查看更多>>摘要：Abstract Inflammation and oxidative stress contribute to the initiation and progression of septic lung injury. MicroRNA-217 (miR-217) is proved to be involved in controlling inflammatory response and oxidative stress, yet its role and underlying mechanism in the pathogenesis of septic lung injury remain elusive. Caecal ligation and puncture surgery were performed to generate sepsis in?vivo and mice were kept for 12?h to imitate septic lung injury. Next, mice were administrated with miR-217 antagomir or agomir to decrease or increase the expression of miR-217 in lung tissue. Moreover, primary peritoneal macrophages were separated and incubated with lipopolysaccharide (LPS) to further verify the role of miR-217 in?vitro. miR-217 was upregulated in septic lungs and primary macrophages. miR-217 antagomir alleviated, whereas miR-217 agomir aggravated inflammation and oxidative stress in septic mice and LPS-stimulated macrophages. Further detection identified SIRT1 was responsible for miR-217 antagomir-mediated anti-inflammatory and anti-oxidant effects, and SIRT1 inhibition abolished the beneficial effects of miR-217 antagomir in?vivo and in?vitro. Our data defined miR-217 as a therapeutic target for treating septic lung injury.
查看更多>>摘要：Abstract In the present study, we examined whether glutathione peroxidase-1 (GPx-1), a major H2O2 scavenger in the brain, affects memory deficits induced by Aβ (1-42) in mice. Treatment with 400?pmol/5?μl Aβ (1-42) (i.c.v.) resulted in a reduction of GPx-1 expression in wild-type (WT) mice. An Aβ (1-42)-induced reduction in acetylcholine (ACh) level was observed in the hippocampus. Treatment with Aβ (1-42) consistently resulted in reduced expression and activity of choline acetyltransferase (ChAT) and in an increase in expression and activity of acetylcholinesterase (AChE). Upon examining each of the muscarinic acetylcholine receptors (mAChRs) and nicotinic AChRs, we noted that Aβ (1-42) treatment selectively reduced the levels of M1 mAChR. In addition, Aβ (1-42) induced a significant reduction in phospho-cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) expression. The cholinergic impairments induced by Aβ (1-42) were more pronounced in GPx-1 knockout mice than in WT mice. Importantly, an adenoviral vector encoded with the GPx-1 gene (Ad-GPx-1) significantly rescued Aβ (1-42)-induced cholinergic impairments in GPx-1 knockout mice. In addition, M1 mAChR antagonist dicyclomine significantly counteracted Ad-GPx-1-mediated increases in p-CREB and BDNF expression, as well as memory-enhancing effects in GPx-1 knockout mice, thus indicating that M1 mAChR might be a critical mediator for the rescue effects of Ad-GPx-1. Combined, our results suggest that GPx-1 gene protected against Aβ (1-42)-induced memory impairments via activation of M1 mAChR-dependent CREB/BDNF signalling.
查看更多>>摘要：Abstract Mitochondrial and immune dysfunctions are often implicated in the aetiology of autism spectrum disorder (ASD). Here, we studied for the first time the relationship between ASD severity measures and mitochondrial respiratory rates in freshly isolated platelets as well as the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in isolated neutrophils. We also verified the impact of hyperbaric oxygen therapy (HBOT) on mitochondrial and immune functions as well as on ASD severity measures. Blood samples were collected from three age-matched male groups (Control (Norm-N), autistic (Aut-N), and autistic?+?HBOT (Aut-H); N ?=?10 per group). Using high resolution respirometry, we found that routine basal respiration, complex I- and complex I?+?II-dependent oxidative phosphorylation rate were significantly impaired in Aut-N platelets. Similarly, deficits in immune response of neutrophils were evidenced through lower rates of oxygen consumption and reactive oxygen species (ROS) production by phagocytic NOX. ASD-related behavioural outcomes were found to moderately correlate with platelets’ mitochondrial bioenergetic parameters as well as with NOX-mediated activity in neutrophils. HBOT was not able to improve mitochondrial dysfunctions or to counteract ASD-related behavioral deficits. Although HBOT improved one measure of the immune response; namely, NOX-mediated superoxide burst, this was not associated with significant changes in trends of recurrent infections between groups. Taken together, our data suggest that ASD-associated mitochondria and immune deficits are detectable in platelets and neutrophils. We also found no evidence that HBOT confers any significant improvement of ASD-associated physiological or behavioural phenotypes.
查看更多>>摘要：Abstract More and more evidence support the concept that RNA oxidation plays a substantial role in the progress of multiple diseases; however, only a few studies have reported RNA oxidation caused by microbial pathogens. Urinary 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dGsn), which are broadly used as indicators of oxidative damage of RNA and DNA, were analyzed in this study to determine which can be used as a biomarker of infection in challenged with Vibrio parahaemolyticus (V. parahaemolyticus). In this work, 24 specific-pathogen-free (SPF) male SD rats were randomly divided into two groups: an infection group and a phosphate-buffered saline (PBS) control group. Our results proved that 8-oxo-Gsn rather than 8-oxo-dGsn was significantly increased after challenged with V. parahaemolyticus in urine and tissue samples of SD rats compared with the PBS control group. Simultaneously, white blood cells (WBCs) counts, intestinal inflammation and inflammatory factors (including CRP, IL-6, IL-1β, TNF-α, IL-10, and IL-17A) were also increased sharply. Which has more clinical value is that the trend of urinary 8-oxo-Gsn was consistent with WBCs, intestinal inflammation and all kinds of inflammatory factors. More importantly is that urinary 8-oxo-Gsn of infection group was positively correlated with WBCs and various inflammatory cytokines. In a word, our results demonstrated that as a systemic RNA oxidation biomarker, we hope 8-oxo-Gsn can be used as a biomarker of the severity of microbial pathogens infection, rather than a specific biomarker of microbial pathogens infection.
查看更多>>摘要：Abstract Bidens pilosa plant has been shown to produce okanin flavanone glycoside and its chalcone derivative. In most other plants, due to chalcone isomerase enzyme, the flavanone tends to exist in higher proportions than their chalcone precursors. Herein we have utilized liquid chromatography–mass spectrometry approach and shown that within the leaves of Bidens pilosa plant the two okanin glycosides exist in unusual equal proportional distribution, which indicates that Bidens pilosa plant is an alternative rich source of these highly sought-after antioxidant molecules. The aglycone okanin chalcone (ONC) and okanin flavanone (ONF) have experimentally been shown to exhibit antioxidant activity. However, experimental findings have not conclusively determined which of the two compounds is a more potent antiradical than the other. Herein, the density functional theory (DFT) method is utilized to establish, from structural and thermodynamic energetic considerations, the preferred antioxidant molecule between the two aglycone okanins. A theoretical study on the antioxidant properties of ONC and ONF has been performed by considering their radical scavenging and metal cation (Mn+, where M?=?Cu(II) or Fe (III)) chelation ability. The study has been performed using B3LYP/6-31?+?G(d,p) method. In the case of the metal chelation mechanism, the LANL2DZ pseudo-potential was selected to describe the selected Mn+ cations. The results of the study suggest that ONC is a better radical scavenger than ONF because of the extended electron delocalization on its neutral radical, which is due to the presence of conjugation within the ONC neutral radical after hydrogen atom abstraction. In the metal chelation mechanism, it is noted that the binding energies depend on the media, the nature of the ligand and the cation and the cation coordination site on the ligand. The charge and the spin density on Mn+ decrease on coordination to the ligand. The ability of the ligands to reduce Mn+ cations, coupled with the strong Mn+ binding properties, has significant implication on the antioxidant ability of both okanins. However, since ONC???M+n interaction results in higher binding energy than ONF???M+n interaction, the implication is that ONC is a preferred free metal ion chelator than ONF.
查看更多>>摘要：Abstract Acute lung injury (ALI) is a life-threatening disease without effective and specific therapeutic strategies except the life-supporting treatments. Inflammation and oxidative stress are essential for the progression of ALI. MicroRNA-499-5p (miR-499-5p) has multiple pathophysiological actions; however, its function and mechanisms in ALI remain elusive. Mice were intravenously injected with miR-499-5p agomir, antagomir or the negative controls for 3 consecutive days and then received a single intratracheal injection of lipopolysaccharide (LPS, 5?mg/kg) to generate ALI model. Twenty four hours prior to LPS injection, EX-527 (1?mg/kg) was applied to inhibit SIRT1 activity. We identified a significant upregulation of miR-499-5p in LPS-treated lung tissues. miR-499-5p antagomir prevented, while miR-499-5p agomir promoted inflammation, oxidative stress and ALI in LPS-treated mice. Further studies indicated that miR-499-5p directly bound to the 3’-untranslated region of Sirtuin 1 (Sirt1) and decreased its protein level. SIRT1 inhibition blocked miR-499-5p antagomir-mediated pulmonary protection against LPS injury. miR-499-5p targets SIRT1 to aggravate LPS-induced ALI and it is a promising therapeutic target for the treatment of ALI.
查看更多>>摘要：Abstract Gasotransmitters are small molecules of gases, including nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO). These three gasotransmitters can be endogenously produced and regulate a wide range of pathophysiological processes by interacting with specific targets upon diffusion in the biological media. By redox and epigenetic regulation of various physiological functions, NO, H2S, and CO are critical for the maintenance of intracellular energy homeostasis. Accumulated evidence has shown that these three gasotransmitters control ATP generation, mitochondrial biogenesis, glucose metabolism, insulin sensitivity, lipid metabolism, and thermogenesis, etc. Abnormal generation and metabolism of NO, H2S, and/or CO are involved in various abnormal metabolic diseases, including obesity, diabetes, and dyslipidemia. In this review, we summarized the roles of NO, H2S, and CO in the regulation of energy homeostasis as well as their involvements in the metabolism of dysfunction-related diseases. Understanding the interaction among these gasotransmitters and their specific molecular targets are very important for therapeutic applications.
查看更多>>摘要：Abstract Silver nanoparticles (AgNPs) are the most widely used nanomaterials as antimicrobial agents. AgNPs have been shown to inhibit the growth of and induce apoptosis-like death in Escherichia coli. However, the precise mechanism of AgNPs-induced apoptosis-like death and association with DNA damage-inducible protein F (dinF), a gene of SOS response, is unknown. Here, AgNPs-contributing depletion of intracellular glutathione levels and deactivation of glutathione peroxidase were shown. This step, indicating disruption of the antioxidant system, resulted in overall oxidative stress. Furthermore, DNA oxidation was accompanied, leading to DNA fragmentation. In addition, AgNPs appeared to induce apoptosis-like death via the SOS response. We used sodium pyruvate – an H2O2 quencher – to study the contribution of H2O2, which showed attenuation of AgNPs-induced DNA damage, SOS response, and apoptosis-like death. In dinF mutant, the strain showed a higher degree of DNA damage and apoptotic features. In conclusion, AgNPs mediate apoptosis-like cell death by H2O2-induced oxidative DNA damage. Furthermore, our result demonstrates that dinF participates in this process, which further supports that AgNPs induces SOS response. Our findings may contribute to expanding the new applications of AgNP-based nanomaterials in biomedical fields.
查看更多>>摘要：Abstract Reactive oxygen species (ROS) has been implicated as a contributor to both the onset and the progression of diabetes, however how does redox state affect diabetes has not been fully understood. Here we study the role of redox interference on pancreatic mitochondria and the progression of diabetes. We applied streptozotocin (STZ) to establish diabetes mellitus (DM) model in rats, applied FeSO4 to produce oxidative stress (OS) and Ganoderma lucidum polysaccharides as antioxidant intervention (AO). Our results showed that in OS and DM group, oxidative stress caused the imbalance of redox state, resulting in higher lipid peroxidation level and lower antioxidant level, while AO treatment group reduced blood glucose by repairing the redox balance. The insulin level has the order of Normal Control (NC)<AO?<?DM?<?OS, suggesting oxidative stress promoted insulin secretion in a compensatory mechanism. The Mn-SOD expression in OS groups of pancreas were significantly lower than other groups, while the p53 expression was significantly higher. The mitochondrial ultrastructure of pancreatic β cells were impaired in DM group, and the damage was more severe in OS group, paralleled with significantly reduced secretory granules, both of which were repaired in the AO group. Our results demonstrated that the redox state can affect the blood glucose of diabetic rats, and oxidative stress can aggravate diabetes, while the early antioxidant treatment can alleviate the process of diabetes through reversing the imbalance of redox state and repairing the pancreatic mitochondria. These results suggest that redox balance plays an important role in the treatment of diabetes.
查看更多>>摘要：Abstract The level of inspired oxygen during surgery may modify free radical release, and reperfusion injury. This controlled trial examined the effect of inspired oxygen on F2-isoprostanes (F2-IsoPs), isofurans (IsoFs), and specialized mediators of inflammation resolution (SPM) during knee replacement surgery. Patients received either 30% O2 (control n?=?21), 50% O2 (n?=?20), or 80% O2 (n?=?19) O2, in a parallel design. Hemoglobin (Hb) was measured throughout the surgery and F2-IsoPs, IsoFs and SPM were analyzed by mass spectrometry. The effect of O2 on F2-IsoPs and IsoFs was examined during tourniquet inflation and after tourniquet release. SPM were measured at baseline and the end of surgery. There was a significant interaction between O2 and Hb concentrations with plasma IsoFs during tourniquet inflation. An increase in plasma IsoFs over time was attenuated in the 80% O2 group (p=.012) compared with the 30% O2 group after adjusting for Hb concentration. After tourniquet release, plasma F2-IsoPs were significantly lower in the 50% and 80% O2 groups (p=.009 and p=.001, respectively) compared with the 30% O2 group after adjustment for Hb concentration. The SPM RvD2 and RvE2 were increased with 50% and 80% O2 (RvD2, p=.014 and p=.002, respectively; RvE2, p=.032 with 50% O2) compared with the 30% O2 group, in analyses that corrected for Hb concentration. We have shown for the first time that higher O2 levels may be beneficial in reducing oxidative stress and increasing resolution of inflammation during surgery that involves reperfusion after application of a tourniquet.
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