunología , Citocinas/metabolismo , Glicosilfosfatidilinositoles/inmunología , Glicosilfosfatidilinositoles/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos BALB C , Fosfoinositido Fosfolipasa C/genética , Edema Pulmonar/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/metabolismo , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismoRESUMEN
BACKGROUND: The incidence rate of nasopharyngeal carcinoma (NPC) has been documented to be high in Southeast Asia. Interleukin-18 (IL-18) is a multifunctional cytokine that augments interferon-γ production and acts as an important immunomediator in the development of several types of cancer. PATIENTS AND METHODS: This case-control study evaluated the role of IL-18 in NPC at the DNA level by genotyping its promoter polymorphisms at positions -656, -607, and -137 in a Taiwanese population. A total of 176 patients with NPC and age- and gender-matched 352 noncancer controls were included in this study. RESULTS: The CC genotype of the IL-18-607 polymorphism was found to be associated with significantly decreased risks of NPC compared to the AA genotype (crude OR =0.50, 95% CI =0.29-0.84, P=0.0093). This significant difference persisted even in the dominant and recessive models. A significantly lower C allele frequency at position -607 was detected in the NPC group(41.8% vs 50.3%; OR =0.77; 95% CI =0.63-1.04, P=0.0089). Regarding IL-18-656 and -137 polymorphisms, there were no differential distributions of their genotypes between the NPC and control groups. After substratification of the subjects according to their smoking, alcohol consumption, and areca chewing status, the genotype distribution of the IL-18-607 polymorphism was found to be different only among nonsmokers between the NPC and control subgroups. CONCLUSION: This study suggests that IL-18 plays an important role in the carcinogenesis of NPC in Taiwan and that the genotype-phenotype correlation of IL-18-607 polymorphism and its contribution to NPC need to be investigated further.
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BACKGROUND: Troponin I is better than other troponin isoforms for monitoring cardiocyte damage, and correlates with sepsis-related mortality. However, hemodynamic factors possibly interact with cardiac function to affect mortality in sepsis. Thus, this study used parameters from pulse-induced contour cardiac output (PiCCO) to investigate the possibility. METHODS: Patients with troponin I tests and sequential organ failure assessment score ≥2 were selected and divided into survivors and nonsurvivors groups and blood troponin I levels between them were compared. Additionally, 65 patients with septic shock and PiCCO records were selected and divided into high cardiac function index (CFI) and low CFI groups and their cardiac function associated with troponin I levels was checked. Furthermore, the patients were classified into 4 subgroups based on CFI and another hemodynamical parameter of PiCCO for identifying if any interaction between CFI and the parameter existed. RESULTS: High blood troponin I levels correlated with high mortality, and with low cardiac function (CFI < 4.5) alone or with low CFI combined with high stroke volume variation (SVV), but did not correlate with global end-diastolic index (GEDI), or systemic vascular resistance index. However, only the subgroup with low CFI and high SVV (CFI < 4.5 and SVV > 10) increased mortality. CONCLUSIONS: Our data give an insight into interactions between cardiac and hemodynamic factors to cause cardiocyte damage and suggest that multiple factors (i.e., low CFI and high SVV) should be considered together to evaluate cardiocyte damage and mortality in sepsis.
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Frecuencia Cardíaca , Corazón/fisiopatología , Choque Séptico , Volumen Sistólico , Troponina I/sangre , Resistencia Vascular , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Choque Séptico/sangre , Choque Séptico/mortalidad , Choque Séptico/fisiopatologíaRESUMEN
The incidence rate of nasopharyngeal cancer (nasopharyngeal carcinoma [NPC]) is much higher in Southeast Asia than in western countries. Interleukin-8 (IL-8), a chemokine produced by macrophages, epithelial cells, airway smooth muscle cells, and endothelial cells, is an important immuno-mediator in the development and progression of many types of cancer. Genetic variations in IL-8 have been associated with the risks of NPC and other cancers. In the current study, we evaluated the role of IL-8 in NPC at the levels of DNA, RNA, and protein in a Taiwanese population. First, in a case-control study, 176 NPC patients and 352 cancer-free controls were genotyped, and the associations of IL-8 Tâ-â251A, Câ+â781T, Câ+â1633T, and Aâ+â2767T polymorphisms with NPC risk were evaluated. Second, the NPC tissue samples were assessed for their IL-8 mRNA and protein expression by real-time quantitative reverse transcription polymerase chain reaction (PCR) and Western blotting, respectively. Regarding the IL-8 promoter Tâ-â251A, the TA and AA genotypes were associated with significantly decreased risks of NPC compared with the wild-type TT genotype (adjusted odds ratioâ=â0.61 and 0.52, 95% confidence interval = 0.47-0.93 and 0.37-0.91, Pâ=â.0415 and .0289, respectively). The mRNA and protein expression levels for NPC tissues revealed no significant associations among the 20 NPC samples with different genotypes. These findings suggest that IL-8 may play an important role in the carcinogenesis of NPC in Taiwan.
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Carcinoma/genética , Predisposición Genética a la Enfermedad , Interleucina-8/genética , Neoplasias Nasofaríngeas/genética , Pueblo Asiatico/genética , Carcinoma/etnología , Carcinoma/metabolismo , Carcinoma/patología , Estudios de Casos y Controles , Femenino , Interacción Gen-Ambiente , Estudios de Asociación Genética , Humanos , Interleucina-8/metabolismo , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/etnología , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , TaiwánRESUMEN
This study tested the hypothesis that the effects of lovastatin on anaplastic thyroid cancer cell growth are mediated by upregulation of transketolase (TKT) expression. The effects of lovastatin on TKT protein levels in ARO cells were determined using western blot and proteomic analyses. After treatment with lovastatin and oxythiamine, the in vitro and in vivo growth of ARO cells was determined using 3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assays and tumor xenografts in nude mice. TKT protein expression in the ARO tumors was assessed using immunohistochemistry analysis. Proteomic analysis revealed that 25 µM lovastatin upregulated TKT expression. Co-treatment of ARO cells with 1 µM lovastatin + 1 µM oxythiamine increased TKT protein expression compared with control levels; however, no differences were observed with 10 µM lovastatin + 1 µM oxythiamine. Furthermore, treatment with either oxythiamine or lovastatin alone reduced ARO tumor expression of TKT, as well as decreased ARO cell proliferation in vitro and tumor growth in vivo. However, mice treated with both lovastatin and oxythiamine at the same time had tumor volumes similar to that of the untreated control group. We conclude that either lovastatin or oxythiamine reduced ARO cell growth; however, the combination of these drugs resulted in antagonism of ARO tumor growth.
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Lovastatina/uso terapéutico , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/patología , Transcetolasa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Lovastatina/farmacología , Masculino , Ratones Desnudos , Oxitiamina/farmacología , Proteómica , Carcinoma Anaplásico de Tiroides/enzimología , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Low concentrations of carbon monoxide (CO) have anti-inflammatory effects and can reduce bone erosion in a murine collagen-induced arthritis model. The objective of this study was to assess the effects of CO on receptor activator of NF-κB ligand (RANKL), one of the key stimulators of osteoclastogenesis. METHODS: The in vivo effects of CO on RANKL expression were assessed in a collagen antibody-induced arthritis model in mice. Cell proliferation and apoptosis were assessed in the RAW246.7 cell line stimulated with RANKL and exposed to either air or CO. The number of tartrate resistant acid phosphatase (TRAP)-positive RAW246.7 cells was also examined after treatment with RANKL and the peroxisome proliferator-activated receptor gamma (PPARγ) agonist, Troglitazone. RESULTS: CO reduced RANKL expression in the synovium of arthritic mice. Although CO slightly increased RAW246.7 cell proliferation, no differences in activated caspase 3 levels were detected. In addition, Troglitazone ameliorated the inhibitory effects of CO on RANKL-induced TRAP expression by RAW246.7 cells. CONCLUSIONS: CO suppresses osteoclast differentiation by inhibiting the RANKL-induced activation of PPAR-γ. Given the role of the PPAR-γ/cFos (AP-1) pathway in regulating the transcription factor, NFATc1, the master regulator of osteoclastogenesis, further studies are warranted to explore CO in treating inflammatory bone disorders.
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Antiinflamatorios no Esteroideos/farmacología , Antimetabolitos/farmacología , Artritis Experimental/tratamiento farmacológico , Monóxido de Carbono/farmacología , Osteoclastos/efectos de los fármacos , Ligando RANK/antagonistas & inhibidores , Fosfatasa Ácida/genética , Fosfatasa Ácida/metabolismo , Administración por Inhalación , Animales , Apoptosis/efectos de los fármacos , Artritis Experimental/genética , Artritis Experimental/metabolismo , Artritis Experimental/patología , Caspasa 3/genética , Caspasa 3/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Cromanos/farmacología , Regulación de la Expresión Génica , Isoenzimas/genética , Isoenzimas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Osteoclastos/metabolismo , Osteoclastos/patología , PPAR gamma/antagonistas & inhibidores , PPAR gamma/genética , PPAR gamma/metabolismo , Ligando RANK/farmacología , Transducción de Señal , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Fosfatasa Ácida Tartratorresistente , Tiazolidinedionas/farmacología , TroglitazonaRESUMEN
AIM: Reliable biomarkers are in urgent need for diagnosis, outcome prediction and treatment-effect monitoring for upper tract urothelial carcinomas (UTUC). Although up-regulation of cyclo-oxygenase 2 (COX2) is found in stroma and tumor cells in more than half of the patients with UTUC investigated, the genomic contribution of COX2 to UTUC has not been studied. The study aimed to evaluate the association of six polymorphic genotypes of COX2 with UTUC within a Taiwanese population. MATERIALS AND METHODS: A total of 218 patients with UTUC and 580 healthy controls were genotyped for six COX2 polymorphisms, namely A-1195G, G-765C, T+8473C, intron 1, intron 5 and intron 6, and examined for their association with UTUC risk. RESULTS: The distribution of genotypes of COX2 G-765C and intron 5 were significantly different between patient and control groups (p=0.0001 and 0.0016, respectively), while others were not (p>0.05). The haplotype analysis showed that compared to the GG/TT haplotype of COX2 G-765C/intron 5, those carrying GG/AT variants have a significantly increased risk of UTUC (odds ratio=4.83, 95% confidence interval=1.79-13.06), while those carrying CG/TT variants have a decreased risk (odds ratio=0.26, 95% confidence interval=0.14-0.49). CONCLUSION: Our results suggest that individual and combined COX2 G-765C/intron 5 genotypes play a role in controlling COX2 expression and UTUC development.
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Carcinoma de Células Transicionales/genética , Ciclooxigenasa 2/genética , Neoplasias Urológicas/genética , Urotelio/patología , Adulto , Anciano , Carcinogénesis/genética , Carcinoma de Células Transicionales/patología , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias Urológicas/patologíaRESUMEN
Colorectal cancer, one million cases of diagnosis worldwide annually, is one of the most common malignant tumors and 20 % incidence caused by low penetrance susceptibility genes. Cyclin D1 (CCND1) regulating cell cycle transition may determine the susceptible individuals to genomic instability and carcinogenesis. The study aimed at examining the contribution of CCND1 genotypes to colorectal cancer risk in Taiwan. The genotypes of CCND1 A870G (rs9344) and G1722C (rs678653) were determined among 362 colorectal cancer patients and 362 age- and gender-matched cancer-free controls. Significant differences were observed between colorectal cancer and control groups in the distributions of genotypic (P = 9.71 × 10(-4)) and allelic (P = 0.0017) frequencies at CCND1 A870G. Additionally, individuals carried AG or GG genotype had 0.56- or 0.51-fold higher of odds ratios for developing colorectal cancer than the AA genotype (95 % confidence intervals = 0.40-0.78 and 0.32-0.81, respectively). Furthermore, G allele of CCND1 A870G performed a protective effects for nonsmokers and nonalcohol drinkers (P = 0.0012 and 0.0007, respectively) on colorectal cancer risk. These findings support the concept that the cell cycle regulation may play a role in colorectal cancer initiation and development and CCND1 A870G genotyping maybe a feasible technology for colorectal cancer early detection.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Ciclina D1/genética , Predisposición Genética a la Enfermedad , Anciano , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Pronóstico , Factores de Riesgo , Fumar , TaiwánRESUMEN
Dermal papillae (DPs) control the formation of hair shafts. In clinical settings, colchicine (CLC) induces patients' hair shedding. Compared to the control, the ex vivo hair fiber elongation of organ cultured vibrissa hair follicles (HFs) declined significantly after seven days of CLC treatment. The cultured DP cells (DPCs) were used as the experimental model to study the influence of CLC on the protein dynamics of DPs. CLC could alter the morphology and down-regulate the expression of alkaline phosphatase (ALP), the marker of DPC activity, and induce IκBα phosphorylation of DPCs. The proteomic results showed that CLC modulated the expression patterns (fold>2) of 24 identified proteins, seven down-regulated and 17 up-regulated. Most of these proteins were presumably associated with protein turnover, metabolism, structure and signal transduction. Protein-protein interactions (PPI) among these proteins, established by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, revealed that they participate in protein metabolic process, translation, and energy production. Furthermore, ubiquitin C (UbC) was predicted to be the controlling hub, suggesting the involvement of ubiquitin-proteasome system in modulating the pathogenic effect of CLC on DPC.
Asunto(s)
Colchicina/farmacología , Folículo Piloso/crecimiento & desarrollo , Proteoma/metabolismo , Vibrisas/citología , Animales , Bases de Datos de Proteínas , Metabolismo Energético , Regulación de la Expresión Génica , Folículo Piloso/efectos de los fármacos , Técnicas de Cultivo de Órganos , Proteoma/química , Proteómica , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Vibrisas/metabolismoRESUMEN
The aim of the present study was to evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and its interaction with early-onset breast cancer risk in Taiwan. Two well-known polymorphic variants of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed and their joint effects with individual age- and estrogen-related factors on breast cancer risk were discussed. In total, 1,232 patients with breast cancer and 1,232 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The MTHFR C677T genotype, but not the A1298C, was differently distributed between cancer and control groups. The T allele of MTHFR C677T was significantly more frequently found in controls than in patients with cancer. In addition, females carrying MTHFR C677T CT or TT genotypes had a higher odds ratio of 1.21 (95% confidence interval=1.03-1.42, p=1.85E-5) for breast cancer, especially before the age of 45.4 years (odds ratio=1.51 and 95% confidence interval=1.20-1.90). Our results indicate that MTHFR C677T T allele was associated with increased risk of breast cancer in Taiwan, especially in cases who were 45.4 old or younger and with earlier menarche age (<12.2 years).
Asunto(s)
Neoplasias de la Mama/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Adulto , Anciano , Neoplasias de la Mama/etiología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , TaiwánRESUMEN
Glioblastoma multiforme (GBM) is the most malignant cancer in the central nervous system with poor clinical prognosis. In this study, we investigated the therapeutic effect of an anti-cancer protein, decorin, by delivering it into a xenograft U87MG glioma tumor in the brain of nude mice through an adeno-associated viral (AAV2) gene delivery system. Decorin expression from the AAV vector in vitro inhibited cultured U87MG cell growth by induction of cell differentiation. Intracranial injection of AAV-decorin vector to the glioma-bearing nude mice in vivo significantly suppressed brain tumor growth and prolonged survival when compared to control non-treated mice bearing the same U87MG tumors. Proteomics analysis on protein expression profiles in the U87MG glioma cells after AAV-mediated decorin gene transfer revealed up- and down-regulation of important proteins. Differentially expressed proteins between control and AAV-decorin-transduced cells were identified through MALDI-TOF MS and database mining. We found that a number of important proteins that are involved in apoptosis, transcription, chemotherapy resistance, mitosis, and fatty acid metabolism have been altered as a result of decorin overexpression. These findings offer valuable insight into the mechanisms of the anti-glioblastoma effects of decorin. In addition, AAV-mediated decorin gene delivery warrants further investigation as a potential therapeutic approach for brain tumors.