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Many microorganisms have mechanisms that protect cells against attack from viruses. The fermentation components of Streptomyces sp. 1647 exhibit potent anti-influenza A virus (IAV) activity. This strain was isolated from soil in southern China in the 1970s, but the chemical nature of its antiviral substance(s) has remained unknown until now. We used an integrated multi-omics strategy to identify the antiviral agents from this streptomycete. The antibiotics and Secondary Metabolite Analysis Shell (antiSMASH) analysis of its genome sequence revealed 38 biosynthetic gene clusters (BGCs) for secondary metabolites, and the target BGCs possibly responsible for the production of antiviral components were narrowed down to three BGCs by bioactivity-guided comparative transcriptomics analysis. Through bioinformatics analysis and genetic manipulation of the regulators and a biosynthetic gene, cluster 36 was identified as the BGC responsible for the biosynthesis of the antiviral compounds. Bioactivity-based molecular networking analysis of mass spectrometric data from different recombinant strains illustrated that the antiviral compounds were a class of structural analogues. Finally, 18 pseudo-tetrapeptides with an internal ureido linkage, omicsynins A1–A6, B1–B6, and C1–C6, were identified and/or isolated from fermentation broth. Among them, 11 compounds (omicsynins A1, A2, A6, B1–B3, B5, B6, C1, C2, and C6) are new compounds. Omicsynins B1–B4 exhibited potent antiviral activity against IAV with the 50% inhibitory concentration (IC50) of approximately 1 µmol∙L–1 and a selectivity index (SI) ranging from 100 to 300. Omicsynins B1–B4 also showed significant antiviral activity against human coronavirus HCoV-229E. By integrating multi-omics data, we discovered a number of novel antiviral pseudo-tetrapeptides produced by Streptomyces sp. 1647, indicating that the secondary metabolites of microorganisms are a valuable source of novel antivirals.

Graphical abstract Schematic illustration of the miR-4521-FAM129A axis in HCC malignancy. FAM129A negatively correlates with miR-4521, leading to suppressed migration and invasion by the TIMP-1/MMP9/MMP2 and EMT pathways. miR-4521-FAM129A axial regulation reduces proliferation and induced apoptosis via the p-FAK/p-AKT/MDM2/P53 and p-FAK/p-AKT /BCL-2/BAX/Cytochrome-C/Caspase-3/Caspase-9 pathways, respectively., Highlights • MiR-4521 deficiency reversely correlates with FAM129A upregulation in HCC. • MiR-4521 suppresses the in vitro migration and invasion capacities of HCC cells. • FAM129A is a direct and efficient target of miR-4521 in HCC cell invasiveness. • MiR-4521-FAM129A axis regulates HCC progression and metastasis via TIMP-1/MMP2/MMP9 and p-FAK/p-AKT pathway., Introduction Globally, hepatocellular carcinoma (HCC) is the sixth most common malignancy and it has the fourth highest mortality. MicroRNAs play a significant part in biological processes in cell formation and advancement by targeting genes in many cancers including HCC. Objective In the present study we examine the involvement of miR-4521 and FAM129A correlations in HCC occurrence and progression. Methods Expression levels of miR-4521 and FAM129A in HCC tissues and cells were detected. Immunohistochemistry was carried out to detect expression of FAM129A, MMP9 and TIMP-1 in HCC tissues. Western blot assays were used to examine expression levels of different genes involve in signaling pathways. Transwell chamber, MTT and wound healing assays were performed to check cell migration, invasion and proliferation rates. Results Overexpression of FAM129A positively correlated with upregulation of MMP9 and negatively correlated with TIMP-1 in HCC patient samples, which encouraged progression and metastasis of HCC. An antagonistic relation between miR-4521 and FAM129A was detected in current study, down-regulation of miR-4521 and up-regulation of FAM129A was demonstrated in HCC tissues and cell lines as compare to normal tissue samples and the normal cell line LO2. Overexpressing miR-4521 and silencing FAM129A impaired HCC cell migratory and invasive properties and suppressed cell proliferation. Mutually, miR-4521-FAM129A axial regulation inhibited in vitro proliferation of cells by promoting apoptosis through the p-FAK/p-AKT/MDM2/P53 and p-FAK/p-AKT/BCL-2/BAX/Cytochrome-C/Caspase-3/Caspase-9 pathways, respectively, and suppressed the migration and invasion capabilities of HCCLM3 and HepG2 cells via the TIMP-1/MMP9/MMP2 and p-FAK/p-AKT pathway. Conclusion Our work found the axial regulation mechanism of miR-4521-FAM129A in HCC. Deficiency of miR-4521 and abundance of FAM129A synergistically enhanced cancer progression by increasing cell proliferation and malignant invasion and by inhibiting apoptosis. These discoveries suggest that miR-4521/FAM129A might play a vital role in hepatic cancer progression and could be a candidate for its therapy.

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

Background. Since 2020 COVID-19 pandemic became an emergent public sanitary incident. The epidemiology data and the impact on prognosis of secondary infection in severe and critical COVID-19 patients in China remained largely unclear.Methods. We retrospectively reviewed medical records of all adult patients with laboratory-confirmed COVID-19 who were admitted to ICUs from January 18th 2020 to April 26th 2020 at two hospitals in Wuhan, China and one hospital in Guangzhou, China. We measured the frequency of bacteria and fungi cultured from respiratory tract, blood and other body fluid specimens. The risk factors for and impact of secondary infection on clinical outcomes were also assessed. Results. Secondary infections were very common (86.6%) when patients were admitted to ICU for >72 hours. The majority of infections were respiratory, with the most common organisms being Klebsiella pneumoniae (24.5%), Acinetobacter baumannii (21.8%), Stenotrophomonas maltophilia (9.9%), Candida albicans (6.8%), and Pseudomonas spp. (4.8%). Furthermore, the proportions of multidrug resistant (MDR) bacteria and carbapenem resistant Enterobacteriaceae (CRE) were high. We also found that age ≥60 years and mechanical ventilation ≥13days independently increased the likelihood of secondary infection. Finally, patients with positive cultures had reduced ventilator free days in 28 days and patients with CRE and/or MDR bacteria positivity showed lower 28 day survival rate.Conclusions. In a retrospective cohort of severe and critical COVID-19 patients admitted to ICUs in China, the prevalence of secondary infection was high, especially with CRE and MDR bacteria, resulting in poor clinical outcomes.

Influenza A viruses (IAV) are responsible for seasonal flu epidemics, which can lead to high morbidity and mortality each year. Like other viruses, influenza virus can hijack host cellular machinery for its replication. Host cells have evolved diverse cellular defense to resist the invasion of viruses. As the main components of promyelocytic leukemia protein nuclear bodies (PML-NBs), PML can inhibit the replication of many medically important viruses including IAV. However, the mechanism of PML against IAV is unclear. In the present study, we found PML was induced in response to IAV infection and ectopic expression of PML could inhibit IAV replication, whereas knockdown of endogenous PML expression could enhance IAV replication. Further studies showed that PML increased the expression of FBXW7 by inhibiting its K48-linked ubiquitination and enhanced the interaction between FBXW7 and SHP2, which negatively regulated IAV replication during infection. Moreover, PML stabilized RIG-I to promote the production of type I IFN. Collectively, these data indicated that PML inhibited IAV replication by enhancing FBXW7 expression in the antiviral immunity against influenza virus and extended the mechanism of PML in antiviral immunity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12250-021-00399-3.

As a major feature of diabetes, inflammation is closely related to macrophage extracellular traps and the expression of hepcidin upregulated by diabetes is reportedly involved in chronic inflammation. Therefore, we aimed to explore whether hepcidin could be implicated in inflammation and macrophage extracellular traps (METs) formation. The diabetic db/db mouse model was established exhibiting insulin resistance (IR), inflammation, macrophages infiltration and higher expression of hepcidin, where samples were obtained from epididymal adipose tissue. We observed that inflammation and IR improved in adipose tissue of mice treated with hepcidin gene silencing. Furthermore, METs formation could be markedly inhibited via hepcidin gene silencing followed by attenuated inflammatory response due to METs, indicating hepcidin gene silencing played a key role in anti-inflammation by inhibiting METs formation. So, we concluded that hepcidin gene silencing has a potential for treatment of diabetes due to its ability to ameliorate inflammation via inhibiting METs formation.

The G‐protein‐coupled receptor 126 (GPR126) may play an important role in tumor development, although its role remains poorly understood. We found that GPR126 had higher expression in most colorectal cancer cell lines than in normal colon epithelial cell lines, and higher expression levels in colorectal cancer tissues than in normal adjacent colon tissues. GPR126 knockdown induced by shRNA inhibited cell viability and colony formation in HT‐29, HCT116, and LoVo cells, decreased BrdU incorporation into newly synthesized proliferating HT‐29 cells, led to an arrest of cell cycle progression at the G1 phase in HCT‐116 and HT‐29 cells, and suppressed tumorigenesis of HT‐29, HCT116, and LoVo cells in nude mouse xenograft models. GPR126 knockdown engendered decreased transcription and translation of histone deacetylase 2 (HDAC2), previously implicated in the activation of GLI1 and GLI2 in the Hedgehog signaling pathway. Ectopic expression of HDAC2 in GPR126‐silenced cells restored cell viability and proliferation, GLI2 luciferase reporter activity, partially recovered GLI2 expression, and reduced the cell cycle arrest. HDAC2 regulated GLI2 expression and, along with GLI2, it bound to the PTCH1 promoter, as evidenced by a chip assay with HT‐29 cells. Purmorphamine, a hedgehog agonist, largely restored the cell viability and expression of GLI2 proteins in GPR126‐silenced HT‐29 cells, whereas GANT61, a hedgehog inhibitor, further enhanced the GPR126 knockdown‐induced inhibitory effects. Our findings demonstrate that GPR126 regulates colorectal cancer cell proliferation by mediating the expression of HDAC2 and GLI2, therefore it may represent a suitable therapeutic target for colorectal cancer treatment., GLI2 binding with HDAC2 to the PTCH1 promoter is regulated by HDAC2 and its expression recovery restores cell viability in GPR126‐silenced cells. A, Western blotting of HDAC2 and GLI2 protein levels in NC‐ and HDAC2‐shRNA‐infected HT‐29 cells. β‐actin was used as a loading control. B, Chromatin from HT‐29 cells was immunoprecipitated with anti‐HDAC2 antibodies and then eluted and immunoprecipitated again with normal mouse IgG(IgG) or anti‐Gli2(GLI2 Ab). Eluted DNA was PCR‐amplified using PTCH1 and GAPDH primers (B1). Quantitative PCR(qPCR) was used to examine the abundance of eluted DNA from B1, with the DNAs from input control as the internal control (B2). C, Ectopic expression of HDAC2 in GPR126‐silenced cells restores transcription activity of GLI2 promoter (Gli2‐Luc). NC or Sh1, cell infected by control virus or GPR126 shRNA virus; pGL3, empty luciferase vector; Gli2‐Luc, luciferase vector with Gli2 promoter; zs‐HDAC2, HDAC2 ectopic expression construct; zs, empty vector for cloning HDAC2 expression vector; ‘‐’, not used in co‐transfection; ‘+’, used in co‐transfection. D‐E, the effect of Purmorphamine (hedgehog agonist) and GANT61 (GLI2 inhibitor), at indicated concentration, on cell viability and GLI2 protein expression in indicate colorectal cancer cells. DMSO, the solvent of Purmorphamine and GANT61. β‐actin was used as a loading control. F, Diagram illustrating the putative mechanisms of GPR126 function in colorectal cancer cells. GPR126 regulates SMO, GLI1, and HDAC2 expression (GSE106696). GLI1 and GLI2, as the downstream components of GPR126 signaling, regulate the expression of hedgehog (HH) target genes, including PTCH1, regulating tumor growth. HDAC2 is regulated by GPR126 regulated HDAC2, mediating GLI2 expression, and binds with GLI2 to the PTCH1 promoter or other promoters of HH target genes. The dotted line indicating ‘Not reported in this article’; solid line indicating ‘Has support in this article’; ‘?’ meaning ‘through unknown mechanism’.

Abnormal glucose metabolism may contribute to cancer progression. As a member of the CRK (v‐crk sarcoma virus CT10 oncogene homologue) adapter protein family, CRKL (CRK‐like) associated with the development and progression of various tumours. However, the exact role and underlying mechanism of CRKL on energy metabolism remain unknown. In this study, we investigated the effect of CRKL on glucose metabolism of hepatocarcinoma cells. CRKL and PI3K were found to be overexpressed in both hepatocarcinoma cells and tissues; meanwhile, CRKL up‐regulation was positively correlated with PI3K up‐regulation. Functional investigations revealed that CRKL overexpression promoted glucose uptake, lactate production and glycogen synthesis of hepatocarcinoma cells by up‐regulating glucose transporters 1 (GLUT1), hexokinase II (HKII) expression and down‐regulating glycogen synthase kinase 3β (GSK3β) expression. Mechanistically, CRKL promoted glucose metabolism of hepatocarcinoma cells via enhancing the CRKL‐PI3K/Akt‐GLUT1/HKII‐glucose uptake, CRKL‐PI3K/Akt‐HKII‐glucose‐lactate production and CRKL‐PI3K/Akt‐Gsk3β‐glycogen synthesis. We demonstrate CRKL facilitates HCC malignancy via enhancing glucose uptake, lactate production and glycogen synthesis through PI3K/Akt pathway. It provides interesting fundamental clues to CRKL‐related carcinogenesis through glucose metabolism and offers novel therapeutic strategies for hepatocarcinoma.

Intrinsic or developing resistance to chemotherapy drugs including cisplatin (CDDP) remains the major limitation of cancer therapeutic efficacy in cancers. Recently, increasing evidence suggested that long noncoding RNAs (lncRNAs) play a critical role in various biological processes of tumors, and have been implicated in resistance to various drugs. However, the role of lncRNAs in cisplatin resistance is poorly understood. Here, we found that the expression of lncRNA CEBPA-DT/CEBPA/BCL2 was upregulated in cisplatin resistance OSCC cells (Cal27-CisR and HSC4-CisR) compared with their parental cells (Cal27 and HSC4). CEBPA-DT overexpression could upregulated both cytoplasmic and nuclear CEBPA expression. Down-regulation of CEBPA-DT enhances cisplatin sensitivity, facilitates cell apoptosis in cisplatin-resistant OSCC cells. In addition, we identified that CEBPA-DT regulates cisplatin chemosensitivity through CEBPA/BCL2-mediated cell apoptosis. Knockdown of CEBPA and BCL2 could alleviate the increasement of cisplatin resistance induced by CEBPA-DT overexpression. Our findings indicate that downregulation of lncRNA CEBPA-DT may be a potential therapy to overcome cisplatin resistance in OSCC.

Cervical cancer (CC) is one of the most common malignant tumors. This study analyzed the impact of protein tyrosine phosphatase, receptor type B (PTPRB) on malignant behavior of CC and explored its possible molecular mechanism. RT-PCR, western blot and Immunohistochemistry were applied to examine the expression of PTPRB in CC specimens and cells. Aberrant PTPRB expression in CC and survival outcomes were constructed using The Cancer Genome Atlas (TCGA) database and tissue microarray cervical squamous cell carcinoma cohort. Cultured human CC cells were assayed for viability, apoptosis, migration, and invasion in vitro and in vivo. Kyoto Encyclopedia of Genes and Genomes (KEGG) assays and gene set enrichment analysis (GSEA) assays were used to delve into PTPRB-related pathways using TCGA datasets. The levels of proteins associated with the epithelial–mesenchymal transition (EMT) pathway and modulated by PTPRB were examined through Western blot. We found that the levels of PTPRB in CC tissues and cells were distinctly up-regulated. PTPRB was also an unfavorable prognostic factor for CC patients. Functionally, PTPRB knockdown exhibits tumor-suppressive function via reducing cell proliferation and metastasis and inducing cell apoptosis. KEGG assays and GSEA assays suggested PTPRB overexpression was associated with several tumor-related pathways. The results of Western blot assays suggested that N-cadherin was decreased in the PTPRB-knockdown CC cells, while E-cadherin was increased. Overall, PTPRB is highly expressed in CC and can effectively enhance the proliferation, metastasis and EMT process of tumor cells. PTPRB is expected to be a therapeutic target for CC.

ObjectiveMicrobiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC.Design18F-FDG (18F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum-induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1.ResultsWe have found F. nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function.ConclusionF. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum.

Coagulation dysfunction in critically ill patients with coronavirus disease 2019 (COVID-19) has not been well described, and the efficacy of anticoagulant therapy is unclear. In this study, we retrospectively reviewed 75 fatal COVID-19 cases who were admitted to the intensive care unit at Jinyintan Hospital (Wuhan, China). The median age of the cases was 67 (62–74) years, and 47 (62.7%) were male. Fifty patients (66.7%) were diagnosed with disseminated intra-vascular coagulation. Approximately 90% of patients had elevated D-dimer and fibrinogen degradation products, which decreased continuously after anticoagulant treatment and was accompanied by elevated albumin (all P

The phytoremediation technology is widely used due to its beautiful appearance and no secondary pollution. The mechanism of how the plants cope with the abiotic stresses imposed by polyaromatic hyd...

Recently, long noncoding RNAs (lncRNAs) were recognized as significant therapeutic targets in tumors. Our previous microarray analysis showed that lncRNA TCONS_000026334 expression was reduced in metastatic colorectal cancer (CRC) tissues. The objective of this study was to research the biological functions of TCONS_000026334 and the potential mechanism during the development of CRC. TCONS_00026334 transcription levels were detected in CRC tissues from 86 patients and different CRC cell lines. The clinical prognosis factors related to TCONS_00026334 expression were then analyzed. TCONS_000026334 was overexpressed from plasmid pcDNA3.1‐TCONS_ 000026334 or knocked down using a small interfering RNA (siRNA). Furthermore, bioinformatics approach and luciferase reporter gene assays were utilized to search for candidate miRNAs of TCONS_00026334 and identify the downstream target genes. The results indicated that TCONS_00026334 expression in 86 CRC tissues was markedly lower than that in non‐cancerous tissues. The aberrant expression of TCONS_00026334 correlated negatively with larger tumor size, distant metastasis, serological carcinoembryonic antigen level, and unfavorable survival of patients with CRC. TCONS_00026334 overexpression could inhibit the aggressive phenotypes of CRC in vitro and in vivo. Conversely, TCONS_00026334 silencing accelerated CRC cell proliferation and invasion. We then verified that TCONS_00026334 upregulated the expression level of TP53INP1, a target gene of miR‐548n, via direct binding to miR‐548n as a competing endogenous RNA. Taken together, our study showed that TCONS_00026334 acts as an anti‐tumor and anti‐metastatic gene by regulating the miR548n/TP53INP1 axis in the development of CRC., Our study showed that lncRNA TCONS_00026334 acts as an anti‐tumor and anti‐metastatic gene by regulating the miR548n/TP53INP1 axis in the development of colorectal cancer.

Isorhamnetin has distinct anti-inflammatory activity and inhibits cell proliferation and migration. These effects are also involved in the pathogenesis of asthma. However, the effect of isorhamnetin on bronchial epithelial cells in patients with asthma has not been examined. Cells of human bronchial epithelial cell line BEAS-2B were cultured with isorhamnetin and tumor necrosis factor (TNF)-α. The effects of isorhamnetin on BEAS-2B cell viability were assessed using CCK8 assay. The EdU (5-ethynyl-2'-deoxyuridine) cell proliferation assay was performed to assess cell proliferation. BEAS-2B cell migration was measured using Transwell and wound healing assays. Real-time PCR and enzyme-linked immunosorbent assay were conducted to measure the expression of pro-inflammatory cytokines. Protein expression levels were determined by western blotting. Immunofluorescence was used to detect nuclear translocation of nuclear factor kappa B (NF-κB). We found that isorhamnetin at 20 and 40 μM reduced the proliferation of BEAS-2B cells induced by TNF-α. Isorhamnetin significantly decreased the expression of interleukin (IL)-1β, IL-6, IL-8, and C-X-C motif chemokine ligand 10 in BEAS-2B cells induced by TNF-α. Additionally, 10 μM isorhamnetin effectively reduced cell migration induced by TNF-α. Treatment with isorhamnetin inhibited the phosphorylation of mitogen-activated protein kinase (MAPK) and NF-κB pathways induced by TNF-α. In summary, isorhamnetin inhibited the inflammation, proliferation, and migration of BEAS-2B cells by regulating the MAPK and NF-κB signaling pathways and is a drug candidate for asthma.

Chinese Gγ+(Aγδβ)0-thalassemia and SEA-HPFH are the most common types of β-globin gene cluster deletion in Chinese population. The aim of the study was to analyze clinical features of deletional Chinese Gγ+(Aγδβ)0-thalassemia and Southeast Asian hereditary persistence of fetal hemoglobin (SEA-HPFH) in South China. A total of 930 subjects with fetal hemoglobin (HbF) level ≥ 2% were selected on genetic research of Chinese Gγ+(Aγδβ)0-thalassemia and SEA-HPFH. The gap polymerase chain reaction was performed to identify the deletions. One hundred cases of Chinese Gγ+(Aγδβ)0-thalassemia were detected, including 90 cases of Chinese Gγ+(Aγδβ)0/βN-thalassemia, 7 cases of Chinese Gγ+(Aγδβ)0 /βN-thalassemia combined with α-thalassemia, 2 cases of Chinese Gγ+(Aγδβ)0-thalassemia combined with β-thalassemia, and 1 case of Chinese Gγ+(Aγδβ)0-thalassemia combined with β-gene mutation. One hundred nine cases of SEA-HPFH were detected, including 97 cases of SEA-HPFH/βN, 9 cases of SEA-HPFH/βN combined with α-thalassemia, 2 cases of SEA-HPFH combined with β-thalassemia, and 1 case of SEA-HPFH combined with β-gene mutation. Statistical analysis indicates significant differences in MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), and HbA2 and HbF levels between Chinese Gγ+(Aγδβ)0-thalassemia heterozygotes and SEA-HPFH heterozygotes (P < 0.001). There are statistical differences in hematological parameters between them. Clinical phenotypic analysis can provide guidance for genetic counseling and prenatal diagnosis.

Ulcerative colitis (UC) is a multifactorial inflammatory disease, and increasing evidence has demonstrated that the mechanism of UC pathogenesis is associated with excessive cellular apoptosis and reactive oxygen species (ROS) production. However, their function and molecular mechanisms related to UC remain unknown. In this study, Rab27A mRNA and protein were proven to be overexpressed in intestinal epithelial cells of UC patients and DSS‐induced colitis mice, compared with control (P

A new species, Bulbophyllum lingii (Orchidaceae: Epidedroideae: Malaxideae) from Hainan, China, is described and illustrated. Detailed morphological comparisons indicate that B. lingii is similar to B. catenarium, but differs in having oblong petals, lip margins from base of side-lobes to lip tip recurved, adaxial surface of top part glabrous, stigma with a rather distinct basal callus, foot with about 1/3 free part. The conservation status of B. lingii is assessed and taxonomic notes are provided.

FLAVIN-BINDING KELCH REPEAT F-BOX 1 (FKF1) encodes an F-box protein that regulates photoperiod flowering in Arabidopsis under long-day conditions (LDs). Gibberellin (GA) is also important for regulating flowering under LDs. However, how FKF1 and the GA pathway work in concert in regulating flowering is not fully understood. Here, we showed that the mutation of FKF1 could cause accumulation of DELLA proteins, which are crucial repressors in GA signaling pathway, thereby reducing plant sensitivity to GA in flowering. Both in vitro and in vivo biochemical analyses demonstrated that FKF1 directly interacted with DELLA proteins. Furthermore, we showed that FKF1 promoted ubiquitination and degradation of DELLA proteins. Analysis of genetic data revealed that FKF1 acted partially through DELLAs to regulate flowering under LDs. In addition, DELLAs exerted a negative feedback on FKF1 expression. Collectively, these findings demonstrate that FKF1 promotes flowering partially by negatively regulating DELLA protein stability under LDs, and suggesting a potential mechanism linking the FKF1 to the GA signaling DELLA proteins.

Graphical abstract, Actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1), a long non-coding RNA transcribed from the antisense strand of protein coding gene AFAP1, has attracted attention in cancer research. Despite, its biological function and regulatory mechanism in hepatocellular carcinoma still unknown. The present study revealed AFAP1-AS1 mediated hepatocarcinoma progression through targeting CRKL. The bidirectional interaction of AFAP1-AS1 and oncogenic protein CRKL, and the deregulation of AFAP1-AS1 effects on Ras, MEK and c-Jun activities were investigated in depth. AFAP1-AS1 was upregulated in surgical tumorous tissues from hepatocarcinoma patients compared with the paired paracancerous non-tumor liver tissues, and in hepatocarcinoma Huh7, HCCLM3 and HepG2 cell lines compared with LO2, a normal liver cell line. AFAP1-AS1 knockdown noticeably suppressed the proliferative, migratory and invasive properties, and the epithelial-mesenchymal transition (EMT) process of HepG2 and HCCLM3 through upregulating E-cadherin and downregulating N-cadherin and vimentin. CRKL knockdown reduced AFAP1-AS1 expression levels in HepG2 and HCCLM3 cells. AFAP1-AS1 suppression impaired CRKL expression in HepG2 and HCCLM3. AFAP1-AS1 level change was positively correlated with the expression level changes of Ras, MEK and c-Jun in mediating the invasiveness of hepatocarcinoma cells. Current work demonstrated AFAP1-AS1 to be an applicable progression indicator of hepatocarcinoma. AFAP1-AS1 probably promotes the proliferation, EMT progression and metastasis of hepatocarcinoma cells via CRKL mediated Ras/MEK/c-Jun and cadherin/vimentin signaling pathways. AFAP1-AS1-CRKL bidirectional feedback signaling is worthy of further study on the monitoring, diagnosis and treatment of cancers.

Wei Xu, Minhao Yu, Jun Qin, Yang Luo, Ming Zhong Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, People’s Republic of ChinaCorrespondence: Ming Zhong Email drzhongming1966@163.comBackground: Colorectal cancer (CRC) is one of the most common aggressive malignancies. LACTB functions as a tumor suppressor, and previous findings have demonstrated that LACTB can inhibit epithelial-to-mesenchymal transition (EMT) and proliferation of breast cancer and CRC cells. However, few studies have investigated the roles of LACTB in autophagy and proliferation in CRC. The current study aimed to identify the roles of LACTB in EMT and proliferation associated with autophagy in CRC and to elucidate the probable molecular mechanisms through which LACTB are involved in these processes.Materials and Methods: Transwell invasion, MTT, transmission electron microscopy, RNA-seq, immunoprecipitation, immunohistochemistry and Western blotting assays were performed to evaluate the migratory, invasive, proliferative and autophagic abilities of CRC cells, and the levels of active molecules involved in PI3K/AKT signaling were examined through Western blotting analysis. In addition, the in vivo function of LACTB was assessed using a tumor xenograft model.Results: Weaker LACTB expression was found in CRC tissue samples than in nonmalignant tissue samples, and LACTB inhibited cell invasion, migration, and proliferation by promoting autophagy in vitro. Furthermore, the regulatory effects of LACTB on autophagy and EMT were partially attributed to the PI3K/AKT signaling pathway. The in vivo results also showed that LACTB modulated CRC tumorigenesis.Conclusion: LACTB can regulate the activity of PIK3R3 to influence the level of PI3K, and it also promotes autophagy and inhibits EMT and proliferation in part through the PI3K/AKT/mTOR signaling pathway.Keywords: colorectal cancer, LACTB, PIK3R3, EMT, proliferation, autophagy

Vitamin A has diverse biological functions and is essential for human survival at every point from embryogenesis to adulthood. Vitamin A and its derivatives have been used to treat human diseases including vision diseases, skin diseases, and cancer. Both insufficient and excessive vitamin A uptake are detrimental, but how its transport is regulated is poorly understood. STRA6 is a multitransmembrane domain cell-surface receptor and mediates vitamin A uptake from plasma retinol binding protein (RBP). STRA6 can mediate both cellular vitamin A influx and efflux, but what regulates these opposing activities is unknown. To answer this question, we purified and identified STRA6-associated proteins in a native mammalian cell type that takes up vitamin A through STRA6 using mass spectrometry. We found that the major protein repeatedly identified as STRA6-associated protein is calmodulin, consistent with the cryogenic electron microscopy (cryo-EM) study of zebrafish STRA6 associated with calmodulin. Using radioactivity-based, high-performance liquid chromatography (HPLC)-based and real-time fluorescence techniques, we found that calmodulin profoundly affects STRA6’s vitamin A transport activity. Increased calcium/calmodulin promotes cellular vitamin A efflux and suppresses vitamin A influx through STRA6. Further mechanistic studies revealed that calmodulin enhances the binding of apo-RBP to STRA6, and this enhancement is much more pronounced for apo-RBP than holo-RBP. This study revealed that calmodulin regulates STRA6’s vitamin A influx or efflux activity by modulating its preferential interaction with apo-RBP or holo-RBP. This molecular mechanism of regulating vitamin A transport may point to new directions to treat human diseases associated with insufficient or excessive vitamin A uptake.

Background Tumor metastasis is one of the main causes of the high mortality of hepatocellular carcinoma (HCC). E-Twenty Six variant gene 6 (ETV6) is a strong transcriptional repressor, associated with the development and progression of tumors. However, the exact role and underlying mechanism of ETV6 in HCC remain unclear. Methods Western blotting, quantitative real-time PCR and immunohistochemistry were used to detect the expression levels of ETV6, CRKL (v-crk sarcoma virus CT10 oncogene homologue (avian)-like) and miR-429 in HCC tissues and cells; Transwell chamber and F-actin cytoskeleton staining assay to examine the effects of ETV6 and CRKL deregulation on the migration, invasion and cytoskeleton of HCC cells; Co-immunoprecipitation assay to determine the interaction between CRKL and ETV6; Chromatin immunoprecipitation assay to investigate the interaction between ETV6 and miR-429. Results We established a novel ETV6-miR-429-CRKL regulatory circuitry contributes to HCC metastasis. ETV6 and CRKL were frequently increased, while miR-429 was downregulated in both hepatocarcinoma tissues and hepatocarcinoma cells. Moreover, ETV6 upregulation was positively correlated with CRKL upregulation, and two negative correlations were also established for ETV6 and CRKL upregulation with miR-429 downregulation in both hepatocarcinoma patients’ tumorous tissues and hepatocarcinoma cells. Functional investigations revealed that overexpression and knockdown of ETV6 was remarkably effective in promoting and suppressing HCC cell migration, invasion, cytoskeleton F-actin expression and arrangement, whereas, CRKL overexpression exhibited similar effects to the overexpression of ETV6. Mechanistically, ETV6 negatively regulates miR-429 expression by directly binding to the promoter region of miR-429; miR-429 negatively regulates CRKL expression by selectively targeting CRKL-3′-UTR; ETV6 directly binds to CRKL and positively regulates its expression, which in turn CRKL positively regulates ETV6 expression. Conclusions Our data demonstrated that ETV6 promotes migration and invasion of HCC cells by directly binding to promoter region of miR-429 via modulating CRKL expression. The newly identified ETV6-miR-429-CRKL regulatory circuitry contributes to the aggressiveness of HCC, which provides new clues for fundamental research on diagnosis and treatment parameters for HCC.

A new species, Liparis mai (Malaxidinae, Epidendroideae, Orchidaceae), from Guangxi, China, is illustrated and described based on morphological and molecular analyses. This new species is similar to L. nervosa but differs by the older pseudobulb often bearing bulbil, larger revolute lateral sepals, obovate-elliptic lip and caniniform callus. Molecular analyses of nuclear (ITS) and plastid (matK) DNA support L. mai as a distinct species, which forms an independent lineage sister to L. nervosa and its allies.

Over a decade after the Cook Inlet beluga (Delphinapterus leucas) was listed as endangered in 2008, the population has shown no sign of recovery. Lack of ecological knowledge limits the understanding of, and ability to manage, potential threats impeding recovery of this declining population. National Oceanic and Atmospheric Administration Fisheries, in partnership with the Alaska Department of Fish and Game, initiated a passive acoustics monitoring program in 2017 to investigate beluga seasonal occurrence by deploying a series of passive acoustic moorings. Data have been processed with semi-automated tonal detectors followed by time intensive manual validation. To reduce this labor intensive and time-consuming process, in addition to increasing the accuracy of classification results, the authors constructed an ensembled deep learning convolutional neural network model to classify beluga detections as true or false. Using a 0.5 threshold, the final model achieves 96.57% precision and 92.26% recall on testing dataset. This methodology proves to be successful at classifying beluga signals, and the framework can be easily generalized to other acoustic classification problems.

Disruption of alveolar-capillary barriers is a major complication of high-volume mechanical ventilation referred to as "ventilator-induced lung injury." The stretching force in alveoli is transmitted to endothelial cells, increasing the tension on underlying endothelial plasma membrane. The mechanosensor Piezo1, a plasma membrane cation channel, was inducibly deleted in endothelial cells of mice (Piezo1iEC-/-), which allowed us to study its role in regulating the endothelial barrier response to alveolar stretch. We observed significant increase in lung vascular permeability in Piezo1iEC-/- mice as compared with control Piezo1fl/fl mice in response to high-volume mechanical ventilation. We also observed that human lung endothelial monolayers depleted of Piezo1 and exposed to cyclic stretch had increased permeability. We identified the calcium-dependent cysteine protease calpain as a downstream target of Piezo1. Furthermore, we showed that calpain maintained stability of the endothelial barrier in response to mechanical stretch by cleaving Src kinase, which was responsible for disassembling endothelial adherens junctions. Pharmacological activation of calpain caused Src cleavage and thereby its inactivation, and it restored the disrupted lung endothelial barrier seen in Piezo1iEC-/- mice undergoing high-volume mechanical ventilation. Our data demonstrate that downregulation of Piezo1 signaling in endothelium is a critical factor in the pathogenesis of ventilator-induced lung injury, and thus augmenting Piezo1 expression or pharmacologically activating Piezo1 signaling may be an effective therapeutic strategy.

Objective Our purpose was to identify up-regulated long noncoding RNA ENST00000512916 in ameloblastoma (AB) and explore its role in the progression of AB. Methods We analyzed lncRNA microarray expression profile between six paired AB and normal oral mucosa (NOM) tissues. An up-regulated lncRNA, ENST00000512916 was identified and validated by real-time qPCR. Cell proliferation, migration and cell cycle were detected by CCK-8 assay, transwell chamber and flow cytometry, respectively. Western blotting analysis was used to measure the expression of cell-cycle-related proteins including CyclinD1 and Cyclin-dependent kinase (CDK) 2/4/6. In addition, Xenograft tumor model was constructed to investigate tumor growth. Results Real-time qPCR confirmed that lncRNA ENST00000512916 was up-regulated in AB tissues. ENST00000512916 knockdown significantly inhibited cell proliferation, migration and the expression of CDK2/4/6 in AM-1 cells. Moreover, ENST00000512916 knockdown suppressed tumor growth in vivo. We also found that ENST00000512916 overexpression significantly promoted the expression of HOXC13 in AM-1 cells. Overexpression of ENST00000512916 promoted cell cycle progression in AM-1 cells, which was reversed by HOXC13 knockdown. Conclusion Our findings reveal that lncRNA ENST00000512916 promotes cell proliferation, migration and cell cycle progression of AB.

A new species, Cleisostoma hainanense (Orchidaceae: Epidedroideae: Aeridinae) from Hainan, China, is described and illustrated. Detailed morphological comparisons indicate that C. hainanense is similar to C. paniculatum, but differs in tauren-shaped mid-lobe with truncated tip, conical spur with inconspicuous septum and arch-shaped back wall callus. The molecular study based on nuclear ribosomal ITS and four plastid (atpI-atpH, matK, psbA-trnH, rbcL) regions support that the new species is sister to C. paniculatum.

1. To evaluate the inbreeding of yellow-feathered chickens (YFCs) and identify genes related to their unique characteristics, whole-genome re-sequencing data were applied to detect runs of homozygosity (ROH) in the genomes of ten YFC breeds. The number, length, distribution of ROH, and inbreeding coefficient in different YFC populations were calculated. Genomic regions with high frequency in ROH were annotated.2. In total, 25,547 ROH with an average length of 335 kb were detected, with most being

Aiming to identify rare high-penetrance mutations in new genes for the underlying predisposition in familial colorectal cancer (CRC), we performed whole-exome sequencing in 24 familial CRCs. Mutations in genes that regulate DNA repair (RMI1, PALB2, FANCI) were identified that were related to the Fanconi anemia DNA repair pathway. In one pedigree, we found a nonsense mutation in CHEK2. CHEK2 played an essential role in cell cycle and DNA damage repair. Somatic mutation analysis in CHEK2 variant carriers showed mutations in TP53, APC, and FBXW7. Loss of heterozygosity was found in carcinoma of CHEK2 variant carrier, and IHC showed loss of Chk2 expression in cancer tissue. We identified a second variant in CHEK2 in 126 sporadic CRCs. A KO cellular model for CHEK2 (CHEK2KO) was generated by CRISPR/Cas9. Functional experiments demonstrated that CHEK2KO cells showed defective cell cycle arrest and apoptosis, as well as reduced p53 phosphorylation, upon DNA damage. We associated germline mutations in genes that regulate the DNA repair pathway with the development of CRC. We identified CHEK2 as a regulator of DNA damage response and perhaps as a gene involved in CRC germline predisposition. These findings link CRC predisposition to the DNA repair pathway, supporting the connection between genome integrity and cancer risk.

Zhifeng Jiang,1,&ast; Song Chen,2,&ast; Lin Zhang,1,&ast; Jie Shen,1 Ming Zhong2,&ast; 1Department of Critical Care Medicine, Jinshan Hospital, Fudan University, Shanghai, 201508, People’s Republic of China; 2Division of Critical Care Medicine, Zhongshan Hospital Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lin ZhangDepartment of Emergency and Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, 201508, People’s Republic of ChinaEmail linzhang0315@fudan.edu.cnMing ZhongDivision of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of ChinaEmail zhong_ming@fudan.edu.cnBackground: Intestinal ischemia-reperfusion (II/R) injury is a common clinical complication associated with high mortality, for which microRNA (miRNA) drives potentially its pathophysiological progression. MiRNAs regulate different messenger RNAs (mRNAs). However, the regulatory network between miRNAs and mRNAs in intestinal ischemia-reperfusion injury is elusive.Methods: We analyzed the different expression of mRNAs and miRNAs in intestinal tissues from patients from three groups (arterial group (group A), venous group (group V), control group (group C)). Common differentially expressed (Co-DE) miRNAs and differentially expressed mRNAs were acquired via concerned analyses among the three groups. Co-DE mRNAs were shared parts of target mRNAs and differentially expression mRNAs. Cytoscape was employed to construct the regulatory network between miRNAs and mRNAs. Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway depicted the functions and potential pathway associated with Co-DE mRNAs. Using the STRING and Cytoscape, we found critical mRNAs in the protein–protein interaction (PPI) network.Results: The miRNA-mRNA network comprised 8 Co-DE miRNAs and 140 Co-DE mRNAs. Of note, 140 Co-DE mRNAs were targets of these 8 miRNAs, and their roles were established through the functional exploration via GO analysis and KEGG analysis. PPI network and Cytoscape revealed COL1A2, THY1, IL10, MMP2, SERPINH1, COL3A1, COL14A1, and P4HA1 as the top 8 key mRNAs.Conclusion: This study has demonstrated a miRNA-mRNA regulatory network in intestinal ischemia-reperfusion injury, and explored the key mRNAs and their potential functions. These findings could provide new insight into prognostic markers and therapeutic targets for patients with intestinal ischemia-reperfusion injury in clinical practice.Keywords: intestinal ischemia-reperfusion injury, microRNA, prognostic marker, bioinformatics

Hepatocellular carcinoma (HCC) is a heterogeneous tumor with an increased incidence worldwide accompanied by high mortality and dismal prognosis. Emerging evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes possess protective effects against various human diseases by transporting microRNAs (miRNAs or miRs). We aimed to explore the role of exosomal miR-15a derived from MSCs and its related mechanisms in HCC. Exosomes were isolated from transduced MSCs and co-incubated with Hep3B and Huh7 cells. miR-15a expression was examined by RT-qPCR in HCC cells, MSCs, and secreted exosomes. CCK-8, transwell, and flow cytometry were used to detect the effects of miR-15a or spalt-like transcription factor 4 (SALL4) on cell proliferative, migrating, invasive, and apoptotic properties. A dual-luciferase reporter gene assay was performed to validate the predicted targeting relationship of miR-15a with SALL4. Finally, in vivo experiments in nude mice were implemented to assess the impact of exosome-delivered miR-15a on HCC. The exosomes from MSCs restrained HCC cell proliferative, migrating, and invasive potentials, and accelerated their apoptosis. miR-15a was expressed at low levels in HCC cells and could bind to SALL4, thus curtailing the proliferative, migrating, and invasive abilities of HCC cells. Exosomes successfully delivered miR-15a to HCC cells. Exosomal miR-15a depressed tumorigenicity and metastasis of HCC tumors in vivo. Overall, exosomal miR-15a from MSCs can downregulate SALL4 expression and thereby retard HCC development.

Our previous work suggested that high SIRT1 expression by cancer cells predicted a poor colorectal cancer (CRC) prognosis, but its role in the tumor microenvironment was unclear. Here, we examined tumor-infiltrating lymphocytes (TILs) in CRC expressing different levels of SIRT1. We also established a co-culture system with monocytes, CD8+ T cells and patient-derived tumor organoids (PDOs) to study the relationships between immune cells and cancer cells. The percentage of CD8+ T cells was decreased and the percentage of macrophages was increased in SIRT1-high (SIRT1-hi) CRC. Co-culture results showed that tumor-associated macrophages (TAMs) from SIRT1-hi CRC inhibited the proliferation and anti-tumor activity of CD8+ T cells. Importantly, SIRT1-hi CRC were shown to modulate the migration and the activity of TAMs. RNA sequencing revealed that CD14+ monocytes in SIRT1-hi patients expressed higher levels of CXCR4. Mechanistically, SIRT1 expression was shown to promote CXCL12 expression by inhibiting the acetylation of p53. Our findings indicate that SIRT1 in CRC induces TAM migration through the CXCR4/CXCL12 pathway, and inhibits the proliferation and activity of CD8+ T cells, resulting in promotion of CRC progression.

International audience; The goal of this project is to use acoustic signatures to detect, classify, and count the calls of four acoustic populations of blue whales so that, ultimately, the conservation status of each population can be better assessed. We used manual annotations from 350 h of audio recordings from the underwater hydrophones in the Indian Ocean to build a deep learning model to detect, classify, and count the calls from four acoustic song types. The method we used was Siamese neural networks (SNN), a class of neural network architectures that are used to find the similarity of the inputs by comparing their feature vectors, finding that they outperformed the more widely used convolutional neural networks (CNN). Specifically, the SNN outperform a CNN with 2% accuracy improvement in population classification and 1.7%-6.4% accuracy improvement in call count estimation for each blue whale population. In addition, even though we treat the call count estimation problem as a classification task and encode the number of calls in each spectrogram as a categorical variable, SNN surprisingly learned the ordinal relationship among them. SNN are robust and are shown here to be an effective way to automatically mine large acoustic datasets for blue whale calls.

Genome-wide association studies (GWASs) implicate 16q22.1 locus in risk for colorectal cancer (CRC). However, the underlying oncogenic mechanisms remain unknown. Here, through comprehensive filtration, we prioritized rs7198799, a common SNP in the second intron of the CDH1, as the putative causal variant. In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript level of biological plausible candidate gene ZFP90 via expression quantitative trait loci analysis. Mechanistically, causal variant rs7198799 resides in an enhancer element and remotely regulate ZFP90 expression by targeting the transcription factor NFATC2. Remarkably, CRISPR/Cas9-guided single-nucleotide editing demonstrated the direct effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype. Furthermore, ZFP90 affects several oncogenic pathways, including BMP4, and promotes carcinogenesis in patients and in animal models with ZFP90 specific genetic manipulation. Taken together, these findings reveal a risk SNP-mediated long-range regulation on the NFATC2-ZFP90-BMP4 pathway underlying the initiation of CRC.

Background: Colorectal cancer (CRC) is one of the high incidence tumors and is ranked second in cancer-related mortality. Even though great progress has been made, there are no effective therapeutic strategies for late stage and metastatic CRC patients. Acidity is one characteristic of the tumor microenvironment. However, how cancer cells respond to this acidic environment surrounding them remains largely unknown, especially in colorectal cancer. Methods: Proton sensor receptor expression was analyzed in GEO and TCGA datasets. The expression of GPR4 in CRC specimens was confirmed by western blotting and immunohistochemistry (IHC). The role of GPR4 in CRC progression was analyzed both in vitro and in vivo. Pharmacological intervention, immunofluorescence and gene set enrichment analyses were performed to reveal the underlying molecular mechanisms of GPR4. Findings: We found that GPR4 was upregulated in CRC samples. In addition, its high expression correlated with late stage tumors and poor overall survival in patients. Furthermore, loss-of-function assays proved that GPR4 promoted CRC carcinogenesis and metastatic ability. Mechanistically, GPR4 was activated by extracellular protons in the tumor microenvironment and enhanced RhoA activation and F-actin rearrangement, leading to LATS activity inhibition, YAP1 nuclear translocation and oncogene transcription. Conclusions: The expression of GPR4 is upregulated in colorectal cancer and is associated with shorter overall survival time in CRCpatients. These findings reveal the novel roles of GPR4 in CRC progression and suggest GPR4 might be a new therapeutic target for CRC treatment. Funding Statement: This work was supported by the grant from the National Natural Science Foundation of China (No.81702300 & No.81873555). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: Study protocol that strictly in line with International Ethical Guidelines for Biomedical Research Involving Human Subjects was approved by the Research Ethics Committee of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. Patients that had received no anti-tumor therapy and signed written informed consent were enrolled in this study.

Long non-coding RNAs (lncRNAs) contribute to colorectal cancer (CRC). However, the role of lncRNAs in CRC metabolism, especially glucose metabolism remains largely unknown. In this study, we identify a lncRNA, GLCC1, which is significantly upregulated under glucose starvation in CRC cells, supporting cell survival and proliferation by enhancing glycolysis. Mechanistically, GLCC1 stabilizes c-Myc transcriptional factor from ubiquitination by direct interaction with HSP90 chaperon and further specifies the transcriptional modification pattern on c-Myc target genes, such as LDHA, consequently reprogram glycolytic metabolism for CRC proliferation. Clinically, GLCC1 is associated with tumorigenesis, tumor size and predicts poor prognosis. Thus, GLCC1 is mechanistically, functionally, and clinically oncogenic in colorectal cancer. Targeting GLCC1 and its pathway may be meaningful for treating patients with colorectal cancer., lncRNA and cellular metabolism are frequently dysregulated in cancer. In this study, the authors discover the lncGLCC1 is increased in colorectal cancer cells under glucose starvation conditions and correlates with poor prognosis in this cancer.

Objective This study aimed to investigate the prevalence of Escherichia coli ST131 and molecularly characterize the O25b-ST131 and O16-ST131 subgroups among urinary tract infection (UTI) E. coli isolates from women in central China. We also assessed the clinical characteristics and outcomes of infections caused by E. coli ST131. Methods Between January 2014 and December 2015, a total of 216 consecutive, non-repetitive E. coli isolates were recovered from UTI urine samples from women in Changsha, China. All isolates were analyzed for phylogenetic groups, antimicrobial resistance and virulence genotypes. ST131 clonal groups were identified using PCR and characterized using O serotyping, CTX-M genotypes, fimH, gyrA, and parC alleles, fluoroquinolone resistance genes and pulsed-field gel electrophoresis (PFGE). Clinical data were obtained from medical records. Results Overall, 41 (19.0%) of 216 E. coli isolates were identified to contain ST131 strains, among which 27 were O25b-ST131 strains and 14 were O16-ST131 strains. The clinical characteristics and outcomes of the ST131 group did not differ significantly from those of the non-ST131 group, except for the presence of urinary stones (43.9% vs 27.4%, P=0.039). Ciprofloxacin resistance was found to be significantly higher in O25b-ST131 isolates than O16-ST131 isolates (96.3% vs 14.3%, P

Vibrio vulnificus is a Gram-negative bacterium that belongs to the Vibrionaceae family. It represents a deadly opportunistic human pathogen which grows in water with the proper temperature and salinity, and is mostly acquired from seafood eating or direct contact. In susceptible individuals, a traumatic infection could be fatal, causing severe wound infection and even septic shock, and may require amputation. Global warming plays an important role in the geographical area expanding of Vibrio disease. The pathogenesis of Vibrio vulnificus-associated sepsis is very complex, including iron intake, cell injury, and adhesion-related protein and virulence regulation. Vibrio vulnificus infection mainly manifests clinical subtypes such as primary sepsis, traumatic infection, and gastroenteritis, with rapid symptom progression and signs of multiple organ dysfunction syndrome (MODS). It is important to assess these pathogenetic mechanisms in order to select more appropriate measures to prevent and treat Vibrio vulnificus infections, including antibiotic usage and surgical intervention. In this work, we report a typical case of successful treatment of necrotizing fasciitis caused by Vibrio vulnificus, and review the epidemiology, pathogenetic mechanism, clinical characteristics, and treatment of Vibrio vulnificus infection.

To develop natural fungicides against Panax notoginseng disease, the antifungal effects of Syzygium aromaticum essential oils (EOs) against the pathogenic fungi causing P. notoginseng disease were investigated. The effects of EOs from S. aromaticum buds and fruits on the growth of pathogenic mycelia were determined with in vitro antifungal experiments using the Oxford cup method. The results suggested that S. aromaticum EOs had a strong inhibitory effect on the growth of pathogenic fungi. At a dose of 50 mg/mL, the inhibitory effects of S. aromaticum buds EOs was greater than those of S. aromaticum fruits. Then the chemical constituents of the S. aromaticum EOs were analyzed by GC–MS. The results indicated that the eugenol content was the highest, accounting for 57.95% of the total constituents in the S. aromaticum buds EOs and 39.26% in the S. aromaticum fruits EOs. The minimum inhibitory concentration (MIC) of EOs, the major constituents, and hymexazol were evaluated. In addition, the antifungal effect of their combination was also determined by the fractional inhibitory concentration (FIC). When the buds EOs were combined with hymexazol, they had a synergistic effect in inhibiting Pythium aphanidermatum, Botrytis cinerea, and Colletotrichum gloeosporioides. The combination of S. aromaticum fruit EOs with hymexazol showed an additive effect on Fusarium solani, P. aphanidermatum, and B. cinerea. The preventive effect of S. aromaticum bud EOs combined with hymexazol was up to 60.77% in in vivo experiments. Overall, S. aromaticum EOs had a broad spectrum of antifungal activities against pathogenic fungi influencing the growth of P. notoginseng, which would provide a scientific basis for the ecological control of P. notoginseng disease.

Objectives The main aim of this study was to investigate the prevalence and molecular characteristics of the mcr-1 gene in Escherichia coli isolates obtained from all patients with bloodstream infections over a year in a Chinese teaching hospital. We also assessed the susceptibility profiles of the mcr-1-positive strains and prognostic impact of this gene on the patients. Methods A total of 144 consecutive, non-repetitive E. coli isolates causing bloodstream infections were collected at a teaching hospital in Changsha, China from January to December 2016. The presence of the mcr-1 gene was assessed by PCR. All mcr-1-positive E coli isolates were characterized by antimicrobial susceptibility testing, multilocus sequence typing (MLST), a conjugation experiment, and plasmid replicon typing. Clinical data were obtained from medical records. Results The mcr-1 gene was detected in three (2.1%) of the 144 E. coli isolates. The three mcr-1-positive E. coli isolates were resistant to colistin. All three isolates showed a lower resistance to other classes of antibacterials, with all three being susceptible to carbapenems. The MLST results indicated that the three E. coli isolates were assigned to three different sequence types: ST457, ST101, and ST1413, respectively. The conjugation experiment showed that the mcr-1 gene was successfully transferred to the recipient (E. coli EC600) from two isolates, one of which possessed IncI1 replicons and the other of which carried IncHI2 and IncN replicons. The patients with bloodstream infections caused by mcr-1-positive isolates had severe underlying diseases and were cured after antibacterial treatment. Conclusion The prevalence of the mcr-1 gene in patients with E. coli bloodstream infection was 2.1% in Changsha, China. The mcr-1-positive E. coli isolates had varied susceptibility profiles, although all three were susceptible to carbapenems. This therapeutic window is crucial given the risk of rapid deterioration in high-incidence areas worldwide.

Significance Increased hydrostatic pressure in lung capillaries experienced during high altitude, head trauma, and left heart failure can lead to disruption of lung endothelial barrier and edema formation. We identified Piezo1 as a mechanical sensor responsible for endothelial barrier breakdown (barotrauma) secondary to reduced expression of the endothelial adherens junction proteins VE-cadherin, β-catenin, and p120-catenin. Endothelial-specific deletion or pharmacological inhibition of Piezo1 prevented lung capillary leakage, suggesting a therapeutic approach for preventing edema and associated lung failure., Increased pulmonary microvessel pressure experienced in left heart failure, head trauma, or high altitude can lead to endothelial barrier disruption referred to as capillary “stress failure” that causes leakage of protein-rich plasma and pulmonary edema. However, little is known about vascular endothelial sensing and transduction of mechanical stimuli inducing endothelial barrier disruption. Piezo1, a mechanosensing ion channel expressed in endothelial cells (ECs), is activated by elevated pressure and other mechanical stimuli. Here, we demonstrate the involvement of Piezo1 in sensing increased lung microvessel pressure and mediating endothelial barrier disruption. Studies were made in mice in which Piezo1 was deleted conditionally in ECs (Piezo1iΔEC), and lung microvessel pressure was increased either by raising left atrial pressure or by aortic constriction. We observed that lung endothelial barrier leakiness and edema induced by raising pulmonary microvessel pressure were abrogated in Piezo1iΔEC mice. Piezo1 signaled lung vascular hyperpermeability by promoting the internalization and degradation of the endothelial adherens junction (AJ) protein VE-cadherin. Breakdown of AJs was the result of activation of the calcium-dependent protease calpain and degradation of the AJ proteins VE-cadherin, β-catenin, and p120-catenin. Deletion of Piezo1 in ECs or inhibition of calpain similarly prevented reduction in the AJ proteins. Thus, Piezo1 activation in ECs induced by elevated lung microvessel pressure mediates capillary stress failure and edema formation secondary to calpain-induced disruption of VE-cadherin adhesion. Inhibiting Piezo1 signaling may be a useful strategy to limit lung capillary stress failure injury in response to elevated vascular pressures.

Hippocampal neurogenesis plays an important role in the onset and treatment of depressive disorders. Previous studies suggest that paeoniflorin could be used as an antidepressant for treating rats subjected to chronic unpredictable stress. In this study, the effects of paeoniflorin on neurogenesis in the hippocampus dentate gyrus and potential mechanism of action are further investigated in chronic unpredictable stress-induced rat. Results suggest that paeoniflorin markedly increased both sucrose consumption and the number of 5-bromo-2-deoxyuridine-positive cells in the dentate gyrus of chronic unpredictable stress-induced rats, and the ratio of co-expressed 5-bromo-2-deoxyuridine and glial fibrillary acidic protein-positive cells, but exerted no significant effect on the ratio of co-expressed 5-bromo-2-deoxyuridine and neuronal nuclei-positive cells. Compared with the vehicle group, a significant increase was detected in the number of brain-derived neurotrophic factor-positive cells and the expression of brain-derived neurotrophic factor mRNA in the hippocampus of the paeoniflorin-treated group. According to the results, paeoniflorin promoted neural stem cell proliferation, their differentiation into astrocytes, and neurogenesis in the hippocampal dentate gyrus of chronic unpredictable stress-induced rats. Apart from enhancing the protein expression and gene transcription of brain-derived neurotrophic factor, it also activated the expression of tropomyosin receptor kinase B (a high-affinity receptor of brain-derived neurotrophic factor). This suggests that paeoniflorin might promote neurogenesis in the hippocampus dentate gyrus of chronic unpredictable stress-induced rats and act as an antidepressant by regulating the brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling pathway.

Background: Cancer is a leading cause of mortality in the world and metastasis is to blame. A number of naphthoquinones (NQs) have shown ability to reduce cancer stemness and metastatic potential. Furano-naphthoquinones (FNQs), which is a class of NQ characterized by the incorporation of an additional furan ring, have demonstrated improved anti-cancer potency as compared to the other classes of NQs. Objective: In this study, the natural origins, synthetic routes and derivatives of migrastatic NQs were reviewed. The anti-invasive and anti-metastatic mechanisms of NQs and the more powerful FNQs in targeting cancer were also discussed. Methods: The articles related to the anti-invasive mechanisms of NQs were comprehensively reviewed. The plant origins, synthetic routes and antitumor effects of more than 360 FNQs were also covered and presented according to their chemical structures. Results: Anti-cancer NQs inhibit cancer invasion by acting on epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and signal transducer and activator of transcription 3 (STAT3) signaling. BBI608, a natural FNQ, has entered phases I and II clinical trials. It has been regarded as a potential candidate for new-generation lead compound acting directly on CSCs to overcome the problem of chemotherapy resistance. Apart from the plant-derived FNQs, there are a number of synthetic FNQs that were found to intervene in cancer invasion and metastasis. Conclusion: The anti-invasive mechanisms of NQs have been thoroughly studied. FNQs generally show higher anti-cancer activity than that of NQs. The mechanisms of action of FNQs are worth further investigation.

Traditional Herbal Medicine (THM) has been used for thousands of years, and is popular worldwide due to its effectiveness in a variety of diseases. THM has also formed the basis of the discovery of modern drugs like artemisinin and paclitaxel. However, at present, studies that focus on development in the field of THM are stagnant because currently, the effective ingredients in the herbal formulations and the ambiguity of the underlying mechanisms of action are unknown. In this review, we have investigated the studies available that focused on the efficacy, active ingredients and bioavailability of THM, and the function of gut microbiota in THM-mediated treatment of disease. We hypothesized that most THMs treat diseases via three mechanisms: (1) metabolizing into active metabolites by the action of gut microbiota, (2) regulation of gut microbiota balance, and (3) regulating the fermentation products of the gut microbes. Therefore, focusing on these aspects can help elucidate the pharmacodynamic constituents of THM preparations, and their therapeutic mechanisms of action.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with a high mortality and poor prognosis. Transforming growth factor (TGF)-β plays crucial roles in the pathogenesis of IPF. To investigate the role of sodium arsenite (SA) on fibroblast differentiation and pulmonary fibrosis, we checked the effects of SA on TGF-β-induced normal human lung fibroblasts (NHLFs) differentiation, and the anti-fibrotic effect of SA on bleomycin (BLM)-induced pulmonary fibrosis in mouse. SA treatment significantly inhibits α-smooth muscle actin and fibronectin (FN) expression in TGF-β treated NHLFs; and SA also inhibits TGF-β stimulated expression of NADPH oxidase 4 and accumulation of intracellular reactive oxygen species. TGF-β-induced the phosphorylation of ERK and Smad3 were also blocked by SA. The administration of SA (IP) suppressed BLM-induced lung fibrosis characterized as the inhibition of collagen deposition, TGF-β accumulation in bronchoalveolar lavage fluid, and the expression of FN and collagen 1a2 in lung tissue. This study revealed that SA inhibits TGF-β-induced lung fibroblast differentiation and BLM-induced pulmonary fibrosis in mice, suggesting that SA could be a potential therapeutic approach to IPF.

In recent years, accumulating evidence has indicated that long non-coding RNAs (lncRNAs) are powerful factors influencing the progression of multiple malignancies. Although a relationship between the lncRNA NEAT1 (nuclear enriched abundant transcript 1) and colorectal cancer has previously been reported, the functional mechanism underlying the involvement of NEAT1 in colorectal cancer remains unknown. In this study, we report that NEAT1 expression is up-regulated in colorectal cancer tissues, which correlates with advanced clinical features, poor overall survival and disease free survival. Up-regulated NEAT1 promotes cell proliferation and metastasis of colorectal cancer both in vitro and in vivo. Moreover, NEAT1 functions as an oncogene influencing cell viability and invasion in part by serving as a competing endogenous RNA (ceRNAs) modulating miRNA-34a expression, leading to subsequent repression of the miR-34a/SIRT1 axis and activation of the Wnt/β-catenin signaling pathway. Taken together, our study demonstrates that the lncRNA NEAT1 may serve as a prognostic biomarker and a potential therapeutic target in colorectal cancer.

Senescence-associated secretory phenotype (SASP) plays a role in aging adipose tissue dysfunction by directly promoting chronic inflammation. The JNK/p53 pathway was reported as a potential mechanism that mediates SASP. In this study, we investigated the effects of L-carnitine, an inhibitor of the JNK/p53 pathway in adipose tissue SASP and dysfunction. Young and aging rat were given L-carnitine by gavage. Next, we detected the senescence, cytokines expression, chronic inflammation and insulin resistance of adipose tissue. Additionally, JNK/p53 pathway was estimated. Our results show a significant increase expression of SASP components in the adipose tissue of aging rats compared to young rats. Further, we found that infiltration of immune cells and the expression of pro-inflammatory cytokines were enhanced in aging adipose tissue while insulin signaling activity was reduced in aging adipose tissue. Interestingly, L-carnitine markedly reduced the expression of SASP factors. L-Carnitine could significantly reduce chronic inflammation, improving insulin resistance. Further, L-carnitine inhibited SASP by inhibiting JNK/p53 pathway. L-Carnitine inhibited SASP by JNK/p53 pathway and attenuated adipose tissue dysfunction of aging.

Ameloblastoma(AB) is an aggressive and slow-growing tumor with high recurrence rate, which arises from odontogenic epithelium. AB mostly shows osteolytic growth, but the specific pathogenesis is not yet clear. Periostin is a considered a prominent oncogene, which was mainly produced by osteoblasts and their precursors cells, it have been proved that Periostin play an important role in bone lysis. However, the precise role of Periostin in AB progression remains unknown. In this article, the surgical specimens from cases of AB were collected, and the Periostin expression was tested and the results were analyzed for possible correlations with clinical characteristics. In addition, the proliferation、cell cycle and migration of AM-1 cells were evaluated after transfection of siPeriostin. The results showed that Periostin levels were significantly higher in patients with AB than in controls. Moreover, Periostin levels in patients with AB were significantly associated with the number of disease. Furthermore, the results suggested that Periostin expression significantly promoted the proliferation and migration, in addition to cell cycle progression of AM-1 cells. The present study demonstrated that Periostin may be important in the pathogenesis and progression of AB and indicated its potential therapeutic value.