Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

OBJECTIVE: Salt-processed Psoraleae Fructus (SPF) is widely used as a phytoestrogen-like agent in the treatment of osteoporosis. However, due to improper clinical use or misuse, resulting in liver damage. In this study, network pharmacology was employed to analyze the mechanism of cholestatic liver damage. An adeno-associated virus overexpressing SULT1E1 (rAAV8-SULT1E1) was constructed and the hepatotoxicity of SPF, psoralen, and isopsoralen was determined. METHODS: By utilizing three databases inclding TCMSP, TCMID, and BATMAN- TCM, the targets of the three databases were summarized, and a total of 45 psoralen compounds were included. Network pharmacology analysis was then performed. The adenoviral vectors were injected into the tail vein of C57BL6 mice to elucidate the role of SULT1E1 in SPF-induced cholestasis-mediated hepatotoxicity in vivo. SPF (10 g/kg), psoralen, and isopsoralen (50 mg/kg each) were intragastrically administered to mice for 30 d. B-ultrasound and samples were collected and examined for follow-up experiments. RESULTS: A total of 854 targets were predicted for 45 active components, with 151 cholestasis-mediated hepatotoxicity-related disease targets obtained for SPF. A total of 126 pathways were enriched based on KEGG pathway analysis, with the "estrogen signaling pathway" identified as one of the top 20 pathways. In terms of pathological hepatic changes, treated mice had visually swollen hepatocytes, dilated bile ducts, and elevated serum biochemical markers, which were more prominent in mice treated with isopsoralen than in those treated with other compounds. Notably, the overexpression of SULT1E1 could reverse liver damage in each treatment group. B-ultrasound was used to observe the size of the gallbladder in vivo. The size of the gallbladder was found to significantly increase on day 30 after treatment in the SPF-, psoralen-, and isopsoralen-treated groups, especially the SPF group. Compared with the expression levels in the negative control group (rAAV8-empty + con), the expression levels of FXR, Mrp2, Bsep, SULT1E1, SULT2A1, Ntcp, and Nrf2 decreased, whereas those of CYP7a1 and IL-6 increased in the SPF-, psoralen-, and isopsoralen-treated groups. CONCLUSION The overexpression of SULT1E1 could alleviate the decreased or increased expression of indicators, indicating that SULT1E1 is an important target gene for SPF-induced liver damage. The severity of liver damage was significantly lower in the rAAV8-SULT1E1 groups than in the rAAV8-empty groups.

Life-space, as a multidimensional structure, is an important indicator for measuring individual movement. Since the first proposal of life-space in 1985, it has gradually been applied in multiple fields. At present, the development of life-space in foreign countries is becoming increasingly mature, while there is little research on this aspect in China. This article reviews the definition, evaluation tools, and application progress of life-space in cardiac rehabilitation, so as to provide reference for the research and application of life-space in home-based cardiac rehabilitation in China.

Objective To study the influence of SCNIA intronic mutations in mRNA splicing in febrile seizures related epilepsy,and investigate the association between splicing changes and genotype-phenotype-inheritance pattern.Methods Molecular cloning of 5 SCN1A intronic mutations was performed in patients with partial epilepsy with antecedent febrile seizures plus (PEFS+) and Dravet syndrome (DS) through constructing mutant and wild-type plasmids of pTragetE2-3-4-5 and E24-25-26 by using Minigene splicing assay,and the in vitro expressions in HENK293 cells were detected.The mRNA splicing changes were analyzed qualitatively and quantitatively by reverse transcription (RT)-PCR and real time quantitative (q)-PCR.Results (1) Using RT-PCR,DS mutants presented a whole exon skipping without significant remain of normal mRNA transcripts,while PEFS+ mutants showed partial exon skipping or intronic insertion with coexistence of normal and aberrant mRNA transcripts.(2) Statistical differences were found between relative quantity (RQ) of aberrant and normal mRNA in PEFS+ mutant (c.473+5G＞A:4.92％±1.05％ and 6.10％±0.21％;c.473+5G＞C:7.97％±1.12％ and 3.94％ ±1.25％) and that in DS mutant (c.602+1G＞A:60.51％±1.81％ and 0.060％±0.022％,P＜0.05);similarly,there were statistical differences between relative RQ of normal and aberrant mRNA in PEFS+ mutant c.4853-25T＞A (71.22％±11.92％ and 7.38％±1.61％) and that in DS mutant c.4853-1G＞C (0.08％±0.01％ and 22.11％±2.83％,P＜0.05).Conclusion The position and difference of splicing patterns of SCNIA intronic mutations are potential molecular pathogenesis for phenotypic difference of febrile seizures related epilepsy.

Objective To explore the effects of different nutritional pathways on nutrition metabolism and respiratory muscle strength in critical elderly patients in Intensive Care Unit (ICU). Methods Totally 99 critical patients admitted in the ICU of Shandong Provincial Third Hospital between January and September 2017 and were equally randomized into enteral nutrition group (EN group), parenteral nutrition group (PN group) and enteral nutrition plus parenteral nutrition group (EN+PN group), which received nutritional support via different pathways. The patients' hemoglobin (Hb), plasma albumin (ALB) and nitrogen balance were measured 7 days post nutritional support; the maximal inspiratory pressure (PImax) was monitored; and the nutritional status and respiratory muscle strength were compared in the patients receiving nutritional support via different pathways. Results After 7 days' nutritional support, EN+PN group showed better Hb (133.52±12.96) g/L, ALB (40.16±4.42) g/L and nitrogen balance (-4.31±1.67) g than PN group and EN group (F=5.602, 4.594, 2.854; P＜0.05). The PImax of EN+PN group was (-34.52±12.96) cmH2O, which was better than EN group and PN group (F=3.651, P＜ 0.05). Conclusions The combined EN and PN support has better effects on improving the nutritional status and respiratory muscle strength in critical elderly patients as compared to simply using EN or PN, and it also shows better short-term clinical outcomes than simply using EN or PN.