Hydrological environment affects the nutrient retention and runoff function of naturally re-wetted agricultural peatland in lowland river floodplain.

Re-wetting of agricultural areas reclaimed by draining peatlands reportedly entails risks of nutrient loads downstream because of leaching of dissolved nutrients from pools in the soil. On floodplain fens, nutrient retention and runoff function have been recognized as dependent upon the hydrological environments of re-wetted agricultural peatland (RAP). Although many studies have been conducted for artificially re-wetted agricultural peatlands (artificial RAPs), knowledge on naturally re-wetted agricultural peatlands (natural RAPs) has been lacking. This study assessed the natural re-wetting of agricultural areas in floodplain fens in terms of risks of nutrient loading in the basin of Kushiro Mire, northern Japan. Flooding of the adjacent river caused by heavy rainfall remarkably increased the water flow, and the inflow and outflow fluxes of nitrogen (N) and phosphorus (P) of a test plot in the natural RAP. Flood waters supplied mainly inorganic nutrients to the test plot, including NO3-N and PO4-P. Larger amounts of dissolved organic N and P, NH4-N, and PO4-P that had accumulated in surface water and surface groundwater in the plot flowed out. Consequently, the test plot represented net runoff of 3 and 0.4 mg m-2 day-1 as total N and total P, respectively, for the average of the whole observation period. The test plot was a source of N loading downstream, which was contrary to results obtained for artificial RAPs in many studies. However, the test plot showed a smaller amount of net phosphorus runoff. Our findings suggest that water level fluctuation and river flood water inflow affect the nutrient retention and runoff functions of RAPs. Repeated inundated and dried conditions, with no continuous inflow of river water, explain the nutrient runoff in the test plot.

Effects of Branched-Chain Amino Acids on Skeletal Muscle, Glycemic Control, and Neuropsychological Performance in Elderly Persons with Type 2 Diabetes Mellitus: An Exploratory Randomized Controlled Trial.

Although branched-chain amino acids (BCAA) are known to stimulate myofibrillar protein synthesis and affect insulin signaling and kynurenine metabolism (the latter being a metabolite of tryptophan associated with depression and dementia), the effects of BCAA supplementation on type 2 diabetes (T2D) are not clear. Therefore, a 24-week, prospective randomized open blinded-endpoint trial was conducted to evaluate the effects of supplementation of 8 g of BCAA or 7.5 g of soy protein on skeletal muscle and glycemic control as well as adverse events in elderly individuals with T2D. Thirty-six participants were randomly assigned to the BCAA group (n = 21) and the soy protein group (n = 15). Skeletal muscle mass and HbA1c, which were primary endpoints, did not change over time or differ between groups. However, knee extension muscle strength was significantly increased in the soy protein group and showed a tendency to increase in the BCAA group. Homeostasis model assessment for insulin resistance did not significantly change during the trial. Depressive symptoms were significantly improved in the BCAA group but the difference between groups was not significant. Results suggested that BCAA supplementation may not affect skeletal muscle mass and glycemic control and may improve depressive symptoms in elderly individuals with T2D.

Simple stain-free screening method for pectinolytic microorganisms under alkalophilic conditions.

OBJECTIVES: To develop a simple pectin-degrading microorganism screening method. RESULTS: We developed a method utilizing the phenomenon whereby cooling an alkaline agar medium containing pectin causes the agar to become cloudy. This highly simplified method involves culturing the microorganisms on pectin-containing agar medium until colony formation is observed, and subsequent overnight cooling of the agar medium to 4 °C. Using this simple procedure, we successfully identified pectin-degrading microorganisms by observing colonies with halos on the clouded agar medium. We used alkaline pectinase and Bacillus halodurans, which is known to secrete alkaline pectinase, to establish the screening method. We demonstrated the screening of pectin-degrading microorganisms using the developed method and successfully isolated pectin-degrading microorganisms (Paenibacillus sp., Bacillus clausii, and Bacillus halodurans) from a soil sample. CONCLUSIONS: The developed method is useful for identifying pectin-degrading microorganisms.

Prognostic significance of the controlling nutritional status score in patients with metastatic renal cell carcinoma diagnosed before an era of first-line immune-oncology combination therapies.

OBJECTIVE: To explore the prognostic role of the controlling nutritional status score in patients with metastatic renal cell carcinoma. METHODS: We retrospectively analyzed 107 patients with metastatic renal cell carcinoma who received their diagnosis between 2007 and 2018 and were treated with or without a first-line interferon or tyrosine kinase inhibitor at a single cancer center. The controlling nutritional status score was based on values for albumin, lymphocyte count and total cholesterol at the metastatic renal cell carcinoma diagnosis. Association of the controlling nutritional status score and clinical variables, including the Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium risk classifications, with overall survival was examined using the Cox proportional hazard model. Predictive accuracy of the prognostic factors was assessed using Harrell's concordance index. RESULTS: First-line interferon and tyrosine kinase inhibitor were given to 48 (45%) and 41 (38%) patients, respectively, and 28 (26%) and 33 (31%) patients underwent cytoreductive nephrectomy and metastasectomy, respectively. During follow-up (median: 36.3 months), 64 patients died. The median controlling nutritional status score was 2 (range: 0-8). A controlling nutritional status score ≥ 2 was significantly associated with shorter overall survival (P < 0.01) independently of the Memorial Sloan-Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium risk classifications. Integration of the controlling nutritional status score into the Memorial Sloan-Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium risk classifications improved concordance index from 0.702 to 0.770 and from 0.698 to 0.749, respectively. CONCLUSION: The controlling nutritional status score may serve as a prognostic biomarker objectively reflecting the general physical condition of patients with metastatic renal cell carcinoma treated with or without first-line interferon or tyrosine kinase inhibitor in terms of nutritional and immuno-inflammatory status.

Proline-arginine poly-dipeptide encoded by the C9orf72 repeat expansion inhibits adenosine deaminase acting on RNA.

A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Unconventional translation of the hexanucleotide repeat expansion generates five dipeptide repeat proteins (DPRs). The molecular mechanism underlying the DPR-linked neurotoxicity is under investigation. In this study, using cell-based models, we show that poly-proline-arginine DPR (poly-PR), the most neurotoxic DPR in vitro, binds to adenosine deaminase acting on RNA (ADAR)1p110 and ADAR2 and inhibits their RNA editing activity. We further show that poly-PR impairs cellular stress response that is mediated by ADAR1p110. These results together suggest that the poly-PR-mediated inhibition of the ADAR activity contributes to C9-ALS/FTD-linked neurotoxicity.

Lactobacillus paracasei KW3110 Suppresses Inflammatory Stress-Induced Premature Cellular Senescence of Human Retinal Pigment Epithelium Cells and Reduces Ocular Disorders in Healthy Humans.

Lactobacillus paracasei KW3110 (KW3110) has anti-inflammatory effects and mitigates retinal pigment epithelium (RPE) cell damage caused by blue-light exposure. We investigated whether KW3110 suppresses chronic inflammatory stress-induced RPE cell damage by modulating immune cell activity and whether it improves ocular disorders in healthy humans. First, we showed that KW3110 treatment of mouse macrophages (J774A.1) produced significantly higher levels of interleukin-10 as compared with other lactic acid bacterium strains (all p < 0.01). Transferring supernatant from KW3110- and E. coli 0111:B4 strain and adenosine 5'-triphosphate (LPS/ATP)-stimulated J774A.1 cells to human retinal pigment epithelium (ARPE-19) cells suppressed senescence-associated phenotypes, including proliferation arrest, abnormal appearance, cell cycle arrest, and upregulation of cytokines, and also suppressed expression of tight junction molecule claudin-1. A randomized, double-blind, placebo-controlled parallel-group study of healthy subjects (n = 88; 35 to below 50 years) ingesting placebo or KW3110-containing supplements for 8 weeks showed that changes in critical flicker frequency, an indicator of eye fatigue, from the week-0 value were significantly larger in the KW3110 group at weeks 4 (p = 0.040) and 8 (p = 0.036). These results suggest that KW3110 protects ARPE-19 cells against premature senescence and aberrant expression of tight junction molecules caused by chronic inflammatory stress, and may improve chronic eye disorders including eye fatigue.

Prognostic Significance of the Controlling Nutritional Status (CONUT) Score in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab after Failure of Prior Tyrosine Kinase Inhibitors.

PURPOSE: The controlling nutritional status (CONUT) score, consisting of albumin, lymphocytes and total cholesterol, is a validated, objective tool for nutritional assessment. Patients with advanced cancer frequently have malnutrition in association with cachexia and chronic inflammation. We explored the prognostic significance of the CONUT score in patients with advanced renal cell carcinoma receiving nivolumab. MATERIALS AND METHODS: This retrospective study included 60 patients with stage IV renal cell carcinoma treated with nivolumab after failure of prior tyrosine kinase inhibitors at 2 cancer centers between 2016 and 2019. Associations of the CONUT score with progression-free survival, cancer specific survival and tumor shrinkage rate were assessed. RESULTS: The median (range) CONUT score was 2 (0-10). During followup periods 29 and 14 patients exhibited disease progression and died of cancer, respectively. Both progression-free survival and cancer specific survival were significantly stratified by CONUT scores of 0 to 1, 2 to 4 and 5 or more (p=0.002). A CONUT score of 5 or more (versus score 0 to 1) was independently associated with unfavorable progression-free survival (HR 5.18, p=0.003) and cancer specific survival (HR 15.34, p=0.014), as was the absence of prior nephrectomy (HR 4.23, p=0.004 and HR 6.57, p=0.001, respectively). C-indices of the CONUT score for predicting progression-free survival and cancer specific survival were 0.694 and 0.737, respectively. The CONUT score was significantly associated with the best response to nivolumab with the median tumor shrinkage rate of -23%, +8% and +24% for CONUT scores of 0 to 1, 2 to 4 and 5 or more, respectively (p=0.021). CONCLUSIONS: The CONUT score may be useful to predict the clinical outcomes and therapeutic response in patients with advanced renal cell carcinoma receiving nivolumab.

Olive leaf tea is beneficial for lipid metabolism in adults with prediabetes: an exploratory randomized controlled trial.

Olive leaves are rich in oleuropein, which has been shown to have beneficial effects on dyslipidemia, type 2 diabetes, and obesity. However, we previously found no significant health benefits of olive leaf tea (OLT) on nonobese and nondiabetic individuals. Thus, we performed this study to further explore the health benefits of OLT in individuals with prediabetes and compare the health benefits between low-concentration OLT (LOLT) and OLT. We hypothesized that OLT will have a more pronounced effect on abdominal obesity as well as glucose and lipid metabolism in prediabetic individuals. Individuals between 40 and 70 years of age with a body mass index of 23.0-29.9 kg/m2 and prediabetes status were recruited and randomly assigned to the OLT or the LOLT group. The intervention, which was the consumption of 330 mL of the test beverage 3 times daily during mealtime, lasted for 12 weeks. After the intervention, serum levels of log-transformed triglycerides (P < .05) and low-density lipoprotein cholesterol (P < .01) decreased significantly in the OLT group (n = 28), with the reductions higher in the OLT group than those in the LOLT group (n = 29, log-transformed triglycerides: P = .079, low-density lipoprotein cholesterol: P < .05). Whereas body weight, waist circumference, and insulin levels were not significantly changed in both groups, fasting plasma glucose levels in the OLT group were significantly decreased compared to those in the LOLT group (P < .05). In conclusion, although the effect of OLT on abdominal obesity and glucose metabolism remains unclear, OLT has been found to have lipid-lowering effects.

The proline-arginine repeat protein linked to C9-ALS/FTD causes neuronal toxicity by inhibiting the DEAD-box RNA helicase-mediated ribosome biogenesis.

A GGGGCC repeat expansion in the C9ORF72 gene has been identified as the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeat expansion undergoes unconventional translation to produce dipeptide repeat (DPR) proteins. Although it has been reported that DPR proteins cause neurotoxicity, the underlying mechanism has not been fully elucidated. In this study, we have first confirmed that proline-arginine repeat protein (poly-PR) reduces levels of ribosomal RNA and causes neurotoxicity and found that the poly-PR-induced neurotoxicity is repressed by the acceleration of ribosomal RNA synthesis. These results suggest that the poly-PR-induced inhibition of ribosome biogenesis contributes to the poly-PR-induced neurotoxicity. We have further identified DEAD-box RNA helicases as poly-PR-binding proteins, the functions of which are inhibited by poly-PR. The enforced reduction in the expression of DEAD-box RNA helicases causes impairment of ribosome biogenesis and neuronal cell death. These results together suggest that poly-PR causes neurotoxicity by inhibiting the DEAD-box RNA helicase-mediated ribosome biogenesis.

Selective peroxisome proliferator-activated receptor-α modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-α pathway and improves lipid metabolism in mice.

AIMS/INTRODUCTION: Peroxisome proliferator-activated receptor-α (PPARα) is a therapeutic target for hyperlipidemia. K-877 is a new selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. The aim of the present study was to assess the effects of K-877 on lipid metabolism in vitro and in vivo compared with those of classical PPARα agonists. MATERIALS AND METHODS: To compare the effects of K-877 on PPARα transcriptional activity with those of the classical PPARα agonists Wy14643 (Wy) and fenofibrate (Feno), the cell-based PPARα transactivation luciferase assay was carried out. WT and Ppara-/- mice were fed with a moderate-fat (MF) diet for 6 days, and methionine-choline-deficient (MCD) diet for 4 weeks containing Feno or K-877. RESULTS: In luciferase assays, K-877 activated PPARα transcriptional activity more efficiently than the classical PPARα agonists Feno and Wy. After being fed MF diet containing 0.001% K-877 or 0.2% Feno for 6 days, mice in the K-877 group showed significant increases in the expression of Ppara and its target genes, leading to marked reductions in plasma triglyceride levels compared with those observed in Feno-treated animals. These K-877 effects were blunted in Ppara-/- mice, confirming that K-877 activates PPARα. In further experiments, K-877 (0.00025%) and Feno (0.1%) equally improved the pathology of MCD diet-induced non-alcoholic fatty liver disease, with increased expression of hepatic fatty acid oxidation genes. CONCLUSIONS: The present data show that K-877 is an attractive PPARα-modulating drug and can efficiently reduce plasma triglyceride levels, thereby alleviating the dysregulation of lipid metabolism.

Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs-eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)-in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

Multicenter phase II randomized study evaluating dose-response of antiperistaltic effect of L-menthol sprayed onto the gastric mucosa for upper gastrointestinal endoscopy.

AIM: Peppermint oil solution was found to be effective for reducing gastric spasm during upper gastrointestinal endoscopy. The aim of the present study was to assess whether the gastric peristalsis-suppressing effect is dose-dependently induced by L-menthol, the major constituent of peppermint oil, and to determine the recommended dose of an L-menthol preparation. METHODS: In this phase II, multicenter, double-blind, dose-response study, 131 eligible patients were randomly assigned to receive 20 mL of 0.4% L-menthol (n = 32), 0.8% L-menthol (n = 35), 1.6% L-menthol (n = 30), or placebo (n = 34). The primary efficacy measure was the proportion of subjects with no peristalsis in two time periods, 75 to 105 s after treatment and immediately before the completion of endoscopy. RESULTS: The peristalsis-suppressing effect of L-menthol increased dose dependently (5.6%, 32.0%, 47.4% and 52.9% in the 0%, 0.4%, 0.8% and 1.6% groups, respectively: P < 0.001, one-tailed Cochran-Armitage trend test). As compared with the placebo group, the proportion of subjects with no peristalsis after administration was significantly higher in the 0.8% group (P = 0.015) and 1.6% group (P = 0.009). Adverse events in the L-menthol dose groups occurred with similar frequencies in the placebo group. CONCLUSION: L-menthol suppresses peristalsis in a dose-dependent manner, and the dose-response reaches a plateau at 0.8% L-menthol. Further Phase III studies are needed to establish the superiority of 0.8% L-menthol over placebo.

Physiological changes in circulating mannose levels in normal, glucose-intolerant, and diabetic subjects.

Mannose is an essential hexose that is required for glycoprotein synthesis. Although circulating mannose levels are known to be influenced by metabolic disorders, how physiological levels of mannose fluctuate in normal and diabetic subjects is largely unknown. We describe a new accurate and sensitive assay for determining circulating mannose levels, which we used to measure plasma mannose levels in 273 normal and diabetic (DM) subjects. Our results revealed a clear correlation (r = 0.754) between fasting plasma mannose (FPM) and fasting plasma glucose (FPG) levels. Our mannose assay showed sensitivity and specificity comparable to that seen for hemoglobin A(1c) (HbA(1c)) assay in subjects with impaired glucose tolerance (IGT) or DM whose FPG levels were normal. Mannose levels were found to increase less than glucose levels in response to an oral glucose tolerance test (OGTT). Furthermore, plasma mannose levels did not significantly change following a meal and more closely correlated with the coefficient of variation (CV) of daily glucose levels than did glucose itself. In conclusion, the close correlation between FPM and FPG levels taken together with the small fluctuations seen in plasma mannose in response to glucose suggests that the measurement of mannose using our assay could potentially play a supplementary role in the diagnosis and screening of patients with mild DM.