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R A Omar

Publications and source records attributed to R A Omar.

At least 19 recordsLinked to original sources
PubMed2001

Induction of NADPH cytochrome P450 reductase by the Alzheimer beta-protein. Amyloid as a "foreign body".

A large body of data suggests that the Alzheimer's amyloid peptide (Abeta) causes degeneration and death of neurons by mechanisms that involve reactive oxygen species. The pathways involved in Abeta-mediated oxidative injury are only partially understood. We theorized that abnormal microaggregates and/or pathological conformations of Abeta peptides may behave as xenobiotics and trigger the induction of NADPH cytochrome P450 reductase (CP450r), an enzyme which, if induced by non-physiological substrates (such as xenobiotics like drugs or other 'foreign molecules'), is known to cause oxidative stress. In order to test this hypothesis, i.e. that Abeta can increase the expression of CP450r, SK-N-SH human neuroblastoma cells were exposed to Abeta25-35 and Abeta1-42 and then examined for induction of this enzyme in immunoblots, using specific antibodies. Following exposure to Abeta peptides, neuroblastoma cells showed a clear-cut induction of CP450r. To determine whether this mechanism is operational in vivo, we investigated the expression of CP450r in a transgenic mouse model of Alzheimer's disease (AD) and in brains from patients afflicted with AD, using an immunocytochemical approach. Tissue sections from brains of transgenic mice exhibited strong immunoreactivity for CP450r, surrounding amyloid deposits. The pattern of expression of CP450r was similar to that exhibited by neuritic and oxidative stress markers. Sections from non-transgenic mice showed no detectable immunoreactivity. Immunostaining of sections from four brains with neuropathologically confirmed AD showed a pattern of abnormality different from transgenic mice that was characterized by abnormal immunoreactivity for CP450r within the cytoplasm of cortical neurons. No labeling was seen in sections from aged-matched control brains. The data showed that CP450r is induced by Alzheimer amyloid peptide and that such a response must be considered as one possible mechanism whereby Abeta causes oxidative stress.

Alzheimer Disease↗
PubMed1999

Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid.

Widespread cerebral deposition of a 40-43-amino acid peptide called the amyloid beta-protein (Abeta) in the form of amyloid fibrils is one of the most prominent neuropathologic features of Alzheimer's disease. Numerous studies suggest that Abeta is toxic to neurons by free radical-mediated mechanisms. We have previously reported that melatonin prevents oxidative stress and death of neurons exposed to Abeta. In the process of screening indole compounds for neuroprotection against Abeta, potent neuroprotective properties were uncovered for an endogenous related species, indole-3-propionic acid (IPA). This compound has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. IPA completely protected primary neurons and neuroblastoma cells against oxidative damage and death caused by exposure to Abeta, by inhibition of superoxide dismutase, or by treatment with hydrogen peroxide. In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity. These findings may have therapeutic applications in a broad range of clinical situations.

Amyloid beta-Peptides↗
PubMed1998

Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer's disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo.

Increased expression of antioxidant enzymes and heat-shock proteins are key markers of oxidative stress. Such proteins are abnormally present within the neuropathological lesions of Alzheimer's disease (AD), suggesting that oxidative stress may play significant but yet undefined roles in this disorder. To gain further insight into the role of oxidative stress in AD, we studied the expression of CuZn superoxide dismutase (SOD) and hemoxygenase-1 (HO-1), two established markers of oxidative stress, in a transgenic mouse model of AD. Immunohistochemistry with anti-SOD and anti-HO-1 antibodies revealed a very pronounced increase of these proteins only in aged transgene-positive mice. Interestingly, the distribution of the oxidative burden was largely overlapping with dystrophic neuritic elements in the mice as highlighted with anti-ubiquitin antibodies. Because the most conspicuous alterations were identified around amyloid (Abeta) deposits, our results provide strong support for the hypothesis that Abeta is neurotoxic in vivo and that such toxicity is mediated by free radicals. To obtain additional experimental evidence for such an interpretation (ie, a cause-effect relationship between Abeta and oxidative neurotoxicity), PC12 cells were exposed to increasing concentrations of Abeta or to oxidative stress. In agreement with the in vivo findings, either treatment caused marked induction of SOD or HO-1 in a dose-dependent fashion. These results validate the transgenic approach for the study of oxidative stress in AD and for the evaluation of antioxidant therapies in vivo.

Aging↗
PubMed1997

Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide.

Studies from several laboratories have generated evidence suggesting that oxidative stress is involved in the pathogenesis of Alzheimer's disease (AD). The finding that the amyloid beta protein (Abeta) has neurotoxic properties and that such effects are, in part, mediated by free radicals has provided insights into mechanisms of cell death in AD and an avenue to explore new therapeutic approaches. In this study we demonstrate that melatonin, a pineal hormone with recently established antioxidant properties, is remarkably effective in preventing death of cultured neuroblastoma cells as well as oxidative damage and intracellular Ca2+ increases induced by a cytotoxic fragment of Abeta. The effects of melatonin were extremely reproducible and corroborated by multiple quantitative methods, including cell viability studies by confocal laser microscopy, electron microscopy, and measurements of intracellular calcium levels. The importance of this finding is that, in contrast to conventional antioxidants, melatonin has a proposed physiological role in the aging process. Secretion levels of this hormone are decreased in aging and more severely reduced in AD. The reported phenomenon may be of therapeutic relevance in AD.

Alzheimer Disease↗
PubMed1996

Immunocytochemical expression of the 70 kD heat shock protein in ischaemic bowel disease.

Heat shock proteins (HSPs) are a family of polypeptides which are induced in response to diverse forms of cell injury including hyperthermia, anoxia, ethanol, heavy metals, and others, with a presumably protective function. Among several species of HSPs, the 70 kD protein (HSP70) is the most abundant and consistently induced in mammalian cells. Anti-HSP70 monoclonal antibody and a standard immunocytochemical method were used to study the expression of HSP70 in 28 surgical specimens of small and large intestines from patients with ischaemic bowel disease. Strong immunoreactivity was observed in viable, regenerating cells of both the crypt and surface epithelium within or adjacent to the necrotic foci in 86 per cent of the ischaemic bowel specimens. Staining was mostly cytoplasmic, but focally both cytoplasmic and nuclear. Smooth muscle cells of the muscularis mucosae in the ischaemic areas of some cases also showed immunoreactivity. On the other hand, HSP70 was not expressed in control specimens of small and large intestine or in colonic specimens of Crohn's disease, ulcerative colitis, and adenocarcinoma. These findings suggest a possible role of HSP70 in intestinal epithelial and smooth muscle cell response to ischaemic injury, especially in the recovery phase.

Aged↗
PubMed1995

Heat-shock induces abnormalities in the cellular distribution of amyloid precursor protein (APP) and APP fusion proteins.

The heat shock or stress response may play a role in the pathogenesis of Alzheimer's disease. We conducted experiments to visualize microscopically the distribution of wild type amyloid precursor protein (APP) and the behavior of an APP deletion mutant under stress. This was achieved by heat-shock treatment of cells expressing fusion recombinant APP proteins tagged with secreted placental alkaline phosphatase (SEAP). The fusion proteins were cleaved and secreted in a manner similar to wild type APP in unstressed control cells. SEAP activity was detected by cytochemical methods within the cytoplasm in less than 10% of transfected unstressed cells. Heat shocked cells showed a striking difference from the control cells in that over 90% of the stressed cells displayed strong intracytoplasmic SEAP activity occurring with Golgi-like pattern and/or membranous distribution. The effects of heat shock were not due to a peculiar behavior of the clones and depended on the APP portion of the constructs. This study shows miscompartmentalization of APP under stress. Such cellular changes may bear important implications in the processing of APP.

Alkaline Phosphatase↗
PubMed1993

Extramedullary plasmacytomas of the head and neck.

Extramedullary plasmacytomas are solitary tumors consisting of neoplastic plasma cell proliferations that occur in locations other than bone. On initial presentation they must be differentiated from multiple myeloma. This may prove to be difficult because a varying percentage may be associated at a later date with the development of multiple myeloma. Solitary extramedullary plasmacytomas represent up to 4% of nonepithelial lesions of the upper respiratory tract. From 1970 to 1990, at West Virginia University Hospitals, seven patients with solitary extramedullary plasmacytoma were identified. In four of these patients the tumor was located in the head and neck, with one tumor located in each of the following sites: temporoparietal scalp, maxillary sinus, nasopharynx, and cervical region. One patient had extensive destruction of the temporal bone, with extension intracranially to the middle cranial fossa. No patient had multiple myeloma, nor did any develop. Diagnosis was based on a combination of histology along with special immunoperoxidase staining for Ig lambda and kappa light chains. This will be demonstrated and discussed. Treatment consisted of radiotherapy in three cases, with doses ranging from 3175 to 6000 rad. One patient, treated with surgical excision, experienced a relapse at a distant site 6 years later. All patients have maintained local control and have been followed for a minimum of 1 1/2 years, with an average of 3 years. We describe our experience with these tumors and present a pertinent review of the literature. While these tumors may present as aggressive locally destructive lesions, their management should be as organ-sparing as possible because excellent control can be achieved in the majority of cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Hydrogen peroxide and reoxygenation cause prostaglandin-mediated contraction of human placental arteries and veins.

OBJECTIVE: Because our previous studies in several vascular preparations suggest that posthypoxic reoxygenation elicits tone responses by generation of hydrogen peroxide we compared the actions of reoxygenation and hydrogen peroxide on isolated human placental arteries and veins. STUDY DESIGN: Endothelium-intact and denuded arteries and veins (1 to 2 mm diameter, from normal term deliveries), incubated under 95% oxygen/5% carbon dioxide or 5% oxygen/5% carbon dioxide (balance nitrogen) and precontracted with 1 to 10 nmol/L U46619, were exposed to hypoxia (95% nitrogen/5% carbon dioxide, PO2 8 to 10 torr) followed by reoxygenation and to 1 to 100 mumol/L hydrogen peroxide in the presence and absence of the inhibitor of prostaglandin biosynthesis, 10 mumol/L indomethacin. RESULTS: In both arteries and veins posthypoxic reoxygenation or exposure to hydrogen peroxide produced vascular contraction that was eliminated or reversed to a modest relaxation by indomethacin, consistent with mediation by prostaglandins. Hypoxia after incubation with 5% oxygen, but not 95% oxygen, caused a modest prostaglandin-independent relaxation. Removal of the endothelium did not alter any of these responses. CONCLUSION: Placental arteries and veins show a similar prostaglandin-mediated contraction to hydrogen peroxide and posthypoxic reoxygenation, consistent with a possible involvement of hydrogen peroxide in the response to reoxygenation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Properties of an endogenous arachidonic acid--elicited relaxing mechanism in human placental vessels.

OBJECTIVE: Our objective was to examine the action of arachidonic acid on tone in isolated human placental arteries and veins (1 to 2 mm diameter) for mechanisms involving endothelium-derived mediators, the stimulation of guanylate cyclase, and prostaglandin and cytochrome P450 metabolites. STUDY DESIGN: Pharmacologic probes and endothelium-removal were used to examine the mechanism of relaxation to arachidonic acid (10 nmol/L to 10 mumol/L) observed in placental arteries and veins obtained after delivery from uncomplicated term pregnancies and precontracted with prostaglandin F2 alpha. RESULTS: Neither removal of the endothelium nor inhibition of prostaglandin biosynthesis with 10 mumol/L indomethacin, arginine-derived nitric oxide formation with 30 mumol/L nitro-L-arginine, or guanylate cyclase stimulation with 10 mumol/L LY83583 altered the observed relaxation to arachidonic acid in either preparation. However, this relaxation was markedly attenuated by 30 mumol/L proadifen (SKF-525A), an inhibitor of cytochrome P450, suggestive of a role for arachidonic acid metabolism by an epoxygenase or monooxygenase pathway. CONCLUSION: Human placental arteries and veins possess an endogenous mechanism of relaxation to arachidonic acid, which seems to be mediated by metabolites formed by a cytochrome P450 enzyme. This endogenous relaxation mechanism could function as a suppressor of vasospasm in the placental circulation.

Arachidonic Acid↗
PubMed1992

Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer's disease.

Membrane and cytoskeletal structures are known targets of oxidative injury. Brains from patients with Alzheimer's disease have cytoskeletal abnormalities and platelet and possible neuronal membrane lesions. The authors have recently demonstrated that superoxide anion is a powerful inducer of heat-shock protein synthesis, and have also shown that in response to oxidative stress or hyperthermia, intracellular levels of antioxidant enzymes increase to several folds. Whether the aforementioned mechanisms play a role in Alzheimer's disease has been suggested but is not totally established. While exploring this possibility, tissue sections from five brains with Alzheimer's disease and five neuropathologically normal age-matched controls were immunostained with polyclonal antibodies against superoxide dismutase (CuZn- and Mn- forms) and catalase. A standard avidin-biotin-peroxidase method was used for antigen detection. A subgroup of neurofibrillary tangles (15-25%) and senile plaques (50%) showed immunoreactivity for both enzymes with a staining pattern similar (but not identical) to that usually observed with antibodies against ubiquitin. Senile plaques displayed a granular pattern of immunostaining. Amyloid cores in mature classical plaques remained unstained. In addition, occasional elements with features consistent with reactive glial cells were strongly immunostained. Tangle-free neurons in both diseased and control brains showed weak to absent intracytoplasmic immunoreactivity. The immunoreactivity was totally abolished by preincubation of the primary antibodies with the corresponding purified antigens. These findings support the hypothesis that oxidative stress may be involved in the pathogenesis of Alzheimer's disease.

Alzheimer Disease↗
PubMed1992

The genesis of the senile plaque. Further evidence in support of its neuronal origin.

Senile plaques are among the most conspicuous neuropathologic changes found in the brains of elderly individuals and patients with Alzheimer's disease (AD). The origin of the amyloid beta protein (A beta P) that accumulates in senile plaques continues to be highly controversial. Recently, using quantitative immunohistochemistry and computerized image analysis, we obtained evidence that at least a subset of early ("diffuse") senile plaques originate from neurons. In the current investigation, we employed monoclonal antibodies to A beta P and the same computerized methodology to examine in further detail the quantitative patterns of A beta P deposition in diffuse plaques in a population of intellectually intact elderly individuals. The presence of neurocentric concentration gradients of A beta P accumulation was confirmed in this study. Most significantly, this was the most predominant pattern of early amyloid deposition in the population studied. The highest concentration of A beta P was centered around neuronal cell bodies or their processes, and occasionally along neuronal plasma membranes. Computerized images showed patterns that can be interpreted as a pathogenetic sequence ranging from initial neurogenic concentration gradients centered around one single neuron to larger deposits (diffuse plaques) composed of several "anastomosing" gradients involving several adjacent neurons. It is proposed that the described very early deposits constitute the initial stage in the development of the senile plaque. Although this study does not fully prove that the accumulated A beta P is synthesized in the neuron or neuronal process it surrounds, the images herein presented suggest that neurons are the initial nidus of plaque formation.

Alzheimer Disease↗
PubMed1991

Image analysis microspectroscopy shows that neurons participate in the genesis of a subset of early primitive (diffuse) senile plaques.

Amyloid is a component of the senile plaques that characterize one of the major neuropathologic changes in patients with Alzheimer's disease (AD). The sequence of events leading to the accumulation of amyloid precursors in senile plaques is unknown. In previous studies, the authors have shown that congophilic deposits in a subset of mature amyloid plaques are angiocentric. In this study, the authors used image analysis microspectroscopy and an antibody directed against a synthetic beta-protein (beta) or A4 sequence to examine the distribution patterns of this protein in serial sections from brains of patients with AD and in normal aged brains after quantitative immunohistochemistry. Image analysis of early primitive plaques disclosed two main patterns of early beta/A4 deposition, which consisted of neurocentric and angiocentric decreasing concentration gradients. In most instances, these gradients were not recognizable by the naked eye but appeared strikingly conspicuous after image subtraction and pseudocoloring. The described neurocentric gradients suggest that deposition of this protein, in at least some early primitive plaques, is related to neurons and possibly originates from these cells. The opposite viewpoint, i.e., that peripherally synthesized beta/A4 protein would 'sink in' toward neurons, is not supported because in very early plaques the highest immunoreactivity within the gradient was the neuronal body itself. A hypothesis is offered to reconcile the presence of both neurocentric and angiocentric depositions of these substances.

Aged↗
PubMed1987

Antioxidant enzymes and survival of normal and simian virus 40-transformed mouse embryo cells after hyperthermia.

Relative cell survival and activity of the free radical scavenging enzymes superoxide dismutase, catalase, and glutathione peroxidase were measured in cloned normal (MEA) and SV40-transformed (SVMEA) mouse embryo cells exposed at 44 degrees C for 0-3 h. At 37 degrees C, all three enzymes were 2-5 times higher in MEA than in SVMEA. Hyperthermia did not significantly alter enzyme levels in either cell line but selectively reduced transformed cell survival to less than 5% while relative survival of normal cells remained above 75%. The latter, however, could be reduced to 25% when normal cells were pretreated with 3 mM diethyldithiocarbamate, an inhibitor of copper- and zinc-containing superoxide dismutase. Similar treatment rendered SVMEA extremely thermosensitive. On the other hand, sublethal heat treatment (15 min at 45 degrees C) of cultured cells resulted in a relative thermal resistance upon subsequent exposure to 45 degrees C for 1-4 h. This induced thermotolerance was associated with a rise in antioxidant enzyme levels and both became significant only 4-6 h after the initial heat treatment. Induced enzyme and thermotolerance levels in transformed cells remained, nonetheless, far below those of normal cells. The data show that inherent (in MEA) as well as induced (in SVMEA) thermotolerance is associated with high antioxidant enzyme levels while the reverse is true in the case of inherent (in SVMEA) and induced (in MEA) thermosensitivity. These findings suggest that increased production of oxygen free radicals may be involved in hyperthermic cell injury, which then becomes a function of basal or inducible levels of antioxidant enzymes. Induction of the latter by hyperthermia is apparently inefficient in transformed cells making them more vulnerable. Enzyme induction seems also to require a lag period of 4-6 h suggesting the possible involvement of an intermediate inducer(s) at molecular level. The so-called heat shock proteins may be candidates for such a role.

Animals↗
PubMed1987

Ovarian follicular fluid beta-endorphin levels in normal and polycystic ovaries.

The possibility of local ovarian production of beta-endorphin prompted us to measure beta-endorphin levels in 19 follicular fluid samples obtained from normal ovaries and compare them with beta-endorphin plasma levels in 19 women with normal ovulation. beta-Endorphin was extracted through Sepharose-treated chromatography columns and assayed with a specific anti-beta-endorphin antibody. Follicular fluid beta-endorphin levels (21.3 +/- 10.8 pg/ml) were significantly higher (p less than 0.01) than the plasma levels (15.5 +/- 3.35 pg/ml). There was no significant correlation between plasma and follicular fluid beta-endorphin concentrations. Follicles greater than 1 cm in size contained more beta-endorphin than follicles less than 1 cm in size (22.7 +/- 3.5 versus 18.7 +/- 4.4 pg/ml, p less than 0.05). Five follicular fluid samples were obtained from polycystic ovaries. The mean beta-endorphin content (45.1 +/- 7.7 pg/ml) in these follicles was significantly higher than that of normal ovaries (p = 0.001). It is concluded that the ovaries produce beta-endorphin and that polycystic ovaries produce more beta-endorphin than normal ovaries.

Endorphins↗
PubMed1987

Immunoreactive beta-endorphin in ovarian sex cord-stromal tumors.

The possible production of the opioid polypeptide beta-endorphin (beta-EP) was investigated in paraffin-embedded tissue from 17 ovarian tumors with the use of a specific anti-beta-EP antibody and the avidin-biotin-peroxidase staining technique. Only sex cord-stromal tumors (ten cases) showed positive staining. Strong beta-EP immunoreactivity was present in Leydig's cells of Sertoli-Leydig cell tumors; weaker sporadic staining was present in cells of granulosa cell tumors, and faint staining was present in occasional, luteinized theca cells of fibrothecomata. These findings suggest that cells with the sex cord-stromal phenotype that are capable of steroid production can also produce beta-EP. The latter may be a component of the "functional" status associated with some ovarian sex cord-stromal tumors and may serve as a helpful marker in distinguishing this type of tumors from germ cell or epithelial neoplasms.

Cystadenocarcinoma↗
PubMed1986

Immunoreactive beta-endorphin in human ovaries.

Beta-endorphin (beta-EP) immunostainable cells were demonstrated in human ovarian tissue using a non-cross-reacting anti-beta-EP serum and the avidin-biotin-peroxidase detection technique. In ovaries from ovulating and premenopausal women, beta-EP immunoreactivity was localized in the luteinized cells of theca interna of maturing follicles with almost negligible staining in granulosa cells; cells of primary follicles did not stain. In corpora lutea, luteinized cells in both theca interna and granulosa, layers were equally positive. In postmenopausal ovaries, staining was detectable only in scattered luteinized stromal cells. This is the first report on the presence of immunoreactive beta-EP in human ovaries, in which beta-EP seems to be produced by the same sex cord cells engaged in active steroidogenesis and may be under gonadotropin central regulation. The significance of this finding is discussed.

Endorphins↗
PubMed1984

Heat shock protein synthesis and cell survival in clones of normal and simian virus 40-transformed mouse embryo cells.

Exposure to hyperthermia induces the synthesis of a set of highly conserved polypeptides known as heat shock proteins (HSPs) in cells of most organisms. Since it has been suggested that these proteins may enhance cell survival by protecting cells from heat-inflicted damage, we studied the synthesis of the major HSPs (Mr 70,000 and 85,000) in clones of normal and SV40-transformed mouse embryo cells. These transformed cells had higher basal HSP levels and consistently synthesized the major HSPs at a higher rate both at physiological temperature and after exposure to heat shock (43-45 degrees). Parallel determination of cell survival showed that the transformed cells were, nevertheless, more susceptible to killing by hyperthermia than were their normal counterparts. Therefore, we conclude that the higher intrinsic resistance of the normal cells to killing by heat is not directly related to basal HSP levels or to the degree to which synthesis of these proteins is induced following exposure to hyperthermia. Considering the abnormal energy metabolism of transformed cells and the known sensitivity of HSP synthesis to energy source restriction, we hypothesize that both basal HSP levels and their induction by heat shock are related to alterations in energy metabolism.

Animals↗