- Mitochondria as a target of organophosphate and carbamate pesticides: Revisiting common mechanisms of action with new approach methodologies. [Journal Article]
- RTReprod Toxicol 2019 Jul 14; 89:83-92
- Mitochondrial toxicity has been proposed as a potential cause of developmental defects in humans. We evaluated 51 organophosphate and carbamate pesticides using the U.S. EPA ToxCast and Tox21 databas…
Mitochondrial toxicity has been proposed as a potential cause of developmental defects in humans. We evaluated 51 organophosphate and carbamate pesticides using the U.S. EPA ToxCast and Tox21 databases. Only a small number of them bind directly to cholinesterases in the parent form. The hydrophobicity of organophosphate pesticides is correlated significantly to TSPO binding affinity, mitochondrial membrane potential reduction in HepG2 cells, and developmental toxicity in Caenorhabditis elegans and Danio rerio (p < 0.05). Structural analysis suggests that in some cases the Krebs cycle is a potential target of organophosphate and carbamate exposure at early life stages. The results support the hypothesis that mitochondrial effects of some organophosphate pesticides-particularly those that require enzymatic activation to the oxon form-may augment the documented effects of disruption of acetylcholine signaling. This study provides a proof of concept for applying new approach methodologies to interrogate mechanisms of action for cumulative risk assessment.
- SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice. [Journal Article]
- SRSci Rep 2019 Jul 15; 9(1):10244
- The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal s…
The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma. SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene. However, clinical diagnostic testing for an SDHC epimutation is not widely available. The objective of this study was to investigate the indications for and the optimum diagnostic pathways for the detection of SDHC epimutations in clinical practice. SDHC promoter methylation analysis of 32 paraffin embedded tumours (including 15 GIST and 17 PPGL) was performed using a pyrosequencing technique and correlated with SDHC gene expression. SDHC promoter methylation was identified in 6 (18.7%) tumours. All 6 SDHC epimutation cases presented with SDH deficient wtGIST and 3/6 cases had multiple primary tumours. No case of constitutional SDHC promoter hypermethylation was detected. Whole genome sequencing of germline DNA from three wtGIST cases with an SDHC epimutation, did not reveal any causative sequence anomalies. Herein, we recommend a diagnostic workflow for the detection of an SDHC epimutation in a service setting.
- Caffeine citrate enhanced cisplatin antitumor effects in osteosarcoma and fibrosarcoma in vitro and in vivo. [Journal Article]
- BCBMC Cancer 2019 Jul 15; 19(1):689
- CONCLUSIONS: This is the first report demonstrating that caffeine citrate has a significantly greater potentiating effect on cisplatin than adding either caffeine or citric acid. The combination of cisplatin with caffeine citrate is a novel treatment that might hold promise for improving the outcome of osteosarcoma and fibrosarcoma, which up till now has generally not responded well to chemotherapy.
- Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. [Journal Article]
- LOLancet Oncol 2019 Jul 10
- CONCLUSIONS: Ramucirumab in combination with pembrolizumab showed a manageable safety profile with favourable antitumour activity in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, and urothelial carcinoma. Our results contribute to the growing evidence that supports dual inhibition of the VEGF-VEGFR2 and PD-1-PD-L1 pathways. This combination could be further explored with or without chemotherapy, especially for patients with tumours for which single-agent checkpoint inhibitors have shown no additional benefit over chemotherapy.
- Metabolomics Differential Analysis Reveals Clinostat Rotation Affects Metabolite Transportation and Increases Organic Acid Production of Aspergillus carbonarius. [Journal Article]
- AEAppl Environ Microbiol 2019 Jul 12
- Contamination by fungi may pose a threat to the long-term operation of the space station because fungi produce organic acids that corrode equipment and mycotoxins that harm human health. Microgravity…
Contamination by fungi may pose a threat to the long-term operation of the space station because fungi produce organic acids that corrode equipment and mycotoxins that harm human health. Microgravity is an unavoidable and special condition in the space station. However, the influence of microgravity on fungal metabolism has not been well studied. Clinostat rotation is widely used to simulate the microgravity condition in studies carried out on Earth. Here, we used metabolomics differential analysis to study the influence of clinostat rotation on the accumulation of organic acids and related biosynthetic pathways in ochratoxin A (OTA)-producing Aspergillus carbonarius As results, clinostat rotation did not affect fungal cell growth or colony appearance, but significantly increased the accumulation of organic acids and OTA both inside cells and in the medium, particularly isocitric acid, citric acid, oxalic acid, as well as a much higher accumulation of some products inside than outside cells, indicating that transport of these metabolites from the cell to the medium was inhibited. This finding corresponded with the change in fatty acid composition of cell membranes and reduced thickness of the cell walls and cell membranes. Amino acid and energy metabolic pathways, particularly the TCA cycle was influenced the most during clinostat rotation compared to normal gravity.IMPORTANCEFungi are ubiquitous in nature and have the ability to corrode various materials by producing metabolites. Research on how the space station environment, especially microgravity, affects fungal metabolism is helpful to understand the role of fungi in space station. This work provides insights on the mechanisms involved in metabolism of corrosive fungus Aspergillus carbonarius under simulated microgravity condition. Our findings have significance not only for preventing material corrosion, but also for ensuring food safety, especially in the space environment.
- Inhibition of anaplerotic glutaminolysis underlies selenite toxicity in human lung cancer. [Journal Article]
- PProteomics 2019 Jul 12; :e1800486
- Large clinical trials and studies in model systems suggest that the chemical form of selenium may dictate chemopreventive and chemotherapeutic efficacy. Selenite induces excess ROS production, which …
Large clinical trials and studies in model systems suggest that the chemical form of selenium may dictate chemopreventive and chemotherapeutic efficacy. Selenite induces excess ROS production, which mediates autophagy and eventual cell death in non-small cell lung cancer (NSCLC) adenocarcinoma A549 cells. The exact mechanisms that underlie these phenotypic effects are unclear, thus the clinical relevance of selenite or other selenocompounds for cancer therapy remains to be determined. Using stable isotope-resolved metabolomics (SIRM) and gene expression analysis, we previously showed that selenite simultaneously disrupts glycolysis, the Krebs cycle, and polyamine metabolism in A549 cells, potentially through perturbed glutaminolysis. Glutaminolysis is a vital anaplerotic process for the proliferation and survival of many cancer cells. Here we investigated the role of key glutaminolytic enzyme glutaminase 1 (GLS1) in selenite's toxicity in A549 cells and in patient-derived lung cancer tissue slices. Using [13 C6 ]-glucose and [13 C5 ,15 N2 ]-glutamine as tracers, we tracked the time course of selenite's action on multiple pathways. We found that selenite inhibited glutaminolysis and glutathione synthesis by suppressing GLS1 expression in addition to blocking the Krebs cycle but transiently activating the pyruvate carboxylase activity. Glutamate supplementation in part rescued these anti-proliferative and oxidative stress activities. Similar metabolic perturbations and tissue necrosis were evident in human patients' cancerous lung tissues in ex vivo experiments with selenite. Altogether, our results support the hypothesis that GLS1 suppression mediates part of the anti-cancer activity of selenite both in vitro and ex vivo. This article is protected by copyright. All rights reserved.
- Gallic acid protects rat liver mitochondria ex vivo from bisphenol A induced oxidative stress mediated damages. [Journal Article]
- TRToxicol Rep 2019; 6:578-589
- Humans are often exposed to bisphenol A (BPA), the monomer of polycarbonate plastics and epoxy resins, through BPA contaminated drinking water, beverages and foods, packaged in polycarbonate plastic …
Humans are often exposed to bisphenol A (BPA), the monomer of polycarbonate plastics and epoxy resins, through BPA contaminated drinking water, beverages and foods, packaged in polycarbonate plastic bottles and cans coated with epoxy resins due to leaching. Several research groups have reported that BPA may cause damage of mitochondria in liver, kidney, heart and brain cells by inducing oxidative stress. The antioxidant efficacy of gallic acid (GA), a polyphenol compound obtained from plants, against different toxicants induced oxidative stress has been well established. The aim of the present study was to examine the protective efficacy of GA against BPA induced oxidative damages of the rat liver mitochondria ex vivo. In our study, we have found a significant decrease in the intactness of mitochondria; a significant increase (P ≤ 0.001) in the levels of lipid peroxidation end product (i.e. malondialdehyde) and protein carbonylation product; and also a significant decrease (P ≤ 0.001) in the reduced glutathione content; when mitochondria were incubated with BPA (160 μM/ml) only. These results indicate that BPA probably causes damage to the cellular macromolecules through oxidative stress. We have observed significant counteractions (P ≤ 0.001) against BPA induced alterations in mitochondrial intactness, lipid peroxidation and protein carbonylation products formation and reduced glutathione content when mitochondria were incubated with BPA and GA (20 μg/ml/ 40 μg/ml/ 80 μg/ml) in combination in a dose-dependent manner. Gallic acid also showed significant restorations (P ≤ 0.001) of the activities of antioxidant enzymes, Krebs cycle enzymes, respiratory chain enzymes and thiolase when mitochondria were incubated with BPA and dosage of GA (20 μg/ml/ 40 μg/ml/ 80 μg/ml) in combination compared to BPA incubated mitochondria. Furthermore, GA significantly (P ≤ 0.001) counteracted the BPA induced decrease in tryptophan and NADH auto-fluroscence levels in mitochondria. This result suggests that GA protects the mitochondria probably by reducing the oxidative stress. Besides, GA protects the mitochondrial surface from BPA induced oxidative damages as viewed under the scanning electron microscope. Considering all the results, it can be concluded that GA shows potent efficacy in protecting the rat liver mitochondria ex vivo from BPA induced oxidative stress mediated damages.
- Peptide ligation by chemoselective aminonitrile coupling in water. [Journal Article]
- NatNature 2019 Jul 10
- Amide bond formation is one of the most important reactions in both chemistry and biology1-4, but there is currently no chemical method of achieving α-peptide ligation in water that tolerates all of …
Amide bond formation is one of the most important reactions in both chemistry and biology1-4, but there is currently no chemical method of achieving α-peptide ligation in water that tolerates all of the 20 proteinogenic amino acids at the peptide ligation site. The universal genetic code establishes that the biological role of peptides predates life's last universal common ancestor and that peptides played an essential part in the origins of life5-9. The essential role of sulfur in the citric acid cycle, non-ribosomal peptide synthesis and polyketide biosynthesis point towards thioester-dependent peptide ligations preceding RNA-dependent protein synthesis during the evolution of life5,9-13. However, a robust mechanism for aminoacyl thioester formation has not been demonstrated13. Here we report a chemoselective, high-yielding α-aminonitrile ligation that exploits only prebiotically plausible molecules-hydrogen sulfide, thioacetate12,14 and ferricyanide12,14-17 or cyanoacetylene8,14-to yield α-peptides in water. The ligation is extremely selective for α-aminonitrile coupling and tolerates all of the 20 proteinogenic amino acid residues. Two essential features enable peptide ligation in water: the reactivity and pKaH of α-aminonitriles makes them compatible with ligation at neutral pH and N-acylation stabilizes the peptide product and activates the peptide precursor to (biomimetic) N-to-C peptide ligation. Our model unites prebiotic aminonitrile synthesis and biological α-peptides, suggesting that short N-acyl peptide nitriles were plausible substrates during early evolution.
- Multi-omics profiling of calcium-induced human keratinocytes differentiation reveals modulation of unfolded protein response signaling pathways. [Journal Article]
- CCCell Cycle 2019 Jul 22; :1-17
- By proteomic, metabolomic and transcriptomic approaches we shed light on the molecular mechanism by which human keratinocytes undergo to terminal differentiation upon in vitro calcium treatment. Prot…
By proteomic, metabolomic and transcriptomic approaches we shed light on the molecular mechanism by which human keratinocytes undergo to terminal differentiation upon in vitro calcium treatment. Proteomic analysis revealed a selective induction of the ribosomal proteins RSSA, an inhibitor of cell proliferation and inducer of differentiation, HSP 60, a protein folding chaperone and GRP78, an unfolding protein response signal. Additionally, we observed an induction of EF1D, a transcription factor for genes that contain heat-shock responsive elements. Conversely, RAD23, a protein involved in regulating ER-associated protein degradation was down-regulated. All these modifications indicated an ER stress response, which in turn activated the unfolded protein response signaling pathway through ATF4, as confirmed both by the modulation of amino acids metabolism genes, such as XBP1, PDI and GPR78, and by the metabolomic analysis. Finally, we detected a reduction of PDI protein, as confirmed by the increase of oxidized glutathione. Metabolome analysis indicated that glycolysis failed to fuel the Krebs cycle, which continued to decrease during differentiation, at glance with the PPP pathway, allowing NADH production and glutathione reduction. Since unfolded protein response is linked to keratinization, these results may be useful for studying pathological mechanisms as well as potential treatments for different pathological conditions. Abbreviation: UPR, unfolded protein response; HEK, human epidermal keratinocytes; HKGS, human keratinocytes growth factor.
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- Linden (Tilia cordata) associated bumble bee mortality: Metabolomic analysis of nectar and bee muscle. [Journal Article]
- PlosPLoS One 2019; 14(7):e0218406
- Linden (Tilia spp.), a profusely flowering temperate tree that provides bees with vital pollen and nectar, has been associated with bumble bee (Bombus spp.) mortality in Europe and North America. Bee…
Linden (Tilia spp.), a profusely flowering temperate tree that provides bees with vital pollen and nectar, has been associated with bumble bee (Bombus spp.) mortality in Europe and North America. Bee deaths have been attributed, with inadequate evidence, to toxicity from mannose in nectar or starvation due to low nectar in late blooming linden. Here, we investigated both factors via untargeted metabolomic analyses of nectar from five T. cordata trees beneath which crawling/dead bumble bees (B. vosnesenskii) were observed, and of thoracic muscle of 28 healthy foraging and 29 crawling bees collected from linden trees on cool mornings (< 30°C). Nectar contained the pyridine alkaloid trigonelline, a weak acetylcholinesterase inhibitor, but no mannose. Principal component analysis of muscle metabolites produced distinct clustering of healthy and crawling bees, with significant differences (P<0.05) in 34 of 123 identified metabolites. Of these, TCA (Krebs) cycle intermediates were strongly represented (pathway analysis; P<0.01), suggesting that the central metabolism is affected in crawling bees. Hence, we propose the following explanation: when ambient temperature is low, bees with energy deficit are unable to maintain the thoracic temperature required for flight, and consequently fall, crawl, and ultimately, die. Energy deficit could occur when bees continue to forage on linden despite limited nectar availability either due to loyalty to a previously energy-rich source or trigonelline-triggered memory/learning impairment, documented earlier with other alkaloids. Thus, the combination of low temperature and nectar volume, resource fidelity, and alkaloids in nectar could explain the unique phenomenon of bumble bee mortality associated with linden.