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Biomedical subjects

B Ramamurthy

Publications and source records attributed to B Ramamurthy.

10 recordsLinked to original sources
PubMed2003

Glutathione reverses early effects of glycation on myosin function.

Nonenzymatic glycosylation (glycation) has been recognized as an important posttranslational modification underlying alterations of structure and function of extracellular proteins during aging and diabetes. Intracellular proteins may also be affected by this modification, and glycation has been suggested to contribute to aging-related impairment in skeletal muscle function. Glycation is the chemical reaction of reducing sugars with primary amino groups resulting in the formation of irreversible advanced glycation end products. Glutathione is an abundant tripeptide in skeletal muscle. To understand the effect of glutathione on glycated myosin function, we used a single-fiber in vitro motility assay in which myosin is extracted from a single muscle fiber segment to propel fluorescent-labeled actin filaments. Myosin function responded to glucose exposure in a dose-dependent manner, i.e., motility speeds were reduced by 10, 34, and 90% of preincubation values after 30-min exposure to 1, 3, and 6 mM glucose, respectively. The 30-min 6 mM glucose incubation was followed by a 20-min 10 mM glutathione incubation. Glutathione treatment restored motility (0.98 +/- 0.06 microm/s, n = 3; P < 0.001) after glucose exposure (0.10 +/- 0.07 microm/s, n = 3), close to preincubation levels (1.12 +/- 0.06 microm/s, n = 3). It is concluded that glucose modifies myosin function in a dose-dependent manner and that glutathione reverses the effect of glucose on myosin function.

Aging↗
PubMed2001

Changes in myosin structure and function in response to glycation.

Nonenzymatic glycosylation (glycation) is recognized as an important post-translational modification underlying alterations of structure and function of extracellular proteins. The effect of glycation on intracellular proteins is, on the other hand, less well known despite the vital importance of intracellular proteins for cell, tissue, and organ function. The aim of this study was to explore the effects of glycation on the structure and function of skeletal muscle myosin. Myosin was incubated for up to 30 min with glucose and subsequently tested for structural and functional modifications by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry and a single-fiber in vitro motility assay, respectively. MALDI spectra revealed glycation-related structural alterations as evidenced by the disappearance of specific Lys-C proteolysis products and the appearance of higher mass peaks that are attributed to cross-linking by glucose. This change was paralleled by a significant reduction in the in vitro motility speed, suggesting a structure-related decline in myosin mechanics in response to glucose exposure. Further evidence that early glycation products form in the regulatory regions of the myosin molecule is derived from the fact that there is complete reversal of motility speed after reaction with the Schiff base-cleaving agent hydroxylamine hydrochloride. Thus, glycation of skeletal muscle myosin has a significant effect on both the structural and functional properties of the protein, a finding that is important in understanding the mechanisms underlying the impairment in muscle function associated with aging and diabetes.

Actins↗
PubMed2001

Effects of aging on regulation of muscle contraction at the motor unit, muscle cell, and molecular levels.

Rodent motor units, muscle fibers, and motor proteins undergo significant aging-related changes. Such changes include spatial organization and physiological properties of fast- and slow-twitch single motor units, regulation of contractile speed and force generation capacity at the muscle fiber level, and altered functional properties of the motor protein myosin. In addition to specific changes, there also appears to be a "disorganization" of the coordinated expression of contractile, sarcoplasmic reticular, and mitochondrial protein isoforms in aging skeletal muscle. This is suggested to have a strong impact on aging-related impairments in muscle function in addition to the changes in specific muscle proteins.

Adaptation, Physiological↗
PubMed2000

Aging-related changes in skeletal muscle. Mechanisms and interventions.

The aging-related motor handicap and the growing population of elderly citizens have enormous socioeconomic effects on the modern healthcare system. The mechanisms underlying impaired motor performance in old age are complex and involve the central and peripheral nervous systems and the muscle tissue itself. It is widely accepted that the aging-related loss of muscle mass, strength and quality has a significant detrimental impact on motor performance in old age and on the ability to recover from falls, resulting in an increased risk of fractures and dependency. Therefore, the prevention of falls and gait instability is a very important safety issue, and different intervention strategies have been used to improve motor performance among the aging population. There is general consensus that physical exercise is a powerful intervention to obtain long term benefits on muscle function, reduce the frequency of falls, and to maintain independence and a high quality of life in older persons. The results from studies using different types of hormone supplementation therapies have shown interesting and encouraging effects on skeletal muscle mass and function. However, the potential risks with both growth hormone and androgen treatment are not known and long term clinical trials are needed to address safety concerns and the effects on skeletal muscle. Recent advancements in cellular/molecular, physiological and molecular biological techniques will significantly facilitate our understanding of aging-related impairments of muscle function and contribute to the evaluation of different intervention strategies.

Actomyosin↗
PubMed1999

An overview of carbohydrate-protein interactions with specific reference to myosin and ageing.

Non-enzymatic glycosylation (glycation), a post-translational modification of proteins, results from the reaction of proteins with reducing sugars. Glycation is implicated in various pathologies like diabetes, Alzheimer's disease and it has been suggested to play an important role in the ageing process. Research on protein glycation has primarily studied extracellular proteins such as albumin, haemoglobin and collagen. However, there is increasing evidence that intracellular proteins may also be affected by glycation, and glycation of myosin is reported to decrease myosin ATPase activity. Glycated adducts are detected by various techniques such as chromatography, electrophoresis, fluorescence and immunochemistry. Inhibition or removal of these adducts has been achieved by chemical compounds such as aminoguanidine (amG), beta-mercaptoethanol (bME) and N-phenacylthiazolium bromide (PTB). In the present pilot study, using a novel in vitro motility assay, we have observed an attenuation in the motility speed of actin (approximately 13%) on myosin extracted from single muscle fibre segments after 15-min glucose incubation. Addition of bME to the incubation medium maintained actin motility speed.

Actins↗
PubMed1996

Analogues of 10-deazaaminopterin and 5-alkyl-5,10-dideazaaminopterin with the 4-substituted 1-naphthoyl group in the place of 4-substituted benzoyl.

10-Deaza modifications of classical antifolate analogues bearing the 1,4-disubstituted naphthalene ring in place of the 1,4-disubstituted benzene ring were prepared and tested for antitumor activity. Naphthalene analogues (9a-c, respectively) of 10-deazaaminopterin, 5-methyl-5, 10-dideazaaminopterin, and 5-ethyl-5,10-dideazaaminopterin were prepared by a route consisting of C-alkylations of the anion derived from 4-carboxyl-1-naphthaleneacetic acid dimethyl ester (2) by 6-(bromomethyl)-2,4-diaminopteridine (1a) and 6-(bromomethyl)-2,4-diamino-5-methyl- and -5-deazapteridines (1b and 1c, respectively) followed by ester hydrolysis and subsequent decarboxylation to give naphthalene analogues (7a-c, respectively) of 4-amino-4-deoxy-10-deazapteroic acid and 4-amino-4-deoxy-5- methyl- and -5-ethyl-5,10-dideazapteroic acids. Peptide coupling of 7a-c with L-glutamic acid dialkyl ester followed by mild ester hydrolysis gave target compounds 9a-c. The key advantage of this route is circumvention of a hydrogenation step requiring selectivity as in earlier approaches involving 9,10-olefinic precursors. Steric limitations thwarted plans to prepare the naphthalene analogue of 10-ethyl-10-deazaaminopterin; attempted alkylations of 2-(4-carboxy-1-naphthyl)butyric acid dimethyl ester with 1a failed as did attempted further alkylation (by EtBr) of the product derived from 1a and 2. Growth inhibition tests against three tumor cell lines (L1210, S180, and HL60) showed 9a to be 4-6-fold more inhibitory than methotrexate but not as inhibitory as 10-ethyl-10-deazaaminopterin; 9b and 9c were no more inhibitory than MTX. In tests against the EO771 mammary adenocarcinoma in mice, 9a was less active than MTX.

Adenocarcinoma↗
PubMed1989

Synthesis and antitubercular activity of N-(2-naphthyl)glycine hydrazide analogues.

N-(2-Naphthyl)glycine hydrazide analogues were synthesized and tested for possible in vitro antitubercular activity. N-(2-Naphthyl)alanine hydrazide (3), N-methyl-N-(2-naphthyl)glycine hydrazide (5), N-(6-methoxy-2-naphthyl)glycine hydrazide (7), and 3-(2-naphthylamino)butyric acid hydrazide (23) showed potent inhibitory action against Mycobacterium tuberculosis H37Rv in Youman's medium at concentrations ranging from 0.5 to 10.0 micrograms/mL. These compounds showed significant inhibitory action against isonicotinic acid hydrazide and streptomycin-resistant strains of M. tuberculosis. N-(6-Quinolyl)glycine hydrazide (18) and 3-(2-quinolylamino)butyric acid hydrazide (24), which are bioisosteres of compounds 1 and 23, showed loss of antitubercular activity at low concentrations.

Antitubercular Agents↗