Molecular Effects of Doxycycline Treatment on Pterygium from Caucasian Patients as Revealed by Massive Transcriptome Sequencing
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE58441 | GEO | 2014/12/02
SECONDARY ACCESSION(S): PRJNA252615
REPOSITORIES: GEO
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Project description:A total of 332 genes were identified which modified their expression in a dose-dependent manner upon exposure to doxycycline. The more represented cellular pathways included all mitochondrial genes, the endoplasmic reticulum stress response, integrins and extracellular matrix components, and growth factors.
2014-12-02 | GSE34736 | GEO
Project description:Pterygium is a lesion of the eye surface which involves cell proliferation, migration, angiogenesis, fibrosis, and extracellular matrix remodelling. Surgery is the only approved method to treat this disorder, but high recurrence rates are common. Recently, it has been shown in a mouse model that treatment with doxycycline resulted in reduction of the pterygium lesions. Here we study the mechanism(s) of action by which doxycycline achieves these results, using massive sequencing techniques. Surgically removed pterygia from 10 consecutive patients were set in short term culture and exposed to 0 (control), 50, 200, and 500 µg/ml doxycycline for 24 h, their mRNA was purified, reverse transcribed and sequenced through Illumina's massive sequencing protocols. Acquired data were subjected to quantile normalization and analyzed using cytoscape plugin software to explore the pathways involved. False discovery rate (FDR) methods were used to identify 332 genes which modified their expression in a dose-dependent manner upon exposure to doxycycline. The more represented cellular pathways included all mitochondrial genes, the endoplasmic reticulum stress response, integrins and extracellular matrix components, and growth factors. A high correlation was obtained when comparing ultrasequencing data with qRT-PCR and ELISA results. Doxycycline significantly modified the expression of important cellular pathways in pterygium cells, in a way which is consistent with the observed efficacy of this antibiotic to reduce pterygium lesions in a mouse model. Clinical trials are under way to demonstrate whether there is a benefit for human patients.
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Project description:Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and often associated with progression from benign to invasive, metastatic stages. Mutations inactivate tumor suppression by p53 and endow the protein with novel gain-of-function (GOF) activities that actively promote tumor progression, metastasis and therapy resistance. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 (mutp53) target gene. A comprehensive pan-cancer analysis revealed a highly significant correlation between GOF p53 mutations and elevated expression of ENTPD5. Mechanistically, regulation of ENTPD5 by mutp53 is mediated by the histone H3 lysine 4 (H3K4) methyltransferase COMPASS complex. ENTPD5 has been shown to function in the endoplasmic reticulum as a UDPase to promote the N-glycosylation and folding of membrane proteins such as growth factor receptors and integrins. We show ENTPD5 to be a mediator of mutp53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals N-glycosylation in the endoplasmic reticulum as a novel mechanism underlying the progression of tumors with mutp53 that could provide new possibilities for treating cancers driven by GOF p53 mutations.
2016-11-29 | E-MTAB-4672 | biostudies-arrayexpress
Project description:To characterize the mitochondrial stress response induced by Doxycycline in vivo in liver and kidneys, we administered doxycycline (Dox) at 500 mg/kg/day (mpkd) in the drinking water to 9 weeks-old germ-free C57BL/6J mice for 16 days, hence eliminating the potential confounding impacts of Doxycycline on the microbiome.
2022-09-14 | GSE202754 | GEO
Project description:In this study, we isolated a potent doxycycline-degrading bacterium, Chryseobacterium sp. WX1, from environmental samples. To elucidate the molecular mechanisms underlying doxycycline degradation by strain WX1, we assessed and interpreted the proteomic profiles of Chryseobacterium sp. WX1 under conditions both with and without doxycycline exposure.
2023-09-07 | PXD045182 | Pride
Project description:The Akita mutation (C96Y) in the insulin gene results in early onset diabetes in both humans and mice. Expression of the mutant proinsulin (C96Y) causes endoplasmic reticulum (ER) stress in pancreatic ?-cells and consequently the cell activates the unfolded protein response (UPR). Since the proinsulin is terminally misfolded however, the ER stress is irremediable and chronic activation of the UPR eventually activates apoptosis in the cell population. We used microarray gene expression arrays to analyze the IRE1-dependent activation of genes in response to misfolded proinsulin expression in an inducible mutant proinsulin (C96Y) insulinoma cell line by inhibiting the IRE1 endoribonucleas activity with a specific inhibitor, 4u8c. Insulinoma cells with doxycycline inducible C96Y-proinsulin expression were either untreated, treated with doxycycline alone or treated with dox and 4u8c. This was done with two biological replicates.
2014-07-16 | E-GEOD-58866 | biostudies-arrayexpress
Project description:Interventions: Doxycycline is a broad-spectrum antibiotic, which prevents the binding of amino-acyltRNA to the messenger RNA-30S ribosomal subunit, preventing polyribosome formation. It is approved in New Zealand for the treatment of chronic prostatitis, sinusitis, syphilis, pelvic inflammatory disease, malaria, recurrent aphthous ulceration, and acne vulgaris. Doxycycline primarily exerts it’s antimicrobial action by bacteriostasis. It also has antinflammatory effects.
Doxycycline will be administered as two 100mg tablets orally each morning, starting two days prior to the first dose of short-course radiotherapy (SCRT), until one day prior to surgery for rectal cancer. Surgery will be performed within three weeks of starting radiotherapy treatment. The duration of doxycycline will be between 12 and 23 days, and will be determined by each participant s individual treatment schedule.
Adherence will be assessed through a combination of a patient diary, and count of the number of tablets remaining in the drug container on the patients admission for rectal cancer surgery.
Primary outcome(s): Difference in the mean immunohistochemistry (IHC) H-scores for CD133 in resected tumours between the doxycycline and control groups.[Based on rectal cancers surgically resected within 3 weeks of radiotherapy.]
Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Type of endpoint: Safety/efficacy
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Project description:The aim of this Phase 2, two-arm, randomized, double blind placebo controlled study is to evaluate the efficacy of combination therapy of doxycycline and Vitamin K1 compared to doxycycline plus placebo for the prevention of acne-like skin rash in mCRC patients receiving first line cetuximab treatment.
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Project description:Mice with mitochondrial complex I deficiency (Ndufs4-/-) suffer from severe energy impairment primarily affecting the brain and die at P55. A small molecule screen developed by our lab using cells harboring human mitochondrial disease mutations identified antibiotics targeting mitochondrial translation as potent inhibitors of cell death under nutrient stress conditions. Doxycycline, which was identified amongst these antibiotics, was administered in the diet of Ndufs4-/- mice after weaning at P21. Mice fed with doxycycline showed improved motor function and significantly increased lifespan relative to untreated Ndufs4-/- mice. In order to investigate the molecular changes promoted by doxycycline in the brains of these mice, Ndufs4-/- doxycycline treated (DOX), Ndufs4-/- untreated (KO), and Ndufs4+/+ (WT) control mice were sacrificed at P55 and their brains harvested. Proteomic analysis revealed doxycycline treatment largely prevented the neuroimmune and inflammatory profile identified in the Ndufs4-/- mice. These findings implicate a potentially causality of these proteins in the neuronal cell death ultimately leading to the observed brain pathology.
2021-09-09 | PXD022860 | Pride
Project description:Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) is an endoplasmic reticulum stress–related gene, which improves cell perseverance against challenges of high levels of protein misfolding during endoplasmic reticulum stress by retaining good activity of oxidative protein folding. Numerous studies have shown abnormal expression of ERo1α in various diseases, but its downstream target are not fully understood. Our work will help in the elucidation of the downstream molecular mechanism of ERO1α.
2024-04-17 | GSE246899 | GEO