Relationships between CASP8, Fas Gene Polymorphisms and the Prognosis of Patients with Non-Hodgkin's Lymphoma in Han Nationality / 中国实验血液学杂志

OBJECTIVE@#To investigate the relationships between caspase-8 (CASP8), fatty acid synthetase (Fas) gene polymorphisms and prognosis of non-Hodgkin's lymphoma patients in Han nationality.@*METHODS@#The clinical data of 85 patients with non-Hodgkin's lymphoma were analyzed retrospectively. The polymorphisms of CASP8 and Fas gene were detected, and prognosis of the patients were analyzed. The polymorphisms of CASP8 and Fas gene in patients with different prognosis were compared, and the relationships between gene polymorphisms and the poor prognosis of the patients were investigated.@*RESULTS@#The incidence rate of poor prognosis of the patients enrolled in the study was 65.88%. The polymorphisms of CASP8 and Fas genes in the patients with poor or good prognosis were in accordance with Hardy Weinberg's law of genetic balance. The frequencies of GG genotype and G allele at rs 1035142 of CASP8 gene, GA genotype and A allele at rs 1377 of Fas gene in patients with poor prognosis were lower than those of the patients with good prognosis (P<0.05). The frequencies of GT, TT and T alleles at rs 1035142 of CASP8 gene, GG and G alleles at rs 1377 of Fas gene in patients with poor prognosis were higher than those of the patients with good prognosis (P<0.05). The proportions of Ann Arbor stage III-IV and high malignancy in patients with poor prognosis were higher than those of the patients with good prognosis (P<0.05). Logistic multiple regression analysis showed that Ann Arbor stage III-IV, moderate malignant, high malignancy, CASP8 rs 1035142 GT genotype, CASP8 rs 1035142 TT genotype and Fas rs 1377 GG genotype were all the risk factors for the poor prognosis of the patients (P<0.05).@*CONCLUSION@#The poor prognosis rate of non-Hodgkin's lymphoma patients in Han nationality is relatively high, and the risk factors for the prognosis of the patients include Ann Arbor stage III-IV, moderate and high malignancy, CASP8 rs 1035142 GT genotype, CASP8 rs 1035142 TT genotype and Fas rs 1377 GG genotype.

Morphometric analysis and pattern of protein and gene expression of apoptosis in focal cerebral ischemia in rats and the neuroprotetive action of hypothermia and ketoprofen / Análisis morfométrico y modelo de expresión de proteína y genes de apoptosis en isquemia cerebral focal en ratas y la acción neuroprotectora de hipotermia y ketoprofeno

This study aimed to investigate the morphometric and the pattern of protein and gene expression related to the extrinsic apoptotic pathway in experimental focal cerebral ischemia and the hole of neuroprotection with hypothermia and ketoprofen. For this analysis, 120 rats were randomly divided into 3 groups (20 animals each): control - no surgery (20 animals); sham - simulation of surgery (20 animals); ischemic - focal ischemia for 1 hour, without reperfusion (80 animals) and divided into four subgroups with 20 animals each: ischemic + intraischemic hypothermia; ischemic + previous intravenous ketoprofen, and ischemic + hypothermia and ketoprofen. The infarct volume was measured using morphometric analysis of infarct areas defined by triphenyl tetrazolium chloride and the patterns of expression of the apoptosis genes (Fas, c-Flip, caspase-8 and caspase-3) and the apoptosis protein caspase-3 were evaluated by quantitative real-time PCR and immunohistochemistry, respectively. Hypo expression of genes of extrinsic pathway of apoptosis was observed: Fas receptor, c-Flip and caspase-8 in the ischemics areas. Increases in the gene and protein caspase-3 in the ischemic areas were also observed, and these increases were reduced by hypothermia and ketoprofen, also noted in the morphometric study. The caspases-3 increase suggests that this gene plays an important role in apoptosis, probably culminating in cell death and that the neuroprotective effect of hypothermia and ketoprofen is involved.

Este estudio tuvo como objetivo investigar la morfometría y el patrón de expresión de proteínas y genes relacionados con la vía apoptótica extrínseca en la isquemia cerebral focal experimental y el agujero de neuroprotección con hipotermia y ketoprofeno. Se dividieron aleatoriamente 120 ratas en 3 grupos (20 animales cada uno): control - sin cirugía (20 animales); simulación - simulación de cirugía (20 animales); isquemia isquemia focal durante 1 hora, sin reperfusión (80 animales) y dividida en cuatro subgrupos con 20 animales cada uno: isquemia + hipotermia intraisquémica; isquemia + ketoprofeno intravenoso previo, e isquemia + hipotermia y ketoprofeno. El volumen del infarto se midió utilizando un análisis morfométrico de áreas de infarto definidas por cloruro de trifenil tetrazolio y los patrones de expresión de los genes de apoptosis (Fas, c-Flip, caspase-8 y caspase-3) y la proteína de apoptosis caspase-3 fueron evaluados por PCR cuantitativa en tiempo real e inmunohistoquímica, respectivamente. Se observó hipoexpresión de genes de la vía extrínseca de la apoptosis: receptor Fas, c-Flip y caspasa-8 en las áreas isquémicas. También se observaron aumentos en el gen y la proteína caspasa-3 en las áreas isquémicas y estos aumentos se redujeron por hipotermia y ketoprofeno, también observado por estudio morfométrico. El aumento de caspasas-3 sugiere que este gen tiene un papel importante en la apoptosis, y probable causa de muerte celular, involucrando el efecto neuroprotector de la hipotermia y el ketoprofeno.

Gene Polymorphisms in FAS (Rs3740286 and Rs4064) Are Involved in Endometriosis Development in Brazilian Women, but not those in CASP8 (rs13416436 and rs2037815) / Polimorfismos do gene FAS (rs3740286 e rs4064) estão envolvidos no desenvolvimento de endometriose em mulheres brasileiras, mas não os no CASP8 (rs13416436 e rs2037815)

Abstract Objective The present study aims to investigate the association between caspase-8 (CASP8) (rs13416436 and rs2037815) and Fas cell surface death receptor (FAS) (rs3740286 and rs4064) polymorphisms with endometriosis in Brazilian women. Methods In the present case-control study, 45 women with a diagnosis of endometriosis and 78 normal healthy women as a control group were included. The genotyping was determined by real-time polymerase chain reaction (PCR) with Taqman hydrolysis probes (Thermo Fisher Scientific, Darmstadt, Germany). Genotypic and allelic frequencies were analyzed using Chi-squared (χ2) test. In order to determine the inheritance models and haplotypes ,SNPStats (Institut Català d'Oncologia, Barcelona, Spain) was used. Levels of 5% (p = 0.05) were considered statistically significant. Results No significant difference was observed in genotypic or allelic frequencies between control and endometriosis groups for rs13416436 and rs2037815 (CASP8 gene). On the other hand, a significant difference between rs3740286 and rs4064 (FAS gene) was found. Regarding polymorphisms in the FAS gene, a statistically significant differencewas found in co-dominant and dominantmodels. Only the haplotype containing the rs3740286A and rs4064G alleles in the FAS gene were statistically significant. Conclusion The polymorphisms in the CASP8 gene were not associated with endometriosis. The results indicate an association between FAS gene polymorphisms and the risk of developing endometriosis.

Resumo Objetivo Investigar a associação entre os polimorfismos dos genes caspase-8 (CASP8) (rs13416436 e rs2037815) e FAS (rs3740286 e rs4064) em mulheres brasileiras com endometriose. Métodos Trata-se de um estudo do tipo caso-controle, no qual foram incluídas 45 mulheres com diagnóstico de endometriose e 78 controles. A genotipagem das amostras foi determinada usando a reação em cadeia de polimerase em tempo real com sondas de hidrólise TaqMan (Thermo Fisher Scientific, Darmstadt, Germany). As frequências genotípicas e alélicas foram analisadas usando o teste do qui-quadrado. O SNPStats (Institut Català d'Oncologia, Barcelona, Espanha) foi usado para determinar os modelos de herança e os haplótipos. Os níveis de significância estatística considerados foram de 5% (p = 0,05). Resultados Não foi observada diferença significativa nas frequências genotípicas ou alélicas entre os grupos de controle e de endometriose para os polimorfismos rs13416436 e rs2037815 (gene CASP8). Por outro lado, foi encontrada uma diferença significativa entre os polimorfismos rs3740286 e rs4064 (gene FAS). Em relação aos polimorfismos do gene FAS, foi encontrada uma diferença estatisticamente significativa nos modelos codominante e dominante. Apenas o haplótipo contendo os alelos rs3740286A e rs4064G no gene FAS foi estatisticamente significativo. Conclusão Não há associação entre os polimorfismos do gene CASP8 e endometriose. Entretanto, há associação entre os polimorfismos do gene FAS e o risco de desenvolver endometriose.

MicroRNA-122 regulates caspase-8 and promotes the apoptosis of mouse cardiomyocytes

Cardiomyocyte apoptosis plays key roles in the pathogenesis of heart diseases such as myocardial infarction. MicroRNAs are important regulators of gene expression, which are also involved in the regulation of cardiomyocyte apoptosis. However, cardiomyocyte apoptosis regulated by microRNA (miR)-122 is largely unexplored. The aim of this study focused on the role of miR-122 in cardiomyocyte apoptosis. Cardiomyocytes were isolated from neonatal mice and primarily cultured. MiR-122 mimic and inhibitor were transfected to cardiomyocytes and verified by qRT-PCR. Cell viability and apoptosis post-transfection were assessed by MTT assay and flow cytometry, respectively. Changes in expression of caspase-8 were quantified by qRT-PCR and western blot. Results showed that miR-122 mimic and inhibitor successfully induced changes in miR-122 levels in cultured cardiomyocytes (P<0.01). MiR-122 overexpression suppressed viability and promoted apoptosis of cardiomyocytes (P<0.05), and miR-122 knockdown promoted cell viability and inhibited apoptosis (P<0.05). The mRNA and protein levels of caspase-8 were elevated by miR-122 overexpression (P<0.01) and reduced by miR-122 knockdown (P<0.001). These results suggest an inductive role of miR-122 in cardiomyocyte apoptosis, which may be related to its regulation on caspase-8.

A six-nucleotide deletion polymorphism in the casp8 promoter is associated with reduced risk of esophageal and gastric cancers in Kashmir valley.

BACKGROUND: Caspase-8 (CASP8) is a key regulator of apoptosis or programmed cell death, an essential defense mechanism against hyperproliferation and malignancy. To evaluate the role of CASP8 polymorphisms in esophageal (EC) and gastric cancers (GC) in the Kashmir valley, we examined the risk due to -652 6N ins/del polymorphism (rs3834129) in the promoter of CASP8 in a case–control study. MATERIALS AND METHODS: Genotypes of the CASP8 polymorphisms (-652 6N ins/del; rs3834129) were determined for 315 patients (135 EC and 108 GC) and 195 healthy controls by polymerase chain reaction. Data was statistically analyzed using Chi-square test and logistic regression model by using the SPSS software. RESULTS: Carriers for the del allele of rs3834129 single nucleotide polymorphism were associated with decreased risk for both EC (odds ratio [OR] = 0.278; 95% confidence interval [95% CI] = 0.090–0.853; P = 0.025) and GC (OR = 0.397; 95% CI = 0.164–0.962; P = 0.041). Also, in a recessive model, our results showed that CASP8 -652 6N ins/del “del/del” allele was conferring significant low risk for both EC (OR = 0.380; 95% CI = 0.161–0.896; P = 0.027) and GC (OR = 0.293; 95% CI = 0.098–0.879; P = 0.029). However, interaction of CASP8 -652 6N ins/del genotypes with smoking and high consumption of salted tea did not further modulate the risk of EC and GC. CONCLUSIONS: Polymorphism in CASP8 -652 6N ins/del polymorphism modulates the risk of EC and GC in Kashmir valley.

Caspase 8 gene variants in healthy North Indian population and comparison with worldwide ethnic group variations.

BACKGROUND: Many strategies are being used for the quest for the disease causing genes. Inter-individual variations in several genes exist. Thus, even if they share the same disease-associated allele, the genomic backgrounds – and hence potential interacting alleles at other loci – of people with different regional ancestries may differ, with a consequent variation in the severity of their disease. MATERIALS AND METHOD: The present study was conducted to determine the distribution of Caspase 8 IVS12-19G/A, Caspase 8D302H, Caspase 8 -652del and Caspase 8 -678del polymorphisms (as frequency distribution of caspases in Indians generally is not yet known), which was then compared with different populations globally. Polymerase chain reaction (PCR)-based analysis was conducted in 205 normal healthy individuals of similar ethnicity. RESULTS: The variant allele frequencies were 17.6% (A) in Caspase 8 IVS12-19G/A, 13.2% (H) in Caspase 8D302H, 23.2% (Del) in Caspase 8 -652del and 24.6% (Del) in Caspase 8 -678del. Further, comparison of frequency distribution of these genes was done with various published studies of different ethnic groups globally. CONCLUSION: It is anticipated from our results that the frequency of these caspase genes exhibits distinctive patterns in India, which could perhaps be attributed to ethnic variation. This study is important as it can form a baseline for screening individuals who are at high risk due to exposure to environmental carcinogens and cancer predisposition, and therefore, might help in investigating linked polymorphisms in a way that will not obscure potential associations between genotype and phenotype.