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Background Mesenchymal stem cells (MSCs) are utilized as a carrier of anti-tumor agents in targeted anti-cancer therapy. Despite the improvements in this area, there are still some unsolved issues in determining the appropriate dose, method of administration, biodistribution, and long-term survival. The current study aimed to determine the influence of toll-like receptor 3 (TLR3) stimulation on the potential of MSCs migration to the neoplasm environment in the mouse melanoma model. Methods and Results Adipose-derived MSCs (ADMSCs) were isolated from the GFP+ transgenic C57BL/6 mouse and treated with different doses (1µg/ml and 10 µg/ml) of polyinosinic-polycytidylic acid [poly(I:C)], the related TLR3 agonist, at various time points (1 and 4 hours). Following the treatment, the expression pattern of targeted genes such as α4, α5, and β1 integrins and TGF-β and IL-10 anti-inflammatory cytokines was determined using real-time PCR. In vivo live imaging evaluated the migration index of the intraperitoneally (IP) injected treated ADMSCs in a lung tumor-bearing mouse (C57BL/6) melanoma model (n = 5). The presented findings demonstrated that TLR3 stimulation led to enhanced migration of ADMSCs to the tumor area compared with control group (n = 5) and enhanced expression of α4, α5, and β1 integrins. It was also detected that the engagement of TLR3 resulted in the anti-inflammatory behavior of the cells, which might influence the directed movement of ADMSCs. Conclusions This research identified that TLR3 activation might improve the migration via the stimulation of stress response in the cells and depending on the agonist concentration and time exposure, these activated pathway drive the migratory behavior of MSCs.

Considering the pivotal role of nitric oxide (NO) pathway in depressive disorders, the aim of the present study was to investigate the antidepressant-like effect of selegiline in mice forced swimming test (FST), and possible involvement of NO-cyclic guanosine monophosphate (cGMP) pathway in this action. After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. All drugs were given intraperitoneally (ip). Selegiline (10 mg/kg) decreased the immobility time in the FST similar to fluoxetine (20 mg/kg). Pretreatment with l-arginine (NO precursor, 750 mg/kg) or sildenafil (a phosphodiesterase 5 inhibitor, 5 mg/kg) significantly reversed the selegiline anti-immobility effect. Sub-effective dose of selegiline (1 mg/kg) showed a synergistic antidepressant effect with NG-nitro-l-arginine methyl ester (L-NAME, inhibitor of NO synthase, 10 mg/kg) or 7-nitroindazole (specific neuronal NO synthase inhibitor, 30 mg/kg), but not with aminoguanidine (specific inducible NO synthase inhibitor, 50 mg/kg). Pretreatment of mice with methylene blue (an inhibitor of NO synthase and soluble guanylyl cyclase, 10 mg/kg) significantly produced a synergistic response with the sub-effective dose of selegiline. Neither of the drugs changed the locomotor activity. Also, hippocampal and prefrontal cortex (PFC) nitrite content was significantly lower in selegiline-injected mice compared to saline-administrated mice. Also, co-injection of 7-nitroindazole with selegiline produced a significant reduction in hippocampal or PFC nitrite contents. It is concluded that selegiline possesses antidepressant-like effect in mice FST through inhibition of l-arginine-NO-cyclic guanosine monophosphate pathway.