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Biomedical subjects

M A Qadar Pasha

Publications and source records attributed to M A Qadar Pasha.

14 recordsLinked to original sources
PubMed2006

Transcriptional downregulation of sterol metabolism genes in murine liver exposed to acute hypobaric hypoxia.

Ascent to high-altitude results in decreased inspired partial pressure of oxygen because of a decrease in barometric pressure. Altitude acclimatization requires physiological and metabolic changes to improve tolerance to altitude hypoxia. Cellular response to hypoxia results into changes in the profile of gene expression and the present study explored the same in murine model. Liver being the largest metabolic organ, the molecular details of acute hypobaric hypoxia (AHH) induced transcriptional changes in the tissue were investigated. Swiss albino mice were exposed to hypobaric hypoxia ( approximately 426mmHg) in a decompression chamber and cDNA microarray was used to study the transcriptional profile in liver. Notably, by the tenth hour several of the genes involved in sterol metabolism such as SREBF1, INSIG1, HMGCS1, FDFT1, SQLE, and HSD3B4 were downregulated more than 2-fold suggesting that AHH suppresses sterol biosynthesis in the liver. Real-time PCR helped validate the downregulation of SREBF1, HMGCS1, FDFT1, and HSD3B4 genes. However, no significant change was observed in the serum cholesterol levels throughout the AHH exposure. The findings are indicative of transcriptional downregulation of SREBP target genes as a part of acclimatization response to hypoxia. The study highlights the significance of SREBP in the regulation of sterol metabolism under the acute hypoxic response.

Adaptation, Physiological↗
PubMed2006

cDNA cloning, gene organization and variant specific expression of HIF-1 alpha in high altitude yak (Bos grunniens).

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) transcription factor consisting of HIF-1alpha and HIF-1beta subunits. HIF-1alpha is the oxygen-regulated subunit of HIF-1, which regulates the transcription of genes involved in oxygen homeostasis in response to hypoxia. Yak (Bos grunniens), a mammal native to high altitude (HA) region ( approximately 3500-5500 m), has successfully adapted over many generations to the chronic hypoxia of HA. In the present work, cDNA encoding HIF-1alpha has been cloned from the blood of yak. Tissue specific expression of the mRNA was analyzed in blood, heart, lung, liver and kidney by RT-PCR with primers from three different regions of cDNA. The HIF-1alpha expression was liver and blood specific. The HIF-1alpha mRNA contains 823 bp long 3'UTR that is AU-rich and contains ten AUUUA pentamers and two overlapping copies of the nonamer UUAUUUAUUUAUU. Three potential microRNAs, hsa-miR-107/mmu-miR-107/rno-miR-107, hsa-miR-18b and hsa-miR-135a/mmu-miR-135a/rno-miR-135a, targeting 3'UTR of yak HIF-1alpha, were identified by using target prediction software. The CDS encodes for 823 residues of amino acids and showed 99%, 95%, 92%, 90% and 90% similarity to domestic cattle, human, plateau pika, mouse and rat HIF-1alpha, respectively. HIF-1alpha cDNA, cloned and sequenced in the present work has revealed the evolutionary conservation through multiple sequence alignment. Liver and blood specific stability of HIF-1alpha mRNA appears miR-107 regulated.

Altitude↗
PubMed2006

Predominance of interaction among wild-type alleles of CYP11B2 in Himalayan natives associates with high-altitude adaptation.

Sojourners visiting high-altitude (HA) (>2500 m) are susceptible to HA disorders; on the contrary, HA natives are well adapted to the extreme hypoxic environment. High aldosterone levels are believed to be involved in HA disorders, we, therefore, envisaged role of CYP11B2 gene variants in HA adaptation and therefore investigated the -344T/C, intron-2 conversion (Iw/Ic), K173R, and A5160C polymorphisms. In addition, polymorphisms in AGT, AT1R, ATP1A1, ADRB2, and GSTP1 genes were also investigated. The study comprised of 662 subjects, comprising of 426 Himalayan highlanders (HLs) and 236 lowlanders (LLs). The -344T/C and K173R polymorphisms were found to be in complete linkage disequilibrium. The wild-type allele -344T and combination of wild-type homozygous genotypes between -344T/C, Iw/Ic, and A5160C polymorphisms, containing all the six wild-type alleles were over-represented in the HLs (p < 0.0001, and p = 0.008, respectively). The wild-type haplotypes -344T-Iw, -344T-5160A, and -344T-Iw-5160A also showed over-representation in the HLs (p < 0.0001). Furthermore, greater the number of wild-type alleles, lower was the ARR (p < 0.05). The genotype distribution in remaining genes did not differ. To conclude, the over-representation of wild-type -344T allele, genotype combinations and haplotypes of CYP11B2, and their correlation with lower aldosterone levels associate with HA adaptation in the HLs. Such an allelic presentation in sojourners may help them cope with adverse HA environment.

Adaptation, Physiological↗
PubMed2006

Structure-activity relationship study between Ornithyl-Proline and Lysyl-Proline based tripeptidomimics as angiotensin-converting enzyme inhibitors.

A designed library of tripeptidomimics of Ornithyl-Proline (Orn-Pro) and Lysyl-Proline (Lys-Pro) conjugated with various unnatural amino acids and carboxylic acid derived heterocyclics was synthesized and screened for possible inhibitors of angiotensin-converting enzyme (ACE). Among the tripeptidomimics 10[MTP-Orn-Pro], 11[HTP-Orn-Pro], 14[TA-Orn-Pro] and 20[BPA-Orn-Pro] showed prominent inhibition with IC50 values in micromolar concentrations. Structure-activity relationship study indicated that C3 side chain of Orn as compared to C4 side chain of Lys at P1' position was better suited to inhibit ACE, with propionic acid (C3) derived heterocyclics and unnatural amino acids.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Endothelin-1 gene variants and levels associate with adaptation to hypobaric hypoxia in high-altitude natives.

High-altitude natives are adapted to hypobaric hypoxia, suggestive of genetic basis of adaptation. Since endothelin-1 (ET-1) is of prime importance in high-altitude disorders in sojourners, we envisaged the role of allelic variants of ET-1 in high-altitude adaptation. Four ET-1 polymorphisms, viz., (CT)(n)-(CA)(n) repeat, -3A/-4A, G2288T, and Lys198Asn, were investigated in 426 highlanders (HLs) and 236 lowlanders (LLs). The plasma ET-1 levels, SBP and BMI were significantly lower in the HLs than those in LLs (p<0.0001). The Longer-repeats (31-45), G allele, Longer-repeats/GG, and Longer-repeats/Lys198Lys combinations were overrepresented in the HLs (p<0.0001, p=0.03, p<0.0001, and p<0.0001, respectively). The Longer-repeats, -3A/-3A, GG and Lys198Lys genotypes associated with significantly lower ET-1 levels in the HLs (p<0.0001, p=0.001, p<0.0001, and p<0.0001, respectively). Combinations of Longer-repeats with -3A/-3A, GG, and Lys198Lys genotypes, and -3A/-3A/Lys198Lys combination revealed association with lower ET-1 levels in the HLs (p<0.001). The study reports over-representation of Longer-repeats, G allele, and wild-type genotype combinations in high-altitude natives. Interaction between these alleles and association with lower ET-1 levels strengthen their association with high-altitude adaptation. Presence of such alleles in sojourners may help in acclimatization.

Adaptation, Physiological↗
PubMed2006

Heterozygotes of NOS3 polymorphisms contribute to reduced nitrogen oxides in high-altitude pulmonary edema.

STUDY OBJECTIVES: High-altitude pulmonary edema (HAPE), which develops on exertion under hypoxic conditions, aggravates due to endothelial dysfunction. Repeat events of the disorder suggests of genetic susceptibility. Endothelial nitric oxide synthase gene (NOS3), a regulator of vasodilation, has emerged as a strong candidate marker. In the present study, we investigated G894T, 27-base-pair 4b/4a (variable number of tandem repeat), -922A/G, and -786T/C polymorphisms of NOS3, individually or in combination, for an association with HAPE. DESIGN: A cross-sectional case control study. SETTINGS: Blood samples of HAPE-resistant lowlanders (HAPE-r) were obtained at sea level, and blood samples of patients with HAPE (HAPE-p) were obtained at Sonam Norboo Memorial Hospital, Leh, at 3,500 m. PARTICIPANTS: The study groups consisted of 60 HAPE-r inducted two to three times to altitudes > 3,600 m; and 72 HAPE-p, who had HAPE on their first visit to high altitude. RESULTS: Nitrogen oxides (NOx) at 77.9 +/- 28.6 micromol/L were significantly elevated in HAPE-r as compared to 42.39 +/- 12.93 micromol/L in HAPE-p (p < 0.0001). Genotype distribution of G894T and 4b/4a polymorphisms was significantly different in the two groups (p = 0.001 and 0.009, respectively). Haplotype analysis revealed -922A/G and -786T/C polymorphisms in complete linkage disequilibrium. The wild-type haplotypes G-b (G894T, 4b/4a), G-A (G894T, -922A/G), and G-b-A (G894T, 4b/4a, -922A/G) were significantly overrepresented in HAPE-r (p < 0.0001, p = 0.03, and p = 0.02, respectively). The heterozygote genotype combination GTba as compared to wild-type combination GGbb was significantly higher in HAPE-p (chi2 = 18.62, p = 0.00009; odds ratio, 7.20; 95% confidence interval, 2.82 to 18.38). The combination of four heterozygotes GTbaAGTC was overrepresented in HAPE-p (p = 0.04), whereas the wild-type genotype combination GGbbAATT was overrepresented in HAPE-r (p = 0.002). Furthermore, the GGbb combination correlated with significantly elevated NOx as compared to remaining combinations as a whole in both HAPE-r and HAPE-p (p = 0.01 and 0.004, respectively). CONCLUSIONS: Reduced NOx and combination of heterozygotes associate with the susceptibility to HAPE. The study impels another step toward application of NOx as a diagnostic marker for HAPE. The NOS3 GTba and GTbaAGTC genotype combinations may find application as genetic markers for predicting the risk for HAPE.

Adult↗
PubMed2005

Simultaneous selection of the wild-type genotypes of the G894T and 4B/ 4A polymorphisms of NOS3 associate with high-altitude adaptation.

The routine performance of high-altitude (HA) natives in the hypoxic environment of HA exemplifies the process of adaptation mainly through natural selection. The recent therapeutic application of nitric oxide (NO) in HA disorders, for the improvement of oxygenation and vasodilation, ushered us to investigate the endothelial nitric oxide synthase gene (NOS3) with respect to HA adaptation. The study subjects, 131 HA monks (HAM), 136 HA controls (HAC), and 170 lowlanders (LLs) were screened for NOS3 G894T (Glu298Asp) and 4B/4A polymorphisms. The NO levels were estimated, for a correlation with the polymorphisms. The three groups were in Hardy-Weinberg equilibrium for the polymorphisms. The overall genotype distributions for the G894T and 4B/4A polymorphisms were significant (P = 0.01 and 0.02, respectively) in the three groups. Wild-type alleles G and 4B were significantly over-represented in the HA groups as compared to the LLs (P = 0.006 and P = 0.02, respectively). The NO levels were in the order of HAM>HAC>LLs (P < 0.0001). Furthermore, combinations of the GG and BB genotypes were distributed significantly more frequently in the HAM (P < 0.0001) and HAC (P = 0.0005) than in LLs. The NO levels contributed by the wild-type genotype combination GG, BB were significantly elevated when compared with the remaining eight genotype combinations together in the HAM, HAC and LLs (P = 0.003, P = 0.0006 and P < 0.0001, respectively). To conclude, the genotype combination of NOS3 wild-type homozygotes (GG, BB) was found significantly more frequently in HA groups than in LLs, by contributing to higher NO levels associated with HA adaptation.

Adaptation, Physiological↗
PubMed2005

CYP11B2 gene polymorphisms and hypertension in highlanders accustomed to high salt intake.

BACKGROUND: High salt intake is the main determinant of hypertension. The alleles, which once had adaptive value in the salt-poor environment, by promoting salt retention, now induce hypertension. It would be interesting to determine whether the variant alleles of the aldosterone synthase gene (CYP11B2), if related to exaggerated expression/altered activity, are associated with hypertension when combined with a salt-rich diet. OBJECTIVE: To investigate the -344T/C, K173R and intron-2 conversion polymorphisms of CYP11B2 for an association with hypertension in highlanders accustomed to a high salt intake. DESIGN AND METHODS: Three CYP11B2 polymorphisms were compared with respect to frequencies and clinical characteristics in 190 normotensive highlanders (NHLs) and 100 hypertensive highlanders (HHLs). One-way ANOVA, chi2 test and logistic regression analysis were carried out to investigate the association of these polymorphisms with hypertension. RESULTS: The HHLs had significantly higher systolic blood pressure (SBP), diastolic blood pressure (DBP) (P < 0.0001), body mass index (BMI) (P = 0.0002), plasma aldosterone levels (P = 0.03) and aldosterone to plasma renin ratio (ARR) (P < 0.0001) and lower plasma renin activity (PRA) (P = 0.007). The -344T/C and K173R polymorphisms were in complete linkage disequilibrium with each other and the intron-2 conversion allele was in absolute association with the T allele. The TC/CC genotypes correlated with higher BMI when compared with TT genotype in the NHLs and the HHLs (P = 0.002 and 0.004, respectively). The intron-2 conversion heterozygotes/homozygotes correlated with higher SBP in the HHLs (P = 0.03) and significantly higher ARR when compared to IwIw (P = 0.02). Genotype combinations between the -344T/C and intron-2 conversion polymorphisms revealed that combinations with TC or CC genotypes inclined towards higher BMI in both the groups (P < 0.05). CONCLUSIONS: Our findings showed a correlation of C allele with high BMI, suggesting that -344T/C polymorphism is in linkage disequilibrium with a functional polymorphism on the adjacent 11-beta hydroxylase gene. The correlation of the intron-2 conversion allele with high SBP and ARR associates it with hypertension. The intron-2 conversion could be a functional variant, since it has been suggested to lead to overexpression of the gene; however, the presence of another functional variant in linkage disequilibrium within the gene cannot be ruled out.

Adult↗
PubMed2004

ACE I allele and eNOS G allele crosstalk may have a role in chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary hypertension, a characteristic of chronic obstructive pulmonary disease (COPD) has led us to investigate polymorphisms in angiotensin-converting enzyme (ACE) and endothelial nitric oxide synthase (eNOS) genes. DESIGN AND METHODS: Sixty-six normal and 27 patients, all of whom were smokers, were screened for ACE Insertion/Deletion (I/D) and eNOS G894T and CA-repeat polymorphisms and for plasma ACE and NO levels. RESULTS: Elevated ACE and decreased NO levels were obtained with the pattern of II to ID to DD and GG to GT to TT conversion, respectively. Furthermore, the genotype combination of II and GG was significantly greater in controls as compared to patients (P = 0.01; OR = 2.43; 95% CI: 1.21-4.87; RR = 2.00, 1.15-3.48). The CA-repeat multialleles showed a trimodal pattern in both the groups with a frequency range of 0.0057-0.103 and 0.0208-0.1875 in the controls and patients, respectively. CONCLUSIONS: The lower ACE and higher NO levels by virtue of the interchromosomal interaction between the I and G alleles appear to cause less vasoconstriction and increase vasodilatation that may be advantageous in the improvement of the disease.

Alleles↗
PubMed2003

Association of high-altitude systemic hypertension with the deletion allele-of the angiotensin-converting enzyme (ACE) gene.

People who visit high-altitude areas are exposed to a stressful environment and a good percentage of them suffer from high-altitude-induced diseases, including systemic hypertension. Identification of genetic markers for high-altitude-induced diseases would help to reduce the rate of morbidity/mortality from such diseases. The development of systemic hypertension on exposure to high altitude (3,500 m) for 30 days in otherwise normotensive natives of low-altitudes was investigated. The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) genotypes and renin-angiotensin-aldosterone system were simultaneously studied. In the hypertensives during their stay at high altitude, the ACE D allele frequency was significantly higher than in the normotensives (0.67 versus 0.32 chi(2)(1) = 10.6, P < 0.05). In the normotensives during their stay at high altitude, there was no significant increase in plasma aldosterone levels despite increased plasma renin activity. Results of the present study suggest that environmental changes and pre-existing genetic factors, namely the ACE D allele, might be two of the factors predisposing natives of low altitudes to systemic hypertension, a polygenic disease, at high altitude.

Adaptation, Physiological↗
PubMed2002

Variations in angiotensin-converting enzyme gene insertion/deletion polymorphism in Indian populations of different ethnic origins.

The pattern of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in the Indian population is poorly known. In order to determine the status of the polymorphism, young unrelated male army recruits were screened. The population had cultural and linguistic differences and lived in an environment that varied significantly from one region to another. Analysis of the genotype, showed higher frequency of the insertion allele in four of the five groups i.e. I allele frequency was significantly higher (P < 0.05) in Dogras, Assamese and Kumaonese. The deletion allele frequency was comparatively higher in the fifth group that belonged to Punjab. A correlation was observed between the genotype and enzyme activity. Involvement of a single D allele in the genotype enhanced the activity up to 37.56 3.13%. The results suggested ethnic heterogeneity with a significant gene cline with higher insertion allele frequency. Such population-based data on various polymorphisms can ultimately be exploited in pharmacogenomics.

Ethnicity↗
PubMed2002

Novel peptidomimics as angiotensin-converting enzyme inhibitors: a combinatorial approach.

One of the efficient mode of treatments of chronic hypertension and cardiovascular disorders has been to restrain the formation of angiotensin-II by inhibiting the action of angiotensin-converting enzyme (ACE) on angiotensin-I. A number of ACE inhibitors (ACEIs) have been put to therapeutic use during the last two decades. The efforts continue towards achieving superior molecules or drugs with improved affinities, better bioavailability and thus long duration of action with minimum side effects. The present work evolves around similar objectives. In order to understand the mode of interaction of inhibitors with the active site of the enzyme and subsequently to have lead compounds as possible inhibitors the novel dipeptidomimics and tripeptidomimics have been designed and synthesized using combinatorial chemistry approach. A Focussed library of 10 di- and tri-peptides, eight dipeptidomemics and forty tripeptidomemics was generated. The pharmacophoric heterocyclic moieties and the amino acids have been selected to have affinities with the S1, S1', and S2' subsites of the active site of the enzyme. ACE inhibition studies clearly demonstrated the structural-activity relationships within these classes of peptidomimics. The dipeptidomimics interacted only with S1' and S2' subsites, whereas the tripeptidomemics had additional interaction with S1 subsite, which accounted for their significant ACE inhibition potencies. The in-vitro screening of these peptidomimics have resulted in identification of four promising tripeptidomimics 34[2-benzimidazolepropionyl-Val-Trp], 35[5hydroxytryptophanyl-Val-Trp], 40[2-benzimidazolepropionyl-Ile-Trp] and 45[2-benzimidazolepropionyl-Lys-Trp] with IC50 values in micromolar concentrations.

Amino Acids↗
PubMed2001

Angiotensin converting enzyme insertion allele in relation to high altitude adaptation.

Angiotensin converting enzyme (ACE) gene I/D polymorphism has been associated with high altitude (HA) disorders as well as physical performance. We, however, envisage that the polymorphism may be associated with adaptation to the hypobaric hypoxia of altitude, thus facilitating physical performance. For this purpose, three unrelated adult male groups, namely (1) the Ladakhis (HLs), who reside at and above a height of 3600 m, (2) lowlanders, who migrated to Ladakh (MLLs), and (3) resident lowlanders (LLs), have been investigated. The HLs had significantly (p & 0.001) greater numbers of the II homozygotes and the ID heterozygotes than the DD homozygotes, the genotype distribution being 0.46, 0.43 and 0.11 for II, ID and DD genotypes respectively. The MLLs comprised 60% II homozygotes, which was higher (p & 0.001) than the HLs (46%). In the LLs, the heterozygotes were greater (p & 0.001) in number than the II and DD homozygotes. The I allele frequency was 0.72 in the MLLs, 0.67 in the HLs and 0.55 in the LLs. Polymorphism study suggested that the II genotype could be associated with altitude adaptation, which might influence physical efficiency.

Adaptation, Physiological↗