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NEW FINDINGS What is the central question of this study? The aim of the experiment was to highlight the regenerative capacity of bone marrow Kit+ cells in the restoration of asthmatic pulmonary function in the rat model. What is the main finding and its importance? Data showed that these cells were recruited successfully to the asthmatic niche after intratracheal administration and accelerated the regeneration of asthmatic lungs by the modulation of inflammation via the control of Gata3 and Tbx21 expression, leading to decreased tracheal responsiveness to methacholine and reduction of pathological remodelling. ABSTRACT Allergic asthma is a T helper (Th) 2 immunological disorder with consequential uncontrolled inflammatory responses. There is an increasing demand to use new methods for the treatment of asthma based on modulation of the Th2-to-Th1 ratio in favour of the Th1 population. Accordingly, we decided to evaluate the effects of intratracheal administration of Kit+ bone marrow cells on tracheal responsiveness and the expression of Gata3 and Tbx21 genes. Forty male Wistar rats were allocated randomly into four experimental groups: healthy rats (control group), sensitized rats (OVA group), sensitized rats receiving Kit- cells (OVA+Kit- group) and sensitized rats receiving Kit+ cells (OVA+Kit+ group). Total and differential white blood cell counts, tracheal responsiveness to cumulative methacholine concentrations and histopathological analysis were evaluated. The results showed a statistically significant increase in total white blood cell, eosinophil and neutrophil counts, tracheal contractility, Gata3 expression and prototypical histopathology of asthma. Along with these conditions, we found that the number of lymphocytes was decreased and expression of Tbx21 diminished in sensitized rats compared with control animals. Monitoring of labelled tagged cells confirmed successful engraftment of transplanted cells in pulmonary tissue. Juxtaposition of Kit+ cells changed the blood leucogram closer to the control values. Kit+ cells increased the expression of Tbx21 and suppressed Gata3 (P

Asthma is a chronic inflammatory disease associated with airway hyper-responsiveness, chronic inflammatory response, and excessive structural remodeling. The current therapeutic strategies in asthmatic patients are based on controlling the activity of type 2 T helper lymphocytes in the pulmonary tissue. However, most of the available therapies are symptomatic and expensive and with diverse side outcomes in which the interruption of these modalities contributes to the relapse of asthmatic symptoms. Up to date, different reports highlighted the advantages and beneficial outcomes regarding the transplantation of different stem cell sources, and relevant products from for the diseases’ alleviation and restoration of injured sites. However, efforts to better understand by which these cells elicit therapeutic effects are already underway. The precise understanding of these mechanisms will help us to translate stem cells into the clinical setting. In this review article, we described current knowledge and future perspectives related to the therapeutic application of stem cell-based therapy in animal models of asthma, with emphasis on the underlying therapeutic mechanisms.

Background There are still challenges regarding c-kit+ cells therapeutic outcome in the clinical setting. Here, we examined of c-kit+ cells effect on the alleviation of asthma by modulating miRNAs expression.MethodsTo induce asthma, male rats were exposed to ovalbumin. Bone marrow-derived c-kit+ cells were enriched by MACS. Animals were classified into four groups (each in 6 rats). Control rats received PBS intratracheally; Ovalbumin-sensitized rats received PBS intratracheally; Ovalbumin-sensitized rats received PBS intratracheally containing 3×105 c-kit+ and c-kit- cells. Cells were stained with Dil fluorescent dye to track in vivo condition. Pathological changes were monitored in asthmatic rats after transplantation of c-kit+ and c-kit- cells. Serum levels of IL-4 and INF-γ were measured by ELISA. Transcription of miRNAs (-126 and 133) were assessed by real-time PCR analysis.ResultsPathological examination, Th1 and Th2 associated cytokines fluctuation confirmed the occurrence of asthma in rats indicated by chronic changes and prominent inflammation compared to the control group (p+ and c-kit- cells were verified in pulmonary niche. Administration of c-kit positive cells had potential to changes INF-γ/IL-4 ratio and closed to the normal values compared to matched-control asthmatic rats (p+ cells regulated the expression of miRNA-126 and -133, indicated by increase of miRNA-133 and decrease of miRNA-126 compared to cell-free sensitized groups (p- cells were unable to promote any therapeutic outcomes in asthmatic milieu.ConclusionsIn overall, c-kit+ cells had potential to diminish asthma-related pathologies presumably by controlling the transcription of miRNA-126 and -133.

Lithium is widely used for the management of neuropsychiatric symptoms in bipolar disorders. A variety of hypotheses have been invoked to explain the mechanism of action of lithium. To determine if lithium exerts direct cardiac protection, in the present study perfused rat heart model was used. The mechanism of lithium-mediated cardioprotection was explored by combined use of lithium and nitro- l -arginine methyl ester (L-NAME, a non-selective nitric oxide synthase inhibitor) or indomethacin (a non-selective cyclooxygenase pathway inhibitor). Rat isolated hearts were used for Langendorff perfusion. Hearts were either non-preconditioned or preconditioned with acute lithium (3 mM) or chronic lithium (600 mg/l in tap water for 4 weeks, 0.265 ± 0.023 mM in serum) before 30 min global ischemia followed by 90 min reperfusion. Within each of these protocols, hearts were divided into two groups; one group was exposed to L-NAME (0.1 mM) and another group was exposed to indomethacin (10 µM). Infarct size was measured by the triphenyltetrazolium chloride method. Left ventricular function was assessed by left ventricular developed pressure (LVDP), heart rate and coronary flow (CF). In our experiment acute and/or chronic administration of lithium before prolonged ischemia offered significant myoprotective effects in terms of infarct size reduction and improved cardiac function against ischemia/reperfusion injury. The effects of lithium pretreatment were prevented by the administration of indomethacin but not L-NAME. In conclusion, our results demonstrate that preconditioning with acute and/or chronic lithium administration improves recovery of the ventricular function and reduces infarct size via cyclooxygenase (COX) pathway in isolated rat heart.

The risk of atherosclerosis and cancer is high in patients on hemodialysis. A breakdown in the natural balance between the activity of the body's antioxidant system and the production of oxidizing agents is suggested to be involved. To investigate the oxidative stress status in Iranian hemodialytic patients, in this study we evaluated plasma vitamin E, malondialdehyde (MDA), reduced glutathione (GSH), and ferric reducing antioxidant power (FRAP) levels in these patients. Twenty-four hemodialytic patients and 24 control subjects (age and sex matched) were included in this study. Each patient was under dialysis, three times per week, four hours in each session. Before and after dialysis, blood was taken for biochemical measurements as well as oxidative stress tests. There was a significant decrease in FRAP and GSH levels after dialysis comparing to before treatment levels. MDA was increased by dialysis and vitamin E levels were less in dialytic patients, both before and after treatment, compared to controls. This study indicates that there is a significant level of oxidative stress in chronic renal patients and this stress is augmented by dialysis. Antioxidant therapy could be considered in these patients.

1. Magnesium deficiency has recently been proposed as a novel factor implicated in the pathogenesis of the complications of diabetes. The purpose of the present study was to determine the relationship between oral Mg supplementation and changes in plasma glucose, calcium, haemoglobin, Ca/Mg ratio, blood pressure and the histology of the pancreas and vascular system in streptozotocin-induced diabetic rats. 2. Ten days after the induction of diabetes in male Wistar rats, half the diabetic animals were divided into six groups, receiving 0, 1, 3, 10, 30 or 50 g/L MgSO4 added into the drinking water for 8 weeks. Plasma glucose and Mg were measured at days 1, 2, 3, 5, 7, 14 and 21 to find the optimum dose of Mg and the time-course of its effect. In addition, histological observations were undertaken. Eight weeks later, all animals were decapitated, the pancreas and thoracic aorta were removed carefully and immersed immediately in 10% formaldehyde for histological study. 3. To evaluate the effects of Mg on plasma glucose, calcium, haemoglobin, Mg and blood pressure, another group of animals was divided into four experimental groups, as follows: (i) non-diabetic controls received tap water for 8 weeks; (ii) acute diabetics received tap water for 10 days; (iii) chronic diabetic controls received tap water for 8 weeks; and (iv) Mg-treated chronic diabetic rats received 10 g/L MgSO4 added into the drinking water 10 days after the induction of diabetes for 8 weeks. 4. Magnesium dose dependently affects plasma glucose levels. The peak effect was reached during the first 24 h following oral administration. Administration of 10 g/L MgSO4 results in the return of normal structure in the diabetic pancreas and aorta. Moreover, this concentration of MgSO4 causes glucose, haemoglobin, calcium, the Ca/Mg ratio and blood pressure to reach normal levels. Although the Mg level increases slightly following the administration of 10 g/L MgSO4 to diabetic rats, it never reaches control levels. 5. On the basis of the results of the present study, it may be concluded that chronic Mg administration may have beneficial effects on diabetes.

SUMMARY 1. The aim of present study was to investigate the effects of magnesium (Mg) on cardiac function and infarct size and to compare it effects with those of adenosine. The mechanism of Mg-mediated cardioprotection was explored by combined use of Mg and a selective adenosine A1 receptor antagonist. 2. Rat isolated hearts were used for Langendorff perfusion. Hearts were either non-preconditioned or preconditioned with Mg (6 mmol/L) or adenosine (1 mmol/L) before 30 min sustained ischaemia followed by 120 min reperfusion. Within each of these protocols, hearts were divided into two groups; one group was exposed to the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 200 nmol/L). Infarct size was measured by the triphenyltetrazolium chloride method. Left ventricular function was assessed by left ventricular developed pressure (LVDP), the product of heart rate × LVDP and coronary flow (CF). 3. The administration of Mg had an anti-infarct effect independent of its effect on postischaemic functional recovery in rats. Both Mg and adenosine equipotently reduced infarct size, but this effect of Mg was not blocked by the simultaneous administration of DPCPX. Cardiac function was improved by both adenosine and Mg and blockade of adenosine A1 receptors attenuated these effects for both agents. 4. In conclusion, the results of the present study indicate that stimulation of adenosine A1 receptors is not responsible for the anti-infarct effect of Mg in ischaemic myocardium in rats, but that the Mg-mediated protection of postischaemic functional recovery in rats is mediated by these receptors.

Abdominal colic, constipation and delay in gastric emptying are symptoms of lead poisoning, but there is scant information about the effect of lead on gastric motility. In the present study, we investigated the effect of lead acetate on gastric motility in rats.Animals were divided into nine groups (n=8); four groups were exposed to lead acetate solution (1%) for 1, 2, 3, and 4 weeks (Pb1, Pb2, Pb3, and Pb4 groups, respectively). Sodium acetate solution was given to another four groups for 1, 2, 3, and 4 weeks (Na1, Na2, Na3, and Na4 groups, respectively) and the control group had free access to tap water. Gastric motility was measured in the basal and acetylcholine (Ach)-stimulated states using a physiograph instrument. Nitric oxide metabolite of gastric tissue was determined by Griess micro-assay.There were no significant differences between basal and Ach-stimulated gastric motility in Pb1, Pb2, Na1, and Na2 groups. However, it was significantly greater in Pb3 and Pb4 groups when compared with Na3 and Na4 groups in both basal and Ach-stimulated states (P0.05). In addition, nitric oxide metabolite of gastric tissue was more in all Pb groups in comparison with their Na counterparts (P0.05).We found that lead exposure could affect gastric motility via the nitric oxide pathway.

AIM: To study the effects of indomethacin on the isolated transverse and longitudinal rat gastric fundus strips. METHODS: The strips were suspended in an organ bath containing oxygenated Krebs solution, and contractile responses to electrical field stimulation were recorded on a physiograph in an isotonic manner after administration of cumulative concentrations of indomethacin. The effects of indomethacin on the strips pretreated with KATP channel modulators, diazoxide and glybenclamide were studied. RESULTS: Treatment of the transverse strips with indomethacin resulted in a concentration-dependent inhibitory response. In longitudinal strips, biphasic responses were seen, which included a stimulatory response at low concentrations of indomethacin, followed by an inhibitory response at higher concentrations. Diazoxide pre-treatment inhibited the stimulatory response of longitudinal strips. Glybenclamide pre-treatment not only blocked inhibitory effect of the low concentrations of indomethacin on transverse strips, but also increased the amplitude of contractions. Moreover, the drug decreased the amplitude of contractions in longitudinal strips. CONCLUSION: Responses of the isolated longitudinal and transverse rat gastric fundus strips to indomethacin are not similar, and are influenced by KATP channel modulators.