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https://www.readbyqxmd.com/read/29165795/therapeutic-potency-of-mtor-signaling-pharmacological-inhibitors-in-the-treatment-of-proinflammatory-diseases-current-status-and-perspectives
#1
REVIEW
Arash Soltani, Amirhossein Bahreyni, Nadia Boroumand, Mostafa Karimi Roshan, Majid Khazaei, Mikhail Ryzhikov, Saman Soleimanpour, Amir Avan, Seyed Mahdi Hassanian
Mammalian target of rapamycin (mTOR) signaling pathway controls cell energy metabolism. There is an interplay between mTOR and proinflammatory signaling pathways, supporting the role of the pathway in the pathogenesis of inflammatory diseases. Inhibition of mTOR signaling using specific pharmacological inhibitors could offer therapeutic promise in several inflammatory-associated diseases. In this review, we summarize recent findings on the regulatory effects of mTOR signaling on inflammation and the therapeutic potency of mTOR pharmacological inhibitors in the treatment of inflammatory diseases including cancer, neurodegenerative diseases, atherosclerosis, sepsis and rheumatoid arthritis for a better understanding and hence a better management of these diseases...
November 22, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29165727/erratum-aucubin-protects-against-tgf%C3%AE-1-induced-cardiac-fibroblasts-activation-by-mediating-the-ampk%C3%AE-mtor-signaling-pathway
#2
Yang Xiao, Wei Chang, Qing-Qing Wu, Xiao-Han Jiang, Ming-Xia Duan, Ya-Ge Jin, Qi-Zhu Tang
No abstract text is available yet for this article.
November 17, 2017: Planta Medica
https://www.readbyqxmd.com/read/29165716/targeting-bcr-abl-independent-tki-resistance-in-chronic-myeloid-leukemia-by-mtor-and-autophagy-inhibition
#3
Rebecca Mitchell, Lisa E M Hopcroft, Pablo Baquero, Elaine K Allan, Kay Hewit, Daniel James, Graham Hamilton, Arunima Mukhopadhyay, Jim O'Prey, Alan Hair, Junia V Melo, Edmond Chan, Kevin M Ryan, Véronique Maguer-Satta, Brian J Druker, Richard E Clark, Subir Mitra, Pawel Herzyk, Franck E Nicolini, Paolo Salomoni, G Vignir Helgason
Background: Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment...
November 20, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29165314/towards-natural-mimetics-of-metformin-and-rapamycin
#4
Alexander Aliper, Leslie Jellen, Franco Cortese, Artem Artemov, Darla Karpinsky-Semper, Alexey Moskalev, Andrew G Swick, Alex Zhavoronkov
Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals-safer, naturally-occurring compounds-that mimic the anti-aging effects of metformin and rapamycin without adverse effects...
November 15, 2017: Aging
https://www.readbyqxmd.com/read/29164996/cptp-a-sphingolipid-transfer-protein-that-regulates-autophagy-and-inflammasome-activation
#5
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/29164883/raspberry-ketone-reduced-lipid-accumulation-in-3t3-l1-cells-and-ovariectomy-induced-obesity-in-wistar-rats-by-regulating-autophagy-mechanisms
#6
Sy-Ying Leu, Yi-Chen Chen, Yung-Chieh Tsai, Yao-Wen Hung, Chih-Hsiung Hsu, Yen-Mei Lee, Pao-Yun Cheng
This study aimed to determine the anti-obesity effects of raspberry ketone (RK), one of the major aromatic compounds contained in raspberry, and its underlying mechanisms. During adipogenesis of 3T3-L1 cells, RK (300 μM) significantly reduced lipid accumulation and downregulated the expression of CCAAT/enhancer-binding protein α (C/EBPα), peroxisome proliferation-activated receptor γ (PPARγ), fatty acid-binding protein 4 (FABP4), and fatty acid synthase (FAS). RK also reduced the expression of light chain 3B (LC3B), autophagy-related protein 12 (Atg12), sirtuin 1 (SIRT1), and phosphorylated-tuberous sclerosis complex 2 (TSC2), whereas it increased the level of p62 and phosphorylated-mammalian target of rapamycin (mTOR)...
November 22, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29164657/resveratrol-protects-leydig-cells-from-nicotine-induced-oxidative-damage-through-enhanced-autophagy
#7
Shengxian Liu, Qinyu Sun, Zhaomin Li
Some studies have revealed that nicotine can damage the male reproductive system through various ways including oxidative stress, which is a primary factor in the pathogenesis of male infertility. The strong antioxidative capacity of resveratrol has been demonstrated previously, but its role in the context of male reproduction remains inconclusive. To explore the biological role of resveratrol in protecting male reproductive function and the potential underlying mechanism, nicotine-induced Leydig cells were used as a cell model of oxidative damage...
November 22, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/29163766/epigallocatechin-3-gallate-egcg-up-regulates-mir-15b-expression-thus-attenuating-store-operated-calcium-entry-soce-into-murine-cd4-t-cells-and-human-leukaemic-t-cell-lymphoblasts
#8
Shaqiu Zhang, Tamer Al-Maghout, Rosi Bissinger, Ni Zeng, Lisann Pelzl, Madhuri S Salker, Anchun Cheng, Yogesh Singh, Florian Lang
CD4(+) T cells are key elements in immune responses and inflammation. Activation of T cell receptors in CD4(+) T cells triggers cytosolic Ca(2+) release with subsequent store operated Ca(2+) entry (SOCE), which is accomplished by the pore forming Ca(2+) release activated Ca(2+) (CRAC) channel Orai1 and its regulator stromal cell-interaction molecule 2 (STIM2). Green tea polyphenol epigallocatechin-3-gallate (EGCG) acts as a potent anti-inflammatory and anti-oxidant agent for various types of cells including immune cells...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29163680/yi-qi-yang-yin-tang-increases-the-sensitivity-of-kg1a-leukemia-stem-cells-to-daunorubicin-by-promoting-cell-cycle-progression-and-regulating-the-expression-of-pten-topoii-and-mtor
#9
Zhe-Xin Shi, Hong-Yu Li, Xiang-Dong Yang, Hong Gao, De-Guan Li, Wen-Hua Yang, Fang Yao, Li-Xiang Yan
The present study aimed to investigate the effects of serum containing a combination of yi-qi-yang-yin-tang (YQYYT) and daunorubicin (DNR) on multidrug resistance in KG1a leukemia stem cells (LSCs). The effects of YQYYT and DNR on proliferation, cell cycle progression and the expression of phosphatase and tensin homolog (PTEN), topoisomerase II (Topo II) and mechanistic target of rapamycin (mTOR) in KG1a cells were investigated in vitro using cell counting kit-8 assay, flow cytometry, reverse transcription-quantitative polymerase chain reaction and western blotting, respectively...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29163427/antimycobacterial-and-anti-inflammatory-mechanisms-of-baicalin-via-induced-autophagy-in-macrophages-infected-with-mycobacterium-tuberculosis
#10
Qingwen Zhang, Jinxia Sun, Yuli Wang, Weigang He, Lixin Wang, Yuejuan Zheng, Jing Wu, Ying Zhang, Xin Jiang
Tuberculosis (TB) remains a leading killer worldwide among infectious diseases and the effective control of TB is still challenging. Autophagy is an intracellular self-digestion process which has been increasingly recognized as a major host immune defense mechanism against intracellular microorganisms like Mycobacterium tuberculosis (Mtb) and serves as a key negative regulator of inflammation. Clinically, chronic inflammation surrounding Mtb can persist for decades leading to lung injury that can remain even after successful treatment...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29163244/peripheral-transcription-of-nrg-erbb-pathway-genes-are-upregulated-in-treatment-resistant-schizophrenia
#11
Md Shaki Mostaid, Ting Ting Lee, Gursharan Chana, Suresh Sundram, Cynthia Shannon Weickert, Christos Pantelis, Ian Everall, Chad Bousman
Investigation of peripheral gene expression patterns of transcripts within the NRG-ErbB signaling pathway, other than neuregulin-1 (NRG1), among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS) is limited. The present study built on our previous work demonstrating elevated levels of NRG1 EGFα, EGFβ, and type I(Ig2) containing transcripts in TRS by investigating 11 NRG-ErbB signaling pathway mRNA transcripts (NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1) in whole blood of TRS patients (N = 71) and healthy controls (N = 57)...
2017: Frontiers in Psychiatry
https://www.readbyqxmd.com/read/29163135/neuroprotective-effect-of-ligustilide-through-induction-of-%C3%AE-secretase-processing-of-both-app-and-klotho-in-a-mouse-model-of-alzheimer-s-disease
#12
Xi Kuang, Hong-Jing Zhou, Amy H Thorne, Xi-Nan Chen, Lin-Jiao Li, Jun-Rong Du
Emerging evidence suggests that alpha-processing single transmembrane proteins, amyloid precursor protein (APP) and anti-aging protein Klotho, are likely to be involved in the progression of Alzheimer's disease (AD). The natural phthalide Ligustilide (LIG) has been demonstrated to protect against aging- and amyloid-β (Aβ)-induced brain dysfunction in animal models. The present study is to investigate the effects of LIG on cognitive deficits and metabolism of both APP and Klotho and its underlying mechanism in AD double-transgenic (APP/PS1) mice and cultured human cells...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/29163060/nmda-receptors-regulate-the-development-of-neuronal-intrinsic-excitability-through-cell-autonomous-mechanisms
#13
Guoqiang Hou, Zhong-Wei Zhang
Maturation of neuronal and synaptic functions during early life is essential for the development of neuronal circuits and behaviors. In newborns synaptic transmission at excitatory synapses is primarily mediated by N-methyl-D-aspartate receptors (NMDARs), and NMDAR-mediated signaling plays an important role in synaptic maturation. Concomitant with synapse development, the intrinsic properties of neurons undergo dramatic changes during early life. However, little is known about the role of NMDARs in the development of intrinsic excitability...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29162840/whey-protein-concentrate-renders-mda-mb-231-cells-sensitive-to-rapamycin-by-altering-cellular-redox-state-and-activating-gsk3%C3%AE-mtor-signaling
#14
Shih-Hsuan Cheng, Yang-Ming Tseng, Szu-Hsien Wu, Shih-Meng Tsai, Li-Yu Tsai
Whey protein concentrate (WPC) is an amino acid-rich supplement that has been shown to increase cellular antioxidant capacity. Mammalian target of rapamycin (mTOR) is a crucial regulator of signaling in mammalian cells, and serves as a therapeutic target for triple-negative breast cancer (TNBC). This study was designed to investigate the effect of combining WPC with rapamycin on MDA-MB-231 human breast cancer cells. These cells were found to be insensitive to rapamycin and exhibited higher glutathione (GSH) and reactive oxygen species levels than non-tumorigenic MCF-10A cells...
November 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29162825/outcomes-of-patients-with-sarcoma-enrolled-in-clinical-trials-of-pazopanib-combined-with-histone-deacetylase-mtor-her2-or-mek-inhibitors
#15
Vikas Dembla, Roman Groisberg, Ken Hess, Siqing Fu, Jennifer Wheler, David S Hong, Filip Janku, Ralph Zinner, Sarina Anne Piha-Paul, Vinod Ravi, Robert S Benjamin, Shreyaskumar Patel, Neeta Somaiah, Cynthia E Herzog, Daniel D Karp, Jason Roszik, Funda Meric-Bernstam, Vivek Subbiah
Pazopanib is US FDA approved for the treatment of advanced soft tissue sarcomas. All patients with this disease ultimately develop resistance to therapy. Mechanisms of resistance include activation of the mTOR, histone deacetylase (HDAC), MAPK, and ERBB4 pathways. We hypothesized that combining pazopanib with other targeted agents inhibiting these pathways would increase response rates. We retrospectively evaluated the safety and efficacy of pazopanib plus vorinostat, everolimus, lapatinib or trastuzumab, and MEK inhibitor in patients with advanced sarcoma...
November 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29162479/mir-145-ameliorates-neuropathic-pain-via-inhibiting-inflammatory-responses-and-mtor-signaling-pathway-by-targeting-akt3-in-a-rat-model
#16
Jinshan Shi, Ke Jiang, Zhaoduan Li
Neuropathic pain perplexes a large population of patients with various diseases. Inflammation plays a key role in the physiopathology of neuropathic pain. Anti-inflammatory can be a promising strategy to treat neuropathic pain. We generated a chronic constriction injury rat model to mimic neuropathic pain by ligating the left ischiadic nerves of rats. Then we performed intrathecal injection of miR-145 mimics to treat these rats for seven consecutive days. Pain behavior tests including mechanical allodynia and thermal hyperalgesia, pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were analyzed...
November 18, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/29162126/targeting-the-master-regulator-mtor-a-new-approach-to-prevent-the-neurological-of-consequences-of-parasitic-infections
#17
REVIEW
Sheila Donnelly, Wilhelmina M Huston, Michael Johnson, Natalia Tiberti, Bernadette Saunders, Bronwyn O'Brien, Catherine Burke, Maurizio Labbate, Valery Combes
A systematic analysis of 240 causes of death in 2013 revealed that parasitic diseases were responsible for more than one million deaths. The vast majority of these fatalities resulted from protozoan infections presenting with neurological sequelae. In the absence of a vaccine, development of effective therapies is essential to improving global public health. In 2015, an intriguing strategy to prevent cerebral malaria was proposed by Gordon et al. 2015 mBio, 6:e00625. Their study suggested that inhibition of the mammalian target of rapamycin prevented experimental cerebral malaria by blocking the damage to the blood brain barrier and stopping the accumulation of parasitized red blood cells and T cells in the brain...
November 21, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/29161812/acute-amino-acid-d-serine-administration-similar-to-ketamine-produces-antidepressant-like-effects-through-the-identical-mechanisms
#18
I-Hua Wei, Kuang-Ti Chen, Mang-Hung Tsai, Ching-Hsiang Wu, Hsien-Yuan Lane, Chih-Chia Huang
D-serine is an amino acid and can work as an agonist at the glycine sites of N-methyl-D-aspartate receptor (NMDAR). Interestingly, both types of glutamatergic modulators, NMDAR enhancers and blockers, can improve depression through common targets, namely alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionaic acid receptors (AMPARs) and mammalian target of rapamycin (mTOR). To elucidate the cellular signaling pathway underlying this counterintuitive observation, we activated NMDARs in rats by using D-serine. Saline, ketamine (NMDAR antagonist), and desipramine (tricyclic antidepressant) were used as controls...
November 22, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29161765/mir-335-inhibited-cell-proliferation-of-lung-cancer-cells-by-target-tra2%C3%AE
#19
Jian Liu, Tingting Bian, Jia Feng, Li Qian, Jianguo Zhang, Daishan Jiang, Qing Zhang, Xiaoli Li, Yifei Liu, Jiahai Shi
Accumulating evidence has suggested that the dysregulation of miRNAs is an important factor in the pathogenesis of lung cancer. Here, we demonstrate that miR-335 expression is reduced in non-small cell lung cancer (NSCLC) tumors relative to non-cancerous adjacent tissues, whilst the expression of Tra2β is increased. In addition, clinical data revealed that the increased Tra2β and decreased miR-335 expression observed in NSCLC cells was associated with poor patient survival rates. In-vitro experimentation showed that the overexpression of miR-335 inhibited the growth, invasion and migration capabilities of A459 lung cancer cells, by targeting Tra2β...
November 21, 2017: Cancer Science
https://www.readbyqxmd.com/read/29161463/the-il-21-mtor-axis-blocks-treg-differentiation-and-function-by-suppression-of-autophagy-in-patients-with-systemic-lupus-erythematosus
#20
Hiroshi Kato, Andras Perl
OBJECTIVES: The mechanistic target of rapamycin (mTOR) has become a therapeutic target in systemic lupus erythematosus (SLE). mTOR regulates normal T-cell lineage specification, including development of regulatory cells (Tregs). Therefore, we investigated whether mTOR is activated within Tregs and causes their depletion and dysfunction in patients with SLE. METHODS: Activities of mTOR complexes 1 (mTORC1) and 2 (mTORC2) were examined by phosphorylation of 4E-BP1, S6K, and Akt, respectively, in SLE patients relative to healthy control females age-matched for each experiment...
November 21, 2017: Arthritis & Rheumatology
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