1,720,984 research outputs found
Impiego di statine e/o fibrati per il trattamento del deficit del trasportatore della carnitina (CAC).
No full textTCA cycle rewiring as emerging metabolic signature of hepatocellular carcinoma
Full text linkHepatocellular carcinoma (HCC) is a common malignancy. Despite progress in treatment, HCC is still one of the most lethal cancers. Therefore, deepening molecular mechanisms underlying HCC pathogenesis and development is required to uncover new therapeutic strategies. Metabolic reprogramming is emerging as a critical player in promoting tumor survival and proliferation to sustain increased metabolic needs of cancer cells. Among the metabolic pathways, the tricarboxylic acid (TCA) cycle is a primary route for bioenergetic, biosynthetic, and redox balance requirements of cells. In recent years, a large amount of evidence has highlighted the relevance of the TCA cycle rewiring in a variety of cancers. Indeed, aberrant gene expression of several key enzymes and changes in levels of critical metabolites have been observed in many solid human tumors. In this review, we summarize the role of the TCA cycle rewiring in HCC by reporting gene expression and activity dysregulation of enzymes relating not only to the TCA cycle but also to glutamine metabolism, malate/aspartate, and citrate/pyruvate shuttles. Regarding the transcriptional regulation, we focus on the link between NF-κB-HIF1 transcriptional factors and TCA cycle reprogramming. Finally, the potential of metabolic targets for new HCC treatments has been explored
Cancer cell metabolism in hypoxia: Role of HIF-1 as key regulator and therapeutic target
Full text linkIn order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells
Role of FOXA and Sp1 in mitochondrial acylcarnitine carrier gene expression in different cell lines
No full textThis study investigates the transcriptional role of the human mitochondrial carnitine/acylcarnitine carrier
(CAC) proximal promoter. Through deletion analysis, an activation domain (334/80 bp) was identified
which contains FOXA and Sp1 active sites. The wild-type (but not mutated) 334/80 bp region of
the CAC gene conferred 74% LUC transgene activity in HepG2 cells, 17% in HEK293 cells and 14% in SK-NSH
cells as compared to that observed with the entire 1503/+3 bp proximal promoter. Overexpression
and silencing of FOXA2 or Sp1 in HepG2 cells enhanced and diminished, respectively, LUC activity, CAC
transcript and CAC protein. In HEK293 and SK-N-SH cells, which do not contain FOXA1-3, LUC activity
was increased by FOXA2 overexpression to a greater extent than in HepG2 cells. Both FOXA2 and Sp1
in HepG2, and only Sp1 in HEK293 and SK-N-SH cells, were found to be bound to the CAC proximal promoter.
These results show that FOXA and Sp1 sites in HepG2 cells and only the Sp1 site in HEK293 and
SK-N-SH cells have a critical role in the transcriptional regulation of the CAC proximal promoter
“The citrate-related inflammatory pathway”
No full textThe mitochondrial citrate carrier (CIC), encoded by the SLC25A1 gene, catalyses the export of citrate from the mitochondrial matrix to the cytosol, where it is cleaved to acetyl-CoA and oxaloacetate by ATP citrate lyase (ACLY). Acetyl-CoA is mainly used for fatty acid synthesis, and oxaloacetate produces NADPH + H+ also necessary for fatty acid production. Both CIC and ACLY enzymes are highly expressed in liver and play an essential metabolic role. Recently, we have identified their involvement in the inflammation pathway. Macrophages and U937 cells treated with lipopolysaccharide (LPS), tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ), show a significantly upregulation of SLC25A1 as well as ACLY through NFkB and STAT1 signaling pathways. We demonstrate that CIC and ACLY activity is required for ROS, nitric oxide and prostaglandins production. Importantly, we show that the citrate exported from mitochondria via CIC and its downstream metabolic intermediate, acetyl-coenzyme A, are necessary for TNFα or IFNγ-dependent inflammatory response. These findings highlight a “citrate pathway” involvement in pro-inflammatory signals and in inflammatory mediator production
Inibitori del carrier del citrato
No full textQuesto brevetto riguarda l'impiego di un nuovo inibitore del carrier della citrato, l'acido 4-cloro-3-(3-nitrofenil-amino)sulfonil)benzoico, nell'infiammamzion
Role of FOXA and Sp1 in mitochondrial acylcarnitine carrier gene expression in Different cell lines
Full text linkMEF2C exon α: Role in gene activation and differentiation
No full textMyocyte enhancer factor 2C (MEF2C) belongs to the MEF2 transcription factors. All products of MEF2 genes have a common amino-terminal DNA binding and dimerization domain. All four vertebrate MEF2 gene transcripts are also alternatively spliced. In the present study we identify two novel MEF2C splice variants, named VP and VP2. These variants are generated by the skipping of exon α. The identified α - variants are ubiquitously expressed, although at very low levels compared to the α + variants. The existence of MEF2C α - variants gave us the opportunity to study for the first time the function of exon α. Transactivation experiments show that the presence of exon α induces a reduction of transcription levels. Moreover, α - variants are significantly expressed during neuronal cell differentiation, indicating a putative role of these variants in development. © 2013 Elsevier B.V
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