miR-199a: A Tumor Suppressor with Noncoding RNA Network and Therapeutic Candidate in Lung Cancer

Lung cancer is the leading cause of cancer death worldwide. miR-199a, which has two mature molecules: miR-199a-3p and miR-199a-5p, plays an important biological role in the genesis and development of tumors. We collected recent research results on lung cancer and miR-199a from Google Scholar and PubMed databases. The biological functions of miR-199a in lung cancer are reviewed in detail, and its potential roles in lung cancer diagnosis and treatment are discussed. With miR-199a as the core point and a divergence outward, the interplay between miR-199a and other ncRNAs is reviewed, and a regulatory network covering various cancers is depicted, which can help us to better understand the mechanism of cancer occurrence and provide a means for developing novel therapeutic strategies. In addition, the current methods of diagnosis and treatment of lung cancer are reviewed. Finally, a conclusion was drawn: miR-199a inhibits the development of lung cancer, especially by inhibiting the proliferation, infiltration, and migration of lung cancer cells, inhibiting tumor angiogenesis, increasing the apoptosis of lung cancer cells, and affecting the drug resistance of lung cancer cells. This review aims to provide new insights into lung cancer therapy and prevention.     

S-Adenosylmethionine Inhibits Cell Growth and Migration of Triple Negative Breast Cancer Cells through Upregulating MiRNA-34c and MiRNA-449a

Triple-negative breast cancer (TNBC) is one of the most common malignancies worldwide and shows maximum invasiveness and a high risk of metastasis. Recently, many natural compounds have been highlighted as a valuable source of new and less toxic drugs to enhance breast cancer therapy. Among them, S-adenosyl-L-methionine (AdoMet) has emerged as a promising anti-cancer agent. MicroRNA (miRNA or miR)-based gene therapy provides an interesting antitumor approach to integrated cancer therapy. In this study, we evaluated AdoMet-induced modulation of miRNA-34c and miRNA-449a expression in MDA-MB-231 and MDA-MB-468 TNBC cells. We demonstrated that AdoMet upregulates miR-34c and miR-449a expression in both cell lines. We found that the combination of AdoMet with miR-34c or miR-449a mimic strongly potentiated the pro-apoptotic effect of the sulfonium compound by a caspase-dependent mechanism. For the first time, by video time-lapse microscopy, we showed that AdoMet inhibited the in vitro migration of MDA-MB-231 and MDA-MB-468 cells and that the combination with miR-34c or miR-449a mimic strengthened the effect of the sulfonium compound through the modulation of β-catenin and Small Mother Against Decapentaplegic (SMAD) signaling pathways. Our results furnished the first evidence that AdoMet exerts its antitumor effects in TNBC cells through upregulating the expression of miR-34c and miR-449a.     

MicroRNA-199b Deregulation Shows Oncogenic Properties and Promising Clinical Value as Circulating Marker in Locally Advanced Rectal Cancer Patients

The identification of robust prognostic markers still represents a need in locally advanced rectal cancer (LARC). MicroRNAs (miRs) have progressively emerged as promising circulating markers, overcoming some limitations that traditional biopsy comprises. Tissue miR-199b deregulation has been reported to predict outcome and response to neoadjuvant chemoradiotherapy (nCRT) in LARC, and was also found to be associated with disease progression in colorectal cancer. However, its biological and clinical relevance remains to be fully clarified. Thus, we observed here that miR-199b regulates cell migration, aggressiveness, and cell growth, and inhibits colonosphere formation and induces caspase-dependent apoptosis. Moreover, miR-199b expression was quantified by real-time PCR in plasma samples from LARC patients and its downregulation was observed in 22.7% of cases. This alteration was found to be associated with higher tumor size (p = 0.002) and pathological stage (p = 0.020) after nCRT. Notably, we observed substantially lower global miR-199b expression associated with patient downstaging (p = 0.009), as well as in non-responders compared to those cases who responded to nCRT in both pre- (p = 0.003) and post-treatment samples (p = 0.038). In concordance, we found that miR-199b served as a predictor marker of response to neoadjuvant therapy in our cohort (p = 0.011). Altogether, our findings here demonstrate the functional relevance of miR-199b in this disease and its potential value as a novel circulating marker in LARC.     

酸性染料橙RXL及酸性染料黄A-4R合成技术解析与应对

该文就酸性染料橙RXL及酸性染料黄A-4R合成工艺分步反应解析与应对作出介绍,并提示一些可供进一步研究完善的意向,以利该两产品达到高质、低耗、低成本和循环利用之目的。     

MicroRNA-199a-5p Affects Porcine Preadipocyte Proliferation and Differentiation

MicroRNAs (miRNAs), a class of small non-coding RNAs, have emerged as novel and potent regulators of adipogenesis. However, few miRNAs have been fully investigated in porcine adipogenesis, given the fact that pig is not only an apropos model of human obesity research, but also a staple meat source of human diet. In this study, we showed that miRNA-199a-5p is highly expressed in porcine subcutaneous fat deposits compared to several other tissue types and organs measured alongside. Overexpression of miR-199a-5p in porcine preadipocytes significantly promoted cell proliferation while attenuating the lipid deposition in porcine adipocytes. By target gene prediction and experimental validation, we demonstrated that caveolin-1 (Cav-1) may be a bona fide target of miR-199a-5p in porcine adipocytes, accounting for some of miR-199a-5p’s functions. Taken together, our data established a role of miR-199a-5p in porcine preadipocyte proliferation and differentiation, which is at least partially played by downregulating Cav-1.     

Circulating microRNA-19a as a Potential Novel Biomarker for Diagnosis of Acute Myocardial Infarction

Acute myocardial infarction (AMI) is a serious cardiovascular disease. Investigating new susceptibility genes for effective methods of early diagnosis of AMI is important. In the current study, peripheral blood miR-19a levels were detected by real-time polymerase chain reaction. Significant differences and logistic correlation analyses were carried out by grouping of disease types and stratification of risk factors. Receiver-operator characteristic curve analysis was used to compare the current common clinical biochemical markers and evaluate the sensitivity and specificity of miR-19a for diagnosing AMI. Circulating miR-19a expression in the AMI group was higher than that in controls. The diagnostic effect of circulating miR-19a levels was superior to current clinical biochemical indices, such as CK, CK-MB, MYO, hs-TnI, and BNP. Our results show that there is a close association of circulating miR-19a levels with susceptibility to AMI. Circulating miR-19a levels could be a candidate diagnostic biomarker for AMI.     

MOF-199@GO改性PVDF荷电纳滤膜的制备及其性能

采用原位生长法制备了MOF-199@氧化石墨烯（GO）纳米复合材料,并对聚偏氟乙烯（PVDF）支撑膜进行表面改性,以克服PVDF膜表面疏水性。通过界面聚合反应,制备了基于MOF-199@GO改性PVDF的聚酰胺复合荷电纳滤膜。采用XRD、SEM、TEM、AFM和zeta电位等手段表征了MOF-199@GO复合材料及MOF-199@GO改性PVDF聚酰胺复合纳滤膜的结构及微观形貌,并测试了MOF-199@GO改性PVDF聚酰胺复合纳滤膜的脱盐性能。结果表明：通过MOF-199@GO复合材料对PVDF支撑膜的表面改性,有效克服了PVDF支撑膜的疏水性,实现了表面聚酰胺薄层的均匀连续生长,荷电纳滤膜表面荷负电性能显著增强,其中经MOF-199@GO充分改性的复合荷电纳滤膜表现出优异的脱盐性能,对MgSO₄、Na₂SO₄、NaCl和MgCl₂四种盐的截留率分别达到了93.56%、93.04%、87.48%和87.11%。     

Preparation and properties of MOF-199@GO modified PVDF charged composite nanofiltration membrane

As novel functional materials, metal-organic framework (MOF) and graphene oxide (GO) have received great attentions in recent years. In this work, MOF@GO nanocomposite (MOF-199@GO) is prepared by an in-situ growth method. A novel and highly efficient nanofiltration (NF) membrane can be facilely fabricated via surface decoration of MOF-199@GO onto poly(vinylidene fluoride) (PVDF) substrate before interfacial polymerization of m-phenylenediamine (MPD) and trimesoyl chloride (TMC) in order to overcome the hydrophobicity of PVDF membrane. The structure and morphology of MOF-199@GO and MOF-199@GO modified PVDF polyamide composite membrane are characterized by XRD, SEM, TEM, AFM and zeta potential. MOF-199@GO modified PVDF composite NF membrane which possesses dense and uniform polyamide thin-layer exhibits higher negative surface potential (up to ~37 mV) at pH 9.5. The performance of MOF-199@GO modified PVDF polyamide composite NF membrane has been investigated by determination of pure water flux and salt rejection. The prepared NF membrane MG3 exhibited highly efficient rejection of MgSO₄, Na₂SO₄, NaCl and MgCl₂, which are 93.56%, 93.04%, 87.48% and 87.11%, respectively. This work provides a worthy reference for designing highly efficient NF membranes modified by MOF and relevant materials.     

PARP抑制剂HD199胶囊的研制

为了克服新型二磷酸腺苷核糖多聚酶PARP抑制剂HD199原料药流动性不佳、黏度大的问题,本文开发出工艺简单易行、方便调整剂量、质量可控的临床研究使用HD199胶囊剂。通过研究助流剂微粉硅胶和稀释剂种类及用量对HD199粉体性质和溶出度的影响,考察原辅料相容性及工艺重现性,筛选确定HD199胶囊的处方组成。HD199流动性和填充性明显改善,HD199休止角由55.5°降低到45.6°,压缩度由44.4%下降到30.7%;原辅料相容性好,各实验条件下,所研究的各种辅料对HD199的稳定性几乎没有影响,有关物质的改变与API相似;优选的处方组成为HD199/微粉硅胶/乳糖/硬脂酸镁（质量比为1∶0.075∶1.5∶0.025）。研制的HD199胶囊溶出行为理想,工艺重现性佳,适于放大生产。     

C．I．直接蓝199工艺改进

对C．I．直接蓝199的老工艺进行了改进。使铜酞菁与氯磺酸的反应温度由原来的130℃升至140℃左右,之后与氯化亚砜的反应温度由60～65℃提高到80℃,而且滴加氯化亚砜的时间从2～2．5延长至4小时,同时氨解用的氨水用有机碱替代。新工艺解决了此染料用于墨水时在盐析前膜过滤困难的问题。     

水处理提高MOF-199催化苯羟基化反应性能

以一水合乙酸铜和均苯三酸为原料,采用常温搅拌法合成金属有机框架化合物MOF-199,用XRD、IR、BET对其表征.将MOF-199用水处理后作为催化剂用于苯羟基化反应,考察了催化剂的用量、反应温度、反应时间、双氧水添加量对催化反应的影响.较优反应条件为:MOF-199(140mg,0.23mmol)、乙腈4mL、苯1.1mL、H₂O₂3.3mL,在60℃的水浴中反应30min,所得苯的氧化物的产率为23.3%,苯酚的选择性为53.1%,转化频率(TOF值)为25.0h^-1.水处理显著提高了MOF-199的催化活性,并形成了一种新的氧化模式,在一定程度上保护了MOF-199的框架结构.     

Atrial Fibrillation in Heart Failure Is Associated with High Levels of Circulating microRNA-199a-5p and 22–5p and a Defective Regulation of Intracellular Calcium and Cell-to-Cell Communication

MicroRNAs (miRNAs) participate in atrial remodeling and atrial fibrillation (AF) promotion. We determined the circulating miRNA profile in patients with AF and heart failure with reduced ejection fraction (HFrEF), and its potential role in promoting the arrhythmia. In plasma of 98 patients with HFrEF (49 with AF and 49 in sinus rhythm, SR), differential miRNA expression was determined by high-throughput microarray analysis followed by replication of selected candidates. Validated miRNAs were determined in human atrial samples, and potential arrhythmogenic mechanisms studied in HL-1 cells. Circulating miR-199a-5p and miR-22-5p were significantly increased in HFrEF patients with AF versus those with HFrEF in SR. Both miRNAs, but particularly miR-199a-5p, were increased in atrial samples of patients with AF. Overexpression of both miRNAs in HL-1 cells resulted in decreased protein levels of L-type Ca²⁺ channel, NCX and connexin-40, leading to lower basal intracellular Ca²⁺ levels, fewer inward currents, a moderate reduction in Ca²⁺ buffering post-caffeine exposure, and a deficient cell-to-cell communication. In conclusion, circulating miR-199a-5p and miR-22-5p are higher in HFrEF patients with AF, with similar findings in human atrial samples of AF patients. Cells exposed to both miRNAs exhibited altered Ca²⁺ handling and defective cell-to-cell communication, both findings being potential arrhythmogenic mechanisms.     

Pyridazino-1,3a,6a-Triazapentalenes as Versatile Fluorescent Probes: Impact of Their Post-Functionalization and Application for Cellular Imaging

Pyridazino-1,3a,6a-triazapentalenes (PyTAP) are compact fused 6/5/5 tricyclic scaffolds which exhibit promising fluorescent properties. Chemically stable, they can be post-functionalized using standard Pd-catalyzed cross-coupling chemistry. Several original PyTAP bearing additional unsaturated substituents in positions 2 and 8 were synthetized and their spectroscopic properties analyzed. They have been successfully tested as fluorescent probes for cellular imaging.     

Tumor-Suppressive and Oncogenic Roles of microRNA-149-5p in Human Cancers

Malignant tumors are always a critical threat to human health, with complex pathogenesis, numerous causative factors, and poor prognosis. The features of cancers, such as gene mutations, epigenetic alterations, and the activation and inhibition of signaling pathways in the organism, play important roles in tumorigenesis and prognosis. MicroRNA (miRNA) enables the control of various molecular mechanisms and plays a variety of roles in human cancers, such as radiation sensitivity and tumor immunity, through the regulation of target genes. MiR-149-5p participates in the process and is closely related to lipogenesis, the migration of vascular endothelial cells, and the expression of stem-cell-related proteins. In recent years, its role in cancer has dramatically increased. In this review, we summarize the regular physiological roles of miRNAs, specifically miR-149-5p, in the organism and discuss the tumor-suppressive or oncogenic roles of miR-149-5p in different human cancers with respect to signaling pathways involved in regulation. Possible clinical applications of miR-149-5p in future targeted therapies and prognosis improvement in oncology are suggested.     

Lateral Flow Immunoassay Based on Time-Resolved Fluorescence Microspheres for Rapid and Quantitative Screening CA199 in Human Serum

Carbohydrate antigen 199 (CA199) is a serum biomarker which has certain value and significance in the diagnosis, prognosis, treatment, and postoperative monitoring of cancer. In this study, a lateral flow immunoassay based on europium (III) polystyrene time-resolved fluorescence microspheres (TRFM-based LFIA), integrated with a portable fluorescence reader, has been successfully establish for rapid and quantitative analysis of CA199 in human serum. Briefly, time-resolved fluorescence microspheres (TRFMs) were conjugated with antibody I (Ab1) against CA199 as detection probes, and antibody II (Ab2) was coated as capture element, and a “TRFMs-Ab1-CA199-Ab2” sandwich format would form when CA199 was detected by the TRFM-based LFIA. Under the optimal parameters, the detection limit of the TRFM-based LFIA for visible quantitation with the help of an ultraviolet light was 4.125 U/mL, which was four times lower than that of LFIA based on gold nanoparticles. Additionally, the fluorescence ratio is well linearly correlated with the CA199 concentration (0.00–66.0 U/mL) and logarithmic concentration (66.0–264.0 U/mL) for quantitative detection. Serum samples from 10 healthy people and 10 liver cancer patients were tested to confirm the performances of the point-of-care application of the TRFM-based LFIA, 20.0 U/mL of CA199 in human serum was defined as the threshold for distinguishing healthy people from liver cancer patients with an accuracy of about 60%. The establishment of TRFM-based LFIA will provide a sensitive, convenient, and efficient technical support for rapid screening of CA199 in cancer diagnosis and prognosis.     

Identification of miR-199a-5p,miR-214-3p and miR-99b-5p as Fibrosis-Specific Extracellular Biomarkers and Promoters of HSC Activation

Liver fibrosis is characterized by the accumulation of extracellular matrix (ECM) resulting in the formation of fibrous scars. In the clinic, liver biopsies are the standard diagnostic method despite the potential for clinical complications. miRNAs are single-stranded, non-coding RNAs that can be detected in tissues, body fluids and cultured cells. The regulation of many miRNAs has been linked to tissue damage, including liver fibrosis in patients, resulting in aberrant miRNA expression/release. Experimental evidence also suggests that miRNAs are regulated in a similar manner in vitro and could thus serve as translational in vitro–in vivo biomarkers. In this work, we set out to identify and characterize biomarkers for liver fibrosis that could be used in vitro and clinically for research and diagnostic purposes. We focused on miRNAs released from hepatic 3D cultures exposed to methotrexate (MTX), which causes fibrosis, and acetaminophen (APAP), an acute hepatotoxicant with no clinically relevant association to liver fibrosis. Using a 3D in vitro model, we corroborated compound-specific responses as we show MTX induced a fibrotic response, and APAP did not. Performing miRNA-seq of cell culture supernatants, we identified potential miRNA biomarkers (miR-199a-5p, miR-214-3p, niRNA-125a-5p and miR-99b-5p) that were associated with a fibrotic phenotype and not with hepatocellular damage alone. Moreover, transfection of HSC with miR-199a-5p led to decreased expression of caveolin-1 and increased α-SMA expression, suggesting its role in HSC activation. In conclusion, we propose that extracellular miR-214-3p, miR-99b-5p, miR-125a-5p and specifically miR-199a-5p could contribute towards a panel of miRNAs for identifying liver fibrosis and that miR-199a-5p, miR-214-3p and miR-99b-5p are promoters of HSC activation.     

The microRNA-202 as a Diagnostic Biomarker and a Potential Tumor Suppressor

MicroRNA-202 (miR-202) is a member of the highly conserved let-7 family that was discovered in Caenorhabditis elegans and recently reported to be involved in cell differentiation and tumor biology. In humans, miR-202 was initially identified in the testis where it was suggested to play a role in spermatogenesis. Subsequent research showed that miR-202 is one of the micro-RNAs that are dysregulated in different types of cancer. During the last decade, a large number of investigations has fortified a role for miR-202 in cancer. However, its functions can be double-edged, depending on context they may be tumor suppressive or oncogenic. In this review, we highlight miR-202 as a potential diagnostic biomarker and as a suppressor of tumorigenesis and metastasis in several types of tumors. We link miR-202 expression levels in tumor types to its involved upstream and downstream signaling molecules and highlight its potential roles in carcinogenesis. Three well-known upstream long non-coding-RNAs (lncRNAs); MALAT1, NORAD, and NEAT1 target miR-202 and inhibit its tumor suppressive function thus fueling cancer progression. Studies on the downstream targets of miR-202 revealed PTEN, AKT, and various oncogenes such as metadherin (MTDH), MYCN, Forkhead box protein R2 (FOXR2) and Kirsten rat sarcoma virus (KRAS). Interestingly, an upregulated level of miR-202 was shown by most of the studies that estimated its expression level in blood or serum of cancer patients, especially in breast cancer. Reduced expression levels of miR-202 in tumor tissues were found to be associated with progression of different types of cancer. It seems likely that miR-202 is embedded in a complex regulatory network related to the nature and the sensitivity of the tumor type and therapeutic (pre)treatments. Its variable roles in tumorigenesis are mediated in part thought its oncogene effectors. However, the currently available data suggest that the involved signaling pathways determine the anti- or pro-tumorigenic outcomes of miR-202’s dysregulation and its value as a diagnostic biomarker.     

Flexible graphite as a heating element

Flexible graphite is an effective heating element. It provides temperatures up to 980 °C (though burn-off occurs in air at 980 °C), response half-time down to 4 s, and heat output at 60 s up to 5600 J. The electrical energy for heating by 1 °C is 1-2 J in the initial portion of rapid temperature rise. The temperature and heat output increase with decreasing thickness and with increasing power.