Feedback Control of the Arachidonate Cascade in Osteoblastic Cells by 15-deoxy-Δ12,14-Prostaglandin J2

15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and an anti-diabetic thiazolidinedione, troglitazone (TRO) are peroxisome proliferator-activated receptor (PPAR)-γ ligands, which regulate immuno-inflammatory reactions as well as adipocyte differentiation. We previously reported that 15d-PGJ2 can suppress interleukin (IL)-1β-induced prostaglandin E2 (PGE2) synthesis in synoviocytes of rheumatoid arthritis (RA). IL-1 also stimulates PGE2 synthesis in osteoblasts by regulation of cyclooxygenase (COX)-2 and regulates osteoclastic bone resorption in various diseases such as RA and osteoporosis. In this study, we investigated the feedback mechanism of the arachidonate cascade in mouse osteoblastic cells, MC3T3-E1 cells, which differentiate into mature osteoblasts. Treatment with 15d-PGJ2 led to a significant increase in IL-1α-induced COX-2 expression and PGE2 production in a dose dependent manner. The effect of 15d-PGJ2 was stronger than that of TRO. However, it did not affect the expression of COX-1. In addition, cell viability of MC3T3-E1 cells was not changed in the condition we established. This means that 15d-PGJ2 exerts a positive feedback regulation of the arachidonate cascade of PGE2 in osteoblastic cells. These results may provide important information about the pathogenesis and treatment of bone resorption in a variety of diseases such as RA and osteoporosis

Novel Oral Derivative UD-017, a Highly Selective CDK7 Inhibitor, Exhibits Anticancer Activity by Inducing Cell-Cycle Arrest and Apoptosis in Human Colorectal Cancer

Objective: This study aimed to investigate the anticancer profile of a new cyclin-dependent kinase 7 (CDK7) inhibitor, UD-017, by examining its mechanism of action using HCT-116 colorectal cancer cells. Methods: The anticancer properties of UD-017 were assessed using several assays, including in vitro kinase, proliferation, and apoptosis assays, western blot analysis, and an in vivo xenograft mouse model. Results: UD-017 significantly inhibited CDK7 activity (IC50 = 16 nM) with high selectivity in an in vitro kinase assay testing a panel of over 300 proteins and lipid kinases. UD-017 also inhibited the growth of HCT-116 cells (GI50 = 19 nM) and inhibited the phosphorylation of various downstream mediators of CDK7 signaling. In cell cycle and apoptosis assays using HCT-116 cells, UD-017 increased the number of cells in both G1 and G2/M phases and induced apoptosis. In vivo, UD-017 inhibited tumor growth in an HCT-116 xenograft mouse model by 33%, 64%, and 88% at doses of 25, 50, and 100 mg/kg, respectively, with clear dose-dependency. Co-administration of 5-FU and 50 mg/kg UD-017 had a strong synergistic effect, as reflected in the complete inhibition of tumor growth. Conclusion: CDK7 may play a major role in colorectal cancer growth by regulating the cell cycle and apoptosis. UD-017 is a promising candidate therapeutic agent for the treatment of cancer involving CDK7 signaling

A comparative method for evaluating ecosystem services from the viewpoint of public works

Nature-based solutions (NbS), such as the implementation of environmental conservation and restoration as public works projects, require accurate and cost-effective assessments of the values related to the projects. The values should represent collective ecosystem services, individual services such as food provision and water purification, and other intangible services. To comprehensively assess such services, we proposed a novel method, which we call the comparative evaluation method. Our method is able to assess the value of each service category of an NbS project from a single questionnaire survey. Survey participants are asked to compare values of multiple services having anchoring prices. Our method determines the permissible economic value of environmental public works (PEP) in response to the quantity of service. The questionnaire results used for analysis are limited to those from respondents who made their PEP evaluation on the basis of their consideration of the appropriate expenditure of taxes. In addition, the method controls for the effect of the satisfaction that a person experiences from doing good deeds to reduce an overestimation of the values of services. Moreover, PEPs are not influenced by the respondent's annual income, age, sex, or educational background, and are based on personal values. Applying this new method, we surveyed residents of the watersheds of Tokyo Bay and Osaka Bay and evaluated nine ecosystem services. Overall, our new method is shown to be an effective method for evaluating the ecosystem services of NbS projects from the viewpoint of public works

Green port structures and their ecosystem services in highly urbanized Japanese bays

Green port structures (i.e. green infrastructure in ports and harbors) featuring habitats for marine organisms have been promoted in Japan as part of a comprehensive policy to reduce the environmental impact of ports and carry out habitat conservation, restoration, and creation. In this study, we evaluated the ecosystem services provided by green port structures in two highly urbanized bays (Tokyo Bay and Osaka Bay) in Japan. Our results show that the provision of some ecosystem services can be limited by circumstances particular to ports and other areas with restricted access. In the case of green port structures that have strong usage restrictions, for example, cultural services can only be provided if relevant authorities are prepared to conduct public events while ensuring participant safety. On the other hand, green port structures with weak usage restrictions are often equipped with incidental facilities such as parking lots and restrooms; these facilities can enhance the provision of cultural services (e.g. recreation and environmental education). Green port structures in highly urbanized bays often have usage restrictions, but their proximity to large populations means that they can potentially provide numerous ecosystem services. However, our study shows that appropriate management goals, such as protecting species and ensuring healthy habitats, are needed to maintain the value of these services in highly urbanized and eutrophic bays

Periostin as a novel biomarker for postoperative recurrence of chronic rhinosinitis with nasal polyps

We previously reported that chronic rhinosinusitis with nasal polyps (CRSwNP) was subdivided into four chronic rhinosinusitis (CRS) subtypes using the JESREC scoring system. We sought to identify the gene expression profile and biomarkers related with CRSwNP by RNA-sequence. RNA-sequencing was performed to identify differentially expressed genes between nasal polyps (NPs) and inferior turbinate mucosa from 6 patients with CRSwNP, and subsequently, quantitative real-time PCR was performed to verify the results. ELISA was performed to identify possible biomarkers for postoperative recurrence. In the RNA-sequencing results, periostin (POSTN) expression was the highest in NP. We focused on POSTN and investigated the protein level of POSTN by immunohistochemistry and ELISA. POSTN was diffusely expressed in moderate and severe eosinophilic CRS using immunohistochemistry, and its staining pattern was associated with the severity of the phenotype of the CRSwNP (P < 0.05). There was a significant difference between the POSTN high/low groups for postoperative recurrence when the cutoff point was set at 115.5 ng/ml (P = 0.0072). Our data suggests that the protein expression level of POSTN was associated with the severity of CRSwNP, and serum POSTN can be a novel biomarker for postoperative recurrence of CRSwNP

Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma

成人T細胞白血病リンパ腫（ATL）におけるゲノム情報と臨床情報を統合したリスクモデルを確立 --ATLの個別化医療を推進--. 京都大学プレスリリース. 2023-04-10.The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment. To identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and high-risk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] 5.46, p < 0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR 2.33, p = 0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATL-PI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (−4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (−2), and GATA3 (−3)

Lifespan-Extending Effects of Royal Jelly and Its Related Substances on the Nematode Caenorhabditis elegans

One of the most important challenges in the study of aging is to discover compounds with longevity-promoting activities and to unravel their underlying mechanisms. Royal jelly (RJ) has been reported to possess diverse beneficial properties. Furthermore, protease-treated RJ (pRJ) has additional pharmacological activities. Exactly how RJ and pRJ exert these effects and which of their components are responsible for these effects are largely unknown. The evolutionarily conserved mechanisms that control longevity have been indicated. The purpose of the present study was to determine whether RJ and its related substances exert a lifespan-extending function in the nematode Caenorhabditis elegans and to gain insights into the active agents in RJ and their mechanism of action.We found that both RJ and pRJ extended the lifespan of C. elegans. The lifespan-extending activity of pRJ was enhanced by Octadecyl-silica column chromatography (pRJ-Fraction 5). pRJ-Fr.5 increased the animals' lifespan in part by acting through the FOXO transcription factor DAF-16, the activation of which is known to promote longevity in C. elegans by reducing insulin/IGF-1 signaling (IIS). pRJ-Fr.5 reduced the expression of ins-9, one of the insulin-like peptide genes. Moreover, pRJ-Fr.5 and reduced IIS shared some common features in terms of their effects on gene expression, such as the up-regulation of dod-3 and the down-regulation of dod-19, dao-4 and fkb-4. 10-Hydroxy-2-decenoic acid (10-HDA), which was present at high concentrations in pRJ-Fr.5, increased lifespan independently of DAF-16 activity.These results demonstrate that RJ and its related substances extend lifespan in C. elegans, suggesting that RJ may contain longevity-promoting factors. Further analysis and characterization of the lifespan-extending agents in RJ and pRJ may broaden our understanding of the gene network involved in longevity regulation in diverse species and may lead to the development of nutraceutical interventions in the aging process

ジンソク デ アンゼンナ ジュウミン ヒナン コウドウ オ ソクシン スル ボウサイ コウドウ ケイカク ノ サクテイ

浸水被害をハード整備で防ぐには膨大な時間と経費を要するため，整備途上でも被害の最小化を図るソフト対策の充実が喫緊の課題である．本研究は2014年8月に那賀町で発生した水害時の行政と住民の対応を検証する．また，過去の那賀川における出水状況を踏まえ，はん濫発生と水位や上流のダムからの放流量の相関関係等を検証するとともに，行政が発信する災害関連情報の種類や伝達方法，住民の避難完了までに必要な時間等も検討する．その結果，住民の避難等が適正に実施されるよう，災害発生前の行政や住民の対応を時系列に沿って「いつ，だれが，何をする」を明確にした「防災行動計画」を提案する．Improvement of disaster prevention facility for a flood is necessary long time and a large amount of budget. The minimization of flood damage is incomplete without enhancement of soft measures in addition to hard measures. The serious flood damage due to Typhoon No.1411 has occurred in Naka town, Tokushima Prefecture. We analyzed the relationships between the disaster information providing by administration and evacuation of residents. Based on the results, we have developed the disaster management action plan which is called "Timeline" of government and residents

Effects of terrigenic He components on tritium–helium dating: A case study of shallow groundwater in the Saijo Basin

Dating using a combination of 3H and 3He is believed to be the most practical method for estimating the short residence time of shallow groundwater. However, this method must estimate tritiogenic 3He alone and tends to overestimate the residence time of groundwater, if terrigenic 3He from the mantle cannot be excluded from the total dissolved 3He. We demonstrate the exclusion of terrigenic 3He in the Saijo Basin, where mantle He is easily released along the major active fault, Median Tectonic Line. The 3He/4He ratios suggest that the west bank of the Kamo River, which lies within the basin, has experienced greater emanations of mantle He than the east bank. We estimate the residence times to be 1.1–96 years by the proposed exclusion method