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.

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.

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.

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.

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.

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.

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.

Improvement of memory by dieckol and phlorofucofuroeckol in ethanol-treated mice: possible involvement of the inhibition of acetylcholinesterase.

Phlorotannins, the polyphonic compounds found in brown Eisenia and Ecklonia algae, have several pharmacologically beneficial effects such as anti-inflammation. In addition, our recent data show that these compounds may improve the cognitive functions of aged humans suggesting the potential ability to enhance memory in several neurodegenerative disorders. To examine the experimental hypothesis that two effective components of Ecklonia cava, dieckol and phlorofucofuroeckol (PFF), have memory-enhancing abilities, both were administered orally to mice before a passive avoidance test. The repeated administration of either dieckol or PFF dose-dependently reduced the inhibition of latency by the administration of ethanol. To investigate the mode of memory-enhancing actions, the levels of major central neurotransmitters in three different regions (striatum, hippocampus, and frontal cortex) of the mouse brain were measured. The levels of some of the neurotransmitters were significantly changed by ethanol. Both dieckol and PFF altered the levels of some neurotransmitters modified by the ethanol treatment. It is noteworthy that both dieckol and PFF increased the level of acetylcholine, and they exerted anticholinesterase activities. Overall, the memory-enhancing abilities of dieckol and PFF may result from, at least in part, the increment of the brain level of acetylcholine by inhibiting acetylcholinesterase.

Chromenes from the brown alga Sargassum siliquastrum.

Sargachromanols A-P (1-16), sixteen new meroterpenoids of the chromene class, were isolated from the brown alga Sargassum siliquastrum collected from Jaeju Island, Korea. On the basis of the combined results of spectral and chemical analyses, the structures of the polyprenyl portions of these chromanol-containing compounds were determined to be linear triprenyls (1 and 2) and tetraprenyls (3-11), while others were the corresponding rearranged (12-15) and cyclized (16) tetraprenyls, respectively. The new compounds exhibited significant antioxidant activity in the DPPH assay. Compounds 7 and 15 also showed inhibitory activity toward butylcholine esterase.

Sargassum hemiphyllum inhibits atopic allergic reaction via the regulation of inflammatory mediators.

Sargassum hemiphyllum (SH) has long been used in Korean folk medicine for the therapeutic treatment of various allergic diseases. The effects of SH in previous experimental models, however, have been inconclusive. We studied the effects of methanol extract of SH on mast cells. Our experiments showed that SH significantly inhibited compound 48/80-induced histamine and beta-hexosaminidase release from rat peritoneal mast cells. SH inhibited interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha release induced by phorbol 12-myristate 13-acetate and A23187 from HMC-1, and it also showed an inhibitory effect on the anti-dinitrophenyl IgE antibody-induced passive cutaneous anaphylaxis reaction. In addition, SH inhibited the increase of TNF-alpha-induced NF-kappaB protein levels, transcription factor of TNF-alpha from 293T cells. A period of 48 h exposure to SH had little effect on HMC-1 cell viability. Our results suggest that SH has an inhibitory effect on the atopic allergic reaction and thus this may be useful in the treatment of allergic inflammatory diseases, such as atopic dermatitis.

Antioxidant and antiinflammatory activities of ventol, a phlorotannin-rich natural agent derived from Ecklonia cava, and its effect on proteoglycan degradation in cartilage explant culture.

Osteoarthritis is thought to be induced by the aging-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 overproduction 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 ventol showed significant antioxidant activities such as DPPH radical scavenging, ferric ion reducing power, peroxynitrite scavenging and inhibition of LDL oxidation, indicating their possible antioxidative interference both in onset and downstream consequences of osteoarthritis. Ventol 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 ventol showed strong therapeutic potentials in arthritic treatment through several in vitro experiments, it is highly encouraged to perform further mechanistic and efficacy studies.