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PubMed2005

Insulin-like growth factor binding protein-5 (IGFBP-5) interacts with thrombospondin-1 to induce negative regulatory effects on IGF-I actions.

Insulin-like growth factor binding protein-5 (IGFBP-5) and thrombospondin-1 (TS-1) are both present in extracellular matrix (ECM). Both proteins have been shown to bind to one another with high affinity. The purpose of these studies was to determine how the interaction between IGFBP-5 and TS-1 modulates IGF-I actions in porcine aortic smooth muscle cells (pSMC) in culture. The addition of increasing concentrations of TS-1 to pSMC cultures enhanced the protein synthesis and cell migration responses to IGF-I; whereas the addition of IGFBP-5 alone resulted in minimal changes. In contrast, the addition of IGFBP-5 to cultures that were also exposed to IGF-I and TS-1 resulted in inhibition of protein synthesis. When the cell migration response was assessed, the response to IGF-I plus TS-1 was also significantly inhibited by the addition of IGFBP-5, whereas 1.0 microg/ml of IGFBP-5 alone had no effect on the response to IGF-I. To determine the molecular mechanism by which this inhibition occurred, a mutant form of IGFBP-5 that does not bind to IGF-I was tested. This mutant was equipotent compared to native IGFBP-5 in its ability to inhibit both protein synthesis and cell migration responses to IGF-I plus TS-1 thus excluding the possibility that IGFBP-5 was inhibiting the response to TS-1 and IGF-I by inhibiting IGF-I binding to the IGF-I receptor. To determine if an interaction between TS-1 and IGFBP-5 was the primary determinant of the inhibitory effect of IGFBP-5, an IGFBP-5 mutant that bound poorly to TS-1 was utilized. The addition of 1.0 microg/ml of this mutant did not inhibit the protein synthesis or cell migration responses to IGF-I plus TS-1. To determine the mechanism by which IGFBP-5 binding to TS-1 inhibited cellular responses to TS-1 plus IGF-I, TS-1 binding to integrin associated protein (IAP) was assessed. The addition of IGFBP-5 (1.0 microg/ml) inhibited TS-1-IAP association. In contrast, a mutant form of IGFBP-5 that bound poorly to TS-1 had a minimal effect on TS-1 binding to IAP. Further analysis showed that IGFBP-5 addition altered the ability of TS-1 to modulate the SHPS-1/IAP interaction. When the IGFBP-5 mutant that did not bind to IGF-I was incubated with TS-1 and IGF-I, it inhibited the capacity of TS-1 to enhance the IGF-I receptor phosphorylation and MAP kinase activation in response to IGF-I. In contrast, the IGFBP-5 mutant that did not bind to TS-1 had no effect on IGF-I stimulated IGF-I receptor phosphorylation or MAP kinase activation. These results indicate that IGFBP-5 inhibits the binding of TS-1 to IAP, and this results in an alteration of the ability of TS-1 to modulate the disruption of the IAP/SHPS-1 interaction which leads to attenuation of the ability of TS-1 to enhance cellular responsiveness to IGF-I.

Animals↗

PubMed2005

Enhanced extrastriate visual response to bandpass spatial frequency filtered fearful faces: time course and topographic evoked-potentials mapping.

We compared electrical brain responses to fearful vs. neutral facial expressions in healthy volunteers while they performed an orthogonal gender decision task. Face stimuli either had a broadband spatial-frequency content, or were filtered to create either low spatial-frequency (LSF) or high spatial-frequency (HSF) faces, always overlapped with their complementary SF content in upside-down orientation to preserve the total stimulus energy. We tested the hypothesis that the coarse LSF content of faces might be responsible for an early modulation of event-related potentials (ERPs) to fearful expressions. Consistent with previous findings, we show that broadband images of fearful faces, relative to neutral faces, elicit a higher global field power of approximately 130 ms poststimulus onset, corresponding to an increased P1 component over lateral occipital electrodes, with neural sources located within the extrastriate visual cortex. Bandpass filtering of faces strongly affected the latency and amplitude of ERPs, with a suppression of the normal N170 response for both LSF and HSF faces, irrespective of expression. Critically, we found that LSF information from fearful faces, unlike HSF information, produced a right-lateralized enhancement of the lateral occipital P1, without any change in the scalp topography, relative to unfiltered (broadband) fearful faces. These results demonstrate that an early P1 response to fear expression depends on a visual pathway preferentially tuned to coarse-magnocellular inputs, and can persist unchanged even when the N170 generators are disrupted by SF filtering.

Adult↗

PubMed1997

Utility of relative cerebral blood volume mapping derived from perfusion magnetic resonance imaging in the routine follow up of brain tumors.

It was recently demonstrated that imaging of brain tumors by relative cerebral blood volume (CBV) maps reconstructed from dynamic magnetic resonance (MR) data provide similar diagnostic information compared to positron emission tomography (PET) or 201Tl single-photon emission computerized tomography (201Tl-SPECT) scans. The authors used relative CBV mapping for routine follow-up evaluation of patients with brain tumors and compared its sensitivity to diagnostic MR imaging, 201Tl-SPECT and clinical assessment. Fifty-nine patients were prospectively followed using 191 concomitant studies of dual section relative CBV maps, MR imaging, 201Tl-SPECT, and neurological evaluations. Studies were repeated every 2 to 3 months (median three evaluations/patient). The relative CBV maps were graded as relative CBV 0 to 4, where Grades 3 and 4 are indicative of proliferating tumors (four = rapid leak). There were 44 high-grade and 15 low-grade tumors followed during treatment. During the follow-up period a change in relative CBV grade was observed in 56% of the patients, revealing an increasing grade in 72% of them. The rapid leak phenomenon was detected in 35% of all studies and in 81% of those with a worsening relative CBV grade. Tumor progression was detected earlier by relative CBV maps as follows: earlier than MR imaging in 32% of the studies (earlier by a median of 4.5 months; p < 0.01); earlier than 201Tl-SPECT in 63% (median 4.5 months; p < 0.01), and earlier than clinical assessment in 55% (median 6 months; p < 0.01). In 82% of studies with positive MR imaging but negative 201Tl-SPECT, the lesions were smaller than 1.5 cm. The relative CBV maps clearly delineated the appearance of rapid leak in these lesions. Routine use of relative CBV maps that can be implemented on any high-field MR unit and added to the regular MR evaluation provides useful functional information in patients with brain tumors. When used as an adjunct follow-up evaluation it proved more sensitive than the other modalities for early prediction of tumor growth. It is very sensitive to small regional changes, unlike functional imaging such as PET or SPECT scans. Based on previous experience with 76 regional CBV studies, the authors conclude that regional CBV mapping correlates with active tumor and it may separate enhancing scar and radiation injury from infiltrative tumor. A new effect named the rapid leak phenomenon was also observed; this phenomenon, as identified on the regional CBV maps, correlates with high malignancy.

Adolescent↗

PubMed2005

Multimodal in vivo optical imaging, including confocal microscopy, facilitates presurgical margin mapping for clinically complex lentigo maligna melanoma.

Knowledge of the accurate margins of a lentigo maligna melanoma (LMM) is crucial in the presurgical evaluation of the patient. Towards this end clinicians have utilized the Wood's lamp and dermoscopy to help delineate the borders of the LMM. However, many LMMs arise on photodamaged skin, making it difficult to determine the border of the LMM and separate it from the background lentiginous skin. We present a case of a patient with a recurrent LMM on the scalp that developed in a background of photodamage with diffuse melanocytic atypia and lentigines, making it virtually impossible to determine the precise margins of the LMM by clinical, Wood's lamp or dermoscopic examination. To avoid subjecting the patient to multiple staged excisions we attempted to determine the margins of the LMM by utilizing in vivo confocal laser scanning reflectance microscopy. Using this, it was apparent that there were increased numbers of atypical/dendritic intraepidermal melanocytes in all layers of the epidermis within the LMM. In contrast, skin not involved with the LMM, as viewed under confocal laser examination, had normal honeycomb architecture and no abnormal melanocytes. The confocally determined border was further confirmed by obtaining multiple punch biopsies that were evaluated by haematoxylin and eosin histology and immunohistochemistry. Based on this information, the presurgical margins were marked and the tumour excised accordingly. The excised tissue was examined with multiple-step sections and the margins were determined to be clear. There has been no evidence of tumour recurrence after 1 year. In conclusion, this case illustrates that confocal reflectance microscopy, in conjunction with other in vivo optical instruments, can be utilized to enhance the accuracy for the presurgical margin mapping of LMM.

Aged↗

PubMed1999

Serotonin stimulates mitogen-activated protein kinase activity through the formation of superoxide anion.

Our previous studies have shown that, through an active transport process, serotonin (5-HT) rapidly elevates O(-)(2). formation, stimulates protein phosphorylation, and enhances proliferation of bovine pulmonary artery smooth muscle cells (SMCs). We presently show that 1 microM 5-HT also rapidly elevates phosphorylation and activation of the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK) 1 and ERK2 of SMCs, and the enhanced phosphorylation is blocked by the antioxidants Tiron, N-acetyl-L-cysteine (NAC), and Ginkgo biloba extract. Inhibition of MAP kinase with PD-98059 failed to block enhanced O(-)(2). formation by 5-HT. Chinese hamster lung fibroblasts (CCL-39 cells), which demonstrate both 5-HT transporter and receptor activity, showed a similar response to 5-HT (i.e., enhanced mitogenesis, O(-)(2). formation, and ERK1 and ERK2 phosphorylation and activation). Unlike SMCs, they also responded to 5-HT receptor agonists. We conclude that downstream signaling of MAP kinase is a generalized cellular response to 5-HT that occurs secondary to O(-)(2). formation and may be initiated by either the 5-HT transporter or receptor depending on the cell type.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗

PubMed2002

EGFR and ErbB2 differentially regulate Raf-1 translocation and activation.

Epidermal growth factor receptor (EGFR) and HER-2/ErbB2 are members of the Erb family of signaling receptors. ErbB2 is overexpressed in many different cancers and has been linked to enhanced malignancy of tumors. We have examined the cellular translocation of Raf-1 during EGF-dependent signal transduction in two breast tumor cell lines, BT20 and SKBR3. Treatment of BT-20 breast cancer cells, which express EGFR, with EGF resulted in rapid (5 minutes) accumulation of EGFR and Raf-1 into plasma membrane-associated endocytotic vesicles. However, at later time points (30 minutes) only EGFR was endocytosed and Raf-1 dissociated from the plasma membrane and was found in the cytosol. In SKBR3 breast cancer cells, which express high levels of EGFR and ErbB2, treatment with EGF also resulted in rapid accumulation of EGFR and Raf-1 into endocytotic vesicles, but EGFR endocytosis was inhibited and Raf-1 remained associated with the plasma membrane for a prolonged period. The role of ErbB2 in the retention of Raf-1 at the plasma membrane was confirmed in BT-20 cells transfected with ErbB2. BT-20 cells expressing ErbB2 and treated with EGF retained Raf-1 at the plasma membrane for prolonged periods, whereas Raf-1 rapidly dissociated from the plasma membrane in EGF-stimulated cells transfected with a control vector. The presence of Raf-1 at the plasma membrane correlated with activation of Raf-1 and MAP kinase. Cells that expressed ErbB2 and treated with EGF showed prolonged activation of Raf-1 and MAP kinase compared with cells that expressed low levels of ErbB2. These results suggest that expression of ErbB2 promoted retention of Raf-1 in the plasma membrane, resulting in prolonged activation of the MAP kinase cascade, which may contribute to enhanced malignancy in ErbB2-expressing cancers.

Breast Neoplasms↗

PubMed2004

Manganese-enhanced magnetic resonance imaging (MEMRI) of brain activity and applications to early detection of brain ischemia.

Divalent manganese ion (Mn2+) has been reported to be a useful contrast agent for functional MRI, through a technique named activity-induced manganese-dependent MRI (AIM). In AIM, signal enhancement is related to functional increases in calcium influx, and therefore AIM is, thus far, the only MRI method able to map brain activation in vivo independently of the surrogate hemodynamic changes used in functional MRI. Because of its high signal-to-noise ratio (SNR) and high sensitivity, AIM allows the use of multi-slice or three-dimensional MRI techniques to map functional activity at high spatial resolution. In the present review, we define AIM as a functional MRI tool based on the administration of divalent ionized manganese through an open or disrupted blood-brain barrier (BBB). The adequacy and efficacy of AIM in detecting neural activation is described in light of supporting experiments on inhibition of calcium channels, FOS expression, and on direct comparison to BOLD- and perfusion-based functional MRI. Two main applications of AIM, mapping brain activation in rat somatosensory cortex, as well stroke research based on the well-established middle cerebral artery occlusion model, are described in detail. Methodological problems associated with a strong dependence on anesthetic conditions, potential corruption due to disruption of the BBB, and unspecific increase of the baseline signal due to acoustical noise are discussed. Finally, recommended preparation methods and experimental protocols for AIM are introduced.

Animals↗

PubMed1991

TPA-induced activation of MAP kinase.

Threonine and tyrosine residue phosphorylation of a 42 kDa protein identified as mitogen-activated protein kinase (MAP kinase) was stimulated in extracts from TPA-pretreated cells. It is further shown that TPA pretreatment leads to the enhancement of an activity that will induce reactivation of dephosphorylated/inactivated MAP kinase. This TPA-induced activity induces the threonine and tyrosine phosphorylation of p42 in extracts from unstimulated cells.

Amino Acid Sequence↗

PubMed2006

Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways.

Most heritable traits, including disease susceptibility, are affected by interactions between multiple genes. However, we understand little about how genes interact because very few possible genetic interactions have been explored experimentally. We have used RNA interference in Caenorhabditis elegans to systematically test approximately 65,000 pairs of genes for their ability to interact genetically. We identify approximately 350 genetic interactions between genes functioning in signaling pathways that are mutated in human diseases, including components of the EGF/Ras, Notch and Wnt pathways. Most notably, we identify a class of highly connected 'hub' genes: inactivation of these genes can enhance the phenotypic consequences of mutation of many different genes. These hub genes all encode chromatin regulators, and their activity as genetic hubs seems to be conserved across animals. We propose that these genes function as general buffers of genetic variation and that these hub genes may act as modifier genes in multiple, mechanistically unrelated genetic diseases in humans.

Animals↗

PubMed2000

CTGF expression is induced by TGF- beta in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis.

Connective tissue growth factor (CTGF) is a cysteine-rich protein induced by transforming growth factor beta (TGF- beta) in connective tissue cells. CTGF can trigger many of the cellular processes underlying fibrosis, such as cell proliferation, adhesion, migration and the synthesis of extracellular matrix; however, its role in acute and chronic cardiac injury is not fully understood. Here, we show that TGF- beta is a specific inducer of CTGF expression in both cardiac fibroblasts and cardiac myocytes. The activity of a CTGF promoter-based reporter construct correlated with endogenous CTGF expression, suggesting that TGF- beta induces CTGF expression most likely by activating its promoter. Upregulation of CTGF coincided with an increase in fibronectin, collagen type I and plasminogen activator inhibitor-1 production. Forskolin, a stimulator of cyclic AMP, blocked TGF- beta induced CTGF expression and reduced the basal level of CTGF, whereas an inhibitor that blocks the MAP kinase signaling pathway (PD 98059) significantly enhanced TGF- beta induced CTGF expression. Furthermore, we found that both TGF- beta and CTGF mRNAs were significantly elevated in the left ventricles and septa of rat hearts 2-16 weeks following myocardial infarction. This correlated well with concomitant increases in fibronectin, and type I and type III collagen mRNA levels in these animal hearts. Significant upregulation of CTGF was also detected in human heart samples derived from patients diagnosed with cardiac ischemia. Based on these findings, we propose that CTGF is an important mediator of TGF- beta signaling in the heart and abnormal expression of this gene could be used as a diagnostic marker for cardiac fibrosis.

Adult↗

PubMed1983

Skeletal muscle myosins from the yak (Bos grunniens), cattle (Bos taurus) and their hybrids.

The skeletal muscle myosins of the yak (Bos grunniens), of cattle (Bos taurus) and of their first and second filial generation hybrids have been studied by ATPase measurements, fluorescence spectroscopy, near-ultraviolet circular dichroism and peptide mapping on polyacrylamide gels. The ATPase activities, the intrinsic tryptophan fluorescence enhancement upon addition of ATP and the circular dichroism spectra of the four myosins were closely comparable. Peptide maps of the myosin heavy chains indicate extensive sequence homologies but do reveal differences between the myosins of the yak and cattle.

Adenosine Triphosphatases↗

PubMed1996

Influence of activated charcoal on the disposition kinetics of methamphetamine enantiomers in the rat following intravenous dosing.

Methamphetamine (MAP) is a central nervous system stimulant that is widely abused by populations of several countries. There is no specific antidote for the treatment of an overdose. Activated charcoal administered orally has been used to enhance the systemic elimination of certain toxic substances via "gastrointestinal dialysis". The results of in vitro studies have shown that MAP can be rapidly adsorbed from solution by activated charcoal. We have evaluated the effect of a single oral dose of activated charcoal on the disposition kinetics of MAP following a short iv infusion. Male Sprague-Dawley rats were given an oral dose of activated charcoal (Actidose-aqua, 1 g/kg) 10 min before a short iv infusion of racemic MAP; whereas the control group was given an equivalent volume of water. Enantiomers of MAP and metabolites in serum and urine were analyzed by an enantiomer-specific method which employed HPLC and detection of a fluorescent derivative. There were no differences in any of the disposition parameters between the two groups. Within each group, the clearance (CLs) of l-MAP was greater than that of d-MAP. However, there were no differences in the steady-state volume of distribution (Vss). The CLs (mL/(min kg)) and Vss (L/kg) values for l- and d-MAP in the control group were (mean +/- SD): 55.8 +/- 20.4, 48.7 +/- 17.9, 2.64 +/- 1.16, and 2.90 +/- 1.36, respectively. The corresponding values in the charcoal-pretreated group were (mean +/- SD): 57.4 +/- 23.4, 51.1 +/- 20.7, 2.79 +/- 1.32, and 2.98 +/- 1.47. These results suggest that oral activated charcoal does not enhance the elimination of MAP from the body.

Animals↗

PubMed2002

Glucocorticoids synergistically enhance nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase.

The recognition of invading microbes followed by the induction of effective innate immune response is crucial for host survival. Human surface epithelial cells are situated at host-environment boundaries and thus act as the first line of host defense against invading microbes. They recognize the microbial ligands via Toll-like receptors (TLRs) expressed on the surface of epithelial cells. TLR2 has gained importance as a major receptor for a variety of microbial ligands. In contrast to its high expression in lymphoid tissues, TLR2 is expressed at low level in epithelial cells. Thus, it remains unclear whether the low amount of TLR2 expressed in epithelial cells is sufficient for mediating bacteria-induced host defense and immune response and whether TLR2 expression can be up-regulated by bacteria during infection. Here, we show that TLR2, although expressed at very low level in unstimulated human epithelial cells, is greatly up-regulated by nontypeable Hemophilus influenzae (NTHi), an important human bacterial pathogen causing otitis media and chronic obstructive pulmonary diseases. Activation of an IKKbeta-IkappaBalpha-dependent NF-kappaB pathway is required for TLR2 induction, whereas inhibition of the MKK3/6-p38alpha/beta pathway leads to enhancement of NTHi-induced TLR2 up-regulation. Surprisingly, glucocorticoids, well known potent anti-inflammatory agents, synergistically enhance NTHi-induced TLR2 up-regulation likely via a negative cross-talk with the p38 MAP kinase pathway. These studies may bring new insights into the role of bacteria and glucocorticoids in regulating host defense and immune response and lead to novel therapeutic strategies for modulating innate immune and inflammatory responses for otitis media and chronic obstructive pulmonary diseases.

Bacterial Proteins↗

PubMed1985

DNA sequences responsible for tissue-specific expression of a chicken alpha-crystallin gene in mouse lens cells.

We have studied the DNA sequences required for high-level expression of a cloned chicken alpha-crystallin gene by introducing a hybrid alpha/delta-crystallin gene into nuclei of mouse lens epithelial cells in primary culture. The level of transient expression of the hybrid gene consisting of the 5' upstream promoter region of the alpha-crystallin gene fused to the structural portion of the delta-crystallin gene was determined by Western blot analysis using anti-delta-crystallin serum. The hybrid gene appears to be expressed in a tissue-specific manner, since it is active in mouse lens cells but not in fibroblasts or in L cells. The DNA sequences located 242-189 bp upstream from the transcription initiation site are required for high-level expression in lens cells. They are active when their orientation is reversed at the original site or when placed approximately 1.7 kbp downstream from the cap site in the second intron of the hybrid gene in either orientation. When these DNA sequences were replaced by the enhancer sequences of Moloney murine leukemia virus, the hybrid gene was expressed in both lens cells and fibroblasts.

Animals↗

PubMed1999

Isolation and radiation hybrid mapping of a highly polymorphic CA repeat sequence at the SREBP cleavage-activating protein (SCAP) locus.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a central regulator of lipid synthesis and uptake in animal cells. A polymorphic dinucleotide (CA) repeat sequence was isolated from a genomic clone containing the SCAP gene and was mapped to chromosome 3p21.3. High heterozygosity (0.89) makes this polymorphism a useful marker in the genetic study of disorders affecting lipid metabolism.

CCAAT-Enhancer-Binding Proteins↗

PubMed2003

A wavelet-based spatially adaptive method for mammographic contrast enhancement.

A method aimed at minimizing image noise while optimizing contrast of image features is presented. The method is generic and it is based on local modification of multiscale gradient magnitude values provided by the redundant dyadic wavelet transform. Denoising is accomplished by a spatially adaptive thresholding strategy, taking into account local signal and noise standard deviation. Noise standard deviation is estimated from the background of the mammogram. Contrast enhancement is accomplished by applying a local linear mapping operator on denoised wavelet magnitude values. The operator normalizes local gradient magnitude maxima to the global maximum of the first scale magnitude subimage. Coefficient mapping is controlled by a local gain limit parameter. The processed image is derived by reconstruction from the modified wavelet coefficients. The method is demonstrated with a simulated image with added Gaussian noise, while an initial quantitative performance evaluation using 22 images from the DDSM database was performed. Enhancement was applied globally to each mammogram, using the same local gain limit value. Quantitative contrast and noise metrics were used to evaluate the quality of processed image regions containing verified lesions. Results suggest that the method offers significantly improved performance over conventional and previously reported global wavelet contrast enhancement methods. The average contrast improvement, noise amplification and contrast-to-noise ratio improvement indices were measured as 9.04, 4.86 and 3.04, respectively. In addition, in a pilot preference study, the proposed method demonstrated the highest ranking, among the methods compared. The method was implemented in C++ and integrated into a medical image visualization tool.

Algorithms↗

PubMed1999

Endothelin-1 activates p38 mitogen-activated protein kinase and cytosolic phospholipase A2 in cat iris sphincter smooth muscle cells.

We have shown previously that cytosolic phospholipase A(2) (cPLA(2)) is responsible for endothelin-1-induced release of arachidonic acid for prostaglandin synthesis in cat iris sphincter smooth muscle (CISM) cells [Husain and Abdel-Latif (1998) Biochim. Biophys. Acta 1392, 127-144]. Here we show that p38 mitogen-activated protein (MAP) kinase, but not p42/p44 MAP kinases, plays an important role in the phosphorylation and activation of cPLA(2) in endothelin-1-stimulated CISM cells. This conclusion is supported by the following findings. Both p38 MAP kinase and p42/p44 MAP kinases were present in the CISM cells and both were activated by endothelin-1. SB203580, a potent specific inhibitor of p38 MAP kinase, but not the p42/p44 MAP kinases specific inhibitor, PD98059, markedly suppressed endothelin-1-enhanced cPLA(2) phosphorylation, cPLA(2) activity and arachidonic acid release. The addition of endothelin-1 resulted in the phosphorylation and activation of cPLA(2). Endothelin-1 stimulated p38 MAP kinase activity in a time- and concentration-dependent manner, and these effects were mediated through the endothelin-A receptor subtype. The protein kinase C (PKC) inhibitor, RO 31-8220, had no inhibitory effect on endothelin-1-induced p38 MAP kinase activation, suggesting that endothelin-1 activation of p38 MAP kinase is independent of PKC. Pertussis toxin inhibited both endothelin-1 and mastoparan stimulation of p38 MAP kinase activity and arachidonic acid release. The inhibitory effects of pertussis toxin are not mediated through cAMP formation. Mastoparan-stimulated [(3)H]arachidonic acid release and cPLA(2) activation was inhibited by SB203580, but not by RO 31-8220. These data suggest that endothelin-1 binds to the endothelin-A receptor to activate the Gi-protein which, through a series of kinases, leads to the activation of p38 MAP kinase and subsequently to phosphorylation and activation of cPLA(2). Activation of cPLA(2) leads to the liberation of arachidonic acid from membrane phospholipids. The ability of the activated endothelin-A receptor, which is coupled to both Gq- and Gi-proteins, to recruit and activate this complex signal transduction pathway remains to be elucidated. Further studies on the mechanism of these relationships could provide important information about the functions of p38 MAP kinase in smooth muscle.

Animals↗

PubMed2006

Perfusion, diffusion and spectroscopy values in newly diagnosed cerebral gliomas.

PURPOSE: To evaluate perfusion, diffusion, and spectroscopy values in enhancing and non-enhancing lesions for patients with newly diagnosed gliomas of different grades. MATERIALS AND METHODS: Sixty-seven patients with newly diagnosed glioma were entered into the study 20 grade II, 26 grade III and 21 grade IV. MR data were acquired at 1.5T and included diffusion weighted images (59/67 patients), dynamic perfusion weighted images (30/67 patients) and 3D H-1 MR spectroscopy (64/67 patients). Enhancing and non-enhancing lesions were delineated by a neuroradiologist and applied to maps of relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC), relative anisotropy (RA) and metabolite intensities. RESULTS: The median rCBV within enhancing regions of grade IV gliomas was significantly elevated relative to enhancing regions in grade III gliomas and normal brain. ADC was elevated relative to normal brain, but was not significantly different between grades or between enhancing and non-enhancing regions. The RA was higher in the non-enhancing region of grade IV gliomas relative to grade II and grade III. Levels of lactate plus lipid were significantly elevated in grade IV relative to grade II and grade III gliomas. Both enhancing and non-enhancing regions in grade IV gliomas showed significant correlations between CBV, ADC and choline levels. CONCLUSION: The data were consistent with grade IV gliomas having higher membrane turnover, increased cell density and increased vascularity within enhancing lesions. Analysis of the correlations among parameters within grade IV gliomas suggested that high vascularity (high rCBV) was correlated with increased cellularity (low ADC) and increased membrane turnover (high choline) in these lesions. The non-enhancing region of grades II and III gliomas had MR parameters consistent with increased cellularity and/or membrane turnover.

Adult↗