ORCID Profile
0000-0003-3721-8225
Current Organisation
Hashemite University
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Publisher: Springer Science and Business Media LLC
Date: 11-04-2019
Publisher: Hindawi Limited
Date: 25-01-2021
DOI: 10.1155/2021/6678924
Abstract: Deletion polymorphism of glutathione S-transferase M1 (GSTM1), a phase II detoxification and antioxidant enzyme, increases susceptibility to end-stage renal disease (ESRD) as well as the development of cardiovascular diseases (CVD) among ESRD patients and leads to their shorter cardiovascular survival. The mechanisms by which GSTM1 downregulation contributes to oxidative stress and inflammation in endothelial cells in uremic conditions have not been investigated so far. Therefore, the aim of the present study was to elucidate the effects of GSTM1 knockdown on oxidative stress and expression of a panel of inflammatory markers in human umbilical vein endothelial cells (HUVECs) exposed to uremic serum. Additionally, we aimed to discern whether GSTM1-null genotype is associated with serum levels of adhesion molecules in ESRD patients. HUVECs treated with uremic serum exhibited impaired redox balance characterized by enhanced lipid peroxidation and decreased antioxidant enzyme activities, independently of the GSTM1 knockdown. In response to uremic injury, HUVECs exhibited alteration in the expression of a series of inflammatory cytokines including retinol-binding protein 4 (RBP4), regulated on activation, normal T cell expressed and secreted (RANTES), C-reactive protein (CRP), angiogenin, dickkopf-1 (Dkk-1), and platelet factor 4 (PF4). GSTM1 knockdown in HUVECs showed upregulation of monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in the regulation of monocyte migration and adhesion. These cells also have shown upregulated intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). In accordance with these findings, the levels of serum ICAM-1 and VCAM-1 (sICAM-1 and sVCAM-1) were increased in ESRD patients lacking GSTM1, in comparison with patients with the GSTM1-active genotype. Based on these results, it may be concluded that incubation of endothelial cells in uremic serum induces redox imbalance accompanied with altered expression of a series of cytokines involved in arteriosclerosis and atherosclerosis. The association of GSTM1 downregulation with the altered expression of adhesion molecules might be at least partly responsible for the increased susceptibility of ESRD patients to CVD.
Publisher: Future Medicine Ltd
Date: 09-2021
Abstract: Background: Overexpression of sFlt-1 or modulation of FKBPL, key antiangiogenic proteins, are important in the pathogenesis of preecl sia. Methods: A newly developed nonviral gene-delivery system, RALA, capable of overexpressing sFlt-1 (e15a isoform) was delivered in vivo in transgenic haploinsufficient ( Fkbpl +/− ) mice. RALA was also used in vitro to deliver human Flt1 (hFlt1) in trophoblast cells. Results: Serum stable and nontoxic RALA/DNA-based nanoparticles induced an increase in sFlt-1 protein levels in the blood and total protein in the urine the effect was more pronounced in Fkbpl +/− mice. In vitro, RALA-hFlt nanoparticles significantly reduced secretion of sFlt-1 in trophoblast cells. Conclusion: The RALA-based genetic nanodelivery system can be safely and effectively applied to emulate preecl sia-like features or reduce sFlt-1 levels in vitro.
Publisher: The Endocrine Society
Date: 03-07-2020
Abstract: Preecl sia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies. To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44. FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preecl sia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling. Human s les prediagnosis (15 and 20 weeks of gestation n ≥ 57), or postdiagnosis (n = 18 for plasma n = 4 for placenta) of preecl sia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid. Preecl sia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed. The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preecl sia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preecl sia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (& .5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis. The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preecl sia, showing promising utilities for early diagnostic and therapeutic purposes.
Publisher: Springer Science and Business Media LLC
Date: 27-10-2022
DOI: 10.1007/S11010-022-04591-1
Abstract: Immunophilins are a family of proteins encompassing FK506-binding proteins (FKBPs) and cyclophilins (Cyps). FKBPs and Cyps exert peptidyl-prolyl cis-trans isomerase (PPIase) activity, which facilitates erse protein folding assembly, or disassembly. In addition, they bind to immunosuppressant medications where FKBPs bind to tacrolimus (FK506) and rapamycin, whereas cyclophilins bind to cyclosporin. Some large immunophilins have domains other than PPIase referred to as tetratricopeptide (TPR) domain, which is involved in heat shock protein 90 (Hsp90) and heat shock protein 70 (Hsp 70) chaperone interaction. The TPR domain confers immunophilins' pleotropic actions to mediate various physiological and biochemical processes. So far, immunophilins have been implicated to play an important role in pathophysiology of inflammation, cancer and neurodegenerative disorders. However, their importance in the development of fibrosis has not yet been elucidated. In this review we focus on the pivotal functional and mechanistic roles of different immunophilins in fibrosis establishment affecting various organs. The vast majority of the studies reported that cyclophilin A, FKBP12 and FKBP10 likely induce organ fibrosis through the calcineurin or TGF-β pathways. FKBP51 demonstrated a role in myelofibrosis development through calcineurin-dependant pathway, STAT5 or NF-κB pathways. Inhibition of these specific immunophilins has been shown to decrease the extent of fibrosis suggesting that immunophilins could be a novel promising therapeutic target to prevent or reverse fibrosis.
Publisher: MDPI AG
Date: 04-01-2023
DOI: 10.3390/MOLECULES28020502
Abstract: Background: Isorhamnetin is a flavonoid that is found in medical plants. Several studies showed that isorhamnetin has anti-inflammatory and anti-obesity effects. This study aims to investigate the anti-diabetic effects of isorhamnetin in a high-fat diet and Streptozotocin-(HFD/STZ)-induced mice model of type 2 diabetes. Materials and Methods: Mice were fed with HFD followed by two consecutive low doses of STZ (40 mg/kg). HFD/STZ diabetic mice were treated orally with isorhamnetin (10 mg/kg) or (200 mg/kg) metformin for 10 days before sacrificing the mice and collecting plasma and soleus muscle for further analysis. Results: Isorhamnetin reduced the elevated levels of serum glucose compared to the vehicle control group (p 0.001). Isorhamnetin abrogated the increase in serum insulin in the treated diabetic group compared to the vehicle control mice (p 0.001). The homeostasis model assessment of insulin resistance (HOMA-IR) was decreased in diabetic mice treated with isorhamnetin compared to the vehicle controls. Fasting glucose level was significantly lower in diabetic mice treated with isorhamnetin during the intraperitoneal glucose tolerance test (IPGTT) (p 0.001). The skeletal muscle protein contents of GLUT4 and p-AMPK-α were upregulated following treatment with isorhamnetin (p 0.01). LDL, triglyceride, and cholesterol were reduced in diabetic mice treated with isorhamnetin compared to vehicle control (p 0.001). Isorhamnetin reduced MDA, and IL-6 levels (p 0.001), increased GSH levels (p 0.001), and reduced GSSG levels (p 0.05) in diabetic mice compared to vehicle control. Conclusions: Isorhamnetin ameliorates insulin resistance, oxidative stress, and inflammation. Isorhamnetin could represent a promising therapeutic agent to treat T2D.
Publisher: Cold Spring Harbor Laboratory
Date: 08-10-2020
DOI: 10.1101/2020.10.06.20208116
Abstract: Diabetes in pregnancy is associated with numerous complications, however the mechanisms are still poorly understood. To investigate the role of new angiogenesis markers, FKBPL and SIRT-1, in pre-gestational (type 1 diabetes, T1D) and gestational diabetes (GDM). Placental FKBPL, SIRT-1, PlGF and VEGF-R1 protein expression was determined from pregnant women with GDM or T1D, and in first trimester trophoblast cells exposed to high glucose and varying oxygen concentrations. Endothelial cell function was assessed in high glucose conditions and FKBPL overexpression. Human placental s les from pregnant women with GDM (n=6) or T1D (n=8) were collected to assess FKBPL and SIRT-1 protein expression compared to non-diabetic controls. To determine the role of placental FKBPL and/or SIRT-1 in diabetic pregnancies, in first trimester trophoblasts and endothelial cell function in high-glucose environment. Placental FKBPL protein expression was downregulated in T1D (FKBPL p .05) whereas PlGF/VEGF-R1 were upregulated (p .05) correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 (p .001) was significantly downregulated even when adjusted for gestational age (r=-0.92, p=0.001). FKBPL and SIRT-1 were also downregulated in ACH-3P cells in high glucose conditions and 6.5%/2.5% oxygen concentrations (p .05). FKBPL overexpression in HUVECs reduced tubule formation compared to empty vector control, in high glucose conditions (junctions p .01, branches p .05). FKBPL and/or SIRT-1 downregulation in response to diabetes may have a role in the development of vascular dysfunction in pregnancy, and associated complications such as preecl sia.
Publisher: MDPI AG
Date: 09-01-2023
Abstract: 2′,3,3,5′-Tetramethyl-4′-nitro-2′H-1,3′-bipyrazole (TMNB) is a novel bipyrazole compound with unknown therapeutic potential in diabetes mellitus. This study aims to investigate the anti-diabetic effects of TMNB in a high-fat diet and streptozotocin-(HFD/STZ)-induced rat model of type 2 diabetes mellitus (T2D). Rats were fed HFD, followed by a single low dose of STZ (40 mg/kg). HFD/STZ diabetic rats were treated orally with TMNB (10 mg/kg) or (200 mg/kg) metformin for 10 days before terminating the experiment and collecting plasma, soleus muscle, adipose tissue, and liver for further downstream analysis. TMNB reduced the elevated levels of serum glucose in diabetic rats compared to the vehicle control group (p 0.001). TMNB abrogated the increase in serum insulin in the treated diabetic group compared to the vehicle control rats (p 0.001). The homeostasis model assessment of insulin resistance (HOMA-IR) was decreased in the diabetic rats treated with TMNB compared to the vehicle controls. The skeletal muscle and adipose tissue protein contents of GLUT4 and AMPK were upregulated following treatment with TMNB (p 0.001, 0.01, respectively). TMNB was able to upregulate GLUT2 and AMPK protein expression in liver (p 0.001, 0.001, respectively). LDL, triglyceride, and cholesterol were reduced in diabetic rats treated with TMNB compared to the vehicle controls (p 0.001, 0.01, respectively). TMNB reduced MDA and IL-6 levels (p 0.001), and increased GSH level (p 0.05) in diabetic rats compared to the vehicle controls. Conclusion: TMNB ameliorates insulin resistance, oxidative stress, and inflammation in a T2D model. TMNB could represent a promising therapeutic agent to treat T2D.
Publisher: Frontiers Media SA
Date: 15-07-2021
DOI: 10.3389/FPHAR.2021.695418
Abstract: The perturbation in plasma free amino acid metabolome has been observed previously in diabetes mellitus, and is associated with insulin resistance as well as the onset of cardiovascular disease in this population. In this study, we investigated, for the first time, changes in the amino acid profile in a group of people with and without type 2 diabetes (T2D) with normal BMI, from Jordan, who were only managed on metformin. Twenty one amino acids were evaluated in plasma s les from 124 people with T2D and 67 healthy controls, matched for age, gender and BMI, using amino acids analyser. Total amino acids, essential amino acids, non-essential amino acids and semi-essential amino acids were similar in T2D compared to healthy controls. Plasma concentrations of four essential amino acids were increased in the presence of T2D (Leucine, p & 0.01, Lysine, p & 0.001, Phenylalanine, p & 0.01, Tryptophan, p & 0.05). On the other hand, in relation to non-essential amino acids, Alanine and Serine were reduced in T2D ( p & 0.01, p & 0.001, respectively), whereas Aspartate and Glutamate were increased in T2D compared to healthy controls ( p & 0.001, p & 0.01, respectively). A semi-essential amino acid, Cystine, was also increased in T2D compared to healthy controls ( p & 0.01). Citrulline, a metabolic indicator amino acid, demonstrated lower plasma concentration in T2D compared to healthy controls ( p & 0.01). These amino acids were also correlated with fasting blood glucose and HbA1c ( p & 0.05). Glutamate, glycine and arginine were correlated with the duration of metformin treatment ( p & 0.05). No amino acid was correlated with lipid profiles. Disturbances in the metabolism of these amino acids are closely implicated in the pathogenesis of T2D and associated cardiovascular disease. Therefore, these perturbed amino acids could be explored as therapeutic targets to improve T2D management and prevent associated cardiovascular complications.
Publisher: Wiley
Date: 14-01-2018
DOI: 10.1111/DME.13523
Abstract: To perform meta-analyses of studies evaluating the risk of pre-ecl sia in high-risk insulin-resistant women taking metformin prior to, or during pregnancy. A search was conducted of the Medline, EMBASE, Web of Science and Scopus databases. Both randomized controlled trials and prospective observational cohort studies of metformin treatment vs. placebo/control or insulin either prior to or during pregnancy were selected. The main outcome measure was the incidence of pre-ecl sia in each treatment group. Overall, in five randomized controlled trials comparing metformin treatment (n = 611) with placebo/control (n = 609), no difference in the risk of pre-ecl sia was found [combined ooled risk ratio (RR), 0.86 (95% CI 0.33-2.26) P = 0.76 I In studies randomizing pregnant women to glucose-lowering therapy, metformin was associated with lower gestational weight gain and a lower risk of pre-ecl sia compared with insulin.
Publisher: Frontiers Media SA
Date: 02-06-2021
DOI: 10.3389/FENDO.2021.650328
Abstract: Diabetes in pregnancy is associated with adverse pregnancy outcomes including preterm birth. Although the mechanisms leading to these pregnancy complications are still poorly understood, aberrant angiogenesis and endothelial dysfunction play a key role. FKBPL and SIRT-1 are critical regulators of angiogenesis, however, their roles in pregnancies affected by diabetes have not been examined before in detail. Hence, this study aimed to investigate the role of FKBPL and SIRT-1 in pre-gestational (type 1 diabetes mellitus, T1D) and gestational diabetes mellitus (GDM). Placental protein expression of important angiogenesis proteins, FKBPL, SIRT-1, PlGF and VEGF-R1, was determined from pregnant women with GDM or T1D, and in the first trimester trophoblast cells exposed to high glucose (25 mM) and varying oxygen concentrations [21%, 6.5%, 2.5% (ACH-3Ps)]. Endothelial cell function was assessed in high glucose conditions (30 mM) and following FKBPL overexpression. Placental FKBPL protein expression was downregulated in T1D (FKBPL p& .05) whereas PlGF/VEGF-R1 were upregulated (p& .05) correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 was significantly downregulated (p& .05) even when adjusted for gestational age (r=-0.92, p=0.001). Both FKBPL and SIRT-1 protein expression was reduced in ACH-3P cells in high glucose conditions associated with 6.5%/2.5% oxygen concentrations compared to experimental normoxia (21% p& .05). FKBPL overexpression in endothelial cells (HUVECs) exacerbated reduction in tubule formation compared to empty vector control, in high glucose conditions (junctions p& .01, branches p& .05). In conclusion, FKBPL and/or SIRT-1 downregulation in response to diabetic pregnancies may have a key role in the development of vascular dysfunction and associated complications affected by impaired placental angiogenesis.
Publisher: Cold Spring Harbor Laboratory
Date: 26-02-2021
DOI: 10.1101/2021.02.24.21252345
Abstract: The disturbances in plasma free amino acid metabolome in diabetes mellitus was studied before but not in Jordanian population. This study aimed to assess the association between type 2 diabetes (T2D) and amino acid metabolome in a representative group of people from Jordan. Blood s les from 124 people with T2D and 67 age-, gender- and BMI-matched healthy controls were collected and assayed for glucose and HbA1c. Twenty one amino acids belonging to different categories (essential, non-essential, semi-essential, and metabolic indicators) were evaluated in both groups using amino acids analyser. Plasma free amino acids concentrations of total amino acids, total essential amino acids, total non-essential amino acids, and total semi-essential amino acids were not different in T2D compared to healthy controls. However, plasma concentrations of four essential amino acids (Leucine, Lysine, Phenylalanine, Tryptophan) were increased in the presence of T2D (Leucine, p .01, Lysine, p .001, Phenylalanine, p .01, Tryptophan, p .05). Conversely, amongst the non-essential amino acids, Alanine and Serine were reduced in type 2 diabetes (Alanine, p .01, Serine, p .001), whereas, Aspartate and Glutamate were increased in T2D compared to healthy control plasma (Aspartate, p .001, Glutamate, p .01). A semi-essential amino acid, Cystine, was also increased in T2D compared to healthy controls (p .01). Citrulline, a metabolic indicator amino acid, demonstrated lower plasma concentration in T2Dcompared to healthy controls (p .01). Several amino acids from different categories are dysregulated in T2D, which could be used as a therapeutic target to improve T2D management and its complications.
Publisher: Springer Science and Business Media LLC
Date: 23-10-2017
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Abdelrahim Alqudah.