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1.
Arch Insect Biochem Physiol ; 117(1): e22148, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39250333

RESUMEN

Our previous research reported the influence of 50 µM selenium (Se) on the cytosolization (endocytosis) pathway, which in turn stimulates the growth and development of Bombyx mori. Lately, dynamin is recognized as one of the key proteins in endocytosis. To explore the underlying mechanisms of Se impact, the dynamin gene was knocked down by injecting siRNAs (Dynamin-1, Dynamin-2, and Dynamin-3). This was followed by an analysis of the target gene and levels of silk protein genes, as well as growth and developmental indices, Se-enrichment capacity, degree of oxidative damage, and antioxidant capacity of B. mori. Our findings showed a considerable decrease in the relative expression of the dynamin gene in all tissues 24 h after the interference and a dramatic decrease in the silkworm body after 48 h. RNAi dynamin gene decreased the silkworm body weight, cocoon shell weight, and the ratio of cocoon. In the meantime, malondialdehyde level increased and glutathione level and superoxide dismutase/catalase activities decreased. 50 µM Se markedly ameliorated these growth and physiological deficits as well as decreases in dynamin gene expression. On the other hand, there were no significant effects on fertility (including produced eggs and laid eggs) between the interference and Se treatments. Additionally, the Se content in the B. mori increased after the dynamin gene interference. The dynamin gene was highly expressed in the silk gland and declined significantly after interference. Among the three siRNAs (Dynamin-1, Dynamin-2, and Dynamin-3), the dynamin-2 displayed the highest interference effects to target gene expression. Our results demonstrated that 50 µM Se was effective to prevent any adverse effects caused by dynamin knockdown in silkworms. This provides practical implications for B. mori breeding industry.


Asunto(s)
Bombyx , Dinaminas , Técnicas de Silenciamiento del Gen , Selenio , Animales , Bombyx/genética , Bombyx/crecimiento & desarrollo , Bombyx/metabolismo , Bombyx/efectos de los fármacos , Selenio/farmacología , Dinaminas/genética , Dinaminas/metabolismo , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Larva/crecimiento & desarrollo , Larva/genética , Larva/metabolismo , Larva/efectos de los fármacos , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Femenino , Seda
2.
Biol Trace Elem Res ; 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38819778

RESUMEN

Recent studies have emphasized the beneficial effects of 50 µM selenium (Se) on the growth and development of the silkworm, Bombyx mori; however, less is known about its underlying mechanism. To unravel the effect of 50 µM Se on the silkworms with neutral endopeptidase 24.11-like gene (NEP-L) knockdown, we injected small interfering RNA (siRNA) into the body cavity of silkworms. Phenotypic characteristics, mRNA expression of the Nep-L gene, and enriched Se content were evaluated in silkworms from each treatment group. After injecting Nep-L siRNA, the body weight, cocoon quality (cocoon weight, cocoon shell weight, and cocoon shell ratio), and egg production of silkworms were significantly reduced, without any significant effect on egg laying number. However, Se treatment could significantly alleviate the inhibition of body weight, and cocoon quality, without significant effects on egg laying number and production. In addition, the gene knockdown increased Se content in the B. mori. On the molecular level, the targeted Nep-L gene was inhibited significantly by siRNA interference, essentially with the strongest effect at 24 h after RNAi, followed by steady recovery. Among the three fragments, the siRNA of Nep-L-3 was the most effective in interfering with target gene expression. Nep-L gene showed the highest expression in Malpighian tubules (MTs). Both at the phenotypic and genotypic levels, our results show that Nep-L knockdown can exert a significant inhibitory effect on silkworms, and 50 µM Se can reverse the negative effect, which provides a practical prospect for strengthening the silkworm food industry.

3.
Diabetol Metab Syndr ; 15(1): 260, 2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-38115042

RESUMEN

BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is considered a new biomarker for atherosclerosis, but its ability to predict cardiovascular outcomes has been controversial. This study aimed to address the lack of data on PCSK9, coronary heart disease (CHD) severity, and major cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 2984 T2DM patients underwent selective coronary angiography, and their serum PCSK9 levels were measured using enzyme-linked immunosorbent assay. Correlation and logistic regression analyses were performed to investigate the association between PCSK9 expression and CHD severity. This study used Cox regression analysis to assess the association between circulating PCSK9 levels and the risk of MACEs. RESULTS: Circulating PCSK9 levels were significantly higher in the CHD group than in the non-CHD group [554.62 (265.11) ng/mL vs. 496.86 (129.05) ng/mL, p < 0.001]. Circulating PCSK9 levels positively correlated with CHD severity (diseased vessels: r = 0.35, p < 0.001; Gensini score: r = 0.46, p < 0.001). Elevated PCSK9 levels are an independent risk factor for CHD risk and severity (CHD group vs. non-CHD group: OR = 2.829, 95% CI: 1.771-4.520, p < 0.001; three vessel disease group vs. one vessel disease group: OR = 4.800, 95% CI: 2.387-9.652, p < 0.001; high GS group vs. low GS group: OR = 5.534, 95% CI: 2.733-11.208, p < 0.001). Through a six-year follow-up and multivariate Cox regression analysis, elevated circulating PCSK9 levels were found to be independently associated with MACEs in all participants (HR: 3.416, 5% CI: 2.485-4.697, p < 0.001; adjusted HR: 2.780, 95% CI: 1.930-4.004, p < 0.001). CONCLUSIONS: Serum PCSK9 levels were positively correlated with multi-vessel CHD and Gensini score. Elevated circulating PCSK9 levels are an independent risk factor for CHD and increased incidence of MACEs in T2DM.

4.
Food Chem ; 404(Pt B): 134549, 2023 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-36283307

RESUMEN

Enzymatic browning has been a significant factor affecting the sale of fresh noodles. This study used a combination of physical and chemical methods to achieve a long-lasting and effective anti-browning effect in fresh noodles. The results showed that the combinations of citric acid (CA), NaOH, and KOH with heat treatment blunted the polyphenol oxidase activity and improved the color of fresh noodles. Specifically, the L* value of fresh noodles stored at 6 °C treated by the combination of CA and 75 °C (CHFN-75) at 72 h (81.71) was significantly higher than that of the control at 72 h (74.42). Mixolab and confocal laser scanning microscopy showed that the combined treatment affected the protein and starch of the flour. However, the hardness and chewiness of the cooked noodles increased only slightly, and the adhesiveness decreased slightly. The innovative combination can be used as an effective way to delay the darkening of fresh noodles.


Asunto(s)
Calor , Triticum , Harina/análisis , Culinaria , Almidón
5.
Zhongguo Zhong Yao Za Zhi ; 46(17): 4410-4416, 2021 Sep.
Artículo en Chino | MEDLINE | ID: mdl-34581044

RESUMEN

This study was mainly based on the compatibility of Puerariae Lobatae Radix and Chuanxiong Rhizoma to prepare submicron emulsion and evaluated its physical and pharmaceutical properties. Firstly, pseudo-ternary phase diagrams were drawn by dripping method which took Chuanxiong oil as the oil phase and the area of microemulsion region as the index. On this basis, suitable emulsifier and co-emulsifier were screened for the preparation of Chuanxiong oil submicron emulsion. Then, the formula realizing the largest oil loading was selected. Finally, puerarin substituted part of emulsifier and co-emulsifier to lower their content, so as to form puerarin-Chuanxiong oil submicron emulsion featuring the combination of medicine and adjuvant. Its particle size, zeta potential, centrifugal stability and storage stability were determined, and the in vitro drug release behavior was investigated by dialysis bag method, based on which the quality of the as-prepared submicron emulsion was evaluated comprehensively. The proposed method was proved feasible for the preparation of Chuanxiong oil submicron emulsion, which adopted polyoxyethylene castor oil(EL-40) as the emulsifier and was free from co-emulsifier. The formula of the maximum oil loading was found as Chuanxiong oil∶EL-40∶water 3∶7∶90. Further, puera-rin successfully replaced up to 10% of the emulsifier in submicron emulsion. Eventually, the optimal drug-loading formula was determined as puerarin∶Chuanxiong oil∶EL-40∶water 7∶30∶63∶900. The quality evaluation results of the as-prepared submicron emulsion demonstrated that the average emulsion droplet size was 333.9 nm, the PDI 0.26, and the zeta potential-10.12 mV. The submicron emulsion had a good centrifugal stability and did not present any instable phenomena such as delamination and precipitation during its standing still for 50 days. The evaluation of in vitro drug release behavior indicated that the submicron emulsion was capable of releasing the drug completely. The puerarin-chuanxiong oil submicron emulsion prepared in this study possessed a stable quality and to some extent increased the solubility of puerarin along with a sustained-release effect. This study provided ideas for the clinical application of puerarin.


Asunto(s)
Isoflavonas , Emulsiones , Tamaño de la Partícula , Solubilidad
6.
Aging Cell ; 19(8): e13194, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32700357

RESUMEN

Sirtuin 2 (SIRT2) is an NAD+ dependent deacetylase that is the most abundant sirtuin protein in the brain. Accumulating evidence revealed the role of SIRT2 in a wide range of biological processes and age-related diseases. However, the pivotal mechanism of SIRT2 played in Alzheimer's disease (AD) remains unknown. Here, we report that pharmacological inactivation of SIRT2 has a beneficial effect in AD. The deacetylase inhibitor of SIRT2 rescued the cognitive impairment in amyloid precursor protein/presenilin 1 transgenic mouse (APP/PS1 mouse), and the BACE1 cleavage was weakened to reduce the ß-amyloid (Aß) production in the hippocampus. Moreover, we firstly identified that Reticulon 4B (RTN4B) played a crucial role between SIRT2/BACE1 regulation in AD. RTN4B, as a deacetylation substrate for SIRT2, the deacetylation by SIRT2 drived the ubiquitination and degradation of RTN4B and then the disturbed RTN4B interacted with and influenced the expression of BACE1. When we overexpressed RTN4B in neurons of the hippocampus in the AD mouse model, the abnormal Aß accumulation and cognitive impairment were ameliorated, consistent with the results of SIRT2 inhibition in vivo. Moreover, we showed that the regulatory effect of SIRT2 on BACE1 is dependent on RTN4B. When RTN4B was knocked down, the effects of SIRT2 inhibition on the BACE1 level, Aß pathology, and AD-liked behaviors were also blocked. Collectively, we provide evidence that SIRT2 may be a potential target for AD; the new found SIRT2/RTN4B/BACE1 pathological pathway is one of the critical mechanisms for the improvement of SIRT2 on AD.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/metabolismo , Proteínas Nogo/metabolismo , Sirtuina 2/antagonistas & inhibidores , Acetilación , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Células HEK293 , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/patología , Isoformas de Proteínas , Sirtuina 2/metabolismo , Ubiquitinación
7.
Zhongguo Zhong Yao Za Zhi ; 45(4): 878-883, 2020 Feb.
Artículo en Chino | MEDLINE | ID: mdl-32237488

RESUMEN

In this experiment, the decoction process of famous classical formula Xiebai San was determined by optimizing the particle size of "Cuo san" and investigating the decoction process parameters, such as boiling container, water volume and duration. Xiebai San was taken as an example to explore the study method of the "Cuo san" in the famous classical formulas. The specific chromatogram of Xiebai San and the determination method of glycyrrhizin and glycyrrhizic acid in Xiebai San were established. Different particle sizes of "Cuo san" and decoction parameters were optimized based on the similarity of specific chromatogram, the specific chromatogram's peak area, the content of glycyrrhizin, the content of glycyrrhizic acid and extract yield rate.The particle size of Xiebai San powder was determined to be 2.00-4.75 mm(by four-mesh sieves). The decoction process was determined as follows: put the prescription amount into a ceramic pot, add 420 mL of water, and boil and simmer until the volume is 300 mL.The similarity of specific chromatogram was above 0.9, the specific chromatogram's peak area was larger, the content of glycyrrhizin was 0.12%, the content of glycyrrhizic acid was 0.21%,and the extract yield rate was 15.05%. The finally determined particle size of "Cuo san" can better represent the quality of Xiebai San, and is easy to prepare and suitable for industrial production.This experimental research method can comprehensively investigate the quality of Xiebai San as a whole, the content of active ingredients, and the situation of extract yield.It is a more comprehensive and objective evaluation method, and can provide experimental basis and reference for the study of other "Cuo san" famous classical formulas.


Asunto(s)
Medicamentos Herbarios Chinos/química , Ácido Glicirrínico/análisis , Tamaño de la Partícula , Tecnología Farmacéutica , Polvos
8.
Exp Mol Pathol ; 112: 104326, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31706988

RESUMEN

The dual expression of CD5 and MYC protein (DECM) on B-lymphocytes may arise at a specific stage of de novo diffuse large B-cell lymphoma (DLBCL). This study retrospectively reviewed 210 patients with de novo DLBCL at the Affiliated Hospital of Jiangnan University between 2006 and 2017. DECM was significantly correlated with a worse prognosis than that in either the CD5+ or MYC+ or CD5-MYC- patients. Furthermore, patients with DECM showed a similar outcome to MYC+BCL2+ lymphoma patients who have extremely poor survival rates. Multivariate analysis demonstrated that DECM was a significant independent predictor for overall survival (P < .0001) and progression-free survival (P < .0001) in DLBCL. DLBCL patients with DECM showed significantly inferior clinical outcomes compared to the CD5+, MYC+ or CD5-MYC- patients. Combinational therapeutic modalities might be a candidate approach to improve the prognosis of these patients.


Asunto(s)
Antígenos CD5/genética , Linfoma de Células B Grandes Difuso/genética , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Anciano , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/epidemiología , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Estudios Retrospectivos , Rituximab/administración & dosificación , Resultado del Tratamiento , Vincristina/administración & dosificación
9.
BMC Cancer ; 19(1): 553, 2019 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-31176361

RESUMEN

BACKGROUND: Liver function is routinely assessed in clinical practice as liver function tests provide sensitive indicators of hepatocellular injury. However, the prognostic value of enzymes that indicate hepatic injury has never been systematically investigated in lymphoma, including diffuse large B-cell lymphoma (DLBCL). METHODS: This study examined the prognostic value of baseline aspartic transaminase (AST) in DLBCL patients. The association between AST and clinical features was analyzed in 179 DLBCL patients treated from 2006 to 2016. All enrolled patients were treated with R-CHOP or R-CHOP-like chemotherapy. Log-rank test, univariable analysis, and subgroup analysis were performed to evaluate the impact of AST on survival. RESULTS: AST 33.3 U/L was considered to be the optimal threshold value for predicting prognosis. A higher AST level was associated with advanced stage (P = 0.001), poorer performance status (P = 0.014), elevated lactate dehydrogenase level (P <  0.0001), presence of B symptoms (P = 0.001), high-risk International Prognostic Index (IPI, IPI 3-5) (P = 0.002), non-germinal center B-cell subtypes (P = 0.038), hepatitis B virus surface antigen positivity (P = 0.045) and more extra nodal involvement (ENI, ENI ≥ 2) (P = 0.027). Patients with a higher AST level had a shorter overall survival (OS) (2-year OS rate, 53.6% vs. 83.6%, P <  0.001). Subgroup analysis indicated that higher AST levels have poorer prognostic values in patients without B symptoms and LDH positive groups. CONCLUSION: A pretreatment AST level is associated with OS in DLBCL patients treated with R-CHOP or similar chemotherapy regimens. A high pretreatment AST level might be a reliable prognostic factor for predicting a dismal outcome in DLBCL patients. Serum AST levels may be investigated for use as an easily determinable, inexpensive biomarker for risk assessment in patients with DLBCL.


Asunto(s)
Aspartato Aminotransferasas/sangre , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Terapia Combinada , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Adulto Joven
10.
J Surg Oncol ; 117(2): 275-283, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28876468

RESUMEN

BACKGROUND: S100 is a superfamily of calcium-binding proteins that regulate multiple biological processes and are involved in many diseases. S100A16 has recently been identified to be involved in several cancers such as bladder cancer, lung cancer, and oral squamous cell carcinoma. However, the role of S100A16 expression in the colorectal cancer (CRC) has not been investigated. METHODS: S100A16 protein expression was detected by immunohistochemistry in 296 cases of CRC. Kaplan-Meier survival analysis and Cox regression analysis were performed to evaluate the prognostic significance of S100A16. RESULT: The results showed that the overall survival (OS) of patients with low membrane S100A16 expression was significantly shorter than patients with high expression (P < 0.05). Chi-square analysis showed that S100A16 expression had a positive correlation with tumor grade (P = 0.02). Multivariate analysis identified membrane S100A16 expression as an independent prognostic marker for OS in CRC patients. (P < 0.05). Univariate analysis showed no significant association between cytoplasmic/nuclear S100A16 expression and OS. CONCLUSION: Membrane S100A16 is associated with the prognosis of CRC patients, indicating that S100A16 may be a potential prognostic biomarker and therapeutic target for CRC.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/patología , Neoplasias Colorrectales/patología , Proteínas S100/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia
11.
Chronic Dis Transl Med ; 2(4): 241-249, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29063049

RESUMEN

OBJECTIVE: A large portion of non-metastatic colorectal cancers (non-mCRCs) recur after curative surgery. In addition to the traditional tumor-related factors, host-related factors are also required to accurately predict prognosis. A few studies have shown an association between the serum lipid profile and the survival and treatment response of patients with colorectal cancer. METHODS: We retrospectively evaluated the prognostic significance of the preoperative serum lipid profile [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)] in patients with non-mCRC treated with curative surgery. The Spearman rank correlation test was used to analyze associations between lipid levels and categorical variables. Lipid levels were modeled as four equal-sized quartiles based on the distribution among the whole cohort. Kaplan-Meier curves were used to estimate survival probabilities, and the log-rank test was used to detect differences between them. Multivariate fractional polynomial (MFP) analysis was used to model any non-linear effects and avoid categorization. To evaluate the added prognostic value of lipids, the predictive power of two models (with and without lipids as covariates) was compared by using Harrell's C-statistic and the Akaike information criterion (AIC). RESULTS: A total of 266 patients with non-mCRC were enrolled in the present study. Spearman rank correlation test showed that TG levels inversely correlated with N stage (r = -0.20, P = 0.00) and Tumor-Node-Metastasis (TNM) stage (r = -0.19, P = 0.00). HDL-C levels positively correlated with perineural invasion (PNI) (r = 0.15, P = 0.02), and LDL-C levels inversely correlated with lymphovascular invasion (LVI) (r = -0.12, P = 0.04). None of the four lipids predicted overall survival (OS) in univariate or multivariate analyses adjusted for age, gender, T stage, N stage, TNM stage, histological grade, tumor deposits, LVI, PNI, and adjuvant treatment (all P > 0.05). In agreement, the Kaplan-Meier curves for OS according to the lipid quartiles were not significantly different, as confirmed by the log-rank test (all P > 0.05). MFP analysis also found no significant associations between lipid levels and OS (all P > 0.05). A prognostic model that included lipids had a higher Harrell's C-statistic and a lower AIC value than did a model that did not include lipids (for Harrell's C-statistic: 0.82 vs. 0.77; for AIC: 398 vs. 432). CONCLUSION: Measuring preoperative serum lipid levels may be a simple and cost-effective way of increasing prognostic accuracy in patients with non-mCRC treated with curative surgery.

12.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 33(7): 978-82, 2013 Jul.
Artículo en Chino | MEDLINE | ID: mdl-24063225

RESUMEN

OBJECTIVE: To observe the synergistic effect of beta-elemene Injection (betaI) combined Paclitaxel Injection (PI) on breast cancer MB-468 cells and to study possible mechanisms. METHODS: Breast cancer MB-468 cells were treated with betaI (2.5, 5.0, 10.0, 20.0, 40.0, 80.0, 160.0, 320.0, and 640.0 microg/mL), PI (0.00100, 0.00200, 0.00400, 0.00800, 0.01600, 0.03125, 0.06250, 0.12500, and 0.25000 microg/mL), and betaI combined PI for 24 h and 48 h respectively. Cell proliferation was determined using SRB assay. Cell apoptosis and cell cycle phase distribution were detected using flow cytometry. The post-intervention expressions of cell cycle proteins [cyclin-dependent kinase (CDK1), cyclin-B1, P21(cip1), and P27(kip1)] were detected by Western blot. RESULTS: Beta-elemene or paclitaxel inhibited the growth of MB-468 cell line. The IC50 and IC20 values treated with beta-elemene for 24 h were 34.20 and 52.59 microg/mL and for 48 h were 10.15 and 17.81 microg/mL respectively, while the IC50 values treated with paclitaxel for 24 h and 48 h were 2.449 and 1.698 microg/mL respectively. Beta-elemene (20 and 40 microg/mL respectively) and Paclitaxel (0.016 and 0.008 microg/mL respectively) synergistically inhibited cell proliferation of MB-468 cells, with Q value > 1.15. Beta-elemene alone (52.59 microg/mL) apparently decreased the expression of cyclin-B1 protein. The expression of cyclin-B1 protein in the combined group was also lower than that in the PI group (1.698 microg/mL). The expression of P27(kip1) was up-regulated when compared with that in the betaI group or the PI group. CONCLUSION: Beta-elemene had synergistic effect with Paclitaxel, and its possible mechanism might be correlated with down-regulating the cell cycle protein cyclin-B1 expression and up-regulating the P27(kip1) expression.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Paclitaxel/farmacología , Sesquiterpenos/farmacología , Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Sinergismo Farmacológico , Femenino , Humanos , Paclitaxel/administración & dosificación , Sesquiterpenos/administración & dosificación
13.
PLoS One ; 8(4): e60967, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23596510

RESUMEN

BACKGROUND: Heart failure due to diastolic dysfunction exacts a major economic, morbidity and mortality burden in the United States. Therapeutic agents to improve diastolic dysfunction are limited. It was recently found that Dynamin related protein 1 (Drp1) mediates mitochondrial fission during ischemia/reperfusion (I/R) injury, whereas inhibition of Drp1 decreases myocardial infarct size. We hypothesized that Dynasore, a small noncompetitive dynamin GTPase inhibitor, could have beneficial effects on cardiac physiology during I/R injury. METHODS AND RESULTS: In Langendorff perfused mouse hearts subjected to I/R (30 minutes of global ischemia followed by 1 hour of reperfusion), pretreatment with 1 µM Dynasore prevented I/R induced elevation of left ventricular end diastolic pressure (LVEDP), indicating a significant and specific lusitropic effect. Dynasore also decreased cardiac troponin I efflux during reperfusion and reduced infarct size. In cultured adult mouse cardiomyocytes subjected to oxidative stress, Dynasore increased cardiomyocyte survival and viability identified by trypan blue exclusion assay and reduced cellular Adenosine triphosphate(ATP) depletion. Moreover, in cultured cells, Dynasore pretreatment protected mitochondrial fragmentation induced by oxidative stress. CONCLUSION: Dynasore protects cardiac lusitropy and limits cell damage through a mechanism that maintains mitochondrial morphology and intracellular ATP in stressed cells. Mitochondrial protection through an agent such as Dynasore can have clinical benefit by positively influencing the energetics of diastolic dysfunction.


Asunto(s)
Cardiotónicos/farmacología , Corazón/efectos de los fármacos , Hidrazonas/farmacología , Mitocondrias Cardíacas/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dinaminas/antagonistas & inhibidores , Dinaminas/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Técnicas In Vitro , Masculino , Ratones , Mitocondrias Cardíacas/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos
14.
Zhonghua Zhong Liu Za Zhi ; 34(2): 147-51, 2012 Feb.
Artículo en Chino | MEDLINE | ID: mdl-22780936

RESUMEN

OBJECTIVE: To compare the efficacy of second-line EGFR-TKIs followed by third-line pemetrexed with second-line pemetrexed followed by third-line EGFR-TKIs in patients with advanced lung adenocarcinoma. METHODS: From March 2007 to August 2008, 83 patients with advanced lung adenocarcinoma who failed standard first-line chemotherapy were included in this study. The patients who received EGFR-TKIs as second-line therapy followed by third-line pemetrexed were designated as group A (n = 45). The patients who received pemetrexed as second-line therapy followed by third-line EGFR-TKIs were designated as group B (n = 38). PFS and MST were estimated with Kaplan-Meier analysis and the difference between groups were compared with Log-rank test. RESULTS: The progression-free survival (PFS) after second-line therapy in the groups A and B was 8.05 months (95% CI, 5.90 to 10.20) and 4.20 months (95% CI, 3.33 to 5.06), respectively (P = 0.001). The PFS after second-line therapy in smokers and non-smokers was 3.69 months (95% CI, 5.00 to 7.59) and 7.12 months (95% CI, 5.51 to 8.38), respectively (P = 0.007). The PFS of male and female patients was 5.56 months (95% CI, 4.02 to 7.10) and 6.85 months (95% CI, 4.98 to 7.58), respectively (P = 0.279). The PFS after third-line therapy in groups A and B was 6.88 months (95% CI, 5.07 to 8.69) and 7.60 months (95% CI, 5.59 to 9.12) respectively, (P = 0.899). The PFS after third-line therapy in smokers and non-smokers was 4.95 months (95% CI, 2.83 to 7.05) and 8.49 months (95% CI, 6.27 to 10.76), respectively (P = 0.050). The PFS after third-line therapy in male and female patients was 5. 96 months (95% CI, 4.02 to 7.91) amd 8.38 months (95% CI, 5.68 to 11.07), respectively (P = 0.176). The MST in groups A and B was 23.60 months (95% CI, 19.23 to 28.00) and 15.58 months (95% CI, 11.85 to 19.32), respectively (P = 0.021). The MST in smokers and non-smokers was 11.99 months (95% CI, 8.55 to 15.49) and 23.18 months (95% CI, 19.33 to 27.02), respectively (P = 0.001). The MST in male and female patients was 17.40 months (95% CI, 13. 19 to 21.61) and 22.74 months (95% CI, 18.29 to 27.19), respectively (P = 0.111). CONCLUSIONS: Second line EGFR TKIs followed by third line pemetrexed regimen improves the PFS and MST compared with the regimen second line pemetrexed followed by third line EGFR TKIs in patients with advanced lung adenocarcinoma. Smoking status is an independent prognostic factor. Survival is not influenced by gender. Prospective clinical trials are needed to confirm these findings.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Adulto , Anciano , Antineoplásicos/uso terapéutico , Supervivencia sin Enfermedad , Clorhidrato de Erlotinib , Femenino , Gefitinib , Glutamatos/uso terapéutico , Guanina/análogos & derivados , Guanina/uso terapéutico , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pemetrexed , Quinazolinas/uso terapéutico , Estudios Retrospectivos , Fumar , Tasa de Supervivencia
15.
Heart Rhythm ; 9(6): 961-7, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22300662

RESUMEN

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder involving diseased cardiac muscle. Bridging integrator 1 (BIN1) is a membrane-associated protein important to cardiomyocyte homeostasis and is downregulated in cardiomyopathy. We hypothesized that BIN1 could be released into the circulation and that blood-available BIN1 can provide useful data on the cardiac status of patients whose hearts are failing secondary to ARVC. OBJECTIVE: To determine whether plasma BIN1 levels can be used to measure disease severity in patients with ARVC. METHODS: We performed a retrospective cohort study of 24 patients with ARVC. Plasma BIN1 levels were assessed for their ability to correlate with cardiac functional status and predict ventricular arrhythmias. RESULTS: Mean plasma BIN1 levels were decreased in patients with ARVC with heart failure (15 ± 7 vs 60 ± 17 in patients without heart failure, P <.05; the plasma BIN1 level was 60 ± 10 in non-ARVC normal controls). BIN1 levels correlated inversely with number of previous ventricular arrhythmia (R = -.47; P <.05), and low BIN1 levels correctly classified patients with advanced heart failure or ventricular arrhythmia (receiver operator curve area under the curve of 0.88 ± 0.07). Low BIN1 levels also predicted future ventricular arrhythmias (receiver operator curve area under the curve of 0.89 ± 0.09). In a stratified analysis, BIN1 levels could predict future arrhythmias in patients without severe heart failure (n = 20) with an accuracy of 82%. In the 7 patients with ARVC with serial blood samples, all of whom had evidence of disease progression during follow-up, plasma BIN1 levels decreased significantly (a decrease of 63%; P <.05). CONCLUSIONS: Plasma BIN1 level seems to correlate with cardiac functional status and the presence or absence of sustained ventricular arrhythmias in a small cohort of patients with ARVC and can predict future ventricular arrhythmias.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/sangre , Arritmias Cardíacas/sangre , Displasia Ventricular Derecha Arritmogénica/complicaciones , Insuficiencia Cardíaca/sangre , Proteínas Nucleares/sangre , Proteínas Supresoras de Tumor/sangre , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiología , Displasia Ventricular Derecha Arritmogénica/sangre , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Biomarcadores/sangre , Ecocardiografía , Electrocardiografía , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Genes Supresores de Tumor , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad
16.
Circ Res ; 110(7): 978-89, 2012 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-22328533

RESUMEN

RATIONALE: The intracellular trafficking of connexin 43 (Cx43) hemichannels presents opportunities to regulate cardiomyocyte gap junction coupling. Although it is known that Cx43 hemichannels are transported along microtubules to the plasma membrane, the role of actin in Cx43 forward trafficking is unknown. OBJECTIVE: We explored whether the actin cytoskeleton is involved in Cx43 forward trafficking. METHODS AND RESULTS: High-resolution imaging reveals that Cx43 vesicles colocalize with nonsarcomeric actin in adult cardiomyocytes. Live-cell fluorescence imaging reveals Cx43 vesicles as stationary or traveling slowly (average speed 0.09 µm/s) when associated with actin. At any time, the majority (81.7%) of vesicles travel at subkinesin rates, suggesting that actin is important for Cx43 transport. Using Cx43 containing a hemagglutinin tag in the second extracellular loop, we developed an assay to detect transport of de novo Cx43 hemichannels to the plasma membrane after release from Brefeldin A-induced endoplasmic reticulum/Golgi vesicular transport block. Latrunculin A (for specific interference of actin) was used as an intervention after reinitiation of vesicular transport. Disruption of actin inhibits delivery of Cx43 to the cell surface. Moreover, using the assay in primary cardiomyocytes, actin inhibition causes an 82% decrease (P<0.01) in de novo endogenous Cx43 delivery to cell-cell borders. In Langendorff-perfused mouse heart preparations, Cx43/ß-actin complexing is disrupted during acute ischemia, and inhibition of actin polymerization is sufficient to reduce levels of Cx43 gap junctions at intercalated discs. CONCLUSIONS: Actin is a necessary component of the cytoskeleton-based forward trafficking apparatus for Cx43. In cardiomyocytes, Cx43 vesicles spend a majority of their time pausing at nonsarcomeric actin rest stops when not undergoing microtubule-based transport to the plasma membrane. Deleterious effects on this interaction between Cx43 and the actin cytoskeleton during acute ischemia contribute to losses in Cx43 localization at intercalated discs.


Asunto(s)
Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Membrana Celular/metabolismo , Conexina 43/metabolismo , Vesículas Citoplasmáticas/metabolismo , Queratinocitos/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Transporte Biológico/fisiología , Línea Celular , Membrana Celular/ultraestructura , Células Cultivadas , Vesículas Citoplasmáticas/ultraestructura , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/ultraestructura , Uniones Comunicantes/metabolismo , Uniones Comunicantes/ultraestructura , Aparato de Golgi/metabolismo , Aparato de Golgi/ultraestructura , Humanos , Queratinocitos/citología , Queratinocitos/ultraestructura , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Modelos Animales , Miocitos Cardíacos/citología , Miocitos Cardíacos/ultraestructura
17.
Heart Rhythm ; 9(5): 812-20, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22138472

RESUMEN

BACKGROUND: Heart failure is a growing epidemic, and a typical aspect of heart failure pathophysiology is altered calcium transients. Normal cardiac calcium transients are initiated by Cav1.2 channels at cardiac T tubules. Bridging integrator 1 (BIN1) is a membrane scaffolding protein that causes Cav1.2 to traffic to T tubules in healthy hearts. The mechanisms of Cav1.2 trafficking in heart failure are not known. OBJECTIVE: To study BIN1 expression and its effect on Cav1.2 trafficking in failing hearts. METHODS: Intact myocardium and freshly isolated cardiomyocytes from nonfailing and end-stage failing human hearts were used to study BIN1 expression and Cav1.2 localization. To confirm Cav1.2 surface expression dependence on BIN1, patch-clamp recordings were performed of Cav1.2 current in cell lines with and without trafficking-competent BIN1. Also, in adult mouse cardiomyocytes, surface Cav1.2 and calcium transients were studied after small hairpin RNA-mediated knockdown of BIN1. For a functional readout in intact heart, calcium transients and cardiac contractility were analyzed in a zebrafish model with morpholino-mediated knockdown of BIN1. RESULTS: BIN1 expression is significantly decreased in failing cardiomyocytes at both mRNA (30% down) and protein (36% down) levels. Peripheral Cav1.2 is reduced to 42% by imaging, and a biochemical T-tubule fraction of Cav1.2 is reduced to 68%. The total calcium current is reduced to 41% in a cell line expressing a nontrafficking BIN1 mutant. In mouse cardiomyocytes, BIN1 knockdown decreases surface Cav1.2 and impairs calcium transients. In zebrafish hearts, BIN1 knockdown causes a 75% reduction in calcium transients and severe ventricular contractile dysfunction. CONCLUSIONS: The data indicate that BIN1 is significantly reduced in human heart failure, and this reduction impairs Cav1.2 trafficking, calcium transients, and contractility.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Canales de Calcio Tipo L/metabolismo , Calcio/metabolismo , Insuficiencia Cardíaca/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Nucleares/metabolismo , ARN Mensajero/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto , Animales , Línea Celular , Humanos , Ratones , Técnicas de Placa-Clamp , Transporte de Proteínas
18.
Mol Biol Rep ; 39(5): 5283-9, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22167330

RESUMEN

Published data on the association of vascular endothelial growth factor (VEGF) -1154G>A polymorphism with cancer risk is inconclusive. To derive a more precise estimation of association between VEGF -1154G>A polymorphism and the risk of cancer, we performed a meta-analysis of 7,071 cancer cases and 7,693 controls from 16 published case-control studies. Our meta-analysis didn't reveal an association between VEGF -1154G>A polymorphism and overall cancer risk (GG vs. AA: OR: 1.08, 95% CI: 0.96-1.20; GA vs. AA: OR: 1.04, 95% CI: 0.93-1.17; recessive model: GG+GA vs. AA: OR: 1.06, 95% CI: 0.95-1.18; dominant model: GG vs. GA+AA, OR: 1.11, 95% CI: 1.00-1.24). Nevertheless, for non-Caucasians, GG homozygote may have higher cancer risk compared with either A carriers (OR: 1.58, 95% CI: 1.12-2.23) or AA homozygote (OR: 1.43, 95% CI: 1.17-1.76). No significant heterogeneity was detected except in the dominant model and "prostate cancer" subgroup analysis. More studies with larger samples are warranted to confirm these findings.


Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias/genética , Polimorfismo de Nucleótido Simple/genética , Factor A de Crecimiento Endotelial Vascular/genética , Estudios de Casos y Controles , Estudios de Asociación Genética , Heterogeneidad Genética , Humanos , Sesgo de Publicación , Factores de Riesgo
19.
Circulation ; 124(17): 1838-47, 2011 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-21947295

RESUMEN

BACKGROUND: A variety of studies carried out using either human subjects or laboratory animals suggest that vitamin D and its analogues possess important beneficial activity in the cardiovascular system. Using Cre-Lox technology we have selectively deleted the vitamin D receptor (VDR) gene in the cardiac myocyte in an effort to better understand the role of vitamin D in regulating myocyte structure and function. METHODS AND RESULTS: Targeted deletion of the exon 4 coding sequence in the VDR gene resulted in an increase in myocyte size and left ventricular weight/body weight versus controls both at baseline and following a 7-day infusion of isoproterenol. There was no increase in interstitial fibrosis. These knockout mice demonstrated a reduction in end-diastolic and end-systolic volume by echocardiography, activation of the fetal gene program (ie, increased atrial natriuretic peptide and alpha skeletal actin gene expression), and increased expression of modulatory calcineurin inhibitory protein 1 (MCIP1), a direct downstream target of calcineurin/nuclear factor of activated T cell signaling. Treatment of neonatal cardiomyocytes with 1,25-dihydroxyvitamin D partially reduced isoproterenol-induced MCIP1 mRNA and protein levels and MCIP1 gene promoter activity. CONCLUSIONS: Collectively, these studies demonstrate that the vitamin D-VDR signaling system possesses direct, antihypertrophic activity in the heart. This appears to involve, at least in part, suppression of the prohypertrophic calcineurin/NFAT/MCIP1 pathway. These studies identify a potential mechanism to account for the reported beneficial effects of vitamin D in the cardiovascular system.


Asunto(s)
Cardiomegalia/etiología , Cardiomegalia/genética , Eliminación de Gen , Miocitos Cardíacos/metabolismo , Receptores de Calcitriol/deficiencia , Receptores de Calcitriol/genética , Animales , Cardiomegalia/metabolismo , Marcación de Gen , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/patología
20.
Cancer Invest ; 29(7): 472-7, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21740084

RESUMEN

We evaluated cancer risk with three VEGF polymorphisms (-460C>T, -2578C>A, 1612G>A) based on current available studies. -460C>T did not appear to influence cancer risks. -2578C carriers had a 30% reduction of colorectal cancer (CRC) risk in comparison with AA homozygote (OR: 0.70, CI: 0.56-0.88). 1612G carriers had a striking 84% reduction of gastric cancer risk in comparison with AA homozygote. Multiple pair-wise comparisons suggested a recessive role for both -2578A and 1612A risk allele. Further studies with larger samples, well-matched controls and homogenous ethnic background are warranted to confirm these findings. We recommend more efforts into the investigation of 1612G>A with cancer risks.


Asunto(s)
Neoplasias/genética , Polimorfismo Genético , Factor A de Crecimiento Endotelial Vascular/genética , Estudios de Casos y Controles , Genotipo , Humanos , Neoplasias/etiología , Riesgo
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