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PubMed1998

Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study.

OBJECTIVES: Inhibitors of nitric oxide synthesis have been suggested to be of value in the treatment of hypotension during sepsis. However, earlier clinical reports only describe the initial effects of these nitric oxide inhibitors. This study was designed to examine the effects of the prolonged inhibition of nitric oxide synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) in patients with severe septic shock. DESIGN: Prospective, nonrandomized, clinical study. SETTING: Medical-surgical intensive care unit in a university hospital. PATIENTS: Eleven consecutive patients with ongoing hyperdynamic septic shock that was unresponsive to fluid resuscitation and vasopressor therapy. INTERVENTIONS: Measurements of hemodynamic, hematologic, and biochemical variables were made before, during, and after the start of a continuous intravenous infusion of 1 mg/kg/hr of L-NAME, an inhibitor of nitric oxide synthesis, for a period of 12 hrs. MEASUREMENTS AND MAIN RESULTS: Continuous infusion of L-NAME resulted in a direct increase in mean arterial pressure from 65 +/- 3 (SEM) to 93 +/- 4 mm Hg and an increase in systemic vascular resistance from 426 +/- 54 to 700 +/- 75 dyne x sec/cm5, reaching a maximum at 0.5 hr. Pulmonary arterial pressure was increased from 31 +/- 2 to a maximum of 36 +/- 2 mm Hg at 1 hr, and pulmonary vascular resistance increased from 146 +/- 13 to a maximum of 210 +/- 23 dyne x sec/cm5 at 3 hrs. Paralleling these changes, cardiac output decreased from 10.8 +/- 0.8 to 8.7 +/- 0.7 L/min and oxygen delivery decreased from 1600 +/- 160 to 1370 +/- 130 mL/min (for all changes p < .05 as compared with the baseline value). Heart rate, cardiac filling pressures, oxygen consumption, urine production, arterial lactate concentration, and other biochemical parameters were not significantly changed by L-NAME administration (all p > .05). Arterial oxygenation was improved during L-NAME infusion, and the dosage of catecholamines could be reduced (both p< .05). Although sustained hemodynamic effects were seen, L-NAME was most effective during the early stages of administration, and the effect of L-NAME on blood pressure and vascular resistance tended to diminish throughout the continuous infusion of L-NAME. Seven of 11 patients ultimately died, with survival time ranging from 2 to 34 days. CONCLUSIONS: Nitric oxide appears to play a role in cardiovascular derangements during human sepsis. The increased blood pressure and vascular resistance values are sustained during prolonged inhibition of nitric oxide synthesis with L-NAME in patients with severe septic shock, although the hemodynamic changes are most significant in the early stages of L-NAME infusion. The high mortality rate in these patients may suggest that L-NAME has only limited effects on outcome.

APACHE↗

PubMed1998

Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors.

1. We have expressed recombinant NR1a/NR2A and NR1a/NR2D N-methyl-D-aspartate (NMDA) receptor channels in Xenopus oocytes and made recordings of single-channel and macroscopic currents in outside-out membrane patches. For each receptor type we measured (a) the individual single-channel activations evoked by low glutamate concentrations in steady-state recordings, and (b) the macroscopic responses elicited by brief concentration jumps with high agonist concentrations, and we explore the relationship between these two sorts of observation. 2. Low concentration (5-100 nM) steady-state recordings of NR1a/NR2A and NR1a/NR2D single-channel activity generated shut-time distributions that were best fitted with a mixture of five and six exponential components, respectively. Individual activations of either receptor type were resolved as bursts of openings, which we refer to as 'super-clusters'. 3. During a single activation, NR1a/NR2A receptors were open for 36 % of the time, but NR1a/NR2D receptors were open for only 4 % of the time. For both, distributions of super-cluster durations were best fitted with a mixture of six exponential components. Their overall mean durations were 35.8 and 1602 ms, respectively. 4. Steady-state super-clusters were aligned on their first openings and averaged. The average was well fitted by a sum of exponentials with time constants taken from fits to super-cluster length distributions. It is shown that this is what would be expected for a channel that shows simple Markovian behaviour. 5. The current through NR1a/NR2A channels following a concentration jump from zero to 1 mM glutamate for 1 ms was well fitted by three exponential components with time constants of 13 ms (rising phase), 70 ms and 350 ms (decaying phase). Similar concentration jumps on NR1a/NR2D channels were well fitted by two exponentials with means of 45 ms (rising phase) and 4408 ms (decaying phase) components. During prolonged exposure to glutamate, NR1a/NR2A channels desensitized with a time constant of 649 ms, while NR1a/NR2D channels exhibited no apparent desensitization. 6. We show that under certain conditions, the time constants for the macroscopic jump response should be the same as those for the distribution of super-cluster lengths, though the resolution of the latter is so much greater that it cannot be expected that all the components will be resolvable in a macroscopic current. Good agreement was found for jumps on NR1a/NR2D receptors, and for some jump experiments on NR1a/NR2A. However, the latter were rather variable and some were slower than predicted. Slow decays were associated with patches that had large currents.

Animals↗

PubMed2003

Evolutionary profiling of the U49 snoRNA gene.

Small nucleolar RNAs (snoRNAs) are involved in precursor ribosomal RNA (pre-rRNA) processing and rRNA base modifications (2'-O-ribose methylation and pseudouridylation). Their genomic organization show great flexibility: some are individually or polycistronically transcribed, while others are encoded within introns of other genes. Here, we present an evolutionary analysis of the U49 gene in seven species. In all species analyzed, U49 contains the typical hallmarks of C and D box motifs, and a conserved 12-15 nt sequence complementary to rRNA that define them as homologs. In mouse, human, and Drosophila U49 is found encoded within introns of different genes, and in plants it is transcribed polycistronically from four different locations. In addition, U49 has two copies in two different introns of the RpL14 gene in Drosophila. The results indicate a substantial degree of duplication and translocation of the U49 gene in evolution. In light of its variable organization we discuss which of the two proposed mechanisms of rearrangement has acted upon the U49 snoRNA gene: chromosomal duplication or transposition through an RNA intermediate.

Animals↗

PubMed1991

Validation studies with Muta Mouse: a transgenic mouse model for detecting mutations in vivo.

MutaMouse is a transgenic mouse engineered to detect mutations in vivo in any tissue of choice by using simple laboratory methods. The target is a bacterial lacZ gene incorporated via lambda phage into the genome of each mouse cell such that a concatamer of approximately 40 copies exists at a single site on both chromosomes of a homologous pair. In order to assess the potential usefulness of MutaMouse in detecting in vivo mutagenesis, several known mutagens/carcinogens were applied to male animals of 8-10 weeks in age. Intraperitoneal injections (single or 5 daily doses) of N-ethyl-N-nitrosourea (ENU), chlorambucil, procarbazine, cyclophosphamide, and acrylamide were investigated for mutagenic effects in bone marrow, liver, and testes. In addition, skin painting studies (single application) were performed with dimethylbenzanthracene (DMBA), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and acetic acid. Increases in mutant frequency were clearly induced by all eight chemicals, the magnitudes of which were dependent on the chemical, dose, method of dosing, tissue analyzed, and the time lapse between treatment and isolation of DNA. Data on variability in mutant frequency was presented relative to the analyzed population of lacZ genes and number of animals per treatment group. Application of the MutaMouse model to the detection of heritable mutations was discussed.

Acrylamide↗

PubMed1987

Organization of multispecific DNA methyltransferases encoded by temperate Bacillus subtilis phages.

B. subtilis phage rho 11s codes for a multispecific DNA methyltransferase (Mtase) which methylates cytosine within the sequences GGCC and GAGCTC. The Mtase gene of rho 11s was isolated and sequenced. It has 1509 bp, corresponding to 503 amino acids (aa). The enzyme's Mr of 57.2 kd predicted from the nucleotide sequence was verified by direct Mr determinations of the Mtase. A comparison of the aa sequence of the rho 11s Mtase with those of related phages SPR and phi 3%, which differ in their methylation potential, revealed generalities in the building plan of such enzymes. At least 70% of the aa of each enzyme are contained in two regions of 243 and 109 aa at the N and C termini respectively, which are highly conserved among the three enzymes. In each enzyme, variable sequences separate the conserved regions. Variability is generated through the single or multiple use of related and unrelated sequence motifs. We propose that the recognition of those DNA target sequences, which are unique for each of the three enzymes, is determined by these variable regions. Evolutionary relationships between the three enzymes are discussed.

Amino Acid Sequence↗

PubMed1977

Solubility profiles and thermodynamics of parabens in aliphatic alcohols.

The solubility of a series of compounds was determined in a wide polarity spectrum of normal aliphatic alcohols over a limited temperature range. The solutes chosen were the methyl through n-butyl p-hydroxybenzoates, several of these being useful preservatives. Solubility profiles were determined for these compounds, and the effect of temperature upon their solubility behavior was investigated. The solubility of the solutes is expressed in several concentration notations; mole fraction plots showed a variable twin peak array as a function of the dielectric constant for the solutes studied. Since heats of fusion were available and data were generated as a function of temperature, thermodynamic parameters for these systems could be calculated. The relationship of these parameters to multiple solubility peak array is discussed.

Alcohols↗

PubMed1998

Mechanism-based inhibition of human folylpolyglutamate synthetase: design, synthesis, and biochemical characterization of a phosphapeptide mimic of the tetrahedral intermediate.

Folylpolyglutamate synthetase (FPGS) catalyzes anATP-dependent ligation reaction that results in the synthesis of poly(gamma-glutamate) metabolites of folates and some antifolates. We have synthesized and characterized the prototype of a new class of mechanism-based FPGS inhibitor in which a phosphonate moiety mimics the tetrahedral intermediate formed during the ligation reaction. This phosphonate, 4-amino-4-deoxy-10-methyl-pteroyl-L-glutamyl-gamma-[Psi¿P(O)(OH)-O¿] glutarate (4-NH2-10-CH3-Pte-L-Glu-gamma-[Psi¿P(O)(OH)-O¿]glutarate), is not a substrate for human FPGS, but is a linear, competitive inhibitor (Kis = 46 nM) with respect to methotrexate as the variable substrate. Inhibition is not time-dependent and preincubation of FPGS with this phosphonate does not increase the degree of inhibition, suggesting that it is not a slow, tight-binding inhibitor involving a time-dependent isomerization, EI --> EI*. Substructures containing the phosphonate moiety but lacking the pterin are much less inhibitory to FPGS, indicating that a significant portion of the inhibitor binding energy is derived from the pterin moiety, a feature also observed in substrate binding. 4-NH2-10-CH3-Pte-L-Glu-gamma-[Psi¿P(O)(OH)-O¿]glutarate is also an analog of a proposed tetrahedral intermediate in the reaction catalyzed by gamma-glutamyl hydrolase (gamma-GH), another enzyme of importance in controlling folate homeostasis in cells. This intermediate would arise from direct attack of H2O on the dipeptide, 4-NH2-10-CH3-Pte-L-Glu-gamma-L-Glu. The fact that 4-NH2-10-CH3-Pte-L-Glu-gamma-[Psi¿P(O)(OH)-O¿]glutarate is not an inhibitor of gamma-GH strongly suggests that hydrolysis of poly-gamma-glutamates catalyzed by gamma-GH does not involve the direct attack of water at the scissile amide bond. Methotrexate, its gamma-glutamyl dipeptide metabolite, and 4-NH2-10-CH3-Pte-L-Glu-gamma-[Psi¿P(O)(OH)-O¿]glutarate are equipotent as inhibitors of human dihydrofolate reductase (the primary target of methotrexate), but the phosphonate does not significantly inhibit another important folate-dependent enzyme, thymidylate synthase. Thus, the phosphonate moiety in this analog represents an important new lead in the development of FPGS inhibitors.

Animals↗

PubMed1981

Histamine-releasing properties of hydroxy-9-methyl-2-ellipticinium acetate.

Previous work on Hydroxy-9-methyl-2-ellipticinium acetate indicated a bronchoconstrictor activity which could be partially offset by antagonists of the H1 histamine receptors, and the absence of any direct effect on smooth muscle. OH-9-CH3-2-E at concentrations of 10 micrograms/ml and 500 micrograms/ml produced a moderate and a variable release of histamine when placed in contract with whole human blood and lung fragments, respectively. In addition, at a dose of 3 mg/kg in the guinea pig, pulmonary airway resistance was raised and the blood histamine level lowered. A significant correlation was found between these two effects. These results demonstrate that OH-9-CH3-2-E possesses a histamine-releasing potency which is partly responsible for its bronchial effects, implying that precautions may have to be taken when it is used as a therapeutic agent in sensitive subjects. However, the moderate intensity of this potency has not so far precluded therapeutic use of the preparation.

Airway Resistance↗

PubMed2003

Opioids: a review.

Recent discoveries in opioid pharmacology help explain the enormous variability in clinical responses to these powerful analgesics. Although there is only one m opioid receptor gene, splice variants of that gene's expression result in a panoply of different functioning receptors. Other sources of variable response include polymorphisms in the m opioid receptor regulatory region, and pharmacokinetic differences because of cytochrome P-450 mono-oxygenase heterogeneity. Analgesic tolerance is likely the key phenomenon limiting the benefit of opioids. A plethora of intracellular pathways affects this. Among them are the N-methyl-D-aspartate receptor, protein kinase C gamma activity, nitric oxide synthase, and GM1 ganglioside content of the neuronal membrane. Clinical studies undercut the routine use of meperidine in most settings. Other studies have shown better ways to diminish opioid side effects.

Analgesics, Opioid↗

PubMed2005

Optimization of the sonication extraction method of Hibiscus tiliaceus L. flowers.

The influence of several experimental parameters on the ultrasonic extraction of Hibiscus tiliaceus L. flowers were investigated: extraction time, solvent polarity, sample amount, solvent volume and sample particle size. It was concluded that the most influential variables were extraction time and solvent polarity. The optimized procedure employed 5 g of ground flowers, 150 mL of methanol and 140 min of extraction. The extracts were fractionated using preparative silica columns and the resulting fractions were analyzed by GC/MS. Some saturated hydrocarbons, fatty acids, fatty acid methyl esters, phytosterols, and vitamin E were identified in the plant extracts.

Flowers↗

PubMed1998

Reserpine attenuates D-amphetamine and MDMA-induced transmitter release in vivo: a consideration of dose, core temperature and dopamine synthesis.

Amphetamine releases dopamine through a transporter-mediated mechanism. The purpose of this report was to further our understanding of the intracellular pool from which amphetamine releases dopamine: the cytoplasmic pool, the vesicular pool, or both. Rats were treated with D-amphetamine (AMPH) (1.0 or 10.0 mg/kg) or an amphetamine analog, methylenedioxymethamphetamine (MDMA) (2.0, 5.0, or 10.0 mg/kg). Pre-treatment with 10.0 mg/kg reserpine (18 h prior to AMPH or MDMA) attenuated dopamine release for high and low AMPH doses; however the low-dose effect showed borderline significance. Pre-treatment with 10.0 mg/kg reserpine attenuated dopamine and serotonin release induced by MDMA. The dopamine effect was seen at all three MDMA doses; the effect on serotonin was only measured at the 10.0 mg/kg dose. Reserpine pre-treatment caused reductions in core body temperature; heating the rats to normal body temperature for 3 h prior to AMPH or MDMA, and during the 4 h post-treatment period partially reversed the reserpine-induced attenuation of dopamine release. However, the intermediate level of dopamine release for the reserpinized-heated animals was not significantly different from either the reserpine group (not heated) or the AMPH or MDMA alone groups. In a separate group of rats, the effects of reserpine and reserpine+heat on dopamine synthesis were measured. DOPA accumulation after treatment with the aromatic acid decarboxylase inhibitor NSD-1015 (100 mg/kg, 30 min before sacrifice), was greater in rats treated with reserpine compared to controls; heating the reserpinized rats did not significantly alter the amount of DOPA accumulation; however there was a trend towards further increase. These results suggest that D-amphetamine releases dopamine that is stored in both vesicles and the cytoplasm. Cooling may contribute to the attenuation of AMPH or MDMA-induced dopamine release observed after reserpine; however, AMPH or MDMA dependence upon vesicular stores most likely explains the diminished release after reserpine. The attenuation of AMPH or MDMA-induced transmitter release by reserpine is thought to be counteracted by a reserpine-induced replenishment of stores. Therefore, all doses of D-amphetamine may use vesicular stores; the degree to which new synthesis counteracts the vesicular depletion may be the variable which differentiates low from high doses of D-amphetamine.

Animals↗

PubMed2000

Inhibition of nitric oxide synthesis increases erythrocyte membrane fluidity and unsaturated fatty acid content.

Changes in the lipid composition of the membrane affect its fluidity and function. These variables are altered in various forms of hypertension. Our hypothesis was that the rapid increase in blood pressure (BP) caused by inhibition of nitric oxide production would lead to alterations in membrane fluidity similar to those observed in genetic hypertension. We used Nomega-nitro L-arginine methyl ester (L-NAME) and vehicle-treated (3 weeks) Wistar-Kyoto rats to study the effects of nitric oxide synthase (NOS) inhibition on membrane fluidity and lipid composition. Erythrocyte membrane fluidity was measured by fluorescence anisotropy. Membrane lipids were separated using Sep-Pak and thin-layer chromatography. Fatty acid methyl esters were produced and analyzed by gas chromatography-mass spectrometry. Nomega-nitro L-arginine methyl ester treatment increased BP and erythrocyte membrane fluidity. The phospholipid and unsaturated fatty acid levels in the membranes from the L-NAME-treated rats were consistent with the increase in fluidity (ie, more unsaturated fatty acid, in particular, arachidonic and docosahexaenoic acid) and a reduction in membrane sphingomyelin content. Fatty acid analysis of individual lipid groups suggested the changes in membrane fatty acid composition may be asymmetric, with the majority of the changes occurring in the outer leaflet. Inhibition of NOS results in changes in membrane composition that may explain the concurrent changes in fluidity. The increased membrane fluidity observed here contrasts with the reduced fluidity observed in genetic hypertension or unchanged fluidity in secondary hypertension. The effects could be related to NOS inhibition or may be a direct effect of L-NAME.

Animals↗

PubMed2006

Dovyalicin-type spermidine alkaloids from Dovyalis species.

Phytochemical investigations of Dovyalis abyssinica, D. hebecarpa, and D. macrocalyx revealed two new spermidine-type alkaloids, dovyalicin E (3) and dovyalicin F (4), along with the previously described dovyalicin A (1), dovyalicin B (2), and dovyalicin C (5). In addition, a new phenol glucoside, 4-hydroxytremulacin (7), and the new 1,2-cyclohexanediol glucoside 9, as well as the known compounds methyl 1-hydroxy-6-oxocyclohex-2-enecarboxylate (6) and tremulacin (8), were isolated. The structures were established using homo- and heteronuclear two-dimensional NMR experiments and chiroptical methods. At ambient temperature, the N-disubstituted amide 4 exists as a mixture of cis and trans conformers. Variable-temperature (1)H NMR studies showed that time-averaged spectra are obtainable at 348 K, and the activation parameters determined for the rotation about the amide bond were DeltaH++ = 89 +/- 4.6 kJ/mol, DeltaS++ = 65 +/- 14 kJ/mol.K, and DeltaG++(298K) = 70 +/- 4.5 kJ/mol.

Alkaloids↗

PubMed2004

Mitochondrial enzymes and endoplasmic reticulum calcium stores as targets of oxidative stress in neurodegenerative diseases.

Considerable evidence indicates that oxidative stress accompanies age-related neurodegenerative diseases. Specific mechanisms by which oxidative stress leads to neurodegeneration are unknown. Two targets of oxidative stress that are known to change in neurodegenerative diseases are the mitochondrial enzyme alpha-ketoglutarate dehydrogenase complex (KGDHC) and endoplasmic reticulum calcium stores. KGDHC activities are diminished in all common neurodegenerative diseases and the changes are particularly well documented in Alzheimer's disease (AD). A second change that occurs in cells from AD patients is an exaggerated endoplasmic reticulum calcium store [i.e., bombesin-releasable calcium stores (BRCS)]. H(2)O(2), a general oxidant, changes both variables in the same direction as occurs in disease. Other oxidants selectively alter these variables. Various antioxidants were used to help define the critical oxidant species that modifies these responses. All of the antioxidants diminish the oxidant-induced carboxy-dichlorofluorescein (cDCF) detectable reactive oxygen species (ROS), but have diverse actions on these cellular processes. For example, alpha-keto-beta-methyl-n-valeric acid (KMV) diminishes the H(2)O(2) effects on BRCS, while trolox and DMSO exaggerate the response. Acute trolox treatment does not alter H(2)O(2)-induced changes in KGDHC, whereas chronic treatment with trolox increases KGDHC almost threefold. The results suggest that KGDHC and BRCS provide targets by which oxidative stress may induce neurodegeneration and a useful tool for selecting antioxidants for reversing age-related neurodegeneration.

Adaptation, Physiological↗

PubMed2004

Targeted inhibition of V(D)J recombination by a histone methyltransferase.

The tissue- and stage-specific assembly of antigen receptor genes by V(D)J recombination is regulated by changes in the chromatin accessibility of target gene segments. This dynamic remodeling process is coordinated by cis-acting promoters and enhancers, which function as accessibility control elements. The basic epigenetic mechanisms that activate or repress chromatin accessibility to V(D)J recombinase remain unclear. We now demonstrate that a histone methyltransferase overrides accessibility control element function and cripples V(D)J recombination of chromosomal gene segments. The recruited histone methyltransferase induces extensive revisions in the local chromatin environment, including altered histone modifications and de novo methylation of DNA. These findings indicate a key function for histone methyltransferases in the tissue- and stage-specific suppression of antigen receptor gene assembly during lymphocyte development.

Animals↗

PubMed1987

Stimulation of choline release from NG108-15 cells by 12-O-tetradecanoylphorbol 13-acetate.

The effects of the potent tumour-promoting phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) on phosphatidylcholine (PtdCho) metabolism were investigated in the neuroblastoma X glioma hybrid cell line NG108-15. TPA (100 nM) stimulated by 150-200% the release into the medium of 3H radioactivity from cells that had been pre-labelled with [3H]choline. H.p.l.c. analysis of the medium revealed that TPA stimulated the release of only free [3H]choline (212 +/- 11% of control), without affecting such other labelled metabolites as [3H]phosphocholine and [3H]glycerophosphocholine. This effect was concentration-dependent, with a half-maximal effect obtained at 27.5 +/- 6.8 nM, and was observable as early as 5-10 min after exposure to TPA. The TPA-induced release of [3H]choline into the medium was accompanied by a small and variable decrease in cellular [3H]PtdCho (to 93 +/- 4% of control). However, the radioactivity associated with water-soluble cellular choline metabolites (mainly [3H]phosphocholine and [3H]glycerophosphocholine) remained unchanged. TPA also stimulated the release of [3H]choline derived from [3H]PtdCho that had been produced via the methylation pathway from [3H]methionine. These data suggest that phosphatidylcholine may serve as the source of free choline released from the cells in response to TPA. The possible enzymic mechanisms underlying this response are discussed.

Cell Line↗

PubMed1984

Inhibition of human natural killer cell activity by (14R,15S)-14,15-dihydroxy-5Z,8Z,10E,12E- icosatetraenoic acid.

The interactions between products of the 15-lipoxygenase cascade and human natural killer (NK) cell activity have been studied. Addition of human leukocyte-derived (14R,15S)-14,15-dihydroxy-5Z,8Z,10E,12E-ic osatetraenoic acid (14,15-DiHETE) to the NK cytotoxicity assay against K562 target cells resulted in inhibition of NK cell activity, whereas addition of other 15-lipoxygenase-associated metabolites [i.e., (15S)-15-hydroperoxy-5Z,8Z,11Z,13E-icosatetra eno ic acid, (15S)-15-hydroxy-5Z,8Z,11Z,13E-icosatetraenoic acid, and (8R,15S)- and (8S,15S)-8,15-dihydroxy-5Z,9E,-11E,13E-icosat etr aenoic acid isomers] resulted in little or no inhibition of NK function. Dose-response studies indicate that leukocyte-derived 14,15-DiHETE and 14,15-DiHETE methyl ester, at micromolar concentrations, inhibit NK function even in the presence of 2.5% fetal calf serum. Synthetic 14,15-DiHETE prepared by total organic synthesis displayed similar biological activities over identical dose ranges. These icosanoids do not inhibit NK target cell binding and they exert only a variable effect in either antibody-dependent cytotoxicity or cytotoxic T-lymphocyte assays. These results demonstrate that the 14,15-DiHETE inhibits NK cell function in vitro. Moreover, they suggest that activation of the 15-lipoxygenase cascade and formation of 14,15-DiHETE in vivo may provide a mode of immune regulation.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1988

Mutational hot spots in Ig V region genes of human follicular lymphomas.

The genes coding for the Ig light chains expressed in two cases of human follicular lymphoma were cloned and sequenced. In each case, multiple independent isolates of the tumor population were compared. Although each tumor represented a single clone of B cells with a unique V/J joint, different cells within each tumor had accumulated multiple point mutations in the V gene during clonal expansion. Most of the mutations observed were silent, but some resulted in amino acid replacements. Identical silent mutations were often observed in independent isolates of each tumor. By combining the current data with VH sequences obtained previously from the same cells, it was apparent that the repetitive silent mutations could not be explained solely by a genealogic tree. Such mutations could represent hot spots whose tendency to mutate may be influenced by neighboring DNA sequences or by the methylation of specific cytosine residues.

Amino Acid Sequence↗