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Jie He and colleagues report exome sequencing of 113 tumor-normal pairs of esophageal squamous cell carcinoma. They highlight mutations in genes involved in cell cycle and apoptosis regulation, histone modifier genes and genes encoding members of the Hippo and Notch pathways. Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers 1 . We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2 ; 19%), KMT2C ( MLL3 ; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1 , FAT2 , FAT3 or FAT4 (27%) or AJUBA ( JUB ; 7%) and NOTCH1 , NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.

NLRP3 inflammasome is a vital player in macrophages pyroptosis, which is a type of proinflammatory cell-death and takes part in the pathogenesis of atherosclerosis. In this study, we used apoE −/− mice and ox-LDL induced THP-1 derived macrophages to explore the mechanisms of MCC950, a selective NLRP3 inhibitor in treating atherosclerosis. For the in vivo study, MCC950 was intraperitoneal injected to 8-week-old apoE −/− mice fed with high-fat diet for 12 weeks. For the in vitro study, THP-1 derived macrophages were treated with ox-LDL and MCC950 for 48 h. MCC950 administration reduced plaque areas and macrophages contents, but did not improve the serum lipid profiles in aortic root of apoE −/− mice. MCC950 inhibited the activation of NLRP3/ASC/Caspase-1/GSDMD-N axis, and alleviated macrophages pyroptosis and the production of IL-1β and IL-18 both in aorta and in cell lysates. However, MCC950 did not affect the expression of TLR4 or the mRNA levels of NLRP3 inflammasome and its downstream proteins, suggesting that MCC950 had no effects on the priming of NLRP3 inflammasome activation in macrophages. The anti-atherosclerotic mechanisms of MCC950 on attenuating macrophages inflammation and pyroptosis involved in inhibiting the assembly and activation of NLRP3 inflammasome, rather than interrupting its priming.

Background. Alleviating mild cognitive impairment (MCI) is crucial to delay the progression of Alzheimer’s disease (AD). Jia-Wei-Kai-Xin-San (JWKXS) is applied for treating AD with MCI. However, the mechanism of JWKXS in the treatment of MCI is unclear. Thus, this study aimed to investigate the effect and mechanism of JWKXS in SAMP8 mice models of MCI. Methods. MCI models were established to examine learning and memory ability and explore the pathomechanisms in brain of SAMP8 mice at 4, 6, and 8 months. The mice were treated for 8 weeks and the effects of JWKXS on MCI were characterized through Morris water maze and HE/Nissl’s/immunohistochemical staining. Its mechanism was predicted by the combination of UPLC-Q-TOF/MS and system pharmacology analysis, further verified with SAMP8 mice, BV2 microglial cells, and PC12 cells. Results. It was found that 4-month-old SAMP8 mice exhibited MCI. Two months of JWKXS treatment improved the learning and memory ability, alleviated the hippocampal tissue and neuron damage. Through network pharmacology, four key signaling pathways were found to be involved in treatment of MCI by JWKXS, including TLR4/NF-κB pathway, NLRP3 inflammasome activation, and intrinsic and extrinsic apoptosis. In vitro and in vivo experiments demonstrated that JWKXS attenuated neuroinflammation by inhibiting microglia activation, suppressing TLR4/NF-κB and NLRP3 inflammasome pathways, and blocking the extrinsic and intrinsic apoptotic pathways leading to neuronal apoptosis suppression in the hippocampus. Conclusion. JWKXS treatment improved the learning and memory ability and conferred neuroprotective effects against MCI by inducing anti-inflammation and antiapoptosis. Limitations. The small sample size and short duration of the intervention limit in-depth investigation of the mechanisms. Future Prospects. This provides a direction for further clarification of the anti-AD mechanism, and provides certain data support for the formulation to move toward clinical practice.

Immune dysfunction caused by environmental factors plays an important role in the development of Graves’ disease (GD), and environmental factors are closely related to the intestinal flora. Our previous study showed significant changes in the intestinal flora in GD patients compared with healthy volunteers. This study analyzed the relationships between changes in the intestinal flora, thyroid function and relevant thyroid antibodies in GD patients before and after methimazole treatment. The subjects were divided into the UGD group (18 newly diagnosed GD patients), the TGD group (10 GD patients with normal or approximately normal thyroid function after methimazole treatment) and the NC group (11 healthy volunteers). Their fresh stool samples were sent for 16S rRNA gene amplification and Illumina platform sequencing. The correlations of the relative abundance of Bifidobacterium with the levels of TRAb, TgAb and TPOAb in the NC group and the UGD group were analyzed. A total of 1,562,445 high-quality sequences were obtained. In the UGD group, the abundances of Bifidobacterium and Collinsella were higher than that in the NC group; Bacteroides abundance in the TGD group was higher than that in the NC group, while Prevotella and Dialister abundances were lower than that in the NC group; Prevotella and Collinsella abundances in the UGD group were higher than that in the TGD group. The predominant abundance distribution of Bifidobacteriaceae in the UGD group at the family level was superior to that in the NC group. The abundance of Bifidobacterium was positively correlated with the levels of TRAb, TgAb, and TPOAb. The biological diversity of the intestinal flora was reduced in GD patients. After methimazole treatment, the composition of the intestinal flora was significantly altered. The change in Bifidobacterium abundance was positively correlated with TRAb, TgAb and TPOAb, suggesting that it might be related to the immune mechanism of GD. The results of this study may deepen our understanding of the pathogenesis of GD and provide a new idea for the treatment of GD.

MicroRNAs (miRs) are a class of small non-coding RNAs that are involved in the regulation of gene expression, and in cancer development and progression. In the present study, miR-320 expression was found to be significantly reduced in glioma tissue in comparison with that in adjacent healthy tissues. In the present study, in vitro analyses demonstrated that overexpression of miR-320 inhibited cell proliferation and metastasis, while antisense miR-320 oligonucleotides enhanced cell proliferation and migration in U251 and SHG-44 glioma cell lines, compared with that in negative control cells. Protein expression of E2F1, a cell-cycle regulator, was negatively regulated by miR-320. Therefore, the present study provides novel insights into the association between miR-320 and glioma development.

Cultivated carrots can be divided into eastern and western types. Much evidence supports the idea that eastern carrots originated in Central Asia, while varying opinions exist on the origin of western carrots, especially orange varieties, and the origin of Chinese orange carrots remains unclear. In this study, we used 119 carrot accessions to investigate the relationship between Chinese carrots and western orange varieties (Western orange) using morphology and simple sequence repeat (SSR) markers. The results demonstrate that Chinese carrots are eastern-type and maintain the primitive traits of strong and pubescent leaves, and early flowering. Despite being morphologically similar, the STRUCTURE and phylogenetic analysis based on SSR markers indicated that Western orange were clearly separated from Chinese carrots. These findings, in conjunction with historical documents suggesting that the first Chinese carrots seem to be yellow, suggest that Chinese orange were derived from Chinese red according to the mixed distribution of red and orange accessions. These results suggest that Chinese orange carrots may have undergone a specific, independent process different from that of Western orange.