Navegando por Palavras-chave "autophagy"
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- ItemSomente MetadadadosAC-1001 H3 CDR peptide induces apoptosis and signs of autophagy in vitro and exhibits antimetastatic activity in a syngeneic melanoma model(Wiley, 2016) Rabaca, Aline N. [UNIFESP]; Arruda, Denise C. [UNIFESP]; Figueiredo, Carlos R. [UNIFESP]; Massaoka, Mariana H. [UNIFESP]; Farias, Camyla F. [UNIFESP]; Tada, Dayane B. [UNIFESP]; Maia, Vera C.; Silva Junior, Pedro I.; Girola, Natalia [UNIFESP]; Real, Fernando [UNIFESP]; Mortara, Renato A. [UNIFESP]; Polonelli, Luciano; Travassos, Luiz R. [UNIFESP]Antibody-derived peptides modulate functions of the immune system and are a source of anti-infective and antitumor substances. Recent studies have shown that they comprise amino acid sequences of immunoglobulin complementarity-determining regions, but also fragments of constant regions. V-H CDR3 of murine mAb AC-1001 displays antimetastatic activities using B16F10-Nex2 murine melanoma cells in a syngeneic model. The peptide was cytotoxic in vitro in murine and human melanoma cells inducing reactive oxygen species (ROS) and apoptosis by the intrinsic pathway. Signs of autophagy were also suggested by the increased expression of LC3/LC3II and Beclin 1 and by ultrastructural evidence. AC-1001 H3 bound to both G- and F-actin and inhibited tumor cell migration. These results are important evidence of the antitumor activity of Ig CDR-derived peptides.
- ItemSomente MetadadadosAutophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications(Frontiers Media Sa, 2018) Uddin, Md. Sahab; Stachowiak, Anna; Al Mamun, Abdullah; Tzvetkov, Nikolay T.; Takeda, Shinya; Atanasov, Atanas G.; Bergantin, Leandro B. [UNIFESP]; Abdel-Daim, Mohamed M.; Stankiewicz, Adrian M.Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid beta (A beta), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of A beta is dysregulated, which leads to the accumulation and aggregation of A beta. Metabolism of A beta and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.
- ItemSomente MetadadadosAvaliação dos gens atg8,ams1 e hrr25 do patógeno cryptococcus neoformans: impactos sobre os fatores de virulência e autofagia(Universidade Federal de São Paulo (UNIFESP), 2016-08-31) Lima, Ricardo Ferreira [UNIFESP]; Pascon, Renata Castiglioni Pascon [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Invasive fungal infections (IFES) increase exponentially in recent years. The IFIs are difficult to treat due to limited options of antifungals, especially cryptococcosis, which presents itself as an infection that causes high mortality in immunocompromised individuals affected by AIDS, transplant or undergoing chemotherapy. The etiological agent of this disease; Cryptococcus neoformans is an opportunistic yeast that besides the medical importance, it is also an excellent biological study model. This micro-organism is easy to grow and genetically manipulate that enable the analysis of the molecular attributes related to pathogenesis. C. neoformans expressed many virulence factors during the infection process, among these, the thermotolerance that enables it to develop at 37°C. In this yeast it was isolated and characterized the mutant ape4 unable to grow at 37°C. The APE4 protein is involved in Cytoplasm to Vacuole Targeting (Cvt) process and autophagy, in Saccharomyces cerevisiae. In S. cerevisiae there are seven proteins involved in the Cvt process (HRR25, ATG8, ATG11, ATG19, APE1, APE4 e AMS1). Using these S. cerevisiae sequences to browse the C. neoformans database at the Broad Institute, we found only 4 sequences (ATG8, AMS1 e HRR25) that are homolog to S. cereivisiae. Therefore, the objective of this study is to explore the biological function of the 3 proteins in C. neoformans relating them to the capacity of this yeast grow at physiological temperature of mammals and autophagy. Moreover, the study of HRR25 coding gene will be further explored using the Degron technique, which is currently being established in C. neoformans.
- ItemSomente MetadadadosCharacterization of unusual families of ATG8-like proteins and ATG12 in the protozoan parasite Leishmania major(Landes Bioscience, 2009-02-16) Williams, Roderick A. M.; Woods, Kerry L.; Juliano, Luiz [UNIFESP]; Mottram, Jeremy C.; Coombs, Graham H.; Univ Strathclyde; Univ Glasgow; Universidade Federal de São Paulo (UNIFESP)Leishmania major possesses, apparently uniquely, four families of ATG8-like genes, designated ATG8, ATG8A, ATG8B and ATG8C, and 25 genes in total. L. major ATG8 and examples from the ATG8A, ATG8B and ATG8C families are able to complement a Saccharomyces cerevisiae ATG8-deficient strain, indicating functional conservation. Whereas ATG8 has been shown to form putative autophagosomes during differentiation and starvation of L. major, ATG8A primarily form puncta in response to starvation-suggesting a role for ATG8A in starvation-induced autophagy. Recombinant ATG8A was processed at the scissile glycine by recombinant ATG4.2 but not ATG4.1 cysteine peptidases of L. major and, consistent with this, ATG4.2-deficient L. major mutants were unable to process ATG8A and were less able to withstand starvation than wad-type cells. GFP-ATG8-containing puncta were less abundant in ATG4.2 overexpression lines, in which unlipidated ATG8 predominated, which is consistent with ATG4.2 being an ATG8-deconjugating enzyme as well as an ATG8A-processing enzyme. In contrast, recombinant ATG8, ATG8B and ATG8C were all processed by ATG4.1, but not by ATG4.2. ATG8B and ATG8C both have a distinct subcellular location close to the flagellar pocket, but the occurrence of the GFP-labeled puncta suggest that they do not have a role in autophagy. L. major genes encoding possible ATG5, ATG10 and ATG12 homologues were found to complement their respective S. cerevisiae mutants, and ATG12 localized in part to ATG8-containing puncta, suggestive of a functional ATG5-ATG12 conjugation pathway in the parasite. L. major ATG12 is unusual as it requires C-terminal processing by an as yet unidentified peptidase.
- ItemAcesso aberto (Open Access)Dopamine induces the accumulation of insoluble prion protein and affects autophagic flux(Frontiers Research Foundation, 2015-02-02) Luz, Marcio Henrique Mello da [UNIFESP]; Peres, Italo T. [UNIFESP]; Santos, Tiago G.; Martins, Vilma R.; Icimoto, Marcelo Yudi [UNIFESP]; Lee, Kil Sun [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Univ Metodista São Paulo; AC Camargo Canc CtrAccumulation of protein aggregates is a histopathological hallmark of several neurodegenerative diseases, but in most cases the aggregation occurs without defined mutations or clinical histories, suggesting that certain endogenous metabolites can promote aggregation of specific proteins. One example that supports this hypothesis is dopamine and its metabolites. Dopamine metabolism generates several oxidative metabolites that induce aggregation of alpha-synuclein, and represents the main etiology of Parkinson's diseases. Because dopamine and its metabolites are unstable and can be highly reactive, we investigated whether these molecules can also affect other proteins that are prone to aggregate, such as cellular prion protein (PrPC). in this study, we showed that dopamine treatment of neuronal cells reduced the number of viable cells and increased the production of reactive oxygen species (ROS) as demonstrated in previous studies. Overall PrPC expression level was not altered by dopamine treatment, but its unglycosylated form was consistently reduced at 100 mu M of dopamine. At the same concentration, the level of phosphorylated mTOR and 4EBP1 was also reduced. Moreover, dopamine treatment decreased the solubility of PrPC, and increased its accumulation in autophagosomal compartments with concomitant induction of LC3-II and p62/SQSTM1 levels. in vitro oxidation of dopamine promoted formation of high-order oligomers of recombinant prion protein. These results suggest that dopamine metabolites alter the conformation of PrPC, which in turn is sorted to degradation pathway, causing autophagosome overload and attenuation of protein synthesis. Accumulation of PrPC aggregates is an important feature of prion diseases. Thus, this study brings new insight into the dopamine metabolism as a source of endogenous metabolites capable of altering PrPC solubility and its subcellular localization.
- ItemSomente MetadadadosMecanismo de ação do composto paladaciclo ferroceno 1:2 em modelos celulares de resistência e metástase tumoral(Universidade Federal de São Paulo (UNIFESP), 2016-06-30) Bechara, Alexandre [UNIFESP]; Trindade, Claudia Bincoletto Trindade [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Cancer therapy is one of the major challenges for medicine since 20th century, when the mechanisms of tumor cell biology in cancer development began to be better understood. Although some pharmacological therapeutic strategies can lead to complete remission, the vast majority of cases eventually relapses and develops into distant metastases, making the pharmacological therapeutic of cancer a complexity theme. The comprehensive understanding of the cellular cues and molecular pathways involved in cell death during new drugs development and more effective therapy approaches are needed. Given the above, this study aimed to elucidate the cellular and molecular mechanisms of the palladacycle Ferrocene 1: 2 (PF12) compound, an emerging antitumor drug prototype, on human osteosarcoma (SaOS-2) and murine melanoma (B16F10 Nex2) cells. These cells lines (SaOS-2 and B16F10Nex2) were used as a model for tumor resistance to conventional anticancer therapy and metastasis, respectively. Through in vitro assays, we found that PF12 has a complex cellular mechanism due mainly, its lysosomotropic features. This cellular effect was associated with the presence of the ferrocene group in its molecule. As a result of the PF12 effects on lysosomes, vesicular acids compartments reduction was observed with the release of calcium from lysosomal stores with extravasation of cathepsin B too. Both (calcium and cathepsin B) have emerged as crucial factors in the cytotoxicity of the compound in Saos-2 cells as their inhibition before PF12 exposure decreased PF12-induced Saos-2 cell death. Furthermore, PF12 induced autophagy in these cells, which appears to occur as a response to the induced damage. Nevertheless, we found that PF12 also showed significant antitumor activity in vivo, reducing the number of lung nodules of melanoma cells in mice. In vitro studies with melanoma cells have demonstrated a cytotoxic action in 24 hours incubation and an inhibitory activity on the tumor cells migration and invasion after 1 hour of exposure. It was also observed that both inhibition and induction of autophagy in this cells (B16F10-Nex2 ) enhanced PF12 cytotoxicity. In cell migration process, when autophagy induction was followed by PF12 exposure, B16F10-Nex2 cells migration ability was significantly reduced. In relation to cellular invasion process, autophagy induction increased cell invasiveness, and the associations between autophagy inhibitor with PF12 and autophagy induction followed by PF12 exposure significantly reduced compound's anti-invasiveness activity. Considering all obtained data, we conclude that PF12 shows significant effectiveness as a cytotoxic compound with the capacity to interact with multiple targets, as well as to consider as a possible ant metastatic agent.
- ItemSomente MetadadadosmTOR inhibitors in pancreas transplant: adverse effects and drug-drug interactions(Taylor & Francis Ltd, 2017) Fernandes-Silva, Gabriel [UNIFESP]; de Paula, Mayara Ivani [UNIFESP]; Rangel, Erika B. [UNIFESP]Introduction: Patient and pancreas allograft survival improved following reductions in surgical complications, tighter donor selection and optimization in immunosuppressive protocols. However, long-term survival of pancreas allografts is adversely affected by rejection and immunosuppressive regimen toxicity.Areas covered: This article reviews the existing literature and knowledge of mammalian target of rapamycin inhibitors (mTORi). Some clinically relevant drug-drug interactions are highlighted. We summarize the nephrotoxic and diabetogenic mechanisms of mTORi after pancreas transplant, the alternatives to minimize these effects, and report on other adverse events.Expert opinion: Calcineurin inhibitor (CNI)-based regimens remain the mainstay treatment after pancreas-kidney transplant. However, long-term use of CNIs may be associated with nephrotoxicity. Switching from CNIs to mTORi (sirolimus/SRL and everolimus/EVR) may preserve kidney function, mainly EVR conversion. However, mTORi promote an imbalance of mTOR signaling during long-term follow-up and may ultimately contribute to proteinuria and hyperglycemia. These drugs disrupt autophagy, inhibit cell proliferation, and downregulate VEGF. Therefore, it is important to comprehend and interpret the experimental data. It is equally important to critically analyze clinical studies. Of importance, minimization of side effects, based on safe approaches, can prolong kidney allograft survival. Additional randomized-controlled studies are required to assess the impact of mTORi on pancreas allograft survival.
- ItemAcesso aberto (Open Access)Osteoporosis and autophagy: What is the relationship?(Assoc Medica Brasileira, 2017) Florencio-Silva, Rinaldo [UNIFESP]; da Silva Sasso, Gisela Rodrigues [UNIFESP]; Simoes, Manuel de Jesus [UNIFESP]; Simoes, Ricardo Santos; Pinheiro Baracat, Maria Candida; Sasso-Cerri, Estela; Cerri, Paulo SergioAutophagy is a survival pathway wherein non-functional proteins and organelles are degraded in lysosomes for recycling and energy production. Therefore, autophagy is fundamental for the maintenance of cell viability, acting as a quality control process that prevents the accumulation of unnecessary structures and oxidative stress. Increasing evidence has shown that autophagy dysfunction is related to several pathologies including neurodegenerative diseases and cancer. Moreover, recent studies have shown that autophagy plays an important role for the maintenance of bone homeostasis. For instance, in vitro and animal and human studies indicate that autophagy dysfunction in bone cells is associated with the onset of bone diseases such as osteoporosis. This review had the purpose of discussing the issue to confirm whether a relationship between autophagy dysfunction and osteoporosis exits.
- ItemSomente MetadadadosOverexpression of -synuclein in an astrocyte cell line promotes autophagy inhibition and apoptosis(Wiley, 2018) Erustes, Adolfo Garcia [UNIFESP]; Stefani, Fernanda Yakel [UNIFESP]; Terashima, Juliana Yoshie [UNIFESP]; Stilhano, Roberta Sessa [UNIFESP]; Monteforte, Priscila Totarelli [UNIFESP]; da Silva Pereira, Gustavo Jose [UNIFESP]; Han, Sang Won [UNIFESP]; Calgarotto, Andrana Karla; Hsu, Yi-Te; Ureshino, Rodrigo Portes [UNIFESP]; Bincoletto, Claudia [UNIFESP]; Smaili, Soraya Soubhi [UNIFESP]α‐Synuclein is the major component of neuronal cytoplasmic aggregates called Lewy bodies, the main pathological hallmark of Parkinson disease. Although neurons are the predominant cells expressing α‐synuclein in the brain, recent studies have demonstrated that primary astrocytes in culture also express α‐synuclein and regulate α‐synuclein trafficking. Astrocytes have a neuroprotective role in several detrimental brain conditions; we therefore analyzed the effects of the overexpression of wild‐type α‐synuclein and its A30P and A53T mutants on autophagy and apoptosis. We observed that in immortalized astrocyte cell lines, overexpression of α‐synuclein proteins promotes the decrease of LC3‐II and the increase of p62 protein levels, suggesting the inhibition of autophagy. When these cells were treated with rotenone, there was a loss of mitochondrial membrane potential, especially in cells expressing mutant α‐synuclein. The level of this decrease was related to the toxicity of the mutants because they show a more intense and sustained effect. The decrease in autophagy and the mitochondrial changes in conjunction with parkin expression levels may sensitize astrocytes to apoptosis.
- ItemAcesso aberto (Open Access)Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma(Impact Journals Llc, 2017) Pereira Eugenio, Angela Isabel [UNIFESP]; Fook-Alves, Veruska Lia [UNIFESP]; de Oliveira, Mariana Bleker [UNIFESP]; Fernando, Rodrigo Carlini [UNIFESP]; Zanatta, Daniela B.; Strauss, Bryan Eric; Regis Silva, Maria Regina [UNIFESP]; Porcionatto, Marimelia Aparecida [UNIFESP]; Braga Colleoni, Gisele Wally [UNIFESP]HSP70 connects multiple signaling pathways that work synergistically to protect tumor cells from death by proteotoxic stress and represents a possible target to establish a new approach for multiple myeloma treatment. Therefore, bioluminescent cell lines RPMI8226-LUC-PURO and U266-LUC-PURO were treated with HSP70 (VER155008) and/or proteasome (bortezomib) inhibitors and immunodeficient mice were used for subcutaneous xenograft models to evaluate tumor growth reduction and tumor growth inhibition after treatment. Bioluminescence imaging was used to follow tumor response. Treatment with bortezomib showed similar to 60% of late apoptosis in RPMI8226-LUC-PURO (without additional benefit of VER155008 in this cell line). However, U266-LUC-PURO showed similar to 60% of cell death after treatment with VER155008 (alone or with bortezomib). RPMI8226-LUC-PURO xenograft presented tumor reduction by bioluminescence imaging after treatment with bortezomib, VER155008 or drug combination compared to controls. Treatment with bortezomib, alone or combined with VER155008, showed inhibition of tumor growth assessed by bioluminescence imaging after one week in both RPMI8226-LUC-PURO and U266-LUC-PURO cell lines when compared to controls. In conclusion, our study shows that the combination of proteasome and HSP70 inhibitors induced cell death in tumor cells in vitro (late apoptosis induction) and in vivo (inhibition of tumor growth) with special benefit in U266-LUC-PURO, bearing 17p deletion.