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Four new leucine-derived cytochalasans, possessing a 5,6,5,8-ring (1) and a 5,6,11-ring core (2-4), were isolated from a cultivated endophytic fungus Xylaria sp. strain WH2D4 (Xylariaceae). This fungus was isolated from leaves of the neotropical tree species Palicourea elata (Sw.) Borhidi (Rubiaceae) collected in Costa Rica. The chemical structures were determined by employing IR, MS as well as 1D- and 2D-NMR experiments. The stereochemistry at C-15 of compound 4 was determined by quantum calculations. The isolated compounds did not affect germination and growth of Trichoderma reesei and the opportunistic human fungal pathogen T. longibrachiatum.

The cell‐to‐cell transfer of α‐synuclein (α‐Syn) greatly contributes to Parkinson's disease (PD) pathogenesis and underlies the spread of α‐Syn pathology. During this process, extracellular α‐Syn can activate microglia and neuroinflammation, which plays an important role in PD. However, the effect of extracellular α‐Syn on microglia autophagy is poorly understood. In the present study, we reported that extracellular α‐Syn inhibited the autophagy initiation, as indicated by LC3‐II reduction and p62 protein elevation in BV2 and cultured primary microglia. The in vitro findings were verified in microglia‐enriched population isolated from α‐Syn‐overexpressing mice induced by adeno‐associated virus (AAV2/9)‐encoded wildtype human α‐Syn injection into the substantia nigra (SN). Mechanistically, α‐Syn led to microglial autophagic impairment through activating toll‐like receptor 4 (Tlr4) and its downstream p38 and Akt‐mTOR signaling because Tlr4 knockout and inhibition of p38, Akt as well as mTOR prevented α‐Syn‐induced autophagy inhibition. Moreover, inhibition of Akt reversed the mTOR activation but failed to affect p38 phosphorylation triggered by α‐Syn. Functionally, the in vivo evidence showed that lysozyme 2 Cre (Lyz2 cre)‐mediated depletion of autophagy‐related gene 5 (Atg5) in microglia aggravated the neuroinflammation and dopaminergic neuron losses in the SN and exacerbated the locomotor deficit in α‐Syn‐overexpressing mice. Taken together, the results suggest that extracellular α‐Syn, via Tlr4‐dependent p38 and Akt‐mTOR signaling cascades, disrupts microglial autophagy activity which synergistically contributes to neuroinflammation and PD development., Autophagy‐dependent and independent machinery synergistically contribute to hα‐Syn‐caused neuroinflammation in PD. The basal autophagy activity restricts microglia inflammation. Extracellular hα‐Syn interacts with and activates Tlr4, resulting in inflammatory responses, as well as autophagy suppression in microglia via Tlr4‐dependent p38 and Akt/mTOR signaling cascades. This impairs the inhibitory effect of autophagy on inflammation, and thus aggravating hα‐Syn‐induced inflammatory responses.

Colorectal cancer is a common malignancy with the third highest incidence and second highest mortality rate among all cancers in the world. Chemotherapy resistance in colorectal cancer is an essential factor leading to the high mortality rate. The ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) confers multidrug resistance (MDR) to a range of chemotherapeutic agents by decreasing their intracellular content. The development of novel ABCG2 inhibitors has emerged as a tractable strategy to circumvent drug resistance. In this study, an ABCG2-knockout colorectal cancer cell line was established to assist inhibitor screening. Additionally, we found that ataxia-telangiectasia mutated (ATM) kinase inhibitor AZ32 could sensitize ABCG2-overexpressing colorectal cancer cells to ABCG2 substrate chemotherapeutic drugs mitoxantrone and doxorubicin by retaining them inside cells. Western blot assay showed that AZ32 did not alter the expression of ABCG2. Moreover, molecule docking analysis predicted that AZ32 stably located in the transmembrane domain of ABCG2. In conclusion, our result demonstrated that AZ32 could potently reverse ABCG2-mediated MDR in colorectal cancer.

Long non-coding RNAs (lncRNAs) have been reported to be involved in multiple biological processes. However, the roles of lncRNAs in the reproduction of half-smooth tongue sole (Cynoglossus semilaevis) are unclear, especially in the molecular regulatory mechanism driving ovarian development and ovulation. Thus, to explore the mRNA and lncRNA mechanisms regulating reproduction, we collected tongue sole ovaries in three stages for RNA sequencing. In stage IV vs. V, we identified 312 differentially expressed (DE) mRNAs and 58 DE lncRNAs. In stage V vs. VI, we identified 1,059 DE mRNAs and 187 DE lncRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DE mRNAs were enriched in ECM-receptor interaction, oocyte meiosis and steroid hormone biosynthesis pathways. Furthermore, we carried out gene set enrichment analysis (GSEA) to identify potential reproduction related-pathways additionally, such as fatty metabolism and retinol metabolism. Based on enrichment analysis, DE mRNAs with a potential role in reproduction were selected and classified into six categories, including signal transduction, cell growth and death, immune response, metabolism, transport and catabolism, and cell junction. The interactions of DE lncRNAs and mRNAs were predicted according to antisense, cis-, and trans-regulatory mechanisms. We constructed a competing endogenous RNA (ceRNA) network. Several lncRNAs were predicted to regulate genes related to reproduction including cyp17a1, cyp19a1, mmp14, pgr, and hsd17b1. The functional enrichment analysis of these target genes of lncRNAs revealed that they were involved in several signaling pathways, such as the TGF-beta, Wnt signaling, and MAPK signaling pathways and reproduction related-pathways such as the progesterone-mediated oocyte maturation, oocyte meiosis, and GnRH signaling pathway. RT-qPCR analysis showed that two lncRNAs (XR_522278.2 and XR_522171.2) were mainly expressed in the ovary. Dual-fluorescence in situ hybridization experiments showed that both XR_522278.2 and XR_522171.2 colocalized with their target genes cyp17a1 and cyp19a1, respectively, in the follicular cell layer. The results further demonstrated that lncRNAs might be involved in the biological processes by modulating gene expression. Taken together, this study provides lncRNA profiles in the ovary of tongue sole and further insight into the role of lncRNA involvement in regulating reproduction in tongue sole.

The structure of intestinal microbiota of black rockfish Sebastes schlegelii in five early development stages were determined in high throughput sequencing with Illumina MiSeq PE300 system. The relationship between intestinal microbial community and the environmental (including culture water and feed) microbiota and the abundance variation trends of core microbiota were investigated, based on which the source of some core microbiota was analyzed in this study. The results show that Proteobacteria and Firmicutes are the most dominant phyla in guts. At the genus level, there are obvious differences between the artificial breeding fish and wild adults in the intestinal microflora structure. The compositions of dominant genera are similar, although the structure of intestinal microbiota gradually changes with the growth of larvae and juveniles. The core microbiota including Bacillus, Acinetobacter, Pseudomonas, Lactobacillus, Lactococcus, Glaciecola, Vibrio, Pseudoalteromonas, Acidovorax, and Aliivibrio were determined in the analysis of dominant and shared species. Compared with the water, the effect of feed microbiota on the structure of the gut microbial community is more obvious. Moreover, the trends of Bacillus, Acinetobacter, Pseudomonas, Lactobacillus, Lactococcus, and Glaciecola were opposite to Vibrio and Pseudoalteromonas in the gut. The correlation analysis suggested that Acidovorax, Glaciecola, Pseudomonas, Lactobacillus, and Acinetobacter might transited from mainly the parents and/or came from the fertilization process. The relative results may provide a theoretical reference for selecting the native probiotics, and supply the basic data for artificially regulating the intestinal microbiota with probiotic during early developmental stage of black rockfish.

Four unprecedented yellow alkaloids named as taberbovines A-D (1-4) were isolated from stems of Tabernaemontana bovina Lour. Their structures were elucidated by the comprehensive spectroscopic data, computational chemistry, and X-ray crystal diffraction. Alkaloids 1-4 possessed a unique 6/6/5/6/5 ring system and were assigned to monoterpenoid quinolines. Biosynthetically, the isolated alkaloids may be derived from Aspidosperma-type alkaloid by oxidation and rearrangements. Taberbovines A-D exhibited the good inhibitory activities of formation NO in LPS induced RAW264.7 macrophages.

Both gonadotropin-inhibitory hormone (GnIH) and kisspeptin play a critical role in the control of reproduction in vertebrates. However, the spatial–temporal expression patterns and possible roles of these two peptides during development are poorly understood. To this end, we evaluated dynamic expression profiles of lpxrfa, the piscine ortholog of gnih, kisspeptin (kiss2) and their receptor mRNAs during embryogenesis and early larval development in a flatfish, Cynoglossus semilaevis. Quantitative RT-PCR analysis indicated that both ligand (lpxrfa and kiss2) and receptor (lpxrfa-r and kiss2r) mRNAs were detected in unfertilized eggs and during embryogenesis, but with different expression profiles. In addition, lpxrfa-r, kiss2 and kiss2r transcripts increased significantly at 6 days post-hatching (dph), while lpxrfa mRNAs did not vary significantly during all larval development. Taken together, these results of the present study suggest that both LPXRFa and kisspeptin systems could be functional and play differential roles during embryogenesis and early larval development in tongue sole.

Leptin (Lep) is a key factor for the regulation of food intake and energy homeostasis in mammals. To date, a number of studies have provided evidence for the existence of multiple leptin genes in teleosts, but not much information is available in fish regarding the regulation of leptin genes by sex steriods. As a first step, two leptin genes (lepa and lepb) and a leptin receptor (lepr) gene were cloned from the half-smooth tongue sole (Cynoglossus semilaevis), a representative species of the order Pleuronectiformes. The full-length cDNAs of tongue sole lepa and lepb were 1265 bp and 1157 bp in length, encoding for proteins of 160 aa and 158 aa, respectively. The three-dimensional structures modeling of tongue sole LepA and LepB showed strong conservation of tertiary structure with other vertebrates. The full-length cDNA of tongue sole lepr was 4576 bp, encoding a protein of 1133 aa which contained all functionally important domains conserved among vertebrate LepRs. Tissue distribution analysis showed that tongue sole lepa mRNA was highly detectable in the ovary and brain, while lepb mRNA was ubiquitously expressed in various tissues. Notably, the tongue sole lepr mRNA was most abundant in the ovary. Using a primary hepatocyte culture system, we evaluated the effects of sex steroids on lep/lepr gene expression. Both 17β-estradiol (E2) and testosterone (T) inhibited hepatic lepa and lepr mRNAs without affecting lepb mRNA levels. In addition, T also suppressed growth hormone receptor 1 (ghr1), ghr2, and insulin-like growth factor 2 (igf-2) mRNA levels, and stimulated expression of igf-1 gene. On the other hand, none of these four genes were altered by E2. To the best of our knowledge, this is the first description of a direct and differential regulation of lep/lepr gene expression by sex steroids at the hepatocyte level of a flatfish, supporting that individual leptin peptide may possess different biological roles in teleosts.

Background Unlike bone tissue, little progress has been made regarding cartilage regeneration, and many challenges remain. Furthermore, the key roles of cartilage lesion caused by traumas, focal lesion, or articular overstress remain unclear. Traumatic injuries to the meniscus as well as its degeneration are important risk factors for long-term joint dysfunction, degenerative joint lesions, and knee osteoarthritis (OA) a chronic joint disease characterized by degeneration of articular cartilage and hyperosteogeny. Nearly 50% of the individuals with meniscus injuries develop OA over time. Due to the limited inherent self-repair capacity of cartilage lesion, the Biomaterial drug-nanomedicine is considered to be a promising alternative. Therefore, it is important to elucidate the gene potential regeneration mechanisms and discover novel precise medication, which are identified through this study to investigate their function and role in pathogenesis. Methods We downloaded the mRNA microarray statistics GSE117999, involving paired cartilage lesion tissue samples from 12 OA patients and 12 patients from a control group. First, we analyzed these statistics to recognize the differentially expressed genes (DEGs). We then exposed the gene ontology (GO) annotation and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses for these DEGs. Protein-protein interaction (PPI) networks were then constructed, from which we attained eight significant genes after a functional interaction analysis. Finally, we identified a potential nanomedicine attained from this assay set, using a wide range of inhibitor information archived in the Search Tool for the Retrieval of Interacting Genes (STRING) database. Results Sixty-six DEGs were identified with our standards for meaning (adjusted P-value < 0.01, |log2 - FC| ≥1.2). Furthermore, we identified eight hub genes and one potential nanomedicine - Selenocysteine based on these integrative data. Conclusion We identified eight hub genes that could work as prospective biomarkers for the diagnostic and biomaterial drug treatment of cartilage lesion, involving the novel genes CAMP, DEFA3, TOLLIP, HLA-DQA2, SLC38A6, SLC3A1, FAM20A, and ANO8. Meanwhile, these genes were mainly associated with immune response, immune mediator induction, and cell chemotaxis. Significant support is provided for obtaining a series of novel gene targets, and we identify potential mechanisms for cartilage regeneration and final nanomedicine immunotherapy in regenerative medicine.

Telomeres, protective DNA-protein complexes at the end of eukaryotic linear chromosomes, play pivotal roles in the maintenance of genomic stability during cell division. When telomeres are severely shortened, cells stop dividing and die, consequently leading to tissues degeneration. Concretely, replicative senescence and genomic damage are generally accompanied with telomere shortening, which may be a potential contributor in the pathogenesis of neurological disorders. Regardless of occasional negative findings, accelerated telomere erosion is routinely found in neurodegenerative diseases and has been believed to be positively correlated with the severity of neurodegenerative diseases. As considerable knowledge of telomeres and telomerase continues to accumulate, telomerase is increasingly being recognized as a promising therapeutic target for neurodegenerative disease. Until now, strong evidence has accumulated that activated telomerase is responsible for telomere elongation that may be sufficient to prevent "mother cells" from replicative aging, and besides, telomerase activators exhibit remarkable neuroprotective effects through the prolongation of telomere length and the promotion of neuronal survival as well as proliferation. Therefore, a consensus is emerging that the activation of telomerase, promoted by peptides, natural herbal extracts, small molecules compounds and others, represents a novel promising treatment strategy for neurodegenerative diseases.

Introns exist not only in coding sequences (CDSs) but also in untranslated regions (UTRs) of a gene. Recent studies in animals and model plants such as Arabidopsis have revealed that the UTR-introns (UIs) are widely presented in most genomes and involved in regulation of gene expression or RNA stability. In the present study, we identified introns at both 5&prime, UTRs (5UIs) and 3&prime, UTRs (3UIs) of sweet orange genes, investigated their size and nucleotide distribution characteristics, and explored the distribution of cis-elements in the UI sequences. Functional category of genes with predicted UIs were further analyzed using GO, KEGG, and PageMan enrichment. In addition, the organ-dependent splicing and abundance of selected UI-containing genes in root, leaf, and stem were experimentally determined. Totally, we identified 825 UI- and 570 3UI-containing transcripts, corresponding to 617 and 469 genes, respectively. Among them, 74 genes contain both 5UI and 3UI. Nucleotide distribution analysis showed that 5UI distribution is biased at both ends of 5&prime, UTR whiles 3UI distribution is biased close to the start site of 3&prime, UTR. Cis- elements analysis revealed that 5UI and 3UI sequences were rich of promoter-enhancing related elements, indicating that they might function in regulating the expression through them. Function enrichment analysis revealed that genes containing 5UI are significantly enriched in the RNA transport pathway. While, genes containing 3UI are significantly enriched in splicesome. Notably, many pentatricopeptide repeat-containing protein genes and the disease resistance genes were identified to be 3UI-containing. RT-PCR result confirmed the existence of UIs in the eight selected gene transcripts whereas alternative splicing events were found in some of them. Meanwhile, qRT-PCR result showed that UIs were differentially expressed among organs, and significant correlation was found between some genes and their UIs, for example: The expression of VPS28 and its 3UI was significantly negative correlated. This is the first report about the UIs in sweet orange from genome-wide level, which could provide evidence for further understanding of the role of UIs in gene expression regulation.

Human endometrial stem cells (hEnSCs), dental pulp stem cells (hDPSCs) and adipose tissue-derived stem cells (hADSCs) are considered to be the promising candidates for the treatment of pancreas diseases. The prognosis is better with in situ injection of mesenchymal stem cells (MSCs) to the damaged pancreas compared with intravenous injection. However, the clinical application of these cells are limited, due to poor engraftment of transplanted cells after delivery. On the other hand, understanding the role of the biomaterials in cell therapy is essential to promote the therapeutic effects of MSCs. Matrigel, a basement membrane matrix biomaterial, is rich in laminin and collagen IV. The aim of this study is to investigate the difference of biological characteristics of hEnSCs, hDPSCs and hADSCs in vitro and their survival situation with Matrigel post intrapancreatic transplantation in vivo. Our findings showed, firstly, there was no significant difference in morphology and immunophenotype of these MSCs. Secondly, the biological properties, including cell proliferation, the ability of adipogenic and osteogenic differentiation and the mRNA expression levels of pancreas development-related genes, have been showed distinct difference among these MSCs. Thirdly, Matrigel can improve the survival of MSCs in vivo, especially for Matrigel-based hDPSCs and Matrigel-based hEnSCs in pancreas parenchyma of SD rats. These results suggest that hDPSCs and hEnSCs are with the greater inherent therapeutic potential for pancreas diseases compared with hADSCs.

In this study, to understand the role of the insulin-like growth factor (IGF) system in the regulation of early development in yellowtail kingfish (YTK, Seriola lalandi), an economically important marine fish species with a high potential for aquaculture, we first cloned the full-length cDNAs for igf1 and igf2 from the liver. YTK igf1 cDNA was 1946 base pairs (bp) in length with an open reading frame (ORF) of 558 bp encoding preproIGF1 of 185 amino acids (aa). The preproIGF1 consisted of 44 aa for the signal peptide, 68 aa for the mature peptide comprising B, C, A, and D domains, and 73 aa for the E domain. YTK igf2 cDNA had an ORF of 648 bp that encoded a total of 215 aa spanning the signal peptide (47 aa), the mature peptide (70 aa), and the E domain (98 aa). At the protein level, both YTK IGF1 and IGF2 exhibited high sequence identities with their corresponding fish counterparts, respectively. Subsequently, quantitative RT-PCR analysis indicated that the highest level of igf1 mRNA expression was recorded in the gonad and liver, while the igf2 mRNA expression was most abundant in the gill and liver. In addition, both igf1 and igf2 were detected in all stages of embryonic development and exhibited different gene expression patterns, supporting that IGF1 and IGF2 could be functional and play important roles during YTK embryogenesis. Overall, this initial study of IGF1 and IGF2 provides an insight into the endocrine mechanism involved in the early development of yellowtail kingfish.

Three new monoterpene indole alkaloids, 3α-hydroxymethyl-ibogamine (1), 3α-acetatemethoxyl-ibogamine (2), 16α-hydroxyl-ibogamine (3) together with six known alkaloids were isolated from the branches and leaves of Tabernaemontana divaricata (Apocynaceae). The structures of these alkaloids were determined by spectroscopic analyses. All isolated compounds showed no significant cytotoxicity against SGC-7901 gastric cancer, HeLa, and A-549 lung cancer cell lines (IC50 > 20 µM). Graphical Abstract Electronic supplementary material The online version of this article (10.1007/s13659-018-0166-x) contains supplementary material, which is available to authorized users.

Background and aim The association between Helicobacter pylori (H. pylori) and gallbladder diseases is still unclear and is controversial. We conducted a retrospective study to clarify the prevalence of gallbladder diseases and factors related to gallbladder diseases and relationships between H. pylori infection, gallstones, cholecystitis, and cholecystic polypus. Methods The retrospective study was performed at the Aerospace Center Hospital in Beijing. The subjects in this study were a healthy population who underwent health examinations at the hospital between 2012 and 2015. The logistic regression models were used to explore the relationships between H. pylori infection and gallbladder diseases. Results There were 7803 (43.4%) subjects with H. pylori infection, 995 (5.5%) with gallstones, 219 (1.2%) with cholecystitis, and 1003 (5.6%) with cholecystic polypus amongst 17 971 subjects, respectively. In subjects aged 45 years or less, the prevalence of gallstones in the H. pylori (+) group was lower than that in the H. pylori (-) group (odds ratio = 0.653; 95% confidence interval: 0.468-0.911; P = 0.012). The prevalence of cholecystic polypus in the H. pylori (+) group was significantly higher than that in the H. pylori (-) group (odds ratio = 1.160; 95% confidence interval: 1.012-1.328; P = 0.033). Conclusions Helicobacter pylori infection was related with cholecystic polypus and gallstones in a Chinese population.

Gonadotropin-inhibitory hormone (GnIH) has been characterized by its ability to inhibit either basal or gonadotropin-releasing hormone (GnRH)-induced gonadotropin synthesis and release in birds and mammals. However, the physiological role of GnIH on the reproductive axis in fish remains inconclusive, with most studies focusing on the orders Cypriniformes and Perciformes. To gain insight into the role of GnIH in the regulation of reproduction in the order Pleuronectiformes, we first cloned the LPXRFa gene, the piscine ortholog of GnIH, in the half-smooth tongue sole. The full-length cDNA of LPXRFa was 918bp in size with an open reading frame (ORF) of 585bp that encoded a 194 amino acids preprohormone with a calculated molecular mass and isoelectric point of 21.73kDa and 6.52, respectively. The LPXRFa precursor encoded two putative peptide sequences that included -MPMRF or -MPQRF motifs at the C-terminal. Tissue distribution analysis showed that LPXRFa transcripts could be detected at high levels in the brains of both sexes and to a lesser extent in the ovary, heart and stomach of females, while a noteworthy expression was observed in the kidney and muscle of males. Furthermore, the expression patterns of LPXRFa mRNA during ovarian maturation were also investigated. In the brain, the mRNA expression of LPXRFa increased significantly at stage III, declined at stage V and reached a maximum at stage VI. In the pituitary, the levels of LPXRFa mRNA remained stable during ovarian maturation and increased significantly to the top level at stage V and then declined back to basal levels. In contrast, the ovarian LPXRFa mRNA levels declined sharply at stage III and remained depressed over the course of ovarian maturation. Taken together, our results provide further evidence for the existence of LPXRFa in the order Pleuronectiformes and suggest its possible involvement in the regulation of reproduction in the female tongue sole.

Objective This study examined the association between iron status and a set of breast cancer risk factors among U.S. adult women aged 20–80 years. Methods Data from National Health and Nutrition Examination Survey (2017–2018) were used to examine the relation between serum ferritin, serum iron and transferrin saturation with a set of breast cancer risk factors [body mass index (BMI), waist circumference, glycosylated hemoglobin (HbA1c), fasting plasma glucose, insulin and HOMA-IR]. The multivariable linear regressions were used controlling for age, race/ethnicity, menopause status, education level, smoking status, alcohol consumption, physical activity, high-sensitivity C-reactive protein (hsCRP) and total energy intake. Results HbA1c, BMI and waist circumference data were available for 1902 women with a fasting sample (n = 913) for fasting plasma glucose, insulin and HOMA-IR. Transferrin saturation had significant, inverse associations with BMI, waist circumference and HbA1c. The size of difference observed were that participants in the fourth quartile of transferrin saturation had a 4.50 kg/m2 smaller BMI, a 9.36 cm smaller waist circumference and a 0.1 % lower HbA1c level than participants in the first quartile. Similarly, serum iron concentrations were inversely associated with BMI and waist circumference. In addition, serum iron had significant, inverse associations with insulin and HOMA-IR. Sensitivity analyses among men gave similar results. For serum ferritin, there was a trend towards a positive association between waist circumference, HbA1c and fasting plasma glucose with serum ferritin. However, the associations did not reach statistical significance among women. Conclusions Iron status may impact breast cancer risk via effects on adiposity or glucose metabolism. The findings should be confirmed with further prospective data.

Kisspeptin (Kiss) plays a critical role in mediating gonadal steroid feedback to the gonadotropin-releasing hormone (GnRH) neurons in mammals. However, little information regarding the regulation of kisspeptin gene by sex steroids is available in teleosts. In this study, we examined the direct actions of estradiol (E2) and testosterone (T) on hypothalamic expression of kisspeptin and other key factors involved in reproductive function of half-smooth tongue sole. As a first step, a partial-length cDNA of kiss2 was identified from the brain of tongue sole and kiss2 transcript levels were shown to be widely expressed in various tissues, notably in the ovary. Then, the actions of sex steroids on kiss2 and other reproduction-related genes were evaluated using a primary hypothalamus culture system. Our results showed that neither kiss2 nor its receptor kiss2r mRNA levels were significantly altered by sex steroids. Moreover, sex steroids did not modify hypothalamic expression of gonadotropin-inhibitory hormone (gnih) and its receptor gnihr mRNAs, either. However, E2 markedly stimulated both gnrh2 and gnrh3 mRNAs levels. Overall, this study provides insights into the role of sex steroids in the reproductive function of Pleuronectiform teleosts.

Simple Summary CircRNAs: as molecules involved in gene regulation, have become a new research hotspot in the non-coding RNA field. CircRNAs show tissue- or developmental stage-specific patterns of expression and can influence the expression levels of their parental genes. Recent studies have documented the potential biological roles of circRNAs in the growth, development, reproduction and health of humans and animals. Tongue sole (Cynoglossus semilaevis) is a marine flatfish that is an economically important farmed species in China. The commercial aquaculture of tongue sole has developed in the last few years because wild resources have decreased. Reproduction is regulated by brain-pituitary-gonad-liver axis which limits the development of artificial tongue sole culture. However, the roles of circRNAs in the ovarian development and maturation of tongue sole has never been reported. The identification of the potential functions of circRNAs provides a foundation for understanding the genetic mechanisms that regulate oocyte growth and maturation, which will allow the efficiency of tongue sole reproduction to be improved. Moreover, our findings extend the knowledge about a new type of endogenous RNA involved in regulating the ovarian development and maturation of tongue sole. Abstract CircRNAs are novel endogenous non-coding small RNAs involved in the regulation of multiple biological processes. However, little is known regarding circRNAs in ovarian development and maturation of fish. Our study, for the first time, provides the genome-wide overview of the types and relative abundances of circRNAs in tongue sole tissues during three ovarian developmental stages. We detected 6790 circRNAs in the brain, 5712 in the pituitary gland, 4937 in the ovary and 4160 in the liver. Some circRNAs exhibit tissue-specific expression, and qRT-PCR largely confirmed 6 differentially expressed (DE) circRNAs. Gene Ontology and KEGG pathway analyses of DE mRNAs were performed. Some DE circRNA parental genes were closely associated with biological processes in key signalling pathways and may play essential roles in ovarian development and maturation. We found that the selected circRNAs were involved in 10 pathways. RNase R digestion experiment and Sanger sequencing verified that the circRNA had a ring structure and was RNase R resistant. qRT-PCR results largely confirmed differential circRNA expression patterns from the RNA-seq data. These findings indicate that circRNAs are widespread in terms of present in production-related tissues of tongue sole with potentially important regulatory roles in ovarian development and maturation.

Kisspeptin (Kiss) acts as a positive regulator of reproduction by acting on gonadotropes and gonadotropin-releasing hormone (GnRH) neurons. Despite its functional significance, the intricate web of intracellular signal transduction pathways in response to Kiss is still far from being fully understood in teleosts. Accordingly, we investigated the molecular mechanism of Kiss action and its possible interaction with LPXRFa signaling in this study. In vitro functional analysis revealed that synthetic tongue sole Kiss2 decapeptide increased the cAMP responsive element-dependent luciferase (CRE-luc) activity in COS-7 cells transfected with its cognate receptor, while this stimulatory effect was markedly reduced by two inhibitors of the adenylate cyclase (AC)/protein kinase A (PKA) pathway. Similarly, Kiss2 also significantly stimulated serum responsive element-dependent luciferase (SRE-luc) activity, whereas this stimulatory effect was evidently attenuated by two inhibitors of the phospholipase C (PLC)/protein kinase C (PKC) pathway. In addition, LPXRFa-2 suppressed Kiss2-elicited CRE-luc activity in a dose-dependent manner. Taken together, Kiss2 utilizes both AC/PKA and PLC/PKC pathways to exert its functions via its cognate receptor and LPXRFa may antagonize the action of Kiss2 by inhibiting kisspeptin signaling. As far as we know, this study is the first to characterize the half-smooth tongue sole kisspeptin and LPXRFa signaling pathway in COS-7 cells transfected with their cognate receptors and provides novel information on the interaction between LPXRFa system and kisspeptin system in teleosts.

Kisspeptin (Kiss) and its receptor, KissR (previously known as GPR54), play a critical role in the control of reproduction and puberty onset in mammals. Additionally, a number of studies have provided evidence of the existence of multiple Kiss/KissR systems in teleosts, but the physiological relevance and functions of these kisspeptin forms (Kiss1 and Kiss2) still remain to be investigated. To this end, we examined the direct actions of Kiss2 on hypothalamic functions in the half-smooth tongue sole (Cynoglossus semilaevis), a representative species of the order Pleuronectiformes. As a first step, the full-length cDNA for kiss2r was identified and kiss2r transcripts were shown to be widely expressed in various tissues, notably in the brain of tongue sole. Then, the effects of Kiss2 decapeptide on reproduction-related gene expression were evaluated using a primary hypothalamus culture system. Our results showed that neither gnrh2 nor gnrh3 mRNA levels were altered by Kiss2. However, Kiss2 significantly increased the amounts of gnih and kiss2 mRNAs. In contrast, Kiss2 elicited an evident inhibitory effect on both gnihr and kiss2r mRNA levels. To the best of our knowledge, this is the first description of a direct and differential regulation of reproduction-related gene expression by Kiss2 at the hypothalamus level of a teleost fish. Overall, this study provides novel information on the role of Kiss2/Kiss2R system in the reproductive function of teleosts.

Aim To explore the association between Helicobacter pylori (H. pylori) infection and obesity/weight gain in a Chinese population. Methods Our primary outcome was the change in body mass index (BMI). The generalized linear models were used to explore the association between H. pylori infection and the change of BMI, and the logistic regression models were used to explore the association between H. pylori infection and obesity. Results A total of 3039 subjects were recruited and analyzed, of which 12.8% were obese. The prevalence of H. pylori infection was 53.9% (1639/3039) overall and 54.6% (212/388) in the obese subjects. The change of BMI in the H. pylori (+) group was not significantly higher than that in the H. pylori (-) group after adjustment for potential confounding factors [RR = 0.988, 95%CI: 0.924-1.057, P = 0.729]. The prevalence of obesity decreased 1.1% in the H. pylori (+) group and 0.5% in the H. pylori (-) group. The RR of H. pylori infection for obesity was 0.831 (95%CI: 0.577-1.197, P = 0.321) after the adjustment. Conclusion H. pylori infection was not associated with overweight/obesity observed from the retrospective study in this Chinese population.

Although gonadotrophins are major regulators of ovarian function in teleosts and other vertebrates, accumulating evidence indicates that the growth hormone (GH)-insulin-like growth factor (IGF) axis also plays an important role in fish reproduction. As a first step to understand the physiological role of the GH-IGF system in the ovarian development of starry flounder (Platichthys stellatus), the expression profiles of GH and IGF messenger RNAs (mRNAs) and plasma GH, IGF-I, estradiol-17β (E2), and testosterone (T) levels during the ovarian development were investigated. The developmental stages of ovaries were divided into five stages (II, III, IV, V, and VI) by histological analysis. The hepatosomatic index (HSI) and gonadosomatic index (GSI) values increased and peaked at stage IV and stage V, respectively, and then declined at stage VI. Pituitary GH mRNA levels decreased sharply at stage III and raised to top level at stage VI. The hepatic IGF-I mRNA levels ascended to maximum value at stage V and then declined significantly at stage VI. However, the hepatic IGF-II mRNA levels remained stable and increased significantly at stage VI. In contrast, the ovarian IGF-I mRNA levels increased gradually and peaked at stage VI. The ovarian IGF-II mRNA levels were initially stable and increased significantly at stage V until the top level at stage VI. Consistent with the pituitary GH mRNA levels, plasma GH levels reduced sharply at stage III and remained depressed until stage V and then raised remarkably at stage VI. Plasma IGF-I level peaked at stage V and then declined to initial level. Plasma E2 level peaked at stage IV and then dramatically descended to the basal level. Plasma T level peaked at stage V and then declined significantly back to the basal level. Based on statistical analysis, significant positive correlations between hepatic IGF-I mRNA and GSI, ovarian IGF-II mRNA and hepatic IGF-II mRNA, ovarian IGF-I mRNA and ovarian IGF-II mRNA, and plasma IGF-I and plasma T were observed, respectively. These results suggest that the GH-IGF system may be involved in the ovarian development of starry flounder; GH and IGFs appear to play distinct roles in the regulation of the ovarian development in paracrine/autocrine manners. These findings extend our knowledge of the roles of the GH-IGF axis on reproduction regulation in fish.

Naringenin (NR), a flavonoid abundant in citrus fruits has been reported to possess anti-inflammatory properties. The present study aimed to investigate the protective of naringenin in rats after spinal cord injury (SCI) and the underlying mechanisms associated with neuroinflammation. Adult male Sprague-Dawley rats were subjected to laminectomy at T9-T11 and compression with a vascular clip. The spinal cords spanning the injury site about 0.8cm were collected for testing. There were five groups (n=7 in each group): (a) Control group; (b) sham group group; (c) SCI+saline; (d) SCI+NR (50mg/kg, p.o.) group and (e) SCI+NR (100mg/kg, p.o.) group. Different doses of NR (50mg/kg, p.o. and 100mg/kg, p.o.) or saline were administered once daily for 11 consecutive days, from 3days prior to surgery to 7days after surgery. The expression level of miR-223, NLRP3 and IL-1β were measured by RT- qPCR. The accumulation of neutrophils at the site of compression, as evaluated by measuring the tissue myeloperoxidase activity, significantly increased with time following the compression, peaking at 24h post compression. The expression of miR-223 was significant elevated in (b). However, spinal cord myeloperoxidase activity and the expression of miR-223 did not increase in sham-operated animals. NR significantly inhibited a SCI-induced activation of neutrophils through repressed miR-223 in group (d) and (e). There was a better effect in group (e) than group (d). miR-223 is thought to act as a fine-tuner of granulocyte production and the inflammatory response. Our findings suggested that repeated administration of naringenin (100mg/kg, p.o) may provide the protective effect of the spinal cord injury in rats, possibly through inhibiting neuroinflammation.

Gliomas are the most common type of primary brain tumor in adults with a high mortality rate. Low-grade gliomas progress to glioblastoma multiforme (GBM) in the majority of cases, forming secondary GBM (sGBM), followed by rapid fatal clinical outcomes. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1)-MET proto-oncogene receptor tyrosine kinase (MET) (ZM) fusion has been identified as a biomarker for sGBM that is involved in glioma progression, but the mechanism of gliomagenesis and pathology of ZM-negative sGBM has remained to be fully elucidated. A whole-transcriptome signature is thus required to improve the outcome prediction for patients with sGBM without ZM fusion. In the present study, whole-transcriptome sequencing on 42 sGBM samples with or without ZM fusion from the Chinese Glioma Genome Atlas database identified mRNAs with differential expression between patients with and without ZM fusion and the most significant survival-associated genes were identified. A 6-gene signature was identified as a novel prognostic model reflecting survival probability in patients with ZM-negative sGBM. Clinical characteristics in patients with a high or low risk score value were analyzed with the Kaplan-Meier method and a two-sided log-rank test. In addition, ZM-negative sGBM patients with a high risk score exhibited an increase in immune cells, NF-κB-induced pathway activation and a decrease in endothelial cells compared with those with a low risk score. The present study demonstrated the potential use of a next-generation sequencing-based cancer gene signature in patients with ZM-negative sGBM, indicating possible clinical therapeutic strategies for further treatment of such patients.

In order to discover novel anti-inflammatory agents for treatment of arthritis and based on preliminary structure–activity relationships, four series (A–D) of total 90 new pyrazolo[4,3-d]pyrimidine compounds were designed and synthesized. All the compounds have been tested for their anti-inflammatory activities by inhibiting of LPS-induced NO production. A clear structure–activity relationship has been concluded step by step, and finally 3,4,5-trimethoxystyryl-1H-pyrazolo[4,3-d]pyrimidine was found to be the most active scaffold. Among them, compound D27 was discovered as the most potent anti-inflammatory agent (IC50 = 3.17 μM) with low toxicity and strong inhibitory of NO release (IR = 90.4% at 10 μM). This compound also showed potent inhibition of iNOS with IC50 value of 1.12 μM. Preliminary mechanism studies indicated that it could interfere with the stability and formation of active dimeric iNOS. The anti-inflammatory effect of this compound was determined by adjuvant-induced arthritis in rat model. W...

Four new species of the genus Mallinella Strand, 1906, from the natural forests of Malaysia, are described as Mallinella bicanaliculata sp. n. (♂♀), M. calautica sp. n. (♂♀), M. laxa sp. n. (♂♀), and M. obliqua sp. n. (♂♀). The four new species belong to four species groups and were collected from the forest litter in Sabah state by sieving.

Three new species of the genus Zodarion Walckenaer, 1826, from China, are described as Zodarionapertumsp. n. (♂♀, from Xinjiang), Z.planumsp. n. (♂, from Shaanxi), and Z.ovatumsp. n. (♂♀, from Yunnan).

BACKGROUND: There is insufficient research on the correlation between the apparent diffusion coefficient and clinicopathological characteristics of breast cancer patients. The present study is to investigate the correlation between the apparent diffusion coefficient and pathological characteristics of patients with invasive breast cancer. METHODS: From January 2019 to September 2020, 122 cases of invasive breast cancer and 21 cases of benign tumors were retrospectively enrolled. The apparent diffusion coefficient was compared between the two groups, and the correlation between the apparent diffusion coefficient and the pathological characteristics of the patients with invasive breast cancer were analyzed. RESULTS: Compared with the benign tumor group, the apparent diffusion coefficient in the invasive breast cancer group was significantly lower (0.89±0.17 vs. 1.47±0.27 10(−3) mm(2)/s, P=0.000). Using the apparent diffusion coefficient to diagnose patients with invasive breast cancer, the area under receiver operating characteristic (ROC) curve was 0.966±0.021 [95% confidence interval (CI): 0.924–1.000, P=0.000], and the best diagnostic cut-off value was 1.16 (10(−3) mm(2)/s), with sensitivity and specificity of 0.905 and 0.902, respectively. The apparent diffusion coefficient was used to diagnose vascular tumor thrombus in patients with invasive breast cancer. The area under the ROC curve was 0.641±0.068 (95% CI: 0.508–0.774, P=0.047), and the best diagnostic threshold was 0.835 (10(−3) mm(2)/s), with sensitivity and specificity of 0.676 and 0.650, respectively. The apparent diffusion coefficient in patients with high expression of Ki-67 (%) was significantly reduced (0.87±0.17 vs. 1.00±0.16 10(−3) mm(2)/s, P=0.000). The apparent diffusion coefficient was not significantly correlated with age, menopause, lesion size, estrogen receptor, progesterone receptor, or lymph node metastasis in patients with invasive breast cancer (P>0.05). CONCLUSIONS: In patients with invasive breast cancer the apparent diffusion coefficient was significantly reduced. It was able to differentiate invasive breast cancer and vascular tumor thrombus, and was also related to Ki-67 (%) high expression.

A carefully performed phytochemical investigation of the roots of Stemona mairei (Stemonaceae) led to the discovery of six so far undescribed dihydrostilbene dimers maistilbene A–F and four monomers maistilbene G–J. This is the first report of stilbenoids of this plant species and the first report of dimeric dihydrostilbenes from this plant family. The absolute configuration of these compounds was determined by a combination of Mo2(AcO)4-induced ECD spectra and quantum chemical calculation of NMR chemical shift, ECD and spin-spin coupling constants. Maistilbene G could increase the glucose consumption in L6 myotubes, disclosing a new hypoglycemic candidate.

miR-124 targets the androgen receptor (AR) transcript, acting as a tumor suppressor to broadly limit the growth of prostate cancer. In this study, we unraveled the mechanisms through which miR-124 acts in this setting. miR-124 inhibited proliferation of prostate cancer cells in vitro and sensitized them to inhibitors of androgen receptor signaling. Notably, miR-124 could restore the apoptotic response of cells resistant to enzalutamide, a drug approved for the treatment of castration-resistant prostate cancer. We used xenograft models to examine the effects of miR-124 in vivo when complexed with polyethylenimine-derived nanoparticles. Intravenous delivery of miR-124 was sufficient to inhibit tumor growth and to increase tumor cell apoptosis in combination with enzalutamide. Mechanistic investigations revealed that miR-124 directly downregulated AR splice variants AR-V4 and V7 along with EZH2 and Src, oncogenic targets that have been reported to contribute to prostate cancer progression and treatment resistance. Taken together, our results offer a preclinical rationale to evaluate miR-124 for cancer treatment. Cancer Res; 75(24); 5309–17. ©2015 AACR.

Methanogenic crude oil degradation is a significant process in subsurface environments and degradation of crude oil n-alkanes has been well documented. However, little is known about the biodegradability of the resulting heavy oil. In this study, a methanogenic consortium enriched from Shengli oilfield generated 1.3–1.9 mmol CH4/g of heavy oil at a rate of 2.9–8.8 μmol CH4/g of oil/day. Four SARA fractions (saturates, aromatics, resins and asphaltenes) of oils experienced a loss in linear aliphatic structures. n-Alkylcyclohexanes, methyl-n-alkylcyclohexanes, n-alkyldecalins, n-alkylbenzenes, n-alkyltoluenes and n-alkylxylenes with alkyl side chains longer than 14 carbons were degraded over 50% compared to the undegraded oil. In addition, the extent of degradation of these hydrocarbons increased with increasing carbon length. Correspondingly, n-fatty acids and naphthenic acids with 1–3 naphthenic rings accumulated over time. 16S rRNA gene analysis revealed that aceticlastic Methanosarcina and Methanothrix dominated in the archaeal domain, and bacterial members related to Dehalococcoidia and Soehngenia were consistently present in the successive transfer cultures. However, neither assA/masD-like genes nor alkyl-substituted succinate metabolites were detected, indicating an alternative degradation pathway, rather than addition to fumarate. This study provides novel insights into methanogenic degradation of long-chain alkyl substituted hydrocarbons in heavy oil, which also extends our understanding of anaerobic degradation of crude oil in subsurface sedimentary environments.

Two new Zodariidae species, collected from the natural forest of Pakse City, Champasak Province, Laos, are described as Asceua adunca sp. nov. (male, female) and Mallinella renaria sp. nov. (male, female). Asceua torquata (Simon, 1909) and A. piperata Ono, 2004 are newly recorded from Laos, and the male of A. piperata is described and illustrated for the first time.

Gonadotropin-inhibitory hormone (GnIH), a novel hypothalamic neuropeptide, serves as a key player in the regulation of reproduction across vertebrates, acting on the brain and pituitary to modulate reproductive physiology and behavior. However, little information is available in teleosts regarding the intracellular signal transduction pathway in response to GnIH. To this end, we first cloned the gene of LPXRFa (the piscine ortholog of GnIH) receptor in the half-smooth tongue sole ( Cynoglossus semilaevis ), a representative species of the order Pleuronectiformes. The full-length cDNA of LPXRFa receptor was 2201 bp in size with an open reading frame (ORF) of 1365 bp that encoded 454 amino acids. Tissue distribution showed that LPXRFa receptor transcripts could be detected at high levels in the brain, to a lesser extent in the pituitary, and at low levels in the ovary and other peripheral tissues. In vitro functional analysis revealed that putative tongue sole LPXRFa-1 and LPXRFa-2 peptides significantly stimulated serum responsive element-dependent luciferase (SRE-luc) activity in COS-7 cells transfected with the novel receptor, and these stimulatory effects were evidently reduced by two inhibitors of the PLC/PKC pathway. In addition, neither LPXRFa-1 nor LPXRFa-2 altered the cAMP-responsive element (CRE)-luc activity, but only LPXRFa-2 could markedly decrease forskolin-induced CRE-luc activity in COS-7 cells expressing its cognate receptor. Taken together, our results encompass the first study reporting the existence of LPXRFa receptor in the order Pleuronectiformes and provide novel evidence of differential activation of signaling pathways by LPXRFa peptides in fish.

Gerbera (Gerbera jamesonii Bolus) is one of the most popular ornamental flowers and one of the top five cut flowers worldwide. In this study, we presented the complete chloroplast genome of it using BGISEQ-500 sequencing. Its chloroplast genome is 151,898 bp in size, containing a large single copy region (83,518 bp) and a small single copy region (18,244 bp), and a pair of IR regions (25,068 bp). The chloroplast genome contains 113 unique genes, including 80 protein-coding genes, 29 tRNAs, and 4 rRNAs. Phylogenetic maximum likelihood analysis based on chloroplast genomes of Gerbera and other 17 plant species indicated that the relationship between Gerbera and other plant species of family Compositae is not very close and its relationship with Atractylodes lancea is the closest.

The complete mitochondrial genomic sequence of Yellowtail Kingfish Seriola aureovittata was determined in this study. The circular mitogenome contains 16,609 bp, encoding 37 typical animal mitochon...

The role of Helicobacter pylori (H. pylori) infection in haematological system diseases is not well understood. We conducted this retrospective study to explore the association between H. pylori infection and anaemia in the Chinese population. This retrospective study was performed in Aerospace Center Hospital in Beijing. We derived the data from the registration system of the physical population between 2012–2016. Logistic regression models were used to explore the association between H. pylori infection and anaemia. Among 17,791 subjects, there were 7,804 (43.9%) subjects with H. pylori infection and 950 (5.3%) with anaemia. The prevalence of anaemia in the H. pylori (+) group was significantly higher than in the H. pylori (−) group after adjusting for age, sex, marriage, underlying diseases and body mass index. Compared to H. pylori (−), the OR of H. pylori (+) was 1.39 for moderate-to-severe anaemia and 1.05 for mild anaemia. The level of haemoglobin was lower in the H. pylori (+) group than in the H. pylori (−) group. This study indicates that H. pylori infection may be related to anaemia and haemoglobin level in the Chinese population.

The membrane progestin receptor α (mPRα) plays an important role in the regulation of oocyte meiotic maturation in fish. However, the endocrine regulation of multiple spawning in fish with asynchronous ovarian development remains to be determined. We identified four genes (FSHβ, LHβ, CGα and mPRα) that are widely expressed in both the reproductive and non-reproductive tissues of rock bream Oplegnathus fasciatus and examined their expression during ovarian maturation. The level of FSHβ transcripts in the pituitary remained high during vitellogenic stages, when the plasma levels of estradiol-17β reached maximum levels and oocyte development was stimulated. LHβ expression in the pituitary and ovary reached maximum levels during oocyte maturation when the plasma levels of testosterone also reached a maximum. A significant correlation between mPRα transcript levels and the gonadosomatic index was observed during vitellogenesis and final maturation. Brain gonadotropin (FSHβ and LHβ) and mPRα were continuously expressed at different stages of ovarian development. The dynamic and diverse nature of gonadotropins and mPRα gene expression patterns suggests that these genes might jointly regulate ovarian development and maturation through the brain–pituitary–ovary axis in the rock bream endocrine system. J. Exp. Zool. 323A: 430–444, 2015. © 2015 Wiley Periodicals, Inc.

In order to elucidate the possible roles of insulin-like growth factors I and II (IGF-I and IGF-II) in the embryonic development of Platichthys stellatus, their cDNAs were isolated and their spatial expression pattern in adult organs and temporal expression pattern throughout embryonic development were examined by quantitative real-time PCR assay. The IGF-I cDNA sequence was 1,268 bp in length and contained an open reading frame (ORF) of 558 bp, which encoded 185 amino acid residues. With respect to IGF-II, the full-length cDNA was 899 bp in length and contained a 648-bp ORF, which encoded 215 amino acid residues. The amino acid sequences of IGF-I and IGF-II exhibited high identities with their fish counterparts. The highest IGF-I mRNA level was found in the liver for both sexes, whereas the IGF-II gene was most abundantly expressed in female liver and male liver, gill, and brain. The sex-specific and spatial expression patterns of IGF-I and IGF-II mRNAs are thought to be related to the sexually dimorphic growth and development of starry flounder. Both IGF-I and IGF-II mRNAs were detected in unfertilized eggs, which indicated that IGF-I and IGF-II were parentally transmitted. Nineteen embryonic development stages were tested. IGF-I mRNA level remained high from unfertilized eggs to low blastula followed by a significant decrease at early gastrula and then maintained a lower level. In contrast, IGF-II mRNA level was low from unfertilized eggs to high blastula and peaked at low blastula followed by a gradual decrease. Moreover, higher levels of IGF-I mRNA than that of IGF-II were found from unfertilized eggs to high blastula, vice versa from low blastula to newly hatched larva, and the different expression pattern verified the differential roles of IGF-I and IGF-II in starry flounder embryonic development. These results could help in understanding the endocrine mechanism involved in the early development and growth of starry flounder.

Serum urate levels are reported to be significantly lowered in patients with Parkinson's disease (PD) and inversely correlated to the risk and progression of PD. However, the mechanism by which urate affects PD is poorly understood. Here we showed that treatment with uric acid (UA) resulted in an autophagy activity enhancement in PC12 cells in dose- and time-dependent manners, as indicated by LC3-II increase and P62 decrease. Moreover, UA was still able to increase the LC3-II level and the number of LC3 puncta in the presence of Bafilomycin A1, a lysosomal inhibitor. These changes of autophagic markers were preceded by mTOR inhibition and ULK1 activation. Co-treatment with 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO), an mTOR activator, abolished the UA-induced LC3-II increase. More importantly, UA reduced SNCA/α-synuclein accumulation in PC12 cells that overexpress wildtype or A53T mutant SNCA, and this was blocked by Bafilomycin A1 co-treatment. The in vivo study showed that UA administration was able to modulate the levels of autophagy markers, increase the autophagosome/autolysosome formation, and reduce SNCA accumulation in the midbrain of SNCAA53T transgenic mice. Taken together, our findings suggest that UA could induce autophagy activation via an mTOR-dependent signaling and ameliorate SNCA accumulation. This implicates that urate-elevating agent may become a potential strategy for PD therapy.

Macro-autophagy is associated with drug resistance in various cancers and can function as an adaptive response to maintain cell survival under metabolic stresses, including androgen deprivation. Androgen deprivation or treatment with androgen receptor (AR) signaling inhibitor (ARSI), Enzalutamide (MDV-3100, ENZA) or bicalutamide induced autophagy in androgen-dependent and in castration-resistant CaP (castration-resistant prostate cancer (CRPC)) cell lines. The autophagic cascade triggered by AR blockage, correlated with the increased light chain 3-II/I ratio and ATG-5 expression. Autophagy was observed in a subpopulation of C4-2B cells that developed insensitivity to ENZA after sustained exposure in culture. Using flow cytometry and clonogenic assays, we showed that inhibiting autophagy with clomipramine (CMI), chloroquine or metformin increased apoptosis and significantly impaired cell viability. This autophagic process was mediated by AMP-dependent protein kinase (AMPK) activation and the suppression of mammalian target of rapamycin (mTOR) through Raptor phosphorylation (Serine 792). Furthermore, small interfering RNA targeting AMPK significantly inhibited autophagy and promoted cell death in CaP cells acutely or chronically exposed to ENZA or androgen deprivation, suggesting that autophagy is an important survival mechanism in CRPC. Lastly, in vivo studies with mice orthotopically implanted with ENZA-resistant cells demonstrated that the combination of ENZA and autophagy modulators, CMI or metformin significantly reduced tumor growth when compared with control groups (P

Summary Shiitake mushroom (Lentinula edodes) caps were puffed using pulsed microwave-vacuum puffing (PMVP), microwave-vacuum puffing (MVP) and microwave puffing (MP). The response surface method was used to optimise the process parameters for using PMVP to puff mushroom caps. The experiments were conducted using a central composite design to determine the visual appearance and initial moisture content (30–50%) of the mushroom caps. The initial moisture content and microwave power intensity showed highly significant linear relations with the expansion ratio and sensory evaluation. The optimal conditions for puffing mushroom caps were initial moisture content, microwave intensity, vacuum pressure and pulse ratio of 35%, 40 W g−1, 77.5 ± 1.5 kPa and 1.35, which resulted in an optimal expansion ratio and sensory score of 163.2% and 6.83, respectively. The caps puffed using PMVP showed better textures, sensory scores and microstructures than those puffed using either MP or MVP.

Background Results of the published reports on the relationship between glutathione S-transferase P1 (GSTP1) gene polymorphism and the adenocarcinomas of lung cancer are still debated. Objective This meta-analysis was performed to evaluate the association between GSTP1 A/G gene polymorphism and the risk of adenocarcinomas of lung cancer. Methods The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. Results 16 reports were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and the risk of adenocarcinomas of lung cancer. The G allele and GG genotype were not associated with the susceptibility of risk of adenocarcinomas. Furthermore, in the sensitivity analysis, the results were similar with those from the non-sensitivity analysis. Conclusions GSTP1 G allele or GG genotype is not a biomarker to be associated with the susceptibility of adenocarcinomas of lung cancer.