Airway obstruction is a hallmark of allergic asthma and is caused primarily by airway smooth muscle (ASM) hypercontractility. Airway inflammation leads to the release of cytokines that enhance ASM contraction by increasing ras homolog gene family, member A (RhoA) activity. The protective mechanisms that prevent or attenuate the increase in RhoA activity have not been well studied. Here, we report that mice lacking the gene that encodes the protein Milk Fat Globule-EGF factor 8 (Mfge8 −/− ) develop exaggerated airway hyperresponsiveness in experimental models of asthma. Mfge8 −/− ASM had enhanced contraction after treatment with IL-13, IL-17A, or TNF-α. Recombinant Mfge8 reduced contraction in murine and human ASM treated with IL-13. Mfge8 inhibited IL-13-induced NF-κB activation and induction of RhoA. Mfge8 also inhibited rapid activation of RhoA, an effect that was eliminated by an inactivating point mutation in the RGD integrin-binding site in recombinant Mfge8. Human subjects with asthma had decreased Mfge8 expression in airway biopsies compared with healthy controls. These data indicate that Mfge8 binding to integrin receptors on ASM opposes the effect of allergic inflammation on RhoA activity and identify a pathway for specific inhibition of ASM hypercontractility in asthma.calcium sensitivity | lactadherin

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The main goal of anti-cancer therapeutic approaches is to induce apoptosis in tumor masses but not in the normal tissues. Nevertheless, the combination of photodynamic irradiation with complementary oncostatic agents contributes to better therapeutic performance. Here, we applied two different cell lines; SKOV3 ovarian carcinoma cells and HUVECs umbilical cord cells as in vitro models to pinpoint whether pharmacological concentration of melatonin in combination with photodynamic therapy induces cell cytotoxicity. The cells were separately treated with various concentrations of melatonin (0 to 10 mM) and photodynamic irradiation alone or in combination. Cells were preliminary exposed to increasing concentrations of melatonin for 24 h and subsequently underwent laser irradiation for 60 s with an output power of 80 mW in continuous mode at 675 nm wavelength and a total light dose of 13.22 J/cm. Cell viability, apoptosis/necrosis rates, and reactive oxygen species levels as well as heat shock protein 70 expression were monitored after single and combined treatments. A statistical analysis was performed by applying one-way analysis of variance (ANOVA) and post hoc Tukey's test. Combination treatment of both cell lines caused a marked increase in apoptosis/necrosis rate, reactive oxygen species generation, and heat shock protein 70 expression compared to incubation of the cells with each agent alone (p < 0.05). SKOV3 cancer cells expressed higher level of heat shock protein 70 under experimental procedure as compared to HUVECs (p < 0.05). Our results introduce melatonin as a potent stimulus for enhancing the efficacy of laser on induction of apoptosis in tumor cells.

Our aim in selecting an appropriate cell fraction and conditioned media (CM) was to achieve the suitable candidate for ameliorating long-term chronic asthmatic changes of respiratory tract. Thirty-six rats were classified into healthy and sensitized groups, which were further divided into three subgroups; rats received systemically 50 μl volume of PBS, CM, or 2 × 10 rat bone marrow-derived mesenchymal stem cells (rBMMSCs). Tracheal responsiveness (TR), immunologic responses, and recruitment of rBMMSCs into the lungs were evaluated. A high degree of TR and total WBC and percentages of eosinophils and neutrophils was significantly recorded in all sensitized groups rather than of controls (p < 0.001 to p < 0.05). Concurrently, a significant improvement of TR and eosinophil and neutrophil return toward normal levels was evident in sensitized rats receiving cells as compared to parallel asthmatic animals. Flow cytometric monitoring of lymphocyte subpopulation revealed a decrease in the number of CD3CD4 and concurrent increase in CD3CD8 in all sensitized rats as compared to control (p < 0.001 to p < 0.05). Noticeably, no significant modulatory effects of either cell or CM administration were achieved on the CD3CD4 and CD3CD8 populations in non-asthmatic rats. Corroborating our results, the number of CD3CD4 tended to increase (p < 0.05) which coincided with a decreased manner of CD3CD8 populations as compared to other asthmatic groups (p < 0.01 to p < 0.05). Moreover, stem cells could efficiently transmigrate to the lung parenchyma, albeit the dynamic of asthmatic changes stimulated the rate of recruited cells. Our study shed light on superior effects of mesenchymal stem cells, but not CM, in attenuating chronic asthmatic changes in the model of rat.