MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2

新兴的证据与肿瘤开发和前进显示出异常地表示的 microRNAs (miRNAs ) 的协会。然而，很少在胃的 carcinogenesis 对 miRNAs 的潜在的角色被知道。这里，我们执行了 miRNA microarray 屏蔽在配对的胃的癌症和他们的邻近的 nontumor 纸巾表示并且发现 miR-375 是的 miRNAs 差别极大地在胃的癌症纸巾的 downregulated。量的即时 PCR 分析证实那 miR-375 表情显著地从经历胃的切除术的病人与他们的 nontumor 对应物相比在超过 90% 主要胃的癌症被减少。miR-375 的 Overexpression 显著地在 vitro 并且在 vivo 禁止了胃的癌症房间增长。在胃的癌症房间的 miR-375 的强迫的表示显著地减少了 Janus kinase 的蛋白质水平 2 ( JAK2 )并且镇压带 JAK2 的 3 鈥? untranslated 区域的一个酶记者的活动，被预言的 miR-375-binding 地点的变化废除，显示那 JAK2 可以是 miR-375 目标基因。由由 RNAi 的 JAK2 的 AG490 或 silencing 的 JAK2 活动的任何一个抑制压制了类似于 miR-375 overexpression 的胃的癌症房间增长。而且， JAK2 的宫外的表示能部分颠倒 miR-375 引起的房间增长的抑制。最后，我们在胃的癌症发现了在 miR-375 表示和 JAK2 蛋白质水平之间的重要反的关联。因此，这些数据建议 miR-375 可以作为肿瘤 suppressor 工作由指向 JAK2 oncogene 潜在地调整胃的癌症房间增长，含有在胃的癌症的致病的 miR-375 的一个角色。

Mannose metabolism normalizes gut homeostasis by blocking the TNF-α-mediated proinflammatory circuit

Mannose is a naturally occurring sugar widely consumed in the daily diet;however,mechanistic insights into how mannose metabolism affects intestinal inflammation remain lacking.Herein,we reported that mannose supplementation ameliorated colitis development and promoted colitis recovery.Macrophage-secreted inflammatory cytokines,particularly TNF-α,induced pathological endoplasmic reticulum stress(ERS)in intestinal epithelial cells(IECs),which was prevented by mannose via normalization of protein N-glycosylation.By preserving epithelial integrity,mannose reduced the inflammatory activation of colonic macrophages.On the other hand,mannose directly suppressed macrophage TNF-αproduction translationally by reducing the glyceraldehyde 3-phosphate level,thus promoting GAPDH binding to TNF-αmRNA.Additionally,we found dysregulated mannose metabolism in the colonic mucosa of patients with inflammatory bowel disease.Finally,we revealed that activating PMM2 activity with epalrestat,a clinically approved drug for the treatment of diabetic neuropathy,elicited further sensitization to the therapeutic effect of mannose.Therefore,mannose metabolism prevents TNF-α-mediated pathogenic crosstalk between IECs and intestinal macrophages,thereby normalizing aberrant immunometabolism in the gut.

Tyrosine phosphatase Shp2 regulates pi 15RhoGEF/Rhodependent dendritic cell migration

The orchestrated migration of dendritic cells(DCs)to secondary lymphoid organs relies on C-C chemokine receptor type 7(CCR7)and its ligand C-C motif chemokine ligand 19(CCL19),and DC migration to lymph nodes is crucial for the initiation and progression of adaptive immune responses.