Predicting the evolution of clinical skin aging in a multi-ethnic population: Developing causal Bayesian networks using dermatological expertise.

INTRODUCTION: Software to predict the impact of aging on physical appearance is increasingly popular. But it does not consider the complex interplay of factors that contribute to skin aging. OBJECTIVES: To predict the +15-year progression of clinical signs of skin aging by developing Causal Bayesian Belief Networks (CBBNs) using expert knowledge from dermatologists. MATERIAL AND METHODS: Structures and conditional probability distributions were elicited worldwide from dermatologists with experience of at least 15 years in aesthetics. CBBN models were built for all phototypes and for ages ranging from 18 to 65 years, focusing on wrinkles, pigmentary heterogeneity and facial ptosis. Models were also evaluated by a group of independent dermatologists ensuring the quality of prediction of the cumulative effects of extrinsic and intrinsic skin aging factors, especially the distribution of scores for clinical signs 15 years after the initial assessment. RESULTS: For easiness, only models on African skins are presented in this paper. The forehead wrinkle evolution model has been detailed. Specific atlas and extrinsic factors of facial aging were used for this skin type. But the prediction method has been validated for all phototypes, and for all clinical signs of facial aging. CONCLUSION: This method proposes a skin aging model that predicts the aging process for each clinical sign, considering endogenous and exogenous factors. It simulates aging curves according to lifestyle. It can be used as a preventive tool and could be coupled with a generative AI algorithm to visualize aging and, potentially, other skin conditions, using appropriate images.

Neuron-derived neurotrophic factor promotes the differentiation of intramuscular and subcutaneous adipocytes in goat.

Adipocyte play an important role in human health and meat quality by influencing the tenderness, flavor, and juiciness of mutton It has been shown that neuron-derived neurotrophic factor (NENF) is closely related to energy metabolism and adipocyte differentiation in bovine. However, the role of NENF in the goats remains unclear. The aim of this study was to detect the expression of NENF in goat subcutaneous and intramuscular adipocytes, temporal expression profiles of the NENF, and overexpressed NENF on the differentiation of different adipocytes. In this study, PCR amplification successfully cloned the goat NENF gene with a fragment length of 521 bp. In addition, the time point of highest expression of NENF differed between these two adipocytes differentiation processes. Overexpression of NENF in intramuscular and subcutaneous adipocytes promoted the expression levels of differentiation markers CEBPß and SREBP, which in turn promoted the differentiation of intramuscular and subcutaneous adipocytes. This study will provide basic data for further study of the role of goats in goat adipocyte differentiation and for the final elucidation of its molecular mechanisms in regulating goat adipocyte deposition.

Effect of DHCR7 on adipocyte differentiation in goats.

Cholesterol is regarded as a signaling molecule in regulating the metabolism and function of fat cells, in which 7-Dehydrocholesterol reductase (DHCR7) is a key enzyme that catalyzes the conversion of 7-dehydrocholesterol to cholesterol, however, the exact function of DHCR7 in goat adipocytes remains unknown. Here, the effect of DHCR7 on the formation of subcutaneous and intramuscular fat in goats was investigated in vitro, and the result indicated that the mRNA level of DHCR7 showed a gradual downward trend in subcutaneous adipogenesis, but an opposite trend in intramuscular adipogenesis. In the process of subcutaneous preadipocytes differentiation, overexpression of DHCR7 inhibited the expression of adipocytes differentiation marker genes (CEBP/α, CEBP/ß, SREBP1 and AP2), lipid metabolism-related genes (AGPAT6, FASN, SCD1 and LPL), and the lipid accumulation. However, in intramuscular preadipocyte differentiation, DHCR7 overexpression showed a promoting effect on adipocyte differentiation marker genes (CEBP/α, CEBP/ß, PPARγ and SREBP1) and lipid metabolism-related genes (GPAM, AGPAT6, DGAT1 and SCD1) expression, and on lipid accumulation. In summary, our work demonstrated that DHCR7 played an important role in regulating adipogenic differentiation and lipid metabolism in preadipocytes in goats, which is of great significance for uncovering the underlying molecular mechanism of adipocyte differentiation and improving goat meat quality.

Association between atherogenic index of plasma and prehypertension or hypertension among normoglycemia subjects in a Japan population: a cross-sectional study.

OBJECTIVE: The atherogenic index of plasma (AIP), consisting of triglycerides and high-density lipoprotein cholesterol, is applied to estimate the cardiovascular disease risk. The evidence regarding the association between AIP and prehypertension or hypertension remains inconclusive. This study was conducted to investigate the association of AIP and prehypertension or hypertension in normoglycemic subjects in Japan. METHODS: In the present cross-sectional study, 15,453 normoglycemic participants aged 18 years or older in Gifu, Japan, were evaluated. The selected participants were separated into four groups in the light of AIP quartiles, ranging from the lowest quartile (Q1) to the highest quartile (Q4). And the association between AIP and prehypertension or hypertension was explored with multivariate logistic regression by gradually adjusting model. RESULTS: Among the 15,453 participants, aged of 43.7 ± 8.9 years, and of whom 45.5% were females, the prevalence rates of prehypertension or hypertension were 27.68% (4,278) and 6.23% (962) respectively. In multivariate logistic regression analyses, participants in the highest AIP quartile had an increase risk in prehypertension and hypertension, compared with participants the lowest one, the odds ratios (OR) were 1.15 (95%CI: 1.00-1.13, P = 0.045) for prehypertension and 1.54 (95%CI:1.16-2.04, P = 0.003) for hypertension after adjusting confounders. In subgroup analyses, the high risk of hypertension was also observed for female participants in the highest AIP quartile (Q4) (OR = 2.19, 95%CI: 1.37-3.49, P = 0.001), especially between the ages of 40 and 60 years (OR = 2.20, 95%CI: 1.24-3.88, P = 0.007). CONCLUSIONS: Higher AIP is significantly and positively associated with the risk of prehypertension or hypertension in normoglycemic subjects in Gifu, Japan, which was more pronounced in the female population, especially between the years of 40 and 60.

Effect of TEA domain transcription factor 1 (TEAD1) on the differentiation of intramuscular preadipocytes in goats.

TEA domain transcription factor 1 (TEAD1), also called TEF-1, acts as a transcriptional enhancer to regulate muscle-specific gene expression. However, the role of TEAD1 in regulating intramuscular preadipocyte differentiation in goats is unclear. The aim of this study was to obtain the sequence of TEAD1 gene and elucidate the effect of TEAD1 on goat intramuscular preadipocyte differentiation in vitro and its possible mechanism. The results showed that the goat TEAD1 gene CDS region sequence was 1311 bp. TEAD1 gene was widely expressed in goat tissues, with the highest expression in brachial triceps (p < 0.01). The expression of TEAD1 gene in goat intramuscular adipocytes at 72 h was extremely significantly higher than that at 0 h (p < 0.01). Overexpression of goat TEAD1 inhibited the accumulation of lipid droplets in goat intramuscular adipocyte. The relative expression of differentiation marker genes SREBP1, PPARγ, C/EBPß were significantly down-regulated (all p < 0.01), but PREF-1 was significantly up-regulated (p < 0.01). Binding analysis showed that there were multiple binding sites between the DNA binding domain of goat TEAD1 and the promoter binding region of SREBP1, PPARγ, C/EBPß and PREF-1. In conclusion, TEAD1 negatively regulates the differentiation of goat intramuscular preadipocytes.

PSTPIP2 is associated with disease severity in patients with pressure ulcer sepsis and has anti-inflammatory effects.

BACKGROUND: One of the common adverse reactions in patients with pressure ulcers (PU) is sepsis, which is mainly related to microbial infections caused by pathogenic organisms. The activation of nuclear factor kappa-B (NF-κB) frequently occurs in conjunction with pathogenic microbial infections. Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) is closely related to inflammatory disorders. The role and mechanism of PSTPIP2 in sepsis because of pressure ulcers is unclear. In this study, we discovered that PSTPIP2 was lowly expressed in peripheral blood of patients with sepsis induced by pressure ulcers. METHODS: Peripheral blood was collected from 20 patients with sepsis due to pressure ulcers and 10 healthy controls, and the expression of PSTPIP2 in peripheral blood was discovered by polymerase chain reaction and Western blot analysis. Information on the clinical characteristics of patients was summarized, and the expression data of PSTPIP2 were correlated with the patients' acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score, and C-reactive protein (CRP) and procalcitonin (PCT) scores by Spearman's correlation analysis. One of the main mediators of Gram-negative sepsis is lipopolysaccharide (LPS). In order to establish an in vitro sepsis model, THP-1 cells were treated with LPS, and the cells were transfected with PSTPIP2. Contents of interleukin 6 (IL-6), interleukin 1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) in each group of cells were detected by enzyme-linked--immunosorbent serologic assay, and NF-κB-related proteins were detected by Western blot analysis. RESULTS: When compared to healthy controls, the peripheral blood of patients with pressure sepsis had lower PSTPIP2 expression, which had a negative correlation with the APACHE II, SOFA, CRP, and PCT scores. LPS-induced THP-1 cells expressed less PSTPIP2 than the untreated control cells, and PSTPIP2 transfection decreased IL-6, IL-1ß, and TNF-α levels and inhibited the activation of NF-κB pathway. CONCLUSION: PSTPIP2 is associated with disease severity in patients with pressure ulcer sepsis and has anti-inflammatory effects.

The Important Role of m6A-Modified circRNAs in the Differentiation of Intramuscular Adipocytes in Goats Based on MeRIP Sequencing Analysis.

Intramuscular fat contributes to the improvement of goat meat quality. N6-Methyladenosine (m6A)-modified circular RNAs play important roles in adipocyte differentiation and metabolism. However, the mechanisms by which m6A modifies circRNA before and after differentiation of goat intramuscular adipocytes remain poorly understood. Here, we performed methylated RNA immunoprecipitation sequencing (MeRIP-seq) and circRNA sequencing (circRNA-seq) to determine the distinctions in m6A-methylated circRNAs during goat adipocyte differentiation. The profile of m6A-circRNA showed a total of 427 m6A peaks within 403 circRNAs in the intramuscular preadipocytes group, and 428 peaks within 401 circRNAs in the mature adipocytes group. Compared with the intramuscular preadipocytes group, 75 peaks within 75 circRNAs were significantly different in the mature adipocytes group. Furthermore, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of intramuscular preadipocytes and mature adipocytes showed that the differentially m6A-modified circRNAs were enriched in the PKG signaling pathway, endocrine and other factor-regulated calcium reabsorption, lysine degradation, etc. m6A-circRNA-miRNA-mRNA interaction networks predicted the potential m6A-circRNA regulation mechanism in different goat adipocytes. Our results indicate that there is a complicated regulatory relationship between the 12 upregulated and 7 downregulated m6A-circRNAs through 14 and 11 miRNA mediated pathways, respectively. In addition, co-analysis revealed a positive association between m6A abundance and levels of circRNA expression, such as expression levels of circRNA_0873 and circRNA_1161, which showed that m6A may play a vital role in modulating circRNA expression during goat adipocyte differentiation. These results would provide novel information for elucidating the biological functions and regulatory characteristics of m6A-circRNAs in intramuscular adipocyte differentiation and could be helpful for further molecular breeding to improve meat quality in goats.

The relationship between preschool teacher trait mindfulness and teacher-child relationship quality: the chain mediating role of emotional intelligence and empathy.

The teacher-child relationship plays an important role in children's future development. However, the existing research mainly focuses on the influence of preschool teachers' external conditions on the teacher-student relationship, while the research on the influence of teachers' internal psychological characteristics on the teacher-student relationship is relatively lacking. In this study, three hundred and seventeen preschool teachers were tested were tested with Five Facet Mindfulness Questionnaire, Emotional Intelligence Scale, Chinese Interpersonal Response Index, and Teacher-student Relationship Scale. The results showed that trait mindfulness positively predicted the quality of parent-teacher relationship (ß = 0.173, p = 0.026). Emotional intelligence played a mediating role in trait mindfulness and teacher-child relationship quality (ß = 0.118, p = 0.004), and empathy played a mediating role in trait mindfulness and teacher-child relationship quality (ß = 0.112, p = 0.001). Meanwhile, emotional intelligence and empathy played a chain mediating role in trait mindfulness and parent-teacher relationship quality (ß = 0.044, p = 0.038). On the one hand, this study enriches attachment theory. The conclusions of this study verify the diversity of proximal factors in attachment theory, and confirm the influence of teachers' own characteristics and abilities on the teacher-child relationship quality. On the other hand, by exploring the factors affecting the teacher-child relationship quality, we can find ways to improve teacher-child relationship from a new perspective, and then provide some new methods and approaches for improving the quality of preschool teacher-child relationship.

The duration of food withdrawal affects the intestinal structure, nutrients absorption, and utilization in broiler chicken.

Food withdrawal is usually used for accurate feed metabolizable energy (ME) assessment in poultry, but its effects on intestinal structure and the absorption of nutrients are unclear. In this study, broilers were fed ad libitum (CT) or withdrew food for 12 (FH12), 24 (FH24), 36 (FH36), or 48 hours (FH48). We showed that food withdrawal increased the energy assimilation when compared with the CT. Food withdrawal improved the digestibility of ether extract and the level of lipid substances and fatty acid-derived ß-hydroxybutyrate in serum. Compared to the CT, food withdrawal did not influence the digestibility of starch. Due to 12 hours or longer food withdrawal duration increased glutamate oxidation and uric acid excretion, the analyzed digestibility of crude protein was underestimated, although the upregulated amino acid transporter genes. In addition, histological analysis showed that short-term food withdrawal (12 hours) increased intestinal villus height, crypt depth, and proliferative cell, whereas prolonged food withdrawal (more than 24 hours) impaired villus structure due to the decreased cell proliferation. Moreover, proteomics analysis revealed upregulated pathways in birds withdrawn food for 36 hours involved in nutrient absorption and amino acid oxidation. In conclusion, food withdrawal changes nutrient absorption and utilization, especially for amino acid and ether extract, and results in increased ME. Both glutamate oxidation and fatty acid incomplete oxidation are involved in energy supply after refeeding. In contrast to short-term food withdrawal, prolonged food withdrawal impairs the intestinal structure and villus renewal. Our findings deserve attention from nutritionists who are analyzing food digestibility.

Chi-Circ_0006511 Positively Regulates the Differentiation of Goat Intramuscular Adipocytes via Novel-miR-87/CD36 Axis.

Goats are an important livestock and goat meat is essential to local people. The intramuscular fat (IMF) content has a great influence on the quality of goat meat. The intramuscular preadipocytes differentiation is closely related to the IMF deposition; however, its potential regulatory mechanisms remain unclear. CircRNAs were revealed to be involved in multiple biological progressions. In this study, we took primary goat intramuscular preadipocyte (GIMPA) as the study model to verify the function and mechanism of chi-circ_0006511, which was abundant and up-regulated in mature adipocytes (GIMA). The results showed that the expression level of chi-circ_0006511 gradually increased in the early stage of GIMPA differentiation, and chi-circ_0006511 was confirmed to promote GIMPA lipid droplets aggregation and up-regulate the adipogenic differentiation determinants, further promoting GIMPA differentiation. Mechanistically, chi-circ_0006511 exerts its function by sponging novel-miR-87, thereby regulating the expression of CD36. The results from this study provided novel significant information to better understand the molecular regulatory mechanism of intramuscular preadipocytes differentiation, thereby providing a new reference for the intramuscular fat adipogenesis in goats.

Transcriptome analysis reveals a molecular understanding of nicotinamide and butyrate sodium on meat quality of broilers under high stocking density.

BACKGROUND: In recent years, increased attention has been focused on breast muscle yield and meat quality in poultry production. Supplementation with nicotinamide and butyrate sodium can improve the meat quality of broilers. However, the potential molecular mechanism is not clear yet. This study was designed to investigate the effects of supplementation with a combination of nicotinamide and butyrate sodium on breast muscle transcriptome of broilers under high stocking density. A total of 300 21-d-old Cobb broilers were randomly allocated into 3 groups based on stocking density: low stocking density control group (L; 14 birds/m2), high stocking density control group (H; 18 birds/m2), and high stocking density group provided with a combination of 50 mg/kg nicotinamide and 500 mg/kg butyrate sodium (COMB; 18 birds/m2), raised to 42 days of age. RESULTS: The H group significantly increased cooking losses, pH decline and activity of lactate dehydrogenase in breast muscle when compared with the L group. COMB showed a significant decrease in these indices by comparison with the H group (P < 0.05). The transcriptome results showed that key genes involved in glycolysis, proteolysis and immune stress were up-regulated whereas those relating to muscle development, cell adhesion, cell matrix and collagen were down-regulated in the H group as compared to the L group. In contrast, genes related to muscle development, hyaluronic acid, mitochondrial function, and redox pathways were up-regulated while those associated with inflammatory response, acid metabolism, lipid metabolism, and glycolysis pathway were down-regulated in the COMB group when compared with the H group. CONCLUSIONS: The combination of nicotinamide and butyrate sodium may improve muscle quality by enhancing mitochondrial function and antioxidant capacity, inhibiting inflammatory response and glycolysis, and promoting muscle development and hyaluronic acid synthesis.

Efficacy and Safety of Complete Mesocolic Excision in Patients With Colon Cancer: Three-year Results From a Prospective, Nonrandomized, Double-blind, Controlled Trial.

OBJECTIVE: The aim of the study was to evaluate the oncological outcomes of complete mesocolic excision (CME) in colon cancer patients. SUMMARY BACKGROUND DATA: CME is considered a standard procedure for colon cancer patients. However, previous evidence regarding the effect of CME on prognosis has fundamental limitations that prevent it from being fully accepted. METHODS: Patients who underwent radical resection for colon cancer were enrolled between November 2012 and March 2016. According to the principles of CME, patients were stratified into 2 groups based on intraoperative surgical fields and specimen photographs. The primary outcome was local recurrence-free survival (LRFS). The clinicopathological data and follow-up information were collected and recorded. The final follow-up date was April 2016. The trial was registered in ClinicalTrials.gov (identifier: NCT01724775). RESULTS: There were 220 patients in the CME group and 110 patients in the noncomplete mesocolic excision (NCME) group. Baseline characteristics were well balanced. Compared with NCME, CME was associated with a greater number of total lymph nodes (24 vs 20, P = 0.002). Postoperative complications did not differ between the 2 groups. CME had a positive effect on LRFS compared with NCME (100.0% vs 90.2%, log-rank P < 0.001). Mesocolic dissection (100.0% vs 87.9%, log-rank P < 0.001) and nontumor deposits (97.2% vs 91.6%, log-rank P < 0.022) were also associated with improved LRFS. CONCLUSIONS: Our findings demonstrate that, compared with NCME, CME improves 3-year LRFS without increasing surgical risks.

Flaxseed diet caused inflammation by altering the gut microbiota of Peking ducks.

To study why flaxseed supplementation causes adverse effects on the performance of poultry, we investigated the gut microbiota of Peking ducks after consumption of a flaxseed diet. A total of 792, 12-day-old white Peking ducks were divided into four groups. In the control group, birds were provided with a basal diet. In the three experimental groups, the birds were fed flaxseed containing diet (10% flaxseed and 90% basal diet) for 30, 20 and 10 d, respectively. On day 42, ceca were collected to evaluate the bacterial diversity of the gut microbiota using microbial 16S rDNA gene profiling; serums were obtained to determine the levels of inflammatory mediators. The flaxseed diet decreased the alpha diversity and shifted the predominant genera of the gut microbiota. Flaxseed-fed groups had higher abundances of Escherichia/Shigella (p < 0.1) and Campylobacter (p < 0.05) than the control group. The abundance of pro-inflammatory bacteria such as Veillonellaceae increased (p < 0.05) at first and then decreased (p < 0.05) with prolonged flaxseed supplementation. The levels of prostaglandin E2 and Leukotriene B4 in serum showed the same pattern as that of the pro-inflammatory bacteria. In conclusion, flaxseed diets are associated with inflammation by altering the cecal microbiota dynamics.

Fatty acid synthase is required for profibrotic TGF-ß signaling.

Evidence is provided that the fibroproliferative actions of TGF-ß are dependent on a metabolic adaptation that sustains pathologic growth. Specifically, profibrotic TGF-ß signaling is shown to require fatty acid synthase (FASN), an essential anabolic enzyme responsible for the de novo synthesis of fatty acids. With the use of pharmacologic and genetic approaches, we show that TGF-ß-stimulated FASN expression is independent of Smad2/3 and is mediated via mammalian target of rapamycin complex 1. In the absence of FASN activity or protein, TGF-ß-driven fibrogenic processes are reduced with no apparent toxicity. Furthermore, as increased FASN expression was also observed to correlate with the degree of lung fibrosis in bleomycin-treated mice, inhibition of FASN was examined in a murine-treatment model of pulmonary fibrosis. Remarkably, inhibition of FASN not only decreased expression of profibrotic targets, but lung function was also stabilized/improved, as assessed by peripheral blood oxygenation.-Jung, M.-Y., Kang, J.-H., Hernandez, D. M., Yin, X., Andrianifahanana, M., Wang, Y., Gonzalez-Guerrico, A., Limper, A. H., Lupu, R., Leof, E. B. Fatty acid synthase is required for profibrotic TGF-ß signaling.

ATP-citrate lyase is essential for high glucose-induced histone hyperacetylation and fibrogenic gene upregulation in mesangial cells.

The goal of this study was to address the role of ATP-citrate lyase (ACL), an enzyme that converts citrate to acetyl-CoA, in high glucose (HG)-induced histone acetylation and profibrotic gene expression. Our recent ChIP-Seq studies have demonstrated that HG induces genome-wide histone hyperacetylation in mesangial cells (MCs). Here, we showed that exposure of MCs to HG markedly increased histone acetylation at the H3K9/14 and H3K18 marks and induced the expression of potent profibrotic factors TGF-ß1, TGF-ß3, and connective tissue growth factor (CTGF). The induction of these profibrotic factors was further enhanced by histone deacetylase inhibitor but suppressed by histone acetyl-transferase inhibitor, confirming the importance of histone acetylation in this regulation. Interestingly, HG not only upregulated ACL expression but also promoted ACL nuclear translocation, evidenced by increased ACL concentration and activity in the nuclear extracts. Consistent with this observation, transfection of MCs with a plasmid-carrying green fluorescent protein (GFP)-ACL fusion protein led to GFP nuclear accumulation when cultured in HG condition. Silencing ACL with siRNAs alleviated HG-induced histone hyperacetylation, as well as upregulation of TGF-ß1, TGF-ß3, CTGF, and extracellular matrix (ECM) proteins fibronectin and collagen type IV, whereas ACL overexpression further enhanced HG induction of histone acetylation, as well as these profibrotic factors and ECM proteins. Collectively, these observations demonstrate that HG promotes ACL expression and translocation into the nucleus, where ACL converts citrate to acetyl-CoA to provide the substrate for histone acetylation, leading to upregulation of fibrogenic genes. Therefore, ACL plays a critical role in epigenetic regulation of diabetic renal fibrosis.

Profibrotic up-regulation of glucose transporter 1 by TGF-ß involves activation of MEK and mammalian target of rapamycin complex 2 pathways.

TGF-ß plays a central role in the pathogenesis of fibroproliferative disorders. Defining the exact underlying molecular basis is therefore critical for the development of viable therapeutic strategies. Here, we show that expression of the facilitative glucose transporter 1 (GLUT1) is induced by TGF-ß in fibroblast lines and primary cells and is required for the profibrotic effects of TGF-ß. In addition, enhanced GLUT1 expression is observed in fibrotic areas of lungs of both patients with idiopathic pulmonary fibrosis and mice that are subjected to a fibrosis-inducing bleomycin treatment. By using pharmacologic and genetic approaches, we demonstrate that up-regulation of GLUT1 occurs via the canonical Smad2/3 pathway and requires autocrine activation of the receptor tyrosine kinases, platelet-derived and epidermal growth factor receptors. Engagement of the common downstream effector PI3K subsequently triggers activation of the MEK and mammalian target of rapamycin complex 2, which cooperate in regulating GLUT1 expression. Of note, inhibition of GLUT1 activity and/or expression is shown to impair TGF-ß-driven fibrogenic processes, including cell proliferation and production of profibrotic mediators. These findings provide new perspectives on the interrelation of metabolism and profibrotic TGF-ß signaling and present opportunities for potential therapeutic intervention.-Andrianifahanana, M., Hernandez, D. M., Yin, X., Kang, J.-H., Jung, M.-Y., Wang, Y., Yi, E. S., Roden, A. C., Limper, A. H., Leof, E. B. Profibrotic up-regulation of glucose transporter 1 by TGF-ß involves activation of MEK and mammalian target of rapamycin complex 2 pathways.

1,25-Dihydroxyvitamin D promotes negative feedback regulation of TLR signaling via targeting microRNA-155-SOCS1 in macrophages.

The negative feedback mechanism is essential to maintain effective immunity and tissue homeostasis. 1,25-dihydroxyvitamin D (1,25[OH]2D3) modulates innate immune response, but the mechanism remains poorly understood. In this article, we report that vitamin D receptor signaling attenuates TLR-mediated inflammation by enhancing the negative feedback inhibition. Vitamin D receptor inactivation leads to hyperinflammatory response in mice and macrophage cultures when challenged with LPS, because of microRNA-155 (miR-155) overproduction that excessively suppresses suppressor of cytokine signaling 1, a key regulator that enhances the negative feedback loop. Deletion of miR-155 attenuates vitamin D suppression of LPS-induced inflammation, confirming that 1,25(OH)2D3 stimulates suppressor of cytokine signaling 1 by downregulating miR-155. 1,25(OH)2D3 downregulates bic transcription by inhibiting NF-κB activation, which is mediated by a κB cis-DNA element located within the first intron of the bic gene. Together, these data identify a novel regulatory mechanism for vitamin D to control innate immunity.

Lycium barbarum (Wolfberry) Branches and Leaves Enhance the Growth Performance and Improve the Rumen Microbiota in Hu Sheep.

The Lycium barbarum branches and leaves (LBL) are known to contain a range of active substances that have positive effects on animal immunity and antioxidation. This study aimed to examine how LBL impacts the growth and slaughter performance as well as rumen fermentation and microbiota in Hu sheep. A total of 50 male Hu sheep of indigenous origin, aged 3 months, were randomly divided into 5 groups of 10 sheep each. The groups were given different levels of LBL supplementation (0%, 3%, 6%, 9%, and 12%) to evaluate growth performance and nutrient apparent digestibility. Rumen fluid samples were collected for analysis of the fermentation parameters and rumen chyme was examined to study the rumen microbiota. The slaughter performance, meat quality, and organ index were evaluated at the conclusion of the experiment. The results showed that the final body weight and average daily gain of the LBL1 group were significantly higher than those of the CON group, LBL3 group, and LBL4 group (p < 0.05). The average dry matter intake of the LBL4 group was significantly lower than that of other experimental groups (p < 0.05). The apparent digestibility of CP in the LBL1 and LBL2 groups was higher than that in other experimental groups (p < 0.05). At the same time, the eye muscle area and grade-rule (GR) value of Hu sheep in the LBL1 group significantly increased and the quality of Hu sheep meat improved (p < 0.05). There was no significant difference in organ weight and organ index between the experimental groups (p > 0.05). The pH of the rumen fluid in the LBL1 group was significantly lower than that in the CON group (p < 0.05). There was no significant difference in the NH3-N content between the experimental groups (p > 0.05). The propionate and valerate in the rumen fluid of Hu sheep in the LBL2 group were significantly higher than those in other experimental groups (p < 0.05). In addition, this had no significant effect on the structure and abundance of the rumen microbiota (p > 0.05). LBL is a promising functional feed. Adding an appropriate amount of LBL to the diet can improve the feed efficiency, growth performance, and meat quality of Hu sheep but has no adverse effects on the rumen. In this experiment, the appropriate supplemental level of LBL in the diet was 3%.

NK4 gene therapy inhibits HGF/Met-induced growth of human cholangiocarcinoma cells.

BACKGROUND AND OBJECTIVE: NK4, a competitive antagonist for hepatocyte growth factor (HGF) and the Met receptor, is a bifunctional molecule that acts as an HGF antagonist and an angiogenesis inhibitor. The objective of this study was to investigate the anti-tumor effects of NK4 on the cholangiocarcinoma (CCA) cell line HuCC-T1. METHODS: We assessed the effects of NK4 on proliferation, invasion, migration, and cell cycle progression in mock-transfected HuCC-T1 clones, empty-vector-transfected clones of HuCC-T1 (Hu-Em), and NK4-transfected clones of HuCC-T1 (Hu-NK4), with HuCC-T1 cells serving as the control cells. Correlated with these effects on cellular functions, the mRNA levels of cyclin D1 and cyclin A were monitored using reverse transcription (RT)-PCR and quantitative PCR, and the corresponding protein levels were monitored using Western blotting. In addition, Met phosphorylation and the activity of its important downstream signaling targets protein kinase B (Akt) and glycogen synthase kinase (GSK)-3ß were evaluated by Western blotting. RESULTS: Our data indicate that cell proliferation, invasion, and cell cycle progression of the three types of clones were essentially the same, while these processes were stimulated by HGF in HuCC-T1 and Hu-Em cells, but not in Hu-NK4 cells. Moreover, when stimulated with HGF, the increases in mRNA levels of cyclin D1 and cyclin A were accompanied by corresponding increases in protein levels, and the phosphorylation of Met, Akt, and GSK-3ß was upregulated in HuCC-T1 and Hu-Em cells, compared to the levels in the Hu-NK4 cells. CONCLUSIONS: These findings suggest that NK4 gene therapy inhibits HGF/Met-induced growth of human CCA cells by arresting cell cycle progression. It also interferes with Met activation and the downstream phosphatidylinositol-3-kinase/Akt/GSK-3ß signaling pathway.

Vitamin D receptor signaling in podocytes protects against diabetic nephropathy.

Vitamin D and its analogs have antiproteinuric activity and podocytes express the vitamin D receptor, but whether vitamin D signaling in podocytes accounts for this renoprotection is unknown. To investigate this question, we used the 2.5 kb podocin promoter to target Flag-tagged human vitamin D receptor (hVDR) to podocytes in DBA/2J mice. After the induction of diabetes with streptozotocin, transgenic mice had less albuminuria than wild-type controls. In transgenic mice, a low dose of the vitamin D analog doxercalciferol prevented albuminuria, markedly attenuated podocyte loss and apoptosis, and reduced glomerular fibrosis, but it had little effect on the progression of diabetic nephropathy in wild-type mice. Moreover, reconstitution of VDR-null mice with the hVDR transgene in podocytes rescued VDR-null mice from severe diabetes-related renal damage. In culture, 1,25-dihydroxyvitamin D suppressed high-glucose-induced apoptosis of podocytes by blocking p38- and ERK-mediated proapoptotic pathways. Taken together, these data provide strong evidence that vitamin D/VDR signaling in podocytes plays a critical role in the protection of the kidney from diabetic injury.