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Autophagy and

Danielle Oliveira Dos Anjos, Eliomara Sousa Sobral Alves, Vinicius Tomaz Gonçalves, Sheila Suarez Fontes, Mateus Lima Nogueira, Ana Márcia Suarez-Fontes, João Batista Neves da Costa, Fabricio Rios-Santos, Marcos André Vannier-Santos
Natural products comprise valuable sources for new antiparasitic drugs. Here we tested the effects of a novel β-lapachone derivative on Trypanosoma cruzi parasite survival and proliferation and used microscopy and cytometry techniques to approach the mechanism(s) underlying parasite death. The selectivity index determination indicate that the compound trypanocidal activity was over ten-fold more cytotoxic to epimastigotes than to macrophages or splenocytes. Scanning electron microscopy analysis revealed that the R72 β-lapachone derivative affected the T...
October 12, 2016: International Journal for Parasitology, Drugs and Drug Resistance
Qinghua Chen, Lulu Zhang, Siyao Chen, Yaqian Huang, Kun Li, Xiaoqi Yu, Huijuan Wu, Xiaoyu Tian, Chunyu Zhang, Chaoshu Tang, Junbao Du, Hongfang Jin
BACKGROUND: The study was designed to investigate if endogenous sulfur dioxide (SO2) was involved in cardiomyocyte autophagy and myocardial hypertrophy stimulated by angiotensin II (Ang II). METHODS: Thirty-two C57 mice were randomly divided into control, SO2, Ang II and Ang II+SO2 groups. Human myocardial cell line H9c2 was divided into four groups including control, SO2, Ang II and Ang II+SO2 groups. Blood pressure and myocardial hypertrophy of the mice were measured two weeks after Ang II administration...
September 30, 2016: International Journal of Cardiology
Yinyan Xu, Xinyan Huang, Juan Xie, Yanni Chen, Jing Fu, Li Wang
Autophagy, identified as type II programmed cell death, has already been known to be involved in the pathophysiology of preeclampsia (PE), which is a gestational disease with high morbidity. The present study aims to investigate the functional role of let-7i, a miRNA, in trophoblastic autophagy. Placental tissue used in this study was collected from patients with severe preeclampsia (SPE) or normal pregnant women. A decreased level of let-7i was found in placenta of SPE. In addition, autophagic vacuoles were observed in SPE and the expression of microtubule associated protein 1 light chain 3 (LC3) II/I was elevated...
October 22, 2016: Journal of Cellular Physiology
Long-Xing Xue, Zhong-Hang Xu, Jiao-Qi Wang, Cui Yang, Hong-Yu Liu, Wen-Zhao Liang, Qiu-Ye Ji, Jin-Ting He, Yan-Kun Shao, Jing Mang, Zhong-Xin Xu
Activin A (Act A), a member of the transforming growth factor-beta (TGF-β), reduces neuronal apoptosis during cerebral ischemia through Act A/Smads signaling pathway. However, little is known about the effect of Act A/Smads pathway on autophagy in neurons. Here, we found that oxygen-glucose deprivation (OGD)-induced autophagy was suppressed by exogenous Act A in a concentration-dependent manner and enhanced by Act A/Smads pathway inhibitor (ActRIIA-Ab) in neuronal PC12 cells. These results indicate that Act A/Smads pathway negatively regulates autophagy in OGD-treated PC12 cells...
October 18, 2016: Biochemical and Biophysical Research Communications
Cheng-Fu Chang, Yi-Chao Lee, Kuen-Haur Lee, Hui-Ching Lin, Chia-Ling Chen, Che-Kun James Shen, Chi-Chen Huang
BACKGROUND: In the central nervous system regions of the sporadic and familial FTLD and ALS patients, TDP-43 has been identified as the major component of UBIs inclusions which is abnormally hyperphosphorylated, ubiquitinated, and cleaved into C-terminal fragments to form detergent-insoluble aggregates. So far, the effective drugs for FTLD and ALS neurodegenerative diseases are yet to be developed. Autophagy has been demonstrated as the major metabolism route of the pathological TDP-43 inclusions, hence activation of autophagy is a potential therapeutic strategy for TDP-43 pathogenesis in FTLD and ALS...
October 21, 2016: Journal of Biomedical Science
Jorge Moscat, Michael Karin, Maria T Diaz-Meco
Adaptor proteins participate in selective autophagy, which is critical for cellular detoxification and stress relief. However, new evidence supports an autophagy-independent key role of the adaptor p62 (encoded by the gene Sqstm1) in signaling functions central to tumor initiation in the epithelium and suppression of tumor progression in the stroma.
October 20, 2016: Cell
Raffaela Torggler, Daniel Papinski, Thorsten Brach, Levent Bas, Martina Schuschnig, Thaddäus Pfaffenwimmer, Sabrina Rohringer, Tamara Matzhold, David Schweida, Andrea Brezovich, Claudine Kraft
Autophagy is a potent cellular degradation pathway, and its activation needs to be tightly controlled. Cargo receptors mediate selectivity during autophagy by bringing cargo to the scaffold protein Atg11 and, in turn, to the autophagic machinery, including the central autophagy kinase Atg1. Here we show how selective autophagy is tightly regulated in space and time to prevent aberrant Atg1 kinase activation and autophagy induction. We established an induced bypass approach (iPass) that combines genetic deletion with chemically induced dimerization to evaluate the roles of Atg13 and cargo receptors in Atg1 kinase activation and selective autophagy progression...
October 20, 2016: Molecular Cell
Ariadne Vlahakis, Jayanta Debnath
In this issue of Molecular Cell, Torggler et al. (2016) leverage innovative synthetic biology approaches to dissect the spatiotemporal activation of Atg1 kinase during selective autophagy, revealing two distinct pathways that coordinately initiate autophagosome formation at the yeast vacuole.
October 20, 2016: Molecular Cell
Oznur Bayraktar, Ozlem Oral, Nur Mehpare Kocaturk, Yunus Akkoc, Karin Eberhart, Ali Kosar, Devrim Gozuacik
The ubiquitin-proteasome system (UPS) degrades soluble proteins and small aggregates, whereas macroautophagy (autophagy herein) eliminates larger protein aggregates, tangles and even whole organelles in a lysosome-dependent manner. VCP/p97 was implicated in both pathways. VCP/p97 mutations cause a rare multisystem disease called IBMPFD (Inclusion Body Myopathy with Paget's Disease and Frontotemporal Dementia). Here, we studied the role IBMPFD-related mutants of VCP/p97 in autophagy. In contrast with the wild-type VCP/p97 protein or R155C or R191Q mutants, the P137L mutant was aggregate-prone...
2016: PloS One
Christopher P Webster, Emma F Smith, Andrew J Grierson, Kurt J De Vos
A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common genetic defect associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Haploinsufficiency and a resulting loss of C9orf72 protein function has been suggested as a possible pathogenic mechanism in C9ALS/FTD. C9ALS/FTD patients exhibit specific ubiquitin and p62/sequestosome-1 positive but TDP-43 negative inclusions in the cerebellum and hippocampus, indicating possible autophagy deficits in these patients...
October 21, 2016: Small GTPases
Kwang-Youn Kim, Hyun-Jun Jang, Yong Ryul Yang, Kwang-Il Park, JeongKon Seo, Il-Woo Shin, Tae-Il Jeon, Soon-Cheol Ahn, Pann-Ghill Suh, Timothy F Osborne, Young-Kyo Seo
Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride...
October 21, 2016: Scientific Reports
Joan Yw Liu, Cheryl Reeves, Beate Diehl, Antonietta Coppola, Aliya Al-Hajri, Chandrashekar Hoskote, Salim Al Mughairy, Mohamed Tachrount, Michael Groves, Zuzanna Michalak, Kevin Mills, Andrew W McEvoy, Anna Miserocchi, Sanjay M Sisodiya, Maria Thom
OBJECTIVE: This study reports on a novel brain pathology in young patients with Frontal Lobe Epilepsy that is distinct from Focal Cortical Dysplasia. METHODS: Surgical specimens from twenty young adults with frontal lobe epilepsy (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of rapamycin pathway activation and inhibition, cellular autophagy, and synaptic vesicle-mediated trafficking as well as proteomics analysis...
October 20, 2016: Annals of Neurology
Alfredo Lagunas-Martínez, Enrique García-Villa, Magaly Arellano-Gaytán, Carla O Contreras-Ochoa, Jisela Dimas-González, María E López-Arellano, Vicente Madrid-Marina, Patricio Gariglio
The E6 oncoprotein can interfere with the ability of infected cells to undergo programmed cell death through the proteolytic degradation of proapoptotic proteins such as p53, employing the proteasome pathway. Therefore, inactivation of the proteasome through MG132 should restore the activity of several proapoptotic proteins. We investigated whether in HPV16 E6-expressing keratinocytes (KE6 cells), the restoration of p53 levels mediated by MG132 and/or activation of the CD95 pathway through apoptosis antigen-1 (APO-1) antibody are responsible for the induction of apoptosis...
October 20, 2016: Apoptosis: An International Journal on Programmed Cell Death
Xin-Shuang Yu, Juan Du, Yu-Jun Fan, Feng-Jun Liu, Li-Li Cao, Ning Liang, De-Guo Xu, Jian-Dong Zhang
OBJECTIVE: This study aims to investigate the effects of endoplasmic reticulum stress (ERS) on autophagy, apoptosis and chemoresistance of human small cell lung cancer (SCLC) cells via the PI3K/AKT/mTOR signaling pathway. RESULTS: The expressions of ERS-related proteins (PEAK, eIF2α and CHOP) up-regulated, autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis-related proteins (Bax and procaspase-3) down-regulated in NCI-H446 and H69 cells after tunicamycin treatment for 24 h...
October 18, 2016: Oncotarget
Yun-Fang Zhen, Song-Tao Li, Yun-Rong Zhu, Xiao-Dong Wang, Xiao-Zhong Zhou, Lun-Qing Zhu
Malignant osteosarcoma (OS) is still a deadly disease for many affected patients. The search for the novel anti-OS agent is extremely urgent and important. Our previous study has proposed that salinomycin is a novel anti-OS agent. Here we characterized DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a primary salinomycin resistance factor in OS cells. DNA-PKcs inhibitors (NU7026, NU7441 and LY294002) or DNA-PKcs shRNA knockdown dramatically potentiated salinomycin-induced death and apoptosis of OS cells (U2OS and MG-63 lines)...
October 17, 2016: Oncotarget
Karen Peynshaert, Stefaan J Soenen, Bella B Manshian, Shareen H Doak, Kevin Braeckmans, Stefaan C De Smedt, Katrien Remaut
: In the last decade the interest in autophagy got an incredible boost and the phenomenon quickly turned into an extensive research field. Interestingly, dysfunction of this cytoplasmic clearance system has been proposed to lie at the root of multiple diseases including cancer. We therefore consider it crucial from a toxicological point of view to investigate if nanomaterials that are developed for biomedical applications interfere with this cellular process. Here, we study the highly promising 'gradient alloyed' quantum dots (QDs) that differ from conventional ones by their gradient core composition which allows for better fluorescent properties...
October 17, 2016: Acta Biomaterialia
Manuela Antonioli, Martina Di Rienzo, Mauro Piacentini, Gian Maria Fimia
Autophagy is a major degradative process activated in a rapid and transient manner to cope with stress conditions. Whether autophagy is beneficial or detrimental depends upon the rate of induction and the appropriateness of the duration. Alterations in both autophagy initiation and termination predispose the cell to death, and affect the execution of other inducible processes such as inflammation. In this review we discuss how stress signaling pathways dynamically control the activity of the autophagy machinery by mediating post-translational modifications and regulatory protein interactions...
October 17, 2016: Trends in Biochemical Sciences
Soojong Park, Ahmad Fudhaili, Sang-Seok Oh, Ki Won Lee, Hamadi Madhi, Dong-Hee Kim, Jiyun Yoo, Hyung Won Ryu, Ki-Hun Park, Kwang Dong Kim
BACKGROUND: Broussonetia papyrifera (B. papyrifera), also known as paper mulberry, has been used as a traditional medicine for the treatment of several diseases, including ophthalmic disorders and impotency. However, the biological activity of kazinol A (1) among flavonols isolated from B. papyrifera has not been identified. PURPOSE: We identified a candidate metabolite for anti-human bladder cancer treatment from B. papyrifera and investigated the possible molecular mechanisms underlying its cytotoxic effects in T24 and cisplatin-resistant T24R2 human bladder cancer cells...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
X F Guo, Y N Zhao, J M Li, C X Chen, S X Li
Objective: To compare the changes in the expression of mTOR and beclin1 in the hippocampus of normal rats and intermittent hypoxia rats with cerebral ischemia/reperfusion, so as to explore the roles of mTOR/autophagy pathway in global cerebral ischemia/reperfusion injure aggravated by intermittent hypoxia. Methods: One hundred healthy male Wistar rats were randomly divided into: sham operation group(SO group, n=20), intermittent hypoxia group(IH group, n=20), merely ischemia/reperfusion group(I/R group, n=20), intermittent hypoxia ischemia/reperfusion group(IH+ I/R group, n=20), intermittent hypoxia ischemia/reperfusion+ mTOR inhibitor group(Inhibitor group, n=20)...
October 7, 2016: Zhonghua Er Bi Yan Hou Tou Jing Wai Ke za Zhi, Chinese Journal of Otorhinolaryngology Head and Neck Surgery
Yuyin Li, Yuejun Sun, Lifang Jing, Jianjun Wang, Yali Yan, Yajuan Feng, Yueying Zhang, Zhenxing Liu, Long Ma, Aipo Diao
The lysosome inhibitors bafilomycin A1 and chloroquine have both lysosomotropic properties and autophagy inhibition ability, and are promising clinical agents to be used in combination with anticancer drugs. In order to investigate this combination effect, HepG2 cells were treated with bafilomycin A1, chloroquine, or/and doxorubicin, and their proliferative ability, induction of apoptosis, and the changes of lysosomal membrane permeabilization and mitochondrial membrane potential were studied. The results demonstrate that treatment with bafilomycin A1 or chloroquine alone at a relatively low concentration promotes the inhibitory effect of doxorubicin on cell growth and apoptosis...
October 21, 2016: Chemotherapy
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