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Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by flora disequilibrium and mucosal immunity disorder. Here, we report that salidroside effectively restricts experimental colitis from two aspects of intestinal macrophage pyroptosis and dysbacteriosis‐derived colonic Th17/Treg imbalance. In innate immunity, the upregulated TREM1 and pyroptosis‐related proteins in inflamed colons were inhibited by salidroside administration and further experiments in vitro showed that salidroside suppressed LPS/ATP‐induced bone marrow‐derived macrophages (BMDMs) pyroptosis evident by the decline of LDH and IL‐1β release as well as the protein level of NLRP3, caspase‐1, and GSDMD p30. Moreover, the TREM1 inhibitor weakened the effect of salidroside on BMDMs pyroptosis, whereas salidroside still could downregulate TREM1 when NLRP3 was inhibited. In adaptive immunity, salidroside improved the gut microflora diversity and Th17/Treg ratio in DSS‐induced mice, especially promoting the abundance of Firmicutes. Clearance of the gut flora blocked the benefit of salidroside on colonic inflammation and Th17/Treg adaptive immunity, but transplanting salidroside‐treated foecal bacterium into flora‐depleted wild mice reproduced the resistance of salidroside to gut inflammation. Taken together, our data demonstrated that salidroside protected experimental colitis via skewing macrophage pyroptosis and Th17/Treg balance, indicating its potential effect on UC and other immune disorders. [ABSTRACT FROM AUTHOR]

Background and Aims There is evidence for a disturbed necroptosis function in many inflammatory diseases, but its role in inflammatory bowel diseases [IBD] and the underlying mechanisms are unclear. Here, we studied the functional significance and molecular mechanisms of ABIN3, a ubiquitin-binding protein, in regulating the ubiquitination and activation of necroptosis in IBD. Methods The expression of necroptosis hallmarks and ABIN3 were assessed in inflamed samples of IBD patients, dextran sodium sulphate [DSS]-induced colitis models, and azoxymethane [AOM]/DSS models in mice. ABIN3 was overexpressed and silenced to explore its function in regulating necroptosis, inflammation, and intestinal barrier function. Immuoprecipitiation [IP] and co-IP assays were performed to investigate the cross-talk between ABIN3 and deubiquitinating enzyme A20, and the mechanisms of coordinating ubiquitination modification to regulate necroptosis. Results Excessive necroptosis is an important contributory factor towards the uncontrolled inflammation and intestinal barrier defects in IBD and experimental colitis. Blocking necroptosis by Nec-1s or GSK'872 significantly prevented cell death and alleviated DSS-induced colitis in vivo, whereas in the AOM/DSS model, necroptosis inhibitors aggravated the severity of colitis-associated colon carcinogenesis [CAC]. Mechanistically, ABIN3 is rapidly recruited to the TNF-RSC complex, which interacts and coordinates with deubiquitinating enzyme A20 to control the K63 deubiquitination modification and subsequent activation of the critical necroptosis kinase, RIPK3, to suppress necroptosis. Conclusions ABIN3 regulates inflammatory response and intestinal barrier function by interacting with A20 and coordinating the K63 deubiquitination modification of necroptosis in IBD. [ABSTRACT FROM AUTHOR]

Barrett's esophagus (BE) is a premalignant lesion of esophageal adenocarcinoma. The aim of the present study was to investigate the possible mechanisms and biomarkers of BE. To identify the differentially expressed microRNAs (DEmiRNAs) and genes (DEGs) in BE, the miRNA expression profile GSE20099 and the gene expression profiles GSE26886, GSE13083 and GSE34619 were obtained from the Gene Expression Omnibus (GEO) database. DEGs and DEmiRNAs were screened for using the GEO2R tool. Using DAVID, functional and pathway enrichment analysis was performed to explore the biological function of identified DEGs. The protein-protein interaction (PPI) network was detected using STRING and constructed by Cytoscape software. Furthermore, targets of identified DEmiRNAs were predicted by the miRecords database, then integrated with the identified DEGs to obtain key genes involved in BE. In total, 311 DEGs were identified. These genes were significantly enriched in the pancreatic secretion, metabolic pathways and cytochrome P450 drug metabolism pathways. In the PPI network, 16 hub genes, including keratin 16, cystic fibrosis transmembrane conductance regulator, involucrin, protein kinase C a and cadherin 17 were identified. Following integration of the predicted target genes of DEmiRNAs with DEGs, three key BE genes were identified: PRKCA, CDH17 and epiregulin. In conclusion, a comprehensive bioinformatics analysis of identified DEGs and DEmiRNAs was performed to elucidate potential pathways and biomarkers involved in the development of BE. [ABSTRACT FROM AUTHOR]

We used periodic DFT calculations to investigate the effect of alkali promoter on the selectivity of the water-gas shift reaction (WGSR) explicitly on the Ni(111) surface. On clean Ni(111), the WGSR redox and carboxyl pathways are both kinetically competitive. The selectivity of the WGSR can be affected by methanation on Ni, in which the C¢O bond cleavage pathway of CHO is the most competitive. A Ni(111) surface modified with K adatoms was used to further understand the promoter effects on the WGSR selectivity. A combined energetic and kinetic analysis from DFT calculations indicates that the K adatom stabilizes certain reactive intermediates (e.g., H2O, CO) thermodynamically but is energetically neutral or even repulsive toward other intermediates. As a result, WGSR pathways benefit from the presence of K adatoms compared to the competing methanation pathway. This study thus confirmed the promoting effects of alkali metals on the WGSR with DFTbased mechanistic insights. [ABSTRACT FROM AUTHOR]

The bacterial canker of kiwifruit caused by Pseudomonas syringae pv. actinidiae ( Psa ) is the most devastating disease threaten-ing the global kiwifruit production. This pathogen delivers multiple effector proteins into plant cells to resist plant immune re-sponses and facilitate their survival. Here, we focused on the unique effector HopZ5 in Psa , which previously has been reported to have virulence functions. In this study, our results showed that HopZ5 could cause macroscopic cell death and trigger a serious immune response by agroinfiltration in Nicotiana benthamiana , along with up-regulated expression of immunity-related genes and significant accumulation of reactive oxygen species and callose. Subsequently, we confirmed that HopZ5 interacted with the phosphoserine-binding protein, GF14C, in both the nonhost plant N. benthamiana (NbGF14C) and the host plant kiwifruit (AcGF14C), and silencing of NbGF14C compromised HopZ5-mediated cell death, suggesting GF14C played a crucial role in the detection of HopZ5. Further studies showed that overexpression of NbGF14C both markedly reduced the infection of Sclerotinia sclerotiorum and Phytophthora capsica in N. benthamiana and overexpression of AcGF14C significantly enhanced the re-sistance of kiwifruit against Psa , indicating that GF14C positively regulates plant immunity. Collectively, our results revealed that the virulence effector HopZ5 could be recognized by plants and interact with GF14C to activate plant immunity.

Accumulating evidence has revealed that m 6 A modification, the predominant RNA modification in eukaryotes, adds a novel layer of regulation to the gene expression. Dynamic and reversible m 6 A modification implements sophisticated and crucial functions in RNA metabolism, including generation, splicing, stability, and translation in messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs). Furthermore, m 6 A modification plays a determining role in producing various m 6 A-labeling RNA outcomes, thereby affecting several functional processes, including tumorigenesis and progression. Herein, we highlighted current advances in m 6 A modification and the regulatory mechanisms underlying mRNAs and ncRNAs in distinct cancer stages. Meanwhile, we also focused on the therapeutic significance of m 6 A regulators in clinical cancer treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Growing evidence indicates that N6-methyladenosine (m 6 A) is the most pervasive RNA modification in eukaryotic cells. However, the specific role of METTL3 in papillary thyroid carcinoma (PTC) initiation and development remains elusive. Here we found that downregulation of METTL3 was correlated with malignant progression and poor prognosis in PTC. A variety of gain- and loss-of-function studies clarified the effect of METTL3 on regulation of growth and metastasis of PTC cells in vitro and in vivo. By combining RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (meRIP-seq), our mechanistic studies pinpointed c-Rel and RelA as downstream m 6 A targets of METTL3. Disruption of METTL3 elicited secretion of interleukin-8 (IL-8), and elevated concentrations of IL-8 promoted recruitment of tumor-associated neutrophils (TANs) in chemotaxis assays and mouse models. Administration of the IL-8 antagonist SB225002 substantially retarded tumor growth and abolished TAN accumulation in immunodeficient mice. Our findings revealed that METTL3 played a pivotal tumor-suppressor role in PTC carcinogenesis through c-Rel and RelA inactivation of the nuclear factor κB (NF-κB) pathway by cooperating with YTHDF2 and altered TAN infiltration to regulate tumor growth, which extends our understanding of the relationship between m 6 A modification and plasticity of the tumor microenvironment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)