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101.
Huifang Hao Yutaka Maeda Takuya Fukazawa Tomoki Yamatsuji Munenori Takaoka Xiao-Hong Bao Junji Matsuoka Tatsuo Okui Tsuyoshi Shimo Nagio Takigawa Yasuko Tomono Motowo Nakajima Iris M. Fink-Baldauf Sandra Nelson William Seibel Ruben Papoian Jeffrey A. Whitsett Yoshio Naomoto 《PloS one》2013,8(8)
Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK. 相似文献
102.
Robert Gramling Kathi L Heffner William MP Klein Laura E Zajac Mary Roberts Charles B Eaton 《BioPsychoSocial medicine》2010,4(1):11
Background
More optimistic perceptions of cardiovascular disease risk are associated with substantively lower rates of cardiovascular death among men. It remains unknown whether this association represents causality (i.e. perception leads to actions/conditions that influence cardiovascular disease occurrence) or residual confounding by unmeasured factors that associate with risk perceptions and with physiological processes that promote cardiovascular disease (i.e. inflammation or endothelial dysfunction). 相似文献103.
104.
Matsuoka RL Chivatakarn O Badea TC Samuels IS Cahill H Katayama K Kumar SR Suto F Chédotal A Peachey NS Nathans J Yoshida Y Giger RJ Kolodkin AL 《Neuron》2011,71(3):460-473
In the vertebrate retina, neurites from distinct neuronal cell types are constrained within the plexiform layers, allowing for establishment of retinal lamination. However, the mechanisms by which retinal neurites are segregated within the inner or outer plexiform layers are not known. We find that the transmembrane semaphorins Sema5A and Sema5B constrain neurites from multiple retinal neuron subtypes within the inner plexiform layer (IPL). In Sema5A?/?; Sema5B?/? mice, retinal ganglion cells (RGCs) and amacrine and bipolar cells exhibit severe defects leading to neurite mistargeting into the outer portions of the retina. These targeting abnormalities are more prominent in the outer (OFF) layers of the IPL and result in functional defects in select RGC response properties. Sema5A and Sema5B inhibit retinal neurite outgrowth through PlexinA1 and PlexinA3 receptors both in vitro and in vivo. These findings define a set of ligands and receptors required for the establishment of inner retinal lamination and function. 相似文献
105.
Matsuoka H Hosoda H Sugawara H Iwama S Kim HS Kangawa K Sugihara S 《Hormone research》2005,64(6):274-279
BACKGROUND AND OBJECTIVE: Ghrelin is a novel gastric peptide which stimulates GH secretion and has been demonstrated to have orexigenic and adipogenic properties. Insulin is a physiological and dynamic modulator of plasma ghrelin, and insulinemia possibly mediates the effect of the nutritional state on the plasma concentrations of ghrelin in adults. No data on the regulation of GH secretion by ghrelin have so far been reported, nor has the possible influence of hypoglycemia on the plasma ghrelin levels in children been reported. METHODS: Provocative studies were performed using a variety of stimuli, including insulin-induced hypoglycemia, and glucagon, arginine and L-dopa loading. We studied a group of 27 children with short stature being investigated for GH deficiency (10 F, 17 M; age 4-14 years; height SDS -0.92 to -3.27); the subjects were instructed to fast overnight, and the following morning, the relationships among the plasma ghrelin, GH and glucose levels were investigated by determining the plasma ghrelin profiles during those provocative tests. Using a new method for determining the two types of ghrelin, samples were obtained for determination of the plasma ghrelin, serum glucose and serum GH levels after the administration of the aforementioned stimulating agents. RESULTS: All the four stimuli caused a significant decrease in the circulating C- and N-ghrelin levels with a nadir at +30 min, with the exception of the N-ghrelin level following the L-dopa loading. During the same period, the plasma GH level increased following insulin, arginine and L-dopa loading, and the plasma glucose level increased significantly following glucagon loading. In the arginine and L-dopa load connected, a significant correlation was observed between the 30-min change in the serum GH level and the 30-min change in the plasma C-ghrelin level. In the multiple regression analysis to explain the 30-min change in the plasma level of C-ghrelin, the baseline plasma level of C-ghrelin (basal), height and % overweight were the only three significant parameters, accounting for 85.2% of the variance. CONCLUSION: This study demonstrated that the inverse relation between the circulating GH and ghrelin levels may indicate the existence of a feedback loop, and also lends support to the assumption of a GH-independent relationship between plasma ghrelin and glucose levels. These observations constitute further evidence to suggest that peripheral ghrelin is a direct growth-promoting hormone. 相似文献
106.
107.
108.
Amelioration of chronic murine colitis by peptide-mediated transduction of the IkappaB kinase inhibitor NEMO binding domain peptide 总被引:1,自引:0,他引:1
109.
Matsuki Y Ohmura-Hoshino M Goto E Aoki M Mito-Yoshida M Uematsu M Hasegawa T Koseki H Ohara O Nakayama M Toyooka K Matsuoka K Hotta H Yamamoto A Ishido S 《The EMBO journal》2007,26(3):846-854
The presence of post-translational regulation of MHC class II (MHC II) under physiological conditions has been demonstrated recently in dendritic cells (DCs) that potently function as antigen-presenting cells (APCs). Here, we report that MARCH-I, an E3 ubiquitin ligase, plays a pivotal role in the post-translational regulation of MHC II in B cells. MARCH-I expression was particularly high in B cells, and the forced expression of MARCH-I induced the ubiquitination of MHC II. In B cells from MARCH-I-deficient mice (MARCH-I KO), the half-life of surface MHC II was prolonged and the ubiquitinated form of MHC II completely disappeared. In addition, MARCH-I-deficient B cells highly expressed exogenous antigen-loaded MHC II on their surface and showed high ability to present exogenous antigens. These results suggest that the function of MHC II in B cells is regulated through ubiquitination by MARCH-I. 相似文献
110.
Tsubaki M Kato C Manno M Ogaki M Satou T Itoh T Kusunoki T Tanimori Y Fujiwara K Matsuoka H Nishida S 《Molecular and cellular biochemistry》2007,304(1-2):53-60
Osteolytic lesions are rapidly progressive during the terminal stages of myeloma, and the bone pain or bone fracture that
occurs at these lesions decreases the patients’ quality of life to a notable degree. In relation to the etiology of this bone
destruction, it has been reported recently that MIP-1α, produced in large amounts in myeloma patients, acts indirectly on
osteoclastic precursor cells, and activates osteoclasts by way of bone-marrow stromal cells or osteoblasts, although the details
of this process remain obscure. In the present study, our group investigated the mechanism by which RANKL expression is induced
by MIP-1α and the effects of MIP-1α on the activation of osteoclasts. RANKL mRNA and RANKL protein expressions increased in
both ST2 cells and MC3T3–E1 cells in a MIP-1α concentration-dependent manner. RANKL mRNA expression began to increase at 1 h
after the addition of MIP-1α; the increase became remarkable at 2 h, and continuous expression was observed subsequently.
Both ST2 and MC3T3-E1 cells showed similar levels of increased RANKL protein expression at 1, 2, and 3 days after the addition
of MIP-1α. After the addition of MIP-1α, the amount of phosphorylated ERK1/2 and Akt protein expressions showed an increase,
as compared to the corresponding amount in the control group. On the other hand, the amount of phosphorylated p38MAPK protein
expression showed a decrease from the amount in the control group after the addition of MIP-1α. U0126 (a MEK1/2 inhibitor)
or LY294002 (a PI3K inhibitor) was added to ST2 and MC3T3-E1 cells, and was found to inhibit RANKL mRNA and RANKL protein
expression in these cells. When SB203580, a p38MAPK inhibitor, was added, RANKL mRNA and RANKL protein expression were increased
in these cells. MIP-1α was found to promote osteoclastic differentiation of C7 cells, an osteoclastic precursor cell line,
in a MIP-1α concentration-dependent manner. MIP-1α promoted differentiation into osteoclasts more extensively in C7 cells
incubated together with ST2 and MC3T3-E1 cells than in C7 cells incubated alone. These results suggested that MIP-1α directly
acts on the osteoclastic precursor cells and induces osteoclastic differentiation. This substance also indirectly induces
osteoclastic differentiation through the promotion of RANKL expression in bone-marrow stromal cells and osteoblasts. The findings
of this investigation suggested that activation of the MEK/ERK and the PI3K/Akt pathways and inhibition of p38MAPK pathway
were involved in RANKL expression induced by MIP-1α in bone-marrow stromal cells and osteoblasts. This finding may be useful
in the development of an osteoclastic inhibitor that targets intracellular signaling factors. 相似文献