BAY 11-7082 Is a Broad-Spectrum Inhibitor with Anti-Inflammatory Activity against Multiple Targets

BAY 11-7082 (BAY) is an inhibitor of κB kinase (IKK) that has pharmacological activities that include anticancer, neuroprotective, and anti-inflammatory effects. In this study, BAY-pharmacological target pathways were further characterized to determine how this compound simultaneously suppresses various responses. Primary and cancerous (RAW264.7 cells) macrophages were activated by lipopolysaccharide, a ligand of toll-like receptor 4. As reported previously, BAY strongly suppressed the production of nitric oxide, prostaglandin E2, and tumor necrosis factor-α and reduced the translocation of p65, major subunit of nuclear factor-κB, and its upstream signaling events such as phosphorylation of IκBα, IKK, and Akt. In addition, BAY also suppressed the translocation and activation of activator protein-1, interferon regulatory factor-3, and signal transducer and activator of transcription-1 by inhibiting the phosphorylation or activation of extracellular signal-related kinase, p38, TANK-binding protein, and Janus kinase-2. These data strongly suggest that BAY is an inhibitor with multiple targets and could serve as a lead compound in developing strong anti-inflammatory drugs with multiple targets in inflammatory responses

Dual Roles of Quercetin in Platelets: Phosphoinositide-3-Kinase and MAP Kinases Inhibition, and cAMP-Dependent Vasodilator-Stimulated Phosphoprotein Stimulation

Background. Progressive diseases including cancer, metabolic, and cardiovascular disorders are marked by platelet activation and chronic inflammation. Studies suggest that dietary flavonoids such as quercetin possess antioxidant, anti-inflammatory, and antiplatelet properties, which could prevent various chronic diseases including atherosclerosis and thrombosis. However, the mechanism and the signaling pathway that links quercetin's antiplatelet activity with its anti-inflammatory property is limited and thus further exploration is required. The aim of this paper was to examine the link between antiplatelet and anti-inflammatory roles of quercetin in agonist-induced platelet activation. Methods. Quercetin effects on agonist-activated platelet-aggregation, granule-secretion, [Ca2+]i, and glycoprotein-IIb/IIIa activation were examined. Its effects on PI3K/Akt, VASP, and MAPK phosphorylations were also studied on collaged-activated platelets. Results. Quercetin dose dependently suppressed collagen, thrombin, or ADP-induced platelet aggregation. It significantly inhibited collagen-induced ATP release, P-selectin expression, [Ca2+]i mobilization, integrin-αIIbβ3 activation, and augmented cAMP and VASP levels. Moreover, quercetin attenuated PI3K, Akt, ERK2, JNK1, and p38 MAPK activations, which were supported by platelet-aggregation inhibition with the respective kinase inhibitors. Conclusion. Quercetin-mediated antiplatelet activity involves PI3K/Akt inactivation, cAMP elevation, and VASP stimulation that, in turn, suppresses MAPK phosphorylations. This result suggests quercetin may have a potential to treat cardiovascular diseases involving aberrant platelet activation and inflammation

Dokaz protutijela protiv velikog metilja Fasciola hepatica u goveda na otoku Ulleung, Koreja.

We performed a cross-sectional study to estimate the seroprevalence of Fasciola hepatica in herds of cattle on Ulleung island, Korea. Blood samples were collected from randomly selected cattle and the sera were separated and analysed with an ELISA to detect antibodies against F. hepatica. The positive samples were classified as mildly, moderately or strongly positive. Out of 405 cattle sera assessed, 38 (9.4%) were seropositive for antibodies against F. hepatica. From these, 2.5% each were moderately or strongly positive and 4.4% were mildly positive. A significantly higher seroprevalence (P<0.05) was observed in young animals (<2 y old, 15.3%) compared to adults (≥2 y old, 5.4%), while no significant difference in seropositivity was found between male and female animals. This is the the first report of F. hepatica seroprevalence in cattle herds in Korea. These findings may be used to establish a base-line of information for future investigations focused on the significance of F. hepatica in Korea.Provedeno je presječno istraživanje radi procjene seroprevalencije invadiranosti velikim metiljem Fasciola hepatica u stadima goveda na otoku Ulleung u Koreji. Uzorci krvi bili su uzeti od nasumce odabranih goveda, a odvojeni uzorci seruma bili su pretraženi imunoenzimnim testom na prisutnost protutijela specifičnih za velikog metilja. Pozitivni uzorci bili su svrstani u skupine: slabo, umjereno i jako pozitivni. Od 405 pretraženih uzoraka seruma, 38 (9,4%) je bilo pozitivnih na protutijela specifična za metilj F. hepatica. Od toga je 2,5% uzoraka bilo umjereno ili jako pozitivno, a 4,4% slabo pozitivno. Značajno veća seroprevalencija (P<0,05) ustanovljena je u mladih životinja (u dobi manjoj od dvije godine, 15,3%) u usporedbi s odraslima (≥2 godine, 5,4%), dok nije ustanovljena značajna razlika u seropozitivnosti između mužjaka i ženki. Ovo je prvo izvješće o seroprevalenciji velikog metilja u stadima goveda u Koreji. Nalazi mogu biti od koristi za buduća istraživanja o značenju velikog metilja F. hepatica u Koreji

Dokaz protutijela protiv velikog metilja Fasciola hepatica u goveda na otoku Ulleung, Koreja.

We performed a cross-sectional study to estimate the seroprevalence of Fasciola hepatica in herds of cattle on Ulleung island, Korea. Blood samples were collected from randomly selected cattle and the sera were separated and analysed with an ELISA to detect antibodies against F. hepatica. The positive samples were classified as mildly, moderately or strongly positive. Out of 405 cattle sera assessed, 38 (9.4%) were seropositive for antibodies against F. hepatica. From these, 2.5% each were moderately or strongly positive and 4.4% were mildly positive. A significantly higher seroprevalence (P<0.05) was observed in young animals (<2 y old, 15.3%) compared to adults (≥2 y old, 5.4%), while no significant difference in seropositivity was found between male and female animals. This is the the first report of F. hepatica seroprevalence in cattle herds in Korea. These findings may be used to establish a base-line of information for future investigations focused on the significance of F. hepatica in Korea.Provedeno je presječno istraživanje radi procjene seroprevalencije invadiranosti velikim metiljem Fasciola hepatica u stadima goveda na otoku Ulleung u Koreji. Uzorci krvi bili su uzeti od nasumce odabranih goveda, a odvojeni uzorci seruma bili su pretraženi imunoenzimnim testom na prisutnost protutijela specifičnih za velikog metilja. Pozitivni uzorci bili su svrstani u skupine: slabo, umjereno i jako pozitivni. Od 405 pretraženih uzoraka seruma, 38 (9,4%) je bilo pozitivnih na protutijela specifična za metilj F. hepatica. Od toga je 2,5% uzoraka bilo umjereno ili jako pozitivno, a 4,4% slabo pozitivno. Značajno veća seroprevalencija (P<0,05) ustanovljena je u mladih životinja (u dobi manjoj od dvije godine, 15,3%) u usporedbi s odraslima (≥2 godine, 5,4%), dok nije ustanovljena značajna razlika u seropozitivnosti između mužjaka i ženki. Ovo je prvo izvješće o seroprevalenciji velikog metilja u stadima goveda u Koreji. Nalazi mogu biti od koristi za buduća istraživanja o značenju velikog metilja F. hepatica u Koreji

Antiatherosclerotic Effect of Korean Red Ginseng Extract Involves Regulator of G-Protein Signaling 5

Regulator of G-protein signaling 5 (RGS5), an inhibitor of Gα(q) and Gα(i) activation, has been reported to have antiatherosclerosis. Previous studies showed antiatherosclerotic effect of Korean red ginseng water extract (KRGE) via multiple signaling pathways. However, potential protective effect of KRGE through RGS5 expression has not been elucidated. Here, we investigated the antiatherosclerotic effect of KRGE in vivo and in vitro and its role on RGS5 mRNA expression. Elevated levels of total cholesterol, lactate dehydrogenase (LDH), and triglyceride (TG) in western diet groups of low-density lipoprotein receptor deficient LDLr−/− mice were reversed by oral administration of KRGE. KRGE suppressed transcriptional activity of tumor necrotic factor alpha (TNF-α), interleukin-6 (IL-6), and leptin in adipose tissue. It also potently repressed western diet-induced atheroma formation in aortic sinus. While KRGE showed reduced mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IL-1β, IL-6, and TNF-α in LPS-stimulated RAW264.7 cells, it enhanced mRNA expression of RGS5. Moreover, RGS5 siRNA transfection of microglia cells pretreated with KRGE reversed its inhibitory effect on the expression of iNOS, COX-2, and IL-1β mRNA. In conclusion, KRGE showed antiatherosclerotic and anti-inflammatory effects in western diet fed LDLr−/− mice and this effect could partly be mediated by RGS5 expression

Functional Roles of p38 Mitogen-Activated Protein Kinase in Macrophage-Mediated Inflammatory Responses

Inflammation is a natural host defensive process that is largely regulated by macrophages during the innate immune response. Mitogen-activated protein kinases (MAPKs) are proline-directed serine and threonine protein kinases that regulate many physiological and pathophysiological cell responses. p38 MAPKs are key MAPKs involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an essential role in regulating cellular processes, especially inflammation. In this paper, we summarize the characteristics of p38 signaling in macrophage-mediated inflammation. In addition, we discuss the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases

Torilin Inhibits Inflammation by Limiting TAK1-Mediated MAP Kinase and NF- κ

Torilin, a sesquiterpene isolated from the fruits of Torilis japonica, has shown antimicrobial, anticancer, and anti-inflammatory properties. However, data on the mechanism of torilin action against inflammation is limited. This study aimed at determining the anti-inflammatory property of torilin in LPS-induced inflammation using in vitro model of inflammation. We examined torilin’s effect on expression levels of inflammatory mediators and cytokines in LPS-stimulated RAW 264.7 macrophages. The involvement of NF-kB and AP-1, MAP kinases, and adaptor proteins were assessed. Torilin strongly inhibited LPS-induced NO release, iNOS, PGE2, COX-2, NF-α, IL-1β, IL-6, and GM-CSF gene and protein expressions. In addition, MAPKs were also suppressed by torilin pretreatment. Involvement of ERK1/2, P38MAPK, and JNK1/2 was further confirmed by PD98059, SB203580, and SP600125 mediated suppression of iNOS and COX-2 proteins. Furthermore, torilin attenuated NF-kB and AP-1 translocation, DNA binding, and reporter gene transcription. Interestingly, torilin inhibited TAK1 kinase activation with the subsequent suppression of MAPK-mediated JNK, p38, ERK1/2, and AP-1 (ATF-2 and c-jun) activation and IKK-mediated I-κBα degradation, p65/p50 activation, and translocation. Together, the results revealed the suppression of NF-κB and AP-1 regulated inflammatory mediator and cytokine expressions, suggesting the test compound’s potential as a candidate anti-inflammatory agent

Chlorin e6 Prevents ADP-Induced Platelet Aggregation by Decreasing PI3K-Akt Phosphorylation and Promoting cAMP Production

A number of reagents that prevent thrombosis have been developed but were found to have serious side effects. Therefore, we sought to identify complementary and alternative medicinal materials that are safe and have long-term efficacy. In the present studies, we have assessed the ability of chlorine e6 (CE6) to inhibit ADP-induced aggregation of rat platelets and elucidated the underlying mechanism. CE6 inhibited platelet aggregation induced by 10 µM ADP in a concentration-dependent manner and decreased intracellular calcium mobilization and granule secretion (i.e., ATP and serotonin release). Western blotting revealed that CE6 strongly inhibited the phosphorylations of PI3K, Akt, c-Jun N-terminal kinase (JNK), and different mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2 (ERK1/2) as well as p38-MAPK. Our study also demonstrated that CE6 significantly elevated intracellular cAMP levels and decreased thromboxane A2 formation in a concentration-dependent manner. Furthermore, we determined that CE6 initiated the activation of PKA, an effector of cAMP. Taken together, our findings indicate that CE6 may inhibit ADP-induced platelet activation by elevating cAMP levels and suppressing PI3K/Akt activity. Finally, these results suggest that CE6 could be developed as therapeutic agent that helps prevent thrombosis and ischemia