川上 歩花, 板東 美香, 髙士 友恵, 杉内 美月, Mizusa Hyodo, 三島 優奈, Masashi Kuroda, 森 博康, 黒田 暁生, 湯本 浩通, 松久 宗英, 阪上 浩, 堤 理恵 : Umami taste sensitivity is associated with food intake and oral environment in subjects with diabetes, The Journal of Medical Investigation : JMI, Vol.70, No.1.2, 241-250, 2023年.
(要約)
Dysgeusia is a serious problem in patients with diabetes because it often leads to overeating, which is associated with disease progression. This study aimed to investigate the association between taste sensitivity, eating habits, and the oral environment. In this cross-sectional study of 75 subjects with diabetes, gustatory function was assessed using the whole-mouth method, and lingual taste receptor gene expression was measured by real-time PCR. Food intake was evaluated using a food frequency questionnaire based on food groups. The oral environment was assessed using xerostomia and periodontal comprehensive examination. In total, 45.3%, 28.0%, and 18.7% of subjects showed lower umami taste sensitivity, low sweet taste sensitivity, and low salt taste sensitivity, respectively. Lower umami sensitivity correlated with lower estimated glomerular filtration rate and higher energy-source food intake. Subjects with diabetes with higher plaque control record showed significantly higher T1R3 gene expression than those with lower plaque control record. Reduced umami taste sensitivity is associated with decreased renal function and high energy food intake in diabetes. Subjects with diabetes with higher plaque control record showed significantly higher T1R3 gene expression, suggesting that the oral environment affects taste gene expression. J. Med. Invest. 70 : 241-250, February, 2023.
The shift of Japanese eating habits from salty and grain-based consumption with low animal protein to a diet with a variety of lipids and animal products after Second World War has significantly reduced the rate of infections and cerebral bleeding. On the other hand, the increase in life-style related diseases such as cancer, heart disease, stroke, diabetes has become a serious problem in our country. However, it is difficult to discuss the nutrition of the elderly in a stereotype because of the diversity in physical and psychological feature. Although there are many important issues that require discussions encompassing broad aspects in taking high protein diet as a main topic, it may be possible to consider a question in the aspects of body weight or body composition in the elderly. In this section, we discuss the `secret key' in nutrition to health for the aged.
(キーワード)
The elderly / 肥満症 (obesity) / 生活習慣病 (lifestyle-related disease) / 栄養 (nutrition) / High protein diet
Kana Beppu, Rie Tsutsumi, Satoshi Ansai, Nana Ochiai, Mai Terakawa, Marie Mori, Masashi Kuroda, Kazuki Horikawa, Takumi Tomoi, Joe Sakamoto, Yasuhiro Kamei, Kiyoshi Naruse and Hiroshi Sakaue : Development of a screening system for agents that modulate taste receptor expression with the CRISPR-Cas9 system in medaka., Biochemical and Biophysical Research Communications, Vol.601, 65-72, 2022.
(要約)
Taste recognition mediated by taste receptors is critical for the survival of animals in nature and is an important determinant of nutritional status and quality of life in humans. However, many factors including aging, diabetes, zinc deficiency, infection with influenza or cold viruses, and chemotherapy can trigger dysgeusia, for which a standard treatment has not been established. We here established an engineered strain of medaka (Oryzias latipes) that expresses green fluorescent protein (GFP) from the endogenous taste 1 receptor 3 (T1R3) gene locus with the use of the CRISPR-Cas9 system. This T1R3-GFP knock-in (KI) strain allows direct visualization of expression from this locus by monitoring of GFP fluorescence. The pattern of GFP expression in the T1R3-GFP KI fish thus mimicked that of endogenous T1R3 gene expression. Furthermore, exposure of T1R3-GFP KI medaka to water containing monosodium glutamate or the anticancer agent 5-fluorouracil resulted in an increase or decrease, respectively, in GFP fluorescence intensity, effects that also recapitulated those on T1R3 mRNA abundance. Finally, screening for agents that affect GFP fluorescence intensity in T1R3-GFP KI medaka identified tryptophan as an amino acid that increases T1R3 gene expression. The establishment of this screening system for taste receptor expression in medaka provides a new tool for the development of potential therapeutic agents for dysgeusia.
(キーワード)
Animals / CRISPR-Cas Systems / Dysgeusia / 遺伝子発現 (gene expression) / Green Fluorescent Proteins / Oryzias / 生活の質 (quality of life) / Taste
Hirofumi Tenshin, Jumpei Teramachi, Mohannad Ashtar, Masahiro Hiasa, Yusuke Inoue, Asuka Oda, Kotaro Tanimoto, Sou Shimizu, Yoshiki Higa, Takeshi Harada, Masahiro Oura, Kimiko Sogabe, Tomoyo Hara, Ryohei Sumitani, Tomoko Maruhashi, Mayu Sebe, Rie Tsutsumi, Hiroshi Sakaue, Itsuro Endo, Toshio Matsumoto, Eiji Tanaka and Masahiro Abe : TGF-β-activated kinase-1 inhibitor LL-Z1640-2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF-α and RANKL expression., Clinical & translational immunology, Vol.11, No.1, 2022.
(要約)
TAK1 inhibition with LLZ may become a novel treatment strategy to effectively alleviate inflammasome-mediated inflammation and RANKL-induced osteoclastic bone destruction in joints alongside its potent suppression of TNF-α and IL-6 production and proteinase-mediated pathological processes in RA.
Kana Beppu, Ayuka Kawakami, Yuna Mishima, Rie Tsutsumi, Masashi Kuroda, Hiroyasu Mori, Akio Kuroda, Munehide Matsuhisa and Hiroshi Sakaue : Taste receptor gene expression is associated with decreased eGFR in patients with diabetes., The Journal of Medical Investigation : JMI, Vol.69, No.1.2, 120-126, 2022.
(要約)
Dysgeusia is not only associated with zinc deficiency but also with certain drugs or diseases, including diabetes and renal failure. It often lowers the patient's quality of life and hinders access to proper nutrition. The underlying mechanism is unclear and there is a lack of awareness among patients. Here, we focused on lingual taste receptor gene expression in diabetes and elucidated the relationship between taste receptor gene expression and renal function. Forty-seven patients with diabetes and 10 healthy subjects (control group) were enrolled. Lingual foliate papillae were scraped and the derived cDNA was quantified by real-time polymerase chain reaction. Dysgeusia was assessed using SALSAVE?. All statistical analyses were performed using JMP? software 13. The expression of T1R1 and T1R2 was significantly upregulated in type 2 diabetes patients as compared with that in healthy subjects (P<0.01) but did not change in type 1 diabetes patients. T1R3 expression positively correlated and Scnn1 expression negatively correlated with estimated glomerular filtration rate, suggesting that altered taste receptor gene expression could reflect impaired renal function. Thus, alterations in T1R3 and Scnn1 expression in diabetes correlated with renal function. Taste receptor gene expression dysregulation could indicate dysgeusia associated with impaired renal function in patients with diabetes. J. Med. Invest. 69 : 120-126, February, 2022.
(キーワード)
Diabetes Mellitus, Type 2 / Dysgeusia / Gene Expression / Humans / Quality of Life / Receptors, G-Protein-Coupled / Taste
Metabolic syndrome is a pathological condition with hyperglycemia, dyslipidemia, or hypertension resulting in cardiovascular and cerebrovascular disease. Factors that affect visceral fat accumulation and weight gain include not only physiological factors such as heredity, constitution, and age, but also behavioral factors and environmental factors. Eating behavior and eating environment are critical for the prevention and treatment of metabolic syndrome. In this report, we will discuss about recent topics of nutrition in metabolic syndrome, especially association with macronutrients such as carbohydrate, fatty acids and protein. In recent years, several publications have determined the benefit of low carbohydrate diet on obesity and diabetes, and the American Diabetes Association has also recommended low carbohydrate diet, Mediterranean diet, and a diet mainly consistent with vegetables and plants. There have been many reports that the effect of carbohydrate restriction has not only the weight loss effect but also reduces risk factors such as cardiovascular disease and cerebrovascular disease. Fanelli et al . recently have shown that half of US adults with diabetes have less than the recommended daily intake of protein, which may lead to poor dietary quality. Diabetic patients with low protein intake had significantly lower dietary nutrient density and 12．5% higher carbohydrate intake, whereas diabetic patients with daily protein intake meeting the recommended amount have shown that the overall quality of the diet was high and almost met the recommended daily amount of vegetables, whole grains, dairy products and added sugars. Therefore, in addition to the prevention of metabolic syndrome, protein is important for treatment of metabolic syndrome and higher QOL. Nutritional research needs further development to deal with metabolic syndrome.
Atsushi Morio, Rie Tsutsumi, Shiho Satomi, Takashi Kondo, Hirotsugu Miyoshi, Takahiro Kato, Masashi Kuroda, Tadahiro Kitamura, Kenta Hara, Noboru Saeki, Hiroshi Sakaue and Yasuo M. Tsutsumi : Leucine imparts cardioprotective effects by enhancing mTOR activity and mitochondrial fusion in a myocardial ischemia/reperfusion injury murine model., Diabetology & Metabolic Syndrome, Vol.13, No.1, 2021.
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mice. Additionally, Leu increased the percentage of fused mitochondria and the mitochondrial volume, and decreased the number of mitochondria per cell in isolated cardiomyocytes. In HFD-induced obese mice, Leu treatment significantly reduced infarct size (41.0% ± 1.1% vs. 51.0% ± 1.4%, n = 7, p < 0.05), which was not induced by ischemic preconditioning, and this effect was inhibited by Rap. Furthermore, we observed enhanced mTOR protein expression and mitochondrial fusion with decreased reactive oxygen species production with Leu treatment in HFD-induced obese mice, but not in mTOR
Rie Tsutsumi, Yuki Yamasaki, Jiro Takeo, Hiroko Miyahara, Mayu Sebe, Masahiro Bando, Yousuke Tanba, Yuna Mishima, Kana Takeji, Nanako Ueshima, Masashi Kuroda, Saeko Masumoto, Nagakatsu Harada, Daiju Fukuda, Ryoko Yoshimoto, Yasuo M. Tsutsumi, Ken-ichi Aihara, Masataka Sata and Hiroshi Sakaue : Long-chain monounsaturated fatty acids improve endothelial function with altering microbial flora, Translational Research : The Journal of Laboratory and Clinical Medicine, Vol.237, 16-30, 2021.
(要約)
Fish oil-derived long-chain monounsaturated fatty acids (LCMUFAs) with a carbon chain length longer than 18 units ameliorate cardiovascular risk in mice. In this study, we investigated whether LCMUFAs could improve endothelial functions in mice and humans. In a double-blind, randomized, placebo-controlled, parallel-group, multi-center study, healthy subjects were randomly assigned to either an LCMUFA oil (saury oil) or a control oil (olive and tuna oils) group. Sixty subjects were enrolled and administrated each oil for 4 weeks. For the animal study, ApoE mice were fed a Western diet supplemented with 3% of either gadoleic acid (C20:1) or cetoleic acid (C22:1) for 12 weeks. Participants from the LCMUFA group showed improvements in endothelial function and a lower trimethylamine-N-oxide level, which is a predictor of coronary artery disease. C20:1 and C22:1 oils significantly improved atherosclerotic lesions and plasma levels of several inflammatory cytokines, including IL-6 and TNF-α. These beneficial effects were consistent with an improvement in the gut microbiota environment, as evident from the decreased ratio of Firmicutes and/ or Bacteroidetes, increase in the abundance of Akkermansia, and upregulation of short-chain fatty acid (SCFA)-induced glucagon-like peptide-1 (GLP-1) expression and serum GLP-1 level. These data suggest that LCMUFAs alter the microbiota environment that stimulate the production of SCFAs, resulting in the induction of GLP-1 secretion. Fish oil-derived long-chain monounsaturated fatty acids might thus help to protect against cardiovascular disease.
Hitoshi Shono, Rie Tsutsumi, Kana Beppu, Rina Matsushima, Suzuno Watanabe, Chisa Fujimoto, Ryo Kanamura, Hiroki Ohnishi, Eiji Kondou, Takahiro Azuma, Gou Satou, Misako Kawai, Hideki Matsumoto, Yoshiaki Kitamura, Hiroshi Sakaue and Noriaki Takeda : Dietary Supplementation with Monosodium Glutamate Suppresses Chemotherapy-Induced Downregulation of the T1R3 Taste Receptor Subunit in Head and Neck Cancer Patients., Nutrients, Vol.13, No.9, 2921, 2021.
(要約)
(Background) We investigated the effect of dietary supplementation with monosodium glutamate (MSG) on chemotherapy-induced downregulation of the T1R3 taste receptor subunit expression in the tongue of patients with advanced head and neck cancer. (Methods) Patients undergoing two rounds of chemoradiotherapy were randomly allocated to a control or intervention group (dietary supplementation with MSG at 2.7 g/day during the second round of chemotherapy). The relative expression of T1R3, a subunit of both umami and sweet taste receptors, in the tongue was assessed by quantitative polymerase chain reaction analysis. Dysgeusia was assessed with a visual analog scale and daily energy intake was evaluated. (Results) T1R3 expression levels in the tongue, taste sensitivity, and daily energy intake were significantly reduced after the first round of chemotherapy compared with before treatment. Furthermore, these parameters significantly decreased after the second round of chemotherapy, but the extent of decrease was significantly attenuated in the MSG group compared with the control group. (Conclusions) MSG supplementation suppresses chemotherapy-induced dysgeusia, possibly due to the inhibition of the T1R3-containing taste receptor downregulation in the tongue, thereby increasing energy intake in patients with advanced head and neck cancer.
(キーワード)
Adult / Aged / Aged, 80 and over / Antineoplastic Agents / Chemoradiotherapy / Dietary Supplements / Down-Regulation / Dysgeusia / Female / Head and Neck Neoplasms / Humans / Male / Middle Aged / Receptors, G-Protein-Coupled / Sodium Glutamate / Taste / Taste Buds / Tongue
Sachiyo Fukushima, Nobuto Nakanishi, Kazumichi Fujioka, Kenichi Suga, Taku Shirakawa, Kayo Osawa, Kanako Hara, Rie Tsutsumi, Maki Urushihara, Ryuji Nakagawa, Hiroyuki Awano, Jun Oto, Hiroshi Sakaue, Kazumoto Iijima and Masafumi Matsuo : Assessment of catabolic state in infants with the use of urinary titin N-fragment., Pediatric Research, 2021.
(要約)
Urinary titin N-fragment levels have been used to assess the catabolic state, and we used this biomarker to evaluate the catabolic state of infants. We retrospectively measured urinary titin N-fragment levels of urinary samples. The primary outcome was its changes according to postmenstrual age. The secondary outcomes included differences between gestational age, longitudinal change after birth, influence on growth, and relationship with blood tests. This study included 219 patients with 414 measurements. Urinary titin N-fragment exponentially declined with postmenstrual age. These values were 12.5 (7.1-19.6), 8.1 (5.1-13.0), 12.8 (6.0-21.3), 26.4 (16.4-52.0), and 81.9 (63.3-106.4) pmol/mg creatinine in full, late, moderate, very, and extremely preterm infants, respectively (p < 0.01). After birth, urinary levels of titin N-fragment exponentially declined, and the maximum level within a week was associated with the time to return to birth weight in preterm infants ( = 0.39, p < 0.01). This was correlated with creatine kinase in full-term infants ( = 0.58, p < 0.01) and with blood urea nitrogen in preterm infants ( = 0.50, p < 0.01). The catabolic state was increased during the early course of the postmenstrual age and early preterm infants. Catabolic state in infants, especially in preterm infants, was expected to be increased, but no study has clearly verified this. In this retrospective study of 219 patients with 414 urinary titin measurements, the catabolic state was exponentially elevated during the early postmenstrual age. The use of the urinary titin N-fragment clarified catabolic state was prominently increased in very and extremely preterm infants.
Atsushi Morio, Rie Tsutsumi, Takashi Kondo, Hirotsugu Miyoshi, Takahiro Kato, Soshi Narasaki, Shiho Satomi, Erika Nakaya, Masashi Kuroda, Hiroshi Sakaue, Tadahiro Kitamura and Yasuo M. Tsutsumi : Leucine induces cardioprotection in vitro by promoting mitochondrial function via mTOR and Opa-1 signaling., Nutrition, Metabolism, and Cardiovascular Diseases : NMCD, 2021.
(要約)
Cardiac myocytes isolated from adult male Wistar rats were incubated and exposed to simulated I/R (SI/R) injury by replacing the air content. Cardiac myocytes were treated with Leu and subsequently, their survival rate was calculated. To elucidate the signaling pathway and mitochondrial function, immunoblots and mitochondrial permeability transition pore were examined. Cell survival rate was decreased with SI/R but improved by 160 μM Leu (38.5 ± 3.6% vs. 64.5 ± 4.2%, respectively, p < 0.001). Although rapamycin (mTOR inhibitor) prevented this cardioprotective effect induced by Leu, wortmannin (PI3K inhibitor) did not interfere with this effect. In addition, we indicated that overexpression of Opa-1 and mitochondrial function are ameliorated via Leu-induced mitochondrial biogenesis. In contrast, knockdown of Opa-1 suppressed Leu-induced cardioprotection.
Manabu Ishihara, Nobuto Nakanishi, Rie Tsutsumi, Kanako Hara, Kyoka Machida, Nobuaki Yamamoto, Yasuhisa Kanematsu, Hiroshi Sakaue, Jun Oto and Yasushi Takagi : Elevated Urinary Titin and its Associated Clinical Outcomes after Acute Stroke., Journal of Stroke & Cerebrovascular Diseases, Vol.30, No.3, 2021.
(要約)
Forty-one patients were included (29 male; age, 68 ± 15 years), 29 had ischemic stroke, 8 had intracerebral hemorrhage, and 4 had subarachnoid hemorrhage. The levels of urinary titin on days 1, 3, 5, and 7 were 9.9 (4.7-21.1), 16.2 (8.6-22.0), 8.9 (4.8-15.2), and 8.7 (3.6-16.2) pmol/mg Cr, respectively. The peak urinary titin level was associated with the mRS score (r = 0.55, p < 0.01), the NIHSS score (r = 0.72, p < 0.01), and the BI (r = -0.59, p < 0.01) upon hospital discharge. In multivariate analysis, the peak urinary titin was associated with poor outcome (p = 0.03).
(キーワード)
Aged / Aged, 80 and over / Biomarkers / Connectin / Disability Evaluation / Female / Functional Status / Humans / Male / Middle Aged / Patient Discharge / Predictive Value of Tests / Prospective Studies / Recovery of Function / Stroke / Time Factors / Treatment Outcome / Up-Regulation / Urinalysis
Yasushi Matsuura, Teruhiro Morishita, Michiko Sato, Nami Sumida, Takafumi Katayama, Rie Tsutsumi, Hiroshi Sakaue, Yutaka Taketani, Koichi Sairyo, Akihiko Kawaura and Eiji Takeda : Effects of daily 1,000-IU vitamin D-fortified milk intake on skeletal muscle mass, power, physical function and nutrition status in Japanese., The Journal of Medical Investigation : JMI, Vol.68, No.3.4, 249-255, 2021.
(要約)
An intervention study was conducted to investigate the effects of daily 1,000-IU vitamin D-fortified milk intake on skeletal muscle mass, power, physical function and nutrition status in 26 healthy people and 8 older adults living in a nursing home. The serum 25-hydroxyvitamin D [25(OH)D] level was 13.4 ± 0.8 ng / mL and it markedly increased to 29.6 ± 0.9 ng / mL after daily 1000-IU vitamin D-fortified milk intake for 6 months. Handgrip strength (kg) also significantly increased in the 21-50 years and total groups, and male subjects, and the timed up and go test significantly improved in the 21-50 years and total groups, and female subjects after 6-month vitamin D intake. However, there were no significant differences between baseline and post-treatment in the Barthel Index (BI), walking speed (m / sec) or skeletal muscle mass (kg, % of BW, kg / m2). Therefore, the present study suggested that vitamin D-fortified milk intake is effective at improving muscle strength and physical function in Japanese, although further studies are needed, particularly for older adults. J. Med. Invest. 68 : 249-255, August, 2021.
(キーワード)
Aged / Animals / 女性 (female) / Hand Strength / Humans / 日本 (Japan) / 男性 (male) / Milk / Muscle Strength / Muscle, Skeletal / Nutritional Status / Postural Balance / Time and Motion Studies / ビタミンD (vitamin D)
Nobuto Nakanishi, Jun Oto, Rie Tsutsumi, Yusuke Akimoto, Yuki Nakano and Masaji Nishimura : Upper limb muscle atrophy associated with in-hospital mortality and physical function impairments in mechanically ventilated critically ill adults: a two-center prospective observational study., Journal of Intensive Care, Vol.8, No.1, 2020.
(要約)
In this two-center prospective observational study, we included adult patients who were expected to require mechanical ventilation for > 48 h and remain in the intensive care unit (ICU) for > 5 days. We used ultrasound to evaluate the cross-sectional area of the biceps brachii on days 1, 3, 5, and 7 and upon ICU discharge along with assessment of physical functions. The primary outcome was the relationship between muscle atrophy ratio and in-hospital mortality on each measurement day, which was assessed using multivariate analysis. The secondary outcomes were the relationships between upper limb muscle atrophy and Medical Research Council (MRC) score, handgrip strength, ICU Mobility Scale (IMS) score, and Functional Status Score for the ICU (FSS-ICU).
Nobuto Nakanishi, Jun Oto, Rie Tsutsumi, Tomoko Yamamoto, Yoshitoyo Ueno, Emiko Nakataki, Taiga Itagaki, Hiroshi Sakaue and Masaji Nishimura : Effect of Electrical Muscle Stimulation on Upper and Lower Limb Muscles in Critically Ill Patients: A Two-Center Randomized Controlled Trial., Critical Care Medicine, Vol.48, No.11, e997-e1003, 2020.
(要約)
In critically ill patients, electrical muscle stimulation prevented upper and lower limb muscle atrophy and attenuated proteolysis and decreased the length of hospitalization.
Yuko Okamatsu-Ogura, Masashi Kuroda, Rie Tsutsumi, Ayumi Tsubota, Masayuki Saito, Kazuhiro Kimura and Hiroshi Sakaue : UCP1-dependent and UCP1-independent metabolic changes induced by acute cold exposure in brown adipose tissue of mice., Metabolism: Clinical and Experimental, Vol.113, 154396, 2020.
(要約)
These results revealed that cold exposure induces UCP1-mediated thermogenesis-dependent glucose utilization and UCP1-independent active lipid metabolism in BAT. In addition, cold exposure largely affects amino acid metabolism in BAT, especially UCP1-dependently enhances glutamine utilization. These results contribute a comprehensive understanding of UCP1-mediated thermogenesis-dependent and thermogenesis-independent metabolism in BAT.
Nobuto Nakanishi, Rie Tsutsumi, Kanako Hara, Takuya Takashima, Emiko Nakataki, Taiga Itagaki, Masafumi Matsuo, Jun Oto and Hiroshi Sakaue : Urinary Titin Is a Novel Biomarker for Muscle Atrophy in Nonsurgical Critically Ill Patients: A Two-Center, Prospective Observational Study., Critical Care Medicine, Vol.2020, No.48(9), 1327-1333, 2020.
(要約)
In nonsurgical critically ill patients, urinary titin level increased 10-30 times compared with the normal level. The increased urinary titin level was associated with lower limb muscle atrophy, occurrence of ICU-acquired weakness, and ICU mortality.
Yumiko Miyatake, Yuna Mishima, Rie Tsutsumi, Tamaki Otani, Naoya Suemasa, Saeko Masumoto, Masashi Kuroda and Hiroshi Sakaue : Assessment of insulin resistance in the skeletal muscle of mice using positron emission tomography/computed tomography imaging., Biochemical and Biophysical Research Communications, Vol.528, No.3, 499-505, 2020.
(要約)
Measuring glucose uptake in the skeletal muscle in vivo is an effective method to determine glucose metabolism abnormalities as the skeletal muscle is the principal tissue responsible for glucose disposal and is a major site of peripheral insulin resistance. In this study, we investigated the pathological glucose metabolism dynamics of the skeletal muscle of C57BL/6J mice in a noninvasive and time-sequential manner using positron emission tomography/computed tomography (PET/CT), an imaging technique that uses radioactive substances to visualize and measure metabolic processes in the body, with [
Nagakatsu Harada, Yuka Gotoda, Adzumi Hatakeyama, Tadahiko Nakagawa, Yumiko Miyatake, Masashi Kuroda, Saeko Masumoto, Rie Tsutsumi, Yutaka Nakaya and Hiroshi Sakaue : Differential regulation of Actn2 and Actn3 expression during unfolded protein response in C2C12 myotubes., Journal of Muscle Research and Cell Motility, 2020.
(要約)
ACTN2 and ACTN3 encode sarcomeric α-actinin-2 and α-actinin-3 proteins, respectively, that constitute the Z-line in mammalian skeletal muscle fibers. In human ACTN3, a nonsense mutation at codon 577 that encodes arginine (R) produces the R577X polymorphism. Individuals having a homozygous 577XX genotype do not produce α-actinin-3 protein. The 577XX genotype reportedly occurs in sprint and power athletes in frequency lower than in the normal population, suggesting that α-actinin-3 deficiency diminishes fast-type muscle function. Among humans who carry 577R alleles, varying ACTN3 expression levels under certain conditions can have diverse effects on atheletic and muscle performance. However, the factors that regulate ACTN3 expression are unclear. Here we investigated whether the unfolded protein response (UPR) under endoplasmic reticulum (ER) stress regulates expression of Actn3 and its isoform Actn2 in mouse C2C12 myotubes. Among UPR-related transcription factors, XBP1 upregulated Actn2, whereas XBP1, ATF4 and ATF6 downregulated Actn3 promoter activity. Chemical induction of ER stress increased Actn2 mRNA levels, but decreased those for Actn3. ER stress also decreased α-actinin-3 protein levels, whereas levels of α-actinin-2 were unchanged. The intracellular composition of muscle contraction-related proteins was altered under ER stress, in that expression of parvalbumin (a fast-twitch muscle-specific protein) and troponin I type 1 (skeletal, slow) was suppressed. siRNA-induced suppression of Actn3 mimicked the inhibitory effect of ER stress on parvalbumin levels. Thus, endogenous expression levels of α-actinin-3 can be altered by ER stress, which may modulate muscle performance and athletic aptitudes, particularly in humans who carry ACTN3 577R alleles.
Hypertrophy, associated with adipocyte dysfunction, causes increased pro-inflammatory adipokine, and abnormal glucose and lipid metabolism, leading to insulin resistance and obesity-related-health problems. By combining DNA microarray and genomic data analyses to predict DNA binding motifs, we identified the transcription factor Interferon Regulatory Factor 7 (IRF7) as a possible regulator of genes related to adipocyte hypertrophy. To investigate the role of IRF7 in adipocytes, we examined gene expression patterns in 3T3-L1 cells infected with a retrovirus carrying the IRF7 gene and found that enforced IRF7 expression induced the expression of monocyte chemoattractant protein-1 (MCP-1), a key initial adipokine in the chronic inflammation of obesity. CRISPR/Cas9 mediated-suppression of IRF7 significantly reduced MCP-1 mRNA. Luciferase assays, chromatin immunoprecipitation PCR analysis and gel shift assay showed that IRF7 transactivates the MCP-1 gene by binding to its proximal Interferon Stimulation Response Element (ISRE), a putative IRF7 binding motif. IRF7 knockout mice exhibited lower expression of MCP-1 in epidydimal white adipose tissue under high-fat feeding conditions, suggesting the transcription factor is physiologically important for inducing MCP-1. Taken together, our results suggest that IRF7 transactivates MCP-1 mRNA in adipocytes, and it may be involved in the adipose tissue inflammation associated with obesity.
Masashi Kuroda, Rumi Onoyama, Waka Sasaki, Mayu Sebe, Tadahiro Kitamura, Saeko Masumoto, Rie Tsutsumi, Nagakatsu Harada and Hiroshi Sakaue : DNA methylation status influences insulin-induced glucose transport in 3T3-L1 adipocytes by mediating p53 expression., Biochemical and Biophysical Research Communications, Vol.525, No.1, 39-45, 2020.
(要約)
Researchers frequently use 3T3-L1 adipocytes as a fat cell line, but the capacity of this line for insulin-mediated glucose transport is lower than that of primary isolated fat cells. In this study, we found that 5-azacytidine (5-aza-C), DNA methyltransferase 1 inhibitor, enhanced insulin-stimulated 2-deoxyglucose (2-DG) transport in 3T3-L1 cells after adipogenic differentiation. We next examined the expression of the genes related to glucose transport and insulin signal transduction. The insulin independent glucose transporter, glucose transporter 1 (GLUT1), showed lower expression in 5-aza-C pre-treated 3T3-L1 adipocytes, than in un-treated control adipocytes, while the expression of insulin dependent transporter GLUT4 remained unchanged. In addition, insulin receptor substrate-1 (IRS-1) was highly expressed in 5-aza-C pre-treated adipocytes. Based on DNA microarray and functional annotation analysis, we noticed that 5-aza-C pretreatment activated the tumor suppressor p53 pathway. We confirmed that in 5-aza-C adipocytes, p53 expression was markedly higher, and the methylation level of CpGs in its promoter region was lower than in un-treated control adipocytes. Moreover, pharmacological inhibition of p53 restored GLUT1 and IRS-1 expression to the same level as in un-treated 3T3-L1 adipocytes, and significantly decreased insulin-mediated 2-DG uptake. These results suggest that glucose transport capacity in adipocytes is influenced by DNA methylation status, and demethylation induced by 5-aza-C increased it possibly through the p53 signaling pathway.
Nobuto Nakanishi, Rie Tsutsumi, Yoshihiro Okayama, Takuya Takashima, Yoshitoyo Ueno, Taiga Itagaki, Yasuo Tsutsumi, Hiroshi Sakaue and Jun Oto : Monitoring of muscle mass in criticaly ill patients: comparison of ultrasound and two bioelectrical impedance analysis devices, Journal of Intensive Care, Vol.7, 61, 2020.
(要約)
Skeletal muscle atrophy commonly occurs in critically ill patients, and decreased muscle mass is associated with worse clinical outcomes. Muscle mass can be assessed using various tools, including ultrasound and bioelectrical impedance analysis (BIA). However, the effectiveness of muscle mass monitoring is unclear in critically ill patients. This study was conducted to compare ultrasound and BIA for the monitoring of muscle mass in critically ill patients. We recruited adult patients who were expected to undergo mechanical ventilation for > 48 h and to remain in the intensive care unit (ICU) for > 5 days. On days 1, 3, 5, 7, and 10, muscle mass was evaluated using an ultrasound and two BIA devices (Bioscan: Malton International, England; Physion: Nippon Shooter, Japan). The influence of fluid balance was also evaluated between each measurement day. We analyzed 93 images in 21 patients. The age of the patients was 69 (interquartile range, IQR, 59-74) years, with 16 men and 5 women. The length of ICU stay was 11 days (IQR, 9-25 days). The muscle mass, monitored by ultrasound, decreased progressively by 9.2% (95% confidence interval (CI), 5.9-12.5%), 12.7% (95% CI, 9.3-16.1%), 18.2% (95% CI, 14.7-21.6%), and 21.8% (95% CI, 17.9-25.7%) on days 3, 5, 7, and 10 ( < 0.01), respectively, with no influence of fluid balance ( = 0.04, = 0.74). The muscle mass did not decrease significantly in both the BIA devices (Bioscan, = 0.14; Physion, = 0.60), and an influence of fluid balance was observed (Bioscan, = 0.37, < 0.01; Physion, = 0.51, < 0.01). The muscle mass assessment at one point between ultrasound and BIA was moderately correlated (Bioscan, = 0.51, < 0.01; Physion, = 0.37, < 0.01), but the change of muscle mass in the same patient did not correlate between these two devices (Bioscan, = - 0.05, = 0.69; Physion, = 0.23, = 0.07). Ultrasound is suitable for sequential monitoring of muscle atrophy in critically ill patients. Monitoring by BIA should be carefully interpreted owing to the influence of fluid change. UMIN000031316. Retrospectively registered on 15 February 2018.
Shiho Satomi, Atsushi Morio, Hirotsugu Miyoshi, Ryuji Nakamura, Rie Tsutsumi, Hiroshi Sakaue, Toshimichi Yasuda, Noboru Saeki and Yasuo M. Tsutsumi : Branched-chain amino acids-induced cardiac protection against ischemia/reperfusion injury., Life Sciences, Vol.245, 2020.
(要約)
Mice treated with BCAAs had a significant reduction in infarct size as a percentage of the area at risk compared to controls (34.1 ± 3.9% vs. 44.7 ± 2.6%, P = 0.001), whereas mice treated with the mTOR inhibitor rapamycin were not protected by BCAA administration (42.2 ± 6.5%, vs. control, P = 0.015). This protection was not detected in our hetero knockout mice of mTOR. Western blot analysis revealed no change in AKT signaling whereas activation of mTOR was identified. Furthermore, BCAAs prevented swelling which was reversed by the addition of rapamycin. In myocytes undergoing simulated I/R, BCAA treatment significantly preserved cell viability (71.7 ± 2.7% vs. 34.5 ± 1.6%, respectively, p < 0.0001), whereas rapamycin prevented this BCAA-induced cardioprotective effect (43.5 ± 3.4% vs. BCAA, p < 0.0001).
Mayu Sebe, Rie Tsutsumi, Takuro Oyama, T Yousuke Horikawa, Yuta Uemura, Nami Kakuta, Yoko Sakai, Atsushi Morio, Hirotsugu Miyoshi, Takashi Kondo, Tomoaki Urabe, Yuko Noda, Satoshi Kamiya, Noboru Saeki, Masashi Kuroda, Katsuya Tanaka, Yasuo Tsutsumi and Hiroshi Sakaue : Assessment of postoperative nutritional status and physical function between open surgical aortic valve replacement and transcatheter aortic valve implantation in elderly patients., The Journal of Medical Investigation : JMI, Vol.67, No.1.2, 139-144, 2020.
(要約)
Background and aims : Severe aortic stenosis (AS) has been normally treated with surgical aortic valve replacement (AVR) whereas recently, transcatheter aortic valve implantation (TAVI) has been introduced as a minimally invasive operation for patients with high surgical risk and frailty. In this study, we have evaluated postoperative physical function and nutrition intake in the patients following AVR and TAVI. Methods : This prospective observational study involved 9 patients with surgical aortic valve replacement (AVR) and 7 patients with transcatheter aortic valve implantation (TAVI). Body composition was measured one day prior surgery, postoperative day (POD) 1, POD 3, POD 5 and POD 7. Hand grip strength, calf circumference and gait speed were measured one day before surgery and on the day of discharge. Results : Skeletal muscle was significantly decreased in AVR patients at postoperative day 3 and 7, while there was no change in TAVI patients. Patients with TAVI showed higher dietary intake after surgery compared to patients with AVR, and they maintained hand grip strength and calf circumference at discharge. Conclusions : In elderly patients with AS, TAVI can improve post-operative recovery maintaining nutritional status and physical function even. J. Med. Invest. 67 : 139-144, February, 2020.
Abhishek Shetty, Thejaswini Venkatesh, Rie Tsutsumi and S Padmanaban Suresh : Gene expression changes and promoter methylation with the combined effects of estradiol and leptin in uterine tissue of the ovariectomized mice model of menopause., Molecular Biology Reports, Vol.47, No.1, 151-168, 2019.
(要約)
Substantial epidemiological studies have shown an association of obesity with the common gynecological malignancy, endometrial cancer. The relevant interactions and contribution of estradiol and the adipose cytokine, leptin, in endometrial lesions are not completely understood. Suitable animal models to understand the physiological response of uterine tissue to the combined effects of estradiol-leptin are lacking. To investigate the effect of estradiol-leptin crosstalk on gene expression and associated altered pathways, we established an ovariectomized mouse model, treated with 17-β estradiol (0.1 µg/mouse subcutaenously., for every 12 h) and/or recombinant mouse leptin (1 μg/g Bwt intraperitoneally., for every 12 h) for 4 h, 20 h, and 40 h. Gene expressions by semi-quantitative RT-PCR, uterine tissue protein phosphorylation status by western blotting and promoter methylation were analyzed in estradiol, progesterone insufficient animals. Semi-quantitative RT-PCR demonstrated significantly increased expression of Esr, Igf1, Igfbp3, Vegfr1, and Vegf, and significantly decreased expression of Mmp9 after co-treatment with estradiol and leptin, indicating a common transcriptional network regulated by the treatments. Ovariectomy-induced histomorphological changes were only reversed by estradiol. Methylation-specific PCR, analyzing methylation of CpG sites of Vegfa, Pgr, and Igf1, revealed that transcriptional regulation after hormonal treatments is independent of methylation at the examined CpG sites. Western blot confirmed the increased expression of PSTAT-3 (Ser-727) and PERK1/2 proteins after estradiol + leptin treatment, confirming the estradiol + leptin cross-talk hypothesis. In conclusion, our in vivo studies determined specific gene expression and signaling protein changes, and further unraveled the molecular targets of estradiol + leptin that may perturb endometrial homeostasis and lead to endometrial hyperplasia development in the chronic stimulated state.
Abhishek Shetty, Thejaswini Venkatesh, Rie Tsutsumi and S Padmanaban Suresh : Regulated expression of Gemin5, Xrn1, Cpeb and Stau1 in the uterus and ovaries after superovulation and the effect of exogenous estradiol and leptin in rodents., Molecular Biology Reports, Vol.46, No.2, 2533-2540, 2019.
(要約)
The aim of this study was to evaluate whether Gemin 5, Cpeb, Xrn1, and Stau1 expression in rodent ovaries and uterine tissues is dependent on gonadotropins, steroid hormones, and leptin in the superovulation and ovariectomized mouse models of menopause. Treatment of pregnant mare serum gonadotropin-primed rats with human chorionic gonadotropin (hCG) significantly induced Stau1 and Gemin 5 messenger RNA expression in rat ovaries. Gemin 5 expression in ovaries was sustained at relatively high levels at 12 h and 24 h post hCG treatment compared to Stau1, suggesting its role in follicle development, ovulation, and luteogenesis in rat ovaries. Induced expression of Stau1 and Gemin 5 in the uterine tissue post hCG treatment at 12 h and 24 h-the duration between ovulation and post-ovulation-suggests their regulation by hCG and/or ovarian steroids, which are required for pregnancy establishment and maintenance. Cpeb expression was significantly higher (p < 0.05) in the uterine tissues after combined treatment of estradiol and leptin at 4 h. Further, the significant upregulation of uterine Gemin 5 and Xrn1 by the synergistic activities of leptin and estradiol at 40 h in ovariectomized mice establishes them as targets of cross-talk. Although these are preliminary data, the combination of Gemin 5, Cpeb, Xrn1, and Stau1 transcript alterations in rodent ovaries and uterine tissue displayed in two different experimental models underscore their importance as therapeutic targets for anovulation or in overcoming endometrial homeostasis disturbances during pregnancy due to obesity.
Mari Miki, Susumu Yasuoka, Rie Tsutsumi, Yoichi Nakamura, Maeda Hajime, Yukiyasu Takeuchi, Keisuke Miki, Seigo Kitada and Ryoji Maekura : Human airway trypsin-like protease enhances interleukin-8 synthesis in bronchial epithelial cells by activating protease-activated receptor 2., Archives of Biochemistry and Biophysics, Vol.664, 167-173, 2019.
(要約)
Human airway trypsin-like protease (HAT) localizes at human bronchial epithelial cells (HBECs). HAT enhanced release of interleukin-8 (IL-8) from HBECs at 10-100 mU/mL and the enhanced release was almost completely abolished by 50 μM leupeptin, a serine protease inhibitor. Previous reports suggested that HAT displays its physiological functions via protease-activated receptor 2 (PAR2). In the present study, we examined the mechanism whereby HAT upregulates IL-8 synthesis in HBECs with a focus on PAR2. Northern blot analysis revealed that HAT enhanced IL-8 mRNA expression at concentrations of 10-100 mU/mL. PAR2 activating peptide (PAR2 AP) also enhanced IL-8 release and IL-8 mRNA expression in HBECs at 50-1,000 μM at similar levels as HAT. Knockdown of PAR2 mRNA by siRNA methods showed that PAR2 mRNA expression was significantly depressed in primary HBECs, and both HAT- and PAR2 AP-induced IL-8 mRNA elevation was significantly depressed in PAR2 siRNA-transfected HBECs. Additionally, HAT cleaved the PAR2 activating site (R
Masahiro Bando, Saeko Masumoto, Masashi Kuroda, Rie Tsutsumi and Hiroshi Sakaue : Effect of olive oil consumption on aging in a senescence-accelerated mice-prone 8 (SAMP8) model., The Journal of Medical Investigation : JMI, Vol.66, No.3.4, 241-247, 2019.
(要約)
Background : Mediterranean diets have been linked to a reduced risk of cancer, vascular illnesses, Parkinson's and Alzheimer's disease. Olive oil is the primary fat source in the Mediterranean diet ; however, only a few studies have investigated the effect of olive oil on aging. In the present study, we aimed to determine whether consumption of olive oil significantly influences aging and memory in senescence-accelerated mouse-prone 8 (SAMP8). Methods : SAMP8 and senescence-accelerated mouse resistant 1 (SAMR1) mice were fed either 7% soy oil or 1% olive oil and 6% soy oil during a six-month study period. Reduction in memory in passive avoidance learning was examined after two months from the initiation of the experiment. Results : The weight of organs including the liver, kidney, spleen, and fat tissue changed significantly and memory performance was reduced in SAMP8 than in SAMR1 mice. There were no significant differences in SAMP8 and SAMR1 mice; however, blood triglyceride level decreased significantly in SAMP8 mice fed on olive oil. Conclusions : These results suggest that consuming olive oil may not have a protective role in aging and memory recall, but beneficial effects may be related to improvement in lipid metabolism. J. Med. Invest. 66 : 241-247, August, 2019.
<p>がんの化学療法中に味覚・嗅覚障害は頻繁に生じ，患者のquality of life(以下，QOLと略)だけでなく，体重低下や栄養状態の悪化を引き起こす深刻な副作用である．しかしながらこれまで確立された治療法や予防策はなく，食事内容や形態の工夫が主な対処法であった．味覚障害は薬剤による亜鉛のキレート化が原因であるとされているが，これに加えて味覚受容体遺伝子の発現変化や口腔粘膜障害の影響も報告されている．本稿では，化学療法中に生じる味覚・嗅覚障害の実態とともに，これに対する栄養的なアプローチを紹介する．</p>
, respectively) and transfected the constructs into HEK293 cells. Similar constructs for the ACTN3 577R gene were used as controls. HEK293 cells carrying the X gene, but not the X
S Padmanaban Suresh, Rie Tsutsumi and Thejaswini Venkatesh : YBX1 at the crossroads of non-coding transcriptome, exosomal, and cytoplasmic granular signaling., European Journal of Cell Biology, Vol.97, No.3, 163-167, 2018.
(要約)
YBX1 (Y box binding protein 1) is an RNA-/DNA-binding multifunctional protein harboring the classical cold shock protein (CSD) domain, an A/P domain, and a long C-terminal domain with alternating positively and negatively charged amino acids. It is a well-established oncogenic transcriptional factor, and regulates apoptosis, translation, cell proliferation, mRNA splicing, repair, differentiation, and stress response. The non-coding transcriptome has added yet another layer of complexity to the YBX1-mediated master regulation of cellular functions. Interestingly, YBX1 has been shown to localize to cytoplasmic granules such as P granules and stress granules. These granules regulate the non-coding transcriptome profile as well as mRNA translation and degradation. In this review, we discuss the recent findings on YBX1 signaling as mediated by various classes of non-coding RNAs, and on the functions of YBX1 at P granules, stress granules, exosomes, and mitochondria. YBX1 is a well-established target for cancer therapy and understanding its functions at organelles and ncRNA transcriptomes will shed new insights for devising organelle based anti-cancer therapies.
(キーワード)
Animals / Cytoplasmic Granules / Exosomes / Humans / RNA, Untranslated / Signal Transduction / Transcriptome / Y-Box-Binding Protein 1
Susumu Yasuoka, Mari Miki, Rie Tsutsumi, Masami Yoshioka, Takashi Bando and Fumiko Michishige : Human airway trypsin-like protease (HAT) is released into saliva., The Journal of Medical Investigation : JMI, Vol.65, No.3.4, 258-267, 2018.
(要約)
We first discovered human airway trypsin-like protease (HAT) in human mucoid sputum. Precursor HAT (47 kDa), a cell surface type Ⅱ transmembrane serine protease, is proteolyzed to mature HAT (27 kDa). Hitherto, HAT has not been detected in other biological fluids except for human sputum. We aimed to clarify whether human saliva contains mature HAT. Trypsin-like protease was isolated from saliva of healthy volunteers by a method adopted for isolation of HAT from sputum using Boc-Phe-Ser-Arg-MCA as the substrate. Biochemical properties of purified protease were similar to those of recombinant HAT (rHAT). HAT concentration in saliva was measured by ELISA, and immunoreactive HAT:total protein ratio (ng/mg) in saliva samples from healthy subjects was similar to that in mucoid sputum. RT-PCR showed that HAT mRNA was expressed in human gingival epithelial cells but not in gingival fibroblasts. Both indirect immunofluorescence and western blotting using monoclonal antibody for α-smooth muscle actin (α-SMA;a myofibroblast marker) showed that HAT enhanced α-SMA fiber expression in gingival fibroblasts. These results indicate that both mucoid sputum and saliva from healthy subjects have similar concentrations of mature HAT, and HAT is related to certain physiological functions and pathological states of myofibroblasts in the oral cavity. J. Med. Invest. 65:258-267, August, 2018.
Chikugo Momoko, Sebe Mayu, Rie Tsutsumi, Iuchi Marina, Jun Kishi, Masashi Kuroda, Nagakatsu Harada, Yasuhiko Nishioka and Hiroshi Sakaue : Effect of Janus kinase inhibition by tofacitinib on body composition and glucose metabolism., The Journal of Medical Investigation : JMI, Vol.65, No.3.4, 166-170, 2018.
(要約)
Tofacitinib is the first Janus Kinase (JAK) inhibitor to treat moderately to severely active RA. In this study, we investigated whether the effect of tofacitinib have any effects on body composition in mice and female patients with RA. Female C57BL/6 mice fed with a high-fat diet were treated with 30 mg/kg/day tofacitinib or vehicle for 70 days. Following treatment, trunk muscle, subcutaneous fat, and visceral fats were measured using X-ray computed tomography CT scan. Glucose tolerance and insulin sensitivity were assessed. In female RA patients treated with biological disease modified anti-rheumatic-drugs (biological DMARDs) or tofacitinib (n=4 per group), we also evaluated the body composition after 3 months from the start of treatment initiation using bioelectrical impedance analysis. Treatment with tofacitinib did not affect the body weight, and body composition in C57BL/6 mice. It also did not affect glucose, and insulin tolerance in mice. In patients with RA, treatment with biological DMARDs did not affect the body composition whereas the muscle mass was unchanged after receiving tofacitinib and the fat mass was significantly increased. J. Med. Invest. 65:166-170, August, 2018.
Rodrigo Scotini, Ian Skinner, Francesca Racioppi, Virginia Fusé, Oliveira Jonas de Bertucci and Rie Tsutsumi : Supporting Active Mobility and Green Jobs through the Promotion of Cycling., International Journal of Environmental Research and Public Health, Vol.14, No.12, 2017.
(要約)
This article is a summary of the main findings of the study "Riding towards the green economy: cycling and green jobs", which was developed in the context of the Transport, Health and Environment pan-European Programme (THE PEP). It builds on previous work under THE PEP, which demonstrated the job creation potential of cycling and of green and healthy transport more generally. The report summarized in this article collected data on jobs associated with cycling directly from city authorities and analysed these to re-assess previous estimates of the job creation potential of cycling. It concluded that the number of cycling-related jobs in the pan-European Region could increase by 435,000 in selected major cities if they increased their cycling share to that of the Danish capital Copenhagen. The implications and potential role of municipal and sub-national authorities in facilitating cycling while supporting economic development are then discussed. These findings indicate that investment in policies that promote cycling could deliver not only important benefits for health, the environment and the quality of urban life, but could also contribute to a sizable creation of job opportunities. Authorities need to be proactive in promoting cycling in order to deliver these benefits.
(キーワード)
Bicycling / Employment / Europe / European Union / Humans
Yasuo Tsutsumi, Takuro Oyama, Nami Kakuta, YT Horikawa, Katsuyoshi Kume, Yoko Sakai, Rie Tsutsumi and Katsuya Tanaka : Effect of oral carbohydrate with amino acid solution on serum oxidative/anti-oxidative status in healthy volunteers., Journal of Anesthesia, Vol.31, No.3, 472-475, 2017.
(要約)
The aim of this work was to investigate the effect of oral carbohydrate with amino acid [oral nutritional supplement (ONS)] solution on oxidative stress in healthy persons. Fourteen healthy volunteers were segregated into control and ONS groups. Volunteers in the ONS group ingested 250 ml of Arginaid Water (Nestle Japan, Tokyo, Japan) in the evening before the experiment and at 7:00 am on the day of the experiment. Volunteers in the control group fasted after dinner and drank only water until 7:00 am on the day of the experiment. In both groups, blood was collected at 9:00 am. The serum total oxidant levels and antioxidant capacity were assessed by d-ROMs (derivatives of reactive oxygen metabolites) test and BAP (biological antioxidant potential) test, respectively. In the ONS group, the serum d-ROMs level was significantly lower than in the control group (297 ± 43 and 327 ± 41 U.CARR, respectively, p = 0.018), while the serum BAP level was significantly higher than the control group (2410 ± 432 and 1979 ± 397 µmol/l, respectively, p = 0.005). The OXY level of Arginaid Water was much higher than preOp drink (Nutricia, Ireland). In conclusion, our study showed that an ONS with arginine loading could decrease oxidative stress and increase antioxidant capacity in healthy volunteers.
There is an increasing interest in elucidating the molecular mechanisms by which voluntary exercise is regulated. In this study, we examined how the central nervous system regulates exercise. We used SPORTS rats, which were established in our laboratory as a highly voluntary murine exercise model. SPORTS rats showed lower levels of serum ghrelin compared with those of the parental line of Wistar rats. Intracerebroventricular and intraperitoneal injection of ghrelin decreased wheel-running activity in SPORTS rats. In addition, daily injection of the ghrelin inhibitor JMV3002 into the lateral ventricles of Wistar rats increased wheel-running activity. Co-administration of obestatin inhibited ghrelin-induced increases in food intake but did not inhibit ghrelin-induced suppression of voluntary exercise in rats. Growth hormone secretagogue receptor (GHSR) in the hypothalamus and hippocampus of SPORTS rats was not difference that in control rats. We created an arcuate nucleus destruction model by administering monosodium glutamate (MSG) to neonatal SPORTS rats. Injection of ghrelin into MSG-treated rats decreased voluntary exercise but did not increase food intake, suggesting that wheel-running activity is not controlled by the arcuate nucleus neurons that regulate feeding. These results provide new insights into the mechanism by which ghrelin regulates voluntary activity independent of arcuate nucleus neurons.
Takako Kadota, Nami Kakuta, Yousuke T. Horikawa, Rie Tsutsumi, Takuro Oyama, Katsuya Tanaka and Yasuo Tsutsumi : Plasma substance P concentrations in patients undergoing general anesthesia: an objective marker associated with postoperative nausea and vomiting, JA Clinical Reports, Vol.2, No.9, 9, 2016.
(要約)
This study investigated plasma concentrations of substance P (SP) in patients undergoing general anesthesia (GA) and postoperative nausea and vomiting (PONV). This prospective, observational, cohort study included 23 patients who underwent scheduled surgery under general anesthesia. Blood was collected from the radial artery at predetermined time points (15-30 mins prior anesthesia, 15-30 mins after surgery/GA, and 24 h after surgery). PONV, SP concentrations, risk factors, and analgesics used were measured. Nine of 23 patients experienced PONV. In patients without PONV, SP concentrations significantly decreased ( < 0.0001) at the end of surgery/GA, compared to baseline, and recovered at 24 h after surgery/GA (452.9 ± 146.2 vs. 666.9 ± 176.5 vs. 580.7 ± 168.6 pg/mL, respectively), whereas SP levels were unchanged during surgery/GA and increased at 24 hours after surgery ( = 0.020) in patients with PONV (726.1 ± 167.8 vs. 655.8 ± 168.0 vs. 779.7 ± 220.7 pg/mL, respectively). These finding suggest that SP levels may be utilized as an objective marker for PONV.
Rie Tsutsumi, Masakazu Goda, Chisa Fujimoto, Kyoko Kanno, Misaki Nobe, Yoshiaki Kitamura, Koji Abe, Misako Kawai, Hideki Matsumoto, Tohru Sakai and Noriaki Takeda : Effects of chemotherapy on gene expression of lingual taste receptors in patients with head and neck cancer., The Laryngoscope, Vol.126, No.3, E103-E109, 2015.
(要約)
We aimed to test the hypothesis that chemotherapy changes the gene expression of taste receptors in the tongue to induce dysgeusia in patients with head and neck cancer. Prospective observation study. We enrolled 21 patients who received chemoradiotherapy and five patients who underwent radiotherapy for head and neck cancer. The messenger RNA (mRNA) levels of the taste receptor subunits T1R1, T1R2, T1R3, and T2R5 were measured in lingual mucosa scrapings obtained with a small spatula. The perception thresholds of umami, sweet, and bitter tastes were assessed by the whole mouth gustatory test. In four patients with severe stomatitis induced by chemoradiotherapy, the mRNA levels of T1R1, T1R2, T1R3, and T2R5 in the lingual mucosa were significantly decreased. However, in 17 patients with mild/moderate stomatitis, the mRNA levels of T1R3 were significantly and transiently decreased, whereas those of T1R1 and T1R2 remained unchanged and those of T2R5 mRNA were significantly and transiently increased after chemotherapy. There was a significant negative correlation between the perception thresholds of umami or sweet tastes and lingual mRNA levels of T1R3 in patients with mild/moderate stomatitis after chemotherapy. Although the perception threshold of bitter taste remained unchanged, lingual mRNA levels of T2R5 were significantly increased in patients who complained of phantogeusia after chemotherapy. Chemotherapy specifically changed the gene expression of T1R3 and T2R5 in head and neck cancer patients with mild/moderate stomatitis, resulting in both dysgeusia of umami and sweet tastes as well as phantogeusia. 4. Laryngoscope, 126:E103-E109, 2016.
(キーワード)
Adult / Aged / Aged, 80 and over / 分散分析 (analysis of variance) / Antineoplastic Agents / Chemoradiotherapy / Cohort Studies / Dysgeusia / Female / 遺伝子発現 (gene expression) / Head and Neck Neoplasms / Humans / 日本 (Japan) / Male / Middle Aged / Prognosis / Prospective Studies / RNA, Messenger / Receptors, G-Protein-Coupled / Risk Assessment / Severity of Illness Index / Taste Buds / Tongue
Tomohiro Soga, Katsuyoshi Kume, Nami Kakuta, Eisuke Hamaguchi, Rie Tsutsumi, Ryosuke Kawanishi, Kohei Fukuta, Katsuya Tanaka and Yasuo M. Tsutsumi : Fosaprepitant versus ondansetron for the prevention of postoperative nausea and vomiting in patients who undergo gynecologic abdominal surgery with patient-controlled epidural analgesia: a prospective, randomized, double-blind study., Journal of Anesthesia, Vol.29, No.5, 696-701, 2015.
(要約)
No (0 %) patient in the NKI group experienced vomiting after surgery; however, 4-6 (20-30 %) of 20 patients in the ONS group experienced vomiting. This difference was significant at 0-24, 0-48, and 0-72 h. During the study period, no significant differences existed between the NK1 and ONS groups in the incidence of PONV, complete response rate, rescue antiemetic use, nausea score, and VAS score for pain.
Tohru Sakai, Tomoyo Taki, Akiko Nakamoto, Shiho Tazaki, Mai Arakawa, Mariko Nakamoto, Rie Tsutsumi and Emi Shuto : Dietary ribonucleic Acid suppresses inflammation of adipose tissue and improves glucose intolerance that is mediated by immune cells in C57BL/6 mice fed a high-fat diet., Journal of Nutritional Science and Vitaminology, Vol.61, No.1, 73-78, 2015.
(要約)
Recent evidence suggests that immune cells play an important role in differentiation of inflammatory macrophages in adipose tissue, which contributes to systemic chronic inflammation. Dietary ribonucleic acid (RNA) has been shown to modulate immune function. We hypothesized that RNA affects immune cell function in adipose tissue and then improves inflammatory response in adipose tissue. C57/BL6 mice and recombination activating gene-1 (RAG-1) knockout mice on a C57BL/6 mice background were fed a high-fat diet containing 1% RNA for 12 wk. An oral glucose tolerance test was performed. Supplementation of dietary RNA in C57BL/6 mice fed a high-fat diet resulted in a smaller area under the curve (AUC) after oral glucose administration than that for control mice. The mRNA expression levels of inflammation-related cytokines in adipose tissue and serum interleukin-6 levels were reduced by dietary RNA supplementation. Interestingly, reduction of the AUC value by RNA supplementation was abolished in T and B cell-deficient RAG-1 knockout mice. These results indicate that RNA improves inflammation in adipose tissue and reduces the AUC value following oral glucose administration in a T and B cell-dependent manner.
Akiko Nakamoto, Emi Shuto, Rie Tsutsumi, Mariko Nakamoto, Yoshitaka Nii and Tohru Sakai : Vitamin A Deficiency Impairs Induction of Oral Tolerance in Mice., Journal of Nutritional Science and Vitaminology, Vol.61, No.2, 147-153, 2015.
(要約)
Oral tolerance is a phenomenon of induction of systemic unresponsiveness to antigens ingested by the oral route and loss of immune response. Studies have shown the importance of vitamin A in oral tolerance in vitro but not in an in vivo experimental model. Therefore, we carried out experiments to determine how vitamin A deficiency affects tolerance induction and the ability of mesenteric lymph node (MLN) CD11c(+) cells to induce regulatory T cells (Tregs). Immunological tolerance was induced by oral ovalbumin (OVA) administration in vitamin A-sufficient mice. OVA-specific antibody and cytokine production were significantly reduced. On the other hand, in vitamin A-deficient mice, both OVA-specific antibody and cytokine production were not suppressed by oral OVA administration. Regarding induction of Tregs, the conversion rate of Foxp3(+) cells from naïve CD4(+) cell by CD11c(+) cells was decreased in vitamin A-deficient mice. Our study indicates that vitamin A deficiency causes the breakdown of oral tolerance in vivo.
Thejaswini Venkatesh, S Padmanaban Suresh and Rie Tsutsumi : New insights into the genetic basis of infertility., The Application of Clinical Genetics, Vol.7, 235-243, 2014.
(要約)
Infertility is a disease of the reproductive system characterized by inability to achieve pregnancy after 12 or more months of regular unprotected sexual intercourse. A variety of factors, including ovulation defects, spermatogenic failure, parental age, obesity, and infections have been linked with infertility, in addition to specific karyotypes and genotypes. The study of genes associated with infertility in rodent models has expanded the field of translational genetics in identifying the underlying cause of human infertility problems. Many intriguing aspects of the molecular basis of infertility in humans remain poorly understood; however, application of genetic knowledge in this field looks promising. The growing literature on the genetics of human infertility disorders deserves attention and a critical concise summary is required. This paper provides information obtained from a systematic analysis of the literature related to current research into the genetics of infertility affecting both sexes.
Yasuo Tsutsumi, Rie Tsutsumi, Yousuke T. Horikawa, Yoko Sakai, Eisuke Hamaguchi, Hiroshi Kitahata, Asuka Kasai, Noriko Kambe and Katsuya Tanaka : Geranylgeranylacetone and volatile anesthetic-induced cardiac protection synergism is dependent on caveolae and caveolin-3., Journal of Anesthesia, Vol.28, No.5, 733-739, 2014.
(要約)
Pharmacological preconditioning, including that with geranylgeranylacetone (GGA) and volatile anesthetics, has been shown to confer cardiac protection from ischemia/reperfusion injury although the mechanisms for this protection are poorly understood. Caveolins, integral membrane proteins that act as scaffolding proteins in caveolar membranes, localize molecules involved in cardiac protection. We have tested the hypothesis that caveolin-3 (Cav-3), the predominant isoform in cardiac myocytes, is essential for the synergistic effect observed between GGA and volatile anesthetics. Mice were randomly assigned to receive GGA, isoflurane [0.5 and 1.0 minimum alveolar concentration (MAC)], or GGA + isoflurane (0.5 MAC). An in vivo mouse model of ischemia/reperfusion injury was tested in wild-type and Cav-3 knockout mice, and the infarct size was determined. Biochemical assays were also performed in excised hearts. Geranylgeranylacetone and therapeutic isoflurane (1.0 MAC) independently reduced infarct size (31.6 ± 6.1 and 28.0 ± 5.0 % of the area at risk, respectively; n = 10) as compared to the controls (45.8 ± 9.4 %; n = 10). The combination GGA + sub-therapeutic isoflurane (0.5 MAC) further decreased the infarct size to 19.3 ± 5.1 % (n = 10). Preconditioning [GGA, isoflurane (1.0 MAC), and GGA + isoflurane] increased the amount of Cav-3 protein in the discontinuous sucrose-gradient buoyant fractions. Additionally, cardiac protection was not observed in Cav-3 knockout mice following the administration of GGA, isoflurane, and GGA + isoflurane. Combined administration of GGA + isoflurane had a synergistic effect, enhancing the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by Cav-3 expression.
Exendin-4 protected cardiac myocytes (CM) from SI/R [35.6 ± 12.6% vs. 64.4 ± 18.0% cell death, P = 0.034] and apoptosis but this protection was abolished by MβCD (71.8 ± 10.8% cell death, P = 0.004). Furthermore, Cav-3/GLP-1R co-localization was observed and membrane fractionation by sucrose density gradient centrifugation of CM treated with MβCD + exendin-4 revealed that buoyant (caveolae enriched) fractions decreased Cav-3 compared to CM treated with exendin-4 exclusively. Furthermore, exendin-4 induced a reduction in infarct size and cardiac troponin relative to control (infarct size: 25.1 ± 8.2% vs. 41.4 ± 4.1%, P < 0.001; troponin: 36.9 ± 14.2 vs. 101.1 ± 22.3 ng/ml, P < 0.001). However, exendin-4 induced cardiac protection was abolished in Cav-3 KO mice (infarct size: 43.0 ± 6.4%, P < 0.001; troponin: 96.8 ± 26.6 ng/ml, P = 0.001).
Rie Tsutsumi, Tomomi Yoshida, Yoshitaka Nii, Naoki Okahisa, Shinya Iwata, Masao Tsukayama, Rei Hashimoto, Yasuko Taniguchi, Hiroshi Sakaue, Toshio Hosaka, Emi Shuto and Tohru Sakai : Sudachitin, a polymethoxylated flavone, improves glucose and lipid metabolism by increasing mitochondrial biogenesis in skeletal muscle., Nutrition & Metabolism, Vol.11, 32, 2014.
(要約)
Obesity is a major risk factor for insulin resistance, type 2 diabetes, and stroke. Flavonoids are effective antioxidants that protect against these chronic diseases. In this study, we evaluated the effects of sudachitin, a polymethoxylated flavonoid found in the skin of the Citrus sudachi fruit, on glucose, lipid, and energy metabolism in mice with high-fat diet-induced obesity and db/db diabetic mice. In our current study, we show that sudachitin improves metabolism and stimulates mitochondrial biogenesis, thereby increasing energy expenditure and reducing weight gain. C57BL/6 J mice fed a high-fat diet (40% fat) and db/db mice fed a normal diet were treated orally with 5 mg/kg sudachitin or vehicle for 12 weeks. Following treatment, oxygen expenditure was assessed using indirect calorimetry, while glucose tolerance, insulin sensitivity, and indices of dyslipidemia were assessed by serum biochemistry. Quantitative polymerase chain reaction was used to determine the effect of sudachitin on the transcription of key metabolism-regulating genes in the skeletal muscle, liver, and white and brown adipose tissues. Primary myocytes were also prepared to examine the signaling mechanisms targeted by sudachitin in vitro. Sudachitin improved dyslipidemia, as evidenced by reduction in triglyceride and free fatty acid levels, and improved glucose tolerance and insulin resistance. It also enhanced energy expenditure and fatty acid β-oxidation by increasing mitochondrial biogenesis and function. The in vitro assay results suggest that sudachitin increased Sirt1 and PGC-1α expression in the skeletal muscle. Sudachitin may improve dyslipidemia and metabolic syndrome by improving energy metabolism. Furthermore, it also induces mitochondrial biogenesis to protect against metabolic disorders.
Rie Tsutsumi and Yasuo Tsutsumi : Peptides and proteins in whey and their benefits for human health., Austin Journal of Nutrition and Food Sciences, Vol.1, No.1, 1-9, 2014.
Toshio Hosaka, Sayaka Sasaga, Yukiko Yamasaka, Yoshitaka Nii, Kazuhiro Edazawa, Rie Tsutsumi, Emi Shuto, Naoki Okahisa, Shinya Iwata, Hiroyuki Tomotake and Tohru Sakai : Treatment with buckwheat bran extract prevents the elevation of serum triglyceride levels and fatty liver in KK-A(y) mice., The Journal of Medical Investigation : JMI, Vol.61, No.3-4, 345-352, 2014.
(要約)
Buckwheat powder or protein has been shown to decrease the total serum cholesterol level in non-diabetic mice or rats. However, the lipid-lowering effect of buckwheat bran extract (BBE) in diabetic mice has not been fully elucidated. KK-A(y) mice that received six-week treatment with BBE showed decreased body weight and liver weight compared to those of control (vehicle) mice. However, there was no significant difference in food intake. BBE treatments prevented liver triglyceride accumulation and decreased the serum level of triglycerides. In addition, mRNA expression levels lipogenic enzyme genes, fatty acid synthase, acetyl-coenzyme a oxidase and stearyl-coenzyme a desaturase 1, but not those of -oxidized enzyme genes, were decreased in BBE-treated mice. Level of transcription factors ChREBP and SREBP1c, transcripts of lipogenic genes, were also decreased in BBE-treated mice. These results suggest that chronic treatment with BBE derivatives could have beneficial effects on hypertriglycemia in patients with type 2 diabetes mellitus.
Tohru Sakai, Tomoyo Taki, Akiko Nakamoto, Emi Shuto, Rie Tsutsumi, Takayuki Toshimitsu, Seiya Makino and Shuuji Ikegami : Lactobacillus plantarum OLL2712 regulates glucose metabolism in C57BL/6 mice fed a high-fat diet., Journal of Nutritional Science and Vitaminology, Vol.59, No.2, 144-147, 2013.
(要約)
The aim of the present study was to determine the effect of oral administration of Lactobacillus plantarum OLL2712 (L. plantarum OLL2712) on glucose and lipid metabolism in mice with high-fat diet-induced obesity. Mice that had been administered 10(9) cfu heat-killed L. plantarum OLL2712 for 12 wk showed significant reduction of blood glucose levels in response to insulin. Furthermore, mRNA expression of interleukin-1β in adipose tissue and serum levels of nonesterified fatty acids in mice administered L. plantarum OLL2712 were significantly lower than those in control mice. These results indicate that L. plantarum OLL2712 regulates glucose metabolism.
Rie Tsutsumi, Yasuo M. Tsutsumi, Yousuke T. Horikawa, Yozo Takehisa, Toshio Hosaka, Nagakatsu Harada, Tohru Sakai and Yutaka Nakaya : Decline in anthropometric evaluation predicts a poor prognosis in geriatric patients., Asia Pacific Journal of Clinical Nutrition, Vol.21, No.1, 44-51, 2012.
(要約)
Malnutrition is frequent in the geriatric population and is often undetected and untreated. Although we often use serum albumin as a nutritional marker, it has limitations in elderly patients in terms of predicting diseases and infections. Anthropometric measurements are not commonly used, despite their simple, easy, and effective characteristics. We evaluated the associations between anthropometric measurements with other nutritional factors and examined its relationship with mortality, decubitus ulcer, length of hospital stay and antibiotic usage. We enrolled 223 patients, performed anthropometric measurements and then followed them for a mean of 24 months. Patients with hypoalbuminemia but with normal body measurements tended to increase serum albumin levels over the next 24 months and had more favorable outcomes including being discharged. Patients with normal albumin but decreased body measurements resulted in a progressive drop in serum albumin and had a higher mortality rate. Additionally, patients with hypoalbuminemia had higher antibiotic usage than patients without hypoalbuminemia. Decreases in anthropometric measurements were related to mortality, length of hospital stay, and decubitus ulcer. Anthropometric measurements are easily obtained and closely associated with mortality, decubitus ulcer, and length of hospital stay. Anthropometric measurements used in conjunction with serum albumin are more predictive of patient outcome then serum albumin alone.
(キーワード)
Aged / Aged, 80 and over / 分散分析 (analysis of variance) / Anthropometry / Anti-Bacterial Agents / Biological Markers / Female / Follow-Up Studies / Geriatric Assessment / Humans / Hypoalbuminemia / 日本 (Japan) / Length of Stay / Male / Malnutrition / Nutrition Assessment / Nutrition Surveys / Nutritional Status / Predictive Value of Tests / Pressure Ulcer / Prevalence / Prognosis / Prospective Studies / Risk Factors / Serum Albumin / Severity of Illness Index / Survival Analysis
(文献検索サイトへのリンク)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22374559
Kayo Hirose, Yasuo M. Tsutsumi, Rie Tsutsumi, Masayuki Shono, Erika Katayama, Michiko Kinoshita, Katsuya Tanaka and Shuzo Oshita : Role of the O-linked -N-acetylglucosamine in the cardioprotection induced by isoflurane., Anesthesiology, Vol.115, No.5, 955-962, 2011.
(要約)
Cardiac protection by volatile anesthetic-induced preconditioning and ischemic preconditioning have similar signaling pathways. Recently, it was reported that augmentation of protein modified with O-linked -N-acetylglucosamine (O-GlcNAc) contributes to cardiac protection. This study investigated the role of O-GlcNAc in cardiac protection induced by anesthetic-induced preconditioning. O-GlcNAc-modified proteins were visualized by immunoblotting. Tolerance against ischemia or reperfusion was tested in vivo (n = 8) and in vitro (n = 6). The opening of the mitochondrial permeability transition pore (mPTP) upon oxidative stress was examined in myocytes treated with calcein AM (n = 5). Coimmunoprecipitation and enzymatic labeling were performed to detect the mitochondrial protein responsible for the mPTP opening. Isoflurane treatment and the consequent augmentation of O-GlcNAc concentrations reduced the infarct size (26 ± 5% [mean ± SD], P < 0.001) compared with the control. The protective effect of O-GlcNAc was eliminated in the group pretreated with the O-GlcNAc transferase inhibitor alloxan (39 ± 5%, P < 0.001). Myocyte survival also showed the same result in vitro. Formation of the mPTP was abrogated in the isoflurane-treated cells (86 ± 4%, P < 0.001) compared with the control and alloxan-plus-isoflurane-treated cells (57 ± 7%, P < 0.001). Coimmunoprecipitation and enzymatic labeling studies revealed that the O-GlcNAc-modified, voltage-dependent anion channel restained the mPTP opening. Isoflurane induced O-GlcNAc modification of mitochondrial voltage-dependent anion channel. This modification inhibited the opening of the mPTP and conferred resistance to ischemia-reperfusion stress.
Yasuo M. Tsutsumi, Rie Tsutsumi, Kazuaki Mawatari, Yutaka Nakaya, Michiko Kinoshita, Katsuya Tanaka and Shuzo Oshita : Compound K, a metabolite of ginsenosides, induces cardiac protection mediated nitric oxide via Akt/PI3K pathway., Life Sciences, Vol.88, No.15-16, 725-729, 2011.
(要約)
Compound K (C-K; 20-O-D-glucopyranosyl-20(S)-protopanaxadiol) is a novel ginsenoside metabolite formed by intestinal bacteria and does not occur naturally in ginseng. In this study, we investigated whether administration of C-K has protective effects on myocardial ischemia-reperfusion injury and its potential mechanisms.
Toshio Hosaka, Yoshitaka Nii, Hiroyuki Tomotake, Takahiro Ito, Aya Tamanaha, Yukiko Yamasaka, Sayaka Sasaga, Kazuhiro Edazawa, Rie Tsutsumi, Emi Shuto, Naoki Okahisa, Shinya Iwata and Tohru Sakai : Extracts of common buckwheat bran prevent sucrose digestion., Journal of Nutritional Science and Vitaminology, Vol.57, No.6, 441-445, 2011.
(要約)
Buckwheat has been shown to have various health benefits such as reduction of hypertension and improvement of hypercholesterolemia; however, its effect on diabetes has not been fully elucidated. In this study, buckwheat bran extracts (BBE) inhibited sucrase activity in vitro more effectively than buckwheat. Balb/c mice pretreated with BBE showed dose-dependent reductions of blood glucose, greater than those observed with control mice, within 60 min following oral sucrose administration. Blood glucose levels in mice pretreated with buckwheat extracts were also significantly lower compared to those in control mice within 30 min following oral administration of sucrose. However, rutin, one of the abundant polyphenols of BBE, did not lower blood glucose level. Our data indicate that components of BBE other than rutin have inhibitory activity against sucrase in vivo. These results suggest that BBE could have beneficial effects on diabetes.
Rie Tsutsumi, Devendra Mistry and Nicholas J. G. Webster : Signaling responses to pulsatile gonadotropin-releasing hormone in LbetaT2 gonadotrope cells., The Journal of Biological Chemistry, Vol.285, No.26, 20262-20272, 2010.
(要約)
The hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) is secreted in a pulsatile fashion by hypothalamic neurons, and alterations in pulse frequency and amplitude differentially regulate gonadotropin synthesis and release. In this study, we investigated the kinetics of G(s) and G(q) signaling in response to continuous or pulsatile GnRH using fluorescence resonance energy transfer reporters in live mouse LbetaT2 gonadotrope cells. cAMP and protein kinase A-dependent reporters showed a rapid but transient increase in fluorescence resonance energy transfer signal with increasing doses of constant GnRH, and in contrast diacylglycerol (DAG) and calcium reporters showed a rapid and sustained signal. Multiple pulses of GnRH caused multiple pulses of cAMP and protein kinase A activation without desensitization, but the DAG and calcium reporters were rapidly desensitized resulting in inhibition of calcium and DAG responses. At the transcriptional level, both a cAMP-dependent cAMP-response element reporter and a DAG/calcium-dependent AP-1 reporter showed a pulse frequency-dependent increase in luciferase activity. However, constant GnRH stimulation gave very little cAMP-response element activation but very strong AP-1 activation. Based on these data, we propose that both the GnRH-R-G(s) and G(q) pathways are responsive to pulses of GnRH, but only the G(q) pathway is responsive to constant GnRH. Furthermore, the G(q) pathway is subject to desensitization with multiple GnRH pulses, but the G(s) pathway is not.
(キーワード)
Animals / Calcium / Cell Line / Cyclic AMP / Cyclic AMP Response Element-Binding Protein / Cyclic AMP-Dependent Protein Kinases / Diglycerides / Fluorescence Resonance Energy Transfer / Gonadotrophs / Gonadotropin-Releasing Hormone / Immunoblotting / Intracellular Space / Kinetics / Luciferases / Mice / Models, Biological / リン酸化 (phosphorylation) / 情報伝達 (signal transduction) / Transcription Factor AP-1 / Transcriptional Activation
目的:急速な高齢化において認知症の早期発見・早期予防が重要であるが，プレクリニカル期における簡易的に検出可能なスクリーニング方法は開発されていない．今回，我々は，認知機能低下と関係の深い日常生活の変化を捉えるべく，認知症の超早期段階における発見チェックシート;The Questionnaires for Earlier Stage of Dementia(Q-ESD)を開発した．認知症と診断されていない高齢者を対象としてQ-ESDを実施し，その有用性に関して老研式活動能力指標との関連性を比較・検討した．対象と方法:全国13施設において，認知症簡易スクリーニング法TOP-Qスコアが1点以下の認知機能低下を認めない高齢者に対し，導入時と4ヵ月後にQ-ESDと老研式活動能力指標の調査をした．結果:対象者134名(男/女=25/109)の平均年齢は75.2±12.0歳，平均Q-ESDスコアは25.0±7.0点であった．Q-ESDと老研式活動能力指標の合計スコアに負の相関(P<0.05)がみられた．Q-ESDの改善・維持群，悪化群では初回調査時の手段的，知的，社会的ADLが有意に低値であった(p<0.05)．結論:Q-ESDは生活機能の低下を早期に検出し，Q-ESDのスコアの高値は将来の認知症発症の予備軍となり得る可能性が示唆された．(著者抄録)
Rie Tsutsumi and G Nicholas J Webster : GnRH pulsatility, the pituitary response and reproductive dysfunction., Endocrine Journal, Vol.56, No.6, 729-737, Jul. 2009.
(要約)
GnRH plays an essential role in neuroendocrine control of reproductive function. In mammals, the pattern of gonadotropin secretion includes both pulse and surge phases, which are regulated independently. The pulsatile release of GnRH and LH plays an important role in the development of sexual function and in the normal regulation of the menstrual cycle. The importance of GnRH pulsatility was established in a series of classic studies. Fertility is impaired when GnRH pulsatility is inhibited by chronic malnutrition, excessive caloric expenditure, or aging. A number of reproductive disorders in women with including hypogonadotropic hypogonadism, hypothlamic amenorrhea, hyperprolactinemia and polycystic ovary syndrome (PCOS) are also associated with disruption of the normal pulsatile GnRH secretion. Despite these findings, the molecular mechanisms of this pulsatile GnRH regulation are not well understood. Here, we review recent studies about GnRH pulsatility, signaling and transcriptional response, and its implications for disease.
Rie Tsutsumi : The power of whey ; the benefit of whey based enteral nutrition in ICU patients,
2.
Masashi Kuroda, Naho Ugawa, Etsuko Ishikawa, Yasuyo Kawabata, Saya Okamoto, Waka Sasaki, Saeko Masumoto, Rie Tsutsumi and Hiroshi Sakaue : Transcription factor IRF7 and energy metabolism, The 11th Scientific Meeting of the Asian Association for the Study of Diabetes., May 2019.
3.
Rie Tsutsumi, Yasuo Tsutsumi, Roth David, Patel Hemal, Tanaka Katsuya and Sakaue Hiroshi : Leucine induces cardioprotection by promoting mitochondrial fusion and function via mTOR and Opa-1 signaling in vitro and diet induced obese mice., Keystone Symposia Conference, Kyoto, Oct. 2015.
4.
Rie Tsutsumi : Obesity and lowered muscle mass in patients with rheumatoid arthritis, Nagoya, Oct. 2015.
5.
Rie Tsutsumi : Identifications of chemotherapy-sensitive taste receptors regulatiing dysgeusia in patients with head and nick cancer, Asian Congress of Dietitian, Aug. 2014.
6.
Eisuke Hamaguchi, Shuzo Oshita, Katsuya Tanaka, Rie Tsutsumi and Yasuo M. Tsutsumi : Glucagon-like peptide-1 induced cardiac protection is dependent on caveolin-3 expression., Experimental Biology Annual Meeting, Boston, Illinois, Apr. 2013.
7.
Rie Tsutsumi, Sasaga Sayaka and Yasuo Tsutsumi : Whey protein promppts TCA cycle and increases energy expenditure via mTOR signaling., the 34th European Society for Clinical nutrition and Metabolism Congress, Barcelona, Spain, Sep. 2012.
8.
Rie Tsutsumi, Takegawa Mariko and Yasuo Tsutsumi : Overfeeding induces nutritional stress and protein catabolism, the 34th European Society for Clinical nutrition and Metabolism Congress, Barcelona, Spain, Sep. 2012.
9.
Rie Tsutsumi, Sasaga Sayaka, Takegawa Mariko and Yasuo Tsutsumi : Whey based formula reduces intestinal atrophy and enhances antioxidant defenses against sepsis., Experimental Biology Annual Meeting, San Diego, California, Apr. 2012.
10.
Yasuo Tsutsumi, Hirose Kayo, Katayama Erika, Rie Tsutsumi, Kinoshita Michiko, Katsuya Tanaka and Shuzo Oshita : Role of O-linked -N-acetylglucosamine in isoflurane induced cardiac protection., Experimental Biology Annual Meeting, Anaheim, California, Apr. 2010.
11.
Rie Tsutsumi, Kazuaki Mawatari, Katayama Erika, Yutaka Nakaya and Yasuo Tsutsumi : Compound K produces cardiac protection by activating Akt phosphorylation., Experimental Biology Annual Meeting, Anaheim, California, Apr. 2010.
12.
E Katayama, Rie Tsutsumi, Yutaka Nakaya, K Hirose, K Tanaka, S Oshita and Yasuo Tsutsumi : Role of mTOR/p70S6K in amino acid-induced caediac protection., Experimental Biology 2010(American Siciety for Nutrition), Anaheim,CA, Apr. 2010.