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Triamterene induces autophagic degradation of lysosome by exacerbating lysosomal integrity
박나연,Doo Sin Jo,Yong Hwan Kim,Ji-Eun Bae,Joon Bum Kim,Hyun Jun Park,Ji Yeon Choi,Ha Jung Lee,Jeong Ho Chang,Heeyoun Bunch,Hong Bae Jeon,Yong-Keun Jung,Dong-Hyung Cho 대한약학회 2021 Archives of Pharmacal Research Vol.44 No.6
The maintenance of lysosomal integrity is essentialfor lysosome function and cell fate. Damaged lysosomesare degraded by lysosomal autophagy, lysophagy. Themechanism underlying lysophagy remains largely unknown;this study aimed to contribute to the understanding of thistopic. A cell-based screening system was used to identifynovel lysophagy modulators. Triamterene (6-phenylpteridine-2,4,7-triamine) was identifi ed as one of the most potentlysophagy inducers from the screening process. We foundthat triamterene causes lysosomal rupture without aff ectingother cellular organelles and increases autophagy fl uxin HepG2 cells. Damaged lysosomes in triamterene-treatedcells were removed by autophagy-mediated pathway, whichwas inhibited by depletion of the autophagy regulator, ATG5or SQSTM1. In addition, treatment of triamterene decreased the integrity of lysosome and cell viability, which were rescuedby removing the triamterene treatment in HepG2 cells. Hence, our data suggest that triamterene is a novel lysophagyinducer through the disruption of lysosomal integrity.
Effects of microstructure and intergranular glassy phases on thermal conductivity of silicon nitride
Kim, Jin-Myung,Ko, Sin-Il,Kim, Ha-Neul,Ko, Jae-Woong,Lee, Jae-Wook,Kim, Hai-Doo,Park, Young-Jo Elsevier 2017 CERAMICS INTERNATIONAL Vol.43 No.7
<P><B>Abstract</B></P> <P>In this study, the binary sintering additives Y<SUB>2</SUB>O<SUB>3</SUB>-Sc<SUB>2</SUB>O<SUB>3</SUB>, were first applied to the Si<SUB>3</SUB>N<SUB>4</SUB> system to investigate their effects on microstructure and thermal conductivity. The microstructure and thermal conductivity of both sintered silicon nitride (SSN) and sintered reaction-bonded silicon nitride (SRBSN) were found to be significantly dependent on the additive composition. Among various combinations of Y<SUB>2</SUB>O<SUB>3</SUB> and Sc<SUB>2</SUB>O<SUB>3</SUB>, 1mol% Y<SUB>2</SUB>O<SUB>3</SUB>−3mol% Sc<SUB>2</SUB>O<SUB>3</SUB> prominently enhanced thermal conductivity, and the enhancement could not be attributed to any difference in microstructure or lattice defects. TEM observation revealed that this composition was more liable to devitrify the glassy phase with a lower degree of stress accumulation, and to possibly produce a grain boundary that was cleaner or with a higher order of atomic arrangement. A microstructure model for thermal conductivity was proposed which took the thermal resistance of the grain boundaries into account. The grain boundary state exerted a remarkable influence on the thermal conductivity of fine microstructures, and the experimentally measured thermal conductivity values were consistent with those given by the proposed model.</P>
Pexophagy: Molecular Mechanisms and Implications for Health and Diseases
Cho, Dong-Hyung,Kim, Yi Sak,Jo, Doo Sin,Choe, Seong-Kyu,Jo, Eun-Kyeong Korean Society for Molecular and Cellular Biology 2018 Molecules and cells Vol.41 No.1
Autophagy is an intracellular degradation pathway for large protein aggregates and damaged organelles. Recent studies have indicated that autophagy targets cargoes through a selective degradation pathway called selective autophagy. Peroxisomes are dynamic organelles that are crucial for health and development. Pexophagy is selective autophagy that targets peroxisomes and is essential for the maintenance of homeostasis of peroxisomes, which is necessary in the prevention of various peroxisome-related disorders. However, the mechanisms by which pexophagy is regulated and the key players that induce and modulate pexophagy are largely unknown. In this review, we focus on our current understanding of how pexophagy is induced and regulated, and the selective adaptors involved in mediating pexophagy. Furthermore, we discuss current findings on the roles of pexophagy in physiological and pathological responses, which provide insight into the clinical relevance of pexophagy regulation. Understanding how pexophagy interacts with various biological functions will provide fundamental insights into the function of pexophagy and facilitate the development of novel therapeutics against peroxisomal dysfunction-related diseases.
Kim, Pan Soo,Shin, Ji Hyun,Jo, Doo Sin,Shin, Dong Woon,Choi, Dong-Hwa,Kim, Woo Jung,Park, Kyuhee,Kim, Jin Kyu,Joo, Chul Gue,Lee, Jong Suk,Choi, Yongmun,Shin, Yong Won,Shin, Joong Jin,Jeon, Hong Bae,Se Elsevier 2018 Biochemical and biophysical research communication Vol.503 No.1
<P><B>Abstract</B></P> <P>Skin pigmentation involves multiple processes, including melanin synthesis, transport, and melanosome release. Melanin content determines skin color and protects against UV radiation-induced damage. Autophagy is a cooperative process between autophagosomes and lysosomes that degrades cellular components and organelles. In the present study, B16F1 cells were treated with <I>Rhizoma Arisaematis</I> extract (RA) and assessed for pigmentation and autophagy regulation. RA treatment suppressed the α-MSH-stimulated increase of melanogenesis and down-regulated the expression of tyrosinase and TRP1 proteins in B16F1 cells. In addition, autophagy was activated in RA-treated cells. Inhibition of autophagy reduced the anti-melanogenic activity of RA in α-MSH-treated B16F1 cells. We identified schaftoside as an effector molecule by LC-MS analysis of RA. Consistently, treatment of schaftoside showed anti-melanogenic effect and induced autophagy activation in B16F1 cells. Inhibition of autophagy by 3 MA treatment reduced the anti-melanogenic effect of the schaftoside and recovered expression level of melanogenesis regulators in α-MSH-treated B16F1 cells. Taken together, our results suggest that schaftoside from RA inhibits skin pigmentation through modulation of autophagy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> <I>Rhizoma Arisaematis</I> extract (RA) suppressed the melanogenesis. </LI> <LI> Inhibition of autophagy reduced the anti-melanogenic activity of RA. </LI> <LI> Schaftoside was identified as an effector molecule of RA. </LI> <LI> Schaftoside has anti-melanogenic effect and induced autophagy activation. </LI> </UL> </P>
Autophagy Regulates Formation of Primary Cilia in Mefloquine-Treated Cells
( Ji Hyun Shin ),( Dong Jun Bae ),( Eun Sung Kim ),( Han Byeol Kim ),( So Jung Park ),( Yoon Kyung Jo ),( Doo Sin Jo ),( Dong Gyu Jo ),( Sang Yeob Kim ),( Dong Hyung Cho ) 한국응용약물학회 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.4
Primary cilia have critical roles in coordinating multiple cellular signaling pathways. Dysregulation of primary cilia is implicated in various ciliopathies. To identify specific regulators of autophagy, we screened chemical libraries and identified mefl oquine, an anti-malaria medicine, as a potent regulator of primary cilia in human retinal pigmented epithelial (RPE) cells. Not only ciliated cells but also primary cilium length was increased in mefloquine-treated RPE cells. Treatment with mefloquine strongly induced the elongation of primary cilia by blocking disassembly of primary cilium. In addition, we found that autophagy was increased in mefloquine-treated cells by enhancing autophagic fl ux. Both chemical and genetic inhibition of autophagy suppressed ciliogenesis in mefloquine-treated RPE cells. Taken together, these results suggest that autophagy induced by mefloquine positively regulates the elongation of primary cilia in RPE cells.
Autophagy Regulates Formation of Primary Cilia in Mefloquine-Treated Cells
Shin, Ji Hyun,Bae, Dong-Jun,Kim, Eun Sung,Kim, Han Byeol,Park, So Jung,Jo, Yoon Kyung,Jo, Doo Sin,Jo, Dong-Gyu,Kim, Sang-Yeob,Cho, Dong-Hyung The Korean Society of Applied Pharmacology 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.4
Primary cilia have critical roles in coordinating multiple cellular signaling pathways. Dysregulation of primary cilia is implicated in various ciliopathies. To identify specific regulators of autophagy, we screened chemical libraries and identified mefloquine, an anti-malaria medicine, as a potent regulator of primary cilia in human retinal pigmented epithelial (RPE) cells. Not only ciliated cells but also primary cilium length was increased in mefloquine-treated RPE cells. Treatment with mefloquine strongly induced the elongation of primary cilia by blocking disassembly of primary cilium. In addition, we found that autophagy was increased in mefloquine-treated cells by enhancing autophagic flux. Both chemical and genetic inhibition of autophagy suppressed ciliogenesis in mefloquine-treated RPE cells. Taken together, these results suggest that autophagy induced by mefloquine positively regulates the elongation of primary cilia in RPE cells.
Silwal Prashanta,Kim Young Jae,Lee Yoon Jee,Kim In Soo,Jeon Sang Min,Roh Taylor,Kim Jin Kyung,Lee Min Joung,Heo Jun Young,Jo Doo Sin,Lee Sang-Hee,Cho Dong-Hyung,Kim Jin Man,Kwon Yong Tae,Jo Eun-Kyeong 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
The Arg/N-degron pathway, which is involved in the degradation of proteins bearing an N-terminal signal peptide, is connected to p62/SQSTM1-mediated autophagy. However, the impact of the molecular link between the N-degron and autophagy pathways is largely unknown in the context of systemic inflammation. Here, we show that chemical mimetics of the N-degron Nt-Arg pathway (p62 ligands) decreased mortality in sepsis and inhibited pathological inflammation by activating mitophagy and immunometabolic remodeling. The p62 ligands alleviated systemic inflammation in a mouse model of lipopolysaccharide (LPS)-induced septic shock and in the cecal ligation and puncture model of sepsis. In macrophages, the p62 ligand attenuated the production of proinflammatory cytokines and chemokines in response to various innate immune stimuli. Mechanistically, the p62 ligand augmented LPS-induced mitophagy and inhibited the production of mitochondrial reactive oxygen species in macrophages. The p62 ligand-mediated anti-inflammatory, antioxidative, and mitophagy-activating effects depended on p62. In parallel, the p62 ligand significantly downregulated the LPS-induced upregulation of aerobic glycolysis and lactate production. Together, our findings demonstrate that p62 ligands play a critical role in the regulation of inflammatory responses by orchestrating mitophagy and immunometabolic remodeling.
Baek, Seung Hyun,Park, So Jung,Jeong, Jae In,Kim, Sung Hyun,Han, Jihoon,Kyung, Jae Won,Baik, Sang-Ha,Choi, Yuri,Choi, Bo Youn,Park, Jin Su,Bahn, Gahee,Shin, Ji Hyun,Jo, Doo Sin,Lee, Joo-Yong,Jang, Cho Society for Neuroscience 2017 The Journal of neuroscience Vol.37 No.20
<P>Excessive mitochondrial fission is a prominent early event and contributes to mitochondrial dysfunction, synaptic failure, and neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. To determine whether dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fragmentation, can be a disease-modifying therapeutic target for AD, we examined the effects of Drp1 inhibitor on mitochondrial and synaptic dysfunctions induced by oligomeric amyloid-beta(A beta) in neurons and neuropathology and cognitive functions in A beta precursor protein/presenilin 1 double-transgenic AD mice. Inhibition of Drp1 alleviates mitochondrial fragmentation, loss of mitochondrial membrane potential, reactive oxygen species production, ATP reduction, and synaptic depression in A beta-treated neurons. Furthermore, Drp1 inhibition significantly improves learning and memory and prevents mitochondrial fragmentation, lipid peroxidation, BACE1 expression, and A beta deposition in the brain in the AD model. These results provide evidence that Drp1 plays an important role in A beta-mediated and AD-related neuropathology and in cognitive decline in an AD animal model. Therefore, inhibiting excessive Drp1-mediated mitochondrial fission may be an efficient therapeutic avenue for AD.</P>