[Chronic intermittent hypoxia activates NLRP1 inflammasome and causes liver injury].

Objective To investigate the liver injury induced by chronic intermittent hypoxia (CIH) activation of NOD-like receptor pyrin domain containing protein 1 (NLRP1) inflammasome. Methods C57BL/6 male mice were randomly divided into control group and CIH group. Mice in CIH group were put into CIH chamber for molding (8 hours a day for 4 weeks). After 4 weeks of molding, liver tissue cells was observed by HE staining, and the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of mice were detected by kit. The levels of reactive oxygen species (ROS) in liver tissue were detected by dihydroethidine (DHE). The expression and localization of NLRP1, apoptosis speck-like protein containing a caspase activation and recruiting domain (ASC) and caspase-1 were detected by immunohistochemical staining. The protein expressions of NLRP1, ASC, caspase-1, interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α) were detected by Western blot analysis. The serum levels of IL-1ß and TNF-α were detected by ELISA. Results Compared with the control group, the CIH group exhibited significant pathological changes in hepatocytes. Hepatocytes showed signs of rupture and necrosis, accompanied by inflammatory cell aggregation. Furthermore, the levels of ALT, AST, ROS, IL-1ß and TNF-α were elevated, along with increased protein expressions of NLRP1, ASC, caspase-1, IL-1ß and TNF-α. Conclusion CIH causes liver injury by activating NLRP1 inflammasome.

Inhibitor screening for volume-sensitive LRRC8A chloride channel.

Leucine-rich repeat-containing protein 8 A (LRRC8A) protein is a critical member of volume-regulated anion channels. It plays a critical roles in the regulation of cellular volume and involves in the development of diseases like osteoarthritis. Screening of lead compounds to modulate its function may provide potential therapeutics of related diseases. Here, we employ virtual screening techniques and molecular dynamics (MD) simulation to screen potential inhibitors against LRRC8A. LRRC8A was regarded as the drug target to investigate potential compounds from the ZINC15 database via molecular docking. The final compound was selected among the top 10 Autodock Vina score (-8.8 Kcal/mol) with the ZINC ID ZINC000018195627 after druggability prediction. The docked complex from the virtual screening was subjected to MD simulation to analyze the stability of the LRRC8A protein-ligand complex, with parameters including root mean square deviation, root mean square fluctuation and radius of gyration. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method was further employed to predict the binding free energies from MD simulation trajectory. Our study provides insightful analysis for the potential compound to modulate LRRC8A and lay the foundation of therapeutics development against osteoarthritis.Communicated by Ramaswamy H. Sarma.

Noise-insensitive defocused signal and resolution enhancement for optical-resolution photoacoustic microscopy via deep learning.

Optical-resolution photoacoustic microscopy suffers from narrow depth of field and a significant deterioration in defocused signal intensity and spatial resolution. Here, a method based on deep learning was proposed to enhance the defocused resolution and signal-to-noise ratio. A virtual optical-resolution photoacoustic microscopy based on k-wave was used to obtain the datasets of deep learning with different noise levels. A fully dense U-Net was trained with randomly distributed sources to improve the quality of photoacoustic images. The results show that the PSNR of defocused signal was enhanced by more than 1.2 times. An over 2.6-fold enhancement in lateral resolution and an over 3.4-fold enhancement in axial resolution of defocused regions were achieved. The large volumetric and high-resolution imaging of blood vessels further verified that the proposed method can effectively overcome the deterioration of the signal and the spatial resolution due to the narrow depth of field of optical-resolution photoacoustic microscopy.

Multiscale photoacoustic imaging without motion using single-pixel imaging.

The conventional photoacoustic microscopy usually uses mechanical raster scanning to obtain three-dimensional information, and the imaging speed is limited. Meanwhile, the conventional photoacoustic microscopy can only be performed at one single scale due to fixed resolution, it cannot make full use of multiscale information for integrated imaging. Here, we proposed a multiscale photoacoustic microscopy based on single-pixel imaging. A sequence of sinusoidal fringes with varying spatial frequencies is used to obtain the Fourier coefficients in the case of a single ultrasonic transducer. By controlling the spatial frequency of fringe, the acquisition of Fourier coefficients can be controlled and multiscale imaging can be achieved. The feasibility of this method is verified by theory and simulation. The results show that the lateral resolution can be tuned from several microns to tens of microns without mechanical scanning. This method will expand the application of photoacoustic imaging in biomedical research.

LncRNA-modulated autophagy in plaque cells: a new paradigm of gene regulation in atherosclerosis?

The development of atherosclerosis is accompanied by the functional deterioration of plaque cells, which leads to the escalation of endothelial inflammation, abnormal vascular smooth muscle cell phenotype switching and the accumulation of lipid-laden macrophages within vascular walls. Autophagy, a highly conserved homeostatic mechanism, is critical for the delivery of cytoplasmic substrates to lysosomes for degradation. Moderate levels of autophagy prevent atherosclerosis by safeguarding plaque cells against apoptosis, preventing inflammation, and limiting the lipid burden, whereas excessive autophagy exacerbates cell damage and inflammation and thereby accelerates the formation of atherosclerotic plaques. Increasing lines of evidence suggest that long noncoding RNAs can be either beneficial or detrimental to atherosclerosis development by regulating the autophagy level. This review summarizes the research progress related to 1) the significant role of autophagy in atherosclerosis and 2) the effects of the lncRNA-mediated modulation of autophagy on the plaque cell fate, inflammation levels, proliferative capacity, and cholesterol metabolism and subsequently on atherogenesis.