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1.
The Effect of Prior Creatine Intake for 28 Days on Accelerated Recovery from Exercise-Induced Muscle Damage: A Double-Blind, Randomized, Placebo-Controlled Trial.
Yamaguchi, S, Inami, T, Ishida, H, Morito, A, Yamada, S, Nagata, N, Murayama, M
Nutrients. 2024;(6)
Abstract
Despite the known beneficial effects of creatine in treating exercise-induced muscle damage (EIMD), its effectiveness remains unclear. This study investigates the recovery effect of creatine monohydrate (CrM) on EIMD. Twenty healthy men (21-36 years) were subjected to stratified, randomized, double-blind assignments. The creatine (CRE) and placebo (PLA) groups ingested creatine and crystalline cellulose, respectively, for 28 days. They subsequently performed dumbbell exercises while emphasizing eccentric contraction of the elbow flexors. The EIMD was evaluated before and after exercise. The range of motion was significantly higher in the CRE group than in the PLA group 24 h (h) post exercise. A similar difference was detected in maximum voluntary contraction at 0, 48, 96, and 168 h post exercise (p = 0.017-0.047). The upper arm circumference was significantly lower in the CRE group than in the PLA group at 48, 72, 96, and 168 h post exercise (p = 0.002-0.030). Similar variation was observed in the shear modulus of the biceps brachii muscle at 96 and 168 h post exercise (p = 0.003-0.021) and in muscle fatigue at 0 and 168 h post exercise (p = 0.012-0.032). These findings demonstrate CrM-mediated accelerated recovery from EIMD, suggesting that CrM is an effective supplement for EIMD recovery.
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2.
Ability of NAD and Sirt1 to epigenetically suppress albuminuria.
Hasegawa, K, Tamaki, M, Shibata, E, Inagaki, T, Minato, M, Yamaguchi, S, Shimizu, I, Miyakami, S, Tada, M, Wakino, S
Clinical and experimental nephrology. 2024
Abstract
The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN.
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Interactions between Intestinal Homeostasis and NAD+ Biology in Regulating Incretin Production and Postprandial Glucose Metabolism.
Nagahisa, T, Kosugi, S, Yamaguchi, S
Nutrients. 2023;(6)
Abstract
The intestine has garnered attention as a target organ for developing new therapies for impaired glucose tolerance. The intestine, which produces incretin hormones, is the central regulator of glucose metabolism. Glucagon-like peptide-1 (GLP-1) production, which determines postprandial glucose levels, is regulated by intestinal homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD+) biosynthesis in major metabolic organs such as the liver, adipose tissue, and skeletal muscle plays a crucial role in obesity- and aging-associated organ derangements. Furthermore, NAMPT-mediated NAD+ biosynthesis in the intestines and its upstream and downstream mediators, adenosine monophosphate-activated protein kinase (AMPK) and NAD+-dependent deacetylase sirtuins (SIRTs), respectively, are critical for intestinal homeostasis, including gut microbiota composition and bile acid metabolism, and GLP-1 production. Thus, boosting the intestinal AMPK-NAMPT-NAD+-SIRT pathway to improve intestinal homeostasis, GLP-1 production, and postprandial glucose metabolism has gained significant attention as a novel strategy to improve impaired glucose tolerance. Herein, we aimed to review in detail the regulatory mechanisms and importance of intestinal NAMPT-mediated NAD+ biosynthesis in regulating intestinal homeostasis and GLP-1 secretion in obesity and aging. Furthermore, dietary and molecular factors regulating intestinal NAMPT-mediated NAD+ biosynthesis were critically explored to facilitate the development of new therapeutic strategies for postprandial glucose dysregulation.
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Anammox Bacterial S-Adenosyl-l-Methionine Dependent Methyltransferase Crystal Structure and Its Interaction with Acyl Carrier Proteins.
Uegaki, T, Takei, T, Yamaguchi, S, Fujiyama, K, Sato, Y, Hino, T, Nagano, S
International journal of molecular sciences. 2023;(1)
Abstract
Ladderane lipids (found in the membranes of anaerobic ammonium-oxidizing [anammox] bacteria) have unique ladder-like hydrophobic groups, and their highly strained exotic structure has attracted the attention of scientists. Although enzymes encoded in type II fatty acid biosynthesis (FASII) gene clusters in anammox bacteria, such as S-adenosyl-l-methionine (SAM)-dependent enzymes, have been proposed to construct a ladder-like structure using a substrate connected to acyl carrier protein from anammox bacteria (AmxACP), no experimental evidence to support this hypothesis was reported to date. Here, we report the crystal structure of a SAM-dependent methyltransferase from anammox bacteria (AmxMT1) that has a substrate and active site pocket between a class I SAM methyltransferase-like core domain and an additional α-helix inserted into the core domain. Structural comparisons with homologous SAM-dependent C-methyltransferases in polyketide synthase, AmxACP pull-down assays, AmxACP/AmxMT1 complex structure predictions by AlphaFold, and a substrate docking simulation suggested that a small compound connected to AmxACP could be inserted into the pocket of AmxMT1, and then the enzyme transfers a methyl group from SAM to the substrate to produce branched lipids. Although the enzymes responsible for constructing the ladder-like structure remain unknown, our study, for the first time, supports the hypothesis that biosynthetic intermediates connected to AmxACP are processed by SAM-dependent enzymes, which are not typically involved in the FASII system, to produce the ladder-like structure of ladderane lipids in anammox bacteria.
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Perilla seed oil in combination with nobiletin-rich ponkan powder enhances cognitive function in healthy elderly Japanese individuals: a possible supplement for brain health in the elderly.
Hashimoto, M, Matsuzaki, K, Maruyama, K, Hossain, S, Sumiyoshi, E, Wakatsuki, H, Kato, S, Ohno, M, Tanabe, Y, Kuroda, Y, et al
Food & function. 2022;(5):2768-2781
Abstract
Perilla (Perilla frutescens) seed oil (PO), rich in α-linolenic acid (ALA), can improve cognitive function in healthy elderly Japanese people. Here, supplements containing either PO alone or PO with nobiletin-rich air-dried immature ponkan powder were examined for their effects on cognitive function in 49 healthy elderly Japanese individuals. Patients were enrolled in a 12-month randomized, double-blind, parallel-armed study. Randomized participants in the PO group received soft gelatin capsules containing 1.47 mL (0.88 g of ALA) of PO daily, and those in the PO + ponkan powder (POPP) group received soft gelatin capsules containing both 1.47 mL of PO and 1.12 g ponkan powder (2.91 mg of nobiletin) daily. At the end of intervention, the POPP group showed significantly higher cognitive index scores than the PO group. The pro-cognitive effects of POPP treatment were accompanied by increases in ALA and docosahexaenoic acid levels in red blood cell plasma membranes, serum brain-derived neurotropic factor (BDNF) levels, and biological antioxidant potential. We demonstrate that 12-month intervention with POPP enhances serum BDNF and antioxidant potential, and may improve age-related cognitive impairment in healthy elderly people by increasing red blood cell ω-3 fatty acid levels. Clinical Trial Registry, UMIN000040863.
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Effect of Branched-Chain Amino Acid Infusion on In-Hospital Mortality of Patients With Hepatic Encephalopathy and End-Stage Kidney Disease: A Retrospective Cohort Study Using a National Inpatient Database.
Okada, A, Yamana, H, Yamaguchi, S, Kurakawa, KI, Michihata, N, Matsui, H, Fushimi, K, Nangaku, M, Yamauchi, T, Yasunaga, H, et al
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2022;(4):432-440
Abstract
OBJECTIVES Renal failure and hepatic cirrhosis are mutually aggravating factors. However, no specific therapeutic strategies for hepatic encephalopathy (HE) and end-stage kidney disease have been established. The coexistence, with an extremely poor prognosis, makes randomized controlled trials unfeasible. We evaluated whether an infusion of branched-chain amino acids was associated with mortality in patients hospitalized for HE and end-stage kidney disease. DESIGN AND METHODS Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified patients with HE and end-stage kidney disease who received hemodialysis within 2 days of admission from July 2011 to March 2017. We divided the patients into those who received branched-chain amino acid infusion within 2 days of admission and those who did not. We conducted analyses using overlap weights based on propensity scores to compare in-hospital mortality between the groups. Sub-group analysis was conducted by stratifying patients by Child-Pugh class. RESULTS We identified 553 eligible patients, including 503 patients who received branched-chain amino acid infusion and 50 who did not. The patients who received branched-chain amino acid infusion had lower mortality than those who did not (10.2% vs. 20.1%, relative risk 0.51, 95% confidence interval 0.27-0.95). Sub-group analysis showed that branched-chain amino acid infusion was associated with decreased in-hospital mortality in patients with Child-Pugh class C (16.2% vs. 39.0%, relative risk 0.41, 95% confidence interval 0.23-0.76). CONCLUSIONS Branched-chain amino acid infusion may improve the prognosis of HE in patients with end-stage kidney disease, particularly those with lower liver function. Further research is necessary to provide a suitable treatment for HE in patients with end-stage kidney disease.
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Change in Cardiovascular Health Metrics and Risk for Proteinuria Development: Analysis of a Nationwide Population-Based Database.
Suzuki, Y, Kaneko, H, Okada, A, Itoh, H, Morita, K, Fujiu, K, Michihata, N, Jo, T, Takeda, N, Morita, H, et al
American journal of nephrology. 2022;(2-3):240-248
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Abstract
INTRODUCTION Evidence is lacking regarding the association between cardiovascular health (CVH) metrics and the risk for proteinuria. METHODS We performed this observational cohort study including 865,087 participants (median age, 46 years, 60.7% men) with negative proteinuria at the initial health check-up, who underwent repeated health check-ups within 4 years. Ideal CVH metrics included nonsmoking, body mass index <25 kg/m2, physical activity at goal, eating breakfast, blood pressure <120/80 mm Hg, fasting plasma glucose <100 mg/dL, and total cholesterol <200 mg/dL. The primary outcome was incident proteinuria, defined as ≥1 + on the urine dipstick test. RESULTS Participants were categorized as having low CVH metrics defined as having 0-2 ideal CVH metrics (n = 84,439), middle CVH metrics defined as having 3-4 ideal CVH metrics (n = 335,773), and high CVH metrics defined as having 5-7 ideal CVH metrics (n = 444,875). Compared with low CVH metrics, middle CVH metrics (odds ratio (OR): 0.61, 95% CI: 0.59-0.63) and high CVH metrics (OR: 0.45, 95% CI: 0.43-0.46) were associated with a lower risk of proteinuria. The OR of a one-point increase in the ideal number of CVH metrics was 0.83 (95% CI: 0.82-0.83). All CVH metrics components except for ideal total cholesterol were associated with a decreased risk of proteinuria. A one-point improvement in the number of ideal CVH metrics at 1 year after the initial health check-up was associated with a decreased incidence of proteinuria (OR: 0.90, 95% CI: 0.89-0.92). CONCLUSION Not only maintaining better CVH metrics but also improving CVH metrics would prevent developing proteinuria in a general population.
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Prediabetes in Young Adults and Its Association With Cardiovascular Health Metrics in the Progression to Diabetes.
Suzuki, Y, Kaneko, H, Okada, A, Matsuoka, S, Itoh, H, Fujiu, K, Michihata, N, Jo, T, Takeda, N, Morita, H, et al
The Journal of clinical endocrinology and metabolism. 2022;(7):1843-1853
Abstract
CONTEXT The natural history of young adults with prediabetes and its association with cardiovascular health (CVH) metrics in progression to diabetes remain unknown. OBJECTIVE We examined the association between CVH metrics and the annual incidence of diabetes in young adults with prediabetes. METHODS This observational cohort study used the JMDC Claims Database. We analyzed 18 908 participants aged 18 to 44 years, with available fasting plasma glucose (FPG) data for 5 consecutive years, and who had prediabetes (FPG 100-125 mg/dL) at the initial health checkup. The ideal CVH metrics were as follows: nonsmoking, body mass index (BMI) less than 25 kg/m2, physical activity at goal, optimal dietary habits, blood pressure less than 120/80 mm Hg, and total cholesterol less than 200 mg/dL. We analyzed the association between CVH metrics and the annual incidence of diabetes. We also examined the relationship between 1-year changes in CVH metrics and the subsequent risk of diabetes. RESULTS The incidence of diabetes was 3.3% at 1 year and 9.5% at 5 years after the initial health checkup. An increasing number of nonideal CVH metrics have been associated with an increased risk of diabetes. Nonideal BMI, smoking, blood pressure, and total cholesterol level were associated with an increased risk of diabetes. This association was observed both in men and women. A one-point increase in the number of nonideal CVH metric components was associated over 1 year with an increased risk of diabetes. CONCLUSION CVH metrics can stratify the risk of diabetes in young adults with prediabetes. Improving CVH metrics may reduce the risk of developing diabetes.
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Combination of TAS-102 and bevacizumab as third-line treatment for metastatic colorectal cancer: TAS-CC3 study.
Yoshida, Y, Yamada, T, Kamiyama, H, Kosugi, C, Ishibashi, K, Yoshida, H, Ishida, H, Yamaguchi, S, Kuramochi, H, Fukazawa, A, et al
International journal of clinical oncology. 2021;(1):111-117
Abstract
BACKGROUND TAS-102 improved the overall survival of metastatic colorectal cancer (CRC) patients with a median progression-free survival (PFS) in the RECOURSE trial. Subsequently, the combination of TAS-102 and bevacizumab was shown to extend the median PFS (C-TASK FORCE study). However, the study included patients who received second- and third-line treatment. Our study exclusively examined patients receiving this combination as a third-line treatment to investigate the clinical impact beyond cytotoxic doublets. METHODS This investigator-initiated, open-label, single-arm, multi-centered phase II study was conducted in Japan. Eligible CRC patients were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin in first- and second-line therapy. TAS-102 (35 mg/m2) was given orally twice daily on days 1-5 and 8-12 in a 4-week cycle, and bevacizumab (5 mg/kg) was administered by intravenous infusion every 2 weeks. The primary endpoint was PFS and the secondary endpoints were time-to-treatment failure, response rate, overall survival (OS), and safety. RESULTS Between June 2016 and August 2017, 32 patients were enrolled. All patients previously received bevacizumab. The median PFS was 4.5 months; the median overall survival was 9.3 months. Partial response was observed in two patients. The most common adverse events above grade 3 were neutropenia followed by thrombocytopenia. There were no non-hematological adverse events above grade 3 and no treatment-related deaths occurred. CONCLUSIONS This study met its primary endpoint of PFS, which is comparable to the results of the C-TASK FORCE study. The TAS-102 and bevacizumab combination has the potential to be a therapeutic option for third-line treatment of metastatic CRC.
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Potential effective treatment of shortening continuous erythropoietin receptor activator treatment interval combined with iron supplementation in hemodialysis patients.
Kawai, Y, Toya, Y, Wakui, H, Fujikawa, T, Ueda, E, Azushima, K, Kinguchi, S, Mitsuhashi, H, Kawano, T, Kuji, T, et al
Journal of pharmacological sciences. 2021;(1):118-125
Abstract
Our previous randomized controlled trial comparing the total dose of weekly versus biweekly continuous erythropoietin receptor activator (CERA) therapy to maintain optimal hemoglobin (Hb) levels showed no significant differences between the two therapies. This post-hoc analysis assessed whether the total dose of weekly versus biweekly CERA therapy to maintain Hb levels among HD patients differed among groups with or without iron supplementation. Of 107 patients, 40 received intravenous iron supplementation due to iron deficiency (iron group) and 67 did not (non-iron group). In the iron group, the weekly therapy tended to require a lower total CERA dose compared with the biweekly therapy (274 ± 274 vs 381 ± 223 μg/12 weeks, P = 0.051). Changes in circulating hepcidin levels, a negative regulator of intestinal iron uptake, after 2 weeks of CERA treatment were significantly lower in the weekly therapy compared with the biweekly therapy (-4.2 ± 6.3 vs 11.1 ± 7.3 ng/mL, P = 0.015). In the non-iron group, there were no significant differences in total CERA dose or changes in hepcidin levels between the two therapies. Shortening the CERA treatment interval combined with iron supplementation may lead to the more efficient treatment of HD patients with iron deficiency.