HMGB1 coordinates with Brahma-related gene 1 to promote epithelial-mesenchymal transition via the PI3K/Akt/mTOR pathway in BEAS-2B cells.

High mobility group protein B1 (HMGB1), a highly conserved non-histone nuclear protein, is highly expressed in fibrotic diseases; however, the role of HMGB1 in pulmonary fibrosis has not been fully elucidated. In this study, an epithelial-mesenchymal transition (EMT) model was constructed using transforming growth factor-ß1 (TGF-ß1) to stimulate BEAS-2B cells in vitro, and HMGB1 was knocked down or overexpressed to observe its effects on cell proliferation, migration and EMT. Meanwhile, string system, immunoprecipitation and immunofluorescence analyses were applied to identify and examine the relationship between HMGB1 and its potential interacting protein Brahma-related gene 1 (BRG1), and to explore the mechanism of interaction between HMGB1 and BRG1 in EMT. The results indicate that exogenous increase in HMGB1 promotes cell proliferation and migration and facilitates EMT by enhancing the PI3K/Akt/mTOR signaling pathway, whereas silencing HMGB1 has the opposite effect. Mechanistically, HMGB1 exerts these functions by interacting with BRG1, which may enhance BRG1 function and activate the PI3K/Akt/mTOR signaling pathway, thereby promoting EMT. These results suggest that HMGB1 is important for EMT and is a potential therapeutic target for the treatment of pulmonary fibrosis.

Glycyrrhizic Acid Attenuates Pulmonary Fibrosis of Silicosis by Inhibiting the Interaction between HMGB1 and BRG1 through PI3K/Akt/mTOR Pathway.

PURPOSE: High mobility group protein 1 (HMGB1) is a highly conserved DNA-binding nuclear protein that participates in the occurrence and development of silicosis. HMGB1 binds to its specific receptor and activates phosphatidylinositol 3-kinase (PI3K)/protein kinase B, (PKB; Akt)/mammalian target of rapamycin (mTOR) pathway. Brahma-related genes 1 (BRG1; SMARCA4) is the core subunit of SWI/SNF. HMGB1 activates the Akt pathway through BRG1 to promote the proliferation of prostate cancer. Glycyrrhizic acid is a new pharmacological inhibitor of HMGB1, which may inhibit the occurrence and development of silicosis. We speculate that glycyrrhizic acid inhibits the interaction between HMGB1 and BRG1 through the PI3K/Akt/mTOR pathway to affect the progression of silicosis. METHODS: We carried out an in vitro study and stimulated A549 with TGF-ß1 to establish an epithelial-mesenchymal transition (EMT) model, knocked down the HMGB1 and BRG1 genes in cells, observed the expression of EMT markers, and detected the interaction between HMGB1 and BRG1 by co-immunoprecipitation. In vivo, we injected glycyrrhizic acid into the mouse silicosis model to inhibit the expression of HMGB1. RESULTS: Both HMGB1 and BRG1 were highly expressed in the process of EMT. After knocking down HMGB1 and BRG1, the process of EMT was inhibited through the PI3K/Akt/mTOR pathway, and their expressions were influenced by each other. HMGB1 and BRG1 interact with each other in A549 cells. HMGB1 and BRG1 are also highly expressed in the mouse silicosis model, and glycyrrhizic acid can inhibit the expression of HMGB1/BRG1 through the PI3K/Akt/mTOR pathway. CONCLUSION: Glycyrrhizic acid can inhibit the interaction between HMGB1 and BRG1 through the PI3K/Akt/mTOR pathway to affect the progression of silicosis.

Chronic vitamin D3 supplementation alleviates cognition impairment via inhibition of oxidative stress regulated by PI3K/AKT/Nrf2 in APP/PS1 transgenic mice.

Oxidative stress plays essential role in the pathogenesis of Alzheimer's disease, and vitamin D3 (VD3) is a nutrient with neuroprotective and antioxidant activities. The present study aimed to confirm the neuroprotective effect and the ameliorative effect of cortical oxidative stress of VD3 in APP/PS1 transgenic mice. APP/PS1 mice were treated with VD3 for 20 weeks. After treatment, Morris Water Maze test was used to evaluate cognitive level. Western blotting was used to determine APP, p-tau, tau and PI3K/AKT/Nrf2 pathway-related protein expression levels. Immunohistochemical staining was performed to determine the levels of ß amyloid peptide (Aß) deposition. Enzyme linked immunosorbent assay was used to determine the 25(OH)D3 levels and oxidative stress status. Our results showed that treatment with VD3 ameliorated behavioral deficits of APP/PS1 mice. In addition, the administration of VD3 significantly increased the cortical 25(OH)D3 levels, while reducing the levels of cortical Aß deposition and decreasing the expression levels of cortical APP, tau and p-tau in APP/PS1 mice. Moreover, VD3 protected the cortex against oxidative stress by enhancing the levels of superoxide dismutase, glutathione and total antioxidant capacity, and downregulating the malondialdehyde levels. Furthermore, VD3 clearly activated the PI3K/AKT/Nrf2 pathway, thereby elevating the expression levels of HO1 and NQO1. We concluded that VD3 improved cognitive function and cortical Alzheimer-like pathology of APP/PS1 mice, which may be related to the inhibition of oxidative stress via activation the PI3K/AKT/Nrf2 pathway.

The association between the dietary pattern in abdominal obesity based on visceral fat index and dyslipidaemia in the Henan Rural Cohort Study.

The present study aimed to explore the association between dietary patterns in abdominal obesity obtained by reduced-rank regression (RRR) with visceral fat index (VFI) as a dependent variable and dyslipidemia in rural adults in Henan, China. A total of 29538 people aged 18-79 were selected from the Henan Rural Cohort Study. RRR analysis was used to identify dietary patterns; logistic regression analysis and restricted cubic spline regression models were applied to analyze the association between dietary patterns in abdominal obesity and dyslipidemia. VFI was used as a mediator to estimate the mediation effect. The dietary pattern in abdominal obesity was characterized by high carbohydrate and red meat intake and low consumption of fresh fruits, vegetables, milk, etc. After full adjustment, the highest quartile of dietary pattern scores was significantly associated with an increased risk of dyslipidemia (OR: 1·33, 95 % CI 1·23-1·44, Ptrend < 0·001), there was a non-linear dose-response relationship between them (Poverall-association < 0·001, Pnon-lin-association = 0·022). The result was similar in dose-response between the dietary pattern scores and VFI. The indirect effect partially mediated by VFI was significant (OR: 1·07, 95 % CI 1·06-1·08). VIF explained approximately 53·3 % of odds of dyslipidemia related to the dietary pattern. Abdominal obesity dietary pattern scores positively affected VFI and dyslipidemia; there was a dose-response in both relationships. Dyslipidemia progression increased with higher abdominal obesity dietary pattern scores. In addition, VFI played a partial mediating role in relationship between abdominal obesity dietary pattern and dyslipidemia.