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Nanoparticle–Based RNA (siRNA) Combination Therapy Toward Overcoming Drug Resistance in Cancer
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
Autophagy is considered to be a cytoprotective process involved in the normal turnover of long-lived proteins and whole organelles to maintain a healthy cellular status [157]. However, recent data strongly demonstrate that autophagy is intimately linked to apoptosis or necrosis and serves both pro-survival and pro-death functions. Autophagy regulation requires an orchestrated interplay between many signaling molecules, including mammalian target of rapamycin (mTOR) kinase, which has the most potent impact on autophagy [158,159]. Once activated, mTOR inhibits autophagy via the phosphorylation of autophagy-related proteins. AMP activated protein kinase (AMPK) activation can lead to autophagy by negatively regulating mTOR [160,161]. The tumor suppressor protein p53 can trigger autophagy by phosphorylating AMPK and further inhibiting the mTOR signaling pathway [160]. Beclin-1 also plays a critical role in autophagosome formation and crosstalk between autophagy and apoptosis [161]. The BH3 domain-mediated binding of Beclin-1 to B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-XL) inhibits autophagy. However, the c-Jun N-terminal kinase (JNK) 1- or extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Bcl-2 or death-associated protein kinase-mediated phosphorylation of Beclin-1 induces the dissociation of the Beclin-1–Bcl-2/Bcl-XL complex, thus inhibiting autophagy [161–165]. Intracellular calcium ions (Ca2+) can regulate the activation of JNK and the apoptotic signaling pathway [166].
Treatment Options for Chemical Sensitivity
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 5, 2017
William J. Rea, Kalpana D. Patel
A major intracellular hub for integrating autophagy-related signals is mTORC1.201 In the presence of abundant nutrients and growth factors including insulin, TORC1 promotes cell growth and metabolic activity while suppressing the ULK1 complex and autophagy. In deprivation or stress, numerous signaling pathways inactivate mTORC1 kinase activity. These both suppress cell growth to reduce energy demand and induces autophagy to enable stress adaptation and survival. A second mTOR complex, mTORC2, positively regulates mTORC1. Upstream of mTORC1 is the cellular energy-sensing pathway controlled by adenosine monophosphate-activated protein kinase (AMPK).202 High concentrations of AMP signal energy depletion, activate AMPK, and inhibit mTORC1, thus promoting autophagy (Figure 6.33).
Compounds of Plant Origin as AMP-Activated Protein Kinase Activators
Published in Alexander V. Kutchin, Lyudmila N. Shishkina, Larissa I. Weisfeld, Gennady E. Zaikov, Ilya N. Kurochkin, Alexander N. Goloshchapov, Chemistry and Technology of Plant Substances, 2017
Daria S. Novikova, Gleb S. Ivanov, Alexander V. Garabadzhiu, Viacheslav G. Tribulovich
AMP-activated protein kinase (AMPK) was discovered more than 20 years ago, but only during the recent years, researchers have got a better understanding of its interactions with multiple signaling cascades. AMPK is considered as the main regulator of energy metabolism; it maintains energy homeostasis, both at cellular and whole-body levels [1]. In stressful conditions, when an increase in the adenosine monophosphate (AMP) level and decrease in the adenosine triphosphate (ATP) level is observed, the activation of AMPK leads to a rapid switching to reserve resources. If there is an energy deficiency, AMPK discontinues processes accompanied by energy consumption and promotes processes aimed at energy production. This switching from energy-consuming to energy-producing reactions enables to maintain the energy status of the body under stressful conditions [2].
Toxicity in vitro reveals potential impacts of microplastics and nanoplastics on human health: A review
Published in Critical Reviews in Environmental Science and Technology, 2022
Qingying Shi, Jingchun Tang, Rutao Liu, Lan Wang
Recently, treatment with plastic particles has been shown to induce autophagy. Lim et al. (2019) pointed out that NPs (10 and 50 μg/mL) induced autophagy and illustrated the mechanism of autophagy related to activation of endoplasmic reticulum (ER) stress. Chiu et al. (2015) demonstrated that amino-functionalized PS particles increased autophagic flux, which is caused by ROS generation and ER stress resulted from protein misfolding. Moreover, the Akt/mTOR and AMPK signaling pathways were involved in the regulation of autophagy cell death triggered by amino-functionalized PS particles. Loos et al. (2014) proved that the both carboxylated and amino-functionalized PS NPs (100 μg/mL), could induce autophagy in leukemia cells. Amino-functionalized PS NPs inhibited mTOR signaling in leukemia cells at the molecular level, and amino-functionalized PS NPs blocked activation of the mTOR downstream targets, Akt and p70 ribosomal S6 kinase 1, and induced overexpression of the cell-cycle regulator p21Cip1/Waf1 and degradation of cyclin B1. Other researchers also pointed out that the damage of amino-functionalized PS NPs (50 μg/mL) to lysosomes probably results in lysosomal dysfunctions, leading to blockage of autophagic flux at the level of lysosomes and the eventual cell death (F. Wang et al., 2018). Song et al. (2015) suggested that the autophagic response to PS NPs (10–100 μg/mL) was mediated by transcription factor EB, and autophagic clearance was observed to depend specifically on the charge of the NPs. In particular, the autophagy reaction to unmodified or carboxylated PS NPs involved enhanced clearance of autophagy cargo, while exposure of amino-functionalized PS NPs to cells will cause transcriptional upregulation of the pathway, but also lead to lysosomal dysfunction, eventually bringing about blockage of autophagic flux.
The protective mechanism underlying total flavones of Dracocephalum (TFD) effects on rat cerebral ischemia reperfusion injury
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Peng Wu, Xu-sheng Yan, Yu Zhang, Dong-sheng Huo, Wei Song, Xin Fang, He Wang, Zhan-jun Yang, Jian-xin Jia
AMP-activated protein kinase (AMPK), a serine threonine kinase, is a key metabolic and stress sensor/effector that is activated under conditions of nutrient deprivation, vigorous exercise or heat shock (Turnley et al. 1999). AMPK plays an important role in oxidative stress and apoptosis in the central nervous system (Deng et al. 2016; Li and McCullough 2010; Manwani and McCullough 2013). Jung et al. (2004) showed that overexpression of active AMPK enhanced oxidative stress and induced apoptosis in mouse neuroblastoma cells through NF-κB activation.
The protective mechanism underlying total flavones of Dracocephalum (TFD) effects on rat cerebral ischemia reperfusion injury
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Peng Wu, Xu-sheng Yan, Yu Zhang, Dong-sheng Huo, Wei Song, Xin Fang, He Wang, Zhan-jun Yang, Jian-xin Jia
AMP-activated protein kinase (AMPK), a serine threonine kinase, is a key metabolic and stress sensor/effector that is activated under conditions of nutrient deprivation, vigorous exercise or heat shock (Turnley et al. 1999). AMPK plays an important role in oxidative stress and apoptosis in the central nervous system (Deng et al. ; Li and McCullough 2010; Manwani and McCullough 2013). Jung et al. (2004) showed that overexpression of active AMPK enhanced oxidative stress and induced apoptosis in mouse neuroblastoma cells through NF-κB activation.