Targeted Degradation of PCSK9 In Vivo by Autophagy-Tethering Compounds.

Proprotein convertase subtilisin/kexin type-9 (PCSK9), a secreted protein that is synthesized and spontaneously cleaved in the endoplasmic reticulum, has become a hot lipid-lowering target chased by pharmaceutical companies in recent years. Autophagosome-tethering compounds (ATTECs) represent a new strategy to degrade targeted biomolecules. Here, we designed and synthesized PCSK9·ATTECs that are capable of lowering PCSK9 levels via autophagy in vivo, providing the first report of the degradation of a secreted protein by ATTECs. OY3, one of the PCSK9·ATTECs synthesized, shows greater potency to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels and improve atherosclerosis symptoms than treatment with the same dose of simvastatin. OY3 also significantly reduces the high expression of PCSK9 caused by simvastatin administration in atherosclerosis model mice and subsequently increases the level of low-density lipoprotein receptor, promoting simvastatin to clear plasma LDL-C and alleviate atherosclerosis symptoms. Thus, we developed a new candidate compound to treat atherosclerosis that could also promote statin therapy.

NLRP3 and Gut Microbiota Homeostasis: Progress in Research.

The inflammasome is a platform for inflammatory signaling, and the NLRP3 inflammasome recognizes stimuli in vitro and in vivo, and releases inflammatory cytokines that trigger inflammation and pyroptosis. In the gut, the NLRP3 inflammasome is a key sensor for protecting the body from damage and exogenous pathogens. It plays a fundamental role in maintaining the stability of the gut's immune system. We focus on the role of NLRP3 as a key node in maintaining the homeostasis of gut microbiota which has not been fully highlighted in the past; gut microbiota and innate immunity, as well as the NLRP3 inflammasome, are discussed in this article.

Hydrogen sulfide against preeclampsia exposure-induced oxidative mitochondrial damage in HTR-8/SVneo cells.

Extravillous trophoblast invasion disorder caused by oxidative stress is involved in the pathogenesis of preeclampsia (PE). In order to identify whether hydrogen sulfide (H2S) can prevent oxidative stress injury in extravillous trophoblasts. HTR-8/SVneo cells were detected by H2S inhibiting H2O2 induced oxidative mitochondrial damage. Reactive oxygen species (ROS) were detected, as well as malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD). JC-1 detected the potential of the mitochondrial membrane in this experiment. Then to detect the expression level of the apoptosis-inducing protein B-cell lymphoma-2 (Bcl-2) associated X protein (Bax), caspase 3, p53, p-p53, the apoptosis-inhibiting protein Bcl-2, PRAP, and the mitochondria fission protein Drp1, p-Drp1. CCK-8 assay, it was demonstrated that cell proliferation in the NaHS group was significantly higher than that in the Mod group, indicating that H2S may induce cell proliferation. Transwell assay elucidated that cell invasion in the NaHS group was recovered compared to the Mod group. ROS concentration no matter in cells or mitochondria was decreased by NaHS, which we could get from the comparison between the Mod group, PAG group, and NaHS group. The concentration of MDA was significantly lower in the NaHS group, and the concentration of SOD was extremely high in the NaHS group. Utilized JC-1 to detect mitochondrial membrane potential and found that cells from the NaHS group had a stable potential while cells from the Mod group and PAG group partly lost their potential, which could demonstrate that NaHS could maintain mitochondrial membrane potential. The western blot results revealed that p-Drp1 had a significant decline in the NaHS group, which means mitochondria fission was decreased in the NaHS group. The expression level of Bax and caspase 3 was significantly lower than in the Mod group and PAG group, and the expression level of Bcl-and PRAP was significantly higher in the NaHS group. That could prove that NaHS protect HTR-8/SVneo cell by inhibiting cell apoptosis. These promising results show that H2S elicits its effects on cell apoptosis by decreasing ROS concentration, maintaining mitochondrial membrane stability, and promoting apoptosis-inhibiting protein expression in cells.