Transcription directionality is licensed by Integrator at active human promoters.

A universal characteristic of eukaryotic transcription is that the promoter recruits RNA polymerase II (RNAPII) to produce both precursor mRNAs (pre-mRNAs) and short unstable promoter upstream transcripts (PROMPTs) toward the opposite direction. However, how the transcription machinery selects the correct direction to produce pre-mRNAs is largely unknown. Here, through multiple acute auxin-inducible degradation systems, we show that rapid depletion of an RNAPII-binding protein complex, Integrator, results in robust PROMPT accumulation throughout the genome. Interestingly, the accumulation of PROMPTs is compensated by the reduction of pre-mRNA transcripts in actively transcribed genes. Consistently, Integrator depletion alters the distribution of polymerase between the sense and antisense directions, which is marked by increased RNAPII-carboxy-terminal domain Tyr1 phosphorylation at PROMPT regions and a reduced Ser2 phosphorylation level at transcription start sites. Mechanistically, the endonuclease activity of Integrator is critical to suppress PROMPT production. Furthermore, our data indicate that the presence of U1 binding sites on nascent transcripts could counteract the cleavage activity of Integrator. In this process, the absence of robust U1 signal at most PROMPTs allows Integrator to suppress the antisense transcription and shift the transcriptional balance in favor of the sense direction.

Fibroblast growth factor 21 mitigates lupus nephritis progression via the FGF21/Irgm 1/NLRP3 inflammasome pathway.

As an endocrine cytokine, fibroblast growth factor 21 (FGF21) exhibits anti-inflammatory properties. With the development of lupus nephritis (LN), which is tightly related to pathogenic factors, including inflammation and immune cell dysregulation, we explored the impact of Fibroblast Growth Factor 21 (FGF21) as well as its underlying mechanism. We induced an in vivo LN model using pristane in both wild-type C57BL/6 and FGF21 knockout (FGF21-/-) mice. LN serum obtained from 32-week-old wild-type LN mice was used to stimulate RAW264.7 and human renal tubular epithelial (HK-2) cells to mimic an in vitro LN model. Moreover, our findings revealed that FGF21-/- mice showed more severe kidney injury compared to wild-type mice, as evidenced by increased levels of renal function markers, inflammatory factors, and fibrosis markers. Notably, exogenous administration of FGF21 to wild-type LN mice markedly mitigated these adverse effects. Additionally, we used tandem mass tag (TMT)-based quantitative proteomics to detect differentially expressed proteins following FGF21 treatment. Results indicated that 121 differentially expressed proteins influenced by FGF21 were involved in biological processes such as immune response and complement activation. Significantly upregulated protein Irgm 1, coupled with modulated inflammatory response, appeared to contribute to the beneficial effects of FGF21. Furthermore, Western blot analysis demonstrated that FGF21 upregulated Irgm 1 while inhibiting nucleotide-binding oligomerization domain-like receptors family pyrin domain including 3 (NLRP3) inflammasome expression. Silencing Irgm 1, in turn, reversed FGF21's inhibitory effect on NLRP3 inflammasome. In summary, FGF21 can potentially alleviate pristane-induced lupus nephritis in mice, possibly through the FGF21/Irgm 1/NLRP3 inflammasome pathway.

Ribosomal frameshifting at normal codon repeats recodes functional chimeric proteins in human.

Ribosomal frameshifting refers to the process that ribosomes slip into +1 or -1 reading frame, thus produce chimeric trans-frame proteins. In viruses and bacteria, programmed ribosomal frameshifting can produce essential trans-frame proteins for viral replication or regulation of other biological processes. In humans, however, functional trans-frame protein derived from ribosomal frameshifting is scarcely documented. Combining multiple assays, we show that short codon repeats could act as cis-acting elements that stimulate ribosomal frameshifting in humans, abbreviated as CRFS hereafter. Using proteomic analyses, we identified many putative CRFS events from 32 normal human tissues supported by trans-frame peptides positioned at codon repeats. Finally, we show a CRFS-derived trans-frame protein (HDAC1-FS) functions by antagonizing the activities of HDAC1, thus affecting cell migration and apoptosis. These data suggest a novel type of translational recoding associated with codon repeats, which may expand the coding capacity of mRNA and diversify the regulation in human.

Algae-Bacteria cooperated microbial ecosystem: A self-circulating semiartificial photosynthetic purifying strategy.

The microbial fuel cell (MFC) is a promising bio-electrochemical technology that enables simultaneous electricity generation and effluent purification. Harnessing solar energy to provide sustainable power for MFC operation holds great potential. In this study, a semiartificial photosynthetic self-circulating MFC ecosystem is successfully established through the collaboration of electrogenic microorganisms and photosynthetic algae. The ecosystem can operate continuously without carbon sources and produces a voltage of 150 mV under irradiation. The irradiation doubles the maximum power density of the ecosystem, reaching 8.07 W/m2 compared to dark conditions. The results of cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) suggest a higher diffusion capacity or faster electron replenishment ability within the ecosystem. Furthermore, the capacity of ecosystem for removing chromium (Cr(VI)) has been investigated comprehensively. Under irradiation, the ecosystem demonstrates a 2.25-fold increase in Cr(VI) removal rate compared to dark conditions. Finally, the results of 16S rRNA amplicon sequencing indicates an increase in the relative abundance of strict and facultative aerobic electroactive bacteria in the ecosystem, including Citrobacter (21 %), Bacillus (15 %) and Enterococcus (6 %). The ecosystem offers a novel, self-sustaining approach to address the challenges of energy recovery and environmental pollution.

Natural hematite as low-cost auxiliary material for improving soil remediation by in-situ microbial community.

Microbial-mineral interaction has a broad application prospect in the field of environmental remediation of organic pollutants. However, the disadvantages of long repair cycle and low repair rate limit its industrial application. In this study, natural hematite was used as an auxiliary material for soil remediation in a bio-electrochemical system. It was found that the power density of soil microbial fuel cell (SMFC) system composed of 2.0 mm hematite was 2.889 mW/m2, which is 2.7 times compared with the blank group (1.068 mW/m2) in the particle size optimization experiment. A similarly increased power density (1.068 to 2.467 mW/m2) was observed when the hematite content changed from 0 to 20% in the concentration optimization experiment. Under 20% and 2.0-mm hematite condition, the phenol removal rate was closed to 99% after 7 days, which is 1.9-folds compared with blank control (53%). These results suggest that addition of hematite enhances soil porosity and conductivity, and increases the number of electron acceptors in soil. These findings inspire that this economic and abundant natural mineral is expected to be a potential auxiliary material in the field of soil organic pollutant purification, and expand the understanding of interactions between hematite and microorganisms in nature.

The development of rare-earth combined Fe-based magnetic nanocomposites for use in biological theranostics.

Iron (Fe)-based nanoparticles (NPs) represented by Fe3O4 exhibit attractive properties, such as high saturation magnetization, low magneto-crystalline anisotropy, and good biocompatibility, and are useful as magnetic resonance imaging (MRI) contrast agents. However, the existence of artifacts makes the single magnetic resonance imaging mode lack accuracy in tumor diagnosis. To overcome this limitation, a strategy where rare-earth elements are combined with Fe-based NPs is applied. Rare earth is the general name of Sc, Y, and elements with unique 4f electronic configurations. Some rare-earth elements like Gd and Lu exhibit magnetic properties due to unpaired electrons, while some, like Er and Ho, fluoresce under excitation ascribed to the electron transition at intermediate energy levels. In this manuscript, attention is focused on multimodal nanomaterials composed of rare-earth elements and Fe-based NPs. We provide an overview of the synthetic routes and current biomedical application of the nanocomposites that show potential for precise diagnosis and efficient treatment of cancers.

Evaluation of prevention and treatment effects of fibroblast growth factor-21 in BLM-induced pulmonary fibrosis.

Pulmonary fibrosis is a progressive and fatal fibrotic lung disease and associated with a high mortality rate. In the study, the prevention and treatment effects of fibroblast growth factor-21 (FGF-21) in bleomycin (BLM)-induced pulmonary fibrosis were investigated in vivo and vitro. In the prevention of pulmonary fibrosis studies, the results showed that interdict of FGF-21 could reduce the related gene and protein expression levels of pulmonary fibrosis. In addition, FGF-21 significantly reduced both the aggregation of inflammatory cells and deposition of collagen in the lung by histopathology. In therapy of pulmonary fibrosis studies, the results indicated that treatment with FGF-21 resulted in an amelioration of the pulmonary fibrosis in mice with reductions of the pathological score, collagen deposition and transforming growth factor (TGF)-ß and α-smooth muscle actin (α-SMA) expressions in the lung tissues at fibrotic stage, and late administration was also able to reduce the degree of pulmonary fibrosis and even better than these in the prevention group. Furthermore, BLM-induced THP-1 macrophage model was verified using FGF-21; the result showed that FGF-21 decreased the related gene expression level of pulmonary fibrosis. FGF-21 may have preventive and therapeutic effects on BLM-induced pulmonary fibrosis via inhibiting myofibroblast differentiation and inflammatory. Thus, FGF-21 represents a potential drug for the prevention and treatment of pulmonary fibrosis.

Development and evaluation of Newcastle disease - avian influenza bivalent vector vaccines in commercial chickens.

Avian influenza (AI) and Newcastle disease (ND) are regarded as the leading viral infectious diseases affecting the global poultry industry. Vaccination is a successful therapeutic intervention to safeguard birds against both ND and AI infections. In this research, ND-AI bivalent vaccines were developed through the incorporation of HA and IRES-GMCSF gene fragments at varying locations of NDV rClone30 vectors. The two constructed vaccines were rClone30-HA-IRES-GMCSF(PM) and rClone30-HA(PM)-IRES-GMCSF(NP). Next, 27-day-old Luhua chickens (the maternal antibody level was reduced to 1.4 log2) were inoculated with the same dose of the vaccines, and humoral and cellular immune responses were assessed at multiple time points. Compared to the commercial vaccine, the levels of anti-NDV antibodies following the administration of the ND-AI vaccines were above the theoretical protection value of 4 log2. The levels of anti-AIV antibodies in the bivalent vaccine group were notably higher than those in the commercial vaccine group. Furthermore, the content of inflammatory factors and transcription levels were significantly increased in chickens administered ND-AI vaccines. The ND-AI vaccines induced stronger proliferative responses of B cells or CD3+, CD8+, and CD4 + T cells. Hematoxylin and eosin staining showed that the tissue damage induced by the two recombinant vaccines was similar to that of commercial vaccines. The outcomes of the study suggest that the two bivalent ND-AI vaccine candidates produced using the reverse genetics approach are both secure and effective. This approach not only enables the multiuse of one vaccine but also provides a new concept for the development of other vaccines against infectious viral diseases.

The transcription factor GhTCP7 suppresses petal expansion by interacting with the WIP-type zinc finger protein GhWIP2 in Gerbera hybrida.

Petal size is a critical factor in plant reproduction and horticulture, and is largely determined by cell expansion. Gerbera hybrida is an important horticultural plant and serves as a model for studying petal organogenesis. We have previously characterized GhWIP2, a Trp-Ile-Pro (WIP)-type zinc protein, that constrains petal size by suppressing cell expansion. However, the underlying molecular mechanism remains largely unclear. Using yeast two-hybrid screening, bimolecular fluorescence complementation, and co-immunoprecipitation, we identified a TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) family transcription factor, GhTCP7, that interacts with GhWIP2 both in vitro and in vivo. Using reverse genetic approaches, we elucidated the function of the GhTCP7-GhWIP2 complex in controlling petal expansion. GhTCP7 overexpression severely reduced cell expansion and petal size, whereas GhTCP7 silencing resulted in increased cell expansion and petal size. GhTCP7 showed similar expression patterns to GhWIP2 in various types of G. hybrida petals. We further identified GhIAA26, which encodes an auxin signalling regulator, that is activated by the GhTCP7-GhWIP2 complex, leading to the suppression of petal expansion. Our findings reveal a previously unknown transcriptional regulatory mechanism that involves protein-protein interactions between two different transcription factor families to activate a negative regulator of petal organogenesis.

In situ degradation of organic pollutants by novel solar cell equipped soil microbial fuel cell.

The soil microbial fuel cell (SMFC) has been widely used for soil remediation for its low cost and being eco-friendly. But low degradation efficiency and high mass transfer resistance limit its performance. This study constructed a solar cell-soil microbial fuel cell (SC-SMFC) with different voltages, which use clean energy to improve system performance. At different voltages, 2.0-V system showed the best performance and the maximum output power increased by 330% compared with SMFC. Moreover, 2.0-V SC-SMFC showed the fastest phenol degradation rate of 14 µg·mL-1·d-1 at the concentration of 80 µg/mL, which was twice of SMFC. Further increasing the concentration to 320 µg/mL, the system showed extremely high concentration limit and degraded 90% within 19 days. Under this condition, SC-SMFC still showed excellent cycle stability, with the third-round degrading 90% phenol in 13 days. Finally, electrochemical impedance spectroscopy (EIS) mechanism study showed that solar cells can accelerate microbial metabolic process and reduce the internal resistance, in which the 2.0-V system was only 87% of SMFC. In conclusion, SC-SMFC provides a green, low-cost, and convenient method for in situ soil remediation in the future.

Oncolytic Newcastle disease virus expressing the co-stimulator OX40L as immunopotentiator for colorectal cancer therapy.

NDV as an attractive candidate for oncolytic immunotherapy selectively lyses tumor cells but shows limited anti-tumor immunity. Immune co-stimulator OX40 ligand (OX40L) boosts anti-tumor immunity response by delivering a potent costimulatory signal to CD4+ and CD8+ T cells. To improve the anti-tumor immunity of NDV, the recombinant NDV expressing the murine OX40L (rNDV-mOX40L) was engineered. The viral growth kinetics was examined in CT26 cell lines. The ability of rNDV-mOX40L to express mOX40L was detected in the infected tumor cells and tumor tissues. The anti-tumor activity of rNDV-mOX40L was studied in the CT26 animal model. Tumor-specific CD4+, CD8+ and OX40+ T cells were examined by immunohistochemistry staining. The virus growth curve showed that the insertion of the mOX40L gene did not affect the growth kinetics of NDV. rNDV-mOX40L expresses mOX40L and effectively inhibits the growth of CT26 colorectal cancer in vivo. The tumor inhibition rate of the rNDV-mOX40L-treated group was increased by 15.8% compared to that of  NDV-treated group in the CT26 model. Furthermore, immunohistochemistry staining of tumor tissues removed from the CT26 model revealed that intense infiltration of tumor-specific CD4+, CD8+ T cells, especially OX40+ T cells were found in the rNDV-mOX40L-treated group. FACS showed that rNDV-mOX40L significantly enhanced the number of CD4+ and CD8+ T cells in spleen. Moreover, compared to the NDV-treated group, the level of mouse IFN-γ protein in the tumor site increased significantly in the rNDV-mOX40L-treated group. Taken together, rNDV-mOX40L exhibited superior anti-tumor immunity by stimulating tumor-specific T cells and may be a promising agent for cancer immunotherapy.

Efficient organic contaminant and Cr (VI) synchronous removing by one-step modified molybdenite cathode microbial fuel cells.

As a novel technique with a wide range of applications, microbial fuel cell (MFC) could simultaneously remove organic contaminants and heavy metals in complex wastewater, despite striking differences in physicochemical properties of these contaminant. But its wastewater treatment efficiency is restricted by its lower generation performance. However, approaches for the modification of MFCs' cathode with appropriate catalyst could effectively overcome this limitation. Herein, a new-type efficient cathode catalyst was invented through modifying natural molybdenite via one-step oxidation method. In this case, molybdenite had many changes in morphology (wave-shaped bending, fragmentation and decrescent diameter) during oxidation modification process, and oxidation-modified molybdenite could provide much more active sites for the cathode. After applying this novel cathode catalyst, the electric generation capacity of MFC system increased by 5.08 times, and its simultaneous degradation efficiency of methyl blue (MB) and Cr (VI) increased by 3.35 times (compared with graphite cathode MFC). This study provides a novel low-carbon and environmentally friendly way to prepare high efficiency cathode catalyst materials and provides a new idea of simultaneous purification for organic and metallic pollutants from complex wastewater.

Fibroblast growth factor 21 attenuates the progression of hyperuricemic nephropathy through inhibiting inflammation, fibrosis and oxidative stress.

Elevated levels of circulating fibroblast growth factor 21 (FGF21) have been reported in patients with hyperuricemia. However, the effect of FGF21 in hyperuricemic nephropathy (HN) remains unexplored. Here, we investigated the effect and mechanism of action of FGF21 on HN. HN model was induced with adenine and potassium oxysalt in wild-type C57BL/6 mice and FGF21-/- mice. For in vitro studies, human renal tubular epithelial (HK-2) cells were exposed to uric acid with/without FGF21 or ß-Klotho-siRNA. Here, we reported aggravated renal dysfunction and structural damage in the FGF21-/- mice compared to the wild-type mice. These were evident in the upsurge of inflammatory factors IL-1ß, TNF-α, IL-6, and IL-18; fibrotic markers Collagen I and α-SMA; and oxidation products ROS and MDA. However, exogenous administration of FGF21 to wild-type HN mice significantly reversed these negative effects. In terms of mechanism, FGF21 significantly inhibited NF-κB/NLRP3 and TGF-ß1/Smad3 pathways and promoted nuclear translocation of Nrf2 both in vivo and in vitro. Furthermore, the silencing of ß-Klotho was marked by the attenuation of the improved effect of FGF21 on cell damage. In conclusion, our studies revealed that exogenous FGF21 treatment significantly improved HN, which was achieved by the inhibition of inflammation, fibrosis, and oxidative stress.

Fibroblast growth factor-21 as a novel metabolic factor for regulating thrombotic homeostasis.

Fibroblast growth factor-21 (FGF-21) performs a wide range of biological functions in organisms. Here, we report for the first time that FGF-21 suppresses thrombus formation with no notable risk of bleeding. Prophylactic and therapeutic administration of FGF-21 significantly improved the degree of vascular stenosis and reduced the thrombus area, volume and burden. We determined the antithrombotic mechanism of FGF-21, demonstrating that FGF-21 exhibits an anticoagulant effect by inhibiting the expression and activity of factor VII (FVII). FGF-21 exerts an antiplatelet effect by inhibiting platelet activation. FGF-21 enhances fibrinolysis by promoting tissue plasminogen activator (tPA) expression and activation, while inhibiting plasminogen activator inhibitor 1 (PAI-1) expression and activation. We further found that FGF-21 mediated the expression and activation of tPA and PAI-1 by regulating the ERK1/2 and TGF-ß/Smad2 pathways, respectively. In addition, we found that FGF-21 inhibits the expression of inflammatory factors in thrombosis by regulating the NF-κB pathway.

Therapeutic effect and mechanism of combined use of FGF21 and insulin on diabetic nephropathy.

Although FGF21 ameliorates diabetic nephropathy (DN), the efficacy is not satisfactory. Studies demonstrate that FGF21 combined with Insulin exhibits reciprocal sensitization on glucose and lipid metabolism in mice with type 2 diabetes. However, therapeutic effect of combined use of FGF21 and Insulin on DN has not been reported. Therefore, this study explored therapeutic effect and mechanism of combined use of FGF21 and Insulin on DN. Our results showed that compared with Insulin or FGF21 alone, FGF21 combined with Insulin further ameliorated blood glucose, HbAlc, OGTT, renal function, liver function, blood lipid, histopathological changes, oxidative stress and AGEs in the mice of DN (BKS-Leprem2Cd479/Gpt). Moreover, FGF21 combined with Insulin further reduced expressions of IL-1ß, IL-6, TNF-α via promoting M1 type macrophage into M2 type macrophage. Results of real-time PCR and Western blot showed that FGF21 combined with Insulin upregulated the expressions of autophagy related genes LC3-Ⅱ and BCL-1. Mesangial cells play an important role in the pathological changes of DN mice. However, the effect of FGF21 on mesangial cells has not been reported. In this study, d-glucose was used in high glucose (HG) model in mesangial cells. The results showed that FGF21 significantly reduced the levels of OS, AGEs and cell overproliferation. Meanwhile, FGF21 significantly ameliorated autophagy level via upregulating the phosphorylation of AMPK and downregulating phosphorylation of mTOR. These effects were reversed in siRNA-ß-klotho transfected mesangial cells. In conclusion, our results demonstrate that combination FGF21 with Insulin exhibits a better therapeutic effect on DN compared with FGF21 or Insulin alone. This study provides a theoretical basis for combined used of FGF21 and Insulin as a new treatment for DN and further provides theoretical support for application of FGF21 in treatment of DN.

Enhanced mechanism of extracellular electron transfer between semiconducting minerals anatase and Pseudomonas aeruginosa PAO1 in euphotic zone.

Focusing the marine euphotic zone, which is the pivotal region for interaction of solar light-mineral-microorganism and the elements cycle, we have conducted the research on the mechanism of semiconducting minerals promoting extracellular electron transfer with microorganisms in depth. Therein, anatase which is one of the most representative semiconducting minerals in marine euphotic zone was selected. The mineralogical characterization of anatase was identified by ESEM, AFM, EDS, Raman, XRD, and its semiconducting characteristics was determined by UV-Vis and Mott-Schottky plots. Determined by the electrochemical measurement of I-t curves, the photocurrent density of anatase was more prominent than dark current density. Pseudomonas aeruginosa PAO1 was widely distributed in the euphotic zone, and its mutants of operons deficient in biosynthesis pyocyanin (Δphz1Δphz2) and pili deficient (ΔpilA) were employed in this study. I-t curves indicated that both direct and indirect extracellular electron transfer processes occurred between anatase and PAO1. The indirect electron transfer depending on pyocyanin secreted by PAO1 was the main electron transfer mode. This work demonstrated the light-driven extracellular electron transfer and further revealed the photo-catalyzed mechanisms between anatase and PAO1 in marine euphotic zone.

FGF21 alleviates chronic inflammatory injury in the aging process through modulating polarization of macrophages.

Previous studies reported that FGF21 prolongs life span and delays the body senescence, but the mechanism is not clear. The present study was designed to investigate the effects of FGF21 on hepatic senescence in aging mice and further research the mechanism. The 14-month-old male mice were administered with PBS, FGF21 or metformin once daily for 6 months. Results showed that FGF21 alleviated liver injury and inhibited accumulation of senescence markers SASP, P53 and P16 in the livers of aging mice. Subsequently we found that the aging mice treated by FGF21 showed transition of type 1 macrophages (M1) to type 2 macrophages (M2) in the livers. Next, we used THP-1 macrophages triggered by LPS to study effects of FGF21 on macrophages. Macrophages triggered by LPS exhibited features of M1, but the addition of FGF21 decreased the expression of M1 markers, and promoted the macrophages to exhibit features of M2. Results showed that the effects of FGF21 on macrophages were associated with the AMPK pathway. After adding AMPK inhibitor, the effects of FGF21 were inhibited, which was associated with the NF-κB signaling pathway. Finally, co-culturing differentiated macrophages and hepatocytes, we found that the large amount of pro-inflammatory factors such as IL-6 promoted hepatocyte senescence, which exhibited enhanced P53, P16 and ß-galactosidase. This was contrary to hepatocytes co-cultured with macrophages treated by FGF21. These results indicate that FGF21 alleviates hepatic senescence injury by modulating the polarization of macrophages through the AMPK /NF-κB signaling pathway.

An immuno-blocking agent targeting IL-1ß and IL-17A reduces the lesion of DSS-induced ulcerative colitis in mice.

In recent decades when biological agents have flourished, a part of patients suffering from inflammatory bowel disease (IBD) have received the treatment of tumor necrosis factor inhibitors or IL-1 antibodies. This study aims to investigate the anti-colitis effects of bispecific antibody (FL-BsAb1/17) targeting IL-1ß and IL-17A comparing with TNF-α soluble receptor medicine etanercept. IBD model in mice was established by drinking 3% DSS (dextran sulfate sodium salt). On the first day of drinking DSS, treatments with etanercept (5 mg/kg) or different doses of FL-BsAb1/17 (1 mg/kg, 5 mg/kg, and 10 mg/kg) were started by intraperitoneal injection every other day. The results demonstrated that FL-BsAb1/17 treatment was more effective than etanercept at the same dose (5 mg/kg) in relieving the typical symptom of ulcerative colitis induced by DSS (such as the severity score and intestinal shortening), and down-regulating the expression of inflammatory factors (IL-17A, IL-6, IL-12, IL-22, IL-1ß, IL-23, TNF-α) in the serum and colon. FL-BsAb1/17 could also reduce the degree of intestinal fibrosis. The same dose of FL-BsAb1/17 (5 mg/kg) performed better than etanercept in down-regulating MDA and up-regulating SOD (superoxide dismutase), CAT (catalase), and T-AOC (total antioxidant capacity) in serum. Both FL-BsAb1/17 and etanercept could reduce the transcription of Bax and increase the transcription of Bcl-2 and slow down apoptosis in colitis colon tissue. We conclude that the blocking of IL-1ß and IL-17A can inhibit DSS-induced ulcerative colitis and FL-BsAb1/17 may have potential to become a new dual-target candidate for colitis treatment.

Development and evaluation of a recombinant VP2 neutralizing epitope antigen vaccine candidate for infectious bursal disease virus.

Infectious bursal disease (IBD) is one of the most economically important infectious diseases. Currently, vaccination is the most effective method to prevent IBD. Medium-virulence vaccines can damage the bursa of Fabricius and result in immunosuppression. Therefore, it is essential to develop a safe and effective vaccine against infectious bursal disease virus (IBDV). In this study, the five neutralizing epitopes of the IBDV VP2 protein were confirmed by neutralizing single chain variable fragment antibodies. Then, the neutralizing epitopes antigen (NEA) protein was constructed with five neutralizing epitopes and expressed by pET-27b. Furthermore, the immune effect and protective immunity of the NEA protein with the following adjuvants were evaluated in specific-pathogen-free chickens: oil emulsion adjuvant (OEA), double emulsion adjuvant (DEA), granulocyte-macrophage colony-stimulating factor (GM-CSF) adjuvant and complete Freund's adjuvant (CFA). The experimental results demonstrated that chickens immunized with NEA vaccines elicited stronger humoral and/or cellular immune responses and inflammatory responses than those in the NEA protein group. Chickens were protected in OEA, CFA and GM-CSF adjuvant groups, which were challenged with virulent IBDV BC6/85. Furthermore, IBDV RNA was not measured, and there appeared to be little apoptosis in the bursa of Fabricius based on TUNEL histology and the expression of Bax and Bcl-2 in the OEA, CFA and GM-CSF adjuvant groups. Based on the experimental results, the advantages and disadvantages of adjuvants and industrial production methods, GM-CSF was found to be the optimal adjuvant. Therefore, NEA with GM-CSF adjuvant is a promising vaccine candidate against IBDV, and it provides a framework for developing other vaccines against infectious viral diseases.

Optimization of oncolytic effect of Newcastle disease virus Clone30 by selecting sensitive tumor host and constructing more oncolytic viruses.

The direct oncolytic effect of Newcastle disease virus (NDV) depends on the following two aspects: the susceptibility of cancer cells to virus infection and the ability of virus itself to lyse cancer cells. First, we investigate the susceptibility of cancer cells to NDV infection, HepG2, MDA-MB-231, and SH-SY5Y cells were susceptible, A549, MCF7, and LoVo cells were less susceptible. To investigate the molecular mechanism responsible for cancer cell susceptibility, transcriptome sequencing was carried out. We found that the levels of alpha-sialic acid acyltransferase were upregulated in MDA-MB-231 cells compared with MCF7 cells, and the interferon was downregulated. Second, to optimize the oncolytic capacity of the wild-type rClone30, a series of chimeric viruses rClone30-Anh(HN), rClone30-Anh(F), and rClone30-Anh(HN-F) were constructed by exchanging the HN gene, F gene or both of non-lytic rClone30 strain with lytic strain Anhinga. rClone30-Anh(F) and rClone30-Anh(HN-F) enhanced the oncolytic effect of the rClone30, and this enhancement is more obvious in the susceptible cells. The oncolytic mechanism of rClone30-Anh(F) was analyzed by transcriptome analyses, in comparison with rClone30, rClone30-Anh(F) upregulated the expression of ATG5, Beclin 1, and MAP1LC3B, thus activating autophagy and promoting the production of syncytia. In conclusion, our study provides a strategy to enhance the oncolytic effect of rClone30.