Usefulness of clopidogrel to protect against diabetes-induced vascular damage.
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ABSTRACT:
SUBMITTER: McClung JA
PROVIDER: S-EPMC5553542 | biostudies-other | 2010 Apr
REPOSITORIES: biostudies-other
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Project description:Daily exposure of humans to nanoparticles from edible plants is inevitable, but significant advances are required to determine whether edible plant nanoparticles are beneficial to our health. Additionally, strategies are needed to elucidate the molecular mechanisms underlying any beneficial effects. Here, as a proof of concept, we used a mouse model to show that orally given nanoparticles isolated from ginger extracts using a sucrose gradient centrifugation procedure resulted in protecting mice against alcohol-induced liver damage. The ginger-derived nanoparticle (GDN)-mediated activation of nuclear factor erythroid 2-related factor 2 (Nrf2) led to the expression of a group of liver detoxifying/antioxidant genes and inhibited the production of reactive oxygen species, which partially contributes to the liver protection. Using lipid knock-out and knock-in strategies, we further identified that shogaol in the GDN plays a role in the induction of Nrf2 in a TLR4/TRIF-dependent manner. Given the critical role of Nrf2 in modulating numerous cellular processes, including hepatocyte homeostasis, drug metabolism, antioxidant defenses, and cell-cycle progression of liver, this finding not only opens up a new avenue for investigating GDN as a means to protect against the development of liver-related diseases such as alcohol-induced liver damage but sheds light on studying the cellular and molecular mechanisms underlying interspecies communication in the liver via edible plant-derived nanoparticles.
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Project description:We demonstrate that transcriptomic profiling of the NER mutant ercc-1 offers better understanding of the complex phenotypes of ercc-1 deficiency in C. elegans, as it does in mammalian models. There is a transcriptomic shift in ercc-1 mutants that suggests a stochastic impairment of growth and development, with a shift towards a higher proportion of males in the population. Extensive phenotypic analyses confirm that NER deficiency in C. elegans leads to severe developmental and growth defects and a reduced replicative lifespan, although post-mitotic lifespan is not affected. Results suggest that these defects are caused by an inability to cope with randomly occurring DNA damage, which may interfere with transcription and replication. The study investigates the developmental and aging phenotypes of different NER deficient C. elegans mutants (xpa-1, ercc-1, xpf-1 and xpg-1), where the transcriptomic profile of ercc-1 mutant is presented. We show that loss of NER function does not affect post-mitotic lifespan, but leads to impaired embryogenesis, germ cell and larval development and causes a reduced replicative lifespan. Phenotypes are most pronounced in ercc-1, xpf-1 and xpg-1 mutant animals. We provide evidence that this more pronounced phenotype is likely caused by the fact that these genes are involved in multiple repair pathways besides NER. Furthermore, transcriptional profiling of ercc-1 mutants confirms these observations, showing that growth and developmental pathways are underrepresented but that insulin signaling is not affected. Our analysis suggests that XPA-1, ERCC-1, XPF-1 and XPG-1 protect animals against replicative aging by preventing the accumulation of randomly acquired DNA damage. Eight mixed stage C. elegans samples were run on Affymetrix GeneChip C. elegans Genome Arrays. Four samples belong to ercc-1 mutant group and four to the wild-type, N2.
2013-09-15 | E-GEOD-39145 | biostudies-arrayexpress
Project description:Metabolic diseases, such as ketosis, are closely associated with decreased reproductive performance (such as delayed estrus and decreased pregnancy rate) in dairy cows. The change of ?-hydroxybutyrate (BHBA) concentration in dairy cattle is an important mechanism leading to ketosis, and its blood concentration in ketotic cows is always significantly higher than in nonketotic cows. Many studies indicated that BHBA can induce oxidative damage in liver and other organs. Proanthocyanidins (PCs) have gained substantial attention in the last decade as strong antioxidative substances. This study aimed to demonstrate a protective effect of PCs against BHBA-induced oxidative stress damage in bovine endometrial (BEND) cells by activating the nuclear erythroid2-related factor2 (Nrf2) signaling pathway. Our research show that PCs could significantly increase activities of catalase (CAT) and glutathione peroxidase (GSH-PX), glutathione (GSH) content, and antioxidant capacity (T-AOC), while significantly decreasing malondialdehyde (MDA) content in BEND cells. Both mRNA and protein expression levels of Nrf2 were significantly increased in BEND cells, and glutamate?cysteine ligase catalytic subunit (GCLC), heme oxygenase 1 (HO-1), manganese superoxide dismutase (Mn-SOD), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were also significantly increased. These results indicate that PCs can antagonize BHBA-induced oxidative damage by activating the Nrf2 signaling pathway to exert an antioxidant effect.
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Project description:BACKGROUND:Excitotoxicity is a central pathological pathway in many neurological diseases with blood-brain barrier (BBB) dysfunction. Kainate, an exogenous excitotoxin, induces epilepsy and BBB damage in animal models, but the direct effect of kainate on brain endothelial cells has not been studied in detail. Our aim was to examine the direct effects of kainate on cultured cells of the BBB and to test three anti-inflammatory and antioxidant drugs used in clinical practice, simvastatin, edaravone and dexamethasone, to protect against kainate-induced changes. METHODS:Primary rat brain endothelial cell, pericyte and astroglia cultures were used to study cell viability by impedance measurement. BBB permeability was measured on a model made from the co-culture of the three cell types. The production of nitrogen monoxide and reactive oxygen species was followed by fluorescent probes. The mRNA expression of kainate receptors and nitric oxide synthases were studied by PCR. RESULTS:Kainate damaged brain endothelial cells and made the immunostaining of junctional proteins claudin-5 and zonula occludens-1 discontinuous at the cell border indicating the opening of the barrier. The permeability of the BBB model for marker molecules fluorescein and albumin and the production of nitric oxide in brain endothelial cells were increased by kainate. Simvastatin, edaravone and dexamethasone protected against the reduced cell viability, increased permeability and the morphological changes in cellular junctions caused by kainate. Dexamethasone attenuated the elevated nitric oxide production and decreased the inducible nitric oxide synthase (NOS2/iNOS) mRNA expression increased by kainate treatment. CONCLUSION:Kainate directly damaged cultured brain endothelial cells. Simvastatin, edaravone and dexamethasone protected the BBB model against kainate-induced changes. Our results confirmed the potential clinical usefulness of these drugs to attenuate BBB damage.
| S-EPMC7008534 | biostudies-literature
Project description:We demonstrate that transcriptomic profiling of the NER mutant ercc-1 offers better understanding of the complex phenotypes of ercc-1 deficiency in C. elegans, as it does in mammalian models. There is a transcriptomic shift in ercc-1 mutants that suggests a stochastic impairment of growth and development, with a shift towards a higher proportion of males in the population. Extensive phenotypic analyses confirm that NER deficiency in C. elegans leads to severe developmental and growth defects and a reduced replicative lifespan, although post-mitotic lifespan is not affected. Results suggest that these defects are caused by an inability to cope with randomly occurring DNA damage, which may interfere with transcription and replication. The study investigates the developmental and aging phenotypes of different NER deficient C. elegans mutants (xpa-1, ercc-1, xpf-1 and xpg-1), where the transcriptomic profile of ercc-1 mutant is presented. We show that loss of NER function does not affect post-mitotic lifespan, but leads to impaired embryogenesis, germ cell and larval development and causes a reduced replicative lifespan. Phenotypes are most pronounced in ercc-1, xpf-1 and xpg-1 mutant animals. We provide evidence that this more pronounced phenotype is likely caused by the fact that these genes are involved in multiple repair pathways besides NER. Furthermore, transcriptional profiling of ercc-1 mutants confirms these observations, showing that growth and developmental pathways are underrepresented but that insulin signaling is not affected. Our analysis suggests that XPA-1, ERCC-1, XPF-1 and XPG-1 protect animals against replicative aging by preventing the accumulation of randomly acquired DNA damage.
2013-09-15 | GSE39145 | GEO
Project description:BackgroundMalaria is one of the most critical global infectious diseases. Severe systemic inflammatory diseases, such as cerebral malaria, lead to the development of cognitive and behavioral alterations, such as learning disabilities and loss of memory capacity, as well as increased anxiety and depression. The consequences are profound and usually contribute to reduce the patient's quality of life. There are no therapies to treat the neurological sequelae of cerebral malaria. Mesenchymal stromal cells (MSCs) may be an alternative, since they have been used as therapy for neurodegenerative diseases and traumatic lesions of the central nervous system. So far, no study has investigated the effects of MSC therapy on the blood-brain barrier, leukocyte rolling and adherence in the brain, and depression like-behavior in experimental cerebral malaria.MethodsMale C57BL/6 mice were infected with Plasmodium berghei ANKA (PbA, 1 × 106 PbA-parasitized red blood cells, intraperitoneally). At day 6, PbA-infected animals received chloroquine (25 mg/kg orally for seven consecutive days) as the antimalarial treatment and were then randomized to receive MSCs (1 × 105 cells in 0.05 ml of saline/mouse) or saline (0.05 ml) intravenously. Parasitemia, clinical score, and survival rate were analyzed throughout the experiments. Evans blue assay was performed at 6, 7, and 15 days post-infection (dpi). Behavioral tests were performed at 5 and 15 dpi. Intravital microscopy experiments and brain-derived neurotrophic factor (BDNF) protein expression analyses were performed at 7 dpi, whereas inflammatory mediators were measured at 15 dpi. In vitro, endothelial cells were used to evaluate the effects of conditioned media derived from MSCs (CMMSC) on cell viability by lactate dehydrogenase (LDH) release.ResultsPbA-infected mice presented increased parasitemia, adherent leukocytes, blood-brain barrier permeability, and reduced BDNF protein levels, as well as depression-like behavior. MSCs mitigated behavioral alterations, restored BDNF and transforming growth factor (TGF)-β protein levels, and reduced blood-brain barrier dysfunction and leukocyte adhesion in the brain microvasculature. In a cultured endothelial cell line stimulated with heme, CMMSC reduced LDH release, suggesting a paracrine mechanism of action.ConclusionA single dose of MSCs as adjuvant therapy protected against vascular damage and improved depression-like behavior in mice that survived experimental cerebral malaria.
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Project description:Lumisterol (L3) is a stereoisomer of 7-dehydrocholesterol and is produced through the photochemical transformation of 7-dehydrocholesteol induced by high doses of UVB. L3 is enzymatically hydroxylated by CYP11A1, producing 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3. Hydroxylumisterols function as reverse agonists of the retinoic acid-related orphan receptors α and γ (RORα/γ) and can interact with the non-genomic binding site of the vitamin D receptor (VDR). These intracellular receptors are mediators of photoprotection and anti-inflammatory activity. In this study, we show that L3-hydroxyderivatives significantly increase the expression of VDR at the mRNA and protein levels in keratinocytes, both non-irradiated and after UVB irradiation. L3-hydroxyderivatives also altered mRNA and protein levels for RORα/γ in non-irradiated cells, while the expression was significantly decreased in UVB-irradiated cells. In UVB-irradiated keratinocytes, L3-hydroxyderivatives inhibited nuclear translocation of NFκB p65 by enhancing levels of IκBα in the cytosol. This anti-inflammatory activity mediated by L3-hydroxyderivatives through suppression of NFκB signaling resulted in the inhibition of the expression of UVB-induced inflammatory cytokines, including IL-17, IFN-γ, and TNF-α. The L3-hydroxyderivatives promoted differentiation of UVB-irradiated keratinocytes as determined from upregulation of the expression at the mRNA of involucrin (IVL), filaggrine (FLG), and keratin 14 (KRT14), downregulation of transglutaminase 1 (TGM1), keratins including KRT1, and KRT10, and stimulation of ILV expression at the protein level. We conclude that CYP11A1-derived hydroxylumisterols are promising photoprotective agents capable of suppressing UVB-induced inflammatory responses and restoring epidermal function through targeting the VDR and RORs.
| S-EPMC7763359 | biostudies-literature
Project description:BackgroundHuman amniotic epithelial cells (hAECs) are attractive candidates for regenerative medical therapy, with the potential to replace deficient cells and improve functional recovery after injury. Previous studies have demonstrated that transplantation of hAECs effectively alleviate chemotherapy-induced ovarian damage via inhibiting granulose cells apoptosis in animal models of premature ovarian failure/insufficiency (POF/POI). However, the underlying molecular mechanism accounting for hAECs-mediated ovarian function recovery is not fully understood.MethodsTo investigate whether hAECs-secreting cytokines act as molecular basis to attenuate chemotherapy-induced ovarian injury, hAECs or hAEC-conditioned medium (hAEC-CM) was injected into the unilateral ovary of POF/POI mouse. Follicle development was evaluated by H&E staining at 1, 2 months after hAECs or hAEC-CM treatment. In addition, we performed a cytokine array containing 507 human cytokines on hAECs-derived serum-free conditioned medium. Finally, we further investigated whether hAECs could affect chemotherapy-induced apoptosis in primary human granulosa-lutein (hGL) cells and the tube formation of human umbilical vein endothelial cells (hUVECs) via a co-culture system in vitro.ResultsWe observed the existence of healthy and mature follicles in ovaries treated with hAECs or hAEC-CM, whereas seriously fibrosis and many atretic follicles were found in the contralateral untreated ovaries of the same mouse. To distinguish cytokines involved in the process of hAECs-restored ovarian function, hAEC-CM was analyzed with a human cytokines array. Results revealed that 109 cytokines in hAEC-CM might participate in a variety of biological processes including apoptosis, angiogenesis, cell cycle and immune response. In vitro experiments, hAECs significantly inhibited chemotherapy-induced apoptosis and activated TGF-β/Smad signaling pathway within primary granulosa-lutein cells in paracrine manner. Furthermore, hAEC-CM was shown to promote angiogenesis in the injured ovaries and enhance the tube formation of human umbilical vein endothelial cells (hUVECs) in co-culture system.ConclusionsThese findings demonstrated that paracrine might be a key pathway in the process of hAECs-mediating ovarian function recovery in animal models of premature ovarian failure/insufficiency (POF/POI).
| S-EPMC5704397 | biostudies-literature
Project description:AimsVascular calcification is a recognized predictor of cardiovascular risk in the diabetic patient, with DNA damage and accelerated senescence linked to oxidative stress-associated pathological calcification. Having previously shown that systemic SIRT1 is reduced in diabetes, the aim was to establish whether SIRT1 is protective against a DNA damage-induced senescent and calcified phenotype in diabetic vascular smooth muscle cells (vSMCs).Methods and resultsImmunohistochemistry revealed decreased SIRT1 and increased DNA damage marker expression in diabetic calcified arteries compared to non-diabetic and non-calcified controls, strengthened by findings that vSMCs isolated from diabetic patients show elevated DNA damage and senescence, assessed by the Comet assay and telomere length. Hyperglycaemic conditions were used and induced DNA damage and enhanced senescence in vSMCs in vitro. Using H2O2 as a model of oxidative stress-induced DNA damage, pharmacological activation of SIRT1 reduced H2O2 DNA damage-induced calcification, prevented not only DNA damage, as shown by reduced comet tail length, but also decreased yH2AX foci formation, and attenuated calcification. While Ataxia Telanglectasia Mutated (ATM) expression was reduced following DNA damage, in contrast, SIRT1 activation significantly increased ATM expression, phosphorylating both MRE11 and NBS1, thus allowing formation of the MRN complex and increasing activation of the DNA repair pathway.ConclusionDNA damage-induced calcification is accelerated within a diabetic environment and can be attenuated in vitro by SIRT1 activation. This occurs through enhancement of the MRN repair complex within vSMCs and has therapeutic potential within the diabetic patient.
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Project description:Neuroinflammation is a critical pathological process of neurodegenerative diseases, and alleviating the inflammatory response caused by abnormally activated microglia might be valuable for treatment. The 18 kDa translocator protein (TSPO), a biomarker of neuroinflammation, is significantly elevated in activated microglia. However, the role of TSPO in microglia activation has not been well demonstrated. In this study, we evaluated the role of TSPO and its ligands PK11195 and Midazolam in LPS-activated BV-2 microglia cells involving mitophagy process and the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation. In the microglia-neuron coculture system, the neurotoxicity induced by LPS-activated microglia and the neuroprotective effects of PK11195 and Midazolam were evaluated. Our results showed that after being stimulated by LPS, the expression of TSPO was increased, and the process of mitophagy was inhibited in BV-2 microglia cells. Inhibition of mitophagy was reversed by pretreatment with PK11195 and Midazolam. And the NLRP3 inflammasome was increased in LPS-activated BV-2 microglia cells in the microglia-neuron coculture system; pretreatment with PK11195 and Midazolam limited this undesirable situation. Lastly, PK11195 and Midazolam improved the cell viability and reduced apoptosis of neuronal cells in the microglia-neuron coculture system. Taken together, TSPO ligands PK11195 and Midazolam showed neuroprotective effects by reducing the inflammatory response of LPS-activated microglia, which may be related to the enhancement of mitophagy and the inhibition of NLRP3 inflammasome.
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