Intracellular Chloride Channels: Novel Biomarkers in Diseases

Rao, Shubha Gururaja; Patel, Niral; Singh, Harpreet

doi:10.3389/fphys.2020.00096

Cited by 81 publications

(59 citation statements)

References 208 publications

(227 reference statements)

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“…The levels of V-ATPase (a proton pump for cellular pH regulation, Pamarthy et al, 2018 ), LAMP-2 (a lysosome-associated membrane glycoprotein), PARP (genomic stability), fibrillarin (a small nucleolar protein, Amin et al, 2007 ), and EGFR (a transmembrane protein) were clearly reduced at the same concentration. Additionally, conversion of LC3B-I into LC3B-II (completion of autophagosome) and expression of OPA1 (localized in the inner mitochondrial membrane) and CLIC1 (principally localized in the cell nucleus, Gururaja Rao et al, 2020 ) proteins did not show significant changes following exposure to DDAC. Secretion of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and MMP-1 (known as interstitial collagenase) was significantly elevated with DDAC concentration, whereas secretion of IFN-γ, MIP-1α, CXCL-1, CXCL-8, and MMP-3 was not affected under the same conditions ( Fig.…”

Section: Resultsmentioning

confidence: 93%

“…Expression of surfactant proteins (SP-A, -B, and -D), ABCA3 and Rab11a, (lamellar body formation, Cheong et al, 2007 ), p-p53 (damaged DNA repair), CLIC4 (primarily localized in the outer mitochondrial membrane, Gururaja Rao et al, 2020 ), Apaf-1 (apoptosome formation), DRP-1 (mitochondrial fission), MFN1 (mitochondrial fusion), and p62 (autophagosome cargo protein) was enhanced in DDAC-treated cells compared to that in the control, and caspase-3 protein was rapidly cleaved at a concentration of 4 μg/mL ( Fig. 7 ).…”

Section: Resultsmentioning

confidence: 99%

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Formation of lamellar body-like structure may be an initiator of didecyldimethylammonium chloride-induced toxic response

Park

Seong

Kang

et al. 2020

Toxicology and Applied Pharmacology

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Due to the pandemic of coronavirus disease 2019, the use of disinfectants is rapidly increasing worldwide. Didecyldimethylammonium chloride (DDAC) is an EPA-registered disinfectant, it was also a component in humidifier disinfectants that had caused idiopathic pulmonary diseases in Korea. In this study, we identified the possible pulmonary toxic response and mechanism using human bronchial epithelial (BEAS-2B) cells and mice. First, cell viability decreased sharply at a 4 μg/mL of concentration. The volume of intracellular organelles and the ROS level reduced, leading to the formation of apoptotic bodies and an increase of the LDH release. Secretion of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and matrix metalloproteinase-1 also significantly increased. More importantly, lamellar body-like structures were formed in both the cells and mice exposed to DDAC, and the expression of both the indicator proteins for lamellar body (ABCA3 and Rab11a) and surfactant proteins (A, B, and D) was clearly enhanced. In addition, chronic fibrotic pulmonary lesions were notably observed in mice instilled twice (weekly) with DDAC (500 μg), ultimately resulting in death. Taken together, we suggest that disruption of pulmonary surfactant homeostasis may contribute to DDAC-induced cell death and subsequent pathophysiology and that the formation of lamellar body-like structures may play a role as the trigger. In addition, we propose that the cause of sudden death of mice exposed to DDAC should be clearly elucidated for the safe application of DDAC.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Formation of lamellar body-like structure may be an initiator of didecyldimethylammonium chloride-induced toxic response

Park

Seong

Kang

et al. 2020

Toxicology and Applied Pharmacology

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“…CLIC5 (mapped on 6p21.1 locus) encodes a protein that belongs to the chloride intracellular ion channel (CLIC) family [ 37 ]. The encoded protein (CLIC5) was shown to be highly expressed in the inner ear, and important for sensorineural hearing [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment

Wonkam‐Tingang

Schrauwen

Esoh

et al. 2020

Genes

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DNA samples from five members of a multiplex non-consanguineous Cameroonian family, segregating prelingual and progressive autosomal recessive non-syndromic sensorineural hearing impairment, underwent whole exome sequencing. We identified novel bi-allelic compound heterozygous pathogenic variants in CLIC5. The variants identified, i.e., the missense [NM_016929.5:c.224T>C; p.(L75P)] and the splicing (NM_016929.5:c.63+1G>A), were validated using Sanger sequencing in all seven available family members and co-segregated with hearing impairment (HI) in the three hearing impaired family members. The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants. Both variants were absent from the genome aggregation database (gnomAD), the Single Nucleotide Polymorphism Database (dbSNP), and the UK10K and Greater Middle East (GME) databases, as well as from 122 apparently healthy controls from Cameroon. We also did not identify these pathogenic variants in 118 unrelated sporadic cases of non-syndromic hearing impairment (NSHI) from Cameroon. In silico analysis showed that the missense variant CLIC5-p.(L75P) substitutes a highly conserved amino acid residue (leucine), and is expected to alter the stability, the structure, and the function of the CLIC5 protein, while the splicing variant CLIC5-(c.63+1G>A) is predicted to disrupt a consensus donor splice site and alter the splicing of the pre-mRNA. This study is the second report, worldwide, to describe CLIC5 involvement in human hearing impairment, and thus confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels.

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“…CLIC1- CLIC5 are highly homologous in size and sequence, whereas the larger CLIC5B and CLIC6 have extended amino-terminal domains [ 24 , 25 ]. CLICs are present in neurons and astrocytes, and they are reported to play critical roles in neuro-physiological and pathological conditions, such as Alzheimer’s disease [ 26 ]. CLIC1 is required for α-amyloid-induced generation of reactive oxygen species by microglia and participate in microglia-mediated α-amyloid-induced neurotoxicity [ 27 – 29 ].…”

Section: Discussionmentioning

confidence: 99%

Chloride intracellular channel 4 participate in the protective effect of Ginkgolide B in MPP+ injured MN9D cells: insight from proteomic analysis

et al. 2020

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Background: Ginkgolide B (GB), the extract of G. biloba leaves, has been shown to be protective against many neurological disorders, including Parkinson's disease (PD). Efforts have been made to synthesized ginkgolides analogs and derivatives with more targeted and smaller molecular weight. In the present study, four GB derivatives (GBHC-1-GBHC-4) were synthesized, and their protective roles in N-methyl-4-phenylpyridinium (MPP +) injured MN9D dopaminergic neuronal cell line were evaluated. Also, cell response mechanisms upon these GB derivatives treatment were analyzed by iTRAQ proteomics. Methods: MN9D cells were treated with MPP + to induce in vitro cell models of PD. Four GB derivatives (GBHC-1-GBHC-4) were synthesized, and their protective roles on cell viability and apoptosis in in vitro PD model cells were evaluated by CCK8 assay, fluorescence-activated cell sorting and DAPI staining, respectively. The proteomic profiles of MPP+ injured MN9D cells pretreated with or without GB and GB derivatives were detected using the isobaric tags for relative and absolute quantification (iTRAQ) labeling technique. Results: Pretreatment with GBHC-1-GBHC-4 noticeably increased cell viability and attenuated cell apoptosis in MPP+-injured MN9D cells. Using proteomic analysis, we identified differentially expressed proteins upon GB and GB derivatives treatment. Chloride intracellular channel 4 (CLIC4) and "protein processing in endoplasmic reticulum" pathways participated in the protective roles of GB and GBHC-4. GB and GBHC-4 pretreatment could significantly reverse MPP+-induced CLIC4 expression and translocation from cytoplasm to nucleus of MN9D cells. Conclusions: Quantitative comparative proteomic analysis identified differentially expressed proteins associated with GB and GB derivatives. We further verified the expression of CLIC4 by western blotting and immunocytochemistry assay. This bio-information on the identified pathways and differentially expressed proteins such as CLIC4 provide more targeted directions for the synthesis of more effective and targeted GB derivatives for the treatment of neurological disorders.

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Intracellular Chloride Channels: Novel Biomarkers in Diseases

Abstract: Frontiers in Physiology | www.frontiersin.org February 2020 | Volume 11 | Article 96 Frontiers in Physiology | www.frontiersin.org absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Cited by 81 publications

References 208 publications

Formation of lamellar body-like structure may be an initiator of didecyldimethylammonium chloride-induced toxic response

Formation of lamellar body-like structure may be an initiator of didecyldimethylammonium chloride-induced toxic response

Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment

Chloride intracellular channel 4 participate in the protective effect of Ginkgolide B in MPP+ injured MN9D cells: insight from proteomic analysis

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