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Hairy cell leukaemia with unusual BRAF mutations 毛细胞白血病伴有不寻常的BRAF突变
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-02 DOI: 10.1111/jcmm.17890
Elsa Maitre, Margaret Macro, Xavier Troussard

Hairy cell leukaemia (HCL) diagnosis is based on the morphologic detection of circulating abnormal hairy cells in the peripheral blood and/or bone marrow, an HCL immunological score of 3 or 4 based on the expression of the CD11c, CD25, CD103 and CD123 and also the presence of a BRAF V600E activating mutation in the B-raf proto-oncogene (BRAF gene) (7q34). When using new generation sequencing of 21 targeted genes in 124 HCL patients, we identified a cohort of 6/124 (2%) patients with unusual BRAF mutations: two patients presented non-V600 mutations (BRAF F595L, BRAF W604L respectively) and four other patients silent BRAF mutations. When using droplet digital PCR (ddPCR) three of the four patients with concomitant BRAF V600E and silent mutation were negative. The respective role of these mutations in the occurrence of HCL or its progression remains to be clarified, but BRAF sequencing is necessary in case of negative BRAF V600E by ddPCR.

毛细胞白血病(HCL)的诊断是基于对外周血和/或骨髓中循环异常毛细胞的形态学检测,基于CD11c、CD25、CD103和CD123的表达以及B-raf原癌基因(BRAF基因)中BRAF V600E激活突变的存在,HCL免疫学评分为3或4 (7q34)。在对124例HCL患者的21个靶基因进行新一代测序时,我们发现了6/124(2%)例BRAF异常突变患者:2例患者出现非v600突变(分别为BRAF F595L和BRAF W604L),另外4例患者无BRAF突变。当使用液滴数字PCR (ddPCR)时,4例合并BRAF V600E和沉默突变的患者中有3例为阴性。这些突变在HCL发生或进展中的各自作用尚不清楚,但在ddPCR BRAF V600E阴性的情况下,需要进行BRAF测序。
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引用次数: 0
Genetic variants of dipeptidyl peptidase IV are linked to the clinicopathologic development of prostate cancer 二肽基肽酶IV的遗传变异与前列腺癌的临床病理发展有关
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-02 DOI: 10.1111/jcmm.17845
Yu-Ching Wen, Chia-Yen Lin, Chi-Hao Hsiao, Shian-Shiang Wang, Hsiang-Ching Huang, Yung-Wei Lin, Kuo-Hao Ho, Lun-Ching Chang, Shun-Fa Yang, Ming-Hsien Chien

CD26/dipeptidyl peptidase IV (DPP4) is a multifunctional cell-surface glycoprotein widely found in many cell types, and a soluble form is present in body fluids. There is longstanding evidence indicating a tumour-promoting or -suppressive role of DPP4 in different cancer types. However, studies focusing on the impacts of genetic variants of DPP4 on cancers are very rare. Herein, we conducted a case–control study to evaluate whether single-nucleotide polymorphisms (SNPs) of DPP4 were associated with the risk or clinicopathologic development of prostate cancer (PCa). We genotyped four loci of DPP4 SNPs, including rs7608798 (A/G), rs3788979 (C/T), rs2268889 (T/C) and rs6741949 (G/C), using a TaqMan allelic discrimination assay in 704 PCa patients and 704 healthy controls. Our results showed that PCa patients with the DPP4 rs7608798 AG+GG genotype or rs2268889 TC+CC genotype had a higher risk of developing an advanced clinical primary tumour (cT) stage (adjusted odds ratio (AOR): 1.680, 95% confidence interval (CI): 1.062–2.659, p = 0.025; AOR: 1.693, 95% CI: 1.092–2.624, p = 0.018). Additionally, in The Cancer Genome Atlas (TCGA) database, we observed that lower DPP4 expression levels were correlated with higher Gleason scores, advanced cT and pathological stages, tumour metastasis, and shorter progression-free survival rates in PCa patients. Furthermore, overexpression of DPP4 suppressed migration/invasion of metastatic PC3 PCa cells. Our findings suggest that DPP4 levels may affect the progression of PCa, and the DPP4 rs7608798 and rs2268889 SNPs are associated with the clinicopathologic development of PCa in a Taiwanese population.

CD26/二肽基肽酶IV (DPP4)是一种广泛存在于多种细胞类型的多功能细胞表面糖蛋白,其可溶形式存在于体液中。长期以来的证据表明,DPP4在不同类型的癌症中具有促进或抑制肿瘤的作用。然而,关注DPP4基因变异对癌症影响的研究非常罕见。在此,我们进行了一项病例对照研究,以评估DPP4的单核苷酸多态性(snp)是否与前列腺癌(PCa)的风险或临床病理发展相关。我们利用TaqMan等位基因鉴别法对704例PCa患者和704例健康对照者的4个DPP4 snp位点进行基因分型,包括rs7608798 (A/G)、rs3788979 (C/T)、rs2268889 (T/C)和rs6741949 (G/C)。我们的研究结果显示,DPP4 rs7608798 AG+GG基因型或rs2268889 TC+CC基因型的前列腺癌患者发展为晚期临床原发性肿瘤(cT)阶段的风险更高(调整优势比(AOR): 1.680, 95%可信区间(CI): 1.062 ~ 2.659, p = 0.025;AOR: 1.693, 95% CI: 1.092 ~ 2.624, p = 0.018)。此外,在癌症基因组图谱(TCGA)数据库中,我们观察到较低的DPP4表达水平与较高的Gleason评分、较晚的cT和病理分期、肿瘤转移和较短的无进展生存率相关。此外,DPP4的过表达抑制了转移性PC3 PCa细胞的迁移/侵袭。我们的研究结果提示DPP4水平可能影响PCa的进展,DPP4 rs7608798和rs2268889 snp与台湾人群PCa的临床病理发展有关。
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引用次数: 0
DCAMCP: A deep learning model based on capsule network and attention mechanism for molecular carcinogenicity prediction DCAMCP:一个基于胶囊网络和注意力机制的深度学习模型,用于分子致癌性预测。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-31 DOI: 10.1111/jcmm.17889
Zhe Chen, Li Zhang, Jianqiang Sun, Rui Meng, Shuaidong Yin, Qi Zhao

The carcinogenicity of drugs can have a serious impact on human health, so carcinogenicity testing of new compounds is very necessary before being put on the market. Currently, many methods have been used to predict the carcinogenicity of compounds. However, most methods have limited predictive power and there is still much room for improvement. In this study, we construct a deep learning model based on capsule network and attention mechanism named DCAMCP to discriminate between carcinogenic and non-carcinogenic compounds. We train the DCAMCP on a dataset containing 1564 different compounds through their molecular fingerprints and molecular graph features. The trained model is validated by fivefold cross-validation and external validation. DCAMCP achieves an average accuracy (ACC) of 0.718 ± 0.009, sensitivity (SE) of 0.721 ± 0.006, specificity (SP) of 0.715 ± 0.014 and area under the receiver-operating characteristic curve (AUC) of 0.793 ± 0.012. Meanwhile, comparable results can be achieved on an external validation dataset containing 100 compounds, with an ACC of 0.750, SE of 0.778, SP of 0.727 and AUC of 0.811, which demonstrate the reliability of DCAMCP. The results indicate that our model has made progress in cancer risk assessment and could be used as an efficient tool in drug design.

药物的致癌性会对人类健康产生严重影响,因此在上市前对新化合物进行致癌性测试是非常必要的。目前,许多方法已被用于预测化合物的致癌性。然而,大多数方法的预测能力有限,仍有很大的改进空间。在本研究中,我们构建了一个基于胶囊网络和注意力机制的深度学习模型DCAMCP,以区分致癌和非致癌化合物。我们通过分子指纹和分子图谱特征,在包含1564种不同化合物的数据集上训练DCAMCP。训练后的模型通过五重交叉验证和外部验证进行验证。DCAMCP的平均精度(ACC)为0.718 ± 0.009,灵敏度(SE)为0.721 ± 0.006,特异性(SP)为0.715 ± 0.014,受试者工作特性曲线下面积(AUC)为0.793 ± 0.012。同时,在包含100种化合物的外部验证数据集上可以获得可比较的结果,ACC为0.750,SE为0.778,SP为0.727,AUC为0.811,这证明了DCAMCP的可靠性。结果表明,我们的模型在癌症风险评估方面取得了进展,可以作为一种有效的药物设计工具。
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引用次数: 2
Mutational landscape of phenylketonuria in Iran 伊朗苯丙酮尿症的突变景观
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-31 DOI: 10.1111/jcmm.17865
Naser Ajami, Anvar Soleimani, Reza Jafarzadeh-Esfehani, Mojtaba Hasanpour, Romina Rashid Shomali, Mohammad Reza Abbaszadegan

To date more than 1000 different variants in the PAH gene have been identified in patients with phenylketonuria (PKU). In Iran, several studies have been performed to investigate the genetics bases of the PKU in different parts of the country. In this study, we have analysed and present an update of the mutational landscape of the PAH gene as well as the population genetics and frequencies of detected variants for each cohort. Published articles on PKU mutations in Iran were identified through a comprehensive PubMed, Google Scholar, Web of Science (ISI), SCOPUS, Elsevier, Wiley Online Library and SID literature search using the terms: “phenylketonuria”, “hyperphenylalaninemia”, and “PKU” in combination with “Iran”, “Iranian population”, “mutation analysis”, and “Molecular genetics”. Among the literature-related to genetics of PKU, 18 studies were on the PKU mutations. According to these studies, in different populations of Iran 1497 patients were included for mutation detection that resulted in detection of 129 different mutations. Results of genetic analysis of the different cohorts of Iranian PKU patients show that the most prevalent mutation in Iran is the pathogenic splice variant c.1066-11G > A, occurring in 19.54% of alleles in the cohort. Four other common mutations were p.Arg261Gln, p.Pro281Leu, c.168 + 5G > C and p.Arg243Ter (8.18%, 6.45%, 5.88% and 3.7%, respectively). One notable feature of the studied populations is its high rate of consanguineous marriages. Considering this feature, determining the prevalent PKU mutations could be advantageous for designing screening and diagnostic panels in Iran.

迄今为止,在苯丙酮尿症(PKU)患者中发现了1000多种不同的多环芳烃基因变异。在伊朗,已经进行了几项研究,以调查该国不同地区PKU的遗传基础。在这项研究中,我们分析并展示了多环芳烃基因突变景观的更新,以及每个队列的群体遗传学和检测到的变异频率。通过PubMed、谷歌Scholar、Web of Science (ISI)、SCOPUS、Elsevier、Wiley Online Library和SID文献检索,检索词为:“phenylketonuria”、“hyperphenylalaninemia”和“PKU”,并结合“Iran”、“Iranian population”、“mutation analysis”和“Molecular genetics”,确定了在伊朗发表的关于PKU突变的文章。在与PKU遗传学相关的文献中,有18篇是关于PKU突变的。根据这些研究,在伊朗的不同人群中,1497名患者被纳入突变检测,结果检测到129种不同的突变。对伊朗PKU患者不同队列的遗传分析结果显示,伊朗人群中最常见的突变是致病性剪接变异体c.1066-11G > A,占队列等位基因的19.54%。其他4个常见突变为p.a g261gln、p.p pro281leu、c.p 168 + 5G > C和p.a g243ter(分别为8.18%、6.45%、5.88%和3.7%)。研究人群的一个显著特征是其高近亲婚姻率。考虑到这一特点,确定普遍的PKU突变可能有利于在伊朗设计筛查和诊断小组。
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引用次数: 0
Phosphorylated MAPK11 promotes the progression of clear cell renal cell carcinoma by maintaining RUNX2 protein abundance 磷酸化的MAPK11通过维持RUNX2蛋白丰度促进透明细胞肾细胞癌的进展
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-31 DOI: 10.1111/jcmm.17870
Xiandong Song, Changming Dong, Xiaojun Man

Previous studies have demonstrated that mitogen-activated protein kinase 11 (MAPK11) functions as an important point of integration in signalling transduction pathways and controlling endocellular processes, including viability of cells, differentiation, proliferation and apoptosis, through the sequence phosphorylation of the substrate protein Ser/Thr kinase protein cascade. Though MAPK 11 plays an important role in various tumours, especially in the invasive and metastatic processes, its expression and molecular mechanism in clear cell renal cell carcinoma (ccRCC) remain unclear. Runt-associated transcription factor 2 (RUNX2), a main transcription factor for osteoblast differentiation and chondrocyte maturation, has high expression in a number of tumours. In this study, the mRNA and protein levels of targeted genes in ccRCC tissues and adjacent tissues are analysed using the Cancer Genome Atlas (TCGA) database and western blotting. The ccRCC cell proliferation was measured with colony formation and EdU assay, and cell migration was examined through transwell assay. The interactive behaviour between proteins was detected with immunoprecipitation. Half-life period of RUNX2 protein was measured with cycloheximide chase assay. The results of the study indicated overexpression of MAPK11 and RUNX2 in ccRCC tissues and cell lines. MAPK11 and RUNX2 promoted the ccRCC cell proliferation and migration. Additionally, physical interaction took place between RUNX2 and P-MAPK11, which functioned to sustain the stability of RUNX2 protein. The high expression of RUNX2 could neutralize the functional degradation in MAPK11. And the outcomes of the study suggest that the P-MAPK11/RUNX2 axis may be used as a potential therapeutic target of ccRCC.

先前的研究表明,丝裂原活化蛋白激酶11 (MAPK11)作为信号转导途径的重要整合点,通过底物蛋白Ser/Thr激酶蛋白级联的序列磷酸化,控制细胞内过程,包括细胞的活力、分化、增殖和凋亡。尽管mapk11在多种肿瘤中发挥重要作用,特别是在侵袭和转移过程中,但其在透明细胞肾细胞癌(ccRCC)中的表达和分子机制尚不清楚。runt相关转录因子2 (RUNX2)是成骨细胞分化和软骨细胞成熟的主要转录因子,在许多肿瘤中高表达。本研究利用Cancer Genome Atlas (TCGA)数据库和western blotting分析ccRCC组织和邻近组织中靶基因的mRNA和蛋白水平。采用集落形成法和EdU法检测ccRCC细胞增殖,transwell法检测细胞迁移。免疫沉淀法检测蛋白间的相互作用行为。采用环己亚胺追踪法测定RUNX2蛋白的半衰期。研究结果表明,MAPK11和RUNX2在ccRCC组织和细胞系中过表达。MAPK11和RUNX2促进ccRCC细胞的增殖和迁移。此外,RUNX2和P-MAPK11之间发生了物理相互作用,这维持了RUNX2蛋白的稳定性。RUNX2的高表达可以中和MAPK11的功能退化。本研究结果提示P-MAPK11/RUNX2轴可能作为ccRCC的潜在治疗靶点。
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引用次数: 0
Silencing of the MEG3 gene promoted anti-cancer activity and drug sensitivity in glioma MEG3基因的沉默促进了胶质瘤的抗癌活性和药物敏感性
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-31 DOI: 10.1111/jcmm.17883
Zehra Degirmenci, Sena Unver, Turker Kilic, Timucin Avsar

Aberrant expression of MEG3 has been shown in various cancers. The purpose of this study is to evaluate the effect of MEG3 on glioma cells and the use of potential chemotherapeutics in glioma by modulating MEG3 expression. Cell viability, migration and chemosensitivity were assayed. Cell death was evaluated in MEG3 overexpressing and MEG3 suppressed cells. MEG3 expression was compared in patient-derived glioma cells concerning IDH1 mutation and WHO grades. Silencing of MEG3 inhibited cell proliferation and reduced cell migration while overexpression of MEG3 promoted proliferation in glioma cells. MEG3 inhibition improved the chemosensitivity of glioma cells to 5-fluorouracil (5FU) but not to navitoclax. On the other hand, there is no significant effect of MEG3 expression on temozolamide (TMZ) treatment which is a standard chemotherapeutic agent in glioma. Suppression of the MEG3 gene in patient-derived oligodendroglioma cells also showed the same effect whereas glioblastoma cell proliferation and chemosensitivity were not affected by MEG3 inhibition. Further, as a possible cell death mechanism of action apoptosis was investigated. Although MEG3 is a widely known tumour suppressor gene and its loss is associated with several cancer types, here we reported that MEG3 inhibition can be used for improving the efficiency of known chemotherapeutic drug sensitivity. We propose that the level of MEG3 should be evaluated in the treatment of different glioma subtypes that are resistant to effective drugs to increase the potential effective drug applications.

MEG3的异常表达已经在各种癌症中显示出来。本研究的目的是通过调节MEG3的表达来评估MEG3对神经胶质瘤细胞的影响以及潜在的化疗药物在神经胶质瘤中的应用。测定细胞活力、迁移和化学敏感性。在MEG3过表达和MEG3抑制的细胞中评估细胞死亡。比较了患者来源的胶质瘤细胞中MEG3的表达,涉及IDH1突变和世界卫生组织分级。MEG3的沉默抑制了细胞增殖并减少了细胞迁移,而MEG3的过表达促进了神经胶质瘤细胞的增殖。MEG3抑制可提高神经胶质瘤细胞对5-氟尿嘧啶(5FU)的化学敏感性,但对navitoclax的化学敏感性没有改善。另一方面,MEG3的表达对替莫唑胺(TMZ)治疗没有显著影响,替莫唑酰胺是神经胶质瘤的标准化疗药物。患者来源的少突胶质瘤细胞中MEG3基因的抑制也显示出相同的效果,而胶质母细胞瘤细胞的增殖和化学敏感性不受MEG3抑制的影响。进一步,作为一种可能的细胞死亡机制,凋亡的作用进行了研究。尽管MEG3是一种广泛已知的肿瘤抑制基因,其缺失与几种癌症类型有关,但我们报道了MEG3抑制可用于提高已知化疗药物敏感性的效率。我们建议,在治疗对有效药物有耐药性的不同神经胶质瘤亚型时,应评估MEG3的水平,以增加潜在的有效药物应用。
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引用次数: 0
Serum lipidomics-based study of electroacupuncture for skin wound repair in rats 电针对大鼠皮肤创伤修复作用的血清脂质组学研究。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-30 DOI: 10.1111/jcmm.17891
Weibin Du, Lihong He, Zhenwei Wang, Yi Dong, Xiaofen He, Jintao Hu, Min Zhang

Lipid metabolism plays an important role in the repair of skin wounds. Studies have shown that acupuncture is very effective in skin wound repair. However, there is little knowledge about the mechanism of electroacupuncture. Thirty-six SD rats were divided into three groups: sham-operated group, model group and electroacupuncture group, with six rats in each group. After the intervention, orbital venous blood was collected for lipid metabolomics analysis, wound perfusion was detected and finally the effect of electroacupuncture on skin wound repair was comprehensively evaluated by combining wound healing rate and histology. Lipid metabolomics analysis revealed 11 differential metabolites in the model versus sham-operated group. There were 115 differential metabolites in the model versus electro-acupuncture group. 117 differential metabolites in the electro-acupuncture versus sham-operated group. There were two differential metabolites common to all three groups. Mainly cholesteryl esters and sphingolipids were elevated after electroacupuncture and triglycerides were largely decreased after electroacupuncture. The electroacupuncture group recovered faster than the model group in terms of blood perfusion and wound healing (p < 0.05). Electroacupuncture may promote rat skin wound repair by improving lipid metabolism and improving local perfusion.

脂质代谢在皮肤损伤的修复中起着重要作用。研究表明,针灸在皮肤伤口修复方面非常有效。然而,关于电针的作用机制却知之甚少。36只SD大鼠分为假手术组、模型组和电针组,每组6只。干预后,收集眼眶静脉血进行脂质代谢组学分析,检测伤口灌注情况,最后结合伤口愈合率和组织学综合评价电针对皮肤伤口修复的影响。脂质代谢组学分析显示,模型组与假手术组有11种不同的代谢产物。与电针组相比,模型中有115种不同的代谢产物。电针组与假手术组的117种不同代谢产物。三组共有两种不同的代谢产物。电针后主要是胆固醇酯和鞘脂升高,甘油三酯明显下降。电针组在血液灌流和伤口愈合方面均快于模型组(p
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引用次数: 0
Analysis of hepatocellular carcinoma associated with hepatitis B virus 乙型肝炎病毒合并肝细胞癌的分析
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-30 DOI: 10.1111/jcmm.17867
Litao Zheng

The hepatitis B virus (HBV) is considered one of the main driving forces in the development of hepatocellular carcinoma (HCC). Human HBV is a partially double-stranded DNA (dsDNA) virus consisting of approximately 3.2 kbp. HBV predominantly infects hepatocytes via the receptor sodium taurocholate cotransporting polypeptide (NTCP) and coreceptor hepatic proteoglycan. The replication of HBV in hepatocytes leads to apoptosis while simultaneously leading to cirrhosis and cancer. Although the integration of dsDNA into the hepatocyte genome seems to be the main cause of mutation, since the discovery of their function, viral proteins have been shown to regulate the P53 pathway or P13K/AKT pathway to prevent host cell apoptosis, causing uncontrolled proliferation of liver cells leading to the formation of solid tumours. The most common treatments involve nucleo(s)tide analogue (NA) and polyethylene glycol (PEG)ylated interferon-alpha (PegIFN-α). NA treatment has been found to be effective for the majority of patients and induces few side effects. Nevertheless, the rate of seroconversion is relatively low. PegIFN treatment is contraindicated during pregnancy and leads to a higher morbidity rate, but the seroconversion rate is high. Since medicines and vaccines have been developed, the incidence and mortality of HBV related to HCC have profoundly decreased compared to those in 2000. This review investigates what can be the potential mechanism that HBV can cause HBV and the treatment used in chronic and acute infection.

乙型肝炎病毒(HBV)被认为是肝细胞癌(HCC)发展的主要驱动力之一。人HBV是一种部分双链DNA (dsDNA)病毒,全长约3.2 kbp。HBV主要通过受体牛磺胆酸钠共转运多肽(NTCP)和肝蛋白聚糖共受体感染肝细胞。HBV在肝细胞中的复制导致细胞凋亡,同时导致肝硬化和癌症。虽然dsDNA整合到肝细胞基因组中似乎是突变的主要原因,但自发现其功能以来,病毒蛋白已被证明可调节P53途径或P13K/AKT途径阻止宿主细胞凋亡,导致肝细胞不受控制的增殖导致实体瘤的形成。最常见的治疗包括核潮汐类似物(NA)和聚乙二醇(PEG)酰化干扰素-α (PegIFN-α)。NA治疗已被发现对大多数患者有效,并且几乎没有副作用。然而,血清转化率相对较低。妊娠期禁用PegIFN治疗,导致较高的发病率,但血清转换率高。由于药物和疫苗的发展,与2000年相比,与HCC相关的乙型肝炎病毒的发病率和死亡率大大降低。本文综述了HBV引起HBV的潜在机制以及慢性和急性感染的治疗方法。
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引用次数: 1
Titin as a potential novel therapeutic target in colorectal cancer 替丁是癌症潜在的新型治疗靶点。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-27 DOI: 10.1111/jcmm.17866
Hongyun Wei, Keyu Ren, Qian Zhang, Yanchun Jin, Bin Cao, Zibin Tian, Tao Mao, Linlin Ren

Colorectal cancer (CRC) is identified as a primary cause of death around the world. The current chemotherapies are not cost-effective. Therefore, finding novel potential therapeutic target is urgent. Titin (TTN) is a muscle protein that is critical in hypertrophic cardiomyopathy. However, its role in CRC is not well understood. The study focused on exploring the possible role of TTN in CRC carcinogenesis. TTN mRNA and protein expression levels presented an obvious downregulation in CRC tissue samples, relative to normal control (p < 0.05). TTN expression significantly correlated with the clinical stage (normal vs. Stage 1, p < 0.05; normal vs. Stage 4, p < 0.05), node metastasis (normal vs. N1, p < 0.05; N1 vs. N2, p < 0.05), histological type (normal vs. adenocarcinoma, p < 0.05), race (Caucasian vs. Asian, p < 0.05; African-American vs. Asian, p < 0.05) and TP53 mutation (normal vs. TP53 mutation, p < 0.05), considering The Cancer Genome Atlas database. However, for patients who had higher TTN expression, the overall survival was remarkably shorter than patients who had low TTN expression. Furthermore, TTN was lowly expressed in four CRC cell lines. TTN overexpression facilitated CRC cells in terms of the proliferation, metastasis and invasion. Based on gene set enrichment analysis, the ERB pathway might be responsible for TTN-related CRC. Besides, TTN was involved in the response to azacitidine. Overall, TTN might serve as a potential novel therapeutic target for treating and overcoming chemotherapy resistance in CRC.

癌症(CRC)被确定为世界各地死亡的主要原因。目前的化疗并不划算。因此,寻找新的潜在治疗靶点迫在眉睫。Titin(TTN)是一种在肥厚型心肌病中起关键作用的肌肉蛋白。然而,它在儿童权利公约中的作用还没有得到很好的理解。本研究的重点是探讨TTN在结直肠癌癌变中的可能作用。与正常对照组相比,CRC组织中TTN mRNA和蛋白表达水平明显下调(p
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引用次数: 0
Astragaloside IV ameliorates peritoneal fibrosis by promoting PGC-1α to reduce apoptosis in vitro and in vivo 黄芪甲苷IV通过在体外和体内促进PGC-1α减少细胞凋亡来改善腹膜纤维化。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-07-26 DOI: 10.1111/jcmm.17871
Mingxia Xie, Bohou Xia, Lan Xiao, Dun Yang, Zhenghong Li, Hanqing Wang, Xiaoye Wang, Xi Zhang, Qinghua Peng

Prolonged exposure of the peritoneum to high glucose dialysate leads to the development of peritoneal fibrosis (PF), and apoptosis of peritoneal mesothelial cells (PMCs) is a major cause of PF. The aim of this study is to investigate whether Astragaloside IV could protect PMCs from apoptosis and alleviate PF. PMCs and rats PF models were induced by high glucose peritoneal fluid. We examined the pathology of rat peritoneal tissue by HE staining, the thickness of rat peritoneal tissue by Masson's staining, the number of mitochondria and oxidative stress levels in peritoneal tissue by JC-1 and DHE fluorescence staining, and mitochondria-related proteins and apoptosis-related proteins such as PGC-1α, NRF1, TFAM, Caspase3, Bcl2 smad2 were measured. We used hoechst staining and flow cytometry to assess the apoptotic rate of PMCs in the PF model, and further validated the observed changes in the expressions of PGC-1α, NRF1, TFAM, Caspase3, Bcl2 smad2 in PMCs. We further incubated PMCs with MG-132 (proteasome inhibitor) and Cyclohexylamine (protein synthesis inhibitor). The results demonstrated that Astragaloside IV increased the expression of PGC-1α by reducing the ubiquitination of PGC-1α. It was further found that the protective effects of Astragaloside IV on PMCs were blocked when PGC-1α was inhibited. In conclusion, Astragaloside IV effectively alleviated PF both in vitro and in vivo, possibly by promoting PGC-1α to enhance mitochondrial synthesis to reduce apoptotic effects.

腹膜长期暴露于高糖透析液会导致腹膜纤维化(PF)的发展,腹膜间皮细胞(PMCs)的凋亡是导致腹膜纤维化的主要原因。本研究的目的是研究黄芪甲苷IV是否能保护PMCs免于凋亡并减轻PF。用高糖腹膜液诱导PMCs和大鼠PF模型。HE染色检测大鼠腹膜组织病理,Masson染色检测大白鼠腹膜组织厚度,JC-1和DHE荧光染色检测腹膜组织线粒体数量和氧化应激水平,并测定线粒体相关蛋白和凋亡相关蛋白如PGC-1α、NRF1、TFAM、Caspase3、Bcl2-smad2。我们使用hoechst染色和流式细胞术来评估PF模型中PMCs的凋亡率,并进一步验证了在PMCs中观察到的PGC-1α、NRF1、TFAM、Caspase3、Bcl2-smad2表达的变化。我们进一步将PMCs与MG-132(蛋白酶体抑制剂)和环己胺(蛋白质合成抑制剂)孵育。结果表明,黄芪甲苷IV通过减少PGC-1α的泛素化来增加PGC-1的表达。进一步发现,当PGC-1α被抑制时,黄芪甲苷IV对PMCs的保护作用被阻断。总之,黄芪甲苷IV在体外和体内都有效地减轻了PF,可能是通过促进PGC-1α增强线粒体合成来减少凋亡作用。
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引用次数: 1
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Journal of Cellular and Molecular Medicine
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