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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
Similar to the NF-κB pathway, the mitogen-activated protein kinase (MAPK) pathway is activated by PRRs and regulates the production of cytokines, which contributes to inflammation (Arthur and Ley 2013). MAPKs belong to a highly conserved family of serine/threonine protein kinases. They include extracellular signal-regulated kinases (Erk 1/2 or p44/42), c-Jun N-terminal kinases (JNKs), and p38 isoforms. A broad range of extracellular stimuli can lead to the activation of MAPKs by phosphorylation. Activation of the MAPK pathway in conjunction with the NF-κB pathway activation induces the expression of multiple genes involved in inflammatory responses (Arthur and Ley 2013). TLR-mediated MAPK signaling can also lead to pro-inflammatory cytokines secretion. This relationship was established in a study using ZnO nanoparticles and primary macrophages derived from Balb/c mice. In this study, silencing TLR6 expression significantly suppressed the expressions of IL-1β, IL-6, and TNF-α. Inhibition of Erk1/2 and p38 also showed a decrease in the secretion of these pro-inflammatory cytokines (Roy et al. 2014b).
Selenium-mediated MAPK signaling pathway regulation in endemic osteoarthritis
Published in Gary Bañuelos, Zhi-Qing Lin, Dongli Liang, Xue-bin Yin, Selenium Research for Environment and Human Health: Perspectives, Technologies and Advancements, 2019
X.X. Dai, Y. Dai, X.F. Wang, C. Jian, Y.M. Xiong, N. Li
Kashin–Beck disease (KBD) is a chronic, endemic osteoarthritis (OA) that occurs in limited endemic areas of China. Low dietary levels of selenium (Se) are thought to be the most important biological and environmental factors causing the disease (Yue et al. 2012). Extracellular signal-regulated kinases (ERKs) and C-Jun N-terminal kinase (JNK) are members of the mitogen-activated protein kinase (MAPK) family and are activated by environmental stress (Krens et al. 2006). Selenium has been shown to exhibit a variety of biological functions, including antioxidant functions and maintenance of cellular redox balance, yet low levels of Se can lead to oxidative stress and apoptosis.
Insights into the mechanisms of arsenic-selenium interactions and the associated toxicity in plants, animals, and humans: A critical review
Published in Critical Reviews in Environmental Science and Technology, 2021
Waqar Ali, Hua Zhang, Muhammad Junaid, Kang Mao, Nan Xu, Chuanyu Chang, Atta Rasool, Muhammad Wajahat Aslam, Jamshed Ali, Zhugen Yang
Cellular stress proteins are well known, as a C-Jun N-terminal kinase (JNK) is a member of a stress-activated protein kinase family activated through cellular stress. Arsenic activated AP-1 activity by inhibiting the JNK tyrosine phosphate protein (Figure 7), resulting in the activation of JNK/AP-1, which was defective in the turning off of activated JNK (Cowan & Storey, 2003; Zarubin & Jiahuai, 2005). Therefore, AsIII and AsV induced apoptosis via the JNK pathway (Eguchi et al., 2011). Potent antagonistic effects between As and Se at the cellular level can cause cell apoptosis as well as cell necrosis in human leukemia cells (HL-60) through incubation with Na2SeO3 and NaASO2/Na2-HASO4 (Zeng, 2001; Zeng et al., 2005). The presence of minerals induced HL-60 cell apoptosis when the concentration of SeIV (3 µM) > AsIII (50 µM) > AsV (50 µM) was higher than that required for cell apoptosis, causing cell necrosis (Drobná et al., 2003). However, the elevated concentration of SeIV, causing toxic necrotic effects and these effects, may have been suppressed or neutralized by AsIII or AsV (Zeng, 2001).
Inhibitory effect of particulate matter on toll-like receptor 9 stimulated dendritic cells by downregulating mitogen-activated protein kinase and NF-κB pathway
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Madeeha Arooj, Irshad Ali, Hee Kyoung Kang, Jin Won Hyun, Young-Sang Koh
Innate immune cells such as dendritic cells (DCs) and macrophages are key endogenous components to counteract pathogens and serve as a link between innate and adaptive immunity. Antigen-presenting cells (APCs) recognize pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs) (Akira and Takeda 2004; Koo et al. 2012). Toll-like receptors (TLRs) interaction with PAMPs activates major signal transduction pathways including mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces cytokine production which serves as a trigger to initiate T-cell-mediated immunity (Akira and Takeda 2004). MAPKs including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 kinase play a key role in apoptosis, cell survival, proliferation, differentiation, and inflammation. NF-κB is a rapid-acting transcription factor that aids in the expression of cytokines and cell survival. Under quiescent conditions, NF-κB, a transcription factor within cytosol is coupled with specific inhibitor nuclear factor of kappa light polypeptide gene enhancer in B-cells, alpha (IκBα). Upon TLR stimulation, IκBα is phosphorylated and ubiquitinated, which leads to proteasomal degradation and translocation of NF-κB into the nucleus where it regulates transcription of various inflammatory genes including cytokines (Akira and Takeda 2004; Blasius and Beutler 2010; Koo et al. 2012).
Oleuropein attenuates the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-perturbing effects on pancreatic β-cells
Published in Journal of Environmental Science and Health, Part A, 2021
Eun Mi Choi, Kwang Sik Suh, Soo Jin Yun, Jinsun Park, So Young Park, Sang Ouk Chin, Suk Chon
Abnormal regulation in activity of cytokines may lead to proinflammatory conditions and disruption of normal immune function. Charles and Shiverick[27] reported that TCDD is able to disrupt the cytokine network pathway and contribute to development of diabetes. TCDD causes adverse immunologic effects including dysfunction of lymphocytes, impaired antibody production, and decreased activity of polymorphonuclear cells.[28] Drozdzik et al. [29] reported that TNF-α induced AhR expression associated with parallel decrease in ARNT and reporter CYP1A1 gene levels. TNF-α may also enhance development of inflammatory processes via AhR activation, resulting from stimulation of the NF-kB and ERK signaling cascades.[30] This may suggest that TCDD-induced cytokine changes play important roles in inflammatory pathologies. The present study found that TCDD treatment of pancreatic beta cells produced an increase in the cytokine TNF-α. Therefore, inhibition of TNF-α by oleuropein may be an important protective mechanism to downregulate the inflammatory process in pancreatic β-cells. TCDD toxicity is triggered by diverse signaling pathways. The mitogen-activated protein kinases (MAPKs), including c-Jun N-terminal kinase (JNK), ERK, and p38, regulate diverse cellular processes such as apoptosis and insulin secretion and action.[31] In pancreatic beta cells, MAPKs are rapidly activated in response to several factors such as proinflammatory cytokines, high glucose, and free fatty acids.[32] Among the MAPKs, JNK has been recognized as the most important mediator in the development of diabetes.[33] The functional consequence of MAPK activation is always contradictory to Akt activation.[34] Protein kinase B, known as Akt, serves as an important regulator of cellular processes, including cell proliferation and insulin synthesis and secretion.[35] Our experiments, in agreement with results obtained in Jurkat T cells,[36] confirm the activation of JNK and inhibition of Akt by TCDD treatment. The observation that oleuropein can prevent these TCDD-induced changes is of interest in view of the ability of phytochemicals to reduce the toxic actions of TCDD in U937 macrophages[37] and of flavones and catechins to suppress the TCDD-induced phosphorylation of ERK1/2 in mouse hepatoma Hepa-1c1c7 cells.[38]