Competing endogenous RNA (ceRNA) cross talk and language in ceRNA regulatory networks: A new look at hallmarks of breast cancer

Breast cancer (BC) is the most frequently occurring malignancy in women worldwide. Despite the substantial advancement in understanding the molecular mechanisms and management of BC, it remains the leading cause of cancer death in women. One of the main reasons for this obstacle is that we have not been able to find the Achilles heel for the BC as a highly heterogeneous disease. Accumulating evidence has revealed that noncoding RNAs (ncRNAs), play key roles in the development of BC; however, the involving of complex regulatory interactions between the different varieties of ncRNAs in the development of this cancer has been poorly understood. In the recent years, the newly discovered mechanism in the RNA world is “competing endogenous RNA (ceRNA)” which proposes regulatory dialogues between different RNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), transcribed pseudogenes, and circular RNAs (circRNAs). In the latest BC research, various studies have revealed that dysregulation of several ceRNA networks (ceRNETs) between these ncRNAs has fundamental roles in establishing the hallmarks of BC development. And it is thought that such a discovery could open a new window for a better understanding of the hidden aspects of breast tumors. Besides, it probably can provide new biomarkers and potential efficient therapeutic targets for BC. This review will discuss the existing body of knowledge regarding the key functions of ceRNETs and then highlights the emerging roles of some recently discovered ceRNETs in several hallmarks of BC. Moreover, we propose for the first time the “ceRnome” as a new term in the present article for RNA research.     

Effect of single nucleotide polymorphisms in SEPS1 and SEPP1 on expression in the protein level in metabolic syndrome in subjects with cardiovascular disease

Molecular Biology Reports - Metabolic syndrome (MetS) results from the interaction between environmental and genetic factors. Several previous studies considered the role of selenium in developing...     

Affinity maturation and characterization of the ofatumumab monoclonal antibody

CD20 molecule, a phosphoprotein with 297 amino acids and four transmembrane domains, is a member of MS4A protein family. Anti-CD20 antibodies such as ofatumumab, which have been developed for cancer treatment and has demonstrated efficacy in relapsed/refractory chronic lymphocytic leukemia, are among the most successful therapies to date. Rational engineering methods can be applied with reasonable success to improve functional characteristics of antibodies. Considering the importance of this issue, we have used in silico modeling approach for the improvement of ofatumumab monoclonal antibody. Four mutated variants of ofatumumab were developed and expressed in Chinese hamster ovary (CHO) cells along with the unmodified antibody. Analysis of affinity of the purified antibodies with CD20 showed significant improvement in antigen-binding characteristics of one of the variants compared with the control antibody. This study represents the first step toward development of the second generation ofatumumab antibody with improved affinity.     

Suppressive effect of exogenous miR-16 and miR-34a on tumorigenesis of breast cancer cells

Recent investigations have shown tumor-suppressive roles for miR-16 and miR-34a. They also share some features in regard to targeting cancer cell signaling pathways which they control. Therefore, in this study, we aimed to further scrutinize whether exogenous induction of mature miR-34a and miR-16 can collaborate in breast tumor suppression. MDA-MB-231 and SK-BR-3 human breast cancer cell lines were cultured and transfected twice with hsa-miR-16-5p and hsa-miR-34a-5p mimics individually or in combination. The cells were analyzed for apoptosis rate and cell cycle indices by flow cytometry. Also, the expression of several invasion and the epithelial-mesenchymal transition markers was evaluated at gene and protein levels by quantitative real-time polymerase chain reaction and western blot analysis, respectively. Assessment of invasiveness and migratory potential of the transfected cells was performed using three-dimensional spheroid formation and wound-healing assay, respectively. In both cell lines, miR-16 and miR-34a induced apoptosis and cell-cycle arrest and also suppressed invasion and migration. Some of these effects, like cell-cycle arrest and induction of apoptosis, were significantly higher when using both microRNAs than when using them individually for transfection of the cells. Our results are indicating that miR-16 and miR-34a can collaborate in breast tumor suppression.     

Curcumin ameliorated myocardial infarction by inhibition of cardiotoxicity in the rat model

Cardiovascular diseases are the main cause of death globally. Many attempts have been done to ameliorate the pathological changes after the occurrence of myocardial infarction. Curcumin is touted as a polyphenol phytocompound with appropriate cardioprotective properties. In this study, the therapeutic effect of curcumin was investigated on acute myocardial infarction in the model of rats. Rats were classified into four groups; control, isoproterenol hydrochloride (ISO) (100 mg/kbw), curcumin (50 mg/kbw), and curcumin plus ISO treatment groups. After 9-day administration of curcumin, levels of lactate dehydrogenase (LDH), creatine kinase (CK), and cardiac troponin I (cTnI) were determined. Superoxide dismutase (SOD) and malondialdehyde (MDA) contents were measured to investigate the oxidative status in infarct rats received curcumin. By using H & E staining, tissue inflammation was performed. Masson’s trichrome staining was conducted to show cardiac remodeling and collagen deposition. The number of apoptotic cells was determined by using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Data showed the serum decrease of LDH, CK, and cTnI in infarct rats after curcumin intake compared to the rats given (ISO) ( P < 0.05). Curcumin was found to reduce oxidative status by reducing SOD and MDA contents ( P < 0.05). Gross and microscopic examinations revealed that the decrease of infarct area, inflammation response and collagen deposition in rats given ISO plus curcumin ( P < 0.05). We noted the superior effect of curcumin to reduce the number of apoptotic cardiomyocytes after 9 days. Data point the cardioprotective effect of curcumin to diminish the complication of infarction by the reduction of cell necrosis and apoptosis in a rat model of experimental infarction.     

The Role of a Novel TRMT1 Gene Mutation and Rare GRM1 Gene Defect in Intellectual Disability in Two Azeri Families

Cognitive impairment or intellectual disability (ID) is a widespread neurodevelopmental disorder characterized by low IQ (below 70). ID is genetically heterogeneous and is estimated to affect 1–3% of the world’s population. In affected children from consanguineous families, autosomal recessive inheritance is common, and identifying the underlying genetic cause is an important issue in clinical genetics. In the framework of a larger project, aimed at identifying candidate genes for autosomal recessive intellectual disorder (ARID), we recently carried out single nucleotide polymorphism-based genome-wide linkage analysis in several families from Ardabil province in Iran. The identification of homozygosity-by-descent loci in these families, in combination with whole exome sequencing, led us to identify possible causative homozygous changes in two families. In the first family, a missense variant was found in GRM1 gene, while in the second family, a frameshift alteration was identified in TRMT1, both of which were found to co-segregate with the disease. GRM1, a known causal gene for autosomal recessive spinocerebellar ataxia (SCAR13, MIM#614831), encodes the metabotropic glutamate receptor1 (mGluR1). This gene plays an important role in synaptic plasticity and cerebellar development. Conversely, the TRMT1 gene encodes a tRNA methyltransferase that dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl methionine as the methyl group donor. We recently presented TRMT1 as a candidate gene for ARID in a consanguineous Iranian family (Najmabadi et al., 2011). We believe that this second Iranian family with a biallelic loss-of-function mutation in TRMT1 gene supports the idea that this gene likely has function in development of the disorder.     

A Molecular Comparison of Plumage and Soil Bacteria Across Biogeographic,Ecological, and Taxonomic Scales

We used molecular methods to determine the microbial community of soil and avian plumage across biogeographic, ecological, and taxonomic scales. A total of 17 soil and 116 feather samples were collected from five avian species across multiple habitat types within one Neotropical and one temperate locality. Hypotheses regarding patterns of microbial composition relative to acquisition and dispersal of plumage bacteria in the ecosystem were tested by comparing microbial communities within and between soil and plumage. Samples from the plumage of American Redstarts (Setophaga ruticilla) were collected across both habitat types and geographic scales for intraspecific comparisons. The microbial diversity in avian plumage was moderately diverse and was dominated by Pseudomonas species. Despite a highly significant individual bird effect on microbial composition of the plumage, we detected significant biogeographic and type of habitat effects. Pseudomonas species were more abundant on the temperate site when all avian species were included in the analysis, and Bacillus subtilis and Xanthomonas groups were more abundant on the Neotropical site for redstarts alone. However, 16S rDNA sequence libraries were not significantly different between Jamaican and Maryland redstarts. Biogeographic and habitat effects were significant and more pronounced for soil samples indicating lower dispersal of soil microbiota. We detected a significant difference between soil and plumage microbial communities suggesting that soil plays a small role in plumage bacterial acquisition. Our results suggest bacterial communities on the plumage of birds are dynamic and may change at different stages in a bird’s annual cycle.     

Interaction of an Fe derivative of TMAP (Fe(TMAP)OAc) with DNA in comparison with free-base TMAP

We investigated the interaction of meso-tetrakis (N-para-methylanilium) porphyrin (TMAP) in its free base and Fe(II) form (Fe(TMAP)OAc) as a new derivative, with high molecular weight DNA at different ionic strengths, using various spectroscopic methods and microcalorimetry. The data obtained by spectrophotometery, circular dichroism (CD), fluorescence quenching and resonance light scattering (RLS) have demonstrated that TMAP association with DNA is via outside binding with self-stacking manner, which is accompanied with the "end-on" type complex formation in low ionic strength. However, in the case of Fe(TMAP)OAc, predominant mode of interaction is groove binding and after increasing in DNA concentration, unstable stacking-type aggregates are formed. In addition, isothermal titration calorimetric measurements have indicated the exothermic process of porphyrins binding to DNA, but the exothermisity in metal derivative of porphyrin is less than the free base. It confirmed the formation of a more organized aggregate of TMAP on DNA surface. Interactions of both porphyrins with DNA show high sensitivity to ionic strength. By addition of salt, the downfield CD signal of TMAP aggregates is shifted to a higher wavelength, which indicates some changes in the aggregates position. In the case of Fe(TMAP)OAc, addition of salt leads to changes in the mode of binding from groove binding to outside binding with self-stacking, which is accompanied with major changes in CD spectra, possibly indicating the formation of "face-on" type complex.     

A kinetic spectrophotometric method for simultaneous determination of glycine and lysine by artificial neural networks

A spectrophotometric method for simultaneous analysis of glycine and lysine is proposed by application of neural networks on the spectral kinetic data. The method is based on the reaction of glycine and lysine with 1,2-naphthoquinone-4-sulfonate (NQS) in slightly basic medium. On the basis of the difference in the rate between the two reactions, these two amino acids can be determined simultaneously in binary mixtures. Feed-forward neural networks have been trained to quantify considered amino acids in mixtures under optimum conditions. In this way, a one-layer network was trained. Sigmoidal and linear transfer functions were used in the hidden and output layers, respectively. Linear calibration graphs were obtained in the concentration range of 1 to 25microgml(-1) for glycine and 1 to 19microgml(-1) for lysine. The analytical performance of this method was characterized by the relative standard error. The proposed method was applied to the determination of considered amino acids in synthetic samples.     

Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci

Autosomal recessive gene defects are arguably the most important, but least studied genetic causes of severe cognitive dysfunction. Homozygosity mapping in 78 consanguineous Iranian families with nonsyndromic autosomal recessive mental retardation (NS-ARMR) has enabled us to determine the chromosomal localization of at least 8 novel gene loci for this condition. Our data suggest that in the Iranian population NS-ARMR is very heterogeneous, and they argue against the existence of frequent gene defects that account for more than a few percent of the cases. Mohammad Mahdi Motazacker and Masoud Garshasbi have contributed equally to this work.