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.

Cancer multidrug resistance (MDR) impairs the therapeutic efficacy of various chemotherapeutics. Novel approaches, particularly the development of MDR reversal agents, are critically needed to address this challenge. This study demonstrates that tenacissoside I (TI), a compound isolated from Marsdenia tenacissima (Roxb.) Wight et Arn, traditionally used in clinical practice as an ethnic medicine for cancer treatment, exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells. TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin (DOX) and paclitaxel (PAC) by downregulating ABCB1 expression and reducing ABCB1 drug transport function. Mechanistically, protein arginine methyltransferase 1 (PRMT1), whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues, was differentially expressed in TI-treated SW620/AD300 cells. SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine (aDMA) and enhanced PRMT1-EGFR interaction compared to their parental cells. Moreover, TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR, PRMT1-EGFR interaction, and EGFR downstream signaling in SW620/AD300 and KBV200 cells. These effects were significantly reversed by PRMT1 overexpression. Additionally, TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities. This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR, suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.
Humans ; Protein-Arginine N-Methyltransferases/antagonists & inhibitors* ; Drug Resistance, Neoplasm/drug effects* ; ErbB Receptors/genetics* ; Animals ; Cell Line, Tumor ; Drug Resistance, Multiple/drug effects* ; Methylation/drug effects* ; Saponins/administration & dosage* ; Mice ; Mice, Nude ; Mice, Inbred BALB C ; ATP Binding Cassette Transporter, Subfamily B/genetics* ; Doxorubicin/pharmacology* ; Paclitaxel/pharmacology* ; Female ; Repressor Proteins

Objective To explore the biological functions of pyroptosis-related genes in pneumonic plague using bioinformatics methods,and to evaluate their potential applicability as diagnostic markers.Methods The pneumonic plague-related dataset GSE220123 was retrieved from the Gene Expression Omnibus(GEO)database and screened for differentially expressed pyroptosis-related genes(DE-PRGs).The functions of DE-PRGs were studied via Gene Ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses,and immune infiltration analysis.The hub genes were identified via protein-protein interaction(PPI)network analysis,and further screened for key genes with sustained high expression characteristics based on differential expression analysis.The relative expression levels of the key genes were verified using the reverse transcription real-time quantitative PCR(qPCR)method.Results A total of 17 DE-PRGs were screened,and PPI network analysis revealed 7 Hub genes.Among them,Casp4 continued to be up-regulated during the course of pneumonic plague.The results of reverse transcription qPCR were consistent with the those of bioinformatic analyses.Conclusion DE-PRGs play a crucial role in the immune response of pneumonic plague,especially Casp4,which has significant applications as a diagnostic biomarker and potential therapeutic target for pneumonic plague.

This article is based on ZHANG Jingyue's theory of yin-yang holism to explore the etiology， pathogenesis， and treatment of acute exacerbation of rheumatoid arthritis-associated interstitial lung disease （RA-ILD）. It is believed that the foundation of acute exacerbation of RA-ILD lies in real yin insufficiency and yin fail to control yang； external pathogen attacking is a common cause of acute exacerbation of RA-ILD. For treatment， it is important to first suppress ministerial fire by prescribing modified Yinhuo Decoction （引火汤）； if ministerial fire submerged， focus should be on nourishing both yin and yang； if real yin deficiency is the main issue， modified Zuogui Pill （左归丸） should be used； if real yang deficiency is prominent as well， modified Yougui Pill （右归丸） can be chosen. When yin and yang balanced， the disease could be solved.

Objective:To investigate the current status of women′s level of birth experience and lactation initiation time and explore the effect of level of birth experience on lactation initiation time.Methods:This was a cross-sectional study. A convenience sampling method was used to select 622 maternal cases attending the Affiliated Hospital of Jining Medical College from November, 2020 to January, 2021, and the distribution of their labor experience level and lactation initiation time was investigated by questionnaire and follow-up assessment.Results:There were 622 women with transvaginal deliveries who had lactation initiation times of more than 72 h in 241 cases (38.75%). The scores for each dimension of the Childbirth Experience Questionnaire (CEQ) were (49.63 ± 8.58)points, and the scores for each dimension of CEQ were perceived safety, professional support, involvement and self-efficacy in descending order. The results of the correlation analysis showed that there was a negative correlation between the scores on each dimension of CEQ and the total score and lactation initiation time ( r values were -0.436 to -0.146, all P<0.01). Stratified regression analysis showed that after controlling for age, number of births, gestational weeks of labour, illness during pregnancy and labour analgesia as the underlying variables affecting lactation initiation time, the scores for self-efficacy, involvement, perceived safety and professional support in the CEQ all affected lactation initiation time after delivery ( t values were -6.76 to -2.02, all P<0.05). Conclusions:The birth experience and lactation of women who deliver via vaginal birth need to be taken into account. The more negative the birth experience, the longer the lactation initiation time. The women′s involvement in the birth process, their own competence, perceived safety and level of professional support are all valid influencing indicators of lactation initiation time.

Objective:To express and purify VP7 protein of group A rotavirus (RVA) G1P[8]. The VP7 polyclonal antibody was prepared and its function was evaluated.Methods:The G1 VP7 protein was expressed by baculovirus expression system and purified by affinity chromatography. Polyclonal antibody against G1 VP7 was obtained by immunizing rabbits with G1 VP7 protein. The function of the G1 VP7 polyclonal antibody was verified by Western blotting (WB), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence assay.Results:The soluble G1 VP7 protein of human RVA G1P[8] was obtained using the baculovirus expression system and the VP7 protein was mainly in trimer state. The G1 VP7 polyclonal antibody was prepared and displayed relatively high binding titer to G1 VP7 protein by ELISA. The VP7 polyclonal antibodies could recognize multiple G-type RVAs by WB and ELISA. Immunofluorescence assay further demonstrated that G1 VP7 polyclonal antibody can bind to different RVAs, including Wa (genotype G1P[8]), DS-1(genotype G2P[4]), SA11 (genotype G3P[2]), and human G9P[8] RV strains. In addition, double sandwich ELISA showed that VP7 polyclonal antibody could be used to detect rotavirus in clinical samples.Conclusions:The soluble G1 VP7 protein was successfully expressed and VP7 antibody was obtained. The G1 VP7 polyclonal antibody could bind to a variety of G-type rotaviruses, which lays a foundation for the establishment of detection method of different G type rotaviruses.

Objective:To construct the recertification evaluation index system for the qualifications of intravenous therapy specialist nurses based on the perspective of specialist nurses, so as to provide a reference basis for the construction of a re-certification management scheme for specialized nurses in China.Methods:Using the purpose sampling method, a total of 12 intravenous therapy specialist nurses from 3 tertiary hospitals in Fangshan District, Beijing were selected as the research objects from February to July 2021 for semi-structured in-depth interviews. Subject analysis method was used to analyze the interview data and extract the evaluation indexes of qualification re-certification.Results:The re-certification evaluation index system of intravenous therapy specialist nurses included 8 topics (professional practice ability, professional theoretical knowledge, professional innovation and development ability, critical thinking ability, communication and coordination ability, professional attitude, legal practice and ethical practice ability, nursing management ability) and 29 sub-topics.Conclusions:The qualification re-certification evaluation index system for specialized nurses based on qualitative interviews with intravenous therapy specialist nurses includes 8 ability themes, which can provide reference for the establishment of a re-certification management system for intravenous therapy specialist nurses.

Objective:To study the influences of different levels of hyperbilirubinemia on the myocardium of newborn rats.Methods:Ninety-six 7-day-old newborn SD rats were selected and randomly assigned into control group (n=32, intraperitoneal injection of normal saline 0.5 ml), test group 1 (n=32, intraperitoneal injection of bilirubin solution 100 mg/kg) and test group 2 (n=32, intraperitoneal injection of bilirubin solution 200 mg/kg). Four time points were set at 0 h, 8 h, 24 h and 48 h. The general conditions of 8 rats from every group at each time point were recorded. The total serum bilirubin (TSB), cardiac troponin I (cTnI),heart fatty acid-binding protein (H-FABP) and B-type natriuretic peptide (BNP) were examined. The heart was removed and the pathological changes of the myocardium were observed under microscope. The caspase-3, B-cell lymphoma-2 protein (bcl-2) and bcl-2-associated X protein (bax) were tested. Using SPSS 20.0 statistical software, two-way ANOVA analysis of variance was conducted.Results:The TSB in test group 1 and 2 at 8~48 h were 2.5~4.4 times and 3.5~7.4 times higher than at 0 h [(20.8±3.0~36.5±10.4) μmol/L and (31.9±12.3~67.4±19.0) μmol/L vs. (8.4±2.1) μmol/L and (9.1±2.9) μmol/L]. No significant changes existed in cardiac histopathology at each time point among the three groups. At 48 h, as TSB level increased, the expression of apoptosis-related proteins caspase-3 and bax increased and the expression of bcl-2 decreased. Significant differences existed in the protein levels between any two groups (all P<0.05), except that bcl-2 in test group 1 was similar to control group ( P=0.255). With the prolonged duration of hyperbilirubinemia in test group 2, the expression of caspase-3 and bax increased, while the expression of bcl-2 decreased. Statistically significant differences existed in the protein levels between any two time points (all P<0.05), except that bax in 8 h subgroup was similar to 12 h subgroup ( P=0.820), and bcl-2 in 8 h subgroup was similar to 0 h subgroup ( P=0.064). The cTnI at 8 h, 24 h and 48 h in test group 1 and 2 were all significantly higher than the control group (all P<0.05),however, no significant differences existed between test group 1 and 2 (all P>0.05). H-FABP and BNP showed no significant differences among the three groups at any time point (all P>0.05). Conclusions:Hyperbilirubinemia can induce apoptosis of myocardial cells in newborn rats in a concentration- and time-dependent manner. Hyperbilirubinemia shows no significant effects on cardiac tissue pathology. Hyperbilirubinemia may cause mild injury to myocardium of newborn rats. The injury shows no correlation with TSB level and BNP level was not influenced.

Objective:To evaluate the activity of iduronate-2-sulfatase (IDS) in fetal villi and peripheral blood plasma of pregnant women at high risk of mucopolysaccharidosis type Ⅱ (MPS Ⅱ), and to discuss the application of gene analysis in prenatal diagnosis of MPS Ⅱ.Methods:The enzymatic testing and gene analysis results of 23 pregnant women at high risk of MPS Ⅱ, who underwent prenatal diagnosis in Guangzhou Women and Children′s Medical Center from February 2013 to December 2020, were analyzed retrospectively.The IDS activity in fetal villi (30 cases) and plasma (28 cases) was detected by artificial substrate fluorescence.The IDS activity in fetal villi (28 cases) and plasma (34 cases) of normal pregnant women was taken as control.Meanwhile, the fetal villi of both pregnant women at high risk of MPS Ⅱ and normal pregnant women were also analyzed by gene testing and for fetal sex identification.Data were compared between groups by the independent samples t test. Results:The normal reference values of the IDS activity in fetal villi and plasma of normal pregnant women were(71.2±23.4) nmol/(mg·4 h) and (611.1±114.5) nmol/(mL·4 h), respectively.Among the 30 cases of high-risk fetal villi, the IDS activity in fetal villi of 8 affected male fetuses was (1.7±0.3) nmol/(mg·4 h), which was significantly lower than that of 11 unaffected male fetuses (83.2±6.3) nmol/(mg·4 h) and that of 9 non-carrier female fetuses (80.0±7.5) nmol/(mg·4 h) ( t=10.8, 8.8; all P<0.01). Meanwhile, the IDS activity was measured in the maternal peripheral plasma of 28 pregnant women at high risk of MPS Ⅱ.Among them, the IDS activity in 8 affected male fetuses was(225.4±20.5) nmol/(mL·4 h), which was significantly lower than that in non-affected male fetuses[(451.0±15.1) nmol/(mL·4 h)] and that in non-carrier female fetuses[(467.7±45.3)nmol/(mL·4 h)]. Eight known pathogenic mutations were found in 30 cases at high risk of MPS Ⅱ of fetal villi, and the mutation types were c. 1048A>C, c.212G>A, c.514C>T, c.257C>T, c.425C>T, and c. 998C>T.Of the 8 cases, 6 affected male fetuses had significantly reduced IDS activities, and the other 2 female carriers had normal IDS enzyme activities. Conclusions:The IDS activity in fetal villi and peripheral plasma of pregnant woman is consistent with the gene analysis results.The IDS activity has an important reference value for the prenatal diagnosis of MPS Ⅱ in the first trimester.When no genetic mutations are found in the probands or the pathogenicity of the new mutation remains unclear, the IDS activity in fetal villi can be detected separately for the prenatal diagnosis of MPS Ⅱ.