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Yihua Wang, Hua Xiong, Dian Liu, Charlotte Hill, Ayse Ertay, Juanjuan Li, Yanmei Zou, Paul Miller, Eileen White, Julian Downward, Robert D Goldin, Xianglin Yuan, Xin Lu
Macroautophagy/autophagy inhibition is a novel anticancer therapeutic strategy, especially for tumors driven by mutant RAS. Here, we demonstrate that autophagy inhibition in RAS-mutated cells induces epithelial-mesenchymal transition (EMT), which is associated with enhanced tumor invasion. This is at least partially achieved by triggering the NFKB/NF-κB pathway via SQSTM1/p62. Knockdown of ATG3 or ATG5 increases oncogenic RAS-induced expression of ZEB1 and SNAI2/Snail2, and activates NFKB activity. Depletion of SQSTM1 abolishes the activation of the NFKB pathway induced by autophagy inhibition in RAS-mutated cells...
February 20, 2019: Autophagy
Jinzhong Zhang, Jing He, Jennifer L Johnson, Farhana Rahman, Evripidis Gavathiotis, Ana Maria Cuervo, Sergio D Catz
Cystinosis is a lysosomal storage disorder caused by defects in CTNS , the gene that encodes the lysosomal cystine transporter cystinosin. Patients with nephropathic cystinosis are characterized by endocrine defects, defective proximal tubule cell (PTC) function, the development of Fanconi syndrome and, eventually, end-stage renal disease. Kidney disease is developed despite the use of cysteamine, a drug that decreases lysosomal cystine overload but fails to correct overload-independent defects. Chaperone-mediated autophagy (CMA), a selective form of autophagy, is defective in cystinotic mouse fibroblasts, and treatment with cysteamine is unable to correct CMA defects in vivo , but whether the vesicular trafficking mechanisms that lead to defective CMA in cystinosis are manifested in human PTCs is not currently known and whether PTC-specific mechanisms are corrected upon CMA upregulation remains to be elucidated...
2019: Frontiers in Endocrinology
Na-Na Liu, Xue-Zhao Jia, Jing Wang, Guo-Qi Zhu, Dan Li, Qing-Ling Li, Qiang Ma
OBJECTIVE: To observe the effect of moxibustion on cardiac function and the expression of autophagy-related proteins microtubule-associated protein 1 light chain 3 (LC3) and selective autophagy receptor signaling adaptor sequestosome 1 (SQSTM1/p62) in rats with chronic heart failure (CHF), so as to explore its underlying mechanisms in preventing and treating CHF. METHODS: Sixty male SD rats were randomly divided into normal, model, moxibustion, autophagy inhibitor 3-methyladenine (3-MA) and autophagy agonist rapamycin (RAPA) groups ( n =12 rats/group)...
January 25, 2019: Zhen Ci Yan Jiu, Acupuncture Research
Melanie Ullrich, Benjamin Aßmus, Anne Marie Augustin, Hannes Häbich, Marco Abeßer, Jorge Martin Machado, Franziska Werner, Ralf Erkens, Anahi-Paula Arias-Loza, Sandra Umbenhauer, Helga Wagner, Peter M Benz, Andreas Unger, Wolfgang A Linke, Stefan Frantz, Hideo A Baba, Michaela Kuhn, Kai Schuh
Cardiac functionality is dependent on a balanced protein turnover. Accordingly, regulated protein decay is critical to maintain cardiac function. Here we demonstrate that deficiency of SPRED2, an intracellular repressor of ERK-MAPK signaling markedly expressed in human heart, resulted in impaired autophagy, heart failure, and shortened lifespan. SPRED2-/- mice showed cardiomyocyte hypertrophy, cardiac fibrosis, impaired electrical excitability, and severe arrhythmias. Mechanistically, cardiomyocyte dysfunction resulted from ERK hyperactivation and dysregulated autophagy, observed as accumulation of vesicles, vacuolar structures, and degenerated mitochondria...
February 13, 2019: Journal of Molecular and Cellular Cardiology
Diego Tapia, Tomás Jiménez, Constanza Zamora, Javier Espinoza, Riccardo Rizzo, Alexis González-Cárdenas, Danitza Fuentes, Sergio Hernández, Viviana A Cavieres, Andrea Soza, Fanny Guzmán, Gloria Arriagada, María Isabel Yuseff, Gonzalo A Mardones, Patricia V Burgos, Alberto Luini, Alfonso González, Jorge Cancino
Inter-organelle signalling has essential roles in cell physiology encompassing cell metabolism, aging and temporal adaptation to external and internal perturbations. How such signalling coordinates different organelle functions within adaptive responses remains unknown. Membrane traffic is a fundamental process in which membrane fluxes need to be sensed for the adjustment of cellular requirements and homeostasis. Studying endoplasmic reticulum-to-Golgi trafficking, we found that Golgi-based, KDEL receptor-dependent signalling promotes lysosome repositioning to the perinuclear area, involving a complex process intertwined to autophagy, lipid-droplet turnover and Golgi-mediated secretion that engages the microtubule motor protein dynein-LRB1 and the autophagy cargo receptor p62/SQSTM1...
February 13, 2019: Nature Communications
Stuart H Ralston, J Paul Taylor
Several rare inherited disorders have been described that show phenotypic overlap with Paget's disease of bone (PDB) and in which PDB is a component of a multisystem disorder affecting muscle and the central nervous system. These conditions are the subject of this review article. Insertion mutations within exon 1 of the TNFRSF11A gene, encoding the receptor activator of nuclear factor kappa B (RANK), cause severe PDB-like disorders including familial expansile osteolysis, early-onset familial PDB and expansile skeletal hyperphosphatasia...
February 13, 2019: Calcified Tissue International
Zhinian Lei, Guangliang Cao, Gang Wei
Mutations in α-synuclein gene have been linked to familial early-onset Parkinson's disease (PD) with Lewy body pathology. A30P mutant α-synuclein is believed to suppress autophagic progression associated with PD pathogenesis. However, the mechanistic link between A30P mutation and autophagy inhibition in PD remains poorly understood. In this study, we identified that A30P mutant α-synuclein resulted in reduced autophagy flux through promoting the decrease of autophagosomal membrane-associated protein LC3 and the increase of SQSTM1/p62 protein levels in midbrain dopaminergic neuron, due to the transcriptional repressor ZKSCAN3 trafficking from the cytoplasm to the nucleus...
February 12, 2019: Cell Death & Disease
Anna Visa, Marta C Sallán, Oscar Maiques, Lía Alza, Elisabet Talavera, Ricard López-Ortega, Maria Santacana, Judit Herreros, Carles Cantí
T-type Ca2+ channels (TTCC) have been identified as key regulators of cancer cell cycle and survival. In vivo studies in glioblastoma (GBM) murine xenografts have shown that drugs able to block TTCC in vitro (such as tetralol derivatives mibefradil/NNC-55-096, or different 3,4-dihydroquinazolines) slow tumor progression. However, currently available TTCC pharmacological blockers have limited selectivity for TTCC, and are unable to distinguish between TTCC isoforms. Here we analyzed the expression of TTCC transcripts in human GBM cells and show a prevalence of Cav3...
February 12, 2019: Cancer Research
Myosotys Rodriguez, Jessica Lapierre, Chet Raj Ojha, Shashank Pawitwar, Mohan Kumar Muthu Karuppan, Fatah Kashanchi, Nazira El-Hage
Accelerated neurological disorders are increasingly prominent among the HIV-infected population and are likely driven by the toxicity from long-term use of antiretroviral drugs. We explored potential side effects of antiretroviral drugs in HIV-infected primary human astrocytes and whether opioid co-exposure exacerbates the response. HIV-infected human astrocytes were exposed to the reverse transcriptase inhibitor, emtricitabine, alone or in combination with two protease inhibitors ritonavir and atazanavir (ERA) with and without morphine co-exposure...
February 11, 2019: Journal of Neurovirology
Changyi Ji, Maoping Tang, Claudia Zeidler, Jörg Höhfeld, Gail Vw Johnson
A major cellular catabolic pathway in neurons is macroautophagy/autophagy, through which misfolded or aggregation-prone proteins are sequestered into autophagosomes that fuse with lysosomes, and are subsequently degraded. MAPT (microtubule associated protein tau) is one of the protein clients of autophagy. Given that accumulation of hyperphosphorylated MAPT contributes to the pathogenesis of Alzheimer disease and other tauopathies, decreasing endogenous MAPT levels has been shown to be beneficial to neuronal health in models of these diseases...
February 11, 2019: Autophagy
Sun Woong Kim, Donald J Brown, James V Jester
PURPOSE: PPARγ plays a critical role in the maturation of immortalized human meibomian gland epithelial cells (hMGEC). To further understand the molecular changes associated with meibocyte differentiation, we analyzed transcriptome profiles from hMGEC after PPARγ activation. METHODS: Three sets of cultivated hMGEC with or without exposure to PPARγ agonist, rosiglitazone were used for RNA-seq analysis. RNA was isolated and processed to generate 6 libraries. The libraries were then sequenced and mapped to the human reference genome, and the expression results were gathered as reads per length of transcript in kilobases per million mapped reads (RPKM) values...
February 8, 2019: Ocular Surface
Liping Ju, Junfeng Han, Xiaoyan Zhang, Yujie Deng, Han Yan, Congrong Wang, Xiaohua Li, Shuqin Chen, Miriayi Alimujiang, Xu Li, Qichen Fang, Ying Yang, Weiping Jia
In obesity, adipocytes exhibit high metabolic activity accompanied by an increase in lipid mobilization. Recent findings indicate that autophagy plays an important role in metabolic homeostasis. However, the role of this process in adipocytes remains controversial. Therefore, we performed an overall analysis of the expression profiles of 322 lysosomal/autophagic genes in the omental adipose tissue of lean and obese individuals, and found that among 35 significantly differentially expressed genes, 34 genes were upregulated...
February 11, 2019: Cell Death & Disease
Aiping Qin, Qian Zhang, Jun Wang, Iqbal Sayeed, Donald G Stein
BACKGROUND: In this proof-of-concept paper, we investigated whether combination treatment with progesterone (P4) and chloroquine (CQ) would reduce ischemic injury more effectively than either agent alone in a transient middle cerebral artery occlusion (tMCAO) model in male rats. METHODS: P4 (8 mg/kg) and CQ (25 mg/kg) were given alone or in combination beginning at different times during surgery and for 3 days post-occlusion. Locomotor activity and grip strength were evaluated as measures of impairment and recovery...
February 4, 2019: Restorative Neurology and Neuroscience
Giovanna Lacava, Fulvio Laus, Andrea Amaroli, Andrea Marchegiani, Roberta Censi, Piera Di Martino, Toru Yanagawa, Maria Giovanna Sabbieti, Dimitrios Agas
With advancing age have been observed bone and bone marrow phenotypic alterations due to the impaired bone tissue homeostatic features, involving bone remodeling, and bone marrow niche ontogeny. The complex "inflamm-aging" pathological scenario that culminates with osteopenia and mesenchymal/stromal and hematopoietic stem cell commitment breakdown, is controlled by cellular and molecular intramural components comprising adapter proteins such as the sequestosome 1 (p62/SQSTM1). p62, a "multiway function" protein, has been reported as an effective anti-inflammatory, bone-building factor...
February 10, 2019: Journal of Cellular Physiology
Imran Tarique, Waseem Ali Vistro, Xuebing Bai, Ping Yang, Chen Hong, Yufei Huang, Abdul Haseeb, Enxue Liu, Noor Samad Gandahi, Mengdi Xu, Yifei Liu, Qiusheng Chen
BACKGROUND: Steroidogenesis is an indispensable process that is indirectly associated with spermatogenesis in the Leydig cell (LC) to utilize the lipid droplets (LDs) that are critical to maintaining normal testosterone synthesis. The regulation of LD mobilization, known as lipophagy, in the LC is still largely unknown. METHOD: In the present study, the LC of the Chinese soft-shelled turtle was investigated to identify the steroidogenic activity and lipophagy during the annual reproductive cycle by light microscopy, immunohistochemistry (IHC), immunofluorescence (IF), and transmission electron microscopy (TEM)...
February 9, 2019: Reproductive Biology and Endocrinology: RB&E
Sahib Zada, Jin Seok Hwang, Mahmoud Ahmed, Trang Huyen Lai, Trang Minh Pham, Deok Ryong Kim
Autophagy, an intracellular degradation process, is essential for maintaining cell homeostasis by removing damaged organelles and proteins under various conditions of stress. In cancer, autophagy has conflicting functions. It plays a key role in protecting against cancerous transformation by maintaining genomic stability against genotoxic components, leading to cancerous transformation. It can also promote cancer cell survival by supplying minimal amounts of nutrients during cancer progression. However, the molecular mechanisms underlying how autophagy regulates the epithelial-to-mesenchymal transition (EMT) and cancer metastasis are unknown...
February 6, 2019: Cells
Chet Raj Ojha, Myosotys Rodriguez, Mohan Kumar Muthu Karuppan, Jessica Lapierre, Fatah Kashanchi, Nazira El-Hage
The connection between Zika virus (ZIKV) and neurodevelopmental defects is widely recognized, although the mechanisms underlying the infectivity and pathology in primary human glial cells are poorly understood. Here we show that three isolated strains of ZIKV, an African strain MR766 (Uganda) and two closely related Asian strains R103451 (Honduras) and PRVABC59 (Puerto Rico) productively infect primary human astrocytes, although Asian strains showed a higher infectivity rate and increased cell death when compared to the African strain...
2019: PloS One
Santiago Serrano-Saenz, Carmen Palacios, Daniel Delgado-Bellido, Laura López-Jiménez, Angel Garcia-Diaz, Yolanda Soto-Serrano, J Ignacio Casal, Rubén A Bartolomé, José Luis Fernández-Luna, Abelardo López-Rivas, F Javier Oliver
Glioblastoma (GBM) is the most common and aggressive brain tumor and is associated with poor prognosis. GBM cells are frequently resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and finding new combinatorial therapies to sensitize glioma cells to TRAIL remains an important challenge. PIM kinases are serine/threonine kinases that promote cell survival and proliferation and are highly expressed in different tumors. In this work, we studied the role of PIM kinases as regulators of TRAIL sensitivity in GBM cells...
January 18, 2019: Cell Death & Disease
Yuji Kakiuchi, Takashi Yurube, Kenichiro Kakutani, Toru Takada, Masaaki Ito, Yoshiki Takeoka, Yutaro Kanda, Shingo Miyazaki, Ryosuke Kuroda, Kotaro Nishida
OBJECTIVE: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates nutrients to execute cell growth. We hypothesized that mTOR is influential in the intervertebral disc-largest avascular, low-nutrient organ. Our objective was to identify the optimal mTOR inhibitor for treating human degenerative disc disease. DESIGN: mTOR complex 1 (mTORC1) regulates p70/S6K, negatively regulates autophagy, and is controlled by Akt. Akt is controlled by PI3K and mTOR complex 2 (mTORC2)...
February 1, 2019: Osteoarthritis and Cartilage
Simon Musyoka Mwangi, Ge Li, Lan Ye, Yunshan Liu, Francois Reichardt, Samantha M Yeligar, C Michael Hart, Mark J Czaja, Shanthi Srinivasan
Glial cell line Derived Neurotrophic Factor (GDNF) is a protein that is required for the development and survival of enteric, sympathetic, and catecholaminergic neurons. We previously reported that GDNF is protective against high fat diet (HFD)-induced hepatic steatosis in mice through suppression of hepatic expression of peroxisome proliferator activated receptor- γ (PPAR-γ) and genes encoding enzymes involved in de novo lipogenesis. We also reported that transgenic overexpression of GDNF in mice prevented the HFD-induced liver accumulation of the autophagy cargo-associated protein p62/sequestosome 1 (p62/SQSTM1) characteristic of impaired autophagy...
February 4, 2019: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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