Lactobacillus rhamnosus GG ameliorates hyperuricemia in a novel model.

Hyperuricemia (HUA) is a metabolic syndrome caused by abnormal purine metabolism. Although recent studies have noted a relationship between the gut microbiota and gout, whether the microbiota could ameliorate HUA-associated systemic purine metabolism remains unclear. In this study, we constructed a novel model of HUA in geese and investigated the mechanism by which Lactobacillus rhamnosus GG (LGG) could have beneficial effects on HUA. The administration of antibiotics and fecal microbiota transplantation (FMT) experiments were used in this HUA goose model. The effects of LGG and its metabolites on HUA were evaluated in vivo and in vitro. Heterogeneous expression and gene knockout of LGG revealed the mechanism of LGG. Multi-omics analysis revealed that the Lactobacillus genus is associated with changes in purine metabolism in HUA. This study showed that LGG and its metabolites could alleviate HUA through the gut-liver-kidney axis. Whole-genome analysis, heterogeneous expression, and gene knockout of LGG enzymes ABC-type multidrug transport system (ABCT), inosine-uridine nucleoside N-ribohydrolase (iunH), and xanthine permease (pbuX) demonstrated the function of nucleoside degradation in LGG. Multi-omics and a correlation analysis in HUA patients and this goose model revealed that a serum proline deficiency, as well as changes in Collinsella and Lactobacillus, may be associated with the occurrence of HUA. Our findings demonstrated the potential of a goose model of diet-induced HUA, and LGG and proline could be promising therapies for HUA.

Anti-Oxidative and Anti-Aging Effects of Probiotic Fermented Ginseng by Modulating Gut Microbiota and Metabolites in Caenorhabditis elegans.

Antioxidative and antiaging abilities of probiotic fermented ginseng (PG) were evaluated in Caenorhabditis elegans (C. elegans). Lifespan and effect on heat stress and acute oxidative stress in C. elegans were significantly enhanced by PG. Antioxidative enzymes such as T-SOD, GSH-PX, CAT were significantly up-regulated, and MDA, ROS and apoptosis levels were significantly down-regulated. At the same time, PG exerted antioxidant and anti-aging activities by reducing the expression of DAF-2 mRNA and increasing the expression of SKN-1 and SOD-3 mRNA in C. elegans. In addition, the mechanism of antioxidative and antiaging activities of PG was explored through gut microbiota sequencing and untargeted metabolomics. The results of gut microbiota indicated that PG could significantly improve the composition and structure of microbes in the gut of C. elegans, and the relative abundance of beneficial bacteria was up-regulated. Untargeted metabolomic results elucidated that PG modulated antioxidant and antiaging activities through neuroactive ligand-receptor interaction, Citrate cycle (TCA cycle), pyruvate metabolism, ascorbate and aldarate metabolism and D-Arginine and D-ornithine metabolism of C. elegans. These results indicated that PG had excellent antioxidant and anti-aging activities, providing research value for the development of functional foods and improvement of aging-related diseases.

Myricetin slows liquid-liquid phase separation of Tau and activates ATG5-dependent autophagy to suppress Tau toxicity.

Intraneuronal neurofibrillary tangles composed of Tau aggregates have been widely accepted as an important pathological hallmark of Alzheimer's disease. A current therapeutic avenue for treating Alzheimer's disease is aimed at inhibiting Tau accumulation with small molecules such as natural flavonoids. Liquid-liquid phase separation (LLPS) of Tau can lead to its aggregation, and Tau aggregates can then be degraded by autophagy. However, it is unclear whether natural flavonoids modulate the formation of phase-separated Tau droplets or promote autophagy and Tau clearance. Here, using confocal microscopy and fluorescence recovery after photobleaching assays, we report that a natural antioxidant flavonoid compound myricetin slows LLPS of full-length human Tau, shifting the equilibrium phase boundary to a higher protein concentration. This natural flavonoid also significantly inhibits pathological phosphorylation and abnormal aggregation of Tau in neuronal cells and blocks mitochondrial damage and apoptosis induced by Tau aggregation. Importantly, using coimmunoprecipitation and Western blotting, we show that treatment of cells with myricetin stabilizes the interaction between Tau and autophagy-related protein 5 (ATG5) to promote clearance of phosphorylated Tau to indirectly limit its aggregation. Consistently, this natural flavonoid inhibits mTOR pathway, activates ATG5-dependent Tau autophagy, and almost completely suppresses Tau toxicity in neuronal cells. Collectively, these results demonstrate how LLPS and abnormal aggregation of Tau are inhibited by natural flavonoids, bridging the gap between Tau LLPS and aggregation in neuronal cells, and also establish that myricetin could act as an ATG5-dependent autophagic activator to ameliorate the pathogenesis of Alzheimer's disease.

Gene expression profiling of ovary identified eggshell proteins regulated by 20-hydroxyecdysone in Bactrocera dorsalis.

The oriental fruit fly, Bactrocera dorsalis, is one of the most destructive pests worldwide. The frequent use of chemical insecticides has led B. dorsalis to develop resistance to many insecticides in recent decades. New high-throughput-sequenced transcriptomes, as well as genomes, have revealed a large number of reference genes for functional target identification. Here, we performed digital gene expression profiling of ovary and testis of B. dorsalis adults. Various genes were identified to be highly expressed in B. dorsalis ovary. The genes encoding components of eggshell, vitelline membrane proteins (Vmps) and chorion-related proteins, were identified to be tissue-specifically expressed in ovary. Five cytochrome P450 genes were also identified to be highly expressed in ovary. Three of them were ecdysone synthesis pathway genes indicating the ovary as a potential synthesis site of female. The up-regulated expression of Vmps by exogenous 20-hydroxyecdysone implied the hormonal regulation of eggshell formation during ovarian development. Many other genes with potential functions in ovarian development were also identified, including vitellogenin receptor, insulin receptor, NASP protein, and odorant binding protein. These findings should promote our understanding of the regulation of vitellogenesis and eggshell formation and enable exploration of potentially novel pest control targets.

Comparison of the Oral Absorption, Distribution, Excretion, and Bioavailability of Zinc Sulfate, Zinc Gluconate, and Zinc-Enriched Yeast in Rats.

SCOPE: The oral absorption, distribution, excretion, and bioavailability of zinc sulfate (ZnS), zinc gluconate (ZnG), and zinc-enriched yeast (ZnY) in rats are fully and systemically compared for the first time. METHODS AND RESULTS: After zinc compounds were orally administered to rats at a single dose of 4 mg Zn kg-1 , blood, tissues, urine, and feces at different time points were collected for the quantification of zinc concentration. Blood was also harvested for the zinc assay in the multiple-dose administration. Plasma zinc levels among three zinc compounds showed no difference, and zinc was widely distributed in various tissues with the level sequence of bone > liver > pancreas > testes. The net Zn balance was 2.993, 5.125, and 7.482% for ZnS, ZnG, and ZnY, respectively. CONCLUSION: ZnS, ZnG, and ZnY show equivalent bioavailability based on plasma and tissues zinc levels, although ZnY was statistically more absorbed and retained than ZnS and ZnG based on the excretion amount.

Comparative Effectiveness of Prophylactic Strategies for Perinatal Transmission of Hepatitis B Virus: A Network Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Perinatal transmission is the main route of hepatitis B virus (HBV) transmission. While several measures have been attempted as means of preventing perinatal HBV transmission, the optimal strategy remains inconclusive. METHODS: We conducted a comprehensive search, through December 2016, for randomized controlled trials (RCTs) that compared the following measures among pregnant women with HBV infection: placebo/none, active immunoprophylaxis (hepatitis B vaccine series starting at birth [HBVac]), passive-active immunoprophylaxis (hepatitis B immunoglobulin and vaccine [HBIG+HBVac]), prenatal HBIG administration (HBIG/HBIG+HBVac), and prenatal antiviral therapy (AVT/HBIG+HBVac). Direct, indirect, and network meta-analyses were performed for all treatment comparisons. RESULTS: Fifteen RCTs involving 2706 infants of HBV carrier mothers were eligible for analysis. Network meta-analysis demonstrated similar results as direct and indirect comparisons. HBVac alone significantly reduced the risk of hepatitis B infection in infants of HBV carrier mothers (relative risk [RR], 0.32; 95% confidence interval [CI], 0.21-0.50). The combination of immunoglobulin with vaccine is superior to vaccine alone (RR, 0.37; 95% CI, 0.20-0.67). Prenatal HBIG administration and antiviral therapy offer further advantages over current passive-active immunoprophylaxis for infants of highly viremic (HBV DNA level higher than 2 × 105 IU/mL) mothers (RR, 0.47; 95% CI, 0.29-0.75; and RR, 0.31; 95% CI, 0.10-0.99, respectively). There was no significant publication bias. CONCLUSIONS: Based on the universal infantile vaccination program, HBIG for infants born to HBV carrier mothers further reduces transmission. For highly viremic mothers whose children are still at risk for transmission under current immunoprophylaxis, prenatal HBIG administration or antiviral therapy in late pregnancy may be considered if more long-term evidence supports its efficacy and safety.

Clinical course and perinatal transmission of chronic hepatitis B during pregnancy: A real-world prospective cohort study.

OBJECTIVE: To determine the clinical course and perinatal transmission of chronic hepatitis B during pregnancy in a real life setting. METHODS: A total of 221 singleton pregnant women with detectable HBV-DNA levels (≥103 copies/mL) were enrolled during January 2011 to June 2015. Forty-three high viraemic patients (≥106 copies/mL) received telbivudine in the 2nd or 3rd trimester according to their intention, while 89 high viraemic and 79 low viraemic (≥103 and <106 copies/mL) patients were the control cohorts. Primary endpoint was the pregnancy outcomes and secondary endpoint the perinatal transmission including intrauterine infection, immunoprophylaxis failure and occult infection. RESULTS: In all, 209 patients completed pregnancy with 209 infants, while 2 in telbivudine-treated cohort had unexplained late stillbirths. Twenty-nine (70.7%) of telbivudine-treated patients and 3 (3.4%) of untreated high viraemic controls achieved undetectable HBV-DNA levels prior delivery. At 7 months postpartum, immunoprophylaxis failure was significantly lower (2.4%) in telbivudine-treated cohort, compared with 16.9% and 10.1% in untreated high and low viraemic cohorts, respectively. CONCLUSIONS: Low viraemic patients may also need antiviral therapy since they bear moderate risk for perinatal transmission of HBV. However, more multicenter, large-scale studies are required before antepartum antiviral therapy is routinely recommended in patients with detectable viral loads.

Association of chronic hepatitis B virus infection with preterm birth: our experience and meta-analysis.

OBJECTIVES: To assess the association of chronic hepatitis B virus (HBV) infection with preterm birth (PTB). METHODS: A cohort of 20,498 pregnant women (497 HBV carriers with 20,001 non-HBV controls) with normal alanine aminotransferase (ALT) levels was selected from the Obstetrics & Gynecology Hospital of Nantong University. The clinical parameters and PTB incidence were compared between HBV carriers and non-HBV subjects. For the meta-analysis, we searched the PubMed, Ovid and Cochrane Library databases for studies comparing PTB incidence between individuals with chronic HBV infection and non-HBV subjects. RESULTS: HBV carriers were slightly older and had slightly higher ALT levels within normal limits. The body mass index, education and history of pregnancy between HBV carrier and non-HBV groups were comparable. PTB incidence was not associated with HBV carrier status [relative risk (RR) 0.98, 95% confidence interval (CI) 0.71-1.37] in our cohort. However, the meta-analysis involving eight published studies and our study revealed a significant association between chronic HBV infection and PTB incidence (pooled RR 1.26, 95% CI 1.19-1.33). CONCLUSION: While maternal HBV carriers did not have a higher incidence of PTB in our cohort, the meta-analysis indicates that individuals with chronic HBV infection appeared to be at risk of PTB as a whole.

Prognostic Implications of Antibodies to Soluble Liver Antigen in Autoimmune Hepatitis: A PRISMA-Compliant Meta-Analysis.

Prognostic evaluation is important for the management of patients with autoimmune hepatitis (AIH). Although some autoantibodies have been associated with disease activity and outcomes, the implication of antibodies to soluble liver antigen (anti-SLA) remains controversial. To conduct a meta-analysis of observational studies which addressed differences in clinical characteristics by anti-SLA status in patients with AIH. Three databases PUBMED, EMBASE, and OVID were systemically searched up to January 2015 using the terms "soluble liver antigen" or "liver-pancreas antigen" and "autoimmune hepatitis" with restriction to English-language. Studies were included if at least 50 patients with objective diagnosis of AIH were enrolled, anti-SLA detection was performed for the patients, and prognostic outcomes and/or disease severity were reported. Two investigators independently reviewed retrieved literature and evaluated eligibility. Discrepancy was resolved by discussion and a third investigator. Quality of included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale (NOS). Data were pooled using fixed-effect or random-effect models. Prognostic outcomes included death from hepatic failure or requirement for liver transplantation, and responses to immunosuppressive therapy regarding remission or relapse. Results were combined on the odds ratio (OR) or standardized mean difference (SMD) scales. Eight studies were enrolled in this study, involving a total of 1297 AIH patients among whom 195 with anti-SLA. Pooled serum AST levels tended to be lower in anti-SLA seropositive patients. The presence of anti-SLA conferred 3.1-fold increased risk of hepatic death in AIH patients. The remission rates were comparable between anti-SLA seropositive and seronegative AIH patients, while anti-SLA positivity was associated with nearly 2-fold increased risk of relapse after drug withdrawal. Human leukocyte antigen (HLA) allotype DR3 was positively associated with anti-SLA. Antibodies to SLA may be an indicator of increased risks of hepatic death and treatment relapse for AIH patients. Our findings suggest that the anti-SLA seropositive patients should be maintained indefinitely on individually adjusted medication to improve their prognosis.

A functional variant in microRNA-196a2 is associated with susceptibility of colorectal cancer in a Chinese population.

BACKGROUND AND AIMS: MicroRNAs (miRNA) can act as oncogenes or tumor suppressors. Polymorphisms present in pri-, pre- and mature miRNAs can potentially modulate the expression of hundreds of genes, broadly affecting miRNA function. Notably, the rs11614913 SNP in miR-196a2 has been implicated in carcinogenesis, but its association with colorectal cancer (CRC) remains unexplored. We performed a case-control study to investigate the genetic association between this functional SNP and CRC susceptibility and progression. METHODS: We genotyped the rs11614913 SNP in 252 CRC patients and 543 healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In addition, we examined miR-196a expression level in colorectal cancer tissues (n = 50) obtained from the studied CRC patients. RESULTS: Frequency of the CC genotype was higher in CRC patients than controls, implying that the subjects with the CC genotype or C allele containing genotypes (CT and CC) have a higher risk of CRC. However, no significant association between this polymorphism and CRC progression was observed. Expression analysis revealed that rs11614913 CC or carrying at least one C allele was associated with a significantly increased level of mature miR-196a (p = 0.010 or = 0.022). CONCLUSIONS: The present study provides the first evidence that miR-196a2 polymorphism may contribute to CRC susceptibility in a Chinese population through modulating mature miR-196a expression.

Pharmacological inhibition of AKT sensitizes MCF-7 human breast cancer-initiating cells to radiation.

BACKGROUND: Caner-initiating cells (CICs or cancer stem cells) have been shown both experimentally and clinically to be resistant to radiation. The mechanism underlying radioresistance remains unclear. METHODS: In the present study, we screened 51 genes which are potentially important in mediating radioresistance of breast CICs. RESULTS: The expression of AKT1 and AKT2 at protein and mRNA levels was dramatically increased among the screened genes by 8 Gy radiation treatment in MCF-7 mammosphere cells (predominantly CD24(-/low)/CD44(+) CICs), but not in the bulk population of MCF-7 cells (predominantly CD24(+)/CD44(+)). Using apoptosis and clonogenic survival assays, we found pharmacological inhibition of AKT with selective inhibitors of AKT sensitized MCF-7 mammosphere cells, but not MCF-7 monolayer cells to radiation. CONCLUSION: The present findings suggest that treatment with AKT inhibitors prior to ionizing radiation treatment may be a potential benefit to patients with breast cancer, in particular to eradiate breast CICs.

STAT1 promotes radioresistance of CD44(+)/CD24(-/low) cells in breast cancer.

Breast cancer-initiating cells are a relatively radioresistant subpopulation of breast cancer cells. However, the mechanism of this radioresistance is still unclear. This study aimed to investigate the effect of radiation on the levels of signal transducer and activator of transcription 1 (STAT1) in mammospheres of cancer-initiating cells and monolayer cultures of MCF-7 cells. We isolated CD44(+)/CD24(-/low) cancer-initiating cells from MCF-7 cells and propagated them as mammospheres. Next we used realtime quantitative reverse-transcriptase polymerase chain reaction to examine the mRNA level of STAT1 in mammospheres of breast cancer-initiating cells and monolayer cultures of MCF-7 cells. The apoptosis rate and surviving fraction using clonogenic assays was observed after treating the cells with a STAT1 inhibitor. After irradiation, the STAT1 level in the mammospheres was higher than that in the monolayer cultures. STAT1 inhibitor treatment did not cause significant changes in the apoptosis rate and surviving fraction in the MCF-7 monolayer cultures. However, the inhibitor treatment caused significant differences in the apoptosis rate and surviving fraction in mammospheres. Our study provides the first evidence that STAT1 signaling contributes to radioresistance in breast cancer-initiating cells and reveals STAT1 as a promising target to reduce radioresistance and enhance the efficacy of radiotherapy for breast cancer.

[Effects of radiosensitivity and X-ray dose on miR-7 expression in nasopharyngeal carcinoma].

OBJECTIVE: To investigate the effects of radiosensitivity and X-ray dose on the expression of miR-7 in nasopharyngeal carcinoma (NPC) cells. METHODS: Low radiosensitive NPC cells CNE-1 and high radiosensitive NPC cells CNE-2 were exposed to 0, 2 and 8 Gy X-ray. The total RNAs of the cell lines were extracted 10 h after radiation for reverse transcription of miR-7 and 18S rRNA by stem-loop primer and random hexamers, respectively. The non-irradiated CNE-1 cells served as the control sample and the relative quantity of the expression level was calculated after real-time PCR using SyBR green. RESULTS: miR-7 expression differed significantly between CNE-1 and CNE-2 cells (4.49-/+3.62 vs 1.29-/+1.10, F=135.483, P<0.001). The radiation dose also significantly affected the expression of miR-7 in NPC cells (F=39.565, P<0.001). CNE-1 cells with a 2 Gy exposure had the highest expression level of miR-7, while the non-irradiated CNE-1 cells had the lowest expression. CNE-2 cells exposed to 2 Gy X-ray had the lowest expression level of miR-7 and the non-irradiated CNE-2 cells had the highest. CONCLUSION: Radiosensitivity and radiation dose of X-ray have significant effect on the expression of miR-7 in NPC cells, indicating that miR-7 plays an important role in radioresistance of NPC cells to X-ray, and suppressed miR-7 expression may elevate the radiosensitivity of NPC cells.

[Ginsenoside Rg1 protects rat hippocampal neurons from radiation injury by regulating NOS activity].

OBJECTIVE: To study the protective effect of ginsenoside Rg1 on cultured rat hippocampal neurons against radiation injury and explore new therapies for preventing radiation encephalopathy. METHODS: Rat hippocampal neurons cultured for 12 days were subjected to a single-dose X-ray exposure of 30 Gy. 4',6-diamidino-2-phenylindole (DAPI) staining was used to detect the neuronal apoptosis and NOS activity kit utilized to evaluate NOS activity in the cells after the exposure. RESULTS: Nuclear condensation was detected in (25.3-/+3.57)% of the neurons 24 h after 30 Gy X-ray exposure, a rate significantly higher than that in the control cells [(1.95-/+0.78)%, P<0.01]. In the neurons pretreated with ginsenoside Rg1, only (7.43-/+1.51)% of the cells presented with nuclear condensation after the exposure, significantly different from the rates in the control cultures and the exposed cultures (P<0.01). The NOS activity of exposed cultures was 6.46-/+0.95 U/ml, significantly higher than that in the control cultures (3.20-/+0.70 U/ml, P<0.01). The NOS activity of the neurons pretreated with ginsenoside Rg1 was 3.85-/+0.69 U/ml, significantly different from that in the control cultures (P<0.05) and the exposed cultures (P<0.01). CONCLUSION: Ginsenoside Rg1 offers significant protective effect on rat hippocampal neurons from radiation-induced apoptosis by reducing the activity of NOS.