Action of HMGB1 on miR221/222 cluster in neuroblastoma cell lines

microRNA (miR/miRNA) are small non-coding RNAs that control gene expression at the post-transcriptional level by targeting mRNAs. Aberrant expression of miRNAs is often observed in different types of cancer. Specific miRNAs function as tumor suppressors or oncogenes and interfere with various aspects of carcinogenesis, including differentiation, proliferation and invasion. Upregulation of miRNAs 221 and 222 has been shown to induce a malignant phenotype in numerous human cancers via inhibition of phosphatase and tensin homolog (PTEN) expression. Neuroblastoma is the most common extracranial solid malignancy in children, which is characterized by cellular heterogeneity that corresponds to different clinical outcomes. The different cellular phenotypes are associated with different gene mutations and miRs that control genetic and epigenetic factors. For this reason miRs are considered a potential therapeutic target in neuroblastoma. The aim of the present study was to investigate the mechanisms by which extracellular high mobility group box 1 (HMGB1) promotes cell growth in neuroblastoma. SK-N-BE(2) and SH-SY5Y neuroblastoma derived cell lines were transfected with the antisense oligonucleotides, anti-miR-221 and -222, followed by treatment with HMGB1 to investigate the expression of the oncosuppressor PTEN. In this study, it was demonstrated that HMGB1, which is released by damaged cells and tumor cells, upregulates miR-221/222 oncogenic clusters in the two human neuroblastoma derived cell lines. The results revealed that the oncogenic cluster miRs 221/222 were more highly expressed by the most undifferentiated cell line [SK-N-BE(2)] compared with the the less tumorigenic cell line (SH-SY5Y) and that exogenous HMGB1 increases this expression. In addition, HMGB1 modulates PTEN expression via miR-221/222, as demonstrated by transiently blocking miR-221/222 with anti-sense oligonucleotides. These results may lead to the development of novel therapeutic strategies for neuroblastoma

Could gestational diabetes mellitus be managed through dietary bioactive compounds? Current knowledge and future perspectives

Gestational diabetes mellitus (GDM) is a serious problem growing worldwide that needs to be addressed with urgency in consideration of the resulting severe complications for both mother and fetus. Growing evidence indicates that a healthy diet rich in fruit, vegetables, nuts, extra-virgin olive oil and fish has beneficial effects in both the prevention and management of several human diseases and metabolic disorders. In this review, we discuss the latest data concerning the effects of dietary bioactive compounds such as polyphenols and PUFA on the molecular mechanisms regulating glucose homoeostasis. Several studies, mostly based on in vitro and animal models, indicate that dietary polyphenols, mainly flavonoids, positively modulate the insulin signalling pathway by attenuating hyperglycaemia and insulin resistance, reducing inflammatory adipokines, and modifying microRNA (miRNA) profiles. Very few data about the influence of dietary exposure on GDM outcomes are available, although this approach deserves careful consideration. Further investigation, which includes exploring the 'omics' world, is needed to better understand the complex interaction between dietary compounds and GDM

Graphene oxide nanoribbons induce autophagic vacuoles in neuroblastoma cell lines

Since graphene nanoparticles are attracting increasing interest in relation to medical applications, it is important to understand their potential effects on humans. In the present study, we prepared graphene oxide (GO) nanoribbons by oxidative unzipping of single-wall carbon nanotubes (SWCNTs) and analyzed their toxicity in two human neuroblastoma cell lines. Neuroblastoma is the most common solid neoplasia in children. The hallmark of these tumors is the high number of different clinical variables, ranging from highly metastatic, rapid progression and resistance to therapy to spontaneous regression or change into benign ganglioneuromas. Patients with neuroblastoma are grouped into different risk groups that are characterized by different prognosis and different clinical behavior. Relapse and mortality in high risk patients is very high in spite of new advances in chemotherapy. Cell lines, obtained from neuroblastomas have different genotypic and phenotypic features. The cell lines SK-N-BE(2) and SH-SY5Y have different genetic mutations and tumorigenicity. Cells were exposed to low doses of GO for different times in order to investigate whether GO was a good vehicle for biological molecules delivering individualized therapy. Cytotoxicity in both cell lines was studied by measuring cellular oxidative stress (ROS), mitochondria membrane potential, expression of lysosomial proteins and cell growth. GO uptake and cytoplasmic distribution of particles were studied by Transmission Electron Microscopy (TEM) for up to 72 h. The results show that GO at low concentrations increased ROS production and induced autophagy in both neuroblastoma cell lines within a few hours of exposure, events that, however, are not followed by growth arrest or death. For this reason, we suggest that the GO nanoparticle can be used for therapeutic delivery to the brain tissue with minimal effects on healthy cells

HMGB1-Induced Cross Talk between PTEN and miRs 221/222 in Thyroid Cancer

High mobility group box 1 (HMGB1) is an ubiquitous protein that plays different roles in the nucleus, cytoplasm and extra-cellular space. It is an important DAMP molecule that allows communication between damaged or tumor cells and the immune system. Tumor cells exploit HMGB1’s ability to activate intracellular pathways that lead to cell growth and migration. Papillary thyroid cancer is a well differentiated tumor and is often used to study relationships between cells and the inflammatory microenvironment as the latter is characterized by high levels of inflammatory cells and cytokines. Anaplastic thyroid cancer is one of the most lethal human cancers in which many microRNAs and tumor suppressor genes are de-regulated. Up-regulation of microRNAs 221 and 222 has been shown to induce the malignant phenotype in many human cancers via inhibition of PTEN expression. In this study we suggest that extracellular HMGB1 interaction with RAGE enhances expression of oncogenic cluster miR221/222 that in turn inhibits tumor suppressor gene PTEN in two cell lines derived from human thyroid anaplastic and papillary cancers. The newly identified pathway HMGB1/RAGE/miR 221/222 may represent an effective way of tumor escape from immune surveillance that could be used to develop new therapeutic strategies against anaplastic tumors

Metal free graphene oxide (GO) nanosheets and pristine-single wall carbon nanotubes (p-SWCNTs) biocompatibility investigation: a comparative study in different human cell lines

The in vitro biocompatibility of Graphene Oxide (GO) nanosheets, which were obtained by the electrochemical exfoliation of graphite electrodes in an electrolytic bath containing salts, was compared with the pristine Single Wall Carbon Nanotubes (p-SWCNTs) under the same experimental conditions in different human cell lines. The cells were treated with different concentrations of GO and SWCNTs for up to 48 h. GO did not induce any significant morphological or functional modifications (demonstrating a high biocompatibility), while SWNCTs were toxic at any concentration used after a few hours of treatment. The cell viability or cytotoxicity were detected by the trypan blue assay and the lactate dehydrogenase LDH quantitative enzymatic test. The Confocal Laser Scanning Microscopy (CLSM) and transmission electron microscopy (TEM) analysis demonstrated the uptake and internalization of GO sheets into cells, which was localized mainly in the cytoplasm. Different results were observed in the same cell lines treated with p-SWCNTs. TEM and CLSM (Confocal Laser Scanning Microscopy) showed that the p-SWCNTs induced vacuolization in the cytoplasm, disruption of cellular architecture and damage to the nuclei. The most important result of this study is our finding of a higher GO biocompatibility compared to the p-SWCNTs in the same cell lines. This means that GO nanosheets, which are obtained by the electrochemical exfoliation of a graphite-based electrode (carried out in saline solutions or other physiological working media) could represent an eligible nanocarrier for drug delivery, gene transfection and molecular cell imaging tests

Effect of cerium on growth and antioxidant metabolism of Lemna minor L

An increasing input rate of rare earth elements in the environment is expected because of the intense extraction of such elements form their ores to face human technological needs. In this study Lemna minor L. plants were grown under laboratory conditions and treated with increasing concentrations of cerium (Ce) ions to investigate the effects on plant growth and antioxidant systems. The growth increased in plants treated with lower Ce concentrations and reduced in plants treated with higher concentrations, compared to control plants. In plants treated with higher Ce concentrations lower levels of chlorophyll and carotenoid and the appearance of chlorotic symptoms were also detected. Increased levels of hydrogen peroxide, antioxidant metabolites and antioxidant activity confirmed that higher Ce concentrations are toxic to L. minor. Ce concentration in plant tissues was also determined and detectable levels were found only in plants grown on Ce-supplemented media. The use of duckweed plants as a tool for biomonitoring of Ce in freshwater is discussed

From human Megakaryocytes to platelets: Effects of aspirin on high-mobility group Box 1/receptor for advanced glycation end products axis

Platelets (PLTs) are the major source of high-mobility group box 1 (HMGB1), a protein that is involved in sterile inflammation of blood vessels and thrombosis. Megakaryocytes (MKs) synthesize HMGB1 and transfer both protein and mRNA into PLTs and PLT-derived microvesicles (MV). Free HMGB1 found in supernatants of in vitro differentiated MKs and in a megakaryoblastic cell line (DAMI cells). Aspirin “in vivo” and “in vitro” not only reduces HMGB1 and receptor for advanced glycation end products expression on MKs and PLTs but also drives the movement of HMGB1 from MKs into PLTs and PLT-derived MV. These findings suggest that consumption of low doses of aspirin reduces the risk of atherosclerosis complications as well as reducing PLT aggregation by the inhibition of COX-1

Curcumin: could this compound be useful in pregnancy and pregnancy-related complications?

Curcumin, the main polyphenol contained in turmeric root (Curcuma longa), has played a significant role in medicine for centuries. The growing interest in plant-derived substances has led to increased consumption of them also in pregnancy. The pleiotropic and multi-targeting actions of curcumin have made it very attractive as a health-promoting compound. In spite of the beneficial effects observed in various chronic diseases in humans, limited and fragmentary information is currently available about curcumin's effects on pregnancy and pregnancy-related complications. It is known that immune-metabolic alterations occurring during pregnancy have consequences on both maternal and fetal tissues, leading to short- and long-term complications. The reported anti-inflammatory, antioxidant, antitoxicant, neuroprotective, immunomodulatory, antiapoptotic, antiangiogenic, anti-hypertensive, and antidiabetic properties of curcumin appear to be encouraging, not only for the management of pregnancy-related disorders, including gestational diabetes mellitus (GDM), preeclampsia (PE), depression, preterm birth, and fetal growth disorders but also to contrast damage induced by natural and chemical toxic agents. The current review summarizes the latest data, mostly obtained from animal models and in vitro studies, on the impact of curcumin on the molecular mechanisms involved in pregnancy pathophysiology, with the aim to shed light on the possible beneficial and/or adverse effects of curcumin on pregnancy outcomes

Novel 1,3-thiazolidin-4-one derivatives as promising anti-Candida agents endowed with anti-oxidant and chelating properties

Pursuing our recent outcomes regarding the antifungal activity of N-substituted 1,3-thiazolidin-4-ones, we synthesized thirty-six new derivatives introducing aliphatic, cycloaliphatic and heteroaromatic moieties at N1-hydrazine connected with C2 position of the thiazolidinone nucleus and functionalizing the lactam nitrogen with differently substituted (NO2, NH2, Cl and F) benzyl groups. These compounds were tested to evaluate their minimum inhibitory concentration (MIC) against several clinical Candida spp. with respect to topical and systemic reference drugs (clotrimazole, fluconazole, ketoconazole, mi- conazole, tioconazole, amphotericin B). Moreover, anti-oxidant properties were also evaluated by using different protocols including free radical scavenging (DPPH and ABTS), reducing power (CUPRAC and FRAP), metal chelating and phosphomolybdenum assays. Moreover, for the most active derivatives we assessed the toxicity (CC50) against Hep2 human cells in order to characterize them as multi-target agents for fungal infections

Cardiorespiratory fitness and sports activities in children and adolescents with solitary functioning kidney

Background: An increasing number of children with chronic disease require a complete medical examination to be able to practice physical activity. Particularly children with solitary functioning kidney (SFK) need an accurate functional evaluation to perform sports activities safely. The aim of our study was to evaluate the influence of regular physical activity on the cardiorespiratory function of children with solitary functioning kidney. Method: Twenty-nine patients with congenital SFK, mean age 13.9 ± 5.0 years, and 36 controls (C), mean age 13.8 ± 3.7 years, underwent a cardiorespiratory assessment with spirometry and maximal cardiopulmonary exercise testing. All subjects were divided in two groups: sedentary (S) and trained (T) patients, by means of a standardized questionnaire about their weekly physical activity. Results: We found that mean values of maximal oxygen consumption (VO2max) and exercise time (ET) were higher in T subjects than in S subjects. Particularly SFK-T presented mean values of VO2max similar to C-T and significantly higher than C-S (SFK-T: 44.7 ± 6.3 vs C-S: 37.8 ± 3.7 ml/min/kg; p < 0.0008). We also found significantly higher mean values of ET (minutes) in minutes in SFK-T than C-S subjects (SFK-T: 12.9 ± 1.6 vs C-S: 10.8 ± 2.5 min; p <0.02). Conclusion: Our study showed that regular moderate/high level of physical activity improve aerobic capacity (VO2max) and exercise tolerance in congenital SFK patients without increasing the risks for cardiovascular accidents and accordingly sports activities should be strongly encouraged in SFK patients to maximize health benefit