75 research outputs found
Acute renal failure in an AIDS patient on tenofovir: a case report
This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens
Mycophenolate mofetil as maintenance therapy for proliferative lupus nephritis: a long-term observational prospective study
Sustained proliferation in cancer: mechanisms and novel therapeutic targets
Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression
Potent and selective chemical probe of hypoxic signaling downstream of HIF-α hydroxylation via VHL inhibition
Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling
Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer.
Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway
INSULIN RESISTANCE AND LIPID DISORDERS IN PRE-PUBERTAL CHILDREN BORN SMALL FOR GESTATIONAL AGE
Risk factors for elevated blood lead levels among children aged 6-36 months living in Greece
Background: Childhood lead poisoning remains a critical environmental health concern because even low blood lead levels (BLLs) can result in permanent adverse health effects. Social factors and living conditions have been correlated with BLLs. There is no recent survey about the prevalence of elevated BLLs among children in Greece. The purpose of this study was to assess BLLs among children aged 6-36months born and living in Greece and to evaluate their association with demographic, socio-economic and housing conditions. Methods: In a cross-sectional hospital-based study including 814 randomly selected children aged 6-36months, BLLs and haematological parameters were evaluated. A questionnaire investigating demographic and socio-economic conditions was completed in all children. Statistical analysis was performed using STATA for Windows v.8.5, and P < 0.05 was considered statistically significant. Results: The mean BLLs of the population were 2.78 (SD = 2.34)μg/dl, and the median was 2.02μg/dl; 11.7% had BLLs above 5μg/dl, while 15 children (1.8%) exceeded 10μg/dl. Being a toddler, being Roma or Asian, living in an industrial/low-income neighbourhood or in an old house, using traditional herbs and/or spices and having a mother with a manual occupation were independent risk factors for elevated BLLs. Conclusion: Lead exposure remains a threat for optimal health especially for toddlers and children of socio-economically disadvantaged families living in Greece. A nationwide survey to assess lead exposure in children is necessary to guide prevention governmental policies. © 2015 John Wiley & Sons Ltd
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