Dynorphin induced magnetic ordering in lipid bilayers as studied by 31P NMR spectroscopy

AbstractLipid bilayers of dimyristoyl phosphatidylcholine (DMPC) containing opioid peptide dynorphin A(1–17) are found to be spontaneously aligned to the applied magnetic field near at the phase transition temperature between the gel and liquid crystalline states (Tm=24°C), as examined by 31P NMR spectroscopy. The specific interaction between the peptide and lipid bilayer leading to this property was also examined by optical microscopy, light scattering, and potassium ion-selective electrode, together with a comparative study on dynorphin A(1–13). A substantial change in the light scattering intensity was noted for DMPC containing dynorphin A(1–17) near at Tm but not for the system containing A(1–13). Besides, reversible change in morphology of bilayer, from small lipid particles to large vesicles, was observed by optical microscope at Tm. These results indicate that lysis and fusion of the lipid bilayers are induced by the presence of dynorphin A(1–17). It turned out that the bilayers are spontaneously aligned to the magnetic field above Tm in parallel with the bilayer surface, because a single 31P NMR signal appeared at the perpendicular position of the 31P chemical shift tensor. In contrast, no such magnetic ordering was noted for DMPC bilayers containing dynorphin A(1–13). It was proved that DMPC bilayer in the presence of dynorphin A(1–17) forms vesicles above Tm, because leakage of potassium ion from the lipid bilayers was observed by potassium ion-selective electrode after adding Triton X-100. It is concluded that DMPC bilayer consists of elongated vesicles with the long axis parallel to the magnetic field, together with the data of microscopic observation of cylindrical shape of the vesicles. Further, the long axis is found to be at least five times longer than the short axis of the elongated vesicles in view of simulated 31P NMR lineshape

genipinはTNF-αが誘導するヒト歯根膜細胞のMMP-1およびMMP-3産生を抑制する

Genipin, the aglycon of geniposide found in gardenia fruit has long been considered for treatment of inflammatory diseases in traditional oriental medicine. Genipin has recently been reported to have some pharmacological functions, such as antimicrobial, antitumor, and anti-inflammatory effects. The aim of this study was to examine whether genipin could modify matrix metalloproteinase (MMP)-1 and MMP-3, which are related to the destruction of periodontal tissues in periodontal lesion, expression in tumor necrosis factor (TNF)-a-stimulated human periodontal ligament cells (HPDLCs). Genipin prevented TNF-a- mediated MMP-1 and MMP-3 productions in HPDLCs. Moreover, genipin could suppress not only extracellular signal-regulated kinase (ERK) and Jun-N-terminal kinase (JNK) phosphorylations but also AMP-activated protein kinase (AMPK) phosphorylation in TNF-a-stimulated HPDLCs. Inhibitors of ERK and AMPK could inhibit both MMP-1 and MMP-3 productions. Moreover, we revealed the ERK inhibitor suppressed AMPK phosphorylation in TNF-a-stimulated HPDLCs. These data provide a new mechanism through which genipin could be used for the treatment of periodontal disease to prevent MMPs expression in periodontal lesion

Melatonin inhibits CXCL10 and MMP-1 production

Melatonin is a hormone that is mainly secreted by the pineal gland and exhibits a wide spectrum of activities, including antioxidant functions. Melatonin has been detected in gingival crevicular fluid. However, the role of melatonin in periodontal tissue is still uncertain. The aim of this study was to examine the effects of melatonin on inflammatory mediator expression in human periodontal ligament cells (HPDLC). Interleukin (IL)-1β induced CXC chemokine ligand (CXCL)10, matrix metalloproteinase (MMP)-1, and tissue inhibitors of metalloproteinase (TIMP)-1 production in HPDLC. Melatonin decreased CXCL10 and MMP-1 production and increased TIMP-1 production in IL-1β-stimulated HPDLC. Western blot analysis showed that melatonin inhibited p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK) phosphorylation, and IκB-α degradation and phosphorylation in IL-1β-stimulated HPDLC. These results suggest that melatonin might inhibit Th1 cell migration by reducing CXCL10 production. Moreover, melatonin might inhibit soft tissue destruction by decreasing MMP-1 production in periodontal lesions

Gomisin N inhibits inflammatory cytokine production.

Gomisin N, which is a lignan isolated from Schisandra chinensis, has some pharmacological effects. However, the anti-inflammatory effects of gomisin N on periodontal disease are uncertain. The aim of this study was to examine the effect of gomisin N on inflammatory mediator production in tumor necrosis factor (TNF)-α-stimulated human periodontal ligament cells (HPDLC). Gomisin N inhibited interleukin (IL)-6, IL-8, CC chemokine ligand (CCL) 2, and CCL20 production in TNF-α-stimulated HPDLC in a dose-dependent manner. Moreover, we revealed that gomisin N could suppress extracellular signal-regulated kinase (ERK) and c-Jun N terminal kinase (JNK) phosphorylation in TNF-α-stimulated HPDLC though protein kinase B (Akt) phosphorylation was not suppressed by gomisin N treatment. In summary, gomisin N might exert antiinflammatory effects by attenuating cytokine production in periodontal ligament cells via inhibiting the TNF-α-stimulated ERK and JNK pathways activation

IL-29 enhances CXCL10 production

Interleukin-29 (IL-29) is a cytokine belonging to the type III interferon family. It was recently detected in the gingival crevicular fluid of periodontitis patients. However, the role of IL-29 in the pathogenesis of periodontal disease remains unknown. The aim of this study was to examine the effects of IL-29 on C-X-C motif chemokine ligand 10 (CXCL10) production in human oral epithelial cells. We measured CXCL10 production in TR146 cells, which is a human oral epithelial cell line, using an enzyme-linked immunosorbent assay. We used Western blot analysis to detect IL-29 receptor expression and the phosphorylation levels of signal transduction molecules, including p38 mitogen-activated protein kinases (MAPK), signal transducer and activator of transcription 3 (STAT3), and nuclear factor (NF)-κB p65, in the TR146 cells. The TR146 cells expressed the IL-29 receptor. IL-29 induced CXCL10 production in the TR146 cells. IL-29 significantly enhanced CXCL10 production in tumor necrosis factor (TNF)-α-stimulated TR146 cells. The p38 MAPK, STAT3, and NF-κB pathways were found to be related to the IL-29-induced enhancement of CXCL10 production in TNF-α-stimulated TR146 cells. IL-29 promotes T helper 1 cell accumulation in periodontal lesions by inducing CXCL10 production in oral epithelial cells

Shikonin inhibits inflammatory cytokine production

Shikonin, which is derived from Lithospermum erythrorhizon, a herb used in traditional medicine, has long been considered to be a useful treatment for various diseases in traditional oriental medicine. Shikonin has recently been reported to have several pharmacological properties, e.g., it has anti-microbial, anti-tumor, and anti-inflammatory effects. The aim of this study was to examine whether shikonin is able to influence the production of interleukin (IL)-6, IL-8, and/or chemokine C-C motif ligand (CCL)20, which contribute to the pathogenesis of periodontal disease, in human periodontal ligament cells (HPDLC). The production levels of IL-6, IL-8, and CCL20 in HPDLC were determined using an ELISA. Western blot analysis was used to detect nuclear factor kappa B (NF-κB) pathway activation in HPDLC. Shikonin prevented IL-1β- or tumor necrosis factor (TNF)-α-mediated IL-6, IL-8, and CCL20 production in HPDLC. Moreover, we found that shikonin suppressed the phosphorylation and degradation of inhibitor of kappa B-alpha (IκB-α) in IL-1β- or TNF-α-stimulated HPDLC. These findings suggest that shikonin could have direct beneficial effects against periodontal disease by reducing IL-6, IL-8, and CCL20 production in periodontal lesions

Activin E Controls Energy Homeostasis in Both Brown and White Adipose Tissues as a Hepatokine

Brown adipocyte activation or beige adipocyte emergence in white adipose tissue (WAT) increases energy expenditure, leading to a reduction in body fat mass and improved glucose metabolism. We found that activin E functions as a hepatokine that enhances thermogenesis in response to cold exposure through beige adipocyte emergence in inguinal WAT (ingWAT). Hepatic activin E overexpression activated thermogenesis through Ucp1 upregulation in ingWAT and other adipose tissues including interscapular brown adipose tissue and mesenteric WAT. Hepatic activin E-transgenic mice exhibited improved insulin sensitivity. Inhibin βE gene silencing inhibited cold-induced Ucp1 induction in ingWAT. Furthermore, in vitro experiments suggested that activin E directly stimulated expression of Ucp1 and Fgf21, which was mediated by transforming growth factor-β or activin type I receptors. We uncovered a function of activin E to stimulate energy expenditure through brown and beige adipocyte activation, suggesting a possible preventive or therapeutic target for obesity

IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different anti-thromboembolic prophylaxis therapeutics

<p>Abstract</p> <p>Background</p> <p>Heparin-induced thrombocytopenia (HIT) is a thromboembolic complication that can occur with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Our objective was to determine and compare the incidence of IgG-class HIT antibodies in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) with different antithrombotic prophylaxis therapies and their contributions to the occurrence of venous thromboembolism (VTE).</p> <p>Methods</p> <p>A prospective observational study was performed for 374 Japanese patients undergoing THA or TKA to determine the incidence of VTE. IgG-class anti-PF4/heparin antibodies were measured using IgG-specific EIA before and after the operation.</p> <p>Results</p> <p>In the clinical outcome, the incidence of symptomatic deep vein thrombosis (DVT) was 15.0% (56/374, TKA; 35, THA; 21) and pulmonary emboli (PE) were not observed. The total seroconversion incidence of IgG-class PF4/heparin antibodies was 19.8% (74/374). The seroconversion incidence of IgG-class PF4/heparin antibodies was higher in patients receiving UFH (32.7%) compared to those receiving LMWH (9.5%) or fondaparinux (14.8%). Furthermore, the seroconversion incidence was significantly higher in patients undergoing TKA compared to those undergoing THA. Based on multivariate analysis, seroconversion of the IgG-class PF4/heparin antibodies was independent a risk factor for symptomatic DVT.</p> <p>Conclusion</p> <p>Our findings show that the seroconversion of IgG-class anti-PF4/heparin antibodies differed with various anti-thrombotic prophylaxis therapeutics and was associated with the risk of DVT in a subset of patients undergoing total joint arthroplasty (TKA and THA).</p