Search PubMed⌕ Search

Biomedical subjects

J M Schmidt

Publications and source records attributed to J M Schmidt.

At least 55 records · Page 3Linked to original sources
PubMed1996

Antineoplastic agents 338. The cancer cell growth inhibitory. Constituents of Terminalia arjuna (Combretaceae).

By means of bioassay-guided separation methods, the cancer cell growth inhibitory constituents residing in the bark, stem and leaves of the Mauritius medicinal plant Terminalia arjuna (Combretaceae) were examined. The cancer cell line active components were found to be gallic acid, ethyl gallate, and the flavone luteolin. Only gallic acid was previously known to occur in this plant. Luteolin has a well established record of inhibiting various cancer cell lines and may account for most of the rationale underlying the use of T. arjuna in traditional cancer treatments. Luteolin was also found to exhibit specific activity against the pathogenic bacterium Neisseria gonorrhoeae.

Antineoplastic Agents↗
PubMed1996

Antineoplastic agents. 340. Isolation and structural elucidation of bryostatins 16-18.

Separation of two trace cancer cell growth inhibitory (P388 leukemia) fractions from about 1000 kg of wet Gulf of Mexico Bugula neritina (Bryozoa) has led to the isolation of bryostatins 16-18 (2-4). A combination of HRFABMS and high-field (400 MHz) 1H- and 13C-NMR spectral analyses were employed to assign the structures. The three new 20-desoxybryostatins 16 (2), 17 (3), and 18 (4) showed significant growth inhibitory activity (P388 ED50, 2, 9.3 x 10(-3) micrograms/mL, 3, 1.9 x 10(-2) micrograms/mL, and 4, 3.3 x 10(-3) micrograms/mL) against murine P388 lymphocytic leukemia.

Animals↗
PubMed1995

Three-dimensional structure of bovine heart fatty-acid-binding protein with bound palmitic acid, determined by multidimensional NMR spectroscopy.

The three-dimensional structure of the holo form of recombinant cellular bovine heart fatty-acid-binding protein (H-FABPc), a polypeptide of 133 amino acid residues with a molecular mass of 15 kDa, has been determined by multidimensional homonuclear and heteronuclear NMR spectroscopy applied to uniformly 15N-labeled and unlabeled protein. A nearly complete set of 1H and 15N chemical shift assignments was obtained. A total of 2329 intramolecular distance constraints and 42 side-chain chi 1 dihedral-angle constraints were derived from cross-relaxation and J coupling information. 3D nuclear Overhauser enhancement and exchange spectroscopy combined with heteronuclear multiple-quantum coherence (NOESY-HMQC) experiments, performed on a sample of uniformly 13C-labeled palmitic acid bound to unlabeled cellular heart fatty-acid-binding protein revealed 10 intermolecular contacts that determine the orientation of the bound fatty acid. An ensemble of protein conformations was calculated with the distance-geometry algorithm for NMR applications (DIANA) using the redundant dihedral-angle constraint (REDAC) strategy. After docking the fatty acid into the protein, the protein-ligand arrangement was subject to distance-restrained energy minimization. The overall conformation of the protein is a beta-barrel consisting of 10 antiparallel beta-strands which form two nearly orthogonal beta-sheets of five strands each. Two short helices form a helix-turn-helix motif in the N-terminal region of the polypeptide chain. The palmitic acid is bound within the protein in a U-shaped conformation close to the two helices. The obtained solution structure of the protein is consistent with a number of fatty-acid-binding-protein crystal structures.

Amino Acid Sequence↗
PubMed1995

Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6(1a)

The antineoplastic constituents of Combretum caffrum (Eckl. and Zeyh) Kuntze (Combretaceae family), a species indigenous to South Africa, have been investigated. Subsequently we isolated a series of closely related bibenzyls, stilbenes, and phenanthrenes from C. caffrum. Some of the stilbenes proved to be potent antimitotic agents which inhibited both tubulin polymerization and the binding of colchicine to tubulin. Combretastatin A-4 has been shown to be the most potent cancer cell growth inhibitor of the series. Presently this cis-stilbene is the most effective inhibitor of colchicine binding to tubulin and the simplest natural product yet described with such potent antitubulin effects. Combretastatin A-4, A-5, and A-6 were also found to inhibit growth of Neisseria gonorrhoeae. Details of the isolation and syntheses of combretastatins A-4 (2a), A-5 (2c), and A-6 (3a) have been described.

Anti-Bacterial Agents↗
PubMed1995

6-Methylene progesterone is cytotoxic to human cancer cell lines independent of its 5-alpha-reductase activity.

This investigation examined the effects of 6-methylene progesterone (6MP), an irreversible inhibitor of 5-alpha-reductase, on prostatic cancer (PC) cell lines. Dose titration microculture tetrazolium assays were used to evaluate cytotoxicity in cultures treated for 72 hr with 6MP (0-20 micrograms/ml). An androgen-sensitive cell line, LNCaP, was drug-sensitive with a mean 50% lethal dose value (LD50) of 2.632 +/- 0.103. Hormone-resistant PC cell lines 1-LN, DU 145, and PC3 also demonstrated sensitivity with LD50 values between 0.8579-1.110 micrograms/ml with a group average of 1.023 +/- 0.082 micrograms/ml. Increasing dosages of dihydrotestosterone in the growth media did not alter 6MP cytotoxicity in androgen-insensitive prostatic cancer cell lines. No correlation between androgen-responsiveness and 6MP-induced cytotoxicity was observed. In nonprostatic malignancies, 6MP inhibited adenocarcinoma cell lines with a mean group LD50 value of 0.7772 micrograms/ml +/- 0.110. J82, a transitional cell carcinoma cell line of bladder origin, exhibited an average LD50 value of 1.041 +/- 0.260. In an epidermoid cervical cancer cell line, ME180, an LD50 value of 0.5356 micrograms/ml +/- 0.010 was noted. In a melanoma cell line, Du Mel 6, a mean LD50 of 0.7428 +/- 0.023 micrograms/ml was achieved with 6MP. We conclude that 6MP, a novel 5-alpha-reductase inhibitor, has potential as a cytotoxic agent in prostatic carcinoma and additional human malignancies. Further study is justified.

Cholestenone 5 alpha-Reductase↗
PubMed1995

Chicken perinatal troponin Ts are generated by a combination of novel and phylogenetically conserved alternative splicing pathways.

During perinatal development, avian and mammalian skeletal muscles express a novel set of troponin T (TnT) isoforms with higher M(r)s and more acidic pIs than their adult counterparts. In mammals, these TnTs result from the incorporation of a developmentally regulated 5'-fetal exon into fast TnT mRNAs. To determine whether chicken perinatal TnTs are generated by a similar mechanism, we sequenced 40 chicken TnT 5'-cDNAs from perinatal and adult pectoralis. Evidence for five 5'-exons not present in the mammalian gene was found, including one, y, whose splicing is developmentally regulated. Although none of these new exons are homologous with the mammalian fetal exon, their alternative splicing, superimposed on three conserved splicing patterns of the phylogenetically shared 5'-exons, generates the chicken perinatal TnT isoforms. These observations indicate that chicken, and most likely other avian species, evolved an independent 5'-alternative splicing mechanism to generate perinatal TnTs that have the same biophysical, and presumably functional, properties as their mammalian homologs.

Aging↗
PubMed1995

Determination of heteronuclear three-bond J-coupling constants in peptides by a simple heteronuclear relayed E.COSY experiment.

A simple heteronuclear relayed E.COSY pulse sequence with a minimum number of pulses is proposed for the quantitative determination of heteronuclear three-bond J-coupling constants in uniformly 13C-enriched polypeptide samples. Numerous heteronuclear three-bond coupling constants, including 3JHNC, 3JHNC beta, 3JH beta C, and 3JH alpha C gamma, can be determined for each residue from a single heteronuclear relayed E.COSY spectrum. Couplings relevant for stereospecific assignments as well as for the determination of dihedral angles in the amino acid backbone and in side chains are obtained. The method is demonstrated on the uniformly 13C-enriched decapeptide antamanide (-Val1-Pro2-Pro3-Ala4-Phe5-Phe6-Pro7-Pro8-Phe9-Phe1 0-).

Amino Acid Sequence↗
PubMed1995

Antineoplastic agents, 326. The stereochemistry of bastadins 8, 10, and 12 from the Bismarck archipelago marine sponge Ianthella basta.

An investigation of cancer cell-growth inhibitory constituents of the Papua New Guinea marine sponge Ianthella basta led to isolation of the C-6 hydroxybastadins 8 [1] 10 [2], and 12 [3]. The absolute stereochemistry (6S) of each bastadin (or its tetramethyl ester derivative) was determined by means of the Mosher-Trost method. Bastadins 10 [2] and 12 [3] were found to significantly inhibit the growth of a selection of human cancer cell lines. Bastadins 8, 10, and 12 inhibited growth of the Gram-positive opportunists Staphylococcus aureus and Enterococcus faecalis.

Animals↗
PubMed1995

Antineoplastic agents, 325. Isolation and structure of the human cancer cell growth inhibitory cyclic octapeptides phakellistatin 10 and 11 from Phakellia sp.

The two new marine sponge (Phakellia sp., western Pacific Ocean) constituents, phakellistatin 10 [1] and 11 [2], were found to be cyclic octapeptides that significantly inhibited growth of the murine P-388 lymphocytic leukemia (ED50 values of 2.1 and 0.20 micrograms/ml, respectively) and human cancer cell lines. The structures were established based on results of extensive tandem ms/ms and high-field (500-MHz) 2D 1H- and 13C-nmr analyses. All of the amino acid units (except Trp, not determined) were found to correspond to the (S)-configuration.

Amino Acid Sequence↗
PubMed1995

Antineoplastic agents 337. Synthesis of dolastatin 10 structural modifications.

New structural modifications of the marine shell-less mollusk peptide constituent dolastatin 10 (1) have been synthesized, and evaluated against a variety of cancer cell lines and for their ability to inhibit tubulin polymerization. A number of useful structure-activity relationships were uncovered. The most important observation was that the dolaphenine unit of dolastatin 10 could be satisfactorily replaced with a phenethylamine. Peptide 11C, designated auristatin PE, was found to exhibit inhibition of cancer cell growth and tubulin assembly comparable to that of dolastatin 10.

Amino Acid Sequence↗
PubMed1995

Interaction of dolastatin 10 with tubulin: induction of aggregation and binding and dissociation reactions.

We have prepared [3H]dolastatin 10 and examined its interactions with tubulin. Binding kinetics appeared to be biphasic, with a rapid initial reaction that could not be accurately measured, followed by a slower second reaction. Bound drug was stable in centrifugal gel filtration, column gel filtration, and high performance liquid chromatography gel filtration, but the bound drug could be displaced by an active isomer of dolastatin 10. Scatchard analysis of binding data was consistent with two classes of binding sites. However, dolastatin 10 induced an aggregation reaction upon binding to tubulin, complicating analysis of the data, and incorporation of [3H]dolastatin 10 into large aggregates was readily demonstrated. The chromatographic properties of the smallest radiolabeled species that could be documented were most consistent with a complex consisting of two molecules of alpha/beta-tubulin dimer and two molecules of [3H]dolastatin 10. The coexistence of an aggregation reaction with a binding reaction at a single site probably underlies the biphasic binding kinetics and the biphasic Scatchard plot. Of peptides that strongly inhibit tubulin polymerization (dolastatin 10, dolastatin 10 isomers, segments, and analogs, dolastatin 15, and phomopsin A), only those previously shown to be strong inhibitors of vinblastine binding and nucleotide exchange also strongly inhibited [3H]dolastatin 10 binding and induced tubulin aggregation (dolastatin 10 itself, two chiral isomers of dolastatin 10, and phomopsin A). The morphology of dolastatin 10-induced aggregates was compared with that of vinblastine-induced aggregates under a variety of reaction conditions. With both drugs the aggregates had a more organized appearance when microtubule-associated proteins were included in the reaction.

Animals↗
PubMed1994

Identification of a fetal exon in the human fast troponin T gene.

A developmentally regulated exon has been identified in the 5'-alternatively spliced region of the human fast Troponin T (TnT) gene. Expressed in fetal (but not adult) muscle, this exon is homologous with the fetal exons recently described in the rabbit and rat fast TnT genes. They all exhibit a split codon organization and encode a highly acidic peptide. To determine if the splicing pathways, including the human fetal exon, are also conserved, we defined the major TnT splicing patterns in fetal muscle. They generate fetal TnT 1, fetal TnT 3, and TnT1f, and TnT3f, species previously described in rabbit and rat skeletal muscles.

Alternative Splicing↗
PubMed1994

Conformation of valine side chains in ribonuclease T1 determined by NMR studies of homonuclear and heteronuclear 3J coupling constants.

A conformational analysis of the valine side chains of ribonuclease T1 (RNase T1) was performed using NMR spectroscopy, in particular homonuclear (1H, 1H and 13C, 13C) and heteronuclear (1H, 15N and 1H, 13C) vicinal spin-spin coupling constants as obtained from E.COSY-type NMR experiments. The coupling constants related to the chi 1 dihedral angle in valine, 3JH alpha H beta, 3JNH beta, 3JC'H beta, 3JH alpha C gamma 1, 3JH alpha C gamma 2, 3JC'C gamma 1, and 3JC'C gamma 2, were evaluated in a quantitative manner. The analysis of 3J data allowed for the stereospecific assignment of the valine methyl resonances. On the basis of various models for motional averaging of coupling constants, a fit of the torsion angles chi 1 to a set of the experimental 3J coupling constants (3JH alpha H beta, 3JNH beta, 3JC'H beta) was carried out. The resulting side-chain conformations were examined with respect to NOE distance informations. Single rotameric states emerged for Val16, Val67, Val79, and Val101, while conformational equilibria between staggered rotamers were found for Val33 and Val78. Using a different model approach, Val52 and Val89 are also likely to exhibit unimodal chi 1 angle distributions. The analysis was found to depend critically on the set of Karplus parameters used. Except for Val52 and Val78, the predominant rotamers obtained from 3J coupling informations agree with the conformation in the crystal structure of ribonuclease T1 (Martinez-Oyanedel et al., 1991).

Magnetic Resonance Spectroscopy↗
PubMed1994

Antineoplastic agents. 278. Isolation and structure of axinastatins 2 and 3 from a western Caroline Island marine sponge.

The Republic of Palau marine sponge Axinella sp. was found to be an exceptionally productive source of cell growth inhibitory substances. The strongly antineoplastic polyether macrocyclic lactones halichondrin B (1) and homohalichondrin B (2) were isolated in 1.2 x 10(-6)% and 5.4 x 10(-7)% yields, respectively. In addition to axinastatin 1 (3), two new and cytostatic (GI50 values of 0.35 to 0.0072 microgram/mL against six human cancer cell lines) cycloheptapeptides designated axinastatins 2 (4) and 3 (5) were discovered in 1.4 x 10(-6)% and 1.25 x 10(-6)% yields. Structures were elucidated by high-resolution FABMS and tandem MS/MS techniques augmented by high-field (400 and 500 MHz) 2D-NMR spectral analyses. The absolute configurations were established by a combination of hydrolysis, derivatization, and chiral gas chromatographic methods.

Amino Acid Sequence↗
PubMed1994

Acute effects of inhaled nitric oxide in children with severe hypoxemic respiratory failure.

To determine the physiologic effects of inhaled nitric oxide (NO) on oxygenation and hemodynamics in children with severe hypoxemic respiratory failure, we studied the acute response to inhaled NO during mechanical ventilation in 17 pediatric patients. Diagnoses included adult respiratory distress syndrome (ARDS) (10 patients), bronchopulmonary dysplasia with viral pneumonitis (6 patients), and acute pneumonitis, caused by respiratory syncytial virus, without chronic lung disease (1 patient). Gas exchange and hemodynamic measurements were compared before and during exposure to inhaled NO (20 ppm) without changing ventilator settings for 30 minutes. Hemodynamic variables, including pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac index, were measured in 10 patients with ARDS. Inhaled NO acutely improved oxygenation in 15 of 17 patients; mean arterial oxygen tension increased from 58 +/- 13 mm Hg (baseline) to 86 +/- 25 mm Hg after 30 minutes (p < 0.01). Inhaled NO lowered mean pulmonary artery pressure (42 +/- 6 mm Hg at baseline to 31 +/- 6 mm Hg; p < 0.01) and intrapulmonary shunt (39% +/- 7% vs 32% +/- 7%; p < 0.01) without changing systemic arterial pressure or pulmonary capillary wedge pressure. Cardiac index increased by 14% (p < 0.01). Fifteen patients were subsequently treated with low-dose inhaled NO (3 to 10 ppm) for 1 to 24 days; 5 (50%) of 10 patients with ARDS and 7 (100%) of the 7 non-ARDS patients survived. We conclude that inhaled NO acutely improves oxygenation and lowers pulmonary vascular resistance without causing adverse hemodynamic effects in severe hypoxemic respiratory failure in pediatric patients. Inhaled NO may be a useful adjuvant therapy in children with acute hypoxemic respiratory failure, including infants with bronchopulmonary dysplasia, but whether prolonged low-dose inhalational NO therapy can reduce morbidity or improve survival rates remains unknown.

Adolescent↗
PubMed1994

Isolation and structure of cephalostatins 10 and 11.

Further investigation of antineoplastic constituents from the marine worm Cephalodiscus gilchristi, employing a 450 kg re-collection from the Indian Ocean (Southeast Africa), has led to isolation and structural determination of two previously undetected members of the cephalostatin series, designated cephalostatins 10 [4] and 11 [5]. Structural analyses were conducted primarily employing high field 2D nmr and high resolution mass spectral techniques. All the stereochemical assignments were deduced using the original X-ray crystal structure of cephalostatin 1 and ROESY 2D nmr methods. Both cephalostatins 10 and 11 strongly inhibited growth of a series of important human cancer cell lines.

Animals↗
PubMed1994

[The development of homeopathy in the United States].

After an enormous spread in the United States of America during the 19th century homeopathy had almost completely vanished from the scene by the beginning of the 20th century. For the past two decades, however, it seems once again to experience a kind of renaissance. Major aspects of this development-in terms of medical and cultural history, sociology, politics, and economics-are illustrated on the basis of a general history of homeopathy in the United States. Using original sources, a first attempt is made to reconstruct the history of homeopathy in San Francisco which has some institutional peculiarities that make it unique within the whole country.

History, 18th Century↗