BILIRUBIN AS A MARKER OF OXIDATIVE STRESS AND NON-COMMUNICABLE DISEASE: CHICKEN OR THE EGG?

Oxidative stress has been implicated in most non-communicable diseases: that is, metabolic syndrome (MetS), atherosclerosis and cancer. LDL cholesterol is rendered more atherogenic by oxidative modification [1] and many carcinogens create free oxygen radicals that damage DNA and other cellular structures, initiating and promoting tumor development [2]. Therefore, antioxidant agents have been extensively evaluated in the prevention of cardiovascular disease and cancer.Vitamin E has been shown to reduce atherosclerotic lesions in animals [3], smooth muscle cell proliferation [4], platelet adherence and aggregation [5]. Epidemiological data indicate an inverse association between cardiovascular or cancer risk and vitamin E intake from dietary sources and/or supplements [6]. However, most randomized controlled trials have failed to confirm a role for vitamin E supplementation in cardiovascular prevention [7-11]. Vitamin E had no significant effect on myocardial infarction, stroke, cardiovascular death, unstable angina, revascularization, and total mortality.Trials of cancer chemoprevention have also been disappointing [12, 13].  Bilirubin has been recognized as a potent antioxidant. Bilirubin suppresses the oxidation of lipid in liposomes more than vitamin E, which is regarded as the best antioxidant of lipid peroxidation [14, 15]. The water-soluble glutathione primarily protects water soluble proteins, whereas the lipophilic bilirubin protects lipids from oxidation [16]. Serum bilirubin has been demonstrated to be a major contributor to the total antioxidant capacity in blood plasma [17] and proven to haveanti-inflammatory properties [18]. Serum bilirubin was shown to be cross-sectionaly associated with MetS in Chinese children, adolescents and adults [19, 20] as well as Korean men and women [21, 22]. Patients with Gilbert syndrome had low levels of oxidative stress associated with enhancement of endothelium-dependent vasodilation [23].Serum bilirubin has been demonstrated to be negatively associated with cardiovascular disease [24-26], hemoglobin A1c [27] and albuminuria [28]. The authorpreviously suggested that serum bilirubin might be a negative predictor of end-stage kidney disease [29].Others reported that serum bilirubin predicted MetS [30, 31]. However, the author demonstrated that serum bilirubin cannot predict the development of MetS and suggested that a decreased serum bilirubin was not a cause of MetS but a marker of oxidative stress [32] which is closely related to inflammation [18] and endothelial dysfunction [23], both of which are thought to be underlying mechanisms of MetS [33].So, further prospective studies are required to conclude whether a decrease in serum bilirubin is a risk factor of non-communicable disease such as MetS [34].   Acknowledgments The author received no financial support and has no conflict of interest.Â&nbsp

MRI multiparametric scoring system for pial blood supply of intracranial meningiomas

Background: Meningiomas are occasionally fed by pial blood supply (PBS). It is postulated that peritumoral flow void (PTFV), peritumoral brain edema (PTBE), and absence of an arachnoid plane (AP) are useful parameters for evaluating PBS. Purpose: To determine whether conventional magnetic resonance imaging (MRI) using a multiparametric scoring system (MSS) is a useful way to predict PBS. Material and Methods: Forty-six patients were included and divided: PBS and non-PBS groups. Differences between the groups in six parameters of MR imaging were analyzed: tumor size, tumor location, PTBE grade, AP grade, PTFV, and MIB1 labeling index (MIB1-LI) grade. Cutoff values were determined using receiver operating characteristic (ROC) curve analysis for the differentiation of both groups based on statistically significant parameters. All cases were scored as 1 (PBS) or 0 (non-PBS) for each parameter according to set thresholds. Individual scores were totaled for each case, yielding a combined score for each case to obtain a cutoff value using ROC curve analysis for the MSS. Results: Peritumoral brain edema grade, AP grade, PTFV, and MIB-LI grade were statistically associated with PBS. Receiver operating characteristic curve analyses showed that PTBE grade 3 or 4, AP grade 3 or 4, and PTFV positivity had the highest accuracy of 69%, 64%, and 68%, respectively. Regarding the MSS, a cutoff value of 2 had the highest accuracy of 71%; PBS diagnosis was indicated by at least two of the three parameters, namely, PTBE grade, AP grade, and PTFV. Conclusion: The MSS is a useful way to predict PBS in intracranial meningiomas on MRI

Vildagliptin Improves Glucose Tolerance and Decreases Plasma Triglycerides in Sprague-Dawley Rats

The number of patients with lifestyle-related diseases, including type 2 diabetes, is increasing. The onset of type 2 diabetes can be prevented by dietary and exercise interventions, as well as drug therapy. Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have attracted attention recently as treatments for diabetes, and incretin hormones have been reported to have a protective effect on pancreatic β-cells. It is not clear whether vildagliptin (VIL) can prevent the progression of lifestyle-related disease. Thus, in the present study, Sprague-Dawley rats were fed a high-fat diet with sucrose water (HFDS) to determine whether VIL could inhibit deterioration in glucose tolerance and improve other biomarkers of lipid disorder. Four-month-old male Sprague-Dawley rats were divided into three groups (n = 7 in each group); one group was fed a normal diet for 4 months, whereas the remaining two groups were fed the HFDS, with or without VIL for 4 months. When rats were 7 months of age, they were subjected to an intraperitoneal glucose tolerance test (IPGTT); biomarkers of lipid disorder were measured in 8-month-old rats. There was a decrease in the glucose spike in the IPGTT 10min after loading in the HFDS + VIL group and plasma triglyceride (TG) levels were significantly lower in these rats compared with the HFDS group. The decreased TG levels in HFDS + VIL rats were accompanied by decreases in plasma chylomicron levels. These results suggest that VIL can prophylactically inhibit decreases in pancreatic β-cell function in type 2 diabetes and reduce the risk of cardiovascular disease due to high TG levels. Thus, VIL administration may contribute to the prevention of lifestyle-related disease

キサンチンオキシダーゼ阻害薬febuxostatはNrf2を活性化し脂肪細胞分化を抑制する

Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3–L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating

LL-Z1640-2 for rheumatoid arthritis

Objectives: Aberrant NLRP3 inflammasome activation has been demonstrated in rheumatoid arthritis (RA), which may contribute to debilitating inflammation and bone destruction. Here, we explored the efficacy of the potent TGF-β-activated kinase-1 (TAK1) inhibitor LL-Z1640-2 (LLZ) on joint inflammation and bone destruction in collagen-induced arthritis (CIA). Methods: LL-Z1640-2 was administered every other day in CIA mice. Clinical and histological evaluation was performed. Priming and activation of NLRP3 inflammasome and osteoclastogenic activity were assessed. Results: NLRP3 inflammasome formation was observed in synovial macrophages and osteoclasts (OCs) in CIA mice. TACE and RANKL were also overexpressed in synovial macrophages and fibroblasts, respectively, in the CIA joints. Treatment with LLZ mitigated all the above changes. As a result, LLZ markedly suppressed synovial hypertrophy and pannus formation to alleviate pain and inflammation in CIA mice. LLZ could block the priming and activation of NLRP3 inflammasome in RAW264.7 macrophage cell line, primary bone marrow macrophages and OCs upon treatment with LPS followed by ATP, thereby suppressing their IL-1β production. LLZ also suppressed LPS-induced production of TACE and TNF-α in bone marrow macrophages and abolished IL-1β-induced production of MMP-3, IL-6 and RANKL in synovial fibroblasts. In addition, LLZ directly inhibits RANKL-mediated OC formation and activation. Conclusion: 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

RANKLが誘導する破骨細胞分化におけるROSの役割と、Febuxostatによる破骨細胞分化抑制効果

Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox’s anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage

デントウ ケンチク デントウ コウゲイ ノ ギジュツ ト ブンカ ノ ケイショウ ニ カンスル タクミ リョウイキ ノ キョウイク ケンキュウ

　伝統的な建築・工芸についての知識と基本技能を修得し、現代社会と呼応しうる新たなデザインを生み出す人材を養成することを目的に、2019年デザイン学科に匠領域が増設された。2017年から継続している伝統建築を通した教育・研究・地域連携の成果、「工芸」「匠」の位置づけ、匠ものデザインプロジェクト、遠州地域との関わりと「織」教育プログラム、旧田代家住宅を活用した学生作品展について報告し、伝統建築・工芸の技術と文化の継承という大きな課題の中での、デザイン教育における「匠」について検証するものである。　In 2019, the Department of Design was expanded to include the field of TAKUMI, with the aim of acquiring knowledge and basic skills in traditional architecture and crafts, cultivating human resources capable of creating new designs that can respond to modern society. This study reports on the results of education, research, and regional collaboration through traditional architecture that have been continuing since 2017, the positions of "KOUGEI" and "TAKUMI", the craftsmanship design project of “TAKUMIMONO”, the relationship with the Enshu region and the "weaving" education program, as well as the exhibition of student works using former Tashiro residence. It also examines "TAKUMI" in design education amid the major issue of inheriting traditional architecture, craft techniques, and culture