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The present study aimed to investigate the effect of simvastatin on acetaminophen (APAP) hepatotoxicity in a mouse model. Male C57BL/6 mice were allocated into the following groups: control, APAP, APAP+SIM10, APAP+SIM20, APAP+SIM100 and APAP+SIM200 groups. The mice in the APAP group were treated with saline intraperitoneally (i.p.) 72 h before and 24 h or 72 h after APAP challenge (i.p., 400 mg/kg of APAP). The simvastatin-treated groups were treated with different doses of simvastatin i.p. (10, 20, 100 and 200 mg/kg/day) as in the APAP group. After 24 h or 72 h of APAP challenge, blood and liver samples were collected to detect hepatic injury and liver regeneration. The results showed that low doses of simvastatin (10 and 20 mg/kg) could significantly reverse the histological change and decrease hepatic injury. Simvastatin also reduced the serum cytokine levels and transcriptional levels of tumor necrosis factor-α and interleukin-6 in the liver. The malonyldialdehyde and myeloperoxidase levels significantly decreased in the simvastatin treatment groups compared with the APAP group. Simvastatin restored the decrease in superoxide dismutase, catalase, glutathione and glutathione peroxidase activities induced by APAP hepatotoxicity. In addition, simvastatin inhibited hepatic C/EBP-homologous protein expression and hepatocyte apoptosis. However, simvastatin had no effect on liver regeneration after APAP hepatotoxicity. Moreover, high doses could aggravate APAP-induced liver injury. In conclusion, low doses of simvastatin had a significant therapeutic effect in APAP-induced liver injury by inhibiting oxidative stress, inflammation and apoptosis. However, high doses of simvastatin had adverse hepatotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: Generation of excessive reactive oxygen species (ROS) leads to mitochondrial dysfunction, apoptosis, and necrosis in renal ischemia–reperfusion (IR) injury. Previously we showed that lentiviral vector-mediated overexpression of superoxide dismutase-1 (SOD1) in proximal tubular epithelial cells (LLC-PK1) reduced cytotoxicity in an in vitro model of IR injury. Here, we examined the effects of SOD1 overexpression on mitochondrial signaling after ATP depletion–recovery (ATP-DR). To examine the role of mitochondrial ROS, a subset of cells was treated with the mitochondrial antioxidant MitoTEMPO. ATP-DR-mediated increase in mitochondrial calcium, loss of mitochondrial membrane potential, and increase in mitochondrial permeability transition pore (MPTP) were attenuated by SOD1 and MitoTEMPO (P <0.01). SOD1 prevented ATP-DR-induced mitochondrial Bax translocation, although the release of proapoptotic proteins from mitochondria was not prevented by SOD1 alone and required the presence of both SOD1 and MitoTEMPO. SOD1 suppressed the increase in c-jun phosphorylation, suggesting that JNK signaling regulates Bax translocation to mitochondria via ROS. ATP-DR-mediated changes in MPTP and mitochondrial signaling increased necrosis and apoptosis, both of which were partially attenuated by SOD1 and MitoTEMPO. These studies show that SOD1 and MitoTEMPO preserve mitochondrial integrity and attenuate ATP-DR-mediated necrosis and apoptosis. [ABSTRACT FROM AUTHOR]

This study examined the time-dependent effects of a cell permeable SOD mimetic, MnTMPyP, on mitochondrial function in renal ischemia-reperfusion injury (IRI). Male SD rats were subject to either sham operation or bilateral renal ischemia for 45 min followed by reperfusion for 1, 4 or 24 h. A sub-set of animals was treated with either saline vehicle or 5 mg/Kg of MnTMPyP (i.p.). EPR measurements showed that at 1-h reperfusion MnTMPyP prevented a decrease in aconitase activity ( p < 0.05) and attenuated the increase in the high spin heme at g = 6 and oxidation of 4Fe4S to 3Fe4S signal at g = 2.015 ( p < 0.01). MnTMPyP was effective in preventing loss of mitochondrial complexes and prevented the loss of cytochrome c and Smac/Diablo from mitochondria early in reperfusion. Following 24 h of reperfusion MnTMPyP was effective in attenuating caspase-3 and blocking apoptosis ( p < 0.05). In conclusion, MnTMPyP has biphasic effects in renal IRI, inhibiting mitochondrial dysfunction at the early phases of reperfusion and prevention of apoptosis following longer durations of reperfusion. [ABSTRACT FROM AUTHOR]

Hypoxic pulmonary hypertension (HPH) is a serious and potentially devastating disorder of the pulmonary circulation with complicated mechanisms. Long non-coding RNA (lncRNA) has been revealed to participate in HPH development. This study aimed to explore how lncRNA Tug1 affected the pulmonary vascular remodeling in HPH. A mouse model of HPH and a pulmonary artery smooth muscle cell (PASMC) model of HPH (HPH-PASMCs) were established, where the expression of lncRNA Tug1 was determined. Then, the interaction among lncRNA Tug1, miR-374c, and Foxc1 was assessed. Finally, in order to determine the effects of lncRNA Tug1 on PASMC activities and pulmonary vascular remodeling after HPH, the expression of lncRNA Tug1 was silenced in HPH-PASMCs and HPH mice, with the proliferation, apoptosis, and migration of PASMCs as well as blood pressure in mice measured, respectively. The obtained data revealed that lncRNA Tug1 was highly expressed in HPH mice and HPH-PASMCs. In addition, lncRNA Tug1 up-regulated the expression of Foxc1 by binding to miR-374c. Notably, silencing of lncRNA Tug1 inhibited the proliferation and migration, but promoted the apoptosis of PASMCs. Moreover, lncRNA Tug1 silencing was observed to attenuate the pulmonary vascular remodeling in HPH mice through the Foxc1-mediated NOTCH signaling pathway. Taken conjointly, silencing of lncRNA Tug1 down-regulated the Foxc1 expression by binding to miR-374c, thereby inhibiting the proliferation and migration, while promoting apoptosis of PASMCs to impede pulmonary vascular remodeling in HPH via the Notch signaling pathway. This study provided novel therapeutic insights for treating HPH. [ABSTRACT FROM AUTHOR]

Angiotensin converting enzyme (ACE) inhibition is a common therapeutic modality in the treatment of autosomal recessive polycystic kidney disease (ARPKD). This study was designed to investigate whether chronic inhibition of ACE would have a therapeutic effect in attenuating the progression of renal cystogenesis in an orthologous rat model of ARPKD, the polycystic kidney (PCK) rat. Lisinopril (3 mg/kg per day) was administered orally for a period of 12 weeks, beginning at post-natal week 4. Lisinopril treatment resulted in an ∼30% improvement in the collecting duct cystic indices (CT CI) of PCK animals. Activation of extracellular signal-regulated kinase 1 (ERK1) and 2 (ERK2), proliferative signaling markers, and proliferating cell nuclear antigen (PCNA), an end-point marker for proliferation, was reduced following chronic treatment with lisinopril compared to that in vehicle-treated PCK rats. To assess whether apoptotic pathways were altered due to chronic ACE inhibition, we examined p38 mitogen activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), which are markers of apoptotic signaling cascades. p38 MAPK was significantly reduced ( P < 0.0001) following chronic treatment with lisinopril, but no change in the activation of SAPK/JNK could be detected by immunoblot analysis. Lisinopril treatment resulted in a significant reduction ( P < 0.01) in cleaved caspase-7 levels, but not caspase-3 activity, in PCK rat kidneys compared to the vehicle-treated PCK rat kidneys. Proteinuria was completely ameliorated in the presence of chronic ACE inhibition in the lisinopril-treated rats compared with the vehicle-treated PCK rats. In all, these findings demonstrated that chronic ACE inhibition can beneficially alter proliferative and apoptotic pathways to promote therapeutic reductions in renal cyst development in ARPKD. [ABSTRACT FROM AUTHOR]