Dietary alpha-ketoglutarate promotes beige adipogenesis and prevents obesity in middle-aged mice

Aging usually involves the progressive development of certain illnesses, including diabetes and obesity. Due to incapacity to form new white adipocytes, adipose expansion in aged mice primarily depends on adipocyte hypertrophy, which induces metabolic dysfunction. On the other hand, brown adipose tissue burns fatty acids, preventing ectopic lipid accumulation and metabolic diseases. However, the capacity of brown/beige adipogenesis declines inevitably during the aging process. Previously, we reported that DNA demethylation in the Prdm16 promoter is required for beige adipogenesis. DNA methylation is mediated by ten-eleven family proteins (TET) using alpha-ketoglutarate (AKG) as a cofactor. Here, we demonstrated that the circulatory AKG concentration was reduced in middle-aged mice (10-month-old) compared with young mice (2-month-old). Through AKG administration replenishing the AKG pool, aged mice were associated with the lower body weight gain and fat mass, and improved glucose tolerance after challenged with high-fat diet (HFD). These metabolic changes are accompanied by increased expression of brown adipose genes and proteins in inguinal adipose tissue. Cold-induced brown/beige adipogenesis was impeded in HFD mice, whereas AKG rescued the impairment of beige adipocyte functionality in middle-aged mice. Besides, AKG administration up-regulated Prdm16 expression, which was correlated with an increase of DNA demethylation in the Prdm16 promoter. In summary, AKG supplementation promotes beige adipogenesis and alleviates HFD-induced obesity in middle-aged mice, which is associated with enhanced DNA demethylation of the Prdm16 gene

CB1 Cannabinoid Receptor Activation Dose-Dependently Modulates Neuronal Activity within Caudal but not Rostral Song Control Regions of Adult Zebra Finch Telencephalon

CB1 cannabinoid receptors are distinctly expressed at high density within several regions of zebra finch telencephalon including those known to be involved in song learning (lMAN and Area X) and production (HVC and RA). Because: (1) exposure to cannabinoid agonists during developmental periods of auditory and sensory-motor song learning alters song patterns produced later in adulthood and; (2) densities of song region expression of CB1 waxes-and-wanes during song learning, it is becoming clear that CB1 receptor-mediated signaling is important to normal processes of vocal development. To better understand mechanisms involved in cannabinoid modulation of vocal behavior we have investigated the dose-response relationship between systemic cannabinoid exposure and changes in neuronal activity (as indicated by expression of the transcription factor, c- Fos) within telencephalic brain regions with established involvement in song learning and/or control. In adults we have found that low doses (0.1 mg/kg) of the cannabinoid agonist WIN-55212-2 decrease neuronal activity (as indicated by densities of c-fos-expressing nuclei) within vocal motor regions of caudal telencephalon (HVC and RA) while higher doses (3 mg/kg) stimulate activity. Both effects were reversed by pretreatment with the CB1-selective antagonist rimonabant. Interestingly, no effects of cannabinoid treatment were observed within the rostral song regions lMAN and Area X, despite distinct and dense CB1 receptor expression within these areas. Overall, our results demonstrate that, depending on dosage, CB1 agonism can both inhibit and stimulate neuronal activity within brain regions controlling adult vocal motor output, implicating involvement of multiple CB1-sensitive neuronal circuits. Originally published Psychopharmacology, Vol. 199, No. 2, Aug 200

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

HEALTH BENEFITS OF DIETARY BIOACTIVE COMPOUND ON INFLAMMATORY BOWEL DISEASE AND COLORECTAL CANCER

The industrial revolution is associated with a surge in the number of cases of inflammatory bowel disease (IBD) in western countries. In recent years, the incidence of IBD is continuously rising in newly industrialized countries. Additionally, the risk of colorectal cancer significantly increased in IBD patients. Diet plays an important role in IBD development, especially for diet with high amounts of processed food and unsaturated fat, but low amounts of vegetables. In this dissertation, the effects of bioactive compounds on inflammatory bowel diseases and colitis associated colorectal cancer were examined by a series of studies. In the first study, mice were subjected to azoxymethane (AOM)/dextran sulfate sodium (DSS) treatment for inducing colorectal cancer. Grape pomace (GP) supplementation decreased tumor number, tumor size and pathological scores. Inflammatory response was also suppressed by dietary GP associated with inhibition of epithelial cell proliferation. Dietary GP protected DNA hypermethylation in the promoter of cdx2, a master regulator in intestinal epithelial differentiation.In the second study, dietary aKG alleviated mucosal damage and macrophage infiltration into colonic tissue induced by DSS, consistent with suppressed gut inflammation and Wnt signaling. Dietary aKG enhanced M1 to M2 macrophage polarization and improved intestinal barrier function. Additionally, aKG supplementation led to elevated colonic aKG levels while decreasing 2-hydroxyglutarate levels suggesting lower glycolytic metabolism.In the third study, the protective effects of dietary glucoraphanin (GRP) on inflammation and oxidative stress were examined in an acute colitis mouse model induced by DSS. Dietary GRP prevented DSS-induced body weight loss and colon shortening, which was associated with decreased inflammatory cytokines. Dietary GRP activated AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α and nuclear factor erythroid 2-related factor 2 (NRF2) in the colonic tissues of DSS-treated mice. Furthermore, GRP supplementation prevented mice from oxidative damage of the colon.In conclusion, this project used DSS and AOM/DSS animal models to demonstrate the beneficial effects of bioactive compounds on IBD and colorectal cancer prevention. Importantly, these studies identified possible molecular targets for the beneficial effects of different bioactive compounds

Essential Oil Blend Could Decrease Diarrhea Prevalence by Improving Antioxidative Capability for Weaned Pigs

Finding an alternative to in-feed antibiotics is important because of increasing contemporary concern regarding drug residues and the development of drug-resistant bacteria. The purpose of this study was to test the hypothesis that essential oils added to the feed would decrease diarrhea prevalence in post-weaned pigs. Ninety weaned piglets (initial body weight (BW): 8.1 ± 1.4 kg) were randomly assigned to one of three dietary diets: (1) a control diet (CON, the basal diet without antibiotics), (2) an antibiotic diet (AB, CON supplemented with colistin sulfate, 20 mg/kg and bacitracin zinc, 40 mg/kg), or (3) an essential oil diet (EO, CON supplemented with an essential oil blend 100 mg/kg) in a completely randomized block design for a 28-day period. The results revealed that AB and EO improved the average daily gain of the piglets from day (d) 15 to 28 (p < 0.05). The diarrhea prevalence in piglets fed AB and EO was lower than that of piglets fed CON (p < 0.05). There was no significant difference in the growth performance or diarrhea prevalence between the AB and EO treatments. Nutrient digestibility was measured at d 28. Compared with CON, EO increased the apparent total tract digestibility of gross energy and crude protein (p < 0.05). Villus height in the duodenum and the ratio of villus height to crypt depth in the jejunum for piglets fed AB and EO was greater than those for piglets fed CON (p < 0.05). The essential oil blend improved the superoxide dismutase (SOD) and catalase (CAT) activities and total antioxidant capacity (T-AOC), but decreased the 8-hydroxy deoxyguanosine content in serum on d 14 (p < 0.05). Decreased malondialdehyde (MDA) and protein carbonyl content were observed on d 28 in comparison with CON (p < 0.05). The mucosa in the jejunum of pigs fed EO had greater T-AOC, SOD levels, and glutathione peroxidase (GSH-Px) activities than that of pigs fed CON (p < 0.05). Pigs fed EO and AB had greater GSH-Px activity in the liver tissue than pigs fed CON (p < 0.05). Not only did jejunal and ileal mucosa have EO upregulated SOD1 mRNA expression (p < 0.05), this was also the case in liver tissue. GPx1 expression in the ileal mucosa and GPx4 expression in the liver tissue were higher for pigs fed EO when compared to those fed CON (p < 0.05). Collectively, a dietary essential oil blend supplementation, which has natural antimicrobial properties, could enhance growth performance and decrease diarrhea prevalence in weaned pigs through increases in antioxidative capacity

Contrast-Enhanced Ultrasound in Residual Tumor of Hepatocellular Carcinoma following Transarterial Chemoembolization: Is It Helpful for Tumor Response?

Aim. To investigate the enhancement pattern of residual tumor on contrast-enhanced ultrasonography (CEUS) in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE). Methods. Our study initially included 76 patients with HCC, 73 of which were finally allocated into two groups: group 1 (43 patients, post-TACE group) and group 2 (30 patients, untreated HCC group). All patients were performed with CEUS using SonoVue, and qualitative and quantitative enhancement characteristics (rise time, peak time, and washout time) were evaluated for the residual tumors. T test or χ2 test was used to estimate for differences between two groups. Results. In group 1, the mean rise time, peak time, and washout times in group 1 were 16.1±2.7 sec, 31.3±3.1 sec, and 191.0±31.3 sec, respectively. In group 2, these were 15.1±3.5 sec, 30.9±3.2 sec, and 142.6±16.1 sec, respectively. The differences in rise time and peak time were not statistically significant (P=0.09 and 0.30, respectively), but the washout time was significantly prolonged in group 1 (P<0.01). The enhanced pattern in arterial phase was inhomogeneous (n=11), regular homogeneous (n=11), partial (n=12), peripheral (n=7), and peripheral rim-like (n=2) in group 1. The average of the longest tumor size of the whole lesion in the 5 types was 4.7±1.3cm, 2.9±1.0cm, 3.1±1.7cm, 2.5±0.6cm, and 2.1 cm. Conclusion. It suggested that the washout time of post-TACE residual lesions was prolonged compared with untreated HCC nodules on CEUS imaging. Combined with the triple-phase enhancement pattern seen on CEUS, the washout time may provide additional information to guide further treatment for residual tumors

Irreversible Electroporation in Patients with Pancreatic Cancer: How Important Is the New Weapon?

Background. Pancreatic cancer (PC) is a deadly disease with poor prognosis in the general population. We aimed to quantitate overall survival of patients with PC after irreversible electroporation (IRE) and the incidence of relevant complications. Methods. We performed a literature search via five electronic databases (PubMed, Embase, Web of Science, Scopus, and Cochrane Library databases) up to August 2017. The primary outcomes were overall survival and prognosis. Secondary outcomes included the response of post-IRE complications. Fixed-effects or random-effects meta-analysis was conducted to pool these data. Results. A total of 15 eligible articles involving 535 patients were included. The primary outcomes showed that the pooled prevalence estimates of overall survival were 94.1% (95% CI: 90.7–97.5), 80.9% (95% CI: 72.5–89.4), 54.5% (95% CI: 38.3–70.6), and 33.8% (95% CI: 14.2–53.5) at 3, 6, 12, and 24 months, and the pooled prevalence data of complete response (CR) at 2 months, partial response (PR) at 3 months, and progression at 3 months were 12.5% (95% CI: 2.9–22.2), 48.5% (95% CI: 39.4–57.6), and 19.7% (95% CI: 7.3–32.2), respectively. The secondary outcomes showed that the pooled prevalence values of post-IRE complications were abscess 6.6% (95% CI: 0.2–13), fistula 10.6% (95% CI: 2.5–18.7), pain 33.5% (95% CI: 14.5–52.5), infection 16.1% (95% CI: 3.9–28.4), thrombosis 4.9% (95% CI: 1.2–8.5), pancreatitis 7.2% (95% CI: 3.1–11.2), bleeding 4.2% (95% CI: −0.5–8.9), cholangitis 4.2% (95% CI: −0.5–8.9), nausea 9.6% (95% CI: 4.4–14.8), biliary obstruction 13.8% (95% CI: 4.2–23.3), chest tightness 7.6% (95% CI: 0.5–14.6), and hypoglycemia 5.9% (95% CI: −0.4–12.2). Conclusions. This meta-analysis indicated a clear survival benefit for PC patients who received irreversible electroporation therapy, although future safety and effectivity monitoring from more large-scale studies will be needed

Alpha-Ketoglutarate Promotes Goblet Cell Differentiation and Alters Urea Cycle Metabolites in DSS-Induced Colitis Mice

The metabolite, alpha-ketoglutarate (aKG), shows promise as an approach for ameliorating colitis, but much remains unknown about the full extent of its effects on the metabolome and mucosal barrier. To further elucidate this matter, C57BL/6 male mice received drinking water with or without 1% aKG for three weeks, then were subjected to 2.5% dextran sulfate sodium (DSS) induction for 7 days followed by 7 days of recovery. Cecal content and intestinal tissue samples were analyzed for changes in metabolite profile and signaling pathways. Gas chromatography-mass spectrometry (GC-MS) metabolomics revealed a separation between the metabolome of mice treated with or without aKG; putrescine and glycine were significantly increased; and ornithine and amide products, oleamide and urea were significantly decreased. Based on a pathway analysis, aKG treatment induced metabolite changes and enriched glutathione metabolism and the urea cycle. Additionally, signaling pathways committing epithelial cells to the secretory lineage were elevated in aKG-treated mice. Consistently, aKG supplementation increased goblet cells staining, mRNA expression of mucin 2, and, trefoil factor 3 and Kr&uuml;ppel-like factor 4, markers of goblet cell differentiation. These data suggest the ameliorating the effects of aKG against chemically induced colitis involves a reduction in harmful metabolites and the promotion of goblet cell differentiation, resulting in a more-fortified mucus layer

Genetic Predisposition to a Higher Whole Body Water Mass May Increase the Risk of Atrial Fibrillation: A Mendelian Randomization Study

Background: Observational studies have found an association between increased whole body water mass (BWM) and atrial fibrillation (AF). However, the causality has yet to be confirmed. To provide feasible protective measures on disease development, we performed Mendelian randomization (MR) design to estimate the potential causal relationship between increased BWM and AF. Methods: We implemented a two-sample MR study to assess whether increased BWM causally influences AF incidence. For exposure, 61 well-powered genetic instruments extracted from UK Biobank (N = 331,315) were used as the proxies of BWM. Summary genetic data of AF were obtained from FinnGen (Ncase = 22,068; Ncontrol = 116,926). Inverse-variance weighted (IVW), MR-Egger and weighted median methods were selected to infer causality, complemented with a series of sensitivity analyses. MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) and Radial MR were employed to identify outliers. Furthermore, risk factor analyses were performed to investigate the potential mechanisms between increased BWM and AF. Results: Genetic predisposition to increased BWM was demonstrated to be significantly associated with AF in the IVW model (OR = 2.23; 95% CI = 1.47–3.09; p = 1.60 × 10−7), and the result was consistent in other MR approaches. There was no heterogeneity or pleiotropy detected in sensitivity analysis. MR-PRESSO identified no outliers with potential pleiotropy after excluding outliers by Radial MR. Furthermore, our risk factor analyses supported a positive causal effect of genetic predicted increased BWM on edematous diseases. Conclusions: MR estimates showed that a higher BWM could increase the risk of AF. Pathological edema is an important intermediate link mediating this causal relationship