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Anna A Belanova, Victor K Chmykhalo, Maxim S Makarenko, Olga V Lyangasova, Maria M Belousova, Anzhela A Aleksandrova, Peter V Zolotukhin
Although NFE2L2 transcription factor is considered to make the most significant contribution to the NFE2L2/AP-1-pathway-dependent antioxidants regulation in the human cell, AP-1 has the potential to provide significant backup and even play an equal role in the cell. Considering this, the present study is focused on revealing how JUN, an AP-1 component, and NFE2L2 contribute to regulation of four target genes containing AREs with embedded TREs-SQSTM1, FTH1, HMOX1 and CBR3 and to cellular oxidative status in general in basal conditions and under pro-oxidative influence...
December 4, 2018: Molecular Biology Reports
Julia Sanchez-Garrido, Vanessa Sancho-Shimizu, Avinash R Shenoy
The multidomain scaffold protein p62 (also called sequestosome-1) is involved in autophagy, antimicrobial immunity, and oncogenesis. Mutations in SQSTM1 , which encodes p62, are linked to hereditary inflammatory conditions such as Paget's disease of the bone, frontotemporal dementia (FTD), amyotrophic lateral sclerosis, and distal myopathy with rimmed vacuoles. Here, we report that p62 was proteolytically trimmed by the protease caspase-8 into a stable protein, which we called p62TRM We found that p62TRM , but not full-length p62, was involved in nutrient sensing and homeostasis through the mechanistic target of rapamycin complex 1 (mTORC1)...
December 4, 2018: Science Signaling
Qi Liang, Yuanyuan Xiao, Kaihua Liu, Caigao Zhong, Ming Zeng, Fang Xiao
BACKGROUND/AIMS: Hexavalent chromium [Cr(VI)] pollution has become a global concern for both ecosystems and human health. Our previous study revealed Cr(VI) could induce both apoptosis and autophagy in L-02 hepatocytes. Here, we sought to explore the underlying mechanism of Cr(VI)-induced autophagy and its exact role in cell death. METHODS: Autophagy ultrastructure was observed under transmission electron microscope (TEM), autophagy flux was measured with double-tagged mCherry-green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) assay, long-lived protein degradation assay, and LC3II expression assay in the presence of lysosomal inhibitor, bafilomycin A1 (BafA1)...
November 30, 2018: Cellular Physiology and Biochemistry
Pablo Sánchez-Martín, Tetsuya Saito, Masaaki Komatsu
p62 is a stress-inducible protein able to change among binding partners, cellular localizations and form liquid-droplet structures in a context-dependent manner. This protein is mainly defined as a cargo receptor for selective autophagy, a process that allows the degradation of detrimental and unnecessary components through the lysosome. Besides this role, its ability to interact with multiple binding partners allows p62 to act as a main regulator of the activation of the Nrf2, mTORC1 and NF-κB signaling pathways, linking p62 to the oxidative defense system, nutrient sensing and inflammation, respectively...
November 30, 2018: FEBS Journal
The Duy Nguyen, Shabnam Shaid, Olesya Vakhrusheva, Sebastian E Koschade, Kevin Klann, Marlyn Thöken, Fatima Baker, Jing Zhang, Thomas Oellerich, Duran Sürün, Anja Derlet, Isabella Haberbosch, Stefan Eimer, Heinz D Osiewacz, Christian Behrends, Christian Münch, Ivan Dikic, Christian H Brandts
Autophagy maintains hematopoietic stem cell integrity and prevents malignant transformation. In addition to bulk degradation, selective autophagy serves as an intracellular quality control mechanism and requires autophagy receptors such as p62 (SQSTM1) to specifically bridge the ubiquitinated cargos into autophagosomes. Here, we investigated the function of p62 in acute myeloid leukemia (AML) in vitro and in murine in vivo models of AML. Loss of p62 impaired expansion and colony-forming ability of leukemia cells and prolonged latency of leukemia development in mice...
November 29, 2018: Blood
Rune Becher, Håkon Valen, Bergitte Pearl Olderbø, Anette Kocbach Bølling, Jan Tore Samuelsen
OBJECTIVES: Cellular responses including cell death are induced by in vitro exposure to the un-polymerized dental monomer 2-hydroxyethyl methacrylate (HEMA). Activation of the Nrf2/ARE signaling pathway has been suggested to mediate the cellular responses. Activation of this pathway may occur either indirectly through generation of increased oxidative stress or through direct binding to cysteine thiols due to the electrophilic properties of HEMA. The objective of this study was to elucidate the potential mechanism of Nrf2/ARE pathway activation after HEMA exposure...
November 26, 2018: Dental Materials: Official Publication of the Academy of Dental Materials
Pei-Feng Liu, Hsueh-Wei Chang, Jin-Shiung Cheng, Huai-Pao Lee, Ching-Yu Yen, Wei-Lun Tsai, Jiin-Tsuey Cheng, Yi-Jing Li, Wei-Chieh Huang, Cheng-Hsin Lee, Luo-Pin Ger, Chih-Wen Shu
Oral squamous cell carcinoma (OSCC) is one of the most common cancer types worldwide and can be divided into three major subsites: buccal mucosal SCC (BMSCC), tongue SCC (TSCC), and lip SCC (LSCC). The autophagy marker microtubule-associated protein light chain 3B (MAP1LC3B) and adaptor sequestosome 1(SQSTM1) are widely used proteins to evaluate autophagy in tumor tissues. However, the role of MAP1LC3B and SQSTM1 in OSCC is not fully understood, particularly in certain subsites. With a tissue microarray comprised of 498 OSCC patients, including 181 BMSCC, 244 TSCC, and 73 LSCC patients, we found that the expression levels of MAP1LC3B and cytoplasmic SQSTM1 were elevated in the tumor tissues of three subsites compared with those in adjacent normal tissues...
November 24, 2018: Journal of Clinical Medicine
Yijing Cao, Yichen Luo, Juan Zou, Jun Ouyang, Zhihong Cai, Xi Zeng, Hui Ling, Tiebing Zeng
Autophagy, which is tightly regulated by a series of autophagy-related genes (ATGs), is a vital intracellular homeostatic process through which defective proteins and organelles are degraded and recycled under starvation, hypoxia or other specific cellular stress conditions. For both normal cells and tumour cells, autophagy not only sustains cell survival but can also promote cell death. Autophagy-related signalling pathways include mTOR-dependent pathways, such as the AMPK/mTOR and PI3K/Akt/mTOR pathways, and non-mTOR dependent pathways, such as the P53 pathway...
November 22, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
Youngmin A Lee, Luke A Noon, Kemal M Akat, Maria D Ybanez, Ting-Fang Lee, Marie-Luise Berres, Naoto Fujiwara, Nicolas Goossens, Hsin-I Chou, Fatemeh P Parvin-Nejad, Bilon Khambu, Elisabeth G M Kramer, Ronald Gordon, Cathie Pfleger, Doris Germain, Gareth R John, Kirk N Campbell, Zhenyu Yue, Xiao-Ming Yin, Ana Maria Cuervo, Mark J Czaja, M Isabel Fiel, Yujin Hoshida, Scott L Friedman
Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap...
November 23, 2018: Nature Communications
Rachel C Sharp, Olajumoke A Effiom, Anuradha Dhingra, Onatolu Odukoya, Adetokunbo Olawuyi, Godwin T Arotiba, Kathleen Boesze-Battaglia, Sunday O Akintoye
OBJECTIVES: Ameloblastoma is an aggressive odontogenic jaw neoplasm. Its unlimited growth confers high potential for malignant transformation and recurrence. It is unclear why ameloblastoma is highly recurrent despite surgical resection with a wide margin of normal tissue. While canonical autophagy can be used to degrade and eliminate damaged cellular components, it is also a protective mechanism that provides energy and vital metabolites for cell survival. We used ameloblastoma-derived cells to test the hypothesis that autophagic processes play a role in survival and reactivation of ameloblastoma...
November 14, 2018: Archives of Oral Biology
You-Cheng Hseu, Yi-Chun Shen, Ming-Ching Kao, Dony Chacko Mathew, Palaniyandi Karuppaiya, Mei-Ling Li, Hsin-Ling Yang
The medicinal fungus Ganoderma, known in Chinese as Lingzhi or Reishi, traditionally has various medicinal uses and has been employed in cancer treatment in Asia for centuries. This study used ethanol-extracted Ganoderma tsugae (GT) and examined its antitumor activities on human chronic myeloid leukemia cells as well as its molecular mechanism of action. Treatment with GT (200-400 μg/mL) significantly reduced cell viability and caused G2/M arrest in K562 cells. In addition, GT induced mitochondrial and death receptor mediated apoptosis, correlated with DNA fragmentation, followed by cytochrome c release, caspase-3/8/9 activation, PARP cleavage, Fas activation, Bid cleavage, and Bax/Bcl-2 dysregulation...
November 19, 2018: Food and Chemical Toxicology
Chunyan Wang, Jiaqi Fu, Meng Wang, Yuhao Cai, Xiuguo Hua, Yuming Du, Zhibiao Yang, Yan Li, Zhenxia Wang, Huiming Sheng, Na Yin, Xiaoyun Liu, Jane E Koehler, Congli Yuan
Bartonella effector proteins (named Beps) are substrates of VirB type IV secretion system for translocation into host cells evolved in Bartonella spp. Among these, BepE has been shown to protect cells from fragmentation effects triggered by other Beps and to promote in vivo dissemination of bacteria from the dermal site of inoculation to the bloodstream. Bacterial pathogens secreted effectors to modulate the interplay with host autophagy, either to combat autophagy to escape its bactericidal effect, or to exploit autophagy to benefit intracellular replication...
November 21, 2018: Cellular Microbiology
Shuo Wang, Hang Xue, Ying Xu, Jiayuan Niu, Ping Zhao
Hypoxic-ischemic brain injury (HIBI) in neonates is one of the major contributors of newborn death and cognitive impairment. Numerous animal studies have demonstrated that autophagy is substantially increased in HIBI and that sevoflurane postconditioning (SPC) can attenuate HIBI. However, if SPC-induced neuroprotection inhibits autophagy in HIBI remains unknown. To investigate if cerebral protection induced by SPC is related to decreased autophagy in the setting of HIBI. Postnatal rats at day 7 (P7) were randomly assigned to 7 different groups: Sham, HIBI, SPC-HIBI, HIBI + rapamycin, SPC-HIBI + rapamycin, HIBI + p-extracellular signal-regulated kinase (p-ERK) inhibitor, and SPC-HIBI + p-ERK inhibitor...
November 20, 2018: Neurochemical Research
Jin-Feng Zhu, Wei Huang, Hong-Mei Yi, Ta Xiao, Jiao-Yang Li, Juan Feng, Hong Yi, Shan-Shan Lu, Xin-Hui Li, Rou-Huang Lu, Qiu-Yan He, Zhi-Qiang Xiao
Annexin A1 (ANXA1) is dysregulated in the various tumors. However, the role and mechanism of ANXA1 in the cancers are poorly understood. In this study, we first showed a clinically positive correlation between ANXA1 and autophagy-associated protein SQSTM1 expression in nasopharyngeal carcinoma (NPC) and ANXA1-regulating SQSTM1 expression through autophagy, and further demonstrated that ANXA1 inhibited BECN1 and ATG5-dependent autophagy in the NPC cells. Using phospho-kinase antibody array to identify signaling through which ANXA1 regulated NPC cell autophagy, we found that ANXA1-suppressed autophagy was associated with PI3K/AKT signaling activation...
November 20, 2018: Cell Death & Disease
Peng Zhang, Yinglu Guan, Jiajie Chen, Xiang Li, Bradley K McConnell, Wei Zhou, Krishna M Boini, Yang Zhang
Accumulating evidence indicates a critical role of autophagy in regulating vascular smooth muscle cell (SMC) homeostasis in atherogenesis. However, little is known about the modulatory role of autophagy in PDGF-BB-induced SMC transition towards the synthetic phenotype and extracellular matrix remodeling. We recently demonstrated that acid sphingomyelinase (ASM, encoded by Smpd1 gene) controls autophagy maturation in coronary arterial SMCs. Here, we demonstrate that PDGF-BB stimulation causes a myofibroblast-like non-canonical synthetic phenotype transition in Smpd1-/- SMCs...
November 19, 2018: Cell Death & Disease
Jiufei Duan, Ting Deng, Jun Kang, Mingqing Chen
Di-isononyl phthalate (DINP) is used as a substitute for traditional phthalates, in a wide range of applications. However, there is growing concern regarding its toxicity. Studies have indicated that DINP is related to thyroid hormone disorder and that phthalates can affect thyroid normal function. In this study, we aim to determine any effects of DINP exposure on autoimmune thyroid disease (AITD), the most common autoimmune disease, and to understand the underlying causal mechanism. AITD model Wistar rats were exposed to 0...
October 30, 2018: Environmental Pollution
Siyao Li, Zhixin Jiang, Wenjie Chai, Yuanyuan Xu, Yi Wang
Emerging evidence indicates that nonylphenol (NP), a widely diffused and stable environmental contaminant, causes damage to the central nervous system (CNS). Although NP could cross the blood-brain barrier (BBB) and accumulate in key brain regions, little is known about the direct effects of NP on neurons. In this study, we aimed to investigate the direct effects of NP exposure on induction of apoptosis and autophagy in primary cortical neurons. Results showed that exposure to NP decreased the cell viability in a concentration-dependent manner...
November 14, 2018: Neurochemistry International
Chengmin Huang, Peng Zhang, Tingting Li, Jun Li, Tianjiao Liu, Anju Zuo, Jiying Chen, Yuan Guo
This study was aimed to explore the role of C1q/TNF-related protein 9 (CTRP9) on atherosclerotic lesion formation. A recombinant lentiviral vector carrying mouse CTRP9 (Lv-CTRP9) was injected intravenously into apolipoprotein E knockout (ApoE-/- ) mice given a high-fat diet (HFD). CTRP9 overexpression substantially attenuated atherosclerotic lesion size of mice. The accumulation of macrophages and smooth muscle cells (SMCs) was significantly decreased in atherosclerotic regions with CTRP9 overexpression by immunohistochemical analysis...
November 13, 2018: Molecular and Cellular Biochemistry
Yong Min Lee, Mi Kyoung Kim, Hyunah Choo, Youhoon Chong
Given the importance of (-)-epigallocatechin gallate (EGCG) as an autophagy-enhancing and thereby lipid-lowering agent, optimization of its activity warrants its therapeutic potential in the treatment of hepatic diseases as well as metabolic disorders. On the basis of our previous observations that structural modifications provided substantial improvements in the bioactivity of EGCG, we investigated the autophagy-enhancing activity of EGCG derivatives. Among 14 EGCG derivatives, E10 with a phenylalanine attached to the D ring of EGCG exhibited the most promising effects in stimulating autophagy in Huh7 cells, which was supported by several lines of evidence: (1) stimulation of autophagy revealed by an increased amount of LC3B-II (4...
November 19, 2018: Journal of Agricultural and Food Chemistry
Seul-Ki Park, D Taylor La Salle, James Cerbie, Jae Min Cho, Amber D Bledsoe, Ashley D Nelson, David E Morgan, Russell S Richardson, Yan-Ting Shiu, Sihem Boudina, Joel D Trinity, J David Symons
Continuous laminar shear stress increases the process of autophagy, activates p-eNOSS1177 , and generates nitric oxide (NO) in bovine and human arterial endothelial cells (ECs) compared to static controls. However, the translational relevance of these findings has not been explored. In the current study, primary ECs were collected from the radial artery (RA) of 7 adult males using sterile j-wires before (Pre) and after (Post) 60-min of rhythmic handgrip exercise (HG) performed with the same arm. After ECs were identified by positive co-staining for VE-cadherin and DAPI, immunofluorescent antibodies were used to assess indices of autophagy, NO generation, and superoxide anion (O2•- ) production...
November 9, 2018: American Journal of Physiology. Heart and Circulatory Physiology
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