Pharmacological vitamin C inhibits mTOR signaling and tumor growth by degrading Rictor and inducing HMOX1 expression.

Pharmacological vitamin C (VC) is a potential natural compound for cancer treatment. However, the mechanism underlying its antitumor effects remains unclear. In this study, we found that pharmacological VC significantly inhibits the mTOR (including mTORC1 and mTORC2) pathway activation and promotes GSK3-FBXW7-mediated Rictor ubiquitination and degradation by increasing the cellular ROS. Moreover, we identified that HMOX1 is a checkpoint for pharmacological-VC-mediated mTOR inactivation, and the deletion of FBXW7 or HMOX1 suppresses the regulation of pharmacological VC on mTOR activation, cell size, cell viability, and autophagy. More importantly, it was observed that the inhibition of mTOR by pharmacological VC supplementation in vivo produces positive therapeutic responses in tumor growth, while HMOX1 deficiency rescues the inhibitory effect of pharmacological VC on tumor growth. These results demonstrate that VC influences cellular activities and tumor growth by inhibiting the mTOR pathway through Rictor and HMOX1, which may have therapeutic potential for cancer treatment.

A novel identified Pseudomonas aeruginosa, which exhibited nitrate- and nitrite-dependent methane oxidation abilities, could alleviate the disadvantages caused by nitrate supplementation in rumen fluid fermentation.

After the occurrence of nitrate-dependent anaerobic methane oxidation (AMO) in rumen fluid culture was proved, the organisms that perform the denitrifying anaerobic methane oxidizing (DAMO) process in the rumen of dairy goat were investigated by establishing two enrichment culture systems, which were supplied with methane as the sole carbon source and NaNO3 or NaNO2 as the electron acceptor. Several Operational Taxonomic Units (OTU) belonging to Proteobacteria became dominant in the two enrichment systems. The identified Pseudomonas aeruginosa, which was isolated from the NaNO2 enrichment system, could individually perform a whole denitrifying anaerobic methane oxidizing process. Further in vitro rumen fermentation showed that supplementation with the isolated P. aeruginosa could reduce methane emissions, alleviate the nitrite accumulation and prevent the decrease in propionic acid product caused by nitrate supplementation.

Paternal chronic folate supplementation induced the transgenerational inheritance of acquired developmental and metabolic changes in chickens.

Increasing evidence indicates that paternal diet can result in metabolic changes in offspring, but the definite mechanism remains unclear in birds. Here, we fed breeder cocks five different diets containing 0, 0.25, 1.25, 2.50 and 5.00 mg kg-1 folate throughout life. Paternal folate supplementation (FS) was beneficial to the growth and organ development of broiler offspring. Most importantly, the lipid and glucose metabolism of breeder cocks and broiler offspring were affected by paternal FS, according to biochemical and metabolomic analyses. We further employed global analyses of hepatic and spermatozoal messenger RNA (mRNA), long non-coding RNA (lncRNA) and micro RNA (miRNA). Some key genes involved in the glycolysis or gluconeogenesis pathway and the PPAR signalling pathway, including PEPCK, ANGPTL4 and THRSP, were regulated by differentially expressed hepatic and spermatozoal miRNAs and lncRNAs in breeder cocks and broiler offspring. Moreover, the expression of ANGPTL4 could also be regulated by differentially expressed miRNAs and lncRNAs in spermatozoa via competitive endogenous RNA (ceRNA) mechanisms. Overall, this model suggests that paternal folate could transgenerationally regulate lipid and glucose metabolism in broiler offspring and the epigenetic transmission may involve altered spermatozoal miRNAs and lncRNAs.

Spermatozoal mRNAs expression implicated in embryonic development were influenced by dietary folate supplementation of breeder roosters by altering spermatozoal piRNA expression profiles.

Dietary folate intake, together with changes in its metabolism process, have effects on male reproduction, sperm epigenetic patterning and offspring outcome. Previous studies have proven that PIWI-interacting RNAs (piRNAs) play important roles in successful spermatogenesis and regulating genes expression of sperm and offspring embryo. Herein, we fed breeder roosters with five different levels (0, 0.25, 1.25, 2.50, and 5.00 mg/kg) of folate throughout life and found that paternal folate supplementation was beneficial to the growth and organ development of offspring broilers. Further spermatozoal mRNAs sequencing analyses implied that the dietary folate supplementation could regulate the spermatozoal mRNA abundance of genes related to the fetal development. Furthermore, global piRNAs analyses of breeder roosters' sperm revealed that differential concentration of dietary folate supplementation could change piRNAs profiles. Combined mRNAs sequencing and target gene prediction of differentially expressed gene-derived piRNAs, embryonic development and metabolism related pathways and biological processes, which were consisted to the regulatory roles of paternal folate supplementations, were significantly affected by the differentially expressed gene-derived piRNAs based on the GO and KEGG analyses. Overall, our results provided a novel insight into the role of piRNAs in response to folate intake, which will broaden the understanding about the relationship between folate and sperm epigenetic patterning of breeder roosters.

Effects of glucose oxidase on growth performance, gut function, and cecal microbiota of broiler chickens.

A study was conducted to study the effects of glucose oxidase (GOD) supplement on the growth performance, gut function, and cecal microbiota in broiler chickens from 1 to 42 d, and further evaluate the use of GOD as an antibiotic substitution. A total of 525 1-d-old healthy Arbor Acres broilers were randomly assigned to five treatments, including control group, antibiotic growth promoters (AGP) supplement group, and three GOD supplement groups, with seven replicates per treatment and 15 birds per replicate. Growth performance, gut function including digestive ability and gut barrier, and cecal microbiota were determined. Compared with the control group, the increased daily body weight gain, improved meat quality, and enhanced digestive ability that indicated from the nutrients apparent digestibility and digestive enzymes were identified in GOD supplement groups, which could have a similar effect with the AGP supplement. The content of secreted immunoglobulin A and the transepithelial electrical resistance were also increased with the GOD supplement, which indicated an enhanced gut barrier. Additionally, 16S rRNA gene of cecal contents was sequenced by high-throughput sequencing. Sequencing data indicated that the Firmicutes phylum, Ruminococcaceae and Rikenellaceae families, Faecalibacterium genus, and F. prausnitzii species were significantly altered. Especially, combined with previous studies, our results indicated that the significantly increased F. prausnitzii, Ruminococcaceae, and Firmicutes could be involved in the effect of GOD on gut function and growth performance of broilers. Our results indicated that dietary GOD supplement could improve the growth performance of broilers in two main ways: by enhancing the digestive function of gut, which concluded from the improved nutrients apparent digestibility and digestive enzyme, and by increasing the abundance of beneficial bacterium, such as F. prausnitzii, Ruminococcaceae, and Firmicutes, which could be further served as an important regulator to improve the growth performance and the gut health.

Simultaneous Supplementation of Bacillus subtilis and Antibiotic Growth Promoters by Stages Improved Intestinal Function of Pullets by Altering Gut Microbiota.

Early nutrition of pullets could determine the overall development and the performance of laying hens. With the aim to reduce the use of antibiotic growth promoters (AGPs) and to maintain the growth and development of pullets, the effect of simultaneous short-termed supplementation of AGPs (bacitracin zinc 20 mg/kg and colistin sulfate 4 mg/kg) and Bacillus subtilis (B. subtilis) DSM17299 probiotic, as well as the effect of supplementation of AGPs (bacitracin zinc 20 mg/kg and colistin sulfate 4 mg/kg) during the whole period (0~16 weeks) on the overall growth and development, intestinal health, and caecal microbiota of pullets were evaluated. In the present study, a total of 630 one-day-old Hy-Line Brown layers were randomly distributed into five equal groups: including the AGPs group (supplemented with AGPs based on basal diets for 16 weeks), the BA3 group (supplemented with AGPs and B. subtilis based on basal diets for 3 weeks), the BA6 group (for 6 weeks), the BA12 group (for 12 weeks), and the BA16 group (for 16 weeks). When compared with the AGPs group, the supplementation of AGPs + B. subtilis for the first 3 weeks could maintain overall growth performance, including the average body weight, average feed intake, average daily weight gain, and feed conversion ratio of pullets at 3, 6, 12, and 16 weeks of age (P > 0.05). Meanwhile, the characteristic growth indexes in different periods were separately measured. At 3 weeks of age, the amylase activity in ileum was elevated (P = 0.028), and the length of tibia was up to the standard in the BA3 group. At 12 weeks of age, the increased villus height (P = 0.046) of jejunum, increased villus height (P = 0.023) and ratio of villus height to crypt depth (P = 0.012) of ileum, decreased crypt depth (P = 0.002) of ileum, and elevated mRNA levels of sucrase in jejunum (P < 0.05) were all identified in the BA3 group. At 16 weeks of age, the secreted immunoglobulin A (sIgA) content in the jejunum mucosa of the BA3 group was greater than the other groups (P < 0.001). Furthermore, altered intestinal microbiota was found in the BA3 group. Specifically, decreased amounts of Alistipes, Bacteroides, Odoribacter, Dehalobacterium, and Sutterella and increased amounts of Lactobacillus, Dorea, Ruminococcus, and Oscillospira were determined (P < 0.05) in the BA3 group at week 6. Meanwhile, decreased amounts of B. fragilis and C. leptum (P < 0.05) were identified in the BA3 group at week 12, which were found to be relevant for the improvement of intestinal morphology (P < 0.05) by Pearson analysis. In conclusion, simultaneous supplementation of AGP and B. subtilis for 0~3 weeks increased the relative abundance of beneficial microbiota in caecum in 0~6 weeks, then improved the intestinal morphology by elevating populations of B. fragilis and C. leptum in 7~16 weeks, and further upregulated sucrase expression and increased sIgA content in the intestinal mucosa in 13~16 weeks.

Transgenerational effects of paternal dietary Astragalus polysaccharides on spleen immunity of broilers.

Our previous study indicated that paternal dietary Astragalus polysaccharides (APS) could induce endotoxin tolerance-like response in jejunum of offspring chickens. There exist positive interaction between intestinal mucosal immunity and systemic immunity. So we studied the transgenerational effect and nutri-epigenetic role of paternal dietary APS on spleen immunity. 64 one-day-old Avein breeder cocks were used in a single-factor design with 0 and 10g/kg APS, respectively, 4 replicated cages each group, and 8 birds each cage. When the breeder cocks at 40-week-age, semen of cocks was collected and used for hatching experiment to get broiler chickens. The paternal dietary APS could transgenerational up-regulated the serum type-I-interferon level of offspring chickens. In spleen of breeder cocks, the dietary APS didn't have any systematic effect on genes transcription. Whereas, the paternal dietary APS supplementation could induce endotoxin tolerance-like immune response (TLR4 pathway) in spleen of broiler chickens. But the APS had no significant effect on transcription of ET related regulators and promotor methylation of core regulators (TRIF, MyD88, and SOCS1). This means that the paternal dietary APS can transgenerational induce endotoxin tolerance-like immune response in spleen, and the fundamental cause of the this response might lies on its effect on intestinal mucosal immunity.

Transgenerational endotoxin tolerance-like effect caused by paternal dietary Astragalus polysaccharides in broilers' jejunum.

To learn the nutri-epigenetics role of Astragalus polysaccharides (APS), we designed and studied the transgenerational effect of paternal dietary APS supplementation in chickens. 160 Avein breeder cocks were randomly allocated into 5 groups and fed with 0, 0.01, 0.1, 1, and 10 g/kg APS supplement, respectively. Sperm of breeder cocks was collected and used for hatching experiment to get broiler chickens when the cocks at 40-weeks-old. It showed that the paternal dietary 10 g/kg APS could transgenerational promote growth performance and jejunal tissue morphology of chickens. As to phenotypes, 10 g/kg APS treatment was chosen for molecular assays. In jejunal mucosa, 10 g/kg dietary APS didn't have any systematic effect on gene transcription of breeder cocks, whereas, the APS could induce transgenerational endotoxin tolerance-like effect through activating the IFNα-SOCS1 pathway in chicks. In both jejunum and sperm, the promoter methylation level of SOCS1 significantly reduced in 10 g/kg APS treatment versus the control group. In addition, the paternal APS significantly affected histone modification in promotor region of TRIF. Our data revealed that the paternal dietary APS supplementation could induce transgenerational endotoxin tolerance-like effect in jejunum mucosa of broiler chickens. And nutri-epigenetic modifications are crucial for this transgenerational effect.

Effect of dietary Astragalus Polysaccharide supplements on testicular piRNA expression profiles of breeding cocks.

Astragalus Polysaccharide (APS), as the main active ingredient of Astragalus membranaceus, has extensive biological activities related to immune, metabolic, and anti-oxidative regulatory processes. Previous studies have proven that piRNAs could play important roles in genital gland. This study aimed to identify the differentially expressed piRNAs in chicken testes in response to dietary APS supplements and further evaluate the roles of these piRNAs related to the effect of dietary APS supplements on testicular changes. We generated piRNA expression profiles of testes from breeding cocks fed without or with extra APS. As results, there were 42 up-regulated and 86 down-regulated piRNAs in APS group, compared with the control group meeting the criteria of P<0.05 and fold change <0.67 or fold change >1.5. The potential targets were subsequently annotated against the Kyoto Encyclopedia of Genes and Genomes databases. The results revealed that dietary APS supplements could regulate tight junction pathways by regulating the piRNA expression profiles, which were related to the regulation of a better testicular condition for spermatogenesis. Our results provided a novel insight into the effect of dietary APS supplements on testicular piRNA expression profiles and its potential roles in testicular condition regulation.

Effect of dietary Astragalus Polysaccharide supplements on testicular miRNA expression profiles and enzymatic changes of breeder cocks.

Astragalus Polysaccharide (APS) is an important feed additive due to its immunomodulatory functions. Previous studies have proven that miRNAs play important roles in posttranscriptional gene regulation. Our goals were to identify differentially expressed miRNAs in testes in responses to APS dietary supplements and to find the effects of APS on breeder cock testes. We measured several enzymatic activities in testes and sperm samples and further generated miRNA expression profiles of testes from breeder cocks fed with control diets and extra APS. As a result, we found APS could increase testicular functional activities of marker enzymes. Meanwhile, there were 16 up-regulated and 17 down-regulated miRNAs in APS group, compared with the control group meeting the criteria of P-values < 0.05. Meanwhile, twelve differentially expressed miRNAs were validated by Mir-XTM miRNA RT-qPCR. Further GO and KEGG analyses of target genes for differentially expressed miRNAs revealed that some miRNAs may be involved in testicular nutrient metabolisms and NK cell mediated cytotoxicity pathway. Moreover, the effect of dietary APS supplements on NK cell mediated cytotoxicity pathway was also validated by RT-qPCR. Our results provided a novel insight into the effect of dietary APS supplements on testicular miRNA expression profiles and enzymatic changes of breeder cocks.

Effectiveness of a stress-relief initiative for primary caregivers of adolescents with intellectual disability.

BACKGROUND: This study provides a perspective on the mental health status and analyses the effectiveness of a stress-relief program for primary caregivers of adolescents with intellectual disability (ID). METHOD: Seventy-seven primary caregivers of people with ID were recruited (intervention group, n = 31; non-intervention group, n = 46) to the study, which involved participation in one stress management workshop (intervention group only) and both groups reading an education booklet on stress management. RESULTS: We found that 22.1% of caregivers in the study were at high risk of depressive stress and in need of mental health consultation; this prevalence was nearly six times that of the general population. The effectiveness of mental health initiatives resulted in a significant reduction in depressive stress for the intervention group. CONCLUSIONS: The study highlights that a "face-to-face" workshop is an effective way to decrease levels of depressive stress.