Perfluorooctanoic acid (PFOA) including linear and branched isomers is one of only three PFAS included in the Stockholm convention on Persistent Organic Pollutants. Unfortunately, PFOA branched isomers have received less attention than the linear due to analytical difficulties and perceived lower environmental concentrations. In this study, we revealed a environmentally relevant pathway for the formation of branched PFOA from PFAS precursors. AFFF samples showed a doubling of branched PFOA concentrations (138 mg/L) after TOP assay oxidation (307 mg/L). These findings indicate that branched PFOA may be more pervasive in the environment than previously thought. Additionally, we investigated the reductive degradability of PFOA using vitamin B12 (VB12) (a naturally occurring electron shuttle) in combination with either zero-valent zinc (ZVZ) or zero-valent iron (ZVI). Linear PFOA, as well as two branched isomers (3-methyl PFOA and 5,5-dimethyl PFOA), resisted reductive defluorination under the experimental conditions. However, all other branched isomers degraded within 10 days in the ZVZ-VB12 system. The experimental rate constants for specific PFOA isomers generally correlate with their calculated reduction potentials, except for 6-methyl PFOA. A potential defluorination pathway was proposed based on high-resolution mass spectrometry (LC-Orbitrap) and density functional theory (DFT) studies.

Cytarabine (Ara-C) is the first-line drug for the treatment of acute myelogenous leukemia (AML). However, resistance eventually develops, decreasing the efficacy of Ara-C in AML patients. The expression of SAMHD1, a deoxynucleoside triphosphate (dNTP) triphosphohydrolase, has been reported to be elevated in Ara-C-resistant AML patients and to play a crucial role in mediating Ara-C resistance in AML. However, the mechanism by which SAMHD1 is upregulated in resistant AML remains unknown. In this study, NONO interacted with and stabilized SAMHD1 by inhibiting DCAF1-mediated ubiquitination/degradation of SAMHD1. Overexpression of NONO increased SAMHD1 expression and reduced the sensitivity of AML cells to Ara-C, and downregulation of NONO had the opposite effects. In addition, the DNA-damaging agents DDP and adriamycin (ADM) reduced NONO/SAMHD1 expression and sensitized AML cells to Ara-C. More importantly, NONO was upregulated in Ara-C-resistant AML cells, resulting in increased SAMHD1 expression in resistant AML cells, and DDP and ADM treatment resensitized resistant AML cells to Ara-C. This study revealed the mechanism by which SAMHD1 is upregulated in Ara-C-resistant AML cells and provided novel therapeutic strategies for Ara-C-resistant AML.

由于肿瘤的遗传多样性和异质性,当前肿瘤的靶向治疗和免疫治疗的效果仍不理想,因此,肿瘤依旧是当今社会威胁人类生命安全最危险的因素之一.凋亡素是一种由鸡贫血病毒(CAV)基因VP3编码而来的非结构性小分子蛋白,通过靶向诱导肿瘤细胞的凋亡,发挥抗肿瘤的功能.近年来,越来越多的科研人员参与到这一领域的研究并进一步阐明了凋亡素抗肿瘤的分子机制.本文将详细综述近年来凋亡素在诱导肿瘤凋亡方面的研究进展. 1 凋亡素概述 CAV是一种单链DNA病毒,属于环病毒属[1],其基因组包含3个完全或部分重叠的开放阅读框,分别编码VP1、VP2和VP3病毒蛋白,其中VP3病毒蛋白能够激活肿瘤细胞凋亡信号从而诱导凋亡,因此被命名为凋亡素[2-3].凋亡素是一种14 kD的小分子蛋白,富含丝氨酸和苏氨酸等碱性氨基酸[3],包括2段核定位信号序列(NLS)和1段核输出信号序列(NES)[4-6],这些结构域对于凋亡素进行核穿梭运动至关重要.

目的:通过建立BALB/c小鼠原位瘤模型,模拟临床肿瘤环境,为观察PTD4-apoptin融合蛋白的抗肿瘤效应提供实验基础.方法:采用两种方法建立BALB/c小鼠宫颈癌原位瘤模型,以PTD4-apoptin融合蛋白进行21天的短期治疗.TUNEL检测PTD4-apoptin融合蛋白的促凋亡效应,HE染色评估肿瘤的形态学变化.结果:与异体异位宫颈癌组织移植法相比,宫颈注射U14宫颈癌细胞悬液的成瘤效果更好.原位瘤给予PTD4-apoptin融合蛋白可显著抑制肿瘤生长,促进肿瘤细胞的凋亡.结论:小鼠宫颈注射U14宫颈癌细胞悬液可建立宫颈癌原位瘤模型,PTD4-apoptin融合蛋白可抑制该原位癌.

上调基因4(up-regulated gene-4,URG4)是受乙肝病毒X蛋白(hepatitis B virus X protein,HBx)激活的下游基因之一,最初在转染HBx的HepG2细胞中被克隆,因其上调细胞增殖效应而得名.研究发现,URG4在HBx转染后的HepG2细胞中表达明显增加,同时细胞生长加速,存活率提高,表明URG4与乙肝病毒相关的肝细胞癌发生可能相关.近年来,人们发现URG4不仅在肝癌细胞中高表达,还与胃癌、骨肉瘤、非小细胞肺癌、神经母细胞瘤等多种癌症相关.本文结合近年来对URG4的研究成果,包括URG4基因及其蛋白质的结构与功能,URG4在癌症发生发展中的作用,以及在癌症早期诊断和预后中的意义进行综述,可望为后续深入地开展URG4与癌症的研究提供参考.

Hypertension is a disease associated with genetic and environmental factors.The etiology of hypertension is not yet clear.Recent studies revealed that dysregulation of more than one gene associated with blood pressure was usually found in hypertensive or potential patients.Many genetic loci associated with hypertension have been studied extensively,therefore,in this review we introduced the research progress of correlation between gene polymorphisms and essential hypertension.

PBK/TOPK是一种丝-苏氨酸蛋白激酶,正常生理情况下,TOPK仅在睾丸和胸腺中表达.近年来研究表明,TOPK在多种恶性肿瘤细胞中呈高表达,调控肿瘤细胞的细胞周期,与肿瘤细胞的增殖、侵袭、转移、抗凋亡过程相关.因此,TOPK成为肿瘤治疗的一个靶标,其特异性抑制剂正在研究当中.目前,使用最多的TOPK抑制剂均能与TOPK分子活性中心结合,直接抑制TOPK的功能,从而达到抑制效果.本文综述了TOPK的结构和功能,以及现用于研究的TOPK抑制剂的抗肿瘤作用.

Small nucleolar RNA (snoRNA) is a kind of small non-coding RNA located in nucleolus.snoRNA plays an important role in the modification of a variety of RNA.With deeper and deeper studies,the structure and function of non-coding RNA like snoRNA has gradually become the hot spot of academic research.Recent discoveries indicated that snoRNA is closely related to the occurrence and development of lung cancer.In order to provide references for subsequent research,we summarized the characteristic of snoRNA in the occurrence and development of lung cancer and its potential value in lung cancer diagnosis and therapy,which was based on the basic structure and function of snoRNA.

Objective To investigate the effects of PTD4-GFP-Apoptin protein on proliferation inhibition and apoptosis-inducing of different types of leukemia cells. Methods Genetic engineering was used to restructure a carrier containing PTD4-GFP-Apoptin gene, and MTT was applied to detect the expressed PTD4-GFP-Apoptin fusion protein and its effect on the leukemia cell proliferation. Flow cytometry (FCM) was used to detect the effects on cell apoptosis. Results MTT cell proliferation inhibitory experiment showed that PTD4-GFP-Apoptin had different degree of proliferation inhibition on different types of leukemia cells;furthermore, the inhibitory effect presented positive correlation with time and concentration. FCM showed that PTD4-GFP-Apoptin had apoptosis-inducing effect on HL-60 cells, and the apoptotic rate had significant difference compared with the control group (P <0.05). Conclusions PTD4 can carry large proteins to penetrate the cell membrane, and PTD4-GFP-Apoptin may produce the inhibiting proliferation in vitro for a variety of leukemia cells. Apoptin can induce tumor cell apoptosis without affecting normal cells, which might become a new agent for the clinical treatment of leukemia.

Worldwide, cervix carcinoma is among the most dangerous cancer types, and novel therapies are under development. Cancer treatments are often hampered because of lack of specificity. The chicken anemia virus-derived apoptin induces apoptosis selectively in tumor cells and leaves normal cells unharmed. Here, we have carried out in-vitro and in-vivo studies on the cytotoxic effect of apoptin in a cervix carcinoma model. Apoptin was fused to the protein transduction domain 4 (PTD4), enabling delivery of the fusion protein across cellular membranes. PTD4-apoptin protein is located in the nuclei of human cervical carcinoma HeLa cells and in the cytoplasm of normal cells L02. By MTT and flow cytometry analysis, we have proven that PTD4-apoptin protein induced apoptosis in the cervical carcinoma cells. PTD4-apoptin enhanced the level of active executioner caspase-3. Neither caspase-3 activation nor apoptin-induced accumulation of the mitochondrial outer-membrane protein Mfn-2 was affected by ectopic Bcl-2 expression. In contrast, apoptin-mediated AKT activation was inhibited by Bcl-2. In vivo, cervix carcinoma xenografts were treated for 7 days with PTD4-apoptin protein. The PTD4-apoptin treatment induced a decrease in the cervix carcinoma, whereas the PTD4-GFP protein-treated controls expanded significantly. TUNEL analysis showed that PTD4-apoptin protein induced apoptosis in cervix carcinoma cells, in contrast to the control PTD-GFP-treated ones. Our results indicate that apoptin is a potential anticancer agent for treating cervix carcinoma.

在基因的表达调控过程中,一系列非编码RNA(non-coding RNA,ncRNA)发挥着广泛作用.然而,作为其重要成员的小激活RNA(small activating RNA,saRNA)却没有得到足够的认识和关注.本篇综述旨在介绍saRNA的机制与功能,并评估它的应用前景.文中归纳该领域的最新进展,特别是有关肿瘤治疗的研究.saRNA能识别基因启动子上特定序列、诱导相应基因的转录,从而实现基因激活.这不仅与siRNA(small interfering RNA)的抑制作用相反,而且有其独特的动力学特征.目前,saRNA研究主要集中于肿瘤领域,并发现它对某些肿瘤的生长和转移具有抑制作用,因而有望开辟肿瘤治疗的新途径.本文结尾简要探讨了saRNA在开发新抗癌药物等方面的应用潜力.

The Mex-3C protein ( also called RKHD2 ) contains two tandem repeat KH domains and a RING domain , allowing it to bind RNA and making it become a ubiquitin E3 ligase. A recent study indicates that this degradation can be inhibited by a deubiquitinating enzyme USP7 and proposes the idea of the RNA-binding E3 ligase which links RNA degeneration and the ubiquitination. Other result has shown that chromosomal instability is the result of a defect of three genes , including MEX3C , named " CIN-suppressor genes " which initiate DNA replication stress. This review will focus on the two theories originating from previous study of this protein.

<正>在真核细胞中,自噬(autophagy)是细胞通过降解自身胞质中的部分蛋白和部分细胞器以度过饥饿,并清除氧化损伤的异常大分子及细胞器,从而在应激中维持细胞稳态的过程。自噬的发生是以双层膜囊泡的形成为特征的,因而这种双层膜囊泡被命名为自噬体(autophagosome)。自噬分为大自噬、小自噬和分子伴侣介导的自噬。大自噬的主

The key role of mitochondria in cell death has been widely accepted,but it remains unclear on how other organelles influence mitochondria to initiate cell death.Recently,Alexei et al.proposed a theory of that explained the mechanism of lysosome-mitochondria interaction based on latest studies in lysosomal functions.Apoptotic factors may permeablize the lysosomal membrane,then through iron-dependent,lipofuscin-related,Bcl-2 family-dependent,or Rho/ROCK-JNK pathways cause in the permeability of mitochondrial membrane and initiate cell death.On the other hand,mitochondrial membrane permeabilization can also permeablize the lysosomal membrane through the ROS-dependent and Bcl-2 family-dependent ways and promotes cell death.The theory of lysosomal-mitochondrial axis was lately being used to explain the pathogenesis of nonalcoholic fatty liver disease and the lysosomal storage diseases.This review introduces the lysosomal-mitochondrial axis theory and discusses it implication in disease conditions.

Well-dispersible aniline/p-phenylenediamine copolymer [P(ANI-co-p-PDA)-F] was synthesized by chemical oxidative polymerization in the presence of nonylphenol ethoxylate (TX-8) with the hydrophilic lipophilic balance (HLB) value of 10–11. The FTIR and 1H NMR spectra proved that there was TX-8 composition in P(ANI-co-p-PDA)-F copolymer. And the P(ANI-co-p-PDA)-F had the smaller particle diameter and better dispersion stability in toluene than that of P(ANI-co-p-PDA) copolymer without TX-8. The anti-corrosion performance of carbon steel samples coated by P(ANI-co-p-PDA)-F/epoxy composite coatings in 5wt% NaCl and 0.1M HCl aqueous solution were evaluated by the potentiodynamic polarization and electrochemical impedance spectroscopy (EIS). The results showed that the P(ANI-co-p-PDA)-F/epoxy coatings on carbon steel possessed good corrosion resistance, and composite coating containing 7wt% P(ANI-co-p-PDA)-F exhibited best anti-corrosive performance.

The purpose of the study is to develop a new formulation for clinically used anti-cancer agent tacrolimus (FK506) to minimize the severe side effects. Toward this end, a new formulation method has been developed by complexation of FK506 with an hydrophilic cyclodextrin derivative, heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) using ultrasonic means. The resulting complex displays dramatically enhanced solubility of FK506. Then bovine serum albumin (BSA) nanoparticles were prepared directly from the preformed FK506/DM-β-CD inclusion complex by the desolvation-chemical crosslinking method, with the size of 148.4–262.9 nm. Stable colloidal dispersions of the nanoparticles were formed with zeta potentials of the range of −24.9 to −38.4 mV. The entrapment efficiency of FK506 was increased as high as 1.57-fold. Moreover, notably FK506 was released from the nanoparticles in a sustained manner. As demonstrated, pharmacokinetic studies reveal that, as compared with FK506-loaded BSA nanoparticles, the FK506/DM-β-CD inclusion complex-loaded BSA nanoparticles have significant increase at Tmax, t1/2, MRT and decrease at Cmax. In summary, these results suggest that the drug/DM-β-CD inclusion complex-loaded BSA nanoparticles display significantly improved delivery efficiency for poorly soluble FK506 or its derivatives.

A disintegrin and metalloproteinase 10 (ADAM10) was identified as a key protease in the ectodomain shedding of various substrates, such as Notch1 protein, ErbB2 and E-cadherin, which are important in the development of non-small cell lung cancer (NSCLC). The aim of this study was to investi-gate the role of ADAM10 in NSCLC metastasis.We characterized the expression of ADAM10 and Notch1 in human NSCLC tissues in vivo. Immunohistochemical analysis indicated that ADAM10 expression was significantly increased in the NSCLC tissues, particularly in the metastatic tissues. Futhermore, ADAM10 overexpression positively correlated with Notch1 expression in the NSCLC tissues. The in vitro downregulation of ADAM10 expression using ADAM10 short hairpin RNA (shRNA) reduced the migration and invasion of NSCLC cells. We present further evidence that ADAM10 promotes NSCLC cell migration and invasion via the activation of the Notch1 signaling pathway. Taken together, our results suggest that ADAM10 may serve as a potential target for the therapeutic intervention of NSCLC metastasis. The data provided in this study may aid in the further understanding of the function of ADAM10 in the progression of NSCLC and open new perspectives for the diagnosis and treatment of NSCLC.

钙是人体内含量最丰富的无机元素之一,人体内钙含量与健康密切相关.在正常成人体内,钙总量为700～1 400 g,约占体质量的1.5%～2.2%,其中99%的钙以羟基磷灰石的形式存在于骨和牙齿中,其余分布于体液和软组织中,以溶解状态存在.细胞外液游离钙的浓度为1.12～1.23 mmol/L.

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