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Biomedical subjects

S Mousa

Publications and source records attributed to S Mousa.

At least 19 recordsLinked to original sources
PubMed2003

Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons.

Opioids mediate their analgesic effects by activating mu-opioid receptors (MOR) not only within the central nervous system but also on peripheral sensory neurons. The peripheral analgesic effects of opioids are best described under inflammatory conditions (e.g., arthritis). The present study investigated the effects of inflammation on MOR binding and G-protein coupling of full versus partial MOR agonists in dorsal root ganglia (DRG) of primary afferent neurons. Our results show that Freund's complete adjuvant (FCA) unilateral hindpaw inflammation induces a significant up-regulation of MOR binding sites (25 to 47 fmol/mg of protein) on DRG membranes without affecting the affinity of either full or partial MOR agonists. In our immunohistochemical studies, the number of MOR-immunoreactive neurons consistently increased. This increase was mostly caused by small-diameter nociceptive DRG neurons. The full agonist DAMGO induced MOR G-protein coupling in DRG of animals without FCA inflammation (EC50 = 56 nM; relative Emax = 100%). FCA inflammation resulted in significant increases in DAMGO-induced MOR G-protein coupling (EC50 = 29 nM; relative Emax = 145%). The partial agonist buprenorphine hydrochloride (BUP) showed no detectable G-protein coupling in DRG of animals without FCA inflammation; however, partial agonist activity of BUP-induced MOR G-protein coupling was detectable in animals with FCA inflammation (EC50 = 1.6 nM; relative Emax = 82%). In behavioral studies, administration of BUP produced significant antinociception only in inflamed but not in noninflamed paws. These findings show that inflammation causes changes in MOR binding and G-protein coupling in primary afferent neurons. They further underscore the important differences in clinical studies testing peripherally active opioids in inflammatory painful conditions.

Animals↗
PubMed2001

High levels of oestrogen receptor-alpha in tumorigenesis: inhibition of cell growth and angiogenic factors.

We previously found that the stable overexpression of oestrogen receptor-alpha in the human endothelial cell line ECV304* inhibits its growth in vitro, and that this inhibition is possibly mediated through a down-regulation of the vasoactive agents endothelin-1 and vascular endothelial growth factor. Here we show an in vivo growth-inhibitory effect of oestrogen receptor-alpha overexpression in tumours initiated in nude mice from the same clone of ECV304. In addition, we show that this growth inhibition is accompanied by an alphavbeta3-mediated inhibition of cell migration in vitro, and a down-regulation of the integrin alphavbeta3, vascular endothelial growth factor and vascularization in vivo. The levels of vascular endothelial growth factor and integrin alphavbeta3, through their effect on cell growth and migration, contribute to the process of angiogenesis and to the pathogenesis of atherosclerosis and cancer. The results shown here demonstrate that a higher level of oestrogen receptor-alpha in the cell, through its effect on certain angiogenic factors, may play a role in the control of angiogenesis.

Animals↗
PubMed2001

Analgesic and antiinflammatory effects of two novel kappa-opioid peptides.

BACKGROUND: This study investigates two new kappa-agonist tetrapeptides, FE 200665 and FE 200666, with high peripheral selectivity as a result of poor central nervous system penetration. METHODS: Four days after administration of Freund adjuvant into the hind paw of male Wistar rats, antinociceptive effects of intraplantar and subcutaneous injection of FE 200665 and FE 200666 were measured by paw pressure algesiometry and compared with the kappa-agonist U-69,593. Peripheral and kappa-receptor selectivity was assessed by the antagonists naloxone methiodide (NLXM) and nor-binaltorphimine, respectively. Antiinflammatory effects were evaluated by paw volume plethysmometry and histologic score. RESULTS: Similar to intraplantar U-69,593, intraplantar FE 200665 (3-100 microg) and FE 200666 (1-30 microg) resulted in significant and dose-related increases of paw pressure thresholds. Higher doses of FE 200665 (0.2-20 mg) and FE 200666 (0.06-6 mg) were required by subcutaneous route to produce similar antinociceptive responses, supporting a peripheral site of action. nor-Binaltorphimine dose-dependently antagonized this effect, implying kappa-opioid selectivity. Analgesic effects of subcutaneous FE 200665 and FE 200666 were abolished by intraplantar nor-binaltorphimine, and both subcutaneous and intraplantar effects were dose-dependently antagonized by subcutaneous NLXM, further demonstrating a peripheral site of action. One to 6 days after Freund adjuvant inoculation, single and repeated intraplantar injections of FE 200665, FE 200666, and U-69,593 significantly reduced paw volume and histologic scores. Both changes were reversed by intraplantar nor-binaltorphimine and subcutaneous NLXM. CONCLUSION: FE 200665 is a peripherally selective kappa-agonist with potent analgesic and antiinflammatory properties that may lead to improved analgesic-antiinflammatory therapy compared with centrally acting opioids or standard nonsteroidal antiinflammatory drugs.

Analgesics, Opioid↗
PubMed2001

Circulating soluble tumor necrosis factor receptor as a marker for diagnosis of pulmonary embolus.

The purpose of this clinical study was to determine the relationship between plasma soluble tumor necrosis factor receptor (T.N.F.R.) and pulmonary embolism. The histological evidence of the interaction between leukocytes and the venous wall of a thrombosed vein, as well as the over-production of TNF in plasma prompted us to assay a more stable polypeptide, namely TNF receptor, as potential markers for pulmonary embolism. Five mL of plasma were obtained from twenty patients, ranging in the age from 24 to 74 years, who had been diagnosed as having pulmonary embolism through pulmonary angiography, and 20 healthy volunteers in the same age group. The samples were then studied by enzyme-link immunosorbent assay (ELISA) for measurement of soluble TNF receptor. Patients with pulmonary embolism maintained a higher serum concentration of soluble TNF receptors. It appears that plasma measurement of soluble TNF receptor could be used as a clinical test for diagnosis of pulmonary embolism.

Adult↗
PubMed2000

Estrogen receptor-alpha in the inhibition of cancer growth and angiogenesis.

A high level of estrogen receptor-alpha (ER-alpha) is believed to be favorable in the prognosis and treatment of certain female cancers. ER-alpha expression in the ER-negative breast cancer cell lines inhibits their proliferation and invasive, metastatic potential in vitro. We stably overexpressed the ER-alpha in the human endometrial cancer cell line Ishikawa and showed that, unlike estradiol, high levels of ER-alpha significantly inhibit the growth of tumors xenografted from the Ishikawa cells. Subsequent to ER-alpha overexpression, in vivo down-regulation of vascular endothelial growth factor was observed in tumor xenografts. In addition, these tumors showed an inhibition of vascularization and of the angiogenic agent, integrin alphavbeta3. Involvement of a switch in the angiogenic pathways during tumorigenesis has been a recent focus of interest. Our results indicate that a high level of ER-alpha may be beneficial in the control of female cancers because of its inhibitory effect on such angiogenic pathways.

Animals↗
PubMed2000

The activation state of alphavbeta 3 regulates platelet and lymphocyte adhesion to intact and thrombin-cleaved osteopontin.

Cleavage of osteopontin by thrombin has been reported to enhance cell adhesion. We asked whether thrombin could regulate the alpha(v)beta(3)-mediated adhesion of platelets and B lymphocytes to this substrate. Although there was no difference in the extent or the avidity of thrombin- and ADP-stimulated platelet adhesion to intact or thrombin-cleaved human osteopontin, both the extent and avidity of phorbol ester-stimulated B cell adhesion to thrombin-cleaved osteopontin was significantly increased. Thus, these data suggest that the ability of alpha(v)beta(3) to recognize osteopontin can be differentially regulated in a cell-specific manner. To localize the alpha(v)beta(3) binding site on osteopontin, we measured cell adhesion to the two thrombin cleavage products of osteopontin and to a series of nested RGD-containing osteopontin peptides cross-linked to albumin. Whereas ADP-stimulated platelets adhered to the amino-terminal but not the carboxyl-terminal osteopontin fragment and to the osteopontin peptide RGDSVVYGLR, phorbol ester-stimulated B cells did not adhere to this peptide, although they did so in the presence of 1 mm Mn(2+). Thus, our data confirm that thrombin cleavage enhances the accessibility of the binding motif for alpha(v)beta(3) on osteopontin, but this enhancement is also a function of the activation state of alpha(v)beta(3). Moreover, they indicate that the sequence RGDSVVYGLR contains sufficient information to specify activation-dependent alpha(v)beta(3)-mediated platelet and lymphocyte adhesion.

Adenosine Diphosphate↗
PubMed2000

A non-transmembrane form of Jagged-1 regulates the formation of matrix-dependent chord-like structures.

Jagged-Notch interactions regulate a transmembrane ligand-receptor signaling pathway involved in the regulation of cell fate determination as well as myoblast and endothelial cell differentiation. To further examine the role of the transmembrane ligand, Jagged-1, in the regulation of cell differentiation, we stably transfected NIH 3T3 cells with a truncated form of Jagged(J)-1, which results in the secretion of a soluble(s) form of the protein. Comparison of gene expression by serial analysis demonstrated that among the 227 transcripts differentially regulated in the sJ-1 transfectants, the expression of the pro-alpha-2(I) collagen transcript and pro-alpha-1(I) collagen translation product was predominantly repressed in sJ-1 transfectants. When plated on extracellular matrices, sJ-1 transfectants formed prominent chord-like structures on type I collagen but not on fibrin, fibronectin, or vitronectin. While the sJ-1 transfectants exhibited growth kinetics similar to control cells and were unable to grow in soft agar, the cells were less sensitive to contact inhibition of growth in vitro and sJ-1 allografts formed tissue masses in nude mice after a prolonged latency period and exhibited an abundance of host-derived microvascular endothelial cells. These data suggest that J-1 may be able to modulate, in a matrix-dependent manner, the organization of cell to cell interactions including its ability to promote the development of chord-like structures.

3T3 Cells↗
PubMed2000

Effects of the novel alphav integrin antagonist SM256 and cis-platinum on growth of murine squamous cell carcinoma PAM LY8.

Increased density of proliferating and migrating tumor cells and neovascular endothelial cells has been associated with tumor progression and poor prognosis in patients with squamous cell carcinoma (SCC). Tumor and neovascular endothelial cells in squamous cell carcinoma have been reported to express integrin heterodimers containing the alphav subunit, which binds to vitronectin and other extracellular matrix proteins that contain the amino acid recognition sequence Arg-Gly-Asp (RGD). In the present study, we examined the effect of the novel non-peptide alphav integrin antagonist SM256 on growth of SCC line PAM LY8 in BALB/c SCID mice, and determined whether SM256 has direct inhibitory effects on growth of murine endothelial and PAM LY8 SCC cells in vitro. SM256 inhibits cell adhesion of murine cells expressing alphavbeta3 and alphavbeta5 integrins in vitro with an IC50 of 35 nM and 30 nM, respectively. Growth of Pam LY8 tumors in vivo was inhibited with 14-day continuous administration of SM256 by subcutaneous osmotic diffusion pump, during which a mean serum concentration of 56 nM was detected. While both murine aortic endothelial cells and PAM LY8 were found to express alphav integrins by fluorescence cytofluorometry, SM256 at 50 nM in MTT assay completely inhibited growth of endothelial cells, but had no significant direct effect on growth of PAM LY8 cells. We compared the effect on growth of PAM LY8 of SM256 infusion versus single agent or combination chemotherapy with a maximally tolerated dose of cis-platinum, which is used as a standard chemotherapy for SCC. When treatment was initiated at either 7 or 21 days following establishment of tumor, 14-day infusion of SM256 had an inhibitory effect on growth that was similar to that obtained with single dose cis-platinum, but no additive effect of concurrent therapy with SM256 and cis-platinum was observed. These results demonstrate the activity and feasibility of use of alphav antagonists such as SM256 for therapy of SCC.

Animals↗
PubMed1999

Stable over-expression of estrogen receptor-alpha in ECV304 cells inhibits proliferation and levels of secreted endothelin-1 and vascular endothelial growth factor.

Studies with mammalian vascular cells have suggested growth inhibitory effects of estrogen on the vascular wall. To investigate the involvement of estrogen receptor-alpha (ER) in the control of endothelial cell proliferation, we have stably transfected human estrogen receptor-alpha cDNA into the endothelial cell line ECV304. The clone ECV-ER, thus obtained, over-expresses estrogen receptor to a level approximately 10-fold higher than the parent cell line. Effects of this over-expression were studied on the cell growth rate, and on the levels of secreted endothelin-1 and vascular endothelial growth factor (VEGF). Similar to the previously reported data in other cell types, we found the transfection of ER in ECV304 cells to be inhibitory to their growth. Our ER-over-expressing clone of ECV304 also showed an inhibition of secreted endothelin-1 and VEGF levels. Moreover, the growth inhibition of this ER-over-expressing clone was reversed by the addition of endothelin-1 or VEGF to the medium. In view of the growth-stimulatory effect of endothelin-1 and VEGF on vascular cells, our results indicate that estrogen receptor-alpha may bring about its growth inhibition partly by suppressing endothelin-1 and/or VEGF production in ECV304 cells.

Arteriosclerosis↗
PubMed1999

Diagnosis of pulmonary embolism by use of urinary TNF alpha and its soluble TNF receptor I.

The purpose of this clinical study was to determine the concentration of soluble tumor necrosis factor in urine of patients with pulmonary embolism (PE), verses voluntary control individuals. Sixteen patients (ages 24 to 74 years) with diagnosis of PE, documented by ventilation perfusion scan or pulmonary angiogram, were the subjects of this study. Ten cc of urine was obtained from each patient and subjected to a solid-phase enzyme-linked immunosorbent assay thus determining the soluble tumor necrosis factor (TNF) receptor I (R I) and TNF alpha levels in these samples. In this pilot study of PE cases, a statistically significant elevation in urinary levels of TNF alpha and soluble TNF R I was demonstrated in PE patients. The average urinary soluble TNF R I in normal subjects was 1,029 pg/mL and in PE patients the average TNF R I was 3,734.4 pg/mL. The clinical diagnosis of PE is a challenging problem for the physician. Late diagnosis and delayed management of this condition could be associated with massive PE. Although pulmonary angiography is the gold standard for diagnosis of PE, it requires expensive equipment, trained radiologists, and the patient could be at risk of sensitivity to contrast agents.

Adult↗
PubMed1999

Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer.

Altered immune, inflammatory, and angiogenesis responses are observed in patients with head and neck squamous cell carcinoma (HNSCC), and many of these responses have been linked with aggressive malignant behavior and a decrease in prognosis. In this study, we examined the hypothesis that HNSCC cells produce cytokines that regulate immune, inflammatory, and angiogenesis responses. We identified important regulatory cytokines in supernatants of well-defined and freshly cultured HNSCC cell lines by ELISA and determined whether these cytokines are detected in tumor cell lines and tissue specimens by immunohistochemistry. The serum concentration of the cytokines and cytokine-dependent acute phase inflammatory responses (i.e., fibrinogen, C-reactive protein, and erythrocyte sedimentation rate) from patients with HNSCC was determined, and the potential relationship of serum cytokine levels to tumor volume was analyzed. Cytokines interleukin (IL)-1alpha, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor were detected in similar concentration ranges in the supernatants of a panel of established University of Michigan squamous cell carcinoma (UM-SCC) cell lines and supernatants of freshly isolated primary HNSCC cultures. Evidence for the expression of IL-1alpha, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, and VEGF in HNSCC cells within tumor specimens in situ was obtained by immunohistochemistry. In a prospective comparison of the cytokine level and cytokine-inducible acute-phase proteins in serum, we report that cytokines IL-6, IL-8, and VEGF were detected at higher concentrations in the serum of patients with HNSCC compared with patients with laryngeal papilloma or age-matched control subjects (at P < 0.05). The serum concentrations of IL-8 and VEGF were found to be weakly correlated with large primary tumor volume (R2 = 0.2 and 0.4, respectively). Elevated IL-1- and IL-6-inducible acute-phase responses were also detected in cancer patients but not in patients with papilloma or control subjects (at P < 0.05). We therefore conclude that cytokines important in proinflammatory and proangiogenic responses are detectable in cell lines, tissue specimens, and serum from patients with HNSCC. These cytokines may increase the pathogenicity of HNSCC and prove useful as biomarkers or targets for therapy.

Acute-Phase Reaction↗
PubMed1998

Synthesis and antiplatelet effects of an isoxazole series of glycoprotein IIb/IIIa antagonists.

Despite the excellent in vitro potency of a series of benzamide glycoprotein IIb/IIIa antagonists, which have been reported previously, poor in vivo potency in the inhibition of platelet aggregation was observed when the most potent inhibitor XU057 was dosed intravenously to dogs. In this communication, we report that replacement of the benzamide in XU057 with an isoxazolecarboxamide resulted in significant improvement in in vivo potency. More importantly, the analogue XU065 showed an excellent oral antiplatelet effect in dogs.

Animals↗
PubMed1998

Diagnosis of deep venous thrombosis by use of soluble necrosis factor receptor.

The purpose of this clinical study was to find a relationship between soluble tumor necrosis factor (TNF) receptor, deep venous thrombosis (DVT), and pulmonary emboli (PE). Clinical diagnosis of deep venous thrombosis and pulmonary emboli is a major dilemma for the clinician. Most existing tests are technician dependent, are expensive, or require sophisticated equipment. Advances in molecular biology will permit investigation of the value of TNF receptor as a test for screening, diagnosis, and evolution of DVT and PE. Forty patients with diagnosis of DVT, documented by real-time ultrasound imaging, were the subject of this clinical study. Five cc of plasma from each patient was studied by enzyme-linked immunosorbent assay (Elisa) for measurement of soluble TNF receptor. Significantly increased concentration of plasma-soluble TNF receptor was present in patients with DVT as opposed to normal individuals. There was a close relationship between plasma concentration of soluble TNF receptor and evaluation of the disease. In this preliminary clinical study, it appears that plasma measurement of soluble TNF receptor could be used as a clinical test for diagnosis of DVT and PE.

Adult↗
PubMed1997

Design, synthesis, and in vitro activities of benzamide-core glycoprotein IIb/IIIa antagonists: 2,3-diaminopropionic acid derivatives as surrogates of aspartic acid.

In an effort to discover novel nonpeptide glycoprotein IIb/IIIa (GPIIb/IIIa, alpha IIb/beta 3) inhibitors, we investigated RGD mimetics featuring a 3-substituted benzoic acid as the core, benzamidine as the basic moiety, and a series of beta- and alpha-substituted beta-alanine derivatives as aspartic acid surrogates. It was found that the use of beta-methyl beta-alanine slightly improved the anti-aggregant potency in human platelet-rich plasma over the unsubstituted beta-alanine compound, while beta-substitution with a trifluoromethyl group resulted in considerable loss in activity. Significant enhancement (up to 100-fold) in potency was obtained when the beta-alanine was replaced with N2-substituted 1-2,3-diaminopropionic acid derivatives. Among the three types of alpha-substituents (carbamate, amide, and sulfonamide) investigated, no apparent preference was observed with respect to in vitro potency. However, alkyl groups were more favorable than arylalkyl groups (Cbz) in the carbamate analogues. We also investigated piperidine, piperazine, and N-formamidinopiperidine as replacements for the benzamidine moiety. The former two replacements led to a drop in potency while the latter replacement resulted in maintenance of activity as compared with the corresponding benzamidine analogue.

Alanine↗
PubMed1996

Calcium, calmodulin and protein kinase C dependence of platelet shape change.

Platelet shape change (PSC) represents the initial phase of platelet activation and is normally investigated in ethylene diamine tetraacetic acid (EDTA) containing platelet rich plasma (PRP); EDTA is a potent chelator of calcium and therefore reduces ionized calcium to negligible levels. It is therefore assumed that it is a process independent of calcium. To test the hypothesis that PSC may be dependent upon intracellular calcium, we examined the effect of 8-(N,N-Diethylamino) octyl 3,4,5-Trimethoxybenzoate hydrochloride (TMB-8), an inhibitor of intercellular calcium mobilization on PSC. It produced a dose dependent inhibition of PSC. We then examined whether PSC was dependent upon calmodulin and protein kinase C, a calcium dependent enzyme which is cardinal to platelet aggregation. Both calmidazolium, a specific inhibitor of calmodulin, and H-9, a specific inhibitor of protein kinase C, produced dose dependent inhibition of PSC. Finally, we investigated whether GP IIb/IIIa receptor which binds fibrinogen was involved in PSC; DMP 728 [(cyclic [D-2-amino-butyryl-N2-methyl-L-arginyl-glycyl-L-aspartyl-3- (a min o-methyl-benzoic acid], methanesulfonic acid salt] a potent GP IIb/IIIa receptor antagonist was without any effect on PSC. We conclude that PSC is a calcium, calmodulin and protein kinase C dependent process like platelet aggregation but that it does not require extracellular calcium or the participation of platelet GP IIb/IIIa complex.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗