Synthesis of novel heterobimetallic copper(I) hydrazone Schiff base complexes: a comparative study on the effect of heterocyclic hydrazides towards interaction with DNA/protein, free radical scavenging and cytotoxicity

Two new copper(I) hydrazone complexes have been synthesised from bivalent copper precursor [CuCl(2)(PPh(3))(2)] and ferrocene containing bidentate hydrazone ligands HL(1) (1) or HL(2) (2). Based on the elemental analyses and spectroscopic data, the complexes are best formulated as [CuL(1)(PPh(3))(2)] (3) and [CuL(2)(PPh(3))(2)] (4) of the monovalent copper ion. Solid state structures of ligand 2 and its corresponding complex 4 were also determined. The DNA/albumin interactions of all the synthesised compounds were investigated using absorption, emission and synchronous fluorescence studies. Further, antioxidant properties of all the compounds have also been checked against ABTS, O(2)(-) and OH radicals. Additionally, the in vitro cytotoxic activity of compounds 1-4 was assessed using tumour (HeLa, A431) and non-tumour (NIH 3T3) cell lines.     

Tannase activity from the marine cyanobacterium Phormidium valderianum BDU140441

The marine cyanobacterium Phormidium valderianum BDU 140441 exhibited the ability to grow at 0.25?mM tannic acid, a known hindering chemical for microbial growth. The tannic acid-degrading ability of the organism is evident from the UV–visible absorption spectrum. In addition, the existence of tannase has been localized by activity staining, and its induction in activity upon tannic acid exposure was confirmed in native gel. The critical tannic acid metabolization enzymes tested for are polyphenol oxidase and esterases; both are well known for tannic acid degradation. Upon tannic acid exposure, increased activity of polyphenol oxidase and expression of few new isoforms of esterase were identified by activity staining.     

Structure prediction of Bestrophin for the induced - fit docking of anthocyanins

Bestrophin, an integral membrane protein existing in basolateral region of the retina is a propitious target for drug discovery. Mutations in the Bestrophin protein cause Best Vitelliform Macular Dystrophy (BVMD) leading to retinal damages and loss of visual acuity. Owing to the lack of three dimensional structure and related structural homologs in the protein data bank, we modeled the bestrophin protein using Robetta ab initio method. Further, no treatment is available for the disease. In this situation, anthocyanins from natural sources are reported to combat retinal damages. Hence, we identified anthocyanins from Syzygium cumini fruit skin using Electrospray Ionization tandem mass spectrometry. These compounds were docked into the predicted bestrophin model to study the interactions within the active site. The results may provide a valuable insight into the structure of bestrophin and efficacy of anthocyanins in molecular docking studies.

Abbreviations

PTP - Putative transmembrane proteins, VMD - Vitelliform macular dystrophy, BVMD - Best''s vitelliform macular dystrophy, RPE - Retinal pigment epithelium, ESI-MS/MS - Electrospray Ionization Tandem Mass Spectrometry, UNIPROT - Universal Protein Resource, PSIPRED - Protein secondary structure prediction, TMH - Transmembrane Helices, SCFS - Syzygium cumini fruit skin DP - Declustering Potential IFD - Induced Fit Docking.     

HumanGFRA1: Cloning, Mapping, Genomic Structure, and Evaluation as a Candidate Gene for Hirschsprung Disease Susceptibility

Congenital aganglionic megacolon, commonly known as Hirschsprung disease (HSCR), is the most frequent cause of congenital bowel obstruction. Germline mutations in theRETreceptor tyrosine kinase have been shown to cause HSCR. Knockout mice forRETand for its ligand, glial cell line-derived neurotrophic factor (GDNF), exhibit both complete intestinal aganglionosis and renal defects. Recently, GDNF and GFRA1 (GDNF family receptor, also known as GDNFR-α), its GPI-linked coreceptor, were demonstrated to be components of a functional ligand for RET. Moreover,GDNFhas been implicated in rare cases of HSCR. We have mappedGFRA1to human chromosome 10q25, isolated human and mouse genomic clones, determined the gene's intron–exon boundaries, isolated a highly polymorphic microsatellite marker adjacent to exon 7, and scanned forGFRA1mutations in a large panel of HSCR patients. No evidence of linkage was detected in HSCR kindreds, and no sequence variants were found to be in significant excess in patients. These data suggest thatGFRA1's role in enteric neurogenesis in humans remains to be elucidated and that RET signaling in the gut may take place via alternate pathways, such as the recently described GDNF-related molecule neurturin and its GFRA1-like coreceptor, GFRA2.     

Nanoplastics alter ecosystem multifunctionality and may increase global warming potential

Although the presence of nanoplastics in aquatic and terrestrial ecosystems has received increasing attention, little is known about its potential effect on ecosystem processes and functions. Here, we evaluated if differentially charged polystyrene (PS) nanoplastics (PS-NH₂ and PS-SO₃H) exhibit distinct influences on microbial community structure, nitrogen removal processes (denitrification and anammox), emissions of greenhouse gases (CO₂, CH₄, and N₂O), and ecosystem multifunctionality in soils with and without earthworms through a 42-day microcosm experiment. Our results indicated that nanoplastics significantly altered soil microbial community structure and potential functions, with more pronounced effects for positively charged PS-NH₂ than for negatively charged PS-SO₃H. Ecologically relevant concentration (3 g kg⁻¹) of nanoplastics inhibited both soil denitrification and anammox rates, while environmentally realistic concentration (0.3 g kg⁻¹) of nanoplastics decreased the denitrification rate and enhanced the anammox rate. The soil N₂O flux was always inhibited 6%–51% by both types of nanoplastics, whereas emissions of CO₂ and CH₄ were enhanced by nanoplastics in most cases. Significantly, although N₂O emissions were decreased by nanoplastics, the global warming potential of total greenhouse gases was increased 21%–75% by nanoplastics in soils without earthworms. Moreover, ecosystem multifunctionality was increased 4%–12% by 0.3 g kg⁻¹ of nanoplastics but decreased 4%–11% by 3 g kg⁻¹ of nanoplastics. Our findings provide the only evidence to date that the rapid increase in nanoplastics is altering not only ecosystem structure and processes but also ecosystem multifunctionality, and it may increase the emission of CO₂ and CH₄ and their global warming potential to some extent.     

Partially saturated canthaxanthin purified from Aspergillus carbonarius induces apoptosis in prostrate cancer cell line

A mutant Aspergillus carbonarius selected for temperature tolerance after UV treatment, when grown in shake flasks, produced mycelia bearing yellow pigment. Since the mutant was affected in sterol biosynthetic pathway, the pigment was apparently produced to maintain membrane fluidity and rigidity for growth sustenance in low-pH culture broth. Nuclear magnetic resonance analyses characterizing the pigment as a partially saturated canthaxanthin, containing beta-ionone end rings, suggested its application as a retinoid. When tested for this property in retinoic acid receptor expressing prostate cancer cell line, LNCaP, the fungal partially saturated canthaxanthin induced apoptosis. Low apoptosis percentage in DU145 prostrate cancer cells that does not express functional retinoic acid receptor-beta (RAR-beta) suggested binding specificity of the partially saturated canthaxanthin for RAR-beta.     

Synthesis, spectral characterization, and single crystal X-ray structures of a series of manganese-2,2′-bipyridine complexes derived from substituted aromatic carboxylic acids

Reaction of [Mn(2,2′-bpy)₂(OAc)](ClO₄)(H₂O) with a series of aromatic carboxylic acids yields new Mn(II)carboxylates [Mn(2,2′-bpy)₂(L)](ClO₄)}₂ (1-3), [Mn(2,2′-bpy)₂(L)₂] (4-5) and [Mn(2,2′-bpy)₂(L)(H₂O)](ClO₄) (6) (L = 2-aminobenzoate (2-aba) (1), 4-hydroxybenzoate (4-hba) (2), thiophene-2-carboxylate (2-tca) (3), 2-hydroxynapthoate (2-hnapa) (4), 3,5-diisopropylsalicylic acid (dipsa) (5), 2,4,6-triisopropylbenzoate (tipba) (6)). The new compounds have been characterized with the aid of elemental analysis, spectroscopy, and single-crystal X-ray diffraction studies. Compounds 1-3, which have been synthesized from less bulky carboxylic acids, are dimeric in the solid-state. Compounds 4-6, which are derived from more bulkier aromaric carboxylic acids, exist as monomeric complexes. In the case of 6, where very bulky 2,4,6-triisopropyl benzoic acid is used as the starting material, only one carboxylate ligand binds to the metal, resulting in a cationic complex. Interestingly in all the six complexes, the C-H hydrogen atoms of the 2,2′-bpy ligands are involved in extensive hydrogen bonding with the carboxylate oxygen atoms of the adjacent molecules and hence form non-covalent 1-D or 2-D aggregates in the solid state.     

Protection of HepG2 cells against acrolein toxicity by 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide via glutathione-mediated mechanism

Acrolein is an environmental toxicant, mainly found in smoke released from incomplete combustion of organic matter. Several studies showed that exposure to acrolein can lead to liver damage. The mechanisms involved in acrolein-induced hepatocellular toxicity, however, are not completely understood. This study examined the cytotoxic mechanisms of acrolein on HepG2 cells. Acrolein at pathophysiological concentrations was shown to cause apoptotic cell death and an increase in levels of protein carbonyl and thiobarbituric acid reactive acid substances. Acrolein also rapidly depleted intracellular glutathione (GSH), GSH-linked glutathione-S-transferases, and aldose reductase, three critical cellular defenses that detoxify reactive aldehydes. Results further showed that depletion of cellular GSH by acrolein preceded the loss of cell viability. To further determine the role of cellular GSH in acrolein-mediated cytotoxicity, buthionine sulfoximine (BSO) was used to inhibit cellular GSH biosynthesis. It was observed that depletion of cellular GSH by BSO led to a marked potentiation of acrolein-mediated cytotoxicity in HepG2 cells. To further assess the contribution of these events to acrolein-induced cytotoxicity, triterpenoid compound 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) was used for induction of GSH. Induction of GSH by CDDO-Im afforded cytoprotection against acrolein toxicity in HepG2 cells. Furthermore, BSO significantly inhibited CDDO-Im-mediated induction in cellular GSH levels and also reversed cytoprotective effects of CDDO-Im in HepG2 cells. These results suggest that GSH is a predominant mechanism underlying acrolein-induced cytotoxicity as well as CDDO-Im-mediated cytoprotection. This study may provide understanding on the molecular action of acrolein which may be important to develop novel strategies for the prevention of acrolein-mediated toxicity.