The Ubiquitin Ligase RPM-1 and the p38 MAPK PMK-3 Regulate AMPA Receptor Trafficking

Ubiquitination occurs at synapses, yet its role remains unclear. Previous studies demonstrated that the RPM-1 ubiquitin ligase organizes presynaptic boutons at neuromuscular junctions in C. elegans motorneurons. Here we find that RPM-1 has a novel postsynaptic role in interneurons, where it regulates the trafficking of the AMPA-type glutamate receptor GLR-1 from synapses into endosomes. Mutations in rpm-1 cause the aberrant accumulation of GLR-1 in neurites. Moreover, rpm-1 mutations enhance the endosomal accumulation of GLR-1 observed in mutants for lin-10, a Mint2 ortholog that promotes GLR-1 recycling from Syntaxin-13 containing endosomes. As in motorneurons, RPM-1 negatively regulates the pmk-3/p38 MAPK pathway in interneurons by repressing the protein levels of the MAPKKK DLK-1. This regulation of PMK-3 signaling is critical for RPM-1 function with respect to GLR-1 trafficking, as pmk-3 mutations suppress both lin-10 and rpm-1 mutations. Positive or negative changes in endocytosis mimic the effects of rpm-1 or pmk-3 mutations, respectively, on GLR-1 trafficking. Specifically, RAB-5(GDP), an inactive mutant of RAB-5 that reduces endocytosis, mimics the effect of pmk-3 mutations when introduced into wild-type animals, and occludes the effect of pmk-3 mutations when introduced into pmk-3 mutants. By contrast, RAB-5(GTP), which increases endocytosis, suppresses the effect of pmk-3 mutations, mimics the effect of rpm-1 mutations, and occludes the effect of rpm-1 mutations. Our findings indicate a novel specialized role for RPM-1 and PMK-3/p38 MAPK in regulating the endosomal trafficking of AMPARs at central synapses

Sargassum fulvellum

Ultraviolet (UV) radiation has been reported to induce cutaneous inflammation such as erythema and edema via induction of proinflammatory enzymes and mediators. Sargassum fulvellum is a brown alga of Sargassaceae family which has been demonstrated to exhibit antipyretic, analgesic, antiedema, antioxidant, antitumor, fibrinolytic, and hepatoprotective activities. The purpose of this study is to investigate anti-inflammatory effects of ethylacetate fraction of ethanol extract of Sargassum fulvellum (SFE-EtOAc) in HaCaT keratinocytes and BALB/c mice. In HaCaT cells, SFE-EtOAc effectively inhibited UVB-induced cytotoxicity (60 mJ/cm2) and the expression of proinflammatory proteins such as cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS). Furthermore, SFE-EtOAc significantly reduced UVB-induced production of proinflammatory mediators including prostaglandin E2 (PGE2) and nitric oxide (NO). In BALB/c mice, topical application of SFE-EtOAc prior to UVB irradiation (200 mJ/cm2) effectively suppressed the UVB-induced protein expression of COX-2, iNOS, and TNF-α and subsequently attenuated generation of PGE2 and NO as well. In another experiment, SFE-EtOAc pretreatment suppressed UVB-induced reactive oxygen species production and exhibited an antioxidant potential by upregulation of antioxidant enzymes such as catalase and Cu/Zn-superoxide dismutase in HaCaT cells. These results suggest that SFE-EtOAc could be an effective anti-inflammatory agent protecting against UVB irradiation-induced skin damages

Protective Effect of Proanthocyanidin against Diabetic Oxidative Stress

We investigated the antidiabetic potential of proanthocyanidin and its oligomeric form in STZ-induced diabetic model rats and db/db type 2 diabetic mice. Proanthocyanidin ameliorated the diabetic condition by significant decreases of serum glucose, glycosylated protein, and serum urea nitrogen as well as decreases of urinary protein and renal-AGE in STZ-induced diabetic rats and decrease of serum glucose as well as significant decrease of glycosylated protein in db/db type 2 diabetic mice. The suppression of ROS generation and elevation of the GSH/GSSG ratio were also observed in the groups administered proanthocyanidin. Moreover, proanthocyanidin, especially its oligomeric form, affected the inflammatory process with the regulation of related protein expression, iNOS, COX-2 and upstream regulators, NF-κB, and the IκB-α. In addition, it had a marked effect on hyperlipidemia through lowering significant levels of triglycerides, total cholesterol, and NEFA. Moreover, expressions in the liver of SREBP-1 and SREBP-2 were downregulated by the administration of proanthocyanidins. The protective effect against hyperglycemia and hyperlipidemia in type 1 and 2 diabetic models was significantly strong in the groups administered the oligomeric rather than polymeric form. This suggests that oligomers act as a regulator in inflammatory reactions caused by oxidative stress in diabetes

Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1

Cancer therapeutics: Extending a drug's reach A new drug that blocks heat shock proteins (HSPs), helper proteins that are co-opted by cancer cells to promote tumor growth, shows promise for cancer treatment. Several drugs have targeted HSPs, since cancer cells are known to hijack these helper proteins to shield themselves from destruction by the body. However, the drugs have had limited success. Hye-Kyung Park and Byoung Heon Kang at Ulsan National Institutes of Science and Technology in South Korea and coworkers noticed that the drugs were not absorbed into mitochondria, a key cellular compartment, and HSPs in this compartment were therefore not being blocked. They identified a new HSP inhibitor that can reach every cellular compartment and inhibit all HSPs. Testing in mice showed that this inhibitor effectively triggered death of tumor cells, and therefore shows promise for anti-cancer therapy. The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity

Intestinal microbiota, chronic inflammation, and colorectal cancer

In addition to genetic and epigenetic factors, various environmental factors, including diet, play important roles in the development of colorectal cancer (CRC). Recently, there is increasing interest in the intestinal microbiota as an environmental risk factor for CRC, because diet also influences the composition of the intestinal microbiota. The human intestinal microbiota comprises about 100 trillion microbes. This microbiome thrives on undigested dietary residues in the intestinal lumen and produces various metabolites. It is well known that the dietary risk factors for CRC are mediated by dysbiosis of the intestinal microbiota and their metabolites. In this review, we describe the bacterial taxa associated with CRC, including Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, Escherichia coli, and butyrate-producing bacteria. We also discuss the host-diet interaction in colorectal carcinogenesis

Development of a standardized in-hospital cardiopulmonary resuscitation set-up

Objective. This study evaluated whether chest compression in a standardized inhospital cardiopulmonary resuscitation (CPR) set-up can be performed as effectively as when the rescuer is kneeling beside the patient lying on the floor. Specifically, the in-hospital test was standardized according to the rescuers’ average knee height. Methods. Experimental intervention (test 1) was a standardized, in-hospital CPR set-up: first, the bed height was fixed at 70 cm. Second, the height difference between the bed and a step stool was set to the average knee height of the CPR team members (45 cm). Control intervention (test 2) was kneeling on floor. Thirty-eight medical doctors on the CPR team each performed 2 minutes of chest compressions in test 1 and 2 in random order (cross-over trial). A Little Anne was used as a simulated patient who had experienced cardiac arrest. Chest compression parameters, such as average depth and rate, were measured using an accelerometer device. Results. In all tests, the average depths were those recommended in the most recent CPR guidelines (50–60 mm); there were no significant differences between Tests 1 and 2 (53.1 ± 4.3 mm vs. 52.6 ± 4.8 mm, respectively; p = 0.398). The average rate in Test 2 (119.1 ± 12.4 numbers/min) was slightly faster than that in Test 1 (116.4 ± 10.2 numbers/ min; p = 0.028). No differences were observed in any other parameters. Conclusions. Chest compression quality in our standardized in-hospital CPR set-up was similar with that performed in a kneeling position on the floor. Trial Registration: Clinical Research Information Service: KCT000159

Quality of Service Control for WLAN-based Converged Personal Network Service

This paper proposes a framework for quality of service (QoS) control in WLAN-based converged personal network service (CPNS). First, we show that the CPNS devices in WLANs occupy the shared wireless channel in an unfair manner; and thus, QoS is degraded. The reasons of such problem are analyzed from two viewpoints of (i) channel access mechanism according to carrier sensing multiple access protocol of WLAN and (ii) TCP congestion control mechanism in response to packet loss. To improve QoS and assure fair channel sharing, we propose an integrated QoS control framework consisting of admission control and rate control. Based on the available capacity, the admission control determines whether or not a specific QoS service can be admitted. The rate control is implemented using congestion window control or token bucket algorithm. The proposed mechanism differentiates QoS service from best-effort (BE) service such that the QoS service is preferentially served to satisfy its QoS requirements and the BE service is served to share the remaining resource in a fair manner. The extensive simulation results confirm that the proposed scheme assures QoS and fair channel sharing for WLAN-based CPNS

Anti-allergic and anti-inflammatory effects of butanol extract from Arctium Lappa L

Background: Atopic dermatitis is a chronic, allergic inflammatory skin disease that is accompanied by markedly increased levels of inflammatory cells, including eosinophils, mast cells, and T cells. Arctium lappa L. is a traditional medicine in Asia. This study examined whether a butanol extract of A. lappa (ALBE) had previously unreported anti-allergic or anti-inflammatory effects.Methods: This study examined the effect of ALBE on the release of ??-hexosaminidase in antigen-stimulated-RBL-2H3 cells. We also evaluated the ConA-induced expression of IL-4, IL-5, mitogen-activated protein kinases (MAPKs), and nuclear factor (NF)-??B using RT-PCR, Western blotting, and ELISA in mouse splenocytes after ALBE treatment.Results: We observed significant inhibition of ??-hexosaminidase release in RBL-2H3 cells and suppressed mRNA expression and protein secretion of IL-4 and IL-5 induced by ConA-treated primary murine splenocytes after ALBE treatment. Additionally, ALBE (100 ??g/mL) suppressed not only the transcriptional activation of NF-??B, but also the phosphorylation of MAPKs in ConA-treated primary splenocytes.Conclusions: These results suggest that ALBE inhibits the expression of IL-4 and IL-5 by downregulating MAPKs and NF-??B activation in ConA-treated splenocytes and supports the hypothesis that ALBE may have beneficial effects in the treatment of allergic diseases, including atopic dermatitis. ?? 2011 Sohn et al; licensee BioMed Central Ltd