Hypomethylation of Notch1 DNA is associated with the occurrence of uveitis

Uveitis is a serious intra-ocular inflammatory disease that can lead to visual impairment even blindness worldwide. Notch signaling can regulate the differentiation of naive CD4⁺ T cells, influencing the development of uveitis. DNA methylation is closely related to the autoimmune diseases. In this study, we measured the Notch1 DNA methylation level, determined the Notch1 and related DNA methylases mRNA expression and evaluated the ratio of T helper type 17 regulatory T cell (Th17/T_reg) in peripheral blood mononuclear cells (PBMCs) from uveitis patients and normal control subjects; we also tested the levels of relevant inflammatory cytokines in serum from the participants. Results indicated that compared with those in normal control individuals, the expression of ten–eleven translocation 2 (TET2) and Notch1 mRNA is elevated in uveitis patients, whereas the methylation level in Notch1 DNA promotor region [−842 ~ −646 base pairs (bp)] is down-regulated, and is unrelated to anatomical location. Moreover, the Th17/T_reg ratio is up-regulated in PBMCs from uveitis patients, accompanied by the elevated levels of proinflammatory cytokines [e.g. interleukin (IL)-2, IL-6, IL-17 and interferon (IFN)-γ] in serum from uveitis patients. These findings suggest that the over-expression of TET2 DNA demethylase may lead to hypomethylation of Notch1, activate the Notch1 signaling, induce naive CD4⁺ T cells to differentiate theTh17 subset and thus disturb the balance of the Th17/T_reg ratio in uveitis patients. Overall, hypomethylation of Notch1 DNA is closely associated with the occurrence of uveitis. Our study preliminarily reveals the underlying mechanism for the occurrence of uveitis related to the hypomethylation of Notch1 DNA, providing a novel therapeutic strategy against uveitis in clinical practice.     

Three patients with 46,X,inv(Y)(p11.2q11.2)pat/45,X and their pedigree analysis

The present study aimed to perform chromosome examination and pedigree analysis on three patients with semen abnormality who had undergone in vitro fertilization–embryo transfer (IVF-ET). Peripheral blood cell culture and chromosome karyotyping were performed on 4,200 individuals who had undergone chromosome examination. Among them, 155 pregnant women who had successfully conceived were subjected to amniotic cell culture and chromosome karyotyping and those with abnormal chromosome karyotype were further subjected to C-banding and whole-genome sequencing. Mosaicism for a 46,X,inv(Y)(p11.2q11.2)pat/45,X karyotype was identified in the probands and immediate adult male relatives. The incidence of this mosaicism in the study population was only 0.07% (3/4,200), which is reported for the first time. For the proband of pedigree A, the results of whole-genome sequencing and other tests were normal, and the chromosome karyotype of IVF fetuses was 46,X,inv(Y)(p11.2q11.2)pat. All the male members of three pedigrees have normal phenotypes, with no features of Turner's syndrome (45,X) or hermaphroditism (45,X/46,XY), suggesting that the inverted Y chromosome is extremely unstable and particularly susceptible to loss in somatic cells. So we speculate this karyotype may be a unique type of inverted Y chromosome in somatic cells.     

The reporting quality and risk of bias of randomized controlled trials of acupuncture for migraine: Methodological study based on STRICTA and RoB 2.0

ObjectivesTo investigate the reporting quality and risk of bias of randomized controlled trials (RCTs) of acupuncture for migraine, to facilitate and improve the quality of RCTs of acupuncture for migraine.MethodsThe Cochrane Library, PubMed and EMBASE were searched from inception to June 11, 2019 using a comprehensive search strategy. The reporting quality and risk of bias of included RCTs were independently evaluated by two investigators using STRICTA and RoB 2.0. Any disagreement was resolved by a third investigator.ResultsA total of 28 eligible RCTs were published in 24 academic journals from 1994 to 2018. Based on STRICTA, four sub-items including “details of other interventions’’ (1/28, 4 %), “setting and context of treatment” (9/28, 32 %), “the extent to which treatment was varied” (11/28, 39 %), and “number of needle insertions per subject per session” (13/28, 46 %), showed low reporting quality. A total of 32 different outcomes were reported in 28 RCTs, and based on RoB 2.0, nine (9/28, 32 %) RCTs were judged to be high RoB, three of which were owing to deviations from intended interventions; 11(11/28, 39 %) RCTs elicited some concerns; and eight (8/28, 29 %) RCTs were low RoB for their outcomes.ConclusionsThe reporting quality and risk of bias of RCTs of acupuncture for migraine remain suboptimal. Therefore, all stakeholders should make a contribution to improve the quality of RCTs of acupuncture for migraine using STRICTA and RoB 2.0, while not limiting this approach solely to studies on migraine, using STRICTA and RoB 2.0 tools.     

Administration with hyperoside sensitizes breast cancer cells to paclitaxel by blocking the TLR4 signaling

Breast cancer is a malignancy and one of the most frequent causes of cancer death among women worldwide. Paclitaxel is a common chemotherapeutic drug and has recently been shown to facilitate tumor cell escape during cytotoxic chemotherapy by inducing inflammatory mediators and pro-survival protein expression. Hyperoside is a flavonoid glycoside compound and exerts anti-inflammation, and anti-tumor growth properties. However, its function in breast cancer chemosensitivity remains poorly elucidated. In this study, hyperoside exhibited little cytotoxicity to normal human breast mammary epithelial cell lines, and also protected against paclitaxel-induced cytotoxicity in MCF-10A. Importantly, treatment with hyperoside engendered not only inhibition of cell viability, but also potentiated cancer cell sensitivity to paclitaxel in TLR4-positive breast cancer MDA-MB-231 cells by suppressing cell viability, and increasing cell apoptosis and caspase-3 activity. Nevertheless, although hyperoside exposure restrained cell viability, its treatment presented little effects to paclitaxel sensitivity in TLR4-null HCC1806 cells. Intriguingly, paclitaxel stimulation activated the TLR4-NF-κB signaling, which was reversed after hyperoside administration. Concomitantly, hyperoside also attenuated paclitaxel-mediated anti-apoptotic Bcl-2 expression, but enhanced the effects of paclitaxel on pro-apoptotic Bax expression, and pro-inflammatory cytokine IL-6 and IL-6 levels in MDA-MB-231 cells. Importantly, restoring the TLR4 pathway overturned hyperoside-evoked chemosensitivity to paclitaxel in MDA-MB-231 cells. Thus, hyperoside may elevate breast cancer cell sensitivity to paclitaxel by blocking TLR4 activation-mediated pro-inflammatory and pro-survival approaches, thereby endorsing its usefulness as a promising therapeutic combination to overcome chemosensitivity in breast cancer.     

Synthesis and Evaluation of Diindole-Based MRI Contrast Agent for In Vivo Visualization of Necrosis

Purpose

Noninvasive imaging of cell necrosis can provide an early evaluation of tumor response to treatments. Here, we aimed to design and synthesize a novel diindole-based magnetic resonance imaging (MRI) contrast agent (Gd-bis-DOTA-diindolylmethane, Gd-DIM) for assessment of tumor response to therapy at an early stage.

Procedures

The oil-water partition coefficient (Log P) and relaxivity of Gd-DIM were determined in vitro. Then, its necrosis avidity was examined in necrotic cells in vitro and in rat models with microwave ablation-induced muscle necrosis (MAMN) and ischemia reperfusion-induced liver necrosis (IRLN) by MRI. Visualization of tumor necrosis induced by combretastatin A-4 disodium phosphate (CA4P) was evaluated in rats bearing W256 orthotopic liver tumor by MRI. Finally, DNA binding assay was performed to explore the possible necrosis-avidity mechanism of Gd-DIM.

Results

The Log P value and T1 relaxivity of Gd-DIM is ??2.15?±?0.01 and 6.61 mM^?1 s^?1, respectively. Gd-DIM showed predominant necrosis avidity in vitro and in vivo. Clear visualization of the tumor necrosis induced by CA4P was achieved at 60 min after administration of Gd-DIM. DNA binding study indicated that the necrosis-avidity mechanism of Gd-DIM may be due to its binding to exposed DNA in necrotic cells.

Conclusion

Gd-DIM may serve as a promising necrosis-avid MRI contrast agent for early assessment of tumor response to therapy.

     

HPLC同时测定斑蝥酸钠维生素B6注射液中斑蝥酸钠和维生素B6的含量

目的 建立斑蝥酸钠维生素B₆注射液中斑蝥酸钠和维生素B₆含量的同时测定方法。方法 采用HPLC，色谱柱为Syncronis C₁₈（250 mm×4.6 mm，5 μm），流动相为0.02 mol·L^-1磷酸二氢钾溶液（磷酸调pH值至2.6）-乙腈，梯度洗脱，流速为1.0 mL·min^-1，检测波长为193，290 nm，波长切换法，柱温：30℃。结果 斑蝥酸钠回归方程为Y=1.926X+0.010（r=0.999 7），在0.064 6~0.322 8 mg·mL^-1内斑蝥酸钠与峰面积的线性关系良好，平均回收率为98.9%，RSD为1.2%（n=9）。维生素B₆回归方程为Y=24.153X+0.670（r=0.999 9），在0.535 9~2.679 7 mg·mL^-1内维生素B₆与峰面积的线性关系良好，平均回收率为100.2%，RSD为1.0%（n=9）；仪器精密度、稳定性和重复性试验的RSD均<2.0%。结论 所建立的方法结果准确、重复性好，可用于斑蝥酸钠维生素B₆注射液的质量控制。     

系膜增生性肾炎肾小管间质损害模型的建立及肾疏宁的保护作用

[目的]建立一种新的系膜增生性肾炎肾小管间质损害模型,并观察肾疏宁的保护作用。[方法]在系膜增生性肾炎(MsPGN)模型基础上,延长造模时间至12～16周,使其自然发展成肾小管间质损害模型,观察肾疏宁对进展性肾小管间质损害的保护作用,并设苯那普利为阳性对照组。[结果]随着造模时间的延长,模型组肾小管间质损害逐渐加重,肾疏宁及苯那普利组损伤程度明显减轻。[结论]系膜增生性肾炎中肾小管间质损害模型成功,中药肾疏宁对肾小管间质损害具有明显的保护作用。     

眩晕定方对血管性眩晕模型家兔体重及肝组织DNA含量的实验研究

目的：研究眩晕定方对血管性眩晕气虚血瘀证模型家兔干预后,家兔体重及肝组织DNA含量的变化。方法：建立实验性血管性眩晕气虚血瘀证家兔模型,采用苯酚法提取兔肝DNA,紫外吸收法测定其DNA含量,观察眩晕定方干预后家兔体重及肝组织DNA含量的改变情况。结果：眩晕定方作用于气虚血瘀型血管性眩晕动物模型后,中剂量组体重为（2.54±0.13）kg,高于西比灵对照组的（2.06±0.10）kg,差异有显著统计学意义（P〈0.01）;中剂量组肝组织DNA含量为（1.1029±0.0916）kg,低于于西比灵组的（1.4236±0.1115）kg,差异有显著统计学意义（P〈0.01）。结论：眩晕定方可增加家兔体重,降低该模型家兔的肝组织DNA含量,从而改善气虚证候。     

中医药抑制肿瘤血管生成抗肿瘤转移的可行性探讨

抑制肿瘤血管生成是控制肿瘤生长和转移的重要途径之一,以肿瘤血管形成为靶点的血管生成抑制剂研究已成为当前肿瘤基础理论和临床研究的热点。本文以传统中医药理论为基础,探讨了中医药抗肿瘤血管生成抗肿瘤转移的可行性及目前中药抗肿瘤血管生成的研究进展。认为从中药中筛选开发具有抑制肿瘤新生血管生成和阻断肿瘤转移途径的新药,对于控制肿瘤侵袭、转移、改善患者预后和提高生存率具有十分重要的意义。     

1990-2019年中国白内障患病率和伤残调整寿命年的趋势分析

目的：评估1990-2019年以来中国白内障疾病的负担变化趋势。

方法：中国白内障相关疾病负担数据来源于大型公共数据库—2019年全球疾病负担研究(GBD 2019)。利用GBD 2019的公开数据，提取中国白内障疾病负担的有关信息。根据GBD 2019的研究结果，对中国白内障患病率和伤残调整寿命年(DALYs)进行分析。同时，进一步探讨中国及其邻国年龄标准化患病率(ASPR)和年龄标准化伤残调整寿命年(ASDR)的变量特征。

结果：1990年至2019年间，我国因白内障致盲和视力丧失患病人数增加223.54%，相应DALYs增加了142.14%。与男性群体相比，女性在过去30年中表现出更高的ASPR和DALYs。同时，65岁至84岁年龄段的人群比其他人更容易患白内障。与周边国家相比，中国ASPR排名从1990年的第9位867.09(95%UI：761.36-975.42)/10万，上升到2019年的第11位991.56(95%UI：861.52-1 131.04)/10万； 同时ASDR从1990年的第9位65.85(95%UI：46.39-89.41)/10万，上升到2019年的第10位59.16(95%UI：41.70-80.15)/10万。然而，从全球范围来看，2019年中国白内障ASDR和ASPR仍保持较低水平。

结论：从1990年到2019年，中国因白内障而导致失明和视力丧失的总人群患病率和DALYs呈总体上升趋势，需要加强早期白内障筛查，尤其是针对老年人和女性群体。