Objective-Sepsis is a major cause of death for intensive care patients. High concentrations of inflammatory cytokines are characteristic of severe systemic inflammation and activated monocytes are their predominant cellular source. To identify targets for antiinflammatory intervention, we investigated the response of human macrophages to inflammatory and antiinflammatory mediators. Methods and Results-We profiled gene expression in human macrophages exposed to lipopolysaccharide (LPS) and interferon (IFN)-␥ in the presence or absence of recombinant activated protein C (APC) or IL-10 and identified Wnt5A as one of the transcripts most highly induced by LPS/IFN-␥ and suppressed by APC and IL-10. We confirmed regulation of Wnt5A protein in macrophages and detected it in sera and bone marrow macrophages of patients with severe sepsis. We established that a functional Wnt5A/frizzled-5/CaMKII signaling pathway was essential for macrophage inflammatory activation. To prove the essential contribution of Wnt5A we measured inflammatory cytokines after stimulation with Wnt5A, silenced Wnt5A by siRNA, and blocked receptor binding with soluble Frizzled-related peptide-1 (sFRP1). Key Words: geneexpression Ⅲ macrophages Ⅲ activated protein C S epsis is a suspected or proven infection with a systemic inflammatory response. In severe sepsis, organ dysfunction also occurs and it is associated with a high mortality and morbidity. Severe sepsis still causes about 9.3% of all deaths in the USA. 1,2 Conclusion-Wnt5A is critically involved in inflammatory macrophage See accompanying article on page 400During sepsis, the extent of plasma protein C depletion correlates with the severity of the outcome. 3 In animal studies 4 and clinical trials APC prevented death from severe sepsis or septic shock. 5 Although this beneficial effect of APC is mostly ascribed to its anticoagulant properties, antiinflammatory effects of APC have also been proposed. 6 The direct modulation of inflammation by APC has recently been described in gene expression profiling studies with human endothelial cells. 7,8 Recently, recombinant human APC has been introduced as a therapeutic agent for treatment of patients with severe sepsis because of its unique anticoagulant and antiinflammatory properties; however, the exact mechanism of antiinflammatory action is still unknown. 9 Macrophages play a central role in inflammation by responding to and releasing of numerous inflammatory cytokines and chemokines, leading to severe systemic inflammation and septic shock. However, the knowledge of antiinflammatory interactions on the level of monocytes/macrophages is scant. Therefore, we decided to expand our investigations on antiinflammatory effects of APC on this cellular system. In the present study, we were using a whole genome expression analysis approach, to define novel targets of APC in an in vitro model of inflammatory macrophage activation. Using probes obtained from human macrophages stimulated by INF-␥ (IFN-␥) and endotoxin (LPS), we consistently found Wnt5A to ...
The dynein motor is recruited to the kinetochore to capture spindle microtubules and control the spindle assembly checkpoint. Gama et al. reveal the molecular mechanism of how the Rod–Zw10–Zwilch complex and Spindly mediate dynein recruitment in Caenorhabditis elegans and human cells.
SummaryBackgroundPolitical, economic, and epidemiological changes in Brazil have affected health and the health system. We used the Global Burden of Disease Study 2016 (GBD 2016) results to understand changing health patterns and inform policy responses.MethodsWe analysed GBD 2016 estimates for life expectancy at birth (LE), healthy life expectancy (HALE), all-cause and cause-specific mortality, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and risk factors for Brazil, its 26 states, and the Federal District from 1990 to 2016, and compared these with national estimates for ten comparator countries.FindingsNationally, LE increased from 68·4 years (95% uncertainty interval [UI] 68·0–68·9) in 1990 to 75·2 years (74·7–75·7) in 2016, and HALE increased from 59·8 years (57·1–62·1) to 65·5 years (62·5–68·0). All-cause age-standardised mortality rates decreased by 34·0% (33·4–34·5), while all-cause age-standardised DALY rates decreased by 30·2% (27·7–32·8); the magnitude of declines varied among states. In 2016, ischaemic heart disease was the leading cause of age-standardised YLLs, followed by interpersonal violence. Low back and neck pain, sense organ diseases, and skin diseases were the main causes of YLDs in 1990 and 2016. Leading risk factors contributing to DALYs in 2016 were alcohol and drug use, high blood pressure, and high body-mass index.InterpretationHealth improved from 1990 to 2016, but improvements and disease burden varied between states. An epidemiological transition towards non-communicable diseases and related risks occurred nationally, but later in some states, while interpersonal violence grew as a health concern. Policy makers can use these results to address health disparities.FundingBill & Melinda Gates Foundation and the Brazilian Ministry of Health.
Alzheimer disease (AD) is a neurodegenerative disease which is characterized by the presence of extracellular senile plaques mainly composed of amyloid-beta peptide (Abeta), intracellular neurofibrillary tangles, and selective synaptic and neuronal loss. AD brains revealed elevated levels of oxidative stress markers which have been implicated in Abeta-induced toxicity. In the present work we addressed the hypothesis that oxidative stress occurs early in the development of AD and evaluated the extension of the oxidative stress and the levels of antioxidants in an in vivo model of AD, the triple-transgenic mouse, which develops plaques, tangles, and cognitive impairments and thus mimics AD progression in humans. We have shown that in this model, levels of antioxidants, namely, reduced glutathione and vitamin E, are decreased and the extent of lipid peroxidation is increased. We have also observed increased activity of the antioxidant enzymes glutathione peroxidase and superoxide dismutase. These alterations are evident during the Abeta oligomerization period, before the appearance of Abeta plaques and neurofibrillary tangles, supporting the view that oxidative stress occurs early in the development of the disease.
Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB). By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM), characterized by a highly heterogeneous cell population (including tumor stem cells), extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the BBB and the concerns that arise when this barrier is affected.
Release of hemoglobin (Hb) into the circulation is a central pathophysiologic event that contributes to morbidity and mortality in chronic hemolytic anemias and severe malaria. These toxicities arise from Hb-mediated vasoactivity, possibly due to NO scavenging and localized tissue oxidative processes. Currently, there is no established treatment that targets circulating extracellular Hb. Here, we assessed the role of haptoglobin (Hp), the primary scavenger of Hb in the circulation, in limiting the toxicity of cell-free Hb infusion. Using a canine model, we found that glucocorticoid stimulation of endogenous Hp synthesis prevented Hb-induced hemodynamic responses. Furthermore, guinea pigs administered exogenous Hp displayed decreased Hbinduced hypertension and oxidative toxicity to extravascular environments, such as the proximal tubules of the kidney. The ability of Hp to both attenuate hypertensive responses during Hb exposure and prevent peroxidative toxicity in extravascular compartments was dependent on Hb-Hp complex formation, which likely acts through sequestration of Hb rather than modulation of its NO-and O 2 -binding characteristics. Our data therefore suggest that therapies involving supplementation of endogenous Hb scavengers may be able to treat complications of acute and chronic hemolysis, as well as counter the adverse effects associated with Hb-based oxygen therapeutics.
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