MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

Purpose The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) –related bone disease. Methodology An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. Recommendations Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability. J Clin Oncol 31:2347-2357. © 2013 by American Society of Clinical Oncology

International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease

Brucine, a weak alkaline indole alkaloid, is one of the main bioactive and toxic constituents of Nux-vomica. Modern pharmacology studies and clinical practice demonstrate that brucine possesses wide pharmacological activities, such as anti-tumor, anti-inflammatory, analgesic, and the effects on cardiovascular system and nervous system, etc. However, its central nervous system toxicity severely limits its clinical application. Herein, the physicochemical properties, pharmacological activities, and toxicity of brucine were reviewed, and the novel strategies to address the toxicity issues were discussed, aiming to bring new insights into further research and application of this active component.

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Brucine: A Review of Phytochemistry, Pharmacology, and Toxicology.

Lung cancer is the leading cause of cancer-associated mortality worldwide. MicroRNAs (miRNAs/miRs) serve a role in the occurrence and development of lung cancer. The aim of the present study was to analyze the expression and function of the proliferation-associated miR-383-5p in lung adenocarcinoma (LAC). Samples of human LAC and matched adjacent normal lung tissues were surgically removed, and miR-383-5p expression and the pathological characteristics of lung adenocarcinoma were investigated. The present study revealed that miR-383-5p expression level was significantly decreased in LAC tissues and its expression levels were markedly associated with tumor size and differentiation. Overexpression of miR-383-5p in A549 and H1299 LAC cell lines inhibited cell proliferation by G1 cell cycle phase arrest and induction of apoptosis. Cancerous inhibitor of protein phosphatase 2A (CIP2A), a potential target gene of miR-383-5p, was inversely associated with miR-383-5p expression level in LAC tissues and cell lines. Furthermore, the results of the present study demonstrated that CIP2A was directly regulated by miR-383-5p and the restoration of CIP2A expression reversed the inhibitory effects of miR-383-5p on LAC cell proliferation. In conclusion, the results of the present study demonstrated that miR-383-5p was downregulated in LAC tissues. By targeting CIP2A, miR-383-5p exerts its anti-proliferative function in LAC, suggesting its use a potential novel potential prognostic biomarker and therapeutic target for LAC.

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MicroRNA-383-5p acts as a prognostic marker and inhibitor of cell proliferation in lung adenocarcinoma by cancerous inhibitor of protein phosphatase 2A.

Inducing apoptosis is an interesting therapeutic approach to develop drugs that act against helminthic parasites. Researchers have investigated how curcumin (CUR), a biologically active compound extracted from rhizomes of Curcuma longa, affects Schistosoma mansoni and several cancer cell lines. This study evaluates how CUR influences the induction of apoptosis and oxidative stress in couples of adult S. mansoni worms. CUR decreased the viability of adult worms and killed them. The tegument of the parasite suffered morphological changes, the mitochondria underwent alterations, and chromatin condensed. Different apoptotic parameters were determined in an attempt to understand how CUR affected adult S. mansoni worms. CUR induced DNA damage and fragmentation and increased the expression of SmCASP3/7 transcripts and the activity of Caspase 3 in female and male worms. However, CUR did not intensify the activity of Caspase 8 in female or male worms. Evaluation of the superoxide anion and different antioxidant enzymes helped to explore the mechanism of parasite death further. The level of superoxide anion and the activity of Superoxide Dismutase (SOD) increased, whereas the activity of Glutathione-S-Transferase (GST), Glutathione reductase (GR), and Glutathione peroxidase (GPX) decreased, which culminated in the oxidation of proteins in adult female and male worms incubated with CUR. In conclusion, CUR generated oxidative stress followed by apoptotic-like-events in both adult female and male S. mansoni worms, ultimately killing them.

https://run.unl.pt/bitstream/10362/36630/1/Curcumin_generates_oxidative_stress_and_induces_apoptosis_in_adult_schistosoma_mansoni_worms.pdf

Curcumin Generates Oxidative Stress and Induces Apoptosis in Adult Schistosoma mansoni Worms.

The aim of this study was to investigate the mechanism of the apoptotic effect of brucine on human multiple myeloma (MM) cells. U266 cells (5x104) were plated in the presence or absence of brucine (0, 0.05, 0.1, 0.2 and 0.4 mg/ml) in 96‑well culture plates for 24‑72 h. The anti-proliferative response to brucine was assessed by MTT assay. Analysis of the cell cycle of U266 cells treated with or without brucine was performed using flow cytometry. The expression change of c-Jun following treatment with brucine or brucine plus the c-Jun N-terminal kinase (JNK)-specific inhibitor SP600125 was detected using RT-PCR. Brucine appeared to have an effect on apoptosis in a dose- and time‑dependent manner. Cell cycle analysis using flow cytometry revealed the accumulation of cells at the sub-G0/G1 phase. The apoptotic rates were 4.137, 10.55, 12.31, 27.67 and 29.67% (0, 0.05, 0.1, 0.2, 0.4 mg/ml brucine, respectively; P<0.01). The gray scale values were 0.7961 ± 0.007 and 0.4683 ± 0.003 (mRNA expression of c-Jun of U266 cells with or without SP600125, respectively). Concentrations of ≤ 0.4 mg/ml brucine induced apoptosis in U266 cells. Thus, brucine‑induced apoptosis in U266 cells occurs via the JNK signaling pathway and phosphorylation of c-Jun.

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Brucine induces the apoptosis of U266 multiple myeloma cells by phosphorylation of c-Jun.

This study investigated the cytotoxic effect of uvangoletin on HL-60 cells, and the effects of uvangoletin on myelosuppression, leucopenia, gastrointestinal tract disturbances and the possible cytotoxic mechanisms by using CCK-8, flow cytometry, western blot, xenograft, cyclophosphamide-induced leucopenia, copper sulfate-induced emesis and ethanol-induced gastric mucosal lesions assays. The results of CCK-8, flow cytometry and western blot assays indicated that uvangoletin showed the cytotoxic effect on HL-60 cells and induced the apoptosis of HL-60 cells by downregulating the expression levels of anti-apoptotic proteins (Survivin, Bcl-xl and Bcl-2), upregulating the expression levels of pro-apoptotic proteins (Smac, Bax, Bad, c-caspase-3 and c-caspase-9), and promoting the release of cytochrome c from mitochondria to cytoplasm. Further, the results of xenograft assay suggested that uvangoletin inhibited the HL-60-induced tumor growth without adverse effect on body weight of nude mice in vivo by regulating the expression levels of above apoptotic proteins. The results indicated that the reductions of WBCs count and thighbone marrow granulocytes percentage in cyclophosphamide-induced leucopenia assay, the incubation period and number of emesis in copper sulfate-induced emesis assay and the gastric mucosal lesions in ethanol-induced gastric mucosal lesions assay were not exacerbated or reversed by uvangoletin. In conclusion, the research preliminarily indicated that uvangoletin induced apoptosis of HL-60 cells in vitro and in vivo without adverse reactions of myelosuppression, leucopenia and gastrointestinal tract disturbances, and the pro-apoptotic mechanisms may be related to mitochondria-mediated apoptotic pathway.

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Uvangoletin induces mitochondria-mediated apoptosis in HL-60 cells in vitro and in vivo without adverse reactions of myelosuppression, leucopenia and gastrointestinal tract disturbances

Multiple myeloma (MM) is one of the most common causes of mortality from hematological malignancy in China. Recent studies have demonstrated that cancerous inhibitor of protein phosphatase 2A (CIP2A) may exhibit a role in promoting the growth of cancer; however, the function of CIP2A in MM remains unknown. In the present study, the expression and molecular mechanism underlying the effects of CIP2A in patients with MM and in MM cell lines were elucidated. Firstly, the expression of CIP2A was detected in patients with MM and in MM cell lines by reverse transcription‑quantitative polymerase chain reaction. Furthermore, silencing of CIP2A with short hairpin RNA was performed in MM cells, and the impact on the proliferation and apoptosis of RPMI‑8226 cells was analyzed (as endogenous CIP2A is highly expressed in RPMI‑8226 cell lines compared with other cells). CIP2A was significantly elevated in patients with MM and in MM cell lines, and silencing of CIP2A could inhibit the proliferation ability of RPMI‑8226 cells in vitro. In addition, CIP2A knockdown induced apoptosis and led to substantial reduction of c‑Myc protein levels in MM cell lines. This study suggested that CIP2A inhibition may provide a promising therapeutic strategy for patients with MM.

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CIP2A regulates proliferation and apoptosis of multiple myeloma cells

MicroRNAs play important roles in the initiation and progression of acute myeloid leukemia (AML). This study aimed to detect serum miR-203 expression levels in AML and explore its potential clinical significance. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to measure the serum miR-203 levels in 134 patients with AML and 70 healthy controls. The results demonstrated that serum miR-203 expression was significantly reduced in AML patients compared with healthy controls. Receiver operating characteristic curve (ROC) analysis revealed miR-203 could distinguish AML cases from normal controls. Low serum miR-203 levels were associated with worse clinical features, as well as poorer overall survival and relapse free survival of AML patients. Moreover, multivariate analysis confirmed low serum miR-203 expression to be an independent unfavorable prognostic predictor for AML. The bioinformatics analysis showed that the downstream genes and pathways of miR-203 was closely associated with tumorigenesis. Downregulation of miR-203 in AML cell lines upregulated the expression levels of oncogenic promoters such as CREB1, SRC and HDAC1. Thus, these findings demonstrated that serum miR-203 might be a promising biomarker for the diagnosis and prognosis of AML.

Diagnostic and prognostic significance of serum miR-203 in patients with acute myeloid leukemia.

Myelodysplastic syndrome (MDS) is characterized by clonal hematopoiesis and impaired differentiation, and may develop to acute myeloid leukemia (AML). We explored the mechanism of histone methyltransferase EZH2/EHMT2 during the transformation of MDS into AML. Expression of EZH2/EHMT2 in patients and NHD13 mice was detected. EZH2 and EHMT2 were silenced or overexpressed in SKM-1 cells. The cell proliferation and cycle were evaluated. Levels of DLX5, H3K27me3, and H3K9me2 in SKM-1 cells were detected. Binding of DLX5 promoter region to H3K27me3 and H3K9me2 was examined. Levels of H3K27me3/H3K9me2 were decreased by EZH2/EHMT2 inhibitor (EPZ-6438/BIX-01294), and changes of DLX5 expression and cell proliferation were observed. EZH2 was poorly expressed in MDS patients but highly expressed in MDS-AML patients. EHMT2 was promoted in both MDS and MDS-AML patients. EZH2 expression was reduced and EHMT2 expression was promoted in NHD13 mice. NHD13 mice with overexpressing EZH2 or EHMT2 transformed into AML more quickly. Intervention of EZH2 or EHMT2 inhibited SKM-1 cell proliferation and promoted DLX5 expression. When silencing EZH1 and EZH2 in SKM-1 cells, the H3K27me3 level was decreased. EZH2 silencing repressed the proliferation of SKM-1 cells. Transcription level of DLX5 in SKM-1 cells was inhibited by H3K27me3 and H3K9me2. Enhanced DLX5 repressed SKM-1 cell proliferation. In conclusion, EZH2/EHMT2 catalyzed H3K27me3/H3K9me2 to inhibit the transcription of DLX5, thus promoting the transformation from MDS to AML.

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EZH2/EHMT2 Histone Methyltransferases Inhibit the Transcription of DLX5 and Promote the Transformation of Myelodysplastic Syndrome to Acute Myeloid Leukemia

Yanping Ma

Papers

Brucine induces the apoptosis of U266 multiple myeloma cells by phosphorylation of c-Jun.

Uvangoletin induces mitochondria-mediated apoptosis in HL-60 cells in vitro and in vivo without adverse reactions of myelosuppression, leucopenia and gastrointestinal tract disturbances

CIP2A regulates proliferation and apoptosis of multiple myeloma cells

Diagnostic and prognostic significance of serum miR-203 in patients with acute myeloid leukemia.

EZH2/EHMT2 Histone Methyltransferases Inhibit the Transcription of DLX5 and Promote the Transformation of Myelodysplastic Syndrome to Acute Myeloid Leukemia