OBJECTIVE:To study the effects of nimesulide combined with oxaliplatin on transplanted tumor growth and im-mune function of rats with esophageal cancer. METHODS:Rats were randomly divided into model group(intragastrically given So-dium carboxymethyl cellulose solution+intravenously given 5% Glucose injection in tail),nimesulide group(intragastrically given 20 mg/kg),oxaliplatin group(intravenously given 13.6 mg/kg in tail)and combination group,10 in each group. Esophageal can-cer Eca109 cells were subcutaneously injected to develop transplanted tumor model. After modeling,rats in each group received rel-evant medicines by corresponding ways,once a day for ig,once every 4 d for iv in tail. Rats were sacrificed after 8 weeks,tumor volume and quality of rats were measured,tumor inhibition rate was calculated,and contents of tumor markers(CEA,CYFRA21-1,SCCAg),percentages of immune cells(CD3+,CD4+,CD8+T cells and NK cell)in peripheral blood were detected. RESULTS:Compared with model group,tumor volume and quality in other 3 groups were decreased (P<0.05);contents of tumor markers were decreased (P<0.05). Percentages of CD3+,CD4+ T cells and NK cell in nimesulide group were increased,percentages of CD8+T cell was decreased(P<0.05). Percentages of CD3+,CD4+T cells and NK cell in oxaliplatin group and combination group were decreased,percentages of CD8+ T cell was increased(P<0.05). Compared with nimesulide group and oxaliplatin group,tu-mor inhibition rate in combination group was increased(P<0.05);contents of tumor markers were decreased(P<0.05);percent-ages of immune cells were lower than nimesulide group and higher than oxaliplatin group(P<0.05). CONCLUSIONS:Nimesulide can enhance the oxaliplatin's antitumor effect on esophageal cancer,and decrease its inhibition degree on immune functions.

Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl4-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl4-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantly decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis.

Protein interacting with C kinase 1 (PICK1) is a scaffolding protein mainly implicated in neurological diseases, however, the function of PICK1 in acute liver injury (ALI) remains unknown. Our study found a dramatical decrease in mRNA and protein levels of PICK1 in liver tissues and isolated Kupffer cells (KCs) from the liver in mice with ALI. Furthermore, pretreatment the mice with ALI with FSC-231, a pharmacological inhibitor of PICK1, could significantly augment inflammatory response. Furthermore, in vitro studies showed that both lipopolysaccharide (LPS) and interferon gamma (IFN-γ) significantly reduced the expression of PICK1, while IL-4 elevated its expression in RAW 264.7 cells. Additionally, over-expression of PICK1 inhibited the expression of M1 biomarkers by suppressing NF-κB activity, and enhanced the expression of M2 biomarkers by promoting STAT6 activity. In contrast, knockdown of PICK1 or FSC-231 pretreatment promoted M1 polarization and suppressed M2 polarization. Besides, caveolin-1 was identified as a potential target gene controlled by PICK1 in RAW 264.7 cells. Mechanistic investigation revealed a dual role of PICK1 in regulating macrophage polarization and implied PICK1 as a potential therapeutic target in ALI.

Objective To screen out the derivative with better anti-inflammatory activity of Hesperidin. And its an-ti-inflammatory activity was also evaluated then. Methods We stimulated RAW264. 7 cell strains with lipopolysac-charide ( LPS) and then inflammation cytokines tumor necrosis factor alpha ( TNF-α) and interleukin 6 ( IL-6 ) were measured by ELISA. And the anti-inflammatory activity was evaluated on three inflammation models( mice ear swelling induced by xylol, mice foot swelling induced by carrageen glue and mice adjuvant-induced arthritis. Re-sults Derivatives of hesperidin 12 ( HY-12 ) had better anti-inflammatory activity; HY-12 ( 100 , 200 , 400 mg/kg) on acute inflammation induced by xylene in mice auricle had different degree of inhibition, HY-12 (200, 400 mg/kg) dose group could significantly inhibit the ear swelling in mice;HY-12 (100 mg/kg) in 3 h, 5 h had obvi-ously inhibitory effect on mice foot swelling, HY-12(200,400 mg/kg) in inflammatory started producing curative effect after 1 h, at all time points it was significantly inhibited. HY-12 also had certain inhibition to inflammation of rheumatoid arthritis mouse model. HY-12 400 mg/kg could significantly inhibit the secondary side paw swelling, serum inflammatory factors, local inflammatory infiltration and the expression of TNF-αand IL-6 in synovial tissues of adjuvant-induced arthritis mice. And nuclear factor kappaB p65 played gets a major role in regulation of inflam-mation response. Conclusion The above results show that HY-12 has strong anti-inflammatory activity through regulating the activation of NF-κB.

Aim To investigate the effect of ASIC1 a ( acid-sensing ion channel 1 a ) on the pathological change of diabetes complication liver fibrosis and the proliferation and activation of hepatic stellate cell ( HSC-T6 ) stimulated by PDGF-BB under hyperglyce-mia. Methods Diabetes rats model was established by streptozotocin ( STZ) , and liver fibrosis rats model was induced by carbon tetrachloride ( CCl4 ) . Then, the liver extent of damage and the expression of ASIC1 a were observed in the diabetic rats, liver fibrosis rats and diabetes complication liver fibrosis rats. In vitro, after pretreated with amiloride, HSC-T6 was treated with high glucose for 24 h and then stimulated with PDGF-BB for another 24 h. The proliferation and acti-vation of HSC-T6 were observed, and the expression of ASIC1a, α-SMA and collagen Ⅰ were detected by Western blot. Results Compared with the control group, rats from diabetic group induced by STZ, liver fibrosis group induced by CCl4 , and the diabetes com-plication liver fibrosis rats co-induced by STZ and CCl4 were all observed with liver damage at different levels, and tissue injury of complication group was most seri-ous. However, the expression of ASIC1a in the three model groups was significantly increased compared to the control group. ASIC1a level was most obvious in the diabetes complication liver fibrosis rats. Amiloride pretreatment significantly decreased ASIC1 a expression and inhibited PDGF-BB mediated proliferation and the expression ofα-SMA and collagenⅠin HSC-T6 under high glucose environment. Conclusion High ambient glucose aggravates HSC activation and hepatic fibrosis, and this may be related with the increasing expression of ASIC1a.

Metabolic syndrome characterized by hyperglycemia contributes to nonalcoholic steatohepatitis-associated liver fibrosis. This study was to investigate the effects of Acid-sensing ion Channel 1a (ASIC1a) on the process of liver fibrosis under hyperglycemia. Results showed that high glucose significantly worsen the pathology of liver fibrosis in vivo. In vitro, high glucose stimulated proliferation, activation and extracellular matrix (ECM) production in HSCs, and enhanced the effect of PDGF-BB on the activation and proliferation of HSCs. These effects could be attenuated by ASIC1a specific inhibitor Psalmotoxin-1(PcTx1) or specific ShRNA for ASIC1a through Notch1/Hes-1 pathways. These data indicate that ASIC1a plays an important role in diabetes complication liver fibrosis.

Objective To study the immunomodulatory activity of HY-12 on immunosuppressive mice. MethodsCy (50 mg/kg) was administered by intraperitoneal ( ip) injection for 2 consecutive days to induce immunosup-pressive model. Carbon clearance, quantitative hemolysis and DNFB-induced delayed-type hypersensitivity were ap-plied to assay effects of HY-12 on nonspecific immunity, humoral immunity and cellular immunity. Results In car-bon clearance test, the clearance index (K) and values of phagocytic index (α) were elevated by HY-12 (100, 200, 400 mg/kg), indicating the phagocytosis of macrophages was enhanced in immunosuppressive mice. In quan-titative hemolysis, productions of IgG and IgM and hemolysin were enhanced by HY-12 (200, 400 mg/kg). HY-12 (200, 400 mg/kg) obviously increased DTH reactivity and enhanced expression of IL-22 in immunosuppressive mice. HY-12 (100, 200, 400 mg/kg) not only increased expression of CD4 + and CD8 +, but also enhanced the ratio of the two. Conclusion HY-12 shows significant immunomodulatory property on immunosuppressive mice through specific and nonspecific immunity.

Telomerase reverse transcriptase (TERT) is the catalytic component of telomerase, especially the rate-limiting determinant of telomerase activity. So far, TERT has been reported to be over-expressed in more than 90% of cancers, thereby playing a critical role in sustained proliferation and survival potentials of various cancer cells. Over the past decade, a comprehensive network of transcription factors has been shown to be involved in the regulation of TERT. Furthermore, accumulating evidence has suggested that TERT could modulate the expression of numerous genes involved in diverse group of cellular processes, including cell cycle regulation and cellular signaling. Therefore, it indicates that TERT is both an effector and a regulator in carcinoma. However, the mechanisms of the interaction between TERT and its target genes are still not fully understood. Thus, it is necessary to consolidate and summarize recent developments of the cross-talk between TERT and related genes in cancer cells or other cells with cancer cell characteristics, and elucidate these relevant mechanisms. In this review, we focus on various signaling pathways and genes that participate in the feedback regulation of TERT and the underlying feedback loop mechanism of TERT, further providing new insights into non-telomeric functions of telomerase and potentially to be used as a novel therapeutic target for cancer.