Hippo pathway monomerizes STAT3 to regulate prostate cancer growth.

Prostate cancer ranks among the most commonly diagnosed malignancies for men and has become a non-negligible threat for public health. Interplay between inflammatory factors and cancer cells renders inflammatory tissue environment as a predisposing condition for cancer development. The Hippo pathway is a conserved signaling pathway across multiple species during evolution that regulates tissue homeostasis and organ development. Nevertheless, whether Hippo pathway regulates cancer-related inflammatory factors remains elusive. Here, we show that high cell density-mediated activation of the Hippo pathway blunts STAT3 activity in prostate cancer cells. Hippo pathway component MST2 kinase phosphorylates STAT3 at T622, which is located in the SH2 domain of STAT3. This phosphorylation blocks the SH2 domain in one STAT3 molecule to bind with the phosphorylated Y705 site in another STAT3 molecule, which further counteracts IL6-induced STAT3 dimerization and activation. Expression of a nonphosphorylatable STAT3 T622A mutant enhances STAT3 activity and IL6 expression at high cell density and promotes tumor growth in a mice xenograft model. Our findings demonstrate that STAT3 is a novel phosphorylation substrate for MST2 and thereby highlight a regulatory cascade underlying the crosstalk between inflammation and the Hippo pathway in prostate cancer cells.

Lipid-soluble green tea extract: Genotoxicity and subchronic toxicity studies.

To assess the potential safety of lipid soluble green tea extract, also referred to as lipid soluble tea polyphenols (LSTP), a series of genotoxicity tests were conducted, including an Ames, in vivo mouse micronucleus, and in vivo mouse sperm abnormality test. The toxicity of LSTP was evaluated in 90- and 30-day feeding studies. LSTP did not show mutagenic activity in the Ames test and no genotoxic potential in the in vivo assays at doses up to 10 g/kg body weight (bw). In the 90-day feeding study, LSTP was given in the diet at levels providing 0, 0.125, 0.25, or 0.50 g/kg bw/day. No significant effects were noted on body weight, food consumption, hematology, clinical chemistry, organ weights, and histopathological examination. The no-observed-adverse-effect level (NOAEL) was therefore considered to be 0.50 g/kg bw/day, the highest dose tested. Likewise, dosing of SD rats by gavage for 30 days also showed no adverse effects of growth, hematology, clinical chemistry, organ weights, or histopathology at doses of 0.58, 1.17, and 2.33 g/kg bw/day. The NOAEL in the 30-day study was considered to be the highest dose tested. These data provide evidence to support the safe use of LSTP in food.

[Association of leptin gene-2548 G/A polymorphism with obesity: a meta-analysis].

OBJECTIVE: To examine the association between a common single nucleotide polymorphism identified in the 5' untranslated region of leptin gene (LEP-2548 G/A SNP) and obesity. METHODS: Meta-analysis of published studies, included if subjects were genotyped at polymorphism LEP-2548 G/A and both obese and nonobese subjects were selected, based on a reported cutoff BMI limit. Meta-analysis of the total and subgroup populations was conducted using dominant and recessive models, and OR and 95% CI were calculated in the fixed-effect model. I2 statistic was calculated to examine heterogeneity, and publication bias was evaluated by Egger test. RESULTS: After testing each control group for Hardy-Woinberg equilibrium, the final selection enrolled 11 studies, including 5210 subjects (2541 obesity subjects and 2669 healthy). In the combined analysis of all eligible studies, none significant association was identified between LEP-2548 G/A SNP and obesity either in dominant model or the recessive one with pooled odds ratios 1.14 (95% CI 0.98-1.31, P = 0.08) and 1.03 (95% CI 0.85-1.25, P = 0.76). However, subgroup analysis found a significant association of GG homozygote in American population [OR = 1.53 (95% CI 1.17-2.00), P = 0.002]. No significant evidence was found in other populations. DISCUSSION: This first metaanalysis of data from published studies did not detect any association between the polymorphism of LEP-2548 G/A and risk of obesity in overall population. Nevertheless, the presence of the GG genotype in the gene appears to be a significant risk factor for obesity in American.

IL-6/STAT3 Axis Activates Glut5 to Regulate Fructose Metabolism and Tumorigenesis.

Cancer cells frequently use fructose as an alternative energy and carbon source, to fuel glycolysis and support the synthesis of various biomacromolecules. Glut5 is the only fructose-specific transporter, which lacks the ability to transport other carbohydrates such as glucose and galactose. Interplay between inflammatory factors and cancer cells renders inflammatory tissue environment as a predisposing condition for cancer development. Nevertheless, how inflammatory factors coordinate with fructose metabolism to facilitate tumor growth remains largely elusive. Here we show that treatment with IL-6 activates fructose uptake and fructolysis in oral squamous cell carcinoma (OSCC) cells and prostate cancer cells. Mechanistic study shows that transcription factor STAT3 associates with Glut5 promoter region and enhances Glut5 transcription in response to IL-6 treatment. Knockdown of Glut5 abolished IL-6-induced fructose uptake and utilization of fructose, and compromises IL-6-elicited tumor cell proliferation. Further, positive correlation between Glut5 and IL-6 expression is observed in multiple cancers. Our findings demonstrate a regulatory cascade underlying the crosstalk between inflammation and fructose metabolism in cancer cells, and highlights Glut5 as a novel oncogenic factor.

[Reproductive toxicity of metadoxine in rats].

OBJECTIVE: To study the reproductive toxicity of metadoxine. METHODS: Male and female rats were given metadoxine before pregnancy and early gestation, i.e. to feed metadoxine to male rats for 60 days before copulation and continue feeding during copulation, and feed metadoxine to female rats for 14 days before copulation. RESULTS: No significant toxic effect was observed in the 400 mg/kg group. A few rats showed paralysis of hind leg in the 800 mg/kg group. The dosage of 1 600 mg/kg caused significant paralysis of hind legs, emaciation, and reduced weight gain. In the 1600 mg/kg group, the mating rate of male rats was significantly affected (P < 0.01). In the 800 and 1 600 mg/kg group, fertility of male rats was markedly reduced (P < 0.01). In the 800 mg/kg group, the effect on sperm counts of epididymis of male rats was markedly reduced (P < 0.05). In the 1 600 mg/kg group, testicle weight and body weight ratio and sperm counts of epididymis rate were significantly (P < 0.001) reduced. In the 1 600 mg/kg group, the fertility rate of female rats was remarkably (P < 0.001) reduced. In the 800 mg/kg group, the weight gain of pregnant rats was significantly reduced (P < 0.001). In both the 800 and 1 600 mg/kg groups, the gestation rate was greatly reduced (P < 0.001). In the 800 mg/kg group, mortality rate before nidation (P < 0.001) and average live fetus number were significantly reduced (P < 0.05). In the 400 mg/kg group, the fetal weight was significantly reduced (P < 0.001). In the 800 mg/kg group, body length, tail length, body weight and sternum development of fetal rats were significantly affected (P < 0.001). CONCLUSION: Under the presented experimental conditions, metadoxine has no teratogenic effects on SD rats and the no effect dose is 400 mg/kg. And the no effect dose for the developmental toxicity is less than 400 mg/kg.

Vitamin A equivalence of spirulina beta-carotene in Chinese adults as assessed by using a stable-isotope reference method.

BACKGROUND: Spirulina is a high-protein food supplement that contains carotenoids. OBJECTIVE: The objective of the study was to determine the vitamin A equivalence of spirulina beta-carotene in humans. DESIGN: Spirulina was grown in a 23 atom% (2)H(2)O cultural solution. Spirulina beta-carotene showed the greatest enrichment as [(2)H(10)]trans beta-carotene. Ten healthy Chinese men with a mean (+/-SD) serum retinol concentration of 1.7 +/- 0.3 micromol/L and a body mass index (in kg/m(2)) of 23 +/- 3 consumed 5.8 micromol [(13)C(10)]retinyl acetate in oil as a reference dose with a breakfast containing 13 g fat. One week later, each subject consumed 7.9 mumol trans beta-carotene in spirulina with a breakfast containing 22 g fat. All subjects followed diets low in carotenoid and vitamin A. Forty blood samples were collected from each subject over a span of 56 d. Concentrations and enrichments of retinol and beta-carotene in serum samples were determined by using HPLC and a mass spectrometer. RESULTS: Compared with the serum response to [(13)C(10)]retinyl acetate dose, the mean conversion factor of spirulina beta-carotene to retinol was 4.5 +/- 1.6 (range: 2.3-6.9) by weight. It was estimated that 80% of the conversion occurred within the first 24 h after spirulina administration. CONCLUSION: In a group of well-nourished, normal-weight Chinese men following low-vitamin A diets, 4.5 mg spirulina beta-carotene consumed with 22 g fat has the same vitamin A activity as does 1 mg retinyl acetate.