Synthesis, structures and luminescent properties of novel coordination polymers constructed by lanthanide salts and benzimidazole-5,6-dicarboxylic acid

Two three-dimensional (3D) novel lanthanide complexes with the H₂Lbenzimidazole-5,6-dicarboxylate [Ln₂L₃(H₂O)] [Ln = Eu (1), Tb (2)] and one two-dimensional (2D) novel lanthanide complex [Pr(L)(HL)H₂O]·H₂O (3) were synthesized by hydrothermal reaction at 180 °C and characterized by elemental analysis, infrared spectra and single-crystal X-ray diffraction. The result showed that complexes 1 and 2 are isostructural and build porous 3D networks by L²⁻ groups linking Ln(III) atoms via tetradentate (bridging and bridging) and pentadentate (bridging/chelating and bridging) coordination modes. Complex 3 is a eight-coordinated Pr(III) chain complex, exhibiting a 2D polymeric network with parallel Pr-carboxylate chains along the crystallographic c-axis. In addition, it is found that in these structures, coordination modes of L²⁻ and HL⁻ are versatile and can adopt different conformations according to distinct dimensions of polymeric structures. The photoluminescent properties of 1, 2 and thermogravimetric analyses of the three complexes were discussed in detail.     

Regulatory effect of vasoactive intestinal peptide on the balance of Treg and Th17 in collagen-induced arthritis

Vasoactive intestinal peptide (VIP) is a well-known anti-inflammatory neuropeptide. The capacity of VIP can be exhibited through inhibiting inflammatory responses, shifting the Th1/Th2 balance in favor of anti-inflammatory Th2 immunity and inducing regulatory T cells (Tregs) with suppressive activity. In addition to pro-inflammatory Th1 response, Th17 are also believed to play important roles in the pathogenesis of rheumatoid arthritis (RA). In this study, we used collagen-induced arthritis (CIA) model in Wistar rats to investigate the role of VIP in the balance of CD4⁺ CD25⁺ Tregs and Th17 on RA. Data presented here showed that administration of VIP decreased incidence and severity of CIA. Disease suppression was associated with the upregulation of CD4⁺ CD25⁺ Tregs, downregulation of Th17- and Th1-type response and influence on the RANK/RANKL/OPG system. The results provide novel evidence that the therapeutic effects of VIP on CIA rats were associated with the balance of CD4⁺ CD25⁺ Tregs and Th17.     

Hepatocyte or serum albumin protein carbonylation by oxidized fructose metabolites: Glyceraldehyde or glycolaldehyde as endogenous toxins?

Excessive sugar intake in animal models may cause tissue damage associated with oxidative and carbonyl stress cytotoxicity as well as inflammation. Fructose became a 100-fold more cytotoxic if hepatocytes were exposed to a non-toxic infusion of H₂O₂ so as to simulate H₂O₂ released by Kupffer cells or infiltrating immune cells. In order to determine the molecular mechanisms involved, protein carbonylation of fructose and its metabolites were determined using the 2,4-dinitrophenylhydrazine method. In a cell-free system, fructose was found to carbonylate bovine serum albumin (BSA) only if low concentrations of FeII/H₂O₂ were added. Protein carbonylation by the fructose metabolites glyceraldehyde or glycolaldehyde was also markedly increased by FeII/H₂O₂. The protein carbonylation may be attributed to glyoxal formation by hydroxyl radicals as the glyoxal trapping agent aminoguanidine or hydroxyl radical scavengers prevented protein carbonylation. Glyoxal was also much more effective than other carbonyls at causing protein carbonylation. When BSA was replaced by isolated rat hepatocytes, fructose metabolite glyceraldehyde in the presence of non-toxic 2 μM FeII:8-hydroxyquinoline (HQ) and a H₂O₂ generating system (glucose/glucose oxidase) markedly increased cytotoxicity, protein carbonylation and reactive oxygen species (ROS)/H₂O₂ formation. Furthermore this was prevented by hydroxyl radical scavengers or aminoguanidine, a glyoxal scavenger. CuII: 8-hydroxyquinoline increased H₂O₂ induced hepatocyte protein carbonylation less but was prevented by aminoguanidine. However, cytotoxicity and protein carbonylation induced by glyceraldehyde/CuII:HQ/H₂O₂ were not affected by hydroxyl radical scavengers. Although fatty liver induced by an excessive sugar diet in animal models has been proposed as the first hit for non-alcoholic steatohepatitis (NASH) we propose that oxidative stress induced by the oxidation of fructose or fructose metabolites catalysed by Fenton FeII/H₂O₂ could be a ‘second hit’. A perpetual cycle of oxidative stress in hepatocytes could lead to cytotoxicity and contribute to NASH development.     

Structure and size variations between 12A and 12D homoeologous chromosomes based on high-resolution cytogenetic map in allotetraploid cotton

Cotton is a model system for studying polyploidization, genomic organization, and genome-size variation because the allotetraploid was formed 1-2 million years ago, which is old enough for sequence divergence but relatively recent to maintain genome stability. In spite of characterizing random genomic sequences in many polyploidy plants, the cytogenetic and sequence data that decipher homoeologous chromosomes are very limited in allopolyploid species. Here, we reported comprehensive analyses of integrated cytogenetic and linkage maps of homoeologous chromosomes 12A and 12D in allotetraploid cotton using fluorescence in situ hybridization and a large number of bacterial artificial chromosomes that were anchored by simple sequence repeat markers in the corresponding linkage maps. Integration of genetic loci into physical localizations showed considerable variation of genome organization, structure, and size between 12A and 12D homoeologous chromosomes. The distal regions of the chromosomes displayed relatively lower levels of structural and size variation than other regions of the chromosomes. The highest level of variation was found in the pericentric regions in the long arms of the two homoeologous chromosomes. The genome-size difference between A and D sub-genomes in allotetraploid cotton was mainly associated with uneven expansion or contraction between different regions of homoeologous chromosomes. As an attempt for studying on the polyploidy homoeologous chromosomes, these results are of general interest to the understanding and future sequencing of complex genomes in plant species.     

Protective effects of pre-germinated brown rice diet on low levels of Pb-induced learning and memory deficits in developing rat

Lead (Pb) is a known neurotoxicant in humans and experimental animals. Numerous studies have provided evidence that humans, especially young children, and animals chronically intoxicated with low levels of Pb show learning and memory impairments. Unfortunately, Pb-poisoning cases continue to occur in many countries. Because the current treatment options are very limited, there is a need for alternative methods to attenuate Pb toxicity. In this study, the weaning (postnatal day 21, PND21) rats were randomly divided into five groups: the control group (AIN-93G diet, de-ionized water), the lead acetate (PbAC) group (AIN-93G diet, 2 g/L PbAC in de-ionized water), the lead acetate + WR group (white rice diet, 2 g/L PbAC in de-ionized water; PbAC + WR), the lead acetate + BR group (brown rice diet, 2 g/L PbAC in de-ionized water; PbAC + BR) and the lead acetate + PR group (pre-germinated brown rice diet, 2 g/L PbAC in de-ionized water; PbAC + PR). The animals received the different diets until PND60, and then the experiments were terminated. The protective effects of pre-germinated brown rice (PR) on Pb-induced learning and memory impairment in weaning rats were assessed by the Morris water maze and one-trial-learning passive avoidance test. The anti-oxidative effects of feeding a PR diet to Pb-exposed rats were evaluated. The levels of reactive oxygen species (ROS) were determined by flow cytometry. The levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), γ-aminobutyric acid (GABA) and glutamate were determined by HPLC. Our data showed that feeding a PR diet decreased the accumulation of lead and decreased Pb-induced learning and memory deficits in developing rats. The mechanisms might be related to the anti-oxidative effects and large amount of GABA in PR. Our study provides a regimen to reduce Pb-induced toxicity, especially future learning and memory deficits in the developing brain.     

Bbs8, together with the planar cell polarity protein Vangl2, is required to establish left-right asymmetry in zebrafish

Laterality defects such as situs inversus are not uncommonly encountered in humans, either in isolation or as part of another syndrome, but can have devastating developmental consequences. The events that break symmetry during early embryogenesis are highly conserved amongst vertebrates and involve the establishment of unidirectional flow by cilia within an organising centre such as the node in mammals or Kupffer's vesicle (KV) in teleosts. Disruption of this flow can lead to the failure to successfully establish left-right asymmetry. The correct apical-posterior cellular position of each node/KV cilium is critical for its optimal radial movement which serves to sweep fluid (and morphogens) in the same direction as its neighbours. Planar cell polarity (PCP) is an important conserved process that governs ciliary position and posterior tilt; however the underlying mechanism by which this occurs remains unclear. Here we show that Bbs8, a ciliary/basal body protein important for intraciliary/flagellar transport and the core PCP protein Vangl2 interact and are required for establishment and maintenance of left-right asymmetry during early embryogenesis in zebrafish. We discovered that loss of bbs8 and vangl2 results in laterality defects due to cilia disruption at the KV. We showed that perturbation of cell polarity following abrogation of vangl2 causes nuclear mislocalisation, implying defective centrosome/basal body migration and apical docking. Moreover, upon loss of bbs8 and vangl2, we observed defective actin organisation. These data suggest that bbs8 and vangl2 act synergistically on cell polarization to establish and maintain the appropriate length and number of cilia in the KV and thereby facilitate correct LR asymmetry.     

Nucleosome deposition and DNA methylation may participate in the recognition of premature termination codon in nonsense-mediated mRNA decay

In non-mammalian eukaryotes, an abnormally long 3′ untranslated region (UTR) is generally thought to be the definitive signal in the recognition of a premature termination codon (PTC) in nonsense-mediated mRNA decay (NMD). However, because the lengths of 3′ UTRs in normal mRNAs are widely distributed, “abnormally long” is hard to define. Distinct peaks of nucleosome deposition and DNA methylation have recently been found at coding region boundaries. We propose that nucleosomes and DNA methylation just upstream of a normal stop codon are ideal indicators for the position of a normal stop codon and may thus serve as signals in PTC recognition.     

Discovery of N-aryl sulphonamide-quinazoline derivatives as anti-gastric cancer agents in vitro and in vivo via activating the Hippo signalling pathway

Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative, compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC₅₀ values of 0.36 μM (MGC-803 cells), 0.70 μM (HCT-116 cells), 1.04 μM (PC-3 cells), and 0.81 μM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo. Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP.     

Functional alterations after cardiac sodium-calcium exchanger overexpression in heart failure

The sodium-calcium exchanger (NCX) is discussed as one of the key proteins involved in heart failure. However, the causal role and the extent to which NCX contributes to contractile dysfunction during heart failure are poorly understood. NCX overexpression was induced by infection with an adenovirus coding for NCX, which coexpressed green fluorescence protein (GFP) (AdNCX) by ex vivo gene transfer to nonfailing and failing rabbit cardiomyocytes. Myocardial gene transfer in rabbits in vivo was achieved by adenoviral delivery via aortic cross-clamping. Peak cell shortening of cardiomyocytes was determined photo-optically. Hemodynamic parameters in vivo were determined by echocardiography (fractional shortening) and tip catheter [maximal first derivative of left ventricular (LV) pressure (dP/dt(max)); maximal negative derivative of LV pressure (-dP/dt(max))]. Peak cell shortening was depressed after NCX gene delivery in isolated nonfailing and in failing cardiomyocytes. In nonfailing rabbits in vivo, basal systolic contractility (fractional shortening and dP/dt(max)) and maximum rate of LV relaxation (-dP/dt(max)) in vivo were largely unaffected after NCX overexpression. However, during heart failure, long-term NCX overexpression over 2 wk significantly improved fractional shortening and dP/dt(max) compared with AdGFP-infected rabbits, both without inotropic stimulation and after beta-adrenergic stimulation with isoproterenol. -dP/dt(max) was also improved after NCX overexpression in the failing rabbits group. These results indicate that short-term effects of NCX overexpression impair contractility of isolated failing and nonfailing rabbit cardiomyocytes. NCX overexpression over 2 wk in vivo does not seem to affect myocardial contractility in nonfailing rabbits. Interestingly, in vivo overexpression of NCX decreased the progression of systolic and diastolic contractile dysfunction and improved beta-adrenoceptor-mediated contractile reserve in heart failure in rabbits in vivo.     

Identification of two major loci that suppress hearing loss and cochlear dysmorphogenesis in Eya1bor/bor mice

The Eya1(bor) mutant hypomorph contains an intracisternal A particle insertion in intron 7 of the Eya1 gene that results in a 50% reduction in wild-type mRNA levels. The homozygous mutants have middle and inner ear defects and variable kidney abnormalities. The severity of the disorder is affected by genetic background. In contrast to complete deafness and cochlear agenesis in the C3HeB/FeJ strain, F2 Eya1(bor/bor) mutants from an intercross between C3HeB/FeJ-Eya1(bor/+) and C57BL/6J showed variable auditory brain-stem responses and cochlear coiling. In this study, using these F2 Eya1(bor/bor) mutants, we have identified two major loci, Mead1 (modifier of Eya1-associated deafness 1) and Mead2, that are responsible for suppression of the original phenotypes. We have narrowed these two loci to 5.4 and 4.4 cM, respectively, in congenic lines. Quantitative PCR demonstrated that this modifying effect did not result from an increase in wild-type Eya1 mRNA, suggesting Mead1 and Mead2 are interacting directly or indirectly with Eya1 during inner ear development.