Immunosuppressants Tacrolimus and Sirolimus revert the cardiac antifibrotic properties of p38-MAPK inhibition in 3D-multicellular human iPSC-heart organoids

Immunosuppressive regimens after a heart transplant can hamper good therapeutic progressions in fibrosis. 京都大学プレスリリース. 2022-11-15.より本物の心臓に近い心臓オルガノイドによる薬剤の効果を評価するシステム --細胞間コミュニケーションを研究できるツールの開発--. 京都大学プレスリリース. 2022-11-21.Cardiac reactive fibrosis is a fibroblast-derived maladaptive process to tissue injury that exacerbates an uncontrolled deposition of large amounts of extracellular matrix (ECM) around cardiomyocytes and vascular cells, being recognized as a pathological entity of morbidity and mortality. Cardiac fibrosis is partially controlled through the sustained activation of TGF-β1 through IL-11 in fibroblasts. Yet, preclinical studies on fibrosis treatment require human physiological approaches due to the multicellular crosstalk between cells and tissues in the heart. Here, we leveraged an iPSC-derived multi-lineage human heart organoid (hHO) platform composed of different cardiac cell types to set the basis of a preclinical model for evaluating drug cardiotoxicity and assessing cardiac fibrosis phenotypes. We found that the inhibition of the p38-MAPK pathway significantly reduces COL1A1 depositions. Yet, concomitant treatment with organ-rejection immunosuppressant drugs Tacrolimus or Sirolimus reverts this effect, opening new questions on the clinical considerations of combined therapies in reducing fibrosis after organ transplantation

Characterization of membrane-bound lipase from a thermophilic Rhizopus oryzae isolated from palm oil mill effluent

The characteristics of the membrane-bound lipase from a thermophilic Rhizopus oryzae were studied. The pH and temperature optima for lipase activity were at 7.0 and 37°C, respectively. The enzyme was stable and acidic conditions, retaining more than 80% of its initial activity at pH 4.0 after 30 min incubation. It was stable up to 50°C with 70% of initial activity retained after 3 h incubation. The enzyme is 1,3 specific and exhibits substrate preference. Monoacid triglyceride substrates were hydrolyzed better than methyl esters, polyoxysorbitan and sorbitan substrates

Am80, a retinoic acid receptor agonist, activates the cardiomyocyte cell cycle and enhances engraftment in the heart

ヒトiPS細胞由来心筋細胞の生着能改善に向けた新しい方法. 京都大学プレスリリース. 2023-07-14.Am80, a retinoic acid receptor agonist, activates cell cycle in induced cardiomyocytes and enhances heart tissue engraftment. 京都大学プレスリリース. 2023-07-14.Human induced pluripotent stem cell-derived (hiPSC) cardiomyocytes are a promising source for regenerative therapy. To realize this therapy, however, their engraftment potential after their injection into the host heart should be improved. Here, we established an efficient method to analyze the cell cycle activity of hiPSC cardiomyocytes using a fluorescence ubiquitination-based cell cycle indicator (FUCCI) system. In vitro high-throughput screening using FUCCI identified a retinoic acid receptor (RAR) agonist, Am80, as an effective cell cycle activator in hiPSC cardiomyocytes. The transplantation of hiPSC cardiomyocytes treated with Am80 before the injection significantly enhanced the engraftment in damaged mouse heart for 6 months. Finally, we revealed that the activation of endogenous Wnt pathways through both RARA and RARB underlies the Am80-mediated cell cycle activation. Collectively, this study highlights an efficient method to activate cell cycle in hiPSC cardiomyocytes by Am80 as a means to increase the graft size after cell transplantation into a damaged heart

Plant Products for Pharmacology: Application of Enzymes in Their Transformations

Different plant products have been subjected to detailed investigations due to their increasing importance for improving human health. Plants are sources of many groups of natural products, of which large number of new compounds has already displayed their high impact in human medicine. This review deals with the natural products which may be found dissolved in lipid phase (phytosterols, vitamins etc.). Often subsequent convenient transformation of natural products may further improve the pharmacological properties of new potential medicaments based on natural products. To respect basic principles of sustainable and green procedures, enzymes are often employed as efficient natural catalysts in such plant product transformations. Transformations of lipids and other natural products under the conditions of enzyme catalysis show increasing importance in environmentally safe and sustainable production of pharmacologically important compounds. In this review, attention is focused on lipases, efficient and convenient biocatalysts for the enantio- and regioselective formation / hydrolysis of ester bond in a wide variety of both natural and unnatural substrates, including plant products, eg. plant oils and other natural lipid phase compounds. The application of enzymes for preparation of acylglycerols and transformation of other natural products provides big advantage in comparison with employing of conventional chemical methods: Increased selectivity, higher product purity and quality, energy conservation, elimination of heavy metal catalysts, and sustainability of the employed processes, which are catalyzed by enzymes. Two general procedures are used in the transformation of lipid-like natural products: (a) Hydrolysis/alcoholysis of triacylglycerols and (b) esterification of glycerol. The reactions can be performed under conventional conditions or in supercritical fluids/ionic liquids. Enzyme-catalyzed reactions in supercritical fluids combine the advantages of biocatalysts (substrate specificity under mild reaction conditions) and supercritical fluids (high mass-transfer rate, easy separation of reaction products from the solvent, environmental benefits based on excluding organic solvents from the production process)

Constraints on redox conditions in the Japan Sea in the last 47,000 years based on Mo and W as palaeoceanographic proxies

Both molybdenum (Mo) and tungsten (W) form soluble oxyanions in oxic seawater, whereas Mo forms insoluble thiomolybdate and W forms soluble thiotungstate in sulfidic seawater. Thus, concentrations and stable isotope ratios of Mo and W in sediments may fluctuate due to changes in redox conditions and can be used to estimate paleoenvironmental changes. The modern Japan Sea is oxic from the surface to the bottom, whereas deep water became anoxic several times from the late Pleistocene to the Holocene. Detailed information on redox conditions is still lacking. In this study, we analyzed a sediment core that was collected from offshore Iwanai, Hokkaido (43°22ʹ36ʺ N, 140°04ʹ10ʺ E, water depth 900 m). To the best of our knowledge, our study is the first to report stable isotope data of Mo and W in sediments of the Japan Sea. We observed maxima in the Mo concentration of up to 29 ppm in the sediment layers of 11–10 ka, 17–14 ka (the last glacial maximum), 31 ka, and 45 ka in accordance with the maxima of total sulfur, thereby indicating the deposition of thiomolybdate MoOxS₄₋x²⁻ (0 ≤ x ≤ 3). δ⁹⁸Mo, however, was between –0.19 and 0.69‰ at these ages, suggesting that the H₂S concentration in bottom water never exceeded 11 μmol kg⁻¹. The concentration and isotopic ratio of W were relatively constant throughout the core; W = 1.2 ± 0.2 ppm and δ¹⁸⁶W = 0.03 ± 0.03‰ (ave ± sd). The authigenic Mo and W ratio, Moauth/Wauth (mol/mol), was 10.5 ± 7.3 except for the above four ages, supporting the control of Mn and Fe (oxyhydr)oxides on Moauth and Wauth under oxic conditions

Distinct basin-scale-distributions of aluminum, manganese, cobalt, and lead in the North Pacific Ocean

Aluminum (Al), manganese (Mn), cobalt (Co), and lead (Pb) are key trace elements in seawater and thus significant in chemical oceanography research. However, although all of these elements are highly scavenged in the ocean, only a few studies focus on the intercomparison of their distributions. Here, we report the basin-scale and full-depth sectional distributions of these elements observed during three GEOTRACES Japan cruises in the North Pacific. We confirmed that a surface maximum of the dissolved (d) species is not a common feature for the four elements and that the d species have the lowest concentrations in the Pacific Deep Water (PDW) as compared to other oceans. The elements showed different speciations and distributions. The fraction of labile particulate (lp) species was calculated as the difference between the total dissolvable (td) species and d species. The lpM/tdM ratio, where M refers to an element, is highest for Al, at 0.66 ± 0.31 (average ± sd, n = 489), and lowest for Pb, at 0.02 ± 0.08 (n = 575). Further, the distribution of each element is uniquely related to ocean circulation. The tdAl concentration is high in the Equatorial Under Current (EUC), the North Equatorial Current (NEC), and the Lower Circumpolar Deep Water (LCDW). Manganese is supplied from reductive sources such as sediments on the continental shelves around the northern boundary. Cobalt is concentrated in the North Pacific Intermediate Water (NPIW) and in the Equatorial Pacific Intermediate Water (EqPIW) owing to the combined effects of supply from the continental shelves, biogeochemical cycling, and scavenging. Lead shows a subsurface maximum centered at ∼35°N and ∼200 m depth, implying an association with the formation of the Subtropical Mode Water (SMW) and the Central Mode Water (CMW). Although the subsurface Pb maximum in the Atlantic has diminished over the last three decades owing to the ban on leaded gasoline use, it has been sustained in the North Pacific through the growth of other anthropogenic sources in Asia and Russia. We propose that the enrichment factor of dM, defined as EF(dM) = (dM/dAl)seawater/(M/Al)upper crust, where (M/Al)upper crust is the molar ratio in upper crustal abundance, can be a good parameter for the sources. The median is 1.3 × 10² (n = 436) for EF(dMn), 3.2 × 10² (n = 430) for EF(dCo), and 1.2 × 10³ (n = 413) for EF(dPb). The EF(dPb) found in this study is on the same order of magnitude as the EF values for aerosols found in the literature, suggesting that the deposition of aerosols is a major source for dPb. Because EF(dMn) and EF(dCo) are ten to hundred times higher than the EF for aerosols, sources other than the aerosol deposition are more significant contributors to the concentrations of Mn and Co

Determination of the tungsten isotope composition in seawater: The first vertical profile from the western North Pacific Ocean

The stable isotope ratio of W is a new tracer in oceanographic studies and a new proxy in paleoceanographic studies; however, precise data for modern seawater have not been reported to date. Because the concentration of W in seawater is as low as 49 pmol kg⁻¹, an ~3000-fold preconcentration is necessary prior to measurement by multicollector inductivity coupled plasma mass spectrometry (MC-ICP-MS). For the preconcentration, we investigated solid-phase extraction using chelating resins, namely, NOBIAS Chelate-PA1 with ethylenediaminetriacetic acid groups and TSK-8HQ with 8-hydroxyquinolie groups. We report that TSK-8HQ is useful because the effects of the seawater matrix are minor thermodynamically and kinetically. We present a novel method for analysis of the concentrations and isotope ratios of W and Mo in seawater, consisting of solid phase extraction, chromatographic separation using anion exchange resin AG1 X8, and measurement by MC-ICP-MS. Both W and Mo are quantitatively recovered by this method, which was applied to seawater samples collected from the North Pacific Ocean. The measured concentration of W and the concentration and isotope ratio of Mo are consistent with those in the literature. The isotope ratio of W is found to be uniform throughout the water column in the western North Pacific Ocean; δ¹⁸⁶/¹⁸⁴W is 0.55 ± 0.12‰ (ave ± 2sd, n = 7) using NIST SRM 3163 as a reference for W. On the basis of this data, we determined that the isotopic difference in δ¹⁸⁶/¹⁸⁴W is ~0.49‰ between seawater and oxic sediments in the modern ocean. This value accords with the reported experimental data for the isotope fractionation of W during adsorption on manganese and iron (oxyhydr)oxides, suggesting the validity of our data