Oxidative stress plays a key part in cardiovascular event. Growth arrest-specific gene 6 (GAS6) is a vitamin K-dependent ligand which has been shown to exert important effects in heart. The effects ...of GAS6 were evaluated against hydrogen peroxide (H.sub.2O.sub.2) âinduced oxidative stress injury in HL-1 cardiomyocytes. A series of experimental methods were used to analyze the effects of GAS6 on cell viability, apoptosis, oxidative stress, mitochondrial function and AMPK/ACC signaling in H.sub.2O.sub.2âinjured HL-1 cells. In this study, we found that H.sub.2O.sub.2 reduced cell viability, increased apoptotic rate and intracellular reactive oxygen species (ROS). Meanwhile, H.sub.2O.sub.2 decreased the protein levels of GAS6, and increased the protein level of p-AMPK/AMPK, p-ACC/ACC. Then, we observed that overexpression of GAS6 significantly reduced cell death, manifested as increased cell viability, improved oxidative stress, apoptosis and upregulated the levels of GAS6, p-Axl/Axl, Nrf2, NQO1, HO-1, Bcl-2/Bax, PGC-1alpha, NRF1, TFAM, p-AMPK/AMPK, and p-ACC/ACC-related protein expression in HL-1 cells and H.sub.2O.sub.2âinjured cardiomyocytes. To further verify the results, we successfully constructed GAS6 lentiviral vectors, and found GAS6 shRNA partially reversed the above results. These data suggest that AMPK/ACC may be a downstream effector molecule in the antioxidant action of GAS6. In summary, our findings indicate that activation GAS6/Axl-AMPK signaling protects H.sub.2O.sub.2âinduced oxidative stress which is accompanied by the amelioration of oxidative stress, apoptosis, and mitochondrial function.
Disclosure of ultraviolet (UV) radiation is the key feature from environment to cause redness of the skin, inflammation, photoaging and skin cancer. 6-Shogaol, a spicy compound secluded from ginger, ...which shows anti-inflammatory effects. Present study was demonstrated the role of 6-Shogaol on UVB induced oxidative stress and photoaging signaling in human epidermal keratinocytes (HaCaT cells). In this study, UVB-irratiation (180 mJ/cm2) significantly elevated the intracellular ROS levels, depletion of antioxidants resulted in apoptotic HaCaT cells. MAPKs signaling are concerned in oxidative stress; these signaling events are measured as differentiation. We found that 6-shogaol prevents over expression of MAPKs (ERK1, JNK1 & p38), in disclosure of UVB in HaCaT cells. Moreover, 6-shogaol infringed Bax and Bcl-2 in which 20 μg 6-shogaol influenced apoptosis in HaCaT cells by investigating augmented appearance of Bax and condensed appearance of Bcl-2 in contrast to control HaCaT cells. These results suggest that 6-shogaol could be a successful healing agent provides fortification against UVB-induced provocative and oxidative skin reimbursement.
•Disclosure of ultraviolet radiation is the key feature from environment to cause inflammation and photoaging.•6-shogaol repressed the UVB induced inflammation retortion which includes the improved appearance of iNOS, COX-2, and TNF-α.•6-shogaol might be an effectual defensive and healing agent shielding against UVB induced skin reimbursement.
Targeting subcellular organelle with multilevel damage has shown great promise for antitumor therapy. Here, we report a core-shell type of nanoagent with iron (III) carboxylate metal-organic ...frameworks (MOFs) as shell while upconversion nanoparticles (UCNPs) as core, which enables near-infrared (NIR) light-triggered synergistically reinforced oxidative stress and calcium overload to mitochondria. The folate decoration on MOFs shells enables efficient cellular uptake of nanoagents. Based on the upconversion ability of UCNPs, NIR light mediates Fe
-to-Fe
reduction and simultaneously activates the photoacid generator (pHP) encapsulated in MOFs cavities, which enables release of free Fe
and acidification of intracellular microenvironment, respectively. The overexpressed H
O
in mitochondria, highly reactive Fe
and acidic milieu synergistically reinforce Fenton reactions for producing lethal hydroxyl radicals (•OH) while plasma photoacidification inducing calcium influx, leading to mitochondria calcium overload. The dual-mitochondria-damage-based therapeutic potency of the nanoagent has been unequivocally confirmed in cell- and patient-derived tumor xenograft models in vivo.
Cell proliferation, apoptosis, autophagy, oxidative stress and metabolic dysregulation are the basis of many diseases. Forkhead box transcription factor O1 (FOXO1) changes in response to cellular ...stimulation and maintains tissue homeostasis during the above-mentioned physiological and pathological processes. Substantial evidences indicate that FOXO1’s function depends on the modulation of downstream targets such as apoptosis- and autophagy-associated genes, anti-oxidative stress enzymes, cell cycle arrest genes, and metabolic and immune regulators. In addition, oxidative stress, high glucose and other stimulations induce the regulation of FOXO1 activity via PI3k-Akt, JNK, CBP, Sirtuins, ubiquitin E3 ligases, etc., which mediate multiple signalling pathways. Subsequent post-transcriptional modifications, including phosphorylation, ubiquitination, acetylation, deacetylation, arginine methylation and O-GlcNAcylation, activate or inhibit FOXO1. The regulation of FOXO1 and its role might provide a significant avenue for the prevention and treatment of diseases. However, the subtle mechanisms of the post-transcriptional modifications and the effect of FOXO1 remain elusive and even conflicting in the development of many diseases. The determination of these questions potentially has implications for further research regarding FOXO1 signalling and the identification of targeted drugs.
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Daphenylline is a structurally unique member of the triterpenoid
natural alkaloids, which exhibit intriguing biological activities. Six total syntheses have been reported, five of which utilize ...aromatization approaches. Herein, we report a concise protecting-group-free total synthesis by means of a novel intramolecular oxidative dearomatization reaction, which concurrently generates the critical seven-membered ring and the quaternary-containing vicinal stereocenters. Other notable transformations include a tandem reductive amination/amidation double cyclization reaction, to assemble the cage-like architecture, and installation of the other two chiral stereocenters via a highly enantioselective rhodium-catalyzed challenging hydrogenation of the diene intermediate (90% e.e.) and an unprecedented remote acid-directed Mukaiyama-Michael reaction of the complex benzofused cyclohexanone (13:1 d.r.).
Summary Treatments for acute ischaemic stroke continue to evolve after the superior value of endovascular thrombectomy was confirmed over systemic thrombolysis. Unfortunately, numerous ...neuroprotective drugs have failed to show benefit in the treatment of acute ischaemic stroke, making the search for new treatments imperative. Increased awareness of the relevance of rigorous preclinical testing, and appropriate selection of study participants, might overcome the barriers to progress in stroke research. Relevant areas of interest include the search for safe and effective treatment strategies that combine neuroprotection reperfusion, better use of advanced brain imaging for patient selection, and wider implementation of prehospital conducted clinical trials. Randomised controlled trials of combination treatments completed within the past 5 years have included growth factors, hypothermia, minocycline, natalizumab, fingolimod, and uric acid; the latter two drugs with alteplase produced encouraging results. Blocking of excitotoxicity is also being reassessed in clinical trials with new approaches, such as the postsynaptic density-95 inhibitor NA-1, or peritoneal dialysis to remove excess glutamate. The findings of these randomised trials are anticipated to improve treatment options and clinical outcomes in of patients with acute stroke.
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•Milk-derived bioactive peptides inhibit lipid peroxidation in Caco-2 cells.•Antioxidant effect of bioactive peptides is exerted activating Nrf2 pathway.•Milk-derived bioactive ...peptides induce overexpression of phase II enzymes.•Docking simulation shows that K-8-K disrupts the Keap1-Nrf2 interaction.
Bioactive peptides are relevant nutritional factors that exhibit many functions including antioxidant, antihypertensive, anticancer and antimicrobial properties. In this paper, four synthetic peptides ARHPHPHLSFM (A-11-M), AVPYPQR (A-7-R), NPYVPR (N-6-R) and KVLPVPEK (K-8-K) with sequences present in milk proteins were examined for their antioxidant properties. The compounds show moderate free radical scavenging activity in the ABTS and crocin assays (A-7-R and N-6-R) and lipid peroxidation inhibition in Caco-2 cells (N-6-R and K-8-K). All peptides, in particular K-8-K, activate the Keap1-Nrf2 system by allowing the translocation of the transcription factor Nrf2 from the cytosol to nucleus. This activation triggers the overexpression of the antioxidant enzymes Trx1, TrxR1, GR, NQO1 and SOD1. Furthermore, molecular modeling shows that K-8-K is able to hinder the interaction of Nrf2 with Keap1. The reported results show that the antioxidant action in cells of these bioactive peptides is mostly due to the activation of Keap1-Nrf2 signaling pathway.
Abstract The concept of mild chronic vascular inflammation as part of the pathophysiology of cardiovascular disease, most importantly hypertension and atherosclerosis, has been well accepted. Indeed ...there are links between vascular inflammation, endothelial dysfunction and oxidative stress. However, there are still gaps in our understanding regarding this matter that might be the cause behind disappointing results of antioxidant therapy for cardiovascular risk factors in large-scale long-term randomised controlled trials. Apart from the limitations of our knowledge, limitations in methodology and assessment of the body's endogenous and exogenous oxidant-antioxidant status are a serious handicap. The pleiotropic effects of antioxidant and anti-inflammation that are shown by some well-established antihypertensive agents and statins partly support the idea of using antioxidants in vascular diseases as still relevant. This review aims to provide an overview of the links between oxidative stress, vascular inflammation, endothelial dysfunction and cardiovascular risk factors, importantly focusing on blood pressure regulation and atherosclerosis. In view of the potential benefits of antioxidants, this review will also examine the proposed role of vitamin C, vitamin E and polyphenols in cardiovascular diseases as well as the success or failure of antioxidant therapy for cardiovascular diseases in clinical trials.
The production of various reactive oxidant species in excess of endogenous antioxidant defense mechanisms promotes the development of a state of oxidative stress, with significant biological ...consequences. In recent years, evidence has emerged that oxidative stress plays a crucial role in the development and perpetuation of inflammation, and thus contributes to the pathophysiology of a number of debilitating illnesses, such as cardiovascular diseases, diabetes, cancer, or neurodegenerative processes. Oxidants affect all stages of the inflammatory response, including the release by damaged tissues of molecules acting as endogenous danger signals, their sensing by innate immune receptors from the Toll-like (TLRs) and the NOD-like (NLRs) families, and the activation of signaling pathways initiating the adaptive cellular response to such signals. In this article, after summarizing the basic aspects of redox biology and inflammation, we review in detail the current knowledge on the fundamental connections between oxidative stress and inflammatory processes, with a special emphasis on the danger molecule high-mobility group box-1, the TLRs, the NLRP-3 receptor, and the inflammasome, as well as the transcription factor nuclear factor-κB.
Autophagy is a major pathway for degradation of cytoplasmic proteins and organelles, and has been implicated in tumor suppression. Here, we report that mice with systemic mosaic deletion of Atg5 and ...liver-specific Atg7⁻/⁻ mice develop benign liver adenomas. These tumor cells originate autophagy-deficient hepatocytes and show mitochondrial swelling, p62 accumulation, and oxidative stress and genomic damage responses. The size of the Atg7⁻/⁻ liver tumors is reduced by simultaneous deletion of p62. These results suggest that autophagy is important for the suppression of spontaneous tumorigenesis through a cell-intrinsic mechanism, particularly in the liver, and that p62 accumulation contributes to tumor progression.
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