Endothelial protective factors BMP9 and BMP10 inhibit CCL2 release by human vascular endothelial cells.

Bone morphogenetic protein 9 (BMP9) and BMP10 are circulating ligands that mediate endothelial cell (EC) protection via complexes of the type I receptor ALK1 and the type II receptors activin type-IIA receptor (ACTR-IIA) and bone morphogenetic type II receptor (BMPR-II). We previously demonstrated that BMP9 induces the expression of interleukin-6, interleukin-8 and E-selectin in ECs and might influence their interactions with monocytes and neutrophils. We asked whether BMP9 and BMP10 regulate the expression of chemokine (C-C motif) ligand 2 (CCL2), a key chemokine involved in monocyte-macrophage chemoattraction. Here, we show that BMP9 and BMP10 repress basal CCL2 expression and release from human pulmonary artery ECs and aortic ECs. The repression was dependent on ALK1 and co-dependent on ACTR-IIA and BMPR-II. Assessment of canonical Smad signalling indicated a reliance of this response on Smad4. Of note, Smad1/5 signalling contributed only at BMP9 concentrations similar to those in the circulation. In the context of inflammation, BMP9 did not alter the induction of CCL2 by TNF-α. As CCL2 promotes monocyte/macrophage chemotaxis and endothelial permeability, these data support the concept that BMP9 preserves basal endothelial integrity.

Biosurfactant-and-bioemulsifier produced by a promising Cunninghamella echinulata isolated from Caatinga soil in the northeast of Brazil.

A Mucoralean fungus was isolated from Caatinga soil of Pernambuco, Northeast of Brazil, and was identified as Cunninghamella echinulata by morphological, physiological, and biochemical tests. This strain was evaluated for biosurfactant/bioemulsifier production using soybean oil waste (SOW) and corn steep liquor (CSL) as substrates, added to basic saline solution, by measuring surface tension and emulsifier index and activity. The best results showed the surface water tension was reduced from 72 to 36 mN/m, and an emulsification index (E24) of 80% was obtained using engine oil and burnt engine oil, respectively. A new molecule of biosurfactant showed an anionic charge and a polymeric chemical composition consisting of lipids (40.0% w/w), carbohydrates (35.2% w/w) and protein (20.3% w/w). In addition, the biosurfactant solution (1%) demonstrated its ability for an oil displacement area (ODA) of 37.36 cm², which is quite similar to that for Triton X-100 (38.46 cm²). The stability of the reduction in the surface water tension as well as of the emulsifier index proved to be stable over a wide range of temperatures, in pH, and in salt concentration (4%-6% w/v). The biosurfactant showed an ability to reduce and increase the viscosity of hydrophobic substrates and their molecules, suggesting that it is a suitable candidate for mediated enhanced oil recovery. At the same time, these studies indicate that renewable, relatively inexpensive and easily available resources can be used for important biotechnological processes.

Cadmium tolerance and removal from Cunninghamella elegans related to the polyphosphate metabolism.

The aim of the present work was to study the cadmium effects on growth, ultrastructure and polyphosphate metabolism, as well as to evaluate the metal removal and accumulation by Cunninghamella elegans (IFM 46109) growing in culture medium. The presence of cadmium reduced growth, and a longer lag phase was observed. However, the phosphate uptake from the culture medium increased 15% when compared to the control. Moreover, C. elegans removed 70%-81% of the cadmium added to the culture medium during its growth. The C. elegans mycelia showed a removal efficiency of 280 mg/g at a cadmium concentration of 22.10 mg/L, and the removal velocity of cadmium was 0.107 mg/h. Additionally, it was observed that cadmium induced vacuolization, the presence of electron dense deposits in vacuoles, cytoplasm and cell membranes, as well as the distinct behavior of polyphosphate fractions. The results obtained with C. elegans suggest that precipitation, vacuolization and polyphosphate fractions were associated to cadmium tolerance, and this species demonstrated a higher potential for bioremediation of heavy metals.

Dichotomy in duration and severity of acute inflammatory responses in humans arising from differentially expressed proresolution pathways.

Lipoxins (Lxs) and aspirin-triggered epi-Lxs (15-epi-LxA(4)) act through the ALX/FPRL1 receptor to block leukocyte trafficking, dampen cytokine/chemokine synthesis, and enhance phagocytic clearance of apoptotic leukocytes-key requisites for inflammatory resolution. Although studies using primarily inbred rodents have highlighted resolution as an active event, little is known about the role resolution pathways play in controlling the duration/profile of inflammatory responses in humans. To examine this, we found two types of responders to cantharidin-induced skin blisters in male healthy volunteers: those with immediate leukocyte accumulation and cytokine/chemokine synthesis followed by early resolution and a second group whose inflammation increased gradually over time followed by delayed resolution. In early resolvers, blister 15-epi-LxA(4) and leukocyte ALX were low, but increased as inflammation abated. In contrast, in delayed resolvers, 15-epi-LxA(4) and ALX were high early in the response but waned as inflammation progressed. Elevating 15-epi-LxA(4) in early resolvers using aspirin increased blister leukocyte ALX but reduced cytokines/chemokines as well as polymorphonuclear leukocyte and macrophage numbers. These findings show that two phenotypes exist in humans with respect to inflammation severity/longevity controlled by proresolution mediators, namely 15-epi-LxA(4). These data have implications for understanding the etiology of chronic inflammation and future directions in antiinflammatory therapy.

Targeting lipoxygenases with care.

Though fish oils possess cardio-protective, anti-inflammatory, and anti-cancer properties, their molecular and biochemical mechanism of action is lacking. In this issue of Chemistry & Biology, Tjonahen and colleagues identify a new metabolite of eicosapentanoic acid, resolvin E2, produced by 5-lipoxygenase.

Apoptosis as a therapeutic target for the treatment of lung disease.

It has been speculated that the destruction of lung tissue, associated with several acute and chronic diseases, is in part mediated through apoptosis or programmed cell death. Thus, it has been shown that both increased endothelial/epithelial cell apoptosis and decreased cell death of inflammatory cells are associated with acute lung injury/acute respiratory distress syndrome, chronic obstructive pulmonary disease, asthma and pulmonary fibrosis. In the light of these observations, it might be possible to use apoptosis modulation as a novel therapeutic approach to the treatment of lung disease.

Caspase-catalyzed cleavage and activation of Mst1 correlates with eosinophil but not neutrophil apoptosis.

We have examined the role of caspase-mediated cleavage of the Ste20-like kinases, mammalian sterile 20-like 1 and 2 (Mst1/Mst2), in the mechanism of human eosinophil and neutrophil apoptosis. Initial measurements of kinase activity, using myelin basic protein (MBP) as a substrate in "in-gel" renaturation assays, showed that constitutive eosinophil and neutrophil apoptosis were associated temporally with the activation of a 36-kd MBP kinase (p36 MBPK) and a 34-kd MBP kinase (p34 MBPK), respectively. A constitutively active 63-kd MBP kinase (p63 MBPK) was also detected in freshly prepared eosinophils but not neutrophils, whose activity was transiently augmented during spontaneous apoptosis. Immunoblotting studies demonstrated the expression of Mst1 and Mst2 in eosinophils but not neutrophils whereas immunoprecipitation studies identified the p63 MBPK activity as being Mst1 and Mst2 and showed that the p36 MBPK activity represented the N-terminal catalytic fragment of Mst1. A role for the p36 MBPK in eosinophil cell death was supported by studies showing increased activation upon exposure to the proapoptotic Fas/CD95-activating antibody, CH-11, and attenuation in the presence of the survival-promoting cytokine, interleukin-5. Furthermore, spontaneous and Fas-induced activation of p36 MBPK was inhibited by catalase and the general caspase inhibitor, z-Asp-CH(2)-DCB, at concentrations that suppressed eosinophil apoptosis. These studies therefore implicate a role for caspase- and H(2)O(2)-mediated cleavage of the Mst1 and the subsequent release of the 36-kd catalytic fragment in the mechanism of eosinophil apoptosis. In contrast, neutrophil apoptosis occurs independently of Mst1 and Mst2 but instead is correlated with the activation of an as-yet-unidentified 34-kd MBPK.