59 research outputs found
An Overview of the Ferroptosis Hallmarks in Friedreich's Ataxia
No full textBackground: Friedreich’s ataxia (FRDA) is a neurodegenerative disease characterized by early mortality due to hypertrophic cardiomyopathy. FRDA is caused by reduced levels of frataxin (FXN), a mitochondrial protein involved in the synthesis of iron-sulphur clusters, leading to iron accumulation at the mitochondrial level, uncontrolled production of reactive oxygen species and lipid peroxidation. These features are also common to ferroptosis, an iron-mediated type of cell death triggered by accumulation of lipoperoxides with distinct morphological and molecular characteristics with respect to other known cell deaths. Scope of review: Even though ferroptosis has been associated with various neurodegenerative diseases including FRDA, the mechanisms leading to disease onset/progression have not been demonstrated yet. We describe the molecular alterations occurring in FRDA that overlap with those characterizing ferroptosis. Major conclusions: The study of ferroptotic pathways is necessary for the understanding of FRDA pathogenesis, and anti-ferroptotic drugs could be envisaged as therapeutic strategies to cure FRDA
Redox modulation and induction of ferroptosis by dimethyl fumarate in cervical carcinoma
No full textCervical cancer (CC) is the fourth most common cause of women death. The papillomavirus (HPV) persistent infection is the lead- ing cause for the development of CC that progresses through multistep transformation. Drug resistance and relapse are fre- quently observed in CC after conventional chemotherapy and radiotherapy. Therefore, there is a need to find new drugs against CC. Dimethyl fumarate (DMF) is an FDA-approved anti-inflam- matory drug and emerging studies suggest that DMF also exert an anti-tumor activity in some cancers. We were interested to fer- roptosis, a type of cell death caused by iron-dependent lipid per- oxidation. Using cell viability and colony assay, we tested the effectiveness of DMF alone in comparison to other well-known inducers of ferroptosis in SiHa and C4I cells. We performed fer- roptosis related-genes expression analysis, lipid peroxidation and malondialdehyde assays demonstrating that DMF induces ferrop- tosis in a concentration-dependent manner in both cell lines. Next, we investigated if the combination of DMF with sub-cyto- toxic ferroptotic-drugs was able to ameliorate ferroptosis. We found that co-treatments of DMF/sulfasalazine (SAS) were asso- ciated with enhanced cell death. To elucidate molecular mecha- nisms underlying these effects we analyzed the NRF2 antioxidant pathway. Real-time PCR and western blot assays showed an induction of NRF2 protein and NRF2-dependent genes, such as SLC7A11 involved in GSH synthesis. In contrast with the observed SLC7A11 increase, we detected a strong reduction of glutathione (GSH) under DMF/SAS treatments. These results indicate that SAS cooperates in GSH depletion favoring ferrop- tosis. Since DMF has been found to influence NF-kB, STAT3 signaling we also tested IL-6 levels, a NF-kB target, and phos- phorylation of STAT3 in DMF/SAS treatments. Our results demonstrate that both these pathways are reduced in presence of SAS, implicating that DMF/SAS exhibited a strong killing-effect than either DMF or SAS alone
DIMETHYLFUMARATE MEDIATES CERVICAL CARCINOMA FERROPTOSIS THROUGH REDOX-RELATED PATHWAYS
No full textCervical cancer (CC) represents the fourth leading cause of women death worldwide. Development of CC is based on papillomavirus (HPV) persistent infections which boosts multistep transformation. CC has a high recurrence rate, and it is a relatively drugresistant disease, indeed acquired resistance to cisplatin is frequently observed. Therefore, there is a need to identify novel drugs against CC. Dimethylfumarate (DMF) is a clinically approved treatment for psoriasis/multiple sclerosis and emerging studies also indicate DMF antitumor activity in some cancers [1]. DMF action involves both Nrf2dependent and independent pathways.
We demonstrate that DMF has an antiproliferative effect in SiHa cells. In particular, we were interested in ferroptosis, a novel form of cell death mediated by iron dependent lipid peroxidation. We compared DMF effectiveness with different wellknown inducers of ferroptosis by using cell viability and colony assays. Malondialdehyde and lipid peroxidation assays demonstrated that in SiHa cells, DMF induces ferroptoticlike cell death. Furthermore, we analyzed the expression of a group of ferroptosisrelated genes. The results showed that mRNA levels of SAT1 (Spermidine/Spermine N1Acetyltransferase 1) and PTGS2 (Prostaglandin endoperoxide synthase2), two well know markers of ferroptosis, were strongly increased upon DMF treatments. Since some studies reported that STAT3 and NRF2 are hyperactivated in tumors, and their interaction can regulate tumor progression, we focused on these pathways. Molecular analyses demonstrated that DMF can intercept both: it stimulates protective Nrf2 activity but also inactivates STAT3 that could finally sensitize these cells to ferroptosis.
Our data albeit in its infancy, suggest therapeutic potentials of DMF for CC treatment and repurpose DMFmediated strategies involving Nrf2STAT3 cross talk as a promising option
microRNA-494 promotes cellular senescence in human diploid fibroblasts by targeting several genes
No full textWe recently identified miR-494 up-regulation as a component of the
program leading to cellular senescence of human diploid IMR90
fibroblasts [1]. To identify miR-494 targets, we used 2D-DIGE coupled
to mass spectrometry analysis to profile protein changes induced by
overexpression of miR-494 in IMR90 cells. miR-494 induced robust
perturbation of the IMR90 proteome by significantly (p≤0.05) affecting
a number of proteins. Combination of mass spectrometry-based
identification of down-regulated proteins and bioinformatic prediction
analysis for miR-494 binding sites on the relevant mRNAs, identified
26 putative targets of miR-494, with 7 of them featuring evolutionary
conservation of miR-494 binding site. Functional miR-494 binding
site were confirmed for hnRNPA3, PDIA3, RAD23B, and SYNCRIP.
siRNA-mediated knockdown of hnRNPA3 and, to a lesser extent,
RAD23B mirrored the senescent phenotype induced by miR-494,
blunting cell proliferation and causing increase of SA-β-gal and DNA
damage. Reintroduction of hnRNPA3 or RAD23B slowed the appearance
of miR-494-induced senescent phenotype in IMR90 cells. Overall, these
findings identify novel miR-494 direct targets involved in senescence.
References: [1]Faraonio R et al. Cell Death Differ. 2012 Apr;19(4):713-
21. doi: 10.1038/cdd.2011.143. Epub 2011 Nov
Targeting the endoplasmic reticulum unfolded protein response to counteract the oxidative stress-Induced endothelial dysfunction
No full textIn endothelial cells, the tight control of the redox environment is essential for the maintenance of vascular homeostasis. The imbalance between ROS production and antioxidant response can induce endothelial dysfunction, the initial event of many cardiovascular diseases. Recent studies have revealed that the endoplasmic reticulum could be a new player in the promotion of the pro- or antioxidative pathways and that in such a modulation, the unfolded protein response (UPR) pathways play an essential role. The UPR consists of a set of conserved signalling pathways evolved to restore the proteostasis during protein misfolding within the endoplasmic reticulum. Although the first outcome of the UPR pathways is the promotion of an adaptive response, the persistent activation of UPR leads to increased oxidative stress and cell death. This molecular switch has been correlated to the onset or to the exacerbation of the endothelial dysfunction in cardiovascular diseases. In this review, we highlight the multiple chances of the UPR to induce or ameliorate oxidative disturbances and propose the UPR pathways as a new therapeutic target for the clinical management of endothelial dysfunction
An Overview of the Ferroptosis Hallmarks in Friedreich’s Ataxia
No full textBackground: Friedreich’s ataxia (FRDA) is a neurodegenerative disease characterized by early mortality due to hypertrophic cardiomyopathy. FRDA is caused by reduced levels of frataxin (FXN), a mitochondrial protein involved in the synthesis of iron-sulphur clusters, leading to iron accumulation at the mitochondrial level, uncontrolled production of reactive oxygen species and lipid peroxidation. These features are also common to ferroptosis, an iron-mediated type of cell death triggered by accumulation of lipoperoxides with distinct morphological and molecular characteristics with respect to other known cell deaths. Scope of review: Even though ferroptosis has been associated with various neurodegenerative diseases including FRDA, the mechanisms leading to disease onset/progression have not been demonstrated yet. We describe the molecular alterations occurring in FRDA that overlap with those characterizing ferroptosis. Major conclusions: The study of ferroptotic pathways is necessary for the understanding of FRDA pathogenesis, and anti-ferroptotic drugs could be envisaged as therapeutic strategies to cure FRDA
Editorial: Advances in metabolic mechanisms of aging and its related diseases, Volume II
No full text- …
