A series of myricetin derivatives containing amide, thioether, and 1,3,4-thiadiazole moieties were designed and synthesized, and their antiviral and antibacterial activities were assessed. The bioassays showed that all the title compounds exhibited potent in vitro antibacterial activities against Xanthomonas citri (Xac), Ralstonia solanacearum (Rs), and Xanthomonas oryzae pv. Oryzae (Xoo). In particular, the compounds 5a, 5f, 5g, 5h, 5i, and 5l, with EC50 values of 11.5⁻27.3 μg/mL, showed potent antibacterial activity against Xac that was better than the commercial bactericides Bismerthiazol (34.7 μg/mL) and Thiodiazole copper (41.1% μg/mL). Moreover, the in vivo antiviral activities against tobacco mosaic virus (TMV) of the target compounds were also tested. Among these compounds, the curative, protection, and inactivation activities of 5g were 49.9, 52.9, and 73.3%, respectively, which were better than that of the commercial antiviral Ribavirin (40.6, 51.1, and 71.1%, respectively). This study demonstrates that myricetin derivatives bearing amide, thioether, and 1,3,4-thiadiazole moieties can serve as potential alternative templates for the development of novel, highly efficient inhibitors against plant pathogenic bacteria and viruses.

The demonstrated role of mitogen-activated protein kinase (MAPK) in both cell apoptosis and the inflammation pathway makes it an attractive target for photoreceptor protection. The aim of this study was to investigate the protective effects of MAPK antagonists against photoreceptor degeneration and retinal inflammation in a rat model of light-induced retinal degeneration.

There is a great unmet clinical need to identify patients with thin primary cutaneous melanomas (T1, Breslow thickness ≤ 1 mm) who have a high risk for tumour recurrence and death from melanoma. Kin of IRRE-like protein 1 (KIRREL/NEPH1) is expressed in podocytes and involved in glomerular filtration. Screening in the Human Protein Atlas portal revealed a particularly high expression of KIRREL in melanoma, both at the mRNA and protein levels. In this study, we followed up on these findings and examined the prognostic value of KIRREL in a population-based cohort. Immunohistochemical expression of KIRREL was examined in tissue microarrays with a subset of primary tumours and paired lymph node metastases from an original cohort of 268 incident cases of melanoma in the Malmö Diet and Cancer study. KIRREL mRNA expression was examined in 103 melanoma cases in The Cancer Genome Atlas (TCGA). Membranous/cytoplasmic expression of KIRREL was detected in 158/185 (85.4%) primary tumours and 18/19 (94.7%) metastases. High expression of KIRREL was significantly associated with several unfavourable clinicopathological factors. High KIRREL protein expression was an independent factor of reduced recurrence free and melanoma specific survival, particularly in thin melanomas, even outperforming absolute thickness and ulceration (HR = 30.85; 95% CI 1.54-616.36 and HR = 6.32 95% CI 1.19-33.65). High mRNA levels of KIRREL were not significantly associated with survival in TCGA. In conclusion, KIRREL is not only a novel potential diagnostic marker for melanoma, but may also be a useful prognostic biomarker for improved stratification of patients with thin melanoma. These findings may be of high clinical relevance and therefore merit further validation.

Until recently, randomized controlled trials have not demonstrated convincing evidence that vitamin D, or vitamin D in combination with calcium supplementation could improve bone mineral density (BMD), osteoporosis and fracture. It remains unclear whether vitamin D levels are causally associated with total body BMD. Here, we performed a Mendelian randomization study to investigate the association of vitamin D levels with total body BMD using a large-scale vitamin D genome-wide association study (GWAS) dataset (including 79 366 individuals) and a large-scale total body BMD GWAS dataset (including 66,628 individuals). We selected three Mendelian randomization methods including inverse-variance weighted meta-analysis (IVW), weighted median regression and MR-Egger regression. All these three methods did not show statistically significant association of genetically increased vitamin D levels with total body BMD. Importantly, our findings are consistent with recent randomized clinical trials and Mendelian randomization study. In summary, we provide genetic evidence that increased vitamin D levels could not improve BMD in the general population. Hence, vitamin D supplementation alone may not be associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture.

Background: Bladder cancer is one of the most common malignancies in urologic system. The glucocorticoid-inducible kinase 2 (SGK2) expression and function were largely unknown in cancers. Current study was aimed to investigate the role of SGK2 in bladder cancer and its potential mechanisms. Methods: SGK2 expression was quantified by western blot (WB) in multiple bladder cancer cell lines (T24, 5637, J82 and UMUC3) compared with normal urothelial cell line (SVHUC). SGK2 knocking down and overexpression model were established by lentivirus transfection. MTT, colony formation, wound healing and transwell assay were used to assess the tumor cell proliferation, migration and invasion abilities, respectively. In addition, molecular function analysis was performed using FunRich software V3. Immunoprecipitation (IP) assay was applied to investigate the interaction between SGK2 and β-catenin at protein level. TCGA database was retrieved to verify the association between these genes and clinical tumor stage as well as prognosis among bladder cancer patients. Results: SGK2 expression was significantly upregulated in multiple bladder cancer cell lines compared with SVHUC at protein level. Cell proliferation, migration and invasion abilities were significantly decreased after knocking down SGK2 in J82 and UMUC3 cell lines. Inversely, cell aggressive phenotypes were significantly increased after overexpressing SGK2 in T24 cell line. Furthermore, functional analyses of SGK2 based on TCGA database showed that SGK2 related genes were involved in receptor activity, ATP binding, DNA repair protein, trans-membrane receptor activity and lipid binding. In addition, protein interaction analysis identified c-Myc was significantly enriched in SGK2 positively associated genes. The prediction was validated by WB and IP assay that SGK2 could directly bind with β-catenin at protein level to regulate their downstream gene c-Myc expression in bladder cancer to influence tumor progression. And clinical data generated from TCGA database also identified these downstream genes were significantly associated with tumor stage and survival status of bladder cancer patients. Conclusion: Taken together, our findings suggest SGK2 promotes bladder cancer progression via mediating β-catenin/c-Myc signaling pathway, which may serve as a potential therapeutic target for bladder cancer patients.

Numerous studies have reported the relationship between Long non-coding RNAs (LncRNAs) expression and prognosis of osteosarcoma, but less consensus has been reached. Our meta-analysis was conducted to quantitatively assess the relationship between the expression of LncRNAs, prognosis and clinical pathology in osteosarcoma development.

Long non-coding RNAs (lncRNAs) are a kind of single-stranded RNA of more than 200 nucleotides in length and have no protein-coding function. Amounting studies have indicated that lncRNAs could play a vital role in the initiation and development of cancers, including gastric cancer (GC). Considering the crucial functions of lncRNAs, the identification and exploration of novel lncRNAs in GC is necessary.

Na+/K+-ATPase (NKA) and carbonic anhydrase (CA) are ion transporters that play important roles in osmotic pressure balance in crustaceans. Oriental river prawn (Macrobrachium nipponense) is one of the most economically important shrimps in China. This species can live in freshwater and low-salt water, but the molecular mechanism of salinity regulation is unclear. In this study, full-length cDNAs of M. nipponense α-NKA and CA were obtained by rapid amplification of cDNA ends (RACE)-PCR (GenBank accession numbers MH378774 and MH827971, respectively), and characterised. Full-length cDNAs of Mnα-NKA (3778bp) and MnCA (1407bp) contain open reading frames of 3030bp and 930bp, respectively, encoding polypeptides of 1009 and 930 amino acids. Bioinformatic analysis showed that Mnα-NKA and MnCA harbour the representative features of NKAs and CAs, and share high homology with orthologs in other crustaceans. Quantitative real-time PCR revealed that Mnα-NKA and MnCA were expressed in various tissues, with highest expression in posterior gills and hepatopancreas. Both Mnα-NKA and MnCA were up-regulated in response to salinity acclimation, but expression patterns differed. Our results provide a theoretical basis for the mechanism regulating salinity acclimation in M. nipponense.

Magnolia zenii is a critically endangered species known from only 18 trees that survive on Baohua Mountain in Jiangsu province, China. Little information is available regarding its molecular biology, with no genomic study performed on M. zenii until now. We determined the complete plastid genome of M. zenii and identified microsatellites. Whole sequence alignment and phylogenetic analysis using BI and ML methods were also conducted. The plastome of M. zenii was 160,048 bp long with 39.2% GC content and included a pair of inverted repeats (IRs) of 26,596 bp that separated a large single-copy (LSC) region of 88,098 bp and a small single-copy (SSC) region of 18,757 bp. One hundred thirty genes were identified, of which 79 were protein-coding genes, 37 were transfer RNAs, and eight were ribosomal RNAs. Thirty seven simple sequence repeats (SSRs) were also identified. Comparative analyses of genome structure and sequence data of closely-related species revealed five mutation hotspots, useful for future phylogenetic research. Magnolia zenii was placed as sister to M. biondii with strong support in all analyses. Overall, this study providing M. zenii genomic resources will be beneficial for the evolutionary study and phylogenetic reconstruction of Magnoliaceae.

Activation of Wnt signaling to β-catenin contributes to the development of colorectal cancer (CRC). Expression of tribbles pseudo-kinase 3 (TRIB3) is increased in some colorectal tumors and associated with poor outcome. We investigated whether increased TRIB3 expression promotes stem cell features of CRC cells and tumor progression by interacting with the Wnt signaling pathway.

Imaging and tracking of near-surface three-dimensional volumetric nanoscale dynamic processes of live cells remains a challenging problem. In this paper, we propose a multi-color live-cell near-surface-volume super-resolution microscopy method that combines total internal reflection fluorescence structured illumination microscopy with multi-angle evanescent light illumination. We demonstrate that our approach of multi-angle interference microscopy is perfectly adapted to studying subcellular dynamics of mitochondria and microtubule architectures during cell migration.

G4C14-A4T14 polymorphism of TP73 gene has been reported with a potential association in cancer risks through affected cell homeostasis; however the results were not consistent. We performed a comprehensive meta-analysis to explore the associations between G4C14-A4T14 polymorphism and cancer susceptibility. Extensive retrieve was performed in PubMed, EMBASE, Google Scholar, Web of Science, Wanfang database and CNKI database up to May 20, 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were conducted to evaluate the overall strength of the associations in five genetic models, as well as in subgroup analyses. Q-test, false-positive report probability analysis and trial sequential analysis, Egger's test and Begg's funnel plot were applied to evaluate the robustness of the results. In silico analysis was managed to demonstrate the relationship of TP73 expression correlated with cancer tissues. Finally, 36 case-control studies with a total of 9493 cancer cases and 13,157 healthy controls were enrolled into the meta-analysis. The pooled results present a significantly higher risk of G4C14-A4T14 polymorphism in all the five genetic models, as well as in the subgroups of Caucasian, cervical cancer, colorectal cancer, H-B subgroup and comfort to Hardy-Weinberg equilibrium subgroup. In silico analysis revealed that the expression of TP73 in cervical cancer tissue is higher than it in corresponding normal tissue, as well as in cervical cancer. All in all, TP73 G4C14-A4T14 polymorphism causes an upgrade cancer risk, especially in Caucasian population. G4C14-A4T14 polymorphism might be a potential biomarker for judging the tumorigenesis of cervical cancer and colorectal cancer.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. In this study, we had analysed the copy number variations and heteroplasmic mutations of mitochondria (MT) in 88 HCC individuals. The average copy number of MT genome in normal samples was significantly greater than that in tumor samples. Overall, the number of heteroplasmic mutations in 88 tumor and their matched normal samples were 241 and 173, respectively. There was higher positive ratio of heteroplasmic mutations in tumor samples (86%) than normal samples (73%). Worthwhile mention, ND1 gene harbored greater mutation frequency and more nonsynonymous mutations in tumor samples. Interestingly, 202 tumor-specific heteroplasmic mutations were detected. Moreover, ND1, ND3, ND4, ND5 and ND6 genes had higher ratio of nonsynonymous versus synonymous mutations in tumor-specific heteroplasmic mutations. It might suggest that the disorder of NADH dehydrogenase (complex I) resulted by heteroplasmic mutations may have close relation with tumorigenesis of hepatocellular carcinoma. This study provided theoretical basis for further understanding mechanism of tumorigenesis from the perspective of mitochondrial heteroplasmic mutations.

Diabetic cardiomyopathy, a major cardiac complication, contributes to heart remodelling and heart failure. Our previous study discovered that CCAAT/enhancer-binding protein β (C/EBPβ), a transcription factor that belongs to a family of basic leucine zipper transcription factors, interacts with the angiotensin-converting enzyme 2 (ACE2) promoter sequence in other disease models. Here, we aimed to determine the role of C/EBPβ in diabetes and whether ACE2 expression is regulated by C/EBPβ. A type 1 diabetic mouse model was generated by an intraperitoneal injection of streptozotocin. Diabetic mice were injected with a lentivirus expressing either C/EBPβ or sh-C/EBPβ or treated with valsartan after 12 weeks to observe the effects of C/EBPβ. In vitro, cardiac fibroblasts and cardiomyocytes were treated with high glucose (HG) to investigate the anti-fibrosis, anti-apoptosis and regulatory mechanisms of C/EBPβ. C/EBPβ expression was down-regulated in diabetic mice and HG-induced cardiac neonatal cells. C/EBPβ overexpression significantly attenuated collagen deposition and cardiomyocyte apoptosis by up-regulating ACE2 expression. The molecular mechanism involved the binding of C/EBPβ to the ACE2 promoter sequence. Although valsartan, a classic angiotensin receptor blocker, relieved diabetic complications, the up-regulation of ACE2 expression by C/EBPβ overexpression may exert greater beneficial effects on patients with diabetic cardiomyopathy.

To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD+ and glutathione (GSH) in subjects with high HS Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD+ biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.

Complete transposition of the great arteries (TGA) is the most frequent cyanotic heart defect diagnosed in neonates. However, the exact etiology of TGA is unknown. The aim of the present study was to assess the association of TGA pathogenesis with single nucleotide polymorphisms (SNPs) in DNA methyltransferases (DNMTs)-1 and 3a- in Chinese children. We genotyped 5 SNPs (rs16999593, rs16999358, and rs2228611 in DNMT1; and rs2276599 and rs2276598 in DNMT3A) in 206 patients with complete TGA and 252 healthy children. Statistical analysis was performed to explore the association of the 5 SNPs with complete TGA susceptibility. Compared with the T/T and C/C genotypes, the heterozygous genotype C/T of rs16999593 correlated with a decreased risk for complete TGA under codominant (OR=0.46; 95% CI=0.29-0.72), dominant (OR=0.58; 95% CI=0.38-0.88), and overdominant (OR=0.44; 95% CI=0.28-0.68) models. In contrast, the genotype C/C of rs16999593 correlated with a higher risk for TGA under a recessive model (OR=3.15; 95% CI=1.14-8.68) compared with the T/T and C/T genotypes. Furthermore, the TGC, TGT, CGC, and CGT haplotypes of DNMT1 did not differ significantly between the two groups, whereas the frequency of the TAC haplotype was lower in the case group (OR<1; P=0.002). No significant differences in the frequencies of the TC, CC, TT, and CT haplotypes of DNMT3A were found between the two groups. Furthermore, logistic regression showed that sex and the rs16999358 SNP were two independent risk factors for complete TGA. Overall, the C/T genotype of the rs16999593 SNP in DNMT1 might decrease the risk of complete TGA pathogenesis in the Southern Chinese population.

Thyroid hormones are important for normal reproductive function. Although 3,5,3'-triiodothyronine (T3) enhances follicle-stimulating hormone (FSH)-induced preantral follicle growth and granulosa cells development in vitro, little is known about the molecular mechanisms regulating ovarian development via glucose. In this study, we investigated whether and how T3 combines with FSH to regulate glucose transporter protein (GLUT) expression and glucose uptake in granulosa cells. In this study, we present evidence that T3 and FSH cotreatment significantly increased GLUT-1/GLUT-4 expression, and translocation in cells, as well as glucose uptake. These changes were accompanied by upregulation of nitric oxide (NO) synthase (NOS)3 expression, total NOS and NOS3 activity, and NO content in granulosa cells. Furthermore, we found that activation of the mammalian target of rapamycin (mTOR) and phosphoinositide 3-kinase (PI3K)/Akt pathway is required for the regulation of GLUT expression, translocation, and glucose uptake by hormones. We also found that l-arginine upregulated GLUT-1/GLUT-4 expression and translocation, which were related to increased glucose uptake; however, these responses were significantly blocked by N(G)-nitro-l-arginine methylester. In addition, inhibiting NO production attenuated T3- and FSH-induced GLUT expression, translocation, and glucose uptake in granulosa cells. Our data demonstrate that T3 and FSH cotreatment potentiates cellular glucose uptake via GLUT upregulation and translocation, which are mediated through the activation of the mTOR/PI3K/Akt pathway. Meanwhile, NOS3/NO are also involved in this regulatory system. These findings suggest that GLUT is a mediator of T3- and FSH-induced follicular development.

Cytoplasmic male sterility (CMS) conferred by the cytoplasm from Gossypium harknessii (D2) is an important system for hybrid seed production in Upland cotton (G. hirsutum). The male sterility of CMS-D2 (i.e., A line) can be restored to fertility by a restorer (i.e., R line) carrying the restorer gene Rf1 transferred from the D2 nuclear genome. However, the molecular mechanisms of CMS-D2 and its restoration are poorly understood.

The prognostic value of serum cystatin-C (Cys-C) in renal cell carcinoma (RCC) remains unknown. The purpose of this study is to explore the prognostic value of Cys-C for RCC patients.

To assess the current evidence of effectiveness and safety of single-incision mini-slings (MiniArc) versus transobturator midurethral slings in the management of female stress urinary incontinence (SUI).