Bofutsushosan, an Oriental Herbal Medicine, Attenuates the Weight Gain of White Adipose Tissue and the Increased Size of Adipocytes Associated with the Increase in Their Expression of Uncoupling Protein 1 in High-Fat Diet-Fed Male KK/Ta mice

Bofutsushosan (BOF), an oriental herbal medicine, has been used as an anti-obesity drug in overweight patients. In the present study, to evaluate the anti-obesity and anti-diabetic effects of BOF, we investigated the effects of BOF on the white adipose tissue (WAT) weight, the size of adipocytes, adiponectin expression, and oral glucose tolerance test results in high-fat diet-fed male KK/Ta mice. In addition, the mRNA expression levels of uncoupling protein 1 (UCP1) and UCP2 mRNA in WAT and brown adipose tissue (BAT) were measured. 6-week-old KK/Ta mice were divided into four groups and fed a purified powdered basal diet (the BD group), a purified high-fat (HF) powdered diet containing suet powder at 37.5 g/100 g diet (the HF group), a high-fat diet plus 1.0% bofutsushosan (BOF) treatment (the HF + BOF group), or a high-fat diet plus 1.0% daisaikoto (DAI) treatment (the HF + DAI group) for 4 weeks. The weight of WAT and the size of adipocytes were increased in the HF group compared with those in the BD group, and these increases in the HF group were significantly inhibited in the HF + BOF group, but not affected in the HF + DAI group. There were no statistically significant differences in plasma levels and tissue mRNA levels of adiponectin among the four groups. There were no significant differences in UCP1 mRNA expression of BAT among the four groups. The expression of UCP1 mRNA in WAT was found in the HF + BOF group, but little expression was seen in the WAT of the BD, HF, or HF + DAI groups. The elevated plasma glucose levels and responses after the glucose loading in the HF group tended to decrease in the HF + BOF group. These results suggest that BOF decreases the weight and size gains of WAT along with up-regulating UCP1 mRNA in WAT in high-fat diet-fed mice

A Mouse Model of Metabolic Syndrome; Increase in Visceral Adipose Tissue Precedes the Development of Fatty Liver and Insulin Resistance in High-Fat Diet-Fed Male KK/Ta Mice

To determine the relative contribution of obesity and visceral white adipose tissue (WAT) to metabolic syndrome, we developed a model that is susceptible to high-fat diet-induced obesity and insulin resistance using male KK/Ta mice. The ratio of WAT weight to body weight was greater in the high-fat diet group compared with the control group in 10-, 14-, and 22-week-old mice. The increase in visceral WAT preceded development of fatty liver and insulin resistance. Adiponectin mRNA expression in WAT was markedly decreased before the decrease in its plasma levels or the development of insulin resistance. Insulin resistance appeared in association with fatty infiltration and TNF-α expression in the liver in 22-week-old mice. These data indicate that our mouse model would be useful for future studies that investigate the role of visceral WAT and its products in the development of metabolic syndrome

a proton pump inhibitor, mediates anti-inflammatory effect in gastric mucosal cells through the induction of heme oxygenase-1 via activation of NF-E2-related factor 2 and oxidation of kelch-like ECH-associating protein 1

ABSTRACT Induction of heme oxygenase-1 (HO-1) expression has been associated with cytoprotective and anti-inflammatory actions of lansoprazole, a proton pump inhibitor, but the underlying molecular mechanisms remain largely unresolved. In this study, we investigate the role of transcriptional NF-E2-related factor 2 (Nrf2), its phosphorylation/activation, and oxidation of Kelch-like ECHassociating protein 1 (Keap1) in lansoprazole-induced HO-1 up-regulation using cultured gastric epithelial cells (rat gastric mucosal cell line, RGM-1). HO-1 expression of RGM-1 cells was markedly enhanced in a time-and dose-dependent manner by the treatment with lansoprazole, and this up-regulation of HO-1 contributed to the inhibition of chemokine production from stimulated RGM-1 cells. Transfection of Nrf2-siRNA suppressed the lansoprazole-induced HO-1. An electrophoretic mobility shift assay showed increases in the nuclear translocation and stress-response elements (StRE) binding activity of Nrf2 proteins in RGM-1 cells treated with lansoprazole. Furthermore, in RGM-1 cells transfected with HO-1 enhancer luciferase reporter plasmid containing mutant StRE, lansoprazole-induced HO-1 reporter gene activity was diminished. Lansoprazole promoted the phosphorylation of extracellular signal-regulated kinase (ERK), and lansoprazole-induced HO-1 up-regulation was suppressed by U0126, an ERKspecific inhibitor. Phosphorylated Nrf2 protein was detected in the phosphoprotein fraction purified by a Pro-Q Diamond Phosphoprotein Enrichment kit. Finally, an oxidative form of the Keap1 protein was detected in lansoprazole-treated RGM-1 cells by analyzing S-oxidized proteins using biotinylated cysteine as a molecular probe. These results indicate that lansoprazole up-regulates HO-1 expression in rat gastric epithelial cells, and the upregulated HO-1 contributes to the anti-inflammatory effects of the drug. Phosphorylation of ERK and Nrf2, activation and nuclear translocation of Nrf2, and oxidation of Keap1 are all involved in the lansoprazole-induced HO-1 up-regulation. Proton pump inhibitors (PPIs) such as lansoprazole and omeprazole are extensively used to treat acid-related disorders, including gastroesophageal reflux disease and peptic ulcer disease caused by stress, nonsteroidal anti-inflammatory drugs, and Helicobacter pylori infection. PPIs are stron

乳幼児期の体重増加と学童期のインスリン抵抗性との関係に関する系統的・探索的解析

第3回日本DOHaD研究会学術集会　抄録集　【ポスター発表

Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer

High expression of thymidylate synthase (TS) and inactivation of p53 are allegedly associated with chemoresistance. The authors evaluated TS and p53 expression in gastric cancer treated with neoadjuvant S-1/cisplatin chemotherapy. Paraffin sections of pretreatment biopsy and surgical specimens from 41 gastric cancers were immunostained for TS and p53 protein after appropriate antigen retrieval. Fifty-one cases without neoadjuvant chemotherapy were also studied. In the pretreatment biopsies, high expression of TS was seen in 8% of the histologic responders, in 28% of the nonresponders and in 31% of the controls. High expression of p53 was observed in 56% of the nonresponders, but in 8% of the responders and in 29% of the controls (P<0.01 and P<0.05, respectively). The TS- and/or p53-high phenotype was seen in 76% of the nonresponders and in 54% of the controls, but in 8% of the responders (P<0.0001 and P<0.005, respectively). The data of the surgical specimens were consistent with those of the pretreatment biopsies. These results suggest that immunostaining for TS and p53 protein is useful for pretreatment selection of gastric cancer patients unresponsive to S-1/cisplatin chemotherapy

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

Effect of noise on sand digging and emergence activities in green turtle (Chelonia mydas) hatchlings

Anthropogenic noise affects animal behavior and physiology. However, relatively few studies have been conducted on the effects of noise on beach-associated animals. This study evaluated the effects of noise on sound emission, sand digging activity, and emergence from the sand surface by green turtle (Chelonia mydas) hatchlings. Acoustic recorders and infrared cameras were used to investigate the behavior of hatchlings in sand-filled chambers under three acoustic conditions: 1) a control treatment, which was silent throughout the experiment; 2) an environmental noise treatment, which exposed the hatchlings to white noise (WN) at a sound pressure level (SPL) approximately 13 dB higher than that of the control, which is similar to that of a natural beach; and 3) a loud noise treatment, which exposed them to WN at an SPL approximately 25 dB higher than that of the control. The WN ranged from 0 to 4 kHz with a repeating cycle of 30 min sound emission and 2 h 30 min silence. Sound emissions from green turtle hatchlings were detected; however, the amount of sound emissions was too small to discuss their ecological significance. The time to emergence and total number of digging bouts in the 24 h pre-emergence periods were not significantly different among treatments; however, the number of digging bouts was significantly higher during loud noise exposure. The response to loud noises may play a role in allowing hatchlings to escape from threats and/or coordinate synchronous behavior among multiple individuals. However, because the number of digging bouts decreased after loud noise exposure, prolonged exposure to loud noise may have detrimental effects on hatchlings, such as depletion of the energy reserves available to the hatchlings. Thus, anthropogenic noise on or around beaches and it effect on animals should be carefully considered

Dietary milk sphingomyelin prevents disruption of skin barrier function in hairless mice after UV-B irradiation

Exposure to ultraviolet-B (UV-B) irradiation causes skin barrier defects. Based on earlier findings that milk phospholipids containing high amounts of sphingomyelin (SM) improved the water content of the stratum corneum (SC) in normal mice, here we investigated the effects of dietary milk SM on skin barrier defects induced by a single dose of UV-B irradiation in hairless mice. Nine week old hairless mice were orally administrated SM (146 mg/kg BW/day) for a total of ten days. After seven days of SM administration, the dorsal skin was exposed to a single dose of UV-B (20 mJ/cm2). Administration of SM significantly suppressed an increase in transepidermal water loss and a decrease in SC water content induced by UV-B irradiation. SM supplementation significantly maintained covalently-bound ?-hydroxy ceramide levels and down-regulated mRNA levels of acute inflammation-associated genes, including thymic stromal lymphopoietin, interleukin-1 beta, and interleukin-6. Furthermore, significantly higher levels of loricrin and transglutaminase-3 mRNA were observed in the SM group. Our study shows for the first time that dietary SM modulates epidermal structures, and can help prevent disruption of skin barrier function after UV-B irradiation