RESUMEN
BACKGROUND: All living cells display a rapid molecular response to adverse environmental conditions, and the heat shock protein family reflects one such example. Hence, failing to activate heat shock proteins can impair the cellular response. In the present study, we evaluated whether the loss of different isoforms of heat shock protein (hsp) genes in Caenorhabditis elegans would affect their vulnerability to Manganese (Mn) toxicity. METHODS: We exposed wild type and selected hsp mutant worms to Mn (30 min) and next evaluated further the most susceptible strains. We analyzed survival, protein carbonylation (as a marker of oxidative stress) and Parkinson's disease related gene expression immediately after Mn exposure. Lastly, we observed dopaminergic neurons in wild type worms and in hsp-70 mutants following Mn treatment. Analysis of the data was performed by one-way or two way ANOVA, depending on the case, followed by post-hoc Bonferroni test if the overall p value was less than 0.05. RESULTS: We verified that the loss of hsp-70, hsp-3 and chn-1 increased the vulnerability to Mn, as exposed mutant worms showed lower survival rate and increased protein oxidation. The importance of hsp-70 against Mn toxicity was then corroborated in dopaminergic neurons, where Mn neurotoxicity was aggravated. The lack of hsp-70 also blocked the transcriptional upregulation of pink1, a gene that has been linked to Parkinson's disease. CONCLUSIONS: Taken together, our data suggest that Mn exposure modulates heat shock protein expression, particularly HSP-70, in C. elegans. Furthermore, loss of hsp-70 increases protein oxidation and dopaminergic neuronal degeneration following manganese exposure, which is associated with the inhibition of pink1 increased expression, thus potentially exacerbating the vulnerability to this metal.
Asunto(s)
Proteínas de Caenorhabditis elegans/biosíntesis , Proteínas de Choque Térmico/biosíntesis , Manganeso/toxicidad , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/antagonistas & inhibidores , Proteínas de Caenorhabditis elegans/genética , Relación Dosis-Respuesta a Droga , Proteínas de Choque Térmico/antagonistas & inhibidores , Proteínas de Choque Térmico/genética , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiologíaRESUMEN
1. The present article reviews the role of immune-competent cells infiltrating the kidney and their association with oxidative stress and renal angiotensin activity in the development of salt-sensitive hypertension. 2. We discuss changes in the pressure-natriuresis relationship resulting from renal inflammation and its improvement resulting from immunosuppressive treatment. 3. The potential role of T-cell-driven reactivity in sustaining the renal inflammation is examined in the light of accumulating evidence of autoimmune mechanisms in experimental and clinical hypertension.
Asunto(s)
Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/inmunología , Autoinmunidad , Hipertensión/etiología , Hipertensión/inmunología , Nefritis/fisiopatología , Cloruro de Sodio Dietético/efectos adversos , Animales , Autoanticuerpos/análisis , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/fisiopatología , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas de Choque Térmico/antagonistas & inhibidores , Proteínas de Choque Térmico/metabolismo , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Túbulos Renales/inmunología , Túbulos Renales/fisiopatología , Macrófagos/inmunología , Natriuresis , Linfocitos T/inmunologíaRESUMEN
Molecular chaperones (or heat shock proteins) are evolutionarily conserved and essential proteins that play a key role in cell survival through cytoprotective mechanisms. Despite their possible clinical applications, the understanding of these structures is still quite limited. The aim of the present study is to review the literature to understand the physiological importance, implication in various diseases (especially in cancer and neurodegenerative diseases), possible applicability, and future prospects of heat shock proteins. The cytoprotective mechanisms of molecular chaperones can be co-opted by oncogenic processes favoring tumor growth, invasion, evasion of apoptosis, and metastasis, thus making inhibitors to these molecules possible therapeutic options for cancer patients. However, there is also evidence showing that upregulation of heat shock proteins can have an antineoplastic effect through immunomodulatory activity. This is why chaperones have already been investigated for conventional chemotherapy under specific conditions, yielding interesting results. The induction of heat shock protein activity is also of potential benefit in many other diseases where structural and functional preservation of proteins may enhance cell survival, including neurodegeneration, trauma, stroke, and cardiovascular disease. In addition, the immune properties of chaperones can potentially be exploited for such diseases as diabetes, atherosclerosis, and other chronic inflammatory conditions. Thus, continuing efforts to clarify the role of chaperones may guide the development of new therapeutic modalities capable of minimizing the impact of diseases such as cancer, heart disease, and diabetes as well as obtaining better results in neurological conditions currently lacking alternative treatments.
Asunto(s)
Chaperonas Moleculares/fisiología , Neoplasias/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Animales , Proteínas de Choque Térmico/antagonistas & inhibidores , Proteínas de Choque Térmico/biosíntesis , Proteínas de Choque Térmico/inmunología , Proteínas de Choque Térmico/fisiología , Humanos , Chaperonas Moleculares/antagonistas & inhibidores , Chaperonas Moleculares/biosíntesis , Chaperonas Moleculares/inmunología , Neoplasias/inmunología , Neoplasias/metabolismo , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/metabolismo , Pliegue de ProteínaRESUMEN
Aerobic bacteria, such as Burkholderia xenovorans LB400, are able to degrade a wide range of polychlorobiphenyls (PCBs). Generally, these bacteria are not able to transform chlorobenzoates (CBAs), which accumulate during PCB degradation. In this study, the effects of CBAs on the growth, the morphology and the proteome of Burkholderia xenovorans LB400 were analysed. 4-CBA and 2-CBA were observed to inhibit the growth of strain LB400 on glucose. Strain LB400 exposed to 4-CBA exhibited increased number and size of electron-dense granules in the cytoplasm, which could be polyphosphates. Two-dimensional (2-D) polyacrylamide gel electrophoresis was used to characterise the molecular response of strain LB400 to 4-CBA. This compound induced the enzymes BenD and CatA of benzoate and catechol catabolic pathways. The induction of molecular chaperones DnaK and HtpG by 4-CBA indicated that the exposure to this compound constitutes a stressful condition for this bacterium. Additionally, the induction of some Krebs cycle enzymes was observed, probably as response to cellular energy requirements. This study contributes to the knowledge on the effects of CBA on the PCB-degrader Burkholderia xenovorans LB400.
Asunto(s)
Burkholderia/efectos de los fármacos , Clorobenzoatos/farmacología , Proteínas de Choque Térmico/biosíntesis , Bifenilos Policlorados/farmacocinética , Proteoma/metabolismo , Biodegradación Ambiental , Burkholderia/enzimología , Burkholderia/crecimiento & desarrollo , Burkholderia/metabolismo , Electroforesis en Gel Bidimensional/métodos , Proteínas de Choque Térmico/antagonistas & inhibidores , Proteínas de Choque Térmico/metabolismo , Microscopía Electrónica/métodos , Factor G de Elongación Peptídica/genética , Factor G de Elongación Peptídica/metabolismo , Bifenilos Policlorados/metabolismo , Análisis de Secuencia de ProteínaRESUMEN
Cellular prion protein (PrP(C)) is a cell surface glycoprotein that interacts with several ligands such as laminin, NCAM (Neural-Cell Adhesion Molecule) and the stress-inducible protein 1 (STI1). PrP(C) association with these proteins in neurons mediates adhesion, differentiation and protection against programmed cell death. Herein, we used an aversively motivated learning paradigm in rats to investigate whether STI1 interaction with PrP(C) affects short-term memory (STM) formation and long-term memory (LTM) consolidation. Blockage of PrP(C)-STI1 interaction with intra-hippocampal infusion of antibodies against PrP(C) or STI1 immediately after training impaired both STM and LTM. Furthermore, infusion of PrP(C) peptide 106-126, which competes for PrP(C)-STI1 interaction, also inhibited both forms of memory. Remarkably, STI1 peptide 230-245, which includes the PrP(C) binding site, had a potent enhancing effect on memory performance, which could be blocked by co-treatment with the competitive PrP(C) peptide 106-126. Taken together, these results demonstrate that PrP(C)-STI1 interaction modulates both STM and LTM and suggests a potential use of ST11 peptide 230-245 as a pharmacological agent.