Liver-Targeted Delivery of Small Interfering RNA of C-C Chemokine Receptor 2 with Tetrahedral Framework Nucleic Acid Attenuates Liver Cirrhosis.

Liver cirrhosis is the end stage of chronic liver diseases without approved clinical drugs. In this study, a new strategy that uses a C-C chemokine receptor 2 (CCR2) small interfering RNA silencing (siCcr2)-based therapy by loading multivalent siCcr2 with tetrahedron framework DNA nanostructure (tFNA) vehicle (tFNA-siCcr2) was established to attenuate liver fibrosis. tFNA-siCcr2 was successfully synthesized without changing the physiochemical properties of tFNA. Compared to the naked siCcr2 molecule, the tFNA-siCcr2 complex altered the accumulation from the kidney to the liver after the intraperitoneal injection. The tFNA-siCcr2 complex also prolonged hepatic retention and mainly colocalized within macrophages and endothelial cells. tFNA-siCcr2 efficiently silenced CCR2 and significantly ameliorated liver fibrosis in prevention and treatment interventions. Single-cell RNA sequencing followed by experimental validation suggested that tFNA-siCcr2 can restore the immune cell landscape and construct an antifibrotic niche by inhibiting profibrotic macrophage and neutrophil accumulation in the murine fibrotic liver. Molecularly, the tFNA-siCcr2 complex reduced inflammatory mediator production by inactivating the NF-κB signaling pathway. In conclusion, the tFNA-based liver-targeted tFNA-siCcr2 delivery complex efficiently ameliorated liver fibrosis by restoring the immune cell landscape and constructing an antifibrotic niche, which makes the tFNA-siCcr2 complex a potential therapeutic candidate for the clinical treatment of liver cirrhosis.

Distribution and effect of ghrelin genotype on plasma lipid and apolipoprotein profiles in obese and nonobese Chinese subjects.

PURPOSE: The hormone ghrelin has an important role in a wide range of metabolic and nonmetabolic processes. Ghrelin gene polymorphisms have been reported to influence obesity or lipid abnormalities in some ethnic groups. This study was conducted mainly to examine the possible association of ghrelin - 604 G > A and Leu72Met polymorphisms with obesity and related traits in a Southwest Chinese population. METHODS: Three hundred and eighty-six Han Chinese individuals (118 obese and 268 normal weight control subjects) in the Chengdu area were studied using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Clinical and biochemical parameters were also analyzed. RESULTS: The genotype and allele frequencies of ghrelin gene polymorphisms in participants with obesity showed no significant difference compared to those in nonobese controls. However, in the nonobese control group, carriers of genotype Met/Met at the Leu72Met site had higher serum TC and LDL-C concentrations than those of the Leu/Leu genotype (P < 0.05). When nonobese subjects were stratified by sex, the genotype-dependent effects on TC and LDL-C were more evident, although this was observed only in females. In addition, genotype-related effects on these lipid parameters at this site were observed in male obese subjects only. CONCLUSIONS: The Leu72Met polymorphism of the ghrelin gene is associated with altered plasma TC and LDL-C concentrations, and the effects on TC and LDL-C levels are sex-dependent in both nonobese and obese subjects in the Chinese population of the Chengdu area.