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The large‐conductance Ca2+‐activated K+ channel KCa1.1 plays a pivotal role in tumor development and progression in several solid cancers. The three‐dimensional (3D) in vitro cell culture system is a powerful tool for cancer spheroid formation, and mimics in vivo solid tumor resistance to chemotherapy in the tumor microenvironment (TME). KCa1.1 is functionally expressed in osteosarcoma and chondrosarcoma cell lines. KCa1.1 activator‐induced hyperpolarizing responses were significantly larger in human osteosarcoma MG‐63 cells isolated from 3D spheroid models compared with in those from adherent 2D monolayer cells. The present study investigated the mechanisms underlying the upregulation of KCa1.1 and its role in chemoresistance using a 3D spheroid model. KCa1.1 protein expression levels were significantly elevated in the lipid‐raft‐enriched compartments of MG‐63 spheroids without changes in its transcriptional level. 3D spheroid formation downregulated the expression of the ubiquitin E3 ligase FBXW7, which is an essential contributor to KCa1.1 protein degradation in breast cancer. The siRNA‐mediated inhibition of FBXW7 in MG‐63 cells from 2D monolayers upregulated KCa1.1 protein expression. Furthermore, a treatment with a potent and selective KCa1.1 inhibitor overcame the chemoresistance of the MG‐63 and human chondrosarcoma SW‐1353 spheroid models to paclitaxel, doxorubicin, and cisplatin. Among several multidrug resistance ATP‐binding cassette transporters, the expression of the multidrug resistance‐associated protein MRP1 was upregulated in both spheroids and restored by the inhibition of KCa1.1. Therefore, the pharmacological inhibition of KCa1.1 may be an attractive new strategy for acquiring resistance to chemotherapeutic drugs in the TME of KCa1.1‐positive sarcomas., The inhibition of large‐conductance Ca2+‐activated K+ channel KCa1.1 may be a promising therapeutic strategy for reversing chemoresistance in human sarcomas.

RNAs are involved in an enormous range of cellular processes, including gene regulation, protein synthesis, and cell differentiation, and dysfunctional RNAs are associated with disorders such as cancers, neurodegenerative diseases, and viral infections. Thus, the identification of compounds with the ability to bind RNAs and modulate their functions is an exciting approach for developing next-generation therapies. Numerous RNA-binding agents have been reported over the past decade, but the design of synthetic molecules with selectivity for specific RNA sequences is still in its infancy. In this perspective, we highlight recent advances in targeting RNAs with synthetic molecules, and we discuss the potential value of this approach for the development of innovative therapeutic agents.

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.

The first successful example of a catalytic enantioselective intramolecular Tishchenko reaction of a meso-dialdehyde in the presence of a chiral iridium complex is described. Chiral lactones were obtained in good yields with up to 91% ee. The obtained enantioenriched lactones were utilized for the first synthesis of (S)-cedarmycins A and B.

The crystal structures of the complexes (SP-4-2)-cis-bis[8-(dimethylphosphanyl)quinoline-κ2 N,P]nickel(II) bis(perchlorate) nitromethane monosolvate, [Ni(C11H12NP)2](ClO4)2·CH3NO2 (1), and (SP-4-2)-cis-bis[8-(dimethylphosphanyl)quinoline-κ2 N,P]platinum(II) bis(tetrafluoroborate) acetonitrile monosolvate, [Pt(C11H12NP)2](BF4)2·C2H3N (2), are reported. In both complex cations, two phosphanylquinolines act as bidentate P,N-donating chelate ligands and form the mutually cis configuration in the square-planar coordination geometry. The strong trans influence of the dimethylphosphanyl donor group is confirmed by the Ni—N bond lengths in 1, 1.970 (2) and 1.982 (2) Å and, the Pt—N bond lengths of 2, 2.123 (4) and 2.132 (4) Å, which are relatively long as compared to those in the analogous 8-(diphenylphosphanyl)quinoline complexes. Mutually cis-positioned quinoline donor groups would give a severe steric hindrance between their ortho-H atoms. In order to reduce such a steric congestion, the NiII complex in 1 shows a tetrahedral distortion of the coordination geometry, as parameterized by τ4 = 0.199 (1)°, while the PtII complex in 2 exhibits a typical square-planar coordination geometry [τ4 = 0.014 (1)°] with a large bending deformation of the ideally planar Me2Pqn chelate planes. In the crystal structure of 2, three F atoms of one of the BF4 − anions are disordered over two sets of positions with refined occupancies of 0.573 (10) and 0.427 (10).

Cancer stem cells (CSCs) are highly tumorigenic, spared by chemotherapy, sustain tumor growth, and are implicated in tumor recurrence after conventional therapies in triple negative breast cancer (TNBC). Lysine-specific histone demethylase 1A (KDM1A) is highly expressed in several human malignancies and CSCs including TNBC. However, the precise mechanistic role of KDM1A in CSC functions and therapeutic utility of KDM1A inhibitor for treating TNBC is poorly understood. The effect of KDM1A inhibition on cell viability, apoptosis, and invasion were examined by Cell Titer Glo, Caspase 3/7 Glo, and matrigel invasion assays, respectively. Stemness and self-renewal of CSCs were examined using mammosphere formation and extreme limiting dilution assays. Mechanistic studies were conducted using RNA-sequencing, RT-qPCR, Western blotting and reporter gene assays. Mouse xenograft and patient derived xenograft models were used for preclinical evaluation of KDM1A inhibitor. TCGA data sets indicated that KDM1A is highly expressed in TNBC. CSCs express high levels of KDM1A and inhibition of KDM1A reduced the CSCs enrichment in TNBC cells. KDM1A inhibition reduced cell viability, mammosphere formation, self-renewal and promoted apoptosis of CSCs. Mechanistic studies suggested that IL6-JAK-STAT3 and EMT pathways were downregulated in KDM1A knockdown and KDM1A inhibitor treated cells. Importantly, doxycycline inducible knockout of KDM1A reduced tumor progression in orthotopic xenograft models and KDM1A inhibitor NCD38 treatment significantly reduced tumor growth in patient derived xenograft (PDX) models. Our results establish that KDM1A inhibition mitigates CSCs functions via inhibition of STAT3 and EMT signaling, and KDM1A inhibitor NCD38 may represent a novel class of drug for treating TNBC.

The maturity of osteoblasts by proliferation and differentiation in preosteoblasts is essential for maintaining bone homeostasis. The beneficial effects of vitamin D on bone homeostasis in mammals have been demonstrated experimentally and clinically. However, the direct actions of vitamin D on preosteoblasts remain to be fully elucidated. In this study, we found that the functional activity of intermediate-conductance Ca2+-activated K+ channels (KCa3.1) positively regulated cell proliferation in MC3T3-E1 cells derived from mouse preosteoblasts by enhancing intracellular Ca2+ signaling. We examined the effects of treatment with vitamin D receptor (VDR) agonist on the expression and activity of KCa3.1 by real-time PCR examination, Western blotting, Ca2+ imaging, and patch clamp analyses in mouse MC3T3-E1 cells. Following the downregulation of KCa3.1 transcriptional modulators such as Fra-1 and HDAC2, KCa3.1 activity was suppressed in MC3T3-E1 cells treated with VDR agonists. Furthermore, application of the KCa3.1 activator DCEBIO attenuated the VDR agonist-evoked suppression of cell proliferation rate. These findings suggest that a decrease in KCa3.1 activity is involved in the suppression of cell proliferation rate in VDR agonist-treated preosteoblasts. Therefore, KCa3.1 plays an important role in bone formation by promoting osteoblastic proliferation under physiological conditions.

Background Recent studies have shown that epigenetic alterations, such as those involving lysine‐specific demethylase 1 (LSD1), lead to oncogenic activation and highlight such alterations as therapeutic targets. However, studies evaluating the effect of LSD1 inhibitors on male fertility are lacking. Objectives We analyzed the potential toxicity of a new selective LSD1 inhibitor, N‐[(1S)‐3‐[3‐(trans‐2‐aminocyclopropyl)phenoxy]‐1‐(benzylcarbamoyl)propyl] benzamide (NCL1), in testes. Materials and methods Human testicular samples were immunohistochemically analyzed. Six‐week‐old male C57BL/6J mice were injected intraperitoneally with dimethyl sulfoxide vehicle (n = 15), or 1.0 (n = 15) or 3.0 (n = 15) mg/kg NCL1 biweekly. After five weeks, toxicity and gene expression were analyzed in testicular samples by ingenuity pathway analysis (IPA) using RNA sequence data and quantitative reverse transcriptase (qRT)–PCR; hormonal damage was analyzed in blood samples. NCL1 treated GC‐1, TM3, and TM4 cell lines were analyzed by cell viability, chromatin immunoprecipitation, flow cytometry, and Western blot assays. Results LSD1 was mainly expressed in human Sertoli and germ cells, with LSD1 levels significantly decreased in a progressive meiosis‐dependent manner; germ cells showed similar expression patterns in normal spermatogenesis and early/late maturation arrest. Histological examination revealed significantly increased levels of abnormal seminiferous tubules in 3.0 mg/kg NCL1–treated mice compared to control, with increased cellular detachment, sloughing, vacuolization, eosinophilic changes, and TUNEL‐positive cells. IPA and qRT–PCR revealed NCL1 treatment down‐regulated LSD1 activity. NCL1 also reduced total serum testosterone levels. Western blots of mouse testicular samples revealed NCL1 induced a marked elevation in cleaved caspases 3, 7, and 8, and connexin 43 proteins. NCL1 treatment significantly reduced GC‐1, but not TM3 and TM4, cell viability in a dose‐dependent manner. In flow cytometry analysis, NCL1 induced apoptosis in GC‐1 cells. Conclusions High‐dose NCL1 treatment targeting LSD1 caused dysfunctional spermatogenesis and induced caspase‐dependent apoptosis. This suggests the LSD1 inhibitor may cause testicular toxicity via the regulation of apoptosis.

Background/Aims: Intestinal fibrosis is a major complication of Crohn’s disease (CD). The profibrotic protein transforming growth factor-β (TGF-β) has been considered to be critical for the induction of the fibrotic program. TGF-β has the ability to induce not only the expression of extracellular matrix (ECM) including collagen, but also the production of plasminogen activator inhibitor-1 (PAI-1) that prevents enzymatic degradation of the ECM during the onset of fibrotic diseases. However, the significance of PAI-1 in the developing intestinal fibrosis has not been fully understood. In the present study, we examined the actual expression of PAI-1 in fibrotic legion of intestinal inflammation and its correlation with the abnormal ECM deposition.Methods: Chronic intestinal inflammation was induced in BALB/c mice using 8 repeated intrarectal injections of 2,4,6-trinitrobenzene sulfonic acid (TNBS). TM5275, a PAI-1 inhibitor, was orally administered as a carboxymethyl cellulose suspension each day for 2 weeks after the sixth TNBS injection.Results: Using a publicly available dataset (accession number, GSE75214) and TNBS-treated mice, we observed increases in PAI-1 transcripts at active fibrotic lesions in both patients with CD and mice with chronic intestinal inflammation. Oral administration of TM5275 immediately after the onset of intestinal fibrosis upregulated MMP-9 (matrix metalloproteinase 9) and decreased collagen accumulation, resulting in attenuation of the fibrogenesis in TNBS-treated mice.Conclusions: PAI-1-mediated fibrinolytic system facilitates collagen degradation suppression. Hence, PAI-1 inhibitor could be applied as an anti-fibrotic drug in CD treatment.

In situ click chemistry has great potential for identifying enzyme inhibitors. However, conventional in situ click chemistry provides extremely low yields of the products, making it incompatible wi...

Dinuclear complex, [Fe2(H2L1,Me)3](ClO4)4 (1Me, H2L1,Me = N,N′-(1,3-phenylene)bis(1-(5-methyl-1H-imidazol-4-yl)methanimine)), and octanuclear complexes, [Fe8(H2L2,H)12](ClO4)16 (2HClO4: H2L2,H = N,...

Fat mass obesity-associated protein (FTO) is a DNA/RNA demethylase involved in the epigenetic regulation of various genes and is considered a therapeutic target for obesity, cancer, and neurological disorders. Here, we aimed to design novel FTO-selective inhibitors by merging fragments of previously reported FTO inhibitors. Among the synthesized analogues, compound 11b, which merges key fragments of Hz (3) and MA (4), inhibited FTO selectively over alkylation repair homologue 5 (ALKBH5), another DNA/RNA demethylase. Treatment of acute monocytic leukemia NOMO-1 cells with a prodrug of 11b decreased the viability of acute monocytic leukemia cells, increased the level of the FTO substrate N6-methyladenosine in mRNA, and induced upregulation of MYC and downregulation of RARA, which are FTO target genes. Thus, Hz (3)/MA (4) hybrid analogues represent an entry into a new class of FTO-selective inhibitors.

Crystal structures and crystallisation behaviours of a series of first-row transition-metal(II) complexes bearing 1,1,1-tris[2-aza-3-(imidazol-4-yl)prop-2-enyl]ethane (H3L), [MII(H3L)]Cl(ClO4) (M = Mn, Fe, Co, Ni and Zn) were examined. These compounds crystallise in an orthorhombic crystal system with a non-enantiogenic (Sohncke) space group P212121, resulting in spontaneous resolution of the chiral complex cations. Hydrogen bonds between the imidazole N–H atoms in the tripodal ligand and chloride anions give enantiomorphic crystals with a homochiral three-dimensional network structure. In order to verify the spontaneous resolution of these compounds, solid-state circular dichroism spectra of the resulting single crystals were measured (KBr disk method). Unexpectedly, the observed spectra indicated that imbalanced formation of the enantiomorphic crystals (i.e., left-handed Λ-form vs. right-handed Δ-form complex cations) in all cases. Moreover, in the cases of NiII and ZnII compounds, predominant enantiomorphic crystals formed by spontaneous resolution were always the same (in at least ten of our recrystallisation experiments). These observations suggest that there is a certain (but as yet unknown) factor that affects the predominant deposition of either enantiomorphic crystal when spontaneous resolution takes place from a solution of a racemic mixture in which rapid racemisation occurs.

Methyl transfer reactions play important roles in many biological phenomena, wherein the methylation cofactor S-adenosyl-l-methionine (SAM) serves as the important currency to orchestrate those reactions. We have developed a fluorescent-probe-based high-throughput screening (HTS) system to search for the compounds that control cellular SAM levels. HTS with a drug repositioning library revealed the importance of catechol-O-methyltransferase (COMT) and its substrates in controlling the SAM concentrations and histone methylation levels in colorectal tumor cells.

Purpose The present study aims to develop a forensic toxicological library to identify 56 natural toxic substances by liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (LC–QTOF-MS/MS). Methods For setting up the library of product ion spectra, individual substances (31 plant toxins, 7 mushroom toxins, 5 marine toxins, 5 frog venoms, 4 mycotoxins, and 4 substances derived from plants) were analyzed by LC–QTOF-MS/MS with positive and negative ionization. The product ion spectra were acquired at the collision energies (CEs) of 20, 35, and 50 eV in single enhanced product ion mode and then in collision energy spread mode in which the CE ramp range was set to 35 ± 15 eV. Results To test the performance of the library, human blood plasma samples were spiked with a mixture of lycorine and domoic acid, extracted by acetonitrile deproteinization and analyzed by LC–QTOF-MS/MS. Identification by our library search could be achieved for these toxins at the purity scores of 79.1 and 67.2, respectively. The method was also applied to postmortem blood from a death case with an aconite intake, and showed that four toxins in an aconite could be identified in the blood sample at the purity scores of 54.6–60.3. Conclusions This library will be more effective for the screening of natural toxic substances in routine forensic toxicological analysis. To our knowledge, there are no reports dealing with development of library for natural toxic substances by LC–QTOF-MS/MS.

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.

The NAD+-dependent deacetylase SIRT2 represents an attractive target for drug development. Here, we designed and synthesized drug-like SIRT2-selective inhibitors based on an analysis of the putative binding modes of recently reported SIRT2-selective inhibitors and evaluated their SIRT2-inhibitory activity. This led us to develop a more drug-like diketopiperazine structure as a "hydrogen bond (H-bond) hunter" to target the substrate-binding site of SIRT2. Thioamide 53, a conjugate of diketopiperazine and 2-anilinobenzamide which is expected to occupy the "selectivity pocket" of SIRT2, exhibited potent SIRT2-selective inhibition. Inhibition of SIRT2 by 53 was mediated by the formation of a 53-ADP-ribose conjugate, suggesting that 53 is a mechanism-based inhibitor targeting the "selectivity pocket", substrate-binding site, and NAD+-binding site. Furthermore, 53 showed potent antiproliferative activity toward breast cancer cells and promoted neurite outgrowth of Neuro-2a cells. These findings should pave the way for the discovery of novel therapeutic agents for cancer and neurological disorders.

Photosynthetic water oxidation is catalyzed by a Mn4CaO5-cluster in photosystem II through an S-state cycle. Understanding the roles of heterogeneity in each S-state, as identified recently by the EPR spectroscopy, is very important to gain a complete description of the catalytic mechanism. We performed herein hybrid DFT calculations within the broken-symmetry formalism and associated analyses of Heisenberg spin models to study the electronic and spin structures of various isomeric structural motifs (hydroxo–oxo, oxyl–oxo, peroxo, and superoxo species) in the S3 state. Our extensive study reveals several factors that affect the spin ground state: (1) (formal) Mn oxidation state; (2) metal–ligand covalency; (3) coordination geometry; and (4) structural change of the Mn cluster induced by alternations in Mn···Mn distances. Some combination of these effects could selectively stabilize/destabilize some spin states. We found that the high spin state (Stotal = 6) of the oxyl–oxo species can be causative for cat...

Prodrug approaches are useful for enhancing the efficacies and reducing the side effects of anticancer drugs. Previously, we proposed a prodrug strategy for targeting cancers overexpressing lysine-specific demethylase 1 (LSD1), namely, conjugates of trans-2-phenylcyclopropylamine (PCPA, an LSD1 inhibitor) and anticancer drugs. In this study, we applied this prodrug strategy to the anticancer agent 5-fluorouracil (5-FU). In vitro assays showed that the PCPA-5-FU conjugate (1) released 5-FU upon the inhibition of LSD1. Furthermore, the conjugate (1) exerted an antiproliferative effect on colon cancer HCT116 cells. Thus, the PCPA-5-FU conjugate (1) was able to function as a prodrug of 5-FU, activated by LSD1 inhibition, and provided a useful new lead structure for further development.

Pharmacological inhibition of histone deacetylase 6 (HDAC6) is an effective therapeutic strategy for cancer and immunological diseases. Most of the previously reported HDAC6 inhibitors have a hydroxamate group as a zinc binding group (ZBG), which coordinates to the catalytic zinc ion of HDAC6. The hydroxamate group is liable to metabolically generate mutagenetic hydroxylamine; therefore, non-hydroxamate HDAC6 inhibitors would be advantageous. In this study, to identify novel non-hydroxamate HDAC6-selective inhibitors, screening of a chemical library and the subsequent structural optimization were performed, which led to the identification of HDAC6-selective inhibitors with 3,3,3-trifluorolactic amide (TFLAM) as a novel ZBG. The identified inhibitor showed potent and selective HDAC6-inhibitory activity in cells and induced regulatory T (Treg) cell differentiation.

Endometrial cancer (EC) often exhibit aberrant activation of PI3K/Akt/mTOR signaling and targeted therapies using mTOR inhibitors showed limited success. The epigenetic modifier, lysine-specific histone demethylase-1A (KDM1A/LSD1) is overexpressed in EC, however, the mechanistic and therapeutic implications of KDM1A in EC are poorly understood. Here, using 119 FDA-approved drugs screen, we identified that KDM1A inhibition is highly synergistic with mTOR inhibitors. Combination therapy of KDM1A and mTOR inhibitors potently reduced the cell viability, survival, and migration of EC cells. Mechanistic studies demonstrated that KDM1A inhibition attenuated the activation of mTOR signaling cascade and abolished rapamycin induced feedback activation of Akt. RNA-seq analysis identified that KDM1A inhibition downregulated the expression of genes involved in rapamycin induced activation of Akt, including the mTORC2 complex. Chromatin immunoprecipitation experiments confirmed KDM1A recruitment to the promoter regions of mTORC2 complex genes and that KDM1A inhibition promoted enrichment of repressive H3K9me2 marks at their promoters. Combination therapy of KDM1A inhibitor and rapamycin reduced the tumor growth in EC xenograft and patient derived xenograft models in vivo and patient derived tumor explants ex vivo. Importantly, in silico analysis of TCGA EC patients data sets revealed that KDM1A expression positively correlated with the levels of PI3K/Akt/mTOR genes. Collectively, our results provide compelling evidence that KDM1A inhibition potentiates the activity of mTOR inhibitors by attenuating the feedback activation of Akt survival signaling. Furthermore, the use of concurrent KDM1A and mTOR inhibitors may be an attractive targeted therapy for EC patients.

Endothelial cell (EC) dysfunction is the underlying cause for the development of several pathologies, and the interdependency between the pancreatic β-cells and ECs has been established in the pathophysiology of diabetes. ECs release several factors that govern the expression of genes involved in the proliferation, physiology, and survival of the β-cells. Of the known factors that collapse this intricately balanced system, endothelial dysfunction is the crucial condition that manifests as the causative factor for micro and macrovascular diseases. Our earlier studies demonstrated that activation of nuclear factor erythroid-related factor (Nrf2) renders protection to the ECs experiencing ER stress. In this study, using a co-culture system, the crosstalk between pancreatic cells under ER stress and ECs and the effect of a novel Nrf2 activator Rosolic Acid (RA), on the crosstalk was investigated. ECs pre-treated with different concentrations RA and co-cultured with thapsigargin-induced ER stressed pancreatic β-cells showed increased levels of Nrf2 and its downstream targets such as heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1), and reduction of ER stress evinced by the decreased levels of glucose-regulated protein (GRP) 78 and C/ERB homologous protein (CHOP). The sensitization of ECs using RA, offered protection to pancreatic cells against ER stress as displayed by increased intracellular insulin and upregulated expression of cell survival and proliferative genes BCl2 and PDX-1. In addition, RA treatment resulted in elevated levels of various angiogenic factors, while inflammatory (TNF-α and IL-1β) and apoptotic markers (CXCL10 and CCL2) decreased. RA treatment normalized the levels of 115 proteins of the 277, which were differentially regulated as revealed by proteomic studies of ER stressed pancreatic β-cells in co-culture conditions. These findings clearly indicate the role of small molecule activators of Nrf2 not only in restoring the functioning of pancreatic cells but also in increasing the cell mass. Further, the study impinges on the strategies that can be developed to balance the pancreatic microenvironment, leading to the restoration of β-cell mass and their normophysiology in diabetic patients.

The discovery and development of isoform-selective histone deacetylase (HDAC) inhibitor is a challenging task because of the sequence homology among HDAC enzymes. In the present work, novel tetrahydro benzo[b]thiophene-3-carbonitrile based benzamides were designed, synthesized, and evaluated as HDAC inhibitors. Pharmacophore modeling was our main design strategy, and two novel series of tetrahydro benzo[b]thiophene-3-carbonitrile derivatives with piperidine linker (series 1) and piperazine linker (series 2) were identified as HDAC inhibitors. Among all the synthesised compounds, 9h with 4-(aminomethyl) piperidine linker and 14n with piperazine linker demonstrated good activity against human HDAC1 and HDAC6, respectively. Both the compounds also exhibited good antiproliferative activity against several human cancer cell lines. Both these compounds (9h and 14n) also induced cell cycle arrest and apoptosis in U937 and MDA-MB-231 cancer cells. Overall, for the first time, this research discovered potent isoform-selective HDAC inhibitors using cyclic linker instead of the aliphatic chain and aromatic ring system, which were reported in known HDAC inhibitors.

Several series of platinum(II), palladium(II), and nickel(II) complexes bearing 8-(diphenylphosphino)quinoline (PQH) or its 2-methyl or 2-phenyl derivatives (PQMe or PQPh) were synthesized, and their crystal structures and behaviors in solution were investigated. Most of the complexes [M(PQR)2]X2 (MII = PtII, PdII, or NiII; R = H, Me or Ph; X = monoanionic ions) characterized in this study have an approximately square-planar coordination geometry with two bidentate P,N-chelating or monodentate P-donating quinolylphosphine ligands in the cis(P,P) configuration. A large steric requirement from the Me or Ph substituent introduced at the 2-position of the quinoline ring gives the resulting complexes severe distortion. The PtII and PdII complex cations maintained the square-planar coordination geometry, but the MII center was displaced from the chelating ligand plane. This bending of the chelate coordination makes the M-N(quinoline) bond weaker, as demonstrated by the longer M-N bonds. In accord with the bond weakening, the partial dissociation of the PQH or PQMe chelates by substitution with halide anions were observed using UV-vis spectroscopy and X-ray crystallography. In contrast, the PQPh complexes were stable in solution toward the addition of halide anions; the intramolecular π-π stacking interaction between the coordinating quinolyl and the 2-substituted phenyl rings protects the MII center from nucleophilic attack. In the corresponding NiII complexes, the steric congestion arising from the mutually cis-positioned PQR ligands resulted in a large tetrahedral distortion around the NiII center. However, the intramolecular π-π stacking interaction was still effective in the PQPh complex, and this interaction can explain some unusual robustness and electrochemical properties of the NiII-PQPh complex.

Lysine demethylase 5 C (KDM5C) controls epigenetic gene expression and is attracting great interest in the field of chemical epigenetics. KDM5C has emerged as a therapeutic target for anti-prostate cancer agents, and recently we identified triazole 1 as an inhibitor of KDM5C. Compound 1 exhibited highly potent KDM5C-inhibitory activity in in vitro enzyme assays, but did not show strong anticancer effects. Therefore, a different approach is needed for the development of anticancer agents targeting KDM5C. Here, we attempted to identify KDM5C degraders by focusing on a protein-knockdown strategy. Compound 3 b, which was designed based on compound 1, degraded KDM5C and inhibited the growth of prostate cancer PC-3 cells more strongly than compound 1. These findings suggest that KDM5C degraders are more effective as anticancer agents than compounds that only inhibit the catalytic activity of KDM5C.

The steric requirement resulting from the substituted methyl or phenyl group at the ortho-position of the coordinating quinoline-N atom in 8-(di­phenyl­phosphan­yl)quinoline enforces the square-planar coordination geometry of the di­chlorido­palladium(II) center to be highly distorted., The crystal structures of di­chlorido­palladium(II) complexes bearing 2-methyl- and 2-phenyl-8-(di­phenyl­phosphan­yl)quinoline, namely, di­chlorido­[8-(di­phenyl­phosphan­yl)-2-methyl­quinoline-κ2 N,P]palladium(II), [PdCl2(C22H18NP)] (1) and di­chlorido­[8-(di­phenyl­phosphan­yl)-2-phenyl­quinoline-κ2 N,P]palladium(II), [PdCl2(C27H20NP)] (2), were analyzed and compared to that of the 8-(di­phenyl­phosphan­yl)quinoline (PQH) analogue (3). In all three complexes, the phosphanyl­quinoline moiety acts as a bidentate P,N-donating chelate ligand. In the PQH complex (3), the PdII center has a typical planar coordination environment; however, both the methyl- and phenyl-substituted phosphanyl­quinoline (PQMe and PQPh, respectively) complexes (1) and (2) exhibit a considerable tetra­hedral distortion around the PdII center, as parameterized by the τ4 values of 0.1555 (4) and 0.1438 (4) for (1) and (2), respectively. The steric inter­action from the substituted group introduced at the 2-position of the quinoline ring enforces the cis-positioned Cl ligand to be displaced from the ideal coordination plane. Also, the ideally planar phosphanyl­quinoline five-membered chelate ring shows a large bending deformation by the displacement of the PdII center from the quinoline plane. In addition, in the phenyl-substituted complex (3), the coordinating quinolyl and the substituted phenyl rings are not co-planar to each other, having a dihedral angle of 33.08 (7)°. This twist conformation prohibits any inter­molecular π–π stacking inter­action between the quinoline planes, which is observed in the crystals of complexes (1) and (2).

International audience; Circularly polarized luminescence (CPL) was evidenced for the first time in single crystals of a chiral-at-metal Dy(III) single-molecule magnet. This CPL is opposite for the enantiomers and was found to appear and become stronger at lower temperatures when the relaxation of the magnetization for the Dy centers is slower. The luminescence dissymmetry factor (glum up to ±0.18) was found to have little dependence on the emission angle which permitted observing a similar CPL for an ensemble of micro-crystals of random orientations. The investigated Dy(III) compounds consist of bimetallic ZnLn units assembled by a Schiff base ligand, control of the stereochemistry of the Ln center was achieved using chiral [3-(trifluoromethylhydroxymethylene)-camphorate]− as anionic ligands. CPL was not found for the Eu(III) homologues.

Endoplasmic reticulum (ER) plays a key role in the folding, modification, and trafficking of proteins. When the homeostasis of the ER is disturbed, un/misfolded proteins accumulate in the ER which leads to ER stress. Sustained ER stress results in apoptosis, which is associated with various diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor in redox homeostasis by regulating various genes associated with detoxification and cell-protective mechanisms. We found that Rosolic acid (RA) treatment dose-dependently activates Nrf2 in endothelial cells using the enzyme fragment complementation assay. The cytoprotective role of RA against ER stress-induced endothelial apoptosis and its molecular mechanism was explored in the present study. The Nrf2 and its target genes, as well as ER stress marker expressions, were measured by qPCR in ER stress-exposed endothelial cells. The contribution of Nrf2 in RA-mediated defense mechanism in endothelial cells was established by knockout studies using Nrf2-CRISPR/Cas9. The treatment with RA to ER stress-induced endothelial cells exhibited activation of Nrf2, as demonstrated by Nrf2 translocation and reduction of ER stress markers. We found that the Nrf2 knockout sensitized the endothelial cells against ER stress, and further, RA failed to mediate its cytoprotective effect. Proteomic studies using LC-MS/MS revealed that among the 1370 proteins detected, we found 296 differentially regulated proteins in ER stress-induced endothelial cells, and RA administration ameliorated 71 proteins towards the control levels. Of note, the ER stress in endothelial cells was attenuated by the treatment with the RA, suggesting the role of the Nrf2 activator in the pathological conditions of ER stress-associated diseases.

Background Zinc plays an important role in many biological processes. Reduced zinc levels have been found in chronic rhinosinusitis (CRS) patients, however, its role in the pathophysiology of this disease remains unknown. This study examined zinc levels in the serum, mucus and tissue from CRS patients in relation to collagen content and eosinophil infiltration. The effect of zinc depletion on inflammatory cytokine production and collagen synthesis was assessed in vitro. Methodology Zinc levels were determined in serum, mucus and tissue from controls, CRS with (CRSwNP) and without nasal polyps (CRSsNP) patients. Tissue zinc levels, collagen and inflammatory cell infiltration was examined using zinquin assays, immunofluorescence and histology on Tissue Micro Arrays. Cytokine expression and collagen synthesis was evaluated in zinc depleted primary human nasal epithelial cells (HNECs) and primary fibroblasts. Results CRSwNP patients showed reduced tissue zinc levels in correlation with a reduction in collagen content, and increased eosinophil numbers. Zinc depletion of HNECs and fibroblasts induced the production of pro-inflammatory cytokines and MUC5AC and reduced collagen secretion. Conclusions These results suggest mucosal zinc depletion associates with tissue eosinophilia and collagen depletion in CRSwNP and induces pro-inflammatory cytokine expression and reduction of collagen synthesis in vitro.

To improve the accuracy and the cost-efficiency of next-generation sequencing in ultralow-frequency mutation detection, we developed the Paired-End and Complementary Consensus Sequencing (PECC-Seq), a PCR-free duplex consensus sequencing approach. PECC-Seq employed shear points as endogenous barcodes to identify consensus sequences from the overlap in the shortened, complementary DNA strand-derived paired-end reads for sequencing error correction. With the high accuracy of PECC-Seq, we identified the characteristic base substitution errors introduced by the end-repair process of mechanical fragmentation-based library preparations, which were prominent at the terminal 7 bp of the library fragments in the 5′-NpCpA-3′ and 5′-NpCpT-3′ trinucleotide context. As demonstrated at the human genome scale (TK6 cells), after removing these potential end-repair artifacts from the terminal 7 bp, PECC-Seq could reduce the sequencing error frequency to mid-10−7 with a relatively low sequencing depth. For TA base pairs, the background error rate could be suppressed to mid-10−8. In mutagen-treated (6 μg/mL methyl methanesulfonate or 12 μg/mL N-nitroso-N-ethylurea) TK6, increases in mutagen treatment-related mutant frequencies could be detected, indicating the potential of PECC-Seq in detecting genome-wide ultra-rare mutations. In addition, our finding on the patterns of end-repair artifacts may provide new insights into further reducing technical errors not only for PECC-Seq, but also for other next-generation sequencing techniques.

Complexation properties of U-shaped ligands, L1 and L2, which are Schiff bases of 5,5'-(9,9-dimethylxanthene-4,5-diyl)bis(salicylaldehyde) (H2xansal) with 3-amino-1-propanol or 2-hydroxybenzylamine, respectively, were investigated to construct polynuclear manganese complexes. In these ligands, two O,N,O-Schiff bases are bridged by a xanthene backbone. The reactions of H4L1 or H4L2 with manganese salts afforded tetra- and dinuclear manganese complexes, including the tetramanganese(ii,ii,iii,iii) complex [Mn4(L1)2(μ-OAc)2] with a Mn4O6 core exhibiting an incomplete double-cubane structure. In the Mn4O6 core, phenolate and alkoxide O atoms bridge the manganese ions. Deprotonated 3-hydroxypropyl groups were crucial to the assembly of four manganese ions because the phenolate-bridged dimanganese(iii,iii) complex [Mn2(H2L1)2]2+ was obtained in the absence of a base, and H4L2, which has 2-hydroxybenzyl groups instead of 3-hydroxypropyl groups in H4L1, afforded the cyclic dimanganese(iv,iv) complex [Mn2(L2)2]. We disclosed that [Mn4(L1)2(μ-OAc)2] was converted to the oxo-bridged tetramanganese(iii,iii,iii,iii) complex [Mn4(L1)(HL1)(μ3-O)(μ-OAc)2]+ by treating with NH4PF6 or NH4BF4: a triply bridging alkoxide was protonated and replaced by an oxide ligand. The cyclic voltammograms of [Mn4(L1)(HL1)(μ3-O)(μ-OAc)2]+ suggested that the reverse reaction forming [Mn4(L1)2(μ-OAc)2] occurred in the electrochemical processes and was assisted by protonation.

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.

Three tetracoordinated cobalt(ii) complexes with a series of unsymmetrical bidentate ligands were synthesized and crystallographically characterized. Although their static magnetic properties are similar, their dynamic magnetic properties differ drastically depending indirectly on intermolecular hydrogen-bonding interactions.

In the context of drug design, C-H···O hydrogen bonds have received little attention so far, mostly because they are considered weak relative to other noncovalent interactions such as O-H···O hydrogen bonds, π/π interactions, and van der Waals interactions. Herein, we demonstrate the significance of hydrogen bonds between C-H groups adjacent to an ammonium cation and an oxygen atom (N+-C-H···O hydrogen bonds) in protein-ligand complexes. Quantum chemical calculations revealed details on the strength and geometrical requirements of these N+-C-H···O hydrogen bonds, and a subsequent survey of the Protein Data Bank (PDB) based on these criteria suggested that numerous protein-ligand complexes contain such N+-C-H···O hydrogen bonds. An ensuing experimental investigation into the G9a-like protein (GLP)-inhibitor complex demonstrated that N+-C-H···O hydrogen bonds affect the activity of the inhibitors against the target enzyme. These results should provide the basis for the use of N+-C-H···O hydrogen bonds in drug discovery.

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.

Background Sirtuin 2 (SIRT2) is a member of the sirtuin family, nicotinamide adenine dinucleotide+-dependent deacylases, which participates in modulation of cell cycle control, neurodegeneration, and tumorigenesis. SIRT2 expression increases in acute myeloid leukemia blasts. Downregulation of SIRT2 using siRNA causes apoptosis of HeLa cells. Therefore, selective inhibitors of SIRT2 are candidate therapeutic agents for cancer. Adult T-cell leukemia/lymphoma (ATL) is a T-cell malignancy that has a poor prognosis and develops after long-term infection with human T-cell leukemia virus (HTLV)-1. Sirtuin 1 inhibition has been shown to induce apoptosis and autophagy in HTLV-1-infected cell lines, whereas the effects of SIRT2 inhibition alone have not been elucidated. Methods We assessed the efficacy of our small molecule selective SIRT2 inhibitors NCO-90/141 to induce leukemic cell death. Cell viability was examined using the cell proliferation reagent Cell Count Reagent SF. Apoptotic cells were detected by annexin V-FITC and terminal deoxynucleotidyl transferase dUTP nick end labeling assays by flow cytometry. Caspase activity was detected using an APOPCYTO Intracellular Caspase Activity Detection Kit. The presence of autophagic vacuoles was assessed using a Cyto-ID Autophagy Detection Kit. Results Our novel small molecule SIRT2-specific inhibitors NCO-90/141 inhibited cell growth of leukemic cell lines including HTLV-1-transformed T-cells. NCO-90/141 induced apoptosis via caspase activation and mitochondrial superoxide generation in leukemic cell lines. However, a caspase inhibitor did not prevent this caspase-associated cell death. Interestingly, NCO-90/141 increased the LC3-II level together with autophagosome accumulation, indicating autophagic cell death. Thus, NCO-90/141 simultaneously caused apoptosis and autophagy. Conclusions These results suggest that NCO-90/141 are highly effective against leukemic cells in caspase-dependent or -independent manners via autophagy, and they may have a novel therapeutic potential for treatment of leukemias including ATL. Electronic supplementary material The online version of this article (10.1186/s12885-018-4710-1) contains supplementary material, which is available to authorized users.

Epigenome regulates gene expression to determine cell fate, and accumulation of epigenomic aberrations leads to diseases, including cancer. NCD38 inhibits lysine-specific demethylase-1 (LSD1), a histone demethylase targeting H3K4me1 and H3K4me2, but not H3K4me3. In this study, we conjugated NCD38 with a potent small molecule called pyrrole (Py) imidazole (Im) polyamide, to analyze whether targets of the inhibitor could be regulated in a sequence-specific manner. We synthesized two conjugates using β-Ala (β) as a linker, i.e., NCD38-β-β-Py-Py-Py-Py (NCD38-β2P4) recognizing WWWWWW sequence, and NCD38-β-β-Py-Im-Py-Py (NCD38-β2PIPP) recognizing WWCGWW sequence. When RKO cells were treated with NCD38, H3K4me2 levels increased in 103 regions with significant activation of nearby genes (P = 0.03), whereas H3K4me3 levels were not obviously increased. H3K27ac levels were also increased in 458 regions with significant activation of nearby genes (P = 3 × 10-10), and these activated regions frequently included GC-rich sequences, but less frequently included AT-rich sequences (P < 1 × 10-15) or WWCGWW sequences (P = 2 × 10-13). When treated with NCD38-β2P4, 234 regions showed increased H3K27ac levels with significant activation of nearby genes (P = 2 × 10-11), including significantly fewer GC-rich sequences (P < 1 × 10-15) and significantly more AT-rich sequences (P < 1 × 10-15) compared with NCD38 treatment. When treated with NCD38-β2PIPP, 82 regions showed increased H3K27ac levels, including significantly fewer GC-rich sequences (P = 1 × 10-11) and fewer AT-rich sequences (P = 0.005), but significantly more WWCGWW sequences (P = 0.0001) compared with NCD38 treatment. These indicated that target regions of epigenomic inhibitors could be modified in a sequence-specific manner and that conjugation of Py-Im polyamides may be useful for this purpose.

Lysine-specific demethylase 1 (LSD1) is a histone modifier for transcriptional repression involved in the regulation of hematopoiesis. We previously reported that a LSD1 inhibitor NCD38 induces transdifferentiation from erythroid lineage to granulomonocytic lineage and exerts anti-leukemia effect through de-repression of the specific super-enhancers of hematopoietic regulators including ERG in a human erythroleukemia cell line, HEL. However, the mechanistic basis for this specificity of NCD38 has remained unclear. Herein, we report major partners associated with LSD1 and clarify the mechanism in HEL cells. Proteome analysis identified 54 candidate proteins associated with LSD1, including several transcription factors such as GFI1B and RUNX1 as well as BRAF-histone deacetylase complex (BHC) components such as CoREST, HDAC1, and HDAC2. NCD38 selectively disrupted the interaction of LSD1 with GFI1B but not with RUNX1, CoREST, HDAC1 and HDAC2. Erg was downregulated in murine erythroid progenitors with prominent upregulation of Gfi1b. NCD38 induced ERG and attenuated an erythroid marker CD235a in HEL while this attenuation was mimicked by the lentiviral overexpression of ERG. The ERG super-enhancer contained the conserved binding motif of GFI1B and was actually occupied by GFI1B. NCD38 dissociated LSD1 and CoREST but not GFI1B from the ERG super-enhancer. Collectively, the selective separation of LSD1 from GFI1B by NCD38 restores the ERG super-enhancer activation and consequently upregulates ERG expression, inducing the transdifferentiation linked to the anti-leukemia effect.

Two geometric isomers of [RuCl2(PPh3)2(O–N)]-type complex were prepared and characterized by X-ray crystallography (PPh3 = triphenylphosphine, O–N = Hpia/pia−, Hpia = 3-hydroxypicolinamide). The electrochemical properties of the complexes upon protonation/deprotonation were investigated. The redox potential of the Ru center was remarkably shifted by isomerization. The UV-vis and electrochemical measurements suggested that slow isomerization from trans(P,Cl),trans(P,N) geometry to trans(P,P) geometry induced the oxidation and deprotonation of the complex.

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.