Defective BACH1/HO-1 regulatory circuits in cystic fibrosis bronchial epithelial cells

Chillappagari, Shashi; Garapati, Virajith; Mahavadi, Poornima; Naehrlich, Lutz; Schmeck, Bernd; Schmitz, M. Lienhard; Güenther, Andreas

doi:10.1016/j.jcf.2020.05.006

Cited by 12 publications

(4 citation statements)

References 31 publications

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“…Furthermore, the depth of the crypts in the small intestine of the mice was increased. Studies have shown that DON exposure caused oxidative stress in the intestine, including changes in the mRNA expressions of CAT, GSH-PX, and the serum MDA content, which led to a cascade of intestinal damage. , HO-1 is a well-known antioxidant factor, and several studies have shown that HO-1 plays an anti-inflammatory and antioxidant role, protecting the body from external damage. − In the present study, the protein and mRNA levels of HO-1 were found to decrease significantly in the DON-exposed group, which is consistent with previous studies. , Likewise, DON exposure reduced the mRNA levels of CAT and SOD-2 in mouse jejunum. In vitro, the results showed that 0.5–2 μM DON significantly reduced the protein and mRNA expressions of HO-1 and increased ROS generation.…”

Section: Discussionsupporting

confidence: 91%

Crucial Function of Caveolin-1 in Deoxynivalenol-Induced Enterotoxicity by Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis

Zhang

et al. 2022

J. Agric. Food Chem.

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Deoxynivalenol (DON) is one of the most pervasive contaminating mycotoxins in grain, and exposure to DON is known to cause acute and chronic intestinal damage. As the gut is the most important target organ of DON, it is essential to identify the pivotal molecules involved in DON-induced enterotoxicity as well as the potential regulatory mechanisms. In the present study, we found that DON treatment dramatically decreased the jejunal villus height and increased the crypt depth in mice. DON exposure induced oxidative stress and NLRP3 inflammasome activation while increasing the levels of pyroptosis-related factors GSDMD, ASC, Caspase-1 P20, and IL-1β and inflammatory cytokines IL-18, TNF-α, and IL-6. In vitro, 0.5−2 μM DON caused cytotoxicity and oxidative stress, as well as NLRP3-mediated pyroptosis in IPEC-J2 cells. Furthermore, DON treatment substantially improved the expression of Caveolin-1 (Cav-1) in vitro and in vivo. Interestingly, Cav-1 knockdown effectively attenuated DON-induced oxidative stress and NLRP3-mediated pyroptosis in IPEC-J2 cells. Meanwhile, treatment with the antioxidant NAC significantly alleviated DON-induced cytotoxicity and pyroptosis in IPEC-J2 cells. Likewise, after inhibiting NLRP3 inflammasome activation with the inhibitor MCC950, DON-induced cytotoxicity, pyroptosis, and inflammatory response were attenuated. However, NLRP3 inhibition did not affect Cav-1 expression. In conclusion, our study demonstrated that pyroptosis may be an underlying mechanism in DON-induced intestinal injury, and Cav-1 plays a pivotal role in DON-induced pyroptosis via regulating oxidative stress, which suggests a novel strategy to overcome DON-induced enterotoxicity.

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Section: Discussionsupporting

confidence: 91%

Crucial Function of Caveolin-1 in Deoxynivalenol-Induced Enterotoxicity by Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis

Zhang

et al. 2022

J. Agric. Food Chem.

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“…HO-1 has anti-inflammatory, anti-oxidative, anti-apoptotic, and anti-proliferative effects. As an adaptive and protective response to noxious stimuli, the production of HO-1 is closely related to some diseases [ 37 , 38 ]. In this study, CD particles induced an increase in cellular ROS, Ca 2+ , and HO-1 levels, and the effect was more pronounced for CD-NPs than for CD-MPs.…”

Section: Discussionmentioning

confidence: 99%

Differences in the characteristics and pulmonary toxicity of nano- and micron-sized respirable coal dust

Zhang

Gao

et al. 2022

Respir Res

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Background The characteristics of coal dust (CD) particles affect the inhalation of CD, which causes coal worker’s pneumoconiosis (CWP). CD nanoparticles (CD-NPs, < 500 nm) and micron particles (CD-MPs, < 5 μm) are components of the respirable CD. However, the differences in physicochemical properties and pulmonary toxicity between CD-NPs and CD-MPs remain unclear. Methods CD was analyzed by scanning electron microscopy, Malvern nanoparticle size potentiometer, energy dispersive spectroscopy, infrared spectroscopy, and electron paramagnetic resonance spectroscopy. CCK-8 assay, ELISA, transmission electron microscope, JC-1 staining, reactive oxygen species activity probe, calcium ion fluorescent probe, AO/EB staining, flow cytometry, and western blot were used to determine the differences between CD-NPs and CD-MPs on acute pulmonary toxicity. CCK-8, scratch healing and Transwell assay, hematoxylin–eosin and Masson staining, immunohistochemistry, immunofluorescence, and western blot were applied to examine the effects of CD-NPs and CD-MPs on pneumoconiosis. Results Analysis of the size distribution of CD revealed that the samples had been size segregated. The carbon content of CD-NPs was greater than that of CD-MPs, and the oxygen, aluminum, and silicon contents were less. In in vitro experiments with A549 and BEAS-2B cells, CD-NPs, compared with CD-MPs, had more inflammatory vacuoles, release of pro-inflammatory cytokines (IL-6, IL-1β, TNFα) and profibrotic cytokines (CXCL2, TGFβ1), mitochondrial damage (reactive oxygen species and Ca2+ levels and decreased mitochondrial membrane potential), and cell death (apoptosis, pyroptosis, and necrosis). CD-NPs-induced fibrosis model cells had stronger proliferation, migration, and invasion than did CD-MPs. In in vivo experiments, lung coefficient, alveolar inflammation score, and lung tissue fibrosis score (mean: 1.1%, 1.33, 1.33) of CD-NPs were higher than those of CD-MPs (mean: 1.3%, 2.67, 2.67). CD-NPs accelerated the progression of pulmonary fibrosis by upregulating the expression of pro-fibrotic proteins and promoting epithelial–mesenchymal transition. The regulatory molecules involved were E-cadherin, N-cadherin, COL-1, COL-3, ZO-1, ZEB1, Slug, α-SMA, TGFβ1, and Vimentin. Conclusions Stimulation with CD-NPs resulted in more pronounced acute and chronic lung toxicity than did stimulation with CD-MPs. These effects included acute inflammatory response, mitochondrial damage, pyroptosis, and necrosis, and more pulmonary fibrosis induced by epithelial–mesenchymal transition.

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“…This could be a result of the cells reaching homeostasis while existing under these conditions. However, recent data showed modulation of the increased levels of BACH1 resulting from increased protein stability in CF cells, did not rescue the decreased HMOX1 levels [ 51 ]. This suggests that a defect in the CFTR regulation may have a more complex impact on the BACH1/HMOX1 regulatory axis.…”

Section: Discussionmentioning

confidence: 99%

BACH1, the master regulator of oxidative stress, has a dual effect on CFTR expression

NandyMazumdar

Paranjapye

Browne

et al. 2021

Biochemical Journal

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The cystic fibrosis transmembrane conductance regulator (CFTR) gene lies within a TAD in which multiple cis-regulatory elements (CREs) and transcription factors (TFs) regulate its cell-specific expression. The CREs are recruited to the gene promoter by a looping mechanism that depends upon both architectural proteins and specific TFs. An siRNA screen to identify TFs coordinating CFTR expression in airway epithelial cells suggested an activating role for BTB Domain and CNC Homolog 1 (BACH1). BACH1 is a ubiquitous master regulator of the cellular response to oxidative stress. Here we show that BACH1 may have a dual effect on CFTR expression by direct occupancy of CREs at physiological oxygen (~8%), while indirectly modulating expression under conditions of oxidative stress. Hence BACH1, can activate or repress the same gene, to fine tune expression in response to environmental cues such as cell stress. Furthermore, our 4C-seq data suggest that BACH1 can also directly regulate CFTR gene expression by modulating locus architecture through occupancy at known enhancers and structural elements, and depletion of BACH1 alters the higher order chromatin structure.

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Defective BACH1/HO-1 regulatory circuits in cystic fibrosis bronchial epithelial cells

Cited by 12 publications

References 31 publications

Crucial Function of Caveolin-1 in Deoxynivalenol-Induced Enterotoxicity by Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis

Crucial Function of Caveolin-1 in Deoxynivalenol-Induced Enterotoxicity by Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis

Differences in the characteristics and pulmonary toxicity of nano- and micron-sized respirable coal dust

BACH1, the master regulator of oxidative stress, has a dual effect on CFTR expression

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