Effects of Retinoids at the Cellular Level (Differentiation, Apoptosis, Autophagy, Cell Cycle Regulation, and Senescence)
Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish in Retinoids in Dermatology, 2019
The role of RA in cell cycle regulation was reported in promyelocytic leukemia and U-937 cells, derived from histiocytic lymphoma, where RA treatment induced G0/G1 arrest. Corresponding gene expression changes included downregulation of c-Myc and cyclin E, increased expression of p21WAF1/CIP1, and increased stability of p27Kip1 (79,80). Treatment with RA also affects CDK5 activity, and several papers described how RA induces cell cycle arrest (81–83). CDK5, together with its activator p35, is important for induction of neuronal differentiation (84). CDK5 also regulates the growth of various cancers, such as thyroid (85), cervical (86), and prostate (87). Activation of CDK5 leads to upregulation of p27, which is the main effector in RA-mediated cell cycle regulation (82).
Role of Oxidative Stress in the Onset of Alzheimer’s Disease
Abhai Kumar, Debasis Bagchi in Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
The tau protein in neurofibrillary tangles become hyperphosphorylated which changes the conformation of tau helices, leading to disruption in tau-microtubule association. Eventually, this leads to loss of necessary cellular function and cell death (Iqbal et al. 1998). Hyperphosphorylated tau is not only found in AD brains but also in a number of other neurodegenerative diseases, such as corticobasal degeneration, frontotemporal dementia, and Niemann pick disease (Wang, Wang, and Tian 2014). The phosphorylation of tau protein can be mediated by several kinases and phosphatases, such as glycogen synthase kinase 3 beta (GSK3β), cyclin-dependent kinase (CDK5), and extracellular signal-related kinases. The phosphorylation via GSK3β can be reversed by protein phosphatase 2A (PP2A). Thus, activation of GSK3β and inhibition of PP2A can lead to a vicious cycle. Due to hyperphosphorylation, tau can form paired helical form aggregates that disrupt the microtubule dynamics (Avila et al. 2004).
Neurological Activities of Seaweeds and their Extracts
Leonel Pereira in Therapeutic and Nutritional Uses of Algae, 2018
Tau is a microtubule-associated protein (MAP) found in axons, and this protein is responsible for regulating the stability of microtubules (Goedert et al. 1988, Drechsel et al. 1992, Hirokawa et al. 1996). Hyper-phosphorylation of tau results in its dissociation from microtubules and aggregation in the form of neurofibrillary tangles (Avila et al. 2006). Hyper-phosphorylated tau protein is a major component in neurofibrillary tangles, which is a hallmark of Alzheimer’s disease, and dysregulation of kinases and phosphatases has been found to increase tau hyper-phosphorylation levels (Selkoe 1997, Hanger et al. 2009). Only three compounds (Spiralisone A, B, and Chromone 6) from seaweed have kinase inhibitory activity, and these compounds have been isolated from brown algae (Phaeophyceae). Besides, these compounds were isolated from a single species, Zonaria spiralis, collected in Australia, and all of them are phloroglucinols. The most active compound is spiralisone B, inhibiting the kinases-cyclin-dependent kinase 5 (CDK5/p25), casein kinase 1 (CK15), and glycogen synthase kinase 3 beta (GSK3ß), with IC50 values of 3, 5, and 5.4 μΜ, respectively (Zhang et al. 2012c).
Investigation of TF-binding lectins from dietary sources and SRL on proliferation and cell cycle progression in human colon HT29 and SW620 cells
Published in Nutrition and Cancer, 2019
Shivakumar Belur, Srikanth Barkeer, Bale M. Swamy, Lu-Gang Yu, Shashikala R. Inamdar
The presence of ABL reduced CDK5 levels and SRL and ACA completely abolished in SRL and ACA- CDK5 expression. CDK5 is a proline-directed serine/threonine kinase and controls various cellular events, including cytoskeletal organization, cell adhesion, membrane trafficking, cell cycle exit, and neuronal differentiation, and thereby regulates multiple aspects of brain development and function (41). CDK5 Overexpression is shown to occur in metastatic tumors in comparison in primary colon tumors. Inhibition of CDK5 expression by gene knockdown or small molecule inhibitors reduced cell proliferation and migration, increased cell death and arrested cells in the G2/M transition in vitro and halted tumor progression and tumor weight in vivo (42). A decreased level of CDK5 in HT29 cells by the presence of SRL and ABL is in consistent with the growth inhibitory effect of these two lectins supports in those cells. Antiproliferative lectins SRL and ABL have reduced the overall expression of Cyclin D1, D2, D3, Cyclin E, and CDK5 which fall in line with their ultimate response.
Cell cycle deregulation in neurodegenerative diseases
Published in International Journal of Neuroscience, 2023
Xiaobo Zhang, Shuxin Song, Wenpeng Peng
Neurodegenerative diseases are caused by progressive degeneration of central nervous system. The pathology consists of denaturation and loss of brain and (or) spinal cord neurons. Normal neurodegenerative diseases contain Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), etc. Increasing numbers of studies focus the mechanism of neurodegenerative disease on deregulation of cell cycle. Up to now, numerous studies have shown that in neurodegenerative diseases there were substantial changes in cell cycle related proteins and novel DNA synthesis. A study of human brain [22] reported that in AD brains more neurons were labeled with BrdU (a nucleoside analog that becomes incorporated into the DNA during S-phase), consistent with the increased expression of PCNA (DNA polymerase processivity factor). Also, up-regulation of cyclin E1, Rb/E2F1 and down-regulation of CDK5 were observed. In addition, several other labs have provided evidence that there were cell cycle related proteins which increase the risk of neuron death in AD [23], PD [24], and ALS [25, 26]. Therefore, neuronal cell cycle reentry is involved in neuronal apoptosis and death. Next we will summarize what is currently known about cell cycle reentry in different diseases.
Morphine reverses the effects of 1-methyl-4-phenylpyridinium in PC12 cells through activating PI3K/Akt
Published in International Journal of Neuroscience, 2019
Yuan Fan, Yan Chen, Se Zhang, Mengbing Huang, Shengdong Wang, Ye Li, Jie Bai
The Parkinson’s disease (PD) is a neurodegenerative disorder which is caused by the loss of dopaminergic neurons and decrease of dopamine level in the substantia nigra pars compacta (SNpc). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is metabolized into toxic 1-methyl-4-phenylpyridinium (MPP+) and transported into dopaminergic neurons and caused a severe parkinsonian syndrome [1]. MPTP/MPP+ induces oxidative stress and apoptosis in dopaminergic neurons. MPTP/MPP+ decreases the expression of thiordoxin-1 (Trx-1) [2]. MPP+ induces cell cycle arrest and Cyclin D1 degradation through inhibiting phosphatidylinositol-3-kinase (PI3K)/Akt pathway [3]. It has been reported that Cyclin-dependent kinase5 (Cdk5) plays a role in neuronal survival and is involved in dopaminergic neuron loss in PD [4,5].
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