幽门螺杆菌相关miRNA与胃癌关系的研究进展

微小核糖核酸(microRNA,miRNA)是一种由内源基因编码长度约为22个核苷酸的非编码RNA,其能抑制靶基因蛋白质表达,有多种生物学功能。越来越多的研究表明,miRNA在多种肿瘤中异常表达,参与肿瘤发生、发展过程。幽门螺杆菌(Helicobacter pylori,Hp)作为胃癌的主要致病因素,可通过调节miRNA的表达,在胃癌中起促进或抑制作用。现就Hp相关miRNA在胃癌中的作用作一概述。     

幽门螺杆菌相关胃癌发生不同阶段miRNAs表达与临床研究

目的 观察幽门螺杆菌（Helicobacter pylori, H. pylori）感染的慢性非萎缩性胃炎（no-atrophic gastritis,NAG）→萎缩性胃炎（chronic atrophic gastritis,CAG）→肠上皮化生（intestinal metaplasia,IM）→非典型增生（dysplasia,DYS）→胃癌（gastric cancer,GC）五个不同阶段miR-1、miR-20a、miR-34a、miR-423-5p表达变化规律及其与临床的关系。方法 收集胃镜及病理证实的上述胃癌发生五个不同阶段且H. pylori感染的患者（依次为44、47、43、50、45例）,胃癌无H. pylori感染者46例,胃黏膜正常（normal gastric mucose,NGM）63例的血清标本,采用Real-time PCR法检测无H. pylori感染者miR-1、miR-20a、miR-34a、miR-423-5p表达。结果 H. pylori感染NAG→GC不同阶段,miR-1、miR-20a、miR-34a、miR-423-5p表达逐渐升高（P<0.05）,GC阶段最高,miR-1、miR-20a CAG→GC阶段均高于NGM（P<0.05）,与NGM比较差异有统计学意义（P<0.05）;其表达程度与GC发生阶段呈正相关（P<0.001）;GC组H. pylori感染者较无H. pylori感染者miR-1、miR-20a、miR-34a、miR-423-5p表达升高（P<0.05）。结论 H. pylori感染CAG→GC阶段miR-1、miR-20a、miR-34a、miR-423-5p表达升高,向胃癌演进中呈逐渐升高趋势,miR-1、miR-20a、miR-34a、miR-423-5p高表达可能是H. pylori感染后导致胃癌发生发展的重要机制,miR-1、miR-20a、miR-34a可作为诊断早期胃癌的标记物。     

S100A9在肿瘤方面的研究进展

S100A9是钙结合蛋白8100蛋白家族中重要的成员之一,其参与炎症反应、调节细胞生长分化、生长抑制、诱导细胞凋亡等,近年来研究发现S100A9时肿瘤的生长、增殖及侵袭有着重要作用,可能会成为肿瘤诊治的新靶点.基于上述思路,本文拟对S100A9与肿瘤的关系进行简要综述.     

幽门螺杆菌与胃癌相关信号通路研究进展

胃癌(gastric cance, GC)是世界范围内最常见的恶性肿瘤之一,其病死率在癌症中位居第二。GC的发病机制目前尚不明确,其发病机制与多种因素有关,其中包括环境因素和遗传因素。幽门螺杆菌( Helicobacter pylori , Hp)感染是GC发生最为重要的环境因素之一。Hp感染在GC的发展过程中,会伴有一些基因和信号通路的异常。现就Hp感染引发GC过程中相关信号通路的异常,包括Hedgehog信号通路、Notch信号通路、Wnt/β-catenin信号通路以及上皮间质转化(epithelial-mesenchymal transition, EMT)相关信号通路等作一概述,为GC的预防及靶向治疗提供理论依据。     

外周血单核细胞CHOP、NLRP3、S100A8/A9 mRNA表达水平与脓毒症患者炎症反应和预后的关系分析

摘要 目的：探讨外周血单核细胞（PBMC）中CCAAT/增强子结合蛋白同源蛋白（CHOP）、核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）、S100A8/A9 信使核糖核酸（mRNA）表达水平与脓毒症患者炎症反应和预后的关系。方法：选取2020年1月～2022年1月新疆维吾尔自治区人民医院收治的170例脓毒症患者为脓毒症组,另选取同期68名健康体检者为对照组。采用酶联免疫吸附法检测血清白介素（IL）-6、IL-10、IL-17、IL-23、转化生长因子-β（TGF-β）水平,实时荧光定量PCR（qRT-PCR）法检测PBMC中CHOP、NLRP3、S100A8/A9 mRNA表达水平,比较脓毒症组与对照组上述指标差异。采用Pearson/Spearman相关系数分析脓毒症患者PBMC中CHOP、NLRP3、S100A8/A9 mRNA表达水平与炎症因子水平的相关性。脓毒症患者根据28d预后差异分为死亡组和存活组,收集临床资料,采用多因素Logistic回归分析脓毒症患者预后的影响因素。结果：脓毒症组PBMC中CHOP、NLRP3、S100A8/A9 mRNA相对表达量和血清IL-6、IL-10、IL-17、IL-23、TGF-β水平均明显高于对照组（P＜0.05）。Pearson/Spearman相关性分析显示,脓毒症患者PBMC中CHOP、NLRP3、S100A8/A9 mRNA表达水平与血清IL-6、IL-10、IL-17、IL-23、TGF-β水平均呈正相关（P＜0.05）。不同预后脓毒症患者比较,死亡组年龄大于存活组,脓毒性休克、多器官功能障碍综合征（MODS）、ICU住院时间≥10 d、机械通气时间≥3 d患者比例、脓毒症相关器官衰竭评估（SOFA）评分、血乳酸、血清IL-6、IL-10、IL-17、IL-23、TGF-β水平以及PBMC中CHOP、NLRP3、S100A8/A9 mRNA相对表达量均高于存活组,而氧合指数低于存活组（P＜0.05）。多因素Logistic回归分析显示,校正其他因素后,PBMC中CHOP mRNA、NLRP3 mRNA、S100A8/A9 mRNA表达水平升高是脓毒症患者预后不良的危险因素（P＜0.05）。结论：脓毒症患者PBMC中CHOP、NLRP3、S100A8/A9 mRNA呈高表达,且表达水平与炎症反应及患者预后密切相关。     

S100A4在胰腺癌中的研究进展

胰腺癌最重要的生物学特性是容易发生转移和侵袭,致使很多患者无法得到根治性治疗。外科手术是胰腺癌惟一可能治愈的手段,但仅有10-20%的患者有机会手术治疗。错过早期诊断、常规疗法普遍不明显及快速肿瘤扩散共同导致患者的预后不良。胰腺癌的发生、发展受多基因调控。S100A4基因是近几年发现的一种具有促肿瘤作用的基因,目前研究认为该蛋白在胰腺癌的侵袭和转移中起重要作用.本文主要就S100A4与胰腺癌的有关研究进展加以综述。     

S100A4 在胰腺癌中的研究进展

胰腺癌最重要的生物学特性是容易发生转移和侵袭,致使很多患者无法得到根治性治疗。外科手术是胰腺癌惟一可能治愈的手段,但仅有10-20%的患者有机会手术治疗。错过早期诊断、常规疗法普遍不明显及快速肿瘤扩散共同导致患者的预后不良。胰腺癌的发生、发展受多基因调控。S100A4基因是近几年发现的一种具有促肿瘤作用的基因,目前研究认为该蛋白在胰腺癌的侵袭和转移中起重要作用.本文主要就S100A4与胰腺癌的有关研究进展加以综述。     

幽门螺杆菌感染与胃癌相关性的研究进展

胃癌(gastric cancer)是人类最常见的恶性肿瘤之一,是全球性的医疗难题,其病因尚未完全明确。自20世纪80年代初两位澳大利亚科学家Marshall和Warren首先从胃黏膜中分离出幽门螺杆菌(helicobacter pylori,Hp)至今,Hp与胃癌的关系为人们所关注。经过多年的研究,人们逐渐接受了Hp感染为胃癌发生发展的重要因素,大多数学者认为根除Hp治疗可以降低胃癌发生的风险。然而,近年来随着研究的不断深入,一些研究报道根除Hp治疗并不能预防胃癌的发生发展,也不能降低胃癌的发生率。胃癌的发病机制错综复杂,Hp感染作为单一致病因素如何引起胃癌的发生目前尚未阐述清楚。本文旨在对Hp感染与胃癌相关性的研究进展做一综述。     

S100A11的表达及其与胃癌的关系

目的:探讨S100A11在胃癌和正常胃粘膜组织中的表达及意义.方法:采用RT-PCR和Western Blot技术检测21对配对胃癌组织和正常胃粘膜组织中S100A11的表达情况.结果:胃癌组织S100A11 mRNA的表达量(1.26±0.03)高于正常胃癌粘膜组织中的表达量(0.75±0.04),两组比较差异有统计学意义(p＜0.05).S100A11蛋白在胃癌组织中的表达量(0.94±0.05)明显高于在正常胃粘膜组织中的表达量(0.39±0.05),两组比较差异有统计学意义(p＜0.05).结论:S100A11在胃癌组织中的表达量明显高于正常组织,提示其与胃癌的发生和发展有关.     

宿主基因单核苷酸多态性与幽门螺杆菌相关胃癌

幽门螺杆菌相关胃癌是一种由遗传、环境、生活方式等因素共同作用所致的特殊类型胃癌。它的发病过程至少包括炎症、萎缩和癌变3个主要阶段。宿主基因单核苷酸多态性(SNP)包括炎症反应、胃酸抑制、免疫识别等相关基因SNP,可能特异性参与了幽门螺杆菌相关胃癌发生发展过程中的不同阶段。文章综述与幽门螺杆菌相关胃癌发病3个主要病理阶段相关的宿主基因SNP及其与胃癌发病风险关系的研究进展。     

The hetero-oligomeric complex of the S100A8/S100A9 protein is extremely protease resistant

S100A8, S100A9 and S100A12 proteins are associated with inflammation and tissue remodelling, both processes known to be associated with high protease activity. Here, we report that homo-oligomeric forms of S100A8 and S100A9 are readily degraded by proteases, but that the preferred hetero-oligomeric S100A8/A9 complex displays a high resistance even against proteinase K degradation. S100A12 is not as protease resistant as the S100A8/A9 complex. Since specific functions have been assigned to the homo- and heterooligomeric forms of the S100A8 and A9 proteins, this finding may point to a post-translational level of regulation of the various functions of these proteins in inflammation and tissue remodelling.     

S100A8/S100A9 and their association with cartilage and bone

S100A8 and S100A9 are calcium-binding proteins expressed in myeloid cells and are markers of numerous inflammatory diseases in humans. S100A9 has been associated with dystrophic calcification in human atherosclerosis. Here we demonstrate S100A8 and S100A9 expression in murine and human bone and cartilage cells. Only S100A8 was seen in preosteogenic cells whereas osteoblasts had variable, but generally weak expression of both proteins. In keeping with their reported high-mRNA expression, S100A8 and S100A9 were prominent in osteoclasts. S100A8 was expressed in alkaline phosphatase-positive hypertrophic chondrocytes, but not in proliferating chondrocytes within the growth plate where the cartilaginous matrix was calcifying. S100A9 was only evident in the invading vascular osteogenic tissue penetrating the degenerating chondrocytic zone adjacent to the primary spongiosa, where S100A8 was also expressed. Whilst, S100A8 has been shown to be associated with osteoblast differentiation, both S100A8 and S100A9 may contribute to calcification of the cartilage matrix and its replacement with trabecular bone, and to regulation of redox in bone resorption.     

Substitution of methionine 63 or 83 in S100A9 and cysteine 42 in S100A8 abrogate the antifungal activities of S100A8/A9: potential role for oxidative regulation

S100A8 and S100A9 and their heterocomplex calprotectin (S100A8/A9) are abundant cytosolic constituents in human neutrophils previously shown to possess antifungal activity. This study was designed to investigate mechanisms involved in the modulation of the antifungal properties of S100A8/A9. S100A8, S100A9 and site-directed mutants of both proteins were tested for their antifungal effect against Candida albicans in microplate dilution assays. Whereas S100A8 alone did not inhibit fungal growth, S100A9 by itself had a moderate antifungal effect. Combining both proteins had the strongest effect. Supporting a potential role for oxidation in S100A8/A9, substitution of methionine 63 or 83 of S100A9 resulted in the loss of antifungal activity. Additionally, the substitution to alanine of cysteine 42 of S100A8 also caused a loss of S100A8's ability to enhance S100A9's antifungal effect. Overall, our data indicate that both S100A8 and S100A9 are required for their fully active antifungal effect and that oxidation regulates S100A8/A9 antifungal activity through mechanisms that remain to be elucidated and evaluated. Finally, together with our previous work describing the oxidation-sensitive anti-inflammatory effects of S100A8/A9, we propose that S100A8/A9 exerts an anti-inflammatory activity in healthy state and that conditions associated with oxidative stress activate the antifungal activity of S100A8/A9.     

S100A8 and S100A9 activate MAP kinase and NF-kappaB signaling pathways and trigger translocation of RAGE in human prostate cancer cells

S100 proteins, a multigenic family of calcium-binding proteins, have been linked to human pathologies in recent years. Deregulated expression of S100 proteins, including S100A8 and S100A9, was reported in association with neoplastic disorders. In a previous study, we identified enhanced expression of S100A8 and S100A9 in human prostate cancer. To investigate potential functional implications of S100A8 and S100A9 in prostate cancer, we examined the influence of over-expressed and of purified recombinant S100A8 and S100A9 proteins in different prostate epithelial cell lines. S100A8 and S100A9 were secreted by prostate cancer cells, a finding which prompted us to analyze a possible function as extracellular ligands. S100A8/A9 induced the activation of NF-kappaB and an increased phosphorylation of p38 and p44/42 MAP kinases. In addition, extracellular S100A8/A9 stimulated migration of benign prostatic cells in vitro. Furthermore, in immunofluorescence experiments, we found a strong speckled co-localization of intracellular S100A8/A9 with RAGE after stimulating cells with recombinant S100A8/A9 protein or by increasing cytosolic Ca2+ levels. In summary, our findings show that S100A8 and S100A9 are linked to the activation of important features of prostate cancer cells.     

The expression of S100A8 in pancreatic cancer-associated monocytes is associated with the Smad4 status of pancreatic cancer cells

The cross-talk between tumour cells and the surrounding supporting host cells (stroma) is a key regulator of cancer growth and progression. By undertaking 2-DE analysis of laser capture microdissected malignant and stromal components of pancreatic tumours and benign ductal elements, we have identified high levels of S100A8 and S100A9 in tumour-associated stroma but not in benign or malignant epithelia. Immunohistochemical analysis (n = 71 patients) revealed strong expression of both proteins in stromal myeloid cells, subsequently identified as CD14(+)/CD68(- )monocytes/macrophages. Co-immunofluorescence revealed that S100A8 was expressed in a subset of S100A9-positive cells. Correlation of the expression of S100A8 and S100A9 to patient parameters revealed that the microenvironments of tumours which lacked expression of the tumour suppressor protein, Smad4, had significantly reduced numbers of S100A8-immunoreactive (p = 0.023) but not S100A9-immunoreactive (p = 0.21) cells. The ratio of S100A8- to S100A9-positive cells within individual tumours was significantly lower in Smad4-negative tumours than in Smad4-positive tumours (p<0.003). Pancreatitic specimens also contained S100A8- and S100A9-expressing cells, although this was not observed in regions displaying extensive fibrosis. In conclusion, our study provides an extensive analysis of S100A8 and S100A9 in pancreatic disease and highlights a potentially important relationship between pancreatic cancer cells and their surrounding microenvironment.     

S100A8/A9 in COVID-19 pathogenesis: Impact on clinical outcomes

Coronavirus disease 2019 (COVID-19) has a broad range of clinical manifestations, highlighting the need for specific diagnostic tools to predict disease severity and improve patient prognosis. Recently, calprotectin (S100A8/A9) has been proposed as a potential biomarker for COVID-19, as elevated serum S100A8/A9 levels are associated with critical COVID-19 cases and can distinguish between mild and severe disease states. S100A8/A9 is an alarmin that mediates host proinflammatory responses during infection and it has been postulated that S100A8/A9 modulates the cytokine storm; the hallmark of fatal COVID-19 cases. However, it has yet to be determined if S100A8/A9 is a bona-fide biomarker for COVID-19. S100A8/A9 is widely implicated in a variety of inflammatory conditions, such as cystic fibrosis (CF) and chronic obstructive pulmonary disorder (COPD), as well as pulmonary infectious diseases, including tuberculosis and influenza. Therefore, understanding how S100A8/A9 levels correlate with immune responses during inflammatory diseases is necessary to evaluate its candidacy as a potential COVID-19 biomarker. This review will outline the protective and detrimental roles of S100A8/A9 during infection, summarize the recent findings detailing the contributions of S100A8/A9 to COVID-19 pathogenesis, and highlight its potential as diagnostic biomarker and a therapeutic target for pulmonary infectious diseases, including COVID-19.     

Oncogenic Kras expression in postmitotic neurons leads to S100A8-S100A9 protein overexpression and gliosis

Previous studies suggest that up-regulation of Ras signaling in neurons promotes gliosis and astrocytoma formation in a cell nonautonomous manner. However, the underlying mechanisms remain unknown. To address this question, we generated compound mice (LSL Kras G12D/+;CamKII-Cre) that express oncogenic Kras from its endogenous locus in postmitotic neurons after birth. These mice developed progressive gliosis, which is associated with hyperactivation of Ras signaling pathways. Microarray analysis identified S100A8 and S100A9 as two secreted molecules that are significantly overexpressed in mutant cortices. In contrast to their usual predominant expression in myeloid cells, we found that overexpression of S100A8 and S100A9 in the mutant cortex is primarily in neurons. This neuronal expression pattern is associated with increased infiltration of microglia in mutant cortex. Moreover, purified S100A8-S100A9 but not S100A8 or S100A9 alone promotes growth of primary astrocytes in vitro through both TLR4 and receptor of advanced glycation end product receptors. In summary, our results identify overexpression of S100A8-S100A9 in neurons as an early step in oncogenic Kras-induced gliosis. These molecules expressed in nonhematopoietic cells may be involved in tumorigenesis at a stage much earlier than what has been reported previously.     

胃癌与胃微生态的研究进展

胃癌(gastric cancer)是我国常见恶性肿瘤之一,有着较高的发病率和死亡率。胃癌的发生是一个相对缓慢、多步骤、复杂的过程,可能与幽门螺杆菌(Helicobacter pylori,H.pylori)感染、环境、基因、吸烟等因素相关。随着高通量测序技术和宏基因组学等技术的发展和运用,大量研究表明胃肠道微生物与消化道系统疾病息息相关,其中胃微生物中H.pylori已被明确列为I类致癌因子。除了H.pylori,胃内其他共生菌与胃癌的发生也有密切的联系。本文将通过胃癌与H.pylori感染、胃癌与H.pylori根除、H.pylori与胃微生态、胃癌与胃微生态四个方面综述胃癌与胃微生物的关系,为日后胃癌的研究提供参考。     

Induction of alarmin S100A8/A9 mediates activation of aberrant neutrophils in the pathogenesis of COVID-19

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胃黏膜菌群与幽门螺杆菌的相关性

除幽门螺杆菌之外,胃黏膜内还定居着大量细菌,占主导地位的是厚壁菌门、变形菌门、拟杆菌门、放线菌门和梭杆菌门。幽门螺杆菌和胃黏膜菌群之间可通过竞争营养和空间、扰乱抑菌肽的分泌以及改变宿主胃生理环境等直接或间接相互影响。本研究总结了胃内正常菌群的组成特征,分析了胃黏膜菌群与幽门螺杆菌之间的相互关系及其潜在机制,并进一步探讨了胃黏膜菌群对幽门螺杆菌相关胃部疾病的影响,有利于深入理解慢性胃病的发病机制,为疾病预防及治疗提供理论依据。