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PubMed2005

Evidence for a second class of S-adenosylmethionine riboswitches and other regulatory RNA motifs in alpha-proteobacteria.

BACKGROUND: Riboswitches are RNA elements in the 5' untranslated leaders of bacterial mRNAs that directly sense the levels of specific metabolites with a structurally conserved aptamer domain to regulate expression of downstream genes. Riboswitches are most common in the genomes of low GC Gram-positive bacteria (for example, Bacillus subtilis contains examples of all known riboswitches), and some riboswitch classes seem to be restricted to this group. RESULTS: We used comparative sequence analysis and structural probing to identify five RNA elements (serC, speF, suhB, ybhL, and metA) that reside in the intergenic regions of Agrobacterium tumefaciens and many other alpha-proteobacteria. One of these, the metA motif, is found upstream of methionine biosynthesis genes and binds S-adenosylmethionine (SAM). This natural aptamer most likely functions as a SAM riboswitch (SAM-II) with a consensus sequence and structure that is distinct from the class of SAM riboswitches (SAM-I) predominantly found in Gram-positive bacteria. The minimal functional SAM-II aptamer consists of fewer than 70 nucleotides, which form a single stem and a pseudoknot. Despite its simple architecture and lower affinity for SAM, the SAM-II aptamer strongly discriminates against related compounds. CONCLUSION: SAM-II is the only metabolite-binding riboswitch class identified so far that is not found in Gram-positive bacteria, and its existence demonstrates that biological systems can use multiple RNA structures to sense a single chemical compound. The two SAM riboswitches might be 'RNA World' relics that were selectively retained in certain bacterial lineages or new motifs that have emerged since the divergence of the major bacterial groups.

Alphaproteobacteria↗

PubMed2004

Ginsenoside-Rd attenuates oxidative damage related to aging in senescence-accelerated mice.

Among the various theories of the aging process, the free radical theory, which proposes that deleterious actions of free radicals are responsible for the functional deterioration associated with aging, has received widespread attention. The theory suggests that enhancement of the antioxidative defence system to attenuate free-radical-induced damage will counteract the aging process. We used senescence-accelerated mice (SAM) to investigate the relationship between aging and the antioxidative defence system and evaluated the effects of ginsenoside-Rd, the saponin from ginseng, by measuring antioxidative defence system parameters, including the glutathione (GSH)/glutathione disulfide (GSSG) redox status, antioxidative enzyme activity and level of lipid peroxidation. SAM at 11 months of age (old SAM) showed a significantly lower hepatic GSH/GSSG ratio, due to decreased GSH and increased GSSG levels, than SAM at 5 weeks of age (young SAM). However, the administration of ginsenoside-Rd at a dose of 1 or 5 mg kg(-1) daily for 30 days to 10-month-old SAM significantly increased GSH, but decreased GSSG, resulting in elevation of the GSH/GSSG ratio. In addition, ginsenoside-Rd increased the activity of glutathione peroxidase (GSH-Px) and glutathione reductase that were both significantly lower in old SAM than in young SAM. This suggests that ginsenoside-Rd could play a crucial role in enhancing the defence system through regulation of the GSH/GSSG redox status. Moreover, decreases in the superoxide dismutase (SOD) and catalase activity in old SAM compared with young SAM were also revealed, indicating that the aging process resulted in suppression of the antioxidative defence system. However, ginsenoside-Rd did not affect SOD and catalase activity. As catalase is localized in peroxisome granules and GSH-Px is present in the cytoplasm and mitochondrial matrix, the site of ginsenoside-Rd action may be the cytoplasm and mitochondrial matrix. Furthermore, the serum and liver malondialdehyde levels, indicators of lipid peroxidation, were elevated with aging, while ginsenoside-Rd inhibited lipid peroxidation. This study indicates that the aging process leads to suppression of the antioxidative defence system and accumulation of lipid peroxidation products, while ginsenoside-Rd attenuates the oxidative damage, which may be responsible for the intervention of GSH/GSSG redox status.

Aging↗

PubMed1994

Ameliorative effects of chronic treatment using DX-9386, a traditional Chinese prescription, on learning performance and lipid peroxide content in senescence accelerated mouse.

DX-9386 is a traditional Chinese prescription consisting of ginseng, polygala, acorus and hoelen. The effect of chronic oral treatment with this preparation on learning behaviors and lipid peroxide concentration was studied in senescence accelerated mouse (SAM). SAM P8, a senescence prone of SAM, and SAM R1, a senescence resistant substrain of SAM, were started on a diet containing 1% of DX-9386 from the age of 2 months. All the experiments were performed at the age of 10 months. The prescription ameliorated the memory disorders of SAM P8, as evaluated in a step down test as well as a spatial memory test. The preparation, however, did not affect the learning behaviors in SAM R1. DX-9386 reduced the elevated levels of lipid peroxide in the serum and liver of SAM P8, while it did not alter that in SAM R1. These results suggested that DX-9386 slowed the aging process of SAM P8 in terms of learning behaviors and lipid peroxidation.

Administration, Oral↗

PubMed1986

Conjugation of salicylamide in the intestinal wall of dogs and rabbits.

The intestinal conjugation of salicylamide (SAM) the formation of SAM sulfate (SAMS) and SAM glucuronide (SAMG) were investigated in dogs and rabbits by using in situ intestinal sac preparation with mesenteric vein cannulation. SAM, SAMS and SAMG in the mesenteric venous blood, sampled at successive intervals after injection of SAM solutions into the sac, were determined. Total recoveries in 1 h were not significantly different in dogs (71%) and rabbits (64%). Both animals, however, showed a quantitative difference in intestinal conjugation. Sulfation predominated over glucuronidation in dog intestine while the formation of the glucuronide was exclusively high in rabbit intestine. Furthermore, the dose-dependent conjugation of SAM was investigated in dog intestine at four doses, 2, 3, 6 and 10 mg/one animal. Upon increasing the doses from 2 to 10 mg, the amounts of SAMS appearing in the blood remained unchanged, those of SAMG increased about two times and those of free SAM increased about six times, while the total recoveries increased parallel to the doses, suggesting saturation kinetics in the formation step of the two conjugates. Simultaneous computer-fitting of the experimental data for 2 and 10 mg doses to a simplified model, containing Michaelis-Menten kinetics in the formation of the conjugates, was examined and good agreement between the observed data and the theoretical values was obtained.

Animals↗

PubMed1992

An assessment of indomethacin-induced mucosal damage in vivo by measuring the metabolism of salicylamide in rabbit intestine.

Indomethacin-induced mucosal damage was assessed in vivo by measuring salicylamide (SAM) metabolism in rabbit intestine. Intestinal mucosal damage 48 h after oral indomethacin (500 mg/kg) administration was examined using a scanning electron microscope. Duodenal, jejunal and ileal mucosal toxicity was compared with that in controls. Intestinal first-pass metabolism of SAM was studied using in situ intestinal sacs with intact mesenteric venous blood collection. The appearance of both SAM and its metabolites in the mesenteric venous blood was measured following cannulation of the mesenteric vein of the exposed intestine and collecting all venous blood draining from the absorbing region. Following oral pretreatment with indomethacin, the appearance of SAM and SAM glucuronide (SAMG) in the mesenteric venous blood was significantly increased. The concentrations of SAM and SAMG in the blood increased following intraduodenal administration of SAM in vivo in rabbits orally pretreated with indomethacin compared with controls. However, after intravenous administration of SAM, the blood concentration of SAM and SAMG was not increased compared with controls. These findings suggest that the differences in intestinal first-pass metabolism of SAM may be due to the intestinal mucosal damage induced by oral indomethacin pretreatment. The results indicate that the alteration of intestinal first-pass metabolism of a marker compound may be utilized to assess intestinal mucosal damage in vivo.

Animals↗

PubMed2003

Quantification of serum and urinary S-adenosylmethionine and S-adenosylhomocysteine by stable-isotope-dilution liquid chromatography-mass spectrometry.

BACKGROUND: We have developed an assay that uses stable-isotope-dilution liquid chromatography-mass spectrometry to assess S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in body fluids to investigate the relationship of these metabolites to hyperhomocysteinemia. METHODS: Commercially obtained SAM (D(3) methyl) and (13)C(5)-SAH uniformly labeled in the adenosyl moiety, which was synthesized using S-adenosylhomocysteine hydrolase, were added to samples followed by perchloric acid protein precipitation, C(18) chromatography, and analysis by liquid chromatography-mass spectrometry with quantification by comparison of the areas of internal standard and endogenous peaks. RESULTS: Estimates of intraassay imprecision (CV) were 5% and 17% for SAM and SAH, respectively (n = 10). SAM decreased and SAH increased in serum and plasma samples at both 4 degrees C and room temperature over 80 h. SAM and SAH were unstable in samples stored longer than 2 years at -20 degrees C. In 48 volunteers, the estimated reference intervals [from mean (2 SD) of log-transformed data] for serum SAM and SAH were 71-168 and 8-26 nmol/L, respectively. Fractional excretion of SAM was higher than that of SAH, and the urinary SAM:SAH ratio was much higher than the serum or erythrocyte SAM:SAH ratios. CONCLUSIONS: Stable-isotope-dilution liquid chromatography-mass spectrometry can be used to quantify SAM and SAH in biological fluids and tissues. Sample handling and storage must be stringently controlled for any epidemiologic or clinical use of such assays.

Adult↗

PubMed2000

Age-related retinal pigment epithelium and Bruch's membrane degeneration in senescence-accelerated mouse.

PURPOSE: To investigate age-related changes in the retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris in the senescence-accelerated mouse (SAM). METHODS: The external and eyecup features and light and electron microscopic findings were examined in three male and two female mice of a senescence-prone mouse strain (SAM P(8)) monthly for 12 months. These results were compared with those in age-matched mice of similar background but senescence resistant (SAM R(1)). Choroidal vascular casts were prepared at 12 months in seven mice each of the SAM P(8) and SAM R(1) strains. Quantitative analysis of area of choriocapillaris was performed by automated image analysis, and the results were analyzed by paired Student's t-test. RESULTS: We found in the SAM P(8) strain that hair loss, coarseness of hair texture, and ulceration of skin appeared and increased as the age advanced (at approximately 5-9 months). Eyecup examination showed no differences. Light and electron microscopy revealed progressively more prominent abnormalities in the RPE and Bruch's membrane mice older than 10 months. Two of the five SAM P(8) mice older than 11 months showed what appeared to be intra-Bruch's membrane choroidal neovascularization. The RPE and Bruch's membrane appeared normal in the SAM R(1) strain. In the SAM P(8), vascular casts of the choriocapillaris showed a mild but significant decrease in vascular area when compared with the SAM R(1) strain at 12 months (P = 0.011). CONCLUSIONS: Senescence accelerated mice develop progressive age-related changes in the RPE-Bruch's-choriocapillaris complex that have features that may be relevant in the study of age-related macular changes in humans.

Aging↗

PubMed2001

Blood determinations of S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine: correlations with diet.

An increasing number of both clinical and experimental studies have shown an association between deficiencies of the dietary sources of physiological methyl groups and cancer formation. The critical metabolic intermediate in a determination of methylation status is S-adenosylmethionine (SAM), the body's chief physiological methyl donor. The present study examined the erythrocyte levels of SAM and of its demethylated metabolite S-adenosylhomocysteine (SAH) in 66 normal subjects (33 men and 33 women), whose blood had been drawn at days 0, 7 and 14 of an experimental period during which they were fed a fixed diet. The plasma levels of homocysteine (HCys) were also determined in the same individuals at the same time points. In addition, the subjects had completed a food frequency questionnaire (FFQ) describing their usual dietary habits before being placed on the dietary regimen. The blood levels of SAM, SAH, and HCys were compared with the dietary intakes of folate, vitamin B(6), fats, and calories, both prior to using the FFQ and during the experimental period. The results indicated that the intraindividual differences were very low, but the interindividual differences were large for the values of SAM, SAH, SAM:SAH ratios, and HCys. Interestingly, the blood levels of SAM and HCys were higher in men than in women and generally showed the expected correlations with folate intake i.e., positive for SAM and negative for HCys. The intakes of folate (276 microg/days) and B(6) (1.87 mg/days) during the 2-week experimental period were relatively low compared with the usual intakes of these vitamins (375 and 2.06 mg/day for folate and B(6), respectively) but correlated well with each other during both periods of the study. Surprisingly, both men and women showed a significant rise in erythrocyte SAM:SAH ratios as a function of age. In addition, the combined results from men and women, even adjusted for gender, showed significant correlations between HCys and both weight and body mass index. On the other hand, during the experimental period of the study, blood SAM levels were inversely correlated with the intakes of both fat and calories when the data for both men and women were combined and adjusted for gender. The blood determinations of SAM and related compounds showed a high degree of reproducibility over time and thus appear to provide a practical marker of methylation status for the assessment of cancer risk from dietary, environmental, and genetic factors.

Body Mass Index↗

PubMedDate not supplied

Stability-indicating proton nuclear magnetic resonance spectroscopic method for determination of S-adenosyl-L-methionine in tablets.

We present a simple, accurate, stability-indicating nuclear magnetic resonance (NMR) method for determining active (S,S) and inactive (R,S) epimers of S-adenosyl-L-methionine (SAM) in tablets. The SCH3 resonances of SAM epimers were well resolved at 300 MHz. Individual assays of 5 SAM tablets gave SAM values of 101.3 +/- 1.7% of declared amounts. Tablet solutions were assayed at a level of 8.0 mg/mL, but the method was linear for SAM concentrations ranging from 64 to 1 mg/mL (correlation coefficient, 0.9996). Reproducibility was indicated by a relative standard deviation of 0.33% for 6 replicate assays for total SAM at a concentration of 8 mg/mL. In contrast to the propietary liquid chromatographic (LC) method, which requires SAM as an external standard, the NMR method uses sodium trimethylsilylpropionate-d4 (TSP) both as an internal standard and as a chemical shift reference. The method was used to test the stability of SAM analytes under various pH levels and temperatures. We found 8% inactivation of SAM due to epimerization over a 24 h period at room temperature and pH 5. SAM solutions showed no detectable inactivation after 14 days when stored below 0 degrees C.

Chromatography, Liquid↗

PubMedDate not supplied

Effect of S-adenosyl-L-methionine on the development of preneoplastic foci and the activity of some carbohydrate metabolizing enzymes in the liver, during experimental hepatocarcinogenesis.

gamma-Glutamyltranspeptidase (GGT)-positive foci and glutathione-S-transferase, placental (GST-P)-positive lesions occupied 36% and 54% of liver parenchyma, respectively, in Wistar rats 8 weeks after initiation with diethylnitrosamine, followed by selection. The administration of S-adenosyl-L-methionine (SAM, 384 mumol/kg/day) caused 77% and 42% falls in the percentage of GGT-positive and GST-P-positive lesions, respectively. There also occurred a 46% decrease in labeling index of GGT-positive foci, in SAM-treated rats. These changes were associated with decrease in liver pyruvate kinase (PK), lactate dehydrogenase and glycerol-3-phosphate dehydrogenase. SAM did not affect these enzymatic activities in normal and uninitiated controls, but it caused a consistent increase in initiated rats. Enolase, fructose-biphosphatase and malic enzyme (ME) activities increased in the liver of initiated rats. SAM did not modify significantly these enzymatic activities, either in control or in initiated rats. Glucose-6-phosphate dehydrogenase (G6PDH) was 113% higher in the liver of initiated rats than in uninitiated controls. SAM treatment did not significantly affect this enzymatic activity in uninitiated rats, but caused a great decrease in initiated ones. As expected, there occurred a marked rise in GGT activity in the liver of initiated rats, with respect to controls. SAM caused an increase in GGT activity in normal and uninitiated controls, but it caused a 77% fall in GGT activity in initiated rats, coupled with a 380% rise in remodeling of GGT-positive lesions. Histochemical determination of G6PDH and ME activities showed that in the absence of SAM many preneoplastic lesions expressed higher G6PDH and ME activities than surrounding liver. SAM did not affect ME-positive lesions, while it caused a decrease in the number of G6PDH-positive lesions. Immunohistochemical determination of PK activity, isoenzyme L, showed a decrease in GST-P-positive lesions. Many of these lesions were no longer recognizable as lesions expressing a low PK activity, in SAM-treated rats. However, a relatively small number of GST-P-positive lesions expressing a low PK activity were still present in these rats. These data suggest that glucose channelled into triacylglycerol and pyruvate synthesis decreases in rat liver, during the development of preneoplastic foci, while the production of reducing equivalents and pentose phosphates increases, thus favoring DNA synthesis and detoxification reactions. Decrease in DNA synthesis, in SAM-treated rats, is paralleled by a partial reversion of carbohydrate metabolic features to those present in normal liver.

Animals↗

PubMed1982

Nonenzymatic methylation of DNA by the intracellular methyl group donor S-adenosyl-L-methionine is a potentially mutagenic reaction.

Incubation of DNA with S-adenosyl-L-methionine (SAM) in neutral aqueous solution leads to base modification, with formation of small amounts of 7-methylguanine and 3-methyladenine. The products have been identified by high performance liquid chromatography of DNA hydrolysates and by the selective release of free 3-methyladenine from SAM-treated DNA by a specific DNA glycosylase. We conclude that SAM acts as a weak DNA-alkylating agent. Several control experiments including extensive purification of [3H-methyl]SAM preparations and elimination of the alkylating activity by pretreatment of SAM with a phage T3-induced SAM cleaving enzyme, have been performed to determine that the activity observed was due to SAM itself and not to a contaminating substance. We estimate that SAM, at an intracellular concentration of 4 X 10(-5) M, causes DNA alkylation at a level similar to that expected from continuous exposure of cells to 2 X 10(-8) M methyl methane-sulphonate. This ability of SAM to act as a methyl donor in a nonenzymatic reaction could result in a background of mutagenesis and carcinogenesis. The data provide an explanation for the apparently universal occurrence of multiple DNA repair enzymes specific for methylation damage.

Chromatography, High Pressure Liquid↗

PubMed2001

Reactions of BBr(n)(+) (n = 0--2) at fluorinated and hydrocarbon self-assembled monolayer surfaces: observations of chemical selectivity in ion--surface scattering.

Ion-surface reactions involving BBr(n)(+) (n = 0--2) with a fluorinated self-assembled monolayer (F-SAM) surface were investigated using a multi-sector scattering mass spectrometer. Collisions of the B(+) ion yield BF(2)(+) at threshold energy with the simpler product ion BF(+)* appearing at higher collision energies and remaining of lower abundance than BF(2)(+) at all energies examined. In addition, the reactively sputtered ion CF(+) accompanies the formation of BF(2)(+) at low collision energies. These results stand in contrast with previous data on the ion-surface reactions of atomic ions with the F-SAM surface in that the threshold and most abundant reaction products in those cases involved the abstraction of a single fluorine atom. Gas-phase enthalpy data are consistent with BF(2)(+) being the thermodynamically favored product. The fact that the abundance of BF(2)(+) is relatively low and relatively insensitive to changes in collision energy suggests that this reaction proceeds through an entropically demanding intermediate at the vacuum--surface interface, one which involves interaction of the B(+) ion simultaneously with two fluorine atoms. By contrast with the reaction of B(+), the odd-electron species BBr(+)* reacts with the F-SAM surface to yield an abundant single-fluorine abstraction product, BBrF(+). Corresponding gas-phase ion--molecule experiments involving B(+) and BBr(+)* with C(6)F(14) also yield the products BF(+)* and BF(2)(+), but only in extremely low abundances and with no preference for double fluorine abstraction. Ion--surface reactions were also investigated for BBr(n)(+) (n = 0-2) with a hydrocarbon self-assembled monolayer (H-SAM) surface. Reaction of the B(+) ion and dissociative reactions of BBr(+)* result in the formation of BH(2)(+), while the thermodynamically less favorable product BH(+)* is not observed. Collisions of BBr(2)(+) with the H-SAM surface yield the dissociative ion-surface reaction products, BBrH(+) and BBrCH(3)(+). Substitution of bromine atoms on the projectile by hydrogen or alkyl radicals suggests that Br atoms may be transferred to the surface in a Br-for-H or Br-for-CH(3) transfer reaction in an analogous fashion to known transhalogenation reactions at the F-SAM surface. The results for the H-SAM surface stand in contrast to those for the F-SAM surface in that enhanced neutralization of the primary ions gives secondary ion signals one to two orders of magnitude smaller than those obtained when using the F-SAM surface, consistent with the relative ionization energies of the two materials.

Journal Article↗

PubMed1988

Evidence for altered methionine methyl-group utilization in the diabetic rat's brain.

The methionine (MET) derivative, S-adenosylmethionine (SAM), provides methyl-groups for methylation reactions in many neural processes. In rats made diabetic with streptozotocin (SZ), brain SAM levels were generally lower (10-20%) than in controls, with a constant decrease being observed five weeks after onset of diabetes. This decrease in SAM levels may be due to reduced precursor (MET) availability because greatly elevating plasma MET concentrations in SZ diabetic rats by dietary manipulation increased their neural SAM concentrations to be approximately or even greater than (5-20%) those of controls. In contrast, neural levels of SAM's demethylated product, S-adenosylhomocysteine (SAH), were reduced to a greater extent (17-44%) than SAM levels in all groups of SZ diabetic rats independent of their plasma MET concentrations or brain SAM levels. This indicates that the decrease in SAH levels is not simply due to substrate (SAM) restriction. These changes in MET metabolites appear to be a general effect of diabetes rather than a non-pancreatic side-effect of SZ, because genetically diabetic BB Wistar rats also exhibited reduced brain SAM (25%) and brain SAH (46%) levels. These results indicate that methyl-groups from MET are handled differently in the brain of the diabetic rat, which considering the variety and importance of neural methylation reactions, could have important consequences for the diabetic.

Administration, Oral↗

PubMed1978

Effects of various S-adenosylmethionine preparations on histamine methylation in vitro and in vivo.

To test possible enhancement of in vivo methylation of histamine, mice were injected with S-adenosylmethionine (SAM) of approximately 96% purity. Instead of the expected enhancement, very strong inhibition of methylation was observed. Tests indicated that S-adenosylhomocysteine (SAH) probably was not the inhibitor. Pure SAM, from another source, showed no inhibition of methylation in rats and guinea pigs, and only slight inhibition in mice. Pure SAM was much more effective than the 96% SAM for histamine methylation in vitro. It seems either that injected SAM cannot enter cells containing the histamine methylating enzyme (HME), or that the endogenous supply of SAM is optimal. The inhibitor may be structurally related to SAM, possibly a by-product of SAM synthesis. As it is very effective even in the presence of large amounts of SAM, in pure form it would probably be the most potent inhibitor of histamine methylation available.

Animals↗

PubMedDate not supplied

Substantia nigra degeneration and tyrosine hydroxylase depletion caused by excess S-adenosylmethionine in the rat brain. Support for an excess methylation hypothesis for parkinsonism.

The major symptoms of Parkinson's disease (PD) are tremors, hypokinesia, rigidity, and abnormal posture, caused by degeneration of dopamine (DA) neurons in the substantia nigra (SN) and deficiency of DA in the neostriatal dopaminergic terminals. Norepinephrine, serotonin, and melanin pigments are also decreased and cholinergic activity is increased. The cause of PD is unknown. Increased methylation reactions may play a role in the etiology of PD, because it has been observed recently that the CNS administration of S-adenosyl-L-methionine (SAM), the methyl donor, caused tremors, hypokinesia, and rigidity; symptoms that resemble those that occur in PD. Furthermore, many of the biochemical changes seen in PD resemble changes that could occur if SAM-dependent methylation reactions are increased in the brain, and interestingly, L-DOPA, the most effective drug used to treat PD, reacts avidly with SAM. So methylation may be important in PD; an idea that is of particular interest because methylation reactions increase in aging, the symptoms of PD are strikingly similar to the neurological and functional changes seen in advanced aging, and PD is age-related. For methylation to be regarded as important in PD it means that, along with its biochemical reactions and behavioral effects, increased methylation should also cause specific neuronal degeneration. To know this, the effects of an increase in methylation in the brain were studied by injecting SAM into the lateral ventricle of rats. The injection of SAM caused neuronal degeneration, noted by a loss of neurons, gliosis, and increased silver reactive fibers in the SN. The degeneration was accompanied with a decrease in SN tyrosine hydroxylase (TH) immunoreactivity, and degeneration of TH-containing fibers. At the injection site in the lateral ventricle it appears that SAM caused a weakening or dissolution of the intercellular substances; observed as a disruption of the ependymal cell layer and the adjacent caudate tissues. SAM may also cause brain atrophy; evidenced by the dilation of the cerebral ventricle. Most of the SAM-induced anatomical changes that were observed in the rat model are similar to the changes that occur in PD, which further support a role of SAM-dependent increased methylation in PD.

Animals↗

PubMed1987

An integrated mechanism for systolic anterior motion of the mitral valve in hypertrophic cardiomyopathy based on echocardiographic observations.

Although many mechanisms have been proposed to explain systolic anterior motion (SAM) of the mitral valve in hypertrophic cardiomyopathy, the precise mechanism of its onset and cessation remain undefined. The Venturi theory, based on increased flow velocity in a narrowed outflow tract, is widely accepted but fails to explain several important characteristics of SAM. It also neglects the potential role of drag forces generated by interposition of the leaflets into the path of ejection and of factors that would decrease the effectiveness of papillary muscle restraint. In order to obtain further insight into the mechanism of SAM, a detailed geometric study of the left ventricle and mitral apparatus was performed with cross-sectional echocardiography in three equal-sized groups of patients with hypertrophic cardiomyopathy and SAM, patients with hypertrophy and no anterior motion, and normal control subjects. A salient finding was that SAM began prior to ejection in patients with hypertrophic cardiomyopathy, which cannot be explained by the Venturi theory. Further, SAM began and was most prominent in the central portion of the leaflet as opposed to its lateral edges; this finding is not predicted by the Venturi mechanism. In addition to outflow tract narrowing, other structural changes unique to patients with SAM included anterior and inward displacement of the papillary muscles, anterior displacement of the mitral leaflets, and elongation of the mitral leaflets, which were, on the average, 1.5 to 1.7 cm longer than in the other subjects (p less than 0.0001). On the basis of these observations, an integrated mechanism for the initiation and resolution of SAM is proposed that would explain observed features such as onset before ejection and central prominence. This mechanism combines the effects of outflow tract narrowing with those of papillary muscle displacement. In particular, anterior and inward displacement of the papillary muscles can be predicted to alter the effectiveness of chordal support so that the central leaflet portions become relatively slack and are more readily displaced anteriorly. The altered distribution of chordal tension can also be predicted to orient the distal leaflets upward into the outflow tract at the onset of systole, prior to aortic valve opening, so that ventricular ejection will actually drag the interposed leaflets anteriorly. The resolution of SAM can be understood in terms of a reverse Venturi effect created by mitral regurgitation, as well as continued traction of the centrally displaced papillary muscles on the lateral leaflet margins.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1983

Proteoglycans from the substratum adhesion sites of MSV-transformed BALB/c 3T3 cells.

Kirsten murine sarcoma virus-transformed Balb/c 3T3 cells (KiMSV) are highly tumorigenic and metastatic in the appropriate murine host, are loosely adherent to the tissue culture substratum, and can be readily detached from the substratum by ethylene glycol bis(beta-aminoethyl ether) N,N'-tetraacetic acid treatment leaving their adhesion sites as substratum-attached material. Both long-term culture-generated adhesion sites (L-SAM) of KiMSV cells and newly formed adhesion sites of reattaching cells (R-SAM) contain high levels of hyaluronate (HA) and chondroitin sulfate (CS) whereas the R-SAM of parental Balb/c 3T3 cells is enriched in heparan sulfate (HS). A sizable fraction of KiMSV L-SAM proteoglycans (PG) and a smaller fraction of R-SAM PG's aggregate into two size classes of supramolecular complexes, after extraction off the substratum with 4 M guanidine hydrochloride, as determined by chromatography on columns of Sepharose CL2B in several buffer systems. Isopycnic density gradient analyses under associative conditions of KiMSV L-SAM generated three classes of material--high-density GA1 which contained some HA but principally CS and HS; intermediate-density GA2 which contained only HA; and low-density GA3 which contained some HA and principally glycoprotein. R-SAM gradients contained no GA2 but a sizable amount of "low-density" HA in GA3. When centrifuged under dissociative conditions, most of GA1 and all of GA2 from L-SAM shifted to the top of the gradient, whereas most of the HS-PG in R-SAM remained at the bottom of dissociative gradients. Comparison of these analyses with previous analyses of Balb/c 3T3 extracts demonstrates that (a) KiMSV cells generate adhesion sites with different PG contents than 3T3 sites; (b) the PG's of KiMSV sites have a reduced potential to aggregate into high-molecular-weight complexes but do form intermediate-size complexes not apparent in material from 3T3 sites; (c) these data support the hypothesis that HA is important in detachment of cells from extracellular matrices; and (d) HS-PG's in newly formed adhesion sites of KiMSV cells are considerably different from sites which have "matured," indicating that there is metabolic activity in these sites during prolonged adherence and movement of transformed cells.

Animals↗

PubMed1995

Effects of thioperamide, a histamine H3 antagonist, on the step-through passive avoidance response and histidine decarboxylase activity in senescence-accelerated mice.

The effect of thioperamide, a histamine H3 receptor antagonist, on learning and memory was studied in the senescence-accelerated mice-prone strain (SAM-P/8) and normal-rate aging strain (SAM-R/1). In a passive avoidance test, SAM-P/8 mice of 12 months showed significant impairment of learning and memory compared with SAM-R/1 mice of the same age. Thioperamide significantly improved the response latency in SAM-P/8 mice when injected intraperitoneally at a dose of 15 mg/kg. The histidine decarboxylase (HDC) activity in the forebrain was significantly lower in SAM-P/8 mice than in SAM-R/1 mice. Thioperamide administration significantly potentiated HDC activity in the forebrain of SAM-P/8 mice as well as improving learning and memory. These results suggest that central histaminergic neurons may be involved in learning and memory impairment of SAM-P/8 mice, although other possibilities are not ruled out.

Aging↗