Neural stem cells neuroprotection by simvastatin via autophagy induction and apoptosis inhibition.

OBJECTIVE: This study was conducted to investigate the effects of Simvastatin (SIM), a member of statin family, on the cellular antioxidant system, autophagy and apoptosis in NSCs exposed to hydrogen peroxide. BACKGROUND: Reduction in cellular oxidative stress increases the survival of neural stem cells (NSCs) after transplantation into the damaged area of the affected central nervous system. MATERIAL AND METHODS: NSCs derived from bone marrow stromal cells (BMSCs) were exposed to H2O2 (100 µM) for 48 hours after pretreatment with SIM (2 µM). Next, the expressions of the master antioxidant transcription factor, Nrf2/nuclear factor erythroid 2 (NFE2)-related factor 2, autophagy-related proteins (microtubule-associated proteins 1A/1B light chain 3B known as LC3I and LC3II and also p62/Sequestosome), and apoptosis (Bcl-2/ B-cell lymphoma 2 and Bax/BCL2 associated X protein) were analyzed. RESULTS: SIM caused Nrf2 over-activation (more localizations in the cellular nucleus), reduction in reactive oxygen species (ROS), induction of autophagy (decrease in p62 expression and increase in LC3II/LC3I ratio) and inhibition of apoptosis (decrease in Bax protein and increase in Bcl-2) in NSCs exposed to H2O2-induced oxidative stress, thereby prolonging the cell viability within 48 hours at low concentration (2 µM). CONCLUSION: SIM protects NSCs against H2O2-induced apoptosis in a pleiotropic signaling manner (Fig. 7, Ref. 35).

Lithium prevents cell apoptosis through autophagy induction.

OBJECTIVE: Bone marrow stromal stem cells (BMSCs) are widely used as an available source for cell therapy, tissue engineering, and cellular differentiation-based techniques. Therefore, it is necessary to apply a simple method through which BMSCs can be protected from cell apoptosis under tough conditions of cell differentiation. Lithium treatment is one of the simple methods in this regard. METHODS: The isolated BMSCs were divided into three groups: (a) control, (b) serum deprivation and (c) LiCl. Cell proliferation and apoptosis and autophagy markers in the presence and absence of LiCl were evaluated. RESULTS: LiCl has shown to increase survival rate of BMSCs under serum deprivation conditions through autophagy induction (reduced P62 and increased LC3II) and apoptosis inhibition (expression of XIAP), so that the cell survival rate, after 12 hours, was 29 %, 59 %, 83 %, 74 %, 49 % for the groups, which received 0, 1, 5, 10, 20 millimolar of LiCl, respectively, as compared to the control group. CONCLUSION: LiCl leads to decreased apoptosis and increased survival rate through autophagy induction under serum deprivation conditions (Ref. 5, Ref. 37).

MELATONIN ALLEVIATES BLEOMYCIN-INDUCED PULMONARY FIBROSIS IN MICE.

Pulmonary fibrosis occurs as a common end-stage sequela of a number of acute and chronic lung diseases. Eicosanoids exert crucial roles in inflammatory processes pertinent to fibrogenesis induction, however, the role of cyclooxygenase 2 (COX-2) is not fully elucidated in most pulmonary fibrosis related-disorders. Recently, melatonin (MLN) has been introduced as an effective immuno-modulator and anti-oxidant agent. The present study aimed to investigate the effect of MLN on COX-2 expression in idiopathic pulmonary fibrosis (IPF). Animals were divided into five groups, including: 1) saline control, 2) 1% ethanol control, 3) MLN control, 4) bleomycin (BLM), in which mice were injected with BLM (15 mg/kg, i.p.) two times per week for four weeks, and 5) BLM+MLN, in which MLN was given to mice (10 mg/kg, i.p.) 30 minutes prior to BLM injections for four weeks. MLN administration significantly reduced body weight loss (P<0.05), the rate of mortality, edema formation, lung injury, COX-2 expression (P>0.05), interstitial tissue percentage volume (P<0.05), and also increased the alveolar space percentage volume. MLN attenuated the BLM-induced lung injury responses such as collagen accumulation and airway dysfunction in mice. Finally, histological evidence supported the ability of MLN to inhibit COX-2 expression. Thus, it may serve as a novel potential therapeutic agent for IPF.