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Mechanisms of chemically induced respiratory toxicities
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
Several studies have examined the distribution and localization of the transferases. Using 1-chloro-2,4-dinitrobenzene as a substrate, transferase activities have been found to be considerably higher in isolated Clara cells than in isolated Type II cells in both the mouse and rat.68,69 Comparative studies have found transferase activities in human lung and rat lung to be comparable but were both less than in hamster and mouse lung.70 Immunohistochemical studies in the lungs of mice showed that the Ya (alpha), Yp (pi) and Yb1 (mu) subunits were all localized in the bronchiolar Clara cells and alveolar Type II cells.71 In addition, Ya was localized in the alveolar Type I and endothelial cells. However, the transferase subunits were all localized to the greatest extent in the Clara cells. Parallel studies using in-situ hybridization and quantitative image analysis demonstrated good agreement between relative amounts of protein and mRNA transcripts. Treatment of mice with 2(3)-tert-butyl-4-hydroxyanisole induced the proteins for Ya and Yp as well as the corresponding mRNA transcripts in the bronchiolar epithelium. Taken together, localization of the cytochrome P450 and transferase enzymes, as well as glutathione, within the same lung cell populations likely provides optimal conditions for the detoxication of reactive metabolites formed from potential pneumotoxicants.
Mitochondrial Genome Damage, Dysfunction and Repair
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Kalyan Mahapatra, Sayanti De, Sujit Roy
The occurrence of mismatch repair system in mammalian mitochondria was established in-vitro by M-13 based assay in which the rat liver mitochondrial extracts showed small but significant mismatch repair (MMR) activity (Mason et al., 2003). Mismatch repair activity in mammalian mitochondria is efficient in cleaving the G:T and G: G mismatches, without showing any activity for discrimination of the parental strand from the sister strand, thus creating the situation more susceptible to several kind of mutations (Mason et al., 2003). Mammalian mitochondrial mismatch repair system is very different from that of nuclear mismatch repair and is independent of MSH2, one of the master regulators of the nuclear mismatch repair system (de Souza-Pinto et al., 2009). Confocal microscopy also confirmed the absence of other classical MMR members viz. MSH3, MSH6 and MLH1 in the mammalian mitochondria (de Souza-Pinto et al., 2009). In yeast and in E. coli mismatch repair component MutS homologue MSH1 is present which repairs the G: A mismatches generated by replication past 8-oxoG (Dzierzbicki et al., 2004). The Y-box binding protein YB-1 protein (NSEP1 and YBX1), previously known to play a major role in nuclear base excision repair pathway and also in repair of cross-linked DNA, is a key component of the mammalian MMR and is mainly involved in mitochondrial mismatch binding activity. RNA interference study also supported the role of YB-1 protein in mitochondrial MMR and YB-1 depletion showed increase in mitochondrial DNA mutagenesis. All these studies strongly suggest the presence of a mismatch repair system in certain mitochondria which is distinct from that of the nuclear mismatch repair, and this pathway is needed to be further characterized.
Comparison of proteomic profiles from the testicular tissue of males with impaired and normal spermatogenesis
Published in Systems Biology in Reproductive Medicine, 2021
Jiaying Liang, Yichun Zheng, Weihong Zeng, Liuqing Chen, Shaofen Yang, Peng Du, Yujiang Wang, Xingsu Yu, Xiqian Zhang
YBX1 is a DNA and RNA binding protein involved in the regulation of transcription, pre-mRNA splicing, and mRNA stability and translation (Lyabin et al. 2014). In the PPI regulatory network of YBX1, FBL, and HNRNPU proteins, HNRNPU is linked to SRSF10, a member of the same family of spliceosome U5 small nuclear RNA (snRNA), and the RNA binding protein YBX1. Although YBX1 function has still not been completely elucidated, existing research suggests that HNRNPU and YBX1 are present in the c-Myc mRNA complex and play a role in mRNA stabilization. HNRNPU and YBX1 were identified as factors involved in promoting c-Myc mRNA stabilization via the CRD (Weidensdorfer et al. 2009). Besides, Du showed that linc02042 regulated c-Myc mRNA stability in an YBX1-dependent mechanism (Du et al. 2020). In addition, YBX1 potentially regulates tumor invasion (Gupta et al. 2019), and YBX1 is reported to be involved in regulating cell proliferation, differentiation, and survival (Wolffe 1994; Bhullar and Sollars 2011). In mice, YBX1 expression in the testis was found to be specifically in the cells on the basement membrane of the seminiferous tubules, which co-localized with undifferentiated spermatogonia (Phillips and Orwig 2010). Also, WB and IHC detected downregulation of YBX1 in the testicular tissues of patients with spermatogenesis disorders, suggesting that it may function in the regulation of spermatogenesis (Alikhani et al. 2017).
Post-translational and transcriptional dynamics – regulating extracellular vesicle biology
Published in Expert Review of Proteomics, 2019
Bethany Claridge, Kenneth Kastaniegaard, Allan Stensballe, David W. Greening
Accumulating evidence supports a role for RNA-binding proteins (RBPs) in the sorting of specific transcripts into EVs derived from various cell types. Recent proteome-wide studies involving RNA interactome capture and system-wide analysis of protein–RNA interactions have significantly increased the number of proteins implicated in RNA binding and uncovered hundreds of additional RBPs lacking conventional RBP domains [94]. Our understanding of ribonucleoproteins (RNPs) is still developing, and while many RBPs have been annotated as such in databases (e.g. RNA Binding Protein database [95], ATtRACT [96], RBPmap [97], and Protein–RNA Interface Database [98] (reviewed [99])), there are undoubtedly still proteins with RNA binding capabilities that have not been discovered, and the RNAs binding these RBPs not yet defined. In the context of EV biology, these RNA and protein complexes (RNPs) range from the well-established, including the hnRNPs involved in RNA export and mRNA maturation [94], to YBX1, suggested to play roles in both RNA splicing and exosomal cargo sorting [100]. While some RBPs have RNA binding domains such as RNA recognition motif (RRM), hnRNP K homology, zinc-finger, or DEAD box helicase domains, most RBPs do not, binding the RNA in unstructured domains where the protein’s flexibility allows [94]. In a reciprocal manner, there have been protein-binding motifs identified in miRNA sequences [70,101] and in the untranslated regions of mRNA [102]; however, most of these still remain unknown. Further, the dynamic expression and activity of RBPs is compounded by PTMs [103–106], cofactor binding or PPIs [107]. This dynamic RNP remodeling is referred to as the epitranscriptome [94,108,109]. It has become clear that RBPs co-operate extensively in recognizing RNA elements and can function to directly connect RNPs to membranes.
Potential of B-cell-targeting therapy in overcoming multidrug resistance and tissue invasiveness associated with P-glycoprotein expressing-B cell compartments
Published in Immunological Medicine, 2021
Shizuyo Tsujimura, Yoshiya Tanaka
The P-gp+ B cell subset that co-expresses CXCR4 are closely related to RA disease activity and serious organ involvement [9]. The upstream CXCR4 gene contains a putative consensus Y-box-binding site (inverted CCAAT box) to which the MDR-1 transcription factor YB-1 can bind [30]. It remains unclear whether activation of YB-1 is directly involved in the upregulation of CXCR4 gene. However, a Syk-dependent IgD-BCR signal, which is triggered by actin cytoskeleton remodeling following CXCL12/CXCR4 axis activation, is initiated and results in induction of Ca+ influx and activation of the ERK pathway [31]. This could lead to induction of P-gp expression through ERK pathway. Fragmented hyaluronan, one of inflammatory extracellular matrix, induces P-glycoprotein expression on lymphocytes through CD44 [32]. Colone et al. [20] reported that P-gp interacts with CD44 through the activation of the ERK and MAPK pathways and results in increase of the invasive behavior, associated with an increase in MMP production and proteolytic activity. CD44 did not increase the invasive behavior in the absence of P-gp. Thus, P-gp may cooperate with molecules involved in induction of own expression and result in increase of migration and invasive potential. P-gp+CXCR4+CD19+ B cells seems to have high-migration capacity and can enhance pathological lesions. In addition to B cells, plasmablasts also coexpress CXCR4 and CD19 [33]. Evidence suggests the involvement of CXCL12/CXCR4 axis in the migration of plasmablasts to the inflamed tissues [34] and the association of P-gp+CXCR4+CD19+ B cells with severe organ injury in RA patients [9,35]. The expression and binding capacity of CXCL12 are increased in the RA synovium in the presence of TNF-α, a cytokine known to induce P-gp [36,37]. In addition to RA, the CXCL12/CXCR4 axis also plays a role in the migration of inflammatory cells in other autoimmune diseases [35,38,39]. For example, marked accumulation of CXCR4+CD19+ B cells was reported in the inflamed mucosa of ulcerative colitis (UC) [38] and significantly high CXCR4 and CXCL12 mRNA levels were reported in bronchoalveolar lavages of pulmonary sarcoidosis [39].