Biology subjects

Noriega, L. G.

Publications and source records attributed to Noriega, L. G..

4 recordsLinked to original sources

bioRxiv2024

Metabolic reprogramming and synergistic cytotoxicity of genistein and chemotherapy in human breast cancer cells

Breast cancer (BCa) is a heterogeneous disease, initially responsive to hormone therapy but often developing resistance to both hormonal and chemotherapy treatments. Novel therapeutic strategies are needed for drug-resistant BCa. Genistein, a phytoestrogen structurally similar to estrogen, competes with estrogen for receptor binding and exhibits anti-cancer effects. In this study, we investigated the cellular and metabolic impacts of genistein, alone or in combination with chemotherapy, in two human BCa cell lines--one estrogen receptor-positive (ER+) and one estrogen receptor-negative (ER-). We observed a strong synergistic effect on cell viability at low concentrations of genistein and chemotherapy, resulting in reduced clonogenic capacity and impaired cell migration. Genistein alone modulated cellular energy metabolism, notably reducing ATP production in MCF7 (ER+) cells. This metabolic shift was linked to a decreased dependence on fatty acids for energy, coupled with a decrease in the rate-limiting mitochondrial translocase CPT1 required for fatty acid oxidation, alongside with an increase in intracellular fatty acid levels. While the most significant changes occurred in ER+ cells, ER- cells also showed responses to genistein treatment. Collectively, our findings suggest that low dose genistein, in combination with conventional chemotherapy, induces synergistic anti-cancer effects, promoting cellular senescence. This effect may be partly mediated by a reduced reliance on fatty acid metabolism in BCa cells.

cancer biology↗

bioRxiv2023

NRF2 pathway activation reverts high-glucose-induced transcriptional memory in endothelial cells

Various diabetes complications, including nephropathy, retinopathy, and cardiovascular disease, arise from vascular dysfunction. In this context, it has been observed that past hyperglycaemic events can induce long-lasting transcriptional changes, a phenomenon termed "metabolic memory". Yet, the underlying mechanisms driving these persistent effects are not fully characterized. In this study, we evaluated the genome-wide gene expression and chromatin accessibility alterations caused by transient high glucose exposure in human endothelial cells (ECs). We found that cells exposed to a transient high glucose episode had decreased glycolytic and oxygen consumption rates. Transcriptional profiling indicated that high glucose exposure induced substantial changes in the expression of genes belonging to pathways known to be impaired in diabetes, such as TGF-beta, TNF, FoxO, p53, and NRF2 pathways, many of which were retained after normalization of glucose concentrations. Furthermore, analysis of chromatin accessibility showed that transient hyperglycaemia can induce persistent modifications in the accessibility landscape, with the majority of differentially accessible regions located in non-promoter regions. Some of these regions were identified as putative enhancers with neighbouring genes persistently altered after transient high glucose exposure. Finally, we showed that activation of the NRF2 pathway through either NRF2 overexpression or supplementation with the plant-derived compound sulforaphane, was able to substantially revert the glucose-induced transcriptional memory in ECs. Our findings demonstrate that transient high glucose can induce persistent changes in both the transcriptomic and chromatin accessibility profiles of ECs, and that pharmacological NRF2 pathway activation is able to prevent and revert the high-glucose-induced transcriptional memory. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/557207v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@b9c938org.highwire.dtl.DTLVardef@1498a43org.highwire.dtl.DTLVardef@1146ab5org.highwire.dtl.DTLVardef@169bfca_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Paneth and Paneth-like cells undergoing necroptosis fuel intestinal epithelial cell proliferation following IFN-γ stimulation.

The quality of life in patients with inflammatory bowel diseases (IBD) is strongly impaired. Alterations of intestinal epithelial homeostasis contribute to the development and establishment of IBD. Intestinal Paneth and Paneth-like cells produce and secrete luminal proteins sustaining epithelial homeostasis. Here we show that IFN-{gamma} stimulates Paneth and Paneth-like cells degranulation that triggers the proliferation of intestinal epithelial cells (IEC) in a Wnt/{beta}-catenin independent manner. Degranulation in Paneth and Paneth-like cells was mTORC1 and necroptosis dependent. Remarkably, lack of IFN-{gamma}, inhibition of mTORC1, or impeding necroptosis reduces IEC proliferation cytokine-mediated. Our findings identify a new role for IFN-{gamma} in stimulating IEC proliferation through inducing degranulation of Paneth and Paneth-like cells which is mTORC1 and necroptosis- dependent. In a mouse model of colitis, mTORC1 activation and necroptosis regulate Paneth and Paneth-like cell secretion. Furthermore, the colitogenic environment triggers PC metaplasia in the distal region of the large intestine to simulate cell proliferation. HighlightsIFN-{gamma} stimulates proliferation, {beta}-catenin independent. IFN-{gamma} enhances mitochondrial activity and proliferation IFN-{gamma} regulates PC biogenesis. mTORC1-dependent necroptosis mediates secretion in Paneth and Paneth-like cells.

physiology↗

bioRxiv2021

Coordination between metabolic transitions and gene expression by NAD+ availability during adipogenic differentiation in human cells.

Adipocytes are the main cell type in adipose tissue, a critical regulator of metabolism, highly specialized in storing energy as fat. Adipocytes differentiate from multipotent mesenchymal stromal cells through adipogenesis, a tightly controlled differentiation process involving closely interplay between metabolic transitions and sequential programs of gene expression. However, the specific gears driving this interplay remain largely obscure. Additionally, the metabolite nicotinamide adenine dinucleotide (NAD+) is becoming increasingly recognized as a regulator of lipid metabolism, being postulated as promising therapeutic target for dyslipidemia and obesity. Here, we explored the effect of manipulating NAD+ bioavailability during adipogenic differentiation from human mesenchymal stem cells. We found a previously unappreciated strong repressive role for NAD+ on adipocyte commitment, while a functional NAD+-dependent deacetylase SIRT1 appeared crucial for terminal differentiation of pre-adipocytes. Remarkably, repressing the NAD+ biosynthetic salvage pathway during adipogenesis promoted the adipogenic transcriptional program, suggesting that SIRT1 activity during adipogenesis is independent from the NAD+ salvage pathway, while two photon microscopy and extracellular flux analyses suggest that its activation relies on the metabolic switch. Interestingly, SIRT1-directed control of subcellular compartmentalization of redox metabolism during adipogenesis was evidenced by two-photon fluorescence lifetime microscopy. Significance StatementAdipocyte differentiation occurs from mesenchymal stem cells through the adipogenic process, involving sequential activation of both transcriptional and metabolic programs in a tightly coordinated manner. However, how transcriptional and metabolic transitions reciprocally interact during adipogenic differentiation remains largely obscure. Here we describe that the metabolite NAD+ is suppresses adipogenesis trough rewiring transcription, while a functional NAD+-dependent deacetylase SIRT1 is essential for terminal differentiation of pre-adipocytes. Using two-photon fluorescence lifetime microscopy, we created a metabolic map of NADH and lipid content simultaneously in live cells and described a new role for SIRT1 in the control of compartmentalization of redox metabolism during adipogenesis. These findings advance our understanding to improve therapeutical approaches targeting the NAD+-SIRT1 axis as treatment for obesity and dyslipemia.

cell biology↗