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1.
目的:检测免疫共刺激分子B7-H4及Fas、FasL在不同宫颈组织中的表达,研究三者的异常表达与宫颈癌免疫逃逸机制的关系。方法:选择陕西省肿瘤医院病理科2014-2018年的石蜡包埋标本162例,采用免疫组织化学方法检测20例正常宫颈、30例宫颈上皮内瘤变(CIN)和112例I期-IV期宫颈癌组织中B7-H4及Fas、FasL的表达水平。结果:B7-H4在正常宫颈组、CIN组、宫颈癌组的阳性表达率分别为0、20.0%、47.32%,两两相比,具有显著性差异(P<0.05)。在112例宫颈癌病例中FIGO临床分期I期至IV期各期别宫颈癌组织B7-H4的阳表达率分别为16.67%、43.18%、70.83%、85.71%,各组间相比差异具有统计学意义。正常对照组Fas的阳性表达率是85.00%,CIN组43.33%,宫颈癌组41.96%,正常组与CIN、正常组与宫颈癌组相比差异均具有统计学意义(P<0.05),CIN组与宫颈癌组相比,无明显差异(P>0.05)。FasL的阳性表达率在正常组为20.00%,CIN组为50.00%,宫颈癌组为56.25%,正常组与CIN、宫颈癌组比较,差异具有统计学意义(P<0.05),CIN组与宫颈癌组比较无显著差异;B7-H4阳性宫颈癌组Fas阳性表达率28.30%明显较B7-H4阴性宫颈癌组Fas阳性表达率54.24%低,差异具有统计学意义(P<0.05);而B7-H4阳性宫颈癌组FasL阳性表达率79.25%明显高于B7-H4阴性宫颈癌组FasL阳性表达率35.59%,差异具有统计学意义(P<0.05)。结论:负性免疫共刺激分子B7-H4和Fas、FasL凋亡蛋白在宫颈癌的发生、进展中起到了重要作用,其协同作用可能为宫颈癌细胞逃逸机体免疫的机制之一。  相似文献   
2.
Objective: To investigate the relation of Fas and Fas ligand (FasL) protein expression with carcinogenesis and metastasis of cardiac carcinoma. Methods: Immunohistochemistry was used to detect Fas and FasL protein expression in 64 cardiac carcinoma tissue samples and 20 normal gastric tissue samples. Relation between FasL and Fas expression, age and gender of gastric cancer patients, and pathological subtype and lymph node metastasis of gastric cancer was analyzed. Results: The Fas expression level was significantly higher in normal gastric tissue samples than in cardiac carcinoma tissue samples (85.0% vs. 25.0%, P<0.001), while the FasL expression level was significantly lower in normal gastric tissue samples than in cardiac carcinoma tissue samples (30.0% vs. 81.3%, P<0.001). The Fas expression level was significantly higher in invasive lymph nodes than in non-invasive lymph nodes (82.9% vs. 56.5%, P<0.003) and in well-differentiated gastric carcinoma tissue samples than in poorly-differentiated cardiac carcinoma tissue samples (50.0% vs. 18.0%, P=0.015). The FasL expression level was significantly lower in well-differentiated cardiac carcinoma tissue samples than in poorly- differentiated cardiac carcinoma tissue samples (42.9% vs. 84.0%, P=0.021). The Fas and FasL expression levels (25.0% and 81.3%) were significantly different in cardiac carcinoma tissue samples (P<0.001), but had a non-linear correlation (P=0.575). Conclusion: Abnormal Fas and FasL expressions in cardiac carcinoma and lymph node tissues are involved in carcinogenesis and metastasis of gastric cancer.  相似文献   
3.
目的 探讨N-乙酰-5-羟色胺(N-acetylserotonin,NAS)对视网膜缺血-再灌注损伤(retina ischemia-reperfusion injury,RIRI)大鼠视网膜Fas、FasL蛋白表达的影响。方法 取健康成年Sprague Dawley大鼠54只,将大鼠随机分为正常组(6只)、RIRI组(24只)与NAS组(24只);采用高眼压法建立大鼠RIRI模型,依据造模后不同时间点将RIRI组与NAS组大鼠又分为6 h、12 h、24 h及72 h四个亚组。NAS组于造模前30 min腹腔注射NAS(5 mg·kg-1),RIRI组腹腔注射等剂量的生理盐水。通过HE染色在光学显微镜下观察各组大鼠视网膜形态学变化,并记录各组大鼠视网膜厚度及视网膜神经节细胞数,采用免疫组织化学染色法检测NAS对RIRI大鼠视网膜Fas、FasL蛋白表达的影响。结果 HE染色显示,正常组大鼠视网膜各层细胞分界清晰,形态正常,神经细胞排列整齐;RIRI组大鼠再灌注后6 h视网膜各层出现水肿,以神经节细胞层及内核层较显著,神经节细胞数较正常组减少;随后视网膜水肿进一步加重,神经节细胞继续减少;NAS组大鼠在再灌注后6 h、12 h、24 h 视网膜水肿程度较 RIRI组轻,NAS组在再灌注后72 h视网膜厚度较 RIRI组厚,NAS组各时间点神经节细胞数均较 RIRI组多,差异均有统计学意义(均为P<0.05)。免疫组织化学染色显示,正常组几乎未见 Fas+细胞。再灌注后6 h,RIRI组视网膜神经节细胞及内核层开始出现少量 Fas+细胞;再灌注后12 h,RIRI组视网膜 Fas+细胞表达逐渐增多;再灌注后24 h视网膜Fas+细胞数达到高峰,棕色阳性染色细胞分布在视网膜神经节细胞层、内丛状层、内核层及神经纤维层;再灌注后 72 h 视网膜 Fas+细胞较再灌注后 24 h 减少。NAS组在再灌注后6 h、12 h、24 h、72 h 视网膜 Fas+细胞数均较 RIRI组各时间点减少,再灌注后24 h,Fas+细胞数达较高水平,随后下降,差异均有统计学意义(均为P<0.05)。正常组视网膜可见 FasL 全层低表达。RIRI组再灌注后 6 h,视网膜神经节细胞层和神经纤维层存在少量 FasL+细胞;再灌注后12 h FasL蛋白表达逐渐增多;再灌注后24 h FasL+细胞数达高峰,可见深棕色的细胞膜及细胞质染色细胞分布在视网膜神经节细胞层、内丛状层、内核层及神经纤维层;再灌注后72 h FasL蛋白的阳性表达逐渐减少。NAS组再灌注后6 h、12 h、24 h、72 h 视网膜FasL+细胞数均少于 RIRI组各时间点阳性细胞数,差异均有统计学意义(均为P<0.05)。结论 NAS可通过抑制RIRI大鼠视网膜细胞Fas、FasL蛋白的表达,减轻缺血再灌注对大鼠视网膜细胞造成的损伤。  相似文献   
4.
Previous studies have demonstrated that excessive free radicals play an essential role in the initiation and progression of epilepsy and that a novel exogenous free radical scavenger edaravone (Ed) exerts some neuroprotective effects on seizure-induced neuronal damage. The purpose of this study was to elucidate the possible molecular mechanisms of Ed associated with procaspase-3 denitrosylation and activation through the FasL-Trx2 pathway in seizures rats. In this study, we investigated the effects of Ed on the regulation of the combination of Fas ligand/Fas receptor and the major components of the death-inducing signaling complex (DISC) in the hippocampus of kainic acid (KA)-treated Sprague Dawley (SD) rats. Treatment with Ed can attenuate the increased expression of FasL induced by KA and prevent procaspase-3 denitrosylation and activation via suppression of the FasL-Trx2 signaling pathway, which alleviates the neuronal damage in seizures. These results provide experimental evidence that Ed functions by preventing the denitrosylation and activation of procaspase-3 and that Ed acts as a therapeutic option for epilepsy.  相似文献   
5.
目的:观察不同时间窗高压氧干预下的大鼠脊髓损伤(SCI)后细胞凋亡和脊髓功能的恢复情况,探讨最佳的高压氧治疗方法(HBOT),为临床治疗SCI提供实验依据。方法:160只SD大鼠随机分为模型对照组、HBO-PC组、HBOT组和HBO-PC+HBOT组。采用Allen's打击法建立SCI模型。模型对照组大鼠仅制模,未进行任何干预;HBO-PC组大鼠于高压氧干预10 d后立即制模,制模后未进行任何干预;HBOT组大鼠于制模后立即行高压氧干预;HBO-PC+HOBT组大鼠于高压氧干预10 d后立即制模,制模后继续高压氧干预。各组大鼠分别于制模后第1、2、7和14天取材,免疫组织化学PV-9000二步法检测大鼠Fas和FasL的表达水平,光镜下观察,并对结果进行统计学分析;采用TUNEL法检测细胞凋亡指数(AI),神经功能评价采用BBB评分。结果:与模型对照组比较,HBO-PC组、HBOT组和HBO-PC+HBOT组大鼠各时间点Fas和FasL表达水平均降低,且差异均有统计学意义(P<0.01);HBO-PC+HBOT组大鼠各时间点Fas和FasL表达水平比HBOT组和HBO-PC组降低,且差异有统计学意义(P<0.05);HBOT组大鼠各时间点Fas和FasL表达水平与HBO-PC组比较差异无统计学意义(P>0.05)。与模型对照组比较,其他各组大鼠细胞AI明显降低,差异均有统计学意义(P<0.01);HBO-PC+HBOT组AI低于HBOT组和HBO-PC组,且差异有统计学意义(P<0.05);HBOT组AI与HBO-PC组比较差异无统计学意义(P>0.05)。术后7和14 d HBO-PC组、HBOT组和HBO-PC+HBOT组大鼠BBB评分均高于模型对照组,且差异有统计学意义(P<0.01);HBO-PC+HBOT组BBB评分高于HBOT组和HBO-PC组,且差异有统计学意义(P<0.05或P<0.01);HBOT组BBB评分高于HBO-PC组,且差异有统计学意义(P<0.05)。结论:高压氧干预可减少SCI后细胞凋亡,促进脊髓功能的恢复;其治疗时间窗应提前到损伤前,HBO-PC联合HBOT法是治疗SCI的较佳方案。  相似文献   
6.
Paternal smoking is associated with infertility, birth defects and childhood cancers. Our earlier studies using cigarette smoke condensate (CSC) demonstrated several deleterious changes in male germ cells. Here, we hypothesize that chronic paternal exposure to CSC causes molecular and phenotypic changes in the sire and the offspring, respectively. In this mouse study, CSC caused DNA damage and cytotoxicity in testes via accumulation of benzo(a)pyrene (B[a]P) and cotinine. Decreased expression of growth arrest and DNA damage inducible alpha (Gadd45a), aryl hydrocarbon receptor (Ahr), and cyclin-dependent kinase inhibitor 1A (P21) was seen in CSC exposed testes. Apoptotic germ cell death was detected by induction of Fas, FasL, and activated caspase-3. The CSC-exposed males displayed reduction in sperm motility and fertilizing ability and sired pups with reduced body weight and crown-rump length, and smaller litter size with higher numbers of resorption. This model of CSC exposure demonstrates testicular toxicity and developmental defects in the offspring.  相似文献   
7.
目的:探讨溃疡性结肠炎患者应用双歧杆菌四联活菌片联合奥沙拉嗪治疗临床疗效,及对免疫功能和Fas/FasL表达的影响.方法:本组96例溃疡性结肠炎患者随机分为观察组(n=48)和对照组(n=48).对照组口服奥沙拉嗪治疗,观察组在对照组基础上结合双歧杆菌四联活菌片治疗.两组均以2周为1个疗程,连续服用2个疗程评价两组临床疗效,对血清炎症因子、免疫功能、C-反应蛋白及Fas/FasL表达的影响.结果:观察组治疗2个疗程后总有效率明显高于对照组,差异具有统计学意义(P<0.05);观察组治疗后白细胞介素-1(IL-1)、白细胞介素-6(IL-6)、白细胞介素-8(IL-8)和肿瘤坏死因子-α(TNF-α)含量均明显低于各组间治疗前及对照组治疗后,差异具有统计学意义(P<0.05);观察组治疗后CD4+、CD4+/CD8+表达高于治疗前及对照组治疗后,而CD8+明显低于治疗前及对照组治疗后,差异具有统计学意义(P<0.05);两组治疗后Fas、FasL表达均低于各组间治疗前,差异具有统计学意义(P<0.05);观察组治疗后C-反应蛋白水平低于各组间治疗前及对照组治疗后,差异具有统计学意义(P<0.05);两组均无明显不良反应发生.结论:溃疡性结肠炎患者应用双歧杆菌四联活菌片联合奥沙拉嗪治疗临床疗效明显,双歧杆菌四联活菌片可使CD4+/CD8+比值恢复正常范围,经逆转Fas/FasL表达异常,而诱导淋巴细胞凋亡,故而具有重要临床研究价值.  相似文献   
8.
Head and neck cancer, which predominantly arises from the oral mucosa, represents the sixth most common malignancy worldwide. These cancer cells can be resistant to programmed cell death triggered by extrinsic stimuli due to innate overexpression of inhibitor of apoptosis proteins (IAPs). The cellular protein second mitochondria-derived activator of caspases (SMAC) can antagonize IAP-induced caspase inhibition and thus trigger apoptosis. Here, we investigate the cell death-sensitizing effects of the SMAC mimetic LCL161 alone and in combination with Fas ligand (FasL) using a panel of six cell lines. Fas receptor (FasR) expression was analyzed by flow cytometry. Cells were treated with FasL and LCL161 alone or in combination, and cytotoxicity was measured using crystal violet assays. Annexin V and cell viability assays using zVAD-fmk and Necrostatin-1 (Nec-1) were carried out to assess the type of programmed cell death induced by LCL161. To demonstrate the sensitizing effects of LCL161, we employed the t-test to compare the effects of FasL alone and in combination with LCL161. Linear regression analysis was performed to determine initial and half maximal inhibitory concentrations (IC10 and IC50, respectively). Distinct FasR expression was detected in each cell line. Four of six cell lines were significantly sensitized to FasL by LCL161 (p < 0.05), and synergistic effects were observed (y < 1). Moreover, the initially resistant cell line SCC-25 was effectively sensitized to FasL by LCL161. Annexin V FACS analysis demonstrated apoptosis-sensitizing and apoptosis-inducing effects of LCL161 across all cell lines. Using specific cell death inhibitors (zVAD-fmk and Nec-1), we demonstrated that LCL161-initiated apoptosis could not be prevented, highlighting the proapoptotic potential of this mimetic in these cells. Our findings show the effectiveness of apoptotic sensitization of OSCC cells by LCL161 in combination with FasL, thus confirming the importance of an IAP-targeting therapeutic approach for oral squamous cell carcinoma.  相似文献   
9.
ObjectiveAmong downstream interleukin-18 (IL-18) targets, Fas ligand (FasL) in particular, has been strongly implicated in many conditions. Our study aims to explore the role of IL-18 in hypertrophic scar through enhancing FasL expression.MethodsIL-18 expression in hypertrophic scar tissues and normal tissues were explored by immunohistochemistry, qRT-PCR and Western blotting, and the expression of IL-18 in normal skin fibroblasts and hypertrophic scar fibroblasts by immunofluorescence. Hypertrophic scar fibroblasts treated with recombinant human IL-18 (rhIL-18) were assessed with MTT, Annexin V-FITC/PI, qRT-PCR, ELISA and western blotting. In the hypertrophic scar of rabbit ears, rhIL-18 was injected to determine histological changes with HE and Masson staining. Additionally, the scars were rated based on contour and overall severity using a visual analog scale scores (VAS).ResultsIL-18 was decreased in hypertrophic scar tissues and fibroblasts compared to normal skin tissues and fibroblasts, respectively. Decreased proliferation and increased apoptosis of hypertrophic scar fibroblasts were found after rhIL-18 treatment with enhanced expression of FasL, sFasL FADD, Caspase-8, Caspase-9 and Caspase-3 in a dose-dependent manner. The VAS and thickness of scars in rabbit ears was decreased as time went on after rhIL-18 treatment, with decreases in scar elevation index (SEI) and the increases in FasL expression.ConclusionIL-18 curbs proliferation and promotes apoptosis of hypertrophic scar fibroblasts by enhancing FasL expression. IL-18is a potential target for treatment of hypertrophic scar.  相似文献   
10.
The Fas/FasL (CD95/CD178) system is required for immune regulation; however, it is unclear in which cells, when, and where Fas/FasL molecules act in the immune system. We found that CD8+CD122+ cells, which are mostly composed of memory T cells in comparison with naïve cells in the CD8+CD122 population, were previously shown to include cells with regulatory activity and could be separated into CD49dlow cells and CD49dhigh cells. We established in vitro and in vivo experimental systems to evaluate the regulatory activity of CD122+ cells. Regulatory activity was observed in CD8+CD122+CD49dlow but not in CD8+CD122+CD49dhigh cells, indicating that the regulatory cells in the CD8+CD122+ population could be narrowed down to CD49dlow cells. CD8+CD122 cells taken from lymphoproliferation (lpr) mice were resistant to regulation by normal CD122+ Tregs. CD122+ Tregs taken from generalized lymphoproliferative disease (gld) mice did not regulate wild-type CD8+CD122 cells, indicating that the regulation by CD122+ Tregs is Fas/FasL-dependent. CD122+ Tregs taken from IL-10–deficient mice could regulate CD8+CD122 cells as equally as wild-type CD122+ Tregs both in vitro and in vivo. MHC class I-missing T cells were not regulated by CD122+ Tregs in vitro. CD122+ Tregs also regulated CD4+ cells in a Fas/FasL-dependent manner in vitro. These results suggest an essential role of Fas/FasL as a terminal effector of the CD122+ Tregs that kill activated T cells to maintain immune homeostasis.Fas (CD95) and its ligand FasL (CD178) compose a unique system that is strongly related to programmed cell death (1). FasL has been considered one of the effector molecules involved in the killing of target cells by cytotoxic T lymphocytes (CTLs) (2). When Fas binds to FasL, it induces downstream signal transduction pathways that subsequently activate cell death induction pathways (3, 4). Thus, the Fas/FasL system appears to act as an effector for CTL-mediated killing of virus-infected or cancer cells, similar to the perforin–granzyme system (5, 6). However, because Fas-mutant (lpr) and FasL-deficient (gld) mice show lymphoproliferative changes, it has been suggested that the Fas/FasL system is important for suppression/regulation of activated effector T cells (7, 8).Molecular mechanisms after Fas activation have been thoroughly investigated, and the signal transduction pathway has been largely elucidated (9, 10). However, research on the cellular events that use the Fas/FasL system has progressed comparatively slowly. There are only a few relevant reports in this respect, mostly of human CD4+Foxp3+ Tregs that use the Fas/FasL system for their regulatory activity. [In this article, we use the term “Treg(s)” for any kind of T cells that show immune regulatory activity.] To complicate matters further, some contradictory reports claim that such Fas/FasL-engaging Tregs do not exist (8, 11, 12). No reliable reports suggesting that CD8+ T cells use the Fas/FasL system for their regulatory action are available. Therefore, it is not clear precisely which subset of T cells express FasL or where Fas/FasL-dependent CD8+ Tregs, if such cells exist, are located and at which point they function. Thus, the ultimate pathophysiological role of the Fas/FasL system is still unknown.Regulation of the immune reaction is of pivotal importance for maintaining health in multicellular organisms. In highly developed animals, Tregs, a subset of T lymphocytes especially known as CD4+CD25+Foxp3+ cells, are the main regulators of the immune response (1316). However, it is not quite clear whether CD8+ regulatory T cells exist; there are only few and contradictory reports on their existence, in contrast to the reports on CD4+ Tregs. A population of predominantly CD8+ suppressor T cells has been described and debated in the 1980s (17, 18). In the 2000s, we found and reported that the cells of central memory phenotype (CD8+CD122+) also possess the regulatory function, and some other reports regarding CD8+ Tregs with some contradictory findings have been published. To date, more than 10 CD8+ Treg populations with different markers have been reported (19).One of the best characterized CD8+ Treg populations is the CD8+CD122+ Treg (122+ Treg) population. To confirm the existence of CD8+ Tregs, markers that may be possible to distinguish Tregs from other T cells were examined. We previously found that CD49d can separate CD8+CD122+ cells into at least two subsets (CD49dlow and CD49dhigh) (20). To judge which cells have a stronger regulatory activity, we prepared two experimental systems: an in vitro system, based on cell culture, and an in vivo system, based on adoptive transfer of T cells.Interestingly, CD8+ Tregs express CD122 (IL-2/IL-15 receptor β chain) in contrast to CD4+ Tregs, which express CD25 (IL-2 receptor α chain), indicating the fundamental importance of IL-2 at the development/maturation of both CD4+ and CD8+ Tregs. Suzuki and coworkers generated CD122-deficient mice using gene targeting (21) and used them to identify 122+ Tregs (22). In this study, which is a follow-up study to our previous report, we performed in vitro and in vivo experiments to gain further understanding of these cells. We found that CD49d might be a good marker for classifying CD8+ T cells into naïve, resting T cells (CD62L+CD122), effector memory T cells (CD62L), and T cells of central memory phenotype (CD122+CD49dlow), by using multicolor staining of CD62L, CD122, and CD49d. To our knowledge, this is the first report on the role of the Fas/FasL system in the action of CD8+CD122+ Tregs (122+ Tregs) (2225). Additionally, we show that CD8+ Tregs are included in the CD49dlow population, which corresponds to the central memory T-cell population, and that their mechanism of suppression depends on the cytotoxicity mediated by the Fas and FasL interaction.  相似文献   
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