In order to evaluate the efficacy and side effects of the non-insulin antidiabetes medications as an adjunct treatment in type 1 diabetes mellitus (T1DM), we conducted systematic searches in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between the date of inception and March 2020 to produce a systematic review and meta-analysis. Overall, 57 studies were included. Compared with placebo, antidiabetes agents in adjunct to insulin treatment resulted in significant reduction in glycosylated hemoglobin (weighted mean difference [WMD], –0.30%; 95% confidence interval [CI], –0.34 to –0.25%; P<0.01) and body weight (WMD, –2.15 kg; 95% CI, –2.77 to –1.53 kg; P<0.01), and required a significantly lower dosage of insulin (WMD, –5.17 unit/day; 95% CI, –6.77 to –3.57 unit/day; P<0.01). Compared with placebo, antidiabetes agents in adjunct to insulin treatment increased the risk of hypoglycemia (relative risk [RR], 1.04; 95% CI, 1.01 to 1.08; P=0.02) and gastrointestinal side effects (RR, 1.99; 95% CI, 1.61 to 2.46; P<0.01) in patients with T1DM. Compared with placebo, the use of non-insulin antidiabetes agents in addition to insulin could lead to glycemic improvement, weight control and lower insulin dosage, while they might be associated with increased risks of hypoglycemia and gastrointestinal side effects in patients with T1DM.

In order to evaluate the efficacy and side effects of the non-insulin antidiabetes medications as an adjunct treatment in type 1 diabetes mellitus (T1DM), we conducted systematic searches in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between the date of inception and March 2020 to produce a systematic review and meta-analysis. Overall, 57 studies were included. Compared with placebo, antidiabetes agents in adjunct to insulin treatment resulted in significant reduction in glycosylated hemoglobin (weighted mean difference [WMD], –0.30%; 95% confidence interval [CI], –0.34 to –0.25%; P<0.01) and body weight (WMD, –2.15 kg; 95% CI, –2.77 to –1.53 kg; P<0.01), and required a significantly lower dosage of insulin (WMD, –5.17 unit/day; 95% CI, –6.77 to –3.57 unit/day; P<0.01). Compared with placebo, antidiabetes agents in adjunct to insulin treatment increased the risk of hypoglycemia (relative risk [RR], 1.04; 95% CI, 1.01 to 1.08; P=0.02) and gastrointestinal side effects (RR, 1.99; 95% CI, 1.61 to 2.46; P<0.01) in patients with T1DM. Compared with placebo, the use of non-insulin antidiabetes agents in addition to insulin could lead to glycemic improvement, weight control and lower insulin dosage, while they might be associated with increased risks of hypoglycemia and gastrointestinal side effects in patients with T1DM.

OBJECTIVE：To compare the an ti-hepatocarcinoma effects of curcumin （CUR）and its derivative hydrazincurcumin （HZC），and to explore the mechanism. METHODS ：MTT assay was used to detect the effects of CUR or HZC （2.5，5，10，20， 40，80 μmol/L）on the proliferation of HepG 2 cells. Flow cytometry was used to detect the effects of CUR or HZC （10，20，40 μmol/L）on cell cycle distribution and apoptosis of HepG 2 cells. Western blotting assay was used to detect the effects of CUR or HZC（10，20，40 μmol/L）on the expression of apoptosis-related protein in HepG 2 cells. The male SD rats were randomly divided into normal control group （n＝10），CUR control group （n＝10），HZC control group （n＝10），model group （n＝30），CUR protection group （n＝30）and HZC protection group （n＝30）. CUR control group and HZC control group were given CUR 85917439。E-mail：zhaoji-an-88@163.com or HZC （80 mg/kg） intraperitoneally. Model group ，CUR protection group and HZC protection group were given diethylnitrosamine （50 mg/kg）intraperitoneally to establish hepatocarcinoma model ；at the same time ，2 protection groups were given CUR or HZC （80 mg/kg）intraperitoneally，twice a day，for consecutive 12 weeks. During medication ，the change of body weight and death of rats were recorded. Twenty four weeks later，liver index of rats was calculated and appearance was observed ；the number of cancer nodules was counted ；HE staining was used to observe the pathological changes of liver tissue and calculate the nuclear division index of hepatocarcinoma ；the proliferating cell nuclear antigen （PCNA）index was detected by immunohistochemistry. RESULTS ：CUR and HZC could increase the inhibitory rate of HepG 2 cells（P＜0.05），and increased the percentage at G 0/G1 phase and apoptotic rate of HepG 2 cells（P＜ 0.05）. CUR and HZC could significantly decrease the protein expression of p-JAK 2，p-STAT3，Bcl-2 and Bcl-xl ，while increased the protein expression of Bax ，Cyt-c，Caspase-9，Caspase-3 and PAPR （P＜0.05）. Above effects of HZC were significantly better than those of CUR （P＜0.05）. The results of animal experiment showed that there was no death ，no liver canceration and no pathological changes in liver appearance and tissue section of the three control groups ；there was no statistical significance in body weight and its increased weight ，liver index ，nuclear division index of carcinoma or PCNA index （P＞0.05）. Compared with model group， survival rate of rats were increased significantly in CUR protection group and HZC protection group ， while hepatocarcinoma incidence and the number of cancer nodules were decreased significantly （P＜0.05）；body weight and its increased weight were increased significantly ，while liver index ，nuclear division index of carcinoma and PCNA index were decreased significantly （P＜0.05）. There were some pathological changes in liver appearance and tissue section ；cancerous lesions with focal necrosis or cancerous lesions with patchy necrosis were observed. There was no statistical significance in the improvement of above indexes in 2 protection groups （P＞0.05）. CONCLUSIONS ：HZC could inhibit the proliferation and induce apoptosis of HepG 2 cells by inhibiting JAK 2/STAT3 signaling pathway and regulating the activation of mitochondrial endogenous pathway，which shows stronger anti-hepatocarcinoma effect in vitro than CUR. On the other hand ，there was no significant difference in the improvement of liver caner indexes in hepatic cancer model rats between HZC and CUR.

OBJECTIVE：To study t he effects of bro mophenylcurcumin（GL63）on the apoptosis ，migration and invasion of human cholangiocarcinoma RBE cells ，and to investigate its mechanism based on JAK/STAT signaling pathway. METHODS ：MTT assay was used to detect the effects of different concentrations of GL 63 [0（blank control ，similarly hereinafter ），1.25，2.5，5，10， 20，40 μ mol/L] on the proliferation of RBE cells after 48 h treatment ；the IC 50 was calculated. The effects of different concentrations of GL 63（0，5，10，20 μmol/L）on colony formation were detected by crystal violet staining after 48 h treatment. Flow cytometry ，Hoechst 33342 staining，cell scratch test and Transwell chamber invasion test were used to detect the effects of different concentrations of GL 63（0，5，10，20 μmol/L）on cell cycle distribution ，apoptosis，migration and invasion ability after 24 h treatment. Western blotting assay was adopted to detect the effects of different concentration of GL 63（0，5，10，20 μmol/L） on the expression of JAK 2/STAT3 signal pathway associated proteins. RESULTS ：The proliferation inhibition rates of RBE cells in different concentrations of GL 63 groups（1.25-40 μmol/L）were significantly increase d，compared with blank control group （P＜ 0.01），and showed a dose-dependent trend ，with IC 50 of （8.46±1.30）μmol/L. Compared with blank control group， 85917439。E-mail：zhaoji-an-88@163.com inhibition rates of RBE cell colony formation were significantly decreased in different concentrations （5，10，20 μmol/L）of GL 63 groups（P＜0.01）. The percentage of RBE cells at G 0/G1 phase increased significantly ，while that at S phase decreased significantly （P＜0.01）. The apoptotic rate increased significantly（P＜0.01），and the nucleus showed dense pyknosis and apoptotic bodies. The rate of cell migration and healing was significantly decreased （P＜0.01），and the number of invasive cells through basement membrane was significantly decreased （P＜ 0.01）. The protein expression of p-JAK 2， p-STAT3， Bcl-2， MMP-2， MMP-9， Pro-caspase-9 and P ro-caspase-3 were down-regulated significantly while the expression of Bax ，Cyt-c，Cleaved-caspase-9 and Cleaved-caspase- 3 were up-regulated significantly（P＜0.01）. CONCLUSIONS ：GL63 may inhibit the proliferation ，migration and invasion of RBE cells and promote its apoptosis by inhibiting JAK 2/STAT3 signal pathway.

As an important part of tumor microenvironment, neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis. Here we defined, at single-cell resolution, CD44-CXCR2- neutrophils as tumor-specific neutrophils (tsNeus) in both mouse and human gastric cancer (GC). We uncovered a Hippo regulon in neutrophils with unique YAP signature genes (e.g., ICAM1, CD14, EGR1) distinct from those identified in epithelial and/or cancer cells. Importantly, knockout of YAP/TAZ in neutrophils impaired their differentiation into CD54+ tsNeus and reduced their antitumor activity, leading to accelerated GC progression. Moreover, the relative amounts of CD54+ tsNeus were found to be negatively associated with GC progression and positively associated with patient survival. Interestingly, GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+ tsNeus. Furthermore, pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC, with no significant inflammation-related side effects. Thus, our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus, opening a new possibility to develop neutrophil-based antitumor therapeutics.
Humans ; Animals ; Mice ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Stomach Neoplasms/pathology* ; Neutrophils/pathology* ; Signal Transduction/genetics* ; YAP-Signaling Proteins ; Tumor Microenvironment ; Hyaluronan Receptors/genetics*