Publications by authors named "Fei Mo"

68 Publications

Apigenin inhibits the growth of colorectal cancer through down-regulation of E2F1/3 by miRNA-215-5p.

Phytomedicine 2021 Aug 24;89:153603. Epub 2021 May 24.

West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address:

Background: Apigenin (API) is a naturally occurring plant-derived flavone, which is abundantly present in common fruits and vegetables, and shows little or no toxicity of daily diet. The treatment of colorectal cancer is limited by high recurrence rate and multidrug resistance.

Purpose: The purpose of this study was to explore the potential therapeutic effect and possible mechanisms of API on colorectal cancer cells.

Methods: Cell proliferation and apoptosis of human colon cancer cell line HCT116 was assessed after API treatment. A comprehensive transcriptome profile of API-treated HCT116 cells was acquired by high-throughput sequencing. The regulation of miRNA215-5p and E2F1/3 were identified by bioinformatics analyses. An inhibitor of miRNA215-5p, inhibitor 215, was applied to confirm the role of this microRNA played in the anti-cancer effect of API. Luciferase reporter gene assay was performed to identify targeting relationship between miRNA215-5p and E2F1/3.

Result: API significantly promoted cell apoptosis and anti-proliferation of HCT116 cells in a dose-dependent manner. Bioinformatics analyses identified several altered miRNAs among which the expression of miRNA-215-5p showed markedly increased. Meanwhile, the expression of E2F1 and E2F3 was decreased by API, which was associated with miRNA215-5p. Luciferase reporter gene assay showed miRNA-215-5p could directly bind to 3' UTR of E2F1/3. Inhibition of miRNA-215-5p significantly inhibited apoptosis and cell cycle arrest at G0/G1 phase induced by API.

Conclusions: The result of this study confirmed the anti-cancer effect of API on human colorectal cancer cells and investigated the underlying mechanism by a comprehensive transcriptome profile of API-treated cells.
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http://dx.doi.org/10.1016/j.phymed.2021.153603DOI Listing
August 2021

Mechanism underlying Polygonum capitatum effect on Helicobacter pylori-associated gastritis based on network pharmacology.

Bioorg Chem 2021 Jun 5;114:105044. Epub 2021 Jun 5.

Department of Basic Clinical Laboratory Medicine, School of Clinical Laboratory Science, Guizhou Medical University, No. 9 Beijing Road, Yunyan District, Guiyang 550004, China; Department of Clinical Laboratory, Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang 550004, China. Electronic address:

Helicobacter pylori (H. pylori) infection is a common disease that can cause H. pylori-associated gastritis (HAG), peptic ulcers, and gastric cancer. As a traditional Chinese medicine, Polygonum capitatum (PC) manifests its unique advantages in the prevention and treatment of complex diseases and chronic diseases, due to its ability to clear heat, detoxify and relieve pain, promote blood circulation, and remove blood stasis. In order to explore the molecular mechanism of PC for HAG, the study collected the predicted targets of active compounds, conducted functional analysis by the STRING database, collected HAG differential expression genes, and conducted KEGG enrichment analysis on the intersection of predicted targets and differential expression genes of gastritis by Cluego. The results show that PC works mainly by affecting phosphorylation of IκBα, NF-κB p65, p38MAPK, and ERK1/2 and nuclear transposition of NF-κB p65 and p-p38MAPK, which has been proved by in vivo and in vitro experiments. These results suggest that PC may act on HAG with multiple targets and pathways, and play a key role in the process of HAG treatment.
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http://dx.doi.org/10.1016/j.bioorg.2021.105044DOI Listing
June 2021

Polyethylene film mulching enhances the microbial carbon-use efficiency, physical and chemical protection of straw-derived carbon in an Entisol of the Loess Plateau.

Sci Total Environ 2021 Jun 17;792:148357. Epub 2021 Jun 17.

State Key Laboratory of Grassland Agro-Ecosystems, School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, PR China.

The global use of agricultural polyethylene mulches has emerged as a widespread farming practice, however, its effects on the fate and dynamics of crop straw-derived C in soil microbial biomass C (MBC), aggregate-associated and chemical recalcitrance-related C fractions are rarely assessed in situ. A two-year field experiment using C-labeled maize stem was carried out to quantify the allocation and dynamics of straw-C in an Entisol with and without plastic mulching. The results indicated that across the treatments, from 49.2% to 56.4% of straw-C was released as CO-C, from 34.9% to 43.1% was sequestrated as SOC pool, and from 6.7% to 9.7% remained undecomposed at the end of the experiment. Compared to non-mulching, plastic mulching significantly decreased the straw-derived CO-C emissions by 14.6%, partially owing to the increased incorporation of straw-C into SOC pool. Across the treatments, the straw-derived MBC ranged from 14.4 to 147.9 mg C kg; and plastic mulching increased straw-derived MBC and microbial C use efficiency (CUE) of straw residue by 41.2% and 35.2% compared with non-mulching, respectively. The allocation dynamics of straw-C in each soil aggregate followed a sustained upward trend with time, while a significantly higher straw-C was incorporated into both macro- (> 0.25 mm) and micro-aggregates (0.25-0.053 mm) with plastic mulching. Compared to the non-mulching, plastic mulching enhanced the inclusion of straw-C in the chimerically more stable C fraction, especially at the late experimental period. We conclude that crop straw return combined with plastic mulching could improve SOC sequestration by enhancing microbial CUE, physical and chemical protection of straw-derived C in this dryland cropping system.
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http://dx.doi.org/10.1016/j.scitotenv.2021.148357DOI Listing
June 2021

Antitumor and Radiosensitization Effects of a CXCR2 Inhibitor in Nasopharyngeal Carcinoma.

Front Cell Dev Biol 2021 26;9:689613. Epub 2021 May 26.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

CXCR2, a member of the G-protein-coupled cell surface chemokine receptor family, is commonly found on leukocytes, endothelial cells and tumor cells including nasopharyngeal carcinoma cells. However, how the activity of CXCR2 and its ligand CXCL8 affects the development of nasopharyngeal carcinoma (NPC) remains unknown. Here, we found that CXCR2 and CXCL8 were both predicted poor prognosis in NPC patients. Furthermore, we identified that treatment with CXCR2 antagonist SB225002 of nasopharyngeal carcinoma cell lines resulted tumorigenesis inhibition and . In addition, we found that SB225002 could enhance NPC cells radiosensitivity through regulating cell circle distribution and interfering with cellular DNA damage repair. SB225002 also exhibited an efficient radiosensitization effect in C666-1 and HONE-1 bearing mice. Functionally, we showed that SB225002 reduced microvessel density and proliferation and induced tumor apoptosis. Furthermore, changes in the tumor microenvironment were also observed in this study. We observed that SB225002 reduced tumor-associated neutrophils (TANs) in the tumors tissue which were recruited especially after irradiation. Taken together, our results suggested that targeting the CXCL8-CXCR2 pathway is a promising therapeutic strategy for comprehensive NPC treatment.
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http://dx.doi.org/10.3389/fcell.2021.689613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188356PMC
May 2021

Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist.

Elife 2021 May 18;10. Epub 2021 May 18.

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States.

Interleukin-2 is a pleiotropic cytokine that mediates both pro- and anti-inflammatory functions. Immune cells naturally differ in their sensitivity to IL-2 due to cell type and activation state-dependent expression of receptors and signaling pathway components. To probe differences in IL-2 signaling across cell types, we used structure-based design to create and profile a series of IL-2 variants with the capacity to titrate maximum signal strength in fine increments. One of these partial agonists, IL-2-REH, specifically expanded Foxp3+ regulatory T cells with reduced activity on CD8+ T cells due to cell type-intrinsic differences in IL-2 signaling. IL-2-REH elicited cell type-dependent differences in gene expression and provided mixed therapeutic results: showing benefit in the in vivo mouse dextran sulfate sodium (DSS) model of colitis, but no therapeutic efficacy in a transfer colitis model. Our findings show that cytokine partial agonists can be used to calibrate intrinsic differences in response thresholds across responding cell types to narrow pleiotropic actions, which may be generalizable to other cytokine and growth factor systems.
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http://dx.doi.org/10.7554/eLife.65777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131104PMC
May 2021

Targeting CXCR2 inhibits the progression of lung cancer and promotes therapeutic effect of cisplatin.

Mol Cancer 2021 04 4;20(1):62. Epub 2021 Apr 4.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.

Background: Drug-resistance and severe side effects of chemotherapeutic agents result in unsatisfied survival of patients with lung cancer. CXCLs/CXCR2 axis plays an important role in progression of cancer including lung cancer. However, the specific anti-cancer mechanism of targeting CXCR2 remains unclear.

Methods: Immunohistochemical analysis of CXCR2 was performed on the microarray of tumor tissues of clinical lung adenocarcinoma and lung squamous cell carcinoma patients. CCK8 test, TUNEL immunofluorescence staining, PI-Annexin V staining, β-galactosidase staining, and Western blot were used to verify the role of CXCR2 in vitro. Animal models of tail vein and subcutaneous injection were applied to investigate the therapeutic role of targeting CXCR2. Flow cytometry, qRT-PCR, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry analysis were performed for further mechanistic investigation.

Results: The expression of CXCR2 was elevated in both human lung cancer stroma and tumor cells, which was associated with patients' prognosis. Inhibition of CXCR2 promoted apoptosis, senescence, epithelial-to-mesenchymal transition (EMT), and anti-proliferation of lung cancer cells. In vivo study showed that tumor-associated neutrophils (TANs) were significantly infiltrate into tumor tissues of mouse model, with up-regulated CXCLs/CXCR2 signaling and suppressive molecules, including Arg-1 and TGF-β. SB225002, a selective inhibitor of CXCR2 showed promising therapeutic effect, and significantly reduced infiltration of neutrophils and enhanced anti-tumor T cell activity via promoting CD8 T cell activation. Meanwhile, blockade of CXCR2 could enhance therapeutic effect of cisplatin via regulation of neutrophils infiltration.

Conclusions: Our finds verify the therapeutic effects of targeting CXCR2 in lung cancer and uncover the potential mechanism for the increased sensitivity to chemotherapeutic agents by antagonists of CXCR2.
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http://dx.doi.org/10.1186/s12943-021-01355-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019513PMC
April 2021

Dasatinib loaded nanostructured lipid carriers for effective treatment of corneal neovascularization.

Biomater Sci 2021 Apr 16;9(7):2571-2583. Epub 2021 Feb 16.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, P. R. China.

Corneal neovascularization (CNV) is one of the most important causes of visual impairment worldwide. Dasatinib, a poorly water-soluble tyrosine kinase inhibitor with dual Src family kinase and platelet derived growth factor receptor inhibiting capability, has great potential in the treatment of CNV. In this study, dasatinib was successfully encapsulated into a nanostructured lipid carrier (Dasa-NLC) and the size was approximately 78 nm with a small polydispersity index. The NLC increased the solubility of dasatinib by more than 1220 times, sustained the drug release, reduced the ocular toxicity and facilitated its penetration into the cornea. Dasa-NLC significantly inhibited the proliferation, migration and tube formation of HUVEC cells, the three most important angiogenesis-related cellular changes of the CNV. Next, the in vivo anti-CNV effect of Dasa-NLC was evaluated using an alkaline burned mice CNV model, in which the development of the CNV and pathological changes of the cornea were significantly inhibited. The immunohistochemistry analysis indicated that Dasa-NLC could inhibit both the expression and activation of Src family kinase, a key component in the angiogenesis cascade. Therefore, Dasa-NLC showed considerable promise in the treatment of CNV.
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http://dx.doi.org/10.1039/d0bm01599gDOI Listing
April 2021

Curcumin-Induced Global Profiling of Transcriptomes in Small Cell Lung Cancer Cells.

Front Cell Dev Biol 2020 12;8:588299. Epub 2021 Jan 12.

Department of Biotherapy, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.

Background: Curcumin, one of the promising candidates for supplementary therapy in cancer treatment, has been demonstrated by numerous preclinical and clinical evidence to be beneficial in treating various cancers. Apart from the critical role in a deluge of pathological processes, some mRNAs, in particular, microRNAs (miRNAs), are also involved in the anti-tumor activity. Therefore, our research focused on the possible effects of curcumin on small cell lung cancer (SCLC) cells and drew a comprehensive transcriptomes profile by high throughput sequencing to understand the molecular mechanism of curcumin as an anti-tumor agent.

Methods: First, we calculated the apoptosis rate of H446 cells (a human SCLC cell line) cultured with curcumin. The high output sequencing uncovered the altered expression profile of genes and miRNAs. KEGG analysis selected the potential signal pathway associated with the antiproliferative property of curcumin. Finally, miRNAs significantly changed, as well as the regulatory roles of those miRNAs in cell apoptosis were determined.

Result: The apoptosis rate of H446 cells increased under the elevated concentration of curcumin treatment. And cell cycle-related genes downregulated in the curcumin-treated cells. Besides, miRNA-548ah-5p of a high level acted as a negative role in the anticarcinogenic activity of curcumin.

Conclusion: Our findings not only enriched the understanding of anti-tumor activity initiated by curcumin through figuring out the downregulated cell cycle-related pathways but also shed light on its novel therapeutic application.
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http://dx.doi.org/10.3389/fcell.2020.588299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835540PMC
January 2021

Publisher Correction: A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity.

Nature 2021 Feb;590(7844):E23

Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.1038/s41586-020-03108-4DOI Listing
February 2021

RssB-mediated σ Activation is Regulated by a Two-Tier Mechanism via Phosphorylation and Adaptor Protein - IraD.

J Mol Biol 2021 02 18;433(3):166757. Epub 2020 Dec 18.

BioBank, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi 710061, China; Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, SW7 2AZ London, United Kingdom; Instrument Analysis Center of Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China. Electronic address:

Regulation of bacterial stress responding σ is a sophisticated process and mediated by multiple interacting partners. Controlled proteolysis of σ is regulated by RssB which maintains minimal level of σ during exponential growth but then elevates σ level while facing stresses. Bacteria developed different strategies to regulate activity of RssB, including phosphorylation of itself and production of anti-adaptors. However, the function of phosphorylation is controversial and the mechanism of anti-adaptors preventing RssB-σ interaction remains elusive. Here, we demonstrated the impact of phosphorylation on the activity of RssB and built the RssB-σ complex model. Importantly, we showed that the phosphorylation site - D58 is at the interface of RssB-σ complex. Hence, mutation or phosphorylation of D58 would weaken the interaction of RssB with σ. We found that the anti-adaptor protein IraD has higher affinity than σ to RssB and its binding interface on RssB overlaps with that for σ. And IraD-RssB complex is preferred over RssB-σ in solution, regardless of the phosphorylation state of RssB. Our study suggests that RssB possesses a two-tier mechanism for regulating σ. First, phosphorylation of RssB provides a moderate and reversible tempering of its activity, followed by a specific and robust inhibition via the anti-adaptor interaction.
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http://dx.doi.org/10.1016/j.jmb.2020.166757DOI Listing
February 2021

Publisher Correction: Heat stress activates YAP/TAZ to induce the heat shock transcriptome.

Nat Cell Biol 2021 Feb;23(2):209

Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.

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http://dx.doi.org/10.1038/s41556-020-00623-4DOI Listing
February 2021

Heat stress activates YAP/TAZ to induce the heat shock transcriptome.

Nat Cell Biol 2020 12 16;22(12):1447-1459. Epub 2020 Nov 16.

Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.

The Hippo pathway plays critical roles in cell growth, differentiation, organ development and tissue homeostasis, whereas its dysregulation can lead to tumorigenesis. YAP and TAZ are transcription co-activators and represent the main downstream effectors of the Hippo pathway. Here, we show that heat stress induces a strong and rapid YAP dephosphorylation and activation. The effect of heat shock on YAP is dominant to other signals known to modulate the Hippo pathway. Heat shock inhibits LATS kinase by promoting HSP90-dependent LATS interaction with and inactivation by protein phosphatase 5. Heat shock also induces LATS ubiquitination and degradation. YAP and TAZ are crucial for cellular heat shock responses, including the heat shock transcriptome and cell viability. This study uncovers previously unknown mechanisms of Hippo regulation by heat shock, as well as physiological functions of YAP, in the heat stress response. Our observations also reveal a potential combinational therapy involving hyperthermia and targeting of the Hippo pathway.
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http://dx.doi.org/10.1038/s41556-020-00602-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757600PMC
December 2020

Development and evaluation of a serological test for diagnosis of COVID-19 with selected recombinant spike proteins.

Eur J Clin Microbiol Infect Dis 2021 May 12;40(5):921-928. Epub 2020 Nov 12.

State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People's Republic of China.

Serological test is a valuable diagnostic tool for coronavirus disease 2019 (COVID-19). However, considerable improvements to these tests are needed, especially in the detection sensitivity. In this study, six recombinant nucleocapsid and spike proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were prepared and evaluated, including three prokaryotic expression nucleocapsid proteins (rN, rN1, rN2) and three eukaryotic expression spike proteins (rS1, rS-RBD, rS-RBD-mFc). The recombinant proteins with the highest ELISA titers (rS1 and rS-RBD-mFc) were selected to develop a double-antigen sandwich colloidal gold immunochromatography assay (GICA) to detect total antibodies against SARS-CoV-2. The clinical evaluation results showed that the sensitivity and specificity of GICA were 92.09% (419/455) and 99.44% (706/710), respectively. Moreover, a significant number (65.63%, 21/32) of COVID-19 patients with undetectable viral RNA were correctly diagnosed by the GICA method. In conclusion, the eukaryotic expression spike proteins (rS1 and rS-RBD-mFc) are more suitable than the prokaryotic expression nucleocapsid proteins for serological diagnosis of SARS-CoV-2. The proposed GICA for detection of total antibodies could be a powerful complement to the current RNA tests for COVID-19.
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http://dx.doi.org/10.1007/s10096-020-04102-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661101PMC
May 2021

Ridge-furrow with grass straw mulching farming system to boost rainfed wheat productivity and water use efficiency in semiarid Kenya.

J Sci Food Agric 2021 May 4;101(7):3030-3040. Epub 2020 Dec 4.

State Key Laboratory of Grassland Agro-Ecosystems, Institute of Arid Agroecology, School of Life Sciences, Lanzhou University, Lanzhou, China.

Background: Ridge-furrow mulching farming systems (RFMs) aim to increase field productivity and improve water use efficiency. To explore environment-friendly and efficient farming systems is a central aspect of rainfed wheat field management in Kenya where rainfall utilization is at a low level. We introduced RFMs (including plastic film and grass straw mulching) to semiarid Kenya to evaluate the effects on field productivity, rainwater utilization, soil quality and economic profitability using old and modern wheat cultivars from 2012 to 2013.

Results: Across the cultivars, the RFMs increased grain yield, aboveground biomass and water use efficiency by 74-163%, 36-104% and 89-273%, respectively, compared with conventional flat planting (control). RFMs significantly shortened the vegetative period while prolonging the reproductive period. The net economic output under RFMs was 74-165% higher than that of the control. Grass straw mulching achieved the highest economic output to input ratio, almost 45% higher than plastic film mulching, despite the former harvested only 82% of the maximum field productivity of the latter. Compared with the control, grass straw mulching promoted the contents of soil organic carbon, total nitrogen and C:N ratio by 14%, 8% and 5%, respectively, while obviously decreased values of these parameters were observed under plastic mulching.

Conclusions: Through reducing soil water loss, and improving rainwater use efficiency and soil quality, ridge-furrow grass straw mulching would be a sustainable option for boosting field productivity and thus ensuring local food security in rainfed agricultural areas of Kenya. © 2020 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.10937DOI Listing
May 2021

A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity.

Nature 2020 10 29;586(7830):572-577. Epub 2020 Jul 29.

Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.
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http://dx.doi.org/10.1038/s41586-020-2599-8DOI Listing
October 2020

In vitro and in vivo effects of the combination of myricetin and miconazole nitrate incorporated to thermosensitive hydrogels, on C. albicans biofilms.

Phytomedicine 2020 Jun 12;71:153223. Epub 2020 May 12.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, P. R. China. Electronic address:

Background: Candida albicans-related infections are common infections in clinic, among which biofilm-associated infections are most devastating and challenging to overcome. Myricetin (MY) is a plant-derived natural product with various pharmacological activities. Its anti-biofilm effect against C. albicans and its ability to increase the antifungal effect of miconazole nitrate (MN) were unclear and yet need to be explored.

Hypothesis/purpose: In this study the anti-biofilm effect of MY and its ability to increase the antifungal effect of MN were investigated in vitro and in vivo.

Study Design And Methods: MY or/and MN were incorporated into a thermosensitive hydrogel (TSH) of poloxamer. The safety of MY or/and MN loaded TSHs towards human umbilical vein endothelial cells (HUVEC) was evaluated by a MTT assay and the in vivo safety towards mice knees was confirmed by histopathological examination. The anti-biofilm effect of MY and its ability to increase the antifungal effect of MN were investigated in vitro with C. albicans ATCC 10231 by broth microdilution method, crystal violet staining and scanning electron microscopy (SEM), as well as in vivo in an established mouse model of periprosthetic joint infection (PJI) by SEM, histological analysis, microorganism culture and detection of the serum levels of interleukin-6 (IL-6). The mechanism of action of MY was analyzed by qRT-PCR assay with C. albicans SC5314.

Results: Our results showed that MY and MN incorporated into TSHs exhibited good stability and safety, excellent temperature sensitivity and controlled drug release property. MY (5-640 µg/ml) exhibited no effect on C. albicans cell viability and MY (≥80 µg/ml) showed a significantly inhibitory effect on biofilm formation. MIC (the lowest concentrations of drugs resulting in 50% decrease of C. albicans growth) and MIC (the lowest concentrations of drugs resulting in 80% decrease of C. albicans growth) of MN were respectively decreased from 2 µg/ml to 0.5 µg/ml and from 4 µg/ml to 2 µg/ml when used in combination with MY (80 µg/ml). The mouse PJI was effectively prevented by MY and MN incorporated into TSH.

Conclusions: Local application of MY and MN incorporated into TSH might be useful for clinical biofilm-associated infections.
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http://dx.doi.org/10.1016/j.phymed.2020.153223DOI Listing
June 2020

Integrated Analysis of mRNA-seq and miRNA-seq to Identify c-MYC, YAP1 and miR-3960 as Major Players in the Anticancer Effects of Caffeic Acid Phenethyl Ester in Human Small Cell Lung Cancer Cell Line.

Curr Gene Ther 2020 ;20(1):15-24

Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China.

Background: Caffeic Acid Phenethyl Ester (CAPE), an active extract of propolis, has recently been reported to have broad applications in various cancers. However, the effects of CAPE on Small Cell Lung Cancer (SCLC) are largely unknown. Therefore, the aim of this study was to determine the anti-proliferative effect of CAPE and explore the underlying molecular mechanisms in SCLC cells using high-throughput sequencing and bioinformatics analysis.

Methods: Small-cell lung cancer H446 cells were treated with CAPE, and cell proliferation and apoptosis were then assessed. Additionally, the regulation mediated by miR-3960 after CAPE treatment was explored and the altered signaling pathways were predicted in a bioinformatics analysis.

Results: CAPE significantly inhibited cell proliferation and induced apoptosis. CAPE decreased the expression of Yes-Associated Protein 1 (YAP1) and cellular myelocytomatosis oncogene (c-MYC) protein. Moreover, the upregulation of miR-3960 by CAPE contributed to CAPE-induced apoptosis. The knockdown of miR-3960 decreased the CAPE-induced apoptosis.

Conclusion: We demonstrated the anti-cancer effect of CAPE in human SCLC cells and studied the mechanism by acquiring a comprehensive transcriptome profile of CAPE-treated cells.
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http://dx.doi.org/10.2174/1566523220666200523165159DOI Listing
July 2021

Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism.

Front Cell Dev Biol 2020 28;8:246. Epub 2020 Apr 28.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.

NAD+, a co-enzyme involved in a great deal of biochemical reactions, has been found to be a network node of diverse biological processes. In mammalian cells, NAD+ is synthetized, predominantly through NMN, to replenish the consumption by NADase participating in physiologic processes including DNA repair, metabolism, and cell death. Correspondingly, aberrant NAD+ metabolism is observed in many diseases. In this review, we discuss how the homeostasis of NAD+ is maintained in healthy condition and provide several age-related pathological examples related with NAD+ unbalance. The sirtuins family, whose functions are NAD-dependent, is also reviewed. Administration of NMN surprisingly demonstrated amelioration of the pathological conditions in some age-related disease mouse models. Further clinical trials have been launched to investigate the safety and benefits of NMN. The NAD+ production and consumption pathways including NMN are essential for more precise understanding and therapy of age-related pathological processes such as diabetes, ischemia-reperfusion injury, heart failure, Alzheimer's disease, and retinal degeneration.
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http://dx.doi.org/10.3389/fcell.2020.00246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198709PMC
April 2020

Oxidized mitochondrial DNA sensing by STING signaling promotes the antitumor effect of an irradiated immunogenic cancer cell vaccine.

Cell Mol Immunol 2020 May 12. Epub 2020 May 12.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, 610041, Chengdu, P.R. China.

Exposure to ionizing radiation, a physical treatment that inactivates live tumor cells, has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials. However, the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored. Here, we demonstrate that oxidized mitochondrial DNA (mtDNA) and stimulator of interferon genes (STING) signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine. Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells. Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells (DCs). Oxidized mtDNA, as a DAMP or adjuvant, activated the STING-TBK1-IRF3-IFN-β pathway in DCs, which subsequently cross-presented irradiated tumor cell-derived antigens to CD8 T cells and elicited antitumor immunity. The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity, which may have implications for new strategies to improve the efficacy of irradiated vaccines.
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http://dx.doi.org/10.1038/s41423-020-0456-1DOI Listing
May 2020

Silver nanoparticles and silver ions cause inflammatory response through induction of cell necrosis and the release of mitochondria in vivo and in vitro.

Cell Biol Toxicol 2021 04 4;37(2):177-191. Epub 2020 May 4.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.

Owing to the excellent antibacterial and antiviral activity, silver nanoparticles have a widespread use in the food and pharmaceutical industries. With the increase in the production and use of the related products, the potential hazard of silver nanoparticles has aroused public attention. The main purpose of this study is to explore the toxicity of silver nanoparticles and induction of lung inflammation in vitro and in vivo. Here, we validated that small amounts of silver ions dissolved from silver nanoparticles caused the depolarization of plasma membrane, resulting in an overload of intracellular sodium and calcium, and eventually led to the cell necrosis. The blockers of calcium or sodium channels inversed the toxicity of silver ions. Then, we instilled silver nanoparticles or silver nitrate (50 μg per mouse) into the lungs of mice, and this induced pulmonary injury and mitochondrial content release, led to the recruitment of neutrophils to the lung tissue via p38 MAPK pathway. Altogether, these data show that released silver ions from nanoparticles induced cell necrosis through Na and Ca influx and triggered pulmonary inflammation through elevating mitochondrial-related contents released from these necrotic cells.
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http://dx.doi.org/10.1007/s10565-020-09526-4DOI Listing
April 2021

Carbon black nanoparticles induce cell necrosis through lysosomal membrane permeabilization and cause subsequent inflammatory response.

Theranostics 2020 15;10(10):4589-4605. Epub 2020 Mar 15.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, PR China.

: The adverse health effects of nano-particulate pollutants have attracted much attention in recent years. Carbon nanomaterials are recognized as risk factors for prolonged inflammatory responses and diffuse alveolar injury. Previous research indicated a central role of alveolar macrophages in the pathogenesis of particle-related lung disease, but the underlying mechanism remains largely unknown. : C57BL/6 mice were intratracheally instilled with carbon black nanoparticles (CBNPs). Cell necrosis and the infiltrated neutrophils in the lungs were detected by flow cytometry. Release of mitochondria was observed with Mito Tracker and mitochondrial DNA (mtDNA) was quantified by qPCR via Taqman probes. TLR9-p38 MAPK signaling pathway was detected by Western blotting. The production of lipid chemoattractant leukotriene B4 (LTB4) in the supernatant and bronchoalveolar lavage fluid (BALF) was quantitated using an enzyme immunoassay (EIA). : In the present study, we found that a single instillation of CBNPs induced neutrophil influx in C57BL/6 mice as early as 4 h post-exposure following the rapid appearance of cell damage indicators in BALF at 30 min. Macrophages exposed to CBNPs showed necrotic features and were characterized by lysosome rupture, cathepsin B release, reactive oxygen species generation, and reduced intracellular ATP level. Necrosis was partly inhibited by a specific lysosomal cathepsin B inhibitor CA074 Me. Further analyses suggested that the resulting leakage of mtDNA from the necrotic cells activated neutrophils and triggered severe inflammation . Pulmonary neutrophilic inflammation induced by mtDNA was reduced in TLR9 mice. Additionally, mtDNA induced LTB4 production from macrophages, which may contribute to neutrophil recruitment. : We demonstrated here that CBNPs induce acute cell necrosis through lysosomal rupture and that mtDNA released from necrotic cells functions as a key event mediating pulmonary neutrophilic inflammation. This study described a novel aspect of the pathogenesis of particle-induced inflammatory response and provided a possible therapeutic target for the regulation of inflammation.
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http://dx.doi.org/10.7150/thno.34065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150486PMC
April 2021

Shallow periorbital injection of triamcinolone acetonide in treatment of lower eyelid entropion related to thyroid-associated ophthalmopathy: Three case reports.

Medicine (Baltimore) 2020 Jan;99(5):e19026

Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing.

Introduction: Entropion and secondary trichiasis can lead to irritative symptoms and essential damage of ocular surface. There is no literature reporting the lower eyelid entropion related to thyroid-associated ophthalmopathy (TAO), let alone the treatment. Treatment based on etiology may yield effective and sustained results. We report 3 case reports of lower eyelid entropion associated with TAO, and provide an effective and persistent alternative to cure this entropion via the administration of shallow periorbital injections of triamcinolone acetonide (TA).

Patient Concerns: Three patients presented irritative symptoms of ocular surface and diplopia.

Diagnosis: According to thyroid dysfunction, physical examination, and imaging findings of extraocular muscle involvement, TAO and unilateral or bilateral lower eyelid entropion were diagnosed.

Interventions: We administered shallow periorbital injections of TA to the affected eye at 3- to 4-week intervals depending on clinical response.

Outcomes: All patients underwent complete correction of the lower eyelid entropion and no recurrence was found.

Conclusion: The cause of lower eyelid entropion related to TAO might be the immunoinflammatory reaction of the lower eyelid retractors, enhancing the traction of pulling the lower eyelid inferoposteriorly. This condition can be treated with shallow periorbital injections of TA. Histopathological evidence and randomized controlled trials are expected to confirm our hypothesis.
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http://dx.doi.org/10.1097/MD.0000000000019026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004750PMC
January 2020

Naringin-loaded polymeric micelles as buccal tablets: formulation, characterization, release, cytotoxicity and histopathology studies.

Pharm Dev Technol 2020 Jun 22;25(5):547-555. Epub 2020 Jan 22.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, P. R. China.

Naringin (NG) has been proved to have numerous notable biological effects, including anti-inflammatory effect, anti-cancer effect, and anti-ulcer effect, yet there are no clinical preparations of naringin due to its poor solubility and low dissolution rate after oral administration. In this study, in order to overcome these problems, NG was encapsulated into MPEG-PCL micelles (NGMs) by using a thin-film hydration method. NMGs were in a typical core-shell structure, with a mall particle size (23.95 ± 0.51 nm), high drug loading, and encapsulation efficiency. release of NGMs indicated that the dissolution of NG was increased after being encapsulated in the micelles. NGMs were nontoxic in the cytotoxicity and histopathology studies. Furthermore, when the freeze-dried NGMs were compressed into buccal tablets (NGBTs) by direct compression, the release speed of NG under simulated oral cavity condition from NGBTs was higher than the control tablets, with the accumulated dissolution at 93.13% in 8 hours. In conclusion, NGMs and NGBTs represent a promising drug delivery system for NG, which has the potential to improve the current treatment of oral diseases.
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http://dx.doi.org/10.1080/10837450.2020.1715427DOI Listing
June 2020

Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.

Signal Transduct Target Ther 2019;4:62. Epub 2019 Dec 17.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.

Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. In this review, we summarize the aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.
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http://dx.doi.org/10.1038/s41392-019-0095-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915746PMC
January 2021

Methylation of PLK1 by SET7/9 ensures accurate kinetochore-microtubule dynamics.

J Mol Cell Biol 2020 07;12(6):462-476

MOE Key Laboratory for Cellular Dynamics & Anhui Key Laboratory for Chemical Biology, CAS Center for Excellence in Molecular Cell Science, Hefei National Science Center for Physical Sciences at Microscale & University of Science and Technology of China, Hefei 230027, China.

Faithful segregation of mitotic chromosomes requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Although the mechanisms underlying PLK1 activation have been extensively studied, the regulatory mechanisms that couple PLK1 activity to accurate chromosome segregation are not well understood. In particular, PLK1 is implicated in stabilizing kinetochore-microtubule attachments, but how kinetochore PLK1 activity is regulated to avoid hyperstabilized kinetochore-microtubules in mitosis remains elusive. Here, we show that kinetochore PLK1 kinase activity is modulated by SET7/9 via lysine methylation during early mitosis. The SET7/9-elicited dimethylation occurs at the Lys191 of PLK1, which tunes down its activity by limiting ATP utilization. Overexpression of the non-methylatable PLK1 mutant or chemical inhibition of SET7/9 methyltransferase activity resulted in mitotic arrest due to destabilized kinetochore-microtubule attachments. These data suggest that kinetochore PLK1 is essential for stable kinetochore-microtubule attachments and methylation by SET7/9 promotes dynamic kinetochore-microtubule attachments for accurate error correction. Our findings define a novel homeostatic regulation at the kinetochore that integrates protein phosphorylation and methylation with accurate chromosome segregation for maintenance of genomic stability.
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http://dx.doi.org/10.1093/jmcb/mjz107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333475PMC
July 2020

A novel fluorescent biosensor based on dendritic DNA nanostructure in combination with ligase reaction for ultrasensitive detection of DNA methylation.

J Nanobiotechnology 2019 Dec 7;17(1):121. Epub 2019 Dec 7.

Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University, Chongqing, 400038, China.

Background: DNA methylation detection is indispensable for the diagnosis and prognosis of various diseases including malignancies. Hence, it is crucial to develop a simple, sensitive, and specific detection strategy.

Methods: A novel fluorescent biosensor was developed based on a simple dual signal amplification strategy using functional dendritic DNA nanostructure and signal-enriching polystyrene microbeads in combination with ligase detection reaction (LDR). Dendritic DNA self-assembled from Y-DNA and X-DNA through enzyme-free DNA catalysis of a hairpin structure, which was prevented from unwinding at high temperature by adding psoralen. Then dendritic DNA polymer labeled with fluorescent dye Cy5 was ligated with reporter probe into a conjugate. Avidin-labeled polystyrene microbeads were specifically bound to biotin-labeled capture probe, and hybridized with target sequence and dendritic DNA. LDR was triggered by adding Taq ligase. When methylated cytosine existed, the capture probe and reporter probe labeled with fluorescent dye perfectly matched the target sequence, forming a stable duplex to generate a fluorescence signal. However, after bisulfite treatment, unmethylated cytosine was converted into uracil, resulting in a single base mismatch. No fluorescence signal was detected due to the absence of duplex.

Results: The obtained dendritic DNA polymer had a large volume. This method was time-saving and low-cost. Under the optimal experimental conditions using avidin-labeled polystyrene microbeads, the fluorescence signal was amplified more obviously, and DNA methylation was quantified ultrasensitively and selectively. The detection range of this sensor was 10 to 10 M, and the limit of detection reached as low as 0.4 fM. The constructed biosensor was also successfully used to analyze actual samples.

Conclusion: This strategy has ultrasensitivity and high specificity for DNA methylation quantification, without requiring complex processes such as PCR and enzymatic digestion, which is thus of great value in tumor diagnosis and biomedical research.
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http://dx.doi.org/10.1186/s12951-019-0552-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898925PMC
December 2019

[Effects of sowing date and seeding rate on soil water consumption and plant nitrogen translocation in dryland wheat].

Ying Yong Sheng Tai Xue Bao 2019 Oct;30(10):3443-3451

CCollege of Agronomy, Northwest A&F University, Yangling 712100, Shanxi, China.

To tackle the issue of rainfall delay during dryland wheat sowing season and further examine the effects of seeding rate on water use and yield formation, a field experiment was conducted at Wenxi Experimental Station, Shanxi Province between 2015 and 2017. We used two sowing dates, i.e. September 20 and October 10 as early (EB) and late (LB) sowing in main plots, and each with three seeding rates as 67.5 (LD), 90 (MD) and 112.5(HD) kg·hm. The results showed that compared with LB, EB increased total soil water consumption by 11-22 mm over the entire growing season. With the increases of seeding density, total soil water consumption increased by 2-20 mm. Soil water consumption before anthesis tended to increase for LB, while there was a significant increase of soil water consumption after anthesis for EB. Compared with LB, the pre-anthesis nitrogen translocation and post-anthesis nitrogen accumulation amount in EB were increased under LD and MD, but decreased under HD. For EB, the pre-anthesis nitrogen translocation amount and post-anthesis nitrogen accumulation amount were highest at LD. Under LB, the pre-anthesis nitrogen translocation amount and post-anthesis nitrogen accumulation amount were greatest at high sowing density. EB significantly increased grain yield by 163-996 kg·hm than LB. EB significantly increased grain yield and water use efficiency by 5%-26% and 2%-21% compared with LB, respectively. The nitrogen absorption efficiency and harvest index were 3%-36% and 11% higher under LB than that under EB. As for seeding rate, a low level tended to gain higher grain yield, water use efficiency, nitrogen uptake efficiency and nitrogen harvest index under EB, whereas a high level tended to gain higher values of grain yield, water use efficiency, nitrogen uptake efficiency and nitrogen harvest index under LB. In addition, the pre-anthesis nitrogen translocation was closely related with 100-200 cm soil water consumption before anthesis, especially for stem + sheath, glume + spike nitrogen translocation. The post-anthesis nitrogen accumulation was significantly correlated with 100-300 cm soil water consumption after anthesis. In conclusion, early sowing with a seeding rate of 67.5 kg·hm and late sowing with a seeding rate of 112.5 kg·hm could be promising options to boost dryland wheat production.
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http://dx.doi.org/10.13287/j.1001-9332.201910.028DOI Listing
October 2019

Pretreatment Inflammatory Indexes as Prognostic Predictors of Survival in Patients Suffering From Synovial Sarcoma.

Front Oncol 2019 24;9:955. Epub 2019 Sep 24.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.

Inflammatory indexes have been considered as important prognostic factors in various types of cancers. This study aimed to evaluate prognostic values of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) in patients with synovial sarcoma (SS). One hundred and three patients diagnosed with SS were collected during 2006-2017 and divided into high or low NLR, PLR, and LMR groups based on receiver operating characteristic curve analysis. Data of clinical variables were collected for univariate and multivariate analyses. The Kaplan-Meier method was used to analyze OS and PFS of SS patients and significance was evaluated by the log-rank test. The optimal cut-off values of NLR, PLR, and LMR were 2.70, 154.99, and 4.16, respectively. Univariate analyses identified resection surgery, distant metastasis, NLR, PLR, and LMR as the potential predictors of progression-free survival (PFS) and overall survival (OS). In the multivariate analyses, NLR was independent predictors for OS (HR 5.074, 95% CI 1.200-21.463, = 0.027). Resection surgery, metastasis and LMR was independent predictors for PFS (HR 5.328, = 0.017; HR 3.114, = 0.04 and HR 0.202, = 0.025, respectively). Resection surgery, distant metastasis, NLR, and LMR were independent prognostic factors of PFS and OS in patients with synovial sarcoma. Surgery as an effective treatment strategy, other than radiotherapy and chemotherapy, can significantly prolong survival of synovial patients. Clinical utility of these inflammatory biomarkers should be validated in a larger sample size study.
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http://dx.doi.org/10.3389/fonc.2019.00955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769112PMC
September 2019

Electrochemical and Optical Biosensing Strategies for DNA Methylation Analysis.

Curr Med Chem 2020 ;27(36):6159-6187

Department of Clinical and Military Laboratory Medicine, College of Medical Laboratory Science, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China

DNA methylation is considered as a crucial part of epigenetic modifications and a popular research topic in recent decades. It usually occurs with a methyl group adding to the fifth carbon atom of cytosine while the base sequence of DNA remains unchanged. DNA methylation has significant influences on maintaining cell functions, genetic imprinting, embryonic development and tumorigenesis procedures and hence the analysis of DNA methylation is of great medical significance. With the development of analytical techniques and further research on DNA methylation, numerous DNA methylation detection strategies based on biosensing technology have been developed to fulfill various study requirements. This article reviewed the development of electrochemistry and optical biosensing analysis of DNA methylation in recent years; in addition, we also reviewed some recent advances in the detection of DNA methylation using new techniques, such as nanopore biosensors, and highlighted the key technical and biological challenges involved in these methods. We hope this paper will provide useful information for the selection and establishment of analysis of DNA methylation.
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http://dx.doi.org/10.2174/0929867326666190903161750DOI Listing
January 2021

Enhanced production of heterologous proteins via engineering the cell surface of Bacillus licheniformis.

J Ind Microbiol Biotechnol 2019 Dec 30;46(12):1745-1755. Epub 2019 Aug 30.

State Key Laboratory of Biocatalysis and Enzyme Engineering, Environmental Microbial Technology Center of Hubei Province, College of Life Sciences, Hubei University, 368 Youyi Avenue, Wuchang District, Wuhan, 430062, Hubei, People's Republic of China.

Cell surface engineering was proven as the efficient strategy for enhanced production of target metabolites. In this study, we want to improve the yield of target protein by engineering cell surface in Bacillus licheniformis. First, our results confirmed that deletions of D-alanyl-lipoteichoic acid synthetase gene dltD, cardiolipin synthase gene clsA and CDP-diacylglycerol-serine O-phosphatidyltransferase gene pssA were not conducive to cell growth, and the biomass of gene deletion strains were, respectively, decreased by 10.54 ± 1.43%, 14.17 ± 1.51%, and 17.55 ± 1.28%, while the concentrations of total extracellular proteins were improved, due to the increases of cell surface net negative charge and cell membrane permeability. In addition, the activities of target proteins, nattokinase, and α-amylase were also improved significantly in gene deletion strains. Furthermore, the triplicate gene (dltD, clsA, and pssA) deletion strain was constructed, which further led to the 45.71 ± 2.43% increase of cell surface net negative charge and 26.45 ± 2.31% increase of cell membrane permeability, and the activities of nattokinase and α-amylase reached 37.15 ± 0.89 FU/mL and 305.3 ± 8.4 U/mL, increased by 46.09 ± 3.51% and 96.34 ± 7.24%, respectively. Taken together, our results confirmed that cell surface engineering via deleting dltD, clsA, and pssA is an efficient strategy for enhanced production of target proteins, and this research provided a promising host strain of B. licheniformis for efficient protein expression.
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http://dx.doi.org/10.1007/s10295-019-02229-8DOI Listing
December 2019
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