Metal ions and metal complexes are important components of nucleic acid biochemistry, participating both in regulation of gene expression and as therapeutic agents. Three new transition metal ...complexes of copper(II), zinc(II) and oxidovanadium(IV) with a ligand derived from o-vanillin and thiophene were previously synthesized and their antitumor properties were studied in our laboratory. To elucidate some molecular mechanisms tending to explain the cytotoxic effects observed over tumor cells, we investigated the interaction of these complexes with DNA by gel electrophoresis, UV–Vis spectroscopy, docking studies and molecular dynamics simulations. Our spectroscopy and computational results have shown that all of them were able to bind to DNA, Cu(II) complex is located in the minor groove while Zn(II) and oxidovanadium(IV) complexes act as major groove binding molecules. Interestingly, only the Cu(II) complex caused double-strand DNA nicks, consistent with its higher cytotoxic activities previously observed in tumor cell lines. We propose that the DNA-complex interaction destabilize the molecule either disrupting the phosphodiester bonds or impairing DNA replication, giving those complexes strong antitumor potential.
Display omitted
•Cu(II), Zn(II) and VO(IV) complexes with Schiff base interact with double strand DNA.•Docking studies predict different site of interaction.•The interaction sites depend on its structural and electronic properties.•Intercalating ability correlates with its different antitumor activities.
Breast cancer is the most common cancer in women, with a high incidence estimated to reach 2.3 million by 2030. Triple-Negative Breast Cancer (TNBC) is the greatest invasive class of breast cancer ...with a poor prognosis, due to the side-effects exerted by the chemotherapy used and the low effectivity of novel treatments. In this sense, copper compounds have shown to be potentially effective as antitumor agents, attracting increasing interest as alternatives to the usually employed platinum-derived drugs. Therefore, the aim of this work is to identify differentially expressed proteins in MDA-MB-231 cells exposed to two copper(II)-hydrazone complexes using label-free quantitative proteomics and functional bioinformatics strategies to identify the molecular mechanisms through which these copper complexes exert their antitumoral effect in TNBC cells. Both copper complexes increased proteins involved in endoplasmic reticulum stress and unfolded protein response, as well as the downregulation of proteins related to DNA replication and repair. One of the most relevant anticancer mechanisms of action found for CuHL1 and CuHL2 was the down-regulation of gain-of-function-mutant p53. Moreover, we found a novel and interesting effect for a copper metallodrug, which was the down-regulation of proteins related to lipid synthesis and metabolism that could lead to a beneficial decrease in lipid levels.
Carpophilus dimidiatus (Fabricius) (Nitidulidae) and Oryzaephilus mercator (L.) (Silvanidae) are insect pests that cause severe damage in important walnut growing regions in the northwest of ...Argentina. The current management approaches for these pests involve the use of unsafe phosphorus pesticides whose overuse have led to farmworker poisoning, pest resistance issues, and environmental contamination. Plant extracts, particularly essential oils, are an alternative source of insect control agents. Excito-repellent essential oils can be used to develop ecofriendly tools for managing the pest population without affecting quality and visual appearance of the stored walnuts. Laboratory studies were conducted to assess the excito-repellent effects of C. dimidiatus and O. mercator of 12 essential oils derived from aromatic plants used as food additives and traditional medicine in Argentina: Aloysia citrodora (AC), Aloysia gratissima (AG), Aloysia gratissima var. Gratissima (AGG), Blepharocalyx salicipholius (BS), Hyptis mutabilis (HM), Lippia junelliana (LJ), Lippia turbinata (LT), Mentha x piperita (MP), Minthostachys mollis (MM), Minthostachys verticillata (MV), Origanum vulgare(OV), and Rosmarinus officinalis (RO). The most bioactive EOs (ER ijk ≥ 70%) were Aloysia gratissima var. Gratissima (AGG), Minthostachys verticillata, and Lippia junelliana. Their bioactivity profile and chemical space, characterized from GC-MS measures, Generalized Estimating Equations, and Hierarchical Cluster Analysis, revealed that they are mixtures of very functionalized molecules with physicochemical properties similar to those of insecticides with low residual property that enter the insect body through the respiratory system by inhalation. The AGG, MV, and LJ oils are promising as protective agents of walnut products. In our laboratory, studies of their formulations for use in integrated pest management programs are still ongoing.
The high percentage of patients carrying germline mutations makes pheochromocytomas/paragangliomas the most heritable of all tumors. However, there are still cases unexplained by mutations in the ...known genes. We aimed to identify the genetic cause of disease in patients strongly suspected of having hereditary tumors.
Whole-exome sequencing was applied to the germlines of a parent–proband trio. Genome-wide methylome analysis, RNA-seq, CRISPR/Cas9 gene editing, and targeted sequencing were also performed.
We identified a novel de novo germline mutation in DNMT3A, affecting a highly conserved residue located close to the aromatic cage that binds to trimethylated histone H3. DNMT3A-mutated tumors exhibited significant hypermethylation of homeobox-containing genes, suggesting an activating role of the mutation. CRISPR/Cas9-mediated knock-in in HeLa cells led to global changes in methylation, providing evidence of the DNMT3A-altered function. Targeted sequencing revealed subclonal somatic mutations in six additional paragangliomas. Finally, a second germline DNMT3A mutation, also causing global tumor DNA hypermethylation, was found in a patient with a family history of pheochromocytoma.
Our findings suggest that DNMT3A may be a susceptibility gene for paragangliomas and, if confirmed in future studies, would represent the first example of gain-of-function mutations affecting a DNA methyltransferase gene involved in cancer predisposition.
Listeria innocua micropopulation lag phase and its variability have been modeled as a function of growth temperature, intensity of heat stress, and the number of surviving cells initiating growth. ...Micropopulation lag phases were found to correlate negatively with inoculum size and growth temperature and positively with heat shock intensity. Validation of the models using experimental milk samples indicated that the average lag phase duration predicted is shorter and more variable than the observed, meaning that they should be considered safe for risk assessment. Our results suggest that the effect of inoculum size on the population lag phase has both stochastic and physiological components.
•Lag is modeled as a function of inoculum size, growth temperature and heat shock.•Lag phases correlate negatively with inoculum size and growth temperature.•Lag phases are directly proportional to previous heat shock–stress-intensity.•Lag phase and lag variability models proposed here are secured.•Predictions of lag phase and its variability must improve QMRA studies.
A catalytic domino reduction–imine formation–intramolecular cyclization–oxidation for the general synthesis of a wide variety of biologically relevant N‐polyheterocycles, such as quinoxaline‐ and ...quinoline‐fused derivatives, and phenanthridines, is reported. A simple, easily available, and environmentally friendly dioxomolybdenum(VI) complex has proven to be a highly efficient and versatile catalyst for transforming a broad range of starting nitroarenes involving several redox processes. Not only is this a sustainable, step‐economical as well as air‐ and moisture‐tolerant method, but also it is worth highlighting that the waste byproduct generated in the first step of the sequence is recycled and incorporated in the final target molecule, improving the overall synthetic efficiency. Moreover, selected indoloquinoxalines have been photophysically characterized in cyclohexane and toluene with exceptional fluorescence quantum yields above 0.7 for the alkyl derivatives.
A catalytic domino reduction / imine formation / intramolecular cyclization / oxidation allows the synthesis of a wide variety of biologically relevant N‐polyheterocycles. The reported process employs an inexpensive and nontoxic dioxomolybdenum(VI) complex as catalyst, easily available nitroarenes as starting materials and different glycols as reducing agents with reuse of the waste reduction carbonyl byproduct, which is embodied into the final compounds.
Essential oils from aerial parts of six aromatic plants were analysed by GC-MS. The major compounds identified were
-terpinene (11.5%), cuminaldehyde (26.6%) and
-terpinen-7-al (40.6%) in
,
-anethol ...(95.2%) in
, α-pinene (11.6%), limonene (21.0%), β-caryophyllene (22.3%) and α-humulene (16.7%) in
, limonene (40.8%) and artemisia ketone (19.3%) in
,
-β-ocimene (15.6%), 4-ethyl-4-methyl-1-hexene (24.5%),
-tagetone (20.5%) and verbenone (27.2%) in
, 1,8-cineole (17.9%),elixene (10.3%) and spathulenol (13.8%) in
. Oils with strong insecticidal activity on
and
were from
(LC
= 4 µl/L; LC
= 10 µl/L) and
(LC
=10.19-12.57 µl/L; LC
=20 µl/L). Scents of
and
were strong insecticides on
(LC
=7.02-7.17 µl/L; LC
=10.00-20.00 µl/L). The insecticidal activity was associated to the whole content of C10 molecules and oxygenated constituents. The
oil is promising as protective agent of nut products.
Mutants able to germinate and perform early growth in medium containing a high NaCl concentration were identified during the course of two independent screenings and named salt resistant (sre) and ...salobreño (sañ). The sre and sañ mutants also were able to germinate in high-osmoticum medium, indicating that they are osmotolerant in a germination assay. Complementation analyses revealed that sre1-1, sre1-2, sañ3-1, and sañ3-2 were alleles of the abscisic acid (ABA) biosynthesis ABA2 gene. A map-based cloning strategy allowed the identification of the ABA2 gene and molecular characterization of four new aba2 alleles. The ABA2 gene product belongs to the family of short-chain dehydrogenases/reductases, which are known to be NAD- or NADP-dependent oxidoreductases. Recombinant ABA2 protein produced in Escherichia coli exhibits a K m value for xanthoxin of 19 μm and catalyzes in a NAD-dependent manner the conversion of xanthoxin to abscisic aldehyde, as determined by HPLC-mass spectrometry. The ABA2 mRNA is expressed constitutively in all plant organs examined and is not upregulated in response to osmotic stress. The results of this work are discussed in the context of previous genetic and biochemical evidence regarding ABA biosynthesis, confirming the xanthoxin→abscisic aldehyde→ABA transition as the last steps of the major ABA biosynthetic pathway.
Bulk segregant analysis (BSA) coupled to high throughput sequencing is a powerful method to map genomic regions related with phenotypes of interest. It relies on crossing two parents, one inferior ...and one superior for a trait of interest. Segregants displaying the trait of the superior parent are pooled, the DNA extracted and sequenced. Genomic regions linked to the trait of interest are identified by searching the pool for overrepresented alleles that normally originate from the superior parent. BSA data analysis is non-trivial due to sequencing, alignment and screening errors.
To increase the power of the BSA technology and obtain a better distinction between spuriously and truly linked regions, we developed EXPLoRA (EXtraction of over-rePresented aLleles in BSA), an algorithm for BSA data analysis that explicitly models the dependency between neighboring marker sites by exploiting the properties of linkage disequilibrium through a Hidden Markov Model (HMM). Reanalyzing a BSA dataset for high ethanol tolerance in yeast allowed reliably identifying QTLs linked to this phenotype that could not be identified with statistical significance in the original study. Experimental validation of one of the least pronounced linked regions, by identifying its causative gene VPS70, confirmed the potential of our method.
EXPLoRA has a performance at least as good as the state-of-the-art and it is robust even at low signal to noise ratio's i.e. when the true linkage signal is diluted by sampling, screening errors or when few segregants are available.
A molybdenum‐catalyzed deoxygenation of pyridine N‐oxides and N‐hydroxybenzotriazoles, as well as other azole N‐oxides, has been developed using pinacol as an environmentally friendly oxo‐acceptor. ...The only by‐products are acetone and water making the process a convenient alternative to established protocols in terms of waste generation. The reaction is highly chemoselective and a variety of functional groups are tolerated. The processes are usually very clean allowing the isolation of the pure deoxygenated products after a simple extraction in most cases.
PDF
