Search

The prevalence of type 2 diabetes mellitus (T2DM) is steadily increasing worldwide in an alarming fashion. Importantly, poor glycemic control is associated with development of various health sequalae's due to glucolipotoxicity, oxidative stress and increased inflammatory cytokines. The aim of the present study was to examine the effect of glycemic control on the relative abundance of inflammatory markers in patients with controlled and uncontrolled T2DM, and to test their association with the glycemic status in diabetic patients in Jordan. An observational cross-sectional study design was used. Patients with T2DM with controlled diabetes [glycated hemoglobin (HbA1c) ≤7.0%, n=110] and age-, sex- and body mass index (BMI)-matched uncontrolled diabetic patients (HbA1c >7.0%, n=105) were recruited. An antibody membrane array was used to examine the relative abundance of inflammatory cytokines and growth factors in the sera of the study subjects, followed by enzyme-linked immunosorbent assay (ELISA) to confirm the results. Fasting blood glucose, serum insulin, triglyceride and homeostatic model assessment for insulin resistance (HOMA-IR) score were significantly elevated in the uncontrolled T2DM group (P<0.05). Antibody membrane array showed that serum epidermal growth factor (EGF) is significantly decreased in the uncontrolled T2DM group, and this was confirmed by ELISA (158.77±111.7 vs. 95.9±82.7 pg/ml, P=0.002). The binary logistic model was used to predict the likelihood of being uncontrolled diabetic based on EGF levels. After controlling for age, sex and BMI, EGF was statistically associated with diabetes control, where lower EGF levels predicted uncontrolled diabetes. Additionally, Pearson's product-moment correlation showed a statistically significant negative correlation between EGF and HbA1c (r=-0.25, P<0.0001), and a positive correlation between HOMA-IR and HbA1c, (r=0.32, P<0.0001). The current data identify a novel link between serum EGF levels and the status of HbA1c indicative of diabetic control. [ABSTRACT FROM AUTHOR]

The production of pro-inflammatory cytokines and chemokines is increased during inflammatory bowel disease (IBD). Previously, it was demonstrated that brain derived neurotrophic factor (BDNF) expression is increased in experimental models of colitis. BDNF is partially responsible for the structural and functional changes that take place during IBD. However, the exact mechanisms underlying the upregulation of BDNF during gut inflammation are unknown. The aim of the present study was to determine the effects of direct treatment of smooth muscle cells with inflammatory cytokines on the synthesis and secretion of BDNF. BDNF expression and secretion levels were measured using ELISA kits on tissue lysates and on incubation media used to culture the rat colon smooth muscle tissues treated for 24 h with either tumor necrosis factor (TNF)-α or interleukin (IL)-1β. Compared with the control tissue samples, treatment with TNF-α and IL-1β resulted in a significant increase in the protein expression levels of BDNF in the incubated smooth muscle tissue. TNF-α and IL-1β also stimulated the secretion of BDNF. Chelation of intracellular Ca2+ with BABTA-AM prevented the TNF-α and IL-1β-induced increase in BDNF protein expression and secretion levels. Furthermore, inhibition of protein kinase A (PKA) significantly reduced BDNF expression levels when treated with cytokines but not secretion. In conclusion, proinflammatory cytokines that are upregulated during IBD, directly stimulated BDNF expression and secretion in a Ca2+ dependent manner. Considering the ability of BDNF to enhance smooth muscle contraction and pain sensation, this autocrine loop may partially explain the characteristic hypercontractility and hypersensitivity associated with IBD. [ABSTRACT FROM AUTHOR]

Previous studies have shown that progesterone could inhibit muscle contraction in various sites of the gastrointestinal tract. The underlying mechanisms responsible for these inhibitory effects of progesterone are not fully known. The aim of the current study was to investigate the effect of progesterone on the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway and muscle contraction in the stomach. Single gastric smooth muscle cells from female Sprague-Dawley rats were used. The expression of progesterone receptor (PR) mRNA was analyzed by reverse transcription polymerase chain reaction. NO and cGMP levels were measured via specific ELISAs. Acetylcholine (ACh)-induced contraction of single gastric muscle cells preincubated with progesterone was measured via scanning micrometry in the presence or absence of the NO synthase inhibitor, Nω-Nitro-L-arginine (L-NNA), or guanylyl cyclase inhibitor, 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and expressed as percent shortening from resting cell length. PR expression was detected in the stomach muscle cells. Progesterone inhibited ACh-induced gastric muscle cell contraction. Furthermore, progesterone increased NO and cGMP levels in single gastric muscle cells. Most notably, pre-incubation of muscle cells with either L-NNA or ODQ abolished the inhibitory action of progesterone on muscle contraction. These present observations suggest that progesterone promotes muscle cell relaxation in the stomach potentially via the NO/cGMP pathway. [ABSTRACT FROM AUTHOR]

Peroxynitrite can be produced in the vasculature from a superoxide anion reaction with nitric oxide. A surplus of peroxynitrite in the intravascular compartment is a common feature of several chronic diseases. The development of pharmacological modalities that interfere with the formation of peroxynitrite or inhibit its oxidative damage may be of utility for the prevention and/or treatment of several pathologies. Our previous investigations showed that catalytically inactivating peroxynitrite-derived free radicals with tempol or scavenging reactive aldehyde species with phenelzine protects the blood plasma and platelets from the oxidative damage of peroxynitrite. However, the degree of inhibition of the cytotoxic effects of peroxynitrite using tempol or phenelzine was modest. In the present study, the aim was to examine if scavenging lipid peroxyl radicals with U-83836E can achieve superior protection from peroxynitrite. This was assessed by treating blood plasma or platelets with 100 µM peroxynitrite alone or in combination with U-83836E, and then measuring the levels of thiobarbituric acid reactive substances (TBARS) and protein carbonyl formation as indices of lipid peroxidation and protein oxidation, respectively. It was observed that scavenging lipid peroxyl radicals with 75–100 µM U-83836E increasingly reversed protein carbonylation induced by peroxynitrite in blood plasma and platelets, in addition to TBARS formation in blood plasma. These findings are further discussed in the context of the mechanisms by which U-83836E may protect against the cell-damaging effects of peroxynitrite. [ABSTRACT FROM AUTHOR]

Various gastrointestinal (GI) disorders have a higher prevalence in women than in men. In addition, estrogen has been demonstrated to have an inhibitory effect on the contractility of GI smooth muscle. Although increased plasma estrogen levels have been implicated in GI disorders, the role of gastric estrogen receptor (ER) in these sex-specific differences remains to be fully elucidated. The present study was designed to investigate the sex-associated differences in the expression of the two ER isoforms, ERα and ERβ, and the effect of estrogen on gastric muscle contraction via the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. Experiments were performed on single gastric smooth muscle cells (GSMCs) isolated from male and female Sprague Dawley rats. The effect of acetylcholine (ACh), a muscarinic agonist, on the contraction of GSMCs was measured via scanning micrometry in the presence or absence of 1 µM 17β-estradiol (E2), an agonist to the majority of ERs, 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), an ERa agonist, or diarylpropionitrile (DPN), an ERβ agonist. The protein expression levels of ER subtypes in GSMCs were measured using a specifically designed ELISA. GSMCs from female rats had a higher expression of ERα and ERβ protein compared with GSMCs from males. ACh induced less contraction in female that in male GSMCs. Pre-treatment of GSMCs with E2 reduced the contraction of GSMCs from both sexes, but to a greater extent in those from females. PPT and DPN inhibited ACh-induced contraction in GSMCs from females. Furthermore, E2 increased NO and cGMP levels in GSMCs from males and females; however, higher levels were measured in females. Of note, pre-incubation of female GSMCs with Nω-nitro-L-arginine, a NO synthase inhibitor, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a guanylyl cyclase inhibitor, reduced the inhibitory effect of estrogen on GSMC contraction. In conclusion, estrogen relaxes GSMCs via an NO/cGMP-dependent mechanism, and the reduced contraction in GSMCs from females by estrogen may be associated with the sex-associated increased expression of ERα and ERß, and greater production of NO and cGMP, compared with that in GSMCs from males. [ABSTRACT FROM AUTHOR]

Evidence of sex-related differences in gastrointestinal (GI) functions has been reported in the literature. In addition, various GI disorders have disproportionate prevalence between the sexes. An essential step in the initiation of smooth muscle contraction is the phosphorylation of the 20-kDa regulatory myosin light chain (MLC20) by the Ca2+/calmodulin-dependent myosin light chain kinase (MLCK). However, whether male stomach smooth muscle inherits different contractile signaling mechanisms for the regulation of MLC20 phosphorylation from that in females has not been established. The present study was designed to investigate sex-associated differences in the regulation of MLC20 phosphorylation and thus muscle contraction in gastric smooth muscle cells (GSMCs). Experiments were performed on GSMCs freshly isolated from male and female rats. Contraction of the GSMCs in response to acetylcholine (ACh), a muscarinic agonist, was measured via scanning micrometry in the presence or absence of the MLCK inhibitor, ML-7. Additionally, the protein levels of MLC20, MLCK and phosphorylated MLC20 were measured by ELISA. The protein levels of MLC20 and MLCK were indifferent between the sexes. ACh induced greater contraction (P<0.05) as well as greater MLC20 phosphorylation (P<0.05) in male GSMCs compared with female. Pretreatment of GSMCs with ML-7 significantly reduced the ACh-induced contraction (P<0.05) and MLC20 phosphorylation (P<0.05) in the male and female cells, and notably, abolished the contractile differences between the sexes. In conclusion, MLC20 phosphorylation and thus muscle contraction may be activated to a greater extent in male rat stomach compared with that in females. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a leading cause of death. The prevalence of T2DM in countries of the Middle East and North Africa (MENA) region, including Jordan, is among the highest worldwide. The reason(s) behind the epidemic nature of T2DM in Jordan are unknown but warrant further exploration. Studies have indicated that T2DM could be influenced by diet and/or genetic background. Evidence suggests that numerous patients with T2DM are deficient in vitamin D. The activity of vitamin D on its target tissues may be influenced by single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene. It was therefore hypothesized that SNPs in VDR could modify the risk of T2DM. To test this hypothesis, 125 patients with T2DM were recruited along with 125 controls. The study subjects were genotyped for variations in rs2228570, rs1544410, rs7975232, and rs731236 SNPs in the VDR. The levels of 25-hydroxyvitamin D [25(OH)D] were measured from the serum. The analysis revealed that reduced 25(OH)D and age were associated with the risk of T2DM (P<0.05). Moreover, under a dominant inheritance model, the GG genotype of rs2228570 was revealed to increase the risk of T2DM in univariate and multivariate analysis (P<0.05). Additionally, a chromosomal block containing the GAAG haplotype of VDR SNPs increased the risk of T2DM (OR=1.909; CI: 1.260-2.891; P=0.0021). Collectively, the present study revealed that low levels of serum 25(OH)D and rs2228570 of the VDR gene are associated with the risk of T2DM. [ABSTRACT FROM AUTHOR]

Diabetes Mellitus (DM) currently ranks as the most common endocrine disorder worldwide. Current opinion views DM as a group of heterogeneous metabolic diseases characterized by hyperglycemia triggered by defects in the ability of the body to produce or use insulin in type 1 and 2 DM, respectively. Brain-derived neurotrophic factor (BDNF), one of the neurotrophin family of growth factors, has been linked to the pathogenesis of DM and insulin resistance. Moreover, vitamin D has been associated with insulin resistance and DM. Recently, the interactions between vitamin D and BDNF have been investigated in diabetic rats. However, this correlation has never been investigated in humans. Thus, the aim of the present study was to assess the alterations in serum BDNF and vitamin D levels in T2DM patients in Jordan, prior to and following vitamin D supplementation. A combination of non-experimental case-control and experimental designed studies were utilized to assess the relationship between serum BDNF and vitamin D levels in T2DM patients. The levels of BDNF and vitamin D were measured using commercially available ELISA kits, and fasting blood glucose (FBG) and HbA1c levels were measured in medical labs. The results showed that diabetic patients had lower levels of serum vitamin D and higher levels of BDNF compared with the healthy controls. Moreover, linear regression analysis indicated that BDNF levels were inversely correlated with serum vitamin D levels. Furthermore, vitamin D supplementation significantly increased vitamin D serum levels and decreased BDNF serum levels in diabetic patients. Intriguingly, FBG and HbA1c levels were significantly improved post vitamin D supplementation. These data demonstrate a positive effect of vitamin D supplementation in diabetic patients suggesting the implementation of vitamin D as part of future T2DM treatment plans. However, additional studies are needed to investigate the direct link between vitamin D, BDNF, and T2DM. [ABSTRACT FROM AUTHOR]

OTHMAN A. AL.SHBOUL SP 1 sp , AYMAN G. MUSTAFA SP 2,4 sp , AMAL ABU OMAR SP 2 sp , AHMED N. AL.DWAIRI SP 1 sp , MOHAMMAD A. ALQUDAH SP 1 sp , MONA S. NAZZAL SP 1 sp , MAHMOUD A. ALFAQIH SP 1 sp , and RAMI A. AL.HADER SP 3 sp Departments of SP 1 sp Physiology and Biochemistry, and SP 2 sp Anatomy, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110; SP 3 sp Department of Physiology and Biochemistry, Princess Basma Teaching Hospital, Faculty of Medicine, Jordan University of Science and Technology, Irbid 21110, Jordan I Correspondence to i : Dr Othman A. Al-Shboul, Department of Physiology and Biochemistry, Faculty of Medicine, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan. [Extracted from the article]

After the publication of the above paper, the last-listed author, Ayman Mustafa, realized that his present address (Qatar University, Doha, Qatar) should have been included in the correspondence information for the manuscript. Departments of SP 1 sp Physiology and Biochemistry, and SP 2 sp Anatomy, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan I Correspondence to i : Dr Othman A. Al-Shboul, Department of Physiology and Biochemistry, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan. [Extracted from the article]