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Background: Abnormal lipid metabolism is involved in the development of osteoarthritis (OA). ATP‐binding cassette protein G1 (ABCG1) is crucial in mediating the outflow of cholesterol, phosphatidylcholine and sphingomyelin and reducing intracellular lipid accumulation. Objective: This study aimed to evaluate whether ABCG1 participates in the abnormal adipogenesis of chondrocytes in osteoarthritic cartilage of temporomandibular joint. Methods: Eight‐week‐old female rats were subjected to unilateral anterior crossbite (UAC) to induce OA in the temporomandibular joint (TMJ). Histochemical staining, immunohistochemical (IHC) staining, and qRT–PCR were performed. Primary condylar chondrocytes of rats were transfected with ABCG1 shRNA or overexpression lentivirus and then stimulated with fluid flow shear stress (FFSS). Cells were collected for oil red O staining, immunofluorescence staining, and qRT–PCR analysis. Results: Abnormal adipogenesis, characterized by increased expression of Adiponectin, CCAAT/enhancer‐binding protein α (Cebpα), fatty acid binding protein 4 (Fabp4) and Perilipin1, was enhanced in the degenerative cartilage of TMJ OA in rats with UAC, accompanied by decreased expression of ABCG1. After FFSS stimulation, we observed lipid droplets in the cytoplasm of cultured cells with increased expression of Adiponectin, Cebpα, Fabp4 and Perilipin1 and decreased expression of ABCG1. Knockdown of Abcg1 induced abnormal adipogenesis and differentiation of condylar chondrocytes. Overexpression of ABCG1 alleviated the abnormal adipogenesis and differentiation of condylar chondrocytes induced by FFSS. Conclusions: Abnormal adipogenesis of chondrocytes and decreased ABCG1 expression were observed in degenerative cartilage of TMJ OA. ABCG1 overexpression effectively inhibits the adipogenesis of chondrocytes and thus alleviates TMJ condylar cartilage degeneration. [ABSTRACT FROM AUTHOR]

Plant-specific YABBY transcription factors play an important role in lateral organ development and abiotic stress responses. However, the functions of the YABBY genes in quinoa remain elusive. In this study, twelve YABBY (CqYAB) genes were identified in the quinoa genome, and they were distributed on nine chromosomes. They were classified into FIL/YAB3, YAB2, YAB5, INO, and CRC clades. All CqYAB genes consist of six or seven exons, and their proteins contain both N-terminal C2C2 zinc finger motifs and C-terminal YABBY domains. Ninety-three cis-regulatory elements were revealed in CqYAB gene promoters, and they were divided into six groups, such as cis-elements involved in light response, hormone response, development, and stress response. Six CqYAB genes were significantly upregulated by salt stress, while one was downregulated. Nine CqYAB genes were upregulated under drought stress, whereas six CqYAB genes were downregulated under cadmium treatment. Tissue expression profiles showed that nine CqYAB genes were expressed in seedlings, leaves, and flowers, seven in seeds, and two specifically in flowers, but no CqYAB expression was detected in roots. Furthermore, CqYAB4 could rescue the ino mutant phenotype in Arabidopsis but not CqYAB10, a paralog of CqYAB4, indicative of functional conservation and divergence among these YABBY genes. Taken together, these results lay a foundation for further functional analysis of CqYAB genes in quinoa growth, development, and abiotic stress responses. [ABSTRACT FROM AUTHOR]

Objectives: To detect whether early growth response 1 (EGR1) in peripheral blood leucocytes (PBLs) indicates temporomandibular joint (TMJ) osteoarthritis (OA) lesions. Materials and Methods: Egr1 mRNA expression levels in PBLs were detected in eight malocclusion patients without temporomandibular disorder (TMD) signs and 16 malocclusion patients with clinical TMD signs with (eight) or without (eight) imaging signs of TMJ OA. Twelve 6‐week‐old rats were randomized to a control group and a unilateral anterior crossbite (UAC) group and were sampled at 4 weeks. The Egr1 mRNA expression levels in PBLs and protein expression levels in different orofacial tissues were measured. Results: Patients with TMD signs with/without TMJ OA diagnosis showed lower Egr1 mRNA expression levels in PBLs than patients without TMD signs. The lower Egr1 mRNA expression was also found in the PBLs of UAC rats, which were induced to exhibit early histo‐morphological signs of TMJ OA lesions. In subchondral bone of UAC rats, EGR1 protein expression was decreased, co‐localization of EGR1 with osterix or dentin matrix protein‐1 was identified, and the number of EGR1 and osterix double‐positive cells was reduced (all p < .05). Conclusion: Egr1 reduction in PBLs potentially indicates subchondral bone OA lesions at an early stage. [ABSTRACT FROM AUTHOR]

Objective: We aimed to develop a mouse model predominating in a proliferative response in the articular cartilage of the temporomandibular joints. Materials and Methods: Bilateral anterior elevation of occlusion was developed by installing metal tubes onto the incisors of mice with edge‐to‐edge relation to prevent tooth wear, leading to an increase in the vertical height of the dental occlusion with time. Morphological changes and expression changes in Cyclin D1, Aggrecan, and type II and type X collagen in the mandibular condylar cartilage were detected. In addition, cells were isolated from the mandibular condylar cartilage and exposed to cyclic tensile strain (CTS). Results: Compared with age‐matched controls, the tooth length was longer at 3 weeks, 7 weeks, and 11 weeks in BAE mice (p < 0.05), with increased condylar cartilage thickness, matrix amount, and cell number (p < 0.05). Compared with the deep zone cells, CTS stimulated the superficial zone cells to express a higher level of proliferating cell nuclear antigen, Cyclin D1, Aggrecan, and type II collagen but a lower level of type X collagen and alkaline phosphatase. Conclusion: Bilateral anterior elevation stimulated the proliferative response in the mandibular condylar cartilage, offering a new therapeutic strategy for cartilage degeneration. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI in relation to oral doses and blood concentrations. This method can be used to estimate DILI risk if the maximal blood concentration (Cmax) of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced, the toxicity separation index (TSI) which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI) which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of 28 compounds, based on TSI and TEI, demonstrating that (1) concentrations where cytotoxicity first becomes evident in vitro (EC10) yielded better metrics than higher toxicity thresholds (EC50); (2) compound incubation for 48 h was better than 24 h, with no further improvement of TSI after 7 days incubation; (3) metrics were moderately improved by adding gene expression to the test battery; (4) evaluation of pharmacokinetic parameters demonstrated that total blood compound concentrations and the 95%-population-based percentile of Cmax were best suited to estimate human toxicity. With a support vector machine-based classifier, using EC10 and Cmax as variables, the cross-validated sensitivity, specificity and accuracy for hepatotoxicity prediction were 100, 88 and 93%, respectively. Concentrations in the culture medium allowed extrapolation to blood concentrations in vivo that are associated with a specific probability of hepatotoxicity and the corresponding oral doses were obtained by reverse modeling. Application of this in vitro/in silico method to the rat hepatotoxicant pulegone resulted in an ADI that was similar to values previously established based on animal experiments. In conclusion, the proposed method links oral doses and blood concentrations of test compounds to the probability of hepatotoxicity. [ABSTRACT FROM AUTHOR]

Summary: Background: The temporomandibular joint (TMJ) disc plays a role in joint movement and in load absorbance and distribution. An experimental unilateral anterior crossbite (UAC) prosthesis induces mandibular condylar cartilage degeneration in rats. However, the changes in the articular disc are still unknown. Objective: To describe changes in the TMJ discs of UAC rats. Methods: The discs of fifty‐four Sprague‐Dawley rats, equally distributed into a UAC group and an age‐matched sham‐operated control group at 4, 12 and 20 weeks (n = 9), were evaluated by gross and histomorphological observation and by detection at the mRNA or protein expression levels of the markers related to the matrix elements. Results: No macro‐ or micro‐morphological differences were observed between groups. However, there were catabolic degradative changes at the molecular level in the UAC group, showing a significant reduction in the mRNA and/or protein expression levels of many molecules. The reduction became worse with time (P < 0.05). The reduced molecules included: (a) those related to the extracellular matrix, such as type I collagen, decorin and fibromodulin; (b) those related to chondrogenesis, such as type II collagen and aggrecan; and (c) those related to osteogenesis, such as alkaline phosphatase and runt‐related transcription factor 2. The mRNA expression of vascular endothelial growth factor did not change. In contrast, fibronectin, which can promote wound healing, and its N‐terminal fragment, which can induce cartilage degradation, were accumulated (P < 0.05). Conclusion: TMJ discs were stimulated to catabolic changes by the aberrant dental occlusion and seemed to go to inanimate with time. [ABSTRACT FROM AUTHOR]

1. Diabetes is often accompanied with depression and hypercholesterolemia. It is possible that paroxetine and pravastatin are co-administered to diabetic patients. The aim of this study was to research the differential effect of pravastatin on plasma exposure of paroxetine in normal and diabetic rats. 2. Pharmacokinetics of paroxetine was investigated following oral administration of paroxetine with and without pravastatin in normal and diabetic rats. Effects of pravastatin on metabolism, intestinal absorption and hepatic uptake of paroxetine were investigated. Activity and expression of hepatic Oatp1 and Oatp2 were also assessed. 3. Pravastatin decreased plasma exposure of paroxetine in normal rats, but increased exposure of paroxetine in diabetic rats. Pravastatin neither affected metabolism nor intestinal absorption of paroxetine. Data from hepatocytes demonstrated that hepatic uptake of paroxetine were involved in Oatp1 and Oatp2. Diabetes suppressed Oatp1 activity and expression, but enhanced Oatp2 activity and expression. Pravastatin stimulated Oatp1 but inhibited Oatp2 activity. 4. We concluded that differential effects of pravastatin on plasma exposure of paroxetine in normal and diabetic rats was partly due to the fact that diabetes suppressed Oatp1 activity and expression but enhanced Oatp2 activity and expression as well as that pravastatin stimulated Oatp1 activity but inhibited Oatp2 activity. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is one of the most harmful and widespread toxic heavy metal contaminants. Long non-coding RNAs (lncRNAs) play vital roles in response to abiotic stress by participating in the gene regulatory network. Here, we performed a transcriptome analysis of lncRNAs in roots of the two contrasting barley genotypes, namely Zhenong8 (ZN, Cd-tolerant) and W6nk2 (Cd-sensitive). In total, 9937 novel lncRNAs were identified, and 5758 lncRNA-target pairs were predicted to be cis-acting and 4159 to be trans-acting. Further comparison of genotypic differences revealed 195 novel lncRNAs as differentially expressed between the two genotypes in response to Cd stress. The miRanda prediction and expression relationship analyses among miRNA, lncRNA, and mRNA revealed that 8 lncRNAs may act as target mimics of miRNAs in barley. Among them, HvGAMYB was predicted to be the target gene of miR319a_1 and miR319b-3p, with LTCONS_00177709 and LTCONS_00185175 acting as endogenous competitors. Barley stripe mosaic virus-induced gene silencing (BSMV-VIGS) of HvGAMYB in ZN8 led to hypersensitivity to Cd stress with significantly increased Cd concentration in both roots and shoots as well as Cd accumulation in shoots. Moreover, silencing HvGAMYB suppressed photosynthesis and antioxidant-related genes but stimulated the production of reactive oxygen species (ROS) after Cd exposure, leading to exacerbated Cd-induced MDA accumulation and cell death. Our findings provide new knowledge and insights into the regulatory functions of lncRNAs in plant Cd tolerance. • Barley Cd-responsive lncRNAs firstly studied by comparing two barley genotypes ZN8 (Cd-tolerant) and W6nk2 (Cd-sensitive). • Identified 195 novel lncRNAs differently expressed in the two genotypes, including 21 Cd tolerance-associated lncRNAs. • lncRNA-miRNA-mRNA-based interaction analysis revealed 8 Cd tolerance-related key lncRNAs with targets such as HvGAMYB. • Silencing of HvGAMYB led to increased Cd concentration in barley and hypersensitivity to Cd stress. [ABSTRACT FROM AUTHOR]

Rhapontin (3, 3′, 5-trihydroxy-4′-methoxystilbene-3-O-glucoside) has anti-thrombotic, anti-allergic and anti-diabetic activities. This study aimed to assess the protective effects of rhapontin on intestinal damage in vivo and in vitro . In a dextran sodium sulfate (DSS)-induced mouse model, oral administration of rhapontin (100 mg/kg) significantly attenuated colonic pathological damage and remarkably inhibited infiltration by inflammatory cells, myeloperoxidase (MPO) activity, NLRP3 inflammasome activation and SIRT1 expression in the colon. Moreover, rhapontin prevented DSS-induced impairment in the colon epithelium barrier by increasing the expression of tight junction proteins, such as zonula occludens-1(ZO-1) and occludin, and reduced apoptosis-associated protein (cyt-c, the ratio of bcl-2/bax and cleaved-capase9) expression in the colon. The in vitro results showed that rhapontin significantly reduced NLRP3 inflammasome activation and cleaved caspase-1 expression as well as lowered IL-1β secretion in LPS-stimulated human-THP-1-derived macrophages. Further study revealed that compound EX257 (an SIRT1 inhibitor) blocked the inhibitory effects of rhapontin on NLRP3-dependent caspase-1 activation and IL-β production in activated macrophages. In addition, in TNF-α-stimulated intestinal epithelial NCM460 cells, rhapontin significantly increased the expressions of occludin and ZO-1 and notably reduced the ratio of bcl-2/bax and cleaved-capase9 expression through SRIT1 signaling. In sum, the protective effect of rhapontin is from blocking the NLRP3 priming cascade reaction and is dependent on SIRT1 activation. Our findings demonstrate that rhapontin might be a potential agent for the treatment of colitis by targeting SIRT1. [ABSTRACT FROM AUTHOR]