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Hereditary Breast and Ovarian Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Functionally, the RING finger motif (residues 24–64) contained within the RING domain (residues 1–109) interacts with BARD1 (BRCA1-associated RING domain protein 1) and dramatically increases the ubiquitin ligase activity of BRCA1, which is fundamental to cell-cycle progression, gene transcription regulation, DNA damage response, and ubiquitination. The two nuclear localization signals (NLS, encoded by exon 11) interact with importin-alpha (involved in BRCA1 transport from the cytosol to the nucleus) and other proteins (e.g., retinoblastoma protein, c-Myc, RAD50, and RAD51) relating to transcription regulation, DNA repair, and cell cycle progression. The C-terminal (BRCT) domain interacts with substrates of DNA damage-activated kinases (e.g., ATM, ATR, Abraxas, CtIP, and BACH1), transcription regulators (e.g., p53 and BACH1), and DNA damage repair proteins (e.g., CtIP and CCDC98). The serine cluster domain (in exons 11–13) contains serine residues (988, 1189, 1387, 1423, 1457, 1524, and 1542) that can be phosphorylated by ATM, ATR, CHK1, or CHK2 [8].
Cardiovascular Disease and Oxidative Stress
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Marco Fernandes, Alisha Patel, Holger Husi
Counter-balance of the deleterious effects of oxidative-stress can also be attainable by promoting activation of up-stream factors responsible for the regulation of cell-mediated response to oxidative stress (Gazaryan and Thomas, 2016). This is in part orchestrated by binding of the nuclear factor erythroid 2-related factor 2 (NFE2L2) to cis-regulatory elements, commonly known as antioxidant response elements (ARE) in the promotor region of target genes (Huang et al., 2000). Without external oxidoreductive stimuli, the Kelch-like ECH-associated protein 1(KEAP) promotes continuous ubiquitination and consequent proteasome degradation of NFE2L2, leading to suppression of its transcriptional activity (Lo et al., 2006). Along this line, a number of drugs are currently being developed to attempt to explore how to disrupt the NFE2L2-KEAP1 interface, like the tecfidera (dimethyl fumarate), bardoxolone, and BTB domain and CNC homolog 1 (Bach1) and consequently activating the NFE2L2/ARE pathway. This would then lead to an increased expression of ROS detoxifying enzymes and/or synthesis of pro-antioxidant molecules (Gazaryan and Thomas, 2016; Gesslbauer and Bochkov, 2017). Another approach encompasses mechanisms to cope with damage induced by oxidative stress without changing either basal activity of detoxifying enzymes or levels of pro-antioxidant molecules (Gesslbauer and Bochkov, 2017), thereby lessen the effect of inflammation and aiming to correct disrupted intracellular events due to ROS-induction damage (Gesslbauer and Bochkov, 2017). Attenuation of inflammation by pharmacological intervention has been addressed by altering or interfering with key players in the inflammatory process, such as acting on secretory mediators like inhibiting IL-18, chemokines, and TNF-alpha, using compounds such as Anakinra (Brown, 1989; Toldo et al., 2012), Etanercept (Gao et al., 2015), Infliximab (Gerlach et al., 2014), and Evasin-3 (Montecucco et al., 2010).
Advances in pharmacotherapy for acute kidney injury
Published in Expert Opinion on Pharmacotherapy, 2022
Yali Xu, Ping Zou, Xiaojing Cao
Vitamin D intervenes in the inflammatory and fibrotic pathways of kidney disease through a variety of mechanisms. Preclinical studies have shown that the lack of vitamin D leads to vascular damage, increases the incidence of AKI. Moreover, vitamin D deficiency is positively associated with the severity of AKI [14]. Vitamin D deficiency can also activate the pro-inflammatory pathway and leads to TGF-upreregulation, thus aggravating the degree of tubular stromal damage and renal fibrosis during ischemia/reperfusion-induced AKI via a modulation of the TLR4-NF-κB pathway [15]. Jiang et al. reported that vitamin D treatment attenuated cisplatin-induced AKI by down-regulating NLRP3/Caspase-1/GSDMD pyroptosis pathway [16]. Vitamin D pretreatment inhibits the vitamin D-mediated inflammatory response, thereby reducing the inflammatory response [17]. In doxorubicin-induced AKI model animals, vitamin D supplementation inhibited the expression of acetylheparase in foot cells, thereby reducing the loss of glomerular foot cells and reducing urine protein [18]. Vitamin D pretreatment can also reduce renal oxidative stress damage by regulating the NADPH oxidase and nitric oxide synthase in the AKI animal models [16]. In addition, its antioxidant activity probably is associated with NrF2/HO-1/BACH1 pathway [19]. A clinical study designed to evaluate whether vitamin D levels are different between critical adults with or without AKI has been completed (NCT02869919), but the results were still not released yet [20].
The level of S-glutathionylated protein is a predictor for metastasis in colorectal cancer and correlated with those of Nrf2/Keap1 pathway
Published in Biomarkers, 2021
Liang-Che Chang, Chung-Wei Fan, Wen-Ko Tseng, Chung-Ching Hua
Bach1, a competitor for Nrf2 binding to antioxidant response element (Sykiotis and Bohmann 2010), plays a role in the metastases of lung cancer and CRC (Anderson and Simon 2019, El-Deek et al.2019). The silencing of Bach1 can inhibit the migration of colon cancer cells (Davudian et al.2016). The correlations between the T/N ratios of Bach1 levels and the others were all significant in CRC with metastasis but none in those without. Glycolysis promotes metastasis in a Bach1-dependent manner (Anderson and Simon 2019, Wiel et al.2019). Glycolysis and pentose cycle interact with the TXN/GSH system through NADPH (Li et al.2015). The correlations between the T/N ratios of the TXN/GSH system and those of Bach1 may suggest their roles in CRC metastasis. CRC with lympho-vascular invasion is prone to have lymph node or distant metastasis (Bosch et al.2013, Lim et al.2010). Lympho-vascular invasion was a positive predictor for metastasis. The expression of ATG5 (autophagy-related gene5) is regulated by Nrf2 (Pajares et al.2016) and is increased in CRC with lympho-vascular invasion (Cho et al.2012). The Nrf2/Keap1 pathway has interaction with autophagy through p62 (Moscat et al.2016). Further investigations are warranted for the roles of the interactions between the Nrf2/Keap1 pathway and autophagy in lympho-vascular invasion and metastasis of CRC.
BTB and CNC homology 1 inhibition ameliorates fibrosis and inflammation via blocking ERK pathway in pulmonary fibrosis
Published in Experimental Lung Research, 2020
Yuan Liu, Yongfu Wang, Fuai Lu, Le Wang, Liu Miao, Xiaoyuan Wang
Bleomycin (BLM) (Nippon Kayaku, Tokyo, Japan) induced PF mice model was constructed according to our previous study.11 C57BL/6 male mice (7–8 weeks old, 18–20 g) were bought from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). All mice were housed with free access to food and water at room temperature (22 ± 3 °C), with a relative humidity of 45–50%, and a 12 hours (h) light/dark cycle. To construct PF model, a dose of 5.0 mg/kg BLM (Nippon Kayaku, Tokyo, Japan) was intratracheally infused into the mice. And the mice intratracheal infused same volume of normal saline were served as control. At 7 days (BLM 7d) and 14 days (BLM 14d) after infusion, computerized tomography (CT) scan and tissue biopsy were performed. After the lung tissues were collected, hematoxylin-eosin (H&E) staining and Masson's trichrome staining were performed. Meanwhile, the expression of Bach1 was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. All animal experiments were approved by the Ethics Committee of Baotou Medical College (approval no. 2018-009). The timeline of all the experiments were shown in Figure 1. In addition, 3 mice were used for each group in the animal experiments.