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Zinc is an essential micronutrient in human body and a vital cofactor for the function of numerous proteins encoded by the human genome. Zinc has a critical role in maintaining many biochemical and physiological processes at the molecular, cellular, and multiple organ and systemic levels. The alteration of zinc homeostasis causes dysfunction of many organs and systems. In the immune system, zinc regulates the differentiation, proliferation and function of inflammatory cells, including T cells, eosinophils, and B cells, by modifying several signaling pathways such as NFκB signaling pathways and TCR signals. An adequate zinc level is essential for proper immune responses and decreased zinc levels were reported in many allergic inflammatory diseases, including atopic dermatitis, bronchial asthma, and chronic rhinosinusitis. Decreased zinc levels often enhance inflammatory activation. On the other hand, the inflammatory conditions alter the intracellular homeostasis of zinc, often decreasing zinc levels. These findings implied that there could be a vicious cycle between zinc deficiency and inflammatory conditions. In this review, we present recent evidence on the involvement of zinc in atopic dermatitis, bronchial asthma, and chronic rhinosinusitis, with insights into the involvement of zinc in the underlying molecular and cellular mechanisms related to these allergic inflammatory diseases.

Four new homodinuclear lanthanoid(III) dithiocarbamato (RR'dtc(-)) complexes bridged by 2,2'-bipyrimidine (bpm) of the form [{Ln(RR'dtc)(3)}(2)(mu-bpm)] {Ln = Nd or Eu; RR' = dimethyl- (Me-2) or pyrrolidine(pyr)} were prepared and their crystal structures and spectroscopic properties were characterized. The crystallographic studies revealed that all of the complexes possess a similar structural motif with an 8:8-coordination geometry, in which the bpm ligand bridges two Ln(III) centers in the kappa N-2(1,1') : kappa N-2(3,3') mode and three RR'dtc(-) ligands coordinate to each Ln(III) center. The complexes exhibit weak but relatively sharp f-f transition bands in the absorption and magnetic circular dichroism (MCD) spectra recorded in the visible region. The MCD spectral studies demonstrated the magneto-optical behavior of the complexes. The spectral features of the dithiocarbamato complexes were distinctly different from those of their beta-diketonato analogues, suggesting the coordination environment around the Ln(III) center influences the electronic structure and spectroscopic symmetry of the complexes in solution.

PURPOSE/OBJECTIVE(S) Sequential boost (SQB) is an IMRT approach that is considered comparable to simultaneous-integrated boost. Dosimetric analysis in SQB using two planning CTs requires advanced dose-accumulation techniques, such as a deformable image registration (DIR) workflow. The purpose of this study was to assess patterns of failure and identify dosimetric features for hypopharyngeal cancer patients treated with SQB-IMRT. MATERIALS/METHODS Between 2013 and 2019, 102 hypopharyngeal cancer patients were treated with definitive SQB-IMRT. In short, both the PTV-high risk, including the primary tumor and metastatic lymph nodes, and the PTV-low risk, including elective nodal regions, received 46 Gy at 2 Gy/fraction using the first planning CT. The PTV-high risk sequentially received an additional 24 Gy using a second planning CT. The doses for the first and second plans were accumulated and registered onto the second planning CT using the DIR workflow. All locoregional recurrences were contoured on the follow-up CT and registered with the second planning CT. Recurrences were classified as in-field (more than 95% of the recurrence volume (Vrec) received 95% of the prescribed dose), marginal (20-95%), or out-of-field (less than 20%). The toxicity was also evaluated using CTCAE ver4.0. RESULTS The median age was 66 years. Stage I, II, III and IV diseases were diagnosed in 3, 23, 20 and 56 patients, respectively. Eighty-three patients (81%) received concurrent chemoradiotherapy, and 19 patients (19%) received radiation therapy alone. The median total dose was 70 Gy. The median follow-up period was 22 months for all patients and 24 months for survivors. The 2-year overall survival rate and locoregional control rate were 79% and 57%, respectively. Thirty-four (33%) locoregional recurrences were observed. All locoregional failures were defined as in-field, and there was no marginal or out-of-field recurrence. The median mean dose and of the Vrec were 72.5 Gy (range, 71.6-74.1). In the patients who experienced locoregional failure, the median mean dose to the elective nodal region was assessed to be 60.1 (range, 55.4-68.4) Gy, and no recurrence occurred in the area. Late toxicities 6 months after RT were evaluated in 34 patients, and 24%, 3%, 25% and 2% of the patients experienced grade 2 and 3 dysphagia, grade 2 dry mouth and G2 dysgeusia, respectively. There were no grade 4/5 late toxicities. CONCLUSION In the detailed dosimetric analysis using DIR, all locoregional relapses after SQB-IMRT were in-field recurrences in the high-dose region. There was no recurrence in the prophylactic dose area, in which the accumulated dose reached as high as 60 Gy. More aggressive treatment for gross tumors and lower prophylactic doses may contribute to improved treatment outcomes and reduced side effects.

Previously, we proposed 12 marker genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2 and Tubb4b) to discriminate mouse genotoxic hepatocarcinogens (GTHC) from non-genotoxic hepatocarcinogens (NGTHC). This was determined by qPCR and principal component analysis (PCA), as the aim of an in vivo short-term screening for genotoxic hepatocarcinogens. For this paper, we conducted an application study of the 12 mouse marker genes to rat data, Open TG-GATEs (public data). We analyzed five typical rat GTHC (2-acetamodofluorene, aflatoxin B1, 2-nitrofluorene, N-nitrosodiethylamine and N-nitrosomorpholine), and not only seven typical rat NGTHC (clofibrate, ethanol, fenofibrate, gemfibrozil, hexachlorobenzene, phenobarbital and WY-14643) but also 11 non-genotoxic non-hepatocarcinogens (NGTNHC; allyl alcohol, aspirin, caffeine, chlorpheniramine, chlorpropamide, dexamethasone, diazepam, indomethacin, phenylbutazone, theophylline and tolbutamide) from Open TG-GATEs. The analysis was performed at 3, 6, 9 and 24 h after a single administration and 4, 8, 15 and 29 days after repeated administrations. We transferred Open TG-GATEs DNA microarray data into log2 data using the “R Project for Statistical Computing”. GTHC-specific dose-dependent gene expression changes were observed and significance assessed with the Williams test. Similar significant changes were observed during 3–24 h and 4–29 days, assessed with Welch’s t-test, except not for NGTHC or NGTNHC. Significant differential changes in gene expression were observed between GTHC and NGTHC in 11 genes (except not Tubb4b) and between GTHC and NGTNHC in all 12 genes at 24 h and 10 genes (except Ccnf and Mbd1) at 29 days, per Tukey’s test. PCA successfully discriminated GTHC from NGTHC and NGTNHC at 24 h and 29 days. The results demonstrate that 12 previously proposed mouse marker genes are useful for discriminating rat GTHC from NGTHC and NGTNHC from Open TG-GATEs.

A series of Nd-III and Eu-III complexes containing achiral or chiral dithiocarbamato (dtc) ligands, [Ln(Xdtc)(3)(NN)] {Ln = Nd or Eu; X = dimethyl- (Me-2), pyrrolidine- (pyr), or (S)-prolinol- (S-proOH); NN = 1,10-phenanthroline (phen) or 2,2'-bipyridine (bpy)}, were prepared and their crystal structures and spectroscopic properties, in particular the natural circular dichroism (CD) and magnetic circular dichroism (MCD), were investigated. The crystal structures of the complexes analyzed by the X-ray diffraction method showed an 8-coordinate geometry around the Ln III center with comparable structural parameters to one another and to the related complexes reported previously. These complexes exhibited similar spectral patterns in their absorption, natural CD and MCD spectra in solution. Weak but characteristic sharp f-f transition bands were observed in the absorption and MCD spectra, but no CD signals associated with these transitions were observed even in the S-proOHdtc complexes. The MCD spectral pattern of the Eu-III complexes revealed a local C-2v symmetry around the Ln(III) center in solution, in contrast to the aqua and the analogous beta-diketonato Eu-III complexes.

For many years, drug discovery studies in the field of epigenetics have focused mainly on specific enzymes such as histone deacetylases (HDACs). However, recently there has been increasing interest in small molecules targeting the multiprotein enzyme/transcription factor complexes that play key roles in the epigenetic control of gene expression. Aberrant function of these complexes often has pathological consequences. Here, we review small molecules that modulate the function of three well-known epigenetic complexes, namely, polycomb repressive complex 2 (PRC2), PRC1, and corepressor of RE1-silencing transcription factor (CoREST) complex, focusing on recent drug discovery studies targeting these epigenetic complexes.

It has long been unclear whether 1,4-dioxane (DO) is a genotoxic hepatocarcinogen (GTHC). Therefore, the present study aimed to evaluate rat GTHCs and non-genotoxic hepatocarcinogens (NGTHCs) via selected gene expression patterns in the liver, as determined by next generation sequencing-targeted mRNA sequencing (RNA-Seq) and principal component analysis (PCA). Previously, we selected 11 marker genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Lrp1, Mbd1, Phlda3, Plk2, and Tubb4b) to discriminate GTHCs and NGTHCs. In the present study, we quantified changes in the expression of these genes following DO treatment, and compared them with treatment with two typical rat GTHCs, N-nitrosodiethylamine (DEN) and 3,3'-dimethylbenzidine·2HCl (DMB), and a typical rat NGTHC, di(2-ethylhexyl)phthalate (DEHP). RNA-Seq was conducted on liver samples from groups of five male, 10-week-old F344 rats after 4 weeks' feeding of chemicals in the water or the food. Rats in the control group were given water and a basal diet. Significant changes in gene expression in experimental groups compared with the control group were observed in eight genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Phlda3 and Plk2), as shown by Tukey's test. Gene expression profiles of the 11 genes under DO treatment differed significantly from those with DEN and DMB, as well as DEHP. Gene expression profiles with DO treatment differed partially from those with typical GTHCs for five genes (Bax, Btg2, Cdkn1a, Lrp1 and Plk2) and were substantially different from treatment with a typical NGTHC (DEHP) for nine genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Mbd1, Phlda3 and Tubb4b) as determined by Tukey's test. Finally, PCA successfully differentiated GTHCs from DEHP and DO with the 11 genes. The present results suggest that RNA-Seq and PCA are useful to evaluate rat typical GTHCs and typical NGTHCs. DO was suggested to result in a different intermediate gene expression profile from typical GTHCs and NGTHC.

A method for simultaneous quantification of fosphenytoin (F-PHT), phenytoin (PHT) and its main metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) in whole blood was developed and validated using ultra-performance liquid chromatography-tandem mass spectrometry. Whole blood samples were pretreated by liquid–liquid extraction with acetonitrile and methanol. Chromatographic separation was performed using a CORTECS™ UPLC® C18 (2.1 × 50 mm i.d., particle size 1.6 μm) analytical column, and water containing 10 mM ammonium formate and acetonitrile as the mobile phase. Quantification of the analytes was carried out using mass chromatography with each product ion referenced against phenytoin-d10 as an internal standard. Calibration curves exhibited good linear relationships in a range from 0.005 to 50 μg/ml with correlation coefficients exceeding 0.995. The limits of detection were estimated to be 0.002–0.01 μg/ml. The accuracies and precisions were 96.2–104.3% and 0.7–10.7%, respectively. The recovery efficiencies were in the range of 42.4–59.2%. Matrix effects were observed for PHT and HPPH, with signal suppression ranging from −6.6 to –32.2%. Matrix effect for F-PHT (−5.0 to 8.9%) was less than those for PHT and HPPH. All analytes were stable under different storage conditions. This method was successfully applied for the quantification of F-PHT, PHT and HPPH in rat whole blood samples taken after bolus intravenous administration of F-PHT.

Toxicoproteomic analysis of steel industry ambient particulate matter (PM) that contain high concentrations of PAHs and metals was done by treating human lung cancer cell-line, A549 and the cell lysates were analysed using quantitative label-free nano LC-MS/MS. A total of 18,562 peptides representing 1576 proteins were identified and quantified, with 196 proteins had significantly altered expression in the treated cells. Enrichment analyses revealed that proteins associated to redox homeostsis, metabolism, and cellular energy generation were inhibited while, proteins related to DNA damage and repair and other stresses were over expressed. Altered activities of several tumor associated proteins were observed. Protein-protein interaction network and biological pathway analysis of these differentially expressed proteins were carried out to obtain a systems level view of proteome changes. Together it could be inferred that PM exposure induced oxidative stress which could have lead into DNA damage and tumor related changes. However, lowering of cellular metabolism, and energy production could reduce its ability to overcome these stress. This kind of disequilibrium between the DNA damage and ability of the cells to repair the DNA damage may lead into genomic instability that is capable of acting as the driving force during PM induced carcinogenesis.

Histone acetylation and deacetylation correlate with diverse biological phenomena through gene transcription. Histone deacetylases (HDACs) regulate deacetylation of histones and other proteins. However, as a member of the HDAC family, HDAC8 function during neurodevelopment is currently unknown. Therefore, we investigated HDAC8 function during neurodevelopment by examining embryoid body (EB) formation in P19 cells. HDAC8-selective inhibitor (NCC-149) (HDAC8i)-treated cells showed smaller EBs than non-treated cells, as well as reduced expression levels of the neuronal marker, NeuN. Additionally, HDAC8i treatment led to inhibition of cellular proliferation by G2/M phase accumulation and downregulated cyclin A2 and cyclin B1 gene expression. Furthermore, two independent HDAC8 knockout cell lines were established by CRISPR-Cas9, which resulted in smaller EBs, similar to HDAC8i-treated cells. These results suggest that HDAC8 regulates neural differentiation by exerting control of EB formation.

Three tetrahedral cobalt(II) complexes [CoX2(H2thp)2] were prepared and characterized (H2thp = 2-(1,4,5,6-tetrahydropyrimidin-2-yl)phenol, X = Cl, Br, and I). X-ray crystallographic analysis indicates that the H2thp ligand coordinates to a Co ion in monodentate fashion in zwitterionic form. In the crystal, all the complexes formed characteristic one-dimensional chain structures via N H···X hydrogen-bonding interactions. The static magnetic measurements showed that the g-factors and axial zero-field splitting parameters for Br− and I− derivatives are quite similar despite the deference in the halide ligand. A significant frequency dependence was observed for all the complexes in dynamic magnetic measurements in the presence of an external field. The relaxation dynamics below 3 K for the Br− and I− derivatives were found to be dominated by Raman relaxation process, while that of the Cl− derivative was dominated by Orbach process. The relatively long intermolecular Co···Co distances > 8 A resulted in no influence in the static magnetic properties and the QTM phenomena.

Molecular and crystal structures of the mononuclear cobalt(III) complexes bearing N’-(pyridin-2-ylmethylene)picolinoylhydrazidate (Lpy–), [Co(Lpy)3] (1) and [Co(Lpy)2]BF4 (2a and 2b), as well as those of the Lpy-bridged CoIII2CoII trinuclear and CoII4 tetranuclear complexes, [Co3(Lpy)4(H2O)2](BF4)4 (3) and [Co4(Lpy)4Cl2(CH3CN)2](BF4)2 (4), were determined by the single-crystal X-ray diffraction method, which revealed a variety of coordination and bridging modes of the multidentate Lpy– ligand. The protonated free hydrazone, HLpy, exists as an E-form (in regard to the imine configuration) in the solid state and in solution. In the mononuclear CoIII complexes, the hydrazonate anion (Lpy–) coordinates to a CoIII center in three different coordination modes: a bidentate κ2N1,N2 mode with the E-form (in 1) and two kinds of tridentate modes with the respective configuration, Z-κ3N1,N2,N4 and E-κ3O,N3,N4, in 2a and 2b. The former tridentate mode was sterically favored in the CoIII complexes, resulting in the five- and six-membered chelate rings, with a conversion of the imine configuration during the complexation. Complex 2a could also serve as a complex ligand toward a CoII ion with the κ2O,N3 mode, forming the CoIII–CoII–CoIII trinuclear complex (3). In the novel tetranuclear CoII complex (4), the E-Lpy– hydrazonates bridged two CoII ions in two different modes: μ-κ2O,N1:κ3O,N3,N4 and μ-κ2N1,N2:κ3O,N3,N4, where all chelate coordinations formed a five-membered ring with the CoII ion.

Growing evidence suggests that changes in histone acetylation in specific sites of the chromatin modulate neuronal plasticity and contribute to antidepressant-like action. Sirtuin 2 (SIRT2) is a class III NAD + -dependent histone deacetylase involved in transcriptional repression of genes regulating synaptic plasticity. Importantly, a key role for the glutamate system in prefrontal cortex (PFC) synaptic plasticity changes induced by antidepressants has been suggested. Here, we asked whether SIRT2 could be a pharmacological target for depression therapy. The compound 2-{3-(3-fluorophenethyloxy)phenylamino}benzamide (33i), a selective SIRT2 inhibitor in vitro , was studied in mice (C57Bl6). Firstly, the inhibitory effect of subchronic 33i (5–15 mg/kg, 10 days) on SIRT2 activity in the PFC was evaluated. Moreover, the effect of SIRT2 inhibition on the expression of synaptic plasticity markers linked to glutamate neurotransmission (VGLUT1, synaptophysin, mGluR4, GluA1, GluN2B, GluN2A) and on serotonin levels was studied. Further, neurochemical and behavioral effects of chronic (5 weeks) 33i (15 mg/kg) on the chronic mild stress (CMS) model were analyzed. Subchronic 33i inhibited SIRT2, increased GluN2A, GluN2B and serotonin levels in the PFC. Moreover, chronic 33i reverted CMS-induced anhedonia and social avoidance. Moreover, 33i upregulated postsynaptic GluN2B and phosphorylated form of GluA1 ( p -GluA1), suggesting that SIRT2 inhibition enhance synaptic strength. Yet, CMS also increased both GluN2A and GluN2B in the postsynaptic fraction. These results suggest that Sirt2 inhibition induce antidepressant-like action and this effect could be mediated by modulation of glutamate and serotonin system in the PFC. Moreover, it highlights the therapeutic potential of SIRT2 inhibitors as new antidepressant agents.

An ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous quantification of batrachotoxin and epibatidine in plasma. Plasma samples were pretreated by liquid-liquid extraction with acetonitrile and methanol. The toxins were separated on a reversed phase C18-column (2.1mm×50mm, 1.7μm) using a formic acid/acetonitrile gradient elution. Quantification was carried out by mass chromatography with each product ion referenced against midazolam-d4 as an internal standard (IS). The two toxins and the IS were separated within 2min. The calibration curves for the two toxins spiked into human plasma showed good linearities in the range from 2.5 to 250ng/mL. The detection limits were estimated to be 0.5ng/mL for batrachotoxin and 1ng/mL for epibatidine with a signal-to-noise ratio of 3:1. Overall recoveries ranged from 69.6% to 98.2%, and no significant matrix effects were observed. The intra- and interday accuracies were 94.7-102.3%, and the precisions were 1.0-10.3%. This method was successfully applied for the quantification of batrachotoxin and epibatidine in rat plasma samples taken after intraperitoneal administration of the toxins. This is the first report to use UPLC-MS/MS to simultaneously quantify batrachotoxin and epibatidine in plasma samples.

A commercially available kit for the quantitation of lithium, the Lithium Assay kit LS, was originally developed to measure lithium in serum or plasma using a conventional microplate reader. We investigated whether use of the kit could be extended to quantify lithium in whole blood and urine samples collected at autopsy. The calibration curve for whole blood showed good linearity ranging from 0.5 to 20 µg/mL with a coefficient of determination of 0.998 when samples were pretreated with methanol followed by acetonitrile. Moreover, for urine, we obtained excellent linearity with a coefficient of determination of 0.999 without any pretreatment. The accuracies and precisions were 106.3–174.7% and 1.9–18.1% for whole blood and 83.3–118.8% and 5.7–33.8% for urine. The values in the lower concentration range (0.5–1 µg/mL) were not satisfactory, whereas those in the higher range (2–20 µg/mL) were acceptable. The Lithium Assay kit LS was successfully applied to the measurement of lithium in whole blood and urine samples collected at autopsies. This method appears to be useful for forensic toxicological investigations because of its simplicity and speed.

The Ca 2+ -activated Cl − channel ANO1 contributes to tumorigenesis and metastasis in several carcinomas including breast cancer (BCA). Cl − channels have recently been attracting attention as ‘transcriptional modulators’. Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 30% of patients with BCA, and anti-HER2 monoclonal antibodies such as trastuzumab have emerged as a treatment for metastatic BCA. Among the seven human BCA cell lines examined in the present study, MDA-MB-453 and YMB-1 cells were HER2-positive; however, YMB-1 cell viability showed resistance to trastuzumab. Whole-cell patch-clamp configurations indicated that ANO1 was the main Cl − conductance in YMB-1 cells, and the pharmacological and siRNA-mediated inhibition of ANO1 significantly prevented HER2 transcription in YMB-1 cells. The expression levels of insulin-like growth factor-binding protein 5 (IGFBP5), which is a risk factor for BCA recurrence and metastasis, was not affected by the inhibition of ANO1 in YMB-1 cells. These results suggest that ANO1 Cl − channels may function as a transcriptional regulator of HER2, and ANO1 inhibitors have potential in the treatment of BCA patients with resistance to HER2-targeted therapy.

Reactions of [(Cp∗Rh)2(μ-OH)3]OH (Cp∗ = η5-C5Me5−) and thymine (=H2thym) in methanol in the presence or absence of a certain metal salt were examined. From the reaction mixture without any template metal salt, a dinuclear hydroxido-bridged complex bearing monodentate monodeprotonated thyminato ligands, [{Cp∗Rh(Hthym-κN1)}2(μ-OH)2], was isolated after recrystallization from water. In the presence of a metal salt MXn {=NaPF6, NaBF4, NaNO3, Ca(NO3)2, Ca(ClO4)2, La(NO3)3, Eu(NO3)3, Dy(NO3)3 and Er(NO3)3} were deposited orange crystals (1P, 1B, 1N, 2N, 2C, 3N, 4N, 5N and 6N, respectively) which consist of a thyminato(2-)-bridged tetranuclear Cp∗Rh complex incorporating a Mn+ cation, [(Cp∗Rh)4(μ-thym)4M]n+. All complexes were characterized by the single-crystal X-ray diffraction method, which revealed that homochiral aggregations of four RhIII centers were achieved to give metallacalix[4]arene-type clusters. It was also observed that the bridging modes of thym2− ligands were dependent on the template metal ion. In the Na+-incorporated clusters (1X, X = P, B or N) a thym2− ligand bridged two RhIII and the third Na+ ions with a μ3-1κN1:2κ2N3,O2:3κO2 mode, while in the Ln3+ analogs (Ln = La, Eu, Dy or Er: 3N–6N) thym2− exhibited a different bridging mode, μ3-1κN1:2κ2N3,O4:3κO2. In the cases of Ca2+-incorporated clusters, the bridging mode is further dependent on the associated anion; only the μ3-1κN1:2κ2N3,O2:3κO2-type cluster was obtained in the NO3− salt (2N), but the ClO4− salt (2C) afforded both types of the bridging clusters piled up alternatively in the crystals. The tetranuclear structures with a template metal cation, [(Cp∗Rh)4(μ-thym)4M]n+, are maintained in solution. The magnetic behaviors of the Dy3+- and Er3+-incorporated complexes (5N and 6N) are also reported.

Background Uterine cervical cancer is a treatable and preventable cancer. Medical efforts to reduce rates of cervical cancer focus on the promotion of human papillomavirus (HPV) vaccination and the promotion of routine cervical cancer screening done by cervical cytology and cervical HPV testing. Urine-based HPV testing would be simple and noninvasive approach to screen for cervical cancer. Methods Two biospecimens (clinician-taken sample from cervix and initial stream urine sample) were provided from a total of 240 healthy women attending for cancer screening provided for HPV testing. We have assessed the HPV detection rates among cervical samples and pellet fraction of urine samples using HPV test (Anyplex™ II HPV28 Detection kit, Seegene, Korea). Results Among 240 samples screened, HPV prevalence was 42.9% in pellet fractions of urine samples. The agreement between the two kinds of samples was 98.4%, k = 0.792. Discordant results were observed in 27 cases; 5 were positive only by urine samples and 22 were positive only by smear samples. Sensitivity and specificity for all HPV DNA in pellet fractions of urine using cervical samples as reference was 68.4% and 99.9%. Conclusions Comparing methodologies of collection of samples for HPV detection, they showed the higher agreements for almost genotypes between cervical samples and pellet fractions of urine samples. These results suggest that urine could be a good noninvasive tool to monitor HPV infection in women. Additional research in a larger and general screening population would be needed.

Complexation of 2-hydroxy-N-(n-aminoalkyl)benzamides, where n-aminoalkyl substituents are 2-amino-2-methylpropyl (H2L2Me2), (R)-2-aminopropyl {(R)-H2L2Me} and 3-aminopropyl (H2L3), with manganese(II) chloride or perchlorate were examined. With the 2-aminopropyl derivatives, dinuclear methoxido-bridged manganese(III) complexes bearing the dianionic ligands, [{Mn(L2Me2 or (R)-L2Me)(MeOH)}2(μ-OMe)2] (2 or 4), were isolated and their crystal structures were determined. There was a weak antiferromagnetic interaction between two axially distorted MnIII centers in 2. Also, with the ligand of (L2Me2)2− a mononuclear manganese(IV) complex, [Mn(L2Me2)2]·DMF (3·DMF) was obtained. In the crystal of 3·DMF a heterochiral dimerization via the intermolecular double hydrogen-bonds was observed. In the case of reactions with H2L3, mononuclear manganese(III) complexes, [Mn(H2L3′)2Cl2]Cl (6) and [Mn(H2L3′)2(MeOH)2]Cl2(ClO4) (7), were afforded, where the ligand (H2L3′) has a phenolate–amide–ammonium type zwitterionic form of H2L3 and coordinates to a MnIII center via the phenolato-O and amide-O atoms to form a six-membered chelate ring. Furthermore, a tetranuclear MnII2MnIII2 double incomplete-cubane type cluster compound, [Mn4(HL3)2Cl2(OMe)6(MeOH)2]·4MeOH (5a·4MeOH) was revealed by the single-crystal X-ray diffraction study, although the bulk crystals (5) obtained from the reaction mixture showed a different PXRD pattern. The elemental analysis of the bulk crystals of 5 suggested that they consist of the same tetranuclear clusters. It is interesting that the bulk crystals of 5 were highly efflorescent, and it was suggested that their coordinated MeO− and MeOH ligands were easily substituted by OH− and H2O, respectively, in atmospheric air. This conversion changed their magnetic behaviors drastically.

A reaction of [Cp*IrCl(Ph2Pqn)]PF6 {Cp* = η5-pentamethylcyclopentadienyl; Ph2Pqn = 8-(diphenylphosphino)quinoline} and Ag(CF3SO3) in methanol afforded orange crystals of the corresponding hydrido complex, [Cp*IrH(Ph2Pqn)]PF6, which was identified by 1H, 31P{1H} NMR and IR spectroscopy as well as X-ray structural analysis. The reactions in deuterated solvents indicated that formation of the hydrido complex proceeded via β-hydrogen elimination of the coordinated methanol molecule. It was also revealed that the hydrido formation was specific for the complex bearing Ph2Pqn ancillary ligand; the analogous complex with 1,2-bis(diphenylphosphino)benzene (diphos) or 1,10-phenanthroline (phen) did not give the corresponding hydrido complex by a similar reaction with Ag+ in methanol. In order to elucidate the reason for the different reactivity among these complexes, the crystal structures of the precursor chlorido complexes, [Cp*IrCl(Ph2Pqn)]PF6, [Cp*IrCl(diphos)]PF6 and [Cp*IrCl(phen)]PF6, as well as an acetonitrile complex of [Cp*Ir(Ph2Pqn)(CH3CN)](PF6)2, were also determined by X-ray analysis. The resulting structural information suggested that a specific formation of the hydrido complex with Ph2Pqn could be originated from the facile formation of the corresponding methanol complex and the hemilabile nature of ancillary Ph2Pqn ligand, which induced the reactivity of the coordinated methanol toward β-hydrogen elimination.

Two new tetranuclear iron(II) complexes, [Fe4(H2LH)6](ClO4)8 (1ClO4: H2LH = N,N′-bis(imidazole-4-ylmethylidene)-1.4-diaminobenzene) and [Fe4(H2LMe)6](BF4)8 (2BF4: H2LMe = N,N′-bis(5-methylimidazole-4-ylmethylidene)-1.4-diaminobenzene), were synthesized from Fe(ClO4 or BF4)2·6H2O, 1.4-diaminobenzene and 4-formylimidazole or 5-methyl-4-formylimidazole. X-ray analysis revealed that these complexes have a tetrahedral structure with four iron(II) ions at the apexes and the bridging bis(bidentate) ligands on the edges. The internal space of the tetrahedron was filled with the phenylene segments of the bridging ligands. Magnetic susceptibility studies indicated that both 1ClO4 and 2BF4 showed gradual but incomplete spin-crossover (SCO) behavior, because the densely packed tetrahedral structure could prevent the contraction of the Fe–N bonds on the high-spin to low-spin transition.

Pin1 is a peptidyl prolyl isomerase that specifically catalyzes cis–trans isomerization of phosphorylated Thr/Ser-Pro peptide bonds in substrate proteins and peptides. Pin1 is involved in many important cellular processes, including cancer progression, so it is a potential target of cancer therapy. We designed and synthesized a novel series of Pin1 inhibitors based on a glutamic acid or aspartic acid scaffold bearing an aromatic moiety to provide a hydrophobic surface and a cyclic aliphatic amine moiety with affinity for the proline-binding site of Pin1. Glutamic acid derivatives bearing cycloalkylamino and phenylthiazole groups showed potent Pin1-inhibitory activity comparable with that of known inhibitor VER-1. The results indicate that steric interaction of the cyclic alkyl amine moiety with binding site residues plays a key role in enhancing Pin1-inhibitory activity.

Trans-bis(acetylacetonato)-bis(4-methylpyridine)cobalt(III)hexafluorophosphate, [AMPC]PF6, was synthesized and characterized by X-ray diffraction and vibrational spectroscopy. The title compound C22H28N2O4Co crystallizes with Z=2 in space group P-1 (#2). The molecular structure and vibrational spectra of this compound were investigated by means of density functional theory (DFT) calculations and the results were compared with the experimental data. The measured IR bands were interpreted in terms of the calculated vibrational normal modes and compared with the tris(acetylacetonate)Co(III) (Co(acac)3) and 4-methylpyridine (4-Mepy) vibrational spectra. The scaled theoretical wavenumbers and the structural parameters were in excellent agreement with the experimental data.

Studies have suggested that sirtuin inhibition may have beneficial effects on several age-related diseases such as neurodegenerative disorders and cancer. Garcinia mangostana is a well-known tropical plant found mostly in South East Asia with several positive health effects. Some of its phytochemicals such as α-mangostin was found to be able to modulate sirtuin activity in mice and was implicated with inflammation, diabetes and obesity. However, comprehensive studies on sirtuin activity by the prenylated xanthones extracted from Garcinia mangostana have yet to be reported. The present study led to the discovery and identification of γ-mangostin as a potent and selective SIRT2 inhibitor. It was demonstrated that γ-mangostin was able to increase the α-tubulin acetylation in MDA-MD-231 and MCF-7 breast cancer cells. It was also found to possess potent antiproliferative activity against both cell lines. In addition, it was able to induce neurite outgrowth in the N2a cells.

(E)-N-Benzylidenepicolinohydrazide (Hbphz) was used to synthesize a series of hydrazonato-bridged homodinuclear Ln(2)(III) dithiocarbamato (RR'dtc(-)) complexes of the form [{Ln(RR' dtc)(2)}(2)(mu-bphz)(2)] {Ln= La, Pr, Nd, Sm or Eu; RR'= dimethyl-(Me-2) or pyrrolidine-(pyr)}. X-ray crystallographic studies revealed that these complexes possessed a common head-to-tail type dinuclear structural motif in which two hydrazonato ligands bridged two Ln(III) centers in the mu- 1 kappa N-2(py),O:2 kappa O-2,N(imine) mode and two RR'dtc ligands coordinated to each Ln(III) center. Interestingly, while the Sm-III and Eu-III complexes crystallized as simple 8:8-coordinate dinuclear molecules, the lighter Ln(III) (i.e. La-III, Pr-III and Nd-III) complexes afforded in some cases 9:9-coordinate molecules, where the ninth coordination site was occupied by a solvent ethanol or methanol molecule. Even for the lighter Ln(III) complexes, the complexes were solved in dichloromethane or chloroform as the 8:8-coordinate dimer, as revealed by H-1 NMR spectroscopy. In the UV-visible absorption and magnetic circular dichroism (MCD) spectra of the complexes, similar spectral patterns for ligand-centered and Laporte forbidden f-f transitions were observed. The MCD spectral studies demonstrated the characteristic magneto-optical behavior of the complexes.

Oxidation of a blue ethanolic mixture containing Co(BF4)2·6H2O and PClPh2 by tetramethylthiuram disulfide afforded a red-colored complex having a cis-[CoIII(Me2dtc)2(P)2] environment (Me2dtc− = N,N-dimethyldithiocarbamate), although the yield was relatively low. Single-crystal X-ray crystallography revealed that the product was [Co(Me2dtc)2{(Ph2PO)2BF2}] (1), where bis(diphenylphosphinito)difluoroborate was probably formed by hydrolysis of PClPh2 followed by reaction with BF4− in ethanol. The same complex was also prepared by hydrolysis of cis-[Co(Me2dtc)2(PHPh2)2]BF4 in a mixture of acetonitrile, methanol and water. The molecular structure and spectroscopic properties of complex 1 were compared with those of the corresponding Ph2POMe complex, cis-[Co(Me2dtc)2(Ph2POMe)2]BF4.

Ruthenium(II) complexes with the general formulas [Ru(H/Cl)(CO)(PPh3)2(L)] and cis/trans-[Ru(PPh3)2(L)2] (L = isoquinoline-1-carboxylate or quinoline-2-carboxylate) were synthesized and characterized by IR, 1H, 13C and 31P NMR, UV–Vis spectroscopy and X-ray crystallography. The experimental studies were completed by quantum chemical calculations, which were used to describe the nature of the interactions between the ligands and the central ion, and the orbital compositions in the frontier electronic structures. Based on a molecular orbital scheme, the calculated results allowed the interpretation of the UV–Vis spectra obtained at an experimental level. The luminescence properties of the complexes were determined.

We have measured the 16O(p, d) reaction using 198-, 295- and 392-MeV proton beams to search for a direct evidence on an effect of the tensor interactions in light nucleus. Differential cross sections of the one-neutron transfer reaction populating the ground states and several low-lying excited states in 15O were measured. Comparing the ratios of the cross sections for each excited state to the one for the ground state over a wide range of momentum transfer, we found a marked enhancement of the ratio for the positive-parity state(s). The observation is consistent with large components of high-momentum neutrons in the initial ground-state configurations due to the tensor interactions.

Syntheses and biological evaluation of novel SRT1720 derivatives are described in search for new candidates of SIRT1 activator. Several parts of the SRT1720 structure, including piperazine moiety, quinoxaline ring on the amide group, and position of the amide function, were modified, and the assay results indicated that transfer of the ortho amide-substituent regarding to the imidazo[1,2-b]thiazole core onto the meta position resulted in improvement of SIRT1 activation ability. Modeling analyses of SRT1720 and the most potent derivative bound to model complex of SIRT1 with peptide substrate were also performed.

X-ray crystal structure analysis and quantum chemical calculations based on density functional theory (DFT) were used for structural and electronic characterizations of two 1,2,3,4-tetrahydropyrimidine derivatives (THPMs), namely, ethyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1) and methyl 4-(4-bromophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2). The results of these studies revealed that the heterocyclic ring adopts a quasi-boat conformation, in which the 4-aryl group occupies the pseudo-axial position. The occurrence of the C4-stereocenter in the heterocyclic ring causes the formation of both R- and S-enantiomers. X-ray diffraction technique indicates that both compounds exist as a racemic mixture in the crystal structure and the enantiomers are orientated to each other via hydrogen bonding between N3 H as donor and the C2 S or C2 O groups as acceptor species, in each layer under formation of an enantio-syndio packing. Most computational bond lengths and angles are well in agreement with experimental data, and support the pseudo-axial orientation of the C4-aryl substitution.

Summary Chemical biology is not a new discipline, as research at the interface of chemistry and biology has been growing for decades. However, the field still needs regional and global support in emerging countries. The meeting organized by Asian Chemical Biology Initiative in Bangkok, Thailand in January 2013, brought together regional communities of young and established researchers to nurture chemical biology research programs and highlight some of the newer developments. Here, we report on the meeting and some of the key research topics discussed.

Four cobalt(III) complexes with the formula of [Co(Ln)2]− bearing tridentate amine-amidato-phenolato-type ligands (Ln: n = 1–4) were synthesized. All of the complexes were characterized by 1H NMR spectroscopy and X-ray analysis. The geometrical selectivity was found to depend on the flexibility of the amine-amidato chelate in combination with the planar 2-oxybenzamido 6-membered chelate; that is, the amine-amidato 5-membered chelate took the mer-type geometry, and the 6-membered chelate took the fac-type geometry. In most of the mer-type complexes, intermolecular double hydrogen bonds via amidato(O) and amino group were selectively formed between their enantiomeric pairs of mononuclear complexes. In the case of two chiral ligands {L22– = 2-amino-1-(2-oxybenzamido)propane; L32− = trans-1-amino-2-(2-oxybenzamido)cyclohexane}, [Co(L3)2]− showed diastereoselectivity while [Co(L2)2]− did not. Furthermore, PPh4[Co(L1)2] (L12− = 2-amino-1-(2-oxybenzamido)-2-methylpropane) showed an apparent solvatochromic behavior in several solvents. Although the molecular structures of [Co(L2 or L3)2]− are quite similar to that of [Co(L1)2]−, these complexes did not exhibit such a solvatochromic behavior.

Recent studies have shown that nitroxyl (HNO) (1HNO/3NO−), which is the one-electron-reduced form of nitric oxide (NO), has unique biological activities, especially in the cardiovascular system, and HNO-releasing agents may have therapeutic potential. Since few HNO donors are available for use under physiological conditions, we synthesized and evaluated a series of Piloty’s acid (PA) derivatives and evaluated their HNO-releasing activity under physiological conditions. N-Hydroxy-2-nitrobenzenesulfonamide (17) was the most efficient HNO donor among our synthesized PA derivatives, including the lead compound, 2-bromo-N-hydroxybenzenesulfonamide (2). The high HNO-releasing activity is suggested to be due to electronic and steric effects. Compound 17 may be a useful tool for biological experiments.

Computational and spectroscopic properties of a novel Schiff base compound, 3-hydroxy-4-methoxybenzylidene(2-hydroxyphenyl)amine were studied. The crystal structures of the title compound and its corresponding zwitterionic form were analyzed by X-ray diffraction. The presence of N-H, C-O and C=N stretching vibrations in IR spectrum strongly suggest that the title compound has zwitterionic form in the solid state. Molecular geometry of the title compound in the ground state has been calculated using the density functional method (DFT) at B3LYP 6-31++G(d,p) basis set and was compared with the experimental data. The calculated results of the title compound show that the optimized geometry can well reproduce the crystal structure. The molecule shows absorption bands at 345 and 363 nm in EtOH. The shoulder-shaped bands at 415 nm can be assigned to n→π(*) transitions. The absorption band is observed at 285 nm in EtOH corresponds to the π→π(*) transitions.

The presence of NO can be detected by circular dichroism (CD) spectroscopy, which is based on an asymmetric transformation in tris(dithiocarbamato)iron(II) complex. The complex [Fe(S-proOHdtc)3]4− {S-proOHdtc2− = 1-dithiocarboxyl-4-hydroxy-S-proline(2−)} in methanol shows a large negative CD peak at 600 nm. It suggests that, in the epimerization equilibrium between Δ(S,S,S) and Λ(S,S,S), the Δ(S,S,S) complex is predominant species in methanol. The reaction of NO with Δ(S,S,S)-[Fe(S-proOHdtc)3]4− in methanol shows a decrease of the negative CD peak at 600 nm. This phenomenon of the CD peak decrease shows the NO presence and it can be used for the detection of NO.

X-ray crystallographic analyses revealed that the Pd–P and Pd–X bond lengths of [PdX2(P–P)] complexes (X− = Cl, Br and I and P–P = Ph2P(CH2)nPPh2; n = 1: dppm, 2: dppe, 3: dppp, 4: dppb) are: Pd–P (dppm, dppe) Pd–X (dppp, dppb). The oxidation potentials values, E½(ox), of the shorter Pd–P and longer Pd–X bond lengths in the dppm and dppe complexes are high and reflect strong dxy (dπ (Pd)) interaction with d x 2 - y 2 (dσ∗ (Pd)) and that this interaction is less dependent on X−. The longer Pd–P and shorter Pd–X bonds for the dppp and dppb complexes reflect that the d x 2 - y 2 (dσ∗ (Pd)) interaction is largely dependent on X−. The reduction potential, E½(red), which reflects the d x 2 - y 2 (dσ∗ (Pd) LUMO energy, and the oxidation potential, E½(ox), which reflects the (dxy (dπ (Pd) HOMO energy were, determined. The E½(red) and E½(ox) values indicate the σ-bonding properties and π-interaction in the system, respectively. Good linear relationships were observed between the potentials difference [E½(ox) − E½(red)] and the ligand-field transition energy (dπ (dxy) → dσ∗ ( d x 2 - y 2 )) in the series of dihalogenopalladium(II) complexes. The linear relationship shows that the energies of the d–d transitions and ΔE(Redox) of the dppm and dppe complexes are less dependent on X− whilst those of the dppp and dppb are largely X− dependent.

New metal complexes with N , N -diacetatodithiocarbamate (Ac 2 dtc 3− ), Na 6 [Co(Ac 2 dtc) 3 ], Ba 3 [Co(Ac 2 dtc) 3 ], Na 4 [Ni(Ac 2 dtc) 2 ], Ba 2 [Ni(Ac 2 dtc) 2 ], Na 4 [Cu(Ac 2 dtc) 2 ] and Ba 2 [Cu(Ac 2 dtc) 2 ], have been synthesized, and their molecular structures and spectroscopic properties have been characterized. The X-ray analysis of Ba 3 [Co(Ac 2 dtc) 3 ]·16H 2 O confirmed a well-organized and rigid network among carboxyl groups of the complex anions, barium cations, and water molecules.

The general aim of the present study is to discriminate between mouse genotoxic and non-genotoxic hepatocarcinogens via selected gene expression patterns in the liver as analyzed by quantitative real-time PCR (qPCR) and statistical analysis. qPCR was conducted on liver samples from groups of 5 male, 9-week-old B6C3F(1) mice, at 4 and 48h following a single intraperitoneal administration of chemicals. We quantified 35 genes selected from our previous DNA microarray studies using 12 different chemicals: 8 genotoxic hepatocarcinogens (2-acetylaminofluorene, 2,4-diaminotoluene, diisopropanolnitrosamine, 4-dimethylaminoazobenzene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, N-nitrosomorpholine, quinoline and urethane) and 4 non-genotoxic hepatocarcinogens (1,4-dichlorobenzene, dichlorodiphenyltrichloroethane, di(2-ethylhexyl)phthalate and furan). A considerable number of genes exhibited significant changes in their gene expression ratios (experimental group/control group) analyzed statistically by the Dunnett's test and Welch's t-test. Finally, we distinguished between the genotoxic and non-genotoxic hepatocarcinogens by statistical analysis using principal component analysis (PCA) of the gene expression profiles for 7 genes (Btg2, Ccnf, Ccng1, Lpr1, Mbd1, Phlda3 and Tubb2c) at 4h and for 12 genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2 and Tubb2c) at 48h. Seven major biological processes were extracted from the gene ontology analysis: apoptosis, the cell cycle, cell proliferation, DNA damage, DNA repair, oncogenes and tumor suppression. The major, biologically relevant gene pathway suggested was the DNA damage response pathway, resulting from signal transduction by a p53-class mediator leading to the induction of apoptosis. Eight genes (Aen, Bax, Btg2, Ccng1, Cdkn1a, Gdf15, Phlda3 and Plk2) that are directly associated with Trp53 contributed to the PCA. The current findings demonstrate a successful discrimination between genotoxic and non-genotoxic hepatocarcinogens, using qPCR and PCA, on 12 genes associated with a Trp53-mediated signaling pathway for DNA damage response at 4 and 48 h after a single administration of chemicals.

HL60RG, a subline of human promyelocytic leukemia HL60 cells, has a increased growth rate than their parental cells. To gain information of the mechanisms involved in the increased growth rate of HL60RG, we performed a multiplex fluorescence in situ hybridization (M-FISH), standard cytogenetics analysis (G-banding) and genome scan using 10K SNP mapping array on both cell types. Characteristic genomic alterations in HL60RG cells were identified including uniparental disomy (UPD) of chromosome 1, and hemizygous deletion in 10p and 11p. However, no such defects were observed in HL60 cells. Changes in gene expression in HL60RG cells were determined using expression arrays (Affymetrix GeneChip, HU133A). Candidate genes associated with the rapid growth of HL60RG cells were identified. Two tumor necrosis factor receptors, TNFRSF1B (type II tumor necrosis factor-α receptor) and TNFRSF8 (also known as a tumor marker CD30), which are adjacently located on chromosome 1 showed opposing changes in gene expression in HL60RG cells—over-expression of TNFRSF8 and repression of TNFRSF1B. Differences in the DNA methylation status in the transcriptional regulatory regions of both genes between HL60 and HL60RG was detected by a methylation-specific PCR assay. In conclusion, alterations in chromosome and gene expression in HL60RG may be associated with increased growth rate.

Nuclear oxidative stress damages genomic DNA and may lead to cell death, leading to aging and aging-related disorders. Though it is important to measure the nuclear oxidative stress separately, there are still little examples that applicable to living cells. We have designed and synthesized three bisbenzimide-nitroxides as probes to selectively visualize nuclear redox changes in terms of fluorescence. Compound 3, containing two radical moieties, showed the largest reduction-induced fluorescence change, with good localization in nuclei. RAW264.7 murine macrophage cells were loaded with compound 3 and then treated with 100μM hydrogen peroxide for 5min to show the fluorescence increase. This fluorescence increase was inhibited by pretreatment of 1mM ascorbic acid. These results show that compound 3 was suitable for nuclear-specific redox imaging in murine macrophages.

A 71Ga(3He, t)71Ge charge-exchange experiment was performed to extract with high precision the Gamow–Teller (GT) transition strengths to the three lowest-lying states in 71Ge, i.e., the ground state ( 1 / 2 − ) , the 175 keV ( 5 / 2 − ) and the 500 keV ( 3 / 2 − ) excited states. These are the relevant states, which are populated via a charged-current reaction induced by neutrinos from reactor-produced 51Cr and 37Ar sources. A precise measurement of the GT transition strengths is an important input into the calibration of the SAGE and GALLEX solar neutrino detectors and addresses a long-standing discrepancy between the measured and evaluated capture rates from the 51Cr and 37Ar neutrino calibration sources, which has recently spawned new ideas about unconventional neutrino properties.

Mononuclear Mn(III) complexes have been prepared via the Mn(II) reaction of an equimolar of Schiff-bases derived from reaction of 2-hydroxy-3-methoxybenzaldehyde or 2-hydroxy-5-methoxybenzaldehyde with 1,2-diaminopropane. Axial ligands L include: pyridine (py) and H(2)O. The resulting complexes have been characterized by FT-IR and UV-vis spectroscopy. The crystal structures of the complexes were determined and indicate that in the solid state the complex adopts a slightly distorted octahedral environment of the imine N and hydroxo O with the two axial ligands. The electrochemical reduction of these complexes at a glassy carbon electrode in acetonitrile solution indicates that the first reduction process corresponding to Mn(III)-Mn(II) is electrochemically quasi-reversible. Thermal stability of these complexes was determined by TG and DTG. Layers of these complexes were formed on nanostructure zinc oxide thin film and a red shift was observed when zinc oxide thin film is modified by complex.