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Biomedical subjects

H Ali

Publications and source records attributed to H Ali.

At least 37 records · Page 2Linked to original sources
PubMed2000

Stimulation of colorectal cancer cell line growth by ET-1 and its inhibition by ET(A) antagonists.

BACKGROUND: The vasoactive peptide endothelin 1 (ET-1) acts via two receptors, endothelin receptors A (ET(A)) and B (ET(B)). ET-1 is overexpressed by human cancers in vivo and in vitro and may be mitogenic for cancer cells. METHOD: To elucidate if ET-1 is a growth regulator the following were investigated in human colorectal cancer cell lines (LIM1215 and HT29): ET-1 production by ELISA; ET receptor expression using radioligand autoradiographic techniques; and responsiveness to ET-1, and to ET(A) and ET(B) antagonism by growth measurements. RESULTS: ET-1 was produced by LIM1215 and HT29 cells (21.3 and 41.7 fmol/ml/10(6) cells (24 hours); 22.6 and 71.7 fmol/ml/10(6) cells (48 hours), respectively). ET(A) and ET(B) receptors were expressed by both cell lines. Addition of ET-1 resulted in a dose dependent increase in cell numbers which was significant at 10(-8)-10(-9) M for LIM1215, with the greatest increase at 10(-8) M (32.7% and 28.4% increase above controls at 48 hours and 72 hours; p<0.05) and at 10(-8)-10(-9) M for HT29, with the greatest increase at 10(-9) M (13.4% and 15.7% increase above controls at 48 hours and 72 hours; p<0.05). ET(A) antagonists BQ123 and BQ610, but not the ET(B) antagonist BQ788, inhibited ET-1 induced proliferation of both LIM1215 and HT29 (p<0.05). CONCLUSION: ET-1 can stimulate the proliferation of colorectal cancer cell lines via the ET(A), but not the ET(B), receptor.

Cell Division↗
PubMed2000

Scintimammography with 11beta-methoxy-(17alpha,20Z)-[123I]iodovinylestrad iol: a complementary role to 99mTc-methoxyisobutyl isonitrile in the characterization of breast tumors.

UNLABELLED: The aim of this study was to investigate a possible relationship between 99mTc-methoxyisobutyl isonitrile (MIBI) uptake and the estrogen receptor (ER) status of breast tumors as determined by 11beta-methoxy-(17alpha,20Z)-[123I]iodovinylestradi ol (MIVE) scintimammography. METHODS: Thirteen patients referred for MIVE scintimammography after abnormal mammography or finding of a suspect mass on physical examination were injected intravenously with MIVE. Planar images of the breasts and axillary region were taken with both radiopharmaceuticals and compared with pathologic examination of the tumor tissue and in vitro ER quantification. RESULTS: The presence of cancerous tissue, as indicated by MIBI uptake, is a prerequisite for the accumulation of MIVE by the breast tumors. There was no statistically significant correlation between the MIBI and MIVE tumor uptake ratios. However, the latter correlate well with the presence of ER, as determined by an in vitro assay. CONCLUSION: MIVE scans add unique information concerning the tumor ER status in breast cancer patients, which could contribute to a better characterization of the tumor and aid in the selection of the most appropriate treatment protocol.

Adult↗
PubMed2000

Chemotherapy in advanced nasopharyngeal cancer.

Chemotherapy is an integral part of treatment for patients with nasopharyngeal carcinoma. Chemotherapy can achieve long-term survival rates of up to 15% to 20%, even in patients with recurrent or metastatic disease. In the majority of studies reported, patients with previously untreated locally advanced stage III and IV nasopharyngeal carcinoma showed improved local control, decreased systemic metastasis, and improved disease-free and overall survival when treated with cisplatin (Platinol)-based combination chemotherapy in conjunction with radiotherapy. In prospective, randomized, phase III trials, concurrent chemoradiotherapy, followed by adjuvant chemotherapy, significantly improved local control, systemic control, and progression-free and overall survival. The authors believe that different sequences of treatment modalities and newer chemotherapy agents need to be investigated in the future.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Chemoattractant receptors activate distinct pathways for chemotaxis and secretion. Role of G-protein usage.

Human leukocyte chemoattractant receptors activate chemotactic and cytotoxic pathways to varying degrees and also activate different G-proteins depending on the receptor and the cell-type. To determine the relationship between G-protein usage and the biological and biochemical responses activated, receptors for the chemoattractants formyl peptides (FR), platelet-activating factor (PAFR), and leukotriene B(4) (BLTR) were transfected into RBL-2H3 cells. Pertussis toxin (Ptx) served as a Galpha(i) inhibitor. These receptors were chosen to represent the spectrum of G(i) usage as Ptx had differential effects on their ability to induce calcium mobilization, phosphoinositide hydrolysis, and exocytosis with complete inhibition of all responses by FR, intermediate effects on BLTR, and little effect on PAFR. Ptx did not affect ligand-induced phosphorylation of PAFR and BLTR but inhibited phosphorylation of FR. In contrast, chemotaxis to formylmethionylleucylphenylalanine, leukotriene B(4), and platelet-activating factor was completely blocked by Ptx. Wortmannin, a phosphotidylinositol 3-kinase inhibitor, also completely blocked ligand-induced chemotaxis by all receptors but did not affect calcium mobilization or phosphoinositide hydrolysis; however, it partially blocked the exocytosis response to formylmethionylleucylphenylalanine and the platelet-activating factor. Membrane ruffling and pseudopod extension via the BLTR was also completely inhibited by both Ptx and wortmannin. These data suggest that of the chemoattractant receptors studied, G-protein usage varies with FR being totally dependent on G(i), whereas BLTR and PAFR utilize both G(i) and a Ptx-insensitive G-protein. Both Ptx-sensitive and -insensitive G-protein usage can mediate the activation of phospholipase C, mobilization of intracellular calcium, and exocytosis by chemoattractant receptors. Chemotaxis, however, had an absolute requirement for a G(i)-mediated pathway.

Animals↗
PubMed1999

Gp-41-mediated astrocyte inducible nitric oxide synthase mRNA expression: involvement of interleukin-1beta production by microglia.

Mechanisms underlying human immunodeficiency virus-1 encephalopathy are not completely known; however, recent studies suggest that the viral protein gp41 may be neurotoxic via activation of inducible nitric oxide synthase (iNOS) in glial cells. In the present study, we investigated the NO-generating activity of primary human fetal astrocytes in response to gp41 and the relationship to microglial cell production of interleukin-1 (IL-1). Gp41 failed to trigger iNOS mRNA expression in highly enriched (>99%) astrocyte or microglial cell cultures. However, gp41-treated microglia released a factor(s) that triggered iNOS mRNA expression and NO production in astrocytes. Because IL-1 receptor antagonist protein blocked gp41-induced NO production, a pivotal role was suggested for microglial cell IL-1 production in astrocyte iNOS expression. Also, gp41 induced IL-1beta mRNA expression and IL-1 production in microglial cell but not astrocyte cultures. Using specific inhibitors, we found that gp41-induced IL-1beta production in microglia was mediated via a signaling pathway involving protein-tyrosine kinase. These data support the hypothesis that gp41 induces astrocyte NO production indirectly by triggering upregulation of microglial cell IL-1 expression.

Astrocytes↗
PubMed1999

Short- and long-term outcome of balloon angioplasty for compromised side branches after intracoronary stent deployment.

During coronary stent deployment there is a risk of compromising side branches, which can result in chest pain. Compromised side branches can be reopened by balloon angioplasty through the side of the stent. In a consecutive series of 10 patients with side-branch compromise and chest pain, balloon angioplasty through the side of the stent resolved the ischemia in all cases. The stented segment showed no deterioration following side-branch angioplasty. Six-month follow-up angiography showed a restenosis in the branch vessel of eight patients. The stented parent vessel restenosed in four patients. Therefore, side-branch balloon angioplasty after coronary stenting for ongoing ischemia is technically feasible and immediately effective. Restenosis of the branch occurs in most cases.

Adult↗
PubMed1999

Nasopharyngeal cancer.

The current standards of treatment for nasopharyngeal cancer include 1. In early disease (stage I and stage II), radiotherapy is the treatment of choice, and the chance for cure is usually high. 2. In locally advanced disease (stage III and stage IV) combination chemotherapy and radiation therapy is indicated. Further clinical trials are warranted, which may include the newer active chemotherapeutic agents. 3. Patients with distant metastases may be treated with chemotherapy alone or other palliative measures.

Chemotherapy, Adjuvant↗
PubMed1999

Biodistribution, dosimetry and metabolism of 11beta-methoxy-(17alpha,20E/Z)-[123I]iodovinylestradiol in healthy women and breast cancer patients.

UNLABELLED: The biodistribution and dosimetry of the 20E and 20Z stereoisomers of 11 beta-methoxy-(17alpha,20)-[123I]iodovinylestradiol (MIVE) were evaluated in six healthy women. Tumor uptake and metabolism of the 20Z isomer were evaluated in 13 women referred after abnormal mammography or after discovery of a suspect mass at physical examination. METHODS: The radiopharmaceuticals were prepared from their corresponding stannyl intermediates and administrated intravenously. Blood samples were drawn at different time intervals and urine was collected for up to 24 h. Metabolites were detected by radiochromatography. Tissue distribution was followed for up to 24 h by scintigraphic imaging. The dosimetry was computed according to the Medical Internal Radiation Dose scheme. RESULTS: The 20E and 20Z isomers exhibit similar biodistribution and dosimetry patterns. Chromatographic analysis of plasma samples of healthy volunteers and cancer patients, as well as in vitro plasma incubations, confirmed the in vivo stability of (20Z)-[123I]MIVE. Radioactivity was rapidly cleared from the blood by the liver and excreted through the gut, which received the highest radiation dose (0.211 mGy/MBq). The effective doses for the adult female and male phantom were 0.054 and 0.046 mSv/MBq, respectively. Among the 13 patients imaged with (20Z)-[123I]MIVE, 3 had fibrocystic disease with no focal uptake, 8 had good agreement with in vitro estrogen receptor determination and 2 were false-positive. CONCLUSION: The radiation dose after intravenous administration of 20E- or (20Z)-[123I]MIVE at imaging dose levels is within acceptable limits. There was a good correlation between uptake of (20Z)-[123I]MIVE and the presence of estrogen receptors in breast cancer patients.

Adult↗
PubMed1998

Differential cross-regulation of the human chemokine receptors CXCR1 and CXCR2. Evidence for time-dependent signal generation.

Neutrophils and transfected RBL-2H3 cells were used to investigate the mechanism of cross-regulation of the human interleukin-8 (IL-8) receptors CXCR1 and CXCR2 by chemoattractants. In neutrophils, Ca2+ mobilization by the CXCR2-specific chemokine, growth-related oncogene alpha (Groalpha), was desensitized by prior exposure to the chemoattractants N-formylated peptides (fMLP) or a complement cleavage product (C5a). In contrast, growth-related oncogene alpha did not desensitize the latter receptors. To investigate this phenomenon, CXCR2 was stably expressed in RBL-2H3 cells and mediated phosphoinositide hydrolysis, Ca2+ mobilization, chemotaxis, and secretion. In cells co-expressing CXCR2 and receptors for either C5a (C5aR) or fMLP (FR), CXCR2 was cross-phosphorylated and cross-desensitized by C5a and fMLP. However, neither C5aR nor FR was cross-phosphorylated or cross-desensitized by CXCR2 activation, although CXCR1 did mediate this process. Receptor internalization induced by IL-8 was more rapid and occurred at lower doses with CXCR2 than CXCR1, although both receptors mediated equipotent chemotaxis and exocytosis in RBL. Truncation of the cytoplasmic tail of CXCR2 (331T) prolonged its signaling relative to CXCR2, increased its resistance to internalization, and induced phospholipase D activation. 331T was resistant to homologous phosphorylation and cross-phosphorylation but not cross-desensitization of its Ca2+ mobilization by fMLP or C5a, indicating an inhibitory site distal to receptor/G protein coupling. In contrast to CXCR2, stimulation of 331T cross-desensitized Ca2+ mobilization by both FR and C5aR. CXCR2 and the mutant 331T induced phospholipase C beta3 phosphorylation to an extent equivalent to that of CXCR1. Taken together, these results suggest that CXCR1 and CXCR2 bind IL-8 to produce a group of equipotent responses, but their ability to generate other signals, including receptor internalization, cross-desensitization, and phospholipase D activation, are very different. The latter phenomena apparently require prolonged receptor activation, which in the case of CXCR2 is precluded by rapid receptor phosphorylation and internalization. Thus, receptors coupling to identical G proteins may trigger different cellular responses dependent on the length of their signaling time, which can be regulated by receptor phosphorylation.

Animals↗
PubMed1998

Opiates transdeactivate chemokine receptors: delta and mu opiate receptor-mediated heterologous desensitization.

An intact chemotactic response is vital for leukocyte trafficking and host defense. Opiates are known to exert a number of immunomodulating effects in vitro and in vivo, and we sought to determine whether they were capable of inhibiting chemokine-induced directional migration of human leukocytes, and if so, to ascertain the mechanism involved. The endogenous opioid met-enkephalin induced monocyte chemotaxis in a pertussis toxin-sensitive manner. Met-enkephalin, as well as morphine, inhibited IL-8-induced chemotaxis of human neutrophils and macrophage inflammatory protein (MIP)-1alpha, regulated upon activation, normal T expressed and secreted (RANTES), and monocyte chemoattractant protein 1, but not MIP-1beta-induced chemotaxis of human monocytes. This inhibition of chemotaxis was mediated by delta and micro but not kappa G protein-coupled opiate receptors. Calcium flux induced by chemokines was unaffected by met-enkephalin pretreatment. Unlike other opiate-induced changes in leukocyte function, the inhibition of chemotaxis was not mediated by nitric oxide. Opiates induced phosphorylation of the chemokine receptors CXCR1 and CXCR2, but neither induced internalization of chemokine receptors nor perturbed chemokine binding. Thus, inhibition of chemokine-induced chemotaxis by opiates is due to heterologous desensitization through phosphorylation of chemokine receptors. This may contribute to the defects in host defense seen with opiate abuse and has important implications for immunomodulation induced by several endogenous neuropeptides which act through G protein-coupled receptors.

Cells, Cultured↗
PubMed1998

Differential regulation of formyl peptide and platelet-activating factor receptors. Role of phospholipase Cbeta3 phosphorylation by protein kinase A.

Formylated peptides (e.g. n-formyl-Met-Leu-Phe (fMLP)) and platelet-activating factor (PAF) mediate chemotactic and cytotoxic responses in leukocytes through receptors coupled to G proteins that activate phospholipase C (PLC). In RBL-2H3 cells, fMLP utilizes a pertussis toxin (ptx)-sensitive G protein to activate PLC, whereas PAF utilizes a ptx-insensitive G protein. Here we demonstrate that fMLP, but not PAF, enhanced intracellular cAMP levels via a ptx-sensitive mechanism. Protein kinase A (PKA) inhibition by H-89 enhanced inositol phosphate formation stimulated by fMLP but not PAF. Furthermore, a membrane-permeable cAMP analog 8-(4-chlorophenylthio)-cAMP (cpt-cAMP) inhibited phosphoinositide hydrolysis and secretion stimulated by fMLP but not PAF. Both cpt-cAMP and fMLP stimulated PLCbeta3 phosphorylation in intact RBL cells. The purified catalytic subunit of PKA phosphorylated PLCbeta3 immunoprecipitated from RBL cell lysate. Pretreatment of intact cells with cpt-cAMP and fMLP, but not PAF, resulted in an inhibition of subsequent PLCbeta3 phosphorylation by PKA in vitro. These data demonstrate that fMLP receptor, which couples to a ptx-sensitive G protein, activates both PLC and cAMP production. The resulting PKA activation phosphorylates PLCbeta3 and appears to block the ability of Gbetagamma to activate PLC. Thus, both fMLP and PAF generate stimulatory signals for PLCbeta3, but only fMLP produces a PKA-dependent inhibitory signal. This suggests a novel mechanism for the bidirectional regulation of receptors which activate PLC by ptx-sensitive G proteins.

Cell Line↗
PubMed1998

Multiple signaling pathways of human interleukin-8 receptor A. Independent regulation by phosphorylation.

Interleukin-8 (IL-8) receptor A (CXCR1) couples to a pertussis toxin-sensitive G protein to mediate phospholipase Cbeta (PLCbeta) activation and cellular responses. Responses to CXCR1 are attenuated by prior exposure of neutrophils to either IL-8, a cleavage product of the fifth component of complement (C5a) or n-formylated peptides (formylmethionylleucylphenylalanine, fMLP). To characterize the role of receptor phosphorylation in the regulation of the CXCR1, a phosphorylation-deficient mutant, M2CXCR1, was constructed. This receptor, stably expressed in RBL-2H3 cells, coupled more efficiently to G protein and stimulated enhanced phosphoinositide hydrolysis, cAMP production, exocytosis, and phospholipase D activation, and was resistant to IL-8-induced receptor internalization. The rate and total amount of ligand stimulated actin polymerization remained unchanged, but interestingly, chemotaxis was decreased by approximately 30% compared with the wild type receptor. To study the role of receptor phosphorylation in cross-desensitization of chemoattractant receptors, M2CXCR1 was coexpressed with cDNAs encoding receptors for either fMLP (FR), C5a (C5aR), or platelet-activating factor (PAFR). Both C5aR and PAFR were cross-phosphorylated upon M2CXCR1 activation, resulting in attenuated guanosine 5'-3'-O-(thio)triphosphate (GTPgammaS) binding in membranes. In contrast, FR and M2CXCR1 were resistant to cross-phosphorylation and cross-inhibition of GTPgammaS binding by other receptors. Despite the resistance of M2CXCR1 to cross-phosphorylation and receptor/G protein uncoupling, its susceptibility to cross-desensitization of its Ca2+ response by fMLP and C5a, was equivalent to CXCR1. Regardless of the enhancement in certain receptor functions in M2CXCR1 compared with the wild type CXCR1, the mutated receptors mediated equivalent PLCbeta3 phosphorylation and cross-desensitization of Ca2+ mobilization by FR, C5aR, and PAFR. The results herein indicate that phosphorylation of CXCR1 regulates some, but not all of the receptors functions. While receptor phosphorylation inhibits G protein turnover, PLC activation, Ca2+ mobilization and secretion, it is required for normal chemotaxis and receptor internalization. Since phosphorylation of CXCR1 had no effect on its ability to induce phosphorylation of PLCbeta3 or to mediate class-desensitization, these activities may be mediated by independently regulated pathways.

Antigens, CD↗
PubMed1997

Regulation of human chemokine receptors CXCR4. Role of phosphorylation in desensitization and internalization.

Members of the chemokine receptor family CCR5 and CXCR4 have recently been shown to be involved in the entry of human immunodeficiency virus (HIV) into target cells. Here, we investigated the regulation of CXCR4 in rat basophilic leukemia cells (RBL-2H3) stably transfected with wild type (Wt CXCR4) or a cytoplasmic tail deletion mutant (DeltaCyto CXCR4) of CXCR4. The ligand, stromal cell derived factor-1 (SDF-1) stimulated higher G-protein activation, inositol phosphate generation, and a more sustained calcium elevation in cells expressing DeltaCyto CXCR4 relative to Wt CXCR4. SDF-1 and phorbol 12-myristate 13-acetate (PMA), but not a membrane permeable cAMP analog induced rapid phosphorylation as well as desensitization of Wt CXCR4. Phosphorylation of DeltaCyto CXCR4 was not detected under any of these conditions. Despite lack of receptor phosphorylation, calcium mobilization by SDF-1 in DeltaCyto CXCR4 cells was partially desensitized by prior treatment with SDF-1. Of interest, the rapid release of calcium was inhibited without affecting the sustained calcium elevation, indicating independent regulatory pathways for these processes. PMA completely inhibited phosphoinositide hydrolysis and calcium mobilization in Wt CXCR4 but only partially inhibited these responses in DeltaCyto CXCR4. cAMP also partially inhibited these responses in both Wt CXCR4 and DeltaCyto CXCR4. SDF-1, PMA, and cAMP caused phosphorylation of phospholipase Cbeta3 in Wt and DeltaCyto CXCR4 cells. Both SDF-1 as well as PMA induced rapid internalization of Wt CXCR4. SDF-1 but not PMA induced internalization of DeltaCyto CXCR4 albeit at reduced levels relative to Wt CXCR4. These results indicate that signaling and internalization of CXCR4 are regulated by receptor phosphorylation dependent and independent mechanisms. Desensitization of CXCR4 signaling, independent of receptor phosphorylation, appears to be a consequence of the phosphorylation of phospholipase Cbeta3.

Amino Acid Sequence↗
PubMed1997

Chemoattractant receptor-induced phosphorylation of L-selectin.

The selectin adhesion molecules and chemoattractant receptors synergistically regulate leukocyte migration into lymphoid tissues and sites of inflammation, but little is known about how these families of receptors modulate each other's function. In this study, L-selectin was found to be phosphorylated in lymphoblastoid cell lines, and phosphorylation was enhanced by phorbol ester (phorbol 12-myristate 13-acetate (PMA)) treatment. Interactions between L-selectin and chemoattractant receptors were therefore examined using transfected rat basophilic leukemia cell lines (RBL-2H3) that expressed human L-selectin along with human leukocyte chemoattractant receptors. L-selectin was rapidly phosphorylated in cells treated with chemoattractants, thrombin, IgE receptor agonists, or PMA. Pertussis toxin or the protein kinase C inhibitor, staurosporine, completely blocked chemoattractant receptor-induced phosphorylation of L-selectin. PMA-induced phosphorylation was on serine residues within the cytoplasmic tail of L-selectin that have been well conserved during recent evolution. Although L-selectin phosphorylation was not essential for basal levels of adhesion through L-selectin in transformed cell lines, the rapid increase in ligand binding activity of L-selectin that occurs following leukocyte activation was blocked by staurosporine. These results demonstrate that L-selectin can be phosphorylated following engagement of chemoattractant receptors and suggest that this may be a physiologically relevant mechanism for the synergistic regulation of these receptors during leukocyte migration.

Animals↗
PubMed1997

Role of phospholipase Cbeta3 phosphorylation in the desensitization of cellular responses to platelet-activating factor.

Platelet-activating factor (PAF) stimulates a diverse array of cellular responses through receptors coupled to G proteins that activate phospholipase C (PLC). Truncation of the cytoplasmic tail of the receptor to remove phosphorylation sites (mutant PAF receptor, mPAFR) results in enhancement of PAF-stimulated responses. Here we demonstrate that PAF or phorbol 12-myristate 13-acetate (PMA) pretreatment inhibited wild type PAFR-induced PLC-mediated responses by approximately 90%, whereas these responses to the phosphorylation-deficient mPAFR were inhibited by approximately 50%, despite normal G protein coupling, suggesting a distal inhibitory locus. PAF and PMA, as well as a membrane permeable cyclic AMP analog, stimulated phosphorylation of PLCbeta3. A protein kinase C (PKC) inhibitor blocked phosphorylation of PLCbeta3 stimulated by PAF and PMA but not by cAMP. Activation of protein kinase A (PKA) by cAMP did not result in inhibition of Ca2+ mobilization stimulated by PAF. In contrast, cAMP did inhibit the response to formylpeptide chemoattractant receptor. These data suggest that homologous desensitization of PAF-mediated responses is regulated via phosphorylation at two levels in the signaling pathway, one at the receptor and the other at PLCbeta3 mediated by PKC but not by PKA. Phosphorylation of PLCbeta3 by PKA could explain the inhibition of formylpeptide chemoattractant receptor signaling by cAMP. As PAF and formylpeptide chemoattractant receptors activate PLC via different G proteins, phosphorylation of PLCbeta3 by PKC and PKA could provide distinct regulatory control for classes of G protein-coupled receptors.

Animals↗