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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].
Mechanisms of Nanotoxicity to Cells, Animals, and Humans
Published in Vineet Kumar, Nandita Dasgupta, Shivendu Ranjan, Nanotoxicology, 2018
Belinda Wong Shu Ee, Puja Khanna, Ng Cheng Teng, Baeg Gyeong Hun
Defective autophagy flux has been implicated in various human diseases such as cancer, myopathy, neurodegenerative diseases, cardiovascular diseases, and immune-mediated diseases (Zhang et al. 2013). One of the hallmarks by which to identify defective autophagic flux is characterized by the accumulation of unusually large autophagic vacuoles containing partially disintegrated contents (Figure 11.5). Assays that detect the degradation of p62 and LC3 turnover rate also serve as quantitative measures to monitor autophagic flux. In an effective autophagy, p62 is broken down along with other autophagosome contents. Failure to do so results in abundant levels of p62. Similarly, an increase in LC3-II/LC3-I ratio can be a marker for defective autophagy flux as cleaved LC3 (LC3-I) is not able to conjugate to phosphatidylethanolamine (PE) to form LC3-II, leading to its failure to incorporate into the autophagosomal membrane (Zhang et al. 2013). Nanoparticle exposure such as AgNPs has been shown to increase the expressions of LC3-II and p62 proteins, followed by autophagosome accumulation in NIH 3T3 mouse embryonic fibroblast cell line (Lee et al. 2014). This implies that AgNPs may not be successfully eliminated due to a defect in the autophagic flux, ultimately leading to apoptosis activation. Thus, nanoparticles can cause harm by damaging the autophagic flux.
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
Autophagy is the only mechanism to degrade large structures such as organelles and protein aggregates. In the absence of stress, basal autophagy serves a housekeeping function. It provides a routine “garbage disposal” service to cells, eliminating damaged components that could otherwise become toxic. Such cellular refreshing is particularly important in quiescent and terminally differentiated cells, where damaged components are not diluted by cell replication. In starvation, autophagy provides a nutrient source, promoting survival. Autophagy is induced by a broad range of other stressors and can degrade protein aggregates, oxidized lipids, damaged organelles, and even intracellular pathogens. Although it is not always possible to resolve the metabolic and garbage disposal roles for autophagy, it is clear that autophagy prevents disease. Defects in autophagy are linked to liver disease, neurogeneration, Crohn's disease, aging, cancer, and metabolic syndrome.184 It is estimated that autophagy eliminates 50–70 million dying or dead cells per day.
Apigenin attenuates tetrabromobisphenol A-induced cytotoxicity in neuronal SK-N-MC cells
Published in Journal of Environmental Science and Health, Part A, 2023
Eun Mi Choi, So Young Park, Kwang Sik Suh, Suk Chon
Autophagy involves the delivery of large protein aggregates, defective organelles, and other cellular debris to lysosomes for degradation and recycling. Generally, autophagy promotes the self-renewal of organisms, which helps recycling of materials and facilitates cell survival in adverse environments.[38,39] On the other hand, excessive autophagy causes structural damage to cellular components, leading to cell senescence or death.[40] Autophagy was upregulated in the brain of AD patients but downregulated in normal aging cohorts, indicating that autophagy protects brain cells from aging in the physiological process but acts as a death mechanism when overactivated in the pathologic event.[41,42] We observed TBBPA-induced cytotoxic, but not pro-survival, autophagy, leading to death of SK-N-MC cells, suggesting that inhibition of autophagy may contribute to the survival of neurons. Moreover, apigenin partially reversed TBBPA‐induced neuronal death through the attenuation of autophagy. Taken together, our data suggest that apigenin has neuroprotective potential against TBBPA through the inhibition of autophagy, apoptosis, and necrosis.
Influence of microcystins-LR (MC-LR) on autophagy in human neuroblastoma SK-N-SH cells
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Yue Yang, Cong Wen, Shuilin Zheng, Wenya Liu, Jihua Chen, Xiangling Feng, Xiaoyan Wang, Fei Yang, Zhen Ding
Autophagy is a physiological mechanism enabling cells to degrade their own impaired organelles, misfolded proteins, and other macromolecules to maintain cellular homeostasis. Under normal physiological conditions, autophagy protects mammalian cells from death. However, abnormal autophagy is associated with various pathological responses including neurodegenerative disorders (Larsen and Sulzer 2002; Long et al. 2014; Nixon 2006; Rubinszstein et al. 2005), Alzheimer’s disease (Yu et al. 2005), Parkinson’ disease (Zhu et al. 2003), prion disease (Sikorska et al. 2004), and amyotrophic lateral sclerosis (Tarabal et al. 2005). Autophagy is known to play an important role in environmental pollutant-mediated CNS dysfunction. In particular, pesticides and cyanobacterial bloom products were found to produce neuronal damage (Chen et al. 2013a; Li et al. 2014; Long et al. 2014; Long and Wu 2008; Wang et al. 2019); however the underlying mechanisms were not examined. Thus, the aim of this study was to determine whether MC-LR potentially induced alterations in autophagy as an underlying mechanism of neurotoxicity by using SK-N-SH cells as a CNS model.
Lead alters intracellular protein signaling and suppresses pro-inflammatory activation in TLR4 and IFNR-stimulated murine RAW 264.7 cells, in vitro
Published in Journal of Toxicology and Environmental Health, Part A, 2019
R.J. Williams, E. Karpuzoglu, H. Connell, D.J. Hurley, S.D Holladay, R.M. Gogal
In a recent study, Kerr et al. (2013) reported that RAW 264.7 cells treated with 2.5 or 5 μM Pb nitrate-induced autophagy after 17 hr incubation. Autophagy is a self-degradative process that cells utilize to regulate cellular function during times of nutrient deficiency or environmental stress by metabolizing cytoplasmic proteins and organelles (Filomeni, De Zio, and Cecconi 2015; Klionsky 2005; Mizushima and Komatsu 2011). While the induction of autophagy, which is a natural process, is generally accepted as damaging, Rautou et al. (2010) noted proactive effects in liver disease, preventing further damage. Evankovich et al. (2012) reported that induction of autophagy in hepatocytes of CaMKIV knockout (KO) mice was significantly suppressed during ischemic-reperfusion injury resulting in increased liver damage. The CaMKIV KO mice also possessed significantly lower cellular expression of the protein LC3. Cultured hepatocytes also exhibited markedly depressed LC3 expression when CaMKIV or the CaMKIV activator CaMK kinases were inhibited. LC3 localizes on the autophagosome in the cytoplasm of cells and is a biomarker of autophagy (Kabeya et al. 2000; Tanida, Minematsu-Ikeguchi, and Kominami 2005). These combined data suggest that protein expression and activation of CaMKIV is key in the induction of autophagy. Zhang et al. (2014) showed that activated CaMKIV was required for isolated murine macrophages and RAW 264.7 cells to induce autophagy. As with the previously described hepatocyte studies, CaMKIV KO in vivo and inhibition in vitro significantly reduced LC3 expression in murine macrophages and RAW 264.7 cells (Zhang et al. 2014). Therefore, the reported induction of autophagy, previously seen in RAW 264.7 cells treated under the same conditions as the current study, might be linked to the activation of cytoplasmic CaMKIV.