Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms

From human and animal studies, estrogen is known to protect the myocardium from an ischemic insult. However, there is limited knowledge regarding mechanisms by which estrogen directly protects cardiomyocytes. In this report, we employed an in vitro model, in which cultured rat cardiomyocytes underwent prolonged hypoxia followed by reoxygenation (H/R), to study the cardioprotective mechanism of estrogen. 17-beta-estradiol (E2) acting via estrogen receptors inhibited H/R-induced apoptosis of cardiomyocytes. Mitochondrial reactive oxygen species (ROS) generated from H/R activated p38alpha MAPK, and inhibition of p38alpha with SB203580 significantly prevented H/R-induced cell death. E2 suppressed ROS formation and p38alpha activation by H/R and concomitantly augmented the activity of p38beta. Unlike p38alpha, p38beta was little affected by H/R. Dominant negative p38beta protein expression decreased E2-mediated cardiomyocyte survival and ROS suppression during H/R stress. The prosurvival signaling molecule, phosphoinositol-3 kinase (PI3K), has previously been linked to cell survival following ischemia-reperfusion injury. Here, E2-activated PI3K was found to inhibit ROS generated from H/R injury, leading to inhibition of downstream p38alpha. We further linked these signaling pathways in that p38beta was activated by E2 stimulation of PI3K. Thus, E2 differentially modulated two major isoforms of p38, leading to cardiomyocyte survival. This was achieved by signaling through PI3K, integrating cell survival mediators.     

Functional estrogen receptors in the mitochondria of breast cancer cells

Steroid hormones have been reported to indirectly impact mitochondrial functions, attributed to nuclear receptor-induced production of proteins that localize in this cytoplasmic organelle. Here we show high-affinity estrogen receptors in the mitochondria of MCF-7 breast cancer cells and endothelial cells, compatible with classical estrogen receptors ERalpha and ERbeta. We report that in MCF-7, estrogen inhibits UV radiation-induced cytochrome C release, the decrease of the mitochondrial membrane potential, and apoptotic cell death. UV stimulated the formation of mitochondrial reactive oxygen species (mROS), and mROS were essential to inducing mitochondrial events of cell death. mROS mediated the UV activation of c-jun N-terminal kinase (JNK), and protein kinase C (PKC) delta, underlying the subsequent translocation of Bax to the mitochondria where oligomerization was promoted. E2 (estradiol) inhibited all these events, directly acting in mitochondria to inhibit mROS by rapidly up-regulating manganese superoxide dismutase activity. We implicate novel functions of ER in the mitochondria of breast cancer that lead to the survival of the tumor cells.     

Reactive oxygen metabolite-induced toxicity to cultured bovine endothelial cells: Status of cellular iron in mediating injury

We aimed to determine the status of iron in mediating oxidant-induced damage to cultured bovine aortic endothelial cells. Chromium-51-labeled cells were exposed to reaction mixtures of xanthine oxidase/hypoxanthine and glucose oxidase/glucose; these produce superoxide and hydrogen peroxide, or hydrogen peroxide, respectively. Xanthine oxidase caused a dose dependent increase of ⁵¹Cr release. Damage was prevented by allopurinol, oxypurinol, and extracellular catalase, but not by superoxide dismutase. Prevention of xanthine oxidase-in-duced damage by catalase was blocked by an inhibitor of catalase, aminotriazole. Glucose oxidase also caused a dose-dependent increase of ⁵¹Ci release. Glucose oxidase-induced injury, which was catalase-inhibitable, was not prevented by extracellular superoxide dismutase. Both addition of and pretreatment with deferoxamine (a chelator of Fe³⁺) prevented glucose oxidase-induced injury. The presence of phenanthroline (a chelator of divalent Fe²⁺) prevented glucose oxidase-induced ⁵¹Cr release, whereas pretreatment with the agent did not. Apotransferrin (a membrane impermeable iron binding protein) failed to influence damage. Neither deferoxamine nor phenanthroline influenced cellular antioxidant defenses, or inhibited lysis by non-oxidant toxic agents. Treatment with allopurinol and oxypurinol, which inhibited cellular xanthine oxidase, failed to prevent glucose oxidase injury. We conclude that (1) among the oxygen species extracellularly generated by xanthine oxidase/hypoxanthine, hydrogen peroxide induces damage via a reaction on cellular iron; (2) deferoxamine and phenanthroline protect cells by chelating Fe³⁺ and Fe²⁺, respectively; and (3) reduction of cellular stored iron (Fe³⁺) to Fe²⁺ may be a prerequisite for mediation of oxidantinduced injury, but this occurs independently of extracellular superoxide or cellular xanthine oxidase-derived superoxide. © 1994 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Changes in serum parameters associated with iron metabolism in male rat exposed to lead

Due to the severe hazardous influences of lead (Pb²⁺) on iron-related diseases, the effects of Pb²⁺ on serum parameters associated with iron metabolism have been studied in this project. Male Wistar rats weighing 200–250 g were treated with Pb²⁺ for the short and long period of times. The animals received daily intraperitoneal injection of 100 mg Pb²⁺ kg^?1 body weight (BW) for 5 days and 4 mg?kg^?1 BW of Pb²⁺ for 30 and 45 days, respectively. The results show that when animals were treated with both low and high concentrations of Pb²⁺, serum iron concentration decreased markedly, by 23.2, 32.8, and 39.9 %, while the sera TIBC and transferrin concentrations increased significantly (p?<?0.05). Following short- and long-term exposures to Pb²⁺, the percentage of serum transferrin saturation was also decreased in comparison with the untreated control group (p?<?0.05). Concentrations of serum copper and ceruloplasmin following Pb²⁺ treatments also reduced significantly (p?<?0.05). The percentage of hematocrit and hemoglobin levels was reduced (p?<?0.05) in all Pb²⁺-treated animals in comparison with the controls. These results suggest that Pb²⁺ changes the serum parameters related to iron metabolism, which may play an important role in producing iron-related diseases.     

Dressings Combined with Injection of Meglumine Antimoniate in the Treatment of Cutaneous Leishmaniasis: A Randomized Controlled Clinical Trial

Background

Cutaneous leishmaniasis (CL) is a neglected infectious disease and a major health problem in several developing countries. Despite some reasonable explanation for their potential benefits, there is only trace evidence regarding the role of dressings in the treatment of CL.

Methods

This randomized, assessor-blind, controlled, clinical trial was conducted in an endemic area for CL caused by Leishmania major in Iran to assess the efficacy of administration of weekly intralesional meglumine antimoniate (i.l.MA) either alone or combined with application of a silver or a non-silver polyester dressing on their lesions for 6 weeks. After screening of 241 patients with CL lesions, 83 eligible patients with 158 lesions were randomly allocated in three arms of the study. Eligibility criteria included parasitologically confirmed CL, age of 12 to 60 years; willingness to participate, duration of lesion<3 months, number of lesions<5, largest ulcer diameter<5 cm. Pregnant or lactating women were excluded. The primary outcome was absolute risk reduction (ARR) based on the proportion of complete healing, which was defined as more than 75% reduction in the size of the lesion compared with baseline in each group at the termination of treatment and 1 month later.

Findings

ARR (95% Confidence Interval [CI]) in i.l.MA versus i.l.MA+non-silver dressing groups was 5.98% (−7.07% to 20.25%), between i.l.MA versus i.l.MA+silver dressing groups was −0.23% (−13.53% to 14.82%), and between i.l.MA+non-silver dressing versus i.l.MA+silver dressing groups was −6.21%(−18.28% to 6.52%) after 6 weeks of treatment. ARR (95% CI) in i.l.MA versus i.l.MA+non-silver dressing groups was −2.22% (−22.12% to 18.10%), between i.l.MA versus i.l.MA+silver dressing groups was 3.64% (−15.36% to 22.82%), and between i.l.MA+non-silver dressing versus i.l.MA+silver dressing groups was 5.86% (−12.86% to 24.31%) 1 month later.

Conclusion

It could not be demonstrated that the efficacy of i.l.MA was improved by either dressing.

Trial Registration

Iranian Registry of Clinical Trials (IRCT.ir) IRCT138707201166N2.     

A combined acidification/PEO flocculation process to improve the lignin removal from the pre-hydrolysis liquor of kraft-based dissolving pulp production process

The presence of lignin impairs the utilization of the hemicelluloses dissolved in the pre-hydrolysis liquor (PHL) of the kraft-based dissolving pulp production process. In this paper, a novel process was developed by combining the acidification and poly ethylene oxide (PEO) flocculation concepts to improve the lignin removal. The results showed that the lignin removal was improved by the addition of PEO to the acidified PHL, particularly at a low pH of 1.5. The main mechanisms involved are the lignin/PEO complex formation and the bridging of the formed complexes. This hypothesis was supported by the turbidity, FTIR and particle size measurements. Interestingly, the hemicelluloses removal from the acidification/PEO flocculation was marginal, which would be beneficial for the down-stream ethanol production from the PHL. Additionally, a process flow diagram was proposed that incorporates this new concept into the existing configuration of kraft-based dissolving pulp production process.     

A comparison between neurally induced bone marrow derived mesenchymal stem cells and olfactory ensheathing glial cells to repair spinal cord injuries in rat

Cell therapy has proven to be a highly promising method in clinical applications, raising so much hope for the treatment of injured tissues with low, if any, self regeneration potential such as central and peripheral nervous system. Neurally induced bone marrow derived mesenchymal stem cells (NIMSCs) as well as olfactory ensheathing cells (OECs) were transplanted in a rat model of sub-acute spinal cord injury and the behavioral and histological analyses were conducted. A balloon-compression technique was used to produce an injury at T8-T9 level of spinal cord. After a week post injury, rats were injected with either NIMSCs or OECs at the center of developing lesion cavity, 3 mm cranial and 3 mm caudal to the cavity. Weekly behavioral assessment using BBB score was done over five-week period post transplantation and finally histological assessment was performed to locate labeled cells in the tissue in order to evaluate the reduction of cavity formation and axonal regeneration. Evaluation of locomotor performance showed significant behavioral improvement in NIMSC group over OEC and control groups. The histological analyses revealed the presence of transplanted cells in the spinal cord parenchyma. Volume of injured area that was occupied with syrinx cavity in NIMSC group was significantly less than control group. In addition, meanwhile neurofilament-positive axons significantly showed higher expression in rats receiving NIMSC compared to the other two groups. In conclusion NIMSC caused both behavioral and histological improvement that potentially makes them a promising candidate for cell therapy approaches of spinal cord injuries.     

Variability in Energy Influences Avian Distribution Patterns Across the USA

Habitat transformations and climate change are among the most important drivers of biodiversity loss. Understanding the factors responsible for the unequal distribution of species richness is a major challenge in ecology. Using data from the North American Breeding Bird Survey to measure species richness and a change metric extracted from the MODerate resolution Imaging Spectroradiometer (MODIS), we examined the influence of energy variability on the geographic distribution of avian richness across the conterminous U.S. and in the different ecoregions, while controlling for energy availability. The analysis compared three groups of birds: all species, Neotropical migrants, and permanent residents. We found that interannual variability in available energy explained more than half of the observed variation in bird richness in some ecoregions. In particular, energy variability is an important factor in explaining the patterns of overall bird richness and of permanent residents, in addition to energy availability. Our results showed a decrease in species richness with increasing energy variability and decreasing energy availability, suggesting that more species are found in more stable and more productive environments. However, not all ecoregions followed this pattern. The exceptions might reflect other biological factors and environmental conditions. With more ecoclimatic variability predicted for the future, this study provides insight into how energy variability influences the geographical patterns of species richness. PR designed study, performed research, analyzed data and wrote paper. CAL, MAL, AMP, VCR, PDC, and EFL designed study and wrote paper.