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Pathophysiology and Management of Shock
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
The physiological circumstances that induce the cytosolic and ER UPR increase the generation of DNA damage such as nucleotide depurination or deamination, oxidative damage, single- and double-strand breaks, and the generation of nonsense mRNA. DNA damage is recognized by, and activates, a family of phosphoinositide-3-kinase-related protein kinases, including ataxia telangiectasia and Rad-3 related, ataxia telangiectasia mutated, DNA-dependent protein kinase, and SMG1, that not only effect DNA repair,j which is important in its own right, but also all converge on the activation of the transcription factor p53. Although more commonly viewed as a tumor suppressor because of its key role in precipitating cell cycle arrest, p53 also exerts pressure on other cellular processes where, for example, it suppresses translation,k increases antioxidant defenses (48), and enhances anaerobic metabolism by activation of AMPdependent protein kinase (49) (AMPK). In persistently unfavorable circumstances p53 enhances autophagy, a highly conserved mechanism for autocannibalizing and recycling old or damaged organelles (see below). This mechanism is invoked under these circumstances in a “last-ditch’’ bid to source cellular substrate for continued cell function, and is driven by p53 both through the downregulation of mTOR and the upregulation of damage-regulated autophagy modulator (50). Finally, where the situation is deemed irrecoverable, p53 invokes a dignified apoptotic cell death both through transrepression of BCL-2 (an inhibitor of apoptosis) as well as upregulation of PUMA, BAX, BIDD, and PIDD. However, in situations where the genetic damage is extensive, overwhelming activation of the enzyme poly-ADP ribose polymerase-1 leads to the rapid cellular depletion of both NAD+ and ATP, culminating in cellular necrosis (51).
CircVMA21 ameliorates lipopolysaccharide (LPS)-induced HK-2 cell injury depending on the regulation of miR-7-5p/PPARA
Published in Autoimmunity, 2022
Fu Wang, Fangfang Zhang, Qiangqiang Tian, Kai Sheng
Yang et al. declared that circVMA21 protected WI-38 cells to relieve LPS-induced inflammatory damage by altering miR-142-3p/NF-κB/JNK pathway [23]. In septic AKI, Shi et al. suggested that circVMA21 was decreased in CLP-induced septic AKI rat model and LPS-induced HK2 cells, and circVMA21 overexpression alleviated the apoptosis, inflammatory injury and oxidative injury in rats and HK2 cells by elevating SMG1 through sponging miR-9-3p [13]. In the present research, reduced expression of circVMA21 was found in sepsis patients and LPS-impaired HK-2 cells. Moreover, circVMA21 overexpression alleviated LPS-mediated suppression in cell viability and promotion in cell apoptosis and inflammation in HK2 cells. The generation of ROS in multiple pathways is reported to be associated with kidney diseases [24]. Oxidative stress and its oxidative damage play vital roles in the occurrence and development of septic AKI [25,26]. Here, our results presented that LPS-induced oxidative injury in HK2 cells was recovered by elevating circVMA21. All these results indicated that LPS-evoked HK2 cell impairments were alleviated by the overexpression of circVMA21.
Translational readthrough inducing drugs for the treatment of inherited retinal dystrophies
Published in Expert Review of Ophthalmology, 2020
Christopher M Way, Dulce Lima Cunha, Mariya Moosajee
PTC-containing transcripts are typically degraded by NMD, reducing their availability. Therefore, inhibition of NMD is proposed to increase mRNA stability and as a consequence, increase the amount of substrate for TRIDs to target. Caffeine inhibits NMD through the inhibition of SMG1 kinase [35,36] (Figure 2(c)). It alone has been shown to rescue the phenotype in fibroblasts carrying a PTC seen in the muscular dystrophy Ullrich’s disease, by increasing mRNA and protein levels of the defective collagen VI α2 [37]. NMDI1 is a tetracyclic compound that traps UPF1 in a hyperphosphorylated state, preventing downstream interactions with SMG5 [38] (Figure 2(d)). It is specific for NMD, does not affect translation efficiency and is non-cytotoxic [38]. In a mouse model of Mucopolysacchardisosis I-Hurler syndrome (MPS I-H) that carries the knock-in Idua p.W392* mutation, NMDI1 application with gentamicin resulted in greater readthrough and functional enzymatic activity than gentamicin alone [39]. However, NMDI1 synthesis is inefficient and technically difficult. In contrast, VG1, a structural analogue of NMDI1 with similar inhibition capability, is more easily produced and shows an improved yield [40]. Its mechanism of action is currently unknown but its application to IRDs is awaited. Amlexanox is a compound with both readthrough and NMD inhibition properties. It has been reported as a combined therapy option for PTCs causing cystic fibrosis (CF) and recessive dystrophic epidermolysis bullosa, showing increased levels of full-length proteins compared to G418 and PTC124 alone [41,42].
Promoter methylation of galanin receptors as epigenetic biomarkers for head and neck squamous cell carcinomas
Published in Expert Review of Molecular Diagnostics, 2019
Takeharu Kanazawa, Kiyoshi Misawa, Kazuya Shinmura, Yuki Misawa, Gen Kusaka, Mikiko Maruta, Toru Sasaki, Yusuke Watanabe, Thomas E. Carey
The differences in the methylation status of promoters of several genes between HPV-positive and HPV-negative HNSCC have been investigated because HPV infection is one of the most important markers predicting responsiveness to chemotherapy and/or radiotherapy [78,79]. Genome-wide methylation analysis between four HPV-positive and four HPV negative cancers has revealed a large list of genes differentially methylated depending on the HPV status [80]. However, experimental evidence that HPV-related promoter methylation can determine clinical outcome is not complete. SMG1 gene silencing in HPV-negative HNSCC cells results in increased radiation sensitivity, whereas SMG1 overexpression protects HPV-positive tumor cells from irradiation [81]. Experiments using genome-wide DNA methylation analysis of primary tumor samples and adjacent normal mucosa from 118 HNSCC patients identified 440 differentially methylated CpG loci in oropharyngeal SCC, and differentially methylated CpG loci were more frequently observed in HPV-positive tumors than in HPV-negative tumors [82]. Two independent global studies demonstrated that promoter hypermethylation occurred in a wide range of genes [83,84]. Cluster analysis based on methylation patterns using 1,505 CpG sites across 807 genes in 68 HNSCC tumor samples revealed significant differences with respect to age, HPV status, and survival by distinct tumor clustering into six categories [84]. The study revealed that 13 individual CpG sites were significantly associated with HPV status, and most of the genes related to these sites regulated the cell cycle and JAK-STAT signaling [84]. The samples derived from 42 HNSCC tumors also yielded similar results for the methylation profiles of HPV-positive and HPV-negative tumors [83]. Other than these results, several global gene studies, including gene-set enrichment analysis and array-based approaches, have demonstrated the association between HPV infection and DNA methylation in HNSCC using clinical databases [85–87]. These studies investigated the differences in gene promoter methylation status between HPV-positive and HPV-negative HNSCC by comprehensive analyses of promoter methylation. Meanwhile, it is considered necessary to elucidate the mechanism by which HPV infection related to individual genes causes the methylation of the promoter.