Non-canonical STING-PERK pathway dependent epigenetic regulation of vascular endothelial dysfunction via integrating IRF3 and NF-κB in inflammatory response

Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis, while the underlying mechanism remains elusive. Here, we report that the non-canonical stimulator of interferon genes (STING)-PKR-like ER kinase (PERK) pathway was significantly activated in both human and mice atherosclerotic arteries. Typically, STING activation leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB)/p65, thereby facilitating IFN signals and inflammation. In contrast, our study reveals the activated non-canonical STING-PERK pathway increases scaffold protein bromodomain protein 4 (BRD4) expression, which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines, thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation process. Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation. Mechanistically, this pathway is triggered by leaked mitochondrial DNA (mtDNA) via mitochondrial permeability transition pore (mPTP), formed by voltage-dependent anion channel 1 (VDAC1) oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation. Especially, compared to macrophages, endothelial STING activation plays a more pronounced role in atherosclerosis. We propose a non-canonical STING-PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3, NF-κB and BRD4 in inflammatory responses, which provides emerging therapeutic modalities for vascular endothelial dysfunction.

Autophagy enhanced by curcumin ameliorates inflammation in atherogenesis via the TFEB-P300-BRD4 axis

Disturbance of macrophage-associated lipid metabolism plays a key role in atherosclerosis. Crosstalk between autophagy deficiency and inflammation response in foam cells (FCs) through epigenetic regulation is still poorly understood. Here, we demonstrate that in macrophages, oxidized low-density lipoprotein (ox-LDL) leads to abnormal crosstalk between autophagy and inflammation, thereby causing aberrant lipid metabolism mediated through a dysfunctional transcription factor EB (TFEB)-P300-bromodomain-containing protein 4 (BRD4) axis. ox-LDL led to macrophage autophagy deficiency along with TFEB cytoplasmic accumulation and increased reactive oxygen species generation. This activated P300 promoted BRD4 binding on the promoter regions of inflammatory genes, consequently contributing to inflammation with atherogenesis. Particularly, ox-LDL activated BRD4-dependent super-enhancer associated with liquid-liquid phase separation (LLPS) on the regulatory regions of inflammatory genes. Curcumin (Cur) prominently restored FCs autophagy by promoting TFEB nuclear translocation, optimizing lipid catabolism, and reducing inflammation. The consequences of P300 and BRD4 on super-enhancer formation and inflammatory response in FCs could be prevented by Cur. Furthermore, the anti-atherogenesis effect of Cur was inhibited by macrophage-specific Brd4 overexpression or Tfeb knock-out in Apoe knock-out mice via bone marrow transplantation. The findings identify a novel TFEB-P300-BRD4 axis and establish a new epigenetic paradigm by which Cur regulates autophagy, inhibits inflammation, and decreases lipid content.

Study on the correlation between male serum calcitonin gene-related peptide and the embryo culture outcome after in vitro fertilization / 中华检验医学杂志

Objective:To investigate the correlation between serum calcitonin gene-related peptide (CGRP) and the culture outcome of in vitro fertilization embryo in male patients with infertility.Methods:In this study, the randomized samples from 25 male patients who received in vitro fertilization-embryo transfer (IVF-ET) in the 1st Affiliated Hospital of Fujian Medical University from June 2019 to October 2019 were analyzed by multiple linear stepwise regression, with some important clinical outcomes, such as the logarithmic conversion index of serum CGRP, fertilization method, masturbation difficulty, age, infertility duration, and prolactin, as independent variables, while total fertilization rate, normal fertilization rate, high quality embryo rate at day 3, blastocyst formation rate as dependent variables.Results:The Pearson correlation analysis showed that the D3 high-quality embryo rate was related to the normal sperm morphology rate in the primary infertility group ( r=0.537, P=0.048), the blastocyst formation rate was correlated with sperm density ( r=0.760, P=0.002), the CGRP logarithm was correlated with the total fertilization rate ( r=0.693, P=0.006). The logarithmic conversion index of serum CGRP was related to the total fertilization rate and normal fertilization rate in the secondary infertility group ( r=0.614, P=0.042 and r=0.611, P=0.046). In the secondary infertility group, there was a linear relationship between normal fertilization rate and total sperm count, serum CGRP log conversion, and sperm normal morphology rate, with standardized regression coefficients of 0.2, -0.729, and 6.8, respectively. Conclusion:Serum CGRP level, together with total sperm count and normal sperm morphology rate may affects normal fertilization rate in male patients with infertility.

Multiple transmission electron microscopic image stitching based on sift features / 南方医科大学学报

We proposed a new stitching method based on sift features to obtain an enlarged view of transmission electron microscopic (TEM) images with a high resolution. The sift features were extracted from the images, which were then combined with fitted polynomial correction field to correct the images, followed by image alignment based on the sift features. The image seams at the junction were finally removed by Poisson image editing to achieve seamless stitching, which was validated on 60 local glomerular TEM images with an image alignment error of 62.5 to 187.5 nm. Compared with 3 other stitching methods, the proposed method could effectively reduce image deformation and avoid artifacts to facilitate renal biopsy pathological diagnosis.