Effects of Remifentanil Pretreatment on Inflammatory Response in Rats with Acute Cerebral Ischemia Injury

[Objectives]This study was conducted to investigate the effects of remifentanil pretreatment on inflammatory factors in rats with acute cerebral ischemia.[Methods]Sixty SD rats were randomly divided into the normal control group,sham operation group,ischemic brain injury group,and remifentanil pretreatment group.Except the normal control group,each group was divided into three subgroups(six in each group)according to the sampling time points of 6,12 and 24 h after execution.After modeling,the rats were scored for neurological deficit,and observed for pathological changes of neurons in the brain tissue by HE staining and the brain infarct volume by TTC staining,and the expression levels of TNF-α,IL-6 and IL-8 were detected by RT-PCR.[Results]HE staining:No significant changes were observed in the pathological morphology of the brain tissue in the blank group and sham operation group;and the neuronal structure of rats in the acute cerebral ischemia group was obviously damaged,and the neuronal damage in the remifentanil pretreatment group was less than that in the acute cerebral ischemia group at each time point.TTC staining:The gray brain infarct area in the remifentanil pretreatment group was significantly smaller than that in the cerebral ischemia group(P<0.05).RT-PCR detection results:The expression levels of TNF-α,IL-6 and IL-8 in the blank group and sham surgery group did not show significant changes at different times(P>0.05);and compared with the cerebral ischemia group,the expression levels of TNF-α,IL-6,and IL-8 in the remifentanil pretreatment group were significantly reduced at all time points(P<0.05).[Conclusions]Remifentanil pretreatment could protect the brain by reducing the expression of inflammatory factors after cerebral ischemia injury.

Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma

Colonization is believed a rate-limiting step of metastasis cascade.However,its underlying mechanism is not well understood.Uveal melanoma(UM),which is featured with single organ liver metastasis,may provide a simplified model for realizing the complicated colonization process.Because DDR1 was identified to be overexpressed in UM cell lines and specimens,and abundant pathological deposition of extracellular matrix collagen,a type of DDR1 ligand,was noted in the microenvironment of liver in metastatic patients with UM,we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival,proliferation,sternness and eventually promoting metastatic colonization in liver.We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver.Mechanistically,UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells(qHSCs)into activated HSCs(aHSCs)which secreted collagen type I.Such a remodeling of extracellular matrix,in turn,activated DDR1,strengthening survival through upregulating STAT3-dependent Mcl-1 expression,enhancing sternness via upregulating STAT3-dependent S0X2,and promoting clonogenicity in cancer cells.Targeting DDR1 by using 7rh,a specific inhibitor,repressed proliferation and survival in vitro and in vivo outgrowth.More importantly,targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice.In conclusion,targeting DDR1 signaling and TGF-β1 signaling may be a novel approach to diminish hepatic metastasis in UM.