JNK Inhibitor SP600125 Attenuates Paraquat-Induced Acute Lung Injury: an In Vivo and In Vitro Study.

Acute lung injury (ALI) is a major complication soon after paraquat poisoning and rapidly progresses with high mortality. However, the specific mechanism underlying paraquat-induced ALI is still unclear. In this study, the mechanism underlying the protective effects of SP600125 on paraquat-induced ALI was investigated according to oxidative stress, inflammation, and apoptosis. The rats were randomly assigned into the control group (CON), the paraquat poisoning group (PQ), and the PQ + SP600125 group (SP). A549 cells were divided into the Con group, Pq group, and Sp group. H&E staining and detection of lung wet/dry ratio were employed to evaluate lung injury. Annexin V-PI staining was done to evaluate A549 cell apoptosis. Dihydroethidium fluorescence was used to measure reactive oxygen species (ROS) in the lungs and A549 cells. ELISA was performed to detect TNF-α and IL-6 in the supernatant of bronchoalveolar lavage fluid (BALF) and A549 cells. RT-qPCR was done to measure the messenger RNA (mRNA) expression of TNF-α and IL-6 in the lungs and A549 cells. Western blotting assay was performed to detect the protein expression of phospho-JNK, total JNK, and cleaved caspase-3. Electrophoretic mobility shift assay was employed to detect the DNA binding activities of AP-1 and P-p65. JNK inhibitor SP600125 reduced JNK phosphorylation, downregulated cleaved caspase-3 protein level, decreased AP-1 transcriptional activity and ROS level, and reduced the transcription and expression of TNF-α and IL-6, which improved ALI and cell apoptosis after paraquat poisoning. Our results indicate that JNK/AP-1 mediates ALI as well as oxidative stress and inflammation deterioration secondary to paraquat poisoning.

Betulin attenuates lung and liver injuries in sepsis.

Sepsis is a complex condition with unacceptable mortality. Betulin is a natural extract with multiple bioactivities. This study aims to evaluate the potential effects of betulin on lung and liver injury in sepsis. Cecal ligation and puncture was used to establish the rat model of sepsis. A single dose of 4mg/kg or 8mg/kg betulin was injected intraperitoneally immediately after the model establishment. The survival rate was recorded every 12h for 96h. The organ injury was examined using hematoxylin and eosin staining and serum biochemical test. The levels of proinflammatory cytokines and high mobility group box 1 in the serum were measured using ELISA. Western blotting was used to detect the expression of proteins in NF-κB and MAPK signaling pathways. Betulin treatment significantly improved the survival rate of septic rats, and attenuated lung and liver injury in sepsis, including the reduction of lung wet/dry weight ratio and activities of alanine aminotransferase and aspartate aminotransferase in the serum. In addition, levels of tumor necrosis factor-α, interleukin-1ß, interleukin-6 and high mobility group box 1 in the serum were also lowered by betulin treatment. Moreover, sepsis-induced activation of the NF-κB and MAPK signaling pathway was inhibited by betulin as well. Our findings demonstrate the protective effect of betulin in lung and liver injury in sepsis. This protection may be mediated by its anti-inflammatory and NF-κB and MAPK inhibitory effects.

Transplantation of olfactory ensheathing cells attenuates acute carbon monoxide poisoning-induced brain damages in rats.

In this study, the therapeutic effect of olfactory ensheathing cells (OEC) transplantation on brain damage was evaluated on acute carbon monoxide (CO) poisoning rat model. Two weeks after primary culture, OECs were microinjected into hippocampus of CO poisoning rats. Survival of OECs in the host was observed and quantified. OECs survived at 2 weeks, but surviving cell number was found sharply decreased at 6 weeks and reduced to less than 10(3) at 8 weeks after transplantation. At 2 weeks after transplantation, motor function test and cerebral edema assay were performed and followed by pathological examination including hematoxylin and eosin and immunohistochemistry staining to observe the neuron injury and synapsin I and growth associated protein-43 (GAP-43) expression. Furthermore, biomarkers of oxidative stress and apoptosis related proteins in the hippocampus were detected. The results showed that CO exposure led to neurological dysfunction and cerebral edema in rats. After OEC transplantation, neurological function was significantly improved and the cerebral edema was alleviated. In addition, the numbers of neurons and Nissl bodies were increased and synapsin I and GAP-43 protein expressions were upregulated in the hippocampus. Compared with CO poisoned rats, superoxide dismutase activity and glutathione content were both increased and methane dicarboxylic aldehyde level was decreased in the hippocampus of OEC transplanted rats. Moreover, OEC transplantation reduced apoptosis induced by CO exposure. The Bcl-2 expression was significantly upregulated and Bax expression was significantly downregulated. The activity of caspase-3 and the cleaved-poly ADP-ribose polymerase expression were decreased. Taken together, our data suggest that OEC attenuates brain damages induced by acute CO poisoning within 2 weeks after transplantation.

Valproic acid protects septic mice from renal injury by reducing the inflammatory response.

BACKGROUND: Valproic acid (VPA), a histone deacetylase inhibitor, has extensive activities against inflammation, oxidation, and malignancy. This study was designed to investigate the protective effect of VPA on the systemic inflammatory response and renal injury in septic mice. MATERIALS AND METHODS: The septic model of mice was established using a cecal ligation-puncture technique. A single dose of VPA (300 mg/kg) was administered at 30 min postoperatively. RESULTS: We found that VPA reduced the tubular swelling and lowered the serum levels of blood urea nitrogen, creatinine, and C-reactive protein. After treatment with VPA, the renal level of malondialdehyde and the activity of myeloperoxidase decreased markedly; the activity of superoxide dismutase and the glutathione content increased accordingly; and the serum levels of tumor necrosis factor α, interleukin 1ß, and interleukin 6 decreased markedly. Furthermore, VPA suppressed the renal expression of cyclooxygenase 2 and inducible nitric oxide synthase and repressed the release of prostaglandin E2 and nitric oxide. CONCLUSIONS: Our results demonstrate that VPA reduces the inflammatory response in a septic model and protects mice from renal injury, showing substantial potential in the treatment of sepsis.