Abstract Objective We analysed the associations of 25 hydroxy vitamin D 25(OH) D and parathyroid hormone (PTH) levels with clinical, anthropometric, biochemical and body composition parameters in ...Asian Indians with nonalcoholic fatty liver disease (NAFLD). Methods In this case–control study, 162 cases and 173 age and sex matched controls were recruited. Clinical, anthropometric, biochemical parameters and liver ultrasound were done. Percentage body fat (%BF), lean body mass and bone mineral density (BMD) were assessed by dual energy X-ray absorptiometry (DXA). Fasting insulin levels, value of homeostasis model assessment of insulin resistance (HOMA-IR), serum 25(OH) D, calcium and PTH levels were measured. Results Subjects with NAFLD had lower serum 25(OH) D (19.4 ± 8.5 vs. 27.8 ± 9.4 ng/ml, p = 0.0001) and higher serum PTH (54.9 ± 19.5 vs. 41.5 ± 18.3 pg/ml, p = 0.0001) levels as compared to controls. We observed significantly high values of systolic blood pressure ( p = 0.002), waist circumference ( p = 0.05), serum triglycerides ( p = 0.002), total cholesterol ( p = 0.002), alanine transaminase ( p = 0.05), fasting insulin ( p = 0.02) and HOMA-IR ( p = 0.03) in the lowest 25(OH) D quartile. Multivariable-logistic regression showed that low serum 25(OH) D OR (95%CI): 4.46 (2.58–7.72), p = 0.0001 and high PTH OR (95%CI): 2.21 (1.50–3.30), p = 0.0001 level were independently associated with NAFLD. Conclusion Low serum 25(OH) D and high PTH levels were independently associated with the presence of NAFLD in Asian Indians residing in north India.
We investigated the effects of dietary intervention with canola or olive oil in comparison with commonly used refined oil in Asian Indians with nonalcoholic fatty liver disease (NAFLD).
This was a ...6-month intervention study including 93 males with NAFLD, matched for age and body mass index (BMI). Subjects were randomized into three groups to receive olive oil (n=30), canola oil (n=33), and commonly used soyabean/safflower oil (control; n=30) as cooking medium (not exceeding 20 g/day) along with counseling for therapeutic lifestyle changes. The BMI, fasting blood glucose (FBG) and insulin levels, lipids, homeostasis model of assessment for insulin resistance (HOMA-IR), HOMA denoting β-cell function (HOMA-βCF), and disposition index (DI) were measured at pre- and post-intervention. Data were analyzed with one-way analysis of variance (ANOVA) and Tukey's Honestly Significant Difference multiple comparison test procedures.
Olive oil intervention led to a significant decrease in weight and BMI (ANOVA, P=0.01) compared with the control oil group. In a comparison of olive and canola oil, a significant decrease in fasting insulin level, HOMA-IR, HOMA-βCF, and DI (P<0.001) was observed in the olive oil group. Pre- and post-intervention analysis revealed a significant increase in high-density lipoprotein level (P=0.004) in the olive oil group and a significant decrease in FBG (P=0.03) and triglyceride (P=0.02) levels in the canola oil group. The pre- and post-intervention difference in liver span was significant only in the olive (1.14 ± 2 cm; P<0.05) and canola (0.66 ± 0.33 cm; P<0.05) oil groups. In the olive and canola oil groups, post-intervention grading of fatty liver was reduced significantly (grade I, from 73.3% to 23.3% and from 60.5% to 20%, respectively P<0.01; grade II, from 20% to 10% and from 33.4% to 3.3%, respectively P<0.01; and grade III, from 6.7% to none and from 6.1% to none, respectively). In contrast, in the control oil group no significant change was observed.
Results suggest significant improvements in grading of fatty liver, liver span, measures of insulin resistance, and lipids with use of canola and olive oil compared with control oils in Asian Indians with NAFLD.
To determine the association of the A55T and K153R polymorphisms of the Myostatin gene with obesity, abdominal obesity and lean body mass (LBM) in Asian Indians in north India.
A total of 335 ...subjects (238 men and 97 women) were assessed for anthropometry, % body fat (BF), LBM and biochemical parameters. Associations of Myostatin gene polymorphisms were evaluated with anthropometric, body composition and biochemical parameters. In A55T polymorphism, BMI (p=0.04), suprailiac skinfold (p=0.05), total skinfold (p=0.008), %BF (p=0.002) and total fat mass (p=0.003) were highest and % LBM (p=0.03) and total LBM (Kg) were lowest (p=0.04) in subjects with Thr/Thr genotype as compared to other genotypes. Association analysis of K153R polymorphism showed that subjects with R/R genotype had significantly higher BMI (p=0.05), waist circumference (p=0.04), %BF (p=0.04) and total fat mass (p=0.03), and lower %LBM (p=0.02) and total LBM (Kg), (p=0.04) as compared to other genotypes. Using a multivariate logistic regression model after adjusting for age and sex, subjects with Thr/Thr genotype of A55T showed high risk for high %BF (OR, 3.92, 95% Cl: 2.61-12.41), truncal subcutaneous adiposity (OR, 2.9, 95% Cl: 1.57-6.60) and low LBM (OR, 0.64, 95% CI: 0.33-0.89) whereas R/R genotype of K153R showed high risk of obesity (BMI; OR, 3.2, 95% CI: 1.2-12.9; %BF, OR, 3.6, 95% CI: 1.04-12.4), abdominal obesity (OR, 2.12, 95% CI: 2.71-14.23) and low LBM (OR, 0.61, 95% CI: 0.29-0.79).
We report that variants of Myostatin gene predispose to obesity, abdominal obesity and low lean body mass in Asian Indians in north India.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Few potential candidate genes coding for type I and II receptors of transforming growth factor beta signaling pathway and the serotonin transporter have been associated with pulmonary hypertension ...(PH). The latter being a phenotype for high altitude pulmonary edema (HAPE), these genes are hypothesized to be crucial markers to investigate under the hypobaric hypoxic environment of high altitude.
We hence aimed to investigate bone-morphogenetic protein-2 (BMP2), bone morphogenetic protein receptor type-II (BMPR-2), activin receptor-like kinase-1 (ALK-1), serotonin transporter (5-HTT) and serotonin (5-HT) for their contribution, individually/epistatically, to clinical endpoints by altering downstream signaling molecules.
In a case–control design, interactions between/among polymorphisms of BMPR-2, ALK-1 and 5-HTT were screened in 200 HAPE-patients (HAPE-p) and 200 HAPE-free sojourners (HAPE-f). Plasma biomarker BMP-2 and 5-HT were estimated. The relative gene expression was also witnessed in 20 humans/10 rats followed by correlation analyses.
The genotype/allele models revealed the prevalence of BMPR-2 rs6717924A-rs4303700A-rs1048829A; ALK-1 rs11169953T-rs3759178C-rs706816C and 5-HTT rs6354C in HAPE (P≤0.05). Multifactor dimensionality reduction for interactions among genes revealed a 4-locus model of BMPR-2 rs6717924G/A; ALK-1 rs11169953C/T-rs706816T/C and 5-HTT rs6354A/C as the best disease predicting (P≤0.001); whereas HapEvolution analysis confirmed the alleles rs6717924A, rs4303700A and rs6354C as the best interacting (P≤0.01). Plasma levels of BMP-2 and 5-HT were elevated in HAPE (P≤0.0001). The expression of BMP-2, ALK-1, 5-HT, 5-HTT was elevated and of BMPR-2 decreased in humans and rats (P≤0.05).
The risk alleles BMPR-2 rs6717924A-rs4303700G-rs1048829A; ALK-1 rs11169953T-rs706816C and 5-HTT rs6354C correlated inversely with arterial oxygen saturation (SaO2) and positively with mean arterial pressure (MAP), BMP-2 and 5-HT in HAPE. Likewise, haplotypes BMPR-2 GGGCGAAAA, AAATAGGGA and ALK-1 CCTCAAAG, CCTTAAAG correlated with clinical markers and biomarkers (P≤0.01). BMP-2 and 5-HT correlated positively with MAP and negatively with SaO2 (P≤0.01).
The genetic-interactions among BMPR-2, ALK-1, and 5-HTT polymorphisms, elevated BMP-2 and 5-HT levels and differential gene expression substantiated the strong genetic contribution in HAPE pathophysiology.
•Genetic interactions among BMPR-2, ALK-1.5-HTT predict risk of HAPE.•Systemic release of BMP-2, 5-HT occurs.•Together, the genetic variants and proteins may induce vasoconstriction to exaggerate HAPE.
High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail ...the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies.
In this study, we have attempted comparison of detailed body composition phenotype of Asian Indians with non-alcoholic fatty liver disease (NAFLD) vs. those without, in a case controlled manner. We ...also aim to analyse prediction equations for NAFLD for non-diabetic Asian Indians, and compare performance of these with published prediction equations researched from other populations.
In this case-control study, 162 cases and 173 age-and sex-matched controls were recruited. Clinical, anthropometric, metabolic, and body composition profiles, and liver ultrasound were done. Fasting insulin levels, value of homeostasis model assessment of insulin resistance (HOMA-IR), and serum high sensitive C-reactive protein (hs-CRP) levels were evaluated. Multivariate logistic and linear regression analyses were used to arrive at prediction equations for fatty liver Indian fatty liver index (IFLI).
As compared to those without fatty liver, those with fatty liver exhibited the following; Excess dorsocervical fat ('Buffalo hump'), skin tags, xanthelasma, 'double chin', arcus; excess total, abdominal and subcutaneous adiposity, and high blood pressure, blood glucose, measures of insulin resistance (fasting insulin and HOMA-IR values), lipids and hs-CRP levels. Two prediction equations were developed; Clinical Indian Fatty Liver Index-Clinical; IFLI-C: 1(double chin) +15.5 (systolic blood pressure) +13.8 (buffalo hump); and IFLI-Clinical and Biochemical (CB): serum triglycerides+12 (insulin)+1(systolic blood pressure) +18 (buffalo hump). On ROC Curve analysis, IFLI performed better than all published prediction equations, except one.
Non-diabetic Asian Indians with NAFLD researched by us were overweight/obese, had excess abdominal and subcutaneous fat, multiple other phenotypic markers, had higher insulin resistance, glycemia, dyslipidemia and subclinical inflammation than those without. Prediction score developed by us for NAFLD; IFLI-C and IFLI-CB, should be useful for clinicians and researchers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The interactions among various biomarkers remained unexplored under the stressful environment of high-altitude. Present study evaluated interactions among biomarkers to study susceptibility for high ...altitude pulmonary edema (HAPE) in HAPE-patients (HAPE-p) and adaptation in highland natives (HLs); both in comparison to HAPE-free sojourners (HAPE-f).
All the subjects were recruited at 3500 m. We measured clinical parameters, biochemical levels in plasma and gene expression using RNA from blood; analyzed various correlations between and among the clinical parameters, especially arterial oxygen saturation (SaO(2)) and mean arterial pressure (MAP) and biochemical parameters like, asymmetric dimethylarginine (ADMA), serotonin (5-HT), 8-iso-prostaglandin F2α (8-isoPGF2α), endothelin-1 (ET-1), plasma renin activity (PRA), plasma aldosterone concentration (PAC), superoxide dismutase (SOD) and nitric oxide (NO) in HAPE-p, HAPE-f and HLs. ADMA, 5-HT, 8-isoPGF2α, ET-1 levels, and PAC were significantly higher (p<0.0001, each), whereas SOD activity and NO level were significantly lower in HAPE-p than HAPE-f (p ≤ 0.001). Furthermore, ADMA, 5-HT, 8-isoPGF2α, NO levels and PAC were significantly higher (p<0.0001), whereas ET-1 level significantly (p<0.0001) and SOD activity non-significantly (p>0.05) lower in HLs than HAPE-f. The expression of respective genes differed in the three groups. In the correlations, SaO(2) inversely correlated with ADMA, 5-HT and 8-isoPGF2α and positively with SOD in HAPE-p (p≤0.009). MAP correlated positively with 5-HT and 8-isoPGF2α in HAPE-p and HLs (p ≤ 0.004). A strong positive correlation was observed between ADMA and 5-HT, 5-HT and 8-isoPGF2α (p≤0.001), whereas inverse correlation of SOD with ET-1 in HAPE-p and HLs (p ≤ 0.004), with 5-HT and 8-isoPGF2α in HAPE-p (p = 0.01) and with 5-HT in HLs (p = 0.05).
The interactions among these markers confer enhanced vascular activity in HLs and HAPE in sojourners.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hypobaric hypoxia poses stress to sojourners traveling to high-altitude. A cascade of physiological changes occurs to cope with or adapt to hypobaric hypoxia. However, an insufficient physiological ...response to the hypoxic condition resulting from imbalanced vascular homeostasis pathways results in high-altitude pulmonary edema (HAPE). The present study aims to identify the implication of miRNAs associating with HAPE and adaptation. We analyzed the expression of 1,113 miRNAs in HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and highland natives (HLs). Based on miRNA profiling and in silico analyses, miR-124-3p emerged relevantly. We observed a significant overexpression of miR-124-3p in HAPE-p. In silico analyses revealed a direct interaction of miR-124-3p with vascular homeostasis and hypoxia-associated genes NOS3 (endothelial nitric oxide synthase), Apelin, and ETS1 (V-Ets avian erythroblastosis virus E2 oncogene homolog 1). Moreover, the transcript and biolevel expression of these genes were significantly decreased in HAPE-p when compared with HAPE-f or HLs. Our in vitro analysis in human umbilical vein endothelial cells demonstrated a significant knockdown of these genes both at transcript and protein levels following miR-124-3p overexpression. Conclusively, our results showed that miR-124-3p might play a plausible role in HAPE pathophysiology by inhibiting the expression of NOS3, Apelin, and ETS1.
Hypoxia-inducible factor stimulates the expression of apelin, a potent vasodilator, in response to reduced blood arterial oxygen saturation. However, aberrations in the apelin system impair pulmonary ...vascular function, potentially resulting in the development of high-altitude (HA)-related disorders. This study aimed to elucidate the genetic and epigenetic regulation of apelin , apelin receptor ( APLNR ), and endothelial nitric oxide synthase ( NOS3 ) in HA adaptation and HA pulmonary edema (HAPE). A genome-wide association study and sequencing identified variants of apelin , APLNR , and NOS3 that were validated in a larger sample size of HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and healthy highland natives (HLs). Apelin-13 and nitrite levels and apelin and NOS3 expression were down-regulated in HAPE-p ( P < 0.001). Among the several studied polymorphisms, apelin rs3761581, rs2235312, and rs3115757; APLNR rs11544374 and rs2282623; and NOS3 4b / 4a , rs1799983, and rs7830 were associated with HAPE ( P < 0.03). The risk allele rs3761581 G was associated with a 58.6% reduction in gene expression ( P = 0.017), and the risk alleles rs3761581 G and rs2235312 T were associated with low levels of apelin-13 and nitrite ( P < 0.05). The latter two levels decreased further when both of these risk alleles were present in the patients ( P < 0.05). Methylation of the apelin CpG island was significantly higher in HAPE-p at 11.92% than in HAPE-f and HLs at ≤7.1% ( P < 0.05). Moreover, the methylation effect was 9% stronger in the 5′ UTR and was associated with decreased apelin expression and apelin-13 levels. The rs3761581 and rs2235312 polymorphisms and methylation of the CpG island influence the expression of apelin in HAPE.
Significance Exposure to a high-altitude (HA) hypobaric hypoxia environment produces physiological changes. Among these, the changes in the apelin signaling system are significant because this system regulates vascular and oxygen homeostasis. This study demonstrates that the HA environment stimulates the apelin system to distinguish genetic variants and the methylation profile of CpG islands that may impair or improve pulmonary vascular function, thereby resulting in HA pulmonary edema (HAPE) in patients or adaptation in healthy controls. Of the several variants of this system, apelin rs3761581 G and rs2235312 T , individually and in combination, and a greater methylation of a CpG island in the 5′ UTR, associated with low levels of apelin-13 and nitrite in HAPE, whereas a reverse trend was observed in the control groups.
Hypobaric hypoxia at high altitude (HA) results in reduced blood arterial oxygen saturation, perfusion of organs with hypoxemic blood, and direct hypoxia of lung tissues. The pulmonary complications ...in the cells of the pulmonary arterioles due to hypobaric hypoxia are the basis of the pathophysiological mechanisms of high-altitude pulmonary edema (HAPE). Some populations that have dwelled at HA for thousands of years have evolutionarily adapted to this environmental stress; unadapted populations may react with excessive physiological responses that impair health. Individual variations in response to hypoxia and the mechanisms of HA adaptation provide insight into physiological responses. Adaptive and maladaptive responses include alterations in pathways such as oxygen sensing, hypoxia signaling, K(+)- and Ca(2+)-gated channels, redox balance, and the renin-angiotensin-aldosterone system. Physiological imbalances are linked with genetic susceptibilities, and nonhomeostatic responses in gene regulation that occur by small RNAs, histone modification, and DNA methylation predispose susceptible humans to these HA illnesses. Elucidation of the interaction of these factors will lead to a more comprehensive understanding of HA adaptations and maladaptations and will lead to new therapeutics for HA disorders related to hypoxic lungs.
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