Preconditioning effects on expression of proto-oncogenes c-fos and c-jun after hepatic ischemia/reperfusion in rats

BACKGROUND: Ischemia/reperfusion is the main cause of hepatic damage in liver transplantation. Immediate early genes (IEGs) encode proteins can regulate expression of cellular response genes after injury, and is associated with tissue repair and cell apoptosis. The purpose of this re- search was to investigate the effects of preconditioning on expression of immediate early genes c-fos and c-jun follow- ing hepatic ischemia/reperfusion (IR) and its roles in cellu- lar regeneration and apoptosis. METHODS: Ninety-six Wistar rats were randomly divided into IR group and hepatic ischemic preconditioning (IPC) group, and each group was further divided into eight sub- groups (n =6). The model of partial liver ischemia/reper- fusion was used. The rats were subjected to 60-minute liver ischemia, preceded by 10-minute preconditioning. After 0-, 0.5-, 1-, 2-, 4-, 8-, 12-, 24-hour reperfusion, the se- rum and liver tissue in each group were collected to detect the level of serum ALT/AST, liver histopathology, expres- sion of c-fos, and c-jun mRNA. Flow cytometer was used to detect Ki67 and Sub-G1 as the quantity indicators of cell regeneration and apoptosis respectively. RESULTS: Compared with IR group, IPC group showed a significantly lower ALT/AST level in 0. 5-hour sub-group to 8-hour sub-group (P<0.05). Ki67 elevated significantly at 0.5, 1, 2 hours, but decreased significantly at 24 hours ( P < 0 . 05). Ap index decreased significantly after 1-hour reperfusion(P<0.05). Expressions of c-fos and c-jun mR- NA were low, especially c-jun at 0.5, 1 and 2 hours after reperfusion. CONCLUSION: Ischemic preconditioning can protect liver cells against ischemia/reperfusion injury, and this protec- tive effect may be related to influence transcription levels of c-fos and c-jun.

Effect of Levodopa Chronic Administration on Behavioral Changes and Fos Expression in Basal Ganglia in Rat Model of PD

To study behavioral character and changes of neuronal activity in the basal ganglia of rat model of levodopa-induced dyskinesia, unilateral 6-hydroxydopamine lesioned rat model of Parkinson disease (PD) was treated with levodopa/benserazide twice daily for 4 weeks and the behavior observed on the 1st, 3rd, 4th, 7th, 9th, 10th, 14th, 21st and 28th day The animals were sacrificed and immunohistochemical technique was used to measure the changes of Fos expression in the caudate putamen (CPU), globus pallidus (GP) and sensorimotor area of cerebral cortex 2 h after the last treatment The results showed that pulsatile treatment with a subthreshold dose of levodopa gradually induced abnormal involuntary movement (AIM), including stereotypy (limb dyskinesia, axial dystonia and masticatory dyskinesia) towards the side contralateral to the dopamine-denervated striatum and increased contraversive rotation The motor pattern of each subtype was highly stereotypic across individual rats, and the proportion of each subtype was not consistent among individual rats Fos positive nuclei in the CPU and GP were increased by levodopa acute administration, and more remarkably in the CPU, but not in the cerebral cortex After repeated levodopa treatment, Fos positive nuclei were reduced remarkably in the CPU, but were increased in the GP and cerebral cortex It was concluded that the neural mechanisms underlying levodopa induced AIM in rat model of PD was very similar to those seen in levodopa-induced dyskinesia (LID) in PD patients and MPTP-lesioned monkeys, and increased striatopallidal neuronal activity might be involved in occurrence of LID

Chemotherapy suppresses SHH gene expression via a specific enhancer

Sonic hedgehog(SHH)signaling is a key regulator of embryonic development and tissue homeostasis that is involved in gastrointestinal(GI)cancer progression.Regulation of SHH gene expression is a paradigm of long-range enhancer function.Using the classical chemotherapy drug 5-fluorouracil(5FU)as an example,here we show that SHH gene expression is suppressed by chemotherapy.SHH is downstream of immediate early genes(IEGs),including Early growth response 1(Egr1).A specific 139 kb upstream enhancer is responsible for its down-regulation.Knocking down EGR1 expression or blocking its binding to this enhancer renders SHH unresponsive to chemotherapy.We further demonstrate that down-regulation of SHH expression does not depend on 5FU’s impact on nucleotide metabolism or DNA damage;rather,a sustained oxidative stress response mediates this rapid suppression.This enhancer is present in a wide range of tumors and normal tissues,thus providing a target for cancer chemotherapy and its adverse effects on normal tissues.We propose that SHH is a stress-responsive gene downstream of IEGs,and that traditional chemotherapy targets a specific enhancer to suppress its expression.