S100B attenuates microglia activation in gliomas: possible role of STAT3 pathway

Despite significant infiltration into tumors, the effector function of macrophages (MPs) and microglia (MG) appears to be suppressed in gliomas. Although STAT3 pathway is thought to play a role in this process, the exact mechanism by which gliomas induce STAT3 activation in MPs and MG is not known. Because activation of receptor for advanced glycation end products (RAGE) can induce STAT3, and because gliomas express high levels of S100B, a RAGE ligand, we hypothesized that MP/MG STAT3 activity may be modulated through S100B-RAGE interaction. Exposure of N9 MG and bone marrow-derived monocytes (BMM) to GL261 glioma condition medium (GCM) and low (nM) levels of S100B increased RAGE expression, induced STAT3 and suppressed MG function in vitro. Furthermore, neutralization of S100B in GCM, partially reversed IL-1β suppression in BMM, suggesting that the inhibitory effect of GCM to be in part due to S100B. Finally, blockage of S100B-RAGE interaction inhibited STAT3 activation in N9 MG and in glioma MG/MP in vivo. These findings suggest that the RAGE pathway may play an important role in STAT3 induction in glioma-associated MG/MPs, and that this process may be mediated through S100B.     

A metallothionein mimetic peptide protects neurons against kainic acid‐induced excitotoxicity

Metallothioneins I and II (MTI/II) are metal‐binding proteins overexpressed in response to brain injury. Recently, we have designed a peptide, termed EmtinB, which is modeled after the β‐domain of MT‐II and mimics the biological effects of MTI/II in vitro. Here, we demonstrate the neuroprotective effect of EmtinB in the in vitro and in vivo models of kainic acid (KA)‐induced neurotoxicity. We show that EmtinB passes the blood–brain barrier and is detectable in plasma for up to 24 hr. Treatment with EmtinB significantly attenuates seizures in C57BL/6J mice exposed to moderate (20 mg/kg) and high (30 mg/kg) KA doses and tends to decrease mortality induced by the high KA dose. Histopathological evaluation of hippocampal (CA3 and CA1) and cortical areas of mice treated with 20 mg/kg KA shows that EmtinB treatment reduces KA‐induced neurodegeneration in the CA1 region. These findings establish EmtinB as a promising target for therapeutic development. © 2009 Wiley‐Liss, Inc.     

Epigallocatechin-gallate suppresses tumorigenesis by directly targeting Pin1

The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG). The human peptidyl prolyl cis/trans isomerase (Pin1) plays a critical role in oncogenic signaling. Herein, we report the X-ray crystal structure of the Pin1/EGCG complex resolved at 1.9 ? resolution. Notably, the structure revealed the presence of EGCG in both the WW and PPIase domains of Pin1. The direct binding of EGCG with Pin1 was confirmed and the interaction inhibited Pin1 PPIase activity. In addition, proliferation of cells expressing Pin1 was inhibited and tumor growth in a xenograft mouse model was suppressed. The binding of EGCG with Arg17 in the WW domain prevented the binding of c-Jun, a well-known Pin1 substrate. EGCG treatment corresponded with a decreased abundance of cyclin D1 and diminution of 12-O-tetradecanoylphorbol-l3-acetate-induced AP-1 or NF-κB promoter activity in cells expressing Pin1. Overall, these results showed that EGCG directly suppresses the tumor-promoting effect of Pin1.     

In situ three-dimensional spider web construction and mechanics

Spiders are nature’s engineers that build lightweight and high-performance web architectures often several times their size and with very few supports; however, little is known about web mechanics and geometries throughout construction, especially for three-dimensional (3D) spider webs. In this work, we investigate the structure and mechanics for a Tidarren sisyphoides spider web at varying stages of construction. This is accomplished by imaging, modeling, and simulations throughout the web-building process to capture changes in the natural web geometry and the mechanical properties. We show that the foundation of the web geometry, strength, and functionality is created during the first 2 d of construction, after which the spider reinforces the existing network with limited expansion of the structure within the frame. A better understanding of the biological and mechanical performance of the 3D spider web under construction could inspire sustainable robust and resilient fiber networks, complex materials, structures, scaffolding, and self-assembly strategies for hierarchical structures and inspire additive manufacturing methods such as 3D printing as well as inspire artistic and architectural and engineering applications.

Spiders are among nature’s most efficient and prolific engineers: they design, build, use, and maintain high-performance and lightweight silk webs. They have inspired applications in the field of biomedicine (1), structural engineering (2), electronics (3), optics (4), art (5, 6), and music (7). Spiders produce silk fibers with outstanding mechanical and biological properties; they are strong and extensible while also being biodegradable and biocompatible. Their superior mechanical properties are rooted in their hierarchical organization that spans from protein amino acid chains to silk fibers to spider webs (8–10). They have survived and prospered through millions of years of evolution owing to their superb adaptation skills (11). Indeed, spiders can spin up to eight different types of silks with different properties and functions and create numerous web architectures that range from simple T webs and typical two-dimensional (2D) orb webs to complex three-dimensional (3D) webs such as funnel, cob, and tangle webs (12). Not only do they produce, build, and tune highly functional silks and large-scale web structures, they also monitor, repair, and recycle webs. Moreover, the complex structures seen in spider webs have been compared to other natural structures such as galaxies (13, 14).Spiders use vibrational information to locate and identify potential mates, prey, predators, and defects on their webs (15–18). Webs avoid catastrophic failure because the interplay between the nonlinear behavior of dragline silk and complex spider web architecture localizes defects, making quick repairs possible (19). This makes the complex of spider, silk, and web a self-sufficient, self-monitored, and self-repairable system. This system can inspire sustainable and high-performance complex new materials, structural designs, and construction procedures (20). Spiders build web structures several times their size with very few external supports, using only silk fibers. Comparing them to traditional construction at the human scale, such a large structure would require bulky scaffolding, large construction equipment, and many workers. Understanding the construction stages of a spider web could lead to more efficient and sustainable construction.Gaining such understanding can begin by analyzing the 2D orb web geometry and construction process by facing a camera to the plane of the web. Orb webs are composed of stiff dragline silk radial threads and extensible and sticky viscid silk spiral threads. Orb web construction starts with the spider building the frame of the web after exploring the site. Orb-weaver spiders build the hub with radial threads and then place the spiral threads using spiral scaffolding as a guide. Compared to 2D orb webs, 3D spider webs are more complicated to describe because of their complex fiber architecture and their nanoscale fibers. Su et al. (12) have reported a method to automatically quantify 3D spider web geometry by taking high-resolution images of slices of the web that are illuminated by a sliding sheet laser. Image-processing algorithms were then used to translate the sequence of 2D images into the fibers and nodes of the 3D web network (12). The scanned spider webs were built on top of a water container, necessary to deter the spider’s escape (21), and then brought to the experimental setup for scanning (12). The original manual scanning and spider web method was developed by Saraceno et al. (5, 22–26). Similarly, Yablonina (27) approximated 3D spider web architecture using infrared cameras and a sliding laser and investigated the importance of supporting threads, reinforcing threads, and joints between threads by recording spider movement during web construction. Arachnologists have studied 3D spider web construction through meticulous behavioral observations and video recordings. Jörger and Eberhard (28) characterized three stages of the construction of Achaearanea tesselata spider webs: exploration, construction of anchor lines and tangle web, and alternating construction of sheet and tangle webs. Other species follow a similar web construction process. For example, Tidarren sisyphoides spiders explore the surroundings, anchor the retreat, build the web scaffolding, and then construct the dome-shaped sheet, horizontal sheet, and upper tangle web (29). Steatoda triangulosa comb-footed spiders explore and then build a 3D supporting structure and gumfooted lines that connect the 3D structure and the substrate (30). Web construction observations have already inspired new automation methods (25) and algorithms (31) for fiber network construction. Other work (32) has recently investigated the mechanical behavior of Cyrtophora citricola 3D spider webs under uniaxial stretching and projectile impact. The interplay between the nonlinear behavior of dragline silk and the complex redundant architecture of the webs leads to robust and resilient webs under uniaxial stretching. The tangle web plays a crucial role in the functionality of the spider webs: it filters in prey and protects the spider from predators.While completed 3D web-construction patterns and topologies have been investigated, little is known about the structure and mechanics of 3D spider webs during construction. We provide insights into these heretofore unknown processes in this paper. In the current study, we will investigate the mechanical behavior of the different construction stages of a T. sisyphoides spider web and determine whether the web can carry out its biological functions during construction. We use image processing and computational simulation methods to quantify and validate what has been observed in nature.Our paper is organized as follows. First, we present the different topological and mechanical properties of the web under construction. Second, we conclude with a summary and investigate future applications of web-inspired structures and construction processes. Finally, we describe the experimental and computational methods to obtain the topology of a 3D spider web during construction. We also describe the mechanical model and simulation setup of the 3D spider web during this time.     

Nonsense mutation p.Q548X in BLM, the gene mutated in Bloom’s syndrome, is associated with breast cancer in Slavic populations

Bloom’s syndrome is a rare autosomal recessive chromosomal instability disorder with a high incidence of various types of neoplasia, including breast cancer. Whether monoallelic BLM mutations predispose to breast cancer has been a long-standing question. A nonsense mutation, p.Q548X, has recently been associated with an increased risk for breast cancer in a Russian case–control study. In the present work, we have investigated the prevalence of this Slavic BLM founder mutation in a total of 3,188 breast cancer cases and 2,458 controls from Bashkortostan, Belarus, Ukraine, and Kazakhstan. The p.Q548X allele was most frequent in Russian patients (0.8 %) but was also prevalent in Byelorussian and Ukrainian patients (0.5 and 0.6 %, respectively), whereas it was absent in Altaic or other non-European subpopulations. In a combined analysis of our four case–control series, the p.Q548X mutation was significantly associated with breast cancer (Mantel–Haenszel OR 5.1, 95 % CI 1.2; 21.9, p = 0.03). A meta-analysis with the previous study from the St. Petersburg area corroborates the association (OR 5.7, 95 % CI 2.0; 15.9, p = 3.7 × 10^?4). A meta-analysis for all published truncating mutations further supports the association of BLM with breast cancer, with an estimated two- to five-fold increase in risk (OR 3.3, 95 %CI 1.9; 5.6, p = 1.9 × 10^?5). Altogether, these data indicate that BLM is not only a gene for Bloom’s syndrome but also might represent a breast cancer susceptibility gene.     

Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs

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 Hb-induced 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 O₂-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.     

Corrosion Properties of Mn-Based Alloys Obtained by Aluminothermic Reduction of Deep-Sea Nodules

Deep-sea manganese nodules are polymetallic oxidic ores that can be found on a seabed. Aluminothermic reduction is one of the possibilities of manganese nodules processing. This process obtains the polymetallic alloy with a high content of Mn and a varying content of Al, depending on the ratio between aluminum and nodules. The corrosion behaviors of three experimental Mn-based alloys produced by aluminothermic reduction with a content of Mn > 50 wt % were studied. The electrochemical testing in potable water and model seawater was used to explain the corrosion mechanism of Mn-based alloys. The results showed that the corrosion rate of experimental Mn-based alloy decreases with the increase in aluminum content in both potable water and model seawater. It was observed that the uniform corrosion of experimental Mn-based alloys is changed with an increase in aluminum content in alloy to localized corrosion, which was caused by microcells in an environment of model seawater. In contrast, the formation of a semi-protective layer of corrosion products was observed on the surface of Mn-based alloys with a higher content of aluminum in potable water. Moreover, the pitting corrosion of tested Mn-based alloys was observed neither in potable water nor in model seawater.