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In this study, we optimized the parameters of diffusion bonding on multi-layered stainless steel 316L and 430 stacks. The preparation process for diffusion bonding is crucial, as the bonding surfaces need to be polished and meticulously cleaned to ensure a smooth bonding process. We fabricated twelve-layer plates consisting of 55 mm × 55 mm × 3 mm and 100 mm × 50 mm × 3 mm dimensions, and the bonding response was investigated by evaluating the tensile strength of the bonding zone under varying bonding conditions, with a bonding temperature ranging from 1000 to 1048 °C, a bond time ranging from 15 to 60 min, pressure ranging from 10 to 25.3 MPa, and under a vacuum environment. SS430 exhibits a significantly higher compression creep rate than SS316L. The compressibility of diffusion welding materials does not impact the diffusion bonding strength. Multi-axial tensile strength tests confirmed strong bonding joint strength in various axes. The tensile strengths of monolithic and Diffusion bonding (DB) specimens tested in parallel are essentially identical. The optimized diffusion bonding parameters (Condition G2C: 1048 °C/25.3 MPa/15 min) are ideal for producing SS316L stainless steel cores in compact heat exchangers, offering a superior bonding quality and reduced costs. These findings have practical implications for the production of stainless steel cores in compact heat exchangers, demonstrating the relevance and applicability of our research.
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Background: Over the past few decades, gout and diseases like metabolic syndrome (MetS) have become more prevalent. Attempts have been made in Taiwan to identify the genes responsible for gout. A few gene loci, among them SLC2A9, have been identified using Taiwan Biobank (TWB) data. We, therefore, examined whether MetS could also account for the association between polymorphism SLC2A9 rs3733591 and gout. Methods: The final analysis consisted of 73,558 subjects, of whom 2,709 had gout. To estimate the likelihood of gout occurrence based on rs3733591 and MetS, we used logistic regression models. Results: Rs3733591-TC + CC compared to TT genotype was associated with gout (OR, 1.15; 95% CI, 1.06-1.25). Also associated with gout was MetS (OR, 1.21; 95% CI, 1.10-1.33). A significant interaction was seen between rs3733591 and MetS (p-value = 0.039). Using rs3733591-TT/no MetS as the reference group, the ORs (95% CI) for gout was 1.24 (1.11-1.38) for TC + CC/no MetS, 1.35 (1.17-1.56) for TT/MetS, and 1.39 (1.22-1.58) for TC + CC/MetS. However, subgroup analysis defined by sex showed no significant associations in women. Conclusion: In summary, metabolic syndrome and SLC2A9 rs3733591 genotypes were interactively associated with gout in Taiwanese men, but not women.
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We report the design, synthesis, and biological evaluation of 13 new and 1 known anthraquinone derivatives which exerted cytotoxicity against PC3, A549 and NTUB1 cell lines. The results indicate that, among these 14, compounds-1 and 14 showed the highest growth inhibitory effect on NTUB1 and PC3 cells, respectively. Compound-1 at lower doses targets DNA, induces DNA damage and subsequently triggers G2/M arrest and apoptotic cell death at 24 h. Previously we reported that 14 induced PC3 cell autophagy and in treated PC3 cells, cleaved caspase-3 and cleaved PARP, and survivin did not increase and increase, respectively. The autophagic and necrotic cell deaths mediated by 14-triggered ROS generation. Our study is the first to investigate the biological mechanism of 14 action in detail. We find that when 14 was co-administrated with Bafilomycin A1 (BAF) in PC3 cells, rapid necrotic cell death occurred with no cleaved caspase-3 and cleaved PARP activation and increasing the expression of survivin. We further show that necrotic signaling in these cells coincided with production of reactive oxygen species. In the present study, we developed methods to synthesize five new 14 analogues for studing the structure-activity relationships. This study could provide valuable sight to find new antitumor agents for cancer therapy.
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Antraquinonas/farmacología , Antineoplásicos/farmacología , Antraquinonas/síntesis química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Estructura Molecular , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
OBJECTIVE: Acute bacterial skin and skin structure infection (ABSSSI) is a common cause of acute admissions in patients with cirrhosis worldwide, but the disease is not well-understood epidemiologically with respect to factors that determine positive blood cultures or patient mortality. The aim of this study was to understand the utility of blood cultures and the association between bacteremia and mortality in cirrhotic patients with ABSSSI. We conducted a retrospective study to investigate factors associated with positive blood cultures and mortality in cirrhotic patients with ABSSSI. METHODS: A retrospective cohort study of hospitalized adult cirrhotic patients with ABSSSI was conducted in a tertiary hospital in Taiwan between March 2015 and December 2016. RESULTS: A total of 122 hospitalized cirrhotic patients with ABSSSI were included. The overall mortality rate was 9% (11/122), and 23 patients had positive blood culture results. Comorbidities that were significant risk factors for a positive blood culture included diabetes mellitus, acute kidney injury (AKI), and acute-on-chronic liver failure (ACLF). Significant risk factors evident in laboratory evaluations included higher model for end-stage liver disease (MELD) score, higher serum lactate, and lower serum albumin level. Bacteremia was also a significant factor associated with mortality. CONCLUSION: A blood culture should be considered for cirrhotic patients with ABSSSI with diabetes mellitus, AKI, ACLF or those exhibiting abnormal albumin, lactate levels, or high MELD score because of the positive correlation between bacteremia and mortality.
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Insuficiencia Hepática Crónica Agudizada , Bacteriemia , Enfermedad Hepática en Estado Terminal , Adulto , Bacteriemia/diagnóstico , Bacteriemia/epidemiología , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Taiwán/epidemiologíaRESUMEN
The effect of cycloheterophyllin, a prenylflavone isolated from Artocarpus heteophyllus, on glutamate release was studied in the rat hippocampus using synaptosome and slice preparations. In rat hippocampal synaptosomes, cycloheterophyllin inhibited 4-aminopyridine (4-AP)-evoked glutamate release and elevation of intrasynaptosomal calcium levels. The inhibitory effect of cycloheterophyllin on 4-AP-evoked glutamate release was prevented in the presence of the vesicular transporter inhibitor, the N- and P/Q-type calcium channel blocker, and the protein kinase C (PKC) inhibitor but was insensitive to the intracellular Ca2+ release inhibitors, the protein kinase A inhibitor, and the mitogen-activated/extracellular signal-regulated kinase inhibitor. Western blotting data in synaptosomes also showed that cycloheterophyllin significantly decreased the level of phosphorylation of PKC. In addition, cycloheterophyllin decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) without influencing the amplitude of sEPSCs and glutamate-activated currents in hippocampal slices, supporting a presynaptic action. Together, these results suggest that cycloheterophyllin inhibits presynaptic glutamate release by suppressing N- and P/Q-type calcium channel and PKC activity in the rat hippocampus.
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Flavonoides/farmacología , Ácido Glutámico/metabolismo , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Animales , Artocarpus/química , Calcio/análisis , Flavonoides/química , Flavonoides/aislamiento & purificación , Ácido Glutámico/análisis , Hipocampo/metabolismo , Masculino , Estructura Molecular , Neuronas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Necrotizing fasciitis is a severe soft-tissue infection with a high mortality rate. There is little literature on the relationship between the ultrasonographic finding of fluid accumulation along the deep fascia and the diagnosis and prognosis of necrotizing fasciitis. This retrospective study showed that when fluid accumulation was present along the deep fascia, patients with clinically suspected necrotizing fasciitis had a higher probability of having necrotizing fasciitis. The ultrasonographic finding of fluid accumulation with a cutoff point of more than 2 mm of depth had the best accuracy (72.7%) for diagnosing necrotizing fasciitis. In regard to the prognosis of necrotizing fasciitis, when fluid accumulation was present along the deep fascia, patients with necrotizing fasciitis had a longer length of hospital stay and were at risk of amputation or mortality. Ultrasonography is a point-of-care imaging tool that facilitates the diagnosis and prognosis of necrotizing fasciitis.
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Líquidos Corporales/diagnóstico por imagen , Edema/diagnóstico por imagen , Edema/fisiopatología , Fascitis Necrotizante/diagnóstico por imagen , Fascitis Necrotizante/fisiopatología , Ultrasonografía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Hyperlactatemia is known to be associated with adverse outcome in critical illness. In this study, we attempted to identify if hyperlactatemia on emergency department (ED) arrival is a reliable predictor for in-hospital mortality in necrotizing fasciitis (NF) patients. METHOD: A prospective cohort study of hospitalized patients with NF was conducted in two tertiary teaching hospitals in Taiwan between March 2010 and March 2018. Blood samples were collected in the ED upon arrival, and the lactate levels were determined. Sequential organ failure assessment (SOFA) scores were calculated during the first 24 h after admission. All collected data were statistically analyzed. RESULT: Of the 707 NF patients, 40 (5.66%) died in the hospital. The median (interquartile range) blood lactate level in all NF patients was 3.6 mmol/l (2.2-4.8). The blood lactate level upon ED arrival was significantly associated with mortality (odds ratio [OR] = 1.35; 95% confidence interval [CI], 1.30-1.46; P < 0.001), even after adjustment for age and SOFA score (OR = 1.27; P < 0.001). Multivariate regression analysis showed that a high blood lactate level (OR = 1.17; 95% CI, 1.07-1.29; P = 0.001) and a high SOFA score (OR = 1.15; 95% CI, 1.11-1.20; P < 0.001) were independent risk factors for in-hospital mortality in NF. Blood lactate achieved an area under-the-receiver-operating-characteristic curve (AUC) of 0.79 (P < 0.001) for predicting mortality that was similar to that of SOFA score (AUC = 0.82; P < 0.001). Blood lactate displayed a sensitivity of 62% and a specificity of 86% in predicting mortality at the optimal cutoff value of 5.80 mmol/l. CONCLUSION: In necrotizing fasciitis patients, hyperlactatemia on ED arrival is independently associated with in-hospital mortality. NF patients with hyperlactatemia on ED arrival should be closely monitored for signs of deterioration and consider early and aggressive intervention to prevent mortality.
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Servicio de Urgencia en Hospital/tendencias , Fascitis Necrotizante/sangre , Fascitis Necrotizante/mortalidad , Mortalidad Hospitalaria/tendencias , Ácido Láctico/sangre , Admisión del Paciente/tendencias , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Fascitis Necrotizante/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
By an ESI-LC/MS analytical method, a racemate 1 consisting of a pair of unprecedented phloroglucinol enantiomers with a 5/6/5/5/6 fused ring system, (-)-garcinielliptone HG [((-)-1a] and (+)-garcinielliptone HH [(+)-1b], was obtained from the isolates of a CH2Cl2 extract of Garcinia subelliptica (heartwood). The gross structure of 1 was elucidated by spectroscopic methods and X-ray single-crystal diffraction data. The absolute configurations of 1a and 1b were unequivocally assigned by analysis on the calculated and experimental circular dichroism spectra and X-ray single-crystal diffraction data.
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BACKGROUND: Hypoalbuminemia is known to be associated with adverse outcomes in critical illness. In this study, we attempted to identify whether hypoalbuminemia on emergency department (ED) arrival is a reliable predictor for in-hospital mortality in necrotizing fasciitis (NF). METHOD: A retrospective cohort study of hospitalized adult patients with NF was conducted in a tertiary teaching hospital in Taiwan between March 2010 and March 2018. Blood samples were collected in the ED upon arrival, and serum albumin levels were determined. We evaluated the predictive value of serum albumin level at ED presentation for in-hospital mortality. All collected data were statistically analyzed. RESULT: Of the 707 NF patients, 40 (5.66%) died in the hospital. The mean serum albumin level was 3.1 ± 0.9 g/dL and serum albumin levels were significantly lower in the non-survivor group than in the survivor group (2.8 ± 0.7 g/dL vs. 3.5 ± 0.8 g/dL). In the multivariable logistic regression model, albumin was significantly associated with in-hospital mortality (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.88â»0.96, p < 0.001). The area under-the-receiver-operating-characteristic curve (AUC) for in-hospital survival was 0.77 (95% CI 0.72â»0.82) and corresponding sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratio were 66%, 74%, 33%, 88%, 2.25, and 0.48, respectively. High sensitivity (96%) for survival was shown at albumin level of 4.0 g/dL and high specificity (91%) for mortality was shown at a level of 2.5 g/dL. CONCLUSION: Initial serum albumin levels strongly predicted in-hospital mortality among patients with necrotizing fasciitis. NF patients with hypoalbuminemia on ED arrival should be closely monitored for signs of deterioration and early and aggressive intervention should be considered to prevent mortality.
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Background: Necrotizing fasciitis (NF) is a rapidly progressive infectious disease that primarily involves the fascia and subcutaneous tissue. If not promptly treated, it can lead to morbidity as well as mortality. It can affect any part of the body, most commonly the extremities. Early and aggressive surgical treatment is the proper way of management. The purpose of this study was to identify the risk factors for mortality in late amputation among NF patients that may be used in routine clinical practice to prevent mortality. Methods: A retrospective cohort study of hospitalized patients with NF was conducted in a tertiary teaching hospital in Taiwan between March 2015 and March 2018. All collected data were statistically analyzed. Results: A total of 582 patients with NF were included; 35 of them had undergone amputation (7 primary and 28 late amputations), with a 6% amputation rate. Thirteen amputated patients still died eventually (all in the late amputation group). Significant risk factors for mortality identified in the late amputation group included hemorrhagic bullae (p = 0.001, OR 4.7, 95% confidence interval (CI) 2.68-8.69), peripheral vascular disease (p < 0.001, OR 3.2, 95% CI 1.12-10.58), bacteremia (p = 0.021, OR 2.87, 95% CI 2.07-5.96), and Laboratory Risk Indicator of Necrotizing Fasciitis (LRINEC) score > 8 (p < 0.001, OR 1.97, 95% CI 1.28-4.61). Vibrio vulnificus was the main causative organism based on our study, but the microbiology results showed no significant correlation. Conclusion: NF patients with hemorrhagic bullae, comorbidity with peripheral vascular disease, presence of bacteremia, or LRINEC score > 8 should receive early and primary amputation in order to prevent mortality.
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Amputación Quirúrgica/mortalidad , Fascitis Necrotizante/cirugía , Anciano , Amputación Quirúrgica/métodos , Distribución de Chi-Cuadrado , Extremidades/microbiología , Extremidades/cirugía , Fascitis Necrotizante/microbiología , Fascitis Necrotizante/mortalidad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , TaiwánRESUMEN
The tautomeric pair of garcinielliptone FC (GFC) is a novel tautomeric pair of polyprenyl benzophenonoid isolated from the pericarps of Garcinia subelliptica Merr. (G. subelliptica, Clusiaceae), a tree with abundant sources of polyphenols. Our previous report demonstrated that GFC induced apoptosis on various types of human cancer cell lines including chemoresistant human colorectal cancer HT-29 cells. In the present study, we observed that many autophagy-related genes in GFC-treated HT-29 cells were up- and down-regulated using a cDNA microarray containing oncogenes and kinase genes. GFC-induced autophagy of HT-29 cells was confirmed by observing the formation of acidic vesicular organelles, LC3 puncta, and double-membrane autophagic vesicles using flow cytometry, confocal microscopy, and transmission electron microscopy, respectively. Inhibition of AKT/mTOR/P70S6K signaling as well as formation of Atg5-Atg12 and PI3K/Beclin-1 complexes were observed using Western blot. Administration of autophagy inhibitor (3-methyladenine and shRNA Atg5) and apoptosis inhibitor Z-VAD showed that the GFC-induced autophagy was cytotoxic form and GFC-induced apoptosis enhanced GFC-induced autophagy. Our data suggest the involvement of autophagy and apoptosis in GFC-induced anticancer mechanisms of human colorectal cancer.
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Antineoplásicos Fitogénicos/farmacología , Autofagia/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Triterpenos/farmacología , Apoptosis/efectos de los fármacos , Proteína 12 Relacionada con la Autofagia/genética , Proteína 12 Relacionada con la Autofagia/metabolismo , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Beclina-1/genética , Beclina-1/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/ultraestructura , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica , Células HT29 , Humanos , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Factores de Tiempo , TransfecciónRESUMEN
Licorice (Glycyrrhiza) species have been widely used as a traditional medicine and a natural sweetener in foods. The 18ß-glycyrrhetinic acid (18ß-GA) is a bioactive compound in licorice that exhibits potential anti-cancer, anti-inflammatory, and anti-microbial activities. Many synthesized derivatives of 18ß-GA have been reported to be cytotoxic and suggested for the treatment of malignant diseases. In this study, we explored the possible pharmacological roles of an 18ß-GA derivative in skin biology using primary human dermal fibroblasts and HaCaT keratinocytes as cell models. We found that this 18ß-GA derivative did not cause cell death, but significantly enhanced the proliferation of dermal fibroblasts and HaCaT keratinocytes. A scratch wound healing assay revealed that the 18ß-GA derivative promoted the migration of fibroblasts. Due to the important role of aquaporin-3 in cell migration and proliferation, we also investigated the expression of aquaporin-3 and found this compound up-regulated the expression of aquaporin-3 in dermal fibroblasts and HaCaT keratinocytes. In dermal fibroblasts, the 18ß-GA derivative induced the phosphorylation of Akt, ERK, and p38. The inhibitor of Akt predominantly suppressed the 18ß-GA derivative-induced expression of aquaporin-3. Collectively, this compound had a positive effect on the proliferation, migration, and aquaporin-3 expression of skin cells, implying its potential role in the treatment of skin diseases characterized by impaired wound healing or dermal defects.
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Acuaporina 3/genética , Dermis/citología , Dermis/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Ácido Glicirretínico/análogos & derivados , Acuaporina 3/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacología , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Ultraviolet (UV) radiation, particularly ultraviolet A (UVA), is known to play a major role in photoaging of the human skin. Many studies have demonstrated that UV exposure causes the skin cells to generate reactive oxygen species and activates the mitogen-activated protein kinase (MAPK) pathway. Previous studies have also demonstrated that cycloheterophyllin has an antioxidant effect and can effectively scavenge free radicals. Extending the aforementioned investigations, in this study, human dermal fibroblasts were used to investigate the protective effect of cycloheterophyllin against UV-induced damage. We found that cycloheterophyllin not only significantly increased cell viability, but also attenuated the phosphorylation of MAPK after UVA exposure. Furthermore, cycloheterophyllin could reduce hydrogen peroxide (H2O2) generation and down-regulate H2O2-induced MAPK phosphorylation. In the in vivo studies, the topical application of cycloheterophyllin before UVA irradiation significantly decreased trans-epidermal water loss (TEWL), erythema, and blood flow rate. These results indicate that cycloheterophyllin is a photoprotective agent that inhibits UVA-induced oxidative stress and damage, and could be used in the research on and prevention of skin photoaging.
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Fibroblastos/metabolismo , Flavonoides/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Protectores contra Radiación/farmacología , Piel/citología , Rayos Ultravioleta/efectos adversos , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/efectos de la radiación , Activación Enzimática/efectos de los fármacos , Activación Enzimática/efectos de la radiación , Fibroblastos/efectos de los fármacos , Fibroblastos/efectos de la radiación , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Envejecimiento de la Piel/efectos de los fármacos , Envejecimiento de la Piel/efectos de la radiaciónRESUMEN
Ganoderma tsugae is a medicinal mushroom. In a continual study on the bioactive constituents of this fungus, a new lanostanoid, 3ß-acetoxy-16α-hydroxy-24ξ-methyl-5α-lanosta-8,25-dien-21-oic acid, named tsugaric acid F (1) and a novel palmitamide, N-(3'α,4'ß-dihydroxy-2'ß-(hydroxymethyl)-1'ß-(cyclobutyl)palmitamide (2) were isolated and characterized from the fruit bodies of G. tsugae, and three novel seco-lanostanoids, 3,4-seco-8α,9α-epoxy-5α-lanosta-21-oic acid 3,4 lactone (5), 3,4-seco-5ß-lanosta-7,9(11),4(29)-trien-3,21-dioic acid-3-methyl ester (6), 3,4-seco-5ß-lanosta-7,9(11),4(29)-trien-3,21-dioic acid (7), and a known compound, 3-oxo-5α-lanosta-8-en-21-oic acid (4) were prepared from 3. The structures of new compounds, 1, 2, 5-7 were determined by spectroscopic methods. Compounds 1 and 4 showed inhibitory effects on xanthine oxidase (XO) with an IC50 values of 313.3 ± 80.0 and 43.9 ± 29.9 µM, respectively when 7 exhibited potent inhibitory effect on superoxide anion generation in rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP)/cytochalasin B (CB) with an IC50 values of 1.3 ± 0.2 µM. Compounds 4-7 showed weak cytotoxic activities against PC3 cells. These results indicated that 4 and 7 may be used as cancer chemopreventive agents.
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Amidas/química , Ganoderma/química , Triterpenos/química , Agaricales/química , Amidas/aislamiento & purificación , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Neutrófilos/efectos de los fármacos , Células RAW 264.7 , Ratas , Triterpenos/aislamiento & purificación , Xantina Oxidasa/antagonistas & inhibidoresRESUMEN
This study adopted an integrated procedure that combines the clustering and classification features of data mining technology to determine the differences between the symptoms shown in past cases where patients died from or survived oral cancer. Two data mining tools, namely decision tree and artificial neural network, were used to analyze the historical cases of oral cancer, and their performance was compared with that of logistic regression, the popular statistical analysis tool. Both decision tree and artificial neural network models showed superiority to the traditional statistical model. However, as to clinician, the trees created by the decision tree models are relatively easier to interpret compared to that of the artificial neural network models. Cluster analysis also discovers that those stage 4 patients whose also possess the following four characteristics are having an extremely low survival rate: pN is N2b, level of RLNM is level I-III, AJCC-T is T4, and cells mutate situation (G) is moderate.
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Minería de Datos/métodos , Neoplasias de la Boca/mortalidad , Redes Neurales de la Computación , Factores de Edad , Consumo de Bebidas Alcohólicas/epidemiología , Árboles de Decisión , Humanos , Modelos Logísticos , Neoplasias de la Boca/patología , Factores Sexuales , Fumar/epidemiología , Análisis de SupervivenciaRESUMEN
Our previous reports showed that justicidin A (JA), a novel and pure arylnaphthalide lignan isolated from Justicia procumbens, induces apoptosis of human colorectal cancer cells and hepatocellular carcinoma cells, leading to the suppression of both tumor cell growth in NOD-SCID mice. Here, we reveal that JA induces autophagy in human colorectal cancer HT-29 cells by conversion of autophagic marker LC3-I to LC3-II. Furthermore, LC3 puncta and autophagic vesicle formation, and SQSTM1/p62 suppression were observed. Administration of autophagy inhibitor (bafilomycin A1 and chloroquine) and transfection of a tandem fluorescent-tagged LC3 (mRFP-GFP) reporter plasmid (ptfLC3) demonstrated that JA induces autophagy flux in HT-29 cells. Expression of LC3, SQSTM1, Beclin 1, and nuclear DNA double-strand breaks (representing apoptosis) were also detected in the tumor tissue of HT-29 cells transplanted into NOD-SCID mice orally administrated with JA. In addition, the expression of autophagy signaling pathway-related molecules p-PDK1, p-mTOR, p-p70S6k/p-RPS6KB2 was decreased, whereas that of class III PI3K, Beclin 1, Atg5-Atg12, and mitochondrial BNIP3 was increased in response to JA. Pre-treatment of the cells with class III PI3K inhibitor 3-methyladenine or Atg5 shRNA attenuated JA-induced LC3-II expression and LC3 puncta formation, indicating the involvement of class III PI3K and Atg5. A novel mechanism was demonstrated in the anticancer compound JA; pre-treatment with 3-methyladenine or Atg5 shRNA blocked JA-induced suppression in cell growth and colony formation, respectively, via inhibition of apoptosis. In contrast, administration of apoptosis inhibitor Z-VAD did not affect JA-induced autophagy. Our data suggest the chemotherapeutic potential of JA for treatment of human colorectal cancer.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Dioxolanos/farmacología , Lignanos/farmacología , Proteínas Asociadas a Microtúbulos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Adenina/análogos & derivados , Adenina/farmacología , Animales , Proteína 5 Relacionada con la Autofagia , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Células HT29 , Humanos , Ratones , Ratones SCID , ARN Interferente Pequeño/metabolismoRESUMEN
Phyla nodiflora is a creeping perennial herb, widely distributed in the most tropical and subtropical regions. It has been used as a folk medicine, herbal beverage, or folk cosmetic. For these usages, the development of a chemical quality control method of this plant is necessary. In the present study, ten compounds, namely, 3,7,4',5'-tetrahydroxy-3'-methoxyflavone (1), nodifloretin (2), 4'-hydroxywogonin (3), onopordin (4), cirsiliol (5), 5,7,8,4'-tetrahydroxy-3'-methoxyflavone (6), eupafolin (7), hispidulin (8), larycitrin (9), and ß-sitosterol were isolated from the methanolic extract of the aerial part of P. nodiflora (PNM) and their structures were identified by 1D-NMR comparing their spectra with the literature. The antioxidant activities of these compounds were evaluated by free radical scavenging activity and tyrosinase inhibitory effect in cell-free systems. Compounds 4, 5, and 7 showed strong antioxidant activity. To control the quality of P. nodiflora, a simple and reliable method of high-performance liquid chromatography combined with ultraviolet detector (HPLC-UV) was established for both the fingerprint analysis and the quantitative determination of two selected active compounds, onopordin (4) and eupafolin (7). Statistical analysis of the obtained data demonstrated that our method achieved the desired linearity, precision, and accuracy. The results indicated that the developed method can be used as a quality evaluation method for PNM.
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Antioxidantes/análisis , Verbenaceae/química , Antioxidantes/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Radicales Libres/química , Monofenol Monooxigenasa/antagonistas & inhibidores , Resonancia Magnética Nuclear Biomolecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Control de CalidadRESUMEN
In an effort to develop potent cyclooxygenase-1 (COX-1) inhibitors used as anticancer agent, a series of 2',5'-dimethoxychalcones was screened to evaluate their antiplatelet effect on human washed platelets suspension. Compound 2 exhibited potent inhibition of human washed platelet aggregation induced by collagen, significantly inhibited collagen- and arachidonic acid-induced thromboxane B2 release, and revealed inhibitory effect on COX-1 activity. Molecular docking studies showed that 1, 2, and 4 were bound in the active site of COX-1. These indicated that the antiplatelet effect of these compounds were mainly mediated through the suppression of COX-1 activity and reduced the thromboxane formation. To investigate the mechanistic action of COX-1 inhibitor enhanced the cytotoxic effect against human bladder cancer cells, NTUB1, we assessed the cytotoxic effect of 2 against NTUB1. Treatment of NTUB1 cells with various concentrations of 2 led to a concentration-dependent increase of cell death and decrease of reactive oxygen species levels. The flow-cytometric analysis showed that 2 induced a G1 phase cell cycle arrest but did not accompany an appreciable sub-G1 phase in NTUB1 cells. In addition, compound 2 increased p21 and p27 expressions and did not inhibit the expression of COX-1 in NTUB1 cells. Our results suggested that 2 enhanced cell growth inhibition or antiproliferative activity in NTUB1 cells through G1 arrest by COX-1 independent mechanism.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Chalcona/análogos & derivados , Chalcona/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Chalcona/química , Ciclooxigenasa 1/metabolismo , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Inhibidores de Agregación Plaquetaria/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Ursolic acid and most of its derivatives are cytotoxic to bladder cancer cells. An ursolic acid derivative, isopropyl 3ß-hydroxyurs-12-en-28-oat (UA17), previously reported that it exhibited potent cytotoxicity against bladder cancer cells, NTUB1 cells. In this study, we further investigated the underlying mechanism of UA17 and evaluated its potential clinical use. UA17 may exert the onset of a p53-mediated p38 MAPK activation to up-regulate GADD153. GADD153, in turn, down-regulated Bcl-2 protein to cause mitochondrial membrane potential loss and apoptosis through intracellular ROS generation. In addition, UA17 markedly decreased the levels of cyclins (D1 and E), cyclin-dependent kinases (CDK2 and CDK4), and caused increase of p21 and p27 levels. To assess the suitability of UA17 as a chemotherapeutic agent against NTUB1 cells, its cytotoxic effects have been further evaluated in the combination with cisplatin. The addition of UA17 to cisplatin induces possibly additive cell growth inhibition which correlated to the accumulation of S phase cells and a corresponding decrease in accumulation of G1 phase cells, accompanied an increased accumulation of sub-G1 phase cells. Furthermore, UA17/cisplatin combination exhibited increase of p21, cyclin E, and p-p53 level, and decrease of p27 and cyclin D1 proteins, and slightly diminishing the level of CDK2. P-p38 up-regulation induced by UA17/cisplatin combination through generation of ROS and Bcl-2 down-regulation induced by UA17/cisplatin combination increased cell death. Finally, the antitumorigenic effects of UA17 or UA17/cisplatin combination were further supported by their inhibition on growth of bladder tumor cells in a therapeutic murine MBT-2 bladder tumor model.
Asunto(s)
Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Triterpenos/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Cisplatino/administración & dosificación , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos C3H , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción CHOP/metabolismo , Triterpenos/administración & dosificación , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Ten new lantabetulic acid (1) derivatives 2-11 were synthesized and their cytotoxicities against human prostate cancer cells were evaluated. PC3 cells treated with 10 µM 8 exhibited the most potent G1 phase arrest. In addition, 10 µM 8 markedly decreased the levels of cyclin E and cdk2 and caused an increase in the p21 and p27 levels, while 20 µM 8 mainly led to cell death through the apoptotic pathway, which correlated with an increase in reactive oxygen species levels, decreased expression levels of Bcl-2 and caspase-8, the induction of mitochondrial changes, and decreased levels of cytochrome c in mitochondria. The dual action of 8 could provide a new approach for the development of chemotherapeutic drugs.