Attenuation of doxorubicin-induced cardiotoxicity by mdivi-1: a mitochondrial division/mitophagy inhibitor

Doxorubicin is one of the most effective anti-cancer agents. However, its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Given the multiple beneficial effects of the mitochondrial division inhibitor (mdivi-1) in a variety of pathological conditions including heart failure and ischaemia and reperfusion injury, we investigated the effects of mdivi-1 on doxorubicin-induced cardiac dysfunction in naïve and stressed conditions using Langendorff perfused heart models and a model of oxidative stress was used to assess the effects of drug treatments on the mitochondrial depolarisation and hypercontracture of cardiac myocytes. Western blot analysis was used to measure the levels of p-Akt and p-Erk 1/2 and flow cytometry analysis was used to measure the levels p-Drp1 and p-p53 upon drug treatment. The HL60 leukaemia cell line was used to evaluate the effects of pharmacological inhibition of mitochondrial division on the cytotoxicity of doxorubicin in a cancer cell line. Doxorubicin caused a significant impairment of cardiac function and increased the infarct size to risk ratio in both naïve conditions and during ischaemia/reperfusion injury. Interestingly, co-treatment of doxorubicin with mdivi-1 attenuated these detrimental effects of doxorubicin. Doxorubicin also caused a reduction in the time taken to depolarisation and hypercontracture of cardiac myocytes, which were reversed with mdivi-1. Finally, doxorubicin caused a significant elevation in the levels of signalling proteins p-Akt, p-Erk 1/2, p-Drp1 and p-p53. Co-incubation of mdivi-1 with doxorubicin did not reduce the cytotoxicity of doxorubicin against HL-60 cells. These data suggest that the inhibition of mitochondrial fission protects the heart against doxorubicin-induced cardiac injury and identify mitochondrial fission as a new therapeutic target in ameliorating doxorubicin-induced cardiotoxicity without affecting its anti-cancer properties

Single beat 3D echocardiography for the assessment of right ventricular dimension and function after endurance exercise: Intraindividual comparison with magnetic resonance imaging

<p>Abstract</p> <p>Background</p> <p>Our study compares new single beat 3D echocardiography (sb3DE) to cardiovascular magnetic resonance imaging (CMR) for the measurement of right ventricular (RV) dimension and function immediately after a 30 km run. This is to validate sb3DE against the "gold standard" CMR and to bring new insights into acute changes of RV dimension and function after endurance exercise.</p> <p>Methods</p> <p>21 non-elite male marathon runners were examined by sb3DE (Siemens ACUSON SC2000, matrix transducer 4Z1c, volume rates 10-29/s), CMR (Siemens Magnetom Avanto, 1,5 Tesla) and blood tests before and immediately after each athlete ran 30 km. The runners were not allowed to rehydrate after the race. The order of sb3DE and CMR examination was randomized.</p> <p>Results</p> <p>Sb3DE for the acquisition of RV dimension and function was feasible in all subjects. The decrease in mean body weight and the significant increase in hematocrit indicated dehydration. RV dimensions measured by CMR were consistently larger than measured by sb3DE.</p> <p>Neither sb3DE nor CMR showed a significant difference in the RV ejection fraction before and after exercise. CMR demonstrated a significant decrease in RV dimensions. Measured by sb3DE, this decrease of RV volumes was not significant.</p> <p>Conclusion</p> <p>First, both methods agree well in the acquisition of systolic RV function. The dimensions of the RV measured by CMR are larger than measured by sb3DE. After exercise, the RV volumes decrease significantly when measured by CMR compared to baseline.</p> <p>Second, endurance exercise seems not to induce acute RV dysfunction in athletes without rehydration.</p

Quality of Water the Slum Dwellers Use: The Case of a Kenyan Slum

As a result of rapid urbanization in a context of economic constraints, the majority of urban residents in sub-Saharan Africa live in slums often characterized by a lack of basic services such as water and sewerage. Consequently, the urban poor often use inexpensive pit latrines and at the same time may draw domestic water from nearby wells. Overcrowding in slums limits the adequate distance between wells and pit latrines so that micro-organisms migrate from latrines to water sources. Sanitary practices in these overcrowded slums are also poor, leading to contamination of these wells. This study sought to assess sanitary practices of residents of a Kenyan urban slum and fecal contamination of their domestic water sources. This cross-sectional study involved 192 respondents from Langas slum, Kenya. Forty water samples were collected from the water sources used by the respondents for laboratory analysis of coliforms. Of these 40 samples, 31 were from shallow wells, four from deep wells, and five from taps. Multiple-tube fermentation technique was used to enumerate coliform bacteria in water. The study found that most people (91%) in the Langas slum used wells as the main source of domestic water, whereas the rest used tap water. Whereas most people used pit latrines for excreta disposal, a substantial percentage (30%) of children excreted in the open field. The estimated distance between the pit latrines and the wells was generally short with about 40% of the pit latrines being less than 15 m from the wells. The main domestic water sources were found to be highly contaminated with fecal matter. Total coliforms were found in 100% of water samples from shallow wells, while 97% of these samples from shallow wells were positive for thermotolerant coliforms. Three out of the four samples from deep wells were positive for total coliforms, while two of the four samples were positive for thermotolerant coliforms. None of the samples from taps were positive for either total or thermotolerant coliforms. Because the presence of thermotolerant coliforms in water indicates fecal contamination, facilitated by the proximity between the wells and pit latrines, the study suggests that the pit latrines were a major source of contamination of the wells with fecal matter. However, contamination through surface runoff during rains is also plausible as indiscriminate excreta disposal particularly by children was also common. Owing to the fecal contamination, there is a high possibility of the presence of disease pathogens in the water; thus, the water from the wells in Langas may not be suitable for human consumption. To address this problem, treatment of the water at community or household level and intensive behavioral change in sanitary practices are recommended. Efforts should be made to provide regulated tap water to this community and to other slums in sub-Saharan Africa where tap water is not accessible. However, more sampling of different water sources is recommended

Zinc-Chelation Contributes to the Anti-Angiogenic Effect of Ellagic Acid on Inhibiting MMP-2 Activity, Cell Migration and Tube Formation

Ellagic acid (EA), a dietary polyphenolic compound, has been demonstrated to exert anti-angiogenic effect but the detailed mechanism is not yet fully understood. The aim of this study was to investigate whether the zinc chelating activity of EA contributed to its anti-angiogenic effect.The matrix metalloproteinases-2 (MMP-2) activity, a zinc-required reaction, was directly inhibited by EA as examined by gelatin zymography, which was reversed dose-dependently by adding zinc chloride. In addition, EA was demonstrated to inhibit the secretion of MMP-2 from human umbilical vein endothelial cells (HUVECs) as analyzed by Western blot method, which was also reversed by the addition of zinc chloride. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), known to down-regulate the MMP-2 activity, was induced by EA at both the mRNA and protein levels which was correlated well with the inhibition of MMP-2 activity. Interestingly, zinc chloride could also abolish the increase of EA-induced RECK expression. The anti-angiogenic effect of EA was further confirmed to inhibit matrix-induced tube formation of endothelial cells. The migration of endothelial cells as analyzed by transwell filter assay was suppressed markedly by EA dose-dependently as well. Zinc chloride could reverse these two effects of EA also in a dose-dependent manner. Since magnesium chloride or calcium chloride could not reverse the inhibitory effect of EA, zinc was found to be involved in tube formation and migration of vascular endothelial cells.Together these results demonstrated that the zinc chelation of EA is involved in its anti-angiogenic effects by inhibiting MMP-2 activity, tube formation and cell migration of vascular endothelial cells. The role of zinc was confirmed to be important in the process of angiogenesis

Ellagitannins of the fruit rind of pomegranate (Punica granatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria

<p>Abstract</p> <p>Background</p> <p>The sun-dried rind of the immature fruit of pomegranate (<it>Punica granatum</it>) is presently used as a herbal formulation (OMARIA, Orissa Malaria Research Indigenous Attempt) in Orissa, India, for the therapy and prophylaxis of malaria. The pathogenesis of cerebral malaria, a complication of the infection by <it>Plasmodium falciparum</it>, is an inflammatory cytokine-driven disease associated to an up-regulation and activity of metalloproteinase-9 and to the increase of TNF production. The <it>in vitro </it>anti-plasmodial activity of <it>Punica granatum (Pg) </it>was recently described. The aim of the present study was to explore whether the anti-malarial effect of OMARIA could also be sustained via other mechanisms among those associated to the host immune response.</p> <p>Methods</p> <p>From the methanolic extract of the fruit rind, a fraction enriched in tannins (<it>Pg</it>-FET) was prepared. MMP-9 secretion and expression were evaluated in THP-1 cells stimulated with haemozoin or TNF. The assays were conducted in the presence of the <it>Pg</it>-FET and its chemical constituents ellagic acid and punicalagin. The effect of urolithins, the ellagitannin metabolites formed by human intestinal microflora, was also investigated.</p> <p>Results</p> <p><it>Pg</it>-FET and its constituents inhibited the secretion of MMP-9 induced by haemozoin or TNF. The effect occurred at transcriptional level since MMP-9 mRNA levels were lower in the presence of the tested compounds. Urolithins as well inhibited MMP-9 secretion and expression. <it>Pg</it>-FET and pure compounds also inhibited MMP-9 promoter activity and NF-kB-driven transcription.</p> <p>Conclusions</p> <p>The beneficial effect of the fruit rind of <it>Punica granatum </it>for the treatment of malarial disease may be attributed to the anti-parasitic activity and the inhibition of the pro-inflammatory mechanisms involved in the onset of cerebral malaria.</p

High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study

<p>Abstract</p> <p>Background</p> <p>To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses.</p> <p>Methods</p> <p>Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H₂O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured.</p> <p>Results</p> <p>Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-α concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed.</p> <p>Conclusions</p> <p>During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators.</p

The Neuropeptide PDF Acts Directly on Evening Pacemaker Neurons to Regulate Multiple Features of Circadian Behavior

Animals use distinct sets of clock neurons to time behaviors in the morning and evening. In this article, the direct neural targets for morning neurons and the neuropeptide pigment dispersing factor are revealed in the fruit fly

Plasma Proteomic Profiling in HIV-1 Infected Methamphetamine Abusers

We wanted to determine whether methamphetamine use affects a subset of plasma proteins in HIV-infected persons. Plasma samples from two visits were identified for subjects from four groups: HIV+, ongoing, persistent METH use; HIV+, short-term METH abstinent; HIV+, long term METH abstinence; HIV negative, no history of METH use. Among 390 proteins identified, 28 showed significant changes in expression in the HIV+/persistent METH+ group over the two visits, which were not attributable to HIV itself. These proteins were involved in complement, coagulation pathways and oxidative stress. Continuous METH use is an unstable condition, altering levels of a number of plasma proteins

Resveratrol-induced cytotoxicity in human Burkitt's lymphoma cells is coupled to the unfolded protein response

<p>Abstract</p> <p>Background</p> <p>Resveratrol (RES), a natural phytoalexin found at high levels in grapes and red wine, has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. However, the underlying molecular mechanisms are at present only partially understood.</p> <p>Method</p> <p>The effects of RES on activation of unfolded protein responses (UPR) were evaluated using Western blotting, semi-quantitative and real-time RT-PCR. Cell death was evaluated using Annexin V/PI staining and subsequent FACS.</p> <p>Results</p> <p>Similar as tunicamycin, treatment with RES lead to the activation of all 3 branches of the UPR, with early splicing of XBP-1 indicative of IRE1 activation, phosphorylation of eIF2α consistent with ER resident kinase (PERK) activation, activating transcription factor 6 (ATF6) splicing, and increase in expression levels of the downstream molecules GRP78/BiP, GRP94 and CHOP/GADD153 in human Burkitt's lymphoma Raji and Daudi cell lines. RES was shown to induce cell death, which could be attenuated by thwarting upregulation of CHOP.</p> <p>Conclusions</p> <p>Our data suggest that activation of the apoptotic arm of the UPR and its downstream effector CHOP/GADD153 is involved, at least in part, in RES-induced apoptosis in Burkitt's lymphoma cells.</p