Dissolved inorganic carbon (DIC) present in groundwaters can affect both the aqueous and surface species of hexavalent uranium (U(VI)) owing to its strong complexation ability with U(VI). However, ...the effect of DIC on U(VI) sorption on illite, which is a critical component of argillaceous rocks, is still unclear. In this study, we investigated the sorption of U(VI) on conditioned illite du Puy with varying DIC concentrations (up to 250 mM DIC) as a function of pH through batch sorption experiments, surface complexation modeling, and cryogenic time-resolved laser fluorescence spectroscopy (TRLFS). The distribution coefficients of U(VI) decreased with an increase in the DIC concentration. At relatively high DIC concentrations with respect to experimentally investigated range (≥100 mM DIC), no U(VI) sorption was observed. The U(VI) sorption on illite was modeled using the two-site protolysis non-electrostatic surface complexation and cation exchange model. Two ternary surface complexation reactions with carbonate were needed to depict the experimental sorption data in addition to binary and ternary hydroxo surface complexation reactions used to describe the U(VI) sorption to illite without carbonate. Cryogenic TRLFS data revealed that U(VI) did sorb to illite at high DIC concentrations (up to 10 mM DIC). The spectra were unchanged with varying DIC concentrations (2.0, 5.0, and 10 mM DIC) at pH ∼8.5, indicating that the surface speciation of U(VI) remained the same. The decay curves were biexponential, which further indicates that at least two surface species were responsible for the sorption. These results could improve the performance assessment of a deep geological disposal system in a sedimentary host rock.
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•Sorption of U(VI) decreased obviously with increasing carbonate concentration.•The sorption data were well predicted by the 2SPNE SC/CE surface complexation model.•Two uranyl-carbonate surface complexes are needed to model the sorption data.
Biotransformation of glucose in organs includes multiple pathways, while quantitative evaluation of percentages of its utilization for individual pathways and their spatial heterogeneity in vivo ...remain unknown. Imaging MS (IMS) and metabolomics combined with a focused microwave irradiation for rapidly fixing tissue metabolism allowed us to quantify and visualize metabolic fluxes of glucose‐derived metabolites in the mouse brain in vivo. At 15 min after the intraperitoneal injection of 13C6‐labeled glucose, the mouse brain was exposed to focused microwave irradiation, which can stop brain metabolism within 1 s. Quantification of metabolic intermediates containing 13C atoms revealed that a majority of the 13C6‐glucose was diverted into syntheses of glutamate, lactate, and uridine diphosphate (UDP)‐glucose. IMS showed that regions rich in glutaminergic neurons exhibited a large signal of 13C2‐labeled glutamate. On the other hand, the midbrain region was enriched with an intensive 13C6‐labeled UDP‐glucose signal, suggesting an active glycogen synthesis. Collectively, application of the current method makes it possible to examine the fluxes of glucose metabolism in a region‐specific manner.
We present the results of matrix-assisted laser desorption/ionization (MALDI) imaging and direct molecular identification using tandem mass spectrometry (MS/MS) in colon cancer liver metastasis. ...Cancer tissue was removed from a Japanese patient and frozen immediately without any fixations. The sections were sliced to a thickness of 3
μm. The matrix for lipid ionization was 2,6-dihydroxy acetophenone. The matrix solution was applied with an airbrush into a thin uniform matrix layer on the tissue surface. After two-dimensional laser scanning, the images were reconstructed as a function of
m/
z from a few hundred obtained spectra. In the obtained images, the existence of molecules was represented by a pseudo-color corresponding to the signal intensity. In a feasibility study, we picked up a localized signal,
m/
z 725 in a cancerous area. The MS/MS result suggested that
m/
z 725 was sphingomyelin(16:0)+Na. Thus, we successfully show the feasibility of MALDI imaging as a tool for the analysis of pathological specimens.
In severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived ...macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity.
Simultaneous imaging of l-dihydroxyphenylalanine (l-DOPA), dopamine (DA) and norepinephrine (NE) in the catecholamine metabolic pathway is particularly useful because l-DOPA is a neurophysiologically ...important metabolic intermediate. In this study, we found that 2,4,6-trimethylpyrillium tetrafluoroborate (TMPy) can selectively and efficiently react with target catecholamine molecules. Specifically, simultaneous visualization of DA and NE as metabolites of l-DOPA with high steric hinderance was achieved by derivatized-imaging mass spectrometry (IMS). Interestingly, l-DOPA showed strong localization in the brainstem, in contrast to the pattern of DA and NE, which co-localized with tyrosine hydroxylase (TH). In addition, to identify whether the detected molecules were endogenous or exogenous l-DOPA, mice were injected with l-DOPA deuterated in three positions (D.sub.3 -l-DOPA), which was identifiable by a mass shift of 3Da. TMPy-labeled l-DOPA, DA and NE were detected at m/z 302.1, 258.1 and 274.1, while their D.sub.3 versions were detected at 305.0, 261.1 and 277.1 in mouse brain, respectively. l-DOPA and D.sub.3 -l-DOPA were localized in the BS. DA and NE, and D.sub.3 -DA and D.sub.3 -NE, all of which are metabolites of L-DOPA and D.sub.3 -l-DOPA, were localized in the striatum (STR) and locus coeruleus (LC). These findings suggest a mechanism in the brainstem that allows l-DOPA to accumulate without being metabolized to monoamines downstream of the metabolic pathway.
The human adrenal cortex secretes aldosterone and cortisol as major corticosteroids. For their production, CYP11B2 and CYP11B1 catalyze the last steps in the syntheses of aldosterone and cortisol, ...respectively. In our previous study, CYP11B2 was the first successfully purified from rat adrenals and human clinical samples and then was proved to be aldosterone synthase. We demonstrated the immunohistochemistry for CYP11B2 of both rats and humans and applied it clinically to visualize the functional histology of aldosterone-producing adenoma (APA) causing primary aldosteronism (PA). We discovered aldosterone-producing cell clusters (APCCs) and possible APCC-to-APA transitional lesions (pAATLs) and further visualized aldosterone-producing lesions for rare forms of PA including familial hyperaldosteronism type 3 and novel non-familial juvenile PA. Here we review the history of our research on aldosterone-producing lesions.
Abstract
The mammalian target of rapamycin (mTOR) is a sensor of nutrient status and plays an important role in cell growth and metabolism. Although inhibition of mTOR signaling promotes tumor cell ...death and several mTOR inhibitors have been used clinically, recent reports have shown that co-treatment with MHY1485, an mTOR activator, enhances the anti-cancer effects of anti-PD-1 antibody and 5-fluorouracil. However, it remains unclear whether MHY1485 treatment alters the effects of radiation on tumor cells. In this study, the radiosensitizing effects of MHY1485 were investigated using murine CT26 and LLC cell lines. We examined mTOR signaling, tumor cell growth, colony formation, apoptosis, senescence, oxidative stress, p21 accumulation and endoplasmic reticulum (ER) stress levels in cells treated with MHY1485 and radiation, either alone or together. We found that MHY1485 treatment inhibited growth and colony formation in both cell lines under irradiation and no-irradiation conditions, results that were not fully consistent with MHY1485’s known role in activating mTOR signaling. Furthermore, we found that combined treatment with MHY1485 and radiation significantly increased apoptosis and senescence in tumor cells in association with oxidative stress, ER stress and p21 stabilization, compared to radiation treatment alone. Our results suggested that MHY1485 enhances the radiosensitivity of tumor cells by a mechanism that may differ from MHY1485’s role in mTOR activation.
Although Ti bone scaffolds are widely used clinically as various hard-tissue scaffolds including dental implants, their limited initial osseointegration property is a significant disadvantage, which ...should be improved. A rough surface and the allied Ca ion release capability might improve initial osteointegration by enhancing the activity of osteoblasts, which dominates osseointegration. In this study, a calcite-coating method, as a Ca ion releaser, is introduced onto rough surfaces of the Ti scaffold by heat carbonation using calcium nitrate as the Ca source below the α-to-β phase transition temperature (~880 °C) of Ti. After this treatment, the Ti scaffolds become whiter with increasing the concentration of the calcium nitrate solution. X-ray diffraction (XRD) and spectroscopic measurements demonstrate that calcite is formed on the Ti scaffold after the treatment. Scanning electron microscopy (SEM) observations show numerous rhombohedral crystals with a size of several micrometers, densely covering the surface of the Ti scaffold, maintaining its rough surface structure. Optimization of the initial calcium nitrate solution concentration controls the amount of calcite coating onto the desired regions on the surface of the Ti scaffolds. The coating strength of the fabricated calcite is ~20 MPa, which is sufficient to resist implanting strength.
•Calcite strongly and uniformly coating onto Ti surface could be fabricated by heat carbonation.•The coating strength is ~20 MPa, which is sufficient to resist implanting strength.•The coating amount of calcite could be easily controlled and optimized.
Calcium carbonate (CaCO3) and particularly its stable phase, calcite, is of great geological significance in the deep carbon cycle since CaCO3 from biomineralized shells and corals form sedimentary ...rocks. Calcite also attracts attention in medical science and pharmacy as a primary or intermediate component in biomaterials because it possesses excellent biocompatibility along with suitable physicochemical properties. Calcite blocks have already been used during surgical procedures as a bone substitute for reconstructing bone defects formed by diseases and injury. When producing CaCO3 biomaterials and bioceramics, in particular, in vivo control of the size and polymorphic nature of CaCO3 is required. In this study, we investigated the effects of PO4 on calcite formation during the phase conversion of calcium sulfate anhydrate (CaSO4, CSA), which is sometimes used as a starting material for bone substitutes because of its suitable setting ability. CSA powder was immersed in 2 mol/L Na2CO3 solution containing a range of PO4 concentrations (0-60 mmol/L) at 40°C for 3 days. The treated samples were investigated by X-ray diffraction, Fourier-transform infrared spectroscopy, X-ray fluorescence spectroscopy, and thermal analysis. In addition, the fine structures of the treated samples were observed by field-emission scanning electron microscopy, and the specific surface area was measured. We found that PO4, which is universally present in vivo, can modulate the calcite crystal size during calcite formation. A fluorescence study and calcite crystal growth experiments indicated that PO4 adsorbs tightly onto the surface of calcite, inhibiting crystal growth. In the presence of high PO4 concentrations, vaterite is formed along with calcite, and the appearance and stability of the CaCO3 polymorphs can be controlled by adjusting the PO4 concentration. These findings have implications for medical science and pharmacology, along with mineralogy and geochemistry.
Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show ...that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRASG12D-induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs.
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•PKM1 promotes tumor growth cell intrinsically in some contexts•PKM1 activates glucose catabolism without interfering with biosynthetic pathways•PKM1-dependent autophagy/mitophagy contributes to malignancy•Expression of PKM1, but not PKM2, is sufficient to support SCLC cell proliferation
The relative importance of PKM isoforms in tumor growth has been controversial. Morita et al. show that PKM1 promotes the growth of multiple tumor models using mouse lines expressing PKM1 or PKM2 from the endogenous Pkm locus. PKM1 is expressed in human SCLC, and it is important for SCLC cell proliferation.
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