Antiproliferative Activities of Cynaropicrin and Related Compounds against Cancer Stem Cells.

Glioblastoma (GBM) has a high mortality rate despite the availability of various cancer treatment options. Although cancer stem cells (CSCs) have been associated with poor prognosis and metastasis, and play an important role in the resistance to existing anticancer drugs and radiation; no CSC-targeting drugs are currently approved in clinical practice. Therefore, the development of antiproliferative agents against CSCs is urgently required. In this study, we evaluated the antiproliferative activities of 21 sesquiterpenoids against human GBM U-251 MG CSCs and U-251 MG non-CSCs. Particularly, the guaianolide sesquiterpene lactone cynaropicrin (1) showed strong antiproliferative activity against U-251 MG CSCs (IC50 = 20.4 µM) and U-251 MG non-CSCs (IC50 = 10.9 µM). Accordingly, we synthesized six derivatives of 1 and investigated their structure-activity relationships. Most of the guaianolide sesquiterpene lactones with the α-methylene-γ-butyrolactone moiety showed antiproliferative activities against U-251 MG cells. We conclude that the 5,7,5-ring and the α-methylene-γ-butyrolactone moiety are both important for antiproliferative activities against U-251 MG cells. The results of this study suggest that the α,ß-unsaturated carbonyl moiety, which has recently become a research hotspot in drug discovery, is the active center of 1. Therefore, we consider 1 as a potential lead for developing novel drugs targeting CSCs.

Plantainoside B in Bacopa monniera Binds to Aß Aggregates Attenuating Neuronal Damage and Memory Deficits Induced by Aß.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by dementia. The most characteristic pathological changes in AD brain include extracellular amyloid-ß (Aß) accumulation and neuronal loss. Particularly, cholinergic neurons in the nucleus basalis of Meynert are some of the first neuronal groups to degenerate; accumulating evidence suggests that Aß oligomers are the primary form of neurotoxicity. Bacopa monniera is a traditional Indian memory enhancer whose extract has shown neuroprotective and Aß-reducing effects. In this study, we explored the low molecular weight compounds from B. monniera extracts with an affinity to Aß aggregates, including its oligomers, using Aß oligomer-conjugated beads and identified plantainoside B. Plantainoside B exhibited evident neuroprotective effects by preventing Aß attachment on the cell surface of human induced pluripotent stem cell (hiPSC)-derived cholinergic neurons. Moreover, it attenuated memory impairment in mice that received intrahippocampal Aß injections. Furthermore, radioisotope experiments revealed that plantainoside B has affinity to Aß aggregates including its oligomers and brain tissue from a mouse model of Aß pathology. In addition, plantainoside B could delay the Aß aggregation rate. Accordingly, plantainoside B may exert neuroprotective effects by binding to Aß oligomers, thus interrupting the binding of Aß oligomers to the cell surface. This suggests its potential application as a theranostics in AD, simultaneously diagnostic and therapeutic drugs.

Bleeding events associated with recombinant human soluble thrombomodulin, classified according to renal function, in sepsis-induced disseminated intravascular coagulation.

OBJECTIVE: Recombinant human soluble thrombomodulin (rhsTM) is a therapeutic agent for sepsis-induced disseminated intravascular coagulation (DIC) and is associated with bleeding events. rhsTM is a renal excretion drug; however, information on the role of rhsTM in renal function is limited. MATERIALS AND METHODS: In this retrospective observational study, we assessed rhsTM-associated bleeding events according to the renal function of patients with sepsis-induced DIC. We analyzed the data of 79 patients administered a standard-dose of rhsTM for sepsis-induced DIC, at a single center. Patients were classified based on estimated glomerular filtration rate (eGFR). We measured fresh bleeding events following rhsTM administration, DIC score efficacy, and 28-day mortality. RESULTS: Fresh bleeding events were observed in 15 patients, with a significant difference in the eGFR, platelet count, and DIC scores. Furthermore, fresh bleeding events tended to increase with the deterioration of renal function (p = 0.039). The DIC scores in all renal function groups decreased after -rhsTM administration. Additionally, the 28-day mortality was less than 30% in all groups. CONCLUSION: Our results indicate that the effectiveness of the standard-dose of rhsTM is not related to renal function. However, standard-dose rhsTM therapy could potentially increase the risk of adverse bleeding events with severe renal function equivalent to G5.

Vancomycin Hydrochloride as a Risk Factor for Acute Kidney Injury: A Retrospective Study.

INTRODUCTION: The incidence of acute kidney injury (AKI) caused by vancomycin hydrochloride (VCM) was reported to be 5-43%. VCM-induced AKI was reported to be more likely to occur 4-17 days after initiating VCM treatment; however, it may occur earlier. The aim of this study was therefore to investigate risk factors for the development of AKI within two (AKI2days) and seven (AKI7days) days of VCM administration. METHODS: This was a single-center, retrospective study including patients who underwent VCM therapy between April 1, 2013, and December 31, 2019. AKI was evaluated based on the Kidney Disease: Improving Global Outcomes criteria. RESULTS: In total, 287 patients were enrolled. The incidence of VCM-induced AKI within 7 days was 10.8% (31/286 cases), and the incidence of AKI within 2 days was 5.9% (15/252 cases). Serum VCM trough concentrations and tazobactam-piperacillin (TZP) were shown to be a risk factor for VCM-induced AKI. The serum VCM trough concentration was 12.67 µg/mL within the 48 h threshold (AKI2days) and 19.03 µg/mL within the 7-day threshold (AKI7days). CONCLUSION: Our study demonstrated that high serum VCM trough concentrations and the combination of VCM and TZP were independent risk factors for VCM-induced AKI. Avoiding the concomitant use of TZP, or thorough monitoring of renal function with the concomitant use of TZP, may be helpful in reducing the occurrence of AKI. Furthermore, monitoring serum VCM trough concentrations within 2 days may effectively reduce the incidence of AKI.

Risk Factors for Lenvatinib-Induced High-Grade Hypothyroidism in Patients with Hepatocellular Carcinoma: A Retrospective Study.

INTRODUCTION: Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used for the treatment of various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events, especially hypothyroidism. This study investigated the incidence of hypothyroidism due to LEN and the relationships between hypothyroidism incidence and patient demographics by analyzing clinical laboratory data from HCC patients treated with LEN. METHODS: This was a single-center, retrospective study of HCC patients who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration. RESULTS: In total, 61 patients with HCC were enrolled. High-grade hypothyroidism (CTCAE Grade 2-3) was found in 36.1% (22/61 patients). In high-grade hypothyroidism, eosinophil (EOSINO) count was significantly low (p = 0.029). The cutoff value of EOSINO count was estimated to be approximately 150/µL. The adjusted odds ratios of high-grade hypothyroidism for current smoking and EOSINO count <150/µL were 0.237 (95% confidence interval: 0.063-0.893) and 4.219 (95% confidence interval: 1.119-15.92), respectively. CONCLUSION: The results showed that noncurrent smoking and EOSINO count <150/µL are risk factors for LEN-induced high-grade hypothyroidism.

Chemical Structures and Anti-proliferative Effects of Valeriana fauriei Constituents on Cancer Stem Cells.

We isolated the new sesquiterpenes, valerianaterpenes IV and V, and the new lignans valerianalignans I-III from the methanol extracts of the rhizomes and roots of Valeriana fauriei and elucidated their structures based on chemical and spectroscopic findings. The absolute configuration of valerianaterpene IV and valerianalignans I-III were established by comparing experimental and predicted electronic circular dichroism (ECD) data. Among the isolated compounds, valerianalignans I and II exerted anti-proliferative activity against human astrocytoma cells (U-251 MG) and their cancer stem cells (U-251 MG CSCs). Interestingly, valerianalignans I and II notably exerted anti-proliferative activities at lower concentrations against CSCs than non-CSCs, and the absolute configurations of these compounds affected their activities.

Antiproliferative Activities of Diterpenes from Leaves of Isodon trichocarpus against Cancer Stem Cells.

Two new diterpenes named trichoterpene I (1) and trichoterpene II (2) were isolated from the extract from the leaves of Isodon trichocarpus together with 19 known diterpenes. Their chemical structures were elucidated on the basis of chemical and physicochemical properties. Among them, oridonin (3), effusanin A (4), and lasiokaurin (9) with the α,ß-unsaturated carbonyl moiety showed antiproliferative activities against breast cancer MDA-MB-231 and human astrocytoma U-251 MG cells [i.e., non-cancer stem cells (non-CSCs)] and their cancer stem cells (CSCs) isolated by sphere formation. In particular, compound 4 (IC50 = 0.51 µM) showed a higher antiproliferative activity against MDA-MB-231 CSCs than against MDA-MB-231 non-CSCs. The antiproliferative activity toward CSCs of compound 4 was equal to adriamycin (positive control, IC50 = 0.60 µM).

An X-ray beam profile monitoring system at a beamline front-end combining a single-crystal diamond film and energy discrimination using droplet analysis.

This work has successfully demonstrated a system for monitoring pink-beam X-rays exiting from a beamline front-end, which has a specific spatial distribution based on each energy component. In this study, the X-rays scattered from a single-crystal chemical-vapor-deposited diamond film were converted into a cross-sectional image using pinhole optics, followed by digitization with a direct detection complementary metal-oxide-semiconductor 2D detector. By using single crystals instead of poly-crystals, good quality images were obtained with no diffraction bright spots. As a result of applying photon energy discrimination using the droplet analysis to the image information, the spatial distribution of each energy component of the undulator radiation was successfully visualized. The result was found to be in good agreement with the theoretically calculated result obtained using the synchrotron radiation calculation code SPECTRA. The new synchrotron radiation beam monitor proposed in this paper can serve as a powerful beam diagnostic tool for diffraction-limited rings that require strict light source stability.

Comparison of the Concentration of Suspended Particles and Their Chemical Composition near the Ground Surface and Dust Extinction Coefficient by LIDAR.

In many epidemiological studies, the dust extinction coefficient measured by light detection and ranging (LIDAR) is used as an indicator of exposure to Asian dust. However, few reports on the relationship between the distribution of total suspended particles (TSPs) near the ground surface and the dust extinction coefficient exist. In this study, we examined the relationship between the concentrations of TSPs near the ground surface, substances indicative of mineral content, and air pollutants that may be transported with Asian dust and dust extinction coefficients in two regions: Imizu and Yurihama-Matsue, from March to May in 2011 and 2013. In both years, large dust extinction coefficients were observed in Imizu and Matsue on days when the concentrations of TSPs and mineral content indicators were high near the ground surface in Imizu and Yurihama, and Asian dust was expected to be highly suspended. In both regions, the concentrations of TSPs and mineral content indicators were significantly positively correlated with the dust extinction coefficient. The concentrations of all air pollutants analyzed were significantly positively correlated with the dust extinction coefficient in each region in 2013, but not in 2011. These results suggest that the dust extinction coefficient is a useful indicator of Asian dust near the ground surface; however, as harmful air pollutants occasionally move with Asian dust, it is necessary to monitor these pollutants near the ground surface when conducting an epidemiological study on the health effect of airborne particles.

Anti-Proliferative Effects of Iridoids from Valeriana fauriei on Cancer Stem Cells.

We isolated seven new iridoid glucosides (valerianairidoids I-VII; 1-3, 6, 7, 9, and 12) and six known compounds from the methanol extract of the dried rhizomes and roots of Valeriana fauriei. Chemical and spectroscopic data were used to elucidate the chemical structures of the seven new iridoid glucosides, and their absolute configurations were determined by comparing their electronic circular dichroism (ECD) spectra with those determined experimentally. Aglycones 1a, 6a, and 9a, which were obtained by enzymatic hydrolysis of the isolated iridoid glucosides, exhibited anti-proliferative activities against cancer stem cells (CSCs) established by a sphere-formation assay using human breast cancer (MDA-MB-231) and human astrocytoma (U-251MG) cells. Interestingly, these iridoids selectively showed anti-proliferative activities against CSCs from MDA-MB-231 cells. These results suggest that the iridoids obtained in this study may have potency as a breast cancer treatment and as preventive agent via exterminating CSCs.

Development and application of a tender X-ray ptychographic coherent diffraction imaging system on BL27SU at SPring-8.

Ptychographic coherent diffraction imaging (CDI) allows the visualization of both the structure and chemical state of materials on the nanoscale, and has been developed for use in the soft and hard X-ray regions. In this study, a ptychographic CDI system with pinhole or Fresnel zone-plate optics for use in the tender X-ray region (2-5 keV) was developed on beamline BL27SU at SPring-8, in which high-precision pinholes optimized for the tender energy range were used to obtain diffraction intensity patterns with a low background, and a temperature stabilization system was developed to reduce the drift of the sample position. A ptychography measurement of a 200 nm thick tantalum test chart was performed at an incident X-ray energy of 2.500 keV, and the phase image of the test chart was successfully reconstructed with approximately 50 nm resolution. As an application to practical materials, a sulfur polymer material was measured in the range of 2.465 to 2.500 keV including the sulfur K absorption edge, and the phase and absorption images were successfully reconstructed and the nanoscale absorption/phase spectra were derived from images at multiple energies. In 3 GeV synchrotron radiation facilities with a low-emittance storage ring, the use of the present system will allow the visualization on the nanoscale of the chemical states of various light elements that play important roles in materials science, biology and environmental science.

C-H Arylation of Benzene with Aryl Halides using H2 and a Water-Soluble Rh-Based Electron Storage Catalyst.

This paper reports the first example of C-H arylation of benzene under mild conditions, using H2 as an electron source {turnover numbers (TONs)=0.7-2.0 for 24 h}. The reaction depends on a Rh-based electron storage catalyst, and proceeds at room temperature and in aqueous solution. Furthermore, the H2 is inactive during the radical transfer step, greatly reducing unwanted side reactions.

Linderapyrone: A Wnt signal inhibitor isolated from Lindera umbellata.

Linderapyrone, a Wnt signal inhibitor was isolated from the methanolic extract of the stems and twigs of Lindera umbellata together with epi-(-)-linderol A. Linderapyrone inhibited TCF/ß-catenin transcriptional activity that was evaluated using cell-based TOPFlash luciferase assay system. To evaluate the structure-activity relationship and mechanism, we synthesized linderapyrone and its derivatives from piperitone. As the results of further bioassay for synthesized compounds, we found both of pyrone and monoterpene moieties were necessary for inhibitory effect. cDNA microarray analysis in a linderapyrone derivative treated human colorectal cancer cells showed that this compound downregulates Wnt signaling pathway. Moreover, we successes to synthesize the derivative of linderapyrone that has stronger inhibitory effect than linderapyrone and ICG-001 (positive control).

Construction of sulfur-containing compounds with anti-cancer stem cell activity using thioacrolein derived from garlic based on nature-inspired scaffolds.

Sulfur-containing compounds, such as cyclic compounds with a vinyl sulfane structure, exhibit a wide range of biological activities including anticancer activity. Therefore, the development of efficient strategies to synthesize such compounds is a remarkable achievement. We have developed a unique approach for the rapid and modular preparation of nature-inspired cyclic and acyclic sulfur-containing compounds using thioacrolein, a naturally occurring chemically unstable intermediate. We constructed thiopyranone derivatives through the regioselective sequential double Diels-Alder reaction of thioacrolein produced by allicin, a major component in garlic, and two molecules of silyl enol ether as the diene partner. The cytotoxicity toward cancer stem cells of the thiopyranones was equal to or higher than that of (Z)-ajoene (positive control) derived from garlic, and the thiopyranones had higher chemical stability than (Z)-ajoene.

Cardiovascular Catheterization Using a New Antiseptic Agent Olanexidine Gluconate.

Olanexidine gluconate 1.5% (Olanedine®) is a colorless and transparent antiseptic agent introduced in 2015. In this study, we examined its usefulness and safety for cardiovascular catheterization and compared them to 10% povidone-iodine (PI). The study included 1,001 and 1,000 consecutively enrolled patients using Olanedine® and PI, respectively [649 (PI, 687) males; mean age: 72.1 ± 9.6 (70.9 ± 9.6) years] who underwent cardiovascular catheterization [diagnostic cardiac catheterization: 624 (509) cases, percutaneous coronary intervention: 288 (390) cases, and endovascular treatment: 89 (101) cases]. Clinically, there were no significant differences in the backgrounds between the two groups. The amount of Olanedine® used per case was approximately 20 mL. Blood tests were performed before and after catheterization. The presence or absence of discoloration on clothes containing cotton by Olanedine® was also examined. One mild rash that disappeared within one day occurred in each of the two groups. Some blood tests before and after cardiac catheterization indicated significant differences, but they did not seem to be clinically relevant. The use of Olanedine® in hemodialysis patients (117 cases) was uneventful. Its use in 37 patients with contraindications for ethanol disinfection was also uneventful. Although PI is extremely difficult to remove from white coats containing cotton, Olanedine® did not cause any discoloration on clothes. This is the first report of cardiovascular catheterization using Olanedine®. The efficacy and safety of Olanedine® and PI seem to be equivalent. Olanedine® could be a new useful option as a disinfectant of cardiovascular catheterization.

Second basic pKa: An overlooked parameter in predicting phospholipidosis-inducing potential of diamines.

In this paper, we present the phospholipidosis-inducing potential (PLIP) of forty fragment-sized diamines derived from N-benzyl-4-(methylamino)piperidine and discuss the relationship between their PLIP and the physicochemical properties. Our results demonstrate that the previously reported methods are not suitable for predicting the PLIP of fragment-sized diamines; the second basic pKa can distinguish PLIP-positive diamines from PLIP-negative diamines more accurately than ClogP or most basic pKa. To the best of our knowledge, this is the first report describing the relationship between PLIP and second basic pKa.

Selective Oxidation of H2 and CO by NiIr Catalyst in Aqueous Solution: A DFT Mechanistic Study.

One of the challenges in utilizing hydrogen gas (H2) as a sustainable fossil fuel alternative is the inhibition of H2 oxidation by carbon monoxide (CO), which is involved in the industrial production of H2 sources. To solve this problem, a catalyst that selectively oxidizes either CO or H2 or one that co-oxidizes H2 and CO is needed. Recently, a NiIr catalyst [NiIICl(X)IrIIICl(η5-C5Me5)], (X = N,N'-dimethyl-3,7-diazanonane-1,9-dithiolate), which efficiently and selectively oxidizes either H2 or CO depending on the pH, has been developed (Angew. Chem. Int. Ed. 2017, 56, 9723-9726). In the present work, density functional theory (DFT) calculations are employed to elucidate the pH-dependent reaction mechanisms of H2 and CO oxidation catalyzed by this NiIr catalyst. During H2 oxidation, our calculations suggest that dihydrogen binds to the Ir center and generates an Ir(III)-dihydrogen complex, followed by subsequent isomerization to an Ir(V)-dihydride species. Then, a proton is abstracted by a buffer base, CH3COO-, resulting in the formation of a hydride complex. The catalytic cycle completes with electron transfer from the hydride complex to a protonated 2,6-dichlorobenzeneindophenol (DCIP) and a proton transfer from the oxidized hydride complex to a buffer base. The CO oxidation mechanism involves three distinct steps, i.e., (1) formation of a metal carbonyl complex, (2) formation of a metallocarboxylic acid, and (3) conversion of the metallocarboxylic acid to a hydride complex. The formation of the metallocarboxylic acid involves nucleophilic attack of OH- to the carbonyl-C followed by a large structural change with concomitant cleavage of the Ir-S bond and rotation of the COOH group along the NiIr axis. During the conversion of the metallocarboxylic acid to the hydride complex, intramolecular proton transfer followed by removal of CO2 leads to the formation of the hydride complexes. In addition, the barrier heights for the binding of small molecules (H2, OH-, H2O, and CO) to Ir were calculated, and the results indicated that dissociation from Ir is a faster process than the binding of H2O and H2. These calculations indicate that H2 oxidation is inhibited by CO and OH- and thus prefers acidic conditions. In contrast, the CO oxidation reactions occur more favorably under basic conditions, as the formation of the metallocarboxylic acid involves OH- attack to a carbonyl-C and the binding of OH- to Ni largely stabilizes the triplet spin state of the complex. Taken together, these calculations provide a rationale for the experimentally observed pH-dependent, selective oxidations of H2 and CO.

Computational Study on the Light-Induced Oxidation of Iridium-Aqua Complex to Iridium-Oxo Complex over WO3(001) Surface.

An iridium aqua complex [IrIII(η5-C5Me5){bpy(COOH)2}(H2O)]2+ under visible light irradiation has been experimentally reported to form an iridium-oxo (Ir-oxo) complex [IrV(η5-C5Me5){bpy(COOH)2}(O)]2+, which oxidizes H2O to O2. However, the mechanism for the formation of this Ir-oxo complex remains unclear, due to the difficulties in observing the unstable Ir-oxo complex and computing light-induced systems having different numbers of electrons. In this study, we perform density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations to investigate more in detail our previously proposed deprotonation and light-induced oxidation reactions composing the formation of the Ir-oxo complex. In particular, we discuss effects of light irradiation and WO3 support on the formation of the Ir-oxo complex. We suggest two distinct mechanisms, that is, direct and indirect for the light-induced oxidation. In the direct mechanism electrons are directly transferred from the occupied π* orbitals of IrIII-OH or IrIV=O• to the conduction band of the WO3 surface, whereas in the indirect mechanism electrons are first excited from the valence band to the conduction band of the WO3 surface due to the UV light, and then the resultant electron hole oxidizes the Ir complex. In the direct mechanism, in particular, we found that the lowest energy of the anode's conduction band determines the adsorption wavelength of the light irradiation, enabling us to predict alternative semiconductor anodes for more efficient formation of the Ir-oxo complex.

Association of Protein and Endotoxin in Outdoor Air with Emergency Department Visits for Children and Adults with Asthma in Fukuoka, Japan.

We examined the association of biological components in airborne particles, i.e., proteins and endotoxins, in outdoor air with asthma exacerbation in the Fukuoka metropolitan area, Fukuoka, Japan. Data on emergency department (ED) visits for asthma in children (age, 0-14 years) and adults (age, 15-64 years) were collected at a medical center from December 2014 to November 2015. One hundred eighty-one children and 143 adults visited the ED for asthma, and the weekly number of ED visits in children increased in autumn, i.e., September (second week) to November (first week). Fine (aerodynamic diameter ≤2.5 µm) and coarse (≥2.5 µm) particles were collected for 3 or 4 weeks per month, and protein and endotoxin concentrations were analyzed. Protein was largely prevalent in fine particles (0.34-7.33 µg/m3), and concentrations were high in April, May, June, and October. In contrast, endotoxin was mainly included in coarse particles (0.0010-0.0246 EU/m3), and concentrations were high in September (third week), October (first, second, and fourth weeks), February (fourth week), and July (first week). The results of a Poisson regression analysis indicated that endotoxin (in fine and coarse particles alike) was a significant factor for ED visits related to asthma in children, even after adjusting for meteorological factors, i.e., temperature, relative humidity, and wind speed. However, there was no association between environmental factors and ED visits for asthma in adults. These results suggest that endotoxin in outdoor air is significantly associated with an increased risk of asthma exacerbation in children.

Giant and highly reflective Goos-Hänchen shift in a metal-dielectric multilayer Fano structure.

We experimentally demonstrated a giant Goos-Hänchen (GH) shift in a metal-dielectric multilayer Fano structure. The observed GH shift was 0.176 mm, which corresponded to (GH shift/λ) = 493, where λ is the incident wavelength. A unique feature of this giant GH shift was that it occurred without attenuation, i.e., reflectivity ∼1, due to Fano interference between surface plasmon polariton and high-Q dielectric waveguide mode. The Q-value is determined by the coupling loss. Therefore, we can enhance the GH shift to an arbitrarily large value by controlling the coupling strength. The unique feature whereby the giant GH shift occurs without attenuation has great potential for real-world applications, such as optical switching, optical filters, and sensors, where the reduction of reflected beam intensity is currently a major drawback.