Targeting antioxidants to mitochondria: a potential new therapeutic strategy for cardiovascular diseases

Mitochondria produce large amounts of free radicals and play an important role in the life and death of a cell. Thus, mitochondrial oxidative damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions including ischemia-reperfusion injury, sepsis, diabetes, atherosclerosis and, consequently, cardiovascular diseases (CVD). In fact, endothelial dysfunction, characterized by a loss of nitric oxide (NO) bioactivity, occurs early on in the development of atherosclerosis, and determines future vascular complications. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are not yet clear, oxidative stress seems to play an important role. This review considers the process of CVD from a mitochondrial perspective. Accordingly, strategies for the targeted delivery of antioxidants to mitochondria are being developed. In this review, we will provide a summary of the following areas: the cellular metabolism of reactive oxygen species (ROS) and its role in pathophysiological processes such as CVD; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; recent developments in mitochondrially-targeted antioxidants that concentrate on the matrix-facing surface of the inner mitochondrial membrane and therefore protect against mitochondrial oxidative damage, and their therapeutic potential for future treatment of CVDs. More pre-clinical and clinical studies, however, are necessary in order to evaluate the effectiveness and toxicity of mitochondrially-targeted antioxidants.     

Serum Ferritin Level Remains a Reliable Marker of Bone Marrow Iron Stores Evaluated by Histomorphometry in Hemodialysis Patients

Background and objectives: As well as being a marker of body iron stores, serum ferritin (sFerritin) has also been shown to be a marker of inflammation in hemodialysis (HD) patients. The aim of this study was to analyze whether sFerritin is a reliable marker of the iron stores present in bone marrow of HD patients.Design: Histomorphometric analysis of stored transiliac bone biopsies was used to assess iron stores by determining the number of iron-stained cells per square millimeter of bone marrow.Results: In 96 patients, the laboratory parameters were hemoglobin = 11.3 ± 1.6 g/dl, hematocrit = 34.3 ± 5%, sFerritin = 609 ± 305 ng/ml, transferrin saturation = 32.7 ± 22.5%, and C-reactive protein (CRP) = 0.9 ± 1.4 mg/dl. sFerritin correlated significantly with CRP, bone marrow iron, and time on HD treatment (P = 0.006, 0.001, and 0.048, respectively). The independent determinants of sFerritin were CRP (β-coef = 0.26; 95% CI = 24.6 to 132.3) and bone marrow iron (β-coef = 0.32; 95% CI = 0.54 to 2.09). Bone marrow iron was higher in patients with sFerritin >500 ng/ml than in those with sFerritin ≤500 ng/ml. In the group of patients with sFerritin ≤500 ng/ml, the independent determinant of sFerritin was bone marrow iron (β-coef = 0.48, 95% CI = 0.48 to 1.78), but in the group of patients with sFerritin >500 ng/ml, no independent determinant of sFerritin was found.Conclusions: sFerritin adequately reflects iron stores in bone marrow of HD patients.Anemia is a common complication of chronic kidney disease (CKD) that mainly affects patients on hemodialysis (HD) therapy. It results from the reduced kidney production of erythropoietin (EPO), as well as from changes in iron homeostasis, which can lead to deficiency of this metal. Thus, the routine monitoring of iron stores is crucial for an adequate management of anemia in that population (1).The most precise tool to evaluate iron status is the measurement of bone marrow iron content, which requires an invasive technique (2,3). Therefore, serum ferritin (sFerritin) and transferrin saturation are currently the main surrogate markers used in daily clinical practice for assessing iron status (4). However, sFerritin is also a positive acute-phase reactant (5). Because inflammation is a frequent finding in HD patients (6), it has been argued that sFerritin can lead to misinterpretation of iron status.Thus, the aim of the present study was to analyze whether sFerritin is a reliable marker of the iron stores present in the bone marrow of HD patients. These stores were assessed by histomorphometric analyses of the bone marrow, a method capable of providing quantitative information about bone marrow iron content.     

Aspirin prevents diabetic oxidative changes in rat lacrimal gland structure and function

The aim of this study is to evaluate whether aspirin reduces Diabetis Mellitus (DM) oxidative damage in the lacrimal gland (LG), and ocular surface (OS). Ten weeks after streptozotocin induced DM and aspirin treatment, LG and OS of rats were compared for tear secretion, hidtology, peroxidase activity, and expression of uncoupling proteins (UCPs). DM reduction of tear secretion was prevented by aspirin (P < 0.01). Alterations of LG morphology and increased numbers of lipofucsin-like inclusions were observed in diabetic but not in aspirin-treated diabetic rats. Peroxidase activity levels were higher and UCP-2 was reduced in DM LG but not in aspirin treated (P = 0.0025 and P < 0.05, respectively). The findings prevented by aspirin indicate a direct inhibitory effect on oxidative pathways in LG and their inflammatory consequences, preserving the LG structure and function against hyperglycemia and/or insulin deficiency damage.     

Complex Methylmercury–Cysteine Alters Mercury Accumulation in Different Tissues of Mice

Abstract: Methylmercury (MeHg) can cause deleterious effects in vertebrate tissues, particularly in the central nervous system. MeHg interacts with sulfhydryl groups from low and high molecular weight thiols in the blood, which can facilitate MeHg uptake into different tissues. The purpose of this study was to examine the effect of MeHg–Cysteine (MeHg‐Cys) complex administration on Hg‐uptake in cerebral areas (cortex and cerebellum), liver and kidney of adult mice. Animals were divided into four groups: control (1 mL/kg distilled water), MeHg (2 mg/kg), Cys (2 mg/kg) and MeHg–Cys complex (0.8 molar ratio). Mice received one intraperitoneal injection per day for 60 consecutive days. Treatment with MeHg significantly increased mercury concentrations in all tissues analysed when compared with the control group. The accumulation of mercury in brain and in liver was further increased in animals that received MeHg–Cys complex when compared with the MeHg alone group. However, renal Hg decreased in MeHg‐Cys treated mice, when compared with the group treated only with MeHg. In summary, the transport of MeHg–Cys complex was tissue‐specific, and we observed an increase in its uptake by liver and brain as well as a decrease in kidney.     

In vitro Reactivating Effects of Standard and Newly Developed Oximes on Malaoxon‐Inhibited Mouse Brain Acetylcholinesterase

Abstract: Malathion is an organophosphate (OP) pesticide whose toxicity depends on its bioactivation to malaoxon. Human malathion poisoning has been treated with oximes (mainly pralidoxime) in an attempt to reactivate OP‐inhibited acetylcholinesterase (AChE). However, pralidoxime has shown unsatisfactory therapeutic effects in malathion poisoning and its routine use has been questioned. In this study, we evaluated the in vitro potency of standards and newly developed oximes in reactivating malaoxon‐inhibited AChE derived from mouse brain supernatants. Malaoxon displayed a concentration‐dependent inhibitory effect on mouse brain AChE (IC₅₀ = 2.36 μM), and pralidoxime caused a modest reactivating effect (30% of reactivation at 600 μM). Obidoxime and trimedoxime, as well as K047 and K075, displayed higher reactivating effects (from 55% to 70% of reactivation at 600 μM) when compared with pralidoxime. The results show that obidoxime, trimedoxime, K074 and K075 present higher reactivating effects on malaoxon‐inhibited AChE under in vitro conditions when compared with pralidoxime. Taking into account the unsatisfactory effects of pralidoxime as antidotal treatment in malathion poisonings, the present results suggest that obidoxime, trimedoxime, K074 and K075 might be interesting therapeutic strategies to reactivate malaoxon‐inhibited AChE in malathion poisonings.     

Overview of venous thromboembolism

Thrombosis occurs at sites of injury to the vessel wall, by inflammatory processes leading to activation of platelets, platelet adherence to the vessel wall and the formation of a fibrin network. A thrombus that goes on to occlude a blood vessel is known as a thromboembolism. Venous thromboembolism begins with deep vein thrombosis (DVT), which forms in the deep veins of the leg (calf) or pelvis. In some cases, the DVT becomes detached from the vein and is transported to the right-hand side of the heart, and from there to the pulmonary arteries, giving rise to a pulmonary embolism (PE). Certain factors predispose patients toward the development of venous thromboembolism (VTE), including surgery, trauma, hospitalization, immobilization, cancer, long-haul travel, increased age, obesity, major medical illness and previous VTE; in addition, there may also be a genetic component to VTE. VTE is responsible for a substantial number of deaths per annum in Europe. Anticoagulants are the mainstay of both VTE treatment and VTE prevention, and many professional organizations have published guidelines on the appropriate use of anticoagulant therapies for VTE. Treatment of VTE aims to prevent morbidity and mortality associated with the disease, and any long-term complications such as VTE recurrence or post-thrombotic syndrome. Generally, guidelines recommend the use of low molecular weight heparins (LMWH), unfractionated heparin (UFH) or fondaparinux for the pharmacological prevention and treatment of VTE, with the duration of therapy varying according to the baseline characteristics and risk profile of the individual. Despite evidence showing that the use of anticoagulation prevents VTE, the availability of several convenient, effective anticoagulant therapies and the existence of clear guideline recommendations, thromboprophylaxis is underused, particularly in patients not undergoing surgery. Greater adherence to guideline-recommended therapies, such as LMWH, which can be administered on an outpatient basis, should reduce the mortality associated with this preventable disease.     

Donor selection for unrelated cord blood transplants

The number of unrelated cord blood transplants is increasing, with more than 8000 patients reported worldwide. Criteria of donor choice have been identified. Cell dose measured by number of nucleated cells is the most important factor, thus increases in cell dose can partially overcome the presence of HLA incompatibilities. Overall, increasing the number of HLA incompatibilities is associated with non-engraftment, but it also decreases the risk of relapse in patients with malignant disease, resulting in an absence of effect of HLA incompatibilities on event-free survival (survival without relapse or complications related to the transplant). However, in patients with non-malignant disorders, increasing the number of HLA incompatibilities decreases the overall survival. These results show that criteria of donor choice based on number of infused cells, number of HLA incompatibilities and diagnosis improve outcomes of unrelated cord blood transplants. Currently, owing to the possibility of using a non HLA identical donor, most patients can find a donor, increasing the need for the development of the inventory of cord blood banks. Methods of improving engraftment are currently under investigation.     

Extensive central ossifying fibroma of the maxilla: a case report with description of an alternative surgical technique

Central ossifying fibroma (COF) is a fibrous-osseous lesion containing fibrous tissue and varying amounts of calcified tissue. Although the lesion is preferentially located in the jaws, it may be found elsewhere. It usually affects patients during their third and fourth decades of life, with a female predilection. The mandibular premolar-molar area is the most common site. Radiographically, COF may present a radiolucent, radiopaque or a mixed appearance. This article reports a case of an extensive COF in the maxilla of a 62-year-old patient. Intraoral examination revealed a swelling with undefined limits in the right side of the upper alveolar ridge, extending towards the palate. The lesion had invaded the maxillary sinus, nasal cavity and orbit. An incision including mucosa, periosteum, and a thin layer of the bone, was performed. The lesion was excised using a flap, and interrupted suture was utilized. The bone which was preserved in the flap was used as graft so that faster and more effective bone formation could occur. The patient has been followed-up for 5 years with no clinical or radiographic signs of recurrence. This article demonstrates that COF has a considerable growth potential. In addition, the surgical technique here in described shows very good cosmetic and functional results, especially when managing very large lesions.     

Comparative therapeutic use of Risedronate and Calcarea phosphorica--allopathy versus homeopathy--in bone repair in castrated rats

Osteoporosis, a disease characterized by progressive bone loss, has been the target of several studies in the past few years. It results in a much higher risk for fractures and might cause slower bone lesion healing. The aim of this work was to study the effects of Risedronate (allopathic medicine) and Calcarea phosphorica 6CH (homeopathic medicine) on the repair of bone lesions in male rats with osteoporosis induced by castration. Eighty-four three-month-old rats were used divided into four groups of twenty-one animals each. Three groups where castrated and one group was submitted to Sham surgery. One month later, cortical lesions were made in all animals' tibiae and, after one day, the different experimental treatments began according to the following groups: CR--castrated/Risedronate (1 mg/kg/day); CCp--castrated/Calcarea phosphorica 6CH (3 drops/day); CP--castrated/placebo and SP--Sham/placebo. The animals were sacrificed at seven, fourteen and twenty-eight days after the beginning of the treatments and had their tibiae removed. Digital radiographs of the tibiae were taken and analyzed in order to evaluate the optical density of the defect area. Then, they were decalcified and processed for histological and histomorphometrical analysis. The data were submitted to ANOVA, and to the Tukey and Dunnett tests (5%). The allopathic and homeopathic treatments led to different bone formation as regards remodeling and maturation aspects. Further research is necessary to access the resistance and quality of the newly formed bone.