Side-chain oxidized oxysterols as metabolic regulators in liver and brain

Oxysterols are oxygenated derivatives of cholesterol characterized by a very short half-life and their ability to pass lipophilic membranes easily, thus they are considered as important intermediates in cholesterol excretion pathways and its conversion to bile acids. The two major oxysterols in the circulation of human and mouse are 24S-hydroxycholesterol (24S-OH) and 27-hydroxycholesterol (27-OH), which are formed by the cytochrome P450 enzymes cholesterol 24-hydroxylase (CYP46A1) and sterol 27-hydroxylase (CYP27A1), respectively. The two oxysterols 27-OH and 24S-OH are both strong inhibitors of cholesterol synthesis and activators of LXR in vitro. However, their role as physio- logical regulators under in vivo conditions is controversial. The overall aim of this thesis was to investigate the regulatory role of side chain oxidized oxysterols as metabolic regulators in vivo. In particular we have studied the role of 24S-and 27-hydroxycholesterols (24S- and 27-OH) as regulators of cholesterol synthesis and activators of LXR. We used mouse models with increased levels of 27-OH (CYP27A1) transgenic mice and Cyp7b1 knock-out mice (Cyp7b1-/-) as well as a mouse model with no detectable levels of 27-OH in their circulation, Cyp27a1 knock-out mice (Cyp 27-/-). The latter mice were treated with cholic acid to compensate for the reduced formation of bile acids. In Paper I, we studied a possible regulatory role of 27-OH and 24S-OH in the brain using human CYP27A1 transgenic mice(CYP27A1tg) and Cyp27a1 knock-out (Cyp 27a1-/-) mice. The levels of 27-OH were increased about 12-fold in the brain of CYP27A1tg mice while the levels of 24S-OH was decreased by about 25%, most probably due to increased metabolism by the CYP27A1 enzyme. The mRNA levels of HMG-CoA reductase and HMG-CoA synthase in the brain were increased. In accordance with increased cholesterol synthesis, most of cholesterol precursors were also increased. The increased cholesterol synthesis is likely due to reduced inhibition by 24S-OH. 27-OH is an activator of LXR and in spite of this, there was no upregulation of the LXR-target genes in the brain of the transgenic mice. In contrast, some of the genes were downregulated. In Cyp27a1-/- mouse brain, cholesterol synthesis was slightly increased with increased levels of cholesterol precursors. The increased synthesis is probably the consequence of the absence of an inhibitory effect of the flux of 27-OH into the brain. The results of this study are consistent with the possibility that both 24S-OH and 27-OH have a suppressive effect on cholesterol synthesis in the brain. Since there was no activation of the LXR-target genes in the brain of the transgenic mice, we concluded that 27-OH is not a general activator of LXR in the brain. In Paper II, this study has examined the role of 27-OH in the liver using the above three mouse models. In the liver of CYP27A1tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1, and Abca1. There was no effect on a number of other LXR-regulated genes. There were no significant effects on cholesterol synthesis at the transcriptional level and cholesterol precursors were not affected as well. However, there was a modest decrease in T-MAS levels in the liver of CYP27A1tg mice. In the liver of the Cyp7b1-/-mice, there were also no effects on cholesterol synthesis neither at the transcriptional level nor in the levels of cholesterol precursors, with the exception of increase in desmosterol. In connection to the LXR-target genes in these mice, there were no differences in the expression between the Cyp7b1-/- and the wild type mice. If the high levels of 27-OH are important, the same effects would be expected in the two mouse models. In the liver of the Cyp27a1-/- mice there was a slight activation of some LXR- regulated genes, Abcg5, Abcg8, Fas and Srebp1c. If 27-OH is of importance as a normal activator of the above genes a suppressing effect would be expected. The overall results do not support the contention that 27-OH is an important regulator of cholesterol homeostasis or an activator of LXR-regulated genes under basal conditions in the liver. In conclusion our results suggest that both 24S-OH and 27-OH may be of some regulatory importance for cholesterol synthesis in the brain but not in the liver. Under normal basal conditions 27-OH does not seem to be a general activator of LXR neither in the brain nor in the liver. The different effects on cholesterol synthesis in the two organs may be related to the fact that almost all oxysterols in the brain are in the free form whereas most of them are esterified in the liver

Emirati female students pursing technical and vocational education and training (TVET): perceptions from the UAE

One way the United Arab Emirates uses to increase the employability skills of its nationals is by promoting and encouraging students to pursue technical and vocational education and training (TVET). This goal includes both female and male Emirati youth. However, studies show that females are still under-represented in TVET. Therefore, this study aims at exploring Emirati female students’ perceptions of their educational experiences in TVET, the challenges they faced, and their future expectations. The study followed a mixed methods design with data collected through an online survey. Findings revealed that participants have an overall positive educational experience despite the academic and cultural challenges they experience. They believe their vocational education enables them to have a better future be it a career or in continuing their education. Despite these positive influences, additional efforts are needed to improve vocational training and alter the mindset and perception of vocational education

Stressors and stress coping strategies of UAE school leaders

Through exploratory quantitative research, 120 school leaders in the United Arab Emirates (UAE) were found to have a moderate level of stress. School leaders have regularly sought social support and focused on the problem as strategies to cope with stress. There was no difference in the means of stress related to the leaders\u27 gender, marital status, age, years of experience, or school size and level. However, interpersonal relations and administrative responsibilities made the largest contribution to the prediction of coping strategies. Considering the quick changes aimed at by the national educational reform, leaders found themselves unaware of their new job descriptions and expectations. Leaders struggled with a combination of little autonomy, limited resources, bureaucracy and intensification, and increased responsibilities. Self-efficacy and self-motivation indicated perseverance in managing stress. School leaders, especially during a reform, face the burden of role expectations and administrative constraints due to changing requirements from authorities

INTERLEUKIN-16 RS4778889 POLYMORPHISM AND ITS INTERACTION WITH INTERLEUKIN-10 RS1800896 POLYMORPHISM INCREASE THE RISK FOR KNEE OSTEOARTHRITIS IN THE LEBANESE POPULATION

To investigate the effect Interleukin-16 (IL-16) and Interleukin-10 (IL-10) polymorphisms, and their interaction, on knee osteoarthritis (KOA) risk in the Lebanese population. Kompetitive Allele Specific PCR (KASP) genotyping assay was performed to determine IL-16 rs4778889, rs11556218, and rs4072111 and IL-10 rs1800896 polymorphisms in 118 patients diagnosed with KOA ( ≥ 2 points on Kellgren-Lawrence (K&L) radiological classification scale) and 70 controls matched for age and gender (K&L score ≤ 1). After adjusting for age, gender, presence of metabolic disorders, smoking and drinking status, our findings suggest that rs4778889 TT genotype increases the risk for KOA compared to the combined CC and TC genotypes (OR=2.131, 95% CI 1.037 – 4.379, p = 0.04) and that the T allele increases KOA risk compared to the C allele (OR=1.8, 95% CI 1.008 – 3.212, p = 0.047). No significant associations with the disease risk were found for the other studied polymorphisms (p \u3e 0.05). Our data suggest that there is an interaction between IL-16 rs4778889 and IL-10 rs1800896 (p = 0.010). IL-16 rs4778889 TT genotype increases the risk for KOA only among individuals carrying IL-10 rs1800896 GG or GA genotypes (OR=4.821, 95% CI 1.847 – 12.583). None of the IL-16 haplotypes was associated with KOA risk in our study population (p \u3e 0.05). Our findings suggest that IL-16 rs4778889 T allele is associated with KOA and that there is an interaction between this polymorphism and IL-10 rs1800896 with regard to KOA

Side-chain oxidized oxysterols as metabolic regulators in vivo

Oxysterols are oxygenated derivatives of cholesterol characterized by a very short half- life and their ability to pass lipophilic membranes easily, and they are considered as important intermediates in the excretion pathways of cholesterol and its conversion to bile acids. Evidence has been presented that the production and flux of oxysterols in the brain may also be of some importance for cognitive functions. The two major oxysterols in the circulation of human and mouse are 24S-hydroxycholesterol (24S- OH) and 27-hydroxycholesterol (27-OH), which are formed by the cytochrome P450 enzymes cholesterol 24-hydroxylase (CYP46A1) and sterol 27-hydroxylase (CYP27A1), respectively. The two oxysterols 27-OH and 24S-OH are both strong inhibitors of cholesterol synthesis and activators of LXR in vitro. However, their role as physiological regulators under in vivo conditions is controversial. The overall aim of this thesis was to investigate the regulatory role of side-chain oxidized oxysterols as metabolic regulators in vivo. In particular, we have studied the role of 24S-OH and 27-OH as regulators of cholesterol synthesis and activators of LXR. We used mouse models with increased levels of 27-OH like human CYP27A1 overexpressor mice (CYP27A1tg) and Cyp7b1 knockout mice (Cyp7b1-/-), as well as a mouse model with no detectable levels of 27-OH in the circulation, Cyp27a1 knockout mice (Cyp 27a1-/-). The latter mice were treated with cholic acid to compensate for the reduced formation of bile acids. Using Cyp27a1-/- mice, we have also studied the possibility that 27-OH mediates the negative effects of dietary cholesterol on memory function in mice. In Paper I, we studied a possible regulatory role of 27-OH and 24S-OH in the brain, using CYP27A1tg mice and Cyp27a1-/- mice. The levels of 27-OH were increased by approximately 12-fold in the brain of CYP27A1tg mice while levels of 24S-OH were decreased by about 25%, most probably due to increased metabolism by the CYP27A1 enzyme. Evidence was presented that cholesterol synthesis was increased in the brain of the two mouse models. There was no upregulation of the LXR-target genes in the brain of either of the two models. The increased synthesis in the brain of the Cyp27a1-/- mice is probably the consequence of the absence of an inhibitory effect of the flux of 27-OH into the brain. The increased cholesterol synthesis in the brain of the CYP27A1tg mice is probably due to the reduced levels of 24S-OH, leading to reduced inhibition of its synthesis. The results of this study are consistent with the possibility that both 24S-OH and 27-OH have a suppressive effect on cholesterol synthesis in the brain. We also conclude that 27-OH is not a general activator of LXR in this tissue. In Paper II, we examined the role of 27-OH in the liver using the three mouse models described above. Only very modest effects on cholesterol synthesis and LXR target genes were observed in the three mouse models. The overall results do not support the contention either that 27-OH is an important regulator of cholesterol homeostasis, or that 27-OH is an activator of LXR-regulated genes under basal conditions in the liver. It has been reported that treatment of mice with dietary cholesterol leads to upregulation of some LXR target genes in the liver. In a study by Chen et al, such upregulation of three different LXR target genes was not seen when treating mice lacking 24S-OH, 25-OH and 27-OH with dietary cholesterol (Chen et al., 2007). It was concluded that a 24-, 25- or 27-hydroxylation step mediated the effect of dietary cholesterol. We show here that similar effects were obtained when treating Cyp27a1-/- mice with dietary cholesterol, suggesting that the effects are mediated by 27-OH. Most of these effects could however not be observed at either the protein level, or at the level of enzyme activity. The results suggest that 27-OH is a mediator of the cholesterol-induced effects on some LXR target genes when the mice are challenged with a high load of dietary cholesterol. The physiological importance of this effect is difficult to evaluate. In Paper III we compared the two mouse models CYP27A1tg and Cyp7b1-/- mice, both of which have high levels of 27-OH in the circulation and the brain. In contrast to CYP27A1tg mice, the levels of 24S-OH in the brain were not decreased in the latter model, and cholesterol synthesis was not affected. This supports the proposal that 24S- OH is of regulatory importance for cholesterol synthesis in the brain. It has been reported that cholesterol synthesis is reduced in the kidney of Cyp7b1-/- mice. Cholesterol synthesis in the kidney of CYP27A1tg mice was not affected, however. We conclude that factors other than high levels of 27-OH are of importance for the reduced cholesterol synthesis in the kidney of the Cyp7b1-/- mice. In Paper IV we tested the possibility that the negative effect of dietary cholesterol on cognition in mice is mediated by 27-OH. The negative effect of dietary cholesterol on spatial memory observed in wild-type mice was not observed in Cyp27a1-/- mice. The latter mice were also treated with cholic acid to compensate for the reduced synthesis of bile acids. Treatment with dietary cholesterol was shown to lead to reduced levels of the “memory protein” Arc (Activity-Regulated Cytoskeleton-associated protein) in the hippocampus of the wildtype mice. This effect was not seen in the hippocampus of Cyp27a1-/- mice. The results are consistent with the possibility that 27-OH is a mediator of the negative effects of dietary cholesterol on cognition. In conclusion, our results suggest that both 24S-OH and 27-OH may be of some regulatory importance for cholesterol synthesis in the brain but not in the liver. Under normal basal conditions 27-OH does not seem to be a general activator of LXR, either in the brain or in the liver. We discuss the possibility that the different effects on cholesterol synthesis in the two organs may be related to the fact that almost all oxysterols in the brain are in the free form, whereas in the liver, most of them are esterified. In addition, we demonstrate that the negative effects of dietary cholesterol on cognition is mediated by 27-hydroxylation

The Effect of a Proposed Instructional Program Based on the Multiple Intelligences Theory on EFL Jordanian Ninth-Grade Students’ Achievement in English

Objectives: This study aimed to investigate the effect of a proposed instructional program based on Multiple Intelligences Theory (MIT) on ninth grade students’ achievement in English. Methods: The participants of the study consisted of 40 students in two sections who were randomly assigned to a control group (20 students) and to an experimental group (20 students). One research instrument was used to collect the data of the study; a comprehensive English achievement test of reading, writing, listening and speaking. Data were analysed using means, standard deviations, ANCOVA and MANCOVA. Results: The findings of the study indicated that there was a statistically significant difference (α=0.05) between the mean score of the students of the experimental group who were taught according to the (MIT) program and that the mean score of the control group who were taught based on the conventional method. This difference was in favour of the experimental group students since the adjusted mean score was (55.20), which was higher than the adjusted mean score of the control group (46.45). Conclusions: The proposed instructional program based on (MIT) was significantly more effective than the conventional method in developing students’ English language skills. The study recommends that (MIT) should be incorporated in English as a foreign language (EFL) curricula in Jordan to improve students’ English language skills

THE CORRELATION BETWEEN SPECIALTY CHOICE AND THE QUALITY OF LIFE OF LEBANESE PHYSICIANS

Doctors suffer a stressful life and are less satisfied than individuals in other careers. A trend has been observed among medical students in USA showing a change of specialty choice to alleviate their quality of life. Even though most medical students choose their career path based on the field they are most pleased with, it sounds reasonable to get an idea about the quality of life in the specialty they will elect to do. The objective of this study is to evaluate the correlation between specialty choice and the quality of life of Lebanese physicians, to see which specialties have the most favorable quality of life and present their personal level of satisfaction regarding their lifestyle. This study conducted an anonymous modified short form survey (SF-36) questionnaire and some demographic data among Lebanese physicians practicing in Lebanon. Data was collected via emails using Lime Survey then entered and analyzed on SPSS software version 23.1. P value less than 0.05 was considered significant. 470 complete responses were retrieved in this research by email via Lime Survey. Specialty choice had a significant effect only on three scales; physical functioning (p \u3c .001), social functioning (p \u3c .001) and role limitations due to emotional problems (p = .25), with no significant effect on energy and fatigue, emotional well-being, role limitations due to physical health, general health and pain. It was also found that specialty had significant effect on personal satisfaction (p =.016). The study concluded that Lebanese physicians who practice laboratory medicine, family medicine, and pathology specialties having the most favorable quality of life based on the scales assessed in the SF-36 and that those practicing pediatrics had lower levels of personal satisfaction compared to those with pathology specialty

Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome

International audiencen.

REVIEW ON CHEMICAL CONSTITUENTS AND BIOLOGICAL ACTIVITIES OF GENUS RUMEX

Genus Rumex belongs to the family Polygonaceae that is distributed worldwide and used in the treatment of different illnesses. Different parts of this plant are employed in the treatment of a number of ailments such as diarrhea, jaundice, hypertension, dermatopathy and inflammation. It was reported that they possess anti-oxidative, antimicrobial, antiviral and anti-cancer activities due to the presence of several phenolic constituents, anthraquinones and flavonoids such as rutin, luteolin and apigenin. Flavonoids play an important role against cardiovascular diseases by reducing oxidation of low-density lipoproteins. This article covers most of constituents of plants of genus Rumex reported from 2001 up to 2022. Furthermore, the biological activities of plants of genus Rumex are presented