MiR-203a-5p Inhibits Multiple Myeloma Cell Proliferation and Cell Cycle Progression via Targeting JAG1 / 中国实验血液学杂志

OBJECTIVE@#To investigate the biological function of miR-203a-5p and the underlying mechanism in multiple myeloma (MM).@*METHODS@#Three miRNA expression profiles (GSE16558, GSE24371 and GSE17498) were downloaded from the GEO database. The three miRNA expression profiles contained 131 MM samples and 17 normal plasmacyte samples. The robust rank aggregation (RRA) method was used to identify the differentially expressed miRNAs between MM and normal plasmacytes. In order to carry out cytological experiments, MM cell line with stable over-expression of miR-203a-5p was constructed with lentivirus. Expression levels of miR-203a-5p in MM cells were quantified by qRT-PCR. The effects of miR-203a-5p on MM cells were investigated using assays of cell viability and cell cycle. Cell proliferation was measured using the Cell Counting kit (CCK)8 assay. The percentage of cells in each cell cycle was measured with a FACSCalibur system. Xenograft tumor models were established to evaluate the role of miR-203a-5p in tumorigenesis in vivo . To elucidate the underlying molecular mechanisms of miR-203a-5p in mediating cell proliferation inhibition and cell cycle arrest in MM, we used TargetScan and miRanda to predict the candidate targets of miR-203a-5p. The potential target of miR-203a-5p in MM cells was explored using the luciferase reporter assay, qRT-PCR, and Western blot.@*RESULTS@#An integrated analysis of three MM miRNA expression datasets showed that the levels of miR-203a-5p in MM were notably downregulated compared with those in normal plasmacytes. Accordingly, the relative expression levels of miR-203a-5p were decreased in MM cell lines. In addition, overexpression of miR-203a-5p inhibited the proliferation and cell cycle progression of RPMI8226 and U266 cells. In vivo experiments demonstrated that upregulation of miR-203a-5p expression could significantly inhibit the tumorigenesis of subcutaneous myeloma xenografts in nude mice. Mechanistic investigation led to the identification of Jagged 1 (JAG1) as a novel and direct downstream target of miR-203a-5p. Interestingly, the reintroduction of JAG1 abrogated miR-203a-5p-induced MM cell growth inhibition and cell cycle arrest.@*CONCLUSION@#Our data demonstrate that miR-203a-5p inhibits cell proliferation and cell cycle progression in MM cells by targeting JAG1, supporting the utility of miR-203a-5p as a novel and potential therapeutic agent for miRNA-based MM therapy.

Radiation-induced Hierarchical Topologically Associated Domain Change and Its Role in Cellular Responses to Radiation / 中国生物化学与分子生物学报

The three-dimensional (3D) genome organization plays an important role in gene regulation. As a basic functional unit of the genome, topologically associated domain (TAD) regulates multiplebiological processes such as gene expression and DNA replication and plays a role in radiation-inducedDNA damage repair. Recent studies showed that TAD is not a completely independent domain butcontains hierarchical internal domains, which could be a new mechanism of gene regulation. To explorethe role of hierarchical TAD in cellular responses to radiation, we apply the OnTAD algorithm, anoptimized nested TAD caller from Hi-C data, to identify hierarchical TAD in 26 Hi-C data from Geneexpression omnibus (GEO) database. These data were from irradiated fibroblasts, lymphoblasts andfibroblasts deficient in the ataxia telangiectasia mutated (ATM) gene with 5 Gy X-ray. We observe thatX-ray can regularly affect the hierarchy of TAD in which high-level TAD is prone to change and low-levelTAD is more conservative. We propose that radiation-induced TAD hierarchy change can regulate cellularresponses to radiation by regulating gene expression, and ATM is a necessary factor for radiation-inducedTAD hierarchy change and recovery. This study provides new insights into the role of the 3D genome inradiation-induced cellular responses from the perspective of hierarchical TAD structures.

Gene coexpression network analysis reveals the role of SRS genes in senescence leaf of maize (Zea mays L.)

Shi-related sequence (SRS) proteins are plant-specific transcription factors that play important roles in developmental processes, including regulating hormone biosynthesis, response or signal transduction. However, systematical analysis of the SRS gene family in maize has not yet been conducted. In this study, 11 SRS genes with 13 transcripts were identified and characterized. The characteristics of the gene family were analysed in terms of phylogenetic relationships, chromosome distribution and gene structure. RNA-sequencing data analysis showed that the expression patterns of SRS genes were quite different from each other in maize, indicating their divergence in function. Interestingly, the GRMZM2G077752 gene is highly expressed in senescent leaves. Using further coexpression network analysis, we determined that the module containing GRMZM2G077752 were over-represented by genes related to abscisic acid (ABA) stimulus and carbohydrate metabolic process. This result indicated that GRMZM2G077752 might perceive ABA signal and cause the activation of carbohydrate remobilization during leaf ageing. This study provides valuable information for understanding the functions of the SRS genes in maize.

Research progress on epigallocatechin-3-gallate in the prevention and treatment of oral cancer / 口腔疾病防治

@#Epigallocatechin-3-gallate (EGCG) has antibacterial, anti-inflammatory, antitumor, and other functions. EGCG and its anticancer mechanism are hot research topics in the prevention and treatment of oral cancer. In this paper, the prevention and treatment effects of EGCG on oral cancer and its anticancer mechanism are reviewed. The results show that EGCG can regulate multiple cell metabolic signaling pathways, such as the G protein coupled receptor signaling pathway, mitogen-activated protein kinase (MAPK), and the Wnt signaling pathway, and it can regulate DNA methylation and act on RNA of oral cancer cells directly or indirectly through the oral cancer cell signal transduction network to inhibit the development of oral precancerous lesions and oral cancer. EGCG combined with 5-fluorouracil can enhance the curative effect and reduce adverse effects and is expected to be a new drug for the prevention and treatment of oral cancer.

The usage of comprehensive geriatric assessment in elderly patients with acute myeloid leukemia: a multicenter, prospective study / 中华血液学杂志

Objective: To evaluate the feasibility and potential value of comprehensive geriatric assessment (CGA) in elderly (≥60 years) patients with newly diagnosed acute myeloid leukemia (AML) in China. Methods: The CGA results of 83 newly diagnosed AML (non-APL) patients from 16 hospitals in Beijing and Tianjin between March 2016 and December 2017 were prospectively collected and analyzed. The clinical data, treatment and follow-up information were also collected. Results: Of 83 newly diagnosed elderly AML patients, 81 patients (97.6%) completed all designated CGA assessment. The median number of impaired scales of the CGA assessment in the studied population was 2(0-6). Sixteen patients (19.3%) showed no impairments according to the geriatric assessment scales implem ented by this study. The distributions of impaired scales were as follows: impairment in ADL, 55.4%; IADL impairment, 42.2%; MNA-SF impairment, 48.2%; cognitive impairment, 15.7%; GDS impairment, 31.7%; HCT-CI impairment, 19.5%, respectively. In patients with "good" ECOG (n=46), the proportion of impairment for each CGA scale ranged from 6.5% to 37.0% and 32 patients (68.9%) had at least one impaired CGA scale. Survival analysis showed that the number of impaired scales of the CGA was significantly correlated with median overall survival (P=0.050). Conclusions: CGA was a tool with feasibility for the comprehensive evaluation in elderly AML patients in China. Combined with age and ECOG, CGA may be more comprehensive in assessing patients' physical condition.

Investigation of Evolution Rules of Phlegm and Blood Stasis Syndrome in Hyperlipidemia and Ath- erosclerosis by NMR-based Metabolic Profiling and Metabonomic Approaches / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To explore evolution rules of phlegm and blood stasis syndrome ( PBSS) in hyperlipidemia and atherosclerosis (AS) using NMR-based metabolic profiling and metabonomic approaches based on formulas corresponding to syndrome.</p><p><b>METHODS</b>Totally 150 SD rats were divided into the normal group, the model group, the Erchen Decoction (ED) group, the Xuefu Zhuyu Decoction (XZD) group, the Lipitor group, 30 in each group. The hyperlipidemia and AS rat model was duplicated by suturing carotid artery, injecting vitamin D3, and feeding with high fat diet. ED and XZD were used as drug probes. Blood samples were withdrawn at week 2, 4, and 8 after modeling. Blood lipids, blood rheology, histopathology and metabolomics were detected and analyzed. Results Results of blood lipids and pathology showed hyperlipidemia and early AS rat models were successfully established. At week 2 after modeling, levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) significantly increased, which reached the peak at week 4 and maintained at higher levels at week 8. ED exerted obvious effect in improving TC and LDL-C levels of early models, while XZD could greatly improve levels of TC and LDL-C of late models. Rheological results showed at week 2, there was no significant difference in whole blood viscosity, plasma viscosity, or hematocrit between the model group and the normal group (P > 0.05). At week 4 partial hemorheological indicators (such as plasma viscosity) were abnormal. Till week 8 whole blood viscosity, plasma viscosity, and hematocrit were significantly abnormal (P <0. 05, P < 0.01). As time went by, whole blood viscosity, plasma viscosity, and hematocrit showed gradual increasing tendency in the ED group, while they showed gradual decreasing tendency in the XZD group. Results of metabonomics showed significant difference in spectra of metabolites between the normal group and the model group. As modeling time was prolonged, contents of acetyl glucoprotein and glucose in the model group increased in late stage, which was in. line with results of blood lipids and hemorheology. ED showed more obvious effect in early and mid-term modeling (at week 2 and 4), and increased contents of partial metabolites (such as choline, phosphatidyl choline, glycerophosphocholine), but these changes in the XZD group were consistent with those of the model group. In late modeling (at week 8) XZD showed more obvious effect in improving contents of lactic acid, acetyl glycoprotein, LDL, creatine, choline, and glucose.</p><p><b>CONCLUSIONS</b>ED and XZD not only showed regulatory effects on lipid disorders, but also could improve dysbolism of Chos. In formulas corresponding to syndrome, damp-phlegm was main pathogenesis of hyperlipidema and AS in early and mid stages. Blood stasis syndrome began to occur along with it progressed. Phlegm can result in blood stasis and intermingles with stasis. Phlegm turbidity runs through the whole process.</p>

Expression and clinical significance of PDCD5 in patients with acute myeloid leukemia / 中国实验血液学杂志

<p><b>OBJECTIVE</b>This study was aimed to investigate the roles of PDCD5 (programmed cell death 5) in pathogenesis of acute myeloid leukemia (AML) and the relevance of PDCD5 with the clinical characteristics and prognosis of patients by testing the PDCD5 expression in adult AML patients.</p><p><b>METHODS</b>The mRNA and intracellular protein levels of PDCD5 from 36 newly diagnosed AML patients were analyzed by real-time fluorescence quantitative polymerase chain reaction (RQ-PCR) and flow cytometry (FCM), respectively. The correlation of mRNA levels and intracellular protein levels of PDCD5 with the clinical characteristics and survival time of patients were analyzed.</p><p><b>RESULTS</b>The intracellular protein expression levels of PDCD5 in AML patients were significantly higher than those in normal controls (P < 0.05). The PDCD5 mRNA levels were not significantly different between patients and controls (P > 0.05). The mRNA and protein levels of PDCD5 did not significantly correlate with sex, age, WBC count, FAB subtype, extramedullary infiltration, WT1 gene, NPM1 gene mutation and the patients response to induction therapy. The patients with positive FLT3/ITD mutation displayed higher protein levels of PDCD5 as compared with negative FLT3/ITD mutation patients (P < 0.05).</p><p><b>CONCLUSION</b>The intracellular protein of PDCD5 significantly increased in AML patients. However, the increased PDCD5 does not exert the pro-apoptotic effects on AML cells. The patients with positive FLT3/ITD mutation show higher protein levels of PDCD5.</p>

Expression and clinical significance of B-cell lymphoma 2 (BCL-2) in hyperleukocytic acute myeloid leukemia / 中国实验血液学杂志

This study was aimed to investigate the role of B-cell lymphoma 2 (BCL-2) in pathogenesis of hyperleukocytic acute myeloid leukemia (AML). The levels of intracellular BCL-2 in 48 AML patients were detected by flow cytometry (FCM). Serum levels of BCL-2 in 40 AML patients were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that the serum levels of BCL-2 in hyperleukocytic AML and non-hyperleukocytic AML patients were significantly higher than that in normal controls (P < 0.05), but intracellular BCL-2 levels were not significantly different, as compared with normal controls (P > 0.05). There were no difference of intracellular and serum BCL-2 levels between hyperleukocytic and non-hyperleukocytic AML patients (P > 0.05). The serum and intracellular levels of BCL-2 between hyperleukocytic AML, non-hyperleukocytic AML patients and normal controls were not statistically correlated. It is concluded that leukemic cells in AML patients produce and secrete too much BCL-2, which may be involved in the pathogenesis of leukemia disease. However, the anti-apoptosis effect of BCL-2 has no significant impact on the pathogenesis of hyperleukocytic AML.

Metabonomic profile of urine from rats administrated with different treatment period of rifampin / 中国医学科学院学报

<p><b>OBJECTIVE</b>To study the effect of rifampin (RFP) on the metabonomic profile of rat urine and its relationship with traditional toxicity evaluation of blood biochemical indicators and histopathology.</p><p><b>METHODS</b>Thirty-six male Wistar rats were randomly divided into control group, 50 mg/kg RFP group, and 100 mg/kg RFP group, with 12 rats in each group. Rats in each group were given intragastric infusion with a daily dose of 0, 50 mg/kg RFP, and 100 mg/kg RFP for 3, 7, and 14 days, respectively. Then 4 rats in each group were killed on the next day of administration to collect blood samples and liver sample for the determination of blood biochemical indicators and for the pathological analysis of the liver. The urine specimens over 24 hours of each rat were collected before and after each treatment until the rat was killed. 1H nuclear magnetic resonance (1H NMR) spectra of these urine specimens were acquired and subjected to data preprocess and principal component analyses (PCA).</p><p><b>RESULTS</b>The level of serum total bilirubin of the rat administrated with 100 mg/(kg x d) RFP for 7 days was significantly higher than that of control group (P < 0.05). Mild hepatotoxicity to the rat, treated with RFP of higher dosage (100 mg/kg) and longer duration (14 days), was revealed by the traditional histopathological method. The metabonomic spectra of rat urine in different groups differed from each other; a trajectory bias in determination of rat urine by 1H NMR occurred depending on the administration duration. As demonstrated by 1H NMR spectra of urine in rats treated with RFP, the concentration of urinary citrate and 2-oxoglutarate decreased, along with the remarkable increase of the concentrations of urinary taurine and glucose (compared with those of the control group).</p><p><b>CONCLUSIONS</b>Being consistent with the results of traditional toxicity evaluation measurements, metabonomic method is more sensitive. The 1H-NMR metabonomic profile of the rat urine is closely related with the duration of RFP. The hepatic toxicity induced by RFP is related to the reduction of energy metabolism in tricarboxylic acid cycle and the perturbation of glucose and lipid metabolism.</p>

Metabonomic study of blood plasma in the assessment of liver graft function / 中国医学科学院学报

<p><b>OBJECTIVE</b>To access the capability of 1H nuclear magnetic resonance (NMR) -based metabonomics in the evaluation of graft function in the perioperation period of liver transplantation.</p><p><b>METHODS</b>Plasma samples of 15 male primary hepatic carcinoma patients were collected for clinical biochemical analysis and 1H NMR spectroscopy 1 day before operation, 1 day and 1 week after the operation. The NMR data were analyzed using principal component analysis.</p><p><b>RESULTS</b>Metabonomic analysis indicated that, compared with those before operation, blood concentrations of valine, alanine, acetone, succinic acid, glutamine, choline, lactate, and glucose increased significantly 1 day after transplantation. One week later, the levels of lipids and choline increased notably, while those of glucose and amino acids decreased. Principal component analysis showed significant difference between metabolic profiles of plasma samples of variant periods of liver transplantation, due to the variation of the levels of glucose, lipids, lactate, and choline. A good agreement was observed between clinical chemistry and metabonomic data.</p><p><b>CONCLUSIONS</b>Metabonomic analysis can clearly identify the difference between the plasma samples of primary hepatic carcinoma patients at different time during the perioperation period of liver transplantation. It therefore may be a promising new technology in predicting the outcomes of liver transplantation.</p>