Ultrastrong and ductile steel welds achieved by fine interlocking microstructures with film-like retained austenite.

The degradation of mechanical properties caused by grain coarsening or the formation of brittle phases during welding reduces the longevity of products. Here, we report advances in the weld quality of ultra-high strength steels by utilizing Nb and Cr instead of Ni. Sole addition of Cr, as an alternative to Ni, has limitations in developing fine weld microstructure, while it is revealed that the coupling effects of Nb and Cr additions make a finer interlocking weld microstructures with a higher fraction of retained austenite due to the decrease in austenite to acicular ferrite and bainite transformation temperature and carbon activity. As a result, an alloying design with Nb and Cr creates ultrastrong and ductile steel welds with enhanced tensile properties, impact toughness, and fatigue strength, at 45% lower material costs and lower environmental impact by removing Ni.

Neuroprotective Effects of Water Extract from Brown Algae Petalonia binghamiae in an Experimental Model of Focal Cerebral Ischemia In Vitro and In Vivo.

Focal cerebral ischemia (fCI) can result in brain injury and sensorimotor deficits. Brown algae are currently garnering scientific attention as potential therapeutic candidates for fCI. This study investigated the therapeutic effects of the hot water extract of Petalonia binghamiae (wPB), a brown alga, in in vitro and in vivo models of fCI. The neuroprotective efficacy of wPB was evaluated in an in vitro excitotoxicity model established using HT-22 cells challenged with glutamate. Afterward, C57/BL6 mice were administered wPB for 7 days (10 or 100 mg/kg, intragastric) and subjected to middle cerebral artery occlusion and reperfusion (MCAO/R) operation, which was used as an in vivo fCI model. wPB co-incubation significantly inhibited cell death, oxidative stress, and apoptosis, as well as stimulated the expression of heme oxygenase-1 (HO-1), an antioxidant enzyme, and the nuclear translocation of its upstream regulator, nuclear factor erythroid 2-related factor 2 (Nrf2) in HT-22 cells challenged with glutamate-induced excitotoxicity. Pretreatment with either dose of wPB significantly attenuated infarction volume, neuronal death, and sensorimotor deficits in an in vivo fCI model. Furthermore, the attenuation of oxidative stress and apoptosis in the ischemic lesion accompanied the wPB-associated protection. This study suggests that wPB can counteract fCI via an antioxidative effect, upregulating the Nrf2/HO-1 pathway.

Water Extract of Mixed Mushroom Mycelia Grown on a Solid Barley Medium Is Protective against Experimental Focal Cerebral Ischemia.

Although the individual consumption of medicinal mushrooms, including Phellinus linteus (PL), Ganoderma lucidum (GL), and Inonotus obliquus (IO), is known to be neuroprotective, the associated mechanisms underlying their therapeutic synergism on focal cerebral ischemia (fCI) have yet to be elucidated. This study aimed to demonstrate the neuroprotective effects of mixed mushroom mycelia (MMM) against experimental fCI. The water-fractions, ethanolic-fractions, and ethyl acetate-fractions of the MMM (PL, GL, and IO) grown in a barley medium using solid-state fermentation techniques were prepared and their protective effects against glutamate-induced excitotoxicity were compared in PC-12 cells. After the identification of the water extracts of MMM (wMMM) as the most suitable form, which possessed the lowest toxicity and highest efficacy, further analyses for evaluating the anti-apoptotic effects of wMMM, including Hoechst 33258-based nuclear staining, fluorescence-activated cell sorting, and reactive oxygen species (ROS) detection assays, were performed. Rats were subjected to a 90 min middle cerebral artery occlusion and reperfusion, after which a wMMM treatment resulted in significant dose-dependent improvements across a number of parameters. Furthermore, measurements of intracellular ROS and levels of antioxidant enzymes revealed a wMMM-mediated ROS attenuation and antioxidant enzyme upregulation. We suggest that wMMM is neuroprotective against fCI through its anti-apoptotic and anti-oxidative effects.

A new class of lightweight, stainless steels with ultra-high strength and large ductility.

Steel is the global backbone material of industrialized societies, with more than 1.8 billion tons produced per year. However, steel-containing structures decay due to corrosion, destroying annually 3.4% (2.5 trillion US$) of the global gross domestic product. Besides this huge loss in value, a solution to the corrosion problem at minimum environmental impact would also leverage enhanced product longevity, providing an immense contribution to sustainability. Here, we report a leap forward toward this aim through the development of a new family of low-density stainless steels with ultra-high strength (> 1 GPa) and high ductility (> 35%). The alloys are based on the Fe-(20-30)Mn-(11.5-12.0)Al-1.5C-5Cr (wt%) system and are strengthened by dispersions of nano-sized Fe3AlC-type κ-carbide. The alloying with Cr enhances the ductility without sacrificing strength, by suppressing the precipitation of κ-carbide and thus stabilizing the austenite matrix. The formation of a protective Al-rich oxide film on the surface lends the alloys outstanding resistance to pitting corrosion similar to ferritic stainless steels. The new alloy class has thus the potential to replace commercial stainless steels as it has much higher strength at similar formability, 17% lower mass density and lower environmental impact, qualifying it for demanding lightweight, corrosion resistant, high-strength structural parts.

HIV-1 Tat enhances purinergic P2Y4 receptor signaling to mediate inflammatory cytokine production and neuronal damage via PI3K/Akt and ERK MAPK pathways.

BACKGROUND: HIV-associated neurocognitive disorders (HANDs) afflict more than half of HIV-1-positive individuals. The transactivator of transcription (Tat) produced by HIV virus elicits inflammatory process and is a major neurotoxic mediator that induce neuron damage during HAND pathogenesis. Activated astrocytes are important cells involved in neuroinflammation and neuronal damage. Purinergic receptors expressed in astrocytes participate in a positive feedback loop in virus-induced neurotoxicity. Here, we investigated that whether P2Y4R, a P2Y receptor subtype, that expressed in astrocyte participates in Tat-induced neuronal death in vitro and in vivo. METHODS: Soluble Tat protein was performed to determine the expression of P2Y4R and proinflammatory cytokines in astrocytes using siRNA technique via real-time PCR, Western blot, and immunofluorescence assays. Cytometric bead array was used to measure proinflammatory cytokine release. The TUNEL staining and MTT cell viability assay were analyzed for HT22 cell apoptosis and viability, and the ApopTag® peroxidase in situ apoptosis detection kit and cresyl violet staining for apoptosis and death of hippocampal neuron in vivo. RESULTS: We found that Tat challenge increased the expression of P2Y4R in astrocytes. P2Y4R signaling in astrocytes was involved in Tat-induced inflammatory cytokine production via PI3K/Akt- and ERK1/2-dependent pathways. Knockdown of P2Y4R expression significantly reduced inflammatory cytokine production and relieved Tat-mediated neuronal apoptosis in vitro. Furthermore, in vivo challenged with Tat, P2Y4R knockdown mice showed decreased inflammation and neuronal damage, especially in hippocampal CA1 region. CONCLUSIONS: Our data provide novel insights into astrocyte-mediated neuron damage during HIV-1 infection and suggest a potential therapeutic target for HANDs.

Magnetism of the hypo-oxide state at the diffuse interface between the ferromagnet and antiferromagnet phases.

At the interface between ferromagnetic and antiferromagnetic phases, various spin configurations with a higher degrees of complexity than in the bulk states can be derived due to the diverse possible interface atomic structures, where coupling interactions among the constituting atoms can form in consistence with altered atomic configurations. The interface magnetic properties then depend on the collective behavior of such spin structures. In the present work, an extended interfacial configuration of a hypo-oxide state was prepared by establishing the gradient of oxygen concentration across the spatially diffuse interface region between ferromagnetic metallic and antiferromagnetic oxide phases at the nanometer scale. With these mixed ferromagnetic and antiferromagnetic couplings among the atoms in the interfacial hypo- or sub-oxide state, novel magnetic behavior can be induced. We report here, for the first time, a significant increase of saturation magnetization with temperature over a broad temperature range, which is against the conventional expectation for any generally known magnetic materials. And the unusual temperature dependent behavior can be understood as the combined effects of competing ferromagnetic and antiferromagnetic couplings acting on atoms in and near the interface region.

Phlorofucofuroeckol Improves Glutamate-Induced Neurotoxicity through Modulation of Oxidative Stress-Mediated Mitochondrial Dysfunction in PC12 Cells.

Stroke is a complex neurodegenerative disorder with a clinically high prevalence and mortality. Despite many efforts to protect against ischemic stroke, its incidence and related permanent disabilities continue to increase. In this study, we found that pretreatment with phlorofucofuroeckol (PFF), isolated from brown algae species, significantly increased cell viability in glutamate-stimulated PC12 cells. Additionally, glutamate-stimulated cells showed irregular morphology, but PFF pretreatment resulted in improved cell morphology, which resembled that in cells cultured under normal conditions. We further showed that PFF pretreatment effectively inhibited glutamate-induced apoptotic cell death in a caspase-dependent manner. Reactive oxygen species (ROS) induced by oxidative stress are closely associated with ischemia-induced neurological diseases. Exposure of PC12 cells to glutamate induced abundant production of intracellular ROS and mitochondrial dysfunction, which was attenuated by PFF in a dose-dependent manner. In vivo studies revealed that PFF-mediated prevention was achieved predominantly through inhibition of apoptosis and mitochondrial ROS generation. Taken together, these results suggest the possibility of PFF as a neuroprotective agent in ischemic stroke.

Blood-brain barrier-permeable fluorone-labeled dieckols acting as neuronal ER stress signaling inhibitors.

We studied the blood-brain barrier (BBB) permeability and intracellular localization of a fluorescein isothiocyanate (FITC)-labeled dieckol (1) and a rhodamine B-labeled dieckol (7), for exploring the possible therapeutic application of fluorone-labeled dieckols in neurodegenerative diseases. Both compounds (1 &7) were synthesized through a click reaction and were found to be localized in the endoplasmic reticulum (ER) of the two types of brain cell lines (SH-SY5Y and BV-2 cells) tested; they also reduced ER stress in the SH-SY5Y human neuroblastoma cells. In addition, 1 and 7 were shown to pass the BBB in rats upon intravenous administration. Altogether, our study demonstrates, for the first time, that targeted ER-stress reduction in brain cells can be achieved by introducing fluorone-dieckol conjugates into systemic circulation. Therefore, 1 and 7 provide a novel and promising ER-targeting therapeutic strategy for neurodegenerative diseases.

Multifunctional activity of polyphenolic compounds associated with a potential for Alzheimer's disease therapy from Ecklonia cava.

Five polyphenols were isolated and purified from a brown alga Ecklonia cava. These compounds showed diverse biological activities such as antioxidative, antiinflammatory, and enzyme inhibitory activities. This led us to investigate the potential of these compounds as Alzheimer's disease drugs. All of the compounds showed moderate acetylcholinesterase inhibitory activity in a micromolar range (IC50 from 16.0 to 96.3 µM). For butyrylcholinesterase, a new target for the treatment of Alzheimer's disease, phlorofucofuroeckol-A (PFF-A), showed a particularly potent inhibitory activity (IC50 0.95 µM), which is over 100-fold greater than for acetylcholinesterase. These compounds inhibited glycogen synthase kinase 3 beta, which is related to the formation of hyperphosphorylated tau and generation Aß. Bieckol and PFF-A inhibited amyloid precursor protein biosynthesis. PFF-A also showed very strong ß-secretase inhibitory activity with IC50 of submicromole. These results render these compounds as interesting potential drug candidates for Alzheimer's disease.

Synthesis of rhodamine-labelled dieckol: its unique intracellular localization and potent anti-inflammatory activity.

Rhodamine-labelled dieckol (1) synthesized through a click reaction was found to be localized in the endoplasmic reticulum (ER) of RAW 264.7 cells. Anti-inflammatory activity of compound was considerably greater than that of dieckol itself.

Suppression of NF-κB by dieckol extracted from Ecklonia cava negatively regulates LPS induction of inducible nitric oxide synthase gene.

Dieckol, extracted from brown algae, Ecklonia cava, is suggested to elicit anti-inflammatory or anti-tumorigenic activities. However, dieckol-mediated regulatory mechanism for inflammatory response still remains elusive. Here, we show that dieckol suppressed lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression in mouse leukemic macrophage Raw264.7 cells. Also, dieckol decreased LPS-induced both nitric oxide (NO) production and iNOS promoter-driven transcriptional activity in a dose-dependent manner. On the other hand, LPS-mediated NF-κB activity was inhibited by dieckol treatment. Moreover, results revealed that dieckol diminished LPS-mediated p65 nuclear translocation or IκBα phosphorylation dose-dependently, and reduced LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs), significantly p38MAPK. Collectively, these findings suggest that dieckol acts as a negative regulator of LPS-mediated iNOS induction through suppression of NF-κB activity, implying a mechanistic role of dieckol in regulation of inflammatory response.

Effects of 12-week oral supplementation of Ecklonia cava polyphenols on anthropometric and blood lipid parameters in overweight Korean individuals: a double-blind randomized clinical trial.

The effects of 12-week supplementation with a polyphenol extract from Ecklonia cava (ECP) on anthropometry, serum biochemistry and hematology have been investigated. Ninety-seven overweight male and female adults (average age 40.5 ± 9.2 yr and body mass index (BMI) of 26.5 ± 1.6 kg/m²) were enrolled in a randomized, double-blind, placebo-controlled trial with parallel-group design. Subjects were randomly allocated into three groups designated as PC (placebo), LD (low-dose, 72 mg-ECP/day) and HD (high-dose, 144 mg-ECP/day). Both LD and HD groups showed significant decreases in BMI, body fat ratio, waist circumference, waist/hip ratio, total cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol/high-density lipoprotein (HDL) cholesterol and atherogenic index (AI) after 12 weeks, as compared with the placebo group. The HD group also showed a significant increase in serum HDL cholesterol as compared with the placebo group. Only the HD group showed significant decreases in serum glucose and systolic blood pressure after 12 weeks. There was no significant adverse event related with ingestion of ECP, and serum biochemical and hematological parameters were maintained within normal range during the intervention period. In conclusion, these results demonstrated that ECP supplementation significantly contributed to lowering body fat and serum lipid parameters such as total and LDL cholesterols with dose dependence. Further studies using different populations, dosages or biological markers are highly recommended to better understand the physiological features of this polyphenol.

Anti-hyperlipidemic Effect of Polyphenol Extract (Seapolynol(™)) and Dieckol Isolated from Ecklonia cava in in vivo and in vitro Models.

The inhibitory effect of polyphenol extracts (Seapolynol(™), SPN) of the marine brown algae Ecklonia cava and dieckol, a major component of SPN, on hyperlipidemia was investigated in ICR mice fed a high-fat diet (HFD) for five weeks. For analysis of the anti-hyperlipidemic effects of SPN and dieckol, these two agents were given orally on a daily basis to HFD-fed mice for four weeks, starting one week after the beginning of HFD feeding. Groups administered with SPN as well as dieckol showed lower body weight gains than the HFD only group. Administration of SPN and dieckol also resulted in a significant reduction of the level of total cholesterol (TCHO), triglyceride (TG), and low-density lipoprotein (LDL) cholesterol in the serum of HFD-fed mice. In Oil Red O staining using 3T3-L1 preadipocytes, it was shown that both SPN and dieckol markedly inhibited lipid accumulation of 3T3-L1 cells. Furthermore, SPN and dieckol (50 µg/mL) significantly inhibited 3-hydroxyl-methyl glutaryl coenzyme A (HMGCoA) reductase activity in vitro. Taken together, these results suggest that polyphenols of Ecklonia cava (SPN) and dieckol reduce body weight gain and fat accumulation in HFD-induced obese mice, and that their hypolipidemic effect is related to the inhibition of adipogenesis of adipocytes and HMGCoA reductase activity.

Isolation of diacyl glycerol acyl transferase (DGAT) inhibitors from Pachydictyon coriaceum.

The pharmacological inhibition of acyl CoA:diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) has emerged as a target for the treatment of obesity and type 2 diabetes. Chromatographic analysis of the brown alga, Pachydictyon coriaceum, led to the isolation of diterpene dictyol E and hydroxyisocrenulatin. Pharmacological assay of these compounds demonstrated DGAT inhibitory activity with IC50 values of 46.0 µM and 23.3 µM, respectively.

Meroditerpenoids from the brown alga Sargassum siliquastrum.

Eleven new meroditerpenoids (7-11, 14-17, 19, 20) and nine known compounds (1-6, 12, 13, 18) were isolated from the brown alga Sargassum siliquastrum. Combined chemical and spectroscopic analyses revealed a common tetraprenyl hydroquinone structure; these compounds belonged to the nahocol, isonahocol, and sargahydroquinoic acid classes. The dihydroquinone moiety of 20 was unique and unprecedented in a brown alga. Stereochemical assignments were made for several of the known compounds based on their chemical reactivity. These compounds exhibited moderate to significant radical-scavenging activity as well as weak inhibitory activities against sortase A and isocitrate lyase.

Monoglycerides from the brown alga Sargassum sagamianum: Isolation, synthesis, and biological activity.

Polyunsaturated fatty acid-derived monoglycerides were characterized from the marine brown alga Sargassum sagamianum, collected from Jeju Island, Korea. A new compound of this structural class was isolated and determined to be 1-octadecatetraenoyl glycerol, by combined spectroscopic methods. Based on the structures and bioactivity of these compounds, a series of monoglycerides were synthesized using glycerol and various fatty acids. Several compounds exhibited moderate to significant inhibition of phospholipase A(2) and cyclooxygenase-2.

Sargaquinoic acid and sargachromenol, extracts of Sargassum sagamianum, induce apoptosis in HaCaT cells and mice skin: Its potentiation of UVB-induced apoptosis.

The plastoquinones sargaquinoic acid and sargachromenol are major components of brown alga Sargassum sagamianum and are known to be involved in neurite growth and survival. In this study, we describe their novel pro-apoptotic activities in vitro and in vivo. In vitro, treatment with sargaquinoic acid or sargachromenol promoted cell death and activation of caspase-3, caspase-8, caspase-9 and poly (ADP-ribose) polymerase (PARP) in a concentration-dependent manner. Sargaquinoic acid- or sargachromenol-induced apoptosis was enhanced by co-treatment with UVB irradiation. It showed much higher levels of cleaved caspase-3, caspase-8, caspase-9, and PARP than with sargaquinoic acid and sargachromenol alone, while it had no effect on Bcl-2 and Bax expression level. Examination by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and immunohistochemistry showed that topical application of sargaquinoic acid (1 mg/ml) before UVB irradiation (2.5 kJ/m(2)) of hairless mice also enhanced apoptosis including activation of caspase-3. Since a combination of phototherapy using UVB with topical reagents has been clinically applied to treat hyperproliferative skin disease, these results suggest that sargaquinoic acid and sargachromenol could be effective therapeutic agents.

Anticholinesterase activity of plastoquinones from Sargassum sagamianum: lead compounds for Alzheimer's disease therapy.

During the search for anticholinesterase compounds from marine organisms, two known plastoquinones, sargaquinoic acid (1) and sargachromenol (2), were isolated from Sargassum sagamianum. Both compounds showed moderate acetylcholinesterase (AChE) inhibitory activity in a micromole range (IC(50) 23.2 and 32.7 microm, respectively). However, for butyrylcholinesterase (BuChE), a new target for the treatment of Alzheimer's disease (AD), compound 1 showed particularly potent inhibitory activity (IC(50) 26 nm), which is 1000-fold greater than for AChE. Hence, sargaquinoic acid represents an effective and selective inhibitor of BuChE with a potency similar to or greater than the anticholinesterases in current clinical use, making it an interesting potential drug candidate for AD.

An antioxidative and antiinflammatory agent for potential treatment of osteoarthritis from Ecklonia cava.

Osteoarthritis is thought to be induced by the ageing-related loss of homeostatic balance between degeneration and repair mechanism around cartilage tissue in which inflammatory mediators such as reactive oxygen species, cytokines and prostaglandins are prone to over-production under undesirable physiological conditions. Phlorotannins are unique polyphenolic compounds bearing dibenzo-1,4-dioxin skeleton which are not found in terrestrial plants but found only in some brown algal species such as Ecklonia and Eisenia families. Phlorotannin-rich extracts of Ecklonia cava including LAD103 showed significant antioxidant activities such as DPPH radical scavenging, ferric ion reduction, peroxynitrite scavenging, and inhibition of LDL oxidation, indicating their possible antioxidative interference both in onset and downstream consequences of osteoarthritis. LAD103 also showed significant down regulation of PGE2 generation in LPS-treated RAW 246.7 cells, and significant inhibition of human recombinant interleukin-1alpha-induced proteoglycan degradation, indicating its beneficial involvement in pathophysiological consequences of osteoarthritis, the mechanism of which needs further investigation. Since LAD103 showed strong therapeutic potentials in arthritic treatment through several in vitro experiments, it is highly encouraged to perform further mechanistic and efficacy studies.