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1.
Article in English | MEDLINE | ID: mdl-38954387

ABSTRACT

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of global mortality. Early intervention and prevention of CVD depend on accurately predicting the risk of CVD. This study aimed to investigate the association between the TyG index and the risk of coronary heart disease (CHD), congestive heart failure (CHF), heart attack (HA), stroke, and hypertension (HTN) among patients without diabetes in the United States. METHODS: In this retrospective, cross-sectional study, we used data from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2020. We conducted several regression analysis models and calculated the sensitivity and specificity of (TyG) index for predicting the onset of CHD, CHF, HA, stroke, and HTN. RESULTS: A total of 10,937 individuals without diabetes participated in our study. Individuals with a TyG index greater than 8.96 displayed significant increasing in various parameters, including BMI, systolic/diastolic blood pressure, total cholesterol, LDL, and Apo-B levels (p < 0.001). Almost all regression models ensured that a higher TyGI value was associated with higher odds of having CHD, CHF, HA, stroke, and HTN, which patients with a TyGI value higher than 8.96 have odds ratios of 2.24-5.58 for CHD, 1.68-4.42 for stroke, 2.45-3.77 for HA and 1.75-3.93 for HTN comparing than patients with a TyGI value lower than 8.11 (p-value < 0.05).We evaluated the predictive value of the TyG index for each endpoint, obtaining the following area under the curve (AUC) values: 54.75% for CHF (95% CI: 0.542-0.614), 52.32% for stroke (95% CI: 0.529-0.584), 55.67% for HA (95% CI: 0.595-0.646), 55.59% for HTN (95% CI: 0.574-0.597), and 50.31% for CHD (95% CI: 0.592-0.646). CONCLUSION: The TyG index showed a strong correlation with cardiovascular risk factors in individuals without diabetes, however it was a poor predictor of almost studied cardiovascular diseases.

2.
BMC Public Health ; 24(1): 938, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38561740

ABSTRACT

BACKGROUND: Vitamin D deficiency is an importance preventable problem in the global and associates with lack levels of awareness about vitamin D. According to prior studies, in the Arab world, there is low of knowledge and awareness toward vitamin D deficiency. The target of our study is evaluating the knowledge level about vitamin D deficiency and determining the associated factors with levels of awareness of its. METHOD: This online cross-sectional study was performed in Syria between 25 February to 29 March 2023 to assess the levels of knowledge about vitamin D deficiency among general Syrian population. The study's survey was obtained from previously published research and we conducted a pilot study to assure the validity and clarity questionnaire. All Syrian individuals aged 18 or older who were able to read and write and willing to participate were included, while, non-Syrian nationality individuals and all medical staff (doctors, nurses, and medical students…), as well, those under 18 age were excluded. The questionnaire consisted of 23 questions separated into four categories. The first section was sociodemographic information of the study population. The second section measured the level awareness of the study population regarding the benefits of vitamin D. In addition, the third and fourth part evaluated knowing of the respondents about sources of and toxicity consequences of vitamin D. The data were analyzed by utilizing multivariate logistic regression in IBM, SPSS V.28 version. RESULTS: Overall, 3172 of the study population accepted to participate in this research and 57.9% the majority of them were aged in the range among 18 and 28. While, the average age of the respondents were 30.80 ± 11.957. Regarding with the awareness toward knowledge of advantages and source of vitamin D and outcomes of vitamin D toxicity. Most of the participants mentioned that vitamin D is used to treat bone disease and rickets and contributes in maintaining calcium and phosphates (91.4% and 84.6%, respectively). Whereas, more than half of them reported that sun exposure does not cause vitamin D poisoning and that vegetarians are more likelihood to have vitamin D than non-vegetarians, (54.1% and 54.9%, respectively). Only, age and occupation out of nine predictors variables were significantly correlated with adequate knowledge of Vitamin D (p-value < 0.05). The respondents aged more than 60 years were high probability to have good recognition of Vitamin D than participants aged between 18 and 28 years. (OR = 7.95). Retired participants have shown lower aware of Vitamin D 0.38 times than students. CONCLUSION: Our research revealed that most of the participated individuals have sufficient comprehension about vitamin D, despite, there were significant gap. Health education via programs by government health-care agencies, NGOs and social workers is necessary to increase the awareness and knowledge toward benefits, source, deficiency and toxicity of vitamin D to avoid injury several diseases such as rickets.


Subject(s)
Rickets , Students, Medical , Vitamin D Deficiency , Humans , Adolescent , Young Adult , Adult , Cross-Sectional Studies , Syria/epidemiology , Pilot Projects , Vitamin D Deficiency/epidemiology , Vitamin D , Rickets/complications , Vitamins
3.
BMC Pregnancy Childbirth ; 24(1): 185, 2024 Mar 07.
Article in English | MEDLINE | ID: mdl-38454336

ABSTRACT

BACKGROUND: Pre-eclampsia (PE) is a major contributor to morbidity and mortality in mothers worldwide. Adequate understanding of this condition improves treatment, control, and prevention. This study evaluated preeclampsia awareness among pregnant women in Syria, and the characteristics related to awareness adequacy. METHODS: This national cross-sectional study was conducted in Syria between 25 October and November 19, 2022. We included pregnant females of all age groups from all Syrian governorates. The questionnaire consisted of sociodemographic characteristics and knowledge of pre-eclampsia and its associated factors, symptoms, and complications. RESULTS: Overall, 706 participants were involved in this research, with a mean age of 38.22. Only 52.1% of them reported that they had heard of preeclampsia. Among the participants, 56.5% stated that they would not terminate a pregnancy if they were determined to be likely to develop preeclampsia, while nearly 55.2% agreed to continue the pregnancy rather than deliver prematurely even if their where a potential risk on their health risks. Participants who reported a family history of PE or had already experienced PE were more likely to have appropriate preeclampsia knowledge than those who did not (OR = 2.27, OR = 3.18, respectively). Respondents aged 25 to 35 years had the highest knowledge scores, and participants living in cities scored higher knowledge than rural residents. CONCLUSION: According to our findings, pregnant women in Syria have a awareness gaps regarding the PE topic. This highlights the need to enhance women's preeclampsia understanding for better pregnancy outcomes. Education through organizations, the media, and national programs is a significant aspect that promotes an adequate understanding of preeclampsia.


Subject(s)
Pre-Eclampsia , Female , Pregnancy , Humans , Adult , Pre-Eclampsia/diagnosis , Pre-Eclampsia/epidemiology , Pre-Eclampsia/prevention & control , Pregnant Women , Cross-Sectional Studies , Syria , Mothers
4.
Cureus ; 16(2): e54162, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38496080

ABSTRACT

INTRODUCTION: Liver disease is among the leading causes of global mortality and morbidity. Given their substantial impact on public health, raising awareness about liver diseases is paramount for their prevention and effective management. This study aimed to evaluate the knowledge, awareness, attitudes, and behaviors of Syrians regarding liver health, chronic liver disorders, and their associated serious and irreversible complications. METHODS: We conducted a cross-sectional study encompassing the adult Syrian population between August 25 and September 29, 2023, excluding non-Syrians and individuals below the age of 18 years. A validated questionnaire, adapted from a previous study, was employed, consisting of 31 questions that covered topics related to knowledge and awareness of liver health and diseases (3-point Likert scale), attitudes towards liver screening, diagnosis, and treatment, and awareness of treatment options and vaccination. Statistical analysis including logistic regression was conducted using Statistical Product and Service Solutions (SPSS, version 28; IBM SPSS Statistics for Windows, Armonk, NY), with statistical significance set established at pp-values below 0.05. RESULTS: This study included 941 participants, with an average age of 26.5 years. While two-thirds of respondents demonstrated awareness of hepatitis B and C as viral diseases (663 (70.4%) and 612 (65.4%), respectively), approximately 66 (7%) were unaware of the potential for hepatitis to induce chronic liver inflammation or lead to liver failure. Over half of the participants were knowledgeable about the non-genetic nature of hepatitis B and C, and 579 (61.7%) were informed about the transmission risks associated with these infections. The most common reason cited for not participating in health screening tests was the perception of being in good health (219, 77.4%), and prescription medication was the most frequently sought treatment for hepatitis (543, 83.9%). Bivariate analysis revealed correlations between participant knowledge and sex, socioeconomic status, educational level, and occupation (P < 0.05). Similarly, the study identified significant associations between participant attitudes and age, gender, economic status, job, and educational level (P < 0.05). Moreover, the multivariate analysis demonstrated that gender, occupation, and educational level significantly influenced both participants' knowledge and attitudes. Specifically, males exhibited lower knowledge and less favorable attitudes than females (P = 0.041 and P < 0.001, respectively). CONCLUSION: The Syrian population possessed moderate knowledge of liver health and liver disorders. To bridge this knowledge gap and enhance preventive measures, it is recommended that additional health programs and awareness initiatives be implemented, involving healthcare providers and leveraging their expertise.

5.
Cureus ; 15(11): e49171, 2023 Nov.
Article in English | MEDLINE | ID: mdl-38130568

ABSTRACT

Ventricular septal defect (VSD) is common in pediatric patients. This study aimed to evaluate the safety and effectiveness of using fast-track anesthesia and comparing it to traditional anesthesia, among children undergoing a transthoracic device closure for VSD. A systematic review following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. Relevant literature was identified through specific search terms in the Scopus, Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (Embase), Web of Science, The Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar databases. The inclusion criteria focused on observational studies that compared fast-track anesthesia with conventional anesthesia in pediatric VSD closure cases. Data extraction, quality assessment, and meta-analysis were performed using standard differences in means. Initially, 6,535 papers were identified, and subsequent screening of titles and abstracts led to the inclusion of four retrospective studies from a total of 51 studies. The analysis encompassed 477 patients, with 235 in the fast-track anesthesia group and 242 in the conventional anesthesia group. No statistically significant disparities were observed between the two groups concerning the operative duration and hemodynamic variations post-intubation or post-procedure (P >0.05). Nevertheless, the fast-track anesthesia group demonstrated significantly reduced healthcare expenses as well as shorter periods of mechanical ventilation, ICU stay, and overall hospitalization compared to conventional anesthesia (P <0.05). The use of fast-track anesthesia in combination with transthoracic device closure for VSD demonstrates a safe and effective approach for pediatric patients. This approach results in reduced healthcare costs (10,000 Renminbi (RMB)) and shorter durations of mechanical ventilation, ICU admission, and hospitalization compared to conventional anesthesia. Further clinical trials are necessary to confirm these results and assess long-term outcomes.

6.
Microsyst Nanoeng ; 9: 74, 2023.
Article in English | MEDLINE | ID: mdl-37303832

ABSTRACT

Electrostatic microelectromechanical (MEMS) switches are the basic building blocks for various radio-frequency (RF) transceivers. However, conventional cantilever-based designs of MEMS switches require a large actuation voltage, exhibit limited RF performance, and suffer from many performance tradeoffs due to their flat geometries restricted in two dimensions (2D). Here, by leveraging the residual stress in thin films, we report a novel development of three-dimensional (3D) wavy microstructures, which offer the potential to serve as high-performance RF switches. Relying on standard IC-compatible metallic materials, we devise a simple fabrication process to repeatedly manufacture out-of-plane wavy beams with controllable bending profiles and yields reaching 100%. We then demonstrate the utility of such metallic wavy beams as RF switches achieving both extremely low actuation voltage and improved RF performance owing to their unique geometry, which is tunable in three dimensions and exceeds the capabilities of current state-of-the-art flat-cantilever switches with 2D-restricted topology. As such, the wavy cantilever switch presented in this work actuates at voltages as low as 24 V while simultaneously exhibiting RF isolation and insertion loss of 20 dB and 0.75 dB, respectively, for frequencies up to 40 GHz. Wavy switch designs with 3D geometries break through the design limits set by traditional flat cantilevers and provide an additional degree of freedom or control knob in the switch design process, which could enable further optimization of switching networks used in current 5G and upcoming 6G communication scenarios.

7.
Sensors (Basel) ; 21(21)2021 Oct 27.
Article in English | MEDLINE | ID: mdl-34770445

ABSTRACT

In this paper, a dual-polarized four-port 2 × 2 series fed antenna array operating at 28 GHz with beam-switching capability is proposed. The antenna array uses a simple passive beamforming network to switch the main beam. The presented antenna design is suitable for 5G user equipment and high data rates applications by which it has a compact size with low cost and complexity. The size of the antenna is 37.2 × 37.2 mm2 including the ground plane, and it produces 10 different switched beams by using only two simple 3 dB/90∘ couplers which create the required amplitudes and phase excitations for the antenna elements. A one-port simple feeding mechanism including Peregrine PE42525 SPDT switch modules and a power divider is used to generate and measure the 10 switched beams. The antenna design is implemented on a two-layer 0.203 mm thick low-loss (tanδ = 0.0027) Rogers 4003C substrate, and it has a measured 10 dB impedance bandwidth of 4 GHz (14.3%, from 26 GHz to 30 GHz) for all ports. Measured peak isolation between any dual-polarized ports of the antenna is better than 30 dB. The antenna has an average measured realized gain of 8.9 dBi and around 10 dB side lobe level (SLL) for all beams. The antenna has 3-dB coverage of 80∘ to 90∘ in 2D space and it has a maximum of ±26∘ beam-steering angle. The antenna is designed and simulated using Ansys HFSS and fabricated using regular PCB processing.

8.
Clin Oral Implants Res ; 32(5): 539-548, 2021 May.
Article in English | MEDLINE | ID: mdl-33565656

ABSTRACT

OBJECTIVE: The objective of this randomized controlled trial was to evaluate the radiographic changes and histologic healing following alveolar ridge preservation (ARP) using autogenous whole tooth (AWTG), test group, versus autogenous demineralized dentin graft (ADDG), control group. MATERIAL AND METHODS: Twenty non-molar teeth indicated for extraction were randomized into two groups (n = 10/group). Extracted teeth were prepared into AWTG or ADDG (0.6N HCl; 30 min), inserted into extraction sockets and covered by collagen membranes. Cone-beam computed tomography (CBCT) scans at baseline and six months were compared to assess ridge-dimensional changes. At six months, bone biopsies of engrafted sites were harvested and analyzed histomorphometrically. RESULTS: All sites healed uneventfully. Reduction was 0.85 ± 0.38 mm and 1.02 ± 0.45 mm in ridge width, 0.61 ± 0.20 mm and 0.72 ± 0.27 mm in buccal and 0.66 ± 0.31 mm and 0.56 ± 0.24 mm in lingual ridge height for the AWTG and ADDG group, respectively (p > .05). Histologically, no inflammatory reactions were noticeable and all samples showed new bone formation. Qualitatively, graft-bone amalgamations were more pronounced in ADDG samples. Histomorphometrically, new bone, graft remnants and soft tissue occupied 37.55% ± 8.94%, 17.05% ± 5.58% and 45.4% ± 4.06% of the areas in the AWTG group and 48.4% ± 11.56%, 11.45% ± 4.13% and 40.15% ± 7.73% in the ADDG group of the examined areas, respectively (p > .05). CONCLUSIONS: AWTG and ADDG are similarly effective in ARP. Yet, histologically ADDG seems to demonstrate better graft remodeling, integration and osteoinductive properties.


Subject(s)
Alveolar Bone Loss , Alveolar Ridge Augmentation , Alveolar Bone Loss/diagnostic imaging , Alveolar Bone Loss/prevention & control , Alveolar Process/diagnostic imaging , Alveolar Process/surgery , Dentin , Humans , Tooth Extraction , Tooth Socket/diagnostic imaging , Tooth Socket/surgery
9.
Front Immunol ; 11: 568795, 2020.
Article in English | MEDLINE | ID: mdl-33584642

ABSTRACT

The mechanisms of diabetic retinopathy (DR), are not yet fully understood. We previously demonstrated an upregulation of retinal bone morphogenetic protein-2 (BMP2) in experimental diabetes and in retinas of diabetic human subjects. The purpose of current study was to investigate the role of non-canonical inflammatory pathway in BMP2-induced retinal endothelial cell (REC) barrier dysfunction. For this purpose, we used RT-PCR and western blotting to evaluate the levels of BMP2 signaling components (BMP2, BMP4, BMP receptors), VEGF, phosphorylated p38 MAPK and NFκB, and oxidative stress markers in cultured human retinal endothelial cells (HRECs) subjected to BMP2 (50ng/ml) for up to 24 h. Also, effect of high glucose (HG, 30mM D-glucose) on the expression of BMP2 and its downstream genes was examined in HRECs. H2-DCF is a fluorogenic dye that measures the levels of cellular reactive oxygen species (ROS) was used to measure the pro-oxidative effect of BMP2. Moreover, we evaluated the effect of inhibiting p38 and VEGF signaling on BMP2-induced HRECs barrier dysfunction by measuring the trans-endothelial cell electrical resistance (TER) using electric cell-substrate impedance sensing (ECIS). We also tested the effect of HG on the integrity of HRECs barrier in the presence or absence of inhibitors of BMP2 signaling. Our data reveals that BMP2 and high glucose upregulates BMP components of the BMP signaling pathway (SMAD effectors, BMP receptors, and TGFß ligand itself) and induces phosphorylation of p38 MAPK and NFκB with nuclear translocation of NFκB. Inhibition of p38 or NFκB attenuated BMP2-induced VEGF expression and barrier dysfunction in HRECs. Also, inhibition of VEGFR2 attenuated BMP2-induced barrier dysfunction. Moreover, BMP2 induces generation of ROS and endothelial nitric oxide synthase (eNOS) expression and activity in HRECs. Finally, HG upregulated BMP2 and its downstream genes (SMAD, BMP4, ALKs, and TGF-ß) in HRECs and BMP2 inhibitors attenuated HG-induced HRECs barrier dysfunction. Our results suggest that in addition to the regular canonical SMAD signaling BMP2 induces non-canonical inflammatory pathway in HRECs via activation of p38/NFκB pathway that causes the upregulation of VEGF and the disruption of HRECs. Inhibition of BMP2 signaling is a potential therapeutic intervention to preserve endothelial cell barrier function in DR.


Subject(s)
Bone Morphogenetic Protein 2/immunology , Endothelial Cells/immunology , Retina/cytology , Animals , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Type 1/immunology , Diabetic Retinopathy/immunology , Humans , Inflammation/immunology , Mice, Inbred C57BL , Oxidative Stress
10.
Diabetologia ; 61(5): 1220-1232, 2018 05.
Article in English | MEDLINE | ID: mdl-29468369

ABSTRACT

AIMS/HYPOTHESIS: Our earlier studies have established the role of 12/15-lipoxygenase (LO) in mediating the inflammatory reaction in diabetic retinopathy. However, the exact mechanism is still unclear. The goal of the current study was to identify the potential role of endoplasmic reticulum (ER) stress as a major cellular stress response in the 12/15-LO-induced retinal changes in diabetic retinopathy. METHODS: We used in vivo and in vitro approaches. For in vivo studies, experimental diabetes was induced in wild-type (WT) mice and 12/15-Lo (also known as Alox15) knockout mice (12/15-Lo-/-); ER stress was then evaluated after 12-14 weeks of diabetes. We also tested the effect of intravitreal injection of 12-hydroxyeicosatetraenoic acid (HETE) on retinal ER stress in WT mice and in mice lacking the catalytic subunit of NADPH oxidase, encoded by Nox2 (also known as Cybb) (Nox2-/- mice). In vitro studies were performed using human retinal endothelial cells (HRECs) treated with 15-HETE (0.1 µmol/l) or vehicle, with or without ER stress or NADPH oxidase inhibitors. This was followed by evaluation of ER stress response, NADPH oxidase expression/activity and the levels of phosphorylated vascular endothelial growth factor receptor-2 (p-VEGFR2) by western blotting and immunoprecipitation assays. Moreover, real-time imaging of intracellular calcium (Ca2+) release in HRECs treated with or without 15-HETE was performed using confocal microscopy. RESULTS: Deletion of 12/15-Lo significantly attenuated diabetes-induced ER stress in mouse retina. In vitro, 15-HETE upregulated ER stress markers such as phosphorylated RNA-dependent protein kinase-like ER-regulated kinase (p-PERK), activating transcription factor 6 (ATF6) and protein disulfide isomerase (PDI) in HRECs. Inhibition of ER stress reduced 15-HETE-induced-leucocyte adhesion, VEGFR2 phosphorylation and NADPH oxidase expression/activity. However, inhibition of NADPH oxidase or deletion of Nox2 had no effect on ER stress induced by the 12/15-LO-derived metabolites both in vitro and in vivo. We also found that 15-HETE increases the intracellular calcium in HRECs. CONCLUSIONS/INTERPRETATION: ER stress contributes to 12/15-LO-induced retinal inflammation in diabetic retinopathy via activation of NADPH oxidase and VEGFR2. Perturbation of calcium homeostasis in the retina might also play a role in linking 12/15-LO to retinal ER stress and subsequent microvascular dysfunction in diabetic retinopathy.


Subject(s)
Arachidonate 15-Lipoxygenase/metabolism , Diabetic Retinopathy/metabolism , Endoplasmic Reticulum Stress , Endoplasmic Reticulum/metabolism , Retinal Vessels/metabolism , 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid/chemistry , Animals , Apoptosis , Calcium/metabolism , Catalytic Domain , Cell Line , Endothelial Cells/metabolism , Humans , Inflammation , Leukocytes/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Confocal , NADPH Oxidases/metabolism , Phosphorylation , Signal Transduction , Vascular Endothelial Growth Factor Receptor-2/metabolism
11.
Sci Rep ; 7(1): 11952, 2017 09 20.
Article in English | MEDLINE | ID: mdl-28931831

ABSTRACT

Hyperhomocysteinemia (HHcy) is associated with several human visual disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Breakdown of the blood-retinal barrier (BRB) is linked to vision loss in DR and AMD. Our previous work revealed that HHcy altered BRB in retinal endothelial cells in vivo. Here we hypothesize that homocysteine (Hcy) alters retinal endothelial cell barrier function and angiogenic potential via activation of oxidative stress. Human retinal endothelial cells (HRECs) treated with and without different concentrations of Hcy showed a reduction of tight junction protein expression, increased FITC dextran leakage, decreased transcellular electrical resistance and increased angiogenic potential. In addition, HRECs treated with Hcy showed increased production of reactive oxygen species (ROS). The anti-oxidant N-acetyl-cysteine (NAC) reduced ROS formation and decreased FITC-dextran leakage in Hcy treated HRECs. A mouse model of HHcy, in which cystathionine-ß-synthase is deficient (cbs -/-), was evaluated for oxidative stress by dichlolorofluorescein (DCF), dihydroethidium (DHE) staining. There was a marked increase in ROS production and augmented GSH reductase and antioxidant regulator NRF2 activity, but decreased antioxidant gene expression in retinas of hyperhomocysteinemic mice. Our results suggest activation of oxidative stress as a possible mechanism of HHcy induced retinal endothelial cell dysfunction.


Subject(s)
Endothelial Cells/pathology , Hyperhomocysteinemia/complications , Hyperhomocysteinemia/pathology , Neovascularization, Pathologic/pathology , Oxidative Stress , Retina/pathology , Retinal Diseases/pathology , Animals , Cells, Cultured , Disease Models, Animal , Humans , Mice, Inbred C57BL , Permeability
12.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1862(6): 636-645, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28351645

ABSTRACT

AIMS: Our previous studies have established a role for 12/15-lipoxygenase (LO) in mediating the inflammatory response in diabetic retinopathy (DR). However, the extent at which the local or systemic induction of 12/15-LO activity involved is unclear. Thus, the current study aimed to characterize the relative contribution of retinal endothelial versus monocytic/macrophagic 12/15-LO to inflammatory responses in DR. MATERIALS & METHODS: We first generated a clustered heat map for circulating bioactive lipid metabolites in the plasma of streptozotocin (STZ)-induced diabetic mice using liquid chromatography coupled with mass-spectrometry (LC-MS) to evaluate changes in circulating 12/15-LO activity. This was followed by comparing the in vitro mouse endothelium-leukocytes interaction between leukocytes isolated from 12/15-LO knockout (KO) versus those isolated from wild type (WT) mice using the myeloperoxidase (MPO) assay. Finally, we examined the effects of knocking down or inhibiting endothelial 12/15-LO on diabetes-induced endothelial cell activation and ICAM-1 expression. RESULTS: Analysis of plasma bioactive lipids' heat map revealed that the activity of circulating 12/15-LO was not altered by diabetes as evident by no significant changes in the plasma levels of major metabolites derived from 12/15-lipoxygenation of different PUFAs, including linoleic acid (13-HODE), arachidonic acid (12- and 15- HETEs), eicosapentaenoic acid (12- and 15- HEPEs), or docosahexaenoic acid (17-HDoHE). Moreover, leukocytes from 12/15-LO KO mice displayed a similar increase in adhesion to high glucose (HG)-activated endothelial cells as do leukocytes from WT mice. Furthermore, abundant proteins of 12-LO and 15-LO were detected in human retinal endothelial cells (HRECs), while it was undetected (15-LO) or hardly detectable (12-LO) in human monocyte-like U937 cells. Inhibition or knock down of endothelial 12/15-LO in HRECs blocked HG-induced expression of ICAM-1, a well-known identified important molecule for leukocyte adhesion in DR. CONCLUSION: Our data support that endothelial, rather than monocytic/macrophagic, 12/15-LO has a critical role in hyperglycemia-induced ICAM-1 expression, leukocyte adhesion, and subsequent local retinal barrier dysfunction. This may facilitate the development of more precisely targeted treatment strategies for DR.


Subject(s)
Arachidonate 12-Lipoxygenase/metabolism , Arachidonate 15-Lipoxygenase/metabolism , Diabetic Retinopathy/enzymology , Endothelial Cells/enzymology , Leukostasis/enzymology , Macrophages/enzymology , Monocytes/enzymology , Retina/enzymology , Animals , Arachidonate 12-Lipoxygenase/genetics , Arachidonate 15-Lipoxygenase/genetics , Cell Adhesion/genetics , Diabetic Retinopathy/genetics , Diabetic Retinopathy/pathology , Endothelial Cells/pathology , Humans , Intercellular Adhesion Molecule-1/biosynthesis , Intercellular Adhesion Molecule-1/genetics , Leukostasis/genetics , Leukostasis/pathology , Macrophages/pathology , Mice , Mice, Knockout , Monocytes/pathology , Retina/pathology , U937 Cells
13.
Invest Ophthalmol Vis Sci ; 58(2): 933-943, 2017 02 01.
Article in English | MEDLINE | ID: mdl-28170537

ABSTRACT

Purpose: We recently demonstrated that adenosine deaminase-2 (ADA2) contributes to diabetic retinopathy (DR) via up-regulating the production of inflammatory cytokines in macrophages. Also, microRNA (miR)-146b-3p has the ability to inhibit ADA2. The goal of this study was to investigate the potential role of ADA2 and therapeutic benefit of miR-146b-3p in retinal inflammation and endothelial barrier dysfunction during diabetes. Methods: Adenosine deaminase-2 activity was determined by colorimetric method in diabetic human vitreous. Human monocyte cell line U937 was differentiated into macrophages and then treated with amadori glycated albumin (AGA), and conditioned medium (CM) was used to assess the changes in ADA2 activity and TNF-α and IL-6 levels by ELISA. Also, macrophages were transfected with miR-146b-3p before treatment with AGA. Permeability of human retinal endothelial cells (hRECs) was assessed by electric cell-substrate impedance sensing (ECIS) after treatment with macrophage CM. Zonula occludens (ZO)-1 was examined by immuno-fluorescence in hRECs. Leukocyte adhesion was assessed in hRECs by measuring myeloperoxidase (MPO) activity and intercellular adhesion molecule-1 (ICAM-1) expression. Results: Adenosine deaminase-2 activity was significantly increased in diabetic human vitreous. ADA2 activity and TNF-α and IL-6 levels were significantly increased in human macrophages by AGA treatment. Amadori glycated albumin-treated macrophage CM significantly increased hREC permeability, disrupted ZO-1 pattern, and increased leukocyte adhesion to hRECs through up-regulating ICAM-1. All these changes were reversed by miR-146b-3p. Conclusions: Adenosine deaminase-2 is implicated in breakdown of the blood-retinal barrier (BRB) in DR through macrophages-derived cytokines. Therefore, inhibition of ADA2 by miR-146b-3p might be a useful tool to preserve BRB function in DR.


Subject(s)
Adenosine Deaminase/metabolism , Capillary Permeability/drug effects , Diabetic Retinopathy/drug therapy , Endothelial Cells/metabolism , MicroRNAs/pharmacology , Retina/metabolism , Retinal Vessels/metabolism , Adenosine Deaminase/drug effects , Blotting, Western , Cell Line , Cytokines/metabolism , Diabetic Retinopathy/metabolism , Diabetic Retinopathy/pathology , Endothelial Cells/drug effects , Enzyme-Linked Immunosorbent Assay , Glycation End Products, Advanced , Humans , Retina/pathology , Retinal Vessels/drug effects , Serum Albumin/pharmacology , Tight Junctions/metabolism , Glycated Serum Albumin
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