The Role of PPARs in Cancer

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. PPARα is mainly expressed in the liver, where it activates fatty acid catabolism. PPARα activators have been used to treat dyslipidemia, causing a reduction in plasma triglyceride and elevation of high-density lipoprotein cholesterol. PPARδ is expressed ubiquitously and is implicated in fatty acid oxidation and keratinocyte differentiation. PPARδ activators have been proposed for the treatment of metabolic disease. PPARγ2 is expressed exclusively in adipose tissue and plays a pivotal role in adipocyte differentiation. PPARγ is involved in glucose metabolism through the improvement of insulin sensitivity and represents a potential therapeutic target of type 2 diabetes. Thus PPARs are molecular targets for the development of drugs treating metabolic syndrome. However, PPARs also play a role in the regulation of cancer cell growth. Here, we review the function of PPARs in tumor growth

Coupling between dynamic 3D tissue architecture and BMP morphogen signaling during Drosophila wing morphogenesis

At the level of organ formation, tissue morphogenesis drives developmental processes in animals, often involving the rearrangement of two-dimensional (2D) structures into more complex three-dimensional (3D) tissues. These processes can be directed by growth factor signaling pathways. However, little is known about how such morphological changes affect the spatiotemporal distribution of growth factor signaling. Here, using the Drosophila pupal wing, we address how decapentaplegic (Dpp)/bone morphogenetic protein (BMP) signaling and 3D wing morphogenesis are coordinated. Dpp, expressed in the longitudinal veins (LVs) of the pupal wing, initially diffuses laterally within both dorsal and ventral wing epithelia during the inflation stage to regulate cell proliferation. Dpp localization is then refined to the LVs within each epithelial plane, but with active interplanar signaling for vein patterning/differentiation, as the two epithelia appose. Our data further suggest that the 3D architecture of the wing epithelia and the spatial distribution of BMP signaling are tightly coupled, revealing that 3D morphogenesis is an emergent property of the interactions between extracellular signaling and tissue shape changes.Peer reviewe

Quantitative Threshold Determination of Auditory Brainstem Responses in Mouse Models

The auditory brainstem response (ABR) is a scalp recording of potentials produced by sound stimulation, and is commonly used as an indicator of auditory function. However, the ABR threshold, which is the lowest audible sound pressure, cannot be objectively determined since it is determined visually using a measurer, and this has been a problem for several decades. Although various algorithms have been developed to objectively determine ABR thresholds, they remain lacking in terms of accuracy, efficiency, and convenience. Accordingly, we proposed an improved algorithm based on the mutual covariance at adjacent sound pressure levels. An ideal ABR waveform with clearly defined waves I–V was created; moreover, using this waveform as a standard template, the experimentally obtained ABR waveform was inspected for disturbances based on mutual covariance. The ABR testing was repeated if the value was below the established cross-covariance reference value. Our proposed method allowed more efficient objective determination of ABR thresholds and a smaller burden on experimental animals.Tanaka K., Ohara S., Matsuzaka T., et al. Quantitative Threshold Determination of Auditory Brainstem Responses in Mouse Models. International Journal of Molecular Sciences 24, 11393 (2023); https://doi.org/10.3390/ijms241411393

Systematic measurement of the intrinsic losses in various kinds of bulk fused silica

We systematically measured and compared the mechanical losses of various kinds of bulk fused silica. Their quality factors ranged widely from 7x10^5 to 4x10^7, the latter being one of the highest reported among bulk fused silica. We observed frequency-dependent losses and a decrease in the losses upon annealing.Comment: 14 pages, 4 figures, Submitted to Phys. Lett.

Promoting effect of basic fibroblast growth factor in synovial mesenchymal stem cell-based cartilage regeneration

Synovial mesenchymal stem cell (SMSC) is the promising cell source of cartilage regeneration but has several issues to overcome such as limited cell proliferation and heterogeneity of cartilage regeneration ability. Previous reports demonstrated that basic fibroblast growth factor (bFGF) can promote proliferation and cartilage differentiation potential of MSCs in vitro, although no reports show its beneficial effect in vivo. The purpose of this study is to investigate the promoting effect of bFGF on cartilage regeneration using human SMSC in vivo. SMSCs were cultured with or without bFGF in a growth medium, and 2 × 105 cells were aggregated to form a synovial pellet. Synovial pellets were implanted into osteochondral defects induced in the femoral trochlea of severe combined immunodeficient mice, and histological evaluation was performed after eight weeks. The presence of implanted SMSCs was confirmed by the observation of human vimentin immunostaining-positive cells. Interestingly, broad lacunae structures and cartilage substrate stained by Safranin-O were observed only in the bFGF (+) group. The bFGF (+) group had significantly higher O’Driscoll scores in the cartilage repair than the bFGF (−) group. The addition of bFGF to SMSC growth culture may be a useful treatment option to promote cartilage regeneration in vivo.Okamura G., Ebina K., Hirao M., et al. Promoting effect of basic fibroblast growth factor in synovial mesenchymal stem cell-based cartilage regeneration. International Journal of Molecular Sciences, 22, 1, 1. https://doi.org/10.3390/ijms22010300

トクシマシ イシカイ ニオケル ザイタク イリョウ エノ トリクミ

Japan is heading toward a super-aging society at a rate unparalleled with other countries. The vast increase in demand for medical treatment and care will exceed existing social resources by 2025 when the baby boom generation becomes older than 75 years. There are concerns that this may lead to the collapse of acute medical care, break out refugee Home Medical Care, and the loss of end-of-life care facilities in various areas. Therefore, Japan is promoting the establishment of a comprehensive community care system designed to allow elderly individuals to live in their own community with dignity for as long as possible. The development of home medical care is being promoted as the core component of this system. The Tokushima City Medical Association has assessed the possible risks associated with this super-aging society that should emerge at a relatively early stage. Furthermore, the development of home medical care for the public to support community medical care is regarded as the best means of tackling future challenges. Therefore, we set up the Home Care Cooperation Committee in 2008 and have worked to develop home care in Tokushima City. The Tokushima City Medical Association participated in the Home Medical Care Cooperation Base Service of commissioned projects by the Ministry of Health, Labour and Welfare as one of 105 institutions in whole country in 2012. Since 2013, we have already been implementing this with Tokushima City administration as a subsidized institution under the three year’s Home Medical Care Cooperation Base Service which was performed by the Tokushima prefecture. This base of operations incorporates the following five mandatory directives : 1. identify solutions to multidisciplinary cooperation issues, 2. develop a multidisciplinary cooperation system and a 24-h response system, 3. raise awareness among residents, 4. educate personnel engaged in home medical care, and 5. set up a consultation service for home medical care. Because of community demands for projects to be implemented in a more area-wise appropriate manner, the Tokushima Home Care Cooperation Committee was newly established following general consensus within the association. This committee was composed of 14members not limited to individuals from medical associations ; individuals from the local government and various professions involved in home medical care were recruited and made decisions regarding operating policies. The current major challenge in Tokushima City is the lack of a means to disseminate proposed solutions for home medical care throughout the entire community. Therefore, we are promoting the establishment of multiple working groups on home medical care to tackle this challenge in the future. In addition, we intend to summarize the various challenges and their solutions that we identified during the course of our operations, draw up guidelines on home medical care based on the agreement of the local government and various professions and disseminate these guidelines throughout the community. We aim to effectively operate and from multiple levels a mutual support system between doctors who have long been working in medical associations, a multidisciplinary, conscientious cooperation system to support patients, a streamlined cooperation system for hospital admission and discharge, and a patient information sharing system utilizing ICT. These systems will be operated in parallel with our base operations. We also aim to promote the future improvement of environments in which as many family doctors as possible can examine their patients at home with ease until their patient’s final breath. This should enable us to provide high-quality home medical care equally and widely throughout the community. We hereby report the home medical care initiatives and future projects of the Tokushima City Medical Association centered on the Home Medical Care Cooperation Based Project

Structural insights into the HBV receptor and bile acid transporter NTCP

B型肝炎ウイルスの受容体“胆汁酸輸送体”の立体構造を解明. 京都大学プレスリリース. 2022-05-18.Roughly 250 million people are infected with hepatitis B virus (HBV) worldwide, and perhaps 15 million also carry the satellite virus HDV, which confers even greater risk of severe liver disease. Almost ten years ago the HBV receptor was identified as NTCP (sodium taurocholate co-transporting polypeptide), which interacts directly with the first 48 amino acid residues of the N-myristoylated N-terminal preS1 domain of the viral large (L) protein. Despite the pressing need for therapeutic agents to counter HBV, the structure of NTCP remains unsolved. This 349-residue protein is closely related to human apical sodium-dependent bile acid transporter (ASBT), another member of the solute carrier family SLC10. Crystal structures have been reported of similar bile acid transporters from bacteria, and these models with ten transmembrane helices are believed to resemble strongly both NTCP and ASBT. Using cryo-electron microscopy we have solved the structure of NTCP bound to an antibody, clearly showing the transporter has no equivalent to the first transmembrane helix of other SLC10 models, leaving the N-terminus exposed on the extracellular face. Comparison of the different structures indicates a common mechanism of bile acid transport, but the NTCP structure also displays a pocket formed by residues known to interact with preS1, presenting new and enticing opportunities for structure-based drug design