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1.
Hum Mol Genet ; 33(R1): R19-R25, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38779769

RESUMO

Human mitochondria harbour a circular, polyploid genome (mtDNA) encoding 11 messenger RNAs (mRNAs), two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs). Mitochondrial transcription produces long, polycistronic transcripts that span almost the entire length of the genome, and hence contain all three types of RNAs. The primary transcripts then undergo a number of processing and maturation steps, which constitute key regulatory points of mitochondrial gene expression. The first step of mitochondrial RNA processing consists of the separation of primary transcripts into individual, functional RNA molecules and can occur by two distinct pathways. Both are carried out by dedicated molecular machineries that substantially differ from RNA processing enzymes found elsewhere. As a result, the underlying molecular mechanisms remain poorly understood. Over the last years, genetic, biochemical and structural studies have identified key players involved in both RNA processing pathways and provided the first insights into the underlying mechanisms. Here, we review our current understanding of RNA processing in mammalian mitochondria and provide an outlook on open questions in the field.


Assuntos
DNA Mitocondrial , Mitocôndrias , Processamento Pós-Transcricional do RNA , RNA Mitocondrial , Humanos , DNA Mitocondrial/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , RNA Mitocondrial/genética , RNA Mitocondrial/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Animais , Transcrição Gênica , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , RNA de Transferência/genética , RNA de Transferência/metabolismo
2.
Cancers (Basel) ; 13(16)2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34439360

RESUMO

Cancer is one of the leading causes of premature death, and, as such, it can be prevented by developing strategies for early and accurate diagnosis. Cancer diagnostics has evolved from the macroscopic detection of malignant tissues to the fine analysis of tumor biomarkers using personalized medicine approaches. Recently, various nanomaterials have been introduced into the molecular diagnostics of cancer. This has resulted in a number of tumor biomarkers that have been detected in vitro and in vivo using nanodevices and corresponding imaging techniques. Atomically precise ligand-protected noble metal quantum nanoclusters represent an interesting class of nanomaterials with a great potential for the detection of tumor biomarkers. They are characterized by high biocompatibility, low toxicity, and suitability for controlled functionalization with moieties specifically recognizing tumor biomarkers. Their non-linear optical properties are of particular importance as they enable the visualization of nanocluster-labeled tumor biomarkers using non-linear optical techniques such as two-photon-excited fluorescence and second harmonic generation. This article reviews liganded nanoclusters among the different nanomaterials used for molecular cancer diagnosis and the relevance of this new class of nanomaterials as non-linear optical probe and contrast agents.

3.
Free Radic Biol Med ; 167: 45-53, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33711415

RESUMO

Ferroptosis is a non-accidental, regulated form of cell death operated by lipid peroxidation under strict control of GPx4 activity. This is consistent with the notion that lipid peroxidation is initiated by radicals produced from decomposition of traces of pre-existing lipid hydroperoxides. The question, therefore, emerges about the formation of these traces of lipid hydroperoxides interacting with Fe2+. In the most realistic option, they are produced by oxygen activated species generated during aerobic metabolism. Screening for metabolic sources of superoxide supporting ferroptosis induced by GSH depletion, we failed to detect, in our cell model, a role of respiratory chain. We observed instead that the pyruvate dehydrogenase complex -as other α keto acid dehydrogenases already known as a major source of superoxide in mitochondria- supports ferroptosis. The opposite effect on ferroptosis by silencing either the E1 or the E3 subunit of the pyruvate dehydrogenase complex pointed out the autoxidation of dihydrolipoamide as the source of superoxide. We finally observed that GSH depletion activates superoxide production, seemingly through the inhibition of the specific kinase that inhibits pyruvate dehydrogenase. In summary, this set of data is compatible with a scenario where the more electrophilic status produced by GSH depletion not only activates ferroptosis by preventing GPx4 activity, but also favors the formation of lipid hydroperoxides. In an attractive perspective of tissue homeostasis, it is the activation of energetic metabolism associated to a decreased nucleophilic tone that, besides supporting energy demanding proliferation, also sensitizes cells to a regulated form of death.


Assuntos
Ferroptose , Morte Celular , Peroxidação de Lipídeos , Peróxidos Lipídicos , Ácido Pirúvico
4.
FEBS Lett ; 594(4): 611-624, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581313

RESUMO

Ras-selective lethal small molecule 3 (RSL3), a drug candidate prototype for cancer chemotherapy, triggers ferroptosis by inactivating the glutathione peroxidase glutathione peroxidase 4 (GPx4). Here, we report the purification of the protein indispensable for GPx4 inactivation by RSL3. Mass spectrometric analysis identified 14-3-3 isoforms as candidates, and recombinant human 14-3-3ε confirms the identification. The function of 14-3-3ε is redox-regulated. Moreover, overexpression or silencing of the gene coding for 14-3-3ε consistently controls the inactivation of GPx4 by RSL3. The interaction of GPx4 with a redox-regulated adaptor protein operating in cell signaling further contributes to frame it within redox-regulated pathways of cell survival and death and opens new therapeutic perspectives.


Assuntos
Proteínas 14-3-3/metabolismo , Carbolinas/farmacologia , Ferroptose/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Animais , Citosol/efeitos dos fármacos , Citosol/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Humanos , Ratos
5.
Redox Biol ; 28: 101328, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31574461

RESUMO

Ferroptosis is a form of cell death primed by iron and lipid hydroperoxides and prevented by GPx4. Ferrostatin-1 (fer-1) inhibits ferroptosis much more efficiently than phenolic antioxidants. Previous studies on the antioxidant efficiency of fer-1 adopted kinetic tests where a diazo compound generates the hydroperoxyl radical scavenged by the antioxidant. However, this reaction, accounting for a chain breaking effect, is only minimally useful for the description of the inhibition of ferrous iron and lipid hydroperoxide dependent peroxidation. Scavenging lipid hydroperoxyl radicals, indeed, generates lipid hydroperoxides from which ferrous iron initiates a new peroxidative chain reaction. We show that when fer-1 inhibits peroxidation, initiated by iron and traces of lipid hydroperoxides in liposomes, the pattern of oxidized species produced from traces of pre-existing hydroperoxides is practically identical to that observed following exhaustive peroxidation in the absence of the antioxidant. This supported the notion that the anti-ferroptotic activity of fer-1 is actually due to the scavenging of initiating alkoxyl radicals produced, together with other rearrangement products, by ferrous iron from lipid hydroperoxides. Notably, fer-1 is not consumed while inhibiting iron dependent lipid peroxidation. The emerging concept is that it is ferrous iron itself that reduces fer-1 radical. This was supported by electroanalytical evidence that fer-1 forms a complex with iron and further confirmed in cells by fluorescence of calcein, indicating a decrease of labile iron in the presence of fer-1. The notion of such as pseudo-catalytic cycle of the ferrostatin-iron complex was also investigated by means of quantum mechanics calculations, which confirmed the reduction of an alkoxyl radical model by fer-1 and the reduction of fer-1 radical by ferrous iron. In summary, GPx4 and fer-1 in the presence of ferrous iron, produces, by distinct mechanism, the most relevant anti-ferroptotic effect, i.e the disappearance of initiating lipid hydroperoxides.


Assuntos
Cicloexilaminas/farmacologia , Ferroptose/efeitos dos fármacos , Fenilenodiaminas/farmacologia , Antioxidantes/farmacologia , Morte Celular/efeitos dos fármacos , Cromatografia Líquida , Cicloexilaminas/química , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ferroptose/genética , Hidrogênio/química , Peroxidação de Lipídeos/efeitos dos fármacos , Peróxidos Lipídicos/metabolismo , Lipidômica/métodos , Lipídeos/química , Modelos Moleculares , Estrutura Molecular , Oxirredução , Fenilenodiaminas/química , Espectrometria de Massas em Tandem
6.
Free Radic Biol Med ; 147: 80-89, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31857233

RESUMO

GPx8 is a glutathione peroxidase homolog inserted in the membranes of endoplasmic reticulum (ER), where it seemingly plays a role in controlling redox status by preventing the spill of H2O2. We addressed the impact of GPx8 silencing on the lipidome of microsomal membranes, using stably GPx8-silenced HeLa cells. The two cell lines were clearly separated by Principal Component Analysis (PCA) and Partial Least Square Discriminant analysis (PLS-DA) of lipidome. Considering in detail the individual lipid classes, we observed that unsaturated glycerophospholipids (GPL) decreased, while only in phosphatidylinositols (PI) a substitution of monounsaturated fatty acids (MUFA) for polyunsaturated fatty acids (PUFA) was observed. Among sphingolipids (SL), ceramides (CER) decreased while sphingomyelins (SM) and neutral glycophingolipids (nGSL) increased. Here, in addition, longer chains than in controls in the amide fatty acid were present. The increase up to four folds of the CER (d18:1; c24:0) containing three hexose units, was the most remarkable species increasing in the differential lipidome of siGPx8 cells. Quantitative RT-PCR complied with lipidomic analysis specifically showing an increased expression of: i) acyl-CoA synthetase 5 (ACSL5); ii) CER synthase 2 and 4; iii) CER transporter (CERT); iv) UDP-glucosyl transferase (UDP-GlcT), associated to a decreased expression of UDP-galactosyl transferase (UDP-GalT). A role of the unfolded protein response (UPR) and the spliced form of the transcription factor XBP1 on the transcriptional changes of GPx8 silenced cells was ruled-out. Similarly, also the involvement of Nrf2 and NF-κB. Altogether our results indicate that GPx8-silencing of HeLa yields a membrane depleted by about 24% of polyunsaturated GPL and a corresponding increase of saturated or monounsaturated SM and specific nGSL. This is tentatively interpreted as an adaptive mechanism leading to an increased resistance to radical oxidations. Moreover, the marked shift of fatty acid composition of PI emerges as a possibly relevant issue in respect to the impact of GPx8 on signaling pathways.


Assuntos
Retículo Endoplasmático , Peróxido de Hidrogênio , Ceramidas , Glutationa Peroxidase/genética , Células HeLa , Humanos , Peroxidases
7.
J Hum Lact ; 28(3): 389-99, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22674962

RESUMO

BACKGROUND: The Baby-Friendly Hospital Initiative (BFHI) is the most widely promoted program for increasing breastfeeding rates. OBJECTIVE: To evaluate the impact of BFHI training on hospital practices and breastfeeding rates during the first 12 months of life. METHODS: Eighty percent of maternity medical and nursing staff at the University Hospital in Split, Croatia, completed the updated and expanded United Nations Children's Fund/World Health Organization 20-hour course. Seven hundred seventy-three mothers (388 in the pre- and 385 in the post-training group) were included in a birth cohort and interviewed at discharge and at 3, 6, and 12 months postpartum to evaluate hospital practices and infant feeding. Six out of 10 Baby-Friendly practices were assessed using standard BFHI forms. RESULTS: Three months after training was completed, 3 of the Baby-Friendly practices assessed (Step 4, "Initiate breastfeeding within a half-hour of birth"; Step 7, "Rooming-in"; and Step 8, "Feeding on demand") had significantly improved. The proportion of newborns exclusively breastfed during the first 48 hours increased from 6.0% to 11.7% (P < .005). There was no difference in breastfeeding rates at discharge or at 3, 6, or 12 months between the pre- and post-training groups. CONCLUSION: Training of health professionals, based on the BFHI, was associated with significant improvement in some Baby-Friendly hospital practices and initial exclusive breastfeeding rates. A high rate of in-hospital supplementation may partly explain the lack of improvement in breastfeeding exclusivity and duration after discharge. Strong institutional support and commitment is needed to enable full implementation of recommended Baby-Friendly practices.


Assuntos
Aleitamento Materno/estatística & dados numéricos , Salas de Parto/normas , Educação Médica Continuada/métodos , Educação Continuada em Enfermagem/métodos , Fidelidade a Diretrizes/estatística & dados numéricos , Cuidado do Lactente/normas , Adulto , Croácia , Salas de Parto/estatística & dados numéricos , Feminino , Seguimentos , Hospitais Universitários/normas , Hospitais Universitários/estatística & dados numéricos , Humanos , Lactente , Cuidado do Lactente/métodos , Cuidado do Lactente/estatística & dados numéricos , Recém-Nascido , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde , Guias de Prática Clínica como Assunto , Avaliação de Programas e Projetos de Saúde , Nações Unidas , Organização Mundial da Saúde
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