INFLUENCE OF BODY WEIGHT ON PULLING FORCE IN HAMMER THROW

In hammer throw it can be considered that the body weight affects the throwing distance because the muscle volume is directly proportional to the body weight. The pulling force of the hammer may also be affected by the body weight. The purpose of this study was to investigate the influence of the body weight on the pulling force during throwing motion in hammer throw

G protein-coupled sphingosine-1-phosphate receptors: potential molecular targets for angiogenic and anti-angiogenic therapies

Sphingosine-1-phosphate (S1P) is a plasma lipid mediator with pleiotropic activities; it is constitutively produced in red blood cells and vascular endothelial cells through phosphorylation of sphingosine by one of two S1P synthesizing enzymes, sphingosine kinase 1 and 2 (SphK 1, 2), and exported into plasma to bind to high density lipoprotein and albumin. Sphingosine-1-phosphate acts through five members of the G protein-coupled S1P receptors (S1PR1-S1PR5) to exert diverse actions, which include vascular maturation in embryonic stage and postnatal angiogenesis, maintenance of functional integrity of vascular endothelium, regulation of vascular tonus, and lymphocyte trafficking. Sphingosine-1-phosphate is unique in its ability to regulate cell migration either positively or negatively by acting through different receptor subtypes. S1PR1 and S1PR3 mediate chemotactic cell migration toward S1P via Gi/Rac pathway, whereas S1PR2 mediates S1P inhibition of chemotaxis via G12/13/Rho-dependent inhibition of Rac. Sphingosine-1-phosphate positively or negatively regulates tumor cell migration, invasion in Matrigel, and hematogenous metastasis in manners strictly dependent on S1P receptor subtypes expressed in tumor cells. S1PR1 (and S1PR3) also mediates activation of Gi/phosphatidylinositol 3-kinase (PI3K)/Akt and stimulation of cell proliferation/survival, whereas S1PR2 could mediate suppression of cell proliferation/survival through G12/13/Rho/Rho kinase/PTEN-dependent Akt inhibition. S1PR1 (and S1PR3) expressed in endothelial cells mediates angiogenic action of S1P by stimulating endothelial cell migration, proliferation and tube formation. In a mouse model of hindlimb ischemia after femoral artery resection, repeated local administration or sustained delivery of S1P, or transgenic overexpression of SphK1, accelerates post-ischemic angiogenesis, through the S1P actions on both endothelial cells and bone marrow-derived myeloid cells (BMDCs). In tumor cells, SphK1 is upregulated especially in advanced stages, through mechanisms involving both activating Ras mutation and hypoxia, which leads to increased S1P production and also decreased cellular content of pro-apoptotic sphingolipid ceramide, a metabolic precursor of S1P. Apoptotic tumor cells also produce S1P through SphK2 activation, thus implicated in tumor angiogenesis by acting on endothelial cells through S1PR1/S1PR3, as well as tumor-infiltrating macrophages and BMDCs. Inhibition of S1PR1 function by either an anti-S1P antibody or FTY720 inhibits tumor angiogenesis and tumor growth. Differently from S1PR1, S1PR2 expressed in host cells mediates inhibition of tumor angiogenesis and tumor growth, through mechanisms involving the suppression of endothelial cell migration, proliferation and tube formation, and inhibition of BMDC recruitment to tumor stroma with suppressed expression of pro-angiogenic factor and matrix metalloprotease 9. These findings provide the molecular basis for S1P receptor subtype-selective targeting strategies aiming at angiogenic therapy for occlusive peripheral arterial diseases, and anti-angiogenic and anti-tumor therapies against cancer.Biomedical Reviews 2011; 22: 15-29

Massive trapezial metastasis from gastric adenocarcinoma resected and reconstructed with a vascularized scapular bone graft: A case report

Rationale: Isolated metastasis to the hand bones is very rare. Only seven cases of metastasis to the trapezium have been reported. To the best of our knowledge, this is the first report of a single metastasis to the trapezium from a gastric adenocarcinoma. Patient concerns: A 62-year-old man presented with pain and massive swelling in the right carpometacarpal joint of the thumb. Diagnoses: The patient was diagnosed with trapezial metastasis of advanced gastric adenocarcinoma. Interventions: The patient underwent systemic chemotherapy with cisplatin and S-1, radiotherapy to the metastatic bone, and treatment with denosumab. One year later, the huge metastatic tumor was resected, and the hand was reconstructed using vascularized scapular bone. Outcomes: Eighteen months postoperatively, the patient was satisfied with the appearance of the reconstructed hand and was able to use his right thumb in activities of daily living. Lessons: Although rare, metastasis to the trapezium should be considered in patients with persistent and progressive thumb CMC joint pain.ArticleMedicine 96(50) : e9294(2017)journal articl

Continued growth of locally aggressive fibrous dysplasia of 22 years duration after reaching adulthood: a case report

Fibrous dysplasia generally stops growing when patients reach adulthood. Locally aggressive fibrous dysplasia is an extremely rare subtype of fibrous dysplasia that is characterized by progressive enlargement after bone maturation, cortical bone destruction and soft tissue invasion but without malignant transformation. At 50 years of age, a tumor was found in the rib of a patient. The tumor gradually enlarged over time and imaging findings suggested a malignant tumor. The case was further complicated by restrictive lung disorder. Biopsies from multiple sites showed no malignant findings, and marginal resection with partial curettage was performed. The final diagnosis was locally aggressive fibrous dysplasia, and the restrictive lung disorder improved postoperatively. The natural history of the disease is also unknown. This is the first report in the literature to describe a case in which a lesion exhibited long-term growth over a period of 22 years after reaching adulthood.ArticleJournal of surgical case reports 2020(2) : rjz406(2020)journal articl

Sphingosine-1-phosphate receptor type 2 (S1P2) inhibits bleomycininduced cellular senescence in murine lung fibroblasts

The lysophospholipid mediator sphingosine-1-phosphate (S1P) exerts diverse biological activities including the regulation of leukocyte migration and vascular barrier integrity, suggesting that S1P signaling could be involved in inflammatory fibrotic diseases. Pulmonary fibrosis is a devastating disease characterized by fibroblast accumulation and extracellular matrix deposition in lungs, and bleomycin–induced pulmonary fibrosis is the most widely used experimental model. We studied the effects of the S1P–specific receptor S1P2 on the phenotypes of lung fibroblasts isolated from bleomycin- and saline-administered wild-type and S1P2–null (S1pr2-/-) mice. The lung fibroblasts from bleomycin-administered wild-type and S1pr2-/- mice failed to proliferate in the presence of serum, unlike fibroblasts from saline-administered mice. The fibroblasts from bleomycin-administered mice also showed the enlarged and flattened morphology compared with fibroblasts from control mice. Bleomycin administration increased the protein expression of the cell cycle inhibitor p16INK4a in fibroblasts and the number of senescence–associated β-galactosidase (SA-β-gal)-positive fibroblasts. In S1pr2-/- fibroblasts, bleomycin administration-induced increases in p16INK4a protein expression and SA–β-gal–positive cells were augmented. Furthermore, bleomycin increased mRNA expression of interleukin-6 and matrix metalloproteinases in S1pr2-/- fibroblasts compared with wild-type fibroblasts. In addition, the activation of Akt in response to platelet–derived growth factor and S1P was enhanced in S1pr2-/- fibroblasts compared with wild-type fibroblasts. These results indicate that S1P2 deletion enhances bleomycin administration–induced cellular senescence of lung fibroblasts, which may lead to inhibition of lung fibrosis through the mechanisms involving increased matrix metalloproteinases expression. Thus, S1P2 may be a novel therapeutic target for lung fibrosis

哺乳動物で生成される内因性マリファナ様物質アナンダミドの生理作用の解明

金沢大学医薬保健研究域医学系内因性マリファナ様物質であるアナンダミドを含むN-アシルエタノールアミン(NAE)がホスファチジルエタノールアミン(PE)からN-アシルPE(NAPE)を経て作られる。我々は2004年にNAPEからアナンダミドを含むNAEの生成を触媒するホスホリパーゼD型酵素(NAPE-PLD)のcDNAクローニングに成功した。本研究では,本酵素により生成されるアナンダミドを含むNAEの生理機能を明らかにするために、NAPE-PLD遺伝子欠損マウス(NAPE-PLD^)の作製・解析を行った。1)NAPE-PLDの触媒活性中心が局在する第3エクソンを標的部位として,Cre/loxPシステムを用いてNAPE-PLD^を作製した。2)NAPE-PLD^はメンデルの法則に従って生まれた。3)各臓器におけるNAPE-PLDの発現の欠如にかかわらず、NAPE-PLD^のNAPE-PLD活性は各臓器で様々な程度で減少したが、完全に消失しなかった。4)NAPE-PLD^の成長・体重の変化・外見(形態的・行動的特徴)に現れる表現型および脳を含む主要な臓器における組織学的異常は認められなかった。5)正常時のNAPE-PLD^の脳内のNAPE量がNAPE-PLD^と比べ、15-20倍増加した。一方、NAPE-PLD^の脳内のNAE量はNAPE-PLD^と比べ、わずかに減少した。6)NAPE-PLD^とNAPE-PLD^の学習・記憶能力に有意な差は認められなかった。以上の結果から、NAPE-PLDが生体内でNAPEからNAEの生成に中心的に働いていることが示された。また、NAPE-PLDを介さないNAEの生合成経路が存在する可能性が示唆された。これまでの予備的検討により上記の結果が得られているが、今後、さらに厳密な検討が必要である。N-Acylethanolamines (NAEs) constitute a large and diverse class of signaling lipids that includes the endogenous cannabinoid anandamide. It is widely accepted that in mammalian tissues all NAEs are principally released from their corresponding N-acyl phosphatidylethanolamines (NAPEs) by the catalysis by a membrane-associated phospholipase D generally abbreviated as NAPE-PLD. Recently, NAPE-PLD was identified as a candidate enzyme involved in the biosynthesis of NAEs by us. To understand the physiological and pathophysiological significance of anandamide and other bioactive NAEs in mammals, we generated and characterized mice with a targeted disruption in the NAPE-PLD gene (NAPE-PLD-1). (1) lb generate mice lacking NAPE-PLD, exon 3 of the NAPE-PLD gene was removed by Cre/loxP system. (2) NAPE-PLD-1- were born at the expected Mendelian frequency, were viable and healthy, and showed no overt differences in their cage behavior compared to wild type littermates. (3) RT-PCR and Western blotting with anti-NAPE-PLD antibodies confirmed the absence of NAPE-PLD mRNA and protein in tissues from NAPE-PLO-h. (4) Tissues from NAPE FED" showed significantly lower NAPE-PLD activity with an N-palmitoyl-PE as substrate compared to wild type tissues. (5) Significant reductions in the levels of saturated NAEs were observed in NAPE-PLO-I brains. On the other hand, complementary profiles of NAPEs were found in NAPE-PLD+/+ and NAPE-PLD-1- brains, with the latter samples possessing 15-20-fold higher levels of saturated N-acyl NAPEs, These data suggest that NAPE-PLD is a principal enzyme responsible for the conversion of NAPEs to NAEs in mammals.研究課題/領域番号:18590297, 研究期間(年度):2006 – 2007出典：研究課題「哺乳動物で生成される内因性マリファナ様物質アナンダミドの生理作用の解明」課題番号18590297（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-18590297/185902972007kenkyu_seika_hokoku_gaiyo/）を加工して作

Sphingosine-1-phosphate signaling and biological activities in the cardiovascular system

金沢大学医薬保健研究域医学系The plasma lysophospholipid mediator sphingosine-1-phosphate (S1P) is produced exclusively by sphingosine kinase (SPHK) 1 and SPHK2 in vivo, and plays diverse biological and pathophysiological roles by acting largely through three members of the G protein-coupled S1P receptors, S1P1, S1P2 and S1P3. S1P1 expressed on endothelial cells mediates embryonic vascular maturation and maintains vascular integrity by contributing to eNOS activation, inhibiting vascular permeability and inducing endothelial cell chemotaxis via Gi-coupled mechanisms. By contrast, S1P2, is expressed in high levels on vascular smooth muscle cells (VSMCs) and certain types of tumor cells, inhibiting Rac and cell migration via a G12/13-and Rho-dependent mechanism. In rat neointimal VSMCs, S1P1 is upregulated to mediate local production of platelet-derived growth factor, which is a key player in vascular remodeling. S1P3 expressed on endothelial cells also mediates chemotaxis toward S1P and vasorelaxation via NO production in certain vascular bed, playing protective roles for vascular integrity. S1P3 expressed on VSMCs and cardiac sinoatrial node cells mediates vasopressor and negative chronotropic effect, respectively. In addition, S1P3, together with S1P2 and SPHK1, is suggested to play a protective role against acute myocardial ischemia. However, our recent work indicates that overexpressed SPHK1 is involved in cardiomyocyte degeneration and fibrosis in vivo, in part through S1P activation of the S1P3 signaling. We also demonstrated that exogenously administered S1P accelerates neovascularization and blood flow recovery in ischemic limbs, suggesting its usefulness for angiogenic therapy. These results provide evidence for S1P receptor subtype-specific pharmacological intervention as a novel therapeutic approach to cardiovascular diseases and cancer. © 2008 Elsevier B.V. All rights reserved