Plasma Lead Concentration and Risk of Late Kidney Allograft Failure: Findings From the TransplantLines Biobank and Cohort Studies.

RATIONALE & OBJECTIVE: Heavy metals are known to induce kidney damage, and recent studies have linked minor exposures to cadmium and arsenic with increased risk of kidney allograft failure, yet the potential association of lead with late graft failure in kidney transplant recipients (KTRs) remains unknown. STUDY DESIGN: Prospective cohort study in The Netherlands. SETTING & PARTICIPANTS: We studied outpatient KTRs (n = 670) with a functioning graft for ≥1 year recruited at a university setting (2008-2011) and followed for a median of 4.9 (interquartile range, 3.4-5.5) years. Additionally, patients with chronic kidney disease (n = 46) enrolled in the ongoing TransplantLines Cohort and Biobank Study (2016-2017, ClinicalTrials.gov identifier NCT03272841) were studied at admission for transplant and at 3, 6, 12, and 24 months after transplant. EXPOSURE: Plasma lead concentration was log2-transformed to estimate the association with outcomes per doubling of plasma lead concentration and also considered categorically as tertiles of lead distribution. OUTCOME: Kidney graft failure (restart of dialysis or repeat transplant) with the competing event of death with a functioning graft. ANALYTICAL APPROACH: Multivariable-adjusted cause-specific hazards models in which follow-up of KTRs who died with a functioning graft was censored. RESULTS: Median baseline plasma lead concentration was 0.31 (interquartile range, 0.22-0.45) µg/L among all KTRs. During follow-up, 78 (12%) KTRs experienced graft failure. Higher plasma lead concentration was associated with increased risk of graft failure (hazard ratio, 1.59 [95% CI, 1.14-2.21] per doubling; P = 0.006) independent of age, sex, transplant characteristics, estimated glomerular filtration rate, proteinuria, smoking status, alcohol intake, and plasma concentrations of cadmium and arsenic. These findings remained materially unchanged after additional adjustment for dietary intake and were consistent with those of analyses examining lead categorically. In serial measurements, plasma lead concentration was significantly higher at admission for transplant than at 3 months after transplant (P = 0.001), after which it remained stable over 2 years of follow-up (P = 0.2). LIMITATIONS: Observational study design. CONCLUSIONS: Pretransplant plasma lead concentrations, which decrease after transplant, are associated with increased risk of late kidney allograft failure. These findings warrant further studies to evaluate whether preventive or therapeutic interventions to decrease plasma lead concentration may represent novel risk-management strategies to decrease the rate of kidney allograft failure.

Ascorbate as a Bioactive Compound in Cancer Therapy: The Old Classic Strikes Back.

Cancer is a disease of high mortality, and its prevalence has increased steadily in the last few years. However, during the last decade, the development of modern chemotherapy schemes, new radiotherapy techniques, targeted therapies and immunotherapy has brought new hope in the treatment of these diseases. Unfortunately, cancer therapies are also associated with frequent and, sometimes, severe adverse events. Ascorbate (ascorbic acid or vitamin C) is a potent water-soluble antioxidant that is produced in most mammals but is not synthesised endogenously in humans, which lack enzymes for its synthesis. Ascorbate has antioxidant effects that correspond closely to the dose administered. Interestingly, this natural antioxidant induces oxidative stress when given intravenously at a high dose, a paradoxical effect due to its interactions with iron. Importantly, this deleterious property of ascorbate can result in increased cell death. Although, historically, ascorbate has been reported to exhibit anti-tumour properties, this effect has been questioned due to the lack of available mechanistic detail. Recently, new evidence has emerged implicating ferroptosis in several types of oxidative stress-mediated cell death, such as those associated with ischemia-reperfusion. This effect could be positively modulated by the interaction of iron and high ascorbate dosing, particularly in cell systems having a high mitotic index. In addition, it has been reported that ascorbate may behave as an adjuvant of favourable anti-tumour effects in cancer therapies such as radiotherapy, radio-chemotherapy, chemotherapy, immunotherapy, or even in monotherapy, as it facilitates tumour cell death through the generation of reactive oxygen species and ferroptosis. In this review, we provide evidence supporting the view that ascorbate should be revisited to develop novel, safe strategies in the treatment of cancer to achieve their application in human medicine.

Antioxidant Cardioprotection against Reperfusion Injury: Potential Therapeutic Roles of Resveratrol and Quercetin.

Ischemia-reperfusion myocardial damage is a paradoxical tissue injury occurring during percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) patients. Although this damage could account for up to 50% of the final infarct size, there has been no available pharmacological treatment until now. Oxidative stress contributes to the underlying production mechanism, exerting the most marked injury during the early onset of reperfusion. So far, antioxidants have been shown to protect the AMI patients undergoing PCI to mitigate these detrimental effects; however, no clinical trials to date have shown any significant infarct size reduction. Therefore, it is worthwhile to consider multitarget antioxidant therapies targeting multifactorial AMI. Indeed, this clinical setting involves injurious effects derived from oxygen deprivation, intracellular pH changes and increased concentration of cytosolic Ca2+ and reactive oxygen species, among others. Thus, we will review a brief overview of the pathological cascades involved in ischemia-reperfusion injury and the potential therapeutic effects based on preclinical studies involving a combination of antioxidants, with particular reference to resveratrol and quercetin, which could contribute to cardioprotection against ischemia-reperfusion injury in myocardial tissue. We will also highlight the upcoming perspectives of these antioxidants for designing future studies.

Plasma cadmium is associated with increased risk of long-term kidney graft failure.

The kidney is one of the most sensitive organs to cadmium-induced toxicity, particularly in conditions of long-term oxidative stress. We hypothesized that, in kidney transplant recipients, nephrotoxic exposure to cadmium represents an overlooked hazard for optimal graft function. To test this, we performed a prospective cohort study and included 672 outpatient kidney transplant recipients with a functioning graft of beyond one year. The median plasma cadmium was 58 ng/L. During a median 4.9 years of follow-up, 78 kidney transplant recipients developed graft failure with a significantly different distribution across tertiles of plasma cadmium (13, 26, and 39 events, respectively). Plasma cadmium was associated with an increased risk of graft failure (hazard ratio 1.96, 95% confidence interval 1.56‒2.47 per log2 ng/L). Similarly, a dose-response relationship was observed over increasing tertiles of plasma cadmium, after adjustments for potential confounders (donor, recipient, transplant and lifestyle characteristics), robust in both competing risk and sensitivity analyses. These findings were also consistent for kidney function decline (graft failure or doubling of serum creatinine). Thus, plasma cadmium is independently associated with an increased risk of long-term kidney graft failure and decline in kidney function. Further studies are needed to investigate whether exposure to cadmium represents an otherwise overlooked modifiable risk factor for adverse long-term graft outcomes in different populations.

Joint Cardioprotective Effect of Vitamin C and Other Antioxidants against Reperfusion Injury in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

Percutaneous coronary intervention (PCI) has long remained the gold standard therapy to restore coronary blood flow after acute myocardial infarction (AMI). However, this procedure leads to the development of increased production of reactive oxygen species (ROS) that can exacerbate the damage caused by AMI, particularly during the reperfusion phase. Numerous attempts based on antioxidant treatments, aimed to reduce the oxidative injury of cardiac tissue, have failed in achieving an effective therapy for these patients. Among these studies, results derived from the use of vitamin C (Vit C) have been inconclusive so far, likely due to suboptimal study designs, misinterpretations, and the erroneous conclusions of clinical trials. Nevertheless, recent clinical trials have shown that the intravenous infusion of Vit C prior to PCI-reduced cardiac injury biomarkers, as well as inflammatory biomarkers and ROS production. In addition, improvements of functional parameters, such as left ventricular ejection fraction (LVEF) and telediastolic left ventricular volume, showed a trend but had an inconclusive association with Vit C. Therefore, it seems reasonable that these beneficial effects could be further enhanced by the association with other antioxidant agents. Indeed, the complexity and the multifactorial nature of the mechanism of injury occurring in AMI demands multitarget agents to reach an enhancement of the expected cardioprotection, a paradigm needing to be demonstrated. The present review provides data supporting the view that an intravenous infusion containing combined safe antioxidants could be a suitable strategy to reduce cardiac injury, thus improving the clinical outcome, life quality, and life expectancy of patients subjected to PCI following AMI.

Post-transplantation plasma malondialdehyde is associated with cardiovascular mortality in renal transplant recipients: a prospective cohort study.

BACKGROUND: In renal transplant recipients (RTRs), cardiovascular mortality is the most common cause of long-term renal graft loss. Oxidative stress (OS) has been associated with cardiovascular disease and is known to be enhanced in RTRs. We aimed to prospectively investigate whether the concentration of the OS biomarker malondialdehyde (MDA) is associated with long-term risk of cardiovascular mortality in a large cohort of RTRs. METHODS: The plasma MDA concentration was measured using the thiobarbituric acid reaction assay in 604 extensively phenotyped RTRs with a functioning allograft for ≥1 year. The association between MDA and cardiovascular mortality was assessed using Cox proportional hazard regression analyses in the overall cohort and within subgroups according to significant effect modifiers. RESULTS: Median circulating MDA concentration at baseline was 5.38 [interquartile range (IQR) 4.31-6.45] µmol/L. During a follow-up period of 6.4 (IQR 5.6-6.8) years, 110 (18%) RTRs died, with 40% of deaths due to cardiovascular causes. MDA concentration was significantly associated with the risk for cardiovascular mortality {hazard ratio [HR] 1.31 [95% confidence interval (CI) 1.03-1.67] per 1-SD increment}, independent of adjustment for potential confounders, including renal function, immunosuppressive therapy, smoking status and blood pressure. The association between MDA concentration and the risk for cardiovascular mortality was stronger in RTRs with relatively lower plasma ascorbic acid concentrations [≤42.5 µmol/L; HR 1.79 (95% CI 1.30-2.48) per 1-SD increment] or relatively lower estimated glomerular filtration rates [≤45 mL/min/1.73 m2; HR 2.09 (95% CI 1.45-3.00) per 1-SD increment]. CONCLUSIONS: Circulating MDA concentration is independently associated with long-term risk for cardiovascular mortality, particularly in RTRs with relatively lower ascorbic acid concentrations or renal function. Further studies are warranted to elucidate whether OS-targeted interventions could decrease cardiovascular mortality in RTRs.

Consumption of fruits and vegetables and cardiovascular mortality in renal transplant recipients: a prospective cohort study.

BACKGROUND: It currently remains understudied whether low consumption of fruits and vegetables after kidney transplantation may be a modifiable cardiovascular risk factor. We aimed to investigate the associations between consumption of fruits and vegetables and cardiovascular mortality in renal transplant recipients (RTRs). METHODS: Consumption of fruits and vegetables was assessed in an extensively phenotyping cohort of RTRs. Multivariable-adjusted Cox proportional hazards regression analyses were performed to assess the risk of cardiovascular mortality. RESULTS: We included 400 RTRs (age 52 ± 12 years, 54% males). At a median follow-up of 7.2 years, 23% of RTRs died (53% were due to cardiovascular causes). Overall, fruit consumption was not associated with cardiovascular mortality {hazard ratio [HR] 0.82 [95% confidence interval (CI) 0.60-1.14]; P = 0.24}, whereas vegetable consumption was inversely associated with cardiovascular mortality [HR 0.49 (95% CI 0.34-0.71); P < 0.001]. This association remained independent of adjustment for several potential confounders. The association of fruit consumption with cardiovascular mortality was significantly modified by estimated glomerular filtration rate (eGFR; Pinteraction = 0.01) and proteinuria (Pinteraction = 0.01), with significant inverse associations in patients with eGFR > 45 mL/min/1.73 m2 [HR 0.56 (95% CI 0.35-0.92); P = 0.02] or the absence of proteinuria [HR 0.62 (95% CI 0.41-0.92); P = 0.02]. CONCLUSIONS: In RTRs, a relatively higher vegetable consumption is independently and strongly associated with lower cardiovascular mortality. A relatively higher fruit consumption is also associated with lower cardiovascular mortality, although particularly in RTRs with eGFR > 45 mL/min/1.73 m2 or an absence of proteinuria. Further studies seem warranted to investigate whether increasing consumption of fruits and vegetables may open opportunities for potential interventional pathways to decrease the burden of cardiovascular mortality in RTRs.

Plasma Antioxidant Potential at Admission is Associated with Length of ICU Stay in Child with Sepsis: A Pilot Study.

OBJECTIVE: To assess the relationship between biomarkers of oxidative stress (OS) and the length of stay in intensive care units (LSICU) in septic children. METHODS: Clinical parameters and biomarkers of OS were measured in 16 children admitted for sepsis in an intensive care unit. The associations between biomarkers of OS and the LSICU were assessed by linear correlation. Multiple linear regression models were constructed to adjust other variables. RESULTS: The mean of LSICU was 7.13 ± 4.17 days. LSICU was associated with the catalase activity (rho =0.56, p-value =0.024) and the ferric reducing ability of plasma (FRAP, r = 0.73, p-value =0.001). However, only FRAP at ICU admission was independently associated with LSICU, which rose 0.21 days for each 10 µmol/l of increase in the FRAP level. CONCLUSION: We conclude for first time that FRAP level at ICU admission is independently associated with LSICU in pediatric patients.

The effects of polyunsaturated fatty acids and antioxidant vitamins on atrial oxidative stress, nitrotyrosine residues, and connexins following extracorporeal circulation in patients undergoing cardiac surgery.

Cardiac surgery with extracorporeal circulation is characterized by different degrees of myocardial ischemia/reperfusion, which is often associated with postoperative atrial fibrillation (POAF). We have previously shown that a novel preventive therapy based on the reinforcement of the antioxidant system using omega-3 fatty acids plus antioxidant vitamin supplementation applied to patients undergoing cardiac surgery reduces POAF occurrence. We hypothesized that oxidative stress and nitrosative stress are involved in the development of an arrhythmogenic substrate by their effect on connexins (Cx40, Cx43 and Cx45) abundance and distribution pattern. Therefore, we have assessed the effect of redox status on atrial tissue in patients undergoing cardiac surgery. Placebo/POAF and supplemented/POAF patients showed 276 and 170% higher reactive oxygen species (ROS) levels and 223 and 96% higher nitrotyrosine residues levels, respectively, compared to sinus rhythm (SR). In POAF tissue, antioxidant supplementation prevented Cx40 and Cx43 lateralization on cardiomyocyte sarcolemma, keeping them at the intercalated disks. POAF samples showed Cx40 heterogeneous distribution pattern, presenting tissue areas lacking this protein (49 and 55% lower levels in placebo/POAF and supplemented/POAF groups, respectively, compared to SR). Of note, Cx45 overexpression occurred in POAF, being 211 and 167% higher in placebo/POAF and supplemented/POAF groups, respectively, compared to SR. It is concluded that treatment with omega-3 fatty acids and antioxidant vitamins reduces oxidative and nitrosative stress and prevents Cx40/Cx43 lateralization in atrial tissue likely contributing to POAF prevention. However, it failed to fully prevent POAF occurrence because these compounds have no effects on the normalization of Cx40 down-regulation and Cx45 up-regulation, which may promote POAF.

Modulation of (Na,K)-ATPase activity by membrane fatty acid composition: therapeutic implications in human hypertension.

Abstract Oxidative stress (OS) plays a key role in the pathophysiology of essential hypertension and is associated with changes in the cell membrane fatty acid composition and fluidity. As (Na,K)-ATPase is modulated by the surrounding lipid microenvironment, lipid peroxidation could alter the interactions of this enzyme with the membrane components. Thus, modifications in the membrane fatty acid profile will translate into effects on (Na,K)-ATPase activity. Accordingly, a decrease in this enzyme activity has been reported in hypertensive patients. The aim of this study was to evaluate the relationship between membrane fluidity and fatty acid composition and (Na,K)-ATPase activity in erythrocytes of essential hypertensive patients supplemented with antioxidant vitamins C and E. A double-blind, randomized, placebo-controlled study was conducted in 120 men with essential hypertension assigned to receive vitamin C (1 g/day) +E (400 IU/day) or placebo for 8 weeks. Measurements included OS related parameters: GSH/GSSG ratio, F2-isoprostanes and antioxidant capacity of plasma, (Na,K)-ATPase activity and erythrocytes membrane fatty acid composition (PUFA, polyunsaturated fatty acids; SAFA, saturated fatty acids). Associations were assessed by Pearson correlation and the differences by Student t-test (p<0.05). Supplemented hypertensive patients showed higher activity of (Na,K)-ATPase and proportion of PUFA, and lower blood pressure, OS markers and proportion of SAFA, versus placebo. The activity of (Na,K)-ATPase correlated negatively with the proportion of SAFA, but positively with that of PUFA in both groups. Supplementation with vitamins C+E resulted in decreased OS and increased fluidity and PUFA proportion in the membrane, both of which positively modulate (Na,K)-ATPase activity, accounting for the blood pressure reduction.

Integrated approach to reducing polypharmacy in older people: exploring the role of oxidative stress and antioxidant potential therapy.

Increased life expectancy, attributed to improved access to healthcare and drug development, has led to an increase in multimorbidity, a key contributor to polypharmacy. Polypharmacy is characterised by its association with a variety of adverse events in the older persons. The mechanisms involved in the development of age-related chronic diseases are largely unknown; however, altered redox homeostasis due to ageing is one of the main theories. In this context, the present review explores the development and interaction between different age-related diseases, mainly linked by oxidative stress. In addition, drug interactions in the treatment of various diseases are described, emphasising that the holistic management of older people and their pathologies should prevail over the individual treatment of each condition.

Exploring antioxidant strategies in the pathogenesis of ALS.

The central nervous system is essential for maintaining homeostasis and controlling the body's physiological functions. However, its biochemical characteristics make it highly vulnerable to oxidative damage, which is a common factor in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). ALS is a leading cause of motor neuron disease, characterized by a rapidly progressing and incurable condition. ALS often results in death from respiratory failure within 3-5 years from the onset of the first symptoms, underscoring the urgent need to address this medical challenge. The aim of this study is to present available data supporting the role of oxidative stress in the mechanisms underlying ALS and to discuss potential antioxidant therapies currently in development. These therapies aim to improve the quality of life and life expectancy for patients affected by this devastating disease.

Novel Multi-Antioxidant Approach for Ischemic Stroke Therapy Targeting the Role of Oxidative Stress.

Stroke is a major contributor to global mortality and disability. While reperfusion is essential for preventing neuronal death in the penumbra, it also triggers cerebral ischemia-reperfusion injury, a paradoxical injury primarily caused by oxidative stress, inflammation, and blood-brain barrier disruption. An oxidative burst inflicts marked cellular damage, ranging from alterations in mitochondrial function to lipid peroxidation and the activation of intricate signalling pathways that can even lead to cell death. Thus, given the pivotal role of oxidative stress in the mechanisms of cerebral ischemia-reperfusion injury, the reinforcement of the antioxidant defence system has been proposed as a protective approach. Although this strategy has proven to be successful in experimental models, its translation into clinical practice has yielded inconsistent results. However, it should be considered that the availability of numerous antioxidant molecules with a wide range of chemical properties can affect the extent of injury; several groups of antioxidant molecules, including polyphenols, carotenoids, and vitamins, among other antioxidant compounds, can mitigate this damage by intervening in multiple signalling pathways at various stages. Multiple clinical trials have previously been conducted to evaluate these properties using melatonin, acetyl-L-carnitine, chrysanthemum extract, edaravone dexborneol, saffron, coenzyme Q10, and oleoylethanolamide, among other treatments. Therefore, multi-antioxidant therapy emerges as a promising novel therapeutic option due to the potential synergistic effect provided by the simultaneous roles of the individual compounds.

Cardioprotection against ischaemia/reperfusion by vitamins C and E plus n-3 fatty acids: molecular mechanisms and potential clinical applications.

The role of oxidative stress in ischaemic heart disease has been thoroughly investigated in humans. Increased levels of ROS (reactive oxygen species) and RNS (reactive nitrogen species) have been demonstrated during ischaemia and post-ischaemic reperfusion in humans. Depending on their concentrations, these reactive species can act either as benevolent molecules that promote cell survival (at low-to-moderate concentrations) or can induce irreversible cellular damage and death (at high concentrations). Although high ROS levels can induce NF-κB (nuclear factor κB) activation, inflammation, apoptosis or necrosis, low-to-moderate levels can enhance the antioxidant response, via Nrf2 (nuclear factor-erythroid 2-related factor 2) activation. However, a clear definition of these concentration thresholds remains to be established. Although a number of experimental studies have demonstrated that oxidative stress plays a major role in heart ischaemia/reperfusion pathophysiology, controlled clinical trials have failed to prove the efficacy of antioxidants in acute or long-term treatments of ischaemic heart disease. Oral doses of vitamin C are not sufficient to promote ROS scavenging and only down-regulate their production via NADPH oxidase, a biological effect shared by vitamin E to abrogate oxidative stress. However, infusion of vitamin C at doses high enough to achieve plasma levels of 10 mmol/l should prevent superoxide production and the pathophysiological cascade of deleterious heart effects. In turn, n-3 PUFA (polyunsaturated fatty acid) exposure leads to enhanced activity of antioxidant enzymes. In the present review, we present evidence to support the molecular basis for a novel pharmacological strategy using these antioxidant vitamins plus n-3 PUFAs for cardioprotection in clinical settings, such as post-operative atrial fibrillation, percutaneous coronary intervention following acute myocardial infarction and other events that are associated with ischaemia/reperfusion.

Potential Role of Natural Antioxidants in Countering Reperfusion Injury in Acute Myocardial Infarction and Ischemic Stroke.

Stroke and acute myocardial infarction are leading causes of mortality worldwide. The latter accounts for approximately 9 million deaths annually. In turn, ischemic stroke is a significant contributor to adult physical disability globally. While reperfusion is crucial for tissue recovery, it can paradoxically exacerbate damage through oxidative stress (OS), inflammation, and cell death. Therefore, it is imperative to explore diverse approaches aimed at minimizing ischemia/reperfusion injury to enhance clinical outcomes. OS primarily arises from an excessive generation of reactive oxygen species (ROS) and/or decreased endogenous antioxidant potential. Natural antioxidant compounds can counteract the injury mechanisms linked to ROS. While promising preclinical results, based on monotherapies, account for protective effects against tissue injury by ROS, translating these models into human applications has yielded controversial evidence. However, since the wide spectrum of antioxidants having diverse chemical characteristics offers varied biological actions on cell signaling pathways, multitherapy has emerged as a valuable therapeutic resource. Moreover, the combination of antioxidants in multitherapy holds significant potential for synergistic effects. This study was designed with the aim of providing an updated overview of natural antioxidants suitable for preventing myocardial and cerebral ischemia/reperfusion injuries.

Antioxidant Protection against Trastuzumab Cardiotoxicity in Breast Cancer Therapy.

Breast cancer is the most frequent malignant neoplastic disease in women, with an estimated 2.3 million cases in 2020 worldwide. Its treatment depends on characteristics of the patient and the tumor. In the latter, characteristics include cell type and morphology, anatomical location, and immunophenotype. Concerning this latter aspect, the overexpression of the HER2 receptor, expressed in 15-25% of tumors, is associated with greater aggressiveness and worse prognosis. In recent times some monoclonal antibodies have been developed in order to target HER2 receptor overexpression. Trastuzumab is part of the monoclonal antibodies used as targeted therapy against HER2 receptor, whose major problem is its cardiac safety profile, where it has been associated with cardiotoxicity. The appearance of cardiotoxicity is an indication to stop therapy. Although the pathophysiological mechanism is poorly known, evidence indicates that oxidative stress plays a fundamental role causing DNA damage, increased cytosolic and mitochondrial ROS production, changes in mitochondrial membrane potential, intracellular calcium dysregulation, and the consequent cell death through different pathways. The aim of this review was to explore the use of antioxidants as adjuvant therapy to trastuzumab to prevent its cardiac toxicity, thus leading to ameliorate its safety profile in its administration.

Endostatin and Cancer Therapy: A Novel Potential Alternative to Anti-VEGF Monoclonal Antibodies.

Angiogenesis is a physiological process that consists of the formation of new blood vessels from preexisting ones. Angiogenesis helps in growth, development, and wound healing through the formation of granulation tissue. However, this physiological process has also been linked to tumor growth and metastasis formation. Indeed, angiogenesis has to be considered as a fundamental step to the evolution of benign tumors into malignant neoplasms. The main mediator of angiogenesis is vascular endothelial growth factor (VEGF), which is overexpressed in certain cancers. Thus, there are anti-VEGF monoclonal antibodies, such as bevacizumab, used as anti-cancer therapies. However, bevacizumab has shown adverse events, such as hypertension and proteinuria, which in the most severe cases can lead to cessation of therapy, thus contributing to worsening patients' prognosis. On the other hand, endostatin is an endogenous protein that strongly inhibits VEGF expression and angiogenesis and shows a better safety profile. Moreover, endostatin has already given promising results on small scale clinical studies. Hence, in this review, we present data supporting the use of endostatin as a replacement for anti-VEGF monoclonal antibodies.

Joint experimental and theoretical study of PbGa2S4 under compression.

The effect of pressure on the structural, vibrational, and optical properties of lead thiogallate, PbGa2S4, crystallizing under room conditions in the orthorhombic EuGa2S4-type structure (space group Fddd), is investigated. The results from X-ray diffraction, Raman scattering, and optical-absorption measurements at a high pressure beyond 20 GPa are reported and compared not only to ab initio calculations, but also to the related compounds α'-Ga2S3, CdGa2S4, and HgGa2S4. Evidence of a partially reversible pressure-induced decomposition of PbGa2S4 into a mixture of Pb6Ga10S21 and Ga2S3 above 15 GPa is reported. Thus, our measurements and calculations show a route for the high-pressure synthesis of Pb6Ga10S21, which is isostructural to the stable Pb6In10S21 compound at room pressure.

Antioxidant Intervention against Male Infertility: Time to Design Novel Strategies.

Infertility is a highly prevalent condition, affecting 9-20% of couples worldwide. Among the identifiable causes, the male factor stands out in about half of infertile couples, representing a growing problem. Accordingly, there has been a decline in both global fertility rates and sperm counts in recent years. Remarkably, nearly 80% of cases of male infertility (MI) have no clinically identifiable aetiology. Among the mechanisms likely plausible to account for idiopathic cases, oxidative stress (OS) has currently been increasingly recognized as a key factor in MI, through phenomena such as mitochondrial dysfunction, lipid peroxidation, DNA damage and fragmentation and finally, sperm apoptosis. In addition, elevated reactive oxygen species (ROS) levels in semen are associated with worse reproductive outcomes. However, despite an increasing understanding on the role of OS in the pathophysiology of MI, therapeutic interventions based on antioxidants have not yet provided a consistent benefit for MI, and there is currently no clear consensus on the optimal antioxidant constituents or regimen. Therefore, there is currently no applicable antioxidant treatment against this problem. This review presents an approach aimed at designing an antioxidant strategy based on the particular biological properties of sperm and their relationships with OS.

Pharmacological Basis for Abrogating Myocardial Reperfusion Injury Through a Multi-Target Combined Antioxidant Therapy.

The main goal of the treatment for acute myocardial infarction is to achieve reperfusion of the affected myocardial tissue, with percutaneous coronary angioplasty being the gold standard procedure. However, this strategy has been associated with additional heart damage termed "lethal reperfusion injury," which is responsible for up to half of the final infarct size. Among the possible underlying mechanisms that are likely to explain this damage, studies suggest that oxidative stress plays a key role. Although this has not been translated into clinical benefits in most studies, recent preclinical studies reported promising results and a possible synergy with the combined use of vitamin C (VC), N-acetylcysteine (NAC), and deferoxamine (DFO). However, to implement a combined therapy with these drugs for patients requires further studies to understand their pharmacokinetic properties. Available data of the clinical trials have not been validated by looking into the pharmacokinetics in their design. Therefore, this article presents an update and comparison of the evidence for the efficacy of these administration schemes for each drug in cardioprotection, their pharmacokinetic properties and mechanisms of action for their use against "lethal reperfusion injury." To achieve a cardioprotective effect using a new pharmacological strategy before the onset of reperfusion, it is helpful to consider the pharmacokinetics of each drug. In this regard, to design a fast and short pharmacologic therapeutic strategy, theoretically VC and DFO concentrations could be modeled by a one-compartment model whereas NAC could be modeled by a three-compartment model with an initial short half-life.