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Purpose: The purpose of this study was to investigate the relationships among plasma concentrations of lenvatinib, angiopoietin (Ang)-1 and Ang-2, and clinical responses to lenvatinib therapy in Japanese patients with thyroid cancer. Methods: Plasma concentrations of lenvatinib (C0) and Ang-1 and -2 were measured by HPLC and ELISA, respectively.Results: The median change rates of Ang-1 and Ang-2 at 1 month after treatment from baseline in 36 patients were -15.3% and -48.4%, respectively. However, the change of Ang-1 and Ang-2 at 1 month from baseline did not correlate with lenvatinib C0. In patients with partial response (PR) and stable disease to lenvatinib, Ang-2 at 1 month were significantly lower than Ang-2 at baseline (P < 0.001 and P < 0.05, respectively), but were not significantly lower in patients with progressive disease. The area under the ROC for PR prediction was 0.667, giving the best sensitivity (69.2%) and specificity (73.9%) at a threshold of the change rate of Ang-2 of -49.83%. A one year overall survival for patients having the change rate of Ang-2 of at least -49.83% and less than -49.83% were 62.5% and 40%, respectively. In patients who continued treatment with lenvatinib for 1 year, Ang-2 at 1 month and 1 year after treatment were significantly lower than those at baseline (each P < 0.001).Conclusion: The change of Ang-2 at 1 month after treatment from baseline rather than simply the Ang-2 level at baseline may be important as a biomarker of the inhibitory effect of angiogenesis by lenvatinib.

The anterior pituitary gland regulates growth, metabolism, and reproduction by secreting hormones. Folliculo-stellate (FS) cells are non-endocrine cells located among hormone-producing cells in the anterior pituitary glands. They form follicular lumens, which are sealed by tight junctions (TJs). Although FS cells are hypothesized to contribute to fine-tuning of endocrine cells, little is known about the exact roles of FS cells. Here, we investigated the molecular composition of TJs in FS cells. We demonstrated that occludin is a good marker for TJs in the pituitary gland and examined the structure of the lumens surrounded by FS cells. We also found that claudin-9 is a major component of TJs in the FS cells. In immunoelectron microscopy, claudin-9 was specifically localized at TJs of the FS cells. The expression of claudin-9 was gradually increased in the pituitary gland after birth, suggesting that claudin-9 is developmentally regulated and performs some specific functions on the paracellular barrier of follicles in the pituitary gland. Furthermore, we found that angulin-1, angulin-2, and tricellulin are localized at the tricellular contacts of the FS cells. Our findings provide a first comprehensive molecular profile of TJs in the FS cells, and may lead us towards unveiling the FS cell functions.

In this study, MgSiN2 is prepared via combustion synthesis under low-pressure nitrogen (0.1 MPa), and the effects of the mixture composition and nitrogen pressure on the obtained products are investigated. The combustion temperature increases with the amount of silicon, and β-Si3N4 is detected as the main impurity when a significant amount of silicon is incorporated. In addition, the combustion temperature increases with the nitrogen pressure, and the purity of MgSiN2 increases because the high pressure restricts the vaporization of magnesium. These results suggest that increasing magnesium content is efficient for the synthesis of single-phase MgSiN2 at 0.1 MPa of nitrogen because magnesium is volatilized from the reaction system under the low nitrogen pressure. Hence, single-phase MgSiN2 can be synthesized under 0.1 MPa of nitrogen using a mixture containing a significant amount of magnesium.

This study aimed to assess the accuracy of predicting pelvic lymph node status using sentinel lymph node (SLN) biopsy with indocyanine green (ICG) and to examine the outcomes of SLN biopsy-guided abdominal radical trachelectomy (ART). Patients with stage IA2–IB2 cervical cancer from January 2009 to January 2021 were included. ICG was injected before ART and SLNs were identified, excised, and assessed intraoperatively using fast-frozen sections. Systemic pelvic lymphadenectomy was subsequently performed. The SLN detection rate, sensitivity, and false-negative rate were determined. Thirty patients desiring fertility preservation were enrolled, of whom 26 successfully completed ART and four underwent radical hysterectomies because of metastatic primary SLNs. Bilateral SLNs were identified in all patients. The sensitivity, false-negative rate, and negative predictive value were 100%, 7.7%, and 92.3%, respectively. Three (12%) patients were lost to follow-up: two relapsed and one died of tumor progression. Of the nine patients who tried to conceive after surgery, four achieved pregnancy and three delivered healthy live infants. In women with early-stage cervical cancer who desired to conserve fertility, SLN mapping with ICG had a very high detection rate, sensitivity, and low false-negative rate. SLN biopsy-guided ART is a feasible and accurate method for assessing pelvic node status.

Acyclic asymmetric quaternary stereocenters, which are composed of four carbon-carbon bonds, were finely constructed by utilizing a face-selective alkylation of enolate intermediates derived from an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,β-unsaturated esters. The present face-selective alkylation was able to employ diverse alkyl halides as an electrophile to afford various Michael adducts having an all-carbon quaternary stereocenter. With regard to the deprotection of the chiral auxiliary, N-iodosuccinimide used in our previous study did not work in the present cases; however, we found that pyridine iodine monochloride in the presence of H2O was effective to remove the bornyl group and the benzyl group on the amino group to provide the β-amino ester derivative.

Confectionery ingredients are expected to enhance the medication adherence of pediatric patients taking bitter-tasting drugs when adequate pediatric medicines are not available in practical settings. Gum is a familiar confectionery, and several drug-loaded gums are on the market as medicated chewing gums. In this study, medical gum tablets composed of confectionery xylitol gum and a drug (ibuprofen or acetaminophen) were prepared and evaluated for the purpose of potential hospital applications. The effect of the sintering process, a heating treatment, on the physical properties of the solid materials was also examined. The sintering process markedly improved the hardness of the gum tablets. The sintering temperature and time affected the hardness of both ibuprofen- and acetaminophen-loaded gum tablets, whereas heat treatment around the melting point of ibuprofen or xylitol and longer heat treatment resulted in failure of the preparation or a reduction in hardness. The sintered gum tablets exhibited a delayed drug release profile in artificial saliva after an in vitro chewing test. The current results provide basic and useful information about the preparation of gum-containing tablets in future clinical settings.

The in vitro antitumor activity (e.g., IC50) of anticancer drugs is important for selecting candidate compounds for in vivo drug efficacy study in the early stage of drug discovery. In this study, ...

In recent, millions of people are living with the human immunodeficiency virus type 1 (HIV-1), which causes acquired immunodeficiency syndrome. HIV-1 reverse transcriptase (RT) is one of the main viral targets for HIV-1 inhibition. Pyrimidine nucleoside derivative, 3′-azido-3′-deoxythymidine (AZT) is a highly active nucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). In this work, hydroxyl (-OH) groups of cytidine structure were modified with different aliphatic and aromatic groups to get 5´-O-acyl- and 2´,3´-di-O-acyl derivatives and then employed for molecular modeling, molecular docking, biological prediction, and pharmacological studies. Herein, we relate the optimization of cytidine and its acylated analogues applying density functional theory (DFT) with B3LYP/3-21G level theory to explore their thermochemical and molecular electrostatic potential (MEP) properties. Prediction of activity spectra for substances (PASS) indicated promising antiviral, anti-carcinogenic, and antifungal functionality of these cytidine esters compared to the antibacterial activities. To support this observation, their cytotoxic prediction and molecular docking studies have been performed against HIV-1 reverse transcriptase (RT) (PDB: 3V4I). Most of the molecules studied out here could bind near the crucial catalytic binding site, Tyr181, Ile94, Ile382, Lys374, Val381, Val90, and Tyr34 of the HIV-1 reverse transcriptase (RT), and the molecules were surrounded by other active site residues like Gln332, Trp406, Asn265, Gly93, His96, Pro95, and Thr165. Finally, these novel molecules were analyzed for their pharmacokinetic properties which expressed that the combination of in silico ADMET prediction, toxicity prediction, and drug-likeness had shown a promising result. The study discusses the performance of molecular docking to suggest the novel molecules active against resistance mutants of RT and/or recombinant strains of HIV-1.

The dopaminergic system is essential for the function of the brain in health and disease. Therefore, detailed studies focused on unraveling the mechanisms involved in dopaminergic signaling are required. However, the lack of probes that mimic dopamine in living tissues, owing to the neurotransmitter's small size, has hampered analysis of the dopaminergic system. The current study aimed to overcome this limitation by developing alkyne-tagged dopamine compounds (ATDAs) that have a minimally invasive and uniquely identifiable alkyne group as a tag. ATDAs were established as chemically and functionally similar to dopamine and readily detectable by methods such as specific click chemistry and Raman scattering. The ATDAs developed here were verified as analogue probes that mimic dopamine in neurons and brain tissues, allowing the detailed characterization of dopamine dynamics. Therefore, ATDAs can act as safe and versatile tools with wide applicability in detailed studies of the dopaminergic system. Furthermore, our results suggest that the alkyne-tagging approach can also be applied to other small-sized neurotransmitters to facilitate characterization of their dynamics in the brain.

Peritonitis, due to a fungal or bacterial infection, leads to injury of the peritoneal lining and thereby forms a hazard for the long-term success of peritoneal dialysis (PD) and remains a lethal complication in patients with PD. This study investigated whether C1 inhibitor (C1-INH) could protect against the progression of peritoneal injuries with five daily administrations of zymosan after mechanical scraping of the rat peritoneum to mimic fungal peritonitis. Severe peritoneal injuries were seen in this model, accompanied by fibrinogen/fibrin exudation and peritoneal deposition of complement activation products such as activated C3 and C5b-9. However, intraperitoneal injection of C1-INH decreased peritoneal depositions of activated C3 and C5b-9, ameliorated peritoneal thickening, reduced the influx of inflammatory cells, and prevented the production of peritoneal fibrous layers with both one and two doses of C1-INH each day. Our results suggest that C1-INH might be useful to protect against peritoneal injuries after causes of peritonitis such as fungal infection. This clinically available agent may thus help extend the duration of PD.

A stable salt-tolerant cell-suspension culture of Alluaudiopsis marnieriana was established, and intracellular compounds that accumulated under salt-stress conditions were investigated. HPLC/MS, and NMR analyses indicated that enhanced accumulation of coniferin was found during the growth phase in medium containing 150 mM NaCl. Coniferin or its derivatives may play an important role in salt-tolerance mechanisms in this plant.

Several fluorescence patterns derived from the excimer states of perylene have been reported, but most of these have been obtained from rigid forms such as crystals or for perylene embedded in hard polymers. We observed perylene excimer emission on absorption of water by a poly-N-isopropylacrylamide gel containing perylene molecules, which were not fixed to the gel framework by chemical bonding. We propose that this emission arises because the hydrophobic perylene molecules cannot dissolve in water and form aggregates. The perylene aggregation was quickly lost on dehydration of the gel, and the luminescence reverted to that of the monomer. In a dehydrated environment, perylene was rapidly dispersed in the gel network. In other words, solid-liquid phase separation of perylene was induced by uptake of water into the gel, and perylene dissolved in the gel on dehydration. Because the outside of the gel is always in an aqueous environment, perylene will remain semipermanently in the gel. Therefore, monomer emission and excimer emission can be switched reversibly and repeatedly.

Biochar-immobilized potassium nickel hexacyanoferrate (KNiFC) as a sorbent for removal of radioactive cesium (Cs) from aqueous solutions was prepared using a novel method. Japanese cedar sawdust loaded with NiSO4 using a ball mill was carbonized at various temperatures. The resultant Ni-loaded biochar was immersed in a K4[Fe(CN)6]·3H2O solution, and biochar-immobilized KNiFC was obtained. For comparison, Ni-loaded biochar was also prepared using the impregnation method. The loading of Ni using the ball mill resulted in a higher Ni amount in the biochar compared with the impregnation method. The carbonization at 400 °C was suitable for Cs adsorption on biochar and synthesis of KNiFC. Consequently, KNiFC immobilization on biochar improved the Cs sorption performance in aqueous solutions with Na+, K+, Ca2+, Mg2+, and Cs+. The sorption performance was selective in aqueous solutions with radioactive Cs and other cations of high concentration. Low-cost Cs adsorbent was prepared using a novel method from bioresource and KNiFC. The application of ball mill was effective for loading Ni on biochar. Immobilization of KNiFC on biochar improved Cs sorption performance. Removal of 134Cs and 137Cs using biochar-immobilized KNiFC was selective.

Nucleoside derivatives are important therapeutic drugs and are the focal point in the ongoing search for novel, more potent drug targets. In this study, a new series of pyrimidine nucleoside i.e., uridine (1) derivatives were synthesized via direct method and evaluated for their antimicrobial potential activity. The title compound uridine (1) was treated with triphenylmethyl chloride in pyridine to give the 5´-O-(triphenylmethyl)uridine derivative (2), which was subsequently derivatized to create a series of 2´,3´-di-O-acyl analogs containing a wide variety of functionalities in a single molecular framework. In vitro antimicrobial functionality tests were determined against both human and plant pathogens by disc diffusion and food poisoned techniques. The chemical structures of the synthesized compounds were confirmed on the basis of their spectral, analytical, physicochemical data. The antimicrobial results indicated that the synthesized derivatives exhibited moderate to good antibacterial and antifungal activity; in particular, they were found to be more effective against fungal phytopathogens than against human bacterial strains. Compounds 7, 9, and 14 were of particular interest as they exhibited noteworthy antifungal and antibacterial properties. In vitro MTT assays revealed that compound 9 was effective against Ehrlich’s ascites carcinoma (EAC) cells, resulting in 7.12% and 1.34% cell growth inhibition at concentrations of 200 and 6.25 µg/ml, respectively. The IC50 value for compound 9 was rather high and found to be 1956.25 µg/ml. Structure-activity relationship (SAR) studies were also conducted to predict structural and pharmacokinetic properties. The findings of this study indicate that the different uridine derivatives are potentially useful antimicrobial agents for the advancement of future pharmaceutical research.

Nucleosides and their analogues are an important, well-established class of clinically useful medicinal agents that exhibit antiviral and anticancer activity. Thus, our research group has focused on the synthesis of new nucleoside derivatives that could be tested for their broad-spectrum biological activity. In this study, two new series of nucleoside derivatives were synthesized from uridine (1) through facile two-step reactions using the direct acylation method, affording 5’-O-acyl uridine derivatives in good yields. The isolated uridine analogs were further transformed into two series of 2’,3’-di-O-acyl derivatives bearing a wide variety of functionalities in a single molecular framework to evaluate their antimicrobial activity. The new synthesized compounds were characterized through physicochemical, elemental and spectroscopic analysis, and all were screened for their in vitro antimicrobial activity against selected human and plant pathogenic strains. The test compounds revealed moderate to good antibacterial and antifungal activities and were more effective against fungal phytopathogens than against bacterial strains, while many of them exhibited better antimicrobial activity than standard antibiotics. Minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) tests against all microorganisms were also conducted for five compounds based on their activity (6, 11, 13, 16, and 17). In addition, all the derivatives were optimized using density functional theory (DFT) B3LYP/6-31g+(d,p) calculations to elucidate their thermal and molecular orbital properties. A molecular docking study was performed using the human protein 5WS1 to predict their binding affinity and modes, and ADMET and SwissADME calculations confirmed the improved pharmacokinetic properties of the compounds. Besides, structure–activity relationship (SAR), thermogravimetric analysis (TGA), and X-ray diffraction (XRD) studies were also performed. Thus, the improvement of the bioactivity of these compounds is expected to significantly contribute to the design of more antimicrobial agents for therapeutic use in the future.

Objectives The combination therapy of phenothrin (PHT) and ivermectin (PI regimen) was effective for pyrethroid‐resistant head lice in Okinawa; however, further investigations have been required to improve the regimen. This study aimed to investigate the efficacy of the modified PI (mPI) regimen, which increased the maximum number of PHT treatments in the PI regimen by one, in Tsukuba, which has a low mutation rate compared to Okinawa. Methods An open‐label, uncontrolled, exploratory study was conducted at the Department of Dermatology, University of Tsukuba Hospital to investigate the treatment effect of mPI regimen. Genotypes were investigated for the knockdown (kdr) mutations at voltage‐sensitive sodium channel (VSSC) and glutamate‐gated chloride receptor‐encoding loci to identify their correlation with drug resistance. Results All the 8 patients treated with the mPI regimen resulted in lice free on day 29. Compared to baseline, the number of bodies, eggs, and itching grade significantly decreased on day 29. Mild erythema appeared after the second application of PHT on day 8 in one patient, persisted for 2 days, and recovered on day 15. No other adverse events were reported. Mutation rates were more than double in head lice collected from one patient for whom PHT was ineffective compared to those in lice from patients who responded to PHT. Furthermore, we identified four new haplotypes of VSSC loci in head lice. Conclusions The mPI regimen is a potential effective treatment for economically combating both PHT‐sensitive and resistant head lice.

BACKGROUND: Removal of radioactive substances, such as cesium (Cs) and strontium (Sr), has become an emerging issue after the Fukushima Daiichi nuclear power plant disaster. It has been reported that hydroxyapatite (HA) and aluminosilicate composite powders can be used to remove Cs and Sr. However, the film type of these materials for the removal of Cs and Sr has not been reported. OBJECTIVE: The aim of this study was to assess the possibility of using HA, aluminosilicate, and aluminosilicate/HA composites for the removal of Cs and Sr radioactive substances. METHODS: Aluminosilicate films and HA films were fabricated using a sputtering technique with diatomaceous earth and HA targets, respectively. The aluminosilicate film was observed by X-ray diffraction (XRD) and scanning electron microscopy (SEM). A comb-shaped HA/aluminosilicate composite film was prepared to take advantage of the adsorption properties of the HA and the aluminosilicate films. The Cs and Sr adsorption on these films were also evaluated. RESULTS: In the XRD patterns, the film sputtered from a diatomaceous earth target under 5.0 Pa of Ar pressure showed aluminosilicate peaks (Na1.82(Al2Si3O10) and Al2SiO5) after 8 h of vapor-phase hydrothermal treatment. The film showed higher adsorption of Cs than Sr in Cs and Sr solutions, while the HA film adsorbed far more Sr than Cs. A HA/aluminosilicate composite film was successfully fabricated, and the SEM images showed that the width of the HA region was 230–260 μm, and that of the aluminosilicate region was 170–200 μm. The HA/aluminosilicate composite film showed 84.8 ± 11.5% Cs adsorption and 28.3 ± 1.4% Sr adsorption in a mixed solution of Cs and Sr. CONCLUSION: This study shows the feasibility of using HA films, aluminosilicate films, and HA/aluminosilicate composite films for the removal of radioactive substances such as Cs and Sr.

Objectives To gain insight into the role of the N-methyl- d -aspartate (NMDA) receptor in bone metabolism by examining the effects of its noncompetitive antagonist, MK-801 (dizocilpine), on bone homeostasis and bone healing in mice. Methods MK-801 (2.5 mg/kg) or saline (in control groups) was intravenously administered to healthy mice and mice with bone-defects daily for seven to 14 days. Bone defects were artificially created in femurs using a drill and reamer. Following euthanasia, bones were extracted and processed for microcomputed tomography (μCT) and histological analyses. The effects of MK-801 on osteoclast differentiation by bone marrow macrophages (BMMs) were examined in vitro. mRNA expressionlevels of Grin3b levels were also examined using reverse-transcription polymerase chain reaction (RT-PCR). Results Bone volume was significantly decreased in mice administered MK-801 for 14 days. Additionally, the number of osteoclasts was reduced, while number of osteoblasts and rate of bone formation were increased in these mice. MK-801 inhibited osteoclast differentiation dose-dependently in vitro. RT-PCR findings suggested expression of Grin3b, a subunit of the NMDA receptor, in BMMs. During the healing process of artificially created defects in femurs, no significant differences were found between the control and MK-801-treated groups, indicating no stimulatory or inhibitory effects by MK-801 administration. Conclusions These results indicate that blockade of the NMDA receptor by MK-801 administration affects bone metabolism but not the healing process of artificial bone defects.

Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) activates particular multifunctional kinases, including CaMKI, CaMKIV, and 5′AMP-activated protein kinase (AMPK), resulting in the regulation of various Ca2+-dependent cellular processes, including neuronal, metabolic, and pathophysiological pathways. We developed and characterized a novel pan-CaMKK inhibitor, TIM-063 (2-hydroxy-3-nitro-7H-benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one) derived from STO-609 (7H-benzimidazo[2,1-a]benz[de]isoquinoline-7-one-3-carboxylic acid), and an inactive analogue (TIM-062) as molecular probes for the analysis of CaMKK-mediated cellular responses. Unlike STO-609, TIM-063 had an inhibitory activity against CaMKK isoforms (CaMKKα and CaMKKβ) with a similar potency (Ki = 0.35 μM for CaMKKα, and Ki = 0.2 μM for CaMKKβ) in vitro. Two TIM-063 analogues lacking a nitro group (TIM-062) or a hydroxy group (TIM-064) completely impaired CaMKK inhibitory activities, indicating that both substituents are necessary for the CaMKK inhibitory activity of TIM-063. Enzymatic analysis revealed that TIM-063 is an ATP-competitive inhibitor that directly targets the catalytic domain of CaMKK, similar to STO-609. TIM-063 suppressed the ionomycin-induced phosphorylation of exogenously expressed CaMKI, CaMKIV, and endogenous AMPKα in HeLa cells with an IC50 of ∼0.3 μM, and it suppressed CaMKK isoform-mediated CaMKIV phosphorylation in transfected COS-7 cells. Thus, TIM-063, but not the inactive analogue (TIM-062), displayed cell permeability and the ability to inhibit CaMKK activity in cells. Taken together, these results indicate that TIM-063 could be a useful tool for the precise analysis of CaMKK-mediated signaling pathways and may be a promising lead compound for the development of therapeutic agents for the treatment of CaMKK-related diseases.

Aim In Japan, no zinc preparation had been approved for therapeutic purposes before March 2017. Zinc acetate hydrate was recently approved for the treatment of hypozincemia. We evaluated the efficacy and safety of treatment with zinc acetate hydrate. Methods A total of 97 patients with cirrhosis complicated by hypozincemia were treated with zinc acetate hydrate, and their serum zinc normalization rates; factors contributing to normalization; changes in blood ammonia levels; branched-chain amino acids-to-tyrosine ratios; levels of albumin, hemoglobin, alkaline phosphatase, serum copper, and iron; incidence of adverse events; improvement in subjective symptoms; and serum zinc levels taken at 3 months post-treatment were determined. Results The cumulative serum zinc normalization rates, when normalization was defined as achievement of a serum zinc level ≥80 μg/dL, after 2, 4, and 6 months of treatment were 64.9%, 80.3%, and 82.5%, respectively. Multivariate analysis identified an albumin level of ≥3.3 g/dL and branched-chain amino acids to tyrosine ratio of ≥3.46 as factors contributing to zinc normalization within 3 months of treatment. Treatment resulted in a significant decrease in blood ammonia and serum copper levels, and significant increases in branched-chain amino acids-to-tyrosine ratios and alkaline phosphatase levels. Seven (7.2%) patients prematurely discontinued treatment due to hypocupremia. By the end of treatment, subjective symptoms had resolved in 46.2% of patients. By 3 months post-treatment, serum zinc levels had reverted to levels close to those at baseline. Conclusions Treatment with zinc acetate hydrate resulted in normalization of serum zinc levels at a high rate. The main reasons for discontinuation of treatment included hypocupremia.

Semiclathrate hydrates of tetra-n-butylammonium fluoride (TBAF) are potential CO2 capture media because they can capture CO2 at near ambient temperature under moderate pressure such as below 1 MPa....

A 63-year-old man with pulmonary adenocarcinoma was treated with nivolumab. High fever developed within several hours after the first administration of nivolumab; subsequently, serum creatinine levels kept increasing daily. We diagnosed acute kidney injury (AKI) as an immune-related adverse event; the patient was initially treated with 50 mg prednisolone, and the dose was then tapered. Renal biopsy pathologically revealed tubulointerstitial inflammation with strong infiltration of only T cells that were CD3+, CD4+, and CD8+. The infiltration of CD163+ M2 macrophage was also observed. AKI within 1 week after the administration of nivolumab seems to be rare; therefore, the present case provides important findings useful in daily clinical practice.

Aim This study aimed to determine the distributions of serum zinc levels and the prevalence of zinc deficiency in patients with chronic liver disease (CLD) in actual clinical practice, and to analyze the association between serum zinc levels and clinical characteristics. Methods This study analyzed 1973 patients with CLD, including 749 with liver cirrhosis, who were admitted to Sapporo Kosei General Hospital in 2017. Results Zinc deficiency, defined as a serum zinc level of

Thermal migration of sodium cation in the cavity of Preyssler-type phosphotungstate is reported here. Heating of a Preyssler-type compound, [P5W30O110Na(side)(H2O)]14¹, in which a sodium cation occupies one of the two side cavities, at 300 °C forms a new compound, [P5W30O110Na(center)]14¹, in which the sodium cation is encapsulated in the central cavity. Characterization by single crystal X-ray structure analysis, NMR spectroscopy, elemental analysis, IR, and ESI-MS confirmed the structure of the compound. The thermal displacement ellipsoid of the central sodium, estimated by the crystallographic study, is elongated along the direction perpendicular to the equatorial plane of the Preyssler molecule. These results confirmed prediction using DFT calculation by López and Poblet (ref. 21, J. Am. Chem. Soc. 2007, 129, 12244.) that the most stable site for sodium is the central cavity with a slight shift from the center of the molecule., This research was supported by the Furukawa Foundation for the Promotion of Technology, JSPS KAKENHI Grant Numbers JP18H02058 (Grant-in-aid for scientific research (B)) and JP19K05510 (Grant-in-aid for scientific research (C)), the Center for Functional Nano Oxide at Hiroshima University, and JSPS Core-to-Core program. MNKW thankfully acknowledges the financial support from the Indonesia Endowment Fund for Education (LPDP), Ministry of Finance, Republik Indonesia for PhD scholarship (PRJ-36/LPDP.3/2017).

Diphenylacetylene derivatives containing different polymeric components, poly(l-lysine) (pLys) or tetra(ethylene glycol) (TEG) were designed as novel Raman imaging probes with high Raman sensitivity and low cytotoxicity in living plant cells. The pLys-conjugated probe is internalized via an endocytosis-dependent pathway, whereas TEG-conjugated probe most likely induces direct penetration into the plant cells., Diphenyl acetylene derivatives containing various polymeric components have been designed as new Raman imaging probes. These are taken up by plant cells via different pathways, and the internalization of exogenous molecules can be visualized.

A series of methyl β-D-galactopyranoside (MGP, 1) analogs were selectively acylated with cinnamoyl chloride in anhydrous N,N-dimethylformamide/triethylamine to yield 6-O-substitution products, which was subsequently converted into 2,3,4-tri-O-acyl analogs with different acyl halides. Analysis of the physicochemical, elemental, and spectroscopic data of these analogs revealed their chemical structures. In vitro antimicrobial testing against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) showed promising antifungal functionality comparing to their antibacterial activities. Minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) tests were conducted for four compounds (4, 5, 6, and 9) based on their activity. MTT assay showed low antiproliferative activity of compound 9 against Ehrlich’s ascites carcinoma (EAC) cells with an IC50 value of 2961.06 µg/mL. Density functional theory (DFT) was used to calculate the thermodynamic and physicochemical properties whereas molecular docking identified potential inhibitors of the SARS-CoV-2 main protease (6Y84). A 150-ns molecular dynamics simulation study revealed the stable conformation and binding patterns in a stimulating environment. In-silico ADMET study suggested all the designed molecules to be non-carcinogenic, with low aquatic and non-aquatic toxicity. In summary, all these antimicrobial, anticancer and in silico studies revealed that newly synthesized MGP analogs possess promising antiviral activity, to serve as a therapeutic target for COVID-19.

SeviL is a recently isolated lectin found to bind to the linear saccharides of the ganglioside GM1b (Neu5Ac\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\alpha$$\end{document}α(2-3)Gal\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β(1-3)GalNAc\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β(1-4)Gal\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β(1-4)Glc) and its precursor, asialo-GM1 (Gal\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β(1-3)GalNAc\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β(1-4)Gal\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β(1-4)Glc). The crystal structures of recombinant SeviL have been determined in the presence and absence of ligand. The protein belongs to the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\beta$$\end{document}β-trefoil family, but shows only weak sequence similarity to known structures. SeviL forms a dimer in solution, with one binding site per subunit, close to the subunit interface. Molecular details of glycan recognition by SeviL in solution were analysed by ligand- and protein-based NMR techniques as well as ligand binding assays. SeviL shows no interaction with GM1 due to steric hindrance with the sialic acid branch that is absent from GM1b. This unusual specificity makes SeviL of great interest for the detection and control of certain cancer cells, and cells of the immune system, that display asialo-GM1.

In the 2010s, a novel lectin family with β-trefoil folding has been identified in marine mussels from the family Mytilidae (phylum Mollusca). "MytiLec-1," the lectin described in this chapter, was the first member of this family to be isolated and characterized from the Mediterranean mussel Mytilus galloprovincialis, a commercially and ecologically important species, spread in marine coastal areas worldwide. MytiLec-1 bound to the sugar moiety of globotriose (Gb3: Galα1-4Galβ1-4Glc), an α-galactoside, leading to apoptosis of Gb3-expressing Burkitt's lymphoma cells. Although the primary structure of MytiLec-1 was quite unusual, its three-dimensional structure was arranged as a β-trefoil fold, which is the typical architecture of "Ricin B chain (or R)-type" lectins, which are found in a broad range of organisms. To date, MytiLec-1-like lectins have been exclusively found in a few species of the mollusk family Mytilidae (M. galloprovincialis, M. trossulus, M. californianus, and Crenomytilus grayanus) and in the phylum Brachiopoda. Transcriptome data revealed the presence of different structural forms of mytilectin in mussels, which included prototype and chimera-type proteins. The primary sequence of these lectins did not match any previously described known protein family, leading to their assignment to the new "mytilectin family." We here report the method of purification of this lectin and describe its use in cell biology.

RATIONALE We recently developed the characterization method for synthetic polymers weighing more than a few tens of kilodalton using electrospray ionization-ion mobility spectrometry-tandem mass spectrometry, in which the m/z value of the most abundant peak was used for characterization. However, the identification of the most abundant peak from the isotopic peaks was often difficult due to the background noise. METHODS Here, we employed a noise reduction method using Fourier transform (FT) filtering. In the power spectrum obtained using FT of the mass spectrum of the multiple charged analytes, the significant signals in the low-frequency region and at frequency z are observed for the analytes of z charges. When the signals in both regions were used for inversed FT (i.e., the signals in other regions were zero padded), a noise-filtered mass spectrum was obtained. RESULTS In the analysis of poly(methylmethacrylate)s weighing 13-17 kDa, mass spectra without noise filtering with relatively high-intensity noise (than signal) were complicated to identify the most abundant peak. On the contrary, the most abundant peak was clearly identified from the mass spectra after FT-based noise filtering, and end group composition was estimated successfully. CONCLUSIONS The proposed FT-based noise filtering for the mass spectrum is effective to characterize multiply charged synthetic polymers weighing more than a few tens of kilodalton using electrospray ionization-ion mobility spectrometry-tandem mass spectrometry.

Lectins facilitate cell–cell contact and are critical in many cellular processes. Studying lectins may help us understand the mechanisms underlying tissue regeneration. We investigated the localization of an R-type lectin in a marine annelid (Perinereis sp.) with remarkable tissue regeneration abilities. Perinereis nuntia lectin (PnL), a galactose-binding lectin with repeating Gln-X-Trp motifs, is derived from the ricin B-chain. An antiserum was raised against PnL to specifically detect a 32-kDa lectin in the crude extracts from homogenized lugworms. The antiserum detected PnL in the epidermis, setae, oblique muscle, acicula, nerve cord, and nephridium of the annelid. Some of these tissues and organs also produced Galactose (Gal) or N-acetylgalactosamine (GalNAc), which was detected by fluorescent-labeled plant lectin. These results indicated that the PnL was produced in the tissues originating from the endoderm, mesoderm, and ectoderm. Besides, the localizing pattern of PnL partially merged with the binding pattern of a fluorescent-labeled mushroom lectin that binds to Gal and GalNAc. It suggested that PnL co-localized with galactose-containing glycans in Annelid tissue; this might be the reason PnL needed to be extracted with haptenic sugar, such as d-galactose, in the buffer. Furthermore, we found that a fluorescein isothiocyanate-labeled Gal/GalNAc-binding mushroom lectin binding pattern in the annelid tissue overlapped with the localizing pattern of PnL. These findings suggest that lectin functions by interacting with Gal-containing glycoconjugates in the tissues.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta coronavirus that was first found during the Wuhan COVID-19 epidemic in 2019 and is listed as a potential global health threat by World Health Organization due to its high mortality. The main protease of SARS-CoV-2 is one of the optimum targets for antiviral drug design and development. Nucleoside derivatives have been investigated since many years, and some of the most clinically effective antiviral agents used currently include purine or pyrimidine nucleoside derivatives. In this study, the hydroxyl (–OH) groups of cytidine structures were modified with different aliphatic and aromatic groups to obtain 5´-O-acyl and 2´,3´-di-O-acyl derivatives, and then, these derivatives were employed for molecular modeling, molecular docking, antiviral prediction, and pharmacological studies. Density functional theory at the B3LYP/3-21G level was employed to analyze the thermochemical stability and molecular electrostatic potential of the modified derivatives to evaluate the effect of the aliphatic and aromatic groups on the drug properties. All the derivatives were more stable than their parent molecule, cytidine. The experimental and computed IR analyses showed the characteristic peaks for various aliphatic and aromatic groups. The antiviral parameters of the modified derivatives revealed promising drug properties compared with those of standard antiviral drugs. Molecular docking was performed using AutoDock Vina to determine binding affinities and interactions between the cytidine derivatives and SARS-CoV-2 main protease. The modified derivatives strongly interacted with prime Cys145 and His41 residues. Finally, the pharmacokinetic characterization of the optimized inhibitors showed the derivatives to be safe due to their improved kinetic properties. Our comprehensive computational and statistical analyses showed that the selected cytidine derivatives can be used as potential inhibitors against SARS-CoV-2.

Nucleoside analogs contribute in pharmaceutical and clinical fields as medicinal agents and approved drugs. This work focused to investigate the antimicrobial, anticancer activities, and structure–activity relationship (SAR) of cytidine and its analogs with computational studies. Microdilution was used to determine the antimicrobial activity, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) of the modified analogs against human and phytopathogenic strains. Compounds (7), (10), and (14) were the most potent against Escherichia coli and Salmonella abony strains with MIC and MBC values from 0.316 ± 0.02 to 2.50 ± 0.03 and 0.625 ± 0.04 to 5.01 ± 0.06 mg/ml, respectively. The highest inhibitory activity was observed against gram-positive bacteria. Numerous analogs (10), (13), (14), and (15) exhibited good activity against the tested fungi Aspergillus niger and Aspergillus flavus. Anticancer activity of the cytidine analogs was examined through MTT colorimetric assay against Ehrlich’s ascites carcinoma (EAC) tumor cells whereas compound 6 showed the maximum antiproliferative activity with an IC(50) value of 1168.97 µg/ml. To rationalize this observation, their quantum mechanical and molecular docking studies have been performed against urate oxidase of A. flavus 1R51 to investigate the binding mode, binding affinity, and non-bonding interactions. It was observed that most of the analogs exhibited better binding properties than the parent drug. In silico ADMET prediction was attained to evaluate the drug-likeness properties that revealed the improved pharmacokinetic profile with lower acute oral toxicity of cytidine analogs. Based on the in vitro and in silico analysis, this exploration can be useful to develop promising cytidine-based antimicrobial drug(s). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00102-0.

Most human malignant tumor cells arise from epithelial tissues, which show distinctive characteristics, such as polarization, cell-to-cell contact between neighboring cells, and anchoring to a basement membrane. When tumor cells invaginate into the stroma, the cells are exposed to extracellular environments, including the extracellular matrix (ECM). Increased ECM stiffness has been reported to promote cellular biological activities, such as excessive cellular growth and enhanced migration capability. Therefore, tumorous ECM stiffness is not only an important clinical tumor feature but also plays a pivotal role in tumor cell behavior. Transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable nonselective cation channel, has been reported to be mechano-sensitive and to regulate tumorigenesis, but the underlying molecular mechanism in tumorigenesis remains unclear. The function of TRPV4 in oral squamous cell carcinoma (OSCC) is also unknown. The current study was conducted to investigate whether or not TRPV4 might be involved in OSCC tumorigenesis. TRPV4 mRNA levels were elevated in OSCC cell lines compared with normal oral epithelial cells, and its expression was required for TRPV4 agonist-dependent Ca2+ entry. TRPV4-depleted tumor cells exhibited decreased proliferation capabilities in three-dimensional culture but not in a low-attachment plastic dish. A xenograft tumor model demonstrated that TRPV4 expression was involved in cancer cell proliferation in vivo. Furthermore, loss-of-function experiments using siRNA or an inhibitor revealed that the TRPV4 expression was required for CaMKII-mediated AKT activation. Immunohistochemical analyses of tissue specimens obtained from 36 OSCC patients showed that TRPV4 was weakly observed in non-tumor regions but was strongly expressed in tumor lesions at high frequencies where phosphorylated AKT expression was frequently detected. These results suggest that the TRPV4/CaMKII/AKT axis, which might be activated by extracellular environments, promotes OSCC tumor cell growth.

Purpose This study aims to investigate the friction behavior of SiC-B4C composite ceramics treated by annealing in air sliding against SiC balls. Design/methodology/approach The dry sliding tests were performed with a ball-on-disk tribometer in ambient air condition. Analysis of friction coefficient, phase compositions of the surfaces, morphologies of worn surfaces of disks and wear scars of balls and surface profiles of wear tracks for disks were carried out using Raman spectroscope, microscope and surface profilometer. Findings The results show that a self-lubricating layer with the main composition of H3BO3 was successfully fabricated on the surface of SiC-B4C composite ceramics by the annealing treatment in air. When the mass fraction of SiC is more than that of B4C, SiC-B4C composite ceramics show higher friction coefficients, the values of which are 0.38 for 80 Wt.%SiC-20 Wt.%B4C and 0.72 for 60 Wt.%SiC-40 Wt.%B4C, respectively. SiC-B4C composite ceramics show lower friction coefficients when the mass fraction of B4C is more than that of SiC. The low friction coefficients of 40 Wt.%SiC-60 Wt.% B4C composite ceramics (0.16) and 20 Wt.%SiC-80 Wt.% B4C composite ceramics (0.20) are attributed to the formation of a sufficient amount of H3BO3 layer, rather than the layer of silicon oxides. Originality/value This study will help to understand the friction behavior of SiC-B4C composite ceramics with different ratios of SiC to B4C treated by annealing in air.

An ionic liquid, N,N,N-trimethyl-N-propylammonium bis(trifluoromethanesulfonyl)imide (TMPA TFSI), was transformed from a liquid phase to another fluidic phase by application of the threshold magnet...

The purpose of the study was to prepare a poly-γ-glutamic acid hydrogel (PGA gel), to evaluate physicochemical properties, its ease of swallowing using texture profile analysis (TPA) and its taste-masking effects on amlodipine besylate (AML) using the artificial taste sensor and human gustatory sensation testing. Using TPA, 0.5 and 1.0% (w/v) PGA gels in the absence of drug were within the range of acceptability for use in people with difficulty swallowing according to permission criteria published by the Japanese Consumers Affairs Agency. The elution of AML from prepared PGA gels was complete within an hour and the gel did not appear to influence the bioavailability of AML. The sensor output of the basic bitterness sensor AN0 in response to AML mixed with 0.5 and 1.0% PGA gels was suppressed to a significantly greater degree than AML mixed with 0.5 and 1.0% agar. In human gustatory sensation testing, 0.5 and 1.0% PGA gels containing AML showed a potent bitterness-suppressing effect. Finally, 1H-NMR spectroscopic analysis was carried out to examine the mechanism of bitterness suppression when AML was mixed with PGA gel. The signals of the proton nearest to the nitrogen atom of AML shifted clearly upfield, suggesting an interaction between the amino group of AML and the carboxyl group of PGA gel. In conclusion, PGA gel is expected to be a useful excipient in formulations of AML, not only increasing ease of swallowing but also masking the bitterness of the basic drug.

Polygalaxanthone III, a xanthone glycoside that is a major constituent of "Polygala Root" (Polygala tenuifolia roots, Onji in the Japanese Pharmacopoeia), has been used as a standard in the quality control of crude drugs. However, we previously noted differences in the chromatographic properties of one of three samples of polygalaxanthone III. Therefore, standardization of the standard itself is extremely important. The structures of three standard samples commercially available as polygalaxanthone III were characterized by LC/MS and NMR. LC/MS analysis revealed that two molecular types exist. Both types are chromatographically separable but have an identical mass number with distinguishable MS/MS spectra. One dimensional (1D)-NMR analyses demonstrated that both had the same xanthone moiety and heteronuclear multiple bond correlation (HMBC) analyses revealed that they are structural isomers at the connecting position of glucose to apiose 1-position. Consequently, the isomers were identified as polygalaxanthone III and its regioisomer, polygalaxanthone XI. Based on the findings, we recommend using the LC-MS/MS detection method, which discriminates polygalaxanthone III and XI, to confirm the quality of the standard.

As alveolar macrophages are attractive targets for the treatment of tuberculosis, effective methods for delivery to alveolar macrophages are under development. We investigated a pulmonary formulation for the efficient delivery of high water-soluble drugs at high concentration targeting alveolar macrophages. In this study, a surfactant-coated high water-soluble drug complex (SDC, a hydrophobic dried emulsion), which can preferably target alveolar macrophages and be expected to deliver drug at a high concentration, was prepared in the first process. OCT313, a high water-soluble sugar derivative with anti-tuberculosis activity was used. Then, a unique two-solution, mixing-type nozzle was used to prepare the SDC nanoparticles in mannitol (MAN) microparticles (SDC/MAN microparticles) because it was difficult to disperse the SDC nanoparticles in aqueous solution. The single micron size of OCT313-SDC/MAN microparticles contained OCT313-SDC nanoparticles (mean particle size of OCT313-SDC nanoparticles, 277.9 nm; drug contents, 1.31 ± 0.041 wt%). We found that the treatment of SDC/MAN microparticles exhibited significantly higher drug accumulation in macrophage cells (Raw264.7 cells, 7.5-fold, at 4 h after treatment) in vitro and in alveolar macrophages in rats (9.1-fold, at 4 h after treatment) in vivo than that of drug alone. These results suggest that the SDC/MAN microparticle formulation prepared by spray drying through a two-solution mixing-type nozzle provides efficient delivery of a water-soluble drug targeting alveolar macrophages and may be useful for tuberculosis treatment.

The complex salt [CpRu(η6-C10H8)][(CpRu)2(μ-Cl)3] ([1][2]) was synthesized and found to be a useful CpRuCl synthon. The ions [1]+ and [2]− cleanly comproportionate into monomeric CpRuCl(L)2 complex...

The use of three-dimensional (3D) printing technology is expanding in various fields. The application of 3D printing is expected to increase in the pharmaceutical industry after 3D-printed tablets were approved by the U.S. Food and Drug Administration (FDA). Fused deposition modeling (FDM), a type of 3D printing, has been extensively studied for the manufacturing of tablets. A drug-loaded polymer filament, the ink of FDM 3D printers, can be prepared using the hot melt extrusion method or a simple drug-soaking method. In the present study, we investigate the influence of the experimental conditions on the loading of curcumin (model drug with fluorescence) into a polyvinylalcohol polymer filament using the soaking method. We show that organic solvent type (isopropanol, methanol, acetone, and ethanol), temperature (25 and 80°C), and drug concentration (2-333 mg/mL) greatly affect drug loading. Around 5% curcumin can be incorporated into the polyvinylalcohol filament using the soaking method. The drug dissolution from 3D-printed tablets depends on the drug content in the polymer filament. The incorporation of a higher amount of curcumin, which has poor water solubility, greatly delays drug dissolution. These results provide useful information on the preparation of 3D-printed tablets using a drug-loaded polymer filament obtained with the soaking method.