Hepatitis C virus(HCV)infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune response.The antigen-specific cytotoxi...Hepatitis C virus(HCV)infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune response.The antigen-specific cytotoxic T cell response is essential for keeping HCV under control,but during persistent infection,these cells become exhausted or even deleted.The exhaustion process is progressive and depends on the infection duration and level of antigenemia.During high antigenic load and long duration of infection,T cells become extremely exhausted and ultimately disappear due to apoptosis.The development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines,such as transforming growth factor beta 1.This cytokine downregulates tumor necrosis factor receptor(TNFR)-associated factor 1(TRAF1),the signal transducer of the T cell co-stimulatory molecule TNFR superfamily member 9(known as 4-1BB).This impairment correlates with the low reactivity of T cells and an exhaustion phenotype.Treatment with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector function.The process of TRAF1 loss and its in vitro recovery is hierarchical,and more affected by severe disease progression.In conclusion,TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV,and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.展开更多
目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB...目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB1表达对肺腺癌增殖的影响仍不清楚。本研究探讨了GPRC5A调控的ABCB1表达对肺腺癌增殖的影响。方法我们采用RT-PCR、Western-blot或免疫组化实验,分析ABCB1在肺腺癌细胞系、人肺腺癌组织以及GPRC5A基因敲除小鼠和野生型小鼠的气管上皮细胞和肺组织中的表达。采用细胞计数试剂盒-8(CCK-8)分析GPRC5A基因敲除小鼠气管上皮细胞对化疗药物的敏感性。采用皮下肿瘤形成实验探讨下调ABCB1表达是否可抑制体内肺腺癌增殖。采用免疫荧光和免疫沉淀实验研究GPRC5A和ABCB1之间潜在的调控关系。结果ABCB1在肺腺癌细胞系和人类肺腺癌组织中表达上调。GPRC5A基因敲除小鼠的气管上皮细胞及肺组织的ABCB1表达高于野生型小鼠。与GPRC5A野生型小鼠的气管上皮细胞相比,GPRC5A基因敲除小鼠的气管上皮细胞对塔立奇达和多柔比星更敏感。注射移植细胞28天后,接受ABCB1基因敲除细胞移植的GPRC5A-/-C57BL/6小鼠的肺肿瘤的体积和重量均明显低于野生型细胞移植小鼠(P=0.0043,P=0.0060)。此外,免疫荧光和免疫沉淀实验表明,GPRC5A通过直接结合方式调控ABCB1的表达。结论GPRC5A通过抑制ABCB1表达降低肺腺癌增殖。GPRC5A调节ABCB1表达的途径有待研究。展开更多
AIM: To examine the effect of the potential interaction between KIF1 B variants(rs17401966 and rs3748578) and environmental factors on the risk of hepatocellular carcinoma(HCC) in a high-risk region in China.METHODS: ...AIM: To examine the effect of the potential interaction between KIF1 B variants(rs17401966 and rs3748578) and environmental factors on the risk of hepatocellular carcinoma(HCC) in a high-risk region in China.METHODS: Three hundred and six patients with HCC and 306 hospital-based control participants residing in the Shunde region of Guangdong Province, China were enrolled. Clinical characteristics were collected by reviewing the complete medical histories from the patient archives, and epidemiological data were collected using a questionnaire and clinical examination. Two single nucleotide polymorphisms(SNPs) of KIF1B(rs17401966 and rs3748578) were chosen for the current study. All subjects were genotypedusing a Taq Man real-time polymerase chain reaction. Multiplicative and additive logistic regression models were used to evaluate various gene-environment interactions.RESULTS: Smoking, frequent consumption of raw freshwater fish, hepatitis B virus(HBV) infection, and a family history of HCC were important risk factors for HCC in this population. Chronic infection with HBV was the most important environmental risk factor for HCC [odds ratio(OR) = 12.02; 95% confidence interval(95%CI): 6.02-24.00]. No significant association was found between the KIF1 B variants alone and the risk of HCC. Nevertheless, a significant additive effect modification was observed between rs17401966 and alcohol consumption(P for additive interaction = 0.0382). Compared with non-drinkers carrying either the AG or GG genotype of rs17401966, individuals classified as alcohol consumers with the AA genotype of rs17401966 had a significantly increased risk of HCC(OR = 2.36; 95%CI: 1.49-3.74).CONCLUSION: The gene-environment interaction between the KIF1 B rs17401966 variant and alcohol consumption may contribute to the development of HCC in Chinese individuals.展开更多
AIdo-keto reductase family 1 member C3 has recently been regarded as a potential therapeutic target in castrate-resistant prostate cancer. Herein, we investigated whether berberine delayed the progression of castrate-...AIdo-keto reductase family 1 member C3 has recently been regarded as a potential therapeutic target in castrate-resistant prostate cancer. Herein, we investigated whether berberine delayed the progression of castrate-resistant prostate cancer by reducing androgen synthesis through the inhibition of Aldo-keto reductase family 1 member C3. Cell viability and cellular testosterone content were measured in prostate cancer cells. Aido-keto reductase family 1 member C3 mRNA and protein level were detected by RT-PCR and Western bolt analyses, respectively. Computer analysis with AutoDock Tools explored the molecular interaction of berberine with Aldo-keto reductase family 1 member C3. We found that berberine inhibited 22Rvl cells proliferation and decreased cellular testosterone formation in a dose-dependent manner. Berberine inhibited Aldo-keto reductase family I member C3 enzyme activity, rather than influenced mRNA and protein expressions. Molecular docking study demonstrated that berberine could enter the active center of Aldo-keto reductase family 1 member C3 and form π-π interaction with the amino-acid residue Phe306 and Phe311. In conclusion, the structural interaction of berberine with Aldo-keto reductase family 1 member C3 is attributed to the suppression of Aldo-keto reductase family I member C3 enzyme activity and the inhibition of 22Rvl prostate cancer cell growth by decreasing the intfacellular androgen synthesis. Our result provides the experimental basis for the design, research, and development of AKRlC3 inhibitors using berberine as the lead compound.展开更多
基金Supported by Instituto de Salud Carlos III and European Structural Funds in SpainEuropean Regional Development Fund,No.PI19/00206.
文摘Hepatitis C virus(HCV)infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune response.The antigen-specific cytotoxic T cell response is essential for keeping HCV under control,but during persistent infection,these cells become exhausted or even deleted.The exhaustion process is progressive and depends on the infection duration and level of antigenemia.During high antigenic load and long duration of infection,T cells become extremely exhausted and ultimately disappear due to apoptosis.The development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines,such as transforming growth factor beta 1.This cytokine downregulates tumor necrosis factor receptor(TNFR)-associated factor 1(TRAF1),the signal transducer of the T cell co-stimulatory molecule TNFR superfamily member 9(known as 4-1BB).This impairment correlates with the low reactivity of T cells and an exhaustion phenotype.Treatment with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector function.The process of TRAF1 loss and its in vitro recovery is hierarchical,and more affected by severe disease progression.In conclusion,TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV,and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.
文摘目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB1表达对肺腺癌增殖的影响仍不清楚。本研究探讨了GPRC5A调控的ABCB1表达对肺腺癌增殖的影响。方法我们采用RT-PCR、Western-blot或免疫组化实验,分析ABCB1在肺腺癌细胞系、人肺腺癌组织以及GPRC5A基因敲除小鼠和野生型小鼠的气管上皮细胞和肺组织中的表达。采用细胞计数试剂盒-8(CCK-8)分析GPRC5A基因敲除小鼠气管上皮细胞对化疗药物的敏感性。采用皮下肿瘤形成实验探讨下调ABCB1表达是否可抑制体内肺腺癌增殖。采用免疫荧光和免疫沉淀实验研究GPRC5A和ABCB1之间潜在的调控关系。结果ABCB1在肺腺癌细胞系和人类肺腺癌组织中表达上调。GPRC5A基因敲除小鼠的气管上皮细胞及肺组织的ABCB1表达高于野生型小鼠。与GPRC5A野生型小鼠的气管上皮细胞相比,GPRC5A基因敲除小鼠的气管上皮细胞对塔立奇达和多柔比星更敏感。注射移植细胞28天后,接受ABCB1基因敲除细胞移植的GPRC5A-/-C57BL/6小鼠的肺肿瘤的体积和重量均明显低于野生型细胞移植小鼠(P=0.0043,P=0.0060)。此外,免疫荧光和免疫沉淀实验表明,GPRC5A通过直接结合方式调控ABCB1的表达。结论GPRC5A通过抑制ABCB1表达降低肺腺癌增殖。GPRC5A调节ABCB1表达的途径有待研究。
文摘AIM: To examine the effect of the potential interaction between KIF1 B variants(rs17401966 and rs3748578) and environmental factors on the risk of hepatocellular carcinoma(HCC) in a high-risk region in China.METHODS: Three hundred and six patients with HCC and 306 hospital-based control participants residing in the Shunde region of Guangdong Province, China were enrolled. Clinical characteristics were collected by reviewing the complete medical histories from the patient archives, and epidemiological data were collected using a questionnaire and clinical examination. Two single nucleotide polymorphisms(SNPs) of KIF1B(rs17401966 and rs3748578) were chosen for the current study. All subjects were genotypedusing a Taq Man real-time polymerase chain reaction. Multiplicative and additive logistic regression models were used to evaluate various gene-environment interactions.RESULTS: Smoking, frequent consumption of raw freshwater fish, hepatitis B virus(HBV) infection, and a family history of HCC were important risk factors for HCC in this population. Chronic infection with HBV was the most important environmental risk factor for HCC [odds ratio(OR) = 12.02; 95% confidence interval(95%CI): 6.02-24.00]. No significant association was found between the KIF1 B variants alone and the risk of HCC. Nevertheless, a significant additive effect modification was observed between rs17401966 and alcohol consumption(P for additive interaction = 0.0382). Compared with non-drinkers carrying either the AG or GG genotype of rs17401966, individuals classified as alcohol consumers with the AA genotype of rs17401966 had a significantly increased risk of HCC(OR = 2.36; 95%CI: 1.49-3.74).CONCLUSION: The gene-environment interaction between the KIF1 B rs17401966 variant and alcohol consumption may contribute to the development of HCC in Chinese individuals.
基金This work was supported by grants from the National Natural Science Foundation of China （81302206 and 81560422）, the Development and Reform Commission of Jilin Province （2013C026-2）, and the Young Scholars Program of Norman Bethune Health Science Center of Jilin University （2013201012）, the Health and Family Planning Commission of Jiangxi Province （20143207） and the Natural Science Foundation of Jiangxi Province of China （20151BAB205016 and 20132BAB205008）.
文摘AIdo-keto reductase family 1 member C3 has recently been regarded as a potential therapeutic target in castrate-resistant prostate cancer. Herein, we investigated whether berberine delayed the progression of castrate-resistant prostate cancer by reducing androgen synthesis through the inhibition of Aldo-keto reductase family 1 member C3. Cell viability and cellular testosterone content were measured in prostate cancer cells. Aido-keto reductase family 1 member C3 mRNA and protein level were detected by RT-PCR and Western bolt analyses, respectively. Computer analysis with AutoDock Tools explored the molecular interaction of berberine with Aldo-keto reductase family 1 member C3. We found that berberine inhibited 22Rvl cells proliferation and decreased cellular testosterone formation in a dose-dependent manner. Berberine inhibited Aldo-keto reductase family I member C3 enzyme activity, rather than influenced mRNA and protein expressions. Molecular docking study demonstrated that berberine could enter the active center of Aldo-keto reductase family 1 member C3 and form π-π interaction with the amino-acid residue Phe306 and Phe311. In conclusion, the structural interaction of berberine with Aldo-keto reductase family 1 member C3 is attributed to the suppression of Aldo-keto reductase family I member C3 enzyme activity and the inhibition of 22Rvl prostate cancer cell growth by decreasing the intfacellular androgen synthesis. Our result provides the experimental basis for the design, research, and development of AKRlC3 inhibitors using berberine as the lead compound.
