GFRA4 improves the neurogenic potential of enteric neural crest stem cells via hedgehog pathway.

BACKGROUND: Hirschsprung disease (HSCR) is a congenital intestinal disease characterised by functional obstruction of the colon. Herein, we investigated the role and mechanism of the gene GFRA4 in HSCR. METHODS: GFRA4 expression in the ganglionic and aganglionic segment tissues in patients with HSCR and healthy colon tissues were detected using qRT-PCR, western blot, and immunohistochemistry. Cell proliferation, cycle distribution, apoptosis, changes in mitochondrial membrane potential, and differentiation were assessed in mouse enteric neural crest stem cells (ENCSCs) using the CCK-8 assay, EdU staining, flow cytometry, JC-1 probe, and immunofluorescence, respectively. GSEA analysis was performed to screen the signaling pathways regulated by GFRA4. RESULTS: GFRA4 was downregulated in aganglionic segment tissues compared to control and ganglionic segment tissues. GFRA4 overexpression promoted proliferation and differentiation, and inhibited apoptosis in ENCSCs, while GFRA4 down-regulation had the opposite result. GFRA4 activated the hedgehog pathway. GFRA4 overexpression enhanced the expression of key factors of the hedgehog pathway, including SMO, SHH, and GLI1. However, GFRA4 down-regulation reduced their expression. An antagonist of hedgehog pathway, cyclopamine, attenuated the effect of GFRA4 overexpression on proliferation, differentiation, and apoptosis of ENCSCs. CONCLUSION: GFRA4 promotes proliferation and differentiation but inhibits apoptosis of ENCSCs via the hedgehog pathway in HSCR. IMPACT: This study confirms that GFRA4 improves the proliferation and differentiation of ENCSCs via modulation of the hedgehog pathway. This study for the first time revealed the role and the mechanism of the action of GFRA4 in HSCR, which indicates that GFRA4 may play a role in the pathological development of HSCR. Our findings may lay the foundation for further investigation of the mechanisms underlying HSCR development and into targets of HSCR treatment.

Social Frailty and Functional Status in Japanese Older Adults: The Mediating Role of Subjective Cognitive Function.

OBJECTIVE: This study aimed to explore the direct and indirect effects of social frailty on functional state trajectories mediated by subjective cognitive function in older adults. DESIGN: Longitudinal study. SETTING AND PARTICIPANTS: Overall, 514 adults aged ≥65 years living in a suburban area of central Japan were included in this study. METHODS: Five-item social frailty index (going out, visiting, feeling helpful, living alone, and talking to others), subjective cognitive function from the Kihon Checklist, and instrumental activities of daily living disability. Latent growth curve models were applied to examine the longitudinal relations among the variables. RESULTS: During the 6-year follow-up in latent growth curve models, the initial level of social frailty in older adults was negatively associated with that of functional status (ß = -0.53, P < .001), and the rate of change in social frailty was negatively associated with that in functional status (ß = -0.78, P < .001). In the mediation model, the indirect effect from the social frailty level to functional status level through subjective cognitive function level was significant (ß = -0.14, 95% CI -0.29, -0.09); the rates of change in subjective cognitive function mediated the relationship between those in social frailty and functional status (ß = -0.35, 95% CI -0.46, -0.25). CONCLUSIONS AND IMPLICATIONS: This study found that there is an association between social frailty and functional status in Japanese older adults. Subjective cognitive function mediated this relationship. Hence, additional research is required to investigate additional potential factors linking social frailty and functional status in order to gain a better understanding of the underlying mechanisms.

Longitudinal assessment of the relationship between frailty and social relationships among Japanese older adults: a random intercept cross-lagged panel model.

OBJECTIVES: This study aimed to explore the bidirectional association between frailty and social relationships in older adults while distinguishing between interpersonal and intrapersonal effects. METHODS: A prospective cohort study of community-dwelling older adults was conducted in Japan in three waves spanning six years with follow-ups in every three years. Random intercept cross-lagged panel model was used to explore temporal associations between frailty and social relationships. RESULTS: Data for 520 participants (mean age 73.02 [SD 6.38] years, 56.7% women) were analyzed. Across individuals, frailty was associated with social relationships (ß = -0.514, p < 0.001). At the interpersonal level, frailty was cross-sectionally associated with social relationships separately at T1(ß = -0.389, p < 0.01), T2 (ß = -0.343, p < 0.001) and T3 (ß = -0.273, p < 0.05). Moreover, social relationships were associated with subsequent increases in symptoms of frailty in all measurement waves (ß = -0.332, p < 0.001; ß = -0.169, p < 0.01) and vice versa (ß = -0.149, p < 0.05; ß = -0.292, p < 0.001). CONCLUSIONS: The results suggest that frailty was associated with lower levels of social relationships. Frailty improvement programs can be combined with interventions to enhance social relationships, which will be beneficial in preventing frailty. The results emphasize the importance of combining clinical treatments of frailty with interventions to improve social relationships.

Unveiling the driving role of pH on community stability and function during lignocellulose degradation in paddy soil.

Introduction: Crop straw, a major by-product of agricultural production, is pivotal in maintaining soil health and preserving the ecological environment. While straw incorporation is widely recognized as a sustainable practice, the incomplete decomposition of crop residues poses challenges to plant growth, increasing the risk of pests and diseases. This necessitates a comprehensive investigation. Methods: The current study employs a 28-day pot experiment to simulate the degradation of rice straw in paddy soils. The impacts of bioaugmentation and biostimulation on lignocellulose degradation are systematically evaluated. Results: Results indicate a high lignocellulose degradation ability in paddy soil, with over 80% straw weight loss within 28 days. Bioaugmentation with a lignocellulolytic microbial consortium enhances straw degradation during the initial stage (0-14 days). In contrast, biostimulation with readily available nutrients leads to soil acidification, hindering straw degradation and reducing microbial diversity. Furthermore, pH emerges as a critical factor influencing microbial community stability and function during lignocellulose degradation. Microbial co-occurrence network analysis reveals that microorganisms occupy ecological niches associated with different cellulose components. Notably, Module M2, comprising Proteobacteria, Firmicutes, Gemmatimonadota, Actinobacteriota, Bacteroidota, Myxococcota, Halobacterota, and Acidobacteriota, positively correlates with pH and weight loss. Discussion: This study significantly advances our understanding of microbial mechanisms in soil decomposition, emphasizing the pivotal role of pH in community stability and function in paddy soil. These findings can inform future strategies for managing rice straw while safeguarding soil ecosystem health.

Effect of berberine on pharmacokinetics and pharmacodynamics of atorvastatin in hyperlipidemia rats.

Atorvastatin, an effective lipid-lowering drug, could reduce the risks of morbidity and mortality of cardiovascular diseases. Patients with cardiovascular diseases often use atorvastatin along with berberine. Atorvastatin is the substrate of CYP3A4 and P-gp. However, berberine is the inhibitor. The combination might lead to DDIs. The aim of this study was to assess the effect of berberine on pharmacokinetics and pharmacodynamics of atorvastatin in rats.Plasma concentrations of atorvastatin with or without berberine were determined by HPLC. Pharmacokinetics parameters were calculated and used to evaluate pharmacokinetics interactions. The effect of berberine on pharmacodynamics of atorvastatin was investigated by detecting blood lipid, SOD, MDA, GSH-Px, AST, ALT, and liver histopathology.Cmax, tmax, and AUC0-t of atorvastatin in combination group significantly increased both in normal and model rats (p < 0.01). The increase of t1/2, AUC0-t in model rats was more significant than that in normal rats (p < 0.05). Pharmacodynamics indexes in treatment groups were significantly improved, especially combination group (p < 0.05). Moreover, it could be found that there is a significant recovery in liver histopathology.In conclusion, berberine could affect pharmacokinetics of atorvastatin, enhance lipid-lowering effect and improve liver injury in rats. More attention should be paid to plasma exposure in clinical to avoid adverse reactions.

Cutaneous manifestations of inflammatory bowel disease: basic characteristics, therapy, and potential pathophysiological associations.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease typically involving the gastrointestinal tract but not limited to it. IBD can be subdivided into Crohn's disease (CD) and ulcerative colitis (UC). Extraintestinal manifestations (EIMs) are observed in up to 47% of patients with IBD, with the most frequent reports of cutaneous manifestations. Among these, pyoderma gangrenosum (PG) and erythema nodosum (EN) are the two most common skin manifestations in IBD, and both are immune-related inflammatory skin diseases. The presence of cutaneous EIMs may either be concordant with intestinal disease activity or have an independent course. Despite some progress in research on EIMs, for instance, ectopic expression of gut-specific mucosal address cell adhesion molecule-1 (MAdCAM-1) and chemokine CCL25 on the vascular endothelium of the portal tract have been demonstrated in IBD-related primary sclerosing cholangitis (PSC), little is understood about the potential pathophysiological associations between IBD and cutaneous EIMs. Whether cutaneous EIMs are inflammatory events with a commonly shared genetic background or environmental risk factors with IBD but independent of IBD or are the result of an extraintestinal extension of intestinal inflammation, remains unclear. The review aims to provide an overview of the two most representative cutaneous manifestations of IBD, describe IBD's epidemiology, clinical characteristics, and histology, and discuss the immunopathophysiology and existing treatment strategies with biologic agents, with a focus on the potential pathophysiological associations between IBD and cutaneous EIMs.

Fabrication of dendritic PdCu alloy supported on 3D N-doped hollow graphene for efficient ethanol electrooxidation.

Fabricating highly efficient Pd-based nanocatalysts with a well-defined structure is desired for the commercialization of direct ethanol fuel cell (DEFC). Herein, a series of hierarchical three-dimensional N-doped hollow graphene spheres (NHGS) supported dendritic PdCu alloy catalysts PdxCu(d)-NHGS (x: Cu/Pd theoretical molar ratio of 4, 2, and 1) are assembled by one-pot ascorbic acid reduction-immobilization method. Aiming to maximize the Pd utilization and realize the efficient ethanol electrooxidation, this novel electrocatalyst offers potent activity sites and promotes electron and ion kinetics simultaneously. Characterization indicates that the as-obtained Pd4Cu(d) alloy nanoparticles with average sizes of approximately 55 nm are evenly dispersed on the NHGS supporting materials obtained by using the SiO2 nanospheres template strategy. Three catalysts all exhibit enhanced electrocatalytic activity, of which the Pd4Cu(d)-NHGS shows the highest mass current activity (2683 mA mgPd-1), which is 2.59 times of the commercial Pd/C toward ethanol electrooxidation in alkaline medium. Based on the results, we believed that the Pd4Cu(d)-NHGS could exhibit extensive application prospect in alkaline DEFC.

Influence of Gegenqinlian decoction on pharmacokinetics and pharmacodynamics of saxagliptin in type 2 diabetes mellitus rats.

Gegenqinlian decoction (GQD) is a classic prescription of traditional Chinese medicine (TCM), which originated from Shanghanlun. The combination of GQD and hypoglycemic drugs (saxagliptin, Sax, metformin) is often used to treat Type 2 diabetes mellitus (T2DM) in TCM clinics. However, the herb-drug interactions (HDIs) between GQD and hypoglycemic drugs are still unclear. In order to determine the safety of the combination, we assessed the influences of GQD on the pharmacokinetics and pharmacodynamics of Sax in T2DM rats. The plasma concentration of Sax (5 mg/kg) pretreated with GQD (freeze-dried powder, 1.35 g/kg) or not was determined by high-performance liquid chromatography (HPLC), and pharmacokinetics parameters were calculated. The influence of GQD on the pharmacodynamics of Sax was investigated by detecting the levels of weight, (see abbreviations list) OGTT, TC, TG, LDL-C, HDL-C, FBG, FINS, HOMA-IR, QUICKI, AST, ALT, and the liver coefficient. The Cmax , AUC0-t ,and AUC0-∞ of Sax increased significantly in the combination group whether in normal or T2DM rats. The results of pharmacodynamics showed that the weight of rats in each treatment group increased. FBG, TC, TG, LDL-C, and HOMA-IR decreased, HDL-C, FINS, and QUICKI increased significantly (p < 0.05) compared with the model control group. The result showed that the combination of GQD and Sax could not only improve the hypoglycemic effect but also increase the plasma exposure of Sax. The potential HDIs between GQD and Sax should be taken into consideration in clinics. Moreover, for the complexity of the human compared with experimental animals, as well as genetic differences, the in-depth study should be carried out to assess the uniformity of the pharmacokinetics and pharmacodynamics between rats and humans.

Improved simultaneous nitrification-denitrification in fixed-bed baffled bioreactors treating mariculture wastewater: Performance and microbial community behaviors.

As mariculture develops, wastewater treatment becomes crucial. In this study, fixed-bed baffled reactors (FBRs) packed with carbon fiber (CFBR) or polyurethane (PFBR) as biofilm carriers were used for mariculture wastewater treatment. Under salinity shocks between 0.10 and 30.00 g/L, the reactors showed efficient and stable nitrogen removal capacities, and the maximum NH4+-N removal rates were 107.31 and 105.42 mg/(L·d) for CFBR and PFBR, respectively, with an initial NH4+-N concentration of 120.00 mg/L. Further, in the independent aerobic chambers of the FBRs for nitrogen removal, taxa enrichment varied depending on the biofilm carrier, and the assembly process was more deterministic in CFBR than in PFBR. Two distinct clusters representing the spatial distribution of the adhering and deposited sludge in CFBR and the front and rear compartments in PFBR were noted. Furthermore, microbial interactions were more numerous and stable in CFBR. These findings improve the application prospects of FBRs in mariculture wastewater treatment.

Latent Subtype of Cognitive Frailty among Multimorbidity Older Adults and Their Association with Social Relationships.

This study aimed to explore all the relevant subtypes of cognitive frailty among Japanese community-dwelling older adults with multimorbidity. Moreover, it examined the associations between these potential subtypes of cognitive frailty and social relationships. This study targeted relevant cross-sectional data regarding community-based older adults with multimorbidity. It employed a person-centered method to perform a latent class analysis and explore the subtypes of cognitive frailty among older adults. Moreover, a multinominal logistic regression analysis was employed to examine the association between potential subtypes of cognitive frailty and social relationships. Data for 396 participants (mean age, 75.8 [SD, 7.3] years; 51.3% females) were analyzed. Three cognitive frailty subtypes were subsequently revealed: the robust group (42.0%), the group with partial cognitive frailty (38.6%), and the group with cognitive frailty (19.4%). People with high levels of social relationships were more likely to be in the robust and the partial cognitive frailty groups. This study identified different subtypes of cognitive frailty among multimorbid older adults and highlighted the significance of social relationships. These findings could serve as a reference for conceptualizing cognitive frailty through the person-centered method. Promoting a high level of social relationships could be useful to prevent the cognitive frailty among older adults with multimorbidity.

Long-circulating doxorubicin and Schizandrin A liposome with drug-resistant liver cancer activity: in vitro and in vivo evaluation.

Co-loading doxorubicin (DOX) and Schizandrin A (SchA) long-circulating liposome (SchA-DOX-Lip) have been confirmed to have good antitumor activity in vitro. However, in vivo pharmacodynamics, targeting, safety, and mechanism of action of SchA-DOX-Lip still need to be further verified. We investigated the tumor inhibition effect, targeting, safety evaluation, and regulation of tumor apoptosis-related proteins of the SchA-DOX-Lip. MTT assay was used to investigate the inhibitory effect of SchA-DOX-Lip on CBRH7919 cells. The drug uptake of CBRH7919 cells was observed by inverted fluorescence microscope. The tumor-bearing nude mice models of CBRH7919 were established, and the anti-tumor effect of SchA-DOX-Lip in vivo was evaluated by tumor biological observation, H&E staining, and TUNEL staining. The distribution and targeting of SchA-DOX-Lip in nude mice models were investigated by small animal imaging and tissue distribution experiment of CBRH7919. The biosafety of SchA-DOX-Lip was evaluated by blood routine parameters, biochemical indexes, and H&E staining. The expression of tumor-associated apoptotic proteins (Bcl-2, Bax, and Caspase-3) was detected by immunohistochemistry anvd western blotting. The results showed that SchA-DOX-Lip had cytotoxicity to CBRH7919 cells which effectively inhibited the proliferation of CBRH7919 cells, improved the uptake of drugs by CBRH7919 cells and the targeting effect of drugs on tumor site. H&E staining and biochemical detection results showed that SchA-DOX-Lip had high biosafety and did not cause serious damage to normal tissues. Western-blotting and TUNEL staining results showed that SchA-DOX-Lip could improve the regulatory effect of drugs on tumor apoptosis proteins. It was demonstrated that SchA-DOX-Lip had high safety and strong tumor inhibition effects, providing a new method for the clinical treatment of hepatocellular carcinoma (HCC).

EMX2OS targeting IGF2BP1 represses Wilms' tumour stemness,epithelial-mesenchymal transition and metastasis.

Wilms' tumour (WT) is the most typical type of renal tumour in children, which has a poor prognosis and high recurrence rate. This study explored whether lncRNA EMX2 opposite strand / antisense RNA (EMX2OS) modulated the stemness, epithelial-mesenchymal transition (EMT) and metastasis of WTcells through the interaction with insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1). The expression levels of EMX2OS, IGF2BP1 and stem cell markers OCT4, Nanog, Sox2 and CD133 were detected by real time quantitative polymerase chain reaction (RT-qPCR). The stemness, migration and invasion of WTcells were determined by sphere formation assay, scratch and transwell assay, respectively. The levels of EMT-related proteins were detected by Western blotting. RNA pull down and RIP assays were utilized to validate the interaction between EMX2OS and IGF2BP1. The tumourigenicity of WTcells in vivo was analysed using a xenograft tumour assay. EMX2OS was downregulated in WT patients, while IGF2BP1 was upregulated. EMX2OS overexpression or IGF2BP1 knockdown suppressed WT cell sphere formation, migration and invasion. Moreover, EMX2OS could directly interact with RNA-binding protein IGF2BP1, and IGF2BP1 overexpression counteracted the inhibitory effect of EMX2OS on WT cell stemness, migration, invasion and EMT. The in vivo tumour growth, stemness and EMT were repressed by EMX2OS through the interaction with IGF2BP1. In conclusion, EMX2OS acted as a tumour suppressor for WT by interacting with IGF2BP1, which might be a novel target for WT diagnosis and therapy.

Production of Diethyl Maleate via Oxidative Depolymerization of Organosolv Lignin from Wheat Stalk over the Cooperative Acidic Ionic Liquid Pair.

Lignin, the second largest component of biomass, is considered as an important alternative source of fossil reserves for the production of fuels and chemicals. Here, we developed a novel method to oxidatively degrade organosolv lignin into value-added four-carbon esters, particularly diethyl maleate (DEM), with the cooperative catalyst consisting of 1-(3-sulfobutyl) triethylammonium hydrogen sulfate ([BSTEA]HSO4) and 1-butyl-3-methylimidazolium ferric chloride ([BMIM]Fe2Cl7). Under optimized conditions (1.00 MPa initial O2 pressure, 160 °C, 5 h), the lignin aromatic ring was effectively cleaved by oxidation to form DEM with a yield of 15.85% and a selectivity of 44.25% in the presence of the synergistic catalyst of [BMIM]Fe2Cl7-[BSMIM]HSO4 (1/3, mol/mol). The structure and composition analysis of lignin residues and liquid products confirmed that the aromatic units in lignin were effectively and selectively oxidized. Furthermore, the catalytic oxidation of lignin model compounds was explored for obtaining a possible reaction pathway of oxidative cleavage of lignin aromatic units to DEM. This study provides a promising alternative method for the production of traditional petroleum-based chemicals.

Producing Lignin and Ethyl Levulinate from Wheat Stalk Using 1-(3-Sulfobutyl) Triethylammonium Hydrogen Sulfate and USY Zeolite.

The facile, green, and efficient strategy for the separation of lignin from straw and subsequent production of value-added chemicals is crucial to the current utilization of straw. Herein, up to 23.72% of lignin was isolated from wheat stalk over cheap and green 1-(3-sulfobutyl) triethylammonium hydrogen sulfate ([BSTEA]HSO4) in aqueous ethanol (Vethanol: Vwater = 4:1). The acquired lignin was verified as a p-hydroxyphenyl-guaiacyl-syringyl type, which had a narrower molecular weight distribution, better thermal stability, and higher purity compared with those of the lignin obtained using 1-methyl-3-(4-sulfobutyl)-imidazolium hydrogen sulfate and 1-(3-sulfobutyl) pyridinium hydrogen sulfate. Moreover, a carbohydrate-rich liquid containing [BSTEA]HSO4 was obtained by water removal from the waste liquid after lignin separation and further converted to ethyl levulinate (EL) by a one-pot process in the presence of inexpensive and stable USY zeolite. The yield of EL reached 30.23% at 200 °C for 60 min over the presence of 40% [BSTEA]HSO4 and 60% USY zeolite. Under optimal conditions, the yields of lignin and EL can respectively reach 83.89 and 72.28% of those catalyzed by a fresh catalyst after five cycles. In short, the above-mentioned methods present a green, economic, and efficient route for the extraction of lignin and further treatment of the liquid waste generated during the extraction process.

Hybridizing electron-mediated H5PMo10V2O40 with CdS/g-C3N4 for efficient photocatalytic performance of Z-scheme heterojunction in wastewater treatment.

Photocatalytic technology has been considered as a promising method to alleviate environmental pollution owing to the dual characteristics of redox. The novel V-based H5PMo10V2O40 (HPA-2) photocatalyst with Z-scheme heterostructure was constructed. The energy level of HPA-2 matches well with CdS and g-C3N4 (CN) according to Mott-Schottky and UV-Vis diffused reflectance tests, which allows the efficient separation of photogenerated electrons. The optimized CdS/HPA-2/CN showed superior ability in Rhodamine B (RhB) degradation and reduction of Cr (Ⅵ) under visible light irradiation. The maximum rate constant reached 0.092 min-1 for RhB degradation at 60 min and 0.260 min-1 for Cr (Ⅵ) reduction at 20 min, respectively. The photocatalytic mechanism was analyzed by adding scavengers. The effect of active species for RhB degradation was determined as h+ > ·O2- > ·OH, while ·O2- and e- were essential for the reduction of Cr (Ⅵ). Besides, cyclic tests exhibit excellent repeatability and stable structure of CdS/HPA-2/CN after four cycles. Meanwhile, the detailed degradation process of RhB involving de-ethylation, hydroxylation, substitution and decarboxylation was determined according to LC-MS and evaluated by Fukui function calculation. Furthermore, total organic carbon content decreased to 6.2% of the initial value. In this work, as an electron mediator, HPA-2 provides the inspiration for construction of Z-scheme heterojunction, and CdS/HPA-2/CN exhibits enormous potential in the environmental remediation by photocatalysis.

Heterologous Expression of a Thermostable α-Galactosidase from Parageobacillus thermoglucosidasius Isolated from the Lignocellulolytic Microbial Consortium TMC7.

α-Galactosidase is a debranching enzyme widely used in the food, feed, paper, and pharmaceuticals industries and plays an important role in hemicellulose degradation. Here, T26, an aerobic bacterial strain with thermostable α-galactosidase activity, was isolated from laboratory-preserved lignocellulolytic microbial consortium TMC7, and identified as Parageobacillus thermoglucosidasius. The α-galactosidase, called T26GAL and derived from the T26 culture supernatant, exhibited a maximum enzyme activity of 0.4976 IU/ml when cultured at 60°C and 180 rpm for 2 days. Bioinformatics analysis revealed that the α-galactosidase T26GAL belongs to the GH36 family. Subsequently, the pET-26 vector was used for the heterologous expression of the T26 α-galactosidase gene in Escherichia coli BL21 (DE3). The optimum pH for α-galactosidase T26GAL was determined to be 8.0, while the optimum temperature was 60°C. In addition, T26GAL demonstrated a remarkable thermostability with more than 93% enzyme activity, even at a high temperature of 90°C. Furthermore, Ca2+ and Mg2+ promoted the activity of T26GAL while Zn2+ and Cu2+ inhibited it. The substrate specificity studies revealed that T26GAL efficiently degraded raffinose, stachyose, and guar gum, but not locust bean gum. This study thus facilitated the discovery of an effective heat-resistant α-galactosidase with potent industrial application. Meanwhile, as part of our research on lignocellulose degradation by a microbial consortium, the present work provides an important basis for encouraging further investigation into this enzyme complex.

EMX2OS Delays Wilms'Tumor Progression via Targeting miR-654-3p.

OBJECTIVE: Wilms' tumor is the most common renal cancer among children, and a number of patients with high-risk histology still have a poor prognosis. This study explored the biological function and its potential mechanisms of lncRNA EMX2 opposite strand/antisense RNA (EMX2OS) in the progression of Wilms' tumor. MATERIALS: Expression of EMX2OS and miR-654-3p was assessed by RT-qPCR. CCK-8 assay was adopted to assess Wilms' tumor cell proliferation. Apoptosis was determined by Annexin V/PI staining. Transwell assay was utilized to detect the migratory and invasive abilities. The interaction between miR-654-3p and EMX2OS was confirmed by dual luciferase assay. The protein levels of apoptosis-related proteins were detected by Western blotting. Xenograft transplantation was carried out to evaluate tumor growth in vivo. RESULTS: EMX2OS expression was lower, while miR-654-3p level was higher in Wilms' tumor patient samples, and there was a negative correlation between EMX2OS and miR-654-3p. Overexpression of EMX2OS repressed growth, migration, invasion, and triggered apoptosis of Wilms' tumor cells. EMX2OS acted as a sponge of miR-654-3p. Overexpression of miR-654-3p abolished EMX2OS-mediated anti-cancer effects on Wilms' tumor cells. Finally, EMX2OS overexpression restrained Wilms' tumor growth in vivo. CONCLUSION: EMX2OS slowed down the progression of Wilms' tumor via targeting miR-654-3p, which provided evidence for the conclusion that EMX2OS may be a novel therapeutic target for Wilms' tumor.

Subtyping of Internalizing and Externalizing Behaviors in Japanese Community-Based Children: A Latent Class Analysis and Association with Family Activities.

Externalizing and internalizing behavioral problems occurs at a high rate among children. However, this has rarely been examined among Japanese children using a person-oriented method. Hence, this study aims to explore its subtypes and clarify their association with family-based group activities. We conducted a cross-sectional survey in a typical community-based suburban area for all families with primary school children in Japan. We investigated children's internalizing and externalizing behaviors based on the Japanese version of the Strengths and Difficulties Questionnaire (SDQ), and different types of activities that family members frequently engaged in. Data from 206 families were collected and used for the analysis. The subtypes were explored using latent class analysis (LCA). The relationship between family activities and latent class membership was analyzed using a logistic regression model. Moreover, three latent class models and their probabilities were identified, namely, risk group (31.3%), moderate group (44.9%), and normal group (23.8%). Frequent family activities including play sports, traveling or hiking, watching TV and communicating, cooking or making a dessert, and doing housework, which were significantly related to the normal group. These results would add evidence to potential types of children's behavioral problems and preventive childcare practices needed in the primary gate of families.

Influence of Gegenqinlian Decoction on Pharmacokinetics and Pharmacodynamics of Atorvastatin Calcium in Hyperlipidemic Rats.

BACKGROUND AND OBJECTIVES: Gegenqinlian decoction (GQD), a classic traditional Chinese medicine (TCM), was described in Shanghan Lun. GQD is often combined with antihyperlipidemic drugs (mainly atrovastatin calcium) in TCM clinics. However, the herb-drug interaction between GQD and atrovastatin calcium (AC) is still unknown. To determine whether the combination is safe, we evaluated the effects of GQD on the activities of cytochrome P450 (CYP) 3A2 enzyme and investigated the impact of GQD on the pharmacokinetics and pharmacodynamics of AC in rats. METHODS: The pharmacokinetics of AC (10 mg/kg) with or without pretreatment with GQD (freeze-dried powder, 1.35 g/kg) were investigated using HPLC. The influence of GQD on pharmacodynamics of AC were determined by detecting the levels of serum total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Moreover, the probe drug method was used to explore the effect of GQD on CYP3A2 activity. RESULTS: The pharmacokinetic parameters of AC combined with GQD were significantly affected (P < 0.05) in hyperlipidemic rats. The serum TC, TG and LDL-C levels of the combination were significantly reduced (P < 0.05), and the serum HDL-C level was significantly increased (P < 0.05) compared with AC/GQD alone. AST and ALT activities treated with both GQD and AC+GQD group were significantly reduced (P < 0.05) compared with AC group. There was a significant difference in the pharmacokinetic parameters of midazolam between control and GQD groups (P < 0.05). Maximum concentration (Cmax), area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration (AUC0-t) and AUC from time 0 to infinity (AUC0-∞) increased significantly in GQD group. CONCLUSIONS: The result suggested that GQD combined with AC can improve the lipid-lowering effect of AC and reduce the damage of AC to the liver simultaneously. However, GQD can inhibit the activity of CYP3A2 in hyperlipidemic rats and increase the blood concentration of AC. Therefore, the clinical dose of AC should be adjusted when they are combined. Since the study was conducted in rats,  further research should be carried out to assess the uniformity of the pharmacokinetics and pharmacodynamics between rats and humans.

Role of Multifaceted Social Relationships on the Association of Loneliness with Depression Symptoms: A Moderated Mediation Analysis.

Strong relationship exists between loneliness and depression in older adults. However, the effect of multifaceted social relationships on the relationship between loneliness and depression has not been explored. The purpose of the current study was to find out how multifaceted social relationships affect the aforementioned processes. We investigated and evaluated the loneliness status, depression symptoms, social relationships, and demographic information of 1116 older adults aged ≥65 years living in rural Japan. The final 555 participants were included in the analysis. Statistical evidence showed a direct effect between loneliness and depression symptoms. Additionally, the mediation model found that social curiosity and participation acted as mediators between loneliness and depression symptoms. Further, independence and participation, independence, and feeling safe played a conditional moderating role in the model of loneliness-social curiosity-depression symptoms and loneliness-participation-depression symptoms, respectively. Interaction can be an individual moderator in the link between loneliness and depression symptoms without any mediator. The moderated mediation model suggests that social curiosity and participation could mediate the association between loneliness and depression symptoms. In this process, independence, participation, and feeling safe may act as moderators.