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PubMed2004

Evidence of preferential protein targets for age-related modifications in peripheral blood lymphocytes.

Oxidatively modified proteins have been analyzed in aging human peripheral blood lymphocytes since protein modification by oxidation and other related pathways are believed to contribute to the intracellular age-related accumulation of damaged proteins, a process that has been associated with the cellular functional deficits that occur with age. Advanced glycation end products (AGE) were quantified and the pattern of glycated proteins analyzed by two-dimensional gel electrophoresis followed by Western blotting using an anti-AGE antibody raised against glycated RNAse. The protein silver stain and the immunoblot patterns were not superimposable, indicating that glycoxidative modifications are targeting only a restricted set of proteins. Modification of proteins with the lipid peroxidation product 4-hydroxy-2-nonenal has also been studied. The patterns of modified proteins have been analyzed using two- dimensional gel electrophoresis followed by Western blotting with an antibody recognizing 4-hydroxy-2-nonenal protein adducts using the same proteomic approach as for glycoxidative modifications. Specific protein targets for these modifications, that might serve as biomarkers of aging lymphocytes, are currently characterized and identified by mass spectrometry.

Adult↗
PubMed2004

Dynamic alterations of specific histone modifications during early murine development.

In order to investigate whether covalent histone modifications may be involved in early embryonic reprogramming events, changes in global levels of a series of histone tail modifications were studied during oocyte maturation and pre-implantation mouse development using indirect immunofluorescence and scanning confocal microscopy. Results showed that histone modifications could be classified into two strikingly distinct categories. The first contains stable 'epigenetic' marks such as histone H3 lysine 9 methylation [Me(Lys9)H3], histone H3 lysine 4 methylation [Me(Lys4)H3] and histone H4/H2A serine 1 phosphorylation [Ph(Ser1)H4/H2A]. The second group contains dynamic and reversible marks and includes hyperacetylated histone H4, histone H3 arginine 17 methylation [Me(Arg17)H3] and histone H4 arginine 3 methylation [Me(Arg3)H4]). Our results also showed that removal of these marks in eggs and early embryos occurs during metaphase suggesting that the enzymes responsible for the loss of these modifications are probably cytoplasmic in nature. Finally, we provide data demonstrating that treatment of cellular histones with peptidylarginine deiminase (PAD) results in loss of staining for the histone H4 arginine 3 methyl mark, suggesting that PADs can reverse histone arginine methyl modifications.

Acetylation↗
PubMed1989

Studies on chemical modification of Tulipa gesneriana lectin.

Modification of lysine, tyrosine, histidine, aspartic acid and glutamic acid residues did not affect the agglutinating activity of the Tulipa gesneriana lectin (TGL). Modification of two arginine residues per subunit in the lectin with either 2,3-butanedione or phenylglyoxal led to an almost complete loss of activity. An inactive lectin modified with 2,3-butanedione recovered a full activity on dialysis against Tris-HCl buffer. The presence of 0.1 M (alpha-1----6) linked mannotriose, a potent inhibitor of the lectin, protected all the arginine residues from modification and the lectin was fully active. Circular dichroism spectroscopy showed that no significant conformational change of TGL occurred following arginine modification. A treatment of the lectin solution with N-bromosuccinimide or 2-hydroxy-5-nitrobenzyl bromide, chemical reagents for tryptophan modification, caused turbidity of the solution, accompanied with complete loss of activity. The fluorescence emission spectrum of the lectin showed a characteristic tryptophan emission with a maximum centered at 336 nm. Upon addition of manno-oligosaccharides a decrease of the fluorescence intensity was observed, indicating that the environment of tryptophan residues altered. These results suggest that arginine and tryptophan residues are importantly involved in the sugar binding of TGL.

Amino Acids↗
PubMed1995

[Effect of efonidipine hydrochloride (NZ-105) on modification of low density lipoprotein induced by rat cultured endothelial cells].

We studied the effects of efonidipine hydrochloride [NZ-105: (+/-)-2-[benzyl (phenyl) amino] ethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorina n-2- yl)-4-(3-nitro-phenyl)-3-pyridinecarboxylate hydrochloride ethanol] and nisoldipine on endothelial cell-induced low density lipoprotein (LDL) modification. The modification of LDL by cultured rat endothelial cells was performed by incubating 3 micrograms protein/well LDL with 5 microM CuSO4 for 24 hr at 37 degrees C in the presence of confluent cells. The extent of modification was assayed by measuring the thiobarbituric acid-reactive substances (TBARS). Efonidipine hydrochloride reduced the TBARS level in a dose-dependent manner. At 3 x 10(-7) M, efonidipine hydrochloride showed a significant effect. On the other hand, the significant effect of nisoldipine was observed only at 10(-5) M. Thus the action of efonidipine hydrochloride on the inhibition of LDL-modification was much more potent than that of nisoldipine. As the modification of LDL was thought to play a key role in the initiation and progression of atherosclerosis, efonidipine hydrochloride may be useful against atherosclerosis.

Animals↗
PubMed2006

Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing.

Transfected siRNAs regulate numerous transcripts sharing limited complementarity to the RNA duplex. This unintended ("off-target") silencing can hinder the use of RNAi to define gene function. Here we describe position-specific, sequence-independent chemical modifications that reduced silencing of partially complementary transcripts by all siRNAs tested. Silencing of perfectly matched targets was unaffected by these modifications. The chemical modification also reduced off-target phenotypes in growth inhibition studies. Key to the modification was 2'-O-methyl ribosyl substitution at position 2 in the guide strand, which reduced silencing of most off-target transcripts with complementarity to the seed region of the siRNA guide strand. The sharp position dependence of 2'-O-methyl ribosyl modification contrasts with the broader position dependence of base-pair substitutions within the seed region, suggesting a role for position 2 of the guide strand distinct from its effects on pairing to target transcripts.

Base Sequence↗
PubMed1994

Effects of chemical modification of arginine residues outside the active site cleft of ricin A-chain on its RNA N-glycosidase activity for ribosomes.

Ricin A-chain, a protein that inactivates ribosomes by a specific RNA N-glycosidase activity, has been shown to be inactivated by chemical modification of a few arginine residues. When two or fewer arginine residues in the A-chain were modified with [14C]phenylglyoxal, arginines at positions of 193, 196, 213, and 234/235 were found to be modified, from amino acid compositions and radioactivities of the modified peptides that were obtained by cyanogen bromide cleavage followed by tryptic and chymotryptic digestion. All these arginines have side chains outside the active site cleft; the side chain of Arg213 is adjacent to the edge of the cleft, while other modified arginines are located on the opposite side of the cleft. Kinetic analysis showed that the modification of two arginine residues caused a 8-fold loss in kcat with a 3-fold increase in Km, suggesting that this modification mainly decrease the rate of depurination with an additional effect on the affinity for ribosomes. Neither the environment of tryptophan 211 at the bottom of the cleft nor an interaction of adenine with the cleft was changed by this modification, as judged by fluorescence spectroscopy, suggesting that a conformational change of the catalytic site does not occur upon the modification. These results, taken together with other works, suggest that some of the above arginine residues outside the active site cleft may additively contribute to the catalysis of depurination and/or the initial formation of the A-chain/ribosome complex.

Adenine↗
PubMed2001

Effects of a community-based lifestyle-modification program on cardiovascular risk factors in middle-aged women.

We investigate the effectiveness of a community-based lifestyle-modification program for reducing blood pressure and other cardiovascular risk factors in sedentary Japanese middle-aged women. Among an initial cohort of 210 middle-aged sedentary women, 195 subjects completed a community-based 12-week lifestyle-modification program for reducing cardiovascular risk factors. Blood pressure, body weight and the serum lipid profile were measured both at baseline and at the end of the 12-week lifestyle-modification program. The program consisted of mild aerobic exercise and a mild hypocaloric diet. After the 12-week program, both systolic and diastolic blood pressure were significantly reduced, especially in subjects who were hypertensive at baseline. Desirable changes in body weight and the serum lipid profile were also found after the 12-week program. Multiple linear regression analysis revealed that, in obese subjects, the decrease in systolic blood pressure was correlated with both the initial systolic blood pressure and the change in estimated maximum oxygen consumption. In addition, the decrease in diastolic blood pressure was correlated with the initial diastolic blood pressure and the change in body weight. On the other hand, in non-obese subjects, the decrease in blood pressure was correlated with the initial blood pressure and the change in salt intake. A community-based lifestyle-modification program that consisted of mild aerobic exercise and a mild hypocaloric diet was considered to be practically effective for reducing multiple cardiovascular risk factors. Individuals who already have one or more mild cardiovascular risk factors still could be good candidates for a community-based lifestyle-modification program.

Blood Pressure↗
PubMed2005

Blood pressure-lowering effects of lifestyle modification: possible involvement of nitric oxide bioavailability.

Lifestyle modification is recommended as a non-pharmacological approach to treatment of hypertension. Many investigators have reported that exercise has antihypertensive effects, and various mechanisms have been proposed to explain this phenomenon. For example, nitric oxide (NO), which may be increased by exercise, has been reported to play a crucial role in preserving vessel homeostasis both by regulating vascular tone and by exerting anti-atherosclerotic effects. NO is known to be exquisitely sensitive to inactivation by superoxide radicals. However, the relationship between the blood pressure-lowering effect of lifestyle modification and NO bioavailability remains unknown. We investigated the effects of a 12-week lifestyle modification program consisting of mild exercise and diet on changes in blood pressure, plasma nitrate/nitrite (NOx), plasma nitrotyrosine, which is the footprint of NO interaction with reactive oxygen species, and plasma extracellular-superoxide dismutase (EC-SOD). The 12-week lifestyle modification program lowered blood pressure and increased plasma NOx. When the subjects were divided into two groups according to the change of plasma nitrotyrosine as an indicator of NO bioavailability, the subjects whose plasma nitrotyrosine decreased exhibited a significant relationship between the blood pressure-lowering effect of the lifestyle modification and the increase in EC-SOD, whereas those without a decrease in plasma nitrotyrosine exhibited a significant relationship between the blood pressure-lowering effect and the increase in maximum oxygen consumption. These results indicate that the level of NO bioavailability influences the mechanism of the blood pressure-lowering effect of aerobic exercise and diet.

Adult↗
PubMed2006

Histone modifications in status epilepticus induced by kainate.

Animal models of epilepsy have allowed the determination of the basic molecular and cellular mechanisms of epileptogenesis. Generalized limbic seizures and subsequent status epilepticus can be induced by either pilocarpine, the muscarinic acetylcholine receptor agonist or kainate, the glutamate receptor agonist. There has been increasing interest that chromatin remodeling might play a critical role in gene regulation even in non-dividing cells such as neurons. One form of chromatin remodeling is histone amino-terminal modification that can generate synergistic or antagonistic affinities for the interactions of transcriptional factors, in turn causing changes in gene activity. Two widely studied histone modification processes are histone acetylation and phosphorylation. While histone hyperacetylation indicates an increase in gene activity, its hypoacetylation marks gene repression. Both states are controlled by a dynamic interplay of histone acetyltransferase (HAT) and histone deacetylase (HDAC). We have found the upregulation of acetylation and phosphorylation of histones, coupled with status epilepticus after kainate administration. c-fos and c-jun mRNA have been sequentially induced in response to kainate, in different hippocampal subpopulations starting from the dentate gyrus and spreading to the cornus ammonis regions well correlated with the spatio-temporal distribution of histone H4 hyperacetylation. Both histone modifications are associated with the c-fos gene promoter after kainate stimulation, while only histone acetylation with the c-jun gene. Pretreatment with curcumin, which has a HAT inhibitory activity specific for CBP/p300, attenuates histone modifications, IEGs expression and also the severity of status epilepticus after kainate treatment. Histone modifications may have a crucial role in the development of epilepsy induced by kainate.

Acetylation↗
PubMed1978

The modification of the lone tryptophan residue in human serum albumin by 2-hydroxy-5-nitrobenzyl bromide. Characterization of the modified protein and the binding of L-tryptophan and benzodiazepines to the tryptophan-modified albumin.

The possible function of the lone tryptophan residue of human serum albumin in the stereospecific binding site for indole and benzodiazepine compounds was investigated by chemical modification. This residue can be selectively modified with 2-hydroxy-5-nitrobenzyl bromide. The modification alters the conformation of the albumin only slightly, as revealed by circular dichroism, fluorescence, and ultraviolet absorption measurements. A decrease in the association constants of L-tryptophan and diazepam of about 30 - 50% and a decrease in the extrinsic Cotton effects of four benzodiazepine derivatives of about 10 - 15% were found as specific effects of the tryptophan modification. The tryptophan modification itself did not change the number of binding sites of diazepam and L-tryptophan. It is suggested that the lone tryptophan residue of human serum albumin is not directly involved in the specific binding site for indole and benzodiazepine compounds. However, the modification alters the properties of the binding site either by an incomplete refolding of the albumin after urea treatment, or a more selective allosteric effect of the modified tryptophan residue.

2-Hydroxy-5-nitrobenzyl Bromide↗
PubMed2006

Initiation and progression of atherosclerosis--enzymatic or oxidative modification of low-density lipoprotein?

Atherosclerosis is widely regarded as a chronic inflammatory disease that develops as a consequence of entrapment of low-density lipoprotein (LDL) in the arterial intima. Native LDL lacks inflammatory properties, so the lipoprotein must undergo biochemical alterations to become atherogenic. Among several other candidates, two different concepts of lipoprotein modification are propagated, the widespread oxidation hypothesis and the less common E-LDL hypothesis, which proposes that modification of LDL occurs through the action of ubiquitous hydrolytic enzymes (enzymatically modified LDL or E-LDL) rather than oxidation. By clearly distinguishing between the initiation and progression of atherosclerotic lesion development, this article reviews comparative studies of both types of lipoprotein modification and submits a viewpoint for discussion proposing that these lipoprotein modifications do not really compete, but rather complement one another. According to this concept, E-LDL might be more important for the initiation of atherosclerosis, while oxidative modification of LDL might be more helpful for diagnosis and prognosis of the disease.

Animals↗
PubMed2004

Olfactory associative discrimination: a model for studying modifications of synaptic efficacy in neuronal networks supporting long-term memory.

This review summarizes research that correlates behavioral performance and cellular physiology leading to modifications in the neuronal networks supporting long-term memory in the mammalian brain. Rats were trained in an olfactory associative discrimination task in which natural odors were replaced by mimetic olfactory stimulations. Olfactory learning induced synaptic modifications that affected behavioral performance along the central olfactory pathways. Starting with an early increase in monosynaptic efficacy in the dentate gyrus on the first session, a polysynaptic modification appeared later on in this hippocampal network, when rats began to make associations between cues and rewards. Therefore, only when rats made consistent associations did a long-term potentiation in the synapses of the piriform cortex pyramidal neurons appear. These modifications may correspond to the long-term storage of the meaning of the cue-reward association in a specific cortical area. Based on these cumulative results, a hypothesis is proposed to account for how, when, and where synaptic modifications in neural networks are required to constitute long-term memory.

Animals↗
PubMed1969

Behavior modification with culturally deprived school children: two case studies.

Techniques of behavior modification were employed with two second-grade Negro girls in a demonstration school for culturally deprived children to increase the girls' appropriate classroom behaviors. A classification system that provided for continuous categorization of behavior was used to code the children's behavior in two classroom situations. Data were also taken on the type, duration, and frequency of the teachers' verbal interactions. The study included four conditions: Baseline, Modification I, Postmodification, and Modification II. The treatment variable was positive social reinforcement-attention and approval contingent upon desirable classroom behaviors-which was presented, withheld, or withdrawn (timeout from social reinforcement). Withholding of social reinforcement was contingent upon inappropriate attention-getting behaviors. Timeout from social reinforcement was contingent upon behaviors classified as aggressive and resistive. After 25 days of Modification I, desirable behavior increased markedly for each girl. The teachers were then asked to return to their Baseline level of performance. The resultant behaviors demonstrated that for one girl, behavior was still primarily under the control of the treatment contingencies. For the second child, many desirable behaviors that had increased in frequency during Modification I remained high, but inappropriate behaviors increased. When treatment was reinstated, the amount of time spent in desirable behaviors increased and remained high for both girls. Three checks during the three months following data collection showed that these behaviors continued to remain high.

Journal Article↗
PubMed1972

Current behavior modification in the classroom: be still, be quiet, be docile.

Classrooms have recently been criticized as total institutions where there is a rigid preoccupation with order and control, and where children are required to be still, to be silent, and to obey. Behavior modification has been described as a major source of change in the classroom. A review of this journal's papers on behavior modification in the classroom indicated that inappropriate behavior has been consistently defined as behavior that interferes with order, quiet, and stillness. It is argued therefore, that behavior modification has supported rather than changed the questionable status quo. Alternative areas for behavior modification in traditional classrooms and the role of behavior modification in the development of open classrooms are discussed.

Journal Article↗
PubMed2004

Posttranslational modifications of tau--role in human tauopathies and modeling in transgenic animals.

Alzheimer's disease (AD) is characterized histopathologically by beta-amyloid-containing plaques, neurofibrillary tangles (NFT), reduced synaptic density, and neuronal loss in selected brain areas. Plaques consist of aggregates of a small peptide termed Abeta which is derived by proteolysis of the larger amyloid precursor protein APP, whereas NFT are composed of hyperphosphorylated forms of the microtubule-associated protein tau. Tau pathology in the presence of scant or no beta-amyloid plaques characterizes additional neurodegenerative disorders collectively called tauopathies. In the course of plaque and NFT formation, the major proteinaceous components of these lesions undergo post-translational modifications. In the case of tau, these include phosphorylation of mainly serine and threonine, but also tyrosine residues. In addition, tau is subject to ubiquitination, nitration, truncation, prolyl isomerization, association with heparan sulfate proteoglycan, glycosylation, glycation and modification by advanced glycation end-products (AGEs). This review aims to provide insight into the complexity of tau modifications in human tauopathies such as AD and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Selected aspects of the post-translational modification of tau have been reproduced in transgenic animal models. Most of this work has been done in mice, but insight has also been gained from studies in the sea lamprey, the nematode C. elegans and Drosophila. Attempts have been made to link specific post-translational modifications with tau aggregation and nerve cell dysfunction.

Animals↗
PubMed1983

Osmotic blood-brain barrier modification: clinical documentation by enhanced CT scanning and/or radionuclide brain scanning.

Results of initial clinical trials of brain tumor chemotherapy after osmotic blood-brain barrier disruption are promising. In general, the procedure is well tolerated. The major complication has been seizures. In this report, data are presented which indicate that the etiology of these seizures is related to the use of contrast agent (meglumine iothalamate) to monitor barrier modification. A series of 19 patients underwent a total of 85 barrier modification procedures. Documentation of barrier disruption was monitored by contrast-enhanced computed tomographic (CT) scanning, radionuclide brain scanning, or a combination of both techniques. In 56 procedures (19 patients) monitored by enhanced CT, seizures occurred a total of 10 times in eight patients. Twenty-three barrier modification procedures (in nine of these 19 patients) documented by nuclear brain scans alone, however, resulted in only one focal motor seizure in each of two patients. In eight of the 19 patients who had seizures after barrier disruption and enhanced CT scan, four subsequently had repeat procedures monitored by radionuclide scan alone. In only one of these patients was further seizure activity noted; a single focal motor seizure was observed. Clearly, the radionuclide brain scan does not have the sensitivity and spatial resolution of enhanced CT, but at present it appears safer to monitor barrier modification by this method and to follow tumor growth between barrier modifications by enhanced CT. Four illustrative cases showing methods, problems, and promising results are presented.

Adult↗
PubMed1992

Further evidence for the involvement of SmI cortical neurons in nociception: modifications of their responsiveness over the early stage of a carrageenin-induced inflammation in the rat.

In this electrophysiological study, changes in the responsiveness of neurons in the primary somatosensory (SmI) cortex in rats were analyzed during the development of carrageenin (CRG)-induced inflammation, an animal model of acute inflammatory hyperalgesia. SmI neurons were characterized as responding to non-noxious light touch, non-noxious articular movement, or noxious pinch. A total of 23 neurons so characterized in three groups were recorded for 60 min (17 of these neurons were recorded for up to 150 min) after an intraplantar injection of CRG. The possible modifications in their background and evoked activities were analyzed over this period of time. After CRG administration, cells responding to noxious pinch stimuli (n = 8) showed a nonsignificant increase in spontaneous activity, but a significant increase in their evoked response to pinch. These results were quite similar to past observations in the ventrobasal nucleus of the thalamus (VB). Cells responding to non-noxious articular stimulation (n = 6) showed variable modifications and no significant increase in the mean evoked response for up to 60 min. These results for articular cells were also quite comparable to results seen for VB responses for similar cells. However, mean spontaneous activity, which showed a highly variable increase, was significantly increased after 60 min. The depressive effect of a local anesthetic, Xylocaine, was tested on the activities of four cells (one pinch, three light touch units) 60 min after CRG administration over a 20-min interval. Xylocaine was found to depress both spontaneous activity and responses to the effective somatic stimulus, thereby implying that the observed central modifications in neuronal discharge are linked to the peripheral inflammation. Modifications observed for each group of cells are compared with past observations in peripheral fibers, in spinal dorsal horn neurons, and especially in the VB under similar inflammatory conditions. These data confirm that the SmI cortex is involved in the nociceptive process. Furthermore, the contrast between some modifications observed at this level and past observations under similar inflammatory conditions suggests a unique role of some cortical neurons, which might partially account for mechanical allodynia.

Afferent Pathways↗
PubMed1995

The susceptibility of low density lipoprotein to chemical oxidation is closely related to proneness to biological modification.

U937 is a monocytic cell line dependent on low density lipoprotein (LDL) receptor-mediated uptake of cholesterol for proliferation. However, exposure of U937 cells to LDL also results in an oxidative modification of LDL. We report here that the oxidative modification of LDL by U937 cells results in inhibition of growth and cell death. This finding suggests that analysis of U937 cell growth in presence of LDL may be used to determine the susceptibility of LDL to biological oxidative modification. There was an inverse association between the effect of LDL on U937 cell growth and the rate of degradation of U937 cell-modified LDL in mouse peritoneal macrophages (r = -0.82, p < 0.05) suggesting a coupling between proneness of LDL to develop cytotoxicity and affinity for scavenger receptors. In a group of young post-infarction patients (n = 18) the susceptibility of LDL to chemical oxidation as determined by analysis of the lag phase for formation of conjugated diens in presence of copper ions was compared with the biological modification of LDL as assessed by analysis of U937 cell growth in presence of LDL. The results demonstrated a close relation between the estimates of chemical oxidation and biological modification (r = 0.86, p < 0.005) suggesting that LDL, which is prone to become oxidised by copper also is more prone to become modified by cells in vivo.

Animals↗