Ontology highlight
ABSTRACT:
PROVIDER: PRJNA623208 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11484113_1.fastq.gz | Fastqsanger.gz | |||
| SRR11484113_2.fastq.gz | Fastqsanger.gz | |||
| SRR11484114_1.fastq.gz | Fastqsanger.gz | |||
| SRR11484114_2.fastq.gz | Fastqsanger.gz | |||
| SRR11484115_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 10 |
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Project description:Coenzyme Q (CoQ) deficiency has been associated to primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In the Coq9R239X mouse model of fatal mitochondrial encephalopathy due to CoQ deficiency, we have tested the therapeutic potential of β-Resorcylic Acid (β-RA), a structural analog of the CoQ precursor 4-hydroxybenzoic acid and the anti-inflammatory salicylic acid. β-RA noticeably rescued the phenotypic, morphological and histopathological signs of the encephalopathy, leading to a significant increase in the survival. Those effects were due to the decrease of the levels of demethoxyubiquinone-9 (DMQ9) and the increase of mitochondrial bioenergetics in peripheral tissues. However, neither CoQ biosynthesis and mitochondrial function changed in the brain after the therapy, suggesting that some endocrine interactions may induce the reduction of the astrogliosis, spongiosis and the secondary down-regulation of astrocytes-related neuroinflammatory genes. Because the therapeutic outcomes of β-RA administration were superior to those after CoQ10 supplementation, its use in the clinic should be considered in CoQ deficiencies.
2018-09-22 | GSE120287 | GEO
Project description:Hydroxybenzoic acids derivatives (HBAs) are natural phenolic compounds that are being used for the experimental treatment of primary CoQ deficiency. Some of these compounds are also able to reduce the animals body weight. However, the mechanisms of these therapeutic effects remain obscure. In this study, we used an analysis of the mitochondrial proteome to evaluate the effect of a high dose of-resorcylic acid (-RA), an HBA potentially useful for the treatment of Coenzyme Q (CoQ) deficiencies, in wild-type animals. The results highlight novel molecular mechanisms of HBAs and provide a translational perspective for the use the -RA in the treatment of CoQ deficiencies, overweight and obesity.
2021-11-03 | PXD018311 | Pride
Project description:4-Hydroxybenzoic acid (4-HB) is the natural precursor for CoQ biosynthesis. Hydroxybenzoic acids derivatives (HBAs) have been recently used for the experimental treatment of primary CoQ deficiency. However, the mechanisms of these therapeutic effects remain obscure. In this study, we performed an analysis in plasma to evaluate the effect of supplementation with-resorcylic acid (-RA) or vanillic acid (VA), two HBAs potentially useful for the treatment of Coenzyme Q (CoQ) deficiencies, in an animal model of mitochondrial encephalopathy due to CoQ deficiency. The results help in the identification of potential biomarkers and/or endocrine factors that contribute to the pathophysiologic characteristics of the disease and its response to treatments, supporting important scientific and medical impacts for the use of -RA or VA in the treatment of CoQ deficiency.
2022-07-15 | PXD030303 | Pride
Project description:β-RA reduces DMQ/CoQ ratio and recues the encephalopathic phenotype in Coq9R239X mice
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Project description:Dose-dependent toxic effects of dietary TCDD on juvenile zebrafish
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Project description:Type 1 diabetes (T1D) is an autoimmune disease leading to dysfunction and loss of insulin-secreting β cells. In β cells, polyamines have been implicated in causing cellular stress and dysfunction. An inhibitor of polyamine biosynthesis, difluoromethylornithine (DFMO), has been shown to delay T1D in mouse models and preserve β cell function in humans with recent-onset T1D. Another small molecule, N1,N11-diethylnorspermine (DENSpm), both inhibits polyamine biosynthesis and accelerates polyamine metabolism and is currently being tested for efficacy in cancer clinical trials. In this study, we show that DENSpm depletes intracellular polyamines as effectively as DFMO in mouse β cells. RNA sequencing analysis, however, suggests that the cellular reponses to DENSpm and DFMO differ, with the two sharing similar effects on cellular proliferation, but the latter showing greater effects on mRNA translation and protein folding pathways. In the low-dose streptozotocin-induced mouse model of T1D, DENSpm administration did not prevent or delay diabetes outcome, but did result in improvements in glucose tolerance and reductions in islet oxidative stress. In non-obese diabetic (NOD) mice, short-term DENSpm administration resulted in slight reduction in insulitis and proinflammatory Th1 cells in the pancreatic lymph nodes. Longer term treatment resulted in a dose-dependent increase in mortality. Notwithstanding the efficacy of both DFMO and DENSpm in reducing potentially toxic polyamine levels in β cells, our results highlight the discordant T1D outcomes that result from differing mechanisms of polyamine depletion and, more importantly, that toxic effects of DENSpm may limit its utility in T1D treatment.
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Project description:Insulin resistance is a major risk factor for human metabolic diseases including type 2 diabetes, cardiovascular diseases and some cancers. We analysed the proteome analyses across in vitro and in vivo models of insulin resistance to find common features of insulin resistance and identified lower expression of enzymes within the mevalonate pathway. mitochondrial CoQ was lower in all models of insulin resistance. Specifically, the coenzyme Q (CoQ) biosynthetic proteins Coq 7 and 9 were decreased in adipose tissue from a mouse model of diet-induced obesity, and mitochondrial CoQ was lower in all models of insulin resistance. Moreover, the mitochondrial content of CoQ in adipose tissue correlated positively with insulin sensitivity in obese humans. Inhibition of CoQ biosynthesis induced insulin resistance, while replenishment of CoQ restored insulin sensitivity in cell culture models and in animals, demonstrating that loss of CoQ is both necessary and sufficient for adipocyte insulin resistance. Mechanistically, loss of CoQ increased mitochondrial peroxides. These findings place defective mitochondrial CoQ homeostasis upstream of increased mitochondrial oxidants in the induction of insulin resistance in adipocytes and highlight the CoQ biosynthetic pathway as an appealing therapeutic target to combat insulin resistance.
2018-02-07 | PXD005128 | Pride
Project description:Identification of disease and therapeutic biomarkers in CoQ deficiency.
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Project description:Adipocytes play a major role in whole body fuel homeostasis. Integrated proteomic analysis of adipose from insulin resistant versus healthy humans or mice or in 3T3-L1 adipocytes revealed defects in the mevalonate/coenzyme Q (CoQ) biosynthesis pathway as a unifying feature of adipocyte insulin resistance. CoQ was decreased selectively in mitochondria in all insulin resistant conditions and this was associated with a selective increase in mitochondrial oxidative stress. CoQ supplementation lowered mitochondrial oxidative stress and reversed insulin resistance in vitro and in vivo. Decreasing mitochondrial CoQ by genetic or pharmacological means caused insulin resistance by increasing mitochondrial oxidants from complex II. Our data suggest that loss of mitochondrial CoQ is a proximal driver of mitochondrial oxidative stress and insulin resistance. These findings may explain why statin use is associated with insulin resistance, and suggest that mitochondrial CoQ may be an effective therapeutic target for treating insulin resistance in humans.
2018-02-09 | PXD006891 | Pride