The effects of EPA + DHA and aspirin on inflammatory cytokines and angiogenesis factors

Objective: In a recent study, we showed that the combination of aspirin plus the ω3 fatty acids eicosapen-taenoic acid (EPA) and docosahexaenoic acid (DHA) synergistically inhibited platelet function. As aspirin, EPA, and DHA have demonstrated anti-inflammatory properties, we hypothesized that the ingestion of EPA and DHA, with and without aspirin, would reduce plasma levels of inflammatory cytokines and angiogenesis factors more than aspirin alone and before aspirin was ingested. Methods: Using multiplex technology, we investigated the effects of aspirin (single-dose 650 mg on day 1), EPA + DHA (3.4 g/d for days 2 - 29), and aspirin with EPA + DHA (day 30) on plasma levels of inflammatory cytokines and angiogenesis factors in healthy adults. Results: Aspirin alone had no effect on any factor versus baseline, but EPA + DHA, with and without aspirin, significantly reduced concentrations of 8 of 9 factors. Although EPA + DHA plus aspirin reduced concentrations of a subset of the factors compared to baseline, neither aspirin alone nor the combination significantly reduced the level of any analyte more robustly than EPA + DHA alone. Conclusions: These data suggest that EPA + DHA has more pronounced down-regulatory effects on inflammation and angiogenesis than aspirin. The implications of these findings for the use of combined therapy for cardiovascular disease remain to be clarified.

Angiogenesis-related cytokines in serum of proliferative diabetic retinopathy patients before and after vitrectomy

AIM: To evaluate serum concentrations of angiogenesis-related cytokines in proliferative diabetic retinopathy (PDR) before and after vitrectomy. METHODS: Serum samples were collected from 30 PDR patients with varying severity before and after vitrectomy. Serum concentrations of vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), interleukin-8 (IL-8) and interferon-inducible protein-10 (IP-10) were determined by enzyme-linked immunosorbent assays(ELISA). RESULTS: Serum concentrations of VEGF, PEDF, IL-8 and IP-10 were significantly higher in PDR patients than that in controls, respectively (P<0.05). VEGF concentration decreased significantly in postoperative samples than that in preoperative samples (P<0.05). The concentrations of PEDF, IL-8 and IP-10 did not exhibit significant changes after vitrectomy. CONCLUSION: Elevated cytokines levels in serum may be diagnostically useful in PDR. Angiogenesis-related cytokines play important roles in the development of PDR, and would instruct the risk assessment of pathogenetic condition in PDR patients.

Circulating cytokines and outcome in metastatic colorectal cancer patients treated with regorafenib

BACKGROUND Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer(mCRC).Regorafenib has shown significant benefits in overall survival and progression free survival in two phase III trials compared to placebo in patients with mCRC who had progressed on previous therapy.AIM To identify an immune profile that might specifically correlate with the outcome in patients treated with regorafenib.METHODS Blood samples were collected from 17 patients before treatment with regorafenib and from 6 healthy volunteers.The proteins evaluated(TNF-α,TGF-β,VEGF,CCL-2,CCL-4,and CCL-5)were selected on the basis of their roles in angiogenesis and colorectal cancer pathogenesis.RESULTS We found that TNF-αbasal level was significantly higher in mCRC patients compared to healthy individuals.Non Responder(NR)patients showing progression of disease(n=12)had higher basal level of TGF-β,TNF-α,VEGF,CCL-2 and CCL-5 compared to Responder(R)patients(complete response CR,n=1;partial response PR,n=1;Stable Disease SD,n=3).On the contrary,plasma basal level of CCL-4 was higher in R compared to NR patients.High values of TGF-βand TNF-αnegatively correlated with progression free survival.CONCLUSION These results suggest a cytokine signature potentially able to discriminate between R and NR patients to treatment with regorafenib.

Tuning zinc content in wollastonite bioceramic endowing outstanding angiogenic and antibacterial functions beneficial for orbital reconstruction

Prosthetic eye is indispensable as filler after enucleation in patients with anophthalmia,whereas there are still many complications including postoperative infection and eye socket depression or extrusion during the conventional artificial eye material applications.Some Ca-silicate biomaterials showed superior bioactivity but their biological stability in vivo limit the biomedical application as long-term or permanent implants.Herein we aimed to understand the physicochemical and potential biological responses of zinc doping in wollastonite bioceramic used for orbital implants.The wollastonite powders with different zinc dopant contents(CSi-Znx)could be fabricated as porous implants with strut or curve surface pore geometries(cubic,IWP)via ceramic stereolithography.The experimental results indicated that,by increasing zinc-substituting-Ca ratio(up to 9%),the sintering and mechanical properties could be significantly enhanced,and meanwhile the bio-dissolution in vitro and biodegradability in vivo were thoroughly inhibited.In particular,an appreciable angiogenic activity and expected antibacterial efficacy(over 90%)were synergistically achieved at 9 mol%Zn dopant.In the back-embedding and enucleation and implantation model experiments in rabbits,the superior continuous angiogenesis was corroborated from the 2D/3D fibrovascular reconstruction in the IWP-pore CSi-Zn9 and CSi-Zn13.5 groups within very short time stages.Totally,the present silicate-based bioceramic via selective Zn doping could produce outstanding structural stability and bifunctional biological responses which is especially valuable for developing the next-generation implants with vascular insertion and fixation in orbital reconstruction prothesis.

Angiogenesis in tissue-engineered nerves evaluated objectively using MICROFIL perfusion and micro-CT scanning

Angiogenesis is a key process in regenerative medicine generally, as well as in the specific field of nerve regeneration. However, no convenient and objective method for evaluating the angiogenesis of tissue-engineered nerves has been reported. In this study, tissue-engineered nerves were constructed in vitro using Schwann cells differentiated from rat skin-derived precursors as supporting cells and chitosan nerve conduits combined with silk fibroin fibers as scaffolds to bridge 10-mm sciatic nerve defects in rats. Four weeks after surgery, three-dimensional blood vessel reconstructions were made through MICROFIL perfusion and micro-CT scanning, and parameter analysis of the tissue-engineered nerves was performed. New blood vessels grew into the tissue-engineered nerves from three main directions： the proximal end, the distal end, and the middle. The parameter analysis of the three-dimensional blood vessel images yielded several parameters, including the number, diameter, connection, and spatial distribution of blood vessels. The new blood vessels were mainly capillaries and microvessels, with diameters ranging from 9 to 301 μm. The blood vessels with diameters from 27 to 155 μm accounted for 82.84% of the new vessels. The microvessels in the tissue-engineered nerves implanted in vivo were relatively well-identified using the MICROFIL perfusion and micro-CT scanning method, which allows the evaluation and comparison of differences and changes of angiogenesis in tissue-engineered nerves implanted in vivo.

多重细胞因子检测试剂的开发及其在骨髓瘤中的应用

目的:开发多重细胞因子检测试剂,分析复发难治性多发性骨髓瘤(RRMM)的细胞因子、血管生成、骨重塑蛋白表达水平变化。方法:采用多重微球流式荧光免疫技术建立多重细胞因子定量检测试剂,并应用于55例RRMM患者和22例健康对照血清样本的测定,分析患者细胞因子、血管生成、骨重塑蛋白表达水平及其与临床特征的相关性。结果:本研究成功开发了十重细胞因子免疫分析检测试剂,平均灵敏度为7.1 pg/ml,平均回收率为97.4%,平均批内变异系数为4.8%,平均批间变异系数为9.0%。此外,RRMM样本结果发现IL-2、IL-17、DKK1、RANKL、OPG水平与IgG单克隆蛋白水平呈正相关,TIMP1与IgG、IgA单克隆蛋白水平呈正相关。结论:本研究开发出10种具有较高灵敏度和特异性的细胞因子检测试剂,并发现IL-2、IL-17、DKK1、RANKL、OPG、TIMP1在RRMM中具有追踪疾病进程的潜在价值。建立的多重细胞因子试剂开发流程对今后拓展蛋白标志物多重检测试剂的研发和应用具有重要参考价值。

骨微环境对组织工程骨再生过程的影响

背景:骨组织缺损是目前骨科最为常见的疾病之一,并且该疾病现行的治疗手段均存在一定的不足。组织工程的发展为骨缺损修复带来了新的希望,通过调控缺损部位生物活性物质的释放和血管化、神经化的进程可以有效改善骨组织微环境并促进骨整合,是大尺寸骨缺损修复最具发展潜力的研究思路。目的:从生物活性物质、血管再生和神经化对骨微环境变化3个方面的影响,探讨近年来调控骨微环境变化在骨缺损修复中的研究进展,为治疗大尺寸骨缺损提供新的思路和策略。方法:在中国知网和万方数据库分别以“骨组织工程,血管生成,神经化,细胞因子,骨形态发生蛋白,血管内皮生长因子,神经肽,骨微环境”为检索词;在Web of Science,Science Direct,PubMed数据库分别以“bone tissue engineering,angiogenesis,neurotization,cytokines,bone morphogenetic protein,vascular endothelial growth factor,neuropeptide,bone microenvironment”为检索词,检索2001-01-01/2022-12-31收录的有关骨微环境变化的影响因素及在骨组织工程中的应用研究,最终纳入109篇文献进行综述分析。结果与结论:①骨微环境是诱导骨组织干细胞生长分化的重要保障,其主要包括骨组织种子的细胞外基质及细胞间的相互作用所需要的生物化学因子、局部血液循环网络和周围的神经组织。②骨缺损修复是一个分为多个阶段的连续过程,这些阶段相互重叠,由多种细胞因子介导,同一种细胞因子在一个或多个愈合阶段可以产生相互协同或拮抗的作用。③新生血管再生是启动骨修复的关键,新生血管不仅为骨修复提供了必需的营养物质、成骨细胞和生长因子,同时更是修复细胞进入损伤区的通道。④除了调控血管诱导因子的释放种类、剂量及时效性等因素以实现血运重建外,多因子差异性释放递送系统的研究和基因转移技术的应用将是未来解决大面积骨缺损的研究方向。⑤神经肽类物质能与相关受体结合并作用于特定的信号通路,通过多种途径引导血管的生长及影响骨愈合、骨再生及成骨与破骨之间的平衡。⑥在建立神经化的组织工程骨时,骨组织微环境变化与神经调控的作用是双向的。骨基质中的细胞因子可以通过血神经屏障参与神经元的信号传导通路。而由神经胶质细胞分泌的神经肽类物质能作用于骨微环境,影响骨愈合、骨再生及成骨与破骨之间的平衡。⑦关于生物活性物质和血管化、神经化的进程对骨微环境的调控还存在诸多尚待解决的问题,如细胞因子在人体内弥散和降解速度过快而易丧失活性、血管生成相关生长因子的时效性及空间分布、通过机体回馈调节机制建立神经化等诸多问题,还需后续研究不断完善。

Recent Progress in the Construction of Functional Artificial Bone by Cytokine-Controlled Strategies

Objective： Combining artificial scaffolds with stimulatory factors to reconstruct lost bone tissues is one of the hottest research directions. The purpose of this review was to conduct a retrospective survey on the latest reports on artificial bone fabrication with functional cytokines. Data Sources： The status of related scientific research from the year 2005 to 2018 was analyzed through the mode of literature retrieval in PubMed and VIP Database. The retrieval words are as follows： ＂bone tissue engineering,＂ ＂angiogenesis,＇＂ ＂cytokines,＂ ＂osteogenesis,＂ ＂biomimetic bone marrow,＂ ＂sol-gel,＂ ＂delivery system,＂ and the corresponding Chinese words. Study Selection： After reading through the title and abstract/br early screening, the lull text of relevant studies was evaluated and those not related with this review had been ruled out. Results： According to the literature retrospective survey, there were three key points for the successful construction of functional artificial bones： （1） the continuous supply of relatively low concentration ofcytokines during the required period; （2） the delivery of two or more cytokines essential to the process and ensure the relatively spatial independence to reduce the unnecessary interference： and （3） supporting the early-stage angiogenesis and late-stage osteogenesis, respectively, regulating and balancing the crosslinking of both to avoid the surface ossification that would probably block the osteogenesis inside. Conclusions： The synergistic effect of both angiogenic factors and osteogenic factors applied in bone regeneration is a key point in the combined functional artificial bone. Through analysis, comparison, and summary of the current strategies, we proposed that the most promising one is to mimic the natural bone marrow function to facilitate the regeneration process and ensure the efficient repair of large weight-bearing bone defect.

调节性T细胞在多发性骨髓瘤发病机制中作用的最新研究进展

多发性骨髓瘤(MM)作为浆细胞恶性增殖性疾病,是血液系统第二常见恶性肿瘤。尽管多种靶向新药的应用已使MM患者的生存期明显延长,但其仍然是一种无法治愈的疾病。近年来,肿瘤微环境与肿瘤细胞之间相互作用引起的免疫抑制机制逐渐引起人们的关注。调节性T细胞(Treg)作为肿瘤微环境(TME)中的一种免疫抑制细胞,对MM的发生发展起着重要作用。它与肿瘤细胞的增殖和转移相关,通过促进肿瘤血管生成和产生免疫抑制性TME而导致MM进展。本文就Treg在MM发病机制中作用的最新研究进展作一综述。

牙髓再生相关细胞因子研究进展

随着分子生物学、生物材料学、组织工程学等学科的不断发展,牙髓根尖周病的再生性治疗面临新的机遇。目前,大量关于牙髓再生的研究表明:细胞因子在促进牙髓干细胞迁移、增殖和成骨向分化等方面发挥重要作用。该文将对近期作为热点研究的几类牙髓再生的相关细胞因子进行综述,分析其在牙髓再生中的作用及调节机制。

脂肪来源干细胞抑制瘢痕疙瘩的研究进展

瘢痕疙瘩是指以无自限性持续生长为特征的病理性瘢痕,是整形外科领域的难题之一。目前,针对瘢痕疙瘩的治疗,尚无被广泛采纳的金标准。基于细胞治疗的再生医学成为目前的研究热点,脂肪来源干细胞(ADSCs)在脂肪组织中储存量大、增殖能力强,可通过相对较小的侵入性方式获得,伦理学上相对无争议。探索ADSCs抑制瘢痕疙瘩可能的机制发现,ADSCs及其衍生物可以促进组织的高质量愈合、重塑胶原、减少纤维化,认为其是一项具有前景的瘢痕疙瘩干预措施。

富血小板纤维蛋白凝胶对糖尿病足溃疡患者血管生成及炎症因子的影响

目的:研究富血小板纤维蛋白(PRF)凝胶对糖尿病足溃疡(DFU)患者血管生成及炎症因子的影响。方法:选择2014年5月至2020年12月三河燕郊福合第一医院糖尿病诊疗中心收治的65例2型糖尿病(T2DM)合并DFU患者作为研究对象。根据治疗方法的不同,将其分为PRF组(n=33例)和对照组(n=32)。给予对照组常规治疗,PRF组在对照组的基础上加用PRF凝胶治疗。比较两组治疗第7 d、第14 d、第21 d的创面面积以及血管内皮生长因子(VEGF)、肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6)的水平。结果:治疗第21 d时,PRF组的创面面积明显小于对照组,差异有统计学意义(P<0.05)。治疗第14 d和第21 d时,PRF组的VEGF水平比基线时(第0 d)均明显升高,TNF-α和IL-6水平比基线时均明显降低,且与对照组同时间点比较差异有统计学意义(P<0.05)。结论:PRF凝胶可促进组织血管生成,控制局部炎症反应,有利于DFU的愈合。

脂氧素A4对肝细胞生长因子诱导HepG2肝癌细胞血管生成相关细胞因子表达的影响

目的:探讨脂氧素A4(LXA4)对肝细胞生长因子(HGF)诱导的HepG2肝癌细胞血管生成相关细胞因子表达的影响。方法:体外培养HepG2肝癌细胞,实验分为空白组、HGF处理组、HGF+LXA4处理组、HGF+脂氧素受体激动剂BML-111处理组。RT-PCR检测脂氧素受体(ALX)表达情况,Western blotting检测COX-2、MMP-2、MMP-9、IκBα和NF-κB p65的表达量,ELISA检测TNF-α、IL-1β、VEGF和TGF-β分泌水平,荧光素酶报告质粒检测NF-κB转录活性。结果:HepG2肝癌细胞表达ALX,LXA4和BML-111下调COX-2、MMP-2和MMP-9,抑制TNF-α、IL-1β、VEGF和TGF-β分泌,并且干扰NF-κB转位及其转录活性。结论:脂氧素抑制HGF诱导HepG2肝癌细胞表达血管生成相关细胞因子,包括VEGF、COX-2、TNF-α、IL-1β、TGF-β、MMP-2及MMP-9,此效应可能通过干扰NF-κB活化实现。

血管生成在子宫内膜异位症发生发展中作用的研究现状

异位内膜的种植、生长必须依赖于足够的血运 ,新生血管形成是子宫内膜异位症的关键步骤。与血管生成有关的因子VEGF、IL - 8、bFGF、整合素等均参与了子宫内膜异位症的病理过程 ,提示血管生成在子宫内膜异位症的发病机理方面是一个值得重视和进一步研究的课题。而且随着对子宫内膜异位症血管生成认识的进一步深入 ,针对抗血管生成的治疗策略极有可能为子宫内膜异位症在现有药物治疗和手术治疗的基础上开辟一个新的天地。

内皮细胞功能及其异质性研究的进展

血管内皮细胞具有广泛的生理功能，本文从血管形成、凝血及血小板和内皮细胞的相互作用、炎症和免疫反应、合成基质成分、调节血管张力和脂质代谢等方面，综述了内皮细胞的功能。重点介绍了各类组织和动物内皮细胞之间的区别，主要体现在形态、功能、表面抗原及对内皮损伤后的反应等方面。

外泌体和细胞因子促进牙髓血管生成的作用与调控机制

背景:随着组织工程技术在口腔领域的应用,构建一种组织工程化的牙髓进行牙髓-牙本质复合体的再生治疗成为可能,而在牙髓再生过程中,形成有功能的血运系统是其必要条件。血管生成是指从已有的毛细血管中形成新的血管,对牙髓再生和维持牙髓内环境稳定具有重要意义。目的:综述外泌体和促进血管生成的细胞因子在牙髓血管生成过程中作用机制的研究进展。方法:应用计算机检索PubMed数据库和CNKI数据库,英文关键词为"tissue engineering,pulp regeneration,regenerative endodontics,angiogenesis,neovascularization,angiogenic,signal molecules,exosomes,factors,role,mechanism",中文关键词为"牙髓再生,组织工程,血管生成,血管再生,信号分子,外泌体,因子,机制",重点查阅从2017至2019年的相关文献并总结。结果与结论:组织工程中移植的牙髓组织能否存活取决于其能否快速形成有功能的血运系统。牙髓再生过程中血管生成是一个不可缺少的过程,许多文献研究了外泌体和多种促血管生成的细胞因子在促进牙髓血管生成中的作用,然而牙髓血管生成的调控机制还有待进一步研究。

姜黄素对糖尿病足溃疡小鼠氧化应激、细胞炎症因子和创面血管新生的影响

目的探讨姜黄素对糖尿病足溃疡小鼠氧化应激、细胞炎症因子和创面血管新生的影响。方法选择SPF级雄性C57小鼠(BKS背景)60只,随机分为对照组、模型组和姜黄素组,每组20只。高脂高糖喂养联合腹腔内注射链脲佐菌素(STZ)建立糖尿病模型,模型组造模成功18只,姜黄素组造模成功17只,3组随机取15只小鼠进行相关研究。姜黄素组给予姜黄素100 mg/kg灌胃,每日1次;对照组和模型组小鼠给予等剂量生理盐水灌胃,每日1次。比较3组小鼠氧化应激、细胞炎症因子、创面血管新生和创面愈合情况。结果与对照组比较,模型组和姜黄素组血浆MDA水平升高,而SOD活性下降(P<0.05);姜黄素组血浆MDA水平低于模型组,而SOD活性高于模型组(P<0.05)。与对照组比较,模型组和姜黄素组血浆IL-1和TNF-α水平升高(P<0.05);姜黄素组血浆IL-1和TNF-α水平低于模型组(P<0.05)。与对照组比较,模型组和姜黄素组新生毛细血管数密度降低(P<0.05);姜黄素组新生毛细血管数密度高于模型组(P<0.05)。与对照组比较,模型组和姜黄素组创面愈合率降低(P<0.05);姜黄素组创面愈合率高于模型组(P<0.05)。结论姜黄素对糖尿病足溃疡小鼠可促进创面血管新生和创面愈合,减轻炎症反应,且具有抗氧化应激作用。

子宫内膜异位症发病机制的研究进展

子宫内膜异位症(EMs)是妇科中的疑难病,会引起患者痛经、慢性盆腔痛、月经异常以及不孕等临床症状。研究发现EMs的发病有明显的遗传背景,并且在激素及其受体、炎症免疫、侵袭黏附、血管生成等相关因素共同作用下,患者盆腔内形成异常微环境而发病。但由于EMs的发病机制复杂,其确切的发病机制仍不清楚。目前针对EMs发病相关的关键靶点进行治疗,能改善治疗效果,但无法根治该病。本文对EMs的内分泌、炎症免疫、遗传、血管生成和侵袭黏附等因素的发病机制的研究进展和针对关键靶点进行治疗的临床应用进行综述。

胰腺癌组织中IL-8 mRNA,TSP-1 mRNA表达及与微血管计数的关系

目的研究胰腺癌IL-8mRNA,TSP-1mRNA表达及其促或抑胰腺癌肿瘤血管生成的作用。方法54例胰腺癌手术切除标本经10%中性福尔马林固定后常规制作石蜡包埋切片,MV染色为常规ABC免疫组化法,IL-8mRNA和TSP-1mRNA染色为原位杂交染色法。结果54例胰腺癌IL-8mRNA和TSP-1mRNA阳性率分别为59.3%和55.6%,MVC为(64.2±11.8)个/HP。高分化腺癌和未转移病例MVC和IL-8mRNA阳性率明显低于中或低分化腺癌及转移病例,均有显著或高度显著差异(<0.05或<0.01),但TSP-1mRNA表达则相反。IL-8mRNA阳性病例和TSP-1mRNA阴性病例MVC明显高于IL-8mRNA阴性病例和TSP-1mRNA阳性病例,均有高度显著差异(<0.01)。IL-8mRNA与TSP-1mRNA表达呈密切负相关(χ2=7.1,<0.01)。结论IL-8mRNA和TSP-1mRNA表达与胰腺癌血管生成密切相关,IL-8具有促血管生成作用,而TSP-1具有抑血管生成作用。

骨髓间质干细胞移植梗死心肌后细胞因子分泌及对血管新生的影响

目的 研究骨髓间质干细胞 (MSCs)移植梗死心肌后细胞因子的分泌及其对血管新生的作用。 方法 贵州香猪 2 4只 ,按照计算器随机数法随机分为对照组、实验组。抽取骨髓液 3ml,按照 Wakitani的方法培养出骨髓间质干细胞 ,经 5 -氮胞苷 (5 - aza)诱导后 ,5 -溴脱氧尿苷 (Brd U)标记备用。开胸结扎左冠状动脉前降支 ,自体骨髓间质干细胞分别经局部注射和结扎的左冠状动脉前降支远端灌注移植入自体急性心肌梗死区域 ,对照组以 DMEM作对照。术后 3周、6周取标本 ,免疫组织化学法、计算机图象分析检测组织血管内皮生长因子 (VEGF)、碱性成纤维细胞生长因子 (b FGF)和 因子表达。 结果 实验组梗死区 3周、6周 b FGF、VEGF灰度值明显高于对照组 (P<0 .0 1) ,微血管计数明显增多 (P<0 .0 1)。 结论 自体骨髓间质干细胞移植梗死心肌后能分泌 VEGF、b FGF,诱导血管新生。