Ramón Rodrigo

University of Chile

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Julia Araya

University of Chile

Camilo G. Sotomayor

Hospital Clínico de la Universidad de Chile

Cleofina Bosco

AGADA Biosciences

Myriam Orellana

University of Chile

Luis A. Videla

University of Chile

Stephan J. L. Bakker

University Medical Center Groningen

Luciano Saso

Sapienza University of Rome

Stefan P. Berger

University Medical Center Groningen

Rodrigo L. Castillo

University of Chile

Lilian Thielemann

University of Chile

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University of Chile

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University Medical Center Groningen

University of Groningen

Hospital Clínico de la Universidad de Chile

Harvard University

Universitat de Barcelona

Instituto de Salud Carlos III

Dialyse Centrum Groningen

Clínica Alemana

Pontificia Universidad Católica de Chile

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Effects of bromoethylamine on antioxidant capacity, lipid peroxidation, and morphological characteristics of rat liver

Journal of Biochemical and Molecular Toxicology (1999)

Lilian Thielemann Cleofina Bosco Ramón Rodrigo Myriam Orellana Luis A. Videla

Administration of bromoethylamine (BEA, 1.2 mmol/kg) to fed rats induced a significant diminution in the activity of hepatic superoxide dismutase (at 1 h after treatment), catalase, and glutathione peroxidase and in the content of nonprotein sulfhydryls (at 15 h after treatment). The content of thiobarbituric acid reactants by the liver was enhanced by 1.9 times over control values (at 3 h). Light microscopy studies revealed that BEA (72 h after treatment) induced periportal fatty accumulation, focal liver cell necrosis, and diffuse inflammatory infiltrates, in addition to hypertrophic Kupffer cells and mitotic hepatocytes. Also, hypertrophic middle tunic or hypertrophic smooth muscle layers of arterioles was observed in the periportal space, with dilated sinusoidal capillaries and free macrophage infiltration. It is concluded that BEA induces a derangement in the antioxidant status of the liver with the consequent lipid peroxidation response, which may constitute a significant hepatotoxic mechanism of the haloaklylamine. © 1998 John Wiley & Sons, Inc. J Biochem Mol Toxicol 13: 47–52, 1999

10.1002/(sici)1099-0461(1999)13:1<47::aid-jbt6>3.3.co;2-m

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Prevention of Reperfusion Injury in Acute Myocardial Infarction: A “flashback” Journey of Novel Strategies Based on the Potential Therapeutic Role of Antioxidants

BENTHAM SCIENCE PUBLISHERS eBooks (2023)

Francisco Salazar-Cornejo Abraham I. J. Gajardo Marcelo J. Kogan Ramón Rodrigo

It has been recognized that oxidative stress plays a key role in the development of cardiac alterations derived from events of ischemia followed by reperfusion, such as in the clinical setting of acute myocardial infarction of patients subjected to coronary angioplasty. During ischemia, due to the occlusion of a coronary branch, biochemical events responsible for anaerobic metabolism, ATP availability and impairment of cell ionic homeostasis are the major deleterious effects. Following the onset of reperfusión, a burst of reactive oxygen species occurs, thus accounting for increased tissue damage due to the endovascular intervention. This iatrogenic damage has not been adequately treated to date. Among the many pharmacological attempts, cardioprotection with antioxidants should be mentioned; however, the experimental studies have not been translated into successful clinical trials aimed to prevent this enhancement of cardiac damage, despite some beneficial effects have been reported in the clinical outcome of the patients. This chapter aimed to present the hypothesis that the combination of antioxidant effects should improve the cardioprotection of the patients subjected to coronary angioplasty following acute myocardial infarction. Therefore, we present an update of previous attempts at cardioprotection with an antioxidant alone and give the basis for the expected improved protection by using two or more antioxidant compounds exerting different mechanisms that could enhance the beneficial protective effect.

Cardioprotection

10.2174/9789815165012123010010

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Duality of Tocopherol Isoforms and Novel Associations with Vitamins Involved in One-Carbon Metabolism: Results from an Elderly Sample of the LifeLines Cohort Study

Nutrients (2020)

Camilo G. Sotomayor Isidor Minović Manfred Eggersdorfer Ineke J. Riphagen Martin H. de Borst

Whether the affinity of serum vitamin E with total lipids hampers the appropriate assessment of its association with age-related risk factors has not been investigated in epidemiological studies. We aimed to compare linear regression-derived coefficients of the association of non-indexed and total lipids-indexed vitamin E isoforms with clinical and laboratory characteristics pertaining to the lipid, metabolic syndrome, and one-carbon metabolism biological domains. We studied 1429 elderly subjects (non-vitamin supplement users, 60–75 years old, with low and high socioeconomic status) from the population-based LifeLines Cohort and Biobank Study. We found that the associations of tocopherol isoforms with lipids were inverted in total lipids-indexed analyses, which may be indicative of overcorrection. Irrespective of the methods of standardization, we consistently found positive associations of α-tocopherol with vitamins of the one-carbon metabolism pathway and inverse associations with characteristics related to glucose metabolism. The associations of γ-tocopherol were often opposite to those of α-tocopherol. These data suggest that tocopherol isoforms and one-carbon metabolism are related, with beneficial and adverse associations for α-tocopherol and γ-tocopherol, respectively. Whether tocopherol isoforms, or their interplay, truly affect the one-carbon metabolism pathway remains to be further studied.

10.3390/nu12020580

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Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease

Trends in Molecular Medicine (2006)

Luis A. Videla Ramón Rodrigo Julia Araya Jaime Poníachik

Steatohepatitis

Steatosis

10.1016/j.molmed.2006.10.001

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Study of Cytochrome P450 2E1 and its allele Variants in Liver Injury of Nondiabetic, Nonalcoholic Steatohepatitis Obese Women

Biological Research (2008)

Nelson Varela Luis A. Quiñones Myriam Orellana Jaime Poníachik Attila Csendes

CYP2E1 enzyme is related to nonalcoholic steatohepatitis (NASH) due to its ability for reactive oxygen species production, which can be influenced by polymorphisms in the gene.The aim of this study was to investigate hepatic levels, activity, and polymorphisms of the CYP2E1 gene to correlate it with clinical and histological features in 48 female obese NASH patients.Subjects were divided into three groups: (i) normal; (ii) steatosis; and (iii) steatohepatitis.CYP2E1 protein level was assayed in microsomes from liver biopsies, and in vivo chlorzoxazone hydroxylation was determined by HPLC.Genomic DNA was isolated for genotype analysis through PCR.The results showed that liver CYP2E1 content was significantly higher in the steatohepatitis (45%; p=0.024) and steatosis (22%; p=0.032) group compared with normal group.Chlorzoxazone hydroxylase activity showed significant enhancement in the steatohepatitis group (15%, p=0.027) compared with the normal group.c2 rare allele of Rsa1/Pst1 polymorphisms but no C allele of Dra1 polymorphism was positively associated with CHZ hydroxylation, which in turn is correlated with liver CYP2E1 content (r=0.59;p=0.026).In conclusion, c2 allele is positively associated with liver injury in NASH.This allele may determine a higher transcriptional activity of the gene, with consequent enhancement in pro-oxidant activity of CYP2E1 thus affording liver toxicity.

Steatosis

Steatohepatitis

Chlorzoxazone

10.4067/s0716-97602008000100010

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Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients

Clinical Science (2004)

Luis A. Videla Ramón Rodrigo Myriam Orellana Virginia Fernández Gladys Tapia

Oxidative stress is implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In the present study, hepatic and plasma oxidative stress-related parameters were measured and correlated with clinical and histological findings in 31 NAFLD patients showing increased body mass index. Liver protein carbonyl content was enhanced by 403% in patients with steatosis (n=15) compared with control values (n=12), whereas glutathione content, superoxide dismutase (SOD) activity and the ferric reducing ability of plasma (FRAP) were decreased by 57%, 48% and 21% (P<0.05) respectively. No changes in microsomal p-nitrophenol hydroxylation and the total content of cytochrome P450 (CYP) or CYP2E1 were observed. Patients with steatohepatitis (n=16) exhibited protein carbonyl content comparable with that of controls, whereas glutathione content, SOD and catalase activities were decreased by 27%, 64% and 48% (P<0.05). In addition, FRAP values in patients with steatohepatitis were reduced by 33% and 15% (P<0.05) when compared with controls and patients with steatosis respectively, whereas p-nitrophenol hydroxylation (52%) and CYP2E1 content (142%) were significantly increased (P<0.05) compared with controls. It is concluded that oxidative stress is developed in the liver of NAFLD patients with steatosis and is exacerbated further in patients with steatohepatitis, which is associated with CYP2E1 induction. Substantial protein oxidation is followed by proteolysis of the modified proteins, which may explain the co-existence of a diminished antioxidant capacity and protein oxidation in the liver of patients with steatohepatitis.

Steatosis

Steatohepatitis

10.1042/cs20030285

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Antioxidant Therapy Reduces Oxidative and Inflammatory Tissue Damage in Patients Subjected to Cardiac Surgery with Extracorporeal Circulation

Basic & Clinical Pharmacology & Toxicology (2010)

Rodrigo L. Castillo Ramón Rodrigo Felipe Pérez Mauricio Cereceda René Asenjo

Abstract: Ischaemia reperfusion injury is a pathophysiological event that occurs after cardiac surgery with extracorporeal circulation. This clinical event has been associated with the induction of oxidative and inflammatory damage in atrial tissue. Here, we tested whether combined omega 3 polyunsaturated fatty acids (n‐3 PUFA)‐antioxidant vitamin protocol therapy reduces oxidative and inflammatory cardiac tissue damage. This trial assigned 95 either‐sex patients to supplementation with n‐3 PUFA (2 g/day), or matching placebo groups, 7 days before on‐pump surgery. Antioxidant vitamins C (1 g/day) and E (400 IU/day) or placebo were added from 2 days before surgery until discharge. Blood and atrial tissue samples were obtained during the intervention. Reduced/oxidized glutathione (GSH/GSSG) ratio, malondialdehyde (MDA) and protein carbonylation were determined in atrial tissue. Leucocyte count and high‐sensitivity C‐reactive protein (hs‐CRP) in blood plus nuclear factor (NF)‐κappaB activation in atrial tissue served for inflammation assessment. Lipid peroxidation and protein carbonylation were 27.5 and 24% lower in supplemented patients ( p < 0.01). GSH/GSSG ratio was 38.1% higher in supplemented patients compared with placebo ( p < 0.01). Leucocyte count and serum hs‐CRP levels were markedly lower throughout the protocol in supplemented patients ( p < 0.01). Atrial tissue NF‐κB DNA activation in supplemented patients was 22.5% lower than that in placebo patients ( p < 0.05). The combined n‐3 PUFA‐antioxidant vitamin protocol therapy here proposed reduced the oxidative stress and inflammation biomarkers, in patients undergoing on‐pump cardiac surgery.

Malondialdehyde

Extracorporeal circulation

10.1111/j.1742-7843.2010.00651.x

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Targeting Ferroptosis against Ischemia/Reperfusion Cardiac Injury

Antioxidants (2021)

José Lillo‐Moya Catalina Rojas-Solé Diego Muñoz-Salamanca Emiliano Panieri Luciano Saso

Ischemic heart disease is a leading cause of death worldwide. Primarily, ischemia causes decreased oxygen supply, resulting in damage of the cardiac tissue. Naturally, reoxygenation has been recognized as the treatment of choice to recover blood flow through primary percutaneous coronary intervention. This treatment is the gold standard therapy to restore blood flow, but paradoxically it can also induce tissue injury. A number of different studies in animal models of acute myocardial infarction (AMI) suggest that ischemia-reperfusion injury (IRI) accounts for up to 50% of the final myocardial infarct size. Oxidative stress plays a critical role in the pathological process. Iron is an essential mineral required for a variety of vital biological functions but also has potentially toxic effects. A detrimental process induced by free iron is ferroptosis, a non-apoptotic type of programmed cell death. Accordingly, efforts to prevent ferroptosis in pathological settings have focused on the use of radical trapping antioxidants (RTAs), such as liproxstatin-1 (Lip-1). Hence, it is necessary to develop novel strategies to prevent cardiac IRI, thus improving the clinical outcome in patients with ischemic heart disease. The present review analyses the role of ferroptosis inhibition to prevent heart IRI, with special reference to Lip-1 as a promising drug in this clinicopathological context.

10.3390/antiox10050667

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Potential Role of Polyphenols in the Prevention of Cardiovascular Diseases: Molecular Bases

Current Medicinal Chemistry (2016)

Juan G. Gormaz Nicolás Valls Camilo G. Sotomayor Thomas L. Turner Ramón Rodrigo

Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. It is widely accepted that oxidative stress plays a key role in their development and progression; hence oxidative damage might be abrogated by antioxidants. Polyphenols are phytochemicals showing extensively studied antioxidant properties in-vivo. Most representative sources of these compounds include fruits, greens, nuts, herbs, cocoa, tea and coffee. Epidemiological evidence suggests an association between the consumption of polyphenol-rich vegetables and the reduction of cardiovascular disease prevalence. This fact could be related to the anti-inflammatory, antithrombotic and vasodilatory effects of polyphenols. Even though these biological effects could be mainly attributed to the antioxidant activity of polyphenols, other pharmacological mechanisms should also be considered. The latter could comprise direct anti-inflammatory effects, modulation of intracellular signaling and gene expression, improvement of nitric oxide homeostasis, as well as platelet antiaggregation. However, it is noticeable that protocols of interventions to evaluate the properties of polyphenols have failed to show the same positive results reported from observational studies. At present, a controversy exists regarding the actual effectiveness of polyphenols in preventing cardiovascular diseases. Therefore, an improvement of the available knowledge about polyphenol pharmacokinetics, together with a better understanding of the mechanisms of action of these compounds, could be of great benefit. Thus, a rational support for the development of interventional designs could provide reliable evidence on the actual role of polyphenols in CVD prevention. Keywords: Polyphenols, cardiovascular diseases prevention, vasodilatation, inflammation, thrombosis, atherogenesis.

10.2174/0929867323666151127201732

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Plasma Malondialdehyde and Risk of New-Onset Diabetes after Transplantation in Renal Transplant Recipients: A Prospective Cohort Study

Journal of Clinical Medicine (2019)

Manuela Yepes-Calderón Camilo G. Sotomayor António W. Gomes‐Neto Rijk O. B. Gans Stefan P. Berger

New-onset diabetes after transplantation (NODAT) is a frequent complication in renal transplant recipients (RTR). Although oxidative stress has been associated with diabetes mellitus, data regarding NODAT are limited. We aimed to prospectively investigate the long-term association between the oxidative stress biomarker malondialdehyde (measured by high-performance liquid chromatography) and NODAT in an extensively phenotyped cohort of non-diabetic RTR with a functioning graft ≥1 year. We included 516 RTR (51 ± 13 years-old, 57% male). Median plasma malondialdehyde (MDA) was 2.55 (IQR, 1.92-3.66) µmol/L. During a median follow-up of 5.3 (IQR, 4.6-6.0) years, 56 (11%) RTR developed NODAT. In Cox proportional-hazards regression analyses, MDA was inversely associated with NODAT, independent of immunosuppressive therapy, transplant-specific covariates, lifestyle, inflammation, and metabolism parameters (HR, 0.55; 95% CI, 0.36-0.83 per 1-SD increase; p < 0.01). Dietary antioxidants intake (e.g., vitamin E, α-lipoic acid, and linoleic acid) were effect-modifiers of the association between MDA and NODAT, with particularly strong inverse associations within the subgroup of RTR with relatively higher dietary antioxidants intake. In conclusion, plasma MDA concentration is inversely and independently associated with long-term risk of NODAT in RTR. Our findings support a potential underrecognized role of oxidative stress in post-transplantation glucose homeostasis.

Malondialdehyde

10.3390/jcm8040453

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Citations (11)