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Angiogenesis is vital during pregnancy for remodeling and enhancing vasodilation of maternal uterine arteries, and increasing uterine blood flow. Abnormal angiogenesis is associated with decreased uteroplacental blood flow and development of pregnancy disorders such as gestational hypertension, preeclampsia, fetal growth restriction, preterm delivery, stillbirth, and miscarriage. The mechanisms that contribute to normal angiogenesis remain obscure. Our previous studies demonstrated that expression of the angiotensin type 2 receptor (AT2R) is increased while the angiotensin type 1 receptor (AT1R) is unchanged in the endothelium of uterine arteries, and that AT2R-mediated pregnancy adaptation facilitates enhanced vasodilation and uterine arterial blood flow. However, the role of AT2R in regulating angiogenesis during pregnancy has never been studied. This study examines whether or not AT2R activation induces angiogenesis and, if so, what mechanisms are involved. To this end, we used primary human uterine artery endothelial cells (hUAECs) isolated from pregnant and nonpregnant women undergoing hysterectomy. The present study shows that Compound 21, a selective AT2R agonist, induced proliferation of pregnant-hUAECs, but not nonpregnant-hUAECs, in a concentration-dependent manner, and that this C21-induced mitogenic effect was blocked by PD123319, a selective AT2R antagonist. The mitogenic effects induced by C21 were inhibited by blocking JNK-but not ERK, PI3K, and p38-signaling pathways. In addition, C21 concentration dependently increased cell migration and capillary-like tube formation in pregnant-hUAECs. The membrane-based antibody array showed that C21 increased expression of multiple angiogenic proteins, including EGF, bFGF, leptin, PLGF, IGF-1, and angiopoietins. Our qPCR analysis demonstrates that C21-induced increase in expression of these angiogenic proteins correlates with a proportional increase in mRNA expression, indicating that AT2R activates angiogenic proteins at the transcriptional level. In summary, the present study shows that AT2R activation induces angiogenesis of hUAECs in a pregnancy-specific manner through JNK-mediated pathways with associated transcriptional upregulation of multiple proangiogenic proteins.

Background: Recently, there have been conflicting results reporting an increased risk of AR or MR associated with oral fluoroquinolones (FQs).This study investigated whether the use of FQs increases the risk of mitral regurgitation (MR) or aortic regurgitation (AR). Methods: A retrospective cohort study was conducted by using the Taiwan National Health Insurance research database. A unidirectional case-crossover design without selecting controls from an external population was adopted in this study. A total of 26,650 adult patients with new onset of AR or MR between January 1, 2000, and December 31, 2012, were identified. The risk of outcomes was compared between the hazard period and one of the randomly selected referent periods of the same individuals. Results: Before exclusion of pneumonia diagnosed within 2 months before the index date, patients who took FQs had a significantly greater risk of AR or MR (adjusted odds ratio [aOR] 1.51, 95% confidence interval [CI] 1.30–1.77), any AR (combined AR and MR) (aOR 1.50, 95% CI 1.10–2.04), and any MR (combined AR and MR) (aOR 1.37, 95% CI 1.16–1.62). After exclusion of pneumonia, FQs exposure remained significantly associated with a greater risk of MR (aOR 1.38, 95% CI 1.17–1.62) and any MR (aOR 1.25, 95% CI 1.05–1.48). Conclusions: The findings suggested that patients treated with FQs could be warned about the potential risk for MR even after considering the possibility of protopathic bias. Reducing unnecessary FQs prescriptions may be considered to reduce the risk of valvular heart disease. [ABSTRACT FROM AUTHOR]

Increasing evidences indicate that gut microbiota composition is associated with multiple inflammatory diseases. However, little is known about how gut microbiota changes with age and correlations with gut inflammation at sexual maturity stage of healthy individuals. Elucidating the dynamic changes of gut microbiota in healthy individuals at the sexual maturity stage and correlations with gut inflammation can provide clues for early risk assessment of gut diseases at the sexual maturity stage. Here, the shift in gut bacteria and its relationship with gut inflammation at the sexual maturity stage were explored. Sprague–Dawley rats at the sexual maturity stage were used in this study. 16S rRNA gene sequencing was performed to decipher gut bacteria shifts from the 7th week to the 9th week, and enzyme-linked immunosorbent assay (ELISA) was used to measure gut inflammation and gut barrier permeability. We found an increase in bacterial richness with age and a decrease in bacterial diversity with age. The gut bacteria were primarily dominated by the phyla Firmicutes and Bacteroides and the genus Prevotella. The relative abundance of Firmicutes increased with age, and the relative abundance of Bacteroides decreased with age. There was a positive correlation between body weight and the Firmicutes:Bacteroides ratio. More and more gut microbiota participated in the host gut inflammation and barrier permeability regulation with age. Ruminococcus was the only gut bacteria participated in gut inflammation and barrier permeability regulation both in the 7th week and the 15th week. These results provide a better understanding of the relationship between gut bacteria and gut inflammation in sexually mature rats and show that Ruminococcus may be a potential indicator for early risk assessment of gut inflammation.

BackgroundMore than 11 million people were estimated to be infected by Schistosoma japonicum in China before the 1950s. However, seldom studies have been conducted to evaluate the longitudinal effects of previous schistosome infection (PSI). We aimed to investigate the association between PSI and hyperuricemia in China.MethodsFrom February 2013 to October 2013, 3,517 Chinese subjects (908 persons with PSI and 2,609 persons without PSI) were recruited from a prospective cohort study of "135". After two years, 113 and 462 participants had developed hyperuricemia in the persons with and without PSI, respectively. Multivariable logistic models were used to estimate Relative Ratios (RR) and 95% confidence intervals (CIs) for hyperuricemia.ResultsThe PSI participants had a decreased risk of hyperuricemia compared with those without PSI [adjusted RR (95%CI): 0.73 (0.55, 0.97)]. Within the PSI group, higher level of fasting plasma glucose was significantly associated with the reduced incidence of hyperuricemia in PSI population (RR: 0.40, 95% CI: 0.26-0.63). For females, hypertension, increased levels of serum creatinine and triglycerides were the risk factors for incident hyperuricemia in the PSI group.ConclusionsOur results suggest that PSI is significantly associated with the lower incidence of hyperuricemia. Moreover, elevated fasting plasma glucose might prevent the onset of hyperuricemia in PSI population.

In Arabidopsis, treating shoots with uniconazole can result in enhanced primary root elongation and bolting delay. Uniconazole spraying has become an important cultivation technique in controlling the flowering and improving the fruit-setting of litchi. However, the mechanism by which uniconazole regulates the complicated developmental processes in litchi remains unclear. This study aimed to determine which signal pathways and genes drive the responses of litchi inflorescences to uniconazole treatment. We monitored the transcriptional activity in inflorescences after uniconazole treatment by Illumina sequencing technology. The global expression profiles of uniconazole-treated litchi inflorescences were compared with those of the control, and 4051 differentially expressed genes were isolated. KEGG pathway enrichment analysis indicated that the plant hormone signal transduction pathway served key functions in the flower developmental stage under uniconazole treatment. Basing on the transcriptional analysis of genes involved in flower development, we hypothesized that uniconazole treatment increases the ratio of female flowers by activating the transcription of pistil-related genes. This phenomenon increases opportunities for pollination and fertilization, thereby enhancing the fruit-bearing rate. In addition, uniconazole treatment regulates the expression of unigenes involved in numerous transcription factor families, especially the bHLH and WRKY families. These findings suggest that the uniconazole-induced morphological changes in litchi inflorescences are related to the control of hormone signaling, the regulation of flowering genes, and the expression levels of various transcription factors. This study provides comprehensive inflorescence transcriptome data to elucidate the molecular mechanisms underlying the response of litchi flowers to uniconazole treatment and enumerates possible candidate genes that can be used to guide future research in controlling litchi flowering.

Metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic syndromes (MetS) have been recognized as the important risk factors for asymptomatic intracranial vertebrobasilar stenosis (IVBS). Although fatty liver index (FLI) is significantly related with these diseases, the association between FLI and IVBS remains unclear. In the present study, 2368 participants (30-75 years) were recruited from a Chinese prospective cohort study of PMMJS. Amongst them, 2281 individuals who did not have IVBS at baseline were enrolled in the 6-year following-up study. In cross-sectional analysis based on the baseline characteristics, the results showed that FLI was positively related with IVBS prevalence. Compared to the participants with FLI < 30, the adjusted OR (95% CI) of IVBS was 2.07 (1.18, 3.62) and 2.85 (1.39, 5.18) in the groups of 30 ≤ FLI < 60 and FLI ≥ 60, respectively. In longitudinal analysis, the results showed that the participants with FLI ≥ 60 had an increased risk of asymptomatic IVBS compared to those with FLI < 30 [adjusted HR (95%CI): 1.65 (1.05, 2.60)]. Moreover, exclusion of persons with hypertension, T2DM and MetS did not alter the associations between FLI and asymptomatic IVBS. Therefore, our results suggest that elevated FLI is an independent risk factor for asymptomatic IVBS in Chinese adults.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. While it is well-accepted that inflammation is central to NAFLD pathogenesis, the immune pathway(s) orchestrating disease progression are poorly defined. Notably, IL-17RA signaling, via IL-17A, plays an important role in obesity-driven NAFLD pathogenesis. However, the role of the IL-17F, another IL-17RA ligand, in NAFLD pathogenesis has not been examined. Further, the cell types expressing IL-17RA and producing IL-17RA ligands in the pathogenesis of NAFLD have not been defined. Here, IL-17RA-/-, IL-17A-/-, IL-17F-/- and wild-type (WT) mice were fed either standard chow diet or methionine and choline deficient diet (MCDD)--a diet known to induce steatosis and hepatic inflammation through beta-oxidation dysfunction--and hepatic inflammation and NAFLD progression were subsequently quantified. MCDD feeding augmented hepatic IL-17RA expression and significantly increased hepatic infiltration of macrophages and IL-17A and IL-17F producing CD4+ and CD8+ T cells in WT mice. In contrast, IL-17RA-/-, IL-17A-/-, and IL-17F-/- mice, despite increased steatosis, exhibited significant protection from hepatocellular damage compared to WT controls. Protection from hepatocellular damage correlated with decreased levels of hepatic T-cell and macrophage infiltration and decreased expression of inflammatory mediators associated with NAFLD. In sum, our results indicate that the IL-17 axis also plays a role in a MCDD-induced model of NAFLD pathogenesis. Further, we show for the first time that IL-17F, and not only IL-17A, plays an important role in NAFLD driven inflammation.

Epidemiological studies suggest that higher serum uric acid (sUA) level is significantly associated with nonalcoholic fatty liver disease (NAFLD) development. However, little information is available on the relationships between sUA and NAFLD remission. In the present study, 841 NAFLD males (30-75 years) were recruited from a Chinese prospective cohort study (PMMJS) and followed up for five years. The baseline sUA levels of participants were categorized into four quartiles: 191 μmol/L≤ sUA ≤ 347 μmol/L, 347 μmol/L < sUA ≤ 392 μmol/L, 392 μmol/L < sUA ≤ 441 μmol/L and 441 μmol/L

BackgroundUbiquitination is a post-translation modification where ubiquitin is attached to a substrate. Ubiquitin-conjugating enzymes (E2s) play a major role in the ubiquitin transfer pathway, as well as a variety of functions in plant biological processes. To date, no genome-wide characterization of this gene family has been conducted in maize (Zea mays).Methodology/principal findingsIn the present study, a total of 75 putative ZmUBC genes have been identified and located in the maize genome. Phylogenetic analysis revealed that ZmUBC proteins could be divided into 15 subfamilies, which include 13 ubiquitin-conjugating enzymes (ZmE2s) and two independent ubiquitin-conjugating enzyme variant (UEV) groups. The predicted ZmUBC genes were distributed across 10 chromosomes at different densities. In addition, analysis of exon-intron junctions and sequence motifs in each candidate gene has revealed high levels of conservation within and between phylogenetic groups. Tissue expression analysis indicated that most ZmUBC genes were expressed in at least one of the tissues, indicating that these are involved in various physiological and developmental processes in maize. Moreover, expression profile analyses of ZmUBC genes under different stress treatments (4°C, 20% PEG6000, and 200 mM NaCl) and various expression patterns indicated that these may play crucial roles in the response of plants to stress.ConclusionsGenome-wide identification, chromosome organization, gene structure, evolutionary and expression analyses of ZmUBC genes have facilitated in the characterization of this gene family, as well as determined its potential involvement in growth, development, and stress responses. This study provides valuable information for better understanding the classification and putative functions of the UBC-encoding genes of maize.

Lung cancer is one of the most common types of cancer and causes 1.38 million deaths annually, as of 2008 worldwide. Identifying natural anti-lung cancer agents has become very important. Gambogenic acid (GNA) is one of the active compounds of Gamboge, a traditional medicine that was used as a drastic purgative, emetic, or vermifuge for treating tapeworm. Recently, increasing evidence has indicated that GNA exerts promising anti-tumor effects; however, the underlying mechanism remains unclear. In the present paper, we found that GNA could induce the formation of vacuoles, which was linked with autophagy in A549 and HeLa cells. Further studies revealed that GNA triggers the initiation of autophagy based on the results of MDC staining, AO staining, accumulation of LC3 II, activation of Beclin 1 and phosphorylation of P70S6K. However, degradation of p62 was disrupted and free GFP could not be released in GNA treated cells, which indicated a block in the autophagy flux. Further studies demonstrated that GNA blocks the fusion between autophagosomes and lysosomes by inhibiting acidification in lysosomes. This dysfunctional autophagy plays a pro-death role in GNA-treated cells by activating p53, Bax and cleaved caspase-3 while decreasing Bcl-2. Beclin 1 knockdown greatly decreased GNA-induced cell death and the effects on p53, Bax, cleaved caspase-3 and Bcl-2. Similar results were obtained using a xenograft model. Our findings show, for the first time, that GNA can cause aberrant autophagy to induce cell death and may suggest the potential application of GNA as a tool or viable drug in anticancer therapies.

Atopic dermatitis (AD) is the initial step of the atopic march: the progression from AD to allergic rhinitis and asthma. There is a close association between skin barrier abnormalities and the development of AD and the atopic march. One of cardinal features of AD is that the lesional skin of the majority of AD patients is chronically colonized with Staphylococcus aureus with half isolates producing superantigen enterotoxin B (SEB). Although diverse roles of SEB in the pathogenesis and severity of AD have been recognized, whether SEB contributes to the dermal inflammation that drives lung inflammation and airway hyperresponsiveness (AHR) has not been examined. Here we show a novel role of S. aureus superantigen SEB in augmenting allergen ovalbumin (Ova) induced atopic march through an IL-17A dependent mechanism. When mice epicutaneously (EC) sensitized with allergen Ova, addition of topical SEB led to not only augmented systemic Th2 responses but also a markedly exaggerated systemic Th17/IL-17 immune environment. The ability of SEB in enhancing Th17/IL-17 was mediated through stimulating lymphocytes in spleen and draining lymph nodes to promote IL-6 production. Epicutaneous sensitization of mice with a combination of Ova and SEB significantly enhanced Ova-induced AHR and granulocytic lung inflammation than Ova allergen alone. When IL-17A was deleted genetically, the effects of SEB on augmenting lung inflammation and AHR were markedly diminished. These findings suggest that chronic heavy colonization of enterotoxin producing S. aureus in the skin of patients with atopic dermatitis may have an important role in the development of atopic march via an IL-17A dependent mechanism.

Previous studies of the conditional ablation of TGF-β activated kinase 1 (TAK1) in mice indicate that TAK1 has an obligatory role in the survival and/or development of hematopoietic stem cells, B cells, T cells, hepatocytes, intestinal epithelial cells, keratinocytes, and various tissues, primarily because of these cells' increased apoptotic sensitivity, and have implicated TAK1 as a critical regulator of the NF-κB and stress kinase pathways and thus a key intermediary in cellular survival. Contrary to this understanding of TAK1's role, we report a mouse model in which TAK1 deletion in the myeloid compartment that evoked a clonal myelomonocytic cell expansion, splenomegaly, multi-organ infiltration, genomic instability, and aggressive, fatal myelomonocytic leukemia. Unlike in previous reports, simultaneous deletion of TNF receptor 1 (TNFR1) failed to rescue this severe phenotype. We found that the features of the disease in our mouse model resemble those of human chronic myelomonocytic leukemia (CMML) in its transformation to acute myeloid leukemia (AML). Consequently, we found TAK1 deletion in 13 of 30 AML patients (43%), thus providing direct genetic evidence of TAK1's role in leukemogenesis.

Interleukin-17F (IL-17F), produced by Th17 cells and other immune cells, is a member of IL-17 cytokine family with highest homology to IL-17A. IL-17F has been shown to have multiple functions in inflammatory responses. While IL-17A plays important roles in cancer development, the function of IL-17F in tumorigenesis has not yet been elucidated. In the current study, we found that IL-17F is expressed in normal human colonic epithelial cells, but this expression is greatly decreased in colon cancer tissues. To examine the roles of IL-17F in colon cancer, we have used IL-17F over-expressing colon cancer cell lines and IL-17F-deficient mice. Our data showed decreased tumor growth of IL-17F-transfected HCT116 cells comparing to mock transfectants when transplanted in nude mice. Conversely, there were increased colonic tumor numbers and tumor areas in Il-17f(-/-) mice than those from wild-type controls after colon cancer induction. These results indicate that IL-17F plays an inhibitory role in colon tumorigenesis in vivo. In IL-17F over-expressing tumors, there was no significant change in leukocyte infiltration; instead, we found decreased VEGF levels and CD31(+) cells. While the VEGF levels were increased in the colon tissues of Il-17f(-/-) mice with colon cancer. Together, our findings demonstrate a protective role for IL-17F in colon cancer development, possibly via inhibiting tumor angiogenesis.