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1.
J Reprod Immunol ; 156: 103920, 2023 03.
Article in English | MEDLINE | ID: mdl-36863074

ABSTRACT

Antiphospholipid syndrome (APS) is an established cause of recurrent pregnancy loss (RPL). It is necessary to detect persistently positive antiphospholipid antibodies to diagnose APS. This study aimed to explore risk factors for persistent anticardiolipin (aCL) positivity. Women with a history of RPL or with a history of one or more intrauterine fetal deaths after 10 weeks underwent examinations to determine the causes of RPL, including antiphospholipid antibodies. If aCL-IgG or aCL-IgM antibodies were positive, retests were performed at least 12 weeks apart. Risk factors for persistent aCL antibody positivity were retrospectively investigated. The number and percentage of cases above the 99th percentile were 74/2399 (3.1%) for aCL-IgG, and 81/2399 (3.5%) for aCL-IgM. Of the initially tested cases, 2.3% (56/2399) for aCL-IgG and 2.0% (46/2289) for aCL-IgM were ultimately positive above the 99th percentile in retests. Retest values after 12 weeks were significantly lower than the initial values for both IgG and IgM immunoglobulin classes. Initial aCL antibody titers were significantly higher in the persistent-positive group than in the transient-positive group for both IgG and IgM immunoglobulin classes. The cut-off values for predicting persistent positivity of aCL-IgG antibodies and aCL-IgM antibodies were 15 U/mL (99.1 percentile) and 11 U/mL (99.2 percentile), respectively. The only risk factor for persistently positive aCL antibodies is a high antibody titer during the initial test. When the aCL antibody titer in the initial test exceeds the cut-off value, therapeutic strategies can be defined in subsequent pregnancies without waiting for 12 weeks.


Subject(s)
Abortion, Habitual , Antiphospholipid Syndrome , Pregnancy , Humans , Female , Antibodies, Anticardiolipin , Retrospective Studies , beta 2-Glycoprotein I , Antiphospholipid Syndrome/diagnosis , Antibodies, Antiphospholipid , Abortion, Habitual/diagnosis , Risk Factors , Immunoglobulin G , Immunoglobulin M
2.
Cell Death Dis ; 5: e1189, 2014 Apr 24.
Article in English | MEDLINE | ID: mdl-24763046

ABSTRACT

Obesity-related disorders are closely associated with the development of age-related hearing impairment (ARHI). Adiponectin (APN) exerts protective effects against obesity-related conditions including endothelial dysfunction and atherosclerosis. Here, we investigated the impact of APN on ARHI. APN-knockout (APN-KO) mice developed exacerbation of hearing impairment, particularly in the high frequency range, compared with wild-type (WT) mice. Supplementation with APN prevented the hearing impairment in APN-KO mice. At 2 months of age, the cochlear blood flow and capillary density of the stria vascularis (SV) were significantly reduced in APN-KO mice as compared with WT mice. APN-KO mice also showed a significant increase in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells in the organ of Corti in the cochlea at 2 months of age. At the age of 6 months, hair cells were lost at the organ of Corti in APN-KO mice. In cultured auditory HEI-OC1 cells, APN reduced apoptotic activity under hypoxic conditions. Clinically, plasma APN levels were significantly lower in humans with ARHI. Multiple logistic regression analysis identified APN as a significant and independent predictor of ARHI. Our observations indicate that APN has an important role in preventing ARHI.


Subject(s)
Adiponectin/deficiency , Aging/pathology , Disease Progression , Hearing Loss/metabolism , Adiponectin/blood , Adiponectin/metabolism , Adiponectin/pharmacology , Animals , Apoptosis/drug effects , Auditory Threshold/drug effects , Capillaries/pathology , Cell Line , Evoked Potentials, Auditory, Brain Stem/drug effects , Hair Cells, Auditory/drug effects , Hair Cells, Auditory/pathology , Hearing Loss/blood , Hearing Loss/pathology , Hearing Loss/physiopathology , Humans , Male , Mice, Knockout , Middle Aged , Organ of Corti/blood supply , Organ of Corti/drug effects , Organ of Corti/pathology , Organ of Corti/physiopathology , Regional Blood Flow/drug effects
3.
Curr Med Chem ; 19(32): 5459-66, 2012.
Article in English | MEDLINE | ID: mdl-22876923

ABSTRACT

This review focuses on the recent findings that adiponectin plays a significant role of in cardiovascular diseases. Adipose tissue functions as an endocrine organ by secreting adipocytokines that can directly affect nearby or remote organs. Adiponectin is an adipocytokine whose concentration is down-regulated in subjects with obesity-related disorders. Low levels of circulating adiponectin appear to associate with the increased prevalence of obesity-linked diseases including atherosclerosis and ischemic heart disease. A number of experimental studies have shown that adiponectin exerts beneficial effects on the cardiovascular system by directly acting on the component cells in the heart and blood vessels. The cardiovascular protection by adiponectin is mediated through its ability to attenuate inflammatory responses and apoptotic activities in the target organs. Thus, adiponectin could represent a therapeutic target molecule for prevention or treatment of cardiovascular diseases.


Subject(s)
Adiponectin/metabolism , Cardiovascular Diseases/metabolism , Animals , Blood Vessels/cytology , Blood Vessels/metabolism , Humans , Myocardium/cytology , Myocardium/metabolism , Receptors, Adiponectin/metabolism
4.
Radiat Prot Dosimetry ; 143(2-4): 365-9, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21156785

ABSTRACT

It is known that carcinogenesis by low-dose radiation will start from DNA damage by ionising radiation. After the long time period, these very small effects will appear on a cellular scale by accumulation of various intracellular biological responses and finally grow to the tumour with clonal expansion of cancer cell. Thus, the biological radiation effects are phenomena with a very wide scale from DNA damage (10(-9) m, 10(-6) s) to the tumour (10(-3) m, 10(5) s); so the risk estimation of low-dose radiation is difficult to study by the experiments. To overcome these difficult situations at low-dose radiation effects' problems, it is good to study the process of carcinogenesis using a biologically based mathematical model. This study's cellular-scale mathematical model of tumourigenesis and some results of the statistical calculations about the tumour growth as presented in the work.


Subject(s)
Models, Biological , Neoplasms, Radiation-Induced/pathology , Neoplasms, Radiation-Induced/physiopathology , Animals , Cell Proliferation , Computer Simulation , Humans
5.
Asian J Endosc Surg ; 4(3): 133-7, 2011 Aug.
Article in English | MEDLINE | ID: mdl-22776277

ABSTRACT

INTRODUCTION: The purpose of this study was to elucidate the feasibility of gasless laparoscopically assisted myomectomy (LAM) using a wound retraction system. This method treats symptomatic uterine myomas by combining laparoscopy with a mini-laparotomy to enucleate myoma nodules and to close the uterine myometrium. METHODS: This study includes 275 patients who underwent gasless LAM. For patients with fewer than three myoma nodules, the location of the largest nodule was classified as anterior, fundal, or posterior. The operative outcomes, intraoperative and postoperative courses, and complications were examined. RESULTS: All operations were performed satisfactorily, and no conversions to laparotomy were required. None of the patients developed serious complications. The mean blood loss and operating time were 190.3 mL and 152.2 minutes, respectively. The mean myoma size was 8.9 cm, and the mean number of myomas per patient was 2.8. The average postoperative hospital stay was 5.7 days. There were no significant differences in resected myoma size, blood loss, and surgical duration with respect to the location of the largest nodule. CONCLUSION: Gasless LAM with a wound retractor is feasible and allows surgeons to perform myomectomy safely and cost-effectively, without requiring advanced laparoscopic surgical skills and while maintaining minimum invasiveness.


Subject(s)
Laparoscopy/methods , Laparotomy , Leiomyoma/surgery , Myometrium/surgery , Uterine Neoplasms/surgery , Adult , Blood Loss, Surgical/statistics & numerical data , Feasibility Studies , Female , Humans , Laparoscopy/instrumentation , Length of Stay/statistics & numerical data , Postoperative Complications/epidemiology , Retrospective Studies , Treatment Outcome
6.
Am J Physiol Lung Cell Mol Physiol ; 294(6): L1035-42, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18326826

ABSTRACT

Adiponectin is an adipocyte-derived collectin that acts on a wide range of tissues including liver, brain, heart, and vascular endothelium. To date, little is known about the actions of adiponectin in the lung. Herein, we demonstrate that adiponectin is present in lung lining fluid and that adiponectin deficiency leads to increases in proinflammatory mediators and an emphysema-like phenotype in the mouse lung. Alveolar macrophages from adiponectin-deficient mice spontaneously display increased production of tumor necrosis factor-alpha (TNF-alpha) and matrix metalloproteinase (MMP-12) activity. Consistent with these observations, we found that pretreatment of alveolar macrophages with adiponectin leads to TNF-alpha and MMP-12 suppression. Together, our findings show that adiponectin leads to macrophage suppression in the lung and suggest that adiponectin-deficient states may contribute to the pathogenesis of inflammatory lung conditions such as emphysema.


Subject(s)
Adiponectin/deficiency , Emphysema/physiopathology , Lung/physiology , Macrophages, Alveolar/physiology , Animals , Bronchoalveolar Lavage Fluid/chemistry , Emphysema/etiology , Matrix Metalloproteinases/metabolism , Mice , Mice, Inbred C57BL , Phenotype , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolism
8.
Eur J Clin Invest ; 33(3): 216-22, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12641539

ABSTRACT

BACKGROUND: Patients with lipoprotein lipase (LPL) deficiency had been generally thought to be spared accelerated atherosclerosis in spite of a marked elevation of plasma triglyceride levels. However, it has been recently reported that some heterozygous and homozygous LPL-deficient patients are associated with premature atherosclerosis. In this paper, we report a 55-year-old type I hyperlipidaemic patient with a novel missense mutation in the LPL gene. PATIENT AND RESULTS: The patient had suffered from coronary artery disease, abdominal aortic aneurysm, and stenoses of the bilateral renal arteries and superficial femoral arteries. Sequencing of the genomic DNA revealed that the patient was a homozygote for the mutation, a G to C transition at nucleotide position 1069 in the exon 6, resulting in an amino acid substitution of Phe for Leu303 (L303F). Approximately 6% and approximately 40% of normal LPL activity and LPL mass, respectively, were detected in the patient's postheparin plasma. An in vitro expression study demonstrated that COS7 cells transfected with L303F mutant cDNA produced a 40% amount of LPL protein in cell lysates compared with normal cDNA, but no protein was detected in the media. Lipoprotein lipase activity was completely absent in both lysates and media of the cells transfected with the mutant cDNA, suggesting that this mutation in the LPL gene results in the production of a functionally inactive protein. CONCLUSION: This case suggests that the LPL missense mutation (L303F), which impairs lipolysis but preserves the LPL mass, is proatherogenic.


Subject(s)
Arteriosclerosis/genetics , Hyperlipoproteinemia Type IV/genetics , Lipoprotein Lipase/genetics , Mutation, Missense/genetics , Arteriosclerosis/etiology , Coronary Artery Disease/etiology , Coronary Artery Disease/genetics , Gene Amplification , Humans , Hyperlipoproteinemia Type IV/complications , Male , Middle Aged , Polymerase Chain Reaction/methods
9.
J Biol Chem ; 276(51): 48572-9, 2001 Dec 21.
Article in English | MEDLINE | ID: mdl-11679588

ABSTRACT

The current study demonstrates that aquaporin adipose (AQPap), an adipose-specific glycerol channel (Kishida, K., Kuriyama, H., Funahashi, T., Shimomura, I., Kihara, S., Ouchi, N., Nishida, M., Nishizawa, H., Matsuda, M., Takahashi, M., Hotta, K., Nakamura, T., Yamashita, S., Tochino, Y., and Matsuzawa, Y. (2000) J. Biol. Chem. 275, 20896-20902), is a target gene of peroxisome proliferator-activated receptor (PPAR) gamma. The AQPap mRNA amounts increased following the induction of PPARgamma in the differentiation of 3T3-L1 adipocytes. The AQPap mRNA in the adipose tissue increased when mice were treated with pioglitazone (PGZ), a synthetic PPARgamma ligand, and decreased in PPARgamma(+/-) heterozygous knockout mice. In 3T3-L1 adipocytes, PGZ augmented the AQPap mRNA expression and its promoter activity. Serial deletion of the promoter revealed the putative peroxisome proliferator-activated receptor response element (PPRE) at -93/-77. In 3T3-L1 preadipocytes, the expression of PPARgamma by transfection and PGZ activated the luciferase activity of the promoter containing the PPRE, whereas the PPRE-deleted mutant was not affected. The gel mobility shift assay showed the direct binding of PPARgamma-retinoid X receptor alpha complex to the PPRE. DeltaPPARgamma, which we generated as the dominant negative PPARgamma lacking the activation function-2 domain, suppressed the promoter activity in 3T3-L1 cells, dose-dependently. We conclude that AQPap is a novel adipose-specific target gene of PPARgamma through the binding of PPARgamma-retinoid X receptor complex to the PPRE region in its promoter.


Subject(s)
Adipose Tissue/metabolism , Aquaporins/genetics , Gene Expression Regulation/physiology , Receptors, Cytoplasmic and Nuclear/physiology , Thiazolidinediones , Transcription Factors/physiology , 3T3 Cells , Animals , Base Sequence , DNA Primers , Gene Expression Regulation/drug effects , Male , Mice , Mice, Inbred C57BL , Promoter Regions, Genetic , RNA, Messenger/genetics , Thiazoles/pharmacology
10.
Diabetes ; 50(9): 2094-9, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11522676

ABSTRACT

Insulin resistance and its dreaded consequence, type 2 diabetes, are major causes of atherosclerosis. Adiponectin is an adipose-specific plasma protein that possesses anti-atherogenic properties, such as the suppression of adhesion molecule expression in vascular endothelial cells and cytokine production from macrophages. Plasma adiponectin concentrations are decreased in obese and type 2 diabetic subjects with insulin resistance. A regimen that normalizes or increases the plasma adiponectin might prevent atherosclerosis in patients with insulin resistance. In this study, we demonstrate the inducing effects of thiazolidinediones (TZDs), which are synthetic PPARgamma ligands, on the expression and secretion of adiponectin in humans and rodents in vivo and in vitro. The administration of TZDs significantly increased the plasma adiponectin concentrations in insulin resistant humans and rodents without affecting their body weight. Adiponectin mRNA expression was normalized or increased by TZDs in the adipose tissues of obese mice. In cultured 3T3-L1 adipocytes, TZD derivatives enhanced the mRNA expression and secretion of adiponectin in a dose- and time-dependent manner. Furthermore, these effects were mediated through the activation of the promoter by the TZDs. On the other hand, TNF-alpha, which is produced more in an insulin-resistant condition, dose-dependently reduced the expression of adiponectin in adipocytes by suppressing its promoter activity. TZDs restored this inhibitory effect by TNF-alpha. TZDs might prevent atherosclerotic vascular disease in insulin-resistant patients by inducing the production of adiponectin through direct effect on its promoter and antagonizing the effect of TNF-alpha on the adiponectin promoter.


Subject(s)
Intercellular Signaling Peptides and Proteins , Proteins/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Thiazolidinediones , Transcription Factors/metabolism , 3T3 Cells , Adipocytes/drug effects , Adipocytes/metabolism , Adiponectin , Adipose Tissue/metabolism , Animals , Blood/metabolism , Female , Humans , Ligands , Male , Mice , Mice, Inbred C57BL , Middle Aged , Osmolar Concentration , Proteins/antagonists & inhibitors , Thiazoles/pharmacology , Tumor Necrosis Factor-alpha/pharmacology
11.
J Biol Chem ; 276(39): 36251-60, 2001 Sep 28.
Article in English | MEDLINE | ID: mdl-11457862

ABSTRACT

Aquaporin adipose (AQPap) is a putative glycerol channel in adipocytes (Kishida, K., Kuriyama, H., Funahashi, T., Shimomura, I., Kihara, S., Ouchi, N., Nishida, M., Nishizawa, H., Matsuda, M., Takahashi, M., Hotta, K., Nakamura, T., Yamashita, S., Tochino, Y., and Matsuzawa, Y. (2000) J. Biol. Chem. 275, 20896-20902). In the current study, we examined the genomic structure of the mouse AQPap gene and its regulation by insulin. The mouse AQPap gene spanned 12 kilobase pairs in chromosome 4 and consisted of 8 exons and 7 introns. The first two exons, designated exon 1 and exon 1', are alternatively spliced to common exon 2, and thus the AQPap gene possessed two potential promoters. The exon 1-derived transcript is dominant in both adipose tissues and adipocytes on the basis of RNase protection assay and promoter analysis. The mRNA increased after fasting and decreased with refeeding. Insulin deficiency generated by streptozotocin enhanced the mRNA in adipose tissue. Insulin down-regulated AQPap mRNA in 3T3-L1 adipocytes. The AQPap promoter contained heptanucleotide sequences, TGTTTTT at -443/-437, similar to the insulin-response element identified previously in the promoters of insulin-repressed genes. Deletion and single base pair substitution analysis of the promoter revealed that these sequences were required for insulin-mediated repression of AQPap gene transcription. The phosphatidylinositol 3-kinase pathway was involved in this inhibition. We conclude that insulin represses the transcription of AQPap gene via insulin response element in its promoter. Sustained up-regulation of AQPap mRNA in adipose tissue in the insulin-resistant condition may disturb glucose homeostasis by increasing plasma glycerol.


Subject(s)
Aquaporins/chemistry , Aquaporins/genetics , Glycerol/metabolism , Insulin/metabolism , 3T3 Cells , Adipocytes/metabolism , Amino Acid Sequence , Animals , Base Sequence , Blotting, Northern , Blotting, Southern , Cattle , Chromosome Mapping , DNA, Complementary/metabolism , Diabetes Mellitus, Experimental , Dose-Response Relationship, Drug , Down-Regulation , Exons , Gene Deletion , Gene Expression Regulation , Insulin/pharmacology , Introns , Luciferases/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Models, Genetic , Molecular Sequence Data , Phosphatidylinositol 3-Kinases/metabolism , Point Mutation , Promoter Regions, Genetic , RNA, Messenger/metabolism , Radiation Hybrid Mapping , Tissue Distribution , Transfection , Up-Regulation
12.
Obes Res ; 9(7): 388-93, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11445660

ABSTRACT

OBJECTIVE: Adipocytes secrete various cytokines and matrix proteins. Several of them precipitate in obesity-associated diseases, including atherosclerosis. In the current study, we have examined the expression of secreted protein, acidic and rich in cysteine (SPARC) in adipose tissue and its significance in obesity and coronary artery disease (CAD). RESEARCH METHODS AND PROCEDURES: The SPARC mRNA expressions both in vivo and in vitro were detected by Northern blot analysis. Plasma SPARC concentrations were measured by enzyme immunosorbent assay. First, we investigated the plasma SPARC levels of 88 unrelated adult Japanese subjects (62 men and 26 women; average age: [+/- SD] 50 +/- 12 years; body mass index [BMI]: 16 to 46 kg/m(2)). Additionally 31 subjects with CAD diagnosed by coronary angiography (20 men and 11 women) were also investigated. RESULTS: Human adipose tissues expressed abundant SPARC mRNA. SPARC expression in adipose tissues was upregulated in obese db/db mice. Markedly enhanced expression of SPARC mRNA was observed in 3T3-L1 fibroblasts during adipocyte differentiation. Consistent with these results, plasma SPARC levels proved a positive correlation with BMI in humans (r = 0.27; p < 0.01). Interestingly, plasma SPARC concentrations were significantly elevated in age- and BMI-matched subjects with CAD (p < 0.05). DISCUSSION: SPARC was expressed in adipose tissues and its expression was enhanced in obese mice. In human, plasma SPARC levels were elevated in obesity and CAD patients. This elevated SPARC may be involved in the progression of CAD.


Subject(s)
Adipose Tissue/metabolism , Coronary Disease/blood , Obesity/blood , Osteonectin/metabolism , Animals , Blotting, Northern , Body Mass Index , Coronary Disease/genetics , Female , Gene Expression , Humans , Immunoenzyme Techniques , Male , Mice , Mice, Inbred C57BL , Middle Aged , Obesity/genetics , Osteonectin/blood , Osteonectin/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Ribosomal, 28S/genetics , RNA, Ribosomal, 28S/metabolism , Up-Regulation
13.
Pathol Int ; 51(5): 333-7, 2001 May.
Article in English | MEDLINE | ID: mdl-11422790

ABSTRACT

Gonadotropin releasing hormone (GnRH) analogs can cause regression of hormone-dependent breast carcinomas via the specific GnRH receptor (GnRH-R). In an attempt to obtain a better understanding of GnRH actions in human breast carcinoma, the expression of GnRH-R was examined immunohistochemically in 58 invasive ductal carcinomas and correlated with various clinicopathological parameters. GnRH-R was immunolocalized in the cytoplasm of carcinoma cells in 37 of 58 invasive ductal carcinoma cases (64%). Immunoreactivity for GnRH-R was also detected focally in the cytoplasm of morphologically normal glandular epithelia adjacent to the carcinoma. A significant correlation was observed between the immunohistochemical expression of GnRH-R and estrogen receptor labeling index (LI; P = 0.030) or progesterone receptor LI (P = 0.0074). There was a significant inverse correlation between GnRH-R immunoreactivity and Ki-67 LI (P = 0.012). No significant correlations were detected between GnRH-R and other clinicopathological parameters, including patient age, menopausal status, stage, tumor size, lymph node status, histological grade and prognosis. This study indicates that GnRH-R is widely distributed in human breast carcinoma cells and regulates GnRH actions locally. Breast carcinomas positive for GnRH-R maintain some hormonal regulatory mechanisms, and GnRH actions may lead to a low proliferative rate in human breast carcinoma.


Subject(s)
Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Receptors, LHRH/metabolism , Adult , Aged , Aged, 80 and over , Breast Neoplasms/chemistry , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/chemistry , Carcinoma, Ductal, Breast/secondary , Female , Humans , Immunohistochemistry , Ki-67 Antigen/chemistry , Lymph Nodes/pathology , Menopause , Middle Aged , Neoplasm Staging , Receptors, Estrogen/analysis , Receptors, Estrogen/metabolism , Receptors, LHRH/analysis , Receptors, Progesterone/analysis , Receptors, Progesterone/metabolism
14.
Circulation ; 103(8): 1057-63, 2001 Feb 27.
Article in English | MEDLINE | ID: mdl-11222466

ABSTRACT

BACKGROUND: Excessive lipid accumulation in macrophages plays an important role in the development of atherosclerosis. Recently, we discovered an adipocyte-specific plasma protein, adiponectin, that is decreased in patients with coronary artery disease. We previously demonstrated that adiponectin acts as a modulator for proinflammatory stimuli and inhibits monocyte adhesion to endothelial cells. The present study investigated the effects of adiponectin on lipid accumulation in human monocyte-derived macrophages. METHODS AND RESULTS: Human monocytes were differentiated into macrophages by incubation in human type AB serum for 7 days, and the effects of adiponectin were investigated at different time intervals. Treatment with physiological concentrations of adiponectin reduced intracellular cholesteryl ester content, as determined using the enzymatic, fluorometric method. The adiponectin-treated macrophages contained fewer lipid droplets stained by oil red O. Adiponectin suppressed the expression of the class A macrophage scavenger receptor (MSR) at both mRNA and protein levels by Northern and immunoblot analyses, respectively, without affecting the expression of CD36, which was quantified by flow cytometry. Adiponectin reduced the class A MSR promoter activity, as measured by luciferase reporter assay. Adiponectin treatment dose-dependently decreased class A MSR ligand binding and uptake activities. The mRNA level of lipoprotein lipase as a marker of macrophage differentiation was decreased by adiponectin treatment, but that of apolipoprotein E was not altered. Adiponectin was detected around macrophages in the human injured aorta by immunohistochemistry. CONCLUSIONS: The adipocyte-derived plasma protein adiponectin suppressed macrophage-to-foam cell transformation, suggesting that adiponectin may act as a modulator for macrophage-to-foam cell transformation.


Subject(s)
Adipocytes/chemistry , Intercellular Signaling Peptides and Proteins , Lipid Metabolism , Macrophages/drug effects , Proteins/pharmacology , Receptors, Immunologic/biosynthesis , Adiponectin , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Blood Proteins/pharmacology , CD36 Antigens/metabolism , Cell Differentiation/drug effects , Cells, Cultured , Cholesterol Esters/metabolism , Foam Cells/cytology , Foam Cells/drug effects , Humans , Lipoprotein Lipase/genetics , Lipoprotein Lipase/metabolism , Lipoproteins, LDL/metabolism , Macrophages/metabolism , Monocytes/cytology , Peptide Fragments/genetics , Peptide Fragments/metabolism , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Receptors, Scavenger , Scavenger Receptors, Class A
15.
Biophys J ; 79(4): 1903-14, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11023896

ABSTRACT

Cell motion within cellular aggregates consists of both random and coherent components. We used confocal microscopy to study the center of mass displacements and deformations of single endodermal Hydra cells in two kinds of cellular aggregates, ectodermal and endodermal. We first carefully characterize the center of mass displacements using standard statistical analysis. In both aggregates, cells perform a persistent random walk, with the diffusion constant smaller in the more cohesive endodermal aggregate. We show that a simple parametric method is able to describe cell deformations and relate them to displacements. These deformations are random, with their amplitude and direction uncorrelated with the center of mass motion. Unlike for an isolated cell on a substrate, the random forces exerted by the surrounding cells predominate over the deformation of the cell itself, causing the displacements of a cell within an aggregate.


Subject(s)
Hydra/cytology , Animals , Biophysical Phenomena , Biophysics , Cell Aggregation , Cell Movement , Cell Size , Microscopy, Confocal , Models, Biological , Temperature , Viscosity
16.
Circulation ; 102(11): 1296-301, 2000 Sep 12.
Article in English | MEDLINE | ID: mdl-10982546

ABSTRACT

BACKGROUND: Among the many adipocyte-derived endocrine factors, we found an adipocyte-derived plasma protein, adiponectin, that was decreased in obesity. We recently demonstrated that adiponectin inhibited tumor necrosis factor-alpha (TNF-alpha)-induced expression of endothelial adhesion molecules and that plasma adiponectin level was reduced in patients with coronary artery disease (CIRCULATION: 1999;100:2473-2476). However, the intracellular signal by which adiponectin suppressed adhesion molecule expression was not elucidated. The present study investigated the mechanism of modulation for endothelial function by adiponectin. METHODS AND RESULTS: The interaction between adiponectin and human aortic endothelial cells (HAECs) was estimated by cell ELISA using biotinylated adiponectin. HAECs were preincubated for 18 hours with 50 microg/mL of adiponectin, then exposed to TNF-alpha (10 U/mL) or vehicle for the times indicated. NF-kappaB-DNA binding activity was determined by electrophoretic mobility shift assays. TNF-alpha-inducible phosphorylation signals were detected by immunoblotting. Adiponectin specifically bound to HAECs in a saturable manner and inhibited TNF-alpha-induced mRNA expression of monocyte adhesion molecules without affecting the interaction between TNF-alpha and its receptors. Adiponectin suppressed TNF-alpha-induced IkappaB-alpha phosphorylation and subsequent NF-kappaB activation without affecting other TNF-alpha-mediated phosphorylation signals, including Jun N-terminal kinase, p38 kinase, and Akt kinase. This inhibitory effect of adiponectin is accompanied by cAMP accumulation and is blocked by either adenylate cyclase inhibitor or protein kinase A (PKA) inhibitor. CONCLUSIONS: These observations raise the possibility that adiponectin, which is naturally present in the blood stream, modulates the inflammatory response of endothelial cells through cross talk between cAMP-PKA and NF-kappaB signaling pathways.


Subject(s)
Adipose Tissue/metabolism , Cyclic AMP/physiology , Endothelium, Vascular/metabolism , I-kappa B Proteins , Intercellular Signaling Peptides and Proteins , NF-kappa B/physiology , Proteins/physiology , Adenylyl Cyclase Inhibitors , Adiponectin , Aorta/cytology , Biotinylation , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Cyclic AMP/biosynthesis , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , DNA-Binding Proteins/metabolism , Electrophoresis/methods , Endothelium, Vascular/cytology , Enzyme Inhibitors/pharmacology , Enzyme-Linked Immunosorbent Assay , Humans , Immunoblotting , In Vitro Techniques , Monocytes/metabolism , NF-KappaB Inhibitor alpha , NF-kappa B/metabolism , Phosphorylation , Protein Binding , Proteins/metabolism , RNA, Messenger/metabolism , Tumor Necrosis Factor-alpha/pharmacology
17.
Blood ; 96(5): 1723-32, 2000 Sep 01.
Article in English | MEDLINE | ID: mdl-10961870

ABSTRACT

We investigated the functions of adiponectin, an adipocyte-specific secretory protein and a new member of the family of soluble defense collagens, in hematopoiesis and immune responses. Adiponectin suppressed colony formation from colony-forming units (CFU)-granulocyte-macrophage, CFU-macrophage, and CFU-granulocyte, whereas it had no effect on that of burst-forming units-erythroid or mixed erythroid-myeloid CFU. In addition, adiponectin inhibited proliferation of 4 of 9 myeloid cell lines but did not suppress proliferation of erythroid or lymphoid cell lines except for one cell line. These results suggest that adiponectin predominantly inhibits proliferation of myelomonocytic lineage cells. At least one mechanism of the growth inhibition is induction of apoptosis because treatment of acute myelomonocytic leukemia lines with adiponectin induced the appearance of subdiploid peaks and oligonucleosomal DNA fragmentation. Aside from inhibiting growth of myelomonocytic progenitors, adiponectin suppressed mature macrophage functions. Treatment of cultured macrophages with adiponectin significantly inhibited their phagocytic activity and their lipopolysaccharide-induced production of tumor necrosis factor alpha. Suppression of phagocytosis by adiponectin is mediated by one of the complement C1q receptors, C1qRp, because this function was completely abrogated by the addition of an anti-C1qRp monoclonal antibody. These observations suggest that adiponectin is an important negative regulator in hematopoiesis and immune systems and raise the possibility that it may be involved in ending inflammatory responses through its inhibitory functions. (Blood. 2000;96:1723-1732)


Subject(s)
Cell Division/drug effects , Collagen/pharmacology , Hematopoietic Stem Cells/drug effects , Hyaluronan Receptors , Intercellular Signaling Peptides and Proteins , Macrophages/drug effects , Membrane Glycoproteins , Proteins/pharmacology , Adiponectin , Animals , Apoptosis/drug effects , Carrier Proteins , Cell Line , Colony-Forming Units Assay , Gene Expression Regulation/drug effects , HL-60 Cells , Hematopoietic Stem Cells/cytology , Humans , Jurkat Cells , K562 Cells , Leukemia, Myelomonocytic, Acute/pathology , Lipopolysaccharides/pharmacology , Macrophages/cytology , Macrophages/physiology , Mice , Mitochondrial Proteins , Phagocytosis/drug effects , Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/drug effects , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Messenger/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Cell Surface/metabolism , Receptors, Complement/metabolism , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , U937 Cells
18.
Arterioscler Thromb Vasc Biol ; 20(6): 1595-9, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10845877

ABSTRACT

Adiponectin is a novel, adipose-specific protein abundantly present in the circulation, and it has antiatherogenic properties. We analyzed the plasma adiponectin concentrations in age- and body mass index (BMI)-matched nondiabetic and type 2 diabetic subjects with and without coronary artery disease (CAD). Plasma levels of adiponectin in the diabetic subjects without CAD were lower than those in nondiabetic subjects (6.6+/-0.4 versus 7.9+/-0.5 microg/mL in men, 7.6+/-0.7 versus 11.7+/-1.0 microg/mL in women; P<0.001). The plasma adiponectin concentrations of diabetic patients with CAD were lower than those of diabetic patients without CAD (4.0+/-0.4 versus 6.6+/-0.4 microg/mL, P<0.001 in men; 6.3+/-0.8 versus 7.6+/-0. 7 microg/mL in women). In contrast, plasma levels of leptin did not differ between diabetic patients with and without CAD. The presence of microangiopathy did not affect the plasma adiponectin levels in diabetic patients. Significant, univariate, inverse correlations were observed between adiponectin levels and fasting plasma insulin (r=-0.18, P<0.01) and glucose (r=-0.26, P<0.001) levels. In multivariate analysis, plasma insulin did not independently affect the plasma adiponectin levels. BMI, serum triglyceride concentration, and the presence of diabetes or CAD remained significantly related to plasma adiponectin concentrations. Weight reduction significantly elevated plasma adiponectin levels in the diabetic subjects as well as the nondiabetic subjects. These results suggest that the decreased plasma adiponectin concentrations in diabetes may be an indicator of macroangiopathy.


Subject(s)
Diabetes Mellitus, Type 2/blood , Intercellular Signaling Peptides and Proteins , Proteins/analysis , Adiponectin , Adult , Blood Glucose/analysis , Body Mass Index , Coronary Disease/blood , Coronary Disease/complications , Diabetes Mellitus, Type 2/complications , Diabetic Angiopathies/blood , Fasting , Female , Humans , Insulin/blood , Leptin/analysis , Male , Middle Aged , Triglycerides/blood
20.
Arterioscler Thromb Vasc Biol ; 20(5): 1236-43, 2000 May.
Article in English | MEDLINE | ID: mdl-10807738

ABSTRACT

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), a member of the EGF family, has a potent mitogenic activity for vascular smooth muscle cells (SMCs). We previously reported that HB-EGF is involved in atherogenesis of human aorta and coronary arteries. ProHB-EGF (the membrane-anchored form of HB-EGF) has also been demonstrated to possess a mitogenic activity, which is approximately 30-fold increased when coexpressed with CD9 in mouse L cells. Thus, in the process of atherogenesis, CD9 may be involved in the proliferation of SMCs. We immunohistochemically investigated the localization of CD9 and proHB-EGF in the human aorta and coronary arteries. In normal aorta and coronary arteries, CD9 immunostaining was virtually negative, whereas proHB-EGF immunostaining was positive, especially in the arteries of babies. In contrast, in atherosclerotic lesions, some intimal SMCs were strongly positive for CD9 and proHB-EGF immunostaining. The juxtacrine growth activities of human aortic SMCs were inhibited in vitro by adding neutralization antibodies for CD9 or adding the specific inhibitor of HB-EGF. Besides, coexpressed CD9 and proHB-EGF cells markedly incorporated [(3)H]thymidine into the SMCs. CD9 is localized immunohistochemically in the SMCs of the atherosclerotic aorta and coronary arteries. CD9, when coexpressed with proHB-EGF, enhances proHB-EGF activities for SMC growth in a so-called juxtacrine manner in vitro and may be involved in atherogenesis.


Subject(s)
Antigens, CD/analysis , Arteriosclerosis/metabolism , Cell Division , Epidermal Growth Factor/metabolism , Membrane Glycoproteins , Muscle, Smooth, Vascular/pathology , Animals , Antigens, CD/pharmacology , Aorta/chemistry , Arteriosclerosis/pathology , Cells, Cultured , Coronary Vessels/chemistry , Epidermal Growth Factor/analysis , Heparin-binding EGF-like Growth Factor , Humans , Immunohistochemistry , Infant , Intercellular Signaling Peptides and Proteins , Mice , Tetraspanin 29
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