Bromodomain-containing protein 4 (BRD4) is recognized as a member of the bromodomain and extraterminal (BET) family that is involved in the airway inflammation and airway remodeling of asthma. However, the underlying mechanisms of BRD4 in airway smooth muscle cells (ASMCs) proliferation and airway remodeling remain unclear. Primary cultured rat ASMCs and ovalbumin (OVA)-induced rat asthma models were applied to address these issues in the present study. We showed that transforming growth factor β1 (TGF-β1) increased the protein expression of ubiquitin specific peptidase 22 (USP22), which deubiquitinated BRD4 therefore increased its expression, and then resulted in the upregulation of glioma-associated oncogene homolog 1 (GLI1) and osteopontin (OPN) leading to ASMCs proliferation. We further confirmed that induction of TGF-β1 sequentially upregulated USP22, BRD4, GLI1 and OPN leading to airway remodeling in OVA-induced rat asthma models, targeting TGF-β1/USP22/BRD4/GLI1/OPN pathway axis effectively attenuated airway remodeling and asthma development. Our study provides novel sights to understand the role of TGF-β1/USP22/BRD4/GLI1/OPN axis in airway remodeling, and targeting this pathway might have potential value for the prevention and treatment of asthma.
Our previous studies have demonstrated that ubiquitin-specific peptidase 22 (USP22) has the capacity to accelerate renal epithelial-to-mesenchymal transition (EMT) and promote the pathological progression of diabetic tubulointerstitial fibrosis (TIF) by regulating the ubiquitination of Snail1, an EMT transcription factor. Quercetin is a type of flavonol compound widely found in fruits and vegetables that has anti-inflammatory, antioxidant and anti-fibrosis effects. However, whether quercetin promotes the degradation of Snail1 and regulates the pathological progression of TIF by inhibiting USP22 requires further investigation. In this study, we found that quercetin significantly inhibited the expression of USP22 and Snail1 in high glucose (HG)-induced renal tubular epithelial cells (TECs), and reversed the expression of EMT-related proteins and inhibited the overproduction of fibronectin (FN) and Collage Type IV (Collagen IV) induced by high glucose. Additionally, quercetin blocked the deubiquitination of Snail1 mediated by USP22. Further study found that quercetin inhibited the interaction between USP22 and Snail1, thereby reducing the stability of Snail1. Furthermore, quercetin also reduced the protein levels of USP22 and Snail1 in the kidney tissue of diabetic mice and ameliorated renal function, delayed EMT and TIF. In conclusion, quercetin regulates the USP22-Snail1 signal pathway to inhibit the occurrence of EMT both in vitro and in vivo, and ultimately ameliorate the pathological progress of TIF.
Background: Humans with hypertensive heart disease are more likely to experience heart failure, arrhythmia, myocardial infarction, and sudden death, and it is crucial to treat this condition. Fucoidan (FO) is a natural substance derived from marine algae that has antioxidant and immunomodulatory activities. FO has also been shown to regulate apoptosis. However, whether FO can protect against cardiac hypertrophy is unknown.Methods: We investigated the effect of FO in hypertrophic models in vivo and in vitro. C57BL/6 mice were given an oral gavage of FO (300 mg/kg/day) or PBS (internal control) the day before surgery, followed by a 14-day infusion of Ang II or saline. AC-16 cells were treated with si-USP22 for 4 h and then treated with Ang II (100 nM) for 24 h. Systolic blood pressure (SBP) was recorded, echocardiography was used to assess cardiac function, and pathological changes in heart tissues were assessed by histological staining. Apoptosis levels were detected by TUNEL assays. The mRNA level of genes was assessed by qPCR. Protein expression was detected by immunoblotting.Results: Our data showed that USP22 expression was lowered in Ang II-infused animals and cells, which could promote cardiac dysfunction and remodeling. However, treatment with FO significantly upregulated the expression of USP22 and reduced the incidence of cardiac hypertrophy, fibrosis, inflammation, and oxidative responses. Additionally, FO treatment lowered p53 expression and apoptosis while increasing Sirt 1 and Bcl-2 expression.Conclusion: By reducing the level of Ang II-induced apoptosis through the regulation of USP22/Sirt 1 expression, FO treatment might improve cardiac function. According to this study, FO might be potential targeted approach for treating heart failure.
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