The roles of autophagy and hypoxia in human inflammatory periapical lesions

Huang, Hui; Wang, Wen-Chen; Lin, Peng; Huang, Cai; Chen, C. Y.; Chen, Y. K.

doi:10.1111/iej.12782

Cited by 30 publications

(51 citation statements)

References 44 publications

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“…After stably and rapidly accumulating in the nucleus under hypoxic conditions, HIF-1α binds with HIF-1β to activate the HIF-1 heterodimeric complex, which promotes the expression of hypoxia target genes through combining with the hypoxia response element (33,36,37). Studies have revealed that the associations between hypoxia and autophagy are mainly through HIF-1regulated expression of downstream target proteins BNIP3 and BNIP3L, which release Beclin1 to activate autophagy by disrupting the interaction between Beclin1 and Bcl-2/Bcl-xL complexes (33,(38)(39)(40). Another study has suggested that hypoxia-induced cancer cell autophagy was an HIF-1 independent pathway.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

et al. 2018

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Overcoming the chemoresistance of bladder cancer is a pivotal obstacle in clinical treatments. Hypoxia widely exists in solid tumors and has been demonstrated to contribute to chemoresistance through hypoxia-inducible factor 1α (HIF‑1α)-mediated autophagy in several types of cancer. However, it is unclear whether HIF‑1α-mediated autophagy and chemoresistance occur in bladder cancer. The present study demonstrated that HIF‑1α was overexpressed in 20 bladder cancer tissues compared with matched paracarcinoma tissues. Gemcitabine-induced apoptosis during hypoxia was significantly reduced compared with that observed under normoxic conditions. In addition, hypoxia activated autophagy and enhanced gemcitabine-induced autophagy. Combined treatment using gemcitabine and an autophagy inhibitor (3-methyladenine) under hypoxia significantly increased gemcitabine cytotoxicity. Furthermore, it was demonstrated that hypoxia-activated autophagy depended on the HIF‑1α/BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)/Beclin1 signaling pathway. Suppressing HIF‑1α inhibited autophagy, BNIP3 and Beclin1, as well as enhanced gemcitabine-induced apoptosis in bladder cancer cells under hypoxic conditions. Consequently, the results of the present study demonstrated that hypoxia-induced cytoprotective autophagy counteracted gemcitabine-induced apoptosis through increasing HIF‑1α expression. Therefore, targeting HIF‑1α-associated pathways or autophagy in bladder cancer may be a successful strategy to enhance the sensitivity of bladder cancer chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

et al. 2018

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“…As an essential regulator in hypoxia-induced bone development, Hypoxia-induced factor-1 alpha (HIF-1) has an important role in chondrogenesis and osteogenesis [87]. Huang et al investigated HIF-1, BNIP3, pAMPK, and autophagy-related proteins (LC3, beclin-1, Atg5-12, and p62) in human infl ammatory periapical lesions [88]. They evaluated samples from patients with radicular cysts (RCs), Periapical Granulomas (PGs) and healthy dental pulp tissues.…”

Section: Hypoxia and Autophagymentioning

confidence: 99%

“…They evaluated samples from patients with radicular cysts (RCs), Periapical Granulomas (PGs) and healthy dental pulp tissues. After immunohistochemical analysis, the expression of autophagy and hypoxia-related proteins in each group were compared with each other [88]. In periapical lesions, HIF-1, Bnip3, pAMPK, LC3II, and Atg5-12 proteins were signifi cantly higher than those in healthy dental pulp tissues [88].…”

Section: Hypoxia and Autophagymentioning

confidence: 99%

Autophagy and the potential linkage with the human oral diseases

Yaman¹,

Verdı²,

Ataç³

2020

J Dent Probl Solut

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Autophagy is the basic physiological process responsible for the degradation of damaged organelles, toxic protein aggregates, intracellular bacterial or viral pathogens [1-3]. In all eukaryotic cells with autophagy, nutrients are recycled by providing alternative energy for cell metabolism under conditions such as starvation, heat, infl ammation, hypoxia and oxidative stress [4]. Today, three different types of autophagy pathways have been defi ned as micro-autophagy, macroautophagy and chaperone-mediated autophagy [5,6] (Figure 1). Proteins to be degraded by Chaperone-Mediated Autophagy (CMA) contain a unique motif that is biochemically associated with the KFERQ (Figure 1) [6,7]. When the protein is not correctly folded or damaged, this motif is revealed. It is recognized by a molecular chaperone called Hsc70 (Heat shock cognate protein 70). Hsc70 binds to this unique motif and directs the protein to the lysosomal surface by forming the substrate-Hsc70 complex. The lysosomal surface has a protein called Lysosomal Membrane Protein 2A (LAMP-2A). This protein acts as a receptor for the substrate-Hsc70 complex [8]. LAMP-2A creates structural changes to form a hollow, cylindrical transport structure called the CMA translocation complex. The unfolded substrate passes through this translocation complex and enters the lysosomal lumen. After the substrate enters the lysosomal lumen, the CMA translocation complex is immediately disintegrated by Hsc70 and other proteins in the lysosomal membrane. The substrate is degraded by proteases in the lumen and amino acids are released into the cytosol [6,9] (Figure 1). In micro-autophagy; the cytosolic components pass directly into the lysosome by fusing with the lysosome membrane [6,9,10] (Figure 1). Macro-autophagy; hereafter referred to as autophagy, is one of the most studied and therefore the most known molecular details of autophagy. In this autophagy; formation of the phagophore (isolation membrane surrounding the cytoplasmic components), autophagosome (double-membrane vacuole formed by phagophore elongation) and autolysosome (autophagosome and lysosome fusion for degradation of cytosolic components) are important [11,12] (Figure 2).

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“…Compared to normal tissues, autophagic activity significantly increases in periapical lesions (Huang et al . ). More interestingly, studies also revealed the existence of an interplay between autophagy and apoptosis in the pathogenesis of apical periodontitis (Lai et al .…”

Section: Introductionmentioning

confidence: 97%

Simvastatin alleviates bone resorption in apical periodontitis possibly by inhibition of mitophagy‐related osteoblast apoptosis

et al. 2018

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Aim To assess the connection between mitophagy and hypoxia‐induced apoptosis in osteoblasts and whether simvastatin alleviates bone resorption in apical periodontitis through modulation of mitophagy‐related apoptosis. Methodology Hypoxia‐induced generation of reactive oxygen species in mitochondria and changes in mitochondrial membrane potential were evaluated, respectively, by MitoSOX and JC‐1 fluorescence dye signalling. Accumulation of mitophagy markers PTEN‐induced putative kinase 1 (PINK1) and Parkin in mitochondria was examined by Western blotting and immunofluorescence microscopy. Osteoblast apoptosis was assessed by Western analysis of cleaved‐poly (adenosine diphosphate ribose) polymerase (PARP). In a rat model of induced apical periodontitis, the therapeutic effect of simvastatin and its action on osteoblast mitophagy and apoptosis were examined. anova, Fisher's and Student's t‐test were used for data analysis. Results Hypoxia‐induced mitochondrial dysfunction and stimulated mitophagy in osteoblasts. Hypoxia also provoked apoptosis in osteoblasts and inhibition of mitophagy decreased hypoxia‐augmented apoptotic activity. Simvastatin alleviated hypoxia‐induced mitochondrial dysfunction, mitophagy and apoptosis. The protective action of simvastatin against apoptosis was related to its antimitophagy activity. Experiments in the rat model of induced apical periodontitis supported the laboratory findings. Simvastatin treatment mitigated periapical bone loss and reduced the activities of apoptosis and mitophagy in regional osteoblasts. Conclusions The results suggest that modulation of osteoblast mitophagy may help diminish bone loss associated with inflammation and has potential as an auxiliary therapy for apical periodontitis.

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The roles of autophagy and hypoxia in human inflammatory periapical lesions

Cited by 30 publications

References 44 publications

Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

Hypoxia-induced autophagy promotes gemcitabine resistance in human bladder cancer cells through hypoxia-inducible factor 1α activation

Autophagy and the potential linkage with the human oral diseases

Simvastatin alleviates bone resorption in apical periodontitis possibly by inhibition of mitophagy‐related osteoblast apoptosis

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