Evaluation of vascular endothelial growth factor A and leukemia inhibitory factor expressions at the time of implantation in diabetic rats following treatment with Metformin and Pioglitazone

Background: Implantation requires intimate crosstalk between the embryo and uterus for a successful establishment of pregnancy. Type 2 diabetes mellitus may lead to implantation failure. The effect of diabetes and its therapeutic drugs on implantation is still largely unclear. Objective: To assess the endometrial expression changes of vascular endothelial growth factor A (VEGFA) and leukemia inhibitory factor (LIF), at the time of implantation in diabetic rats following treatment with Metformin and Pioglitazone. Materials and Methods: Twenty-eight 6-8-wk-old Wistar female rats weighing 200- 250 gr were divided into four groups (n = 7/each). Type 2 diabetes was induced and Metformin and Pioglitazone were applied for 4 wk. The expression of VEGFA and LIF was measured by real-time reverse transcription-polymerase chain reaction and Western blot. Results: The relative expression of VEGFA transcript was higher in the diabetic (p = 0.02) and Metformin-treated (p = 0.04) rats compared to the control group. Furthermore, the VEGFA transcript level significantly reduced in Pioglitazone-treated diabetic rats (p = 0.03). LIF expression was elevated in the Metformin- and the Pioglitazone-treated rats and reduced in the diabetic group in comparison with the control group. Compared to the diabetic rats, the expression of LIF was significantly elevated in the Metformin- (p = 0.01) and Pioglitazone-treated (p = 0.03) groups. Conclusion: The expressions of LIF and VEGFA were altered in diabetic rats during implantation which may be associated with diabetic-related infertility. Pioglitazone is able to restore the VEGFA and LIF expressions to their baseline levels more efficiently than Metformin. Key words: Embryo implantation, Leukemia inhibitory factor, Vascular endothelial growth factor A, Metformin, Pioglitazone, Rats

Neuromyelitis optica in a pregnant woman with systemic lupus erythematous: A case report.

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Effects of fostriecin on β2-adrenoceptor-driven responses in human mast cells

As part of the intracellular processes leading to mast cell and basophil activation, phosphorylation of key substrates is likely to be important. These processes, mediated by phosphatases, are responsible for regulating phosphorylation. The aim of the present study was to determine effects fostriecin – a selective inhibitor of PP2A (protein phosphatase-2) – on β2-adrenoceptor-driven responses in human mast cells. Here, the effects of fostriecin (PP inhibitors) on the inhibition of histamine release from HLMC, on β-adrenoceptor-driven responses in mast cells and on desensitization were investigated. Long-term incubation (24 h) of mast cells with fostriecin (10−6 M) resulted in a significant (p < 0.001) reduction in the maximal response (from 41.2 [± 3.0] to 29.9 [± 4.2] %) to salbutamol following fostriecin treatment. The results showed that fostriecin pretreatment significantly attenuated the inhibitory effects of salbutamol. Overall, the present study suggested that PP2A has an important role in regulating mast cell β2-adrenoceptors

Diabetes mellitus increased integrins gene expression in rat endometrium at the time of embryo implantation

Background: Diabetes mellitus deeply changes the genes expression of integrin (Itg) subunits in several cells and tissues such as monocytes, arterial endothelium, kidney glomerular cells, retina. Furthermore, hyperglycemia could impress and reduce the rate of successful assisted as well as non-assisted pregnancy. Endometrium undergoes thorough changes in normal menstrual cycle and the question is: What happens in the endometrium under diabetic condition? Objective: The aim of the current study was to investigate the endometrial gene expression of α3, α4, αv, Itg β1 and β3 subunits in diabetic rat models at the time of embryo implantation. Materials and Methods: Twenty-eight rats were randomly divided into 4 groups: control group, diabetic group, pioglitazone-treated group, and metformin-treated group. Real-time PCR was performed to determine changes in the expression of Itg α3, α4, αv, β1, and β3 genes in rat’s endometrium. Results: The expression of all Itg subunits increased significantly in diabetic rats’ endometrium compared with control group. Treatment with pioglitazone significantly reduced the level of Itg subunits gene expression compared with diabetic rats. While metformin had a different effect on α3 and α4 and elevated these two subunits gene expression. Conclusion: Diabetes mellitus significantly increased the expression of studied Itg subunits, therefore untreated diabetes could be potentially assumed as one of the preliminary elements in embryo implantation failure

Comparative Analysis of Apigenin-3 Acetate versus Apigenin and Methyl-Prednisolone in Inhibiting Proliferation and Gene Expression of Th1 Cells in Multiple Sclerosis

Objective: In spite of the advances in therapeutic modalities, morbidity, due to multiple sclerosis (MS), still remains high.Therefore, a large body of research is endeavouring to discover or develop novel therapies with improved efficacy fortreating MS patients. In the present study, we examined the immunomodulatory effects of apigenin (Api) on peripheralblood mononuclear cells (PBMCs) isolated from MS patients. We also developed an acetylated form of Api (apigenin-3-acetate) to improve In its blood-brain barrier (BBB) permeability. Additionally, we compared its anti-inflammatoryproperties to original Api and methyl-prednisolone-acetate (a standard therapy), as a potential option in treating MSpatients.Materials and Methods: The current study was an experimental-interventional research. The half maximal inhibitoryconcentration (IC50) values for apigenin-3-acetate, apigenin, and methyl-prednisolone-acetate were determined inhealthy volunteers’ PBMCs (n=3). Gene expressions of T-box transcription factor (TBX21 or T-bet) and IFN-γ, as wellas proliferation of T cells isolated from MS patients’ PBMCs (n=5), were examined in co-cultures of apigenin-3-acetate,Api and methyl-prednisolone-acetate after 48 hours of treatment, using quantitative reverse transcription polymerasechain reaction (qRT-PCR).Results: Our findings showed that apigenin-3-acetate, apigenin, and methyl-prednisolone-acetate at concentrations of80, 80, and 2.5 M could inhibit Th1 cell proliferation after 48 hours (P=0.001, P=0.036, and P=0.047, respectively); theyalso inhibited T-bet (P=0.015, P=0.019, and P=0.022) and interferon-γ (IFN-γ) gene expressions (P=0.0001).Conclusion: Our findings suggested that Api may have anti-inflammatory properties, possibly by inhibiting proliferationof IFN-producing Th1 cells. Moreover, comparative immunomodulatory effects were found for the acetylated version ofapigenin-3-acetate versus Api and methyl-prednisolone-acetate

Oleuropein as An Effective Suppressor of Inflammation and MicroRNA-146a Expression in Patients with Rheumatoid Arthritis

Objective: Rheumatoid arthritis (RA) is a common progressive autoimmune disorder that causes chronic inflammationof the joints and damage to other organs. Previous studies have reported the important role of miRNA-146a in thepathogenesis of RA. In addition, the anti-inflammatory and modulatory effects of oleuropein (OLEU) on the expressionpattern of microRNAs (miRNAs) have been shown in different diseases. Therefore, this study aimed to evaluate boththe sensitivity and specificity of miRNA-146a and determine the potential effects of OLEU on the expression levels ofmiRNA-146a and tumour necrosis factor-alpha (TNF-α) in RA patients.Materials and Methods: The participants in this experimental study were divided into 2 groups: RA (n=45) and healthycontrols (n=30). The isolated peripheral blood mononuclear cells (PBMCs) were treated with different concentrationsof OLEU; and the level of TNF-α expression, anti-citrullinated protein, and miRNA-146a were determined usingenzyme-linked immunoassay and real-time polymerase chain reaction, respectively. In addition, the receiver operatingcharacteristic (ROC) curve analysis evaluated the sensitivity and specificity of miRNA-146a in RA patients.Results: Results revealed a positive correlation between the levels of miRNA-146a expression with the serum levels ofC-reactive protein (CRP) and rheumatoid factor (RF) in RA patients. In addition, OLEU treatment decreased the levelsof TNF-α and miRNA-146a expression in treated PBMCs samples compared with untreated cells. The ROC curveanalysis showed an 85% sensitivity and 100% specificity of miRNA-146a in RA patients.Conclusion: Therefore, miRNA-146a can be used as a useful biomarker for RA diagnosis, particularly for earlydetection. In addition, OLEU could suppress inflammation in RA patients through the regulation of miRNA-146a

Characterisation of phosphodiesterases in human lung mast cells and basophils

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Effects of thymectomy on multiple sclerosis with myasthenia gravis

Multiple sclerosis (MS) is the most common chronic autoimmune neuromuscular disease with prevalence rates that has increased in Iran especially in Isfahan population. In MS, there is a coordinated attack of innate and adaptive immune cell against central nervous system (CNS). Concurrence of autoimmune disorders is prevalent such as the concurrence of MS and myasthenia gravis (MG). MS could be associated with MG although they have different target organs. The aim of this study was to assess the effects of thymectomy as a proper treatment for both MS and MG. We studied patients who were referred to our MS clinic with the diagnosis of definite MS and MG made by a neurologist according to Isfahan MS Clinics, Isfahan, Iran (2010-2013). Age, sex, family and medical history, general neurologic symptoms and physical examination in all patients were recorded. We analyzed the clinical, laboratory, and brain magnetic resonance imaging (MRI) findings of the patients with MS and MG in an attempt to identify parameters involved in these diseases. We surveyed 12 patients (0.3%) out of 3920 patients who had both MS and MG. One of these patients had secondary progressive MS and the others had relapsing-remitting MS (RRMS). Five of them experienced thymectomy operation and about 4 (80%) of them completely improved after thymectomy, none of the symptoms of diseases were seen. Almost all of patients completely improved after thymus removal. We suggest thymectomy could be a valuable therapy for MS/ MG patients. However, more investigations should be done on this issue. </p

The Effects of Hydroxyethyl Starch 6% and Crystalloid on Volume Preloading Changes following Spinal Anesthesia

Background: Hypotension is one of the most common complications after spinal anesthesia for cesarean delivery. Normally, preloading with fluids, especially crystalloids, is used to prevention of hypotension. Methods: In the present randomized clinical trial study, 120 parturients presenting for elective cesarean section with the American Society of Anesthesiologists Class I and II received either 15 cc normal saline or 7 cc/kg hydroxyethyl starch 6% (Voluven) fluid. Information regarding to systolic, diastolic, mean arterial pressure, and heart rate, incidence of hypotension, adverse effects, the total dose of atropine, and ephedrine were recorded in before and 3, 6, 9, 15, and 20 min after spinal anesthesia. Furthermore, Apgar score of newborn at the 1st and 5th min after birth was recorded. Results: There was no significant difference in mean arterial pressure at different stages such as: Exactly after spinal and 3, 6, 15, and 20 min after spinal anesthesia between two groups (P > 0.05). Total dose of ephedrine and atropine were similar between groups (P > 0.05), respectively. There was no significant difference in Apgar score at the 1st and 5th min after birth between two groups. There were not any adverse effects of drugs in two groups. Conclusions: The results of this study show that hydroxyethyl starch 6% compared to normal saline are similar to prevent hypotension during spinal anesthesia for cesarean delivery

The effect of cyclic nucleotide analog drugs on the mediators release from basophils

Background: The cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), are intracellular second messengers that play an important role in modulating inflammatory cells involved in allergic diseases. In general, cAMP suppresses the activity of immune and inflammatory cells. We aim to evaluate the roles of cAMP and cGMP in regulating basophil activity. Materials and Methods: Basophil-enriched preparations were incubated with analogs and then challenged with anti-IgE or IL-3 (4 or 24 hours). Supernatants were assayed for histamine, IL-4, and IL-13 release. The effects of Sp-8-CPT-cAMPS and Sp-8-CPT-cGMPS on IL-3-dependent mediator release from basophils were determined. The cells were pre-incubated with an analog and then incubated with IL-3 for 24 hours. Results: Sp-8-CPT-cAMPS was an effective (P < 0.05) inhibitor of IL-4, IL-13, and histamine release from basophils. However, paradoxically, Sp-8-CPT-cGMPS enhanced histamine release and IL-13 generation, but by contrast, had little effect on IL-4 generation. Sp-8-CPT-cGMPS inhibited cytokine generation, but enhanced the release of histamine release to a modest extent. Conclusion: This study shows that the cAMP/protein kinase A (PKA) pathway may be inhibitory to the IgE- and non-IgE-dependent release of mediators from basophils