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R S Jacobs

Publications and source records attributed to R S Jacobs.

At least 19 recordsLinked to original sources
PubMed2006

7,11-epi-thyrsiferol: completion of its synthesis, evaluation of its antimitotic properties, and the further development of an SAR model.

We (a) describe the completion of a total synthesis of 7,11-epi-thyrsiferol (4), (b) compare the antimitotic activities of thyrsiferol (2), Delta15,28-dehydrothyrsiferol (3), and 7,11-epi-thyrsiferol (4), (c) evaluate the synergistic behavior of the title compound and colchicine to inhibit cell proliferation, and (d) describe the results of conformational searches that provide additional insight concerning the SAR profile of the thyrsiferol family of natural products.

Animals↗
PubMed2000

An 18.5 kDa protein from the amebocyte of Limulus polyphemus, homologous to the previously described amebocyte aggregation factor, expresses alternative phospholipase A2 activity.

A protein expressing phospholipase A2 activity was purified from the granular amebocyte of the horseshoe crab, Limulus polyphemus by cation-exchange, size-exclusion chromatography and semi-preparative reverse-phase-high pressure liquid chromatography (RP-HPLC). The protein had an apparent mass of 17.7 kDa by SDS-polyacrylamide gel electrophoresis (SDS-PAGE), but a more accurate estimate of 18.5 kDa was assigned by electrospray ionization-mass spectrometry (ESI-MS). A partial sequence of this protein demonstrated total sequence homology with an 18.5 kDa protein with cell aggregating properties from Limulus reported by Fujii et al. [J. Biol. Chem. 267:22452.]. In these studies, the Limulus protein demonstrated a positive cross-reaction to polyclonal anti-human recombinant phospholipase A2 (group II, 14 kDa). The protein did not display a significant loss of biological activity after boiling, but all enzymatic activity was lost after boiling in the presence of the reducing agent betamercaptoethanol (beta-mercaptoethanol). The Limulus protein was inhibited by manoalide, a covalent irreversible phospholipase A2 inhibitor, in a dose-dependent fashion with 50% inhibition occurring at a concentration of 0.48 microM. The Limulus protein displayed no activity in a triglyceride lipase assay. These studies characterize an alternative phospholipase A2 activity for the previously described 18.5 kDa protein from the L. polyphemus amebocyte.

Amino Acid Sequence↗
PubMed1999

The effect of temperature and solution pH on the nucleation of tetragonal lysozyme crystals.

Part of the challenge of macromolecular crystal growth for structure determination is obtaining crystals with a volume suitable for x-ray analysis. In this respect an understanding of the effect of solution conditions on macromolecule nucleation rates is advantageous. This study investigated the effects of supersaturation, temperature, and pH on the nucleation rate of tetragonal lysozyme crystals. Batch crystallization plates were prepared at given solution concentrations and incubated at set temperatures over 1 week. The number of crystals per well with their size and axial ratios were recorded and correlated with solution conditions. Crystal numbers were found to increase with increasing supersaturation and temperature. The most significant variable, however, was pH; crystal numbers changed by two orders of magnitude over the pH range 4.0-5.2. Crystal size also varied with solution conditions, with the largest crystals obtained at pH 5.2. Having optimized the crystallization conditions, we prepared a batch of crystals under the same initial conditions, and 50 of these crystals were analyzed by x-ray diffraction techniques. The results indicate that even under the same crystallization conditions, a marked variation in crystal properties exists.

Animals↗
PubMed1999

Homo- and nor-plakotenin, new carboxylic acids from the Palauan sponge Plakortis lita.

A specimen of Plakortis lita from Palau yielded the new carboxylic acids, homo-plakotenin (2a), the sodium salt of homo-plakotenin (2b), the sodium salt of nor-plakotenin (3), the sodium salt of plakotenin (1b), and the known compound plakotenin (1a). The structures of the new acids were elucidated by interpretation of spectral data and by comparison with the known compound. Compounds 1a, 1b, and 2a were found to significantly reduce proliferation of rheumatoid synovial fibroblasts.

Animals↗
PubMed1998

Phospholipid composition of the granular amebocyte from the horseshoe crab, Limulus polyphemus.

The phospholipid composition was determined for the amebocyte of the primitive arthropod Limulus polyphemus. The total fatty acid composition of the cells' lipids was analyzed by gas chromatography/mass spectrometry (GC/MS) of fatty acid methyl esters (FAME). The FAME analysis revealed high levels of 20-carbon polyunsaturated fatty acids (PUFA), especially arachidonic (20:4n-6) and eicosapentaenoic (20:5n-3) acids. Almost 20% of the total lipid profile was comprised of dimethyl acetals of 16- to 20-carbon chain lengths, indicative of plasmalogens in the phospholipid pool. Phospholipids, analyzed by high-pressure liquid chromatography, included phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylinositol (PI), sphingomyelin (SPH), and cardiolipin (CL). PE and PC levels predominated at 42.2 and 36.3%, respectively. Smaller amounts of PS (9.0%) and PI (6.2%) were present, as well as low levels of SPH (4.6%), CL (1.6%), and trace amounts of lysophosphatidylcholine. The major phospholipid species, PE, PC, PS and PI, were collected and their molecular species were examined by electrospray-ionization mass spectrometry. The molecular species within the phospholipid classes reflected the high levels of PUFA seen in the total lipid profile. PI was mainly composed of 18:0a/20:4. Over half of the PS consisted of 18:0a/18:1 and 18:0a/20:4. The major PE species were 20:1p/20:5, 20:1p/20:4, 18:0p/20:5, and 18:0p/20:4. PC had the largest distribution of molecular species, and its most abundant species were 16:0e/20:5, 16:0e/20:4, and 16:0p/20:4. The presence of 16:0e/20:4 is the first documentation of a specific precursor to platelet-activating factor in an invertebrate hemocyte. Note: at the sn-1 position: [a=1=O-acyl, e = 1-O-alkylether, and p = 1-O-alk-1'-enyl (plasmalogen)].

Animals↗
PubMed1998

Pharmacological characterization of the pseudopterosins: novel anti-inflammatory natural products isolated from the Caribbean soft coral, Pseudopterogorgia elisabethae.

Pseudopterosin E (PSE), a C-10 linked fucose glycoside and pseudopterosin A (PSA), a C-9 xylose glycoside isolated from the marine gorgonian Pseudopterogorgia elisabethae were both effective in reducing PMA-induced mouse ear edema when administered topically (ED50 (microg/ear) PSE(38), PSA(8)) or systemically (ED50 (mg/kg, i.p.) PSE (14), PSA (32)). Both compounds exhibited in vivo analgesic activity in phenyl-p-benzoquinone-induced writhing (ED50 (mg/kg, i.p.) PSE(14), PSA(4). PSE inhibited zymosan-induced writhing (ED50 = 6 mg/kg, i.p.), with a concomitant dose-dependent inhibition of peritoneal exudate 6-keto-prostaglandin F1alpha (ED50 = 24 mg/kg) and leukotriene C4 (ED50 = 24 mg/kg). In vitro, the pseudopterosins were inactive as inhibitors of phospholipase A2, cyclooxygenase, cytokine release, or as regulators of adhesion molecule expression. PSA inhibited prostaglandin E2 and leukotriene C4 production in zymosan-stimulated murine peritoneal macrophages (IC50 = 4 microM and 1 microM, respectively); however, PSE was much less effective. These data suggest that the pseudopterosins may mediate their anti-inflammatory effects by inhibiting eicosanoid release from inflammatory cells in a concentration and dose-dependent manner.

Animals↗
PubMed1996

Biosynthesis of arachiodonic acid metabolites in Limulus polyphemus amebocytes: analysis by liquid chromatography-electrospray ionization mass spectrometry.

Eicosanoid metabolites were generated by isolated granular amebocytes of the primitive arthropod, Limulus polyphemus, when stimulated by the calcium ionophore A23187 and/or exogenous arachidonic acid. The metabolites were isolated, identified, and the major metabolite was quantified using reverse-phase high pressure liquid chromatography (RP-HPLC) coupled to electrospray ionization mass spectrometry (ESI-MS). Qualitative examination revealed putative metabolites and the major product, 8-hydroxyeicosatetraenoic acid (8-HETE), which was quantified using standard curves generated from extracted ion profiles of the molecular ion. Electrospray ionization of the HETEs in negative ion mode produces a base peak for all isomers which corresponded to the molecular ion [(M-H)-: m/z 319]. The molecular ion was accompanied by the neutral loss of water and carbon dioxide [(M-H -H2O)-: m/z 301; (M-H -H2O -CO2)-: m/z 257], as well as daughter ions which were dependent upon the position of hydroxy substitution. Standard curves were generated in full scan mode for standards ranging from 6.25 to 100 ng, whereas selected ion recording was used for the lower levels of 0.8 to 6.25 ng.

Animals↗
PubMed1996

CNS role: an experience in retitling and role clarification.

A LITERATURE REVIEW and survey were undertaken to identify the appropriate titling for individuals in clinical nursing and other advanced practice roles, to establish components in each role, and to determine the educational level necessary for each role. Based upon review and survey results, a CNS task force at the University of Iowa Hospitals and Clinics proposed a change in the titles of nurses in advanced practice at their institution to reflect the American Nurses' Association's definition of advanced practice nursing and recommended graduate level education for these advanced positions. Five specific titles and primary role components were identified: advanced registered nurse practitioners. CNS, education nurse specialist, research nurse specialist, and informatics nurse specialist. Retitling aided in clearly identifying major responsibilities of the position, clarifying role expectations, and creating evaluation tools.

Education, Nursing, Graduate↗
PubMed1995

Structure and biosynthesis of novel conjugated polyene fatty acids from the marine green alga Anadyomene stellata.

Novel polyunsaturated fatty acids with four conjugated double bonds were found in extracts of the green macroalga, Anadyomene stellata. The isolation of five of these with different chain lengths and varying degrees of unsaturation--16:5, 18:4, 20:5, 20:6, and 22:7--was accomplished by organic extraction followed by a combination of vacuum and high-performance liquid chromatography. One of these that was a novel substance (22:7) was characterized as 4Z,7Z,9E,11E,13Z,16Z,19Z-do cosaheptaenoic acid and assigned the trivial name stellaheptaenoic acid. The structure of this new compound, isolated as its methyl ester derivative, was deduced from detailed nuclear magnetic resonance, gas chromatography/mass spectrometry (GC/MS), and other spectroscopic methods. Incubation of a chloroplast preparation, isolated from a crude algal homogenate by differential centrifugation, with six unsaturated fatty acids (palmitoleic, 6Z,9Z,12Z,15Z-octadecatetraenoic acid, arachidonic acid, eicosapentaenoic acid, 7Z,10Z,13Z,16Z-docosatetraenoic acid, and 4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoi c acid) resulted in substantially increased synthesis of unique tetraene compounds as detected by ultraviolet spectrophotometry and tentatively identified by GC/MS.

Chlorophyta↗
PubMed1994

Inactivation of bee venom phospholipase A2 by a sesquiterpene furanoic acid marine natural product.

A sesquiterpene furanoic acid (SFA) marine natural product isolated from soft corals of the genus Sinularia (Bowden et al., Aust J Chem 36: 371-376, 1983) was found to inactivate bee venom phospholipase A2 (bvPLA2, EC 3.1.1.4) in vitro. In this study, we characterized the kinetics of inactivation of bvPLA2 by this compound. The apparent IC50 value was 0.5 microM, and the inactivation of bvPLA2 was time dependent. The drug-enzyme binding appeared to be of a non-competitive, high-affinity nature that was irreversible by aqueous dialysis. The inactivation was prevented by the simultaneous addition of excess lysophosphatidylcholine (lysoPC) during the initial binding step, suggesting that modification of the enzyme by SFA occurs at or near the substrate binding site. Activation of bvPLA2 was observed with lysoPC addition at concentrations equimolar to bvPLA2 and higher. Saturation of activation occurred at concentrations greater than 10 microM lysoPC, and preincubation of bvPLA2 with 100 microM lysoPC did not inhibit the enzyme. Analysis of the post-incubation mixture of SFA-inhibited enzyme in the presence of lysoPC revealed the presence of unaltered enzyme exhibiting typical Michaelis-Menten kinetics. The significance of these observations is discussed in light of the recent discussion by Ortiz on the manoalide binding site on bvPLA2.

Bee Venoms↗
PubMed1993

A marine natural product, patellamide D, reverses multidrug resistance in a human leukemic cell line.

A cyclic octapeptide (patellamide D) isolated from the marine tunicate, Lissaclinum patella, acts as a resistance-modifying agent in the multidrug resistant CEM/VLB100 human leukemic cell line. A three-day microculture tetrazolium proliferation assay was used to determine the 50% inhibitory concentration (IC50) for vinblastine, colchicine and adriamycin and calculate the degree of resistance modulation. Patellamide D at 3.3 microM was compared with 5.1 microM verapamil in modulating drug resistance in vitro. The IC50 for vinblastine was reduced from 100 ng/ml to 1.5 ng/ml in the presence of patellamide D or to 2.1 ng/ml when exposed to verapamil. Colchicine cytotoxicity was enhanced only 1.4-fold by verapamil, as compared with 2.8-fold using patellamide D (IC50 was reduced from 140 ng/ml to 100 ng/ml or 50 ng/ml). Adriamycin toxicity was reduced from IC50 > 1000 ng/ml to 110 ng/ml and 160 ng/ml when coexposed to patellamide D and verapamil, respectively. Our results indicate that patellamide D acts as a selective antagonist in multidrug resistance and stresses the importance of investigating marine-derived compounds as a potential new source for modulators of the drug-resistance phenotype.

Amino Acid Sequence↗
PubMed1992

Phospholipase A2 inhibitors from marine organisms.

This review of phospholipase A2 (PLA2) inhibitors from marine organisms presents a compilation of research in this field over the past decade. As an introduction to the research on marine natural products, there is an overview of the role of PLA2 in inflammation that provides a rationale for seeking inhibitors of PLA2 as anti-inflammatory agents. A radiometric assay to measure inhibition of bee venom PLA2 is described in detail. Examples of marine natural products that inhibit PLA2 are manoalide and its derivatives, scalaradial and related compounds, the pseudopterosins, the vidalols, and a group of terpenoids that contain masked 1,4-dicarbonyl moieties.

Animals↗
PubMed1992

Fuscoside: an anti-inflammatory marine natural product which selectively inhibits 5-lipoxygenase. Part II: Biochemical studies in the human neutrophil.

Fuscoside (FSD) is a potent and long-lasting anti-inflammatory drug that selectively inhibits leukotriene production in murine models of inflammation. In the present study, the effects of FSD on the lipoxygenase pathways in human polymorphonuclear leukocytes are explored in order to better understand the mechanism of action of this novel drug. In adherent and suspended polymorphonuclear leukocytes, FSD irreversibly inhibits leukotriene B4 (LTB4) synthesis (IC50 = 10 microM) and the release of 14C-labeled LTB4 from neutrophils prelabeled with [14C]arachidonic acid. Unlike the reversible 5-lipoxygenase inhibitor L-651,896, FSD has no observable effect on LTB4 biosynthesis in whole blood, but does express activity as blood is successively diluted. In 10,000 x g supernatants of human platelets and polymorphonuclear leukocytes, FSD does not inhibit platelet 12-lipoxygenase, but is extremely effective in inhibiting the metabolism of arachidonic acid and 5-hydroperoxyeicosatetraenoic acid to LTB4 via neutrophil 5-lipoxygenase. FSD has no effect on the conversion of leukotriene A4 to LTB4 in this system. Interestingly, concurrent with FSD inhibition of leukotriene synthesis is a concentration-dependent increase in 5-hydroxyeicosatetraenoic acid, suggesting that FSD may selectively inhibit the leukotriene A4 synthase activity associated with human 5-lipoxygenase. FSD is therefore representative of a new class of nonantioxidant 5-lipoxygenase inhibitors that may be effective local therapeutic agents in the management of diseases such as psoriasis, arthritis and inflammatory bowel and lung diseases.

Anti-Inflammatory Agents↗
PubMed1992

Fuscoside: an anti-inflammatory marine natural product which selectively inhibits 5-lipoxygenase. Part I: Physiological and biochemical studies in murine inflammatory models.

The biological and biochemical pharmacology of fuscoside, a novel anti-inflammatory marine natural product isolated from the Caribbean gorgonian Eunicea fusca, has recently been characterized using murine (part I) and human (part II) models of inflammation. Topically applied fuscoside (FSD) effectively inhibits phorbol myristate acetate (PMA)-induced edema in mouse ears at levels comparable with indomethacin over a 3.3-hr exposure period, and is significantly more efficacious than indomethacin over 24 hr in the PMA model. Histological preparations and quantification of the neutrophil-specific marker, myeloperoxidase, demonstrate that FSD inhibits neutrophil infiltration into PMA-induced regions of edema and inflammation. In systemic studies, where FSD is injected i.p. before the topical application of PMA, negligible effects on ear inflammation are observed. FSD does not inhibit bee venom or human synovial fluid phospholipase A2 up to concentrations of 500 microM. In calcium ionophore-activated cultures of mouse peritoneal macrophages, FSD selectively and irreversibly inhibits leukotriene C4 biosynthesis (IC50 = 8 microM), yet has negligible effects on prostaglandin E2 production. FSD is also without effect on the conversion of arachidonic acid to prostaglandin E2 by ram seminal vesicle cyclooxygenase. Chromatographic and spectroscopic studies suggest that FSD is not metabolized, and that drug uptake/binding by macrophages is time dependent, saturable and independent of active transport mechanisms. These studies represent the first report of an anti-inflammatory marine natural product that selectively inhibits leukotriene biosynthesis.

Animals↗
PubMed1992

Selective inhibition of cytokinesis in sea urchin embryos by the marine natural product pseudopterolide.

Low concentrations (1-10 microM) of the marine natural product pseudopterolide inhibited cytokinesis and induced formation of multinucleate cells in fertilized Strongylocentrotus purpuratus embryos. As determined by immunofluorescence microscopy using fluorescent stains for actin filaments, microtubules, and chromosomes, pseudopterolide inhibited cytokinesis selectively by disrupting the contractile ring, whereas spindle microtubule organization and mitotic chromosome segregation to opposite spindle poles were unimpaired. At somewhat higher concentrations (16-20 microM), pseudopterolide induced formation of microtubule spiral asters, which are believed to be caused by rotation of the cytoplasm relative to the cell cortex. The effects of pseudopterolide on cytokinesis were cell-cycle dependent. The actions of pseudopterolide in fertilized sea urchin embryos were strikingly similar to the actions of another marine natural product, stypoldione, a structurally unrelated orthoquinone that reacts covalently with the sulfhydryl groups of glutathione, beta-mercaptoethanol, cysteine, and a number of proteins [Mol. Pharmacol. 35:635-642 (1989)]. In the present study, pseudopterolide was also found to react with sulfhydryl groups of glutathione, beta-mercaptoethanol, and cysteine. The results indicate that the cellular target for pseudopterolide, like the target for stypoldione, may be an especially sensitive sulfhydryl-containing protein involved in the formation or function of the contractile ring.

Actins↗