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At least 793 records · Page 44Linked to original sources
PubMed2006

Trans-10, cis-12 conjugated linoleic acid causes inflammation and delipidation of white adipose tissue in mice: a microarray and histological analysis.

A combined histological and microarray analysis of the white adipose tissue (WAT) of mice fed trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) was performed to better define functional responses. Mice fed t10c12 CLA for 14 days lost 85% of WAT mass, 95% of adipocyte lipid droplet volume, and 15 or 47% of the number of adipocytes and total cells, respectively. Microarray profiling of replicated pools (n = 2 per day x diet) of control and treated mice (n = 140) at seven time points after 1-17 days of t10c12 CLA feeding found between 2,682 and 4,216 transcript levels changed by twofold or more. Transcript levels for genes involved in glucose and fatty acid import or biosynthesis were significantly reduced. Highly expressed transcripts for lipases were significantly reduced but still abundant. Increased levels of mRNAs for two key thermogenesis proteins, uncoupling protein 1 and carnitine palmitoyltransferase 1, may have increased energy expenditures. Significant reductions of mRNAs for major adipocyte regulatory factors, including peroxisome proliferator activated receptor-gamma, sterol regulatory binding protein 1, CAAT/enhancer binding protein-alpha, and lipin 1 were correlated with the reduced transcript levels for key metabolic pathways in the WAT. A prolific inflammation response was indicated by the 2- to 100-fold induction of many cytokine transcripts, including those for IL-6, IL-1beta, TNF ligands, and CXC family members, and an increased density of macrophages. The mRNA changes suggest that a combination of cell loss, increased energy expenditure, and residual transport of lipids out of the adipocytes may account for the cumulative mass loss observed.

Adipocytes↗
PubMed2004

Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells: association with distinct malignant phenotypes.

Molecular mechanisms active in transforming human pleural cells remain incompletely understood. Our previous microarray analysis of malignant pleural mesothelioma revealed alterations in components of the insulin-like growth factor (IGF) system, implicating this signaling axis in tumorigenesis. Therefore, in this current study, we characterized the molecular phenotype and investigated the key signaling pathways of the IGF system in malignant pleural mesothelioma specimens. For the major IGF components, we assessed mRNA abundance and total protein levels. We measured IGF-I ligand-dependent activation of signaling pathways downstream of the type I IGF receptor in a subset of malignant pleural mesothelioma cell lines and determined the corresponding biological consequences. At the transcriptional level, we observed consistent changes in IGF components that may contribute to a malignant phenotype. IGF-I stimulation of cells resulted in enhanced activation of type I IGF receptor and IRS adaptor proteins. Differential activation of IRS-1 signaling was associated with cell growth, whereas IRS-2 signaling was associated with cell motility. Thus, these data suggest that multiple mechanisms likely contribute to malignant pleural mesothelioma tumorigenesis. Therefore, IGF system components represent novel malignant pleural mesothelioma therapeutic targets for investigation.

Cell Line, Transformed↗
PubMed2006

Two transforming C-RAF germ-line mutations identified in patients with therapy-related acute myeloid leukemia.

Mutations leading to activation of the RAF-mitogen-activated protein kinase/extracellular signal-regulated (ERK) kinase (MEK)-ERK pathway are key events in the pathogenesis of human malignancies. In a screen of 82 acute myeloid leukemia (AML) samples, 45 (55%) showed activated ERK and thus were further analyzed for mutations in B-RAF and C-RAF. Two C-RAF germ-line mutations, S427G and I448V, were identified in patients with therapy-related AML in the absence of alterations in RAS and FLT3. Both exchanges were located within the kinase domain of C-RAF. In vitro and in vivo kinase assays revealed significantly increased activity for (S427G)C-RAF but not for (I448V)C-RAF. The involvement of the S427G C-RAF mutation in constitutive activation of ERK was further confirmed through demonstration of activating phosphorylations on C-RAF, MEK, and ERK in neoplastic cells, but not in nonneoplastic cells. Transformation and survival assays showed oncogenic and antiapoptotic properties for both mutations. Screening healthy individuals revealed a <1/400 frequency of these mutations and, in the case of I448V, inheritance was observed over three generations with another mutation carrier suffering from cancer. Taken together, these data are the first to relate C-RAF mutations to human malignancies. As both mutations are of germ-line origin, they might constitute a novel tumor-predisposing factor.

Acute Disease↗
PubMed2005

SV40-dependent AKT activity drives mesothelial cell transformation after asbestos exposure.

Human malignant mesothelioma is an aggressive cancer generally associated with exposure to asbestos, although SV40 virus has been involved as a possible cofactor by a number of studies. Asbestos fibers induce cytotoxicity in human mesothelial cells (HMC), although cell survival activated by key signaling pathways may promote transformation. We and others previously reported that SV40 large T antigen induces autocrine loops in HMC and malignant mesothelioma cells, leading to activation of growth factor receptors. Now we show that SV40 induces cell survival via Akt activation in malignant mesothelioma and HMC cells exposed to asbestos. Consequently, prolonged exposure to asbestos fibers progressively induces transformation of SV40-positive HMC. As a model of SV40/asbestos cocarcinogenesis, we propose that malignant mesothelioma originates from a subpopulation of transformed stem cells and that Akt signaling is a novel therapeutic target to overcome malignant mesothelioma resistance to conventional therapies.

Apoptosis↗
PubMed2006

Immortalization of primary endothelial cells by the K1 protein of Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to three different human cancers: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The Kaposi's sarcoma lesion expresses high levels of angiogenic factors and is comprised of a mixed cell population, including endothelial cells that are infected with KSHV. We find that the KSHV K1 protein is expressed in Kaposi's sarcoma lesions and can immortalize and extend the life span of primary human umbilical vein endothelial cells in culture. Vascular endothelial growth factor (VEGF) is critical for the survival of endothelial cells, and we show that expression of K1 in endothelial cells resulted in increased levels of secreted VEGF and the activation of key signaling pathways, including the VEGF/VEGF receptor and the phosphatidylinositol-3'-OH-kinase (PI3K) pathway. The SH2 binding motifs present in the cytoplasmic tail of K1 were critical for K1's ability to activate these pathways. Activation of PI3K by K1 results in activation of Akt kinase and mammalian target of rapamycin and inactivation of the proapoptotic proteins FKHR, glycogen synthase kinase-3, and Bad, which are events indicative of cell survival. Because activation of the PI3K pathway is critical for transformation of many human cells, we suggest that PI3K activation by K1 is involved in endothelial cell immortalization and contributes to KSHV-associated tumorigenesis. We also report that K1 enhances angiogenesis in vivo and increases tumor vasculature and tumor size.

Animals↗
PubMed2004

Serum insulin-like growth factor-I is positively associated with serum prostate-specific antigen in middle-aged men without evidence of prostate cancer.

We have examined the relationship between serum insulin-like growth factor-I (IGF-I) and prostate-specific antigen in 367 healthy men without evidence of prostate cancer and found a positive association (P = 0.05). In men without prostate cancer, serum prostate-specific antigen is closely related to prostate size, and our findings, therefore, suggest that IGF-I may induce prostatic epithelial proliferation. Higher circulating levels of IGF-I have been associated with increased risk of both prostate cancer and possibly benign prostatic hyperplasia. Greater rates of cell proliferation induced by IGF-I may be a key biological pathway underlying these disorders.

Age Distribution↗
PubMedDate not supplied

The carotid compression test for therapeutic occlusion of the internal carotid artery. Comparison of angiography with transcranial Doppler sonography.

BACKGROUND: The anterior communicating artery is a key collateral pathway in patients with internal carotid artery (ICA) occlusions. Diagnostic balloon or manual occlusion of the ICA is a qualified test for the collateral function of the circle of Willis. The aim of our study was to test whether transcranial Doppler sonography (TCD) with manual carotid compression is able to predict the degree of cross-over flow and tolerance of ICA occlusion. METHODS: A prospective study was performed on 88 patients suffering from neck tumors or inoperable ICA aneurysms with planned ligation or permanent balloon occlusion of the ICA. Preceding a balloon occlusion lasting 20 min we performed TCD with manual carotid compression test. Insufficient cross-over flow during transient carotid occlusion was defined angiographically as missing opacification of the middle cerebral artery (MCA) after selective injection of contrast media in the contralateral ICA, and sonographically as a decrease greater than 60% in flow velocity of the MCA ipsilateral to the carotid occlusion. RESULTS: TCD and angiography could be compared in 70 of 88 patients. Angiography showed no or insufficient collateral flow in 26%. All patients (n = 10) with a decrease in MCA velocity greater than 60% on angiography showed missing or poor cross-over flow. A greater than 50% increase in the anterior cerebral artery (ACA) predicted moderate or good cross-over flow in 98%. Clinical observation revealed 11 transient neurological deficits. Eight of them showed insufficient cross-over flow angiographically and sonographically. In 2 of 11 only TCD revealed such low collateral supply. Neither technique predicted hemodynamic ischemia in only 1 of the 11. CONCLUSION: TCD with carotid compression test is a valid method for predicting interhemispheric flow and clinically relevant hemodynamic compromise in cases of occlusion of the ICA.

Aneurysm↗
PubMed2002

Alterations of cell cycle-regulatory genes in prostate cancer.

Deregulated proliferation is one of the main events in neoplastic transformation, and this has prompted increased attention being given to the understanding of the mechanisms involved in cell cycle regulation and its alterations. The 'retinoblastoma pathway', a key effector controlling G1-S phase transition, includes several oncogenes and tumour suppressor genes which display a wide range of abnormalities with potential usefulness as markers of evolution or treatment response in prostate cancer. Among these, the existence of p53 mutations seems to predict resistance to radiotherapy or systemic treatment, and p16 overexpression or p27 downregulation seems to serve as markers of poor evolution. The well-established existence of a critical hormonal role in prostate carcinogenesis coupled with the relationship of androgenic activity and regulation of several cell cycle modulators forces cell cycle control in the prostate to be envisioned as a highly complex steroid-influenced system, which will undoubtedly have critical implications in the future management of prostate cancer patients.

Carcinoma↗
PubMed2004

Genetic and genomic approaches to study placental development.

Recent technological advances in genetic manipulation and expression profiling offer excellent opportunities to elucidate the molecular mechanisms controlling developmental processes during embryogenesis. Thus, this revolution also strongly benefits studies of the molecular genetics of placental development. Here we review the findings of several expression profiling analyses in extraembryonic tissues and assess how this work can contribute to the identification of essential components governing placental development. We further discuss the relevance of these components in the context of genetic manipulation experiments. In conclusion, the intelligent combination of genetic and genomic approaches will substantially accelerate the progress in identifying the key molecular pathways of placental development.

Animals↗
PubMed2005

Adrenomedullin impairs the profibrotic effects of transforming growth factor-beta1 through recruiting Smad6 protein in human renal tubular cells.

Adrenomedullin (AM) was originally identified as a vasodilator peptide, and has recently been shown to be an antiproliferative factor in renal mesangial cells, suggesting that adrenomedullin may impair the progression of glomerulosclerosis. This study was to investigate the effect of adrenomedullin on transforming growth factor-beta1 (TGF-beta1)-stimulated cell growth, synthesis of extracellular matrix (ECM) components and the related molecular mechanism in a human tubular epithelial cell line HK-2. TGF-beta1 inhibited cell proliferation induced by fetal bovine serum, but neither AM itself affectted cell proliferation, nor did AM influence TGF-beta1-caused cell growth arrest. However, AM beginning at 10(-8) M alleviated the action of TGF-beta1-stimulated cellular collagen synthesis and secretion of fibronectin into cell culture supernatant. Activation of Smad proteins is known to be the key signaling pathway of the profibrotic effect of TGF-beta1, AM at 10(-8) M exerted no effect on TGF-beta1-induced Smad2 phosphorylation, but prevented the suppression of the inhibitory Smad6 protein by TGF-beta1 and restored Smad2-Samd6 complex formation. Our results suggest that AM can attenuate TGF-beta1-mediated renal tubulointerstitial ECM turnover via an antagonistic mechanism of inhibitory Smad in TGF-beta1-elicited signaling.

Adrenomedullin↗
PubMed1982

A Histochemical study of the coronary vasculature in euthyroid and hyperthyroid rats.

Coronary arteries and arterioles in the left and right ventricles from normal and hyperthyroid rats were examined histochemically to determine and to compare their metabolic activities. The test animals were made hyperthyroid by administration of desiccated thyroid for 8-10 weeks. Using histochemical techniques, selected enzymes and components of key metabolic pathways were examined. These pathways included an evaluation of aerobic (oxidative phosphorylation, Kreb's cycle and respiratory chain) and anaerobic metabolic capacity, hexose-monophosphate shunt activity, amounts of deoxyribonucleic and ribonucleic acids present and activity of beta-oxidation of fatty acids. Our results indicate that normal coronary arteriolar metabolism is predominantly aerobic. The findings also suggest a reduction in aerobic metabolism with an accompanying increase in anaerobic potential in the hyperthyroid coronary arterioles. Thus, during thyrotoxicosis, the coronary arterioles may partially shift from aerobic to anaerobic metabolism. Moreover, in both the normal and thyrotoxic rat heart, the coronary microvasculature appears quite stable with little cell proliferation. In contrast, both the control and hyperthyroid rat coronary arteries appear to utilize primarily anaerobic pathways, while the control and hyperthyroid myocardium seem highly dependent upon aerobic metabolism. The tremendous reduction in glucose-6-phosphate dehydrogenase activity in hyperthyroid, when compared to normal coronary arteries and some larger arterioles, implies a reduced capacity for nucleic acid and protein synthesis in the test animals.

Animals↗
PubMed1985

Metabolism of coronary vasculature in euthyroid, hyperthyroid and recovering hyperthyroid rats: a histochemical study.

Coronary arteries and arterioles from normal rats, from rats made hyperthyroid by administration of desiccated thyroid for 10 weeks, and from hyperthyroid rats which were then fed normal control diets for 10 weeks, were examined histochemically to determine the activity of key metabolic pathways. The primary aims of this study were to determine if the alterations in particular enzyme and substrate activities that occur in thyrotoxic rat myocardium, arteries and arterioles were reversible and would return to normal levels following cessation of the hyperthyroid state. Our results suggest that hyperthyroid rats, even after 10 weeks on the normal diet, still show some compromise in arteriolar aerobic metabolism in favor of anaerobic pathways, while coronary arteries still demonstrate little glucose-6-phosphate dehydrogenase activity. Myocardial metabolic activity approximates that of normal control animals by the end of the 10th week on the normal diet.

Animals↗
PubMedDate not supplied

A histochemical study of cerebral cortical vessels and ganglionic vessels of the caudatoputamen in aging normotensive rats.

The goal was to describe the metabolic profile of ganglionic and cortical arteries and arterioles in aging normotensive male rats. Five enzymes indicative of key metabolic pathways in the vessel walls were semiquantitatively evaluated using bright-field histochemical microscopy. Lactate dehydrogenase showed significant reactivity which increased with vessel diameter in cortical and ganglionic vessels in all age groups tested. Succinate dehydrogenase and cytochrome oxidase showed little reactivity in both cortical and ganglionic vessels, suggesting a reduced role for aerobic metabolic pathways. Myosin ATPase reactivity was high in cortical and ganglionic vessels. Only this enzyme showed an increased reactivity that was correlated with the age and diameter of the vessel. Glucose-6-phosphate dehydrogenase reactivity was more pronounced in cortical than ganglionic vessels, suggesting that the hexose-monophosphate-shunt may be more active in the cortical vessels. There were no regional differences in enzyme reactivity throughout the caudatoputamen. In conclusion, both the cortical and ganglionic vessels are metabolically active, with significant anaerobic glycolysis, and reduced, but observable capacity for aerobic metabolism. The decreased myosin ATPase reactivity and the low level of glucose-6-phosphate dehydrogenase reactivity in the ganglionic arterioles of senescent rats may contribute to the susceptibility of these vessels to cerebrovascular accidents.

Adenosine Triphosphatases↗
PubMed2004

Inhaled carbon monoxide confers antiinflammatory effects against ventilator-induced lung injury.

Ventilator-induced lung injury (VILI) is a major cause of morbidity and mortality in intensive care units. The stress-inducible gene product, heme oxygenase-1, and carbon monoxide (CO), a major by-product of heme oxygenase catalysis of heme, have been shown to confer potent antiinflammatory effects in models of tissue and cellular injury. In this study, we observed increased expression of heme oxygenase-1 mRNA and protein in a rat model of VILI. To assess the physiologic function of heme oxygenase-1 induction in VILI, we determined whether low concentration of inhaled CO could serve to protect the lung against VILI. Low concentration of inhaled CO significantly reduced tumor necrosis factor-alpha levels and total cell count in lavage fluid, while simultaneously elevating levels of antiinflammatory interleukin-10 levels. To better characterize the mechanism of CO-mediated antiinflammatory effects, we examined key signaling pathways, which may mediate CO-induced antiinflammatory effects. We demonstrate that inhaled CO exerts antiinflammatory effects in VILI via the p38 mitogen-activated protein kinase pathway but independent of activator protein-1 and nuclear factor-kappaB pathways. Our data lead to a tempting speculation that inhaled CO might be useful in minimizing VILI.

Administration, Inhalation↗
PubMed1999

Glucocorticoids inhibit proliferation, cyclin D1 expression, and retinoblastoma protein phosphorylation, but not activity of the extracellular-regulated kinases in human cultured airway smooth muscle.

We have previously shown that glucocorticoids inhibit mitogen-stimulated proliferation of human cultured airway smooth muscle (ASM) cells. The present study analyzed the effect of glucocorticoids on key regulatory pathways leading to passage of cells through the restriction point of the cell cycle, including those mediated by extracellular-regulated kinases (ERK) 1 and 2; the ERK upstream regulator MAPK kinase (MEK1); cyclin D1 levels; and levels and phosphorylation of retinoblastoma protein (pRb). Fluticasone propionate, a new inhaled glucocorticoid, was at least 10-fold more potent than dexamethasone in inhibiting thrombin-stimulated DNA synthesis and increases in cell number. Thrombin-stimulated increases in the levels and hyperphosphorylation of pRb were inhibited by glucocorticoids, which also reduced thrombin-stimulated cyclin D1 protein and messenger RNA (mRNA) levels. PD98059 (10 microM), an inhibitor of MEK1 activation, markedly attenuated thrombin stimulation of ERK activity and phosphorylation, DNA synthesis, and cyclin D1 levels. However, glucocorticoids had no effect on ERK activity or phosphorylation at 5 min, 2 h, or 12 h after addition of thrombin. In conclusion, glucocorticoid-induced reduction of cyclin D1 mRNA and protein levels, and of pRb phosphorylation, is sufficient to account for inhibition of ASM proliferation. Furthermore, these inhibitory effects of glucocorticoids on cyclin D1 and pRb occur on a component of the mitogen signaling cascade that is either downstream of or parallel to the ERK pathway.

Androstadienes↗
PubMed2006

The proteome of central and peripheral retina with progression of age-related macular degeneration.

PURPOSE: A growing understanding of the molecular events in age-related macular degeneration (AMD) has lead to targeted therapies for a select group of patients with advanced AMD. Development of therapies for the earlier stages requires further elucidation of disease mechanisms. In this study, a proteomics approach was used to identify proteins that had altered content in human donor eyes with progression of AMD. METHODS: The early molecular events associated with AMD were identified by comparing the proteome of the macular and peripheral neurosensory retina during four progressive stages of AMD. Proteins were resolved and quantified by two-dimensional gel electrophoresis. Twenty-six proteins exhibited changes in content and were identified by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. Two-dimensional (2-D) and semiquantitative one-dimensional (1-D) Western blot analyses were used to determine whether changes identified by proteomic analysis were specific for a protein subpopulation or representative of the entire protein population. RESULTS: Twenty-six proteins were identified that exhibited changes at disease onset or with progression (indicating potential causal mechanisms) and at end-stage disease (indicating potential secondary consequences). These proteins are involved in key functional pathways, such as microtubule regulation and protection from stress-induced protein unfolding. Approximately 60% of the proteins exhibited changes specific to either the macula or periphery, with the remaining 40% changing in both regions. These results imply that both the macula and periphery are affected by AMD. CONCLUSIONS: This study provides the first direct evidence of AMD stage- and region-specific changes in retinal protein levels and highlights potential novel, disease-related proteins and biochemical pathways for future studies of AMD.

Adult↗
PubMed2005

Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis.

Joint ankylosis is a major cause of disability in the human spondyloarthropathies. Here we report that this process partially recapitulates embryonic endochondral bone formation in a spontaneous model of arthritis in DBA/1 mice. Bone morphogenetic protein (BMP) signaling appears to be a key molecular pathway involved in this pathological cascade. Systemic gene transfer of noggin, a BMP antagonist, is effective both as a preventive and a therapeutic strategy in the mouse model, mechanistically interfering with enthesial progenitor cell proliferation in early stages of the disease process. Immunohistochemical staining for phosphorylated smad1/5 in enthesial biopsies of patients with spondyloarthropathy reveals active BMP signaling in similar target cells. Our data suggest that BMP signaling is an attractive therapeutic target for interfering with structural changes in spondyloarthropathy either as an alternative or complementary approach to current antiinflammatory treatments.

Animals↗
PubMed2004

Status and prospects of in vitro tests in risk assessment.

According to the new chemicals policy of the European Union (EU), most chemicals, i.e. the 20,000 chemicals manufactured or imported at 1-10 tons annually, should be tested primarily by using in vitro methods. Also, for other chemicals, the use of in vitro methods is encouraged in the testing strategies given in the draft EU legislation. However, the validation and international acceptance of in vitro tests has been slow. Only recently has the OECD approved four new in vitro test methods, validated by the European Centre for the Validation of Alternative Methods. An analysis of ten randomly selected risk assessment reports of the EU Existing Chemicals Risk Assessment Programme showed that in vitro studies, for example, on cytotoxicity to different cell cultures, cell transformation, metabolism and skin penetration (a total of 115 studies) were used for the assessments. Key metabolic pathways and mechanisms of toxicity have been elucidated, for some chemicals, by using in vitro methods. On the other hand, the results of in vitro studies were regarded as secondary or unreliable in some cases. For several toxic endpoints, in vitro methods will probably serve as screening tools and for mechanistic studies, while target organ toxicity or physiologically regulated adverse effects caused by long-term exposure are difficult to observe without the use of animal models.

Animal Testing Alternatives↗