High Glucose Stimulates Expression of MFHAS1 to Mitigate Inflammation via Akt/HO-1 Pathway in Human Umbilical Vein Endothelial Cells.

Hyperglycemia is a highly dangerous factor to various diseases, even resulting in death of people. Inflammation plays a key role in this process. The aim of this study was to explore the role of malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) in high-glucose induced inflammation. Our research showed that high glucose stimulated the expression of MFHAS1, and overexpression of MFHAS1 can attenuate high-glucose induced inflammation in endothelial cells by decreasing the secretion of cytokines interleukin-1ß (IL-1ß), interleukin-1α (IL-1α), adhesion molecule intercellular adhesion molecule-1 (ICAM), interleukin-6 (IL-6), interleukin-8 (IL-8), and chemokine ligand 1 (CXCL-1). Furthermore, we found that MFHAS1 promoted the phosphorylation of Akt and the expression of heme oxygenase-1 (HO-1). Our results indicated that MFHAS1 deadened high-glucose induced inflammation by activating AKT/HO-1 pathway, suggesting that MFHAS1 may act as a new therapeutic target of diabetes mellitus.

MFHAS1 Is Associated with Sepsis and Stimulates TLR2/NF-κB Signaling Pathway Following Negative Regulation.

Malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) has a potential immunoregulatory role dependent on Toll-like receptors (TLRs). TLR2, associated with deleterious systemic inflammation, cardiac dysfunction, and acute kidney injury, acts synergistically in sepsis. The role of MFHAS1 in targeting TLR2 involved in sepsis has not been examined thus far. This study aimed to examine the relationship of MFHAS1 and sepsis, and the effect of MFHAS1 on the TLR2 signaling pathway. Blood samples were collected from eight sepsis patients after surgery and eight patients undergoing selective surgery to determine blood MFHAS1 levels. HEK 293 cells, RAW 264.7 macrophages and THP-1 monocytes were used to confirm the effect of MFHAS1 on TLR2 signaling pathway. Our study showed that blood MFHAS1 was significantly elevated in septic patients, and MFHAS1 was more increased in mononuclear cells from septic patients. Pam3CSK4 (TLR2 ligand) was found to induce MFHAS1 production in RAW 264.7 murine macrophages and THP-1 human monocytes in a time-dependent manner. MFHAS1 has dual effects on TLR2 signaling pathway and inflammation, i.e., inhibitory effect at 6 hours, and then stimulatory effect after 24 hours through the activation of TLR2/NF-κB signaling pathway, and MFHAS1 induced the phosphorylation of JNK and p38 after TLR2 stimulation.

Dexmedetomidine renders a brain protection on hippocampal formation through inhibition of nNOS-NO signalling in endotoxin-induced shock rats.

BACKGROUND: Endotoxin shock (ES) and its severe complications, such as brain injury, remain a handicap clinically. Therefore, it is a clinical significance of developing a new drug to treat brain damage induced by ES. AIM: The present study aimed to observe the protective effect of dexmedetomidine (Dex) on hippocampal formation in endotoxin-induced shock rats and explore its possible mechanism. METHODS: High and low doses of Dex were tail intravenously administered slowly. After a 5-minute interval, lipopolysaccharide was tail intravenous injected slowly to establish the ES rats. Six hours after Dex administration, these rats were immediately sacrificed. Then, the brain water content was determined. NO amounts in homogenate, cerebrospinal fluid and serum were detected by Griess Reagent assay. nNOS mRNA in hippocampal formation was measured by RT-PCR and nNOS protein was determined by Western blotting and immunohistochemistry. RESULTS: ES rats showed that cerebral water contents were significantly increased, NO concentrations in brain tissues, serum and cerebrospinal fluid were each obviously raised and meanwhile expressions of nNOS mRNA and its protein in hippocampal formation were notably augmented. Treatment of these rats with Dex evidently decreased cerebral water contents, NO concentrations and nNOS mRNA and its protein expressions. CONCLUSION: These results demonstrated that Dex exerted a brain protection on hippocampal formation through inhibition of the nNOS-NO signalling in ES rats and Dex may have a favourably therapeutic value in treating brain damage in patients with endotoxin shock.

Dose-response and mechanism of protective functions of selective alpha-2 agonist dexmedetomidine on acute lung injury in rats.

OBJECTIVE: To investigate the protective functions of dexmedetomidine on lipopolysaccharide-induced acute lung injury in the lung tissues of rats. METHODS: The experiment was conducted from May 2008 to December 2009 in Zhongshan Hospital, Shanghai, China. Forty Sprague Dawley rats were randomized into a normal group (NS group), a lipopolysaccharide model group (LPS group), and dexmedetomidine groups in high dosages (HD), moderate dosages (MD), and low dosages (LD). After the acute lung injury model was duplicated by lipopolysaccharide, the rats in the LD, MD, and HD groups were injected with 0.5 ug/kg, 1.5 ug/kg, and 4.5 ug/kg of dexmedetomidine. The rats in the NS group were injected with normal saline. Immuno-histochemical and reverse transcription polymerase chain reaction techniques were used to assess the damage of lung tissue in each group. RESULTS: The nuclear factor-KappaB and Toll-like receptor 4 messenger RNA expression in the lung tissues of the rats in the MD and HD groups were inhibited compared to the LPS group. The amount of tumor necrosis factor-beta, interleukin-1beta, and interleukin-6 as well as the lung tissue wet to dry weight ratio were also reduced in the MD and HD groups. CONCLUSION: The inflammatory reactions in lung tissues can be effectively inhibited at doses ranging from 1.5-4.5 ug/kg, resulting in a protective effect on lung tissue.