Search

Objectives: Triterpenoid saponins of Ilex pubescens (IPTS), the main active components of Ilex pubescens, has a therapeutic effect on atherosclerosis (AS). The ingredients in IPTS that could be intracellularly transported by human umbilical vein endothelial cells (HUVECs) may play an essential role in AS. This study attempted to explore its mechanism from the perspectives of HUVECs' inflammation, apoptosis, and autophagy. Methods: By using a tumour necrosis factor-α (TNF-α)-induced HUVECs injury model, cell viability and the expression of intercellular adhesion molecule 1 (ICAM1), matrix metalloproteinase 9 (MMP9), cleave-caspase-3 and cleave-caspase-9, in combination with the results of flow cytometry, JC-1 and Hoechst 33258 staining were investigated to evaluate the anti-inflammatory and anti-apoptotic impact effects of IPTS on HUVECs. Afterwards, the expression of microtubule-associated proteins light chain 3II (LC3II) and sequestosome 1 (p62) was determined to test the effect of IPTS on autophagy. Finally, by adding an autophagy inhibitor 3-methyladenine (3-MA), we investigated whether IPTS exerts anti-inflammatory and anti-apoptotic effects through the autophagy pathway. Key findings: We firstly demonstrated that pretreatment with IPTS could increase the cell viability, maintain the cell morphology and reduce TNF-α-induced inflammation and apoptosis of HUVECs. Moreover, IPTS pretreatment was proved to raise the expression of LC3II /LC3I while decreasing the expression of p62, which indicated that IPTS could activate HUVECs' autophagy. IPTS has been shown for the first time to exert anti-inflammatory and anti-apoptotic effects through autophagy and thereby resisting TNF-α-induced inflammatory injury of HUVECs. Conclusions: This study preliminarily confirmed that IPTS ameliorated HUVECs' inflammation and apoptosis by increasing autophagy. [ABSTRACT FROM AUTHOR]

Elevated expression and genetic aberration of IRTKS, also named as BAIAP2L1, have been observed in many tumors, especially in tumor progression. however, the molecular and cellular mechanisms involved in the IRTKS-enhanced tumor progression are obscure. Here we show that higher IRTKS level specifically increases histone H3 lysine 9 trimethylation (H3K9me3) by promoting accumulation of the histone methyltransferase SETDB1. Furthermore, we reveal that IRTKS recruits the deubiquitinase OTUD4 to remove Lys48-linked polyubiquitination at K182/K1050 sites of SETDB1, thus blocking SETDB1 degradation via the ubiquitin-proteasome pathway. Interestingly, the enhanced IRTKS–OTUD4–SETDB1–H3K9me3 axis leads to a general decrease in chromatin accessibility, which inhibits transcription of CDH1 encoding E-cadherin, a key molecule essential for maintaining epithelial cell phenotype, and therefore results in epithelial-mesenchymal transition (EMT) and malignant cell metastasis. Clinically, the elevated IRTKS levels in tumor specimens correlate with SETDB1 levels, but negatively associate with survival time. Our data reveal a novel mechanism for the IRTKS-enhanced tumor progression, where IRTKS cooperates with OTUD4 to enhance SETDB1-mediated H3K9 trimethylation that promotes tumor metastasis via suppressing E-cadherin expression. This study also provides a potential approach to reduce the activity and stability of the known therapeutic target SETDB1 possibly through regulating IRTKS or deubiquitinase OTUD4. • Higher levels of IRTKS increase H3K9me3 by promoting SETDB1 accuumulation. • IRTKS recruits the deubiquitinase OTUD4 to blocking SETDB1 degradation. • The enhanced IRTKS–OTUD4–SETDB1–H3K9me3 axis decreases chromatin accessibility, and inhibits E-cadherin transcription, resulting in EMT and tumor metastasis. • Clinically, elevated IRTKS levels in tumor correlate with SETDB1 levels, and negatively associate with survival time. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that vitamin D (VD) has a therapeutic effect on non-alcoholic fatty liver disease (NAFLD). Pyroptosis and gut microbiota have been recognized as critical factors of the progression of NAFLD. However, the effect of VD on the pyroptosis and gut microbiota in NAFLD remains inconclusive. Herein, rats were fed high fat diet (HFD) for 12 weeks and concurrently treated with 5 μ g/kg 1,25(OH) 2 D 3 twice a week. BRL-3A cells were stimulated with 0.4 mmol/L palmitic acid (PA) and 1 μ g/ml lipopolysaccharide (LPS) for 16 h and treated with 10−6 mol/L 1,25(OH) 2 D 3. Effect of VD on the hepatic injury, lipid accumulation, activation of NLRP3 inflammasome and pyroptosis was determined in vivo and in vitro. Next, gasdermin D N -terminal (GSDMD-N) fragment was overexpressed in BRL-3A cells to investigate the role of pyroptosis in the therapeutic effect of VD on NAFLD. In addition, gut microbiota in NAFLD rats was also analyzed. Results showed that VD attenuated HFD-induced hepatic injury in vivo and PA-LPS-induced impairment of cell viability in vitro , and inhibited lipid accumulation, activation of NLRP3 inflammasome and pyroptosis in vivo and in vitro. GSDMD-N fragment overexpression suppressed the protective effect of VD on PA-LPS-induced activation of NLRP3 inflammasome, impairment of cell viability and lipid accumulation, indicating that VD might attenuate NAFLD through inhibiting pyroptosis. Additionally, VD also restored HFD-induced gut microbiota dysbiosis by increasing the relative abundance of Lactobacillus and reducing that of Acetatifactor , Oscillibacter and Flavonifractor. This study provides a novel mechanism underlying VD therapy against NAFLD. • Vitamin D inhibited activation of NLRP3 inflammasome and pyroptosis in NAFLD rat. • Vitamin D might attenuate HFD-induced NAFLD by inhibiting pyroptosis in NAFLD rat. • Vitamin D restored HFD-induced gut microbiota dysbiosis in NAFLD rat. [ABSTRACT FROM AUTHOR]

In this study, the pathogenic fungus of stem spot disease of pitaya (Hylocereus spp.) stems was identified by isolation and purification, pathogenicity test, morphological characteristics, and analysis of rDNA-ITS sequences. The results turned out that the rDNA-ITS sequences of the H1 strain showed 100% of identity with Botryosphaeria dothidea, indicating that the pathogenic fungus of stem spot disease of pitaya stems was Botryosphaeria dothidea. Meanwhile, the H1 strain was then used as a reference strain to screen some commercial fungicides. The bioassay test results indicated that prochloraz had an obvious inhibitory effect on Botryosphaeria dothidea with the EC50 value of 0.0798 μg/mL. Our study could provide a theoretical basis for the effective control method of stem spot disease of pitaya. [ABSTRACT FROM AUTHOR]