MicroRNAs and liver cancer associated with iron overload: Therapeutic targets unravelled

Primary liver cancer is a global disease that is on the increase.Hepatocellular carcinoma(HCC)accounts for most primary liver cancers and has a notably low survival rate,largely attributable to late diagnosis,resistance to treatment,tumour recurrence and metastasis.MicroRNAs(miRNAs/miRs)are regulatory RNAs that modulate protein synthesis.miRNAs are involved in several biological and pathological processes including the development and progression of HCC.Given the poor outcomes with current HCC treatments,miRNAs represent an important new target for therapeutic intervention.Several studies have demonstrated their role in HCC development and progression.While many risk factors underlie the development of HCC,one process commonly altered is iron homeostasis.Iron overload occurs in several liver diseases associated with the development of HCC including Hepatitis C infection and the importance of miRNAs in iron homeostasis and hepatic iron overload is well characterised.Aberrant miRNA expression in hepatic fibrosis and injury response have been reported,as have dysregulated miRNA expression patterns affecting cell cycle progression,evasion of apoptosis,invasion and metastasis.In2009,miR-26a delivery was shown to prevent HCC progression,highlighting its therapeutic potential.Several studies have since investigated the clinical potential of other miRNAs with one drug,Miravirsen,currently in phaseⅡclinical trials.miRNAs also have potential as biomarkers for the diagnosis of HCC and to evaluate treatment efficacy.Ongoing studies and clinical trials suggest miRNA-based treatments and diagnostic methods will have novel clinical applications for HCC in the coming years,yielding improved HCC survival rates and patient outcomes.     

基于指纹图谱、多指标定量及网络药理学的大黄质量标志物预测分析

目的 建立大黄HPLC指纹图谱及多指标定量分析方法,结合网络药理学预测大黄潜在质量标志物。方法 采用HPLC对20批掌叶大黄样品中的没食子酸、儿茶素、表儿茶素等13种指标性成分进行含量测定,采用中药色谱指纹图谱相似度评价系统进行相似度分析,以13种指标成分含量进行主成分分析、正交偏最小二乘判别分析,采用网络药理学预测大黄相关成分的作用靶点和通路,构建成分-靶点-通路网络图并对核心靶点进行器官定位分析以预测大黄的潜在质量标志物。结果 指纹图谱相似度在0.882~0.998,共确定了15个共有峰,大黄素甲醚、儿茶素、大黄素-1-O-葡萄糖苷、大黄素甲醚-8-O-葡萄糖苷、芦荟大黄素-8-O-葡萄糖苷是差异化合物,可用于鉴别和区分大黄质量。经筛选得到15个化合物,8个核心靶点,包括AKT1、TP53、JUN、HSP90AA1、CASP3、EGF、TNF、IL-6,涉及对氧化应激的反应、对脂多糖的反应、内肽酶活性,涉及脂质和动脉硬化、MAPK信号传导途径、AGE-RAGE信号通路在糖尿病并发症中的作用、非酒精性脂肪性肝病等通路,并构建成分-靶点-通路图,预测没食子酸、儿茶素、芦荟大黄素、大黄酸、大黄素等为大黄潜在的质量标志物。结论 所建立的大黄指纹图谱特征性强,可用于控制其质量,特征谱和网络药理学分析预测了大黄的质量标志物,这为进一步研究大黄的作用机制提供参考。     

基于网络药理学和生物信息学方法的白藜芦醇治疗三阴性乳腺癌的机制研究

目的 探索白藜芦醇抗三阴性乳腺癌（triple negative breast cancer,TNBC）的潜在作用机制。方法 利用PharmMapper、SwissTargetPrediction、SuperPred、DrugBank数据库,筛选整合白藜芦醇可能作用的靶点。与CTD、DisGeNET、MalaCards数据库中筛选得到的TNBC靶点相映射后得到白藜芦醇抗TNBC可能作用的靶点。利用DAVID数据库对得到的靶点进行基因功能（Gene ontology,GO）和京都基因与基因组数据库（Kyoto Encyclopedia of Genes and Genomes,KEGG）通路注释分析,利用STRING数据库和Cytoscape软件构建靶点间的蛋白互作网络,筛选出核心靶点及核心模块。结果 共筛选得到422个白藜芦醇可能作用的靶点,1 799个TNBC相关靶点,映射后共得到白藜芦醇治疗TNBC的潜在作用靶点130个,并从中进一步筛选出了10个核心基因（MAPK1、MAPK3、TP53、SRC、PIK3CA、AKT1、PIK3R1、MAPK8、PTPN11、JAK2）,KEGG通路富集提示核心基因主要涉及PI3K-Akt等信号通路。结论 白藜芦醇可能是通过靶向作用于多个靶点及通路,形成相互协调的作用网络从而发挥抗TNBC作用,其中PI3K/Akt通路可能发挥重要作用,为白藜芦醇在TNBC治疗方面的进一步研究提供参考。     

Diagnosis,classification, and assessment in psoriatic arthritis

There have been considerable advances in the classification and assessment of psoriatic arthritis (PsA). In this report, we give an overview of historic and current classification criteria and discuss its role and limitations in research and clinical practice. We discuss the most commonly used assessment instruments for arthritis, psoriasis, onychodystrophy, enthesitis, dactylitis and axial PsA with a focus on clinical practice. We pay particular attention to the current evidence for the use of composite outcome measures, and their use in randomised controlled trials and routine care.     

MicroRNAs in laser-induced choroidal neovascularization in mice and rats: their expression and potential therapeutic targets

Choroidal neovascularization characterizes wet age-related macular degeneration. Choroidal neovascularization formation involves a primarily angiogenic process that is combined with both inflammation and proteolysis. A primary cause of choroidal neovascularization pathogenesis is alterations in pro-and anti-angiogenic factors derived from the retinal pigment epithelium, with vascular endothelium growth factor being mainly responsible for both clinical and experimental choroidal neovascularization. MicroRNAs(miRNAs) which are short, non-coding, endogenous RNA molecules have a major role in regulating various pathological processes, including inflammation and angiogenesis. A review of recent studies with the mouse laser-induced choroidal neovascularization model has shown alterations in miRNA expression in choroidal neovascularization tissues and could be potential therapeutic targets for wet age-related macular degeneration. Upregulation of miR-505(days 1 and 3 post-laser), miR-155(day 14) occurred in retina; miR-342-5 p(days 3 and 7), miR-126-3 p(day 14) in choroid; miR-23 a, miR-24, miR-27 a(day 7) in retina/choroid; miR-505(days 1 and 3) in retinal pigment epithelium/choroid; downregulation of miR-155(days 1 and 3), miR-29 a, miR-29 b, miR-29 c(day 5), miR-93(day 14), miR-126(day 14) occurred in retinal pigment epithelium/choroid. Therapies using miRNA mimics or inhibitors were found to decrease choroidal neovascularization lesions. Choroidal neovascularization development was reduced by overexpression of miR-155, miR-188-5 p, miR-(5,B,7), miR-126-3 p, miR-342-5 p, miR-93, miR-126, miR-195 a-3 p, miR-24, miR-21, miR-31, miR-150, and miR-184, or suppression of miR-505, miR-126-3 p, miR-155, and miR-23/27. Further studies are warranted to determine miRNA expression in mouse laser-induced choroidal neovascularization models in order to validate and extend the reported findings. Important experimental variables need to be standardized; these include the strain and age of animals, gender, number and position of laser burns to the eye, laser parameters to induce choroidal neovascularization lesions including wavelength, power, spot size, and duration.     

Next Wave of Targets in the Treatment of Advanced Renal Cell Carcinoma

While surgical resection has remained the mainstay of treatment in early-stage renal cell carcinoma (RCC), therapeutic options in the advanced setting have remarkably expanded over the last 20 years. Tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor (VEGF-TKIs) and anti-programmed cell death 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) have become globally accepted options in the upfront metastatic setting, with different ICI-based combination strategies improving overall survival compared to single-agent Sunitinib. Although some patients benefit from long-term responses, most eventually develop disease progression. Ongoing efforts to better understand the biology of RCC and the different mechanisms of acquired resistance have led to the identification of promising therapeutic targets. Belzutifan, a novel agent targeting the angiogenic pathway involving hypoxia-inducible factors (HIFs), has already been approved for the treatment of early-stage tumors associated with VHL disease and represents a very promising therapy in advanced RCC. Other putative targets include epigenetic regulation enzymes, as well as several metabolites such as adenosine, glutaminase and tryptophan, which are critical players in cancer cell metabolism and in the tumor microenvironment. Different methods of immune regulation are also being investigated, including CAR-T cell therapy and modulation of the gut microbiome, in addition to novel agents targeting the interleukin-2 (IL-2) pathway. This review aims to highlight the emergent novel therapies for RCC and their respective completed and ongoing clinical trials.     

CCNB2 as a potential biomarker of bladder cancer via the high throughput technology

Bladder cancer and oral squamous cell carcinoma (OSCC) seriously affect people’s health. However, the relationship between bladder cancer and OSCC remains unclear. Got {"type":"entrez-geo","attrs":{"text":"GSE138206","term_id":"138206"}}GSE138206, {"type":"entrez-geo","attrs":{"text":"GSE146483","term_id":"146483"}}GSE146483, {"type":"entrez-geo","attrs":{"text":"GSE184616","term_id":"184616"}}GSE184616, and bladder cancer datasets {"type":"entrez-geo","attrs":{"text":"GSE65635","term_id":"65635"}}GSE65635, {"type":"entrez-geo","attrs":{"text":"GSE100926","term_id":"100926"}}GSE100926 from Gene Expression Omnibus database. Weighted gene co-expression network analysis was used to identify the significant module. Functional enrichment analysis was performed via the Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes. Furthermore, the Gene Set Enrichment Analysis was also used to complete the enrichment analysis. Comparative Toxicogenomics Database found most relevant diseases to core genes. TargetScan is used to forecast analysis of microRNA and target genes. In Gene Ontology analysis, differentially expressed genes were mostly concentrated in cell differentiation, extrallular region, structural molecule activity, and actin binding. In Kyoto Encyclopedia of Genes and Genomes analysis, the differentially expressed genes were mainly enriched in PI3K-Akt signaling pathway, pathway in cancer, and extracellular matrix-receptor interaction. Seven hub genes (cyclin B2 [CCNB2], TK1, CDC20, PCNA, CKS1B, CDCA5, MCM4) were obtained. Hub genes (CCNB2, CDC20) are highly expressed in OSCC and bladder cancer samples. CCNB2 was one common oncogene of bladder cancer and OSCC.     

脂质代谢与肺癌相关性及其潜在治疗靶点

脂质代谢调节机制在肿瘤发生发展中的重要性已得到广泛关注.通过增加多种脂肪生成酶的表达,肿瘤细胞可以诱导新生脂肪形成,甚至有研究者认为新生脂肪组织生成的增加可作为多种侵袭性肿瘤的新型标志[1].肺部肿瘤常存在血管异构,在限制肿瘤细胞营养供应的同时,造成细胞缺氧微环境,最终诱导肿瘤细胞发生包括脂代谢在内的多方面代谢变化[2...     

基于网络药理学的康莱特注射液3种主要成分抗肿瘤机制研究

目的 利用网络药理学分析康莱特注射液3种主要成分的抗肿瘤作用机制。方法 以康莱特注射液中具有抗肿瘤作用的甘油三油酸酯、薏苡仁酯、薏苡素为研究对象,依托中药系统药理学数据库（TCMSP）、反向分子对接服务器（PharmMapper）、人类基因组注释数据库（GeneCards）、药物治疗靶标数据库（TTD）进行靶点预测和筛选,借助Cytoscape 3.5.1软件构建活性成分-靶点-疾病网络,借助STRING平台构建靶蛋白相互作用网络,通过DAVID平台对靶点基因本位生物过程和KEGG信号通路进行富集分析。结果 康莱特注射液活性成分作用于EGFR、PGR、PTGS2、AR、MAPK1等25个潜在抗肿瘤靶点,调控FoxO、前列腺癌、癌症、Rap1、TNF、Ras、MAPK信号通路,参与细胞增殖调控、蛋白激酶B信号调控、环氧合酶途径、细胞迁移调控等生物过程,可用于20多种癌症的治疗。结论 本研究为进一步深入研究康莱特注射液抗肿瘤机制提供了新的线索与思路。     

多靶点调控手术治疗难治性精神病80例近期疗效观察

目的:探讨立体定向技术和多靶点组合对难治性精神病的治疗意义,综合评估临床疗效。方法:在立体定向基础上,应用CT、电阻值和微电极电生理进行核团定位,对80例难治性精神病患者,采用杏仁核、内侧隔区、扣带回等多靶点组合射频热凝治疗。应用临床疗效总评量表(clinicalgrobalimpressionsscale,CGl)、简明精神病评定量表(briefpsychiatricratingscale,BPRS)、阴性和阳性综合量表(thepostitveandnegativesyndrome,PNSS)精神病评定量表在术后6个月对治疗效果进行评定。结果:依据减分率标准,80例患者中,显著进步46例,进步31,无变化3例。手术前后量表评分有显著差异(P<0.05)无严重并发症和后遗症发生。结论:多靶点组合的立体定向技术是难治性精神病的有效治疗方法之一,靶点组合设计和亚核团的准确定位,对提高疗效,降低并发症有较大意义。