Autophagy in Human Health and Disease

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
New England Journal of Medicine (Impact Factor: 55.87). 02/2013; 368(7):651-62. DOI: 10.1056/NEJMra1205406
Source: PubMed
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Available from: Stefan W Ryter, Feb 01, 2015
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    • "In autophagy, portions of membranes are sequestered at the cytosol and form a double membrane structure denominated autophagosomes (Kumar et al. 2013). The MAP-LC3 system acts as regulatory machinery in which the microtubule-associated protein 1 light chain 3B (LC3B) is a useful marker for identifying autophagosomes because it is located in their membranes (Choi et al. 2013; Tanida 2011). Autophagy plays an important role in the pathogenicity of many bacteria, and its study is increasing in order to understand whether the process acts against the pathogen, as a protective role in the host cell, or whether the pathogen takes advantage of it (Deretic and Levine 2009; Herr and Finley 2013; Liu and Klionsky 2015). "
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    ABSTRACT: The MAP-LC3 system regulates the intracellular formation of autophagy-associated vacuoles. These vacuoles contain the LC3 protein; thus it has been utilized as a marker to identify autophagosomes. The aim of our study was to investigate whether Haemophilus influenzae strains and their supernatants could activate autophagy in human larynx carcinoma cell line (HEp-2). We demonstrate that higher expression of the LC3B-II protein was induced, particularly by nontypeable Haemophilus influenzae (NTHi) 49766 and by supernatants, containing <50 kDa proteins, of both strains. Ultrastructural studies demonstrate vacuoles with a double membrane and/or membrane material inside, showing similar features to those of autophagic vacuoles. Together, our findings demonstrate that H. influenzae strains and their supernatants trigger an autophagic process.
    Archives of Microbiology 11/2015; DOI:10.1007/s00203-015-1167-3 · 1.67 Impact Factor
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    • "However, the role of autophagy in cancer remains incompletely clear. In established tumours, some reports support that autophagy may offer a survival advantage on tumour cells, but contrasting findings also suggest that autophagy may also promote tumour cell death in apoptosis-resistant tumour cells (Choi et al., 2013). Thus, it is important to clarify the role of autophagy in different types of tumours. "
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    ABSTRACT: Xanthohumol is the major prenylated flavonoid in the hop plant (Humulus lupulus L.). The aim of our study was to determine the effects of xanthohumol on the U87 glioma cell line. In the present study, the U87 glioma cell line was treated with xanthohumol. Our results showed that xanthohumol reduced cell viability and induced apoptosis detected by the MTT assay and PI-Annexin V doubling staining, respectively, in glioma cells. In the acridine orange staining experiments, we also found that xanthohumol induced autophagy, as detected by flow cytometry and confocal microscopy. Western blot also showed that xanthohumol inhibited the Akt/mTOR/S6K pathway and promoted LC3-II formation and p62 degradation. Moreover, we found that the Erk inhibitor or JNK inhibitor could partially reversed the xanthohumol-induced LC3-II formation and cell death. Otherwise, autophagy inhibition by bafilomycin A1, Atg5 shRNA, or Atg7 shRNA partially protected xanthohumol-induced cell death. These findings indicated that xanthohumol may induce glioma cell death through induction of autophagy. In addition, we also demonstrated that xanthohumol inhibited tumour growth in a mouse xenograft model. In conclusion, xanthohumol may induce autophagy in glioma cells through both Akt/mTOR/S6K pathway and MAPK cascade and inhibit tumour growth in vivo. Our findings also support that autophagy induction may provide benefits to increasing therapeutic efficacy of anti-cancer drugs for the treatment of glioblastoma multiforme.
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    • "Consequently, using a pharmacological approach to re-establish physiological levels of autophagy may be beneficial in treating certain diseases. Nevertheless, several clinical trials are currently based on the employment of agents acting on autophagy induction (Choi et al, 2013; Jiang & Mizushima, 2014). "
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    ABSTRACT: Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately 0.3-0.5% of the population and is characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Cerebral cavernous malformation is a genetic disease that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Causative loss-of-function mutations have been identified in three genes, KRIT1 (CCM1), CCM2 (MGC4607), and PDCD10 (CCM3), which occur in both sporadic and familial forms. Autophagy is a bulk degradation process that maintains intracellular homeostasis and that plays essential quality control functions within the cell. Indeed, several studies have identified the association between dysregulated autophagy and different human diseases. Here, we show that the ablation of the KRIT1 gene strongly suppresses autophagy, leading to the aberrant accumulation of the autophagy adaptor p62/SQSTM1, defective quality control systems, and increased intracellular stress. KRIT1 loss-of-function activates the mTOR-ULK1 pathway, which is a master regulator of autophagy, and treatment with mTOR inhibitors rescues some of the mole-cular and cellular phenotypes associated with CCM. Insufficient autophagy is also evident in CCM2-silenced human endothelial cells and in both cells and tissues from an endothelial-specific CCM3-knockout mouse model, as well as in human CCM lesions. Furthermore, defective autophagy is highly correlated to endothelial-to-mesenchymal transition, a crucial event that contributes to CCM progression. Taken together, our data point to a key role for defective autophagy in CCM disease pathogenesis, thus providing a novel framework for the development of new pharmacological strategies to prevent or reverse adverse clinical outcomes of CCM lesions.
    EMBO Molecular Medicine 09/2015; 7(11). DOI:10.15252/emmm.201505316 · 8.67 Impact Factor
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