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Biomedical subjects

D Kaul

Publications and source records attributed to D Kaul.

At least 19 recordsLinked to original sources
PubMed2005

Genomic effect of vitamin 'C' and statins within human mononuclear cells involved in atherogenic process.

Deregulated crosstalk within nuclear receptor/transcription factor family, comprising of peroxisome proliferator-activated receptors (PPARs) and liver X receptor-alpha (LXR-alpha), can give rise to cooperativity between lipid peroxidation and inflammation leading to atherogenic process. The present study addressed to explore the effect of statins and vitamin 'C' on transcriptional expression of genes coding for this nuclear receptor/transcription factor family within mononuclear cells revealed for the first time that both mevastatin and vitamin 'C' have common action in that they significantly downregulate the expression of PPARs (alpha, gamma) genes and upregulate LXR-alpha gene expression as compared to the control. The similar phenomenon was observed in mononuclear cells obtained from coronary heart disease (CHD) patients who were receiving atorvastatin treatment (20 mg HS). Further, the observed upregulatory effect of LXR-alpha gene expression was in conformity with the downregulatory effect of LXR-alpha on its effector gene matrix metalloproteinase-9. Based on these results, we propose that LXR-alpha-dependent signaling pathway may be a crucial target for the therapeutic intervention in human CHD, and in addition to statins, vitamin 'C' deserves a close scrutiny for the treatment of CHD.

Animals↗
PubMed2004

Effect of green tea polyphenols on the genes with atherosclerotic potential.

The genomics of atherosclerosis can arise as a result of cross-talk between the genes coding for the LDL-receptor (LDL-R), LXR-alpha, PPARs (alpha, gamma), CD36 and C-myc because these genes control lipid metabolism, cytokine production and cellular activity within the arterial wall. The effect of green tea polyphenols (GTPs) upon such genomics revealed their ability to down-regulate genes coding for PPAR-gamma, CD36, LXR-alpha, C-myc coupled with up-regulation of genes coding for LDL-R and PPAR-alpha at the transcriptional level. Based upon these results, it is proposed that GTPs have the inherent capacity to inhibit the development of atherosclerotic lesions.

Arteriosclerosis↗
PubMed2004

Cholesterol-sensor initiates M. tuberculosis entry into human macrophages.

Cholesterol-mediated mycobacteria entry into and survival within macrophages has added a new dimension to Tuberculosis research. The molecular mechanism through which cholesterol initiates this process is still poorly understood. The present study addressed to resolve this mechanism revealed that Mycobacterium tuberculosis possesses cholesterol-specific Receptor 'Ck'-like molecule responsible for mycobacterial entry into macrophages. Further human Receptor-Ck was found to regulate transcriptional expression of a gene that codes for Tryptophan-Aspartate containing coat (TACO) protein responsible for survival of mycobacteria within cells. Based upon these results, we propose that interaction of Receptor-Ck with cholesterol-rich membrane domains helps to create a 'Synaptic-junction' between mycobacteria and macrophage resulting in signalling events that are responsible for mycobacterium entry into and survival within macrophages.

Bacterial Proteins↗
PubMed2003

Regulation of PPAR-gamma gene in human promyelocytic HL-60 cell line.

The present study employed human promyelocytic cell line, HL-60, as an archetype model to understand the role of cholesterol receptors (Receptor-C(k) and oxysterol-specific receptor-transcription factor LxR-alpha) in the regulation of PPAR-gamma gene recognized to control cellular differentiation and apoptosis. Such a study revealed that Receptor "C(k)"-dependent signalling pathway not only regulates PPAR-gamma gene transcription but also provides ligands for the activation of this nuclear receptor superfamily of transcription factors that control hematopoiesis. Based upon these and our earlier results, we propose a molecular cross-talk pathway between cholesterol-specific cell surface Receptor-C(k) and nuclear receptors (LxR-alpha and PPAR-gamma), which may add a new dimension in the understanding and control of leukemogenesis.

DNA-Binding Proteins↗
PubMed2002

Expression of Bcl2 proto-oncogene in primary tumors of the central nervous system.

The present study was addressed to find out the expression of Bcl2 proto-oncogene in tumor tissues derived from 25 patients with primary central nervous system tumors. Brain parenchyma in 8 cases, with deeply located tumor, was also examined for Bcl2 expression which served as control. Both benign and malignant tumors (confirmed by histopathological examination) expressed Bcl2 gene product. Tumors exhibited 2-6 fold increase in Bcl2 expression as compared to the normal parenchyma adjacent to some of these tumors studied. However, no correlation was found between the histopathological types of tumor, glial fibrillary acidic protein positivity and degree of Bcl2 expression. Based on this study, we propose that the overexpression of Bcl2 gene product found in primary CNS tumors may be an important molecular event which is known to make the various types of tumor resistant to chemotherapy or radiotherapy.

Adenoma↗
PubMed2001

Clinical manifestations and management of pediatric HIV infection.

HIV infection has emerged as a colossal problem with epidemic proportions. According to an estimate from UNAIDS about 36.1 million people all over the world are infected at present. In India about 3.5 million people are infected. The infection has evolved into phase II process of disease evolution, spreading from high-risk population to the general population. The antenatal HIV seropositivity has shown a steady increase from 0.1% to 2% in some tertiary care hospitals in Mumbai. Pediatric HIV infection presents with diverse clinical manifestations. In developing countries like India, diagnosis of infection during first year of life in perinatally exposed infants poses a problem due to lack of easy accessibility and increased cost of diagnostic facilities like HIV-PCR, CD4/CD8 counts and viral cultures. Moreover, lack of adequate drugs and exorbitant cost of sustaining antiretroviral therapy complicates the management issues. An assortment of antiretovirals is available in USA and other developed countries. In India drugs like zidovudine, lamivudine, stavudine, nevirapine and indinavir are available and are used in symptomatic patients. CDC has defined definite treatment guidelines for pediatric population recently. These guidelines need to be modified in our set up. At the present juncture in India the emphasis remains on the prevention and treatment of opportunistic infections like tuberculosis and pneumocystis carinii and on prevention of perinatal transmission with zidovudine. This brief review deals with various clinical manifestations as relevant in a developing country like India and recent advances in antiretroviral therapy.

AIDS-Related Opportunistic Infections↗
PubMed2001

Molecular link between cholesterol, cytokines and atherosclerosis.

Current investigation on the origin of atherosclerosis has initiated an intense debate over whether atherosclerosis results from hypercholesterolemia or an inappropriate immune response to vascular injury. Although the role of the immune system has been questioned, the overwhelming body of evidence clearly indicates that atherogenesis is initiated by the interplay between cholesterol and cellular secretion of cytokines (especially IL-6) and apolipoprotein 'E' within the arterial wall. Recent studies have revealed that cells possess two cholesterol-sensors: (a) Receptor-Ck which senses the extracellular cholesterol and initiates signalling pathway responsible for the regulation of genes involved in the cell cycle, cell death, cellular cholesterol homeostasis and cytokines including IL-6; (b) LxR alpha which senses intracellular oxysterols and controls genes involved in cell death, cellular cholesterol homeostasis and cytokine IL-8. These cholesterol sensors define the molecular mechanism responsible for cholesterol-depended regulation of cellular synthesis and secretion of cytokines (IL-6, IL-8) within arterial wall. On the basis of this mechanism, presence of cholesterol and its oxy-derivative in the modified LDL will result in transient activation/deactivation of Receptor-Ck-dependent genes which will give rise to repeated cycles of growth coupled with apoptosis leading to a situation where apoptotic-deficient cells in the arterial wall, would be selected resulting in their accumulation and formation of oligoclonal atherosclerotic plaque.

Animals↗
PubMed2001

Receptor-Ck regulates membrane-bound 125 kDa protein having affinity for genomic sterol regulatory sequence.

The study addressed, to resolve the role of Receptor-Ck activation in the proteolytic maturation of 125 kDa (membrane bound) sterol regulatory element binding protein (SREBP), revealed that Receptor-Ck dependent signalling is not only responsible for the proteoloytic cleavage of this 125 kDa SREBP resulting in the generation of an active 47 kDa factor but also Receptor-Ck protein has high binding affinity for both 125 kDa SREBP as well as its cleaved 47 kDa product. Based upon these coupled with our earlier findings, we propose that Receptor-Ck may be regulating genes, have sterol regulatory element (SRE) in their promoter region, through the proteolytic maturation of 125 kDa SREBP into an active 47 kDa transcription factor.

Blotting, Western↗
PubMed2001

Receptor-Ck regulates giardia encystation process.

The study addressed to resolve the mechanism involved in cholesterol-dependent regulation of giardia encystation process, revealed that (a) the trophozoites have the ability to express genes coding for receptor-Ck and sterol element binding protein (SREBP); (b) inhibition of cholesterol dependent activation of receptor-Ck results in the upregulation of CWP-1 gene expression leading to encystation process. Based upon these findings, we propose that receptor-Ck dependent signalling is responsible for the regulation of giardia encystation process by cholesterol.

Animals↗
PubMed2000

Expression of receptor-Ck and SREBP genes in mononuclear cells from acute leukemia patients.

We have recently shown that Receptor-Ck regulated genes, involved in cellular growth and death through a transcriptional factor (SREBP) which has affinity for sterol regulatory element (SRE) present in the promoter region of these genes. The present study revealed that blasts, derived from both ALL and AML patients, were unable to express SREBP gene product although they had the capacity to express Receptor-Ck gene product. These results which depict defective Receptor-Ck-dependent signalling are in conformity with our previous results which showed that lymphocytes from CML patients as well as other human leukemic cell lines are unable to express gene coding for Receptor-Ck leading again to a state of impaired Receptor-Ck-dependent signalling. On the basis of these results, we propose that deregulated Receptor-Ck-dependent signalling may have an important role in leukemogenesis.

Blast Crisis↗
PubMed2000

Molecular basis of cholesterol feedback lesion in CNS tumours.

An important feature of malignant transformation of tumours is the loss of cholesterol feedback inhibition mechanism (cholesterol-feedback lesion) that regulates mevalonate pathway recognized to play a crucial role in cellular growth, death and differentiation. Recently, it was shown that Receptor-C(k)-dependent signalling regulates genes involved in maintaining cellular cholesterol homeostasis through a transcription factor sterol response element binding protein (SREBP) having affinity for sterol regulatory element (SRE) present in the promoter region of these genes. The present study revealed that CNS tumours exhibit overexpression of Receptor-C(k) gene product which was accompanied by their inability to express SREBP gene product and this phenomenon has the inherent capacity to initiate the cholesterol feedback lesion in these tumours. Based upon these and our earlier studies, we propose for the first time that this loss of cholesterol feedback control may be responsible for the initiation of these tumours.

Adult↗
PubMed1999

Molecular mechanism involved in TPA-induced myelopoietic programming.

The study, addressed to understand the mechanism responsible for 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced myeloid differentiation, revealed that the inherent capacity of TPA to induce expression of Receptor-C(K) in HL-60 cells (which are unable to express Receptor-C(K) in their native state) is responsible for its ability to induce phenotypic differentiation of HL-60 cells. Based upon these results, we propose that Receptor-C(K) dependent signalling is the Critical 'Molecular Switch' responsible for TPA-induced myelopoietic programming.

Cell Differentiation↗
PubMed1999

Receptor-Ck regulates the expression of cyclin-dependent kinase inhibitors (p16; p27).

The present study was addressed to understand the interrelationship between Receptor-Ck induction-activation coupling; isoprenoids (derived from mevalonate pathway) and cyclin-dependent kinase inhibitors. The results reported here unambiguously reveal that isoprenoids regulate the expression of genes coding for CDK inhibited p16 and p27. Further, Receptor-Ck dependent signalling, known to control the mevalonate pathway, had a direct effect upon the p27 gene expression. Based upon these studies coupled with our earlier findings we propose that Receptor-Ck has an important role in the regulation of cell cycle machinery.

Cell Cycle↗
PubMed1999

Meal composition effects on the oral bioavailability of indinavir in HIV-infected patients.

PURPOSE: To study the influence of large-volume high-calorie protein, fat, and carbohydrate meals and a non-caloric hydroxypropylmethyl cellulose (HPMC) viscous meal on the oral bioavailability of indinavir in HIV-infected subjects. METHODS: Seven male HIV-infected subjects received caloric meal treatments and control meals in a randomized crossover fashion and the viscosity meal as a final treatment. The total volume of each meal treatment was 500 mL and the caloric meals each contained 680 kcal. Gastric pH was also monitored by radiotelemetry from one hour before to four hours after drug and caloric meal administration. A single Crixivan (indinavir sulfate) dose equivalent to 600 mg indinavir was administrated orally with 100 mL of water immediately following meal administration. Indinavir plasma concentrations were obtained using reverse-phase HPLC. RESULTS: All meal treatments significantly decreased the extent of indinavir absorption as compared to fasted control. AUC0-infinity decreased by 68%, 45%, 34%, and 30% for protein, carbohydrate, fat, and viscosity meal treatments versus fasted control, respectively (p < 0.05). The mean Cmax was significantly decreased 74%, 59%, 46% and 36% (p < 0.05) and the mean tmax was significantly delayed from I hr in fasted controls to 3.8, 3.6, 2.1 and 2.0 hrs (p < 0.05) for protein, carbohydrate, fat, and viscosity meal treatments, respectively. The elimination half-life of indinavir determined in the fasted state was decreased in HIV-infected subjects as compared to the reported half-life in normal healthy subjects. CONCLUSIONS: Reductions in indinavir plasma concentrations compared to drug administration in the fasted state are most severe with the high-calorie protein meal. This is consistent with an influence of elevated gastric pH on drug precipitation. Significant drug plasma concentration reductions observed with administration of the other meals in the absence of appreciably elevated gastric pH profile indicate that other factors are playing a role in the meal effects. The similarity in indinavir plasma profiles with protein and carbohydrate versus fat and viscosity suggests that the latter meals may reduce the impact of drug precipitation compared to the former meals.

Adult↗
PubMed1999

Genetic polymorphism in muscle biopsies of Duchenne and Becker muscular dystrophy patients.

Duchenne muscular dystrophy (DMD), with an incidence of one in 3500 male new borns, and its milder variant, Becker muscular dystrophy (BMD), are allelic X-linked recessive disorders, caused by mutations in the gene coding for dystrophin, a 427 kD cytoskeleton protein. There are no available molecular markers to differentiate these two. The purpose of this study was to study genetic polymorphism in muscular dystrophy and explore its potential in discriminating these two allelic forms of the disease. The results revealed unambiguously the presence of three transcripts : 598bp, 849bp and 1583bp long which are selectively expressed in the muscles afflicted with muscular dystrophy as compared to the normal muscle. 1583bp gene transcript was conspicuously present in the muscle tissues of both DMD and BMD patients whereas 598bp and 849bp long transcripts were exclusively present in DMD but not in BMD patients or normal human subjects. These gene transcripts had no sequence homology with dystrophin gene and these were also present in the families belonging to DMD and BMD patients. These results point to the fact that based upon the selective expression of these three gene transcripts, one could not only differentiate between DMD and BMD diseases at the molecular level, but also between normal and dystrophic muscle. Further, these findings also reveal that apart from dystrophin gene, these gene transcripts may also be responsible for the differential progression of DMD/BMD phenotype.

Biopsy↗
PubMed1998

Receptor-Ck controls the expression of Bcl-2 and cyclin d genes.

By making use of receptor-Ck positive lymphocytes (from normal human subjects) as well as receptor-Ck negative lymphocytes (from untreated chronic myeloid leukemic (CML) patients) as cellular models, we were able to show that receptor-Ck-dependent signalling is involved in the regulation of genes coding for Bcl-2 and cyclin D. Further, experiments directed to resolve the mechanism by which this receptor regulates these genes revealed that receptor-Ck, upon activation by cholesterol, initiates the cleavage of a 125 kDa cytoplasmic protein leading to the generation of a 47 kDa factor having specific affinity for genomic sterol regulatory element (SRE)/SRE-like sequence present in the promoter region of genes coding for Bcl-2 and cyclin D. Based upon these observations, we propose that the inability of leukemic cells to express receptor-Ck is responsible for the deregulated over-expression of genes coding for Bcl-2 and cyclin D and this phenomenon may be of importance in understanding leukemic haematopoiesis.

Base Sequence↗