1,720,995 research outputs found
Autophagy, physiology and cell pathology
Get PDFAutophagy plays an important role in human pathologies, such as myopathies and neurodegenerative diseases. Moreover, metabolic disease processes such as diabetes and pancreatitis, as well as tumor cells and cancer chemotherapy, activate autophagy. Furthermore, a selective type of autophagy of pancreatic zymogen granules has been discovered and characterized as a protective cellular process triggered by acute pancreatitis. In this review we describe the physiological bases and molecular mechanisms in the autophagic process and the possible role of autophagy in human disease. Understanding the events and molecular mechanisms of this complex cellular process will help in the design of new strategies for more effective diagnosis and treatment.Fil: Vaccaro, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentin
Autophagy and pancreas disease
Get PDFAutophagy is an evolutionarily preserved degradation process of cytoplasm cellular constituents, which has been known for its roles in protecting cells against stresses such as starvation and in eliminating defective cellular constituents including sub-cellular structures. It is essentially a form of self-cannibalism hence the name that means, “self-eating” in which the cell breaks down its own components. By mostly morphological studies, autophagy has been linked to a variety of pathological processes such as neurodegenerative diseases and tumorigenesis, which highlights its biological and medical importance. However, whether autophagy protects from or causes disease is unclear. Autophagic morphology was described in human pancreatitis by Helin H. et al in 1980. Actually, acute pancreatitis is one of the earlier pathological processes where autophagy has been described in a human tissue. Autophagy, autodigestion and cell death are early cellular events in acute pancreatitis. The aim of this review is to introduce a description of the autophagic process and to discuss the possible role of autophagy in acute pancreatitis.Fil: Vaccaro, Maria Ines. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin
Beclin 1
Get PDFBeclin 1/ATG6/Vps30 (UniProtKB/Swiss-Prot Q14457) is a 450 amino-acids length protein, with three domains; BH3 (aminoacid 114 to 123), Coiled Coil domain (CCD; aminoacid 144 to 269) and the Evolutionarily Conserved Domain (ECD; aminoacid 244 to 337). BH3 proteins are part of the Bcl-2 family; they are pro-apoptotic damage sensors that play an important role in protecting against cancer (1). The BH3-only domain of Beclin 1 can interact with Bcl-2 and Bcl-XL (2;3). Both cellular and viral Bcl-2 (vBcl-2), or more specifically ER-targeted Bcl-2, inhibit Beclin 1-dependent autophagy by interfering with the Beclin 1-PtdIns 3-kinase interaction (PI3K) and the Beclin 1-associated PI3K activity (3,4). The interaction between Bcl-2 and Beclin 1 is greatly reduced upon starvation, which suggests that the dissociation of Bcl-2 from Beclin1 is important for activating autophagy. We demonstrated that, VMP1 (Vacuole Membrane Protein 1) displaces Bcl-2 from Beclin 1, partitioning Beclin 1 to the autophagic pathway (Molejon et al., Sci Rep. 2012; In press).Fil: Molejon, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; ArgentinaFil: Ropolo, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; ArgentinaFil: Vaccaro, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentin
VMP1 is a new player in the regulation of the autophagy-specific phosphatidylinositol 3-kinase complex activation
Get PDFWe have elucidated a novel mechanism through which the autophagy-specific class III phosphatidylinositol 3-kinase (PtdIns3K) complex can be recruited to the PAS in mammalian cells, through the interaction between BECN1 and the vacuole membrane protein 1 (VMP1), an integral autophagosomal membrane protein. This interaction involves the binding between the C-terminal 20 amino acids of the VMP1 hydrophilic domain, which we have named the VMP1 autophagy-related domain (VMP1-AtgD), and the BH3 domain of BECN1. The association between these two proteins allows the formation of the autophagy-specific PtdIns3K complex, which activity favors the generation of phosphatidylinositol-3-phosphate (PtdIns3P) and the subsequent association of the autophagy-related (ATG) proteins, including ATG16L1, with the phagophore membranes. Therefore, VMP1 regulates the PtdIns3K activity on the phagophore membrane through its interaction with BECN1. Our data provide a novel model describing one of the key steps in phagophore assembly site (PAS) formation and autophagy regulation, and positions VMP1 as a new interactor of the autophagy-specific PtdIns3K complex in mammalian cells.Fil: Molejon, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina;Fil: Ropolo, Alejandro Javier. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina;Fil: Vaccaro, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina
The VMP1-Beclin 1 interaction regulates autophagy induction
Get PDFFil: Molejon, Maria Ines. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina;Fil: Ropolo, Alejandro Javier. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina;Fil: Lo Ré, Andrea Emilia. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina;Fil: Boggio, Veronica Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiopatología; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina;Fil: Vaccaro, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina
Translational Pancreatology. New Approaches in the Development of Novel Biomarkers as Screening Methodologies for Pancreatic Cancer
Get PDFPancreatic Ductal Adenocarcinoma (PDAC) is one of the rare cancers for which no significant improvements in diagnosis and therapy have been made in the last 30 years. Despite considerable progress the median survival of most patients is 5 to 6 months. Currently, 80% of patients diagnosed with pancreatic adenocarcinoma present with locally invasive and/or metastatic disease, resulting in a poor 5-year survival of <5%. Hence, less than 20% of patients with PDAC undergo potentially curative surgery, whereas the remaining patients, can only be offered palliative treatment. Only 15–20% of patients undergo resection. The development of a diagnostic tool for early detection of patients with this malignancy may significantly impact their prognosis. Pancreatic cancer has a strong correlation between tumor stage and prognosis. The size of the tumors is also important in a general sense, the smaller ones have metastases less frequently than the larger ones at the time of diagnosis and, therefore, are more likely to be cured by surgery. Therefore, it is evident that the earliest detection of cancers is one of the keys to reducing deaths from these diseases and this includes the cancer of the pancreas with its high mortality rates. However, effective early diagnosis remains difficult and depends mainly on imaging modalities and the development of screening methodologies with highly sensitive and specific biomarkers. This review summarizes recent advances in effective screening for early diagnosis of PDAC using novel molecular biomarkers discovered from various studies including protein biomarkers, mutant DNA templates identified in the circulation in blood samples (ctDNA), DNA promoter hypermethylation and measurement of microRNA as other possible noninvasive biomarker for early detection of Pancreatic Cancer. These data have high translational relevance and suggest that early detection is the key issue for improving the prognosis of this aggressive disease. Although many biomarkers for early detection of Pancreatic Cancer (PC) have been discovered through various methods, effective panels of noninvasive biomarkers for screening and early detection of Pancreatic Ductal Adenocarcinoma (PDAC) are not available yet. The increased number of translational studies would be able to provide this remarkable diagnostic tool in a near future. Nevertheless, larger scale and rigorous validation is required before their application in the clinic. ofPDAC using novel molecular biomarkers discovered from various studies including proteinbiomarkers, mutant DNA templates identified in the circulation in blood samples (ctDNA),DNA promoter hypermethylation and measurement of microRNA as other possiblenoninvasive biomarker for early detection of Pancreatic Cancer.These data have high translational relevance and suggest that early detection is the keyissue for improving the prognosis of this aggressive disease. Although many biomarkers forearly detection of Pancreatic Cancer (PC) have been discovered through various methods,effective panels of noninvasive biomarkers for screening and early detection of PancreaticDuctal Adenocarcinoma (PDAC) are not available yet.The increased number of translational studies would be able to provide this remarkablediagnostic tool in a near future. Nevertheless,Fil: Vaccaro, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Resnik, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentin
Secretory Autophagy and Its Relevance in Metabolic and Degenerative Disease
Get PDFProteins to be secreted through so-called “conventional mechanisms” are characterized by the presence of an N-terminal peptide that is a leader or signal peptide, needed for access to the endoplasmic reticulum and the Golgi apparatus for further secretion. However, some relevant cytosolic proteins lack of this signal peptides and should be secreted by different unconventional or “non-canonical” processes. One form of this unconventional secretion was named secretory autophagy (SA) because it is specifically associated with the autophagy pathway. It is defined by ATG proteins that regulate the biogenesis of the autophagosome, its representative organelle. The canonical macroautophagy involves the fusion of the autophagosomes with lysosomes for content degradation, whereas the SA pathway bypasses this degradative process to allow the secretion. ATG5, as well as other factors involved in autophagy such as BCN1, are also activated as part of the secretory pathway. SA has been recognized as a new mechanism that is becoming of increasing relevance to explain the unconventional secretion of a series of cytosolic proteins that have critical biological importance. Also, SA may play a role in the release of aggregation-prone protein since it has been related to the autophagosome biogenesis machinery. SA requires the autophagic pathway and both, secretory autophagy and canonical degradative autophagy are at the same time, integrated and highly regulated processes that interact in ultimate cross-talking molecular mechanisms. The potential implications of alterations in SA, its cargos, pathways, and regulation in human diseases such as metabolic/aging pathological processes are predictable. Further research of SA as potential target of therapeutic intervention is deserved.Fil: González, Claudio Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Resnik, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Vaccaro, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentin
Autophagy in development, cell differentiation, and homeodynamics: from molecular mechanisms to diseases and pathophysiology
Get PDFThe focus of this special issue is to highlight the role of autophagy in cellular homeodynamics, cell differentiation, and development with an outlook to diseases. Autophagy is an evolutionarily conserved catabolic process where cytoplasmic components are sequestered into double-membrane vesicles called autophagosomes, which then fuse with lysosomes and their content is degraded. Despite the significant progress observed over recent years in our understanding of the molecular mechanisms of autophagy, the elucidation of its role in developmental processes still remains a challenge for the scientific community. Given the role of autophagy in pathophysiology and diseases, it is essential to uncover how the mechanisms of autophagy function during developmental processes in the context of tissue and organismal physiology. This special issue contains a collection of four original research papers, four review articles, and one methodology report, covering a broad range of topics.Fil: Nezis, Ionnis P.. University of Warwick; Reino UnidoFil: Vaccaro, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Devenish, Rodney J.. Monash University; AustraliaFil: Juhász, Gábor. Eötvös University, Budapest; Argentin
Targeting Autophagy In Cancer Therapy
No full textMacroautophagy is a physiological cellular process that sequesters senescent or damaged organelles and proteins in autophagosomes for recycling of their products. Autophagy is also involved in the removal of cells that have undergone classical type 1 apoptosis. Hence, autophagy can be generally considered as a protector of cells against various stressors and a cellular response to routine wear-and-tear. On the other hand, autophagy may also lead to a form of non-apoptotic cell death, which is called type 2 programmed cell death. Thus, autophagy can either protect cells or promote cell death, depending on the cellular and environmental context. So far, contradictory data are available regarding the activity of autophagy and its regulation in cancer cells. In nonmalignant healthy tissues, autophagy seems to suppress the transition of normal to cancer cells. In addition, an exaggerated autophagy rate might drive neoplastic cells to death through several mechanisms, many of which are still not elucidated. Nevertheless, experimental evidence pointed at autophagy as a cancer cell mechanism to survive under adverse environmental conditions, or as a defective programmed cell death mechanism that favors cancer cell resistance to treatment. In the end, the role of autophagy in cancer is complex and it seems to depend on histology, stage, and multiple genetic variations and epigenetic changes. The tumor surrounding microenvironment exhibits a very complex set of interactions with autophagy at cancer tissues and represents another factor that is able to regulate tumor cell-kinetics and growth, as well as the response to therapies. In summary, while there is certain evidence that autophagy may act as a barrier to tumor initiation in some specific tissues, there is mounting evidence that autophagy has a significant pro-tumorigenic role in established cancers. Cancer therapies, including chemotherapy, radiotherapy and immunotherapy, are also associated with relevant changes into the autophagy intensity and flow. Some antineoplastic agents increase the autophagy rate; some other are associated with a reduction of the autophagy rate. Autophagy may modulate anticancer immunity by affecting several cellular and humoral mechanisms involved at these critical processes. Immunotherapeutic agents recently introduced in oncology clearly induce relevant modifications on autophagy flow in several tumor types. In addition, it has been demonstrated that certain non-antineoplastic drugs may exert some autophagy inducing effect on cancer cells. On the other hand, other agents block autophagy flow synergizing with the effect of some antineoplastic agents. Autophagy modulation is at this moment, a clear target for further development of cancer therapy. A description of the mechanisms that regulate autophagy in cancer cells and their surrounding micro-environment and the potential consequences of the pharmacologically induced modifications of these processes, constitute the main objective of this chapter.Fil: Vaccaro, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: González, Claudio Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentin
Glycoconjugation: An approach to cancer therapeutics
Get PDFCancer constitutes the second leading cause of death globally and is consideredto have been responsible for an estimated 9.6 million fatalities in 2018. Although treatments against gastrointestinal tumors have recently advanced, those interventions can only be applied to a minority of patients at the time ofdiagnosis. Therefore, new therapeutic options are necessary for advanced stagesof the disease. Glycosylation of antitumor agents, has been found to improvepharmacokinetic parameters, reduce side effects, and expand drug half-life incomparison with the parent compounds. In addition, glycosylation of therapeuticagents has been proven to be an effective strategy for their targeting tumor tissue, thereby reducing the doses of the glycodrugs administered to patients. This review focusses on the effect of the targeting properties of glycosylated antitumor agents on gastrointestinal tumors.Fil: Molejon, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias de la Tierra y Ambientales de La Pampa. Universidad Nacional de La Pampa. Facultad de Ciencias Exactas y Naturales. Instituto de Ciencias de la Tierra y Ambientales de La Pampa; ArgentinaFil: Weiz, Gisela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias de la Tierra y Ambientales de La Pampa. Universidad Nacional de La Pampa. Facultad de Ciencias Exactas y Naturales. Instituto de Ciencias de la Tierra y Ambientales de La Pampa; ArgentinaFil: Breccia, Javier Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias de la Tierra y Ambientales de La Pampa. Universidad Nacional de La Pampa. Facultad de Ciencias Exactas y Naturales. Instituto de Ciencias de la Tierra y Ambientales de La Pampa; ArgentinaFil: Vaccaro, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentin
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