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Micronutrients in Prevention and Improvement of the Standard Therapy in Hearing Disorders
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
MicroRNAs are expressed in the normal inner ear cells, and play an essential role in their development, differentiation, and survival.97,98 In mouse embryonic inner ears, increased expressions of miR-376a-3p, miR-376-b-3p, and miR-376-c-3p that regulate the levels of phosphoribosyl pyrophosphate synthetase 1 (PRPS 1) were found.99 The PRPS 1 protein is important for preserving hair cell function. Mutations in the gene coding for this protein are associated with a spectrum of non-syndromic and syndromic forms of hearing loss. MiR-96 and miR-183 was found to regulate the levels of chloride intracellular channel 5 (CLIC5) protein in inner hair cell line (HE1-OC1 cells), Overexpression of these microRNAs reduced the levels of CLIC5.100 Expression of 157 microRNAs in the inner ear sensory epithelial cells and 53 microRNAs in the cochlear and vestibular cells were differently expressed.101 Among these, miR-135b regulates the levels of PSIP1-p75 that had multiple cellular functions including DNA repair102 and attenuates oxidative stress.103 Using embryonic inner ear cell line (UB/OC-1), it was shown that overexpression of miR-210 supports differentiation from epithelial cells to sensory hair cells.104 There were 455 microRNAs common to both the cochlear and vestibular sensory epithelial cells, with 30 microRNAs unique to the cochlea, and 44 microRNAs unique to the vestibule. Among these, miR-675-5p with its target protein Arhgap12, a GTPase activating protein has been identified.105 MiR-194 is expressed in the spiral ganglia neurons of mouse inner ear where it may play a role in differentiation of neurons.106 The family of miR-183 consisting of miR-96, miR-182, and miR-183 was strongly expressed in the inner ear hair cells where they play a role in differentiation of primary sensory cells.107,108 MiR-124 regulates the fate of cells in the developing organ of Corti that contains sensory hair cells and supporting cells.109
Ion Channels in Immune Cells
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Devasena Ponnalagu, Shridhar Sanghvi, Shyam S. Bansal, Harpreet Singh
Amid the several cellular processes that they regulate, CLIC channel activity is also considered to be important for immune cell activation. Bone marrow-derived dendritic cells (BMDCs) isolated from clic1−/− mice showed diminished antigen presentation due to impaired phagosomal acidification148. In DCs, phagocytosis triggered the translocation of cytoplasmic CLIC1 to a phagosomal membrane, where it was shown to regulate phagosomal pH and proteolysis of the antigen148. Pharmacological blockage of the DCs isolated from wild-type mice with CLIC inhibitor indanyloxyacetic acid (IAA-94) also showed a similar defect in their antigen presentation ability, indicating that the channel activity of CLICs contributes to this function148. CLIC1, CLIC4, and CLIC5, as shown in Figure 10.1, are present in the circulating monocytes of mice as well. It was observed that CLIC1 expression increased in PBMCs in chronic inflammatory conditions of the central nervous system, such as Alzheimer’s disease, and can be considered as a potential biomarker for neurodegenerative disease conditions149. The absence of CLIC1 impaired phagosomal acidification and reduced ROS generation in macrophages150,151. CLICs also play a role in NLRP3 inflammasome complex formation by macrophages118,119. NLRP3 is a multiprotein inflammasome complex formed by the innate immune sensor protein NLRP3, adapter protein ASC, and proteolysis enzyme caspase 1152,153. NLRP3 complex formation is required for the secretion of pro-inflammatory cytokines such as IL-1β and IL-18 against stress conditions or upon infection. K+ efflux is known to cause mitochondrial damage, increasing the ROS production by the mitochondria and leading to activation of NLRP3 inflammasome complex154. The mitochondrial ROS generated in this process was shown to induce translocation of CLICs (CLIC1, CLIC4, and CLIC5) to the plasma membrane, leading to chloride efflux and thus contributing to inflammasome assembly and IL-1β secretion118,154. These studies provide substantial evidence that the CLIC-mediated upstream event is a prerequisite for the regulation of NLRP3 activation, and Cl− flux changes facilitated by them play a key role in activating the innate immune system. Because CLICs are mitochondrial ion channel proteins that affect mitochondrial physiology117, their specific role in both innate and adaptive immune cell activation via modulating mitochondrial function needs to be addressed. In addition, the increasing evidence implicating the role of chloride flux changes in immune cell activation, development, and function cannot be ignored, and more attention should be given to the molecular identification of other uncharacterized chloride channels in immune cells.
Chloride intracellular channel protein 2 in cancer and non-cancer human tissues: relationship with tight junctions
Published in Tissue Barriers, 2019
Yoshitomo Ueno, Saya Ozaki, Akihiro Umakoshi, Hajime Yano, Mohammed E. Choudhury, Naoki Abe, Yutaro Sumida, Jun Kuwabara, Rina Uchida, Afsana Islam, Kohei Ogawa, Kei Ishimaru, Toshihiro Yorozuya, Takeharu Kunieda, Yuji Watanabe, Yasutsugu Takada, Junya Tanaka
Immunohistochemical localization of CLIC2 in cancer and non-cancer tissues was investigated (Figure 3). In accordance with the qPCR and western blotting data, CLIC2 immunoreactivity was found mainly in non-cancer tissues (Figure 3Aa and Ba) in Kupffer cells (yellow arrowheads) and endothelial cells forming the liver sinusoids (pink arrowheads). Hepatocytes did not express CLIC2. In Colon cancer cases, cells in the interstitial tissues but not columnar epithelial cells expressed CLIC2 (Figure 3Ca). Only faint CLIC2 expression was found in cancer tissues of the HCC and Meta cases (Figure 3Ab and Bb). Although CLIC2 immunoreactivity was strongly observed in Colon cases, it was not found in cancer cells but in the interstitial tissues. Predominant CLIC2 expression in non-cancer tissues was clearly observed in the border zone between cancer and non-cancer tissues of Meta and Colon cases (Figure 3D,E). In contrast to CLIC2, CLIC1, 4, and 5 appeared to be evenly distributed in cancer and non-cancer tissues (supplementary Figure 1). Strong CLIC1 immunoreactivity was diffusely distributed within the cytoplasm of cancer and non-cancer cells. CLIC5 was characteristically localized in the nuclei of cancer and non-cancer cells.