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https://www.readbyqxmd.com/read/28109197/everolimus-is-better-than-rapamycin-in-attenuating-neuroinflammation-in-kainic-acid-induced-seizures
#1
Ming-Tao Yang, Yi-Chin Lin, Whae-Hong Ho, Chao-Lin Liu, Wang-Tso Lee
BACKGROUND: Microglia is responsible for neuroinflammation, which may aggravate brain injury in diseases like epilepsy. Mammalian target of rapamycin (mTOR) kinase is related to microglial activation with subsequent neuroinflammation. In the present study, rapamycin and everolimus, both as mTOR inhibitors, were investigated in models of kainic acid (KA)-induced seizure and lipopolysaccharide (LPS)-induced neuroinflammation. METHODS: In vitro, we treated BV2 cells with KA and LPS...
January 21, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28108421/tlr4-knockout-attenuated-high-fat-diet-induced-cardiac-dysfunction-via-nf-%C3%AE%C2%BAb-jnk-dependent-activation-of-autophagy
#2
Nan Hu, Yingmei Zhang
Obesity is commonly associated with a low grade systematic inflammation, which may contribute to the onset and development of myocardial remodeling and contractile dysfunction. Toll-like receptor 4 (TLR4) plays an important role in innate immunity and inflammation although its role in high fat diet-induced obesity cardiac dysfunction remains elusive. This study was designed to examine the effect of TLR4 ablation on high fat diet intake-induced cardiac anomalies, if any, and underlying mechanism(s) involved...
January 17, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28107584/targeting-of-tumor-growth-and-angiogenesis-underlies-the-enhanced-antitumor-activity-of-lenvatinib-in-combination-with-everolimus
#3
Masahiro Matsuki, Yusuke Adachi, Yoichi Ozawa, Takayuki Kimura, Taisuke Hoshi, Kiyoshi Okamoto, Osamu Tohyama, Kaoru Mitsuhashi, Atsumi Yamaguchi, Junji Matsui, Yasuhiro Funahashi
The combination of lenvatinib-a multiple receptor tyrosine kinase (RTK) inhibitor-plus everolimus-a mammalian target of rapamycin (mTOR) inhibitor-significantly improved clinical outcomes versus everolimus monotherapy in a phase 2 clinical study of metastatic renal cell carcinoma (RCC). Here, we investigated potential mechanisms underlying the antitumor activity of the combination treatment in preclinical RCC models. Lenvatinib plus everolimus showed greater antitumor activity than either monotherapy in 3 human RCC xenograft mouse models (A-498, Caki-1, and Caki-2)...
January 20, 2017: Cancer Science
https://www.readbyqxmd.com/read/28107277/suppressive-effect-of-1%C3%AE-25-dihydroxyvitamin-d3-on-th17-immune-responses-in-kidney-transplant-recipients-with-tacrolimus-based-immunosuppression
#4
Byung Ha Chung, Bo-Mi Kim, Kyoung Chan Doh, Ji-Won Min, Mi-La Cho, Kyoung Woon Kim, Chul Woo Yang
BACKGROUND: The aim of this study was to investigate whether 1α,25-dihydroxyvitamin D3 can regulate Th17-related-immune responses in kidney transplant recipients (KTRs) being treated with tacrolimus (Tac)-based immunosuppression. METHODS: First, we evaluated the effect of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on Th17-immune responses in an in vitro study using peripheral blood mononuclear cells (PBMCs) from healthy volunteers or KTRs. Next, we investigated mTOR/STAT3 signaling as a mechanism by which 1,25(OH)2D3 exerted its effect on T cells using the Jurkat cell line...
October 6, 2016: Transplantation
https://www.readbyqxmd.com/read/28106827/neuroprotective-strategy-in-retinal-degeneration-suppressing-er-stress-induced-cell-death-via-inhibition-of-the-mtor-signal
#5
REVIEW
Bin Fan, Ying-Jian Sun, Shu-Yan Liu, Lin Che, Guang-Yu Li
The retina is a specialized sensory organ, which is essential for light detection and visual formation in the human eye. Inherited retinal degenerations are a heterogeneous group of eye diseases that can eventually cause permanent vision loss. UPR (unfolded protein response) and ER (endoplasmic reticulum) stress plays an important role in the pathological mechanism of retinal degenerative diseases. mTOR (the mammalian target of rapamycin) kinase, as a signaling hub, controls many cellular processes, covering protein synthesis, RNA translation, ER stress, and apoptosis...
January 19, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28106723/inhibition-of-autophagic-degradation-process-contributes-to-claudin-2-expression-increase-and-epithelial-tight-junction-dysfunction-in-tnf-%C3%AE-treated-cell-monolayers
#6
Cong Zhang, Junkai Yan, Yongtao Xiao, Yujie Shen, Jiazheng Wang, Wensong Ge, Yingwei Chen
Tight junction dysfunction plays a vital role in some chronic inflammatory diseases. Pro-inflammatory cytokines, especially tumor necrosis factor alpha (TNF-α), act as important factors in intestinal epithelial tight junction dysfunction during inflammatory conditions. Autophagy has also been shown to be crucial in tight junction function and claudin-2 expression, but whether autophagy has an effect on the change of claudin-2 expression and tight junction function induced by TNF-α is still unknown. To answer this question, we examined the expression of claudin-2 protein, transepithelial electrical resistance (TER), and permeability of cell monolayers, autophagy flux change, and lysosomal pH after TNF-α with or without PP242 treatment...
January 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28106077/mesenchymal-stem-cell-transplantation-in-tight-skin-mice-identifies-mir-151-5p-as-a-therapeutic-target-for-systemic-sclerosis
#7
Chider Chen, Dandan Wang, Alireza Moshaverinia, Dawei Liu, Xiaoxing Kou, Wenjing Yu, Ruili Yang, Lingyun Sun, Songtao Shi
Systemic sclerosis (SSc), an autoimmune disease, may cause significant osteopenia due to activation of the IL4Rα/mTOR pathway. Mesenchymal stem cell transplantation (MSCT) can ameliorate immune disorders in SSc via inducing immune tolerance. However, it is unknown whether MSCT rescues osteopenia phenotype in SSc. Here we show that MSCT can effectively ameliorate osteopenia in SSc mice by rescuing impaired lineage differentiation of the recipient bone marrow MSCs. Mechanistically, we show that donor MSCs transfer miR-151-5p to the recipient bone marrow MSCs in SSc mice to inhibit IL4Rα expression, thus downregulating mTOR pathway activation to enhance osteogenic differentiation and reduce adipogenic differentiation...
January 20, 2017: Cell Research
https://www.readbyqxmd.com/read/28105863/the-role-of-mtor-inhibition-as-second-line-therapy-in-metastatic-renal-carcinoma-clinical-evidence-and-current-challenges
#8
José Luis González-Larriba, Pablo Maroto, Ignacio Durán, Julio Lambea, Luis Flores, Daniel Castellano
Sequential treatment with targeted agents is the standard of care for patients with metastatic renal cell carcinoma (mRCC). Although first-line therapy with tyrosine kinase inhibitors (TKIs) is recommended for most patients, eventually all patients become resistant to them. Therefore, optimal selection of second-line therapy is crucial. Areas covered: We have reviewed the recent literature through pubmed search and recent congress presentations to briefly describe the clinical evidence for mTOR inhibition as a valid strategy in the treatment of mRCC after progression during anti-VEGFR therapy...
January 20, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28105368/clinical-and-immunologic-correlates-of-response-to-pd-1-blockade-in-a-patient-with-metastatic-renal-medullary-carcinoma
#9
Kathryn E Beckermann, Pradeep C Jolly, Ju Y Kim, Jennifer Bordeaux, Igor Puzanov, W Kimryn Rathmell, Douglas B Johnson
BACKGROUND: Renal medullary carcinoma (RMC) is a rare kidney tumor that occurs in adolescent and young adults, typically in association with sickle cell trait. RMC exhibits rapid disease progression, frequent metastases at diagnosis, and dismal clinical outcomes. Currently available therapies, including cisplatin-based combination chemotherapy, multi-tyrosine kinase, and mTOR inhibitor strategies demonstrate either transient responses or minimal activity. Therefore, further molecular characterization and additional treatment strategies are urgently needed in this aggressive disease...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28105210/mammalian-target-of-rapamycin-inhibitor-rad001-sensitizes-endometrial-cancer-cells-to-paclitaxel-induced-apoptosis-via-the-induction-of-autophagy
#10
Huan Wang, Dandan Li, Xiaomao Li, Xueling Ou, Suiling Liu, Yu Zhang, Jie Ding, Bo Xie
The aim of the present study was to investigate the effects of the mammalian target of rapamycin (mTOR) inhibitor, RAD001, on the growth of human endometrial cancer cells. The effects of RAD001 on human endometrial cancer Ishikawa and HEC-1A cell proliferation were determined by MTT assay. Green fluorescent protein microtubule-associated protein 1 light chain 3α (GFP-LC3) protein aggregates were observed under a confocal microscope, and Ishikawa and HEC-1A cell apoptosis was detected using flow cytometry. The expression levels of LC3-I, LC3-II and mTOR proteins were detected by western blot analysis...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28104700/inhibition-of-4ebp-phosphorylation-mediates-the-cytotoxic-effect-of-mtor-kinase-inhibitors-in-aggressive-b-cell-lymphomas
#11
Chengfeng Bi, Xuan Zhang, Ting Lu, Xiaoyan Zhang, Xianhuo Wang, Bin Meng, Huilai Zhang, Ping Wang, Julie M Vose, Wing C Chan, Timothy W McKeithan, Kai Fu
Mechanistic target of rapamycin complex 1 (mTORC1) is a central integrator of nutrient and growth factor inputs that controls cell growth in eukaryotes. The second generation of mTOR kinase inhibitors (TORKi), directly targeting the mTOR catalytic site, are more effective than rapamycin and its analogs in cancer treatment, particularly in inducing apoptosis. However, the mechanism underlying the cytotoxic effect of TORKi remains elusive. Herein, we demonstrated that TORKi-induced apoptosis is predominantly dependent on loss of mTORC1-mediated 4EBP activation...
January 19, 2017: Haematologica
https://www.readbyqxmd.com/read/28104295/systematic-drug-sensitivity-testing-reveals-synergistic-growth-inhibition-by-dasatinib-or-mtor-inhibitors-with-paclitaxel-in-ovarian-granulosa-cell-tumor-cells
#12
Ulla-Maija Haltia, Noora Andersson, Bhagwan Yadav, Anniina Färkkilä, Evgeny Kulesskiy, Matti Kankainen, Jing Tang, Ralf Bützow, Annika Riska, Arto Leminen, Markku Heikinheimo, Olli Kallioniemi, Leila Unkila-Kallio, Krister Wennerberg, Tero Aittokallio, Mikko Anttonen
OBJECTIVE: Resistance to standard chemotherapy poses a major clinical problem in the treatment of ovarian cancer patients. Adult-type granulosa cell tumor (AGCT) is a unique ovarian cancer subtype for which efficient treatment options are lacking in advanced disease. To this end, systematic drug response and transcriptomics profiling were performed to uncover new therapy options for AGCTs. METHODS: The responses of three primary and four recurrent AGCTs to 230 anticancer compounds were screened in vitro using a systematic drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA sequencing...
January 16, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28103683/simultaneous-targeting-of-npc1-and-vdac1-by-itraconazole-leads-to-synergistic-inhibition-of-mtor-signaling-and-angiogenesis
#13
Sarah A Head, Wei Q Shi, Eun Ju Yang, Benjamin A Nacev, Sam Y Hong, Kalyan K Pasunooti, Ruo-Jing Li, Joong Sup Shim, Jun O Liu
The antifungal drug itraconazole was recently found to exhibit potent antiangiogenic activity and has since been repurposed as an investigational anticancer agent. Itraconazole has been shown to exert its antiangiogenic activity through inhibition of the mTOR signaling pathway, but the molecular mechanism of action was unknown. We recently identified the mitochondrial protein VDAC1 as a target of itraconazole and a mediator of its activation of AMPK, an upstream regulator of mTOR. However, VDAC1 could not account for the previously reported inhibition of cholesterol trafficking by itraconazole, which was also demonstrated to lead to mTOR inhibition...
January 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28102849/berberine-sonodynamic-therapy-induces-autophagy-and-lipid-unloading-in-macrophage
#14
Jiayuan Y Kou, Ying Li, Zhaoyu Y Zhong, Yueqing Q Jiang, Xuesong S Li, Xiaobo B Han, Zhongni N Liu, Ye Tian, Liming M Yang
Impaired autophagy in macrophages accompanies the progression of atherosclerosis and contributes to lipid loading in plaques and ineffective lipid degradation. Therefore, evoking autophagy and its associated cholesterol efflux may provide a therapeutic treatment for atherosclerosis. In the present study, berberine-mediated sonodynamic therapy (BBR-SDT) was used to induce autophagy and cholesterol efflux in THP-1 macrophages and derived foam cells. Following BBR-SDT, autophagy was increased in the macrophages, autophagy resistance in the foam cells was prevented, and cholesterol efflux was induced...
January 19, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28102733/plk1-polo-like-kinase-1-inhibits-mtor-complex-1-and-promotes-autophagy
#15
Stefanie Ruf, Alexander Martin Heberle, Miriam Langelaar-Makkinje, Sara Gelino, Deepti Wilkinson, Carolin Gerbeth, Jennifer Jasmin Schwarz, Birgit Holzwarth, Bettina Warscheid, Chris Meisinger, Marcel A T M van Vugt, Ralf Baumeister, Malene Hansen, Kathrin Thedieck
Mechanistic target of rapamycin complex 1 (MTORC1) and PLK1 (polo like kinase 1) are major drivers of cancer cell growth and proliferation, and inhibitors of both protein kinases are currently being investigated in clinical studies. To date, MTORC1's and PLK1's functions are mostly studied separately, and reports on their mutual crosstalk are scarce. Here, we identify PLK1 as a physical MTORC1 interactor in human cancer cells. PLK1 inhibition enhances MTORC1 activity under nutrient sufficiency and in starved cells, and PLK1 directly phosphorylates the MTORC1 component RPTOR/RAPTOR in vitro...
January 19, 2017: Autophagy
https://www.readbyqxmd.com/read/28101526/rapamycin-resistant-mtor-activity-is-required-for-sensory-axon-regeneration-induced-by-a-conditioning-lesion
#16
Weitao Chen, Na Lu, Yue Ding, Yuan Wang, Leung Ting Chan, Xu Wang, Xin Gao, Songshan Jiang, Kai Liu
Neuronal mammalian target of rapamycin (mTOR) activity is a critical determinant of the intrinsic regenerative ability of mature neurons in the adult central nervous system (CNS). However, whether its action also applies to peripheral nervous system (PNS) neurons after injury remains elusive. To address this issue unambiguously, we used genetic approaches to determine the role of mTOR signaling in sensory axon regeneration in mice. We showed that deleting mTOR in dorsal root ganglion (DRG) neurons suppressed the axon regeneration induced by conditioning lesions...
November 2016: ENeuro
https://www.readbyqxmd.com/read/28101248/expression-of-cancerous-inhibitor-of-protein-phosphatase-2a-in-human-triple-negative-breast-cancer-correlates-with-tumor-survival-invasion-and-autophagy
#17
Shan Li, Ting-Ting Feng, Yang Guo, Xianjun Yu, Qiuyue Huang, Liang Zhang, Wei Tang, Ying Liu
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently characterized oncoprotein which is involved in the progression of several human malignancies. The present study aimed to investigate its biological function in human triple negative breast cancer (TNBC). The expression of CIP2A in TNBC cells was examined and it was observed that CIP2A was elevated in the TNBC cell line compared with poorly invasive breast cancer cells. CIP2A depletion in TNBC cell lines inhibited proliferation, and induced apoptosis and autophagy...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28101201/diosmetin-inhibits-cell-proliferation-and-induces-apoptosis-by-regulating-autophagy-via-the-mammalian-target-of-rapamycin-pathway-in-hepatocellular-carcinoma-hepg2-cells
#18
Jie Liu, Hao Ren, Bin Liu, Qingyu Zhang, Mingyi Li, Runzhi Zhu
Hepatocellular carcinoma (HCC), which is a type of malignant tumor, is the fifth most common cancer in men and ninth in women worldwide. The aim of the present study was to investigate the antitumor effect of diosmetin (DIOS) in hepatocellular carcinoma HepG2 cells. The proliferation, apoptosis and autophagy rates of HepG2 cells were measured following treatment with DIOS. The effects of DIOS treatment on HepG2 cell proliferation and apoptosis rates were analyzed using MTT assays and Annexin V staining, respectively...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28100467/an-essential-role-of-cbl-and-cbl-b-ubiquitin-ligases-in-mammary-stem-cell-maintenance
#19
Bhopal Mohapatra, Neha Zutshi, Wei An, Benjamin Goetz, Priyanka Arya, Timothy A Bielecki, Insha Mustaq, Matthew D Storck, Jane L Meza, Vimla Band, Hamid Band
CBL and CBL-B ubiquitin ligases are negative regulators of tyrosine kinase signaling with established roles in the immune system. However, their physiological roles in epithelial tissues are unknown. Here we used the MMTV-Cre-mediated Cbl gene deletion on a Cbl-b-null background as well as a tamoxifen-inducible mammary stem cell (MaSC)-specific Cbl/Cbl-b double knockout (DKO), using Lgr5-GFP-CreERT, to demonstrate a mammary epithelial cell-autonomous requirement of CBL and CBL-B in the maintenance of MaSCs...
January 18, 2017: Development
https://www.readbyqxmd.com/read/28100106/systemic-lupus-erythematosus-in-the-light-of-the-regulatory-effects-of-galectin-1-on-t-cell-function
#20
Á Hornung, É Monostori, L Kovács
Galectin-1 is an endogenous immunoregulatory lectin-type protein. Its most important effects are the inhibition of the differentiation and cytokine production of Th1 and Th17 cells, and the induction of apoptosis of activated T-cells. Galectin-1 has been identified as a key molecule in antitumor immune surveillance, and data are accumulating about the pathogenic role of its deficiency, and the beneficial effects of its administration in various autoimmune disease models. Initial animal and human studies strongly suggest deficiencies in both galectin-1 production and responsiveness in systemic lupus erythematosus (SLE) T-cells...
January 1, 2017: Lupus
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