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Biomedical subjects

D Kaul

Publications and source records attributed to D Kaul.

At least 37 records · Page 2Linked to original sources
PubMed1998

Human platelets contain a novel 47 kDa thiol-oxidase having affinity for genomic sterol-regulatory sequence.

The present study provides evidence to support that human platelets possess a 47 kDa dual functional molecule having thiol-oxidase activity as well as high affinity for the SRE sequence in the human genome. On the basis of these as well as earlier results, we propose that Receptor 'Ck' dependent regulation of this dual functional 47 kDa molecule may provide a mechanism for the maintenance of cellular cholesterol homeostasis. Further, this mechanism may also explain the molecular basis of cholesterol-feedback lesion observed under premalignant conditions.

Blood Platelets↗
PubMed1998

Receptor-Ck-dependent regulation of genes involved in the cell cycle.

The present study was addressed to understand the interrelationship between Receptor-Ck activation, mevalonate pathway and primary response genes such as c-fos, c-myc and cyclin 'D' involved in the cell cycle. The results reported here unambiguously revealed that the phosphatidic acid (generated through the activation of Receptor-Ck by cholesterol) regulates mevalonate pathway, DNA synthesis as well as expression of genes coding for c-fos, c-myc and cyclin 'D'. By using the specific blockers of ras farnesylation as well as phospholipase D, it became apparent that phosphatidic acid regulates two processes: (a) activation of Gap-ras pathway leading to the expression of c-fos, c-myc proto-oncogenes probably through the activation of NF1 transcription factor; (b) cleavage of 125 kDa endoplasmic reticulum protein leading to the generation of 47 kDa protein factor which not only regulates mevalonate pathway but also has an ability to heterodimerize with Receptor-Ck protein and this heterodimer may be responsible for the regulation of cyclin 'D' expression probably by binding to the SRE like sequence present in the promoter region of this gene. On the basis of these findings, we propose a pathway through which Receptor-Ck upon endocytosis regulate these primary response genes (c-fos, c-myc, cyclin 'D') involved in the cell cycle.

Butanols↗
PubMed1998

RNA-mediated regulation of Bc1-2 and cyclin 'D' genes in human platelets.

The aim of this study was to understand the RNA-mediated regulation of genes coding for Bc1-2 and cyclin 'D'. Evidence was provided that these genes are regulated by receptor-C(k)-dependent signalling in human platelets. Further experiments to resolve the mechanism through which receptor-C(k) regulates these genes revealed that receptor-C(k)-dependent signalling is involved in the cleavage of a 125-kDa protein present in endoplasmic reticulum, resulting in generation of a 47-kDa factor that has affinity for a genomic sterol regulatory element as well as the platelet mRNA pool. Based upon these findings we propose a receptor-C(k) dependent signalling pathway for the regulation of Bc1-2 and cyclin 'D' genes at the post-transcriptional level.

Journal Article↗
PubMed1998

Mucosal responses to parenteral and mucosal vaccines.

Most human pathogens are acquired through mucosal portals of entry, and replicate in the mucosal tissues. Subsequently, the infecting agent may invade the blood stream and produce disease at distant systemic sites. However, a large number of pathogenic organisms are limited to development of disease only at the site of initial mucosal replication. Studies carried out with naturally acquired infections and mucosally delivered vaccines have provided strong evidence for the existence of a common mucosal immune system in the organized lymphoid follicles in respiratory and intestinal epithelium, and in the mucosa of genital tract, mammary glands, conjunctiva, upper airways, and the middle ear cavity. Mucosal application of live attenuated oral poliovaccine (OPV), rubella virus vaccine (RA 27/3), adenoviruses, influenza A virus, rotavirus, salmonella, and cholera vaccines have demonstrated consistent development of secretory IgA, serum antibody, and cellular immune responses. Mucosal immunization appears to result in preferential expression of several integrins and cell adhesion molecules associated with homing of lymphocytes to mucosal sites of immunization. Induction of mucosal immune responses often result in specific protection against reinfection challenge and against illness. Replicating agents introduced via the parenteral route also result in the development of mucosal responses and protection against systemic illness. Parenteral immunization with non-replicating agents often fails to induce specific mucosal responses. Such immunization, however, is quite effective in mounting high levels of serum antibody with development of protection against systemic illness. Parenteral vaccines, such as enhanced potency inactivated polio vaccine (eIPV), Haemophilus influenzae type B (HIB), hepatitis B virus (HBV), and other non-mucosal vaccines, have been highly effective in preventing systemic disease during subsequent exposure to natural infection. Recent evidence has shown that parenteral immunization can also be quite effective in inducing varying degrees of functional mucosal antibody responses as detected by ELISA and less frequently by neutralization. Systemic illnesses such as poliomyelitis and Haemophilus influenzae meningitis and community circulation of these agents has been eliminated or significantly limited in many parts of the world with the exclusive use of inactivated vaccines. Based on these observations, it is suggested that development of serum immunological responses are effective in the prevention of systemic disease regardless of the types of vaccines or route of their administration. However, induction of pathogen-specific antibody or cellular immunity at the mucosal sites is best elicited by mucosal application of the antigen.

Antibodies, Viral↗
PubMed1997

LDL-dependent regulation of Bcl-2 and cyclin 'D' gene expression in lymphocytes from normal and CML patients.

Effect of low-density lipoprotein (LDL) on the expression of Bcl-2 as well as cyclin 'D' genes was studied in Receptor 'Ck' (+ve) and Receptor 'Ck'(-ve) human lymphocytes. LDL had no effect upon the elevated levels of Bcl-2 and cyclin 'D' gene products in Receptor 'Ck' (-ve) lymphocytes (from untreated CML patients), whereas in Receptor 'Ck' (+ve) lymphocytes (from normal subjects), the exposure to LDL regulated the level of cyclin 'D' gene product without initiating the expression of bcl-2 gene product. However, blockage of Receptor 'Ck' in normal lymphocytes, through its specific antibody (Ab-RCk) in presence or absence of LDL, resulted in the induction of both cyclin 'D' (at 4 h interval) and bcl-2 (at 12 h interval) gene products. Based upon these results, we propose that Receptor 'Ck' deficiency in cells may inherit defective apoptosis and capacity proliferation leading to leukemic transformation.

Cyclin D↗
PubMed1997

Does receptor-'Ck' deficiency initiate leukaemia?

We have developed a polyclonal monospecific antibody (designated Ab-Ck) which recognises specifically a novel cell surface Receptor-'Ck', having inherent ability to regulate mevalonate pathway that is vital for many cellular functions ranging from growth control to differentiation. By using this 'Ab-Ck' as a probe, the Western blot analysis of protein fractions derived from various types of normal and cancerous cells/tissues revealed not only that this Receptor-'Ck' was ubiquitously present in various human organs, especially adrenal cortex, aorta, liver and brain, but also that leukaemic cell lines as well as lymphocytes from CML patients were specifically and selectively deficient in this receptor. Based upon these observations, we propose that leukaemic process may be initiated as a consequence of the deficiency of this novel Receptor-'Ck'.

Antibodies↗
PubMed1997

Receptor-'Ck' dependent signalling regulates the LDL-receptor gene transcription.

Evidence of a novel receptor, having affinity for cholesterol in lipoproteins and intrinsic tyrosine kinase activity (designated as Receptor 'Ck') prompted us to explore its role in LDL-dependent transcriptional regulation of apoprotein-B specific LDL receptor gene in human lymphocytes. The results of this study revealed that LDL dependent activation of this Receptor 'Ck' was essential for the regulation of apoprotein-B specific LDL receptor gene transcription. Further, by using various blockers of as well as simulating the Receptor 'Ck'-dependent signalling in human lymphocytes, we were able to show that Receptor 'Ck'-dependent signalling was involved in the LDL-dependent transcriptional regulation of 160 kDa apoprotein B specific LDL receptor gene. Based upon these results, we conclude that cholesterol derived from LDL. catabolism within the cell does not have any role in the transcriptional regulation of apoprotein B specific LDL receptor gene.

Apolipoproteins B↗
PubMed1997

RNA-mediated regulation of Receptor-Ck gene in human platelets.

The study addressed to understand the regulation of Receptor-'Ck' gene at the translational level revealed that exogenous cholesterol has the inherent capacity to regulate the endogenous synthesis of Receptor-'Ck' by initiating intracellular targeting of the Receptor-'Ck' to the mRNP pool within human platelets and this effect could be reversed when the platelets were incubated with cholesterol coupled with either dB cAMP or dB cGMP. Based upon these observations, we propose that Receptor-'Ck' initiated signalling, which involves second messengers like PA, cAMP and cGMP, may be responsible for the autoregulation of Receptor-'Ck' gene expression at the translational level.

Blood Platelets↗
PubMed1996

Sterol dependent LDL-receptor gene transcription in lymphocytes from normal and CML patients.

Sterol regulatory element (SRE) has been recognized to regulate various key genes coding for especially low density lipoprotein (LDL)-receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and HMG-CoA synthase known to play a crucial role in the cholesterol feedback mechanism. The deranged cholesterol feedback mechanism has been widely recognised in initiation as well as progression of various types of cancers including chronic myeloid leukaemia (CML). Consequently, the present study was addressed to understand this phenomenon and revealed the existence of a unique 47 kDa protein factor having affinity for this SRE sequence in lymphocytes from normal subjects as well as its absence in lymphocytes from untreated CML patients. However, this factor appeared when the CML patients achieved complete haematological remission (CHR) through alpha-interferon therapy. Further, an inverse relationship was also observed between sterol modulated LDL-receptor gene transcription and the binding affinity of this 47 kDa factor to the SRE sequence. Based upon these results we propose that alpha-interferon through its receptor initiates phosphatidic acid dependent signalling which in turn regulates the affinity of 47 kDa sterol regulatory element binding factor as well as LDL-receptor gene transcription in lymphocytes from CML patients.

Bucladesine↗
PubMed1996

Evidence and nature of a novel thiol-oxidase in human platelets.

The study, addressed to understand whether or not human platelets possess a unique thiol-oxidase whose activity could be modulated by signalling pathway initiated upon the activation of Receptor-'C'k revealed the existence of disulphide-dependent oxidation within these cells and this phenomenon was regulated by Receptor-'C'k-dependent generation of second messengers especially phosphatidic acid(PA); cAMP and cGMP. Purification of this activity revealed the existence of 47 kDa protein having thiol-oxidase activity. Keeping in view these results we propose that the existence of this novel 47 kDa Thiol-oxidase within human platelets may provide a 'crucial switch' for the regulation of Receptor-'C'k-dependent mevalonate pathway in human platelets.

Blood Platelets↗
PubMed1996

Lymphocytes from CML patients lack a 47 kDa factor having affinity for a genomic sterol regulatory sequence.

Deranged cellular cholesterol homeostasis has been widely recognized in the initiation as well as progression of various types of cancers including chronic myeloid leukaemia (CML). Since the human genomic sterol regulatory element (SRE) has been shown to regulate various key genes involved in this phenomenon, the present study revealed the existence of a unique 47 kDa protein factor having affinity for this SRE sequence in lymphocytes from normal subjects, as well as its absence in lymphocytes from untreated CML patients. However, this factor appeared when these CML patients achieved complete haematological remission (CHR) through alpha-interferon therapy. Furthermore, an inverse relationship was also observed between the LDL receptor gene expression at the transcriptional level and the binding affinity of this 47 kDa protein factor to the SRE sequence. Based upon these results we propose that this factor may have a role in pathophysiology of chronic myeloid leukaemia.

Antineoplastic Agents↗
PubMed1996

Lack of expression of c-myc oncogene in peripheral blood mononuclear cells of patients with active rheumatoid arthritis.

We looked for the expression of c-myc oncogene, one of the genes that enhance apoptosis, in 11 patients with active rheumatoid arthritis (RA) along with five patients with osteoarthritis (OA) knee as disease controls and six healthy volunteers. A dot-blot assay using a probe specific for c-myc oncogene was performed on total RNA obtained from peripheral blood mononuclear cells. There was no expression in patients with active RA and healthy volunteers. One patient with OA expressed c-myc. Lack of expression of c-myc suggests that in active RA circulating lymphocytes are not in the replicative phase despite ongoing disease activity.

Adult↗
PubMed1995

Lipoprotein receptor 'CK'--dependent signalling in human platelets.

The study addressed to understand whether or not lipoproteins at low concentrations could modulate Receptor-'C' dependent platelet signalling revealed that LDL, like exogenous cholesterol, had the capacity to initiate PLD-dependent platelet signalling in a dose dependent fashion and this effect was inhibited in presence of HDL; cAMP; DTT; Zn++ and butanol whereas cGMP had no effect upon this PLD-dependent signalling. Further Receptor 'C' from platelet in the purified-form displayed LDL-or cholesterol-dependent autophosphorylation at the tyrosine residues and this Receptor-'C' tyrosine kinase (Receptor-Ck) activity contributed to the observed LDL-or cholesterol -dependent PLD activity in human platelets. Based upon these results coupled with earlier results, an attempt was made to define the lipoprotein-dependent platelet signalling pathway.

Adenosine Triphosphate↗
PubMed1994

A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire.

Previously, six T cell clones, which are specific for an encephalitogenic determinant of myelin proteolipid protein (PLP) peptide residues 139 to 151 (HSLGKWLGHPDKF), were derived from SJL mice and shown to use diverse TCR genes. To design TCR antagonist peptides that could interfere with the activation of these clones in vitro and inhibit experimental allergic encephalomyelitis (EAE) in vivo, we first determined the TCR and MHC contact residues of the encephalitogenic peptide. The analysis indicated that residues 144 (tryptophan) and 147 (histidine) were the TCR binding sites and that residues 145 (leucine) and 148 (proline) were important for MHC class II (IAs) binding. On the basis of this information, a peptide analogue (leucine 144/arginine 147), in which both of the major TCR contact residues were substituted, was synthesized. This analogue acts as a TCR antagonist for the panel of PLP 139-151-specific T cell clones, does not cause EAE by itself, blocks the induction of disease by the native 139-151 peptide, and prevents clinical disease progression if administered at the first signs of disease. Thus, although multiple TCR genes are used by PLP 139-151-specific clones, a single peptide analogue can interfere with the disease process. This approach should be feasible for designing peptide analogues that can be tested for therapeutic efficacy in human autoimmune diseases in which the pathogenic Ags are known and TCR use is diverse.

Amino Acid Sequence↗
PubMed1994

Exogenous cholesterol--initiated transmembrane signalling pathway regulates cholesterogenesis in human platelets.

Incubation of gel-filtered human platelets with cholesterol in the absence of divalent ions revealed that exogenous cholesterol had the ability to down-regulate the cholesterol biosynthesis in a dose-dependent fashion and this phenomenon was paralleled by an increase in phospholipase D activity. However, exogenous calcium in the presence of either cholesterol or phosphatidic acid had the capacity to up-regulate the platelet cholesterol synthesis in a dose-dependent manner. Further, cyclic nucleotides (cAMP, cGMP) also had the ability to influence directly the regulation of platelet cholesterol synthesis. Based upon these, as well as our earlier findings, we propose that exogenous cholesterol through its specific receptor regulates cholesterogenesis either directly or by initiating the transmembrane-signalling pathway involving cyclic nucleotides.

Blood Platelets↗
PubMed1994

'Lupus-prone' mice are susceptible to organ-specific autoimmune disease, experimental allergic encephalomyelitis.

Immunization with the multideterminant autoantigen myelin basic protein (MBP) causes experimental allergic encephalomyelitis (EAE), a T-cell-mediated autoimmune disease that serves as a model for multiple sclerosis (MS). MBP peptides Ac1-11 and p35-47 induce potent EAE in mice of the H-2u haplotype. T cells specific for Ac1-11 predominantly utilize one T-cell receptor (TCR) V beta gene segment, V beta 8.2. All T-cell clones and hybridomas analyzed, regardless of TCR V beta usage, utilize D beta 2 and J beta 2 elements. The NZW mouse strain (H-2z), which contributes to the spontaneous 'lupus-like' illness in (NZB x NZW)F1 mice, has a genomic deletion encompassing D beta 2 and J beta 2 gene segments. The NZW strain expresses class II (I-A and I-E) genes which share identical sequences with H-2u class II. We investigated whether these strains are susceptible to EAE induced with intact MBP and known encephalitogenic MBP peptides. In vitro analysis demonstrated that NZW antigen-presenting cells (APC) can present MBP and MBP peptide Ac1-11 to an encephalitogenic T-cell clone derived from an H-2u mouse, confirming the functional identity of NZW class-II (I-A) molecules with their respective H-2u class-II gene products. In vivo results demonstrated that NZW and (NZB x NZW)F1 mice are susceptible to EAE induced with intact MBP and Ac1-11. MBP p35-47 caused EAE in (NZB x NZW)F1 mice, which express alleles for both the normal (NZB) TCR beta-gene locus, and the abnormal (NZW) TCR beta-gene locus containing the J beta 2 deletion.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Initiator-promoter coupling of phospholipases D and A2 in platelets upon cholesterol incorporation.

Since phospholipases exist within a membrane lipid environment, it is not unreasonable to assume that cholesterol capable of changing the lipid environment can effect the coupling relationship among the signal transducing components. Our previous study showed that the 'molecular switch' through which membrane cholesterol modulates cyclic nucleotide levels and Na+/H+ exchange within human platelets is phospholipase A2. We demonstrate here that membrane cholesterol initiates the activation of phosphatidyl choline phospholipase D and phosphatidic acid thus generated promotes the activation of its phospholipase A2 in the presence of extraplatelet calcium. More important, inhibition of phospholipase D by zinc blocks the activation of phosphatidic acid phospholipase A2 in platelets upon cholesterol incorporation. Our result led us to postulate that membrane cholesterol induced initiation promotion coupling of phospholipases D and A2 in human platelets may be responsible for the hypersensitized state of platelets in hypercholesterolemic patients.

Blood Platelets↗