C-Kit+ cells can modulate asthmatic condition via differentiation into pneumocyte-like cells and alteration of inflammatory responses via ERK/NF-ƙB pathway.

Objectives: The exact role of the progenitor cell types in the dynamic healing of asthmatic lungs is lacking. This investigation was proposed to evaluate the effect of intratracheally administered rat bone marrow-derived c-kit+ cells on ovalbumin-induced sensitized male rats. Materials and Methods: Forty rats were randomly divided into 4 groups; healthy rats received phosphate-buffered saline (PBS) (C); sensitized rats received PBS (S); PBS containing C-kit- cells (S+C-kit-); and PBS containing C-kit+ cells (S+C-kit+). After two weeks, circulatory CD4+/CD8+ T-cell counts and pulmonary ERK/NF-ƙB signaling pathway as well as the probability of cellular differentiation were assessed. Results: The results showed that transplanted C-Kit+ cells were engrafted into pulmonary tissue and differentiated into epithelial cells. C-Kit+ cells could increase the number of CD4+ cells in comparison with the S group (P<0.001); however, they diminished the level of CD8+ cells (P<0.01). Moreover, data demonstrated increased p-ERK/ERK ratio (P<0.001) and NF-ƙB level (P<0.05) in sensitized rats compared with the C group. The administration of C-kit+, but not C-Kit-, decreased p-ERK/ERK ratio and NF-ƙB level compared with those of the S group (P<0.05). Conclusion: The study revealed that C-Kit+ cells engrafted into pulmonary tissue reduced the NF-ƙB protein level and diminished p-ERK/ERK ratio, leading to suppression of inflammatory response in asthmatic lungs.

c-kit+ cells offer hopes in ameliorating asthmatic pathologies via regulation of miRNA-133 and miRNA-126.

OBJECTIVES: There are still challenges regarding c-kit+ cells' therapeutic outcome in the clinical setting. Here, we examined the c-kit+ cell effect on the alleviation of asthma by modulating miRNAs expression. MATERIALS AND METHODS: To induce asthma, male rats were exposed to ovalbumin. Bone marrow-derived c-kit+ cells were enriched by MACS. Animals were classified into four groups (6 rats each). 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) was assessed by real-time PCR analysis. RESULTS: Pathological examination and Th1 and Th2 associated cytokine fluctuation confirmed the occurrence of asthma in rats indicated by chronic changes and prominent inflammation compared with the control group (P<0.05). Both c-kit+ and c-kit- cells were verified in pulmonary niche. Administration of c-kit positive cells had the potential to change INF-γ/IL-4 ratio close to the normal values compared with matched-control asthmatic rats (P<0.05). We also found that c-kit+ cells regulated the expression of miRNA-126 and -133, indicated by an increase of miRNA-133 and decrease of miRNA-126 compared with cell-free sensitized groups (P<0.05). CONCLUSION: c-kit- cells were unable to promote any therapeutic outcomes in the asthmatic milieu. c-kit+ cells had the potential to diminish asthma-related pathologies presumably by controlling the transcription of miRNA-126 and -133.

Unraveling the therapeutic effects of mesenchymal stem cells in asthma.

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.

Lead exposure changes gastric motility in rats: role of nitric oxide (NO).

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (P<0.05). In addition, nitric oxide metabolite of gastric tissue was more in all Pb groups in comparison with their Na counterparts (P<0.05). CONCLUSION: We found that lead exposure could affect gastric motility via the nitric oxide pathway.

Lead exposure changes gastric acid secretion in rat: role of nitric oxide (NO).

Sub chronic exposure to lead in rats slows gastric emptying, but little is known about the effects of lead on gastric secretion. This study was designed to investigate the effects of lead on gastric acid secretion and its possible mechanisms in rats. Lead acetate was dissolved in drinking water in a concentration of 1%. Sodium acetate-containing water with a molar concentration similar to lead was also prepared. We had nine groups of animals (n=8); four of them were exposed to lead 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). Gastric secretion was collected by washout technique and its acid output was measured in the basal (Basal Acid Output, BAO), vogotomy (Vagotomized Acid Output, VAO), and vagally stimulated (Vagally Stimulated Acid Output, VSAO) states using titrator instrument. Nitric oxide (NO) metabolite of gastric tissue was determined by Griess micro assay method to evaluate the possible mechanism of lead effect on gastric secretion. VSAO was significantly less in Pb1 and Pb2 groups than Na1 and Na2 ones respectively (1.75 ± 0.17, 2.10 ± 0.30 vs. 5.79 ± 0.20, 6.18 ± 0.27 µmol/15min) (P=0.001, P=0.001). BAO was significantly more in Pb3 and Pb4 groups than Na3 and Na4 ones respectively (2.77 ± 0.37, 2.80 ± 0.31 vs. 1.73 ± 0.16, 1.79 ± 0.34 µmol/15min) (P=0.01, P=0.02), but it was the same after vagotomy. VSAO was more in Pb3 and Pb4 groups than their Na counterparts (P=0.001, P=0.0001). NO metabolite of gastric tissue was more in all Pb groups in comparison to their Na counterparts (P=0.0001). In this study, it seems that lead exposure, via NO mechanism, has different effects on acid secretion. Nitric oxide in small and large amounts decrease and increase gastric acid secretion, respectively.

Preconditioning with acute and chronic lithium administration reduces ischemia/reperfusion injury mediated by cyclooxygenase not nitric oxide synthase pathway in isolated rat heart.

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 microM). 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.

Assessment of plasma antioxidant status in hemodialysis patients.

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.

Effect of indomethacin on electrical field stimulation-induced contractions of isolated transverse and longitudinal rat gastric fundus strips.

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 K(ATP) 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 K(ATP) channel modulators.

Effects of administration of oral magnesium on plasma glucose and pathological changes in the aorta and pancreas of diabetic rats.

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.