Project description:This study compares flare type self-expandable metal stent with conventional D-type self-expandable metal stent for malignant colorectal obstruction.
Project description:The natural product holomycin contains a unique cyclic disulfide and exhibits broad-spectrum antimicrobial activities. Reduced holomycin chelates metal ions with high affinity and disrupts metal homeostasis in the cell. To identify cellular metalloproteins that are affected by holomycin, reactive-cysteine profiling was performed using isotopic Tandem Orthogonal Proteolysis–Activity-based Protein Profiling. This chemoproteomic analysis showed that holomycin treatment increases the reactivity of metal-coordinating cysteine residues in several zinc-dependent and iron-sulfur cluster-dependent enzymes. Whole-proteome abundance analysis revealed that holomycin treatment induces zinc starvation, iron starvation, and cellular stress. This study sets the stage for investigating the impact of metal-binding molecules on metalloproteomes using chemoproteomics.
Project description:DHPM-thiones rescue Ab-mediated toxicity in a metal-dependent manner that strongly synergizes with clioquinol, a known metal-binding and cytoprotective compound. RNA-seq experiments reveal a modest, yet specific effect on metal-responsive genes that do not change with the inactive control compound.
Project description:A convergence of technological breakthroughs in the past decade has facilitated the development of rapid screening tools for biomarkers of toxicant exposure and effect. Platforms using the whole adult organism to evaluate the genome-wide response to toxicants are especially attractive. Recent work demonstrates the feasibility of this approach in vertebrates using the experimentally robust zebrafish model. In the present study, we evaluated gene expression changes in whole adult zebrafish following an acute 24 hour exposure to three metals with known human health risks. Male adult zebrafish were exposed to nickel chloride, cobalt chloride, and sodium dichromate concentrations corresponding to their respective 96 hr LC20, LC40 and LC60. Histopathology was performed on a subset of metal-exposed zebrafish to phenotypically anchor transcriptional changes associated with each metal. Comparative analysis identified subsets of differentially expressed transcripts both overlapping and unique to each metal. Application of gene ontology (GO) and transcription factor enrichment algorithms revealed a number of key biological processes perturbed by metal exposures and the master transcriptional regulators mediating gene expression changes. Metal exposures differentially activated biological processes associated with ribosome biogenesis, proteosomal degradation and p53 signaling cascades, while repressing oxygen-generating pathways associated with amino acid and lipid metabolism. Despite appreciable effects on gene regulation, nickel exposures did not induce any morphological alterations in zebrafish organs and tissues. Histopathological effects of cobalt remained confined to the olfactory system, while chromium targeted the gills, pharynx and intestinal mucosa. A number of enriched transcription factors mediate the observed gene response to metal exposure, including known targets such as p53, HIF1M-oM-^AM-! and the myc oncogene and novel regulatory factors such as XBP1, GATA6 and HNF3M-oM-^AM-". This work uses an experimentally innovative approach to capture global responses to metal exposures and provides mechanistic insights into metal toxicity mechanisms. Metal induced changes in gene expression in zebrafish were measured after 24 h exposures to each of three metals (nickel, chromium or cobalt). A total of 48 arrays were processed - 16 arrays per metal with 4 replicates for each exposure condition (control, low, mid, and high).
Project description:Background: Prolonged exposure to toxic heavy metals leads to deleterious health outcomes such as kidney injury and irreversible progression to chronic kidney disease. For example, veterans return from the battlefield with increasing amounts of retained metal fragments. Certain community water sources in the US are contaminated with varying levels of heavy metals, including uranium and lead. One of the key challenges is to detect damage to kidney tissue before glomerular filtration rate is affected. Methods: High-throughput transcriptomics (HTT) has recently been demonstrated have high sensitivity and specificity as a rapid and cost-effective assay for detecting tissue toxicity. To better understand the molecular signature of early kidney damage, we performed RNA-seq analysis on renal tissue using a rat model of soft tissue-embedded metal exposure. We them performed small RNA-seq analysis on serum samples from the same animals in an effort to identify miRNA biomarkers of kidney damage. Results: We found that metals, especially lead and depleted uranium, induces oxidative damage that mainly cause dysregulated mitochondrial gene expression. Utilizing publicly available single-cell RNA-seq datasets, we demonstrate that deep learning-based cell type decomposition effectively identified cells within the kidney that were affected by metal exposure. By combining random forest feature selection and statistical methods, we further identify miRNA-423 as a promising early systemic marker of kidney injury. Conclusion: Our data suggests that combining HTT and deep learning represents a promising approach for identifying cell injury in kidney tissue. We propose miRNA-423 as a potential serum biomarker for early detection of kidney injury.
Project description:A convergence of technological breakthroughs in the past decade has facilitated the development of rapid screening tools for biomarkers of toxicant exposure and effect. Platforms using the whole adult organism to evaluate the genome-wide response to toxicants are especially attractive. Recent work demonstrates the feasibility of this approach in vertebrates using the experimentally robust zebrafish model. In the present study, we evaluated gene expression changes in whole adult zebrafish following an acute 24 hour exposure to three metals with known human health risks. Male adult zebrafish were exposed to nickel chloride, cobalt chloride, and sodium dichromate concentrations corresponding to their respective 96 hr LC20, LC40 and LC60. Histopathology was performed on a subset of metal-exposed zebrafish to phenotypically anchor transcriptional changes associated with each metal. Comparative analysis identified subsets of differentially expressed transcripts both overlapping and unique to each metal. Application of gene ontology (GO) and transcription factor enrichment algorithms revealed a number of key biological processes perturbed by metal exposures and the master transcriptional regulators mediating gene expression changes. Metal exposures differentially activated biological processes associated with ribosome biogenesis, proteosomal degradation and p53 signaling cascades, while repressing oxygen-generating pathways associated with amino acid and lipid metabolism. Despite appreciable effects on gene regulation, nickel exposures did not induce any morphological alterations in zebrafish organs and tissues. Histopathological effects of cobalt remained confined to the olfactory system, while chromium targeted the gills, pharynx and intestinal mucosa. A number of enriched transcription factors mediate the observed gene response to metal exposure, including known targets such as p53, HIF1 and the myc oncogene and novel regulatory factors such as XBP1, GATA6 and HNF3. This work uses an experimentally innovative approach to capture global responses to metal exposures and provides mechanistic insights into metal toxicity mechanisms.