UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.

Ubiquitin fold modifier 1 is a small ubiquitin-like protein modifier that is essential for embryonic development of metazoans. Although UFMylation has been connected to endoplasmic reticulum homeostasis, the underlying mechanisms and the relevant cellular targets are largely unknown. Here, we show that HRD1, a ubiquitin ligase of ER-associated protein degradation (ERAD), is a novel substrate of UFM1 conjugation. HRD1 interacts with UFMylation components UFL1 and DDRGK1 and is UFMylated at Lys610 residue. In UFL1-depleted cells, the stability of HRD1 is increased and its ubiquitination modification is reduced. In the event of ER stress, the UFMylation and ubiquitination modification of HRD1 is gradually inhibited over time. Alteration of HRD1 Lys610 residue to arginine impairs its ability to degrade unfolded or misfolded proteins to disturb protein processing in ER. These results suggest that UFMylation of HRD1 facilitates ERAD function to maintain ER homeostasis.

Pathophysiologic Role of Molecules Determining Arteriovenous Differentiation in Adult Life.

The structural differences between arteries and veins are genetically predetermined. Vascular identity markers, the molecular markers specific to veins and arteries, determine the differential development of vessels during embryogenesis and their expression persists in adult vessels. It is revealed that they can be reactivated under various pathophysiologic conditions even after vessel differentiation. Thus, once considered as quiescent in adults, vascular identity markers may actually play significant roles in vascular remodeling. Manipulation of vascular identity and the underlying molecular mechanisms might be a novel strategy to improve vascular remodeling for clinical application.

Efficacy and safety of left atrial appendage occlusion in atrial fibrillation patients with chronic kidney disease: a systematic review and meta-analysis.

Atrial fibrillation (AF) is the most common arrhythmia among the elderly, and more frequently occur in those with chronic kidney disease (CKD). Left atrial appendage occlusion (LAAO) is used as a mechanical alternative approach for prevention of AF-related thromboembolisms. This meta-analysis was conducted to provide suggestions for the clinical application of LAAO in AF patients with CKD. The incidence of perioperative adverse events and other clinical effects after operation was by a single rate meta-analysis. Results showed that incidence of adverse events in the perioperative period after LAAO was generally low, with only pericardial effusion / tamponade (1.90%) and mortality rate (1.10%). During the follow-up period, the incidence of stroke/transient ischemic attack (TIA) and bleeding were 2.17% and 4.53%, respectively. A low incidence rate of adverse events was found in the perioperative period following LAAO. These results indicate that LAAO more effectively prevents the occurrence of stroke/TIA and minimizes bleeding events than oral anticoagulants.

[The effect of RNA interfering TLR4 signal pathway on phagocytosis of Kupffer cells].

OBJECTIVE: To investigate the effect of RNA interfering TLR4 signal pathway on phagocytosis of Kupffer cells. METHODS: RAW2647 mice mononuclear macrophage leukemia cells were observed. The tested group was interfered by Tlr4-mus-1567 RNA which had the best result confirmed by QPCR, cells interfered by Negative Control RNA as NC group, and normal cell as control. We perform the phagocytosis test on each group. RESULTS: The tested group has lower phagocytes percentage than control (17.67% +/- 3.51% vs 32.00% +/- 3.00%, P < 0.01), and lower phagocytic index (46.33% +/- 7.51% vs 82.00% +/- 6.08%, P < 0.01). CONCLUSIONS: Decreased phagocytic activity was observed on Kupffer cells by RNA interference.

[Activation of Kupffer cell and related signal pathway proteins in the liver of high fat and high fructose diet induced NAFLD mice].

OBJECTIVE: To investigate the expression of F4/80, NF-kappaB, p-AKT, AKT in the liver of nonalcoholic fatty liver disease (NAFLD) mice. To determine the role of Kupffer cells (KCs) in the development of NASH (non-alcoholic steatohepatitis), and understand the pathogenic mechanism of NASH. METHODS: Five C3H/HeN mice fed with normal diet were served as controls, while fifteen fed with high fat, high fructose, high fat combined fructose diet respectively for 16 weeks were as NAFLD mice models. The liver inflammation and hepatic damage were examined, and the expression of F4/80, NF-Kb, p-AKT, AKT and the content of lipid in the liver were also detected. RESULTS: Chronic intake of high fat and 30% fructose solution caused a significant increase in hepatic steatosis in animals in comparison to water controls. Liver F4/80 and NF-kappaB were significantly higher in high fat and high fat combined fructose diet fed mice than that in controls (P < 0.01, P < 0.01), F4/80 protein were higher in high fat diet treated mice than those in fructose and high fat combined fructose groups (P < 0.01, P < 0.01). Markers of insulin resistance (e. g, hepatic phospho-AKT, AKT) were only altered in fructose-fed or high fat combined fructose animals (P < 0.01, P < 0.01). CONCLUSION: High fat and fructose diet may induce NAFLD in C3H/HeN mice. Kupffer cells and signal pathway proteins were activated, and they may play key roles in the initiation and progression of NASH.