Search

To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P

BackgroundGRAS transcription factors perform indispensable functions in various biological processes, such as plant growth, fruit development, and biotic and abiotic stress responses. The development of whole-genome sequencing has allowed theGRASgene family to be identified and characterized in many species. However, thorough in-depth identification or systematic analysis ofGRASfamily genes in foxtail millet has not been conducted.ResultsIn this study, 57GRASgenes of foxtail millet (SiGRASs) were identified and renamed according to the chromosomal distribution of theSiGRASgenes. Based on the number of conserved domains and gene structure, theSiGRASgenes were divided into 13 subfamilies via phylogenetic tree analysis. TheGRASgenes were unevenly distributed on nine chromosomes, and members of the same subfamily had similar gene structures and motif compositions. Genetic structure analysis showed that mostSiGRASgenes lacked introns. SomeSiGRASgenes were derived from gene duplication events, and segmental duplications may have contributed more toGRASgene family expansion than tandem duplications. Quantitative polymerase chain reaction showed significant differences in the expression ofSiGRASgenes in different tissues and stages of fruits development, which indicated the complexity of the physiological functions ofSiGRAS. In addition, exogenous paclobutrazol treatment significantly altered the transcription levels of DELLA subfamily members, downregulated the gibberellin content, and decreased the plant height of foxtail millet, while it increased the fruit weight. In addition,SiGRAS13andSiGRAS25may have the potential for genetic improvement and functional gene research in foxtail millet.ConclusionsCollectively, this study will be helpful for further analysing the biological function ofSiGRAS. Our results may contribute to improving the genetic breeding of foxtail millet.

This study is aimed at investigating mechanisms and effects of Krüppel-like factor 16 (KLF16) affects myocardial ischemia-reperfusion. Patients with myocardial ischemia-reperfusion and normal volunteer were collected. C57BL6J male mice were located left anterior descending coronary artery (LAD). H9c2 cell was induced with hydrogen peroxide (H2O2) and Lipopolysaccharide (LPS). Serum KLF16 mRNA expression was increased in myocardial ischemia-reperfusion. Serum mRNA of KLF16 was positive correlation with serum creatine kinase MB (CK-MB) or creatine kinase (CK) levels in patients with myocardial ischemia-reperfusion. The expression of KLF16 mRNA and protein in mice with myocardial ischemia-reperfusion were also increased. The inhibition of KLF16 reduced oxidative stress and inflammation, and presented myocardial ischemia (MI) in vivo model of myocardial ischemia-reperfusion. Mitochondrial transcription factor A (TFAM)/peroxisome proliferator-activated receptor-beta (PPARβ) signal passage is target spot of KLF16 in Myocardial ischemia-reperfusion. TFAM interlink KLF16 in myocardial ischemia-reperfusion. TFAM participate in KLF16 affects myocardial ischemia-reperfusion. PPARβ promoter region KLF16 affects myocardial ischemia-reperfusion. These results firstly demonstrated that knock-out KLF16 reduced oxidative stress and inflammation, and presented MI in vivo model of myocardial ischemia-reperfusion through the induction of PPARβ by TFAM, may provide a novel therapeutic strategy for myocardial ischemia-reperfusion.

Human pancreatic ductal adenocarcinoma (PDAC) harboring one KRAS mutant allele often displays increasing genomic loss of the remaining wild-type (WT) allele (known as LOH at KRAS) as tumors progress to metastasis, yet the molecular ramification of this WT allelic loss is unknown. In this study, we showed that the restoration of WT KRAS expression in human PDAC cell lines with LOH at KRAS significantly attenuated the malignancy of PDAC cells both in vitro and in vivo, demonstrating a tumor-suppressive role of the WT KRAS allele. Through RNA-Seq, we identified the HIPPO signaling pathway to be positively regulated by WT KRAS in PDAC cells. In accordance with this observation, PDAC cells with LOH at KRAS exhibited increased nuclear localization and activation of transcriptional co-activator YAP1. Mechanistically, we discovered that WT KRAS expression sequestered YAP1 from the nucleus, through enhanced 14-3-3zeta interaction with phosphorylated YAP1 at S127. Consistently, expression of a constitutively-active YAP1 mutant in PDAC cells bypassed the growth inhibitory effects of WT KRAS. In patient samples, we found that the YAP1-activation genes were significantly upregulated in tumors with LOH at KRAS, and YAP1 nuclear localization predicted poor survival for PDAC patients. Collectively, our results reveal that the WT allelic loss leads to functional activation of YAP1 and enhanced tumor malignancy, which explains the selection advantage of the tumor cells with LOH at KRAS during pancreatic cancer clonal evolution and progression to metastasis, and should be taken into consideration in future therapeutic strategies targeting KRAS.

Background Members of the basic helix-loop-helix (bHLH) transcription factor family perform indispensable functions in various biological processes, such as plant growth, seed maturation, and abiotic stress responses. However, the bHLH family in foxtail millet (Setaria italica), an important food and feed crop, has not been thoroughly studied. Results In this study, 187 bHLH genes of foxtail millet (SibHLHs) were identified and renamed according to the chromosomal distribution of the SibHLH genes. Based on the number of conserved domains and gene structure, the SibHLH genes were divided into 21 subfamilies and two orphan genes via phylogenetic tree analysis. According to the phylogenetic tree, the subfamilies 15 and 18 may have experienced stronger expansion in the process of evolution. Then, the motif compositions, gene structures, chromosomal spread, and gene duplication events were discussed in detail. A total of sixteen tandem repeat events and thirty-eight pairs of segment duplications were identified in bHLH family of foxtail millet. To further investigate the evolutionary relationship in the SibHLH family, we constructed the comparative syntenic maps of foxtail millet associated with representative monocotyledons and dicotyledons species. Finally, the gene expression response characteristics of 15 typical SibHLH genes in different tissues and fruit development stages, and eight different abiotic stresses were analysed. The results showed that there were significant differences in the transcription levels of some SibHLH members in different tissues and fruit development stages, and different abiotic stresses, implying that SibHLH members might have different physiological functions. Conclusions In this study, we identified 187 SibHLH genes in foxtail millet and further analysed the evolution and expression patterns of the encoded proteins. The findings provide a comprehensive understanding of the bHLH family in foxtail millet, which will inform further studies on the functional characteristics of SibHLH genes.

Acute lung injury (ALI) is characterized by excessive production of inflammatory factors and alveolar epithelial damage, type II alveolar epithelial (ATII) cells participate in the repairment of the damaged lung tissue in ALI. Recently, microRNAs (miRNAs) have been found to play crucial roles in the amelioration of various inflammation-induced diseases, including ALI. However, the biological function and the mechanisms of action of miRNAs in the regulation of inflammation, and how ATII cells repair damaged lung tissue in ALI remain unknown. In this study, a model of ALI was established using LPS, and ATII cells were isolated and treated with LPS. Hematoxylin and eosin staining revealed the injury to lung tissues. In this study we found that miR-541-5p expression was significantly decreased in ALI tissue and in the LPS-induced ATII cell model. Additionally, the LPS-induced model showed suppression of ATII cell proliferation and activity. Furthermore, overexpression of miR-541-5p was found to promote cell activity and proliferation in the LPS-induced ATII cell model. Moreover, a luciferase assay illustrated that HMGB1 is a target of miR-541-5p, HMGB1 knockdown blocked the inhibitory effect of miR-541-5p on LPS-induced ATII cells. Ultimately, our study demonstrated that expression of p38, JNK, and ERK in LPS-induced ATII cells increased significantly. These results suggest that miR-541-5p is a key effector in ALI tissue, and that LPS-induced ATII cells act by regulating HMGB1 expression. This effect may be related to excessive activation of the JNK/ERK/p38 signaling pathway.

Background Tumor-associated macrophages (TAMs) are the most abundant stromal cells in the tumor microenvironment. Turning the TAMs against their host tumor cells is an intriguing therapeutic strategy particularly attractive for patients with immunologically “cold” tumors. This concept was mechanistically demonstrated on in vitro human and murine lung cancer cells and their corresponding TAM models through combinatorial use of nanodiamond-doxorubicin conjugates (Nano-DOX) and a PD-L1 blocking agent BMS-1. Nano-DOX are an agent previously proved to be able to stimulate tumor cells’ immunogenicity and thereby reactivate the TAMs into the anti-tumor M1 phenotype. Results Nano-DOX were first shown to stimulate the tumor cells and the TAMs to release the cytokine HMGB1 which, regardless of its source, acted through the RAGE/NF-κB pathway to induce PD-L1 in the tumor cells and PD-L1/PD-1 in the TAMs. Interestingly, Nano-DOX also induced NF-κB-dependent RAGE expression in the tumor cells and thus reinforced HMGB1’s action thereon. Then, BMS-1 was shown to enhance Nano-DOX-stimulated M1-type activation of TAMs both by blocking Nano-DOX-induced PD-L1 in the TAMs and by blocking tumor cell PD-L1 ligation with TAM PD-1. The TAMs with enhanced M1-type repolarization both killed the tumor cells and suppressed their growth. BMS-1 could also potentiate Nano-DOX’s action to suppress tumor cell growth via blocking of Nano-DOX-induced PD-L1 therein. Finally, Nano-DOX and BMS-1 achieved synergistic therapeutic efficacy against in vivo tumor grafts in a TAM-dependent manner. Conclusions PD-L1/PD-1 upregulation mediated by autocrine and paracrine activation of the HMGB1/RAGE/NF-κB signaling is a key response of lung cancer cells and their TAMs to stress, which can be induced by Nano-DOX. Blockade of Nano-DOX-induced PD-L1, both in the cancer cells and the TAMs, achieves enhanced activation of TAM-mediated anti-tumor response. Graphic abstract

BACKGROUND Autoimmune hepatitis (AIH) is an immune-mediated liver disease affecting all age groups. Associations between hepatitis A virus (HAV) and AIH have been described for many years. Herein, we report a case of an AIH/primary biliary cholangitis (PBC) overlap syndrome with anti-HAV immunoglobulin M (IgM) false positivity. CASE SUMMARY A 55-year-old man was admitted with manifestations of anorexia and jaundice along with weakness. He had marked transaminitis and hyperbilirubinemia. Viral serology was positive for HAV IgM and negative for others. Autoantibody screening was positive for anti-mitochondria antibody but negative for others. Abdominal ultrasound imaging was normal. He was diagnosed with acute hepatitis A. After symptomatic treatment, liver function tests gradually recovered. Several months later, his anti-HAV IgM positivity persisted and transaminase and bilirubin levels were also more than 10 times above of the upper limit of normal. Liver histology was prominent, and HAV RNA was negative. Therefore, AIH/primary biliary cholangitis (PBC) overlap syndrome diagnosis was made based on the “Paris Criteria”. The patient was successfully treated by immunosuppression. CONCLUSION This case highlights that autoimmune diseases or chronic or acute infections, may cause a false-positive anti-HAV IgM result because of cross-reacting antibodies. Therefore, the detection of IgM should not be the only method for the diagnosis of acute HAV infection. HAV nucleic acid amplification tests should be employed to confirm the diagnosis.

National foodborne pathogen surveillance is a system that collects data regarding food contamination by pathogenic bacteria, viruses, parasites, and other harmful microbial factors. The surveillance data are used to understand the potential microbial risks in different categories of food and to provide science-based data for risk assessment and development of reference standards in the form of maximum limits. This review introduces stepwise expansion of the foodborne pathogen surveillance in China, relevant policies, function and duties of different organizations and institutions, surveillance plans, and quality control. Achievements of the surveillance system and future challenges are also presented.

Lung inflammation is a hallmark of coronavirus disease 2019 (COVID-19). In this study, we show that mice develop inflamed lung tissue after being administered exosomes released from the lung epithelial cells exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp12 and Nsp13 (exosomesNsp12Nsp13). Mechanistically, we show that exosomesNsp12Nsp13 are taken up by lung macrophages, leading to activation of nuclear factor κB (NF-κB) and the subsequent induction of an array of inflammatory cytokines. Induction of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β from exosomesNsp12Nsp13-activated lung macrophages contributes to inducing apoptosis in lung epithelial cells. Induction of exosomesNsp12Nsp13-mediated lung inflammation was abolished with ginger exosome-like nanoparticle (GELN) microRNA (miRNA aly-miR396a-5p. The role of GELNs in inhibition of the SARS-CoV-2-induced cytopathic effect (CPE) was further demonstrated via GELN aly-miR396a-5p- and rlcv-miR-rL1-28-3p-mediated inhibition of expression of Nsp12 and spike genes, respectively. Taken together, our results reveal exosomesNsp12Nsp13 as potentially important contributors to the development of lung inflammation, and GELNs are a potential therapeutic agent to treat COVID-19., Graphical Abstract, COVID-19 is a disease affecting the pulmonary system with devastating inflammation. Teng et al. have shown that exosomes released from SARS-CoV-2-infected lung epithelia cells are preferentially taken up by lung macrophages that subsequently induce lung inflammation. Ginger exosome-like nanoparticle miRNA inhibits SARS-CoV-2-induced lung inflammation and viral replication.

Objective To understand the protective effect of NF-κB signaling pathway inhibitor pyrrolidinedithiocarbamate (PDTC) on mice with chronic atrophic gastritis (CAG). Methods Helicobacter pylori (H. pylori) infection combined with high-salt diet was used to construct the CAG mouse model, and 100 or 200 mg/kg/day PDTC was intragastrically treated for 8 weeks. Then, hematoxylin and eosin (HE) and Alcian blue-periodic acid-Schiff (AB-PAS) staining were used to observe the pathology of gastric mucosa, while immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immuno sorbent assay (ELISA) and western blotting were determined to detect the expression of related molecules. Results The nuclear content of NF-κB p65 in the gastric mucosa of the CAG mice was increased accompanying by the structural disorder of the gastric mucosal epithelium, inflammatory cell infiltration, intestinal metaplasia, and increased MUC2 expression, but the symptoms were alleviated after PDTC treatment. In addition, the expressions of TNF-α, IL-1β, IL-6 and COX2 in the gastric mucosa and serum of CAG mice were higher than those control mice, which were reduced in CAG mice treated with either 100 or 200 mg/kg PDTC. Furthermore, 100 mg/kg and 200 mg/kg PDTC treatments reduced the serum PGE2 in CAG mice with the decreased PCNA and Ki-67 expression in gastric mucosa. The therapeutic effect of 200 mg/kg PDTC was significantly better than that of 100 mg/kg PDTC. Conclusion PDTC inhibited inflammation and the excessive proliferation of gastric mucosal epithelial cells, thereby exerting a potential therapeutic effect on CAG.

Emerging research has revealed regulation of colorectal cancer metabolism by bacteria. Fusobacterium nucleatum (Fn) plays a crucial role in the development of colorectal cancer, however, whether Fn infection modifies metabolism in patients with colorectal cancer remains unknown. Here, LC-MS/MS-based lipidomics identified the upregulation of cytochrome P450 monooxygenases, primarily CYP2J2, and their mediated product 12,13-EpOME in patients with colorectal cancer tumors and mouse models, which increased the invasive and migratory ability of colorectal cancer cells in vivo and in vitro by regulating the epithelial–mesenchymal transition (EMT). Metagenomic sequencing indicated a positive correlation between increased levels of fecal Fn and serum 12,13-EpOME in patients with colorectal cancer. High levels of CYP2J2 in tumor tissues also correlated with high Fn levels and worse overall survival in patients with stage III/IV colorectal cancer. Moreover, Fn was found to activate TLR4/AKT signaling, downregulating Keap1 and increasing NRF2 to promote transcription of CYP2J2. Collectively, these data identify that Fn promotes EMT and metastasis in colorectal cancer by activating a TLR4/Keap1/NRF2 axis to increase CYP2J2 and 12,13-EpOME, which could serve as clinical biomarkers and therapeutic targets for Fn-infected patients with colorectal cancer. Significance: This study uncovers a mechanism by which Fusobacterium nucleatum regulates colorectal cancer metabolism to drive metastasis, suggesting the potential biomarker and therapeutic utility of the CYP2J2/12,13–EpOME axis in Fn-infected patients.

The presence of SARS-CoV-2 mutants, including the emerging variant B.1.1.7, has raised great concerns in terms of pathogenesis, transmission, and immune escape. Characterizing SARS-CoV-2 mutations, evolution, and effects on infectivity and pathogenicity is crucial to the design of antibody therapies and surveillance strategies. Here, we analyzed 454,443 SARS-CoV-2 spike genes/proteins and 14,427 whole-genome sequences. We demonstrated that the early variant B.1.1.7 may not have evolved spontaneously in the United Kingdom or within human populations. Our extensive analyses suggested that Canidae, Mustelidae or Felidae, especially the Canidae family (for example, dog) could be a possible host of the direct progenitor of variant B.1.1.7. An alternative hypothesis is that the variant was simply yet to be sampled. Notably, the SARS-CoV-2 whole-genome represents a large number of potential co-mutations. In addition, we used an experimental SARS-CoV-2 reporter replicon system to introduce the dominant co-mutations NSP12_c14408t, 5′UTR_c241t, and NSP3_c3037t into the viral genome, and to monitor the effect of the mutations on viral replication. Our experimental results demonstrated that the co-mutations significantly attenuated the viral replication. The study provides valuable clues for discovering the transmission chains of variant B.1.1.7 and understanding the evolutionary process of SARS-CoV-2.

Background Calcific aortic valve disease (CAVD) is the most common subclass of valve heart disease in the elderly population and a primary cause of aortic valve stenosis. However, the underlying mechanisms remain unclear. Methods The gene expression profiles of GSE83453, GSE51472, and GSE12644 were analyzed by ‘limma’ and ‘weighted gene co-expression network analysis (WGCNA)’ package in R to identify differentially expressed genes (DEGs) and key modules associated with CAVD, respectively. Then, enrichment analysis was performed based on Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, DisGeNET, and TRRUST database. Protein–protein interaction network was constructed using the overlapped genes of DEGs and key modules, and we identified the top 5 hub genes by mixed character calculation. Results We identified the blue and yellow modules as the key modules. Enrichment analysis showed that leukocyte migration, extracellular matrix, and extracellular matrix structural constituent were significantly enriched. SPP1, TNC, SCG2, FAM20A, and CD52 were identified as hub genes, and their expression levels in calcified or normal aortic valve samples were illustrated, respectively. Conclusions This study suggested that SPP1, TNC, SCG2, FAM20A, and CD52 might be hub genes associated with CAVD. Further studies are required to elucidate the underlying mechanisms and provide potential therapeutic targets.

The abundance of genetic abnormalities and phenotypic heterogeneities in acute myeloid leukemia (AML) poses significant challenges to the development of improved treatments. Here, we demonstrated that a key growth arrest-specific gene 6/AXL axis is highly activated in cells from patients with AML, particularly in stem/progenitor cells. We developed a potent selective AXL inhibitor that has favorable pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation (PDX) models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in PDX models. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition, alone or in combination with venetoclax, potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells and shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. Inhibition of AXL or BCL-2 also differentially targets key signaling proteins to synergize in leukemic cell killing. These findings have a direct translational impact on the treatment of AML and other cancers with high AXL activity.

Socio-sexual environment can have critical impacts on reproduction and survival of animals. Consequently, they need to prepare themselves by allocating more resources to competitive traits that give them advantages in the particular social setting they have been perceiving. Evidence shows that a male usually raises his investment in sperm after he detects the current or future increase of sperm competition because relative sperm numbers can determine his paternity share. This leads to the wide use of testis size as an index of the sperm competition level, yet testis size does not always reflect sperm production. To date, it is not clear whether male animals fine-tune their resource allocation to sperm production and other traits as a response to social cues during their growth and development. Using a polygamous insect Ephestia kuehniella, we tested whether and how larval social environment affected sperm production, testis size, and body weight. We exposed the male larvae to different juvenile socio-sexual cues and measured these traits. We demonstrate that regardless of sex ratio, group-reared males produced more eupyrenes (fertile and nucleate sperm) but smaller testes than singly reared ones, and that body weight and apyrene (infertile and anucleate sperm) numbers remained the same across treatments. We conclude that the presence of larval social, but not sexual cues is responsible for the increase of eupyrene production and decrease of testis size. We suggest that male larvae increase investment in fertile sperm cells and reduce investment in other testicular tissues in the presence of conspecific juvenile cues.

Bioremediation of chlorinated ethenes in anoxic aquifers hinges on organohalide-respiring Dehalococcoidia expressing vinyl chloride (VC) reductive dehalogenase (RDase). The tceA gene encoding the trichloroethene-dechlorinating RDase TceA is frequently detected in contaminated groundwater but not recognized as a biomarker for VC detoxification. We demonstrate that tceA-carrying Dehalococcoides mccartyi (Dhc) strains FL2 and 195 grow with VC as an electron acceptor when sufficient vitamin B12 (B12) is provided. Strain FL2 cultures that received 50 μg L-1 B12 completely dechlorinated VC to ethene at rates of 14.80 ± 1.30 μM day-1 and attained 1.64 ± 0.11 × 108 cells per μmol of VC consumed. Strain 195 attained similar growth yields of 1.80 ± 1.00 × 108 cells per μmol of VC consumed, and both strains could be consecutively transferred with VC as the electron acceptor. Proteomic analysis demonstrated TceA expression in VC-grown strain FL2 cultures. Resequencing of the strain FL2 and strain 195 tceA genes identified non-synonymous substitutions, although their consequences for TceA function are currently unknown. The finding that Dhc strains expressing TceA respire VC can explain ethene formation at chlorinated solvent sites, where quantitative polymerase chain reaction analysis indicates that tceA dominates the RDase gene pool.

Winter oil rapeseed ‘18 R-1’ (Brassica rapa L.) is a new variety that can survive in northern China where the extreme low temperature is −20 °C to −32 °C. It is different from traditional B. rapa and Brassica napus. In this study, the complete chloroplast (cp) genome of ‘18 R-1’ was sequenced and analyzed to assess the genetic relationship. The size of cp genome is 153,494 bp, including one large single copy (LSC) region of 83,280 bp and one small single copy (SSC) region of 17,776 bp, separated by two inverted repeat (IR) regions of 26,219 bp. The GC content of the whole genome is 36.35%, while those of LSC, SSC, and IR are 34.12%, 29.20%, and 42.32%, respectively. The cp genome encodes 132 genes, including 87 protein-coding genes, eight rRNA genes, and 37 tRNA genes. In repeat structure analysis, 288 simple sequence repeats (SSRs) were identified. Cp genome of ‘18 R-1’ was closely related to Brassica chinensis, B. rapa and Brassica pekinesis.

This study aimed to explore the molecular mechanism by which mesenchymal stem cells (MSCs) mediate lung cancer progression. Extracellular vesicles (EVs) were isolated from transfected or untransfected MSCs, and were co-cultured with lung cancer cells with/without microRNA-130b-3p (miR-130b-3p) inhibitor, mimic, overexpression plasmids of FOXO3/NFE2L2, or shRNAs. CCK-8 assay, colony formation, transwell assay, and flow cytometry were carried out to determine the biological functioning of lung cancer cells. Furthermore, FOXO3, Keap1, NFE2L2, and TXNRD1 expression was determined by qRT-PCR and western blot analysis. A tumor xenograft mouse model was used to determine role of EVs-miR-130b-3p and its target FOXO3 in lung cancer progression in vivo. miR-130b-3p was highly expressed in lung cancer tissues and MSC-derived EVs. Moreover, the MSC-derived EVs transferred miR-130b-3p to lung cancer cells to promote cell proliferation, migration, and invasion while repress cell apoptosis. miR-130b-3p directly targeted FOXO3, and FOXO3 elevated Keap1 expression to downregulate NFE2L2, thus inhibiting TXNRD1. FOXO3 overexpression or silencing of NFE2L2 or TXNRD1 diminished lung cancer cell proliferation, invasion, and migration but enhanced apoptosis. EV-delivered miR-130b-3p or FOXO3 silencing promoted lung cancer progression in vivo. In summary, MSC-derived EVs with upregulated miR-130b-3p suppressed FOXO3 to block the NFE2L2/TXNRD1 pathway, thus playing an oncogenic role in lung cancer progression., Graphical Abstract, The study mainly addresses the oncogenic role of miR-130b-3p contained in mesenchymal stem cell-derived extracellular vesicles in the malignant progression of lung cancer, which was associated with the FOXO3/NFE2L2/TXNRD1 axis, thus highlighting a potential therapeutic action against lung cancer.

The biological activities of chemokine (C-C motif) ligand 2 (CCL2) are mediated via C-C chemokine receptor-2 (CCR2). Increased CCL2 level is associated with metastasis of many cancers. In this study, we investigated the role of the CCL2/CCR2 axis in the development of spontaneous intestinal tumorigenesis using the ApcMin/+ mouse model. Ablation of CCR2 in ApcMin/+ mice significantly increased the overall survival and reduced intestinal tumor burden. Immune cell analysis showed that CCR2-/- ApcMin/+ mice exhibited significant reduction in the myeloid cell population and increased IFNγ producing T cells both in spleen and mesenteric lymph nodes (mLN) compared to ApcMin/+ mice. The CCR2-/- ApcMin/+ tumors showed significantly reduced levels of IL-17 and IL-23 and increased IFNγ and Granzyme B compared to ApcMin/+ tumors. Transfer of CCR2+/+ ApcMin/+ CD4+ T cells into Rag2-/- mice led to development of colitis phenotype with increased CD4+ T cells hyper proliferation and IL-17 production. In contrast, adoptive transfer of CCR2-/- ApcMin/+ CD4+ T cells into Rag2-/- mice failed to enhance colonic inflammation or IL-17 production. These results a suggest novel additional role for CCR2, where it regulates migration of IL-17 producing cells mediating tumor-promoting inflammation in addition to its role in migration of tumor associated macrophages. This article is protected by copyright. All rights reserved.

Transcription suppressor Musculin (MSC) is enriched in pro-inflammatory Th17 and IL-22-producing ILC3s. While MSC+/+ mice survived DSS-induced colitis, MSC-/- mice showed elevated pro-inflammatory cytokines with severer pathology, reduced body weight, and earlier death. Reversal of colitis symptoms in MSC-/- mice by IL-22 antagonism suggests the existence of MSC:IL-22 regulatory axis.

Summary Recruitment of immune cells to the site of inflammation by the chemokine CCL1 is important in the pathology of inflammatory diseases. Here, we examined the role of CCL1 in pulmonary fibrosis (PF). Bronchoalveolar lavage fluid from PF mouse models contained high amounts of CCL1, as did lung biopsies from PF patients. Immunofluorescence analyses revealed that alveolar macrophages and CD4+ T cells were major producers of CCL1 and targeted deletion of Ccl1 in these cells blunted pathology. Deletion of the CCL1 receptor Ccr8 in fibroblasts limited migration, but not activation, in response to CCL1. Mass spectrometry analyses of CCL1 complexes identified AMFR as a CCL1 receptor, and deletion of Amfr impaired fibroblast activation. Mechanistically, CCL1 binding triggered ubiquitination of the ERK inhibitor Spry1 by AMFR, thus activating Ras-mediated profibrotic protein synthesis. Antibody blockade of CCL1 ameliorated PF pathology, supporting the therapeutic potential of targeting this pathway for treating fibroproliferative lung diseases.

Hypochlorous acid (HClO) is a significant signaling species which plays a decisive role in the immune system as an excellent defense against invasive bacteria. Therefore, it is significant to monitor HClO accurately and quickly in organisms. Herein, a new turn-on fluorescent probe (BM-HA) with a simple structure for rapid sensing of HClO is presented. BM-HA has favorable properties, including high selectivity, a large turn-on fluorescence signal (140-fold), and fast response (about 15 s). Additionally, quantum chemical calculations with DFT and TDDFT proved that reduced fluorescence of the BM-HA probe was possible due to the a-PET effect and the non-coplanarity of the coumarin and the benzothiazole. Furthermore, imaging in living cells and zebrafish indicates that the probe can potentially be used to detect HClO in complex biosystems.

Species of Clavaria (Clavariaceae, Agaricales) collected from China were studied using morphological and molecular methods. Two species, C. griseolilacina and C. sinensis were described as new species; both possess branched and pale purple-tinged fruit bodies. However, the former possess a few branched, while the latter is profusely branched. The phylogenetic analysis based on the internal transcribed spacer (ITS) sequences confirmed the distinctions between these two new species and their close relationships with C. rubicundula and C. fumosa in the genus. An evolutionary tendency in genus Clavaria was discussed. Additionally, morphological features of the two new species were described in detail and were illustrated with line drawings and photographs. Holotypes of the new species are deposited in the Mycological Herbarium of Hunan Normal University (MHHNU). The ITS sequences generated in this study were deposited in GenBank. A key is provided for the known Clavaria species in China.

Frontier evidence suggests that dysregulation of long noncoding RNAs (lncRNA) is ubiquitous in all human tumors, indicating that lncRNAs might have essential roles in tumorigenesis. Therefore, an in-depth study of the roles of lncRNA in nasopharyngeal carcinoma (NPC) carcinogenesis might be helpful to provide novel therapeutic targets. Here we report that lncRNA TINCR was significantly upregulated in NPC and was associated positively with poor survival. Silencing TINCR inhibited NPC progression and cisplatin resistance. Mechanistically, TINCR bound ACLY and protected it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. Accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulated the peptidyl arginine deiminase 1 (PADI1)–MAPK–MMP2/9 pathway. In addition, insulin-like growth factor 2 mRNA-binding protein 3 interacted with TINCR and slowed its decay, which partially accounted for TINCR upregulation in NPC. These findings demonstrate that TINCR acts as a crucial driver of NPC progression and chemoresistance and highlights the newly identified TINCR–ACLY–PADI1–MAPK–MMP2/9 axis as a potential therapeutic target in NPC. Significance: TINCR-mediated regulation of a PADI1–MAPK–MMP2/9 signaling pathway plays a critical role in NPC progression and chemoresistance, marking TINCR as a viable therapeutic target in this disease.

Antibiotic-resistant bacteria are a serious threat to human and animal health. Metabolite-enabled eradication of drug-resistant pathogens is an attractive strategy, and metabolite adjuvants, such as fumarate, are used for restoring the bactericidal ability of antibiotics. However, we show that metabolites in the TCA cycle increase the viability of Edwardsiella tarda against chloramphenicol (CAP), based on the survival assay of differential metabolites identified by LC-MS/MS. Furthermore, NADPH promotes CAP resistance in the CAP-resistant strain, while oxidants restore the bactericidal ability. Finally, we show that the intracellular redox state determines the sensitivity to CAP, and the total antioxidative capacity is decreased significantly in the antibiotic-resistant strain. Considering that the metabolites promote CAP resistance, metabolite adjuvants should be applied very cautiously. Overall, our research expands on the knowledge that the redox state is related to the bactericidal ability of CAP.

Fluorinated organic compounds have emerged as environmental constituents of concern. We demonstrate that the alkane degrader Pseudomonas sp. strain 273 utilizes terminally monofluorinated C7-C10 alkanes and 1,10-difluorodecane (DFD) as the sole carbon and energy sources in the presence of oxygen. Strain 273 degraded 1-fluorodecane (FD) (5.97 ± 0.22 mM, nominal) and DFD (5.62 ± 0.13 mM, nominal) within 7 days of incubation, and 92.7 ± 3.8 and 90.1 ± 1.9% of the theoretical maximum amounts of fluorine were recovered as inorganic fluoride, respectively. With n-decane, strain 273 attained (3.24 ± 0.14) × 107 cells per μmol of carbon consumed, while lower biomass yields of (2.48 ± 0.15) × 107 and (1.62 ± 0.23) × 107 cells were measured with FD or DFD as electron donors, respectively. The organism coupled decanol and decanoate oxidation to denitrification, but the utilization of (fluoro)alkanes was strictly oxygen-dependent, presumably because the initial attack on the terminal carbon requires oxygen. Fluorohexanoate was detected as an intermediate in cultures grown with FD or DFD, suggesting that the initial attack on the fluoroalkanes can occur on the terminal methyl or fluoromethyl groups. The findings indicate that specialized bacteria such as Pseudomonas sp. strain 273 can break carbon-fluorine bonds most likely with oxygenolytic enzyme systems and that terminally monofluorinated alkanes are susceptible to microbial degradation. The findings have implications for the fate of components associated with aqueous film-forming foam (AFFF) mixtures.

Species of Tricholomopsis are known to be lignicolous and to cause white rot. Several collections of Tricholomopsis that grow near bamboo were sampled from southern China and morphologically could not be assigned to any known species of Tricholomopsis. Furthermore, phylogenetic analyses inferred from nuclear ribosomal internal transcribed spacer region (ITS) and the D1-D2 domains of the 28S rDNA large subunit indicated that it is an independent lineage with undescribed species. As a result of morphological data and phylogenetic analyses the new lineage is formally described as T. rubroaurantiacus. This species is characterized by its light orange to yellowish orange squamulose pileus with reddish disc, mostly clavate-shaped cheilocystidia, absence of pleurocystidia, subglobose to broadly ellipsoid basidiospores 5.0–5.8 × (4.0–)4.3–5.0 μm, a cutis-type pileipellis, and is usually habitat with bamboo. Morphological description, color photos, phylogenetic placement and phenotypic comparison with the closely related taxa within the genus are presented.

Background To investigate the effects of electroacupuncture at different acupoints on the histomorphology of neurogenic bladder and the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in interstitial cells of Cajal (ICC) in a rat model of suprasacral spinal cord injury (SCI). Methods A incomplete suprasacral SCI rat model was induced using a MASCIS impactor. Rats were randomly divided into a sham operation group, SCI model group, Ciliao treatment group or Guanyuan treatment group. The histomorphology of bladder cells was observed after hematoxylin and eosin (H&E) staining of bladder tissue sections. The expression of HCN channel proteins in ICC cells was detected by western blot and immunofluorescence, and HCN channel mRNA expression was measured using real-time PCR. Results In terms of histomorphology, the level of bladder cells after SCI increased significantly, and marked inflammation and edema were observed. Electroacupuncture treatment at the Ciliao acupoint significantly reduced inflammation and edema, whilst electroacupuncture treatment at the Guanyuan point partially reduced inflammation and edema. In terms of HCN channel protein and mRNA expression, western blotting, immunofluorescence and real-time PCR all confirmed that HCN channel expression after SCI was significantly upregulated, while electroacupuncture treatment at the Ciliao and Guanyuan acupoints inhibited HCN channel expression. Conclusions Electroacupuncture treatment at the Ciliao acupoint significantly reduced histomorphological abnormalities in ICCs, and inhibited the expression of HCN channel proteins after SCI.

Orientin is a flavonoid monomer. In recent years, its importance as a source of pharmacological active substance is growing rapidly due to its properties such as anti-myocardial ischemia, anti-apoptosis, anti-radiation, anti-tumor, and anti-aging. However, the neuroprotective effects of Orientin on stroke injury have not been comprehensively evaluated. The aim of the present study was thus to investigate the neuroprotective capacity and the potential mechanisms of Cyperus esculentus L. orientin (CLO) from Cyperus esculentus L. leaves against ischemia/reperfusion (I/R) injury using standard orientin as control. For in vitro studies, we treated HT22 cells with CoCl2 as an in vitro ischemic injury model. HT22 cells in the control group were treated with CoCl2. For in vivo studies, we used rat models of middle cerebral artery occlusion, and animals that received sham surgery were used as controls. We found that CLO protected CoCl2-induced HT22 cells against ischemia/reperfusion injury by lowering lipid peroxidation and reactive oxygen species formation as well as decreasing protein oxidation. However, CLO did not reduce the release of lactate dehydrogenase nor increase the activity of superoxide dismutase. Results showed that CLO could decrease neurological deficit score, attenuate brain water content, and reduce cerebral infarct volume, leading to neuroprotection during cerebral ischemia-reperfusion injury. Our studies indicate that CLO flavonoids can be taken as a natural antioxidant and bacteriostastic substance in food and pharmaceutical industry. The molecular mechanisms of CLO could be at least partially attributed to the antioxidant properties and subsequently inhibiting activation of casepase-3. All experimental procedures and protocols were approved on May 16, 2016 by the Experimental Animal Ethics Committee of Xinjiang Medical University of China (approval No. IACUC20160516-57).

ObjectiveMacrophages are among the most abundant cells in the colon tumour microenvironment, and there is a close relationship among monocytes, macrophages and the gut microbiota. Alterations in the gut microbiota are involved in tumour development, but the underlying mechanisms remain unclear. We aim to elucidate the temporal changes in macrophage subsets and functions, and how these dynamics are regulated by microbial cues in the initiation of colitis-associated cancer.DesignA mouse model of colitis-associated tumourigenesis was established to determine macrophage dynamics. The role of monocyte-like macrophage (MLM) was confirmed by targeting its chemotaxis. The effects of the gut microbiota were assessed by antibiotic treatment and faecal microbiota transplantation.ResultsA selective increase in MLMs was observed in the initial stages of colitis-associated cancer, with an enhanced secretion of inflammatory cytokines. MLM accumulation was regulated by CCL2 expression of colonic epithelial cells, which was influenced by bacteria-derived lipopolysaccharide (LPS). LPS further stimulated interleukin 1β production from MLMs, inducing interleukin-17-producing T-helper cell activation to promote inflammation. These observations were also supported by altered microbial composition associated with human colitis and colorectal cancer, evolving transcriptional signature and immune response during human colitis-associated tumourigenesis.ConclusionsThe gut microbiota uses LPS as a trigger to regulate MLM accumulation in a chemokine-dependent manner and generate a precancerous inflammatory milieu to facilitate tumourigenesis.

Background Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC). However, the epigenetic mechanisms underlying NPC metastasis remains poorly understood. We aimed to find functional genes which regulate the metastasis of NPC and identify therapeutic targets for NPC treatment. Methods Bisulfite pyrosequencing was used to analyze zinc finger protein 582 (ZNF582) methylation in NPC tissues and cell lines. Quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) and Western blotting were used to determine the expression of ZNF582. In vitro and in vivo experiments were performed to evaluate the biological function of ZNF582 in NPC. ZNF582‐targeting genes were identified by chromatin immunoprecipitation sequencing (ChIP‐seq) and were confirmed by ChIP‐qPCR and luciferase assay. Results ZNF582 promoter was hypermethylated in NPC, and both the mRNA and protein levels of ZNF582 were down‐regulated in NPC tissues and cell lines. The restoration of ZNF582 inhibited NPC migration, invasion, and metastasis, while the knockdown of ZNF582 promoted NPC migration, invasion, and metastasis in vitro and in vivo. ZNF582 directly regulated the transcription and expression of adhesion molecules Nectin‐3 and NRXN3. Both Nectin‐3 and NRXN3 were identified as functional targets of ZNF582, and the restoration or abrogation of these genes reversed the tumor suppressor effect of ZNF582 in NPC metastasis. Conclusions ZNF582 acts as a tumor suppressor gene in NPC by regulating the transcription and expression of adhesion molecules Nectin‐3 and NRXN3, which may provide novel therapeutic targets for NPC treatment.

Purpose The development of esophageal squamous cell carcinoma (ESCC) is a complicated process in which cell adhesion and motility, mediated by integrins, are involved through connecting the cytoskeleton to extracellular matrix. Different mechanisms via which integrin β6 participates in cancer invasion and metastasis have been described by numerous studies; however, the expression and clinical significance of integrin β6 in ESCC remain unknown. Methods To investigate the differential expression of integrin β6 in ESCC, qPCR and immunohistochemistry assays were performed in 10 paired human samples. A total of 137 ESCC samples were further enrolled to evaluate the expression levels of integrin β6 and its endocytic trafficking regulator HS1-associated protein X-1 (HAX-1), followed by the evaluation of their correlation with clinicopathological parameters. The overall survival was analyzed using the Kaplan-Meier method, with significant variables further evaluated by multivariate Cox regression analyses. Results The expression of integrin β6 was markedly increased in ESCC compared with matched adjacent normal tissues. Among the ESCC samples, positive expression of integrin β6 was observed in 41.6% tumors, which was associated with histological differentiation, lymph node metastasis and TNM stage. High expression of HAX-1 was detected in 47.4% tumors, and there was a positive relationship between the expression levels of integrin β6 and HAX-1. Furthermore, the expression of integrin β6 and HAX-1 were independent unfavorable indicators for prognosis. Patients with positive integrin β6 and high HAX-1 expression demonstrated worst outcomes. Conclusion The present findings suggested the predictive value of integrin β6 and HAX-1 as independent indicators of poor prognosis for patients with ESCC, both of which may contribute to the tumor proliferation and metastasis, leading to ESCC progression. Therefore, combined targeting of integrin β6 and HAX-1 may provide a potential novel approach for the treatment of ESCC.

It has been well documented that organic amendment affects soil nematode community structure. However, little is known about the effect of organic amendment amount on soil nematodes. To assess the effect of the amount of organic amendments on soil nematode community structure and metabolic activity, the community composition, abundance, and metabolic footprints of soil nematodes were determined in a long-term field experiment with various amounts of organic amendment in Northeast China. Fertilization treatments included an unfertilized control (CK), chemical fertilizer without manure amendment (OM0), manure applied at 7.5 Mg ha–1 plus chemical fertilizer (OM1), and manure applied at 22.5 Mg ha–1 plus chemical fertilizer (OM2). A total of 46 nematode genera were found. Treatments with the largest amount of organic amendment had the smallest number of plant parasite genera (5), but a largest number of dominant genera (7). Soil nematodes, bacterivores, and fungivores were the most abundant in OM2, followed by OM1, and the lowest in OM0 and CK. Organic amendment increased the enrichment index (EI), and the large amount of organic amendment increased the metabolic footprints of bacterivore (Baf) and fungivore (Fuf) and enrichment footprint (Ef). The relationships between Baf (or Fuf) and the increases in soil organic carbon (ΔSOC) and total nitrogen (ΔTN) were stronger than those of bacterivore (or fungivore) abundance with ΔSOC and ΔTN, except for the relationship between bacterivore abundance and ΔSOC. The EI and Ef were positively correlated with ΔSOC and ΔTN. These findings suggest that the amount of organic amendment affects soil nematode activity and function at entry levels in soil food web, and that metabolic footprints of soil nematodes may be better indicators than their abundances in assessing their relationships with soil nutrients.

Background Salt and drought are the main abiotic stresses that restrict the yield of crops. Peroxidases (PRXs) are involved in various abiotic stress responses. Furthermore, only few wheat PRXs have been characterized in the mechanism of the abiotic stress response. Results In this study, a novel wheat peroxidase (PRX) gene named TaPRX-2A, a member of wheat class III PRX gene family, was cloned and its response to salt stress was characterized. Based on the identification and evolutionary analysis of class III PRXs in 12 plants, we proposed an evolutionary model for TaPRX-2A, suggesting that occurrence of some exon fusion events during evolution. We also detected the positive selection of PRX domain in 13 PRXs involving our evolutionary model, and found 2 or 6 positively selected sites during TaPRX-2A evolution. Quantitative reverse transcription–polymerase chain reaction (qRT–PCR) results showed that TaPRX-2A exhibited relatively higher expression levels in root tissue than those exhibited in leaf and stem tissues. TaPRX-2A expression was also induced by abiotic stresses and hormone treatments such as polyethylene glycol 6000, NaCl, hydrogen peroxide (H2O2), salicylic acid (SA), methyljasmonic acid (MeJA) and abscisic acid (ABA). Transgenic wheat plants with overexpression of TaPRX-2A showed higher tolerance to salt stress than wild-type (WT) plants. Confocal microscopy revealed that TaPRX-2A-eGFP was mainly localized in cell nuclei. Survival rate, relative water content, and shoot length were higher in TaPRX-2A-overexpressing wheat than in the WT wheat, whereas root length was not significantly different. The activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were enhanced in TaPRX-2A-overexpressing wheat compared with those in the WT wheat, resulting in the reduction of reactive oxygen species (ROS) accumulation and malondialdehyde (MDA) content. The expression levels of downstream stress-related genes showed that RD22, TLP4, ABAI, GST22, FeSOD, and CAT exhibited higher expressions in TaPRX-2A-overexpressing wheat than in WT under salt stress. Conclusions The results show that TaPRX-2A plays a positive role in the response to salt stress by scavenging ROS and regulating stress-related genes.

Background: Kallistatin and ENOX1 are regulators of inflammation and oxidative stress which are typical pathological reactions in atherosclerosis. However, there is limited information of kallistatin and ENOX1 in coronary heart disease (CHD). Methods: Fifty healthy controls, 56 stable angina pectoris (SAP) patients, and 47 acute coronary syndrome (ACS) patients were included in this study. Levels of kallistatin and ENOX1 in serum were measured by ELISA. χ2 test was performed to analyze categorical data. ANOVA, Pearson correlation analysis, and multiple linear regression were performed to analyze the numerical data. Finally, receiver operating characteristic (ROC) curve was applied to assess the diagnostic value of kallistatin in CHD. Results: Among the 153 participants, 59.5% were male and the average age was 63.8 ± 11.39 years. Compared with the control group, kallistatin expression was decreased in the SAP and ACS groups while expression of ENOX1 was increased in the ACS group (p < 0.05). Pearson correlation analysis showed that the kallistatin level was negatively correlated with the Gensini score (r = −0.210, p < 0.01), white blood cell (WBC) count (r = −0.283, p < 0.001), and triglyceride levels (r = −0.242, p < 0.01) and positively correlated with age (r = 0.353, p < 0.001) and high-density lipoprotein cholesterol (r = 0.310, p < 0.001). ENOX1 expression was positively correlated with WBC count (r = 0.244, p < 0.01), international normalized ratio (r = 0.177, p < 0.05), and Gensini score (r = 0.201, p < 0.05). Multiple linear regression showed that Cr, alanine transaminase, glucose, and kallistatin are independent predictors for Gensini score. The ROC curve showed that kallistatin had the highest diagnostic significance (p = 0.007) when the area under curve was 0.636, with a sensitivity of 0.735 and a specificity of 0.495. Conclusion: Expression of kallistatin was decreased in CHD patients and that of ENOX1 was increased in ACS patients. Kallistatin and ENOX1 were closely connected with the severity of CHD, and kallistatin may be helpful in the diagnosis of CHD.

Increasing evidence indicates that long non-coding RNAs (lncRNAs) play vital roles in the tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in nasopharyngeal carcinoma (NPC) are still largely unknown. Our previous lncRNA expression profiles identified that LINC01503 was overexpressed in NPC. Here, we verified that LINC01503 was highly expressed in NPC and correlated with poor prognosis. LINC01503 promoted NPC cell proliferation, migration, and invasion in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, LINC01503 recruited splicing factor proline-and glutamine-rich (SFPQ) to activate Fos like 1 (FOSL1) transcription, and ectopic expression of FOSL1 reversed the suppressive effect of LINC01503 knockdown on NPC progression. Moreover, androgen receptor (AR)-mediated transcription activation was responsible for the overexpression of LINC01503, and AR ligand-dependent cell growth, migration, and invasion in NPC cells. Taken together, our findings reveal that AR-induced LINC01503 can promote NPC progression through the SFPQ-FOSL1 axis, which represents a novel prognostic biomarker and therapeutic target for NPC patients.

The use of immune checkpoint therapies targeting programmed death-1 (PD-1) and its ligand (PD-L1) continue to show limited, durable success in clinical cases, despite widespread application. While some patients achieve complete responses and disease remission, others are completely resistant to the therapy. Recent evidence in the field suggests that tumor-derived exosomes could be responsible for mediating systemic immunosuppression that antagonizes anti-PD-1 checkpoint therapy. In this opinion article, we discuss our claim that endogenous tumor exosomal PD-L1 and tumor-derived exosome-induced PD-L1 are two of the most notable mechanisms of exosome-mediated resistance against anti-tumor immunity and we also discuss how this resistance could directly influence immune checkpoint therapy failure.

Exosomes are small vesicles secreted by a variety of cells that contain vrious biological macromolecules, including RNA, non-coding RNA and protein. An increasing number of studies have demonstrated that exosomes and particularly the non-coding RNAs they contain, serve important roles in many cellular processes, including the transmission of information. It is well established that the occurrence and development of gastric cancer, one of the four most common malignant tumors worldwide, involves the transmission of information. Based on the urgent need for the elucidation of the mechanism involved in this process, as well as advances in the diagnosis and treatment of gastric cancer, numerous reports have assessed the association between non-coding RNAs in exosomes and gastric cancer. The purpose of the present review was to summarize recent evidence on certain non-coding RNAs associated with the development, diagnosis and treatment of gastric cancer.

The information commons for rice (IC4R) database is a collection of 18 million single nucleotide polymorphisms (SNPs) identified by resequencing of 5152 rice accessions. Although IC4R offers ultra-high density rice variation map, these raw SNPs are not readily usable for the public. To satisfy different research utilizations of SNPs for population genetics, evolutionary analysis, association studies, and genomic breeding in rice, raw genotypic data of these 18 million SNPs were processed by unified bioinformatics pipelines. The outcomes were used to develop a daughter database of IC4R – SnpReady for Rice (SR4R). SR4R presents four reference SNP panels, including 2,097,405 hapmapSNPs after data filtration and genotype imputation, 156,502 tagSNPs selected from linkage disequilibrium-based redundancy removal, 1180 fixedSNPs selected from genes exhibiting selective sweep signatures, and 38 barcodeSNPs selected from DNA fingerprinting simulation. SR4R thus offers a highly efficient rice variation map that combines reduced SNP redundancy with extensive data describing the genetic diversity of rice populations. In addition, SR4R provides rice researchers with a web interface that enables them to browse all four SNP panels, use online toolkits, as well as retrieve the original data and scripts for a variety of population genetics analyses on local computers. SR4R is freely available to academic users at http://sr4r.ic4r.org/.

Obesity is a metabolic disease and causes significant changes in host and gut microbial metabolite levels. However, little research has been done on the relationship between host and gut microbial metabolites. Thus, this study investigated the connection of the chemicals, based on the different effects of two Inonotus obliquus extracts on high-fat-diet-induced mice and their mechanisms. In this study, C57BL6/J mice fed with a high-fat diet were given I. obliquus ethanol extract (IOE) and polysaccharide (IOP). 1H NMR-based metabolomics, 16S rRNA sequencing, and real-time reverse transcription polymerase chain reaction (RT-PCR) were used to detect metabolites, cecal microbes, and expressions of genes in liver. IOE and IOP effectively improved the obesity of mice, including the adjustment of body weight gain, energy intake, energy efficiency, liver glucose metabolism and triglyceride metabolism, tricarboxylic acid (TCA) cycle, and degradation of three major nutrients (carbohydrate, lipid, and protein). IOE significantly increased cecal propionate based on Bacteroides and Akkermansia, thereby inhibiting energy intake and fat accumulation in mice. IOP remarkably improved the level of cecal butyrate by Lactobacillus and the Bacteroidales S24-7 group, resulting in increased energy consumption, and fat degradation by regulating the TCA cycle of the host. Two extracts containing different bioactive substances of I. obliquus improved obesity in mice through different effects on production of cecal microbial metabolites. Moreover, cecal butyrate (not propionate) was connected with chemicals of mice, including four metabolites of the TCA cycle and other metabolism-related chemicals.

Chemoresistance of colorectal cancer (CRC) leads to tumor recurrence and metastasis and new strategies are urgently needed to improve the outcomes of conventional chemotherapy. Sirtuin (SIRT) inhibitors prevent tumor cell growth by increasing the levels of acetylated histones and non-histones, as well as disrupting survival-related pathways. The aim of the present study was to determine the effect of SIRT inhibitors on CRC chemotherapy. The CompuSyn software program was used to evaluate the synergistic or antagonistic effects of various drugs, and the status of the protein deacetylation regulatory genes in microarray datasets were analyzed using bioinformatics. In HCT116 cells expressing wild-type (wt) TP53, SIRT inhibitors were found to act antagonistically with multiple chemotherapeutic agents (cisplatin, 5-fluorouracil, oxaliplatin, gefitinib, LY294002 and metformin), and decreased the anti-tumor effects of these agents. By contrast, SIRT inhibitors sensitized TP53-mutant (mut) SW620 cells to various chemotherapeutic drugs. Bioinformatics analysis indicated that SIRT1 and protein deacetylation related genes were highly expressed in TP53wt CRC cells when compared to TP53mut cells. Therefore, it was hypothesized that the likely mechanism underlying the antagonistic effect of SIRT inhibitors on TP53wt CRC cells was a reduction in the level of stable p53 protein. The present results indicated that divergent TP53 status may translate to a different chemosensitivity profile, and suggested that a combination therapy of SIRT inhibitors and first-line chemotherapeutic drugs may be beneficial for the treatment of patients with TP53mut CRC.

Objective. To investigate the effects of cerium dioxide (CeO2) nanoparticles on the inflammatory response of peritonitis rats induced by Staphylococcus epidermidis infection. Methods. Green tea polyphenol CeO2 nanoparticles were synthesized and characterized by transmission microscopy, ultraviolet-visible spectroscopy, FT-IR, and powder diffractometer. 40 male adult SD rats were randomly divided into 4 groups (n = 10 each): a control group, a model group, a CeO2 group, and a CeO2 + model group. Staphylococcus epidermidis solution was injected intraperitoneally with 107 CFU/ml of bacterial solution in the model group, while the control group was injected intraperitoneally with the same amount of normal saline, and the CeO2 and CeO2 + model groups were injected with 0.5 mg/kg CeO2 nanoparticles through the tail vein for 2 h and then injected with saline or bacterial solution for 2 h, respectively. After 0 h, 3 h, 12 h, 24 h, and 48 h of model construction, rats were sacrificed, and serum and peritoneal lavage fluid were collected. The total number of leukocytes and the percentage of each type of leukocytes in the peritoneal lavage fluid were determined. Enzyme-linked immunosorbent assay (ELISA) was used to detect the level of inflammatory factor TNF-α in serum and peritoneal lavage fluid, and myeloperoxidase (MPO) activity in peritoneal tissue was also measured. In addition, real-time fluorescence quantitative PCR (RT-PCR) was used to measure the expression of TLR2 and TLR4 in peritoneal tissue, and western blotting was used to detect the expression of TLR2, TLR4, and the activation of NF-κB signaling pathways as well. Results. The CeO2 has an average size of 37 ± 3 nm with binding activity to proteins, phenolic compounds, and alkaloids. After counting the white blood cells in the peritoneal lavage fluid, it was found that the total number of white blood cells and the percentage of neutrophils in the model group were significantly increased (both P<0.05), and CeO2 treatment significantly reversed the above changes (both P<0.05). The ELISA results showed that compared with the control group, the TNF-α in the peritoneal lavage fluid and serum of the model group increased in a time-dependent manner (all P<0.05); however, there was no significant change in the CeO2 group (P>0.05); at the same time in the CeO2 + model group, the TNF-α content was significantly reduced (all P<0.05). Detection of MPO activity in peritoneal tissue revealed that MPO activity was significantly increased under peritonitis (all P<0.05), and CeO2 treatment could mitigate that increase (all P<0.05). RT-PCR results showed that compared with the control group, the expression of TLR2 and TLR4 mRNA levels in the peritoneum of the model group were increased in a time-dependent manner (all P<0.05), and there was no significant change in the CeO2 group (P>0.05); however, TLR2 and TLR4 mRNA levels were significantly reduced in the CeO2 + model group (all P<0.05). Western blotting test was performed on the peritoneal tissue collected after 48 h of the model establishment. Compared with the control group, the levels of TLR2, TLR4, p–NF–κB, and p-IκBα protein in the model group were significantly increased (all P<0.05), while CeO2 group showed no significant changes (P>0.05) and administration of CeO2 before model construction can significantly reverse the above protein activation (all P<0.05). Conclusion. CeO2 nanoparticles have anti-inflammatory effects in peritonitis caused by Staphylococcus epidermidis infection.

Macrophages have been linked to tumor initiation, progression, metastasis, and treatment resistance. However, the transcriptional regulation of macrophages driving the protumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct binding sites within a conserved noncoding sequence of the Csf-1r gene and promotes M2-like macrophage–mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating the TCA cycle and UDP-GlcNAc biosynthesis, thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAMs) and regulates TAM immunosuppressive function. Deletion of c-Maf specifically in myeloid cells results in reduced tumor burden with enhanced antitumor T cell immunity. Inhibition of c-Maf partly overcomes resistance to anti–PD-1 therapy in a subcutaneous LLC tumor model. Similarly, c-Maf is expressed in human M2 and tumor-infiltrating macrophages/monocytes as well as circulating monocytes of human non–small cell lung carcinoma (NSCLC) patients and critically regulates their immunosuppressive activity. The natural compound β-glucan downregulates c-Maf expression on macrophages, leading to enhanced antitumor immunity in mice. These findings establish a paradigm for immunosuppressive macrophage polarization and transcriptional regulation by c-Maf and suggest that c-Maf is a potential target for effective tumor immunotherapy.

The nutritional value of Tartary buckwheat is much higher than that of common buckwheat. Tartary buckwheat is rich in nutrients, some of them unique, and has good medicinal properties. It also serv...

Certain agricultural management practices are known to affect the soil microbial community structure; however, knowledge of the response of the fungal community structure to the long-term continuous cropping and rotation of soybean, maize and wheat in the same agroecosystem is limited. We assessed the fungal abundance, composition and diversity among soybean rotation, maize rotation and wheat rotation systems and among long-term continuous cropping systems of soybean, maize and wheat as the effect of crop types on fungal community structure. We compared these fungal parameters of same crop between long-term crop rotation and continuous cropping systems as the effect of cropping systems on fungal community structure. The fungal abundance and composition were measured by quantitative real-time PCR and Illumina MiSeq sequencing. The results revealed that long-term continuous soybean cropping increased the soil fungal abundance compared with soybean rotation, and the fungal abundance was decreased in long-term continuous maize cropping compared with maize rotation. The long-term continuous soybean cropping also exhibited increased soil fungal diversity. The variation in the fungal community structure among the three crops was greater than that between long-term continuous cropping and rotation cropping. Mortierella, Guehomyces and Alternaria were the most important contributors to the dissimilarity of the fungal communities between the continuous cropping and rotation cropping of soybean, maize and wheat. There were 11 potential pathogen and 11 potential biocontrol fungi identified, and the relative abundance of most of the potential pathogenic fungi increased during the long-term continuous cropping of all three crops. The relative abundance of most biocontrol fungi increased in long-term continuous soybean cropping but decreased in long-term continuous maize and wheat cropping. Our results indicate that the response of the soil fungal community structure to long-term continuous cropping varies based upon crop types.

Deinococcus radiodurans is famous for its extreme resistance to various stresses such as ionizing radiation (IR), desiccation and oxidative stress. The underlying mechanism of exceptional resistance of this robust bacterium still remained unclear. However, the antioxidative system of D. radiodurans has been considered to be the determinant factor for its unparalleled resistance and protects the proteome during stress, then the DNA repair system and metabolic system exert their functions to restore the cell to normal physiological state. The antioxidative system not only equipped with the common reactive oxygen species (ROS) scavenging enzymes (e.g., catalase and superoxide dismutase) but also armed with a variety of non-enzyme antioxidants (e.g., carotenoids and manganese species). And the small manganese complexes play an important role in the antioxidative system of D. radiodurans. Recent studies have characterized several regulators (e.g., PprI and PprM) in D. radiodurans, which play critical roles in the protection of the bacteria from various stresses. In this review, we offer a panorama of the progress regarding the characteristics of the antioxidative system in D. radiodurans and its application in the future.

Background Prostate cancer (PCa) is the second most frequent cancer and the fifth leading cause of cancer-related death in men while the mechanisms remain unclear. Methods Differentially expressed mRNAs (DEmRNAs) and miRNAs (DEmiRNAs) between PCa and non-tumor controls were identified by using microarray analysis. Functional annotation of DEmRNAs, construction of protein-protein interaction (PPI) network and prediction of upstream transcription factors and downstream target DEmRNAs of DEmiRNAs were conducted to further research functions of key DEmRNAs and DEmiRNAs. Validation of selected DEmRNAs and survival analysis were conducted by using The Cancer Genome Atlas (TCGA). Results Total of 91 DEmRNAs and 62 DEmiRNAs were obtained. Thrombospondin-4 precursor (THBS4) was the most significantly up-regulated DEmRNA whose product was predicted to interact with the hub protein of the PCa-specific PPI network, collagen type I alpha 1 chain (COL1A1). Both ATP binding cassette subfamily C member 4 (ABCC4) and endothelin receptor type B (EDNRB) have great prognostic value for PCa. Thrombospondin type 1 domain containing 4 (THSD4) was a down-regulated DEmRNA regulated by several cancer-related miRNAs including has-miR-107, hsa-miR-3175 and hsa-miR-484. Two miRNAs (hsa-miR-428 and hsa-miR-4284) involve in PCa by regulating BMP5-BAMBI interaction and TGF-beta signaling pathway. The expression of selected DEmRNAs between PCa and non-tumor controls in TCGA was consistent with that in our microarray analysis, generally. Conclusions Key DEmRNAs and DEmiRNAs between PCa and non-tumor controls were identified in this study which provided clues for exploring the molecular mechanism and developing potential biomarkers and therapeutic target sites for PCa.