Role Of Oxidative Stress In Pathophysiology Research Articles

Oxidative Stress, Atherogenic Dyslipidemia, and Cardiovascular Risk.

Oxidative stress is the consequence of an overproduction of reactive oxygen species (ROS) that exceeds the antioxidant defense mechanisms. Increased levels of ROS contribute to the development of cardiovascular disorders through oxidative damage to macromolecules, particularly by oxidation of plasma lipoproteins. One of the most prominent features of atherogenic dyslipidemia is plasma accumulation of small dense LDL (sdLDL) particles, characterized by an increased susceptibility to oxidation. Indeed, a considerable and diverse body of evidence from animal models and epidemiological studies was generated supporting oxidative modification of sdLDL particles as the earliest event in atherogenesis. Lipid peroxidation of LDL particles results in the formation of various bioactive species that contribute to the atherosclerotic process through different pathophysiological mechanisms, including foam cell formation, direct detrimental effects, and receptor-mediated activation of pro-inflammatory signaling pathways. In this paper, we will discuss recent data on the pathophysiological role of oxidative stress and atherogenic dyslipidemia and their interplay in the development of atherosclerosis. In addition, a special focus will be placed on the clinical applicability of novel, promising biomarkers of these processes.

The Role of Oxidative Stress and the Importance of miRNAs as Potential Biomarkers in the Development of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the primary cause of blindness in developed countries. With the progressive aging of the population, AMD is a significant ophthalmological problem in the population over 50 years of age. The etiology of AMD is known to be based on various biochemical, immunological and molecular pathways and to be influenced by a range of genetic and environmental elements. This review provides an overview of the pathophysiological role of oxidative stress and free radicals in the retina with a special focus on the DNA repair efficiency and enzymatic antioxidant defense. It also presents a correlation between miRNA profile and AMD, and indicates their involvement in inflammation, angiogenesis, increased oxidation of cellular components, enzymatic antioxidant capacity and DNA repair efficiency, which play particularly important roles in AMD pathogenesis. Gene silencing by miRNAs can induce changes in antioxidant enzymes, leading to a complex interplay between redox imbalance by free radicals and miRNAs in modulating cellular redox homeostasis.

Oxidative Stress, Proton Fluxes, and Chloroquine/Hydroxychloroquine Treatment for COVID-19.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been proposed as treatments for COVID-19. These drugs have been studied for many decades, primarily in the context of their use as antimalarials, where they induce oxidative stress-killing of the malarial parasite. Less appreciated, however, is evidence showing that CQ/HCQ causes systemic oxidative stress. In vitro and observational data suggest that CQ/HCQ can be repurposed as potential antiviral medications. This review focuses on the potential health concerns of CQ/HCQ induced by oxidative stress, particularly in the hyperinflammatory stage of COVID-19 disease. The pathophysiological role of oxidative stress in acute respiratory distress syndrome (ARDS) has been well-documented. Additional oxidative stress caused by CQ/HCQ during ARDS could be problematic. In vitro data showing that CQ forms a complex with free-heme that promotes lipid peroxidation of phospholipid bilayers are also relevant to COVID-19. Free-heme induced oxidative stress is implicated as a systemic activator of coagulation, which is increasingly recognized as a contributor to COVID-19 morbidity. This review will also provide a brief overview of CQ/HCQ pharmacology with an emphasis on how these drugs alter proton fluxes in subcellular organelles. CQ/HCQ-induced alterations in proton fluxes influence the type and chemical reactivity of reactive oxygen species (ROS).

Improvement of a Novel Proposal for Antioxidant Treatment Against Brain Damage Occurring in Ischemic Stroke Patients.

The underlying mechanism of cerebral injury occurring in patients with acute ischemic stroke involves a key pathophysiological role of oxidative stress. Thus, reactive oxygen species are related to the development of brain edema, calcium overload, mitochondrial dysfunction, excitotoxicity, iron release and inflammation. Nevertheless, although experimental studies have tested the use of antioxidants as an adjuvant therapy in this setting, clinical data and randomized trials are still lacking. Current approved pharmacological therapy is aimed at reperfusion strategies; however, the therapeutic window is limited and also challenged by the injury known to result from the reperfusion. We have recently defined a time-course occurrence of pathological events triggered by reperfusion-dependent increased reactive oxygen species, thus suggesting the beneficial role of the pertinent use of antioxidants. The present study was aimed to support the hypothesis that an enhanced antioxidant neuroprotection could be achieved by the use of two or more antioxidants opportunely provided to ischemic stroke patients focused against the specific mechanism occurring throughout the pathophysiological process. From this paradigm, using an underexplored therapeutic principle, it could be suggested that antioxidant-based therapy is a novel, promising, safe, available and cost-effective strategy against the deleterious effects of ischemic stroke that needs to be further studied in clinical protocols.

Skin autofluorescence of advanced glycation end products and course of affective disorders in the lifelines cohort study, a prospective investigation

BackgroundSkin autofluorescence (SAF), indicating concentration of advanced glycation end products in the skin and oxidative stress, is cross-sectionally associated with affective disorders. Prospective studies of oxidative stress markers will help to clarify the pathophysiological role of oxidative stress. MethodsData of a population-based cohort study were used. Presence of major depressive disorder, dysthymia, generalised anxiety disorder, panic disorder or social phobia was assessed at baseline and at 5-year follow-up with the Mini-International Neuropsychiatric Interview. Associations between SAF at baseline and incidence and persistence/recurrence of affective disorders were assessed with logistic regression. ResultsOf 43,267 participants with no disorder at baseline, 2885 (6.7%) developed an incident disorder during follow-up. In 1360 of 3648 participants (37.3%) with an affective disorder at baseline, a persisting/recurrent disorder was present at follow-up. A modest association existed between SAF and incident affective disorders (OR=1.07 [95%CI 1.03–1.12], P<.001), specifically major depressive disorder (OR=1.11 [95%CI 1.04–1.19], P=.003); this association lost statistical significance after adjustment for sociodemographic factors. Associations between SAF and persistence/recurrence were not significant. LimitationsMany confounders might also act as intermediate: extensive adjustment for confounders caused overfitting and possibly masked effects of SAF on course of affective disorders. Relatively small sample sizes for analyses of SAF and persistence/recurrence of affective disorders resulted in a low power. ConclusionsIncreased SAF modestly raises the odds of incident affective disorders, particularly major depressive disorder, providing evidence that oxidative stress plays a role in subsequent occurrence of affective disorders. However, significance of effects faded after adjustment for socioeconomic status.

Role of Oxidative Stress and Antioxidant Therapies in Endometriosis

Endometriosis (EMS) is a common gynecological disorder characterized by the presence of endometrial tissue outside the uterine cavity. It is commonly associated with pelvic pain and infertility. The exact pathogenesis remains unclear and many hypotheses have been suggested. In recent years, accumulating evidence indicates that oxidative stress (OS) plays a role in the development of EMS. The treatment of EMS remains a challenge. Antioxidant therapies for effective management of reactive oxygen species and inflammation have generated considerable research interest. Antioxidant agents such as Vitamins C and E, resveratrol, curcumin, melatonin, epigallocatechin-3-gallate, and others have been studied for the treatment of EMS. This review presents the role of OS in pathophysiology of EMS and the antioxidant therapies in its management.

Oxidative Stress Assessment in Alzheimer's Disease: A Clinic Setting Study.

Oxidative stress (OS) is a physiological age-related brain process, dramatically overexpressed in neurodegenerative disorders like Alzheimer's disease (AD). Nevertheless, the pathophysiological role of OS in AD pathology has not been clarified yet. OS as a biomarker for AD is a controversial issue. A comparison of previous data is difficult due to a remarkable methodological variability. Most of the previous studies have shown higher levels of OS markers and lower antioxidant power in patients with dementia when compared to mild cognitive impairment (MCI) and healthy controls. We followed a strict protocol in order to limit intrasite variability of OS assessment. In addition, we have taken into account possible confounding factors. In agreement with previous reports, we found both lower plasmatic OS and higher plasmatic antioxidant defenses when comparing patients with AD having dementia that is stably treated to patients with MCI-AD. A speculative hypothesis based on correlative data is provided.

Expression of Reactive Oxygen Species-Related Transcripts in Egyptian Children With Autism.

The molecular basis of the pathophysiological role of oxidative stress in autism is understudied. Herein, we used polymerase chain reaction (PCR) array to analyze transcriptional pattern of 84 oxidative stress genes in peripheral blood mononuclear cell pools isolated from 32 autistic patients (16 mild/moderate and 16 severe) and 16 healthy subjects (each sample is a pool from 4 autistic patients or 4 controls). The PCR array data were further validated by quantitative real-time PCR in 80 autistic children (55 mild/moderate and 25 severe) and 60 healthy subjects. Our data revealed downregulation in GCLM, SOD2, NCF2, PRNP, and PTGS2 transcripts (1.5, 3.8, 1.2, 1.7, and 2.2, respectively;P < .05 for all) in autistic group compared with controls. In addition, TXN and FTH1 exhibited 1.4- and 1.7-fold downregulation, respectively, in severe autistic patients when compared with mild/moderate group (P = .005 and .0008, respectively). This study helps in a better understanding of the underlying biology and related genetic factors of autism, and most importantly, it presents suggested candidate biomarkers for diagnosis and prognosis purposes as well as targets for therapeutic intervention.

The blocking of angiotensin II type 1 receptor and RhoA/Rho kinase activity in hypertensive patients: Effect of olmesartan medoxomil and implication with cardiovascular-renal remodeling.

The pathophysiological role of oxidative stress (OxSt) in hypertension and target organ damage is recognized. Angiotensin II (Ang II) induces OxSt via NAD(P)H oxidase activation and production of proinflammatory cytokines/growth factors leading to cardiovascular-renal remodeling. Ang II stimulates the RhoA/Rho kinase (ROCK) pathway, which is deeply involved in the development of cardiovascular-renal remodeling via OxSt induction. Olmesartan, an Ang II type 1 receptor blocker, possesses antioxidant and activating nitric oxide system-related effects, which we have shown in terms of p22(phox) reduction, heme oxygenase-1 and calcitonin gene-related peptide increase. This study evaluates in 15 untreated hypertensive patients the effect of olmesartan treatment on p63RhoGEF, key in Ang II-induced ROCK activation, and MYPT-1 phosphorylation, a marker of ROCK activity. The p63RhoGEF protein level and MYPT-1 phosphorylation (Western blot) were evaluated at baseline, and after three and six months of olmesartan treatment. Olmesartan normalized systolic and diastolic BP (p < 0.001), reduced p63RhoGEF level: 1.3±0.25 d.u. (baseline) vs 1.0±0.29 (three months), p < 0.0001 vs 1.0±0.22, (six months), p < 0.0001 and MYPT-1 phosphorylation: 1.2 ±0.14 (baseline) vs 0.9±0.19 (three months), p = 0.008, vs 0.8±0.16 (six months), p = 0.001. These data added to our previous results further provide a mechanistic rationale for olmesartan's antioxidant/anti-inflammatory potential translation, in the long term, toward anti-atherosclerotic/anti-remodeling effects reported by clinical trials.

Pathophysiological role of oxidative stress in systolic and diastolic heart failure and its therapeutic implications.

Systolic and diastolic myocardial dysfunction has been demonstrated to be associated with an activation of the circulating and local renin-angiotensin-aldosterone system (RAAS), and with a subsequent inappropriately increased production of reactive oxygen species (ROS). While, at low concentrations, ROS modulate important physiological functions through changes in cellular signalling and gene expression, overproduction of ROS may adversely alter cardiac mechanics, leading to further worsening of systolic and diastolic function. In addition, vascular endothelial dysfunction due to uncoupling of the nitric oxide synthase, activation of vascular and phagocytic membrane oxidases or mitochondrial oxidative stress may lead to increased vascular stiffness, further compromising cardiac performance in afterload-dependent hearts. In the present review, we address the potential role of ROS in the pathophysiology of myocardial and vascular dysfunction in heart failure (HF) and their therapeutic targeting. We discuss possible mechanisms underlying the failure of antioxidant vitamins in improving patients' prognosis, the impact of angiotensin-converting enzyme inhibitors or AT1 receptor blockers on oxidative stress, and the mechanism of the benefit of combination of hydralazine/isosorbide dinitrate. Further, we provide evidence supporting the existence of differences in the pathophysiology of HF with preserved vs. reduced ejection fraction and whether targeting mitochondrial ROS might be a particularly interesting therapeutic option for patients with preserved ejection fraction.

Association of restless legs syndrome with oxidative stress and inflammation in patients undergoing hemodialysis

BackgroundRestless legs syndrome (RLS) is a common comorbidity in patients undergoing hemodialysis, but clinical factors predictive of RLS risk and severity have not been identified. The aims of this multicenter cross-sectional study were to document RLS prevalence and severity in patients undergoing hemodialysis and to identify associated risk factors. MethodsOne-hundred and fifty-nine stable patients on maintenance hemodialysis were enrolled (113 men, 46 women; mean age: 68 ± 11 years; mean duration of dialysis: 54 ± 60 months). Diagnosis of RLS was based on the criteria proposed by the International Restless Legs Syndrome Study Group (IRLSSG), and RLS severity was assessed using the IRLSSG Severity Scale. Potential factors associated with RLS and IRLSSG Severity Scale score were assessed by univariate and multivariate regression analyses. ResultsRLS affected 22% of the study population. The RLS subgroup had a significantly longer duration of hemodialysis and higher cardiothoracic ratio compared to the non-RLS subgroup. The RLS subgroup also had significantly higher serum levels of high-sensitivity C-reactive protein, interleukin-6, ferritin, N-terminal pro-B-type natriuretic peptide, and 8-hydroxy-2′-deoxyguanosine (8-OHdG), and a significantly lower transferrin saturation level compared to the non-RLS subgroup, suggesting a chronic inflammatory state and associated oxidative stress in comorbid patients. Serum 8-OHdG level was an independent risk factor for high IRLSSG Severity Scale score. ConclusionThis study confirms the high prevalence of RLS among hemodialysis patients and identifies the oxidative stress marker serum 8-OHdG as a significant independent predictor of RLS severity. Further studies are needed to identify detailed risk factors and the pathophysiological role of oxidative stress in RLS.

Nitrous oxide related behavioral and histopathological changes may be related to oxidative stress

Nitrous oxide (N2O) toxicity can result in myelin loss and hyperhomocysteinemia similar to cobalamin (Cbl) deficiency. Studies on N2O exposure can help in understanding the mechanism of demyelination. In view of paucity of studies on N2O toxicity in rats this study was undertaken. Six male wistar rats were exposed to 1.5L/min N2O with 1:1 O2 for 90min daily for 1 month. After 1-month exposure blood homocysteine (HCY) and oxidative stress parameters glutathione (GSH) and total antioxidant capacity (TAC) were measured. Brain and spinal cord was subjected to histopathological examination. The neurobehavioral changes, oxidative stress parameters and histopathological changes were correlated with serum B12 and HCY level. After 1-month exposure, the rats appeared sluggish, lethargic and developed predominantly hind limb weakness for 1–1.5h. In the exposed group, the total distance traveled (2001.66±118.27cm; p=0.037), time moving (80.16±5.7s; p=0.028), number of rearing (10.33±1.45; p=0.014) and grip strength (1042.40±51.3N; p=0.041) were significantly decreased whereas, resting time significantly increased (219.83±5.7s; p=0.030) compared to controls. Serum HCY level was significantly increased (20.56±1.296μm/ml; p=0.0007) in the exposed group. However, serum B12 and folic acid levels were not significantly different. GSH significantly decreased (2.21±0.60mg/dl; p=0.018) along with TAC (0.76±0.16 Trolox_Eq_mmol/l; p=0.036). The histopathological studies revealed shrinkage and vacuolation of neurons in cerebral cortex, focal myelin loss, vacuolation in subcortical white matter and spinal cord. N2O exposure results in behavioral alterations, hyperhomocysteinemia, cortical and spinal cord demyelination which were associated with decrease GSH and TAC highlighting pathophysiological role of oxidative stress.

274 Antioxidant Supplementation Improves Inflammatory Nitrergic Dysfunction in Diabetic Biobreeding Prone Rats

Introduction: Loss of intestinal nitrergic motor control has been reported in Biobreeding diabetes-prone (BBDP) rats (Zandecki 2008). We previously demonstrated that loss of jejunal neuronal nitric oxide synthase (nNOS) mRNA expression occurs in the BBDP, which is related to transient intestinal inflammation (myeloperoxidase: MPO activity) and inducible nitric oxide synthase (iNOS) expression, and which is independent from the development of hyperglycemia (Kindt DDW 2009). Studies in enteric neuron cultures suggest that iNOS overexpression downregulates nNOS expression through oxidative stress (Zandecki 2006). Moreover, aminoguanidine an iNOS inhibitor, counteracts the inflammation-induced nitrergic dysfunction and prevents intestinal elongation and dilatation caused by a 3cm H2O pressure stimulus in normoglycemic BBDP (Masaoka DDW 2011). Aim: To investigate the pathophysiological role of oxidative stress in inflammatory nitrergic dysfunction, we designed a controlled antioxidant supplementation study. Methods: BBDP were fed chow supplemented with 2% vitamin E (α-tocopherol) and 2g/l vitamin C (ascorbic acid) in the drinking water from 21days onwards. After onset of diabetes, 1% vitamin E and 1g/l vitamin C were supplemented to compensate for polyphagia and polydypsia. All rats were sacrificed at 220days. Jejunal inflammation, spontaneous intestinal motility, nitrergic neuron number and nNOS mRNA expression were analyzed respectively by MPO measurements, organ bath (37°C) video analysis, NADPH-diaphorase staining and realtime PCR, both in antioxidant supplemented animals and in a control group of age-matched non-supplemented diabetic animals. Results: Compared with controls (n=7), MPO activity decreased significantly in the antioxidant supplemented group (n=6) (9.9±3.9 vs. 2.1±1.4 U/mg, p 0.05) of a 5-cm jejunum segment in response to intraluminal pressure rise In Vitro. Conclusion: Antioxidant supplementation improves inflammation-induced nitrergic dysfunction and partially prevents intestinal dysmotility in diabetic BBDP.

4-Hydroxynonenal and neurodegenerative diseases

The development of oxidative stress, in which production of highly reactive oxygen species (ROS) overwhelms antioxidant defenses, is a feature of many neurological diseases: ischemic, inflammatory, metabolic and degenerative. Oxidative stress is increasingly implicated in a number of neurodegenerative disorders characterized by abnormal filament accumulation or deposition of abnormal forms of specific proteins in affected neurons, like Alzheimer’s disease (AD), Pick’s disease, Lewy bodies related diseases, amyotrophic lateral sclerosis (ALS), and Huntington disease. Causes of neuronal death in neurodegenerative diseases are multifactorial. In some familiar cases of ALS mutation in the gene for Cu/Zn superoxide dismutase (SOD1) can be identified. In other neurodegenerative diseases ROS have some, usually not clear, role in early pathogenesis or implications on neuronal death in advanced stages of illness. The effects of oxidative stress on “post-mitotic cells”, such as neurons may be cumulative, hence, it is often unclear whether oxidative damage is a cause or consequence of neurodegeneration. Peroxidation of cellular membrane lipids, or circulating lipoprotein molecules generates highly reactive aldehydes among which one of most important is 4-hydroxynonenal (HNE). The presence of HNE is increased in brain tissue and cerebrospinal fluid of AD patients, and in spinal cord of ALS patients. Immunohistochemical studies show presence of HNE in neurofibrilary tangles and in senile plaques in AD, in the cytoplasm of the residual motor neurons in sporadic ALS, in Lewy bodies in neocortical and brain stem neurons in Parkinson’s disease (PD) and in diffuse Lewy bodies disease (DLBD). Thus, increased levels of HNE in neurodegenerative disorders and immunohistochemical distribution of HNE in brain tissue indicate pathophysiological role of oxidative stress in these diseases, and especially HNE in formation of abnormal filament deposites.