Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2.

Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 µM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.

PtrABR1 Increases Tolerance to Drought Stress by Enhancing Lateral Root Formation in Populus trichocarpa.

Roots are the main organ for water uptake and the earliest part of a plant's response to drought, making them of great importance to our understanding of the root system's response to drought. However, little is known about the underlying molecular mechanisms that control root responses to drought stress. Here, we identified and functionally characterized the AP2/ERF family transcription factor (TF) PtrABR1 and the upstream target gene zinc-finger protein TF PtrYY1, which respond to drought stress by promoting the growth and development of lateral roots in Populus trichocarpa. A root-specific induction of PtrABR1 under drought stress was explored. The overexpression of PtrABR1 (PtrABR1-OE) promoted root growth and development, thereby increasing tolerance to drought stress. In addition, PtrYY1 is directly bound to the promoter of PtrABR1 under drought stress, and the overexpression of PtrYY1 (PtrYY1-OE) promoted lateral root growth and development and increased tolerance to drought stress. An RNA-seq analysis of PtrABR1-OE with wild-type (WT) poplar identified PtrGH3.6 and PtrPP2C44, which share the same pattern of expression changes as PtrABR1. A qRT-PCR and cis-element analysis further suggested that PtrGH3.6 and PtrPP2C44 may act as potential downstream targets of PtrABR1 genes in the root response pathway to drought stress. In conclusion, these results reveal a novel drought regulatory pathway in which PtrABR1 regulates the network through the upstream target gene PtrYY1 and the potential downstream target genes PtrGH3.6 and PtrPP2C44, thereby promoting root growth and development and improving tolerance to drought stress.

N6-methyladenosine-modified circIRF2, identified by YTHDF2, suppresses liver fibrosis via facilitating FOXO3 nuclear translocation.

Circular RNA (circRNA) has been implicated in liver fibrosis and modulated by multiple elusive molecular mechanisms, while the effects of N6-methyladenosine (m6A) modification on circRNA are still elusive. Herein, we identify circIRF2 from our circRNA sequencing data, which decreased in liver fibrogenesis stage and restored in resolution stage, indicating that dysregulated circIRF2 may be closely associated with liver fibrosis. Gain/loss-of-function analysis was performed to evaluate the effects of circIRF2 on liver fibrosis at both the fibrogenesis and resolution in vivo. Ectopic expression of circIRF2 attenuated liver fibrogenesis and HSCs activation at the fibrogenesis stage, whereas downregulation of circIRF2 impaired mouse liver injury repair and inflammation resolution. Mechanistically, YTHDF2 recognized m6A-modified circIRF2 and diminished circIRF2 stability, partly accounting for the decreased circIRF2 in liver fibrosis. Microarray was applied to investigate miRNAs regulated by circIRF2, our data elucidate cytoplasmic circIRF2 may directly harbor miR-29b-1-5p and competitively relieve its inhibitory effect on FOXO3, inducing FOXO3 nuclear translocation and accumulation. Clinically, circIRF2 downregulation was prevalent in liver fibrosis patients compared with healthy individuals. In summary, our findings offer a novel insight into m6A modification-mediated regulation of circRNA and suggest that circIRF2 may be an exploitable prognostic marker and/or therapeutic target for liver fibrosis.

miR-301a-3p promotes hepatic stellate cells activation and liver fibrogenesis via regulating PTEN/PDGFR-ß.

Hepatic fibrosis is an essential pathology of multiple chronicliverdiseases. The aim of this study was to investigate the role of miR-301a-3p in hepatic fibrosis. We found that miR-301a-3p was upregulated in hepatic fibrosis patients and in culture-activated human hepatic stellate cells (HSCs). Interestingly, miR-301a-3p expression was increased in hepatic fibrosis progression mice while decreased in hepatic fibrosis recovery mice, indicating that miR-301a-3p may participate in the hepatic fibrosis pathology. Functionally, the effects of miR-301a-3p both on hepatic fibrosis progression and regression were assessed in vivo. Inhibiting miR-301a-3p amelioratedmouse liver fibrogenesis and collagen deposition and suppressed HSC activation and fibrogenic factor expression. Whereas, in hepatic fibrosis regression, upregulating miR-301a-3p impaired mouse hepatic fibrosis recovery by inducing HSC activation and triggering inflammation. Consistently, gain-of-function and loss-of-function analysis of miR-301a-3p were performed to evaluate its effects on human HSCs LX-2 cell. We found that suppressing miR-301a-3p inhibited LX-2 cell activation and proliferation, and induced LX-2 cell apoptosis, accompaniedby decreased fibrotic mediators expression. Collectively, these findings suggest miR-301a-3p drives liver fibrogenesis and HSC activation in hepatic fibrosis. Mechanistically, we demonstrated miR-301a-3p binds directly to phosphatase and tensin homolog (PTEN) by luciferase reporter analysis, pull-down, and RIP assay. Indicating that miR-301a-3p plays a critical rolein promotingliverfibrogenesis viamodulating the PTEN/platelet derived growth factor ß (PDGFR-ß) pathway. In conclusion, our findings demonstrate that miR-301a-3p expression is closely correlated with hepatic fibrosis pathology, and that enhancing miR-301a-3p maintains the HSC profibrogenic phenotype, triggers inflammatoryresponses, promotes fibrogenic factor production, and further exacerbates liver fibrogenesis. These findings suggest that miR-301a-3p may serve as a promising diagnostic and prognosis biomarker for hepatic fibrosis treatment.

Pubertal maturation and weight status are associated with dyslipidemia among children and adolescents in Northwest China.

Dyslipidemia is one of major risk factors for cardiovascular disease. The early detection and treatment of dyslipidemia can reduce cardiovascular disease risk. A cross-sectional study was carried out in Ningxia, China to determine the prevalence of dyslipidemia and its association with body mass index (BMI) and pubertal stage. A total of 1783 students were selected from middle schools and high schools in September 2014 using stratified random cluster sampling. Serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured by using MOL-300 automatic biochemical analyzer with associated kits. The prevalence of adolescents with one abnormal serum lipid component was 43.2% and was significantly different across three pubertal stages (p < 0.0001). The abnormal rates of HDL-C and TG increased as the students maturated through the early, middle, and late stages of puberty (all p < 0.0001). Similar results were obtained when separate analyses were performed for boys and girls. In linear regression analysis, BMI was positively associated with serum levels of TC, LDL-C, and TG, but inversely associated with serum levels of HDL-C after the adjustment for age, sex, and race. In multivariable logistic regression analysis, obesity was associated with an increased risk of developing high TC, while pubertal maturation was associated with an elevated risk of experiencing low HDL-C and high TG (all p < 0.05). In conclusions, dyslipidemia is common in an adolescent population of Northwest China and its prevalence rates substantially vary with weight status and pubertal stage.

Serum 25-hydroxyvitamin D and bone mineral density among children and adolescents in a Northwest Chinese city.

Although vitamin D is essential for bone health, little is known about prevalence of vitamin D deficiency and low bone mineral density (BMD) among children, especially those in developing countries. It also remains unclear whether serum 25-hydroxyvitamin D [25(OH)D] is associated with BMD among children. We investigated these questions among children and adolescents in Yinchuan (latitude: 38°â€¯N), Ningxia, an economically underdeveloped province in Northwest China. A total of 1582 children (756 boys and 826 girls), aged 6-18 years, were recruited from schools using the stratified random sampling method in fall 2015. Serum 25(OH)D concentrations were measured by enzyme-linked immunosorbent assay, and BMD was quantified by dual-energy X-ray absorptiometry. Vitamin D deficiency (defined as serum 25(OH)D ≤ 37.5 nmol/L) was present in 35.5% of study subjects. There were no clear patterns of differences in serum 25(OH)D concentrations across the four age groups compared (6-9 years, 10-13 years, 14-16 years, and 17-18 years). The prevalence of low total body less head (TBLH) BMD (defined as a Z-score of ≤ -2.0 standard deviations away from the mean BMD values of the Chinese pediatric reference population) among children examined was 1.8% and was not significantly different among the four age groups considered. Linear regression analysis revealed that age, weight, and height were significantly and positively associated with TBLH BMD and that the strongest determinant of TBLH BMD was age in boys and weight in girls. There were no significant correlations between serum 25(OH)D concentrations and BMD obtained for total body and at various skeletal sites (r ranged from -0.005 to 0.014) regardless of whether children evaluated were sufficient, insufficient, or deficient in vitamin D. In conclusion, more than one-third of children and adolescents in a Northwest Chinese city were deficient in vitamin D but only <2% of them developed low BMD.

The comparative pharmacokinetics of four bioactive ingredients after administration of Ramulus Cinnamomi-Radix Glycyrrhizae herb pair extract, Ramulus Cinnamomi extract and Radix Glycyrrhizae extract.

Ramulus Cinnamomi (RC)-Radix Glycyrrhizae (RG) is a classic herb pair, which is commonly used as a fixed form to treat cardiovascular disease in the clinic. Our work aimed to compare the pharmacokinetic difference of cinnamic acid, liquiritin, isoliquiritigenin and glycyrrhetinic acid in rats after oral administration of the RC-RG herb pair extracts [Guizhigancao Decoction (GGD) and Lingguizhugan Decoction (LGZGD)] and the single RC or RG extract. A HPLC-MS method was developed and validated to study comparative pharmacokinetics. The pharmacokinetic parameters (Cmax , AUC, MRT) of four compounds between the RC-RG herb pair group and the single herb (RC or RG) group showed significant differences (p < 0.05). Compared with the single herb (RC or RG) group, higher peak concentration, slower elimination and larger exposure could be observed after giving the RC-RG herb-pair extracts. The pharmacokinetic differences might indicate the relativity of remedy in the RC-RG herb pair and provide scientific information for rational administration of the drug in the clinic. Copyright © 2016 John Wiley & Sons, Ltd.

Diaphorobacter polyhydroxybutyrativorans sp. nov., a novel poly(3-hydroxybutyrate-co-3-hydroxyvalerate)-degrading bacterium isolated from biofilms.

A novel Gram-stain-negative, facultatively aerobic and rod-shaped strain, designated SL-205(T), was isolated from the biofilms of a denitrifying reactor using poly(3-hydoxybutyrate-co-3-hydroxyvalerate) as the sole carbon source in Beijing, PR China. A polyphasic taxonomic characterization was performed on the novel isolate. Phylogenetic analyses based on the 16S rRNA gene sequence revealed that strain SL-205(T) is a member of the genus Diaphorobacter. High levels of 16S rRNA gene sequence similarity were found between strain SL-205(T) and Diaphorobacter nitroreducens NA10B(T) (99.4%) and Diaphorobacter oryzae RF3(T) (98.5%), respectively. However, the DNA-DNA relatedness values between strain SL-205(T) and D. nitroreducens NA10B(T) and D. oryzae RF3(T) were 57 ± 1% and 45 ± 1.5%, respectively. The G+C content of the genomic DNA of strain SL-205(T) was 66.8 mol%. The major fatty acids consisted of summed feature 3 (including C16 : 1ω7c and/or iso-C15 : 0 2-OH), C16 : 0 and C18 : 1ω7c. Ubiquinone Q-8 was the only respiratory quinone; the polar lipid profile comprised phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and one uncharacterized phospholipid. We conclude that strain SL-205(T) represents a novel species of the genus Diaphorobacter for which the name Diaphorobacter polyhydroxybutyrativorans is proposed; the type strain is SL-205(T) ( = ACCC 19739(T) = DSM 29460(T)).