490 research outputs found
Synthesis and anticancer activity of CDDO and CDDO-me, two derivatives of natural triterpenoids
Triterpenoids are natural compounds synthesized by plants through cyclization of squalene, known for their weak anti-inflammatory activity. 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), and its C28 modified derivative, methyl-ester (CDDO-Me, also known as bardoxolone methyl), are two synthetic derivatives of oleanolic acid, synthesized more than 20 years ago, in an attempt to enhance the anti-inflammatory behavior of the natural compound. These molecules have been extensively investigated for their strong ability to exert antiproliferative, antiangiogenic, and antimetastatic activities, and to induce apoptosis and differentiation in cancer cells. Here, we discuss the chemical properties of natural triterpenoids, the pathways of synthesis and the biological effects of CDDO and its derivative CDDO-Me. At nanomolar doses, CDDO and CDDO-Me have been shown to protect cells and tissues from oxidative stress by increasing the transcriptional activity of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2). At doses higher than 100 nM, CDDO and CDDO-Me are able to modulate the differentiation of a variety of cell types, both tumor cell lines or primary culture cell, while at micromolar doses these compounds exert an anticancer effect in multiple manners; by inducing extrinsic or intrinsic apoptotic pathways, or autophagic cell death, by inhibiting telomerase activity, by disrupting mitochondrial functions through Lon protease inhibition, and by blocking the deubiquitylating enzyme USP7. CDDO-Me demonstrated its efficacy as anticancer drugs in different mouse models, and versus several types of cancer. Several clinical trials have been started in humans for evaluating CDDO-Me efficacy as anticancer and anti-inflammatory drug; despite promising results, significant increase in heart failure events represented an obstacle for the clinical use of CDDO-Me
Approach combining the Rietveld method and pairs distribution function analysis to study crystalline materials under high-pressure and/or temperature: Application to rhombohedral Bi2Te3 phase
An approach combining the Rietveld method and pairs distribution function
analysis to study crystalline materials under high pressure or temperature was
early proposed by us, and in this study, it was applied to investigate de
effect of high pressure on the rhombohedral Bi2Te3 phase. The refined
structural parameters obtained from the Rietveld refinement of the XRD patterns
measured for pressures up to 9.1 GPa were used as input data to simulate the
partial and total structure factors SBiBi, SBiTe, STeTe, and SBi2Te3. Fourier
transformation of the Sij factors permitted to obtain the partial and total
pairs distribution functions GBiBi, GBiTe, GTeTe, and GBi2Te3. The first
coordination shells of these Gij functions are formed by subshells and, with
increasing pressure in the 1.1 to 6.3 GPa range, occur a partial separation of
subshells. Also, the increase of pressure in this range promotes a drastic
reduction in the values of the intralayer angles TeBiTe, and consequently, in
the intralayer distance TeTe. A drastic reduction in the interlayers distance
Te-Te was also observed. Several studies are reported in the literature,
including one carried out by us, show the presence of an ETT in this pressure
range. The obtained results suggest that the ETT is related with the decrease
of the intralayer angles TeBiTe, and intra- and interlayer distance TeTe.
Experimental results describing the pressure dependence the thermoelectric
power, electrical resistivity, and power fator for rhombohedral Bi2Te3 are
reported, and an enhancement of the power factor in the 1.1 to 6.3 GPa range is
observed. The results obtained in this study give evidence that this
enhancement in the power factor is related with the decrease of the intralayer
angles TeBiTe, and with the decrease of intralayer- and interlayers homopolar
TeTe bonds
DNA Topoisomerase I differentially modulates R-loops across the human genome
Background: Co-transcriptional R-loops are abundant non-B DNA structures in mammalian genomes. DNA Topoisomerase I (Top1) is often thought to regulate R-loop formation owing to its ability to resolve both positive and negative supercoils. How Top1 regulates R-loop structures at a global level is unknown. Results: Here, we perform high-resolution strand-specific R-loop mapping in human cells depleted for Top1 and find that Top1 depletion results in both R-loop gains and losses at thousands of transcribed loci, delineating two distinct gene classes. R-loop gains are characteristic for long, highly transcribed, genes located in gene-poor regions anchored to Lamin B1 domains and in proximity to H3K9me3-marked heterochromatic patches. R-loop losses, by contrast, occur in gene-rich regions overlapping H3K27me3-marked active replication initiation regions. Interestingly, Top1 depletion coincides with a block of the cell cycle in G0/G1 phase and a trend towards replication delay. Conclusions: Our findings reveal new properties of Top1 in regulating R-loop homeostasis in a context-dependent manner and suggest a potential role for Top1 in modulating the replication process via R-loop formation
A DNA Tool for the Identification of Heavily Exploited Atlantic Billfishes
Due to the morphological similarities among species, the International Commission for the Conservation of the Atlantic Tunas has recommended the use of diagnostic molecular tools to allow for robust species-level identifications of the billfishes. In this study, a protocol for the molecular identification of all six Atlantic billfishes was developed utilizing a PCR–RFLP approach, targeting the mitochondrial gene cytochrome c oxidase subunit 1. A survey of 28 restriction endonucleases identified two enzymes (TaqI and HaeIII) that produced species-specific banding patterns sufficient to distinguish species. The protocol was validated against billfishes captured across their Atlantic distributions
Circulating and Tumor-Associated Neutrophils in the Era of Immune Checkpoint Inhibitors: Dynamics, Phenotypes, Metabolism, and Functions.
Neutrophils are the most abundant myeloid cells in the blood and are a considerable immunological component of the tumor microenvironment. However, their functional importance has often been ignored, as they have always been considered a mono-dimensional population of terminally differentiated, short-living cells. During the last decade, the use of cutting-edge, single-cell technologies has revolutionized the classical view of these cells, unmasking their phenotypic and functional heterogeneity. In this review, we summarize the emerging concepts in the field of neutrophils in cancer, by reviewing the recent literature on the heterogeneity of both circulating neutrophils and tumor-associated neutrophils, as well as their possible significance in tumor prognosis and resistance to immune checkpoint inhibitors
Circulating and Tumor-Associated Neutrophils in the Era of Immune Checkpoint Inhibitors: Dynamics, Phenotypes, Metabolism, and Functions
Simple Summary Neutrophils are the most abundant leukocytes in the circulation, represent the first line of defense in the immune system and mediate inflammation. Increasing evidence suggests that neutrophils constitute a large population of cells with phenotypic and functional heterogeneity. In this review, we summarize and discuss new findings delineating that both circulating neutrophils and tumor-associated neutrophils have a role in tumor prognosis and resistance to immune checkpoint inhibitors. Neutrophils are the most abundant myeloid cells in the blood and are a considerable immunological component of the tumor microenvironment. However, their functional importance has often been ignored, as they have always been considered a mono-dimensional population of terminally differentiated, short-living cells. During the last decade, the use of cutting-edge, single-cell technologies has revolutionized the classical view of these cells, unmasking their phenotypic and functional heterogeneity. In this review, we summarize the emerging concepts in the field of neutrophils in cancer, by reviewing the recent literature on the heterogeneity of both circulating neutrophils and tumor-associated neutrophils, as well as their possible significance in tumor prognosis and resistance to immune checkpoint inhibitors
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