Biomedical subjects
Publications and source records attributed to W F Reynolds.
An investigation of Agave americana and Agave barbadensis resulted in the isolation of a new homoisoflavanoid, 7-hydroxy-3-(4-methoxybenzyl)-chroman (3), together with known compounds 7-hydroxy-3-(4-methoxybenzyl)-chroman-4-one (1), 5,7-dihydroxy-3-(4-methoxybenzyl)-chroman-4-one (2), cantalasaponin-1 (4), and 2-hydroxy-butanedioic acid-1-methyl ester (5).
Bioactive soyasaponins are present in soybean (Glycine max). In this study, the isolation of soyasaponins in relatively pure form (>80%) using precipitation, solid phase extraction and reverse phase low pressure liquid chromatography (RP-LPLC) is described. Soy flour soyasaponins were separated from non-saponins by methanol extraction and precipitation with ammonium sulphate. Acetylated group A soyasaponins were isolated first by solid phase extraction followed by RP-LPLC (solvent: ethanol-water). Soyasaponins, from a commercial preparation, were saponified and fractionated into deacetylated group A and group B soyasaponins by solid phase extraction (methanol-water). Partial hydrolysis of group B soyasaponins produced a mixture of soyasaponin III and soyasapogenol B monoglucuronide. RP-LPLC of deacetylated group A soyasaponins separated soyasaponin A1 and A2 (38% methanol); of group B soyasaponins isolated soyasaponin I (50% ethanol); and of the partial hydrolysate separated soyasaponin III from soyasapogenol B monoglucuronide (50% ethanol). This methodology provides soyasaponin fractions that are suitable for biological evaluation.
Two new bis(monoterpenoid) indole alkaloid glucosides, bahienoside A (1) and bahienoside B (2), together with five known compounds, 5alpha-carboxystrictosidine, angustine, strictosamide, and (E)- and (Z)-vallesiachotamine, were isolated from the aerial parts of Psychotria bahiensis collected in Trinidad, West Indies. The structures of the compounds were elucidated using 1D and 2D NMR spectral methods, viz., (1)H, (13)C, (13)C DEPT, (1)H-(1)H COSY, HSQC, HMQC, HMBC, and TOCSY aided by IR, UV, and circular dichroism measurements.
The hepatitis C virus (HCV) is a major cause of liver disease and the complications of cirrhosis. Liver biopsies, performed prior to the development of liver cirrhosis, characteristically show an inflammatory cell infiltrate with varying degrees of fibrosis. Precisely how HCV infection induces hepatic fibrogenesis is unknown. Recent studies suggest the release of oxidants, cytokines and proteases from the host immune system are key to the development of fibrosis. Macrophages and neutrophils, cells heavily represented in the inflammatory cell response, contain the oxidant generating enzyme myeloperoxidase (MPO). Cellular levels of MPO can be influenced by a functional promotor polymorphism, -463G/A, which precedes the MPO gene. We examined the relationship between this MPO promotor genotype and the degree of fibrosis in 166 patients with chronic HCV infection. All patients had previously participated in clinical drug trials for the treatment of chronic HCV infection. The MPO genotype was determined from cryo-preserved lymphocytes obtained from patients prior to treatment. The degree of fibrosis was estimated from liver biopsy specimens obtained prior to treatment. We found that patients with the MPO GA/AA genotype were more likely to have advanced fibrosis scores compared with those with the GG genotype: Of the patients with GG genotype, 78% (79 of 102 cases) had lower Knodell Fibrosis scores of 0 or 1, compared to 56% (37 of 64 cases) of patients with GA/AA genotype (P < 0.05). The mechanism(s) by which MPO contributes to fibrosis progression remains to be determined.
EAE is a demyelinating disease which serves as an animal model for multiple sclerosis (MS). Myeloperoxidase (MPO) has been implicated in MS through its presence in invading macrophages, and by association of a -463G/A promoter polymorphism with increased risk. Also, MPO at 17q23.1 is within a region identified in genome scans as a MS susceptibility locus. We here examine the incidence of EAE in MPO knockout (KO) mice. MPO is detected in invading macrophages in the CNS of wild-type mice, yet unexpectedly, MPO-KO mice have significantly increased incidence of EAE: Ninety percent of MPO-KO mice developed complete hind limb paralysis as compared to 33% of wildtype (WT) littermates (P<0.0001). This is the first evidence that MPO plays a significant role in EAE, consistent with its postulated role in MS.
Squamulosone (aromadendr-1(10)-en-9-one), isolated in large quantity from the plant Hyptis verticillata Jacq. (Labiatae), was incubated with the fungus Curvularia lunata ATCC 12017 in two different growth media. Six metabolites were isolated from each medium. with five of the products being common to both fermentations. All seven metabolites are novel. The insecticidal activity of these aromadendranes was evaluated against the sweet potato weevil Cylas formicarius elegantus.
Extracts of the fruit of Clusia havetiodes var. stenocarpa have yielded three new prenylated benzophenone derivatives, 28,29-epoxyplukenetione A (1), 33-hydroperoxyisoplukenetione C (2), and 15,16-dihydro-16-hydroperoxyplukenetione F (3), as well as four which have been previously described, plukenetiones C, F, and G and sampsonione G.
Extracts of the stems of Jatropha divaricata have yielded the two new diterpenes ent-3 beta,14 alpha-hydroxypimara-7,9(11),15-triene-12-one (3) and the rearranged pimarane ent-15(13-->8)abeo-8 beta(ethyl)pimarane (4), which appears to be a new skeletal type. The rare cleistanthane diterpenes spruceanol (1) and cleistanthol (2) were also obtained.
The new ergostane steroid ergosta-5,24(24')-diene-3beta,4beta,22R-triol (1), a pregnane, (E)-volkendusin, characterised as the diacetate (3), cycloartanes 4-6 and protolimonoids 7-9 were obtained from the leaves and twigs of Trichilia reticulata.
BACKGROUND: Myeloperoxidase (MPO) is present in senile plaques and surrounding reactive microglia, but not in normal brain parenchyma. MPO in plaques is highest in APOE epsilon4 carriers, suggesting a functional interaction. An MPO promoter polymorphism (-463G/A) linked to increased MPO expression has been associated with increased risk of AD. METHODS: To further define the possible interaction of MPO and APOE epsilon4, we examined 127 patients with AD and 174 controls from a genetically homogeneous Finnish population. RESULTS: A significantly higher percentage of male patients with AD carried the MPO A and APOE epsilon4 alleles relative to men carrying neither allele (p < 0.001; OR, 11.4; 95% CI, 3.6 to 6.7). Male APOE epsilon4 carriers lacking the MPO A allele had an OR of 3.0 (p = 0.01; 95% CI, 1.3 to 6.9), indicating that MPO A enhances AD risk by 3.8-fold. Age at onset was lower in men carrying the MPO A and APOE epsilon4 alleles (Kaplan-Meier survival analysis; p = 0.01). Also, the MPO AA genotype was associated with selective mortality in men, but not in women. AA genotypes were absent from 159 male patients with AD and controls, representing the expected 5% to 6% in women and male controls younger than age 20. The -463A creates an estrogen receptor binding site that may contribute to these gender differences. CONCLUSIONS: MPO A and APOE epsilon4 alleles interact to increase the risk of AD in men but not in women in this Finnish cohort.
The reaction of substituted diarylidene acetones with hydroxylamine hydrochloride affords isomeric N-hydroxy diaryl piperidinone oximes as main products. The structures as well as conformational equilibria of these products were established by 1H and 13C NMR spectroscopy and further studied by variable temperature NMR. It was found that the cis/trans ratio of 2,6-substituted piperidine derivatives depended on the position of the substituent on the aromatic ring.
A new sesquiterpene derivative named mochiquinone (1) was isolated from the Caribbean gorgonian coral Pseudopterogorgia rigida collected off northeastern Venezuela, along with the known compounds, alpha-curcumene, (-)-curcuphenol, (-)-curcuquinone, and (-)-curcuhydroquinone. The structure of the new compound was determined by spectroscopic analysis of its acetylated derivative and comparison with known compounds.
Four structurally novel isomeric sesquiterpenes have been isolated from the aerial parts of Capraria biflora. Caprariolides A (1), B (2), C (3), and D (4) have been determined by NMR spectroscopy experiments to be the (3S,5S,9R), (3R,5S,9R), (3R,5R,9R), and (3S,5R, 9R) isomers of 7-(furan-3'-yl)-3,9-dimethyl-1-oxaspiro[4. 5]dec-6-en-2-one, respectively. Both 1 and 2 were found to exhibit insecticidal activity against adult Cylas formicarius elegantulus, one of the most destructive insect pests of the sweet potato, Ipomoea sp.
A previously isolated trihydroxy-gorgosterol derivative (2), a new gorgosterol (3), and the known sterol cholestane-3beta,5alpha, 6beta-triol are reported from the Caribbean octocoral Eunicea laciniata collected off northeast Venezuela. Using high-resolution 2D NMR techniques, the total structural assignment and detailed stereochemistry of 2 is presented for the first time and the full structure of 3 advanced.
Three new monotetrahydrofuran (mono-THF) acetogenins, anmontanins A-C (1-3) were isolated from the leaves of Annona montana. Anmontanin C (3) is the first stereochemically pure acetogenin reported to have a gamma-hydroxymethyl-gamma-lactone moiety. Two known mono-THF acetogenins, murisolin and annonacin, were isolated from the seeds of the plant. The structures of compounds 1-3 were elucidated by spectral methods and chemical derivatization.
The structures of three new compounds isolated from Peperomia proctorii, named proctoriones A-C, have been established by spectroscopic and chemical methods as 2,3-dihydro-5, 8-dihydroxy-2-pentadecyl-4H-benzopyran-4-one (1) and enolic forms of 4-hydroxy-2-octadecanoylcyclohexane-1,3-dione (2) and 4-hydroxy-2-octadec-(11Z)-enoylcyclohexane-1,3-dione (3).
The isoflavones tectoridin (TTR) and 3'-hydroxy TTR (3'-TTR) were isolated from an Ayurvedic herbal preparation Vacä and evaluated for their affinity and effect on ryanodine receptors (RyR) using junctional sarcoplasmic reticulum vesicles (JSRVs). In [(3)H]ryanodine displacement binding affinity assays, TTR and 3'-TTR exhibited IC(50) values of 17.3 +/- 1.3 microM (K(d) = 6.7 +/- 0.4 microM) and 6.6 +/- 1.4 microM (K(d) = 2.4 +/- 0.2 microM), respectively, for fast skeletal muscle RyR (RyR1) compared with an IC(50) value for ryanodine of 6.2 +/- 0.4 nM (K(d) = 2.4 nM). TTR demonstrated a 3-fold higher affinity for cardiac RyR (RyR2) [IC(50) value of 5.2 +/- 0.6 microM (K(d) = 0.95 +/- 0.3 microM)] than for RyR1. The displacement isotherms for both TTRs paralleled that for ryanodine, consistent with the notion that all three are likely binding to similar site(s) on the receptors. Calcium efflux from and calcium influx into JSRVs were used to measure function effects of TTRs on binding to RyR. In calcium efflux assays, TTR (up to 1 mM) enhanced the release of (45)Ca(2+) from JSRVs in a concentration-dependent manner (EC(50act) of 750 microM). Higher concentrations deactivated (partially closed) RyR1. 3'-TTR had similar effects, but was approximately 2-fold more potent, exhibiting an EC(50act) value of 480 microM. Using passive calcium influx assays, TTR activated and deactivated RyR1 in a time- and concentration-dependent manner. The aglycone tectorigenin also was effective in displacing [(3)H]ryanodine from RyR1 but not from RyR2. These results demonstrate that TTRs are capable of interacting at ryanodine binding sites to differentially modulate fast skeletal and cardiac calcium-release channels.
Myeloperoxidase (MPO) is a myeloid-specific enzyme that generates hypochlorous acid and other reactive oxygen species. MPO is present at high levels in circulating neutrophils and monocytes but is not detectable in microglia, brain-specific macrophages, in normal brain tissue. However, an earlier study indicated that MPO is present in macrophage-microglia at multiple sclerosis lesions, suggesting that reactivation of MPO gene expression may play a role in neurodegenerative diseases involving macrophage-microglia. In the present study, MPO is shown to colocalize with amyloid beta (Abeta) in senile plaques in cerebral cortex sections from Alzheimer's disease (AD) brain tissue. Microglia costaining for MPO and CD68 are closely associated with plaques, suggesting that plaque components induce MPO expression in microglia. In support of this interpretation, treatment of rodent microglia with aggregated Abeta(1-42) was shown to induce MPO mRNA expression. Also, the ApoE4 allele, the major AD risk factor associated with increased Abeta deposition, was shown to correlate with increased MPO deposition in plaques (P = 0.01, ANOVA). Finally, a genetic polymorphism links MPO expression to Alzheimer's risk, in that a higher expressing SpSp MPO genotype was associated with increased incidence of AD in females, and decreased incidence in males (P = 0.006). These findings suggest that the MPO polymorphism is a gender-specific risk factor for Alzheimer's disease.