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https://www.readbyqxmd.com/read/29223072/alteration-of-autophagy-related-proteins-in-peripheral-blood-mononuclear-cells-of-patients-with-parkinson-s-disease
#1
Yasuo Miki, Shuji Shimoyama, Tomoya Kon, Tatsuya Ueno, Ryo Hayakari, Kunikazu Tanji, Tomoh Matsumiya, Eiki Tsushima, Fumiaki Mori, Koichi Wakabayashi, Masahiko Tomiyama
Previous postmortem studies demonstrated dysregulation of autophagy in patients with Parkinson's disease (PD). To clarify whether this alteration reflects a fundamental aspect of PD or represents the final stage of autophagy dysregulation resulting from a long neurodegenerative process, we focused on basal autophagy in peripheral blood mononuclear cells (PBMCs) of PD patients (n = 35) and controls (n = 23). The whole-transcriptome assay revealed downregulation of mRNAs for 6 core regulators of autophagy (UNC-51-like kinase [ULK] 3, autophagy-related [Atg] 2A, Atg4B, Atg5, Atg16L1, and histone deacetylase 6)...
November 21, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29219022/effectiveness-of-radiofrequency-hyperthermia-for-treating-cartilage-in-guinea-pigs-with-primary-osteoarthritis
#2
Kenji Takahashi, Hiroshi Nakamura, Hitoshi Ozawa, Sanshiro Hashimoto, Norio Iijima, Shimpei Higo, Hiroshi Watanabe, Yusuke Mochizuki, Shinro Takai
Objective Autophagy was reported to be essential for maintaining chondrocyte function, and reduced autophagy leads to osteoarthritis (OA). Previous studies showed involvement of heat shock stress in the control of autophagy in cells. This study sought to investigate the effect of hyperthermia on the expression of autophagy-related proteins in articular cartilage and the progression of naturally occurring OA in Hartley guinea pigs. Design Radiofrequency pulses of 13.56 MHz were applied to the animals' knees for 20 minutes to induce hyperthermia...
January 2018: Cartilage
https://www.readbyqxmd.com/read/29218081/tetramethylpyrazine-phosphate-and-borneol-combination-therapy-synergistically-attenuated-ischemia-reperfusion-injury-of-the-hypothalamus-and-striatum-via-regulation-of-apoptosis-and-autophagy-in-a-rat-model
#3
Bin Yu, Ming Ruan, Tao Liang, Shi-Wen Huang, Sheng-Jin Liu, Hai-Bo Cheng, Xiang-Chun Shen
The combination of tetramethylpyrazine (TMP) and borneol (BO) has shown promise for treatment of cerebral ischemia in clinical and experimental studies. However, the mechanism for the synergistic effect of these compounds is unclear. In this study, global cerebral ischemia-reperfusion (GCIR) was induced in rats that were subsequently treated with tetramethylpyrazine phosphate (TMPP) (13.3 mg/kg), BO (0.16 g/kg), or the combination TMPP + BO. Neuronal ultrastructure and intracellular calcium [Ca2+]i levels were evaluated in hypothalamus and striatum...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/29208687/increased-autophagy-signaling-but-not-proteasome-activity-in-human-skeletal-muscle-after-prolonged-low-intensity-exercise-with-negative-energy-balance
#4
Marcus Moberg, Gina Hendo, Madelene Jakobsson, C Mikael Mattsson, Elin Ekblom-Bak, Mikael Flockhart, Marjan Pontén, Karin Söderlund, Björn Ekblom
Little is known about the molecular regulation of skeletal muscle protein turnover during exercise in field conditions where energy is intake inadequate. Here, 17 male and 7 female soldiers performed an 8 days long field-based military operation. Vastus lateralis muscle biopsies, in which autophagy, the ubiquitin-proteasome system, and the mTORC1 signaling pathway were studied, were collected before and after the operation. The 187 h long operation resulted in a 15% and 29% negative energy balance as well as a 4...
December 2017: Physiological Reports
https://www.readbyqxmd.com/read/29196462/p38-mapk-inhibits-autophagy-and-promotes-microglial-inflammatory-responses-by-phosphorylating-ulk1
#5
Yingli He, Hua She, Ting Zhang, Haidong Xu, Lihong Cheng, Manuel Yepes, Yingren Zhao, Zixu Mao
Inflammation and autophagy are two critical cellular processes. The relationship between these two processes is complex and includes the suppression of inflammation by autophagy. However, the signaling mechanisms that relieve this autophagy-mediated inhibition of inflammation to permit a beneficial inflammatory response remain unknown. We find that LPS triggers p38α mitogen-activated protein kinase (MAPK)-dependent phosphorylation of ULK1 in microglial cells. This phosphorylation inhibited ULK1 kinase activity, preventing it from binding to the downstream effector ATG13, and reduced autophagy in microglia...
December 1, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29173006/systematic-analysis-of-atg13-domain-requirements-for-autophagy-induction
#6
Nora Wallot-Hieke, Neha Verma, David Schlütermann, Niklas Berleth, Jana Deitersen, Philip Böhler, Fabian Stuhldreier, Wenxian Wu, Sabine Seggewiß, Christoph Peter, Holger Gohlke, Noboru Mizushima, Björn Stork
Macroautophagy/autophagy is an evolutionarily conserved cellular process whose induction is regulated by the ULK1 protein kinase complex. The subunit ATG13 functions as an adaptor protein by recruiting ULK1, RB1CC1 and ATG101 to a core ULK1 complex. Furthermore, ATG13 directly binds both phospholipids and members of the Atg8 family. The central involvement of ATG13 in complex formation makes it an attractive target for autophagy regulation. Here, we analyzed known interactions of ATG13 with proteins and lipids for their potential modulation of ULK1 complex formation and autophagy induction...
November 26, 2017: Autophagy
https://www.readbyqxmd.com/read/29172540/discovery-of-a-small-molecule-bromodomain-containing-protein-4-brd4-inhibitor-that-induces-amp-activated-protein-kinase-modulated-autophagy-associated-cell-death-in-breast-cancer
#7
Liang Ouyang, Lan Zhang, Jie Liu, Leilei Fu, Dahong Yao, Yuqian Zhao, Shouyue Zhang, Guan Wang, Gu He, Bo Liu
Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of the pharmacophore and WPF interaction optimization, we designed a small-molecule inhibitor of BRD4, 9f (FL-411) which was validated by cocrystal structure with BD1 of BRD4. Subsequently, 9f was discovered to induce ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction and thus activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells...
December 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29164996/cptp-a-sphingolipid-transfer-protein-that-regulates-autophagy-and-inflammasome-activation
#8
Shrawan Kumar Mishra, Yong-Guang Gao, Yibin Deng, Charles E Chalfant, Edward H Hinchcliffe, Rhoderick E Brown
The macroautophagy/autophagy and inflammasome pathways are linked through their roles in innate immunity and chronic inflammatory disease. Ceramide-1-phosphate (C1P) is a bioactive sphingolipid that regulates pro-inflammatory eicosanoid production. Whether C1P also regulates autophagy and inflammasome assembly/activation is not known. Here we show that CPTP (a protein that traffics C1P from its site of phosphorylation in the trans-Golgi to target membranes) regulates both autophagy and inflammasome activation...
November 22, 2017: Autophagy
https://www.readbyqxmd.com/read/29160747/lipopolysaccharide-mediates-hepatic-stellate-cell-activation-by-regulating-autophagy-and-retinoic-acid-signaling
#9
Ming Chen, Jiaxing Liu, Wenqi Yang, Wenhua Ling
Bacterial translocation and lipopolysaccharide (LPS) leakage occur at a very early stage of liver fibrosis in animal models. We studied the role of LPS in hepatic stellate cell (HSC) activation and the underlying mechanisms in vitro and in vivo. Herein, we demonstrated that LPS treatment led to a dramatic increase in autophagosome formation and autophagic flux in LX-2 cells and HSCs, which was mediated through the AKT-MTOR and AMPK-ULK1 pathway. LPS significantly decreased the lipid content, including the lipid droplet (LD) number and lipid staining area in HSCs; pretreatment with macroautophagy/autophagy inhibitors or silencing ATG5 attenuated this decrease...
November 21, 2017: Autophagy
https://www.readbyqxmd.com/read/29156790/kaempferol-induces-autophagic-cell-death-of-hepatocellular-carcinoma-cells-via-activating-ampk-signaling
#10
Bing Han, Yi-Qun Yu, Qi-Lian Yang, Chun-Ying Shen, Xiao-Juan Wang
In the present study, we demonstrate that Kaempferol inhibited survival and proliferation of established human hepatocellular carcinoma (HCC) cell lines (HepG2, Huh-7, BEL7402, and SMMC) and primary human HCC cells. Kaempferol treatment in HCC cells induced profound AMP-activated protein kinase (AMPK) activation, which led to Ulk1 phosphorylation, mTOR complex 1 inhibition and cell autophagy. Autophagy induction was reflected by Beclin-1/autophagy gene 5 upregulation and p62 degradation as well as light chain 3B (LC3B)-I to LC3B-II conversion and LC3B puncta formation...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29154199/ultraviolet-b-radiation-down-regulates-ulk1-and-atg7-expression-and-impairs-the-autophagy-response-in-human-keratinocytes
#11
Xu Chen, Li Li, Song Xu, Wenbo Bu, Kun Chen, Min Li, Heng Gu
Autophagy is a self-digestive pathway that helps to maintain cellular homeostasis, and many autophagy-related gene (ATG)s involved the regulation of the autophagy process. Ultraviolet light is a common stressor of skin, but it is unclear how autophagy is regulated after ultraviolet exposure in epidermal keratinocytes. Here, we found that the mRNAs of some key ATG genes such as ULK1, ATG5 and ATG7 exhibited significantly lower levels in the skin tissues of the face and chest with solar ultraviolet exposure, compared with perineal skin...
September 4, 2017: Journal of Photochemistry and Photobiology. B, Biology
https://www.readbyqxmd.com/read/29148569/exome-sequence-analysis-and-follow-up-genotyping-implicates-rare-ulk1-variants-to-be-involved-in-susceptibility-to-schizophrenia
#12
Mariam M Al Eissa, Alessia Fiorentino, Sally I Sharp, Niamh L O'Brien, Kate Wolfe, Giovanni Giaroli, David Curtis, Nicholas J Bass, Andrew McQuillin
Schizophrenia (SCZ) is a severe, highly heritable psychiatric disorder. Elucidation of the genetic architecture of the disorder will facilitate greater understanding of the altered underlying neurobiological mechanisms. The aim of this study was to identify likely aetiological variants in subjects affected with SCZ. Exome sequence data from a SCZ cas-control sample from Sweden was analysed for likely aetiological variants using a weighted burden test. Suggestive evidence implicated the UNC-51-like kinase (ULK1) gene, and it was observed that four rare variants that were more common in the Swedish SCZ cases were also more common in UK10K SCZ cases, as compared to obesity cases...
November 17, 2017: Annals of Human Genetics
https://www.readbyqxmd.com/read/29148068/gastrodin-protects-myocardial-cells-against-hypoxia-reoxygenation-injury-in-neonatal-rats-by-inhibiting-cell-autophagy-through-the-activation-of-mtor-signals-in-pi3k-akt-pathway
#13
Xiang Li, Qinhui Zhu, Yuanyuan Liu, Zhiyong Yang, Bin Li
OBJECTIVES: This study aimed to investigate the protective effect of gastrodin (GAS) on myocardial cells with hypoxia/reoxygenation (H/R) injury in neonatal rats and explore the underlying mechanism. METHODS: Myocardial cells were extracted from neonatal rats and divided into six groups: control, H/R, H/R + Low-Concentration GAS, H/R + Middle-Concentration GAS, H/R + High-Concentration GAS and H/R + High-Concentration GAS + AKT Inhibitor groups. After 48-h treatment, cell viability, autophagosome quantity and the expression levels of LC3-II, p62, Akt, pAkt, mammalian target of rapamycin (mTOR) and uncoordinated 51-like kinase 1 (ULK1) in myocardial cells were made comparisons among each group...
November 17, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/29129717/a-chemoproteomic-approach-to-query-the-degradable-kinome-using-a-multi-kinase-degrader
#14
Hai-Tsang Huang, Dennis Dobrovolsky, Joshiawa Paulk, Guang Yang, Ellen L Weisberg, Zainab M Doctor, Dennis L Buckley, Joong-Heui Cho, Eunhwa Ko, Jaebong Jang, Kun Shi, Hwan Geun Choi, James D Griffin, Ying Li, Steven P Treon, Eric S Fischer, James E Bradner, Li Tan, Nathanael S Gray
Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. In this study, we designed a multi-kinase degrader by conjugating a highly promiscuous kinase inhibitor with a cereblon-binding ligand, and used quantitative proteomics to discover 28 kinases, including BTK, PTK2, PTK2B, FLT3, AURKA, AURKB, TEC, ULK1, ITK, and nine members of the CDK family, as degradable...
November 7, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29128638/ulk1-regulated-autophagy-a-mechanism-in-cellular-protection-for-aldh2-against-hyperglycemia
#15
Min Liu, Songhe Lu, Wei He, Le Zhang, Ying Ma, Ping Lv, Meijuan Ma, Wenjun Yu, Jiaxing Wang, Mingming Zhang, Yingmei Zhang, Yan Li
Mitochondrial aldehyde dehydrogenase 2 (ALDH2), an important enzyme in the elimination of toxic aldehydes, is involved in cardioprotection against diabetes mellitus. This study was designed to examine the mechanism behind ALDH2-offered protection against high glucose exposure with a focus on autophagy. H9C2 cells were cultured with normal or high glucose medium in the presence or absence of the ALDH2 agonist Alda-1. GFP-LC3 puncta and immunofluorescence were employed to assess autophagosome formation. Western blotting was applied to evaluate autophagy protein markers Atg5, LC3, p62, ULK1 phosphorylation and ALDH2...
November 8, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29109831/microrna-93-regulates-hypoxia-induced-autophagy-by-targeting-ulk1
#16
Wen Li, Yue Yang, Zhaoyu Ba, Shupeng Li, Hao Chen, Xiaoyan Hou, Linlin Ma, Pengcheng He, Lei Jiang, Longxuan Li, Rongrong He, Liangqing Zhang, Du Feng
The expression of the core autophagy kinase, Unc51-like kinase 1 (ULK1), is regulated transcriptionally and translationally by starvation-induced autophagy. However, how ULK1 is regulated during hypoxia is not well understood. Previously, we showed that ULK1 expression is induced by hypoxia stress. Here, we report a new ULK1-modulating microRNA, miR-93; its transcription is negatively correlated with the translation of ULK1 under hypoxic condition. miR-93 targets ULK1 and reduces its protein levels under hypoxia condition...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29099309/the-autophagy-inducing-kinases-ulk1-and-ulk2-regulate-axon-guidance-in-the-developing-mouse-forebrain-via-a-noncanonical-pathway
#17
Bo Wang, Rekha Iyengar, Xiujie Li-Harms, Joung Hyuck Joo, Christopher Wright, Alfonso Lavado, Linda Horner, Mao Yang, Jun-Lin Guan, Sharon Frase, Douglas R Green, Xinwei Cao, Mondira Kundu
Mammalian ULK1 (unc-51 like kinase 1) and ULK2, Caenorhabditis elegans UNC-51, and Drosophila melanogaster Atg1 are serine/threonine kinases that regulate flux through the autophagy pathway in response to various types of cellular stress. C. elegans UNC-51 and D. melanogaster Atg1 also promote axonal growth and defasciculation; disruption of these genes results in defective axon guidance in invertebrates. Although disrupting ULK1/2 function impairs normal neurite outgrowth in vitro, the role of ULK1 and ULK2 in the developing brain remains poorly characterized...
November 3, 2017: Autophagy
https://www.readbyqxmd.com/read/29091866/combination-of-ulk1-and-lc3b-improve-prognosis-assessment-of-hepatocellular-carcinoma
#18
Dong-Hao Wu, Tian-Tian Wang, Dan-Yun Ruan, Xing Li, Zhan-Hong Chen, Jing-Yun Wen, Qu Lin, Xiao-Kun Ma, Xiang-Yuan Wu, Chang-Chang Jia
BACKGROUND: Autophagy involves in both prevention and promotion in cancer, and its role probably changed during tumor development. Defined the dynamic function of autophagy in cancer may advance precision diagnostics, treatment, and guide drug design. Autophagy related protein ULK1 is key regulator of autophagy, and its role in hepatocellular carcinoma (HCC) was still unclear. This study aims to investigate ULK1's capacity along with other autophagic markers in predicting prognosis of HCC and explore position of these biomarkers in dynamic function of autophagy during HCC progression...
November 6, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29079139/the-antipsychotic-agent-clozapine-induces-autophagy-via-the-ampk-ulk1-beclin1-signaling-pathway-in-the-rat-frontal-cortex
#19
Se Hyun Kim, Soyoung Park, Hyun Sook Yu, Kyung Hee Ko, Hong Geun Park, Yong Sik Kim
Clozapine, a representative atypical antipsychotic, has superior efficacy compared to other antipsychotic agents and is used for the treatment of severe psychotic disorders. Therefore, studies on its mechanisms of action are important for understanding the mechanisms of therapeutic approaches to psychosis. Adenosine monophosphate-activated protein kinase (AMPK) is a serine-threonine kinase that plays a major role in maintaining metabolic homeostasis. Unc-51-like kinase 1 (ULK1) and Beclin1 are downstream substrates of AMPK and activate the autophagic process...
October 25, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/29073722/inhibition-of-autophagy-initiation-potentiates-chemosensitivity-in-mesothelioma
#20
Carlo Follo, Yao Cheng, William G Richards, Raphael Bueno, Virginia Courtney Broaddus
The benefits of inhibiting autophagy in cancer are still controversial, with differences in outcome based on the type of tumor, the context and the particular stage of inhibition. Here, we investigated the impact of inhibiting autophagy at different stages on chemosensitivity using 3-dimensional (3D) models of mesothelioma, including ex vivo human tumor fragment spheroids. As shown by LC3B accumulation, we successfully inhibited autophagy using either an early stage ULK1/2 inhibitor (MRT 68921) or a late stage inhibitor (hydroxychloroquine)...
October 26, 2017: Molecular Carcinogenesis
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