Recombinant L. lactis vaccine LL-plSAM-WAE targeting four virulence factors provides mucosal immunity against H. pylori infection.

BACKGROUND: Helicobacter pylori (H. pylori) causes chronic gastric disease. An efficient oral vaccine would be mucosa-targeted and offer defense against colonization of invasive infection in the digestive system. Proteolytic enzymes and acidic environment in the gastrointestinal tract (GT) can, however, reduce the effectiveness of oral vaccinations. For the creation of an edible vaccine, L. lactis has been proposed as a means of delivering vaccine antigens. RESULTS: We developed a plSAM (pNZ8148-SAM) that expresses a multiepitope vaccine antigen SAM-WAE containing Urease, HpaA, HSP60, and NAP extracellularly (named LL-plSAM-WAE) to increase the efficacy of oral vaccinations. We then investigated the immunogenicity of LL-plSAM-WAE in Balb/c mice. Mice that received LL-plSAM-WAE or SAM-WAE with adjuvant showed increased levels of antibodies against H. pylori, including IgG and sIgA, and resulted in significant reductions in H. pylori colonization. Furthermore, we show that SAM-WAE and LL-plSAM-WAE improved the capacity to target the vaccine to M cells. CONCLUSIONS: These findings suggest that recombinant L. lactis could be a promising oral mucosa vaccination for preventing H. pylori infection.

The transcriptional factor Clr-5 is involved in cellulose degradation through regulation of amino acid metabolism in Neurospora crassa.

BACKGROUND: Filamentous fungi are efficient degraders of plant biomass and the primary producers of commercial cellulolytic enzymes. While the transcriptional regulation mechanisms of cellulases have been continuously explored in lignocellulolytic fungi, the induction of cellulase production remains a complex multifactorial system, with several aspects still largely elusive. RESULTS: In this study, we identified a Zn2Cys6 transcription factor, designated as Clr-5, which regulates the expression of cellulase genes by influencing amino acid metabolism in Neurospora crassa during growth on cellulose. The deletion of clr-5 caused a significant decrease in secreted protein and cellulolytic enzyme activity of N. crassa, which was partially alleviated by supplementing with yeast extract. Transcriptomic profiling revealed downregulation of not only the genes encoding main cellulases but also those related to nitrogen metabolism after disruption of Clr-5 under Avicel condition. Clr-5 played a crucial role in the utilization of multiple amino acids, especially leucine and histidine. When using leucine or histidine as the sole nitrogen source, the Δclr-5 mutant showed significant growth defects on both glucose and Avicel media. Comparative transcriptomic analysis revealed that the transcript levels of most genes encoding carbohydrate-active enzymes and those involved in the catabolism and uptake of histidine, branched-chain amino acids, and aromatic amino acids, were remarkably reduced in strain Δclr-5, compared with the wild-type N. crassa when grown in Avicel medium with leucine or histidine as the sole nitrogen source. These findings underscore the important role of amino acid metabolism in the regulation of cellulase production in N. crassa. Furthermore, the function of Clr-5 in regulating cellulose degradation is conserved among ascomycete fungi. CONCLUSIONS: These findings regarding the novel transcription factor Clr-5 enhance our comprehension of the regulatory connections between amino acid metabolism and cellulase production, offering fresh prospects for the development of fungal cell factories dedicated to cellulolytic enzyme production in bio-refineries.

Tritium and Carbon-14 Contamination Reshaping the Microbial Community Structure, Metabolic Network, and Element Cycle in the Seawater Environment.

The potential ecological risks caused by entering radioactive wastewater containing tritium and carbon-14 into the sea require careful evaluation. This study simulated seawater's tritium and carbon-14 pollution and analyzed the effects on the seawater and sediment microenvironments. Tritium and carbon-14 pollution primarily altered nitrogen and phosphorus metabolism in the seawater environment. Analysis by 16S rRNA sequencing showed changes in the relative abundance of microorganisms involved in carbon, nitrogen, and phosphorus metabolism and organic matter degradation in response to tritium and carbon-14 exposure. Metabonomics and metagenomic analysis showed that tritium and carbon-14 exposure interfered with gene expression involving nucleotide and amino acid metabolites, in agreement with the results seen for microbial community structure. Tritium and carbon-14 exposure also modulated the abundance of functional genes involved in carbohydrate, phosphorus, sulfur, and nitrogen metabolic pathways in sediments. Tritium and carbon-14 pollution in seawater adversely affected microbial diversity, metabolic processes, and the abundance of nutrient-cycling genes. These results provide valuable information for further evaluating the risks of tritium and carbon-14 in marine environments.

Effects of long-term herbaceous plant restoration on microbial communities and metabolic profiles in coal gangue-contaminated soil.

The soil microbial diversity in the gangue accumulation area is severely stressed by a variety of heavy metals, while the influence of long-term recovery of herbaceous plants on the ecological structure of gangue-contaminated soil is to be explored. Therefore, we analysed the differences in physicochemical properties, elemental changes, microbial community structure, metabolites and expression of related pathways in soils in the 10- and 20-year herbaceous remediation areas of coal gangue. Our results showed that phosphatase, soil urease, and sucrase activities of gangue soils significantly increased in the shallow layer after herbaceous remediation. However, in zone T1 (10-year remediation zone), the contents of harmful elements, such as Thorium (Th; 1.08-fold), Arsenic (As; 0.78-fold), lead (Pb; 0.99-fold), and uranium (U; 0.77-fold), increased significantly, whereas the soil microbial abundance and diversity also showed a significant decreasing trend. Conversely, in zone T2 (20-year restoration zone), the soil pH significantly increased by 1.03- to 1.06-fold and soil acidity significantly improved. Moreover, the abundance and diversity of soil microorganisms increased significantly, the expression of carbohydrates in soil was significantly downregulated, and sucrose content was significantly negatively correlated with the abundance of microorganisms, such as Streptomyces. A significant decrease in heavy metals was observed in the soil, such as U (1.01- to 1.09-fold) and Pb (1.13- to 1.25-fold). Additionally, the thiamin synthesis pathway was inhibited in the soil of the T1 zone; the expression level of sulfur (S)-containing histidine derivatives (Ergothioneine) was significantly up-regulated by 0.56-fold in the shallow soil of the T2 zone; and the S content in the soil significantly reduced. Aromatic compounds were significantly up-regulated in the soil after 20 years of herbaceous plant remediation in coal gangue soil, and microorganisms (Sphingomonas) with significant positive correlations with benzene ring-containing metabolites, such as Sulfaphenazole, were identified.

Nonoxidative Coupling of Methane to Produce C2 Hydrocarbons on FLPs of an Albite Surface.

The characteristics of active sites on the surface of albite were theoretically analyzed by density functional theory, and the activation of the C-H bond of methane using an albite catalyst and the reaction mechanism of preparing C2 hydrocarbons by nonoxidative coupling were studied. There are two frustrated Lewis pairs (FLPs) on the (001) and (010) surfaces of albite; they can dissociate H2 under mild conditions and show high activity for the activation of methane C-H bonds. CH4 molecules can undergo direct dissociative adsorption on the (010) surface, whereas a 50.07 kJ/mol activation barrier is needed on the (001) surface. The prepared albite catalyst has a double combination function of the (001) and (010) surfaces; these surfaces produce a spillover phenomenon in the process of CH4 activation reactions, where CH3 overflows from the (001) surface with CH3 adsorbed on the (010) surface to achieve nonoxidative high efficiently C-C coupling with an activation energy of 18.51 kJ/mol. At the same time, this spillover phenomenon inhibits deep dehydrogenation, which is conducive to the selectivity of the C2 hydrocarbons. The experimental results confirm that the selectivity of the C2 hydrocarbons is maintained above 99% in the temperature range of 873 K to 1173 K.

Controlled Synthesis and Visible-Light-Driven Photocatalytic Activity of BiOBr Particles for Ultrafast Degradation of Pollutants.

For the purpose of regulating the visible-light-driven photocatalytic properties of photocatalysts, we selected BiOBr as the research target and various routes were used. Herein, via the use of a hydrothermal method with various solvents, BiOBr particles with controllable morphology and photocatalytic activities are obtained. In particular, through changing the volume ratio of ethylene glycol (EG) to ethanol (EtOH), BiOBr compounds possess microspheres, in which samples synthesized by using EG:EtOH = 1:2 have the highest photocatalytic activity, and can completely decompose RhB under visible light irradiation within 14 min. Furthermore, we also used different volume ratios of EG and H2O reaction solvents to prepare BiOBr particles so as to further improve its pollutant removal ability. When the volume ratio of EG to H2O is 1:1, the synthesized BiOBr particles have the best photocatalytic activity, and RhB can be degraded in only 10 min upon visible light irradiation. Aside from the reaction solvent, the impact of sintering temperature on the photocatalytic properties of BiOBr particles is also explored, where its pollutant removal capacities are restrained due to the reduced specific surface area. Additionally, the visible-light-triggered photocatalytic mechanism of BiOBr particles is determined by h+, ·OH and ·O2- active species.

Degradation of Uranium-Contaminated Decontamination Film by UV Irradiation and Microbial Biodegradation.

This research provides a complete degradation scheme for acrylic copolymer/cellulose acetate butyrate peelable decontamination films. This study analyzed the removal efficiency of uranium by peelable decontamination film. More importantly, the degradability of the films was evaluated by a combined treatment with UV radiation and microbial biodegradation. The results showed that UV radiation would rupture the surface of the decontamination films, which leaded the weight-average molecular weight decreased by 55.3% and number-average molecular weight decreased by 75.83%. Additionally, the microbial flora induced light-degradable decontamination film weight-average molecular weight and number-average molecular weight decreased by 9.3% and 30.73%, respectively. 16S rRNA microbial diversity analysis indicated that Pantoea, Xylella, Cronobacter, and Olivibacter were the major degrading bacteria genera. Among them, 4 key strains that can be stripped of decontamination films have been isolated and identified from the dominant degrading bacteria group. The results show that UV radiation combined with microbial flora can achieve rapid degradation of the decontamination films.

Porcine Reproductive and Respiratory Syndrome Virus Enhances Self-Replication via AP-1-Dependent Induction of SOCS1.

Porcine reproductive and respiratory syndrome virus (PRRSV) has caused tremendous economic losses in the swine industry since its emergence in the late 1980s. PRRSV exploits various strategies to evade immune responses and establish chronic persistent infections. Suppressor of cytokine signaling (SOCS) 1, a member of the SOCS family, is a crucial intracellular negative regulator of innate immunity. In this study, it was shown that SOCS1 can be co-opted by PRRSV to evade host immune responses, facilitating viral replication. It was observed that PRRSV induced SOCS1 production in porcine alveolar macrophages, monkey-derived Marc-145 cells, and porcine-derived CRL2843-CD163 cells. SOCS1 inhibited the expression of IFN-ß and IFN-stimulated genes, thereby markedly enhancing PRRSV replication. It was observed that the PRRSV N protein has the ability to upregulate SOCS1 production and that nuclear localization signal-2 (NLS-2) is essential for SOCS1 induction. Moreover, SOCS1 upregulation was dependent on p38/AP-1 and JNK/AP-1 signaling pathways rather than classical type I IFN signaling pathways. In summary, to our knowledge, the findings of this study uncovered the molecular mechanism that underlay SOCS1 induction during PRRSV infection, providing new insights into viral immune evasion and persistent infection.

Epigenetic and somaclonal divergence in Dendrocalamus farinosus for physiological augmentation and lignin degradation.

Epigenetic and molecular variation is a key approach for the improvement of plants. From in vitro tissue culture of Dendrocalamus farinosus; 30 plants were regenerated and after 2 years, the physiological, biochemical, and genomic studies were conducted. The results highlighted that for all phenotypic characteristics, the 30 regenerated plants were superior in comparison with the control (CK). From genetical analysis, a total of 97 bands were witnessed ranging between 212 bp and 2.2 kb. The results for OPU14 showed one additional specific band (723 bp) and one band (700 bp) were missing. The 10 plants were having genetic variability and can be termed as somaclones while the other plants have epigenetic variations. The cellulose and lignin analysis highlighted that somaclone No. 30 has the least cellulose content of 35%; while the somaclones No. 102 and No. 213 have the least 3.21% and 3.48% of lignin contents. Therefore, somaclones No. 30, No. 102, and No. 213 were selected for the histochemical localization. The lignin investigation revealed that somaclone No. 30 is greater while somaclones No. 102 and No. 213 were reduced in vascular bundles in comparison with the CK along with the high expression level of 4CL, C3H, C4H, COMT, and CCoAOMT1 genes.

Toxicity analysis of TNT to alfalfa's mineral nutrition and secondary metabolism.

KEY MESSAGE: Alfalfa has the ability to degrade TNT. TNT exposure caused root disruption of mineral nutrient metabolism. The exposure of TNT imbalanced basal cell energy metabolism. The mechanism of 2,4,6-trinitrotoluene (TNT) toxicity effects was analyzed in alfalfa (Medicago sativa L.) seedlings by examining the mineral nutrition and secondary metabolism of the plant roots. Exposure to 25-100 mg·L-1 TNT in a hydroponic solution for 72 h resulted in a TNT absorption rate of 26.8-63.0%. The contents of S, K, and B in root mineral nutrition metabolism increased significantly by 1.70-5.46 times, 1.38-4.01 times, and 1.40-4.03 times, respectively, after TNT exposure. Non-targeted metabolomics analysis of the roots identified 189 significantly upregulated metabolites and 420 significantly downregulated metabolites. The altered metabolites were primarily lipids and lipid-like molecules, and the most significant enrichment pathways were alanine, aspartate, and glutamate metabolism and glycerophospholipid metabolism. TNT itself was transformed in the root system into several intermediate products, including 4-hydroxylamino-2,6-dinitrotoluene, 4-amino-2,6-dinitrotoluene, 2-hydroxylamino-4,6-dinitrotoluene, 2,4',6,6'-tetranitro-2',4-azoxytoluene, 4,4',6,6'-tetranitro-2,2'-azoxytoluene, and 2,4-dinitrotoluene. Overall, TNT exposure disturbed the mineral metabolism balance, and significantly interfered with basic plant metabolism.

Chitosan Oligosaccharides Alleviate Colitis by Regulating Intestinal Microbiota and PPARγ/SIRT1-Mediated NF-κB Pathway.

Chitosan oligosaccharides (COS) have been shown to have potential protective effects against colitis, but the mechanism underlying this effect has not been fully elucidated. In this study, COS were found to significantly attenuate dextran sodium sulfate-induced colitis in mice by decreasing disease activity index scores, downregulating pro-inflammatory cytokines, and upregulating Mucin-2 levels. COS also significantly inhibited the levels of nitric oxide (NO) and IL-6 in lipopolysaccharide-stimulated RAW 264.7 cells. Importantly, COS inhibited the activation of the NF-κB signaling pathway via activating PPARγ and SIRT1, thus reducing the production of NO and IL-6. The antagonist of PPARγ could abolish the anti-inflammatory effects of COS in LPS-treated cells. COS also activated SIRT1 to reduce the acetylation of p65 protein at lysine 310, which was reversed by silencing SIRT1 by siRNA. Moreover, COS treatment increased the diversity of intestinal microbiota and partly restored the Firmicutes/Bacteroidetes ratio. COS administration could optimize intestinal microbiota composition by increasing the abundance of norank_f_Muribaculaceae, Lactobacillus and Alistipes, while decreasing the abundance of Turicibacte. Furthermore, COS could also increase the levels of propionate and butyrate. Overall, COS can improve colitis by regulating intestinal microbiota and the PPARγ/SIRT1-mediated NF-κB pathway.

A new perspective on the inhibition of plant photosynthesis by uranium: decrease of root activity and stomatal closure.

Uranium (U) is difficult to be transported from roots to leaves, but it has been reported to inhabit photosynthesis in leaves, so how does this work? In the present study, the effects of U (0-25 µM) on the development and photosynthesis in V. faba seedlings were studied under hydroponics. The results showed that U significantly inhibited the growth and development of V. faba plants, including decreased biomass, water content, lateral root number and root activity. U also led to a large accumulation of reactive oxygen species (ROS) in the leaves which affects leaf structural traits (e.g., decreased leaf area and chlorophyll a content). When U concentration was 25 µM, the net photosynthetic rate (Pn) and transpiration rate (Tr) were inhibited, which were only 66.53% and 41.89% of the control, respectively. Further analysis showed that the stomatal density of leaves increased with the increase of U concentration, while the stomatal aperture and stomatal conductance (Gs) were on the contrary. The results of chlorophyll fluorescence showed that the non-photochemical quenching coefficient (NPQ) increased and the electron transfer rate (ETR) decreased after U exposure, but fortunately, photosystem II (PSII) suffered little damage overall. In conclusion, the accumulation of U in the roots inhibited the root activity, resulting in water shortage in the plants. To prevent water loss, leaves have to regulated stomatal closure at the cost of weakening photosynthesis. These results provide a new insight into the mechanism by which U affects plant photosynthesis.

In situ restoration of soil ecological function in a coal gangue reclamation area after 10 years of elm/poplar phytoremediation.

The soil ecological health risks and toxic effects of coal gangue accumulation were examined after 10 years of elm/poplar phytoremediation. The changes in soil enzyme activities, ionome metabolism, and microbial community structure were analyzed at shallow (5-15 cm), intermediate (25-35 cm), and deep (45-55 cm) soil depths. Soil acid phosphatase activity in the restoration area increased significantly by 4.36-7.18 fold (p < 0.05). Soil concentrations of the metal ions Cu, Pb, Ni, Co, Bi, U, and Th were significantly reduced, as were concentrations of the non-metallic element S. The repair effect was shallow > middle > deep. The soil community structure, determined by 16S diversity results, was changed significantly in the restoration area, and the abundance of microorganisms increased at shallow soil depths. Altererythrobacter and Sphingomonas species were at the center of the microbial weight network in the restoration area. Redundancy analysis (RDA) showed that S and Na are important driving forces for the microbial community distributions at shallow soil depths. The KEGG function prediction indicated enhancement of the microbial function of the middle depth soil layers in the restoration area. Overall, phytoremediation enhanced the biotransformation of soil phosphorus in the coal gangue restoration area, reduced the soil content of several harmful metal elements, significantly changed the structure and function of the microbial community, and improved the overall soil ecological environment.

Response mechanism of Chlamydomonas reinhardtii to nanoscale bismuth oxyiodide (nano-BiOI): Integrating analysis of mineral nutrient metabolism and metabolomics.

Nanoscale bismuth oxyiodide (nano-BiOI) is widely studied and applied in environmental applications and biomedical fields, with the consequence that it may be deposited into aquatic environments. However, the impact of nano-BiOI on aquatic ecosystems, especially freshwater microalga, remains limited. Herein, the nano-BiOI was synthesized and its response mechanism towards microalga Chlamydomonas reinhardtii was evaluated. Results showed that a low concentration of nano-BiOI (5 mg/L) could stimulate algal growth at the early stage of stress. With the increase in concentration, the growth rate of algal cells was inhibited and showed a dose effect. Intracellular reactive oxygen species (ROS) were significantly induced and accompanied by enhanced lipid peroxidation, decreased nonspecific esterase activity, and significantly upregulated glutathione S-transferase activity (GST) activity. Mineral nutrient metabolism analysis showed that nano-BiOI significantly interfered with the mineral nutrients of the algae. Non-targeted metabolomics identified 35 different metabolites (DEMs, 22 upregulated, and 13 downregulated) under 100 mg/L BiOI stress. Metabolic pathway analysis demonstrated that a high concentration of nano-BiOI significantly induced metabolic pathways related to amino acid biosynthesis, lipid biosynthesis, and glutathione biosynthesis, and significantly inhibited the sterol biosynthesis pathway. This finding will contribute to understanding the toxicological mechanisms of nano-BiOI on C. reinhardtii.

Non-targeted metabolomics reveals the stress response of a cellulase-containing penicillium to uranium.

Human industrial activities have caused environmental uranium (U) pollution, resulting in uranium(VI) had radiotoxicity and chemical toxicity. Here, a cellulase-producing Penicillium fungus was screened and characterized by X-ray fluorescence (XRF), and Fourier transform infrared reflection (FT-IR), as well as by GC/MS metabolomics analysis, to study the response to uranium(VI) stress. The biomass of Penicillium decreased after exposure to 100 mg/L U. Uranium combined with carboxyl groups, amino groups, and phosphate groups to form uranium mineralized deposits on the surface of this fungal strain. The α-activity concentration of uranium in the strain was 2.57×106 Bq/kg, and the ß-activity concentration was 2.27×105 Bq/kg. Metabolomics analysis identified 118 different metabolites, as well as metabolic disruption of organic acids and derivatives. Further analysis showed that uranium significantly affected the metabolism of 9 amino acids in Penicillium. These amino acids were related to the TCA cycle and ABC transporter. At the same time, uranium exhibited nucleotide metabolism toxicity to Penicillium. This study provides an in-depth understanding of the uranium tolerance mechanism of Penicillium and provides a theoretical basis for Penicillium to degrade hyper-enriched plants.

Enhancing bile tolerance of Lactobacilli is involved in the hypolipidemic effects of liraglutide.

Liraglutide is an analog of human glucagon-like peptide-1 which play essential roles in regulation of glycolipid metabolism. To investigate role of lactic acid bacteria (LAB) in lipid-lowering effect of liraglutide, 40 mice were divided into normal food diet (NFD), high-fat food (HFD), 10.0 mg/kg/d simvastatin-treated HFD (SIM + HFD), 200 and 400 µg/kg/d liraglutide-treated HFD (LL + HFD and HL + HFD) groups for 5 weeks. We found that liraglutide could upregulate cholesterol 7α-hydroxylase (CYP7A1) and LDL-receptor (LDLR), whereas downregulate 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Besides, liraglutide enhance abundance of lactobacillaceae in gut of hyperlipidemic mice and increase bile tolerance ability of LAB by upregulating bile salt hydrolases, and the lysate of liraglutide-sensitive LAB could also directly downregulate HMGCR, the key enzyme in cholesterol synthesis, and inhibit hepatocyte steatosis. These findings might provide new theoretical guidance for clinical application of liraglutide and research and development of antiobesity, hypolipidemic, and cholesterol-lowering drugs or functional foods.

α-Glucosidase Inhibition Action of Major Flavonoids Identified from Hypericum Attenuatum Choisy and Their Synergistic Effects.

Hypericum attenuatum Choisy is a traditional Chinese herbal plant with multiple therapeutic effects. In this study, bioactivity-guided fractionation of Hypericum attenuatum Choisy extracts afforded three major flavonoids (including astragalin, guaijaverin and quercetin), which possessed α-Glucosidase inhibitory activity with IC50 values of 33.90±0.68 µM, 17.23±0.75 µM and 31.90±0.34 µM, respectively. Circular dichroism analysis revealed that all the three compounds could interact with α-glucosidase by inducing conformational changes of the enzyme. Molecular docking results indicated that they could bind to the active site in α-glucosidase, and the binding force was driven mainly by hydrogen bond. Additionally, isobolographic analysis of the interactions between two compounds showed that all the combinations presented a synergistic α-glucosidase inhibitory effect at lower concentrations, and the combination between quercetin and guaijaverin or astragalin exhibited the best synergistic effect. This research might provide a theoretical basis for the application of Hypericum attenuatum Choisy in treating hyperglycemia.

Biodegradation and physiological response mechanism of Bacillus aryabhattai to cyclotetramethylenete-tranitramine (HMX) contamination.

This study aims to reveal the biodegradation and interaction mechanism of cyclotetramethylenete-tranitramine (HMX) by a newly isolated bacteria. In this study, a bacterial strain (Bacillus aryabhattai) with high efficiency for HMX degradation was used as the test organism to analyze the changes in growth status, cell function, and mineral metabolism following exposure to different stress concentrations (0 and 5 mg L-1) of HMX. Non-targeted metabonomics was used to reveal the metabolic response of this strain to HMX stress. The results showed that when the HMX concentration was 5 mg L-1, the removal rate of HMX within 24 h of inoculation with Bacillus aryabhatta was as high as 90.5%, the OD600 turbidity was 1.024, and the BOD5 was 225 mg L-1. Scanning electron microscope (SEM) images showed that the morphology of bacteria was not obvious Variety, Fourier transform infrared spectroscopy (FTIR) showed that the cell surface -OH functional groups drifted, and ICP-MS showed that the cell mineral element metabolism was disturbed. Non-targeted metabonomics showed that HMX induced the differential expression of 254 metabolites (133 upregulated and 221 downregulated). The main differentially expressed metabolites during HMX stress were lipids and lipid-like molecules, and the most significantly affected metabolic pathway was purine metabolism. At the same time, the primary metabolic network of bacteria was disordered. These results confirmed that Bacillus aryabhattai has a high tolerance to HMX and can efficiently degrade HMX. The degradation mechanism involves the extracellular decomposition of HMX and transformation of the degradation products into intracellular purines, amino sugars, and nucleoside sugars that then participate in cell metabolism.

Human Papillomavirus E6/E7 and Long Noncoding RNA TMPOP2 Mutually Upregulated Gene Expression in Cervical Cancer Cells.

TMPOP2 was previously suggested to be an oncogenic long noncoding RNA which is excessively expressed in cervical cancer cells and inhibits E-cadherin gene expression by recruiting transcription repressor EZH2 to the gene promoter. So far, the function and regulation of TMPOP2 in cervical cancer remain largely unknown. Herein, we found that TMPOP2 expression was correlated with human papillomavirus 16/18 (HPV16/18) E6 and E7 in cervical cancer cell lines CaSki and HeLa. Tumor suppressor p53, which is targeted for degradation by HPV16/18, was demonstrated to associate with two p53 response elements in the TMPOP2 promoter to repress the transcription of the TMPOP2 gene. Reciprocally, ectopic expression of TMPOP2 was demonstrated to sequester tumor repressor microRNAs (miRNAs) miR-375 and miR-139 which target HPV16/18 E6/E7 mRNA and resulted in an upregulation of HPV16/18 E6/E7 genes. Thereby, HPV16/18 E6/E7 and the long noncoding RNA (lncRNA) TMPOP2 form a positive feedback loop to mutually derepress gene expression in cervical cancer cells. Moreover, results of RNA sequencing and cell cycle analysis showed that knockdown of TMPOP2 impaired the expression of cell cycle genes, induced cell cycle arrest, and inhibited HeLa cell proliferation. Together, our results indicate that TMPOP2 and HPV16/18 E6/E7 mutually strengthen their expression in cervical cancer cells to enhance tumorigenic activities.IMPORTANCE Human papillomaviruses 16 and 18 (HPV16/18) are the main causative agents of cervical cancer. Viral proteins HPV16/18 E6 and E7 are constitutively expressed in cancer cells to maintain oncogenic phenotypes. Accumulating evidences suggest that HPVs are correlated with the deregulation of long noncoding RNAs (lncRNAs) in cervical cancer, although the mechanism was unexplored in most cases. TMPOP2 is a newly identified lncRNA excessively expressed in cervical cancer. However, the mechanism for the upregulation of TMPOP2 in cervical cancer cells remains largely unknown and its relationship with HPVs is still elusive. The significance of our research is in revealing the mutual upregulation of HPV16/18 E6/E7 and TMPOP2 with the molecular mechanisms explored. This study will expand our understandings of the oncogenic activities of human papillomaviruses and lncRNAs.

Chitooligosaccharides Modulate Glucose-Lipid Metabolism by Suppressing SMYD3 Pathways and Regulating Gut Microflora.

Chitooligosaccharides (COS) have a variety of biological activities due to their positively charged amino groups. Studies have shown that COS have antidiabetic effects, but their molecular mechanism has not been fully elucidated. The present study confirmed that COS can reduce hyperglycemia and hyperlipidemia, prevent obesity, and enhance histological changes in the livers of mice with type 2 diabetes mellitus (T2DM). Additionally, treatment with COS can modulate the composition of the gut microbiota in the colon by altering the abundance of Firmicutes, Bacteroidetes, and Proteobacteria. Furthermore, in T2DM mice, treatment with COS can upregulate the cholesterol-degrading enzymes cholesterol 7-alpha-hydroxylase (CYP7A1) and incretin glucagon-like peptide 1 (GLP-1) while specifically inhibiting the transcription and expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the key enzyme in cholesterol synthesis. Furthermore, using an oleic acid-induced hepatocyte steatosis model, we found that HMGCR can be directly transactivated by SET and MYND domain containing 3 (SMYD3), a transcriptional regulator, via 5'-CCCTCC-3' element in the promoter. Overexpression of SMYD3 can suppress the inhibitory effect of COS on HMGCR, and COS might regulate HMGCR by inhibiting SMYD3, thereby exerting hypolipidemic functions. To the best of our knowledge, this study is the first to illustrate that COS mediate glucose and lipid metabolism disorders by regulating gut microbiota and SMYD3-mediated signaling pathways.