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Biomedical subjects

V Narayanan

Publications and source records attributed to V Narayanan.

34 records · Page 2Linked to original sources
PubMed1997

Identification of compounds with preferential inhibitory activity against low-Nm23-expressing human breast carcinoma and melanoma cell lines.

We have used the COMPARE computer algorithm and Nm23 expression as a marker of tumor metastatic potential to examine the in vitro antiproliferative activity of chemotherapeutic drugs on human breast carcinoma and melanoma cell lines. None of 171 compounds in clinical use or under development and only 40 of 30,000 repository compounds exhibited preferential growth inhibition of low-Nm23-expressing, metastatically aggressive cell lines with a Pearson correlation coefficient of < or = -0.64. Characterization of one compound, NSC 645306, is presented including in vivo activity in a hollow fiber assay. The data demonstrate a novel approach to drug identification for aggressive human tumors.

Algorithms↗
PubMed1996

Expression of members of the proteolipid protein gene family in the developing murine central nervous system.

Two homologous cDNAs were previously isolated by expression cloning with a monoclonal antibody that recognized a CNS neuronal membrane protein. Both cDNAs, M6a and M6b, bore significant homology with the major myelin proteolipid protein, PLP/DM20. Our initial studies of M6 gene expression in the adult mouse brain showed that M6a was present in neurons, PLP/DM20 in oligodendrocytes, and M6b in both neurons and glia. This led to the recognition of a novel gene family that included the oligodendrocyte-specific PLP/DM20 gene and the neuronal M6 genes. These observations supported the idea that PLP/DM20 may have functions other than myelination. In this report, we describe the spatial and temporal patterns of expression of M6a, M6b, and PLP/DM20 in the developing nervous system. PLP expression was limited to the white matter. M6a appeared in post-mitotic neurons of the brain and spinal cord as early as E10, and later in the hippocampus, cerebral cortex, and the granule cells of the cerebellum. In contrast, M6b was expressed at early embryonic stages in the ventricular zone of the spinal cord, and later during development in both neurons and glia. The early appearance of M6a and M6b mRNAs in the murine CNS suggested that these molecules might play an important role in the development of a variety of neural cell types.

Animals↗
PubMed1996

Chromosomal mapping of the human M6 genes.

M6 is a neuronal membrane glycoprotein that may have an important role in neural development. This molecule was initially defined by a monoclonal antibody that affected the survival of cultured cerebellar neurons and the outgrowth of neurites. The nature of the antigen was discovered by expression cDNA cloning using this monoclonal antibody. Two distinct murine M6 cDNAs (designated M6a and M6b) whose deduced amino acid sequences were remarkably similar to that of the myelin proteolipid protein were previously isolated. We have isolated partial human cDNA and genomic clones encoding M6a and M6b and have characterized them by restriction mapping, Southern hybridization with cDNA probes, and sequence analysis. We have localized these genes within the human genome by FISH (fluorescence in situ hybridization). The human M6a gene is located at 4q34, and the M6b gene is located at Xp22.2. A number of human neurological disorders have been mapped to the Xp22 region, including Aicardi syndrome (MIM 304050), Rett syndrome (MIM 312750), X-linked Charcot-Marie-Tooth neuropathy (MIM 302801), and X-linked mental retardation syndromes (MRX1, MIM 309530). This raises the possibility that a defect in the M6b gene is responsible for one of these neurological disorders.

Amino Acid Sequence↗
PubMed1996

Episodic ataxia and myokymia syndrome: a new mutation of potassium channel gene Kv1.1.

Episodic ataxia and myokymia syndrome is an autosomal dominant disorder characterized by persistent myokymia and attacks of unsteadiness, slurred speech, and tremulousness. This disease has been associated with point mutations in the potassium channel gene Kv1.1 (KCNA1), located at chromosome 12p13. Here, we describe a novel mutation within this gene in a newly diagnosed family.

Ataxia↗
PubMed1996

Oral and maxillofacial manifestations of hereditary sensory neuropathy.

Hereditary sensory neuropathies are a rare group of neurological disorders manifested from early childhood by diminished or absent sensibility to pain, touch and temperature. A Kashmiri family with four members affected by congenital sensory neuropathy and its oral manifestations is described. Pain and temperature sensation was lost in various parts of the body including the orofacial region resulting in mutilating acropathy, particularly of the limbs and face. Orofacial motor function was normal. Three of the four members had corneal opacification due to scarring from keratitis. To prevent any further mutilation, any corrective surgery is best delayed until the patient is old enough. A discussion of the oral manifestations of this condition with a review of the literature is presented.

Adult↗
PubMed1996

Synthesis of substituted quinazolone derivatives as potential anti-HIV agents (Part III).

Several 1-[2-phenyl-4(4H)-oxo-3-quinazolinyl]-2-methyl-4-arylidine -5-oxo-imidazolines (Va-1), 2-phenyl-3-(aroyl amino)-4(4H)-oxo quinazolines (Vla-I) and N1-2-methyl-4(4H)-oxo-3-quinazolinyl-N2-aryl-thioureas (Vlla-k), have been synthesised and tested for anti-HIV activity. The structures of these compounds have been established on the basis of elemental analysis and spectral data.

Antiviral Agents↗
PubMed1995

Novel sulfonated and phosphonated analogs of distamycin which inhibit the replication of HIV.

A series of novel distamycin-related polyanionic compounds were compared for their anti-HIV activity. Several were highly potent inhibitors of HIV virus-induced cell killing and viral replication of a wide variety of laboratory isolates, as well as a monocytotropic virus and a clinical isolate in human peripheral blood lymphocytes. These compounds are structurally different from other sulfonic acid containing compounds reported to be potent inhibitors of the human immunodeficiency virus (HIV) in two respects: (1) they are structurally related to the non-toxic minor groove DNA binder distamycin; and (2) a number of them contain the aromatic phosphonic acid group. The compounds that were evaluated can be categorized into monomeric or dimeric ureido structural classes incorporating the bisamido-N-methylpyrrolenaphthalene-sulfonic acid group, with differences in the number and position of the sulfonic acids on the naphthalene rings. Broader structure-activity studies were made possible through the synthesis and evaluation of the compounds containing only a single N-methylpyrrole unit, those incorporating the N-methylpyrazole structure, and compounds having the isosteric phosphonic acid group substituted for the sulfonic acid group. One of the most potent of the inhibitors was 2,2'[4,4'[[aminocarbonyl]amino]bis[N,4'-di[pyrrole-2-carboxamide- 1,1'-dimethyl]]-4,6,8 naphthalenetrisulfonic acid] hexasodium salt, NSC 651015. This compound, the phosphonic acid analog NSC 662162, and the monomeric compound NSC 651018 were studied to determine the mechanism of their inhibitory activity. Mechanistic studies revealed that inhibition was due to the disruption of virus attachment to CD(4+)-susceptible cells and a further restraint on fusion of virus and cell membranes. The relative tolerance of these compounds in mice suggests that sufficient antiviral concentrations could be reached in vivo and thus may prove valuable in the treatment of AIDS patients.

Amino Acid Sequence↗
PubMed1995

Rett syndrome studies of natural history and search for a genetic marker.

The commonly held notion that Rett syndrome (RS) is a neurodegenerative disorder with normal early development was examined by an epidemiological survey and review of medical records and serial neurological and development evaluations. In some subjects, deviance from normal development was evident from the perinatal period, and gradually became more prominent with age. These findings are convincing when seen in conjunction with a reduction in velocity of brain growth, as early as 2-4 months of life, well before the recognition of gross neurological deficits. Neurodevelopmental evaluations provide no indication that there is progressive loss of adaptive behaviors, or communication skills to indicate a neurodegenerative process. Taken together with the known neuropathological and neurochemical changes in RS brain we hypothesize that RS is a neurodevelopmental disorder, which has a genetic basis, and affects subsets of neurons and their connections during a period of vigorous brain growth, when synapse formation and pruning are at a peak. Studies of mitochondrial (mt) DNA in brain to understand the genetic mechanisms underlying matrilineal inheritance in the few familial cases, and mt structural and enzyme deficiencies have been unrevealing to date.

Adolescent↗
PubMed1994

Partial structure and mapping of the human myelin P2 protein gene.

The myelin P2 protein, a 14,800-Da cytosolic protein found primarily in peripheral nerves, belongs to a family of fatty acid binding proteins. Although it is similar in amino acid sequence and tertiary structure to fatty acid binding proteins found in the liver, adipocytes, and intestine, its expression is limited to the nervous system. It is detected only in myelin-producing cells of the central and peripheral nervous systems, i.e., the oligodendrocytes and Schwann cells, respectively. As part of a program to understand the regulation of expression of this gene, to determine its function in myelin-producing cells, and to study its role in peripheral nerve disease, we have isolated and characterized overlapping human genomic clones encoding the P2 protein. We report here on the partial structure of this gene, and on its localization within the genome. By using a panel of human-hamster somatic cell hybrids and by in situ hybridization, we have mapped the human P2 gene to segment q21 on the long arm of chromosome 8. This result identifies the myelin P2 gene as a candidate gene for autosomal recessive Charcot-Marie-Tooth disease type 4A.

Amino Acid Sequence↗
PubMed1993

Characterization of the cis-acting elements of the mouse myelin P2 promoter.

Myelin P2 is a basic protein of an apparent molecular weight of 14,800. Expression of P2 has been found largely in the cytosol of Schwann cells in the peripheral nervous system. Although the function of P2 is unknown, its striking homology to a family of fatty acid binding proteins has led to the idea that P2 may function as a fatty acid transport molecule. To investigate the DNA elements that control the expression of P2, sequences 5' to the coding region were cloned upstream of the cat reporter gene. A series of 3' and 5' promoter mutants was constructed and their activity determined following transfection into secondary Schwann cells and the MT4H1 Schwann cell line. Using this strategy, we have identified a 217 bp silencer region and a 142 bp positive regulatory region. In addition, we have localized the 5' flanking sequences in the promoter that are responsive to cAMP induction and to the transcription factor CCAAT/enhancer binding protein (C/EBP).

Adenylyl Cyclases↗
PubMed1993

Molecular cloning of M6: identification of a PLP/DM20 gene family.

M6 is a membrane glycoprotein that is expressed on central neurons and certain polarized epithelia from early developmental stage. Antibodies against M6 interfere with cerebellar neurite outgrowth in vitro. Two closely related cDNAs were obtained by expression cloning, both of which showed high homology with the major CNS myelin protein PLP/DM20. Although M6 and PLP/DM20 share many molecular characteristics, in situ hybridization revealed nonoverlapping distributions of their mRNAs in mouse CNS. The identification of a gene family including neuron-specific M6 and glia-specific PLP/DM20 in CNS suggests a broader functional role for these molecules than myelination.

Amino Acid Sequence↗
PubMed1991

Structure of the mouse myelin P2 protein gene.

Myelin P2 protein is a small (14,800 Da) protein found in peripheral and central nervous system myelin. To investigate the regulation of expression of this myelin protein, a mouse genomic library was screened with a rabbit P2 cDNA (pSN2.2-2), and a single positive phage clone containing a 20-kb insert was obtained. This insert contained a single internal SalI restriction site and several EcoRI sites. The EcoRI fragments from this insert were subcloned into Bluescript. The rabbit P2 cDNA (pSN2.2-2) hybridized with a 4-kb EcoRI fragment, and this 4-kb fragment was then sequenced after the creation of nested deletions. The mouse gene contained four exons: exon 1 coded for amino acids 1-24, exon 2 for amino acids 24-81, exon 3 for amino acids 82-115, and exon 4 for amino acids 116-131. The three introns were 1.2 kb, 150 bp, and 1.3 kb in length. Primer extension analysis revealed two transcription start sites at +1 and +47, consistent with the presence of two P2 mRNAs, with the larger transcript appearing more abundant. The amino acid sequences predicted from the mouse DNA indicate that the mouse protein differs from the rabbit protein at 16 different positions, with most of the differences located in exon 3. When the gene structure of fatty acid binding protein (FABP) genes were compared, the P2 gene had the same overall structure as others in the FABP family, suggesting a common ancestral gene for members of this family. The 5'-flanking region contains candidate TATA and CAAT sequences, as well as two AP-1 binding sites that may be important in modulation of the expression of this gene.

Animals↗
PubMed1988

Characterization of a cloned cDNA encoding rabbit myelin P2 protein.

Myelin P2 is a 14,800-Da cytosolic protein found in rabbit sciatic nerves. It belongs to a family of fatty acid binding proteins and shows a 72% amino acid sequence similarity to aP2/422, the adipocyte lipid binding protein, a 58% sequence similarity to rat heart fatty acid binding protein, and a 40% sequence similarity to cellular retinoic acid binding protein. In order to isolate cDNA clones representing P2, a cDNA library was constructed from poly(A+) RNA isolated from sciatic nerves of 10-day-old rabbit pups. By use of a mixed synthetic oligonucleotide probe based on the rabbit P2 amino sequence, 12 cDNA clones were selected from about 25,000 recombinants. Four of these were further characterized. They contained an open reading frame, which when translated, agreed at 128 out of 131 residues with the known rabbit P2 amino acid sequence. These cDNAs recognize a 1.9-kilobase mRNA present in sciatic nerve, spinal cord, and brain, but not present in liver or heart. The levels of P2 mRNA parallel myelin formation in sciatic nerve and spinal cord with maximal amounts being detected at about 15 postnatal days. This initial study will allow characterization of the P2 gene and its regulation, as well as further studies into the role of P2, the first metabolically active myelin-specific protein to be characterized at the genetic level.

Amino Acid Sequence↗
PubMed1985

Comparison of anterior cerebral artery blood flow velocity and cerebral blood flow during hypoxia.

Measurement of anterior cerebral artery blood flow velocity with a continuous wave bidirectional Doppler was compared with cerebral blood flow (CBF) measured with radioactive microspheres in 11 paralyzed newborn lambs during hypoxic hypoxia. The Doppler probe was maintained in a fixed position during each experiment. The objectives of the study were to validate this noninvasive technique that is being used widely in the clinical setting to qualitatively assess changes in CBF, and to evaluate which of the velocity parameters measured provide the most information. Diastolic velocity (DV), peak systolic velocity (PSV), area under the velocity curve (AUC), and pulsatility index (PI) were examined under conditions of varied arterial oxygen content and compared to microsphere CBF. DV (r = 0.72, p less than 0.001), AUC (r = 0.72, p less than 0.001), and PSV (r = 0.63, p less than 0.001) demonstrated stronger correlations with changes in CBF than did the PI (r = -0.41, p less than 0.05). DV (r = 0.81, p less than 0.001), AUC (r = 0.80, p less than 0.001), and PSV (r = 0.75, p less than 0.001) also exhibited stronger relationships with changes in arterial oxygen content than did the PI (r = -0.36, p less than 0.05). These data demonstrate that changes in cerebral blood flow velocity are useful qualitative measures of changes in cerebral blood flow. However, the utility of this technique is dependent upon a stable probe position, and assessment of the actual velocity measurements (DV, PSV, AUC) rather than simply the pulsatility index.

Animals↗
PubMedDate not supplied

Hypoglycemic effect of macrocyclic binuclear oxovanadium (IV) complex on streptozotocin-induced diabetic rats.

Though vanadium complexes mimic the action of insulin, owing to their toxicity, research is still in progress for a new vanadium complex with maximum efficacy at low concentration and without any side effects. A novel macrocyclic binuclear oxovanadium complex was synthesized, its composition and structure were confirmed by spectral studies and its efficacy was studied in streptozotocin-induced diabetic rats over a period of 30 days. The oral administration of the complex normalizes the blood glucose level in the diabetic rats and also maintains normoglycemia after a glucose load. The biochemical studies revealed that the complex is not toxic to the system. The nontoxic nature of this complex may be due to the presence of the vanadyl ions in an intact form. The study highlights the nontoxic and hypoglycemic effects of the new macrocyclic binuclear oxovanadium complex.

Animals↗