المؤلفون: Tanaka, Hiroyoshi Y.¹ (AUTHOR), Nakazawa, Takuya² (AUTHOR), Miyazaki, Takuya³ (AUTHOR), Cabral, Horacio⁴ (AUTHOR), Masamune, Atsushi⁵ (AUTHOR), Kano, Mitsunobu R.^1,2 (AUTHOR) mikano-tky@umin.net

المصدر: Journal of Controlled Release. May2024, Vol. 369, p283-295. 13p.

مصطلحات موضوعية: *PANCREATIC cancer, *TUMOR microenvironment, *YAP signaling proteins, *PERMEABILITY, *EXTRACELLULAR matrix, *CELL culture, *NANOMEDICINE, *FIBRONECTINS, *MACROMOLECULAR dynamics

مستخلص: Pancreatic cancer is characterized by a densely fibrotic stroma. The fibrotic stroma hinders the intratumoral penetration of nanomedicine and diminishes therapeutic efficacy. Fibrosis is characterized by an abnormal organization of extracellular matrix (ECM) components, namely the abnormal deposition and/or orientation of collagen and fibronectin. Abnormal ECM organization is chiefly driven by pathological signaling in pancreatic stellate cells (PSCs), the main cell type involved in fibrogenesis. However, whether targeting signaling pathways involved in abnormal ECM organization improves the intratumoral penetration of nanomedicines is unknown. Here, we show that targeting transforming growth factor-β (TGFβ)/Rho-associated kinase (ROCK) 1/2 signaling in PSCs normalizes ECM organization and concomitantly improves macromolecular permeability of the fibrotic stroma. Using a 3-dimensional cell culture model of the fibrotic pancreatic cancer microenvironment, we found that pharmacological inhibition of TGFβ or ROCK1/2 improves the permeation of various macromolecules. By using an isoform-specific pharmacological inhibitor and siRNAs, we show that targeting ROCK2, but not ROCK1, alone is sufficient to normalize ECM organization and improve macromolecular permeability. Moreover, we found that ROCK2 inhibition/knockdown attenuates Yes-associated protein (YAP) nuclear localization in fibroblasts co-cultured with pancreatic cancer cells in 3D. Finally, pharmacological inhibition or siRNA-mediated knockdown of YAP normalized ECM organization and improved macromolecular permeability. Our results together suggest that the TGFβ/ROCK2/YAP signaling axis may be therapeutically targeted to normalize ECM organization and improve macromolecular permeability to augment therapeutic efficacy of nanomedicines in pancreatic cancer. [Display omitted] • Fibrosis is a hallmark of pancreatic cancer and impedes intratumoral drug delivery. • Pancreatic stellate cells (PSCs) abnormally remodel the extracellular matrix (ECM). • Macromolecular delivery through fibrotic tissue assessed in a 3D in vitro model. • Targeting TGFβ/ROCK/YAP in PSCs attenuated ECM remodeling and improved delivery. • Targeting ROCK2, rather than ROCK1, was more effective. [ABSTRACT FROM AUTHOR]

المؤلفون: Chapman, Andrew, Ertekin, Elif, Kubota, Masanobu, Nagao, Akihide, Bertsch, Kaila, Macadre, Arnaud, Tsuchiyama, Toshihiro, Masamura, Takuro, Takaki, Setsuo, Komoda, Ryosuke, Dadfarnia, Mohsen, Somerday, Brian, Staykov, Alexander Tsekov, Sugimura, Joichi, Sawae, Yoshinori, Morita, Takehiro, Tanaka, Hiroyoshi, Yagi, Kazuyuki, Niste, Vlad, Saravanan, Prabakaran, Onitsuka, Shugo, Yoon, Ki Seok, Ogo, Seiji, Matsushima, Toshinori, Tumen-Ulzii, Ganbaatar, Klotz, Dino, Nguyen, Dinh Hoa, Harrington, George, Adachi, Chihaya, Matsumoto, Hiroshige, Kwati, Leonard, Takahashi, Yukina, Kosem, Nuttavut, Ishihara, Tatsumi, Yamauchi, Miho, Saha, Bidyut Baran, Islam, Md Amirul, Miyawaki, Jin, Sivasankaran, Harish, Kohno, Masamichi, Fujikawa, Shigenori, Selyanchyn, Roman, Tsuji, Takeshi, Higashi, Yukihiro, Kirchheim, Reiner, Sofronis, Petros

المصدر: Chapman , A , Ertekin , E , Kubota , M , Nagao , A , Bertsch , K , Macadre , A , Tsuchiyama , T , Masamura , T , Takaki , S , Komoda , R , Dadfarnia , M , Somerday , B , Staykov , A T , Sugimura , J , Sawae , Y , Morita , T , Tanaka , H , Yagi , K , Niste , V , Saravanan , P , Onitsuka , S , Yoon , K S , Ogo , S , Matsushima , T , Tumen-Ulzii ....

مصطلحات موضوعية: Carbon neutral, Energy, Materials, /dk/atira/pure/subjectarea/asjc/1600, name=Chemistry(all), /dk/atira/pure/sustainabledevelopmentgoals/affordable_and_clean_energy, name=SDG 7 - Affordable and Clean Energy

الوصف: Current greenhouse gas emissions suggest that keeping global temperature increase below 1.5 degrees, as espoused in the Paris Agreements will be challenging, and to do so, the achievement of carbon neutrality is of utmost importance. It is also clear that no single solution can meet the carbon neutral challenge, so it is essential for scientific research to cover a broad range of technologies and initiatives which will enable the realization of a carbon free energy system. This study details the broad, yet targeted research themes being pioneered within the International Institute for Carbon-Neutral Energy Research (I2CNER). These approaches include hydrogen materials, bio-mimetic catalysts, electrochemistry, thermal energy and absorption, carbon capture, storage and management and refrigerants. Here we outline the state of the art for this suite of technologies and detail how their deployment, alongside prudent energy policy implementation can engender a carbon neutral Japan by 2050. Recognizing that just as no single technological solution will engender carbon neutrality, no single nation can expect to achieve this goal alone. This study represents a recognition of conducive international policy agendas and is representative of interdisciplinary, international collaboration.

العلاقة: https://researchportal.bath.ac.uk/en/publications/117e89ee-9a9b-49f0-a663-4e2c742bd090Test

الإتاحة: https://doi.org/10.1246/bcsj.20210323Test
https://researchportal.bath.ac.uk/en/publications/117e89ee-9a9b-49f0-a663-4e2c742bd090Test
http://www.scopus.com/inward/record.url?scp=85123887927&partnerID=8YFLogxKTest

المؤلفون: Tanaka, Hiroyoshi, Ratoi, Monica, Sugimura, Joichi

المصدر: RSC Advances ; volume 11, issue 2, page 726-738 ; ISSN 2046-2069

الوصف: Hydrogen content and wear rate in bearing steel under rolling contact depend on the base oil type and the composition of tribofilm they generate on the wear track.

الإتاحة: https://doi.org/10.1039/d0ra00294aTest
http://pubs.rsc.org/en/content/articlepdf/2021/RA/D0RA00294ATest

المؤلفون: Tanaka, Hiroyoshi, Ratoi, Monica, Sugimura, Joichi

الوصف: Bearing steels suffer from a degradation of mechanical properties when atomic hydrogen diffuses into the steel from the contact surface. In rolling contact fatigue tests this can lead to a significant reduction in fatigue lives of the specimens as the amount of hydrogen diffused into the steel increases. To mitigate this challenge synthetic oils of different chemistry have been studied so as to identify their efficiency and mechanism of retarding or preventing hydrogen permeation. Thrust bearing type tests were conducted with three synthetic base oils. The effect of base oil chemistry on hydrogen generation and permeation in bearing steel was explored by relating the concentration of hydrogen species in specimens with changes in the surface and subsurface of the wear track and the condition of the oil.

وصف الملف: text

العلاقة: https://eprints.soton.ac.uk/446201/1/Text_The_role_of_synthetic_oils_in_controlling_H2_reviewed.pdfTest; https://eprints.soton.ac.uk/446201/2/synthetic_oils.pdfTest; https://eprints.soton.ac.uk/446201/3/Figures_reviewed.pdfTest; Tanaka, Hiroyoshi, Ratoi, Monica and Sugimura, Joichi (2020) The role of synthetic oils in controlling hydrogen permeation of rolling/sliding contacts. RSC Advances. (doi:10.1039/D0RA00294A ).

الإتاحة: https://doi.org/10.1039/D0RA00294ATest
https://eprints.soton.ac.uk/446201Test/
https://eprints.soton.ac.uk/446201/1/Text_The_role_of_synthetic_oils_in_controlling_H2_reviewed.pdfTest
https://eprints.soton.ac.uk/446201/2/synthetic_oils.pdfTest
https://eprints.soton.ac.uk/446201/3/Figures_reviewed.pdfTest

المؤلفون: Ratoi, Monica, Tanaka, Hiroyoshi, Mellor, Brian, Sugimura, Joichi

الوصف: While it is well known that during RCF tests the formation of nascent catalytic sites on the wear track can break down hydrocarbon molecules to release atomic hydrogen, the potential of the hydrogen environment in fuel cells to hydrocrack the hydrocarbon lubricant in high pressure rolling contacts has so far been ignored. Here we investigate for the first time the ability of the hydrogen environment to generate a chemical tribofilm on the wear track most likely through lubricant hydrocracking, as compared with argon and air environments. Despite the ability of the hydrogen environment to generate a notably larger amount of atomic hydrogen, the chemical tribofilm significantly prevents the formation of atomic hydrogen and its subsequent diffusion through the lattice of steel rolling element bearings. This is of great importance in the lubrication of hydrogen technology and the prevention of Hydrogen embrittlement (HE). An investigation into the prospects of high energy micro-computed-tomography (Micro-CT) as a non-destructive technique for sub-surface damage characterisation in RCF was comparatively performed alongside traditional sectioning methods.

وصف الملف: text

العلاقة: https://eprints.soton.ac.uk/437667/1/Text_Hydrocarbon_Lubricants_Can_Control_Hydrogen_Embrittlement_final.docxTest; https://eprints.soton.ac.uk/437667/2/Figs_Hydrocarbon_lubricants_can_control_HE.pdfTest; https://eprints.soton.ac.uk/437667/3/Hydrocarbon_Lubricants.pdfTest; Ratoi, Monica, Tanaka, Hiroyoshi, Mellor, Brian and Sugimura, Joichi (2020) Hydrocarbon lubricants can control hydrogen embrittlement. Scientific Reports, 10 (1), 1-14, [1361]. (doi:10.1038/s41598-020-58294-y ).

الإتاحة: https://doi.org/10.1038/s41598-020-58294-yTest
https://eprints.soton.ac.uk/437667Test/
https://eprints.soton.ac.uk/437667/1/Text_Hydrocarbon_Lubricants_Can_Control_Hydrogen_Embrittlement_final.docxTest
https://eprints.soton.ac.uk/437667/2/Figs_Hydrocarbon_lubricants_can_control_HE.pdfTest
https://eprints.soton.ac.uk/437667/3/Hydrocarbon_Lubricants.pdfTest

المؤلفون: Morii, Chiharu, Tanaka, Hiroyoshi Y., Izushi, Yasuhisa, Nakao, Natsumi, Yamamoto, Masaya, Matsubara, Hiromi, Kano, Mitsunobu R., Ogawa, Aiko

المصدر: Frontiers in Bioengineering and Biotechnology ; volume 8 ; ISSN 2296-4185

مصطلحات موضوعية: Biomedical Engineering, Histology, Bioengineering, Biotechnology

الإتاحة: https://doi.org/10.3389/fbioe.2020.00482Test

المؤلفون: Tanaka, Hiroyoshi Y., Nakazawa, Takuya, Enomoto, Atsushi, Masamune, Atsushi, Kano, Mitsunobu R.

المصدر: Cancers

مصطلحات موضوعية: pancreatic cancer, tumor microenvironment, nanomedicine, fibrosis, extracellular matrix, fibroblast

الوصف: Simple Summary Pancreatic cancer is difficult to treat. Novel treatment strategies are urgently needed to improve the survival rate, which is approximately 10% five years after diagnosis. The use of nanomedicines, which are formulated within a characteristic size range that favors its specific delivery to the diseased tissue, is being actively explored in cancer treatment. However, fibrosis (the abnormal accumulation of a cell type called fibroblasts and the fibrous protein network that they create) is characteristically seen in pancreatic cancer and hinders the delivery of nanomedicines into cancerous tissue. The decreased efficiency of delivery limits the therapeutic effects of nanomedicine in pancreatic cancer. We call this the "fibrotic barrier" to nanomedicine. To overcome the fibrotic barrier, we could target the fibrotic process and/or optimize the nanomedicine design. In this review, we give a detailed overview of strategies to overcome the fibrotic barriers in pancreatic cancer and highlight key gaps in our understanding. Pancreatic cancer is notorious for its dismal prognosis. The enhanced permeability and retention (EPR) effect theory posits that nanomedicines (therapeutics in the size range of approximately 10-200 nm) selectively accumulate in tumors. Nanomedicine has thus been suggested to be the "magic bullet"-both effective and safe-to treat pancreatic cancer. However, the densely fibrotic tumor microenvironment of pancreatic cancer impedes nanomedicine delivery. The EPR effect is thus insufficient to achieve a significant therapeutic effect. Intratumoral fibrosis is chiefly driven by aberrantly activated fibroblasts and the extracellular matrix (ECM) components secreted. Fibroblast and ECM abnormalities offer various potential targets for therapeutic intervention. In this review, we detail the diverse strategies being tested to overcome the fibrotic barriers to nanomedicine in pancreatic cancer. Strategies that target the fibrotic tissue/process are discussed first, which are followed by ...

العلاقة: info:pmid/36765684; https://ousar.lib.okayama-u.ac.jp/files/public/6/64414/20230310115156984323/fulltext.pdfTest; https://ousar.lib.okayama-u.ac.jp/64414Test

الإتاحة: https://doi.org/10.3390/cancers15030724Test
https://ousar.lib.okayama-u.ac.jp/files/public/6/64414/20230310115156984323/fulltext.pdfTest
https://ousar.lib.okayama-u.ac.jp/64414Test

المؤلفون: Watanabe, Sumiyo, Hayashi, Kotaro, Toh, Kazuko, Kim, Hyun Jin, Liu, Xueying, Chaya, Hiroyuki, Fukushima, Shigeto, Katsushima, Keisuke, Kondo, Yutaka, Uchida, Satoshi, Ogura, Satomi, Nomoto, Takahiro, Takemoto, Hiroyasu, Cabral, Horacio, Kinoh, Hiroaki, Tanaka, Hiroyoshi Y., Kano, Mitsunobu R., Matsumoto, Yu, Fukuhara, Hiroshi, Uchida, Shunya, Nangaku, Masaomi, Osada, Kensuke, Nishiyama, Nobuhiro, Miyata, Kanjiro, Kataoka, Kazunori

المصدر: Nature Communications ; volume 10, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. Many previous studies encapsulated oligonucleotides into ~100-nm nanoparticles. However, such nanoparticles inevitably accumulate in liver and spleen. Further, some intractable cancers, e.g., tumours in pancreas and brain, have inherent barrier characteristics preventing the penetration of such nanoparticles into tumour microenvironments. Herein, we report an alternative approach to cancer-targeted oligonucleotide delivery using a Y-shaped block catiomer (YBC) with precisely regulated chain length. Notably, the number of positive charges in YBC is adjusted to match that of negative charges in each oligonucleotide strand (i.e., 20). The YBC rendezvouses with a single oligonucleotide in the bloodstream to generate a dynamic ion-pair, termed unit polyion complex (uPIC). Owing to both significant longevity in the bloodstream and appreciably small size (~18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.

الإتاحة: https://doi.org/10.1038/s41467-019-09856-wTest
https://www.nature.com/articles/s41467-019-09856-w.pdfTest
https://www.nature.com/articles/s41467-019-09856-wTest

المؤلفون: Saravanan, Prabakaran, Selyanchyn, Roman, Tanaka, Hiroyoshi, Fujikawa, Shigenori, Lyth, Stephen Matthew, Sugimura, Joichi

المساهمون: Japan Science and Technology Agency

المصدر: Wear ; volume 432-433, page 102920 ; ISSN 0043-1648

مصطلحات موضوعية: Materials Chemistry, Surfaces, Coatings and Films, Surfaces and Interfaces, Mechanics of Materials, Condensed Matter Physics

الإتاحة: https://doi.org/10.1016/j.wear.2019.05.035Test
https://api.elsevier.com/content/article/PII:S0043164819301814?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0043164819301814?httpAccept=text/plainTest

المؤلفون: Tanaka, Hiroyoshi Y., Kano, Mitsunobu R.

المساهمون: Kato Memorial Bioscience Foundation, Japan Foundation for Applied Enzymology, Yasuda Memorial Medical Foundation, Council for Science and Technology Policy, Japan Society for the Promotion of Science

المصدر: Cancer Science ; volume 109, issue 7, page 2085-2092 ; ISSN 1347-9032 1349-7006

الوصف: Pancreatic cancer is known for its dismal prognosis despite efforts to improve therapeutic outcome. Recently, cancer nanomedicine, application of nanotechnology to cancer diagnosis and treatment, has gained interest for treatment of pancreatic cancer. The enhanced permeability and retention ( EPR ) effect that promotes selective accumulation of nanometer‐sized molecules within tumors is the theoretical rationale of treatment. However, it is clear that EPR may be insufficient in pancreatic cancer as a result of stromal barriers within the tumor microenvironment ( TME ). These limit intratumoral accumulation of macromolecules. The TME and stromal barriers inside it consist of various stromal cell types which interact both with each other and with tumor cells. We are only beginning to understand the complexities of the stromal barriers within the TME and its functional consequences for nanomedicine. Understanding the complex crosstalk between barrier stromal cells is challenging because of the difficulty of modeling pancreatic cancer TME . Here we provide an overview of stromal barriers within the TME . We also describe the preclinical models, both in vivo and in vitro, developed to study them. We furthermore discuss the critical gaps in our understanding, and how we might formulate a better strategy for using nanomedicine against pancreatic cancer.

الإتاحة: https://doi.org/10.1111/cas.13630Test