Circulating ceramide levels and ratios in Emirati youth under 18 years: associations with cardiometabolic risk factors.

BACKGROUND: Circulating ceramide (Cer) drives various pathological processes associated with cardiovascular diseases, liver illness, and diabetes mellitus. Although recognized as predictors of cardiometabolic diseases (CMD) in research and clinical settings, their potential for predicting CMD risk in individuals under 18 remains unexplored. OBJECTIVES: This study was designed to utilize Liquid Chromatography-Mass Spectrometry (LC-MS/MS) methodology to determine the biological reference ranges for Cer in plasma samples of Emirati children and develop a risk assessment score (CERT-1) based on Cer concentrations. METHODS: Using LC-MS/MS, we developed a method to measure five Cer species in plasma samples of 582 Emirati participants aged 5-17. We used the circulating concentrations of these Cer to determine their reference intervals in this population. We employed traditional statistical analyses to develop a risk score (CERT-1) and assess the association between Cer levels and conventional biomarkers of CMD. RESULTS: We validated a high-throughput methodology using LC-MS/MS to quantify five Cer species in human plasma. Reference values for this population (n = 582) were quantified: CerC16:0 (0.12-0.29 µmol/L), CerC18:0 (0.019-0.067 µmol/L), CerC22:0 (0.102-0.525 µmol/L), CerC24:0 (0.65-1.54 µmol/L) and CerC24:1 (0.212-0.945 µmol/L). We devised a risk assessment score (CERT-1) based on plasma Cer content in the study participants, showing that 72.5% have low to moderate risk and 9.3% are at a higher risk of developing CMD. Our analyses also revealed a significant correlation (P < 0.05) between this score and the conventional risk factors linked to CMD, indicating its potential clinical implication. CONCLUSION: This study presents a clinical-scaled LC-MS/MS methodology for assessing clinically relevant Cer, setting reference ranges, and developing a risk score (CERT-1) for young Emirati individuals. Our findings can enhance primary risk prediction and inform the management and follow-up of CMD from an early age.

Galectin-3 and Autophagy in Renal Acute Tubular Necrosis.

Acute kidney injury (AKI) is a public health burden with increasing morbidity and mortality rates and health care costs. Acute tubular necrosis (ATN) is the most common cause of AKI. Cisplatin (CIS) is a platinum-based chemotherapeutic agent used in the treatment of a wide variety of malignancies such as lung, breast, ovary, testis, bladder, cervix, and head and neck cancers. Autophagy plays an important role in AKI. Galectin-3 (Gal-3) is significantly increased in renal tubules in AKI; however, its role in autophagy is not well understood. Male C57B6/J and B6.Cg-Lgals3 /J Gal-3 knockout (KO) mice were used to induce AKI using a CIS mouse model of ATN. Renal Gal-3 and autophagy proteins' expression were measured using standard histologic, immunofluorescent, and enzyme-linked immunosorbent assay techniques. The data were presented as the mean ± S.E. Statistically significant differences (p < 0.05) were calculated between experimental groups and corresponding control groups by one-way analysis of variance. There was a significant increase in renal concentrations of Gal-3 in the Gal-3 wild-type CIS-treated mice when compared with sham control mice. There were significantly higher concentrations of renal LC3B, ATG13, Ulk-1, Beclin, ATG5, ATG12, ATG9A, and p-AMPK in the CIS-treated Gal-3 KO mice than in the Gal-3 wild-type CIS-treated mice. Further, there were significantly higher concentrations of mTOR, p- NF-κB, beta-catenin, and p62 in the kidneys of the Gal-3 wild-type CIS-treated mice than in the Gal-3 KO CIS-treated mice. Our findings affirm the connection between Gal-3 and autophagy, revealing its central role as a connector with prosurvival signaling proteins. Gal-3 plays a pivotal role in orchestrating cellular responses by interacting with prosurvival signal pathways and engaging with autophagy proteins. Notably, our observations highlight that the absence of Gal-3 can enhance autophagy in CIS-induced ATN.

Does Hypertension Affect the Recovery of Renal Functions after Reversal of Unilateral Ureteric Obstruction?

Research has demonstrated that hypertension can lead to an exaggeration in the renal functional and histological changes caused by ureteral obstruction. These changes were particularly observed shortly after the release of a relatively brief period of unilateral ureteral obstruction (UUO). However, the long-term impact of hypertension on the recovery of renal functions has not been investigated beyond the immediate period after UUO reversal. In order to investigate this effect, a group of spontaneously hypertensive rats (G-SHR, n = 11) and a group of normotensive Wistar Kyoto rats (G-NTR, n = 11) were subjected to a 48 h reversible left UUO. The impact of UUO was then examined 45 days after the reversal of obstruction. The glomerular filtration rate, renal blood flow, and the fractional excretion of sodium in the post-obstructed left kidney (POK) showed similarities to the non-obstructed right kidney (NOK) in both groups. However, the changes in the albumin creatinine ratio, renal injury markers, pro-apoptotic markers, and histological changes in the G-SHR were much more pronounced compared to the G-NTR. We conclude that hypertension continues to have a significant impact on various aspects of renal injury and function, even several weeks after UUO reversal.

The Effect of Hypertension on the Recovery of Renal Dysfunction following Reversal of Unilateral Ureteral Obstruction in the Rat.

Both ureteral obstruction (UO) and hypertension are common conditions that affect kidney functions. Hypertension and chronic kidney disease are closely associated with an overlapping and intermingled cause-and-effect relationship. The effect of hypertension on the renal dysfunction following reversible UO has not been studied previously. To study this effect, spontaneously hypertensive (G-HT, n = 10) and normotensive Wistar (G-NT, n = 10) rats underwent 48-h reversible left unilateral UO (UUO), and the effect of UUO was studied 96 h following UUO reversal. The glomerular filtration rate, renal blood flow, and renal tubular functions such as the fractional excretion of sodium in the post-obstructed left kidney (POK) in both groups were significantly altered compared with the non-obstructed right kidney (NOK). However, the alterations in the G-HT were significantly more exaggerated when compared with the G-NT. Similar findings were observed with the histological features, gene expression of kidney injury markers, pro-inflammatory, pro-fibrotic and pro-apoptotic cytokines, and pro-collagen, as well as tissue levels of apoptotic markers. We conclude that hypertension has significantly exaggerated the alterations in renal functions and other parameters of renal injury associated with UUO.

Vitamin D deficiency associations with metabolic, bone turnover and adverse general health markers in community free living adults.

BACKGROUND: Although there is some evidence that vitamin D deficiency is highly prevalent in the Middle East, however its health impact is still not clear. The aim of this study was to assess the prevalence, causes and health implications of vitamin D deficiency in local United Arab Emirates (UAE) citizens. METHODS: A cross-sectional study was conducted on community free living adults living in the city of Al Ain, UAE. Following informed written consent eligible subject's blood and urine samples were taken for measurements of vitamin D [25(OH)D], metabolic and bone turnover markers. Clinical assessment that includes general and self-rated health, muscle health, and physical activity were also performed. RESULTS: A total of 648 subjects (491 female) were included in this analysis. Their mean (SD) age was 38 (12) years. Mean 25(OH)D was 24 ng/ml (range: 4-67) with 286 (44%) subjects found to have vitamin D deficiency (< 20 ng/ml), 234 (36%) subjects have insufficiency (20-32 ng/ml) and 128 (20%) subjects have optimal concentrations (> 32 ng/ml). 25(OH)D concentrations were significantly higher in local indigenous UAE subjects compared to other Arab expatriates (p = 0.071). Although there were no statistically significant differences in clinical markers between groups, however, utra-sensitive C-reactive protein (us-CRP), parathyroid hormone (PTH), body mass index (BMI) and the bone markers U-PYD and PYD/CR were higher in vitamin D deficient older subjects aged ≥50 years and female subjects younger than 50 years respectively compared to those with insufficiency or optimal concentrations (p value < 0.05. Multiple logistic regression analysis revealed significant and independent association between 25(OH)D status and age and sex (p < 0.05). CONCLUSION: Older subjects with vitamin D deficiency have increased BMI, inflammation and PTH compared with those with insufficiency or optimal concentrations. Co-existence of obesity and vitamin D deficiency may have increased adverse health effects.

A randomized, double-blind, placebo-controlled trial of vitamin D supplementation with or without calcium in community-dwelling vitamin D deficient subjects.

BACKGROUND: Although vitamin D deficiency is highly prevalent in the Middle East, very few studies have attempted to measure its health impact. AIMS: We aimed to assess whether vitamin D3 and calcium, either alone or in combination, have health benefit. METHODS: In a 2 × 2 factorial design double-blind, placebo-controlled trial, Community free living adults living in the city of Al Ain, UAE were randomly assigned to receive daily 2000 IU oral vitamin D3 alone, 600 mg calcium alone, oral vitamin D3 (2000 IU per day) combined with 600 mg calcium, or a placebo for 6 months. Primary outcomes were self-rated health and bone turnover markers. RESULTS: Of the 545 randomized, 277 subjects completed 6 months follow up. 25(OH)D levels marginally increased in the two groups received vitamin D3 alone or combined with calcium compared to the decline seen in those who received calcium supplement alone or a placebo. Sub-group analysis revealed that parathyroid hormone (PTH) concentration decreased and Calcium/creatinine ratio increased significantly in the combined vitamin D and Calcium group compared to the vitamin D alone or Calcium alone in contrast to the increase seen in the placebo group [p < 0.05 for between group difference at 6 months]. There were no statistically significant differences between the supplement and placebo groups at the 6 months follow-up in body weight, body mass index (BMI), blood pressure, body pains and general health. CONCLUSION: PTH concentration decreased and calcium/creatinine ratio increased in subjects who received vitamin D and Calcium together compared to those who received vitamin D alone. TRIAL REGISTRATION: NCT02662491 , First registered on 25 January 2016 ( https://register. CLINICALTRIALS: gov/prs/app/action/SelectProtocol?sid=S00060CE&selectaction=Edit&uid=U0001M6P&ts=3&cx=scu4cb , Last update: 05 August 2019.

Early Doxorubicin Myocardial Injury: Inflammatory, Oxidative Stress, and Apoptotic Role of Galectin-3.

Doxorubicin (DOXO) is an effective drug that is used in the treatment of a large number of cancers. Regardless of its important chemotherapeutic characteristics, its usage is restricted because of its serious side effects; the most obvious is cardiotoxicity, which can manifest acutely or years after completion of treatment, leading to left ventricular dysfunction, dilated cardiomyopathy, and heart failure. Galectin 3 (Gal-3) is a beta galactoside binding lectin that has different roles in normal and pathophysiological conditions. Gal-3 was found to be upregulated in animal models, correlating with heart failure, atherosclerosis, and myocardial infarction. Male C57B6/J and B6.Cg-Lgals3 /J Gal-3 knockout (KO) mice were used for a mouse model of acute DOXO-induced cardiotoxicity. Mice were given DOXO or vehicle (normal saline), after which the mice again had free access to food and water. Heart and plasma samples were collected 5 days after DOXO administration and were used for tissue processing, staining, electron microscopy, and enzyme-linked immunosorbent assay (ELISA). There was a significant increase in the heart concentration of Gal-3 in Gal-3 wild type DOXO-treated mice when compared with the sham control. There were significantly higher concentrations of heart cleaved caspase-3, plasma troponin I, plasma lactate dehydrogenase, and plasma creatine kinase in Gal-3 KO DOXO-treated mice than in Gal-3 wild type DOXO-treated mice. Moreover, there were significantly higher heart antioxidant proteins and lower oxidative stress in Gal-3 wild type DOXO-treated mice than in Gal-3 KO DOXO-treated mice. In conclusion, Gal-3 can affect the redox pathways and regulate cell survival and death of the myocardium following acute DOXO injury.

Galectin-3 Possesses Anti-Necroptotic and Anti-Apoptotic Effects in Cisplatin-Induced Acute Tubular Necrosis.

BACKGROUND/AIMS: Acute kidney injury (AKI) is a public health burden with increasing morbidity, mortality and health care cost. It is associated with increased risk for the development of chronic kidney disease and death. Acute tubular necrosis (ATN) is the most common cause of AKI. Apoptosis and tissue necrosis play an important role in ATN. Galectin 3 (GAL-3), a beta galactoside binding lectin, is known to have a role in inflammation, apoptosis and oxidative stress but its role in cisplatin induced acute tubular necrosis is not clearly elucidated. METHODS: Male C57B6-J and C57BL-6 -GAL-3 knock-out mice were used to induce ATN using cisplatin mouse model of acute tubular necrosis. GAL-3 expression, apoptotic, necrotic and necroptotic proteins in kidneys were measured using standard histologic, immunohistochemical, and enzyme-linked immunosorbent assay techniques. Data were presented as mean ± S.E. Statistically significant differences (p<0.05) was calculated between experimental groups and corresponding control groups by one-way analysis of variance. RESULTS: There was a significant increase in GAL-3 in kidneys of cisplatin treated GAL-3 wild mice when compared with its control mice. In addition, there were significant higher percentage of ATN, higher levels of plasma urea and creatinine, and higher levels of cathepsin B and cathepsin D, in kidneys of cisplatin-treated GAL-3 KO mice than cisplatin-treated GAL-3 wild mice. Likewise, there were significant higher levels of necroptosis proteins RIPK1, RIPK3, and MLKL in kidneys of cisplatin-treated GAL-3 KO mice than cisplatin-treated GAL-3 wild mice. Moreover, there were significant higher levels of kidney pro-apoptotic proteins; cleaved caspase-3, cleaved PARP, TRAIL and FAS in cisplatin treated GAL-3 KO mice when compared with cisplatin treated GAL-3 wild mice. CONCLUSION: GAL-3 can affect cell survival and death through its interaction with necroptotic, apoptotic and pro-survival proteins in renal tubules during cisplatin-induced acute tubular necrosis.

Exacerbation of Coagulation and Cardiac Injury in Rats with Cisplatin-Induced Nephrotoxicity Following Intratracheal Instillation of Cerium Oxide Nanoparticles.

BACKGROUND/AIMS: Exposure to particulate air pollution is associated with increased cardiovascular morbidity and mortality. These effects are particularly aggravated in patients with pre-existing kidney diseases. Cerium oxide nanoparticles (CNPs), used as diesel fuel additives, are emitted in vehicle exhaust and affect humans when inhaled. However, thrombotic and cardiac injury resulting from pulmonary exposure to CNPs in experimental acute kidney injury (AKI) is not fully understood. The objective of the present study was to evaluate the thrombotic and cardiac injury effects of CNPs in a rat model of AKI. METHODS: AKI was induced in rats by a single intraperitoneal injection of cisplatin (CDDP, 6 mg/kg). Six days after injection, rats were intratracheally (i.t.) instilled with either CNPs (1 mg/kg) or saline (control), and various cardiovascular variables and markers of inflammation, oxidative stress and DNA injury were assessed by enzyme linked immunosorbent assay, colorimetric assay, single-cell gel electrophoresis assay and immunohistochemistry, the following day. RESULTS: Compared with individual CDDP or CNPs treatments, the combined CDDP + CNPs treatment elevated significantly the coagulation function, relative heart weight, and troponin I, lactate dehydrogenase, interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and total nitric oxide levels in the plasma. In heart homogenates, the combination of CDDP and CNPs induced a significant increase in IL-6, TNFα, catalase, and glutathione. Furthermore, significantly more DNA damage was observed in this group than in the CDDP or CNPs groups. Immunohistochemical analysis of the heart revealed that expression of nuclear factor erythroid-derived 2-like 2 (Nrf2) and glutathione peroxidase by cardiac myocytes and endothelial cells was increased in the CDDP + CNPs group more than in either CDDP or CNPs group. CONCLUSION: I.t. administration of CNPs in rats with AKI exacerbated systemic inflammation, oxidative stress, and coagulation events. It also aggravated cardiac inflammation, DNA damage, and Nrf2 expression.

Risk factor comparison in young patients presenting with acute coronary syndrome with atherosclerotic coronary artery disease vs. angiographically normal coronaries.

Background: Acute myocardial infarction is a relatively rare phenomenon in the young population. The incidence has nevertheless increased from years past, likely due to the presence of multiple risk factors from an increasingly younger age. Regardless of whether they have atherosclerotic coronary artery disease or normal coronary angiogram, young patients with risk factors for coronary artery disease (CAD), chest pain, and positive troponin, are initially treated in a similar fashion. Our goal was to shed light on whether risk factors between these two groups differ to help guide physicians in clinically determining whether or not an atherosclerotic cardiovascular event has occurred, as well as to potentially identify young patients at risk of acute coronary syndrome (ACS) despite normal coronary arteries. Methods: A retrospective cross sectional study was undertaken over an 8 year period at Tawam Hospital. 576 patients aged 50 or under who underwent coronary angiography were selected for the study. Medical records were analyzed for the patient's demographics and CAD risk factor profile, including the following variables: family history of CAD, smoking status, Body Mass Index category, lipid profile, and diagnosis of hyperlipidemia, diabetes, or hypertension. Details of the coronary angiogram were also reviewed. Results: Statistically significant outcomes included a higher prevalence of diabetes, hyperlipidemia, and smoking history in patients with CAD compared to the patients with normal coronary angiogram. Diabetes was one of the strongest risk factors in CAD patients, with an odds ratio of 1.98 (p= 0.011), followed by hyperlipidemia at 1.85 (p= 0.021). Smoking history had an odds ratio of 2.93 (p <0.001). Conclusion: Risk factors were present in both groups, but significantly more in the CAD group. No particular risk factor stood out for the development of ACS in those with normal coronary arteries, other than mean BMI being slightly higher in this group. Based on our analysis, no single variable can accurately predict the risk for ACS in normal coronaries. To our knowledge, few studies have been done in the young population with angiographically normal coronary arteries to determine possible risk factors for development of ACS. Further research needs to be done to determine whether the risk factors that were common amongst both groups are coincidental, or a cause of ACS in those with normal coronary arteries.

Impact of Sodium Dichloroacetate Alone and in Combination Therapies on Lung Tumor Growth and Metastasis.

Metabolic reprogramming has been recognized as an essential emerging cancer hallmark. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been reported to have anti-cancer effects by reversing tumor-associated glycolysis. This study was performed to explore the anti-cancer potential of DCA in lung cancer alone and in combination with chemo- and targeted therapies using two non-small cell lung cancer (NSCLC) cell lines, namely, A549 and LNM35. DCA markedly caused a concentration- and time-dependent decrease in the viability and colony growth of A549 and LNM35 cells in vitro. DCA also reduced the growth of tumor xenografts in both a chick embryo chorioallantoic membrane and nude mice models in vivo. Furthermore, DCA decreased the angiogenic capacity of human umbilical vein endothelial cells in vitro. On the other hand, DCA did not inhibit the in vitro cellular migration and invasion and the in vivo incidence and growth of axillary lymph nodes metastases in nude mice. Treatment with DCA did not show any toxicity in chick embryos and nude mice. Finally, we demonstrated that DCA significantly enhanced the anti-cancer effect of cisplatin in LNM35. In addition, the combination of DCA with gefitinib or erlotinib leads to additive effects on the inhibition of LNM35 colony growth after seven days of treatment and to synergistic effects on the inhibition of A549 colony growth after 14 days of treatment. Collectively, this study demonstrates that DCA is a safe and promising therapeutic agent for lung cancer.

Effect of angiotensin II on diabetic glomerular hyperpermeability: an in vivo permeability study in rats.

Angiotensin II drives the pathogenesis of diabetic kidney disease, and its systemic administration induces glomerular hyperpermeability in normal rats. However, the response of diabetic glomerular permeability to angiotensin II is largely unknown. In the present study, we investigated the impact of extended systemic administration of angiotensin II on the glomerular permeability of streptozotocin (STZ)-induced late diabetes in rats. We examined the changes in the glomerular permeability after subcutaneous infusion of angiotensin II at 200 ng·kg-1·min-1 for 7 days in male Wistar diabetic rats with 3 mo of STZ-induced diabetes (i.e., blood glucose of ∼20 mmol/L). We also compared these changes with the effects on nondiabetic rats. The sieving coefficients (θ) for inert polydisperse Ficoll molecules, which had a radius of 10-90 Å (Ficoll70-90 Å), were measured in vivo. The θ for large Ficoll molecules was selectively enhanced after infusion of extended angiotensin II in both diabetic (θ for Ficoll70-90 Å = 0.00244 vs. 0.00079, P < 0.001) and nondiabetic animals (θ for Ficoll70-90 Å = 0.00029 vs. 0.00006, P < 0.001). These changes were compatible with the more than twofold increase in the macromolecular glomerular transport through the large-pore pathways after infusion of angiotensin II in both diabetic and nondiabetic animals. Angiotensin II infusion enhanced the large shunt-like glomerular transport pathway of STZ-induced late diabetes. Such defects can account for the large-molecular-weight IgM-uria that is observed in severe diabetic kidney disease.

Despite initial recovery of GFR, long-term renal functions deteriorate following short periods of unilateral ureteral obstruction.

Following the release of short periods of unilateral ureteral obstruction (UUO), glomerular filtration rate (GFR) recovers by time. However, research in experimental animal models has demonstrated the presence of an ongoing element of renal interstitial fibrosis a few weeks following UUO reversal. Interstitial fibrosis can cause deterioration in GFR, and it is not known whether it leads to an ongoing slow deterioration in other renal functions despite the apparent initial recovery postreversal. To investigate this, rats underwent a 72-h reversible UUO. Renal functions of nonobstructed and previously obstructed kidneys were measured 1, 4, and 18 mo postreversal. GFR in nonobstructed and previously obstructed kidneys was similar up to 18 mo postreversal. However, there was ongoing tubulointerstitial fibrosis, and the degree of tubular atrophy and dilatation deteriorated by time. This was associated with an increase in urinary albumin leakage and alterations in renal injury markers, proinflammatory and profibrotic cytokines, and p53 from 4 mo onward despite the recovery in GFR. In conclusion, several aspects of renal functions continue to deteriorate following reversal of relatively short periods of UUO despite the initial recovery in GFR. This might stimulate further research in this area and might have clinical implications in terms of determining the best time for intervention following acute ureteral obstruction and long-term monitoring of these individuals.

Waterpipe Tobacco Smoke Inhalation Triggers Thrombogenicity, Cardiac Inflammation and Oxidative Stress in Mice: Effects of Flavouring.

The consumption of water-pipe smoking (WPS) has been promoted by the use of flavoured tobacco. However, little is known about the impact of flavouring on the cardiovascular toxicity induced by WPS inhalation. Here, we compared the cardiovascular effects and underlying mechanism of actions of plain (P) (unflavoured) versus apple-flavoured (AF) WPS (30 minutes/day, 5 days/week for 1 month) in mice. Control mice were exposed to air. Both P- and AF-WPS inhalation induced an increase in systolic blood pressure, thrombogenicity and plasma concentration of fibrinogen and von Willebrand factor. In heart homogenates, AF-WPS inhalation caused an increase of 8-isoprostane and a decrease in the levels of reduced glutathione (GSH) and superoxide dismutase (SOD). Nevertheless, P-WPS decreased only the activity of SOD. The concentrations of tumour necrosis factor α and interleukin 1ß were increased only in heart homogenates of mice exposed to AF-WPS. Although both P- and AF-WPS increased the concentration of troponin I in heart homogenates and induced DNA damage, the concentration of cleaved caspase 3 was only increased in mice exposed to AF-WPS. Immunohistochemical analysis of the hearts showed that both P- and AF- WPS inhalation decreased the expression of SOD. Moreover, the expression of nuclear factor erythroid-derived 2-like 2 at nuclear level in the heart was higher in both AF-WPS and P-WPS compared with control group, and the effect observed in AF-WPS group was more significant than that seen in P-WPS group. Likewise, the concentration of heme oxygenase-1 was significantly increased in both P-WPS and AF-WPS groups compared with control group, and the effect seen in AF-group was higher than that observed in P-WPS group. In conclusion, our findings showed that both P- and AF-WPS induce thrombogenicity and cardiac injury, and that this toxicity is potentiated by the presence of flavouring.

Significantly Elevated Levels of Plasma Nicotinamide, Pyridoxal, and Pyridoxamine Phosphate Levels in Obese Emirati Population: A Cross-Sectional Study.

Water-soluble vitamins like B3 (nicotinamide), B6 (pyridoxine), and B9 (folic acid) are of utmost importance in human health and disease, as they are involved in numerous critical metabolic reactions. Not surprisingly, deficiencies of these vitamins have been linked to various disease states. Unfortunately, not much is known about the physiological levels of B6 vitamers and vitamin B3 in an ethnically isolated group (such as an Emirati population), as well as their relationship with obesity. The aim of the present study was to quantify various B6 vitamers, as well as B3, in the plasma of obese and healthy Emirati populations and to examine their correlation with obesity. A sensitive and robust HPLC-MS/MS-based method was developed for the simultaneous quantitation of five physiologically relevant forms of vitamin B6, namely pyridoxal, pyridoxine, pyridoxamine, pyridoxamine phosphate, and pyridoxal phosphate, as well as nicotinamide, in human plasma. This method was used to quantify the concentrations of these vitamers in the plasma of 57 healthy and 57 obese Emirati volunteers. Our analysis showed that the plasma concentrations of nicotinamide, pyridoxal, and pyridoxamine phosphate in the obese Emirati population were significantly higher than those in healthy volunteers (p < 0.0001, p = 0.0006, and p = 0.002, respectively). No significant differences were observed for the plasma concentrations of pyridoxine and pyridoxal phosphate. Furthermore, the concentrations of some of these vitamers in healthy Emirati volunteers were significantly different than those published in the literature for Western populations, such as American and European volunteers. This initial study underscores the need to quantify micronutrients in distinct ethnic groups, as well as people suffering from chronic metabolic disorders.

Impact of Pulmonary Exposure to Cerium Oxide Nanoparticles on Experimental Acute Kidney Injury.

BACKGROUND/AIMS: Cerium oxide nanoparticles (CeO2 NPs) are released from diesel engines that use cerium compounds as a catalytic agent to decrease the diesel exhaust particles, leading to human exposure by inhalation to CeO2 NPs. We have recently demonstrated that pulmonary exposure to CeO2 NPs induces lung inflammation, thrombosis, and oxidative stress in various organs including kidneys. It is well known that particulate air pollution effects are greater in patients with renal diseases. The aim of this study is to investigate the effects of pulmonary exposure to CeO2 NPs in a rat model of acute kidney injury (AKI). METHODS: AKI was induced in rats by a single intraperitoneal injection of cisplatin (CP, 6 mg/kg). Six days later, the rats were intratracheally (i.t.) instilled with either CeO2 NPs (1 mg/kg) or saline (control), and various renal and pulmonary endpoints were assessed 24 h afterward using histological, colorimetric assay, enzyme-linked immunosorbent assay and Comet assay techniques. RESULTS: CP alone decreased body weight, and increased water intake, urine volume and relative kidney weight. CP also increased the plasma concentrations urea and creatinine, and decreased creatinine clearance. In the kidneys, CP significantly increased renal injury molecule-1, interleukin-6 (IL-6), tumor necrosis factor α (TNFα) and glutathione concentrations, and caused renal tubular necrosis, and DNA injury assessed by Comet assay. All these actions were significantly aggravated in rats given both CP and CeO2 NPs. Histopathological changes in lungs of CeO2 NPs-treated rats included marked interstitial cell infiltration and congestion. These were aggravated by the combination of CP + CeO2 NPs. Moreover, this combination exacerbated the increase in the concentrations of TNFα and IL-6, and the decrease in the activity of pulmonary catalase and total nitric oxide concentration, and lung DNA damage. CONCLUSION: We conclude that the presence of CeO2 NPs in the lung exacerbated the renal and lung effects of CP-induced AKI.

Total adiponectin in overweight and obese subjects and its response to visceral fat loss.

BACKGROUND: Visceral obesity and related diabetes is reaching epidemic proportions in the United Arab Emirates (UAE). Adiponectin is a hormone that is secreted by adipose tissue and may play an important role in obesity-related morbidity. The aim of this study was to investigate total adiponectin levels in overweight and obese UAE subjects visiting health care facilities for weight management. METHODS: All overweight and obese subjects visiting community health centers were invited to take part in the study. Two hundred and six participants received individualized structured dietary education for weight management. Demographic data, anthropometric measurements and fasting venous blood samples were taken for measurements of total adiponectin and markers of inflammation and nutritional status at baseline and follow up. Multivariate analysis was performed to determine the independent effects of prognostic factors on serum adiponectin levels. RESULTS: A total of 193 (93%) females with a mean age (±SD) 36 ± 11 years were included in the analysis. During a follow up period of 427 ± 223 days, participants received 13 ± 5 structured dietary education sessions. We observed decreased levels of total adiponectin with increasing quartiles of both waist circumference (WC) and body mass index (BMI). Male gender and history of both gestational and type 2 diabetes were associated with significantly lower total adiponectin levels (p < 0.05). After adjusting for age, gender, BMI and hip circumference, multiple regression analysis revealed a significant and independent association between waist circumference and total adiponectin levels. At follow up visceral fat loss was associated with a significant decrease in inflammatory markers and a non-significant increase in total adiponectin levels. CONCLUSION: Increased visceral fat in overweight and obese subjects is associated with decreased total adiponectin levels. The health benefits of increasing adiponectin levels using different dietary intervention strategies need to be explored in larger studies. TRIAL REGISTRATION: NCT01691365 , registered on 11/09/2012.

Chronic exposure to water-pipe smoke induces cardiovascular dysfunction in mice.

Water-pipe tobacco smoking is becoming prevalent in all over the world including Western countries. There are limited data on the cardiovascular effects of water-pipe smoke (WPS), in particular following chronic exposure. Here, we assessed the chronic cardiovascular effects of nose-only WPS exposure in C57BL/6 mice. The duration of the session was 30 minutes/day, 5 days/week for 6 consecutive months. Control mice were exposed to air. WPS significantly increased systolic blood pressure. The relative heart weight and plasma concentrations of troponin-I and B-type natriuretic peptide were increased in mice exposed to WPS. Arterial blood gas analysis showed that WPS caused a significant decrease in [Formula: see text] and an increase in [Formula: see text] WPS significantly shortened the thrombotic occlusion time in pial arterioles and venules and increased the number of circulating platelet. Cardiac lipid peroxidation, measured as thiobarbituric acid-reactive substances, was significantly increased, while superoxide dismutase activity, total nitric oxide activity, and glutathione concentration were reduced by WPS exposure. Likewise, immunohistochemical analysis of the heart revealed an increase in the expression of inducible nitric oxide synthase and cytochrome c by cardiomyocytes of WPS-exposed mice. Moreover, hearts of WPS-exposed mice showed the presence of focal interstitial fibrosis. WPS exposure significantly increased heart DNA damage assessed by Comet assay. We conclude that chronic nose-only exposure to WPS impairs cardiovascular homeostasis. Our findings provide evidence that long-term exposure to WPS is harmful to the cardiovascular system and supports interventions to control the spread of WPS, particularly amid youths.NEW & NOTEWORTHY No data are available on the chronic cardiovascular effects of water-pipe smoke (WPS). Our findings provide experimental evidence that chronic exposure to WPS increased blood pressure, relative heart weight, troponin I, and B-type natriuretic peptide in plasma and induced hypoxemia, hypercapnia, and thrombosis. Moreover, WPS caused cardiac oxidative stress, DNA damage, and fibrosis.

Chronic Exposure to Water-Pipe Smoke Induces Alveolar Enlargement, DNA Damage and Impairment of Lung Function.

BACKGROUND/AIM: Epidemiological evidence indicates that water-pipe smoking (WPS) adversely affects the respiratory system. However, the mechanisms underlying its effects are not well understood. Recent experimental studies reported the occurrence of lung inflammation and oxidative stress following acute and subacute exposure to WPS. Here, we wanted to verify the extent of inflammation and oxidative stress in mice chronically-exposed to WPS and to evaluate, for the first time, its effect on alveolar injury and DNA damage and their association with impairment of lung function. METHODS: Mice were nose-only exposed to mainstream WPS (30 min/day; 5 days/week for 6 consecutive months). Control mice were exposed using the same protocol to atmospheric air only. At the end of the exposure period, several respiratory parameters were assessed. RESULTS: In bronchoalveolar lavage fluid, WPS increased neutrophil and lymphocyte numbers, lactate dehydrogenase, myeloperoxidase and matrix metallopeptidase 9 activities, as well as several proinflammatory cytokines. In lung tissue, lipid peroxidation, reactive oxygen species, superoxide dismutase activity and reduced glutathione were all increased by WPS exposure. Along with oxidative stress, WPS exposure significantly increased lung DNA damage index. Histologically the lungs of WPS-exposed mice had foci of mixed inflammatory cells infiltration in the interalveolar interstitium which consisted of neutrophils, lymphocytes and macrophages. Interestingly, we found dilated alveolar spaces and alveolar ducts with damaged interalveolar septae, and impairment of lung function following WPS exposure. CONCLUSION: We show the persistence of lung inflammation and oxidative stress in mice chronically-exposed to WPS and demonstrate, for the first time, the occurrence of DNA damage and enlargement of alveolar spaces and ducts associated with impairment of lung function. Our findings provide novel mechanistic elucidation for the long-term effects of WPS on the respiratory system.

Prolonged Pulmonary Exposure to Diesel Exhaust Particles Exacerbates Renal Oxidative Stress, Inflammation and DNA Damage in Mice with Adenine-Induced Chronic Renal Failure.

BACKGROUND/AIMS: Epidemiological evidence indicates that patients with chronic kidney diseases have increased susceptibility to adverse outcomes related to long-term exposure to particulate air pollution. However, mechanisms underlying these effects are not fully understood. METHODS: Presently, we assessed the effect of prolonged exposure to diesel exhaust particles (DEP) on chronic renal failure induced by adenine (0.25% w/w in feed for 4 weeks), which is known to involve inflammation and oxidative stress. DEP (0.5m/kg) was intratracheally (i.t.) instilled every 4th day for 4 weeks (7 i.t. instillation). Four days following the last exposure to either DEP or saline (control), various renal endpoints were measured. RESULTS: While body weight was decreased, kidney weight increased in DEP+adenine versus saline+adenine or DEP. Water intake, urine volume, relative kidney weight were significantly increased in adenine+DEP versus DEP and adenine+saline versus saline. Plasma creatinine and urea increased and creatinine clearance decreased in adenine+DEP versus DEP and adenine+saline versus saline. Tumor necrosis factor α, lipid peroxidation and reactive oxygen species were significantly increased in adenine+DEP compared with either DEP or adenine+saline. The antioxidant calase was significantly decreased in adenine+DEP compared with either adenine+saline or DEP. Notably, renal DNA damage was significantly potentiated in adenine+DEP compared with either adenine+saline or DEP. Similarly, systolic blood pressure was increased in adenine+DEP versus adenine+saline or DEP, and in DEP versus saline. Histological evaluation revealed more collagen deposition, higher number of necrotic cell counts and dilated tubules, cast formation and collapsing glomeruli in adenine+DEP versus adenine+saline or DEP. CONCLUSION: Prolonged pulmonary exposure to diesel exhaust particles worsen renal oxidative stress, inflammation and DNA damage in mice with adenine-induced chronic renal failure. Our data provide biological plausibility that air pollution aggravates chronic renal failure.