Mitigation of copper toxicity by DNA oligomers in green paramecia.
Ontology highlight
ABSTRACT: Impact of transition metals which catalyze the generation of reactive oxygen species (ROS), on activation of cell death signaling in plant cells have been documented to date. Similarly in green paramecia (Paramecium bursaria), an aquatic protozoan species harboring symbiotic green algae in the cytoplasm, toxicities of various metallic ions have been documented. We have recently examined the effects of double-stranded GC-rich DNA fragments with copper-binding nature and ROS removal catalytic activity as novel plant cell-protecting agents, using the suspension-cultured tobacco cells. Here, we show that above DNA oligomers protect the cells of green paramecia from copper-induced cell death, suggesting that the phenomenon firstly observed in tobacco cells is not limited only within higher plants but it could be universally observable in wider range of organisms.
Project description:Generation and extensive characterization of a gender-balanced, racially/ethnically diverse library of iPSCs from forty clinically healthy human individuals who range in age from 22-61. Specifically, here we provide mRNAseq data of duplicate samples of one clone from each of these forty iPSC lines.
Project description:Baseline transcriptomic signatures of cardiomyocytes differentiated from hiPSC lines generated from clinically well-characterized, diverse healthy human individuals. We provide mRNAseq data of various replicate samples of cardiomyocytes differentiated from 6 hiPSC lines.
Project description:The effects of copper (Cu)-pH interactions on the levels of hormones and related metabolites (HRMs) in Citrus sinensis leaves and roots were investigated. Our findings indicated that increased pH mitigated Cu toxicity-induced alterations of HRMs, and Cu toxicity increased low-pH-induced alterations of HRMs. Increased pH-mediated decreases in ABA, jasmonates, gibberellins, and cytokinins, increases in (±)strigol and 1-aminocyclopropanecarboxylic acid, and efficient maintenance of salicylates and auxins homeostasis in 300 μM Cu-treated roots (RCu300); as well as efficient maintenance of hormone homeostasis in 300 μM Cu-treated leaves (LCu300) might contribute to improved leaf and root growth. The upregulation of auxins (IAA), cytokinins, gibberellins, ABA, and salicylates in pH 3.0 + 300 μM Cu-treated leaves (P3CL) vs. pH 3.0 + 0.5 μM Cu-treated leaves (P3L) and pH 3.0 + 300 μM Cu-treated roots (P3CR) vs. pH 3.0 + 0.5 μM Cu-treated roots (P3R) might be an adaptive response to Cu toxicity, so as to cope with the increased need for reactive oxygen species and Cu detoxification in LCu300 and RCu300. Increased accumulation of stress-related hormones (jasmonates and ABA) in P3CL vs. P3L and P3CR vs. P3R might reduce photosynthesis and accumulation of dry matter, and trigger leaf and root senescence, thereby inhibiting their growth.
Project description:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. The purpose of this study was to clarify effects of brazilian green propolis and the active ingredient against ALS-associated mutant copper-zinc superoxide dismutase (SOD1)-mediated toxicity. Ethanol extract of brazilian green propolis (EBGP) protected N2a cells against mutant SOD1-induced neurotoxicity and reduced aggregated mutant SOD1 by induction of autophagy. Kaempferide and kaempferol, the active ingredients of EBGP, also inhibited mutant SOD1-induced cell death and reduced the intracellular mutant SOD1 aggregates. Both kaempferide and kaempferol significantly suppressed mutant SOD1-induced superoxide in mitochondria. Western blot analysis showed that kaempferol potentially induced autophagy via the AMP-activated protein kinase (AMPK) - the mammalian target of rapamycin (mTOR) pathway. These results suggest that EBGP containing the active ingredient against mutant SOD1-mediated toxicity is a promising medicine or health food for prevention and treatment of ALS.
Project description:Single cell transcriptomic signatures of cardiomyocytes differentiated from hiPSC lines generated from clinically well-characterized, diverse healthy human individuals. We provide single cell mRNAseq data of cardiomyocytes differentiated from 4 hiPSC lines.
Project description:Although it is universally accepted that dopamine transporters (DATs) exist in monomers, dimers and tetramers (i.e. dimers of dimers), it is not known whether the oligomeric organization of DAT is a prerequisite for its ability to take up dopamine (DA), or whether each DAT protomer, the subunit of quaternary structure, functions independently in terms of DA translocation. In this study, copper phenanthroline (CuP) was used to selectively target surface DAT: increasing concentrations of CuP gradually cross-linked natural DAT dimers in LLC-PK1 cells stably expressing hDAT and thereby reduced DA uptake functionality until all surface DATs were inactivated. DATs that were not cross-linked by CuP showed normal DA uptake with DA Km at ~ 0.5 μM and DA efflux with basal and amphetamine-induced DA efflux as much as control values. The cocaine analog 2β-carbomethoxy-3β-[4-fluorophenyl]-tropane (CFT) was capable to bind to copper-cross-linked DATs, albeit with an affinity more than fivefold decreased (Kd of CFT = 109 nM after cross-linking vs 19 nM before). A kinetic analysis is offered describing the changing amounts of dimers and monomers with increasing [CuP], allowing the estimation of dimer functional activity compared with a DAT monomer. Consonant with previous conclusions for serotonin transporter and NET that only one protomer of an oligomer is active at the time, the present data indicated a functional activity of the DAT dimer of 0.74 relative to a monomer.
Project description:Impact of redox active transition metals on activation of cell death signaling in plant cells have been documented to date. We have recently reported that GC-rich DNA oligomers with high affinity for binding of copper and catalytic activity for removal of ROS as novel plant cell-protecting agents. Here, we show that similar DNA oligomers protect the mouse macrophage-like RAW264.7 cells from copper-induced cell death, suggesting that the phenomenon firstly observed in plant model can be expanded to a wider range of cells and/or organisms including mammalian cells.
Project description:Well-defined heparin like oligosaccharides up to decasaccharides were synthesized. It was discovered for the first time that heparin oligosaccharides, as short as tetrasaccharides, can bind with the most toxic tau species, i.e., tau oligomers with nM KD. The binding significantly reduced the cellular uptake of toxic tau oligomers and protected the cells from tau oligomer induced cytotoxicity.
Project description:Picocyanobacteria from the genus Synechococcus are ubiquitous in ocean waters. Their phylogenetic and genomic diversity suggests ecological niche differentiation, but the selective forces influencing this are not well defined. Marine picocyanobacteria are sensitive to Cu toxicity, so adaptations to this stress could represent a selective force within, and between, “species” also known as clades. We compared Cu stress responses in cultures and natural populations of marine Synechococcus from two co-occurring major mesotrophic clades (I and IV). Using custom microarrays and proteomics to characterize expression responses to Cu in the lab and field, we found evidence for a general stress regulon in marine Synechococcus. However, the two clades also exhibited distinct responses to copper. The Clade I representative induced expression of genomic island genes in cultures and Southern California Bight populations, while the Clade IV representative downregulated Fe-limitation proteins. Copper incubation experiments suggest that Clade IV populations may harbor stress-tolerant subgroups, and thus fitness tradeoffs may govern Cu-tolerant strain distributions. This work demonstrates that Synechococcus has distinct adaptive strategies to deal with Cu toxicity at both the clade and subclade level, implying that metal toxicity and stress response adaptations represent an important selective force for influencing diversity within marine Synechococcus populations.
Project description:Anti-tuberculosis (AT) medications, including isoniazid (INH), can cause drug-induced liver injury (DILI), but the underlying mechanism remains unclear. In this study, we aimed to identify genetic factors that may increase the susceptibility of individuals to AT-DILI and to examine genetic interactions that may lead to isoniazid (INH)-induced hepatotoxicity. We performed a targeted sequencing analysis of 380 pharmacogenes in a discovery cohort of 112 patients (35 AT-DILI patients and 77 controls) receiving AT treatment for active tuberculosis. Pharmacogenome-wide association analysis was also conducted using 1048 population controls (Korea1K). NAT2 and ATP7B genotypes were analyzed in a replication cohort of 165 patients (37 AT-DILI patients and 128 controls) to validate the effects of both risk genotypes. NAT2 ultraslow acetylators (UAs) were found to have a greater risk of AT-DILI than other genotypes (odds ratio [OR] 5.6 [95% confidence interval; 2.5-13.2], P = 7.2 × 10-6). The presence of ATP7B gene 832R/R homozygosity (rs1061472) was found to co-occur with NAT2 UA in AT-DILI patients (P = 0.017) and to amplify the risk in NAT2 UA (OR 32.5 [4.5-1423], P = 7.5 × 10-6). In vitro experiments using human liver-derived cell lines (HepG2 and SNU387 cells) revealed toxic synergism between INH and Cu, which were strongly augmented in cells with defective NAT2 and ATP7B activity, leading to increased mitochondrial reactive oxygen species generation, mitochondrial dysfunction, DNA damage, and apoptosis. These findings link the co-occurrence of ATP7B and NAT2 genotypes to the risk of INH-induced hepatotoxicity, providing novel mechanistic insight into individual AT-DILI susceptibility. Yoon et al. showed that individuals who carry NAT2 UAs and ATP7B 832R/R genotypes are at increased risk of developing isoniazid hepatotoxicity, primarily due to the increased synergistic toxicity between isoniazid and copper, which exacerbates mitochondrial dysfunction-related apoptosis.