Bioenergetics of murine lungs infected with respiratory syncytial virus.

BACKGROUND: Cellular bioenergetics (cellular respiration and accompanying ATP synthesis) is a highly sensitive biomarker of tissue injury and may be altered following infection. The status of cellular mitochondrial O(2) consumption of the lung in pulmonary RSV infection is unknown. METHODS: In this study, lung fragments from RSV-infected BALB/c mice were evaluated for cellular O(2) consumption, ATP content and caspase activity. The disease was induced by intranasal inoculation with the RSV strain A2 and lung specimens were analyzed on days 2-15 after inoculation. A phosphorescence O(2) analyzer that measured dissolved O(2) concentration as a function of time was used to monitor respiration. The caspase-3 substrate analogue N-acetyl-asp-glu-val-asp-7-amino-4-methylcoumarin (Ac-DEVD-AMC) was used to monitor intracellular caspases. RESULTS: O(2) concentration declined linearly with time when measured in a sealed vial containing lung fragment and glucose as a respiratory substrate, revealing its zero-order kinetics. O(2) consumption was inhibited by cyanide, confirming the oxidation occurred in the respiratory chain. Cellular respiration increased by 1.6-fold (p<0.010) and ATP content increased by 3-fold in the first week of RSV infection. Both parameters returned to levels found in uninfected lungs in the second week of RSV infection. Intracellular caspase activity in infected lungs was similar to uninfected lungs throughout the course of disease. CONCLUSIONS: Lung tissue bioenergetics is transiently enhanced in RSV infection. This energy burst, triggered by the virus or virus-induced inflammation, is an early biomarker of the disease and may be targeted for therapy.

Biocompatibility of calcined mesoporous silica particles with cellular bioenergetics in murine tissues.

A novel in vitro system was developed to investigate the effects of two forms of calcined mesoporous silica particles (MCM41-cal and SBA15-cal) on cellular respiration of mouse tissues. O(2) consumption by lung, liver, kidney, spleen, and pancreatic tissues was unaffected by exposure to 200 µg/mL MCM41-cal or SBA15-cal for several hours. Normal tissue histology was confirmed by light microscopy. Intracellular accumulation of the particles in the studied tissues was evident by electron microscopy. The results show reasonable in vitro biocompatibility of the mesoporous silicas with murine tissue bioenergetics.

Serum 25-hydroxyvitamin D is not related to cardiac natriuretic peptide in nulliparous and lactating women.

BACKGROUND: Vitamin D deficiency is associated with heightened risk of cardiovascular disease. Potential mechanisms include involvement of vitamin D in regulation of renin-angiotensin system and manufacture and secretion of cardiac natriuretic peptides. Our aim was to document relationships between 25 hydroxyvitamin [25(OH)D] and N-terminal pro B-type natriuretic peptide (NT-proBNP) and plasma renin activity (PRA) levels and to document the effect of vitamin D administration on NT-proBNP and PRA levels in vitamin D deficient subjects. METHODS: Serum 25(OH)D, parathyroid hormone (PTH), plasma or serum NT-proBNP and PRA levels were measured at baseline in nulliparous and lactating women and after 2 months of oral vitamin D2 (2,000 IU/day or 60,000 IU/month) supplementation to lactating women. RESULTS: Baseline levels of 25(OH)D were low (<50 nmol/L) in most women whereas PRA and NT-proBNP levels were within the normal range. There were no significant correlations between baseline 25(OH)D or PTH with NT-proBNP and PRA. Vitamin D administration over a 2-month period in lactating women was associated with a decline in NT-proBNP (by 9.1 +/- 2.0 pmol/L; p < 0.001) and PRA (by 0.32 +/- 0.17 nmol/L/hr; p = 0.064). However, there were no significant correlations between the changes from baseline in 25(OH)D and either NT-proBNP (r = -0.04, p = 0.8) or PRA (r = -0.04, p = 0.8). CONCLUSION: We found no significant correlations between 25(OH)D or PTH with NT-proBNP and PRA in vitamin D deficient women. Further information is required to clarify the effects of vitamin D administration on cardiac structure and function.

Effect of combined maternal and infant vitamin D supplementation on vitamin D status of exclusively breastfed infants.

Severe vitamin D deficiency in mothers and their breastfed infants is a significant health problem in the Middle East. Supplementation of the breastfed infant alone with the recommended dose of vitamin D may be insufficient in high-risk population. We investigated the effect of combined maternal and infant vitamin D supplementation on vitamin D status of the breastfed infant. We examined also the effect of supplementation on vitamin D antirachitic activity of breast milk in a subset of mothers. Healthy breastfeeding mothers (n = 90) were randomly assigned to 2000 IU daily (group 1) or 60,000 IU monthly (group 2) of vitamin D(2), and all their infants (n = 92) received 400 IU daily of vitamin D(2) for 3 months. Most infants had vitamin D deficiency - 25-hydroxyvitamin D [25(OH)D]

Interrelationships between B-type natriuretic peptides and vitamin D in patients on maintenance peritoneal dialysis.

OBJECTIVE: Experimental evidence suggests that vitamin D deficiency impairs cardiac structure and function. Our objective was to observe relationships between circulating levels of the cardiac natriuretic peptides and vitamin D levels in patients on chronic peritoneal dialysis. METHOD: Measurements were made of circulating levels of 25-hydroxyvitamin D [25(OH)D] and plasma B-type natriuretic peptide (BNP) levels in patients receiving chronic peritoneal dialysis. RESULTS: Both BNP and the 1-76 amino-terminal fragment of pro-BNP correlated inversely with 25(OH)D levels (rs = -0.60, p = 0.007, and rs = -0.64, p = 0.003, respectively) in patients on peritoneal dialysis. CONCLUSIONS: Vitamin D deficiency in chronic renal failure may impair cardiac function, as manifested by elevated levels of B-type cardiac natriuretic peptides.

Cytokine Syntheses by T-Cell Subsets From Chronic Myeloid Leukemia Patients: Relationship Between Pre-Treatment Levels and Response to Imatinib Therapy.

BACKGROUND: Although T-cell cytokine's role in the long-term control of chronic myeloid leukemia (CML) is well established, previous studies showed contradicting results regarding imatinib (IM) effect on the endogenous T-cell function by IM. The purpose of this study was to determine the relation between the endogenous T-cell function prior to therapy and the degree of response to IM therapy in CP CML. In addition, modulation of the endogenous T-cell function during IM therapy was studied. METHODS: We evaluated Th1 (gamma interferon (IFN-γ)), Th2 (interleukin (IL-4)) and tumor necrosis factor (TNF)-α cytokine synthesis by activated T-cell subsets in 20 patients with newly diagnosed CML in chronic phase (CP CML) using flow cytometry before and during IM therapy compared to patients with IM resistance (IM Res) and healthy donors. RESULTS: Patients with optimal response (CML OR) to IM demonstrated a lower pre-treatment Th1 cytokine compared to that of healthy donors, and a higher percentage of Th2 and TNF-α producing T cells compared to that of healthy donors, non-optimal responders (CML nOR) and those with IM Res. A shift from Th2 profile to Th1 profile and initial decline of TNF-α producing T cells was detected early during therapy in optimal responders which was coinciding with complete hematological remission with a significant increase in the percentages of CD4+ve/IFN-γ+ve cells (P = 0.01) and a significant drop of in CD8+ve/IL-4+ve T cells (P = 0.04). CONCLUSION: We believe that pre-treatment levels of IL-4 and/or TNF-α may have a role in identifying CP CML patients who may respond to IM therapy; however, further investigation is needed.

Efficacy of daily and monthly high-dose calciferol in vitamin D-deficient nulliparous and lactating women.

BACKGROUND: We previously found a high prevalence of vitamin D deficiency and low medication regimen compliance in Arab and East Indian women residing in the United Arab Emirates (UAE). The appropriate dosing regimen for improving vitamin D status in this population is not known. OBJECTIVE: We aimed to determine the efficacy of daily and monthly supplementation with vitamin D2, the only high-dose calciferol available in the UAE, in lactating and nulliparous women. DESIGN: Healthy lactating (n = 90) and nulliparous (n = 88) women were randomly assigned to consume 2000 IU vitamin D2/d or 60,000 IU vitamin D2/mo for 3 mo. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured by radioimmunoassay at baseline and every month. RESULTS: Most women had vitamin D deficiency [ie, 25(OH)D < 50 nmol/L] at study entry. Mean +/- SD 25(OH)D concentrations at 3 mo were significantly higher than baseline in both lactating (39.8 +/- 12.4 and 25.2 +/- 10.7 nmol/L, respectively) and nulliparous (40.4 +/- 23.4 and 19.3 +/- 12.2 nmol/L, respectively) women (P < 0.001 for both). In total, vitamin D supplementation was effective in achieving serum 25(OH)D concentrations of >or=50 nmol/L in 21 (30%) of 71 women at endpoint. CONCLUSIONS: Oral vitamin D2 supplementation with 2000 IU/d or 60,000 IU/mo for 3 mo was safe, and it increased serum 25(OH)D concentrations significantly; however, only a small proportion of the women studied achieved concentrations of >or=50 nmol/L. This suggests that, when sunlight exposure is limited, doses of vitamin D2 higher than those currently studied may be needed. Monthly dosing appears to be a safe and effective alternative to daily dosing.

Predictors and relationships of serum 25 hydroxyvitamin D concentration with bone turnover markers, bone mineral density, and vitamin D receptor genotype in Emirati women.

OBJECTIVES: To determine factors influencing serum 25 hydroxyvitamin D (25OHD) concentration and relationships between serum 25OHD concentration, bone turnover markers, bone mineral density (BMD), and vitamin D receptor (VDR) genotype in Emirati women. METHODS: Serum 25OHD, parathyroid hormone (PTH), osteocalcin (OC), vitamin D binding protein (VDBP), and urinary deoxypyrdinoline (UDPD) concentrations and VDR genotype were determined in Emirati women volunteers who were participating in a study aiming at establishing a reference database for BMD. RESULTS: Serum 25OHD concentration in the 259 women volunteers was 25.3 +/- 10.8 nmol/l (mean +/- SD), and all had vitamin D deficiency (25OHD <80 nmol/l). Mean serum 25OHD was highest in April (29.2 +/- 13.0 nmol/l), which marks the end of the short and cooler winter season, and lowest in August (18.2 +/- 5.9 nmol/l). No significant difference in 25OHD concentration was noted among Emirati women wearing different dress styles, but the mean serum 25OHD was significantly lower in comparison with non-Arab Caucasian women volunteers who dressed in a Western style (P < 0.001). Serum 25OHD correlated positively with age (r = 0.2), number of pregnancies (r = 0.16), dietary vitamin D intake (r = 0.15), serum calcium (r = 0.14), phosphorus (r = 0.14), VDBP (r = 0.15), and urinary calcium/creatinine (r = 0.2), and inversely with PTH (r = -0.22), OC (r = -0.13), and UDPD/creatinine (r = -0.15); P < 0.05 for all correlations. Multiple linear regression analysis showed that age, dietary vitamin D intake, multivitamin intake, and cooler season were independent positive predictors of serum 25OHD concentration (R(2) = 0.18). The frequencies of VDR genotypes were 36% GG, 44.1% AG, and 19.9% AA. Allele frequencies were 58% for G allele and 42% for A allele and were in Hardy-Weinberg equilibrium (x(2) = 1.44; P > 0.1). There was no statistically significant influence of VDR genotype on bone turnover or BMD. CONCLUSIONS: Vitamin D deficiency is highly prevalent in Emirati women and appears largely attributable to insufficient sunlight exposure. It is associated with increased bone turnover. VDR genotype does not appear to influence bone turnover markers or BMD in Emirati women.

Alterations in atrial natriuretic peptide and its receptor levels in long-term, streptozotocin-induced, diabetes in rats.

Diabetes mellitus (DM) shows a markedly increased incidence of cardiovascular pathology that leads to hypertension, endothelial macro- and microangiopathy, diabetic nephropathy, and myocardial infarction. Atrial natriuretic peptide (ANP), is a 28 amino acid peptide hormone synthesized mainly by the heart atria and ventricles. It has potent diuretic and natriuretic properties. In this article the effect of long-term DM on blood plasma, kidney, and heart atrial and ventricular ANP concentrations were evaluated in streptozotocin (STZ)-induced 8-month diabetic and control rats by using radioimmunoassay (RIA). Moreover, ANP receptors in STZ-induced, 8-month diabetic rat kidneys were studied by receptor autoradiography. In addition, the expression of ANP concentrations in the kidney of diabetic and control rats was evaluated by means of immunohistochemistry. Body weight loss and increased blood glucose levels were used as indices of DM in the STZ-induced diabetic rats. Our results showed significantly higher ANP concentrations in diabetic plasma (P < 0.05), kidney (P < 0.01), heart atria (P < 0.05), and ventricles (P < 0.01) compared to controls. We also demonstrated a significant decrease in ANP receptors in the outer cortex (P < 0.05), juxtaglomerular medulla (P < 0.05), and papilla (P < 0.05) of 8-month diabetic rat kidneys compared to controls. The observed increase in ANP levels in plasma and kidney could play a role in the development of diabetic nephropathy: probably by reducing the levels of ANP receptors in diabetic kidney. Furthermore, the role of ANP in the STZ-induced diabetic heart merits additional study.

Serum interleukin-5 levels are elevated in mild and moderate persistent asthma irrespective of regular inhaled glucocorticoid therapy.

BACKGROUND: Interleukin-5 (IL-5) is thought to play a pivotal role in the pathogenesis of asthma. High levels of circulating IL-5 have been documented in acute asthma. However, serum IL-5 levels in mild to moderate asthmatics and the influence of regular use of inhaled glucocorticoids, is not known. METHODS: Fifty-six asthmatics and 56 age and sex matched controls were recruited prospectively from an outpatient department. Information on asthma severity and treatment was gathered by a questionnaire. Serum IL-5, total IgE and specific IgE levels were measured in a blinded fashion. RESULTS: There were 32 atopic and 24 non-atopic mild-to-moderate asthmatics. The median serum IL-5 levels in atopic asthmatics (9.5 pg/ml) and in non-atopic asthmatics (8.1 pg/ml) were significantly higher than in normal controls (4.4 pg/ml, both p < 0.003). However, median serum IL-5 levels in atopic and non-atopic asthmatics were not significantly different. The median serum IL-5 level was insignificantly higher in fourteen moderate persistent asthmatics (10.6 pg/ml) compared to forty-two mild persistent asthmatics (7.3 pg/ml) (p = 0.13). The median serum IL-5 levels in asthmatics using regular inhaled steroids (7.8 pg/ml) was not significantly different from those not using inhaled steroids (10.2 pg/ml). Furthermore, serum total IgE levels and eosinophil counts were not significantly different in those using versus those not using inhaled glucocorticoids. CONCLUSION: Serum IL-5 levels are elevated in mild and moderate persistent atopic and non-atopic asthmatics. Regular use of inhaled glucocorticoids may not abrogate the systemic Th2 type of inflammatory response in mild-moderate persistent asthma.

Respiratory syncytial virus increases lung cellular bioenergetics in neonatal C57BL/6 mice.

We have previously reported that lung cellular bioenergetics (cellular respiration and ATP) increased in 4-10 week-old BALB/c mice infected with respiratory syncytial virus (RSV). This study examined the kinetics and changes in cellular bioenergetics in ≤ 2-week-old C57BL/6 mice following RSV infection. Mice (5-14 days old) were inoculated intranasally with RSV and the lungs were examined on days 1-10 post-infection. Histopathology and electron microscopy revealed preserved pneumocyte architectures and organelles. Increased lung cellular bioenergetics was noted from days 1-10 post-infection. Cellular GSH remained unchanged. These results indicate that the increased lung cellular respiration (measured by mitochondrial O2 consumption) and ATP following RSV infection is independent of either age or genetic background of the host.

Cellular bioenergetics, caspase activity and glutathione in murine lungs infected with influenza A virus.

Inhibition of cellular respiration, oxidation of glutathione and induction of apoptosis have been reported in epithelial cells infected in vitro with influenza A virus (IAV). Here, the same biomarkers were investigated in vivo by assessing the lungs of BALB/c mice infected with IAV. Cellular respiration declined on day 3 and recovered on day 7 post-infection. For days 3-5, the rate (mean±SD) of respiration (µMO2min(-1)mg(-1)) in uninfected lungs was 0.103±0.021 (n=4) and in infected lungs was 0.076±0.025 (n=4, p=0.026). Relative cellular ATP (infected/uninfected) was 4.7 on day 2 and 1.07 on day 7. Intracellular caspase activity peaked on day 7. Cellular glutathione decreased by ≥10% on days 3-7. Lung pathology was prominent on day 3 and caspase-3 labeling was prominent on day 5. IAV infection was associated with suppression of cellular respiration, diminished glutathione, and induction of apoptosis. These functional biomarkers were associated with structural changes noted in infected mice.

ANP and BNP responses to dehydration in the one-humped camel and effects of blocking the renin-angiotensin system.

The objectives of this study were to investigate and compare the responses of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the circulation of hydrated, dehydrated, and dehydrated losartan - treated camels; and to document the cardiac storage form of B-type natriuretic peptide in the camel heart. Eighteen male camels were used in the study: control or hydrated camels (n = 6), dehydrated camels (n = 6) and dehydrated losartan-treated camels (n = 6) which were dehydrated and received the angiotensin II (Ang II) AT-1 receptor blocker, losartan, at a dose of 5 mg/kg body weight intravenously for 20 days. Control animals were supplied with feed and water ad-libitum while both dehydrated and dehydrated-losartan treated groups were supplied with feed ad-libitum but no water for 20 days. Compared with time-matched controls, dehydrated camels exhibited a significant decrease in plasma levels of both ANP and BNP. Losartan-treated camels also exhibited a significant decline in ANP and BNP levels across 20 days of dehydration but the changes were not different from those seen with dehydration alone. Size exclusion high performance liquid chromatography of extracts of camel heart indicated that proB-type natriuretic peptide is the storage form of the peptide. We conclude first, that dehydration in the camel induces vigorous decrements in circulating levels of ANP and BNP; second, blockade of the renin-angiotensin system has little or no modulatory effect on the ANP and BNP responses to dehydration; third, proB-type natriuretic peptide is the storage form of this hormone in the heart of the one-humped camel.

Responses to dehydration in the one-humped camel and effects of blocking the renin-angiotensin system.

Our objectives were to compare the levels of circulating electrolytes, hormones, and renal function during 20 days of dehydration in camels versus the level in non-dehydrated camels and to record the effect of blocking angiotensin II AT1 receptors with losartan during dehydration. Dehydration induced significant increments in serum sodium, creatinine, urea, a substantial fall in body weight, and a doubling in plasma arginine vasopressin (AVP) levels. Plasma aldosterone, however, was unaltered compared with time-matched controls. Losartan significantly enhanced the effect of dehydration to reduce body weight and increase serum levels of creatinine and urea, whilst also impairing the rise in plasma AVP and reducing aldosterone levels. We conclude that dehydration in the camel induces substantial increments in serum sodium, creatinine, urea and AVP levels; that aldosterone levels are altered little by dehydration; that blockade of angiotensin II type 1 receptors enhances the dehydration-induced fall in body weight and increase in serum creatinine and urea levels whilst reducing aldosterone and attenuating the rise in plasma AVP.

In vitro biocompatibility of calcined mesoporous silica particles and fetal blood cells.

BACKGROUND: The biocompatibility of two forms of calcined mesoporous silica particles, labeled as MCM41-cal and SBA15-cal, with fetal blood mononuclear cells was assessed in vitro. METHODS AND RESULTS: Fetal mononuclear cells were isolated from umbilical cord blood and exposed to 0.5 mg/mL of MCM41-cal or SBA15-cal for several hours. Transmission electron micrographs confirmed the presence of particles in the cytosol of macrophages, neutrophils, and lymphocytes without noticeable damage to the cellular organelles. The particles (especially MCM41-cal) were in close proximity to plasma, and nuclear and mitochondrial membranes. Biocompatibility was assessed by a functional assay that measured cellular respiration, ie, mitochondrial O(2) consumption. The rate of respiration (k(c), in µM O(2) per minute per 10(7) cells) for untreated cells was 0.42 ± 0.16 (n = 10), for cells treated with MCM41-cal was 0.39 ± 0.22 (n = 5, P > 0.966) and for cells treated with SBA15-cal was 0.44 ± 0.13 (n = 5, P > 0.981). CONCLUSION: The results show reasonable biocompatibility of MCM41-cal and SBA15-cal in fetal blood mononuclear cells. Future studies are needed to determine the potential of collecting fetal cells from a fetus or neonate, loading the cells in vitro with therapeutic MCM41-cal or SBA15-cal, and reinfusing them into the fetus or neonate.

Acetylsalicylic acid-induced oxidative stress, cell cycle arrest, apoptosis and mitochondrial dysfunction in human hepatoma HepG2 cells.

It is widely accepted that non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, reduce the risk of cancer. The anti-cancer and anti-inflammatory effects of NSAIDs are associated with the inhibition of prostaglandin synthesis and cyclooxygenase-2 activity. Several other mechanisms which contribute to the anti-cancer effect of these drugs in different cancer models both in vivo and in vitro are also presumed to be involved. The precise molecular mechanism, however, is still not clear. We investigated, therefore, the effects of acetylsalicylic acid (ASA, aspirin) on multiple cellular and functional targets, including mitochondrial bioenergetics, using human hepatoma HepG2 cancer cells in culture. Our results demonstrate that ASA induced G0/G1 cell cycle arrest and apoptosis in HepG2 cells. ASA increased the production of reactive oxygen species, reduced the cellular glutathione (GSH) pool and inhibited the activities of the mitochondrial respiratory enzyme complexes, NADH-ubiquinone oxidoreductase (complex I), cytochrome c oxidase (complex IV) and the mitochondrial matrix enzyme, aconitase. Apoptosis was triggered by alteration in mitochondrial permeability transition, inhibition of ATP synthesis, decreased expression of the anti-apoptotic protein Bcl-2, release of cytochrome c and activation of pro-apoptotic caspase-3 and the DNA repairing enzyme, poly (-ADP-ribose) polymerase (PARP). These findings strongly suggest that ASA-induced toxicity in human hepatoma HepG2 cells is mediated by increased metabolic and oxidative stress, accompanied by mitochondrial dysfunction which result in apoptosis.

Measurement of oxygen consumption by murine tissues in vitro.

INTRODUCTION: A novel in vitro system was developed to measure O2 consumption by murine tissues over several hours. METHODS: Tissue specimens (7-35 mg) excised from male Balb/c mice were immediately immersed in ice-cold Krebs-Henseleit buffer, saturated with 95% O2:5% CO2. The specimens were incubated at 37 °C in the buffer, continuously gassed with O2:CO2 (95:5). [O2] was determined as a function of time from the phosphorescence decay rates (1/τ) of Pd(II) meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. The values of 1/τ were linear with [O2]: 1/τ=1/τo + kq [O2]; 1/τo=the decay rate for zero O2, kq=the rate constant in s⁻¹ µM⁻¹. RESULTS: NaCN inhibited O2 consumption, confirming oxidation occurred in the mitochondrial respiratory chain. The rate of respiration in lung specimens incubated in vitro for 3.9≤t≤12.4 h was 0.24±0.03 µM O2 min⁻¹ mg⁻¹ (mean±SD, n=28). The corresponding rate for the liver was 0.27±0.13 (n=11, t≤4.7 h), spleen 0.28± 0.07 (n=10, t≤5h), kidney 0.34±0.12 (n=7, t≤5h) and pancreas 0.35±0.09 (n=10, t≤4h). Normal tissue histology at hour 5 was confirmed by light and electron microscopy. There was negligible number of apoptotic cells by caspase 3 staining. DISCUSSION: This approach allows accurate assessment of tissue bioenergetics in vitro.

Alterations in mitochondrial respiratory functions, redox metabolism and apoptosis by oxidant 4-hydroxynonenal and antioxidants curcumin and melatonin in PC12 cells.

Cellular oxidative stress and alterations in redox metabolisms have been implicated in the etiology and pathology of many diseases including cancer. Antioxidant treatments have been proven beneficial in controlling these diseases. We have recently shown that 4-hydroxynonenal (4-HNE), a by-product of lipid peroxidation, induces oxidative stress in PC12 cells by compromising the mitochondrial redox metabolism. In this study, we have further investigated the deleterious effects of 4-HNE on mitochondrial respiratory functions and apoptosis using the same cell line. In addition, we have also compared the effects of two antioxidants, curcumin and melatonin, used as chemopreventive agents, on mitochondrial redox metabolism and respiratory functions in these cells. 4-HNE treatment has been shown to cause a reduction in glutathione (GSH) pool, an increase in reactive oxygen species (ROS), protein carbonylation and apoptosis. A marked inhibition in the activities of the mitochondrial respiratory enzymes, cytochrome c oxidase and aconitase was observed after 4-HNE treatment. Increased nuclear translocation of NF-kB/p65 protein was also observed after 4-HNE treatment. Curcumin and melatonin treatments, on the other hand, maintained the mitochondrial redox and respiratory functions without a marked effect on ROS production and cell viability. These results suggest that 4-HNE-induced cytotoxicity may be associated, at least in part, with the altered mitochondrial redox and respiratory functions. The alterations in mitochondrial energy metabolism and redox functions may therefore be critical in determining the difference between cell death and survival.

Association of TCF7L2 polymorphism with diabetes mellitus, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects.

AIMS: The prevalence of type 2 diabetes mellitus (DM) among Emirati subjects is one of the highest in the world. This has been attributed to rising prevalence of obesity acting on genetically susceptible individuals. We analyzed the associations between TCF7L2 polymorphism and DM, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects. METHODS: We genotyped the two TCF7L2 single nucleotide polymorphisms (SNPs) rs12255372 and rs7903146 in 368 adult subjects. Homeostatic model assessment (HOMA) was used to assess beta cell function (HOMA2-%B) and insulin resistance (HOMA2-IR). The SNP genotypes were analyzed against disease stage [normal glucose=0 (n=188), pre-diabetes=1 (n=85), and DM=2 (n=95)] and against clinical and biochemical measures. Age and sex were included as covariates in all association analyses. Additional adjustments were made for body mass index (BMI) and waist circumference in several analyses. RESULTS: Diabetes disease stage was marginally significantly associated with the frequency of the T variant at rs12255372 (p=0.057; adjusted p=0.017) but not at rs7903146 (p=0.5; adjusted p=0.2). Comparison between subjects with normal glucose and the combined DM/pre-diabetes showed a significant association with rs12255372 (OR 1.47, CI 1.04-2.08; p=0.03) but not with rs7903146 (OR 1.16, CI 0.81-1.64; p=0.4). We found no association with metabolic syndrome, or with insulin and glucose levels, HOMA2-%B or HOMA2-IR. The age-standardized prevalence rate for metabolic syndrome was 43.9% in men and 42.1% in women. CONCLUSION: These data suggest that TCF7L2 variants are associated with increased risk for DM in Emirati subjects. We also demonstrate a high prevalence of the metabolic syndrome in this population.

Prevalence of diabetes mellitus and its complications in a population-based sample in Al Ain, United Arab Emirates.

AIMS: To determine the prevalence of diabetes mellitus (DM) and its complications in the adult population of the United Arab Emirates (UAE) and assess the degree of metabolic control in subjects with diagnosed DM. METHODS: A random sample of houses of Emirati citizens living in Al Ain, UAE was surveyed. Fasting blood glucose was determined by glucose meter and an oral glucose tolerance test (OGTT) was conducted if blood sugar was <7 mmol/l. DM was defined according to the WHO criteria. Pre-diabetes status was based on fasting venous blood glucose concentration of 5.6-6.9 mmol/l or 2h post-OGTT venous blood glucose level of 7.8-11.0 mmol/l. RESULTS: There were 2455 adults (>18) living in the 452 surveyed houses of which 10.2% reported having the diagnosis of DM. A total of 373 men and non-pregnant women underwent testing, and after adjustment for factors affecting participation probability the prevalence of diagnosed DM, undiagnosed DM and pre-diabetes was 10.5, 6.6 and 20.2%, respectively. Age-standardized rates for DM (diagnosed and undiagnosed) and pre-diabetes among 30-64 years old were 29.0 and 24.2%, respectively. Logistic regression analysis showed that only age and body mass index (BMI) were significantly independently related to undiagnosed DM. In patients with diagnosed DM, the prevalence rates for retinopathy, neuropathy, nephropathy, peripheral vascular disease and coronary heart disease were 54.2, 34.7, 40.8, 11.1 and 10.5%, respectively. A significant proportion of subjects with undiagnosed DM and pre-diabetes also had micro- and macro-vascular complications. The proportion of subjects with diagnosed DM who achieved internationally recognized targets for HbA1c (<7%), LDL-C (<2.6 mmol/l) and blood pressure (<130/80 mmHg) was 33.3, 30.8 and 42.1%, respectively. CONCLUSION: This study confirms the previously reported high prevalence of DM in the UAE. Diabetic complications were highly prevalent among subjects with diagnosed and undiagnosed DM. Metabolic control was suboptimal in most subjects with diagnosed DM. Greater efforts are urgently needed to screen early and effectively treat DM in the UAE in order to prevent long-term complications.