• 생명과학회지
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• 제27권8호
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• pp.958-964
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• 2017

Autophagy는 세포 내에서 세포의 재활용과 다양한 스트레스에 세포 homeostasis와 survival에 중요한 역할을 한다. 최근 연구에서는 autophagy 활성이 oncogenes과 tumor suppressor genes의 발현이 조절됨으로써 암이 발달되거나 억제됨이 보고되고 있다. Autophagy의 유도는 정상세포에서는 암 발생을 예방하는데 관여하며, 손상된 세포사멸 기능을 가진 암세포에서는 특정세포사멸기전을 유발하는데 중요한 역할을 한다. 또한 autophagy 억제는 항암약물과 치료법에 저항을 나타내는 암세포를 민감하게 만들어 치료효능을 증가시킨다고 증명되고 있다. 그러나 cancer 치료에서의 autophagy의 역할은 아직까지 완전히 이해되지 않았다. Oral squamous cell carcinoma(OSCC)는 구강암의 90% 이상을 차지하고 있으며, 전세계적으로 6th 가장 흔한 암중의 하나로, 최근 2배 이상 증가하고 있으며 높은 mortality rate를 보이고 있다. 구강암에서의 autophagy의 역할은 다른 암들과 마찬가지로 종양형성의 초기 단계 동안 종양억제성을 보이나, 종양진행 동안은 종양세포 생존에 관여하는 두 가지의 기능을 나타내는 것으로 보고되고 있다. 본 리뷰에서는, 암에서의 autophagy의 조절에 대한 다양한 역할을 요약하고, 이를 바탕으로 효과적인 암 치료를 위한 유망한 target으로 autophagy의 가능성을 제시하고자 한다.

• BMB Reports
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• 제50권7호
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• pp.345-354
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• 2017

Autophagy, a catabolic process necessary for the maintenance of intracellular homeostasis, has recently been the focus of numerous human diseases and conditions, such as aging, cancer, development, immunity, longevity, and neurodegeneration. However, the continued presence of autophagy is essential for cell survival and dysfunctional autophagy is thought to speed up the progression of neurodegeneration. The actual molecular mechanism behind the progression of dysfunctional autophagy is not yet fully understood. Emerging evidence suggests that basal autophagy is necessary for the removal of misfolded, aggregated proteins and damaged cellular organelles through lysosomal mediated degradation. Physiologically, neurodegenerative disorders are related to the accumulation of amyloid ${\beta}$ peptide and ${\alpha}-synuclein$ protein aggregation, as seen in patients with Alzheimer's disease and Parkinson's disease, respectively. Even though autophagy could impact several facets of human biology and disease, it generally functions as a clearance for toxic proteins in the brain, which contributes novel insight into the pathophysiological understanding of neurodegenerative disorders. In particular, several studies demonstrate that natural compounds or small molecule autophagy enhancer stimuli are essential in the clearance of amyloid ${\beta}$ and ${\alpha}-synuclein$ deposits. Therefore, this review briefly deliberates on the recent implications of autophagy in neurodegenerative disorder control, and emphasizes the opportunities and potential therapeutic application of applied autophagy.

• 대한한의학방제학회지
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• 제29권4호
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• pp.155-165
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• 2021

Objectives : Recent studies have suggested that Platycodonis Radix has various pharmacological effects such as anti-cancer, antioxidant, anti-asthma, anti-diabetes, anti-obesity, hepatoprotective, and cardiovascular protection effects. The aim of this study was to investigate the role of water extract of Platycodonis Radix (WPR)-induced autophagy in H460 human lung cancer cells. Methods : H460 cells were treated with WPR and cell viability was calculated by an MTT assay. To evaluate changes in apoptosis- and autophagy-related genes, Western blotting was performed. Two kinds of autophagy inhibitors, 3-Methyladenine (3-MA) and bafilomycin A1, were pretreated to confirm the role of WPR-induced autophagy. Results : WPR reduced the viability of H460 cells in a treatment concentration-dependent manner, which was associated with induction of apoptosis. It was also confirmed that WPR induced autophagy based on the formation of specific intracellular vacuoles and changes in the expression of autophagy-related genes. Interestingly, pretreatment with 3-MA and bafilomycin A1 increased WPR-induced cytotoxicity and apoptosis. Conclusions : WPR induced autophagy at low concentrations and early stages of treatment, but promoted apoptosis at high concentrations and late stages. Moreover, WPR-induced autophagy had a cytoprotective role in H460 cells.

• Biomolecules & Therapeutics
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• 제28권6호
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• pp.503-511
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• 2020

Autophagy is a major catabolic process that maintains cell metabolism by degrading damaged organelles and other dysfunctional proteins via the lysosome. Abnormal regulation of this process has been known to be involved in the progression of pathophysiological diseases, such as cancer and neurodegenerative disorders. Although the mechanisms for the regulation of autophagic pathways are relatively well known, the precise regulation of this pathway in the treatment of cancer remains largely unknown. It is still complicated whether the regulation of autophagy is beneficial in improving cancer. Many studies have demonstrated that autophagy plays a dual role in cancer by suppressing the growth of tumors or the progression of cancer development, which seems to be dependent on unknown characteristics of various cancer types. This review summarizes the key targets involved in autophagy and malignant transformation. In addition, the opposing tumor-suppressive and oncogenic roles of autophagy in cancer, as well as potential clinical therapeutics utilizing either regulators of autophagy or combinatorial therapeutics with anti-cancer drugs have been discussed.

• Molecules and Cells
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• 제41권1호
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• pp.65-72
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• 2018

Autophagy is an evolutionally conserved cytoplasmic degradation system in which varieties of materials are sequestered by a double membrane structure, autophagosome, and delivered to the lysosomes for the degradation. Due to the wide varieties of targets, autophagic activity is essential for cellular homeostasis. Recent genetic evidence indicates that autophagy has a crucial role in the regulation of animal lifespan. Basal level of autophagic activity is elevated in many longevity paradigms and the activity is required for lifespan extension. In most cases, genes involved in autophagy and lysosomal function are induced by several transcription factors including HLH-30/TFEB, PHA-4/FOXA and MML-1/Mondo in long-lived animals. Pharmacological treatments have been shown to extend lifespan through activation of autophagy, indicating autophagy could be a potential and promising target to modulate animal lifespan. Here we summarize recent progress regarding the role of autophagy in lifespan regulation.

• BMB Reports
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• 제49권8호
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• pp.424-430
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• 2016

Autophagy, an evolutionarily conserved cellular degradation pathway of the lysosome, is associated with many physiological and pathological processes. The hallmark of autophagy is the formation of the autophagosome that engulfs and degrades cytosolic components via its fusion with the lysosome, in either a selective or a non-selective manner. Autophagy is tightly regulated by proteins encoded by autophagy-related (atg) genes. Among these proteins, ATG8/LC3 is essential for autophagosome biogenesis/maturation and it also functions as an adaptor protein for selective autophagy. In mammalian cells, several homologs of yeast Atg8 such as MAP1LC3, GABARAP, and GABARAPL 1/2 have been identified. However, the biological relevance of this gene diversity in higher eukaryotes, and their specific roles, are largely unknown. In this review, we describe the mammalian ATG8/LC3 family and discuss recent advancements in understanding their roles in the autophagic process.

• BMB Reports
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• 제52권1호
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• pp.64-69
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• 2019

The loss of skeletal muscle, called sarcopenia, is an inevitable event during the aging process, and significantly impacts quality of life. Autophagy is known to reduce muscle atrophy caused by dysfunctional organelles, even though the molecular mechanism remains unclear. Here, we have discuss the current understanding of exercise-induced autophagy activation in skeletal muscle regeneration and remodeling, leading to sarcopenia intervention. With aging, dysregulation of autophagy flux inhibits lysosomal storage processes involved in muscle biogenesis. AMPK-ULK1 and the $FoxO/PGC-1{\alpha}$ signaling pathways play a critical role in the induction of autophagy machinery in skeletal muscle, thus these pathways could be targets for therapeutics development. Autophagy has been also shown to be a critical regulator of stem cell fate, which determines satellite cell differentiation into muscle fiber, thereby increasing muscle mass. This review aims to provide a comprehensive understanding of the physiological role of autophagy in skeletal muscle aging and sarcopenia.

• Molecules and Cells
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• 제39권5호
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• pp.410-417
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• 2016

During the lactation cycle of the bovine mammary gland, autophagy is induced in bovine mammary epithelial cells (BMECs) as a cellular homeostasis and survival mechanism. Interferon gamma ($IFN-{\gamma}$) is an important antiproliferative and apoptogenic factor that has been shown to induce autophagy in multiple cell lines in vitro. However, it remains unclear whether $IFN-{\gamma}$ can induce autophagy and whether autophagy affects milk synthesis in BMECs. To understand whether $IFN-{\gamma}$ affects milk synthesis, we isolated and purified primary BMECs and investigated the effect of $IFN-{\gamma}$ on milk synthesis in primary BMECs in vitro. The results showed that $IFN-{\gamma}$ significantly inhibits milk synthesis and that autophagy was clearly induced in primary BMECs in vitro within 24 h. Interestingly, autophagy was observed following $IFN-{\gamma}$ treatment, and the inhibition of autophagy can improve milk protein and milk fat synthesis. Conversely, upregulation of autophagy decreased milk synthesis. Furthermore, mechanistic analysis confirmed that $IFN-{\gamma}$ mediated autophagy by depleting arginine and inhibiting the general control nonderepressible-2 kinase (GCN2)/eukaryotic initiation factor $2{\alpha}$ ($eIF2{\alpha}$) signaling pathway in BMECs. Then, it was found that arginine supplementation could attenuate $IFN-{\gamma}$-induced autophagy and recover milk synthesis to some extent. These findings may not only provide a novel measure for preventing the $IFN-{\gamma}$-induced decrease in milk quality but also a useful therapeutic approach for $IFN-{\gamma}$-associated breast diseases in other animals and humans.

• Nutrition Research and Practice
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• 제14권5호
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• pp.478-489
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• 2020

BACKGROUND/OBJECTIVES: Morusin, a marker component of Morus alba L., possesses anti-cancer activity. The objective of this study was to determine autophagy-inducing effect of morusin in non-small cell lung cancer (NSCLC) cells and investigate the underlying mechanism. SUBJECTS/METHODS: Autophagy induction and the expression of autophagy-related proteins were analyzed by LC3 immunofluorescence and western blot, respectively. The role of autophagy and AMP-activated protein kinase (AMPK) was determined by treating NSCLC cells with bafilomycin A1, an autophagy inhibitor, and compound C, an AMPK inhibitor. Cytotoxicity and apoptosis induction were determined by MTT assay, trypan blue exclusion assay, annexin V-propidium iodide (PI) double staining assay, and cell cycle analysis. RESULTS: Morusin increased the formation of LC3 puncta in the cytoplasm and upregulated the expression of autophagy-related 5 (Atg5), Atg12, beclin-1, and LC3II in NSCLC cells, demonstrating that morusin could induce autophagy. Treatment with bafilomycin A1 markedly reduced cell viability but increased proportions of sub-G1 phase cells and annexin V-positive cells in H460 cells. These results indicate that morusin can trigger autophagy in NSCLC cells as a defense mechanism against morusin-induced apoptosis. Furthermore, we found that AMPK and its downstream acetyl-CoA carboxylase (ACC) were phosphorylated, while mammalian target of rapamycin (mTOR) and its downstream p70S6 kinase (p70S6K) were dephosphorylated by morusin. Morusin-induced apoptosis was significantly increased by treatment with compound C in H460 cells. These results suggest that morusin-induced AMPK activation could protect NSCLC cells from apoptosis probably by inducing autophagy. CONCLUSIONS: Our findings suggest that combination treatment with morusin and autophagy inhibitor or AMPK inhibitor might enhance the clinical efficacy of morusin for NSCLC.

• Biomolecules & Therapeutics
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• 제27권6호
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• pp.570-576
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• 2019

Particulate matter (PM), which refers to the mixture of particles present in the air, can have harmful effects. Damage to cells by PM, including disruption of organelles and proteins, can trigger autophagy, and the relationship between autophagy and PM has been well studied. However, the cellular regulators of PM-induced autophagy have not been well characterized, especially in keratinocytes. The Aryl Hydrocarbon Receptor (AhR) is expressed in the epidermis and is activated by PM. In this study, we investigated the role of the AhR in PM-induced autophagy in HaCaT cells. Our results showed that PM led to AhR activation in keratinocytes. Activation of the AhR-target gene CYP1A1 by PM was reduced by co-treatment with ${\alpha}$-naphthoflavone (${\alpha}-NF$), an AhR inhibitor. We also evaluated activation of the autophagy pathway in PM-treated keratinocytes. In HaCaT cells, treatment with PM treatment led to the induction of microtubules-associated proteins light chain 3 (LC3) and p62/SQSTM1, which are essential components of the autophagy pathway. To study the role of the AhR in mediating PM-induced autophagy, we treated cells with ${\alpha}-NF$ or used an siRNA against AhR. Expression of LC3-II induced by PM was decreased in a dose dependent manner by ${\alpha}-NF$. Furthermore, knockdown of AhR with siAhR diminished PM-induced expression of LC3-II and p62. Together, these results suggest that inhibition of the AhR decreases PM-induced autophagy. We confirmed these results using the autophagy-inhibitors BAF and 3-MA. Taken together, our results indicate that exposure to PM induces autophagy via the AhR in HaCaT keratinocytes.