Systemic hypoxia increases leukocyte emigration and vascular permeability in conscious rats

2000 ◽  
Vol 89 (4) ◽  
pp. 1561-1568 ◽  
Author(s):  
John G. Wood ◽  
Jennifer S. Johnson ◽  
Leone F. Mattioli ◽  
Norberto C. Gonzalez
Keyword(s):  
Vascular Function ◽  
Microvascular Permeability ◽  
Hypoxic Exposure ◽  
Ros Generation ◽  
Leukocyte Adherence ◽  
Conscious Animal ◽  
Subsequent Decrease ◽  
Conflicting Evidence ◽  
Systemic Hypoxia

We recently observed that acute systemic hypoxia produces rapid increases in leukocyte adherence in the mesenteric microcirculation of the anesthetized rat Wood JG, Johnson JS, Mattioli LF, and Gonzalez NC. J Appl Physiol 87: 1734–1740, 1999; Wood JG, Mattioli LF, and Gonzalez NC. J Appl Physiol 87: 873–881, 1999. Hypoxia-induced leukocyte adherence is associated with an increase in reactive oxygen species (ROS) generation and is attenuated by antioxidants or interventions that increase tissue levels of nitric oxide (NO). These results suggest that the acute effects of hypoxia on leukocyte-endothelial interactions are caused by a change in the ROS-NO balance. The present experiments were designed to extend our observations of the initial microcirculatory response to hypoxia; specifically, we wanted to determine whether the response to systemic hypoxia involves increased microvascular permeability and leukocyte emigration and whether ROS generation and decreased NO levels contribute to these responses. At this time, there is conflicting evidence, from in vitro studies, regarding the effect of hypoxia on these indexes of vascular function. Our studies were carried out in the physiological setting of the conscious animal, in which a prolonged hypoxic exposure is possible without the adverse effects that may develop under anesthesia. The central observation of these studies is that conscious animals exposed for 4 h to environmental hypoxia show increased microvascular permeability and emigration of leukocytes into the extravascular space of the mesenteric circulation. Furthermore, these events are dependent on increased ROS generation and, possibly, a subsequent decrease in tissue NO levels during systemic hypoxia. Our results show that systemic hypoxia profoundly affects vascular endothelial function through changes in the ROS-NO balance in the conscious animal.

Leukotriene B4 promotes reactive oxidant generation and leukocyte adherence during acute hypoxia

2001 ◽  
Vol 91 (3) ◽  
pp. 1160-1167 ◽  
Author(s):  
Dawn R. S. Steiner ◽  
Norberto C. Gonzalez ◽  
John G. Wood
Keyword(s):  
Acute Hypoxia ◽  
Leukotriene B4 ◽  
Ros Generation ◽  
Leukocyte Adherence ◽  
Systemic Hypoxia ◽  
Microvascular Alterations ◽  
Reactive Oxidant ◽  
Underlying Mechanisms ◽  
Mesenteric Microcirculation

Acute systemic hypoxia produces rapid leukocyte adherence in the rat mesenteric microcirculation, although the underlying mechanisms are not fully known. Hypoxia is known to increase reactive oxygen species (ROS) generation, which could result in formation of the lipid inflammatory mediator leukotriene B4 (LTB4). The goal of this study was to examine the role of LTB4 in hypoxia-induced microvascular alterations. Using intravital microscopy, we determined the effect of the LTB4 antagonist, LTB4-dimethyl amide (LTB4-DMA), on ROS generation and leukocyte adherence in mesenteric venules during hypoxia. Exogenous LTB4 increased ROS generation to 144 ± 8% compared with control values and also promoted leukocyte adherence. These responses to LTB4 were blocked by pretreating the mesentery with LTB4-DMA. Leukopenia did not significantly attenuate the LTB4-induced increase in ROS generation (142 ± 12.1%). LTB4-DMA substantially, though not completely, reduced hypoxia-induced ROS generation from 66 ± 18% to 11 ± 4% above control values. Hypoxia-induced leukocyte adherence was significantly attenuated by LTB4-DMA. Our results support a role for LTB4in the mechanism of hypoxia-induced ROS generation and leukocyte adherence in the rat mesenteric microcirculation.

Systemic hypoxia promotes leukocyte-endothelial adherence via reactive oxidant generation

1999 ◽  
Vol 87 (5) ◽  
pp. 1734-1740 ◽  
Author(s):  
John G. Wood ◽  
Jennifer S. Johnson ◽  
Leone F. Mattioli ◽  
Norberto C. Gonzalez
Keyword(s):  
Functional Relationship ◽  
Ros Generation ◽  
Oxygen Species ◽  
Leukocyte Adherence ◽  
Systemic Hypoxia ◽  
Signal Changes ◽  
Adhesive Interactions ◽  
Reactive Oxidant ◽  
Mesenteric Microcirculation

We recently demonstrated that systemic hypoxia during reduced inspired [Formula: see text] produces a rapid increase in leukocyte adherence to rat mesenteric venules. Evidence suggests that the mechanism of this response involves decreased nitric oxide (NO) levels. One possible pathway for NO depletion could involve increased reactive oxygen species (ROS) generation resulting in inactivation of NO. The overall goal of the present study was to examine the role of ROS in promoting leukocyte-endothelial adherence during systemic hypoxia. Experiments were designed to 1) evaluate changes in ROS generation in the mesenteric microcirculation during systemic hypoxia, 2) determine how the ROS signal changes when [Formula: see text] levels return to normal after a period of systemic hypoxia, 3) assess the effect of antioxidants on ROS generation during hypoxia, and 4) utilize antioxidants to examine the functional relationship between ROS generation and leukocyte adherence during hypoxia. The major findings from this study are that systemic hypoxia increases ROS generation within the mesenteric microcirculation and that antioxidants prevent the increase in leukocyte-endothelial adhesive interactions observed in hypoxia.

scholarly journals Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

2012 ◽  
Vol 302 (9) ◽  
pp. L875-L890 ◽  
Author(s):  
Helen Christou ◽  
Ossama M. Reslan ◽  
Virak Mam ◽  
Alain F. Tanbe ◽  
Sally H. Vitali ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Function ◽  
Vascular Reactivity ◽  
Ex Vivo ◽  
Systolic Pressure ◽  
Mesenteric Arteries ◽  
Hypoxic Exposure ◽  
Sprague Dawley ◽  
Vsmc Proliferation

Pulmonary hypertension (PH) is characterized by pulmonary arteriolar remodeling with excessive pulmonary vascular smooth muscle cell (VSMC) proliferation. This results in decreased responsiveness of pulmonary circulation to vasodilator therapies. We have shown that extracellular acidosis inhibits VSMC proliferation and migration in vitro. Here we tested whether induction of nonhypercapnic acidosis in vivo ameliorates PH and the underlying pulmonary vascular remodeling and dysfunction. Adult male Sprague-Dawley rats were exposed to hypoxia (8.5% O2) for 2 wk, or injected subcutaneously with monocrotaline (MCT, 60 mg/kg) to develop PH. Acidosis was induced with NH4Cl (1.5%) in the drinking water 5 days prior to and during the 2 wk of hypoxic exposure (prevention protocol), or after MCT injection from day 21 to 28 (reversal protocol). Right ventricular systolic pressure (RVSP) and Fulton's index were measured, and pulmonary arteriolar remodeling was analyzed. Pulmonary and mesenteric artery contraction to phenylephrine (Phe) and high KCl, and relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined ex vivo. Hypoxic and MCT-treated rats demonstrated increased RVSP, Fulton's index, and pulmonary arteriolar thickening. In pulmonary arteries of hypoxic and MCT rats there was reduced contraction to Phe and KCl and reduced vasodilation to ACh and SNP. Acidosis prevented hypoxia-induced PH, reversed MCT-induced PH, and resulted in reduction in all indexes of PH including RVSP, Fulton's index, and pulmonary arteriolar remodeling. Pulmonary artery contraction to Phe and KCl was preserved or improved, and relaxation to ACh and SNP was enhanced in NH4Cl-treated PH animals. Acidosis alone did not affect the hemodynamics or pulmonary vascular function. Phe and KCl contraction and ACh and SNP relaxation were not different in mesenteric arteries of all groups. Thus nonhypercapnic acidosis ameliorates experimental PH, attenuates pulmonary arteriolar thickening, and enhances pulmonary vascular responsiveness to vasoconstrictor and vasodilator stimuli. Together with our finding that acidosis decreases VSMC proliferation, the results are consistent with the possibility that nonhypercapnic acidosis promotes differentiation of pulmonary VSMCs to a more contractile phenotype, which may enhance the effectiveness of vasodilator therapies in PH.

Mesenteric microvascular inflammatory responses to systemic hypoxia are mediated by PAF and LTB4

2003 ◽  
Vol 94 (6) ◽  
pp. 2313-2322 ◽  
Author(s):  
Alfred J. Casillan ◽  
Norberto C. Gonzalez ◽  
Jennifer S. Johnson ◽  
Dawn R. S. Steiner ◽  
John G. Wood
Keyword(s):  
Inflammatory Response ◽  
Vascular Permeability ◽  
Inflammatory Responses ◽  
Platelet Activating Factor ◽  
Ros Generation ◽  
Leukocyte Adherence ◽  
Anesthetized Rats ◽  
Systemic Hypoxia ◽  
Paf Receptor ◽  
Web 2086

Systemic hypoxia produces a rapid microvascular inflammatory response characterized by increased reactive oxygen species (ROS) levels, leukocyte-endothelial adherence and emigration, and increased vascular permeability. The lipid inflammatory mediator leukotriene B4 (LTB4) is involved in the early hypoxia-induced responses (ROS generation and leukocyte adherence). Whether other lipid inflammatory mediators participate in this phenomenon is not known. The objective of these experiments was to study the role of platelet-activating factor (PAF) in the microvascular inflammatory response to hypoxia and its potential interactions with LTB4 in this response. Intravital microscopy was used to examine mesenteric venules of anesthetized rats. We found that WEB-2086, a PAF receptor antagonist, completely prevented the increase in ROS levels and leukocyte adherence during a brief reduction in inspired Po 2 to anesthetized rats; administration of either WEB-2086 or the LTB4 antagonist LTB4-DMA attenuated leukocyte emigration and the increase in vascular permeability to the same extent during prolonged systemic hypoxia in conscious rats. Furthermore, no additive effect was observed in either response when both antagonists were administered simultaneously. This study demonstrates a role for PAF in the rapid microvascular inflammatory response to hypoxia, as well as contributions of PAF and LTB4 to the slowly developing responses observed during sustained hypoxia. The incomplete blockade of the hypoxia-induced increases in vascular permeability and leukocyte emigration by combined administration of both antagonists indicates that factors in addition to LTB4 and PAF participate in these phenomena.

Synthesis and Biological Evaluations of Organoruthenium Scaffolds: A Comprehensive Update

2018 ◽  
Vol 15 (2) ◽  
pp. 179-207
Author(s):  
Ashaparna Mondal ◽  
Priyankar Paira
Keyword(s):  
Singlet Oxygen ◽  
Anticancer Agents ◽  
Ruthenium Complexes ◽  
Chemotherapeutic Agents ◽  
Quantum Yields ◽  
Ros Generation ◽  
Standard Drug ◽  
Cellular Environment ◽  
Theranostic Agents

Background: Currently ruthenium complexes are immerging as effective anticancer agents due to their less toxicity, better antiproliferative and antimetastatic activity, better stability in cellular environment and most importantly variable oxidation and co-ordination states of ruthenium allows binding this molecule with a variety of ligands. So in past few years researchers have shifted their interest towards organoruthenium complexes having good fluorescent profile that may be applicable for cancer theranostics. Nowadays, photodynamic therapy has become more acceptable because of its easy and effective approach towards killing cancer cells. Objective: Objective of this review article is to shed light on synthesis, characterization, stability and fluorescence studies of various ruthenium [Ru(II) and Ru(III)] complexes and different bioactivity studies conducted with the synthesized compounds to test their candidacy as potent chemotherapeutic agents. Methods: Various heterocyclic ligands containing N,O and S as heteroatom mainly were prepared and subjected to complexation with ruthenium-p-cymene moiety. In most cases [Ru(η6-p-cymene)(µ-Cl)Cl]2 was used as ruthenium precursor and the reactions were conducted in various alcohol medium such as methanol, ethanol or propanol. The synthesized complexes were characterized by 1H NMR and 13C NMR spectroscopy, GC-MS, ESI-MS, elemental analysis and single crystal X-ray crystallography methods. Fluorescence study and stability study were conducted accordingly using water, PBS buffer or DMSO. Stable compounds were considered for cell viability studies. To study the efficacy of the compounds in ROS generation as photosensitizers, in few cases, singlet oxygen quantum yields in presence of light were calculated. Suitable compounds were selected for in vitro & in vivo antiproliferative, anti-invasive activity studies. Result: Many newly synthesized compounds were found to have less IC50 compared to a standard drug cysplatin. Those compounds were also stable preferably in physiological conditions. Good fluorescence profile and ROS generation ability were observed for few compounds. Conclusion: Numerous ruthenium complexes were developed which can be used as cancer theranostic agents. Few molecules were synthesized as photosensitizers which were supposed to generate reactive singlet oxygen species in targeted cellular environment in presence of a particular type of light and thereby ceasing cancer cell growth.

Repositioning of Difluorinated Propanediones as Inhibitors of Histone Methyltransferases and their Biological Evaluation in Human Leukemic Cell Lines

2019 ◽  
Vol 18 (13) ◽  
pp. 1892-1899 ◽  
Author(s):  
Tanushree Pal ◽  
Asmita Sharda ◽  
Bharat Khade ◽  
C. Sinha Ramaa ◽  
Sanjay Gupta
Keyword(s):  
Cell Lines ◽  
Physiological Role ◽  
Leukemic Cell ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Leukemic Cell Lines ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Subsequent Decrease

Background: At present, ‘pharmaco-epigenomics’ constitutes the hope in cancer treatment owing to epigenetic deregulation- a reversible process and playing a role in malignancy. Objective: Chemotherapy has many limitations like host-tissue toxicity, drug resistance. Hence, it is imperative to unearth targets to better treat cancer. Here, we intend to repurpose a set of our previously synthesized difluorinated Propanediones (PR) as Histone lysine Methyltransferase inhibitors (HMTi). Methods: The cell lines of leukemic origin viz. histiocytic lymphoma (U937) and acute T-cell leukemia (JURKAT) were treated with PR-1 to 7 after docking studies with active pocket of HMT. The cell cycle analysis, in vitro methylation and cell proliferation assays were carried out to delineate their physiological role. Results: A small molecule PR-4, at 1 and 10µM, has shown to alter the methylation of histone H3 and H4 in both cell lines. Also, treatment shows an increase in G2/M population and a subsequent decrease in the G0/G1 population in U937. In JURKAT, an increase in both G2/M and S phase population was observed. The sub-G1 population showed a steady rise with increase in dose and prolonged time intervals in U937 and JURKAT cell lines. In SRB assay, the PR showed a cell growth of 42.6 and 53.4% comparable to adriamycin; 44.5 and 53.2% in U937 and JURKAT, respectively. The study suggests that PR-4 could emerge as a potential HMT inhibitor. Conclusion: The molecule PR-4 could be a lead in developing more histone lysine methyltransferases inhibitors with potential to be pro-apoptotic agents.

scholarly journals Fe3O4@Pt nanoparticles to enable combinational electrodynamic/chemodynamic therapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Tong Chen ◽  
Qiang Chu ◽  
Mengyang Li ◽  
Gaorong Han ◽  
Xiang Li
Keyword(s):  
Fenton Reaction ◽  
Pt Nanoparticles ◽  
Therapeutic Modality ◽  
Ros Generation ◽  
Tumor Treatment ◽  
Superior Efficacy ◽  
Platinum Nanocrystals ◽  
First Time

AbstractElectrodynamic therapy (EDT) has recently emerged as a potential external field responsive approach for tumor treatment. While it presents a number of clear superiorities, EDT inherits the intrinsic challenges of current reactive oxygen species (ROS) based therapeutic treatments owing to the complex tumor microenvironment, including glutathione (GSH) overexpression, acidity and others. Herein for the first time, iron oxide nanoparticles are decorated using platinum nanocrystals (Fe3O4@Pt NPs) to integrate the current EDT with chemodynamic phenomenon and GSH depletion. Fe3O4@Pt NPs can effectively induce ROS generation based on the catalytic reaction on the surface of Pt nanoparticles triggered by electric field (E), and meanwhile it may catalyze intracellular H2O2 into ROS via Fenton reaction. In addition, Fe3+ ions released from Fe3O4@Pt NPs under the acidic condition in tumor cells consume GSH in a rapid fashion, inhibiting ROS clearance to enhance its antitumor efficacy. As a result, considerable in vitro and in vivo tumor inhibition phenomena are observed. This study has demonstrated an alternative concept of combinational therapeutic modality with superior efficacy.

scholarly journals Crocodile blood supplementation protects vascular function in diabetic mice

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Chui Yiu Bamboo Chook ◽  
Francis M. Chen ◽  
Gary Tse ◽  
Fung Ping Leung ◽  
Wing Tak Wong
Keyword(s):  
Endothelial Cells ◽  
Vascular Function ◽  
Quantitative Polymerase Chain Reaction ◽  
Functional Study ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Gene Expressions ◽  
Inflammatory State ◽  
Crocodile Blood

Abstract Cardiovascular disease is a major cause of mortality in diabetic patients due to the heightened oxidative stress and pro-inflammatory state in vascular tissues. Effective approaches targeting cardiovascular health for diabetic patients are urgently needed. Crocodile blood, an emerging dietary supplement, was suggested to have anti-oxidative and anti-inflammatory effects in vitro, which have yet to be proven in animal models. This study thereby aimed to evaluate whether crocodile blood can protect vascular function in diabetic mice against oxidation and inflammation. Diabetic db/db mice and their counterparts db/m+ mice were treated daily with crocodile blood soluble fraction (CBSF) or vehicle via oral gavage for 4 weeks before their aortae were harvested for endothelium-dependent relaxation (EDR) quantification using wire myograph, which is a well-established functional study for vascular function indication. Organ culture experiments culturing mouse aortae from C57BL/6 J mice with or without IL-1β and CBSF were done to evaluate the direct effect of CBSF on endothelial function. Reactive oxygen species (ROS) levels in mouse aortae were assessed by dihydroethidium (DHE) staining with inflammatory markers in endothelial cells quantified by quantitative polymerase chain reaction (qPCR). CBSF significantly improved deteriorated EDR in db/db diabetic mice through both diet supplementation and direct culture, with suppression of ROS level in mouse aortae. CBSF also maintained EDR and reduced ROS levels in mouse aortae against the presence of pro-inflammatory IL-1β. Under the pro-inflammatory state induced by IL-1β, gene expressions of inflammatory cytokines were downregulated, while the protective transcripts UCP2 and SIRT6 were upregulated in endothelial cells. Our study suggests a novel beneficial effect of crocodile blood on vascular function in diabetic mice and that supplementation of diet with crocodile blood may act as a complementary approach to protect against vascular diseases through anti-oxidation and anti-inflammation in diabetic patients. Graphical abstract

Protocatechuic Acid Protects Platelets from Apoptosis via Inhibiting Oxidative Stress-Mediated PI3K/Akt/GSK3β Signaling

2021 ◽  
Author(s):  
Fuli Ya ◽  
Kongyao Li ◽  
Hong Chen ◽  
Zezhong Tian ◽  
Die Fan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Caspase 3 ◽  
Protocatechuic Acid ◽  
Human Platelets ◽  
Ros Generation ◽  
Inhibitory Effects ◽  
Platelet Apoptosis ◽  
Phosphatidylserine Exposure ◽  
Underlying Mechanisms

AbstractOxidative stress plays crucial roles in initiating platelet apoptosis that facilitates the progression of cardiovascular diseases (CVDs). Protocatechuic acid (PCA), a major metabolite of anthocyanin cyanidin-3-O-β-glucoside (Cy-3-g), exerts cardioprotective effects. However, underlying mechanisms responsible for such effects remain unclear. Here, we investigate the effect of PCA on platelet apoptosis and the underlying mechanisms in vitro. Isolated human platelets were treated with hydrogen peroxide (H2O2) to induce apoptosis with or without pretreatment with PCA. We found that PCA dose-dependently inhibited H2O2-induced platelet apoptosis by decreasing the dissipation of mitochondrial membrane potential, activation of caspase-9 and caspase-3, and decreasing phosphatidylserine exposure. Additionally, the distributions of Bax, Bcl-xL, and cytochrome c mediated by H2O2 in the mitochondria and the cytosol were also modulated by PCA treatment. Moreover, the inhibitory effects of PCA on platelet caspase-3 cleavage and phosphatidylserine exposure were mainly mediated by downregulating PI3K/Akt/GSK3β signaling. Furthermore, PCA dose-dependently decreased reactive oxygen species (ROS) generation and the intracellular Ca2+ concentration in platelets in response to H2O2. N-Acetyl cysteine (NAC), a ROS scavenger, markedly abolished H2O2-stimulated PI3K/Akt/GSK3β signaling, caspase-3 activation, and phosphatidylserine exposure. The combination of NAC and PCA did not show significant additive inhibitory effects on PI3K/Akt/GSK3β signaling and platelet apoptosis. Thus, our results suggest that PCA protects platelets from oxidative stress-induced apoptosis through downregulating ROS-mediated PI3K/Akt/GSK3β signaling, which may be responsible for cardioprotective roles of PCA in CVDs.

scholarly journals Betulinic Acid Protects DOX-Triggered Cardiomyocyte Hypertrophy Response through the GATA-4/Calcineurin/NFAT Pathway

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 53
Author(s):  
Jung Joo Yoon ◽  
Chan Ok Son ◽  
Hye Yoom Kim ◽  
Byung Hyuk Han ◽  
Yun Jung Lee ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Betulinic Acid ◽  
Cardiomyocyte Hypertrophy ◽  
Ros Generation ◽  
H9c2 Cells ◽  
Myosin Light Chain 2 ◽  
Cardiovascular Morbidity And Mortality

Cardiac hypertrophy is a major risk factor for heart failure and leads to cardiovascular morbidity and mortality. Doxorubicin (DOX) is regarded as one of the most potent anthracycline antibiotic agents; however, its clinical usage has some limitations because it has serious cardiotoxic side effects such as dilated cardiomyopathy and congestive heart failure. Betulinic acid (BA) is a pentacyclic-cyclic lupane-type triterpene that has been reported to have anti-bacterial, anti-inflammatory, anti-vascular neogenesis, and anti-fibrotic effects. However, there is no study about its direct effect on DOX induced cardiac hypertrophy and apoptosis. The present study aims to investigate the effect of BA on DOX-induced cardiomyocyte hypertrophy and apoptosis in vitro in H9c2 cells. The H9c2 cells were stimulated with DOX (1 µM) in the presence or absence of BA (0.1–1 μM) and incubated for 24 h. The results of the present study indicated that DOX induces the increase cell surface area and the upregulation of hypertrophy markers including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta-myosin heavy chain (β-MHC), and Myosin Light Chain-2 (MLC2) in H9c2 cells. However, the pathological hypertrophic responses were downregulated after BA treatment. Moreover, phosphorylation of JNK, ERK, and p38 in DOX treated H9c2 cells was blocked by BA. As a result of measuring the change in ROS generation using DCF-DA, BA significantly inhibited DOX-induced the production of intracellular reactive oxygen species (ROS) when BA was treated at a concentration of over 0.1 µM. DOX-induced activation of GATA-4 and calcineurin/NFAT-3 signaling pathway were remarkably improved by pre-treating of BA to H9c2 cells. In addition, BA treatment significantly reduced DOX-induced cell apoptosis and protein expression levels of Bax and cleaved caspase-3/-9, while the expression of Bcl-2 was increased by BA. Therefore, BA can be a potential treatment for cardiomyocyte hypertrophy and apoptosis that lead to sudden heart failure.

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