Article

The Battle over mTOR: An Emerging Theatre in Host–Pathogen Immunity

The Fox Chase Cancer Center, United States of America
PLoS Pathogens (Impact Factor: 7.56). 09/2012; 8(9):e1002894. DOI: 10.1371/journal.ppat.1002894
Source: PubMed
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    • "Autophagic lysosomal digestion is triggered by many environmental stressors including caloric restriction (CR), hypoxia, ROS, exercise, many toxins and phytochemicals, and sunlight and vitamin D mediated via the vitamin D receptor-VDR (Chatterjee etal., 2014; Delmas et al., 2011; Ferrari et al., 2011; Mestre and Colombo, 2013; Moore et al., 2008; Scherz-Shouval and Elazar, 2011; Wu and Sun, 2011; Zhang et al., 2012). Autophagy, triggered by inhibition of mTOR and other mTORindependent pathways (e.g., SIRT 1 and VDR), is probably an important component of hormetic responses, particularly in antiageing processes (Blagosklonny, 2011, Kim et al., 2012; Martins et al., 2011; Moore and Stebbing, 1976; Rubinsztein et al., 2011; Salminen et al., 2012; Wu and Sun, 2011). mTOR (mTORC1) is also a nutrient and stress sensor that regulates lysosomal autophagy, apoptosis (Type 1 programmed cell death – PCD 1) and senescence , that when inhibited can have beneficial consequences as indicated above. "
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    ABSTRACT: Living and taking recreation in rural and coastal environments promote health and wellbeing, although the causal factors involved are unclear. It has been proposed that such environments provide a counter to the stresses of everyday living, leading to enhanced mental and physical health. Living in natural environments will result in airborne exposure to a wide range of biogenic chemicals through inhalation and ingestion of airborne microbiota and particles. The "biogenics" hypothesis formulated here is that regular exposure to low concentrations of mixtures of natural compounds and toxins in natural environments confers pleiotropic health benefits by inhibiting the activities of interconnected cell signalling systems, particularly PI3K/Akt/mTORC1. When overactive, Akt and mTOR (mTORC1) can lead to many pathological processes including cancers, diabetes, inflammation, immunosuppression, and neurodegenerative diseases. There is a substantial body of evidence that many natural products (i.e., from bacteria, algae, fungi and higher plants) inhibit the activities of these protein kinases. Other mTOR-related interconnected metabolic control "switches" (e.g., PTEN & NF-κB), autophagy and other cytoprotective processes are also affected by natural products. The "biogenics" hypothesis formulated here is that regular intermittent exposure to a mixture of airborne biogenic compounds in natural environments confers pleiotropic health benefits by inhibiting activities of the highly interconnected PI3K/Akt/mTORC1 system. It is proposed that future experimental exposures to biogenic aerosols in animal models coupled with epidemiology, should target the activities of the various kinases in the PI3K/Akt/mTORC1 systems and related physiological processes for selected urban, rural and coastal populations in order to test this hypothesis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Environmental Research
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    • "Phone: +852 2766-6696 Email: pkwan@polyu.edu.hk or scienstein@msn.com (Received July 12, 2013; Revised: July 19, 2013; Accepted July 20, 2013; Published online July 23, 2013) the nutrient from the host to survive and facilitate the invasion by manipulating the mTOR in order to hijack the cellular metabolic processes [2]. In human cytomegalovirus (HCMV) infection, for example, mTOR is substantial in the viral replication cycle as it supports the transcription and translation signals [3]. "
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    ABSTRACT: Ageing and infectious disease are common health concerns global wide. Considering the emergence of MERS-CoV in the Middle East, H7N9 in Mainland China and first human case of H6N1 in Taiwan, it is imperative to look into the mechanisms underlying these problems and thereby developing effective countermeasures. Based on well established relationship between viral infections and various IFN signaling including STAT pathway and leads to modulation of T cells immunity, peruse of the role of mTOR plays upon pathogen intrusion is warranted. After the overview on the mTOR signaling, this review series now provides a recapitulation on heretofore findings of immunity and viral replication regulation upon infections provision by mTOR. Using influenza A virus as an illustration, we underscore the research opportunity on the potential linkage connecting these two physiological events with the final goal of identifying pharmaceutical targets to improve human health with minimal side effects.
    Full-text · Article · Jul 2013
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    ABSTRACT: Severe H1N1 pneumonia with acute respiratory failure results in infiltration of lungs due to the presence of hyperactive immune cells. Rapamycin and corticosteroids inhibit this immune response by blocking the activation of T and B cells. Open-label prospective randomized controlled trial. A tertiary medical center, Chang Gung Memorial Hospital, located in Taiwan. Between 2009 and 2011, of 4,012 H1N1-infected patients, 38 patients with severe H1N1 pneumonia and acute respiratory failure were enrolled. Thirty-eight patients with confirmed H1N1 pneumonia and on mechanical ventilatory support were randomized to receive adjuvant treatment of corticosteroids with an mTOR inhibitor, either with sirolimus (Rapamune 2 mg/d) (sirolimus group, n = 19) for 14 days or without sirolimus (nonsirolimus group, n = 19). The clinical values measured included PaO2/FIO2, Sequential Organ Failure Assessment score, duration of ventilatory support, and mortality. The baseline demography was similar between the two groups. After treatment, the PaO2/FIO2 values on day 3 (167.5 [95% CI, 86.7-209.2 mm Hg], n = 19 vs 106.8 [95% CI, 73.0-140.7 mm Hg], n = 19; p = 0.025] and day 7 (241.6 [95% CI, 185.2-297.9 mm Hg], n = 19 vs 147.0 [95% CI, 100.7-193.7 mm Hg], n = 17; p = 0.008) in the sirolimus group were significantly better over the nonsirolimus group. Similarly, the Sequential Organ Failure Assessment score on day 3 (4.3 [95% CI, 3.1-5.5]; p = 0.029) and day 7 (5.9 [95% CI, 4.8-6.9], n = 19 and 6.2 [95% CI, 4.7-7.8], n = 17, respectively) significantly improved in the sirolimus group. The liberation from a mechanical ventilator at 3 months was also better in the sirolimus combined with corticosteroids treatment. Similarly, the duration of ventilator use was significantly shorter in the sirolimus group (median, 7 vs 15 d; p = 0.03 by log-rank test). In the sirolimus combined with corticosteroids treatment group, a rapid clearance of virus also occurred after 7 days of treatment. In patients with severe H1N1 pneumonia, early adjuvant treatment with corticosteroids and an mTOR inhibitor was associated with improvement in outcomes, such as hypoxia, multiple organ dysfunction, virus clearance, and shortened liberation of ventilator and ventilator days.
    No preview · Article · Oct 2013 · Critical care medicine
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