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Synapses
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
The phosphate group is hydrolyzed back to an OH– group by enzymes referred to as phosphatases, and the process is known as dephosphorylation. Protein phosphatase 1 (PP1) dephosphorylates a variety of proteins as well as K+ and Ca2+ channels, NMDA, and AMPA glutamate receptors. Protein phosphatase 2A (PP2A) also dephosphorylates a range of proteins that overlap with those of PP1, in addition to tau protein that stabilizes microtubules of the cytoskeleton. Excessive phosphorylation of tau protein is associated with Alzheimer’s disease. Protein phosphatase 2B (PP2B), also known as calcineurin, is abundant in neurons and is activated by Ca2+. It activates T cells of the immune system and dephosphorylates AMPA receptors. Protein phosphorylation and dephosphorylation are of fundamental importance in cell functioning as it is the major molecular mechanism through which protein activity in a cell is regulated both in and outside the nervous system.
Codelivery in Nanoparticle-based siRNA for Cancer Therapy
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
Gold nanoparticles (AuNPs) have emerged as a promising siRNA delivery carrier due to their excellent biocompatibility, ease of synthesis, high surface-to-volume ratio, and facile surface functionalization [110]. Recently, various types of AuNPs have been widely investigated for siRNA delivery. These include AuNPs functionalized with cationic quaternary ammonium or bPEI, cationic lipid bilayer coated AuNPs, and oligonucleotide-modified AuNPs [110–112]. Gold nanorods also have the potential to deliver siRNA to target cells or tissues. The Prasad group developed gold nanorod-DARPP-32 siRNA complexes to target and reduce expression of the key proteins (DARPP-32, extracellular signal-regulated kinase [ERK], and protein phosphatase 1 [PP-1]) in the dopaminergic signaling pathway in the brain for therapy of drug addiction [113]. Using dark-field imaging and confocal microscopy, they demonstrated that the siRNA was efficiently delivered into dopaminergic neuronal (DAN) cells after treatment with the gold nanorod-siRNA conjugates. Moreover, the delivery of nanoplexes containing siRNA targeted to the DARPP-32 gene in DAN cells resulted in the silencing not only of DARPP-32 but also of other key downstream effector molecules in this pathway, such as ERK and PP-1, with greater efficiency than commercial transfection agents. Recently, Kim et al. reported that AuNPs stably functionalized with covalently attached oligonucleotides activate immune-related genes and pathways in human peripheral blood mononuclear cells, but not an immortalized, lineage-restricted cell line [114]. These later findings suggest that assessment of the toxic potential of engineered nanoparticles in immortalized, lineage-restricted cell lines may not predict their phenotypic effects in relevant biological systems.
Applications of imaging genomics beyond oncology
Published in Ruijiang Li, Lei Xing, Sandy Napel, Daniel L. Rubin, Radiomics and Radiogenomics, 2019
Xiaohui Yao, Jingwen Yan, Li Shen
Suggestive novel associations have also been discovered in protein phosphatase 1 regulatory subunit 3B (PPP1R3B) [35] and alpha-ketoglutarate dependent dioxygenase (FTO) [36]. Recently, a large scale meta-analysis of GWAS presented a list of “top” genes susceptible to LOAD, from which 11 genes were reported as new AD susceptibility loci in addition to eight genes previously identified in independent studies [18].
Circular RNA expression profiles following MC-LR treatment in human normal liver cell line (HL7702) cells using high-throughput sequencing analysis
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Shuilin Zheng, Cong Wen, Shu Yang, Yue Yang, Fei Yang
More than 100 naturally occurring variants of MCs were identified with a common chemical structure cyclo-(D-Ala-X-D-MeAsp-Y-Adda-D-Glu-Mdha-), where X and Y represent variable L-amino acids (Wei et al. 2019, Yang et al. 2018a, 2019). Of these variants, microcystin-LR (MC-LR) is the most abundant and toxic, and persists in the environment for months (Chorus et al. 2000; Wu et al. 2019; Yang et al. 2018d). In order to reduce health risks associated with MC-LR exposure, the World Health Organization [World Health Organization (WHO), 1998] set a provisional upper value of 1 µg/L MC-LR in drinking water resources and this guideline level was adopted by many countries including China, USA, and Australia. Cao et al. (2019a, 2019b) also reported that MC-LR produced adverse effects on the gastrointestinal and cardiovascular systems. However, the primary target tissue for MC-LR- mediated damage is the liver (Chen et al. 2019b; Yang et al. 2018b; Zurawell et al. 2005). MacKintosh et al. (1990) proposed that inhibition of the activity of protein phosphatase 1 (PP1) and protein phosphatase2A (PP2A) might be the molecular mechanism underlying MC-LR-induced acute and chronic liver dysfunctions. Subsequent to enzymic phosphoproteins inhibition, gene expression, DNA repair systems, oxidative stress, and apoptosis were noted (Campos and Vasconcelos 2010; Chen et al. 2019a, 2019b). However, the complex interactive molecular mechanisms underlying MC-LR-mediated hepatic toxicity still remain to be determined.
Effects of microcystins-LR on genotoxic responses in human intestinal epithelial cells (NCM460)
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Cong Wen, Shuilin Zheng, Yue Yang, Xiaoyu Li, Jihua Chen, Xiaoyan Wang, Xiangling Feng, Fei Yang
Previous reports demonstrated that MC-LR specifically inhibited the activity of protein phosphatase 1 (PP1) and 2A (PP2A) resulting in downstream protein hyperphosphorylation, leading to cellular toxicity (MacKintosh et al. 1990; Yang et al. 2018). Several investigators showed that MC-LR induced DNA damage in intestine in vivo or in vitro (Gaudin et al. 2008; Žegura et al. 2008). Žegura et al. (2008) noted that MC-LR produced a time- and concentration-dependent rise DNA damage in CaCo-2 cells at non-cytotoxic concentrations using comet assay. Further, Gaudin et al. (2008) found that DNA lesions were induced in the intestine after an intraperitoneal injection of 25 or 40µg/kg MC-LR for 24 hr in mice. Although MC-LR is known to affect intestinal metabolism, functions and pathophysiology, the mechanisms underlying the influence of this cyanobacterium on the intestine is not completely understood. Thus, the aim of this study was to examine the effect of MC-LR on intestinal DNA damage and the potential mechanisms underlying these actions using human normal intestinal epithelium cell (NCM460) as a model.
Isolation, molecular identification, and characterization of a unique toxic cyanobacterium Microcystis sp. found in Hunan Province, China
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Pin Liu, Jia Wei, Kun Yang, Isaac Yaw Massey, Jian Guo, Chengcheng Zhang, Fei Yang
The frequent occurrence of cyanobacterial blooms has become a global environmental problem attributed to eutrophication and climate change (Taranu et al. 2017). Toxigenic cyanobacteria produce secondary metabolites containing cyanotoxins which are toxic to humans and animals and threaten public health through ingestion of drinking water, swimming or agricultural practices (Drobac et al. 2017; Massey et al. 2018; Zurawell et al. 2005). Microcystins (MC) a species of cyanotoxins, inhibit protein phosphatase 1 and 2A to induce hepatotoxicity and promote tumor growth (Martins and Vasconcelos 2009; Yang et al. 2018a; Zhou, Tu, and Xu 2015). In order to effectively manage and potentially treat the health hazards attributed to exposure to harmful cyanobacterial blooms, it is important to isolate, identify, and establish the toxigenic characteristics of these predominant cyanobacteria (Dong et al. 2016). Various investigators reported on the isolation and characterization of Microcystis worldwide during cyanobacteria blooms (Belykh et al. 2013; Davis et al. 2009; Karan, Erenler, and Altuner 2017; Kurmayer et al. 2002; Zurawell et al. 2005). It is of interest that in China the isolation and species identification of Microcystis has also been reported in various waterways (Li et al. 2014; Liu, Zha, and Li 2010; Wang et al. 2007. However, at present, the cyanobacteria have not been isolated, identified or characterized from Hunan Province located in Middle of China.