2q35-rs13387042 variant and the risk of breast cancer: a case–control study

Molecular Biology Reports - Breast Cancer is the most frequent neoplasm diagnosed among women worldwide. Genetic background and lifestyle/environment play a significant role in the disease...     

Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain

Ubiquitin ligases play a pivotal role in substrate recognition and ubiquitin transfer, yet little is known about the regulation of their catalytic activity. Nedd4 (neural-precursor-cell-expressed, developmentally down-regulated 4)-2 is an E3 ubiquitin ligase composed of a C2 domain, four WW domains (protein-protein interaction domains containing two conserved tryptophan residues) that bind PY motifs (L/PPXY) and a ubiquitin ligase HECT (homologous with E6-associated protein C-terminus) domain. In the present paper we show that the WW domains of Nedd4-2 bind (weakly) to a PY motif (LPXY) located within its own HECT domain and inhibit auto-ubiquitination. Pulse-chase experiments demonstrated that mutation of the HECT PY-motif decreases the stability of Nedd4-2, suggesting that it is involved in stabilization of this E3 ligase. Interestingly, the HECT PY-motif mutation does not affect ubiquitination or down-regulation of a known Nedd4-2 substrate, ENaC (epithelial sodium channel). ENaC ubiquitination, in turn, appears to promote Nedd4-2 self-ubiquitination. These results support a model in which the inter- or intra-molecular WW-domain-HECT PY-motif interaction stabilizes Nedd4-2 by preventing self-ubiquitination. Substrate binding disrupts this interaction, allowing self-ubiquitination of Nedd4-2 and subsequent degradation, resulting in down-regulation of Nedd4-2 once it has ubiquitinated its target. These findings also point to a novel mechanism employed by a ubiquitin ligase to regulate itself differentially compared with substrate ubiquitination and stability.     

Combined anticancer effects of simvastatin and arsenic trioxide on prostate cancer cell lines via downregulation of the VEGF and OPN isoforms genes

Arsenic trioxide (ATO) and statins have been demonstrated to have anti‐neoplastic properties; however, the data regarding their combination therapy is limited. Thus, we aimed to study the effects of ATO, Simvastatin and their combination in proliferation, apoptosis and pathological angiogenesis in prostate cancer cell lines. The human prostate cell lines were treated with different concentrations of Simvastatin and ATO alone and combined to find effective doses and IC50 values. In addition, the percentage of apoptotic cells was evaluated by annexin/PI staining, and mRNA expression levels of the apoptotic gene, including OPN isoforms and VEGF, were investigated using real‐time PCR. Our data displayed that Simvastatin (12 and 8 μM in PC3 and LNCaP cell lines respectively), ATO (8 and 5 μM in PC3 and LNCaP cell lines respectively), and also their combination (12 μM Simvastatin and 8 μM ATO in PC3, 8 μM Simvastatin and 5 μM ATO in LNCaP cell lines respectively) significantly increased the percentage of apoptotic cells. Also, we showed that the combination therapy by Simvastatin and ATO increased cell apoptosis and inhibited cell proliferation, providing anti‐proliferative and anti‐angiogenic properties, possibly via downregulation of the expression of VEGF and OPN genes. These results provide new perceptions regarding the anticancer roles of ATO and statins’ combination therapy in prostate cancer.     

Inhibitory effect of methanol extract of Rosa damascena Mill. flowers on α-glucosidase activity and postprandial hyperglycemia in normal and diabetic rats

The effect of a methanol extract of Rosa damascena Mill. flowers was studied, in comparison to the α-glucosidase inhibitor acarbose, in normal and diabetic rats. The inhibition mode of this extract was examined by measuring enzyme activity in different concentrations of substrate for Lineweaver–Burk plot analysis. The results show that Rosa damascena extract has an intensive inhibitory effect on α-glucosidase. Its inhibition was found to be noncompetitive. Oral administration of this plant extract (100 to 1000 mg/kg body wt.) significantly decreased blood glucose after maltose loading in normal and diabetic rats in a dose-dependent manner. These results suggest that Rosa damascena might exert an anti-diabetic effect by suppressing carbohydrate absorption from the intestine and can reduce the postprandial glucose level.     

Angiogenic activity of mitochondria; beyond the sole bioenergetic organelle

Angiogenesis is a complex process that involves the expansion of the pre-existing vascular plexus to enhance oxygen and nutrient delivery and is stimulated by various factors, including hypoxia. Since the process of angiogenesis requires a lot of energy, mitochondria play an important role in regulating and promoting this phenomenon. Besides their roles as an oxidative metabolism base, mitochondria are potential bioenergetics organelles to maintain cellular homeostasis via sensing alteration in oxygen levels. Under hypoxic conditions, mitochondria can regulate angiogenesis through different factors. It has been indicated that unidirectional and bidirectional exchange of mitochondria or their related byproducts between the cells is orchestrated via different intercellular mechanisms such as tunneling nanotubes, extracellular vesicles, and gap junctions to maintain the cell homeostasis. Even though, the transfer of mitochondria is one possible mechanism by which cells can promote and regulate the process of angiogenesis under reperfusion/ischemia injury. Despite the existence of a close relationship between mitochondrial donation and angiogenic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible role of mitochondria concerning angiogenesis, especially the role of mitochondrial transport and the possible relation of this transfer with autophagy, the housekeeping phenomenon of cells, and angiogenesis.     

Non-Communicable Disease Risk Factors among Employees and Their Families of a Saudi University: An Epidemiological Study

ObjectivesTo assess the prevalence of noncommunicable disease (NCD) risk factors among Saudi university employees and their families; to estimate the cardiovascular risk (CVR) amongst the study population in the following 10years.MethodsThe NCD risk factors prevalence was estimated using a cross-sectional approach for a sample of employees and their families aged ≥ 18 years old, in a Saudi university (Riyadh in Kingdom of Saudi Arabia; KSA). WHO STEPwise standardized tools were used to estimate NCD risk factors and the Framingham Coronary Heart Risk Score calculator was used to calculate the CVR.ResultsFive thousand and two hundred subjects were invited, of whom 4,500 participated in the study, providing a response rate of 87%. The mean age of participants was 39.3±13.4 years. The majority of participants reported low fruit/vegetables consumption (88%), and physically inactive (77%). More than two thirds of the cohort was found to be either overweight or obese (72%), where 36% were obese, and 59% had abdominal obesity. Of the total cohort, 22–37% were found to suffer from dyslipidaemia, 22% either diabetes or hypertension, with rather low reported current tobacco use (12%). One quarter of participants was estimated to have >10% risk to develop cardiovascular disease within the following 10-years.ConclusionThe prevalence of NCD risk factors was found to be substantially high among the university employees and their families in this study.     

Design and synthesis of new fused carbazole-imidazole derivatives as anti-diabetic agents: In vitro α-glucosidase inhibition,kinetic, and in silico studies

Twenty three fused carbazole–imidazoles 6a–w were designed, synthesized, and screened as new α-glucosidase inhibitors. All the synthesized fused carbazole-imidazoles 6a-w were found to be more active than acarbose (IC₅₀?=?750.0?±?1.5?µM) against yeast α-glucosidase with IC₅₀ values in the range of 74.0?±?0.7–298.3?±?0.9?µM. Kinetic study of the most potent compound 6v demonstrated that this compound is a competitive inhibitor for α-glucosidase (K_i value?=?75?µM). Furthermore, the in silico studies of the most potent compounds 6v and 6o confirmed that these compounds interacted with the key residues in the active site of α-glucosidase.     

Diversity and Antimicrobial Activity of Actinomycetes Isolated from Lut Desert: The Extremely Arid Climatic Zones of Iran

Lut desert is situated in one of the extremely arid climatic zones of Iran and is one of the hottest deserts in our plant with the extreme fluctuation of temperature over a day. The main objective of this study is to characterize the diversity of the culturable actinomycetes and preliminary evaluation of their extracts as antimicrobial components on drug resistant pathogens. Twenty-four soil samples were collected, successively diluted and inoculated into the different culture media to support the growth of most culturable bacteria including actinomycetes. Phenotypic and molecular methods were used for accurate identification of recovered isolates particularly actinomycetes at the genus and species levels. The isolates were also evaluated for their inhibitory activities against drug resistant Acinetobacter baumannii, Enterococcus faecium, Klebsiella pneumoniae and Staphylococcus aureus. A total of 56 isolates recovered from the samples. Based on phenotypic tests, 41 isolates were identified as actinomycetes, amongst them 8 isolates were active against drug resistant pathogens. Our study revealed Lut desert, as one of the hottest deserts in the world, is the habitat to diverse taxa of bacteria particularly actinomycetes which have potential novel antimicrobial components.

     

Decellularized amniotic membrane Scaffolds improve differentiation of iPSCs to functional hepatocyte-like cells

Human-induced pluripotent stem cells-derived hepatocyte-like cells (hiPSCs-HLCs) holds considerable promise for future clinical personalized therapy of liver disease. However, the low engraftment of these cells in the damaged liver microenvironment is still an obstacle for potential application. In this study, we explored the effectiveness of decellularized amniotic membrane (dAM) matrices for culturing of iPSCs and promoting their differentiation into HLCs. The DNA content assay and histological evaluation indicated that cellular and nuclear residues were efficiently eliminated and the AM extracellular matrix component was maintained during decelluarization. DAM matrices were developed as three-dimensional scaffolds and hiPSCs were seeded into these scaffolds in defined induction media. In dAM scaffolds, hiPSCs-HLCs gradually took a typical shape of hepatocytes (polygonal morphology). HiPSCs-HLCs that were cultured into dAM scaffolds showed a higher level of hepatic markers than those cultured in tissue culture plates (TCPs). Moreover, functional activities in term of albumin and urea synthesis and CYP3A activity were significantly higher in dAM scaffolds than TCPs over the same differentiation period. Thus, based on our results, dAM scaffold might have a considerable potential in liver tissue engineering, because it can improve hepatic differentiation of hiPSCs which exhibited higher level of the hepatic marker and more stable metabolic functions.