Publications by authors named "Mohamed A Elrayess"

40 Publications

Protein tyrosine phosphatase 1B inhibition improves endoplasmic reticulum stress‑impaired endothelial cell angiogenic response: A critical role for cell survival.

Mol Med Rep 2021 Sep 23;24(3). Epub 2021 Jul 23.

Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713 Doha, Qatar.

Endoplasmic reticulum (ER) stress contributes to endothelial dysfunction, which is the initial step in atherogenesis. Blockade of protein tyrosine phosphatase (PTP)1B, a negative regulator of insulin receptors that is critically located on the surface of ER membrane, has been found to improve endothelial dysfunction. However, the role of ER stress and its related apoptotic sub‑pathways in PTP1B‑mediated endothelial dysfunction, particularly its angiogenic capacity, have not yet been fully elucidated. Thus, the present study aimed to investigate the impact of PTP1B suppression on ER stress‑mediated impaired angiogenesis and examined the contribution of apoptotic signals in this process. Endothelial cells were exposed to pharmacological ER stressors, including thapsigargin (TG) or 1,4‑dithiothreitol (DTT), in the presence or absence of a PTP1B inhibitor or small interfering (si)RNA duplexes. Then, ER stress, angiogenic capacity, cell cycle, apoptosis and the activation of key apoptotic signals were assessed. It was identified that the inhibition of PTP1B prevented ER stress caused by DTT and TG. Moreover, ER stress induction impaired the activation of endothelial nitric oxide synthase (eNOS) and the angiogenic capacity of endothelial cells, while PTP1B inhibition exerted a protective effect. The results demonstrated that blockade or knockdown of PTP1B prevented ER stress‑induced apoptosis and cell cycle arrest. This effect was associated with reduced expression levels of caspase‑12 and poly (ADP‑Ribose) polymerase 1. PTP1B blockade also suppressed autophagy activated by TG. The current data support the critical role of PTP1B in ER stress‑mediated endothelial dysfunction, characterized by reduced angiogenic capacity, with an underlying mechanism involving reduced eNOS activation and cell survival. These findings provide evidence of the therapeutic potential of targeting PTP1B in cardiovascular ischemic conditions.
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http://dx.doi.org/10.3892/mmr.2021.12304DOI Listing
September 2021

Metabolomic Profiling of Pregnancies With Polycystic Ovary Syndrome Identifies a Unique Metabolic Signature and Potential Predictive Biomarkers of Low Birth Weight.

Front Endocrinol (Lausanne) 2021 15;12:638727. Epub 2021 Jun 15.

Biomedical Research Center (BRC), Qatar University, Doha, Qatar.

Background: Polycystic ovary syndrome (PCOS) is a complex syndrome with clinical features of an endocrine/metabolic disorder. Various metabolites show significant association with PCOS; however, studies comparing the metabolic profile of pregnant women with and without PCOS are lacking. In this study, metabolomics analysis of blood samples collected from PCOS women and age and BMI matched controls in the second trimester of pregnancy was performed to identify metabolic differences between the two groups and determine their association with pregnancy outcome.

Methods: Sixteen PCOS and fifty-two healthy women in their second trimester underwent targeted metabolomics of plasma samples using tandem mass spectrometry with the Biocrates MxP Quant 500 Kit. Linear regression models were used to identify the metabolic alterations associated with PCOS, followed by enrichment and Receiver Operating Characteristic (ROC) analyses to determine the best indicators of pregnancy outcomes.

Results: PCOS women had lower birth weight babies compared to healthy controls. As a group, systolic blood pressure (SBP) at both second trimester and at delivery negatively correlated with birth weight. Regression models indicated significant increases in the triglycerides C20:4_C34:3 and C18:2_C38:6 in the PCOS group [false discovery rate (FDR) <0.05]. Enrichment analysis revealed significant elevations in triglycerides containing arachidonic acid, linoleic acid and palmitic acid in the PCOS group. A number of indicators of baby birth weight were identified including SBP at delivery, hexosylceramide (d18:2/24:0), ceramide (d18.0/24.1) and serine, with an AUC for all predictors combined for low birth weight (≤2500grams) of 0.88 (95%CI: 0.75-1.005, p<0.001).

Conclusions: PCOS pregnancies resulted in babies with a lower birth weight, marked by a unique metabolic signature that was enriched with specific triglycerides and unsaturated fatty acids. The functional significance of these associations needs further investigation.
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http://dx.doi.org/10.3389/fendo.2021.638727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239387PMC
June 2021

Age and Sport Intensity-Dependent Changes in Cytokines and Telomere Length in Elite Athletes.

Antioxidants (Basel) 2021 Jun 28;10(7). Epub 2021 Jun 28.

Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar.

Background: Exercise-associated immune response plays a crucial role in the aging process. The aim of this study is to investigate the effect of sport intensity on cytokine levels, oxidative stress markers and telomere length in aging elite athletes.

Methods: In this study, 80 blood samples from consenting elite athletes were collected for anti-doping analysis at an anti-doping laboratory in Italy (FMSI). Participants were divided into three groups according to their sport intensity: low-intensity skills and power sports (LI, = 18); moderate-intensity mixed soccer players (MI, = 31); and high-intensity endurance sports (HI, = 31). Participants were also divided into two age groups: less than 25 ( = 45) and above 25 years old ( = 35). Serum levels of 10 pro and anti-inflammatory cytokines and two antioxidant enzymes were compared in age and sport intensity groups and telomere lengths were measured in their respective blood samples.

Results: Tumor necrosis factor-alpha (TNF-α) was the only cytokine showing significantly higher concentration in older athletes, regardless of sport intensity. Interleukin (IL)-10 increased significantly in HI regardless of age group, whereas IL-6 concentration was higher in the older HI athletes. IL-8 showed a significant interaction with sport intensity in different age groups. Overall, significant positive correlations among levels of IL-6, IL-10, IL-8 and TNF-α were identified. The antioxidant catalase activity was positively correlated with levels of TNF-α. Telomere length increased significantly with sport intensity, especially in the younger group.

Conclusion: HI had longer telomeres and higher levels of pro- and anti-inflammatory cytokines, suggesting less aging in HI compared to low and moderate counterparts in association with heightened immune response. Investigation of the functional significance of these associations on the health and performance of elite athletes is warranted.
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http://dx.doi.org/10.3390/antiox10071035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300746PMC
June 2021

Level of maternal respiratory syncytial virus (RSV) F antibodies in hospitalized children and correlates of protection.

Int J Infect Dis 2021 Jun 10;109:56-62. Epub 2021 Jun 10.

Biomedical Research Center, Qatar University, Qatar; College of Health Sciences, Qatar University, Qatar. Electronic address:

Background: Respiratory syncytial virus (RSV) is a major cause of lower respiratory infection among children and no vaccine is available. The stabilized form of the fusion (F) protein - pre-F - is a leading vaccine candidate to target different populations, including pregnant women. This study aimed to determine the magnitude and nature of RSV-directed maternal antibodies (matAbs) in hospitalized children with RSV infection.

Methods: Sixty-five paired blood samples were collected from RSV-infected children aged <6 months and their corresponding mothers. All pairs were screened for levels of pre-F and post-F antibodies using ELISA. The neutralizing antibodies (NAbs) in both groups were measured in vitro against mKate RSV-A2 using H28 cells.

Results: It was found that 14% of matAbs (log 12.8) were present in infants at hospitalization, with an average log EP titer of 10.2 directed to both F-protein conformations. Additionally, 61.4% of maternal NAbs (log EC = 9.4) were detected in infants (log EC = 8.7), which were mostly pre-F exclusive (81%). Pre-F antibodies in children showed a positive correlation with matAbs titers and negative correlations with age and bronchiolitis score.

Conclusions: The maintenance of neutralizing activity in infants relative to maternal titers was greater than the maintenance of antibody binding based on ELISA, suggesting that higher-potency antibodies may have a longer half-life than weakly neutralizing antibodies.
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http://dx.doi.org/10.1016/j.ijid.2021.06.015DOI Listing
June 2021

Sestrin2 suppression aggravates oxidative stress and apoptosis in endothelial cells subjected to pharmacologically induced endoplasmic reticulum stress.

Eur J Pharmacol 2021 Jun 9;907:174247. Epub 2021 Jun 9.

Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; Biomedical and Pharmaceutical Research Unit (BPRU), QU Health, Qatar University, P.O. Box 2713, Doha, Qatar; Office of Vice President for Research and Graduate Studies, Qatar University, P.O. Box 2713, Doha, Qatar. Electronic address:

Endoplasmic reticulum (ER) stress is an inflammatory response that contributes to endothelial cell dysfunction, a hallmark of cardiovascular diseases, in close interplay with oxidative stress. Recently, Sestrin2 (SESN2) emerged as a novel stress-inducible protein protecting cells from oxidative stress. We investigated here, for the first time, the impact of SESN2 suppression on oxidative stress and cell survival in human endothelial cells subjected to pharmacologically (thapsigargin)-induced ER stress and studied the underlying cellular pathways. We found that SESN2 silencing, though did not specifically induce ER stress, it aggravated the effects of thapsigargin-induced ER stress on oxidative stress and cell survival. This was associated with a dysregulation of Nrf-2, AMPK and mTORC1 signaling pathways. Furthermore, SESN2 silencing aggravated, in an additive manner, apoptosis caused by thapsigargin. Importantly, SESN2 silencing, unlike thapsigargin, caused a dramatic decrease in protein expression and phosphorylation of Akt, a critical pro-survival hub and component of the AMPK/Akt/mTORC1 axis. Our findings suggest that patients with conditions characterized by ER stress activation, such as diabetes, may be at higher risk for cardiovascular complications if their endogenous ability to stimulate and/or maintain expression levels of SESN2 is disturbed or impaired. Therefore, identifying novel or repurposing existing pharmacotherapies to enhance and/or maintain SESN2 expression levels would be beneficial in these conditions.
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http://dx.doi.org/10.1016/j.ejphar.2021.174247DOI Listing
June 2021

The Impact of Acute and Chronic Exercise on Immunoglobulins and Cytokines in Elderly: Insights From a Critical Review of the Literature.

Front Immunol 2021 14;12:631873. Epub 2021 Apr 14.

Biomedical Research Center, Qatar University, Doha, Qatar.

The level of immunoglobulins and cytokines changes with an ageing immune system. This review summarizes findings from studies that have examined the impact of acute and chronic exercise on immunoglobulins and cytokines in the elderly. Our literature analysis revealed that acute endurance exercise resulted in increased secretory salivary immunoglobulin A (SIgA), while acute bouts of muscle strengthening exercise (i.e., isokinetic, eccentric, knee extensor exercise) increased plasma/muscle interleukin (IL)-6, IL-8 and tumor necrosis factor alpha (TNF-α) levels. Chronic exercise in the form of short-term endurance training (i.e., 12-16 weeks) and long-term combined endurance and resistance training (i.e., 6-12 months) induced increases in salivary SIgA concentration. We additionally identified that short-term endurance training at moderate intensities and the combination of endurance, strength, balance, and flexibility training increase plasma IL-10 and reduce plasma IL-6 and TNF-α in healthy elderly adults and male patients with chronic heart failure. Strength training for 6-12 weeks did not alter plasma IL-1β, IL-2, IL-6 and TNF-α concentration in healthy elderly adults and patients with chronic-degenerative diseases, while 12 weeks of resistance training decreased muscle TNF-α mRNA in frail elderly individuals. Short-term (i.e., 10-24 weeks) moderate- to high-intensity strength training reduced LPS-IL-6, LPS, IL-1β, LPS-TNF-α and circulating concentrations of TNF-α and increased IL-10 in healthy elderly women and older people with cognitive impairment, respectively. In conclusion, it appears that acute bouts of endurance exercise and short-term chronic exercise training exercise are appropriate methods to enhance mucosal immune function, reduce systemic markers of inflammation, and promote anti-inflammatory processes in elderly individuals.
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http://dx.doi.org/10.3389/fimmu.2021.631873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079972PMC
April 2021

Association of Complement-Related Proteins in Subjects With and Without Second Trimester Gestational Diabetes.

Front Endocrinol (Lausanne) 2021 30;12:641361. Epub 2021 Mar 30.

Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar.

Introduction: Gestational Diabetes Mellitus (GDM) development is related to underlying metabolic syndrome that is associated with elevated complement C3 and C4. Elevated C3 levels have been associated with preeclampsia and the development of macrosomia.

Methods: This case-control study included 34 pregnant women with GDM and 16 non-diabetic (ND) women in their second trimester. Complement-related proteins were measured and correlated with demographic, biochemical, and pregnancy outcome data.

Results: GDM women were older with a higher BMI (p<0.001); complement C3, C4 and Factor-H were significantly elevated (p=0.001, p=0.05, p=0.01, respectively). When adjusted for age and BMI, Complement C3 (p=0.04) and Factor-H (p=0.04) remained significant. Partial correlation showed significant correlation between C4 with serum alanine aminotransferase (ALT) (p<0.05) and 2 term diastolic blood pressure (p<0.05); Factor-H and C-reactive protein (CRP; p<0.05). Pearson bivariate analysis revealed significant correlations between C3, C4, and Factor-H and CRP; p<0.05; C3 and gestational age at delivery (GA; p<0.05); C4 and ALT and second-trimester systolic blood pressure (STBP) (p=0.008 and p<0.05, respectively); Factor-H and glycated hemoglobin (HbA1c) (p<0.05). Regression analysis showed that the elevation of C3 could be accounted for by age, BMI, GA and CRP, with CRP being the most important predictor (p=0.02). C4 elevation could be accounted for by ALT, CRP and STBP. CRP predicted Factor-H elevation.

Conclusion: The increased C3, C4 and Factor-H during the second trimester of pregnancy in GDM are not independently associated with GDM; inflammation and high BMI may be responsible for their elevation. The elevation of second trimester C3 in GDM is associated with earlier delivery and further work is needed to determine if this is predictive.
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http://dx.doi.org/10.3389/fendo.2021.641361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043150PMC
March 2021

SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways.

Sci Rep 2021 Apr 14;11(1):8177. Epub 2021 Apr 14.

Department of Microbiology and Immunology, Weill Cornell Medicine-Qatar, Qatar Foundation, Doha, Qatar.

The NAD-dependent deacetylase SIRT1 controls key metabolic functions by deacetylating target proteins and strategies that promote SIRT1 function such as SIRT1 overexpression or NAD boosters alleviate metabolic complications. We previously reported that SIRT1-depletion in 3T3-L1 preadipocytes led to C-Myc activation, adipocyte hyperplasia, and dysregulated adipocyte metabolism. Here, we characterized SIRT1-depleted adipocytes by quantitative mass spectrometry-based proteomics, gene-expression and biochemical analyses, and mitochondrial studies. We found that SIRT1 promoted mitochondrial biogenesis and respiration in adipocytes and expression of molecules like leptin, adiponectin, matrix metalloproteinases, lipocalin 2, and thyroid responsive protein was SIRT1-dependent. Independent validation of the proteomics dataset uncovered SIRT1-dependence of SREBF1c and PPARα signaling in adipocytes. SIRT1 promoted nicotinamide mononucleotide acetyltransferase 2 (NMNAT2) expression during 3T3-L1 differentiation and constitutively repressed NMNAT1 and 3 levels. Supplementing preadipocytes with the NAD booster nicotinamide mononucleotide (NMN) during differentiation increased expression levels of leptin, SIRT1, and PGC-1α and its transcriptional targets, and reduced levels of pro-fibrotic collagens (Col6A1 and Col6A3) in a SIRT1-dependent manner. Investigating the metabolic impact of the functional interaction of SIRT1 with SREBF1c and PPARα and insights into how NAD metabolism modulates adipocyte function could potentially lead to new avenues in developing therapeutics for obesity complications.
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http://dx.doi.org/10.1038/s41598-021-87759-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046990PMC
April 2021

Comparing Levels of Metabolic Predictors of Coronary Heart Disease between Healthy Lean and Overweight Females.

Metabolites 2021 Mar 15;11(3). Epub 2021 Mar 15.

Biomedical Research Center, Qatar University, P. O. Box 2713 Doha, Qatar.

Screening for the metabolomic signature of coronary heart disease (CHD) before disease onset could help in early diagnosis and potentially disease prevention. In this study, the levels of 17 CHD metabolic biomarkers in apparently healthy overweight females were compared to lean counterparts, and their associations with conventional clinical risk factors were determined. Clinical and metabolic data from 200 apparently healthy non-obese Qatari females were collected from Qatar Biobank (discovery cohort). Logistic regression was used to assess the association between body mass index (BMI) groups and 17 CHD metabolic biomarkers, and receiver operating characteristic (ROC) analysis was used to evaluate the prognostic value of CHD metabolic biomarkers in overweight. Stepwise linear regression was performed to identify the classical risk factors associated with CHD metabolites differentiating the two BMI groups. Validation of the association of CHD metabolic biomarkers with BMI groups was performed in 107 subjects (replication cohort). Out of the tested CHD metabolic biomarkers, five were significantly different between lean and overweight females in the discovery cohort (AUC = 0.73). Among these, the association of mannose, asparagine, and linoleate with BMI groups was confirmed in the replication cohort (AUC = 0.97). Significant correlations between predictors of CHD in overweight healthy women and classical risk factors were observed, including serum levels of cholesterol, testosterone, triiodothyronine, thyroxine, creatinine, albumin, bilirubin, glucose, c-peptide, uric acid, calcium and chloride. Apparently, healthy overweight females exhibit significantly different levels of specific CHD metabolites compared to their lean counterparts, offering a prognostic potential with preventative value.
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http://dx.doi.org/10.3390/metabo11030169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999722PMC
March 2021

Metabolic consequences of obesity on the hypercoagulable state of polycystic ovary syndrome.

Sci Rep 2021 Mar 5;11(1):5320. Epub 2021 Mar 5.

Royal College of Surgeons in Ireland Bahrain, Adliya, Kingdom of Bahrain.

Polycystic ovary syndrome (PCOS) women have a hypercoagulable state; however, whether this is intrinsically due to PCOS or, alternatively, a consequence of its metabolic complications is unclear. We determined plasma coagulation pathway protein levels in PCOS (n = 146) and control (n = 97) women recruited to a PCOS biobank. Circulating levels of a panel of 18 clotting pathway proteins were determined by Slow Off-rate Modified Aptamer-scan plasma protein measurement. Cohorts were age matched, though PCOS had elevated body mass index (p < 0.001), insulin (p < 0.001) and C-reactive protein (CRP) (p < 0.0001). Eight pro-coagulation proteins were elevated in PCOS: plasminogen activator inhibitor-1 (p < 0.0001), fibrinogen (p < 0.01), fibrinogen gamma chain (p < 0.0001), fibronectin (p < 0.01), von Willebrand factor (p < 0.05), D-dimer (p < 0.0001), P-selectin (p < 0.05), and plasma kallikrein (p < 0.001). However, two anticoagulant proteins, vitamin K-dependent protein-S (p < 0.0001) and heparin cofactor-II (p < 0.001) were elevated and prothrombin was decreased (p < 0.05). CRP, as a marker of inflammation, and insulin resistance (HOMA-IR) correlated with 11 and 6 of the clotting proteins, respectively (p < 0.05). When matched for BMI < 25 (16 PCOS, 53 controls) HOMA-IR remained elevated (p < 0.05) and heparin cofactor-II was increased (p < 0.05). In a multivariate analysis accounting for inflammation, insulin resistance and BMI, there was no correlation of PCOS with any of the coagulation proteins. The hypercoagulable state in PCOS is not intrinsic to the disease as it can be fully accounted for by BMI, inflammation and insulin resistance.
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http://dx.doi.org/10.1038/s41598-021-84586-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935919PMC
March 2021

apoA2 correlates to gestational age with decreased apolipoproteins A2, C1, C3 and E in gestational diabetes.

BMJ Open Diabetes Res Care 2021 03;9(1)

Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar.

Introduction: Pregnant women with gestational diabetes mellitus (GDM) are at risk of adverse outcomes, including gestational hypertension, pre-eclampsia, and preterm delivery. This study was undertaken to determine if apolipoprotein (apo) levels differed between pregnant women with and without GDM and if they were associated with adverse pregnancy outcome.

Research Design And Methods: Pregnant women (46 women with GDM and 26 women without diabetes (ND)) in their second trimester were enrolled in the study. Plasma apos were measured and correlated to demographic, biochemical, and pregnancy outcome data.

Results: apoA2, apoC1, apoC3 and apoE were lower in women with GDM compared with control women (p=0.0019, p=0.0031, p=0.0002 and p=0.015, respectively). apoA1, apoB, apoD, apoH, and apoJ levels did not differ between control women and women with GDM. Pearson bivariate analysis revealed significant correlations between gestational age at delivery and apoA2 for women with GDM and control women, and between apoA2 and apoC3 concentrations and C reactive protein (CRP) as a measure of inflammation for the whole group.

Conclusions: Apoproteins apoA2, apoC1, apoC3 and apoE are decreased in women with GDM and may have a role in inflammation, as apoA2 and C3 correlated with CRP. The fact that apoA2 correlated with gestational age at delivery in both control women and women with GDM raises the hypothesis that apoA2 may be used as a biomarker of premature delivery, and this warrants further investigation.
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http://dx.doi.org/10.1136/bmjdrc-2020-001925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938976PMC
March 2021

Signal Transducer and Activator of Transcription 3 (STAT3) Suppresses STAT1/Interferon Signaling Pathway and Inflammation in Senescent Preadipocytes.

Antioxidants (Basel) 2021 Feb 23;10(2). Epub 2021 Feb 23.

Department of Microbiology and Immunology, Weill Cornell Medicine-Qatar (WCM-Q), Qatar Foundation, Doha 24144, Qatar.

Obesity promotes premature aging and dysfunction of white adipose tissue (WAT) through the accumulation of cellular senescence. The senescent cells burden in WAT has been linked to inflammation, insulin-resistance (IR), and type 2 diabetes (T2D). There is limited knowledge about molecular mechanisms that sustain inflammation in obese states. Here, we describe a robust and physiologically relevant in vitro system to trigger senescence in mouse 3T3-L1 preadipocytes. By employing transcriptomics analyses, we discovered up-regulation of key pro-inflammatory molecules and activation of interferon/signal transducer and activator of transcription (STAT)1/3 signaling in senescent preadipocytes, and expression of downstream targets was induced in epididymal WAT of obese mice, and obese human adipose tissue. To test the relevance of STAT1/3 signaling to preadipocyte senescence, we used Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology to delete STAT1/3 and discovered that STAT1 promoted growth arrest and cooperated with cyclic Guanosine Monophosphate-Adenosine Monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) to drive the expression of interferon β (IFNβ), C-X-C motif chemokine ligand 10 (CXCL10), and interferon signaling-related genes. In contrast, we discovered that STAT3 was a negative regulator of STAT1/cGAS-STING signaling-it suppressed senescence and inflammation. These data provide insights into how STAT1/STAT3 signaling coordinates senescence and inflammation through functional interactions with the cGAS/STING pathway.
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http://dx.doi.org/10.3390/antiox10020334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927067PMC
February 2021

Assessment of Serum Cytokines and Oxidative Stress Markers in Elite Athletes Reveals Unique Profiles Associated With Different Sport Disciplines.

Front Physiol 2020 15;11:600888. Epub 2020 Oct 15.

Biomedical Research Center, Qatar University, Doha, Qatar.

Objectives: Circulating cytokines and oxidative stress markers vary in response to different exercise regimens. This study aims to compare the immune-inflammatory and oxidative stress profiles of elite athletes from different sport disciplines as potential biomarkers of muscle damage, and cardiovascular demand.

Methods: Serum samples from 88 consented elite male athletes from different sports disciplines (aquatics, = 11, athletics, = 22, cycling, = 19, football, = 28 and weightlifting, = 8) collected at the anti-doping lab in Italy were screened for 38 cytokines and oxidative stress markers. Comparisons were made between different level of power, cardiovascular demand (CD) and endurance, as well as among the sport types.

Results: The anti-inflammatory interleukin (IL)-10 was higher ( = 0.04) in moderate power compared with the high power group. Conversely, superoxide dismutase (SOD; = 0.001) and malondialdehyde (MDA; = 0.007) levels were greater in the higher power groups compared with the lower power counterpart. Among athletes who belong to different CD ranks, IL-1β and monocyte chemoattractant protein-1(MCP1) levels were higher ( = 0.03) in the low CD-rank group compared with high CD counterpart, whereas, SOD levels were higher ( = 0.001) in high and moderate CD-rank groups compared to low counterpart. For endurance groups, IL-10 and macrophage inflammatory protein (MIP)-1beta were increased ( = 0.03) in low/moderate endurance compared with the high endurance group. Finally, MIP1-beta, SOD and catalase varied significantly among the sports groups.

Conclusion: Specific markers of inflammation and oxidative stress are associated with different sports disciplines and could be utilized as potential biomarkers of athletes' health, performance, and recovery from injury.
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http://dx.doi.org/10.3389/fphys.2020.600888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593763PMC
October 2020

Metabolomics of Lean/Overweight Insulin-Resistant Females Reveals Alterations in Steroids and Fatty Acids.

J Clin Endocrinol Metab 2021 Jan;106(2):e638-e649

Biomedical Research Center (BRC), Qatar University, Doha, Qatar.

Background: The global diabetes epidemic is largely attributed to obesity-triggered metabolic syndrome. However, the impact of insulin resistance (IR) prior to obesity on the high prevalence of diabetes and the molecular mediators remain largely unknown. This study aims to compare the metabolic profiling of apparently healthy lean/overweight participants with IR and insulin sensitivity (IS), and identify the metabolic pathways underlying IR.

Methods: In this cross-sectional study, clinical and metabolic data for 200 seemingly healthy young female participants (100 IR and 100 IS) was collected from Qatar Biobank. Orthogonal partial least square analysis was performed to assess the extent of separation between individuals from the 2 groups based on measured metabolites. Classical linear models were used to identify the metabolic signature of IR, followed by elastic-net-regularized generalized linear model (GLMNET) and receiver operating characteristic (ROC) analysis to determine top metabolites associated with IR.

Results: Compared to lean/overweight participants with IS, those with IR showed increased androgenic steroids, including androsterone glucuronide, in addition to various microbiota byproducts, such as the phenylalanine derivative carboxyethylphenylalanine. On the other hand, participants with IS had elevated levels of long-chain fatty acids. A ROC analysis suggested better discriminatory performance using 20 metabolites selected by GLMNET in comparison to the classical clinical traits (area under curve: 0.93 vs 0.73, respectively).

Conclusion: Our data confirm the multifactorial mechanism of IR with a diverse spectrum of emerging potential biomarkers, including steroids, long-chain fatty acids, and microbiota metabolites. Further studies are warranted to validate these markers for diagnostic and therapeutic applications.
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http://dx.doi.org/10.1210/clinem/dgaa732DOI Listing
January 2021

Metabolic profiling of pre-gestational and gestational diabetes mellitus identifies novel predictors of pre-term delivery.

J Transl Med 2020 09 24;18(1):366. Epub 2020 Sep 24.

Biomedical Research Center (BRC), Qatar University, Doha, Qatar.

Background: Pregnant women with gestational diabetes mellitus (GDM) or type 2 diabetes mellitus (T2DM) are at increased risks of pre-term labor, hypertension and preeclampsia. In this study, metabolic profiling of blood samples collected from GDM, T2DM and control pregnant women was undertaken to identify potential diagnostic biomarkers in GDM/T2DM and compared to pregnancy outcome.

Methods: Sixty-seven pregnant women (21 controls, 32 GDM, 14 T2DM) in their second trimester underwent targeted metabolomics of plasma samples using tandem mass spectrometry with the Biocrates MxP Quant 500 Kit. Linear regression models were used to identify the metabolic signature of GDM and T2DM, followed by generalized linear model (GLMNET) and Receiver Operating Characteristic (ROC) analysis to determine best predictors of GDM, T2DM and pre-term labor.

Results: The gestational age at delivery was 2 weeks earlier in T2DM compared to GDM and controls and correlated negatively with maternal HbA1C and systolic blood pressure and positively with serum albumin. Linear regression models revealed elevated glutamate and branched chain amino acids in GDM + T2DM group compared to controls. Regression models also revealed association of lower levels of triacylglycerols and diacylglycerols containing oleic and linoleic fatty acids with pre-term delivery. A generalized linear model ROC analyses revealed that that glutamate is the best predictors of GDM compared to controls (area under curve; AUC = 0.81). The model also revealed that phosphatidylcholine diacyl C40:2, arachidonic acid, glycochenodeoxycholic acid, and phosphatidylcholine acyl-alkyl C34:3 are the best predictors of GDM + T2DM compared to controls (AUC = 0.90). The model also revealed that the triacylglycerols C17:2/36:4 and C18:1/34:1 are the best predictors of pre-term delivery (≤ 37 weeks) (AUC = 0.84).

Conclusions: This study highlights the metabolite alterations in women in their second trimester with diabetes mellitus and identifies predictive indicators of pre-term delivery. Future studies to confirm these associations in other cohorts and investigate their functional relevance and potential utilization for targeted therapies are warranted.
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http://dx.doi.org/10.1186/s12967-020-02531-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517617PMC
September 2020

Suppression of GATA-3 increases adipogenesis, reduces inflammation and improves insulin sensitivity in 3T3L-1 preadipocytes.

Cell Signal 2020 11 11;75:109735. Epub 2020 Aug 11.

Biomedical Research Center (BRC), Qatar University, Doha, Qatar. Electronic address:

Impaired adipogenesis plays an important role in the development of obesity-associated insulin resistance and type 2 diabetes. Adipose tissue inflammation is a crucial mediator of this process. GATA-3 plays important roles in adipogenesis and inflammation. The aim of this study is to investigate the impact of GATA-3 suppression on improving adipogenesis, lowering inflammation and reversing insulin resistance. GATA-3 levels were measured in subcutaneous (SC) and omental (OM) adipose tissues obtained from insulin sensitive (IS) and insulin resistant (IR) obese individuals during weight reduction surgeries. The effect of GATA-3 suppression on adipogenesis, expression of inflammatory cytokines and insulin resistance biomarkers was performed in 3T3L-1 mouse preadipocytes via transfection with GATA-3-specific DNAzyme. GATA-3 expression was higher in OM compared to SC adipose tissues and in stromal vascular fraction-derived differentiating preadipocytes from IR obese individuals compared to their IS counterparts. Suppression of GATA-3 expression in 3T3L-1 mouse preadipocytes with GATA-3 specific inhibitor reversed 4-hydroxynonenal-induced impaired adipogenesis and triggered changes in the expression of insulin signaling-related genes. GATA-3 inhibition also modulated the expression of IL-6 and IL-10 and lowered the expression of insulin resistance biomarkers (PAI-1 and resistin) and insulin resistance phosphoproteins (p-BAD, p-PTEN and p-GSK3β). Inhibiting GATA-3 improves adipocytes differentiation, modulates the secretion of inflammatory cytokines and improves insulin sensitivity in insulin resistant cells. Suppression of GATA-3 could be a promising tool to improve adipogenesis, restore insulin sensitivity and lower obesity-associated inflammation in insulin resistant individuals.
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http://dx.doi.org/10.1016/j.cellsig.2020.109735DOI Listing
November 2020

Prevalence and Predictors of Insulin Resistance in Non-Obese Healthy Young Females in Qatar.

Int J Environ Res Public Health 2020 07 15;17(14). Epub 2020 Jul 15.

Human Nutrition Department, College of Health Science, QU-Health, Qatar University, Doha 2713, Qatar.

The state of Qatar suffers from diabetes epidemic due to obesity-associated metabolic syndrome. However, the prevalence of insulin resistance prior to obesity, which could play an important role in the high prevalence of diabetes, has not yet been described. This study aims to compare the prevalence of insulin resistance in apparently healthy non-obese and obese participants from Qatar and identify the predictors of insulin resistance in different body mass index (BMI)-groups. In this cross-sectional study, 150 young healthy females from Qatar were dichotomized into four groups (underweight, normal weight, overweight and obese) based on their BMI. Anthropometric measures as well as fasting plasma levels of lipids, adipokines, blood glucose and insulin were recorded. The prevalence of insulin resistance as per homeostatic model assessment of insulin resistance (HOMA-IR) was estimated and differences between insulin sensitive and insulin resistant were compared. Linear models were used to identify predictors of insulin resistance in every BMI group. Prevalence of insulin resistance in non-obese healthy females from Qatar ranges between 7% and 37% and increases with BMI. Overall, predictors of insulin resistance in the Qatari population are triglycerides/high-density lipoprotein (HDL) ratio and free fat mass but vary according to the BMI group. The main predictors were triglycerides in normal weight, triglycerides/HDL in overweight and triglycerides/HDL and interleukin-6 (IL-6) in obese individuals. The high prevalence of insulin resistance in non-obese Qataris may partially explain diabetes epidemic. Larger studies are warranted to confirm these findings and identify underlying causes for insulin resistance in non-obese individuals in Qatar, aiming at targeted intervention before diabetes onset.
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http://dx.doi.org/10.3390/ijerph17145088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399794PMC
July 2020

GATA-3 as a Potential Therapeutic Target for Insulin Resistance and Type 2 Diabetes Mellitus.

Curr Diabetes Rev 2021 ;17(2):169-179

Biomedical Research Center, Qatar University, Doha, Qatar.

Impaired adipogenesis plays an important role in the development of obesity-associated insulin resistance and type 2 diabetes as it leads to ectopic fat deposition. The anti-adipogenic transcription factor GATA-3 was identified as one of the potential molecular targets responsible for the impairment of adipogenesis. The expression of GATA-3 is higher in insulinresistant obese individuals compared to BMI-matched insulin-sensitive counterparts. Adipose tissue inflammation is a crucial mediator of this process. Hyperglycemia mediates the activation of the immune system, partially through upregulation of GATA- 3, causing exacerbation of the inflammatory state associated with obesity. This review discusses the evidence supporting the inhibition of GATA-3 as a useful therapeutic strategy in obesity-associated insulin resistance and type 2 diabetes, through up-regulation adipogenesis and amelioration of the immune response.
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http://dx.doi.org/10.2174/1573399816666200705210417DOI Listing
March 2021

Genome-Wide Association Study Reveals a Novel Association Between MYBPC3 Gene Polymorphism, Endurance Athlete Status, Aerobic Capacity and Steroid Metabolism.

Front Genet 2020 16;11:595. Epub 2020 Jun 16.

Biomedical Research Institute (BRC), Qatar University, Doha, Qatar.

Background: The genetic predisposition to elite athletic performance has been a controversial subject due to the underpowered studies and the small effect size of identified genetic variants. The aims of this study were to investigate the association of common single-nucleotide polymorphisms (SNPs) with endurance athlete status in a large cohort of elite European athletes using GWAS approach, followed by replication studies in Russian and Japanese elite athletes and functional validation using metabolomics analysis.

Results: The association of 476,728 SNPs of Illumina DrugCore Gene chip and endurance athlete status was investigated in 796 European international-level athletes (645 males, 151 females) by comparing allelic frequencies between athletes specialized in sports with high ( = 662) and low/moderate ( = 134) aerobic component. Replication of results was performed by comparing the frequencies of the most significant SNPs between 242 and 168 elite Russian high and low/moderate aerobic athletes, respectively, and between 60 elite Japanese endurance athletes and 406 controls. A meta-analysis has identified rs1052373 (GG homozygotes) in Myosin Binding Protein (; implicated in cardiac hypertrophic myopathy) gene to be associated with endurance athlete status ( = 1.43 × 10, odd ratio 2.2). Homozygotes carriers of rs1052373 G allele in Russian athletes had significantly greater VO than carriers of the AA + AG ( = 0.005). Subsequent metabolomics analysis revealed several amino acids and lipids associated with rs1052373 G allele (1.82 × 10) including the testosterone precursor androstenediol (3beta,17beta) disulfate.

Conclusions: This is the first report of genome-wide significant SNP and related metabolites associated with elite athlete status. Further investigations of the functional relevance of the identified SNPs and metabolites in relation to enhanced athletic performance are warranted.
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http://dx.doi.org/10.3389/fgene.2020.00595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308547PMC
June 2020

Metabolomics and doping analysis: promises and pitfalls.

Bioanalysis 2020 Jun 12;12(11):719-722. Epub 2020 Jun 12.

Biomedical Research Center (BRC), Qatar University, Doha, Qatar.

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http://dx.doi.org/10.4155/bio-2020-0137DOI Listing
June 2020

The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis.

Eur J Appl Physiol 2020 Mar 22;120(3):665-673. Epub 2020 Jan 22.

Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.

Purpose: Iron is an important component of the oxygen-binding proteins and may be critical to optimal athletic performance. Previous studies have suggested that the G allele of C/G rare variant (rs1799945), which causes H63D amino acid replacement, in the HFE is associated with elevated iron indexes and may give some advantage in endurance-oriented sports. The aim of the present study was to investigate the association between the HFE H63D polymorphism and elite endurance athlete status in Japanese and Russian populations, aerobic capacity and to perform a meta-analysis using current findings and three previous studies.

Methods: The study involved 315 international-level endurance athletes (255 Russian and 60 Japanese) and 809 healthy controls (405 Russian and 404 Japanese). Genotyping was performed using micro-array analysis or by PCR. VO in 46 male Russian endurance athletes was determined using gas analysis system.

Results: The frequency of the iron-increasing CG/GG genotypes was significantly higher in Russian (38.0 vs 24.9%; OR 1.85, P = 0.0003) and Japanese (13.3 vs 5.0%; OR 2.95, P = 0.011) endurance athletes compared to ethnically matched controls. The meta-analysis using five cohorts (two French, Japanese, Spanish, and Russian; 586 athletes and 1416 controls) showed significant prevalence of the CG/GG genotypes in endurance athletes compared to controls (OR 1.96, 95% CI 1.58-2.45; P = 1.7 × 10). Furthermore, the HFE G allele was associated with high V̇O in male athletes [CC: 61.8 (6.1), CG/GG: 66.3 (7.8) ml/min/kg; P = 0.036].

Conclusions: We have shown that the HFE H63D polymorphism is strongly associated with elite endurance athlete status, regardless ethnicities and aerobic capacity in Russian athletes.
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http://dx.doi.org/10.1007/s00421-020-04306-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042188PMC
March 2020

Metabolic GWAS of elite athletes reveals novel genetically-influenced metabolites associated with athletic performance.

Sci Rep 2019 12 27;9(1):19889. Epub 2019 Dec 27.

Biomedical Research Center, Qatar University, Doha, Qatar.

Genetic research of elite athletic performance has been hindered by the complex phenotype and the relatively small effect size of the identified genetic variants. The aims of this study were to identify genetic predisposition to elite athletic performance by investigating genetically-influenced metabolites that discriminate elite athletes from non-elite athletes and to identify those associated with endurance sports. By conducting a genome wide association study with high-resolution metabolomics profiling in 490 elite athletes, common variant metabolic quantitative trait loci (mQTLs) were identified and compared with previously identified mQTLs in non-elite athletes. Among the identified mQTLs, those associated with endurance metabolites were determined. Two novel genetic loci in FOLH1 and VNN1 are reported in association with N-acetyl-aspartyl-glutamate and Linoleoyl ethanolamide, respectively. When focusing on endurance metabolites, one novel mQTL linking androstenediol (3alpha, 17alpha) monosulfate and SULT2A1 was identified. Potential interactions between the novel identified mQTLs and exercise are highlighted. This is the first report of common variant mQTLs linked to elite athletic performance and endurance sports with potential applications in biomarker discovery in elite athletic candidates, non-conventional anti-doping analytical approaches and therapeutic strategies.
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http://dx.doi.org/10.1038/s41598-019-56496-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934758PMC
December 2019

Profiling the Oral Microbiome and Plasma Biochemistry of Obese Hyperglycemic Subjects in Qatar.

Microorganisms 2019 Dec 3;7(12). Epub 2019 Dec 3.

Biomedical Research Center, Qatar University, Doha 2713, Qatar.

The present study is designed to compare demographic characteristics, plasma biochemistry, and the oral microbiome in obese ( = 37) and lean control ( = 36) subjects enrolled at Qatar Biobank, Qatar. Plasma hormones, enzymes, and lipid profiles were analyzed at Hamad Medical Cooperation Diagnostic Laboratory. Saliva microbiome characterization was carried out by 16S rRNA amplicon sequencing using Illumina MiSeq platform. Obese subjects had higher testosterone and sex hormone-binding globulin (SHBG) concentrations compared to the control group. A negative association between BMI and testosterone ( < 0.001, r = -0.64) and SHBG ( < 0.001, r = -0.34) was observed. Irrespective of the study groups, the oral microbiome was predominantly occupied by , , and species. A generalized linear model revealed that the Firmicutes/Bacteroidetes ratio (2.25 ± 1.83 vs. 1.76 ± 0.58; corrected -value = 0.04) was higher, and phylum Fusobacteria concentration (4.5 ± 3.0 vs. 6.2 ± 4.3; corrected -value = 0.05) was low in the obese group compared with the control group. However, no differences in microbiome diversity were observed between the two groups as evaluated by alpha (Kruskal-Wallis ≥ 0.78) and beta (PERMANOVA = 0.37) diversity indexes. Certain bacterial phyla (Acidobacteria, Bacteroidetes, Fusobacteria, Proteobacteria, Spirochaetes, and Firmicutes/Bacteroidetes) were positively associated ( = 0.05, r ≤ +0.5) with estradiol, fast food consumption, creatinine, breastfed during infancy, triglycerides, and thyroid-stimulating hormone concentrations. In conclusion, no differences in oral microbiome diversity were observed between the studied groups. However, the Firmicutes/Bacteroidetes ratio, a recognized obesogenic microbiome trait, was higher in the obese subjects. Further studies are warranted to confirm these findings in a larger cohort.
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http://dx.doi.org/10.3390/microorganisms7120645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955820PMC
December 2019

Metabolic signature of obesity-associated insulin resistance and type 2 diabetes.

J Transl Med 2019 10 22;17(1):348. Epub 2019 Oct 22.

Weill Cornell Medicine-Qatar, Doha, Qatar.

Background: Obesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear.

Methods: In this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals.

Results: Our results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively.

Conclusion: This pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality.
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http://dx.doi.org/10.1186/s12967-019-2096-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805293PMC
October 2019

Liposome mediated-CYP1A1 gene silencing nanomedicine prepared using lipid film-coated proliposomes as a potential treatment strategy of lung cancer.

Int J Pharm 2019 Jul 30;566:185-193. Epub 2019 Apr 30.

Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China. Electronic address:

The occurrence of lung cancer is linked with tobacco smoking, mainly through the generation of polycyclic aromatic hydrocarbons (PAHs). Elevated activity of cytochrome P4501A1 (CYP1A1) plays an important role in the metabolic processing of PAHs and its carcinogenicity. The present work aimed to investigate the role of CYP1A1 gene in PAH-mediated growth and tumor development in vitro and using an in vivo animal model. RNAi strategy was utilized to inhibit the overexpression of CYP1A1 gene using cationic liposomes generated using a lipid film-coated proliposome microparticles. Treatment of PAH-induced human alveolar adenocarcinoma cell line with cationic liposomes carrying CYP1A1 siRNA resulted in down regulation of CYP1A1 mRNA, protein as well as its enzymatic activity, triggering apoptosis and inhibiting multicellular tumor spheroids formation in vitro. Furthermore, silencing of CYP1A1 gene in BALB/c nude xenografts inhibited tumor growth via down regulation of CYP1A1 expression. Altogether, our findings showed that liposome-based gene delivery technology is a viable and stable approach for targeting cancer causing genes such as CY1PA1. This technology facilitated by the use of sugar particles coated with lipid films has demonstrated ability to generate anticancer effects that might be used in the future for therapeutic intervention and treatment of lung cancer.
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http://dx.doi.org/10.1016/j.ijpharm.2019.04.078DOI Listing
July 2019

New Three-Dimensional Poly(decanediol-co-tricarballylate) Elastomeric Fibrous Mesh Fabricated by Photoreactive Electrospinning for Cardiac Tissue Engineering Applications.

Polymers (Basel) 2018 Apr 19;10(4). Epub 2018 Apr 19.

Pharmaceutics & Polymeric Drug Delivery Research Laboratory, College of Pharmacy, Qatar University, P.O. Box 2713, Doha, Qatar.

Reactive electrospinning is capable of efficiently producing in situ crosslinked scaffolds resembling the natural extracellular matrix with tunable characteristics. In this study, we aimed to synthesize, characterize, and investigate the in vitro cytocompatibility of electrospun fibers of acrylated poly(1,10-decanediol--tricarballylate) copolymer prepared utilizing the photoreactive electrospinning process with ultraviolet radiation for crosslinking, to be used for cardiac tissue engineering applications. Chemical, thermal, and morphological characterization confirmed the successful synthesis of the polymer used for production of the electrospun fibrous scaffolds with more than 70% porosity. Mechanical testing confirmed the elastomeric nature of the fibers required to withstand cardiac contraction and relaxation. The cell viability assay showed no significant cytotoxicity of the fibers on cultured cardiomyoblasts and the cell-scaffolds interaction study showed a significant increase in cell attachment and growth on the electrospun fibers compared to the reference. This data suggests that the newly synthesized fibrous scaffold constitutes a promising candidate for cardiac tissue engineering applications.
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http://dx.doi.org/10.3390/polym10040455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415264PMC
April 2018

Metabolic profiling of elite athletes with different cardiovascular demand.

Scand J Med Sci Sports 2019 Jul 29;29(7):933-943. Epub 2019 Apr 29.

Anti Doping Laboratory Qatar, Doha, Qatar.

Intensive exercise of elite athletes can lead to physiological alterations in the cardiovascular system in response to increased stroke volume and blood pressure, known collectively as cardiovascular demand (CD). This study aimed to compare metabolic differences in elite athletes with high vs low/moderate CD and to reveal their underlying metabolic pathways as potential biomarker signatures for assessing health, performance, and recovery of elite athletes. Metabolic profiling of serum samples from 495 elite athletes from different sport disciplines (118 high CD and 377 low/moderate CD athletes) was conducted using non-targeted metabolomics-based mass spectroscopy combined with ultra-high-performance liquid chromatography. Results show that DAGs containing arachidonic were enriched in high CD together with branched-chain amino acids, plasminogens, phosphatidylcholines, and phosphatidylethanolamines, potentially indicating increased risk of cardiovascular disease in the high CD group. Gamma-glutamyl amino acids and glutathione metabolism were increased in low/moderate CD group, suggesting more efficient oxidative stress scavenging mechanisms than the high CD group. This first most comprehensive metabolic profiling of elite athletes provides an evidence that athletes with different CD show a unique metabolic signature that reflects energy generation and oxidative stress and potentially places the high CD group at a higher risk of cardiovascular disease. Further studies are warranted for confirmation and validation of findings in other sport groups in light of potential confounders related to limited available information about participants.
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http://dx.doi.org/10.1111/sms.13425DOI Listing
July 2019

Metabolomics profiling of xenobiotics in elite athletes: relevance to supplement consumption.

J Int Soc Sports Nutr 2018 Sep 27;15(1):48. Epub 2018 Sep 27.

Anti Doping Laboratory Qatar, ADLQ, Sports City, P.O Box 27775, Doha, Qatar.

Background: Supplements are widely used among elite athletes to maintain health and improve performance. Despite multiple studies investigating use of dietary supplements by athletes, a comprehensive profiling of serum supplement metabolites in elite athletes is still lacking. This study aims to analyze the presence of various xenobiotics in serum samples from elite athletes of different sports, focusing on metabolites that potentially originate from nutritional supplements.

Methods: Profiling of xenobiotics in serum samples from 478 elite athletes from different sports (football, athletics, cycling, rugby, swimming, boxing and rowing) was performed using non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography. Multivariate analysis was performed using orthogonal partial least squares discriminant analysis. Differences in metabolic levels among different sport groups were identified by univariate linear models.

Results: Out of the 102 detected xenobiotics, 21 were significantly different among sport groups including metabolites that potentially prolong exercise tolerance (caffeic acid), carry a nootropic effect (2-pyrrolidinone), exert a potent anti-oxidant effect (eugenol, ferulic acid 4 sulfate, thioproline, retinol), or originate from drugs for different types of injuries (ectoine, quinate). Using Gaussian graphical modelling, a metabolic network that links various sport group-associated xenobiotics was constructed to further understand their metabolic pathways.

Conclusions: This pilot data provides evidence that athletes from different sports exhibit a distinct xenobiotic profile that may reflect their drug/supplement use, diet and exposure to various chemicals. Because of limitation in the study design, replication studies are warranted to confirm results in independent data sets, aiming ultimately for better assessment of dietary supplement use by athletes.
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http://dx.doi.org/10.1186/s12970-018-0254-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161339PMC
September 2018

Preparation and optimization of monodisperse polymeric microparticles using modified vibrating orifice aerosol generator for controlled delivery of letrozole in breast cancer therapy.

Drug Dev Ind Pharm 2018 Dec 25;44(12):1953-1965. Epub 2018 Sep 25.

a Pharmaceutics and Polymeric Drug Delivery Research Laboratory, College of Pharmacy , Qatar University , Doha , Qatar.

Letrozole (LTZ) is effective for the treatment of hormone-receptor-positive breast cancer in postmenopausal women. In this work, and for the first time, using vibrating orifice aerosol generator (VOAG) technology, monodisperse poly-ε-caprolactone (PCL), and poly (D, L-Lactide) (PDLLA) LTZ-loaded microparticles were prepared and found to elicit selective high cytotoxicity against cancerous breast cells with no apparent toxicity on healthy cells in vitro. Plackett-Burman experimental design was utilized to identify the most significant factors affecting particle size distribution to optimize the prepared particles. The generated microparticles were characterized in terms of microscopic morphology, size, zeta potential, drug entrapment efficiency, and release profile over one-month period. Long-term cytotoxicity of the microparticles was also investigated using MCF-7 human breast cancer cell lines in comparison with primary mammary epithelial cells (MEC). The prepared polymeric particles were monodispersed, spherical, and apparently smooth, regardless of the polymer used or the loaded LTZ concentration. Particle size varied from 15.6 to 91.6 µm and from 22.7 to 99.6 µm with size distribution (expressed as span values) ranging from 0.22 to 1.24 and from 0.29 to 1.48 for PCL and PDLLA based microparticles, respectively. Upon optimizing the manufacture parameters, span was reduced to 0.162-0.195. Drug entrapment reached as high as 96.8%, and drug release from PDLLA and PCL followed a biphasic zero-order release using 5 or 30% w/w drug loading in the formulations. Long-term in vitro cytotoxicity studies indicated that microparticles formulations significantly inhibited the growth of MCF-7 cell line over a prolonged period of time but did not have toxic effects on the normal breast epithelial cells.
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http://dx.doi.org/10.1080/03639045.2018.1503298DOI Listing
December 2018
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