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Biomedical subjects

S Mandel

Publications and source records attributed to S Mandel.

At least 19 recordsLinked to original sources
PubMed2006

The copper chelator, D-penicillamine, does not attenuate MPTP induced dopamine depletion in mice.

In MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and 6-hydroxydopamine induced dopaminergic neurotoxicity and Parkinson's disease iron accumulates in substantia nigra pars compacta which has been suggested to participate in oxidative stress induced neurodegeneration. Pretreatment with iron chelators desferal, clioquinol, VK-28 and M30 are neuroprotective in both models. To determine the specificity of chelation neuroprotective activity we have examined the effect of D-penicillamine, a relatively specific copper chelator, in the mice model of MPTP-induced dopamine depletion. Our studies show that D-penicillamine, employed for removal of copper in Wilson disease is relatively weak in preventing dopaminergic neurotoxicity induced by MPTP, as compared to iron chelators previously studied. The results indicate that for prevention of MPTP-induced dopamine depletion and dopamine neurodegeneration, iron rather than copper chelation may be more effective and specific.

Acetylcysteine↗
PubMed2006

Reduction of iron-regulated amyloid precursor protein and beta-amyloid peptide by (-)-epigallocatechin-3-gallate in cell cultures: implications for iron chelation in Alzheimer's disease.

Brain iron dysregulation and its association with amyloid precursor protein (APP) plaque formation are implicated in Alzheimer's disease (AD) pathology and so iron chelation could be considered a rational therapeutic strategy for AD. Here we analyzed the effect of the main polyphenol constituent of green tea, (-)-epigallocatechin-3-gallate (EGCG), which possesses metal-chelating and radical-scavenging properties, on the regulation of the iron metabolism-related proteins APP and transferrin receptor (TfR). EGCG exhibited potent iron-chelating activity comparable to that of the prototype iron chelator desferrioxamine, and dose dependently (1-10 microm) increased TfR protein and mRNA levels in human SH-SY5Y neuroblastoma cells. Both the immature and full-length cellular holo-APP were significantly reduced by EGCG, as shown by two-dimensional gel electrophoresis, without altering APP mRNA levels, suggesting a post-transcriptional action. Indeed, EGCG suppressed the translation of a luciferase reporter gene fused to the APP mRNA 5'-untranslated region, encompassing the APP iron-responsive element. The finding that Fe(2)SO(4) reversed the action of EGCG on APP and TfR proteins reinforces the likelihood that these effects are mediated through modulation of the intracellular iron pool. Furthermore, EGCG reduced toxic beta-amyloid peptide generation in Chinese hamster ovary cells overexpressing the APP 'Swedish' mutation. Thus, the natural non-toxic brain-permeable EGCG may provide a potential therapeutic approach for AD and other iron-associated disorders.

Amyloid beta-Peptides↗
PubMed2006

Involvement of multiple survival signal transduction pathways in the neuroprotective, neurorescue and APP processing activity of rasagiline and its propargyl moiety.

Our recent studies aimed to elucidate the molecular and biochemical mechanism of actions of the novel anti-Parkinson's drug, rasagiline, an irreversible and selective monoamine oxidase (MAO)-B inhibitor and its propargyl moiety, propargylamine. In cell death models induced by serum withdrawal in rat PC12 cells and human SH-SY5Y neuroblastoma cells, both rasagiline and propargylamine exerted neuroprotective and neurorescue activities via multiple survival pathways, including: stimulation of protein kinase C (PKC) phosphorylation; up-regulation of protein and gene levels of PKCalpha, PKCepsilon and the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w; and up-regulation of the neurotrophic factors, BDNF and GDNF mRNAs. Rasagiline and propargylamine inhibited the cleavage and subsequent activation of pro-caspase-3 and poly ADP-ribose polymerase. Additionally, these compounds significantly down-regulated PKCgamma mRNA and decreased the level of the pro-apoptotic proteins, Bax, Bad, Bim and H2A.X. Rasagiline and propargylamine both regulated amyloid precursor protein (APP) processing towards the non-amyloidogenic pathway. These structure-activity studies have provided evidence that propargylamine promoted neuronal survival via neuroprotective/neurorescue pathways similar to that of rasagiline. In addition, recent study demonstrated that chronic low doses of rasagiline administered to mice subsequently to 1 methyl-4 phenyl 1,2,3,6 tetrahydropyridine (MPTP), rescued dopaminergic neurons in the substantia nigra pars compacta via activation of the Ras-PI3K-Akt survival pathway, suggesting that rasagiline may possess a disease modifying activity.

Amyloid beta-Protein Precursor↗
PubMed2005

Genome-wide linkage scans for prediabetes phenotypes in response to 20 weeks of endurance exercise training in non-diabetic whites and blacks: the HERITAGE Family Study.

AIMS/HYPOTHESIS: Impaired insulin secretion, insulin action, insulin-independent glucose effectiveness, glucose tolerance and the associated abnormalities in insulin and glucose metabolism phenotypes are precursors of type 2 diabetes. Genome-wide multipoint variance component linkage scans were carried out using 654 markers to identify quantitative trait loci for insulin sensitivity, acute insulin response to glucose, disposition index and glucose effectiveness training responses in whites and blacks in the HERITAGE Family Study. METHODS: These phenotypes were obtained from an IVGTT with the minimal model. The distributions of insulin sensitivity, acute insulin response to glucose and disposition index training responses (post-training minus baseline) were approximately normalised using a square-root transformation. All phenotypes were adjusted for the effects of age, BMI and their respective baseline values within sex and generation by race prior to linkage scans. RESULTS: In blacks, a promising linkage with a maximum lod score of 3.1 on 19q (54-62 Mb) for glucose effectiveness training response was found. Six interesting linkages with lod scores of at least 1.0 were found for disposition index training response in whites. They included 1p (30 Mb), 3q (152 Mb), 6p (23-42 Mb), 7q (95-96 Mb), 10p (15 Mb) and 12q (119-126 Mb). CONCLUSIONS/INTERPRETATION: Quantitative trait loci for 20 weeks of endurance exercise training responses in insulin action and glucose metabolism phenotypes were found on chromosome 19q as well as 6p and 7q, with nominal (6p, 7q) but consistent (6p) linkages across the races.

Adolescent↗
PubMed2005

Green tea polyphenol (-)-epigallocatechin-3-gallate induces neurorescue of long-term serum-deprived PC12 cells and promotes neurite outgrowth.

Our previous studies have shown that the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) prevents neuronal cell death caused by several neurotoxins. The present study sought to determine the neuroprotective effect of EGCG when it is administered after the induction of cell damage ('neurorescue'). In an attempt to imitate a progressive mode of death, PC12 cells were initially subjected to serum-starvation conditions for a period of 1 or 3 days before administration of EGCG (0.1-10 microM) for up to 3 days. In spite of the high percentage of cell death, single or repetitive administration of EGCG (1 microM) significantly attenuated cell death. The neurorescue effect of EGCG was abolished by pre-treatment with the protein kinase C inhibitor GF109203X (2.5 microM), suggesting the involvement of the protein kinase C pathway in neurorescue by the drug. This is consistent with the rapid (15 min) translocation of the protein kinase C alpha isoform to the cell membrane in response to EGCG. The correlative neurite outgrowth activity of EGCG on PC12 cells may also contribute to its neurorescue effect. The present findings suggest that EGCG may have a positive impact on aging and neurodegenerative diseases to retard or perhaps even reverse the accelerated rate of neuronal degeneration.

Animals↗
PubMed2004

Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes.

Gene expression profiling of human substantia nigra pars compacta (SNpc) from Parkinson's disease (PD) patients, was examined employing high density microarrays. We identified alterations in the expression of 137 genes, with 68 down regulated and 69 up regulated. The down regulated genes belong to signal transduction, protein degradation (e.g. ubiquitin-proteasome subunits), dopaminergic transmission/metabolism, ion transport, protein modification/phosphorylation and energy pathways/glycolysis functional classes. Up-regulated genes, clustered mainly in biological processes involving cell adhesion/cytoskeleton, extracellular matrix components, cell cycle, protein modification/phosphorylation, protein metabolism, transcription and inflammation/stress (e.g. key iron and oxygen sensor EGLN1). One major finding in the present study is the particular decreased expression of SKP1A, a member of the SCF (E3) ligase complex specifically in the substantia nigra (SN) of sporadic parkinsonian patients, which may lead to a wide impairment in the function of an entire repertoire of proteins subjected to regulatory ubiquitination. These findings reveal novel players in the neurodegenerative scenario and provide potential targets for the development of novel drug compounds.

Aged↗
PubMed2004

Placental protein 13 (PP-13): effects on cultured trophoblasts, and its detection in human body fluids in normal and pathological pregnancies.

Placental tissue protein 13 (PP-13), one of the 56 known placental proteins identified till today, was purified from placentas obtained from women at delivery, and used to evoke antibodies against it. The purified PP-13 was lysed to peptides, which were sequenced, leading to the full-length cDNA sequencing and its expression in Escherichia coli. Sequence analysis in databases showed homology to the galectin family. Of the various antibody preparations developed, a pair of monoclonal antibodies (MAbs) coupled to the recombinant PP-13 (PP-13-R) was used for the immunodetection of PP-13 in pregnant women's serum with the solid-phase ELISA format. With a dynamic range of 25-500 pg/mL with no background in non-pregnant women's serum and men's serum, the ELISA test was suitable for the detection of PP-13 in the 1st, 2nd, and 3rd trimesters. PP-13 levels slowly increase during pregnancy. In the 1st trimester, lower than normal PP-13 levels were found in fetal growth restriction (IUGR), preeclampsia (PE), and particularly in early PE (<34 weeks of gestation). In the 2nd and 3rd trimesters, higher than normal concentrations were found in PE, IUGR and in preterm delivery (PTD). Application of PP-13 to cultured trophoblasts elicited depolarization carried by calcium ions, followed by liberation of linoleic and arachidonic acids from the trophoblast membrane, and a subsequent elevation of prostacyclin and thromboxane. These effects were negligible when PP-13 derived from the placentas of patients with IUGR, PE or PTD was used. The results are discussed in view of the potential utilization of PP-13 for early serum screening to assess the risk to develop placental insufficiency, coupled to a differential analysis of the various pathologies by analyzing cultured trophoblasts.

Amino Acid Sequence↗
PubMed2003

The use of laparoscopy in abdominal emergencies.

BACKGROUND: The purpose of this article is to describe our experience using laparoscopy in the management of emergent and acute abdominal conditions. METHODS: Between March 1997 and November 2001, 277 consecutive minimally invasive procedures were performed for various nontrauma surgical emergencies. The indications for operation were nonspecific abdominal pain in 129 cases (46%), peritonitis in 64 cases (23%), small bowel obstruction in 52 cases (19%), complications after previous surgery or invasive procedures in 24 cases (9%), and sepsis of unknown origin in 8 cases (3%). RESULTS: Laparoscopy obtained a correct diagnosis in 98.6% of the cases. In 207 patients (75%), the procedure was completed laparoscopically. An additional 35 patients (12.5%) required a target incision. The remaining 35 patients (12.5%) underwent formal laparotomy. The morbidity rate was 5.8%. No laparoscopy-related mortality was observed. CONCLUSIONS: For patients with abdominal emergencies, the laparoscopic approach provides diagnostic accuracy and therapeutic options, avoids extensive preoperative studies, averts delays in operative intervention, and appears to reduce morbidity.

Abdomen↗
PubMed2003

Inclusion body myositis in connective tissue disorders: case report and review of the literature.

We report a patient with systemic lupus erythematosus (SLE) and secondary Sjögren's syndrome (SS) who developed inclusion body myositis (IBM) which, contrary to the typical presentation of this disorder, was symmetrical in nature although the diagnosis was only made after electron microscopy was performed. Therapy with increased doses of methotrexate proved to be beneficial, with the patient having full recovery after 8 months of therapy. It appears that a subset of IBM may be related to autoimmune disorders, an issue that was disputed in the past, and these patients may have a better prognosis than typical IBM patients. This is the first case report of IBM in a patient who had the dual diagnosis of SLE and SS.

Biopsy, Needle↗
PubMed2001

Which plasma antioxidants are most related to fruit and vegetable consumption?

Substantial evidence suggests that fruit and vegetable intake reduces the risk of some cancers and other chronic diseases. While a varied diet containing fruits and vegetables may confer benefits greater than those of any single nutrient, it would be useful to have data on the plasma nutrients most influenced by fruit and vegetable intake. The authors examined the correlation between fruit and vegetable intake as measured by the abbreviated CLUE II food frequency questionnaire and several plasma antioxidants. This study includes 116 male subjects aged 35-72 years who were nonsmokers and nonusers of vitamin supplements and who provided blood samples in the CLUE II Study in Washington County, Maryland. Plasma was assayed for ascorbic acid, beta-carotene, beta-cryptoxanthin, and alpha- and gamma-tocopherol. Lipid- and energy-adjusted partial correlation for the relation with fruit and vegetable intake was r = 0.64 for ascorbic acid, r = 0.44 for beta-carotene, and r = 0.50 for beta-cryptoxanthin. While this study does not address efficacy, the stronger association of ascorbic acid with fruit and vegetable intake seen here may imply that ascorbic acid is an important component of the protective effect seen for fruits and vegetables in numerous epidemiologic studies.

Adult↗
PubMed2001

Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV Infection Recruitment Network.

BACKGROUND: The optimal approach for diagnosing primary HIV-1 infection has not been defined. OBJECTIVE: To determine the usefulness of symptoms and virologic tests for diagnosing primary HIV-1 infection. DESIGN: Prospective cohort study. SETTING: A teaching hospital in Los Angeles and a university research center in San Diego, California. PATIENTS: 436 patients who had symptoms consistent with primary HIV infection. MEASUREMENTS: Clinical information and levels of HIV antibody, HIV RNA, and p24 antigen. RESULTS: Primary infection was diagnosed in 54 patients (12.4%). The sensitivity and specificity of the p24 antigen assay were 88.7% (95% CI, 77.0% to 95.7%) and 100% (CI, 99.3% to 100%), respectively. For the HIV RNA assay, sensitivity was 100% and specificity was 97.4% (CI, 94.9% to 98.9%). Fever, myalgia, rash, night sweats, and arthralgia occurred more frequently in patients with primary infection (P < 0.05). CONCLUSIONS: No sign or symptom allows targeted screening for primary infection. Although assays for HIV RNA are more sensitive than those for p24 antigen in diagnosing primary infection, they are more expensive and are more likely to yield false-positive results.

Antibodies, Viral↗
PubMed2001

Laryngeal myasthenia gravis: report of 40 cases.

Myasthenia gravis, an autoimmune disorder of the neuromuscular junction, is usually recognized because of ocular complaints or generalized weakness. We report a series of 40 patients who presented with dysphonia as their initial and primary complaint. Diagnostic testing included strobovideolaryngoscopy, electromyography (EMG) with repetitive stimulation and Tensilon testing, and laboratory and radiographic evaluation. Strobovideolaryngoscopy most commonly revealed fluctuating impairment of vocal fold mobility, either unilateral or bilateral. EMG detected evidence of neuromuscular junction abnormalities in all patients. Only one patient had evidence of antiacetylcholine receptor (ACh-R) antibodies, but many other abnormalities suggestive of autoimmune dysfunction were present. Pyridostigmine therapy was initiated in 34 patients but was not tolerated in 4. Of the remaining 30 patients, 23 reported improvement of symptoms. We conclude that myasthenia gravis can present with symptoms confined primarily to the larynx and should be included in the differential diagnosis of dysphonia.

Adult↗
PubMed2001

Laryngeal manifestations of postpoliomyelitis syndrome.

Postpoliomyelitis syndrome (PPS) is a disease that may occur in survivors of acute poliomyelitis several decades after their initial infection. It can present as dysphonia, with vocal weakness and fatigue. Swallowing, respiratory, and other laryngopharyngeal symptoms may be manifestations of the disease or they may represent worsening of previously stable and compensated deficits. Three cases of laryngeal changes in PPS with videostroboscopic and laryngeal electromyography findings highlight the features of this disorder. We review possible etiologies of laryngeal PPS, diagnostic criteria, and treatment, as well as the current literature.

Acute Disease↗
PubMed2001

Gene expression analysis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice model of Parkinson's disease using cDNA microarray: effect of R-apomorphine.

To establish the possible roles of oxidative stress, inflammatory processes and other unknown mechanisms in neurodegeneration, we investigated brain gene alterations in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of Parkinson's disease using Atlas mouse cDNA expression array membrane. The expression of 51 different genes involved in oxidative stress, inflammation, glutamate and neurotrophic factors pathways as well as in still undefined processes, such as cell cycle regulators and signal transduction molecules, was differentially affected by the treatment. The present study indicates the involvement of an additional cascade of events that might act in parallel to oxidative stress and inflammation to converge eventually into a common pathway leading to neurodegeneration. The attenuation of these gene changes by R-apomorphine, an iron chelator-radical scavenger drug, supports our previous findings in vivo where R-apomorphine was neuroprotective.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Green tea polyphenol (-)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration.

In the present study we demonstrate neuroprotective property of green tea extract and (-)-epigallocatechin-3-gallate in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice model of Parkinson's disease. N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxin caused dopamine neuron loss in substantia nigra concomitant with a depletion in striatal dopamine and tyrosine hydroxylase protein levels. Pretreatment of mice with either green tea extract (0.5 and 1 mg/kg) or (-)-epigallocatechin-3-gallate (2 and 10 mg/kg) prevented these effects. In addition, the neurotoxin caused an elevation in striatal antioxidant enzymes superoxide dismutase (240%) and catalase (165%) activities, both effects being prevented by (-)-epigallocatechin-3-gallate. (-)-Epigallocatechin-3-gallate itself also increased the activities of both enzymes in the brain. The neuroprotective effects are not likely to be caused by inhibition of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine conversion to its active metabolite 1-methyl-4-phenylpyridinium by monoamine oxidase-B, as both green tea and (-)-epigallocatechin-3-gallate are very poor inhibitors of this enzyme in vitro (770 microg/mL and 660 microM, respectively). Brain penetrating property of polyphenols, as well as their antioxidant and iron-chelating properties may make such compounds an important class of drugs to be developed for treatment of neurodegenerative diseases where oxidative stress has been implicated.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Effects of R- and S-apomorphine on MPTP-induced nigro-striatal dopamine neuronal loss.

In order to establish whether the antioxidant and iron-chelating activities of R-apomorphine (R-APO), a D(1)-D(2) receptor agonist, may contribute to its neuroprotective property, its S-isomer, which is not a dopamine agonist, was studied. The neuroprotective property of R- and S-APO has been studied in the MPTP model of Parkinson's disease (PD). Both S-APO (0.5-1 mg/kg, subcutaneous) and R-APO (10 mg/kg) pretreatment of C57-BL mice, protected against MPTP (24 mg/kg, intraperitoneally) induced dopamine (DA) depletion and reduction in tyrosine hydroxylase (TH) activity. However, only R-APO prevented nigro-striatal neuronal cell degeneration, as indicated by the immunohistochemistry of TH positive neurones in substantia nigra and by western analysis of striatal TH content. R-APO prevented the reduction of striatal-GSH and the increase in the ratio of GSSG over total glutathione, caused by MPTP treatment. In vitro both R-APO and S-APO inhibited monoamine oxidase A and B activity at relatively high concentrations (100 and 300 micromol/L, respectively). The elevated activity of TH induced by the two enantiomers may contribute to the maintenance of normal DA levels, suggesting that one of the targets of these molecules may involve upregulation of TH activity. It is suggested that the antioxidant and iron-chelating properties, possible monoamine oxidase inhibitory actions, together with activation of DA receptors, may participate in the mechanism of neuroprotection by APO enantiomers against MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗