Publications by authors named "Xiaowei Zhang"

801 Publications

Probiotic GR-1 and RC-14 as an Adjunctive Treatment for Bacterial Vaginosis Do Not Increase the Cure Rate in a Chinese Cohort: A Prospective, Parallel-Group, Randomized, Controlled Study.

Front Cell Infect Microbiol 2021 6;11:669901. Epub 2021 Jul 6.

Department of Obstetrics and Gynaecology, Peking University Shenzhen Hospital, Shenzhen, China.

The purpose of this study was to evaluate the effectiveness of metronidazole and oral probiotics adjunct to metronidazole in the treatment of bacterial vaginosis (BV). One hundred and twenty-six Chinese women with BV were enrolled in this parallel, controlled trial, and were randomly assigned into two study arms: the metronidazole group, which was prescribed metronidazole vaginal suppositories for 7 days, and the adjunctive probiotic group, which received GR-1 and RC-14 orally for 30 days as an adjunct to metronidazole. Clinical symptoms and Nugent scores at the initial visit, 30 days and 90 days were compared. There was no significant difference of the 30-day total cure rate between the adjunctive probiotic group (57.69%) and the metronidazole group (59.57%), with an odds ratio (OR) of 0.97 (95% confidence interval (CI), 0.70 to 1.35, -value = 0.04), or of the 90-day total cure rate (36.54% vs. 48.94%, OR, 0.75; 95% CI, 0.47 to 1.19; value = 0.213). Also, no significant difference of the vaginal and faecal microbial diversity and structure between the two groups at 0, 30 or 90 days were shown based on 16S rRNA sequences. The probiotic species were rarely detected in either the vaginal microbiota or the faecal microbiota after administration which may revealed the cause of noneffective of oral probiotics. No serious adverse effects were reported in the trial. The study indicated that oral probiotic adjunctive treatment did not increase the cure rate of Chinese BV patients compared to metronidazole.
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http://dx.doi.org/10.3389/fcimb.2021.669901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291149PMC
July 2021

A Functional Variant Rs492554 Associated With Congenital Heart Defects Modulates Expression Through POU2F1.

Front Cell Dev Biol 2021 23;9:668474. Epub 2021 Jun 23.

Institute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.

Hypoxia exposure is responsible for the high incidence of congenital heart defects (CHDs) in high-altitude areas, which is nearly 20 times higher than that in low-altitude areas. However, the genetic factors involved are rarely reported. Sestrin2 (), a hypoxia stress-inducible gene, protects cardiomyocyte viability under stress; thus, polymorphism may be a potential risk factor for CHD. We performed an association study of the polymorphisms with CHD risk in two independent groups of the Han Chinese population from two different altitude areas. The allele-specific effects of lead single-nucleotide polymorphisms (SNPs) were assessed by expression quantitative trait locus, electrophoretic mobility shift, and luciferase reporter assays. The molecular mechanism of action against hypoxia-induced cell injury was investigated in embryonic rat-heart-derived H9c2 cells treated with or without hypoxia-mimetic cobalt chloride. SNP rs492554 was significantly associated with reduced CHD risk in the high-altitude population, but not in the low-altitude population. The protective T allele of rs492554 was correlated with higher expression and showed a preferential binding affinity to POU2F1. We then identified SNP rs12406992 in strong linkage disequilibrium with rs492554 and mapped it within the binding motif of POU2F1. The T-C haplotype of rs492554-rs12406992 could increase luciferase expression, whereas POU2F1 knockdown effectively suppressed it. Mechanistically, increased protects against oxidative stress and cell apoptosis and maintains cell viability and proliferation. In summary, CHD-associated SNP rs492554 acts as an allele-specific distal enhancer to modulate expression via interaction with POU2F1, which might provide new mechanistic insights into CHD pathogenesis.
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http://dx.doi.org/10.3389/fcell.2021.668474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260953PMC
June 2021

Phosphorylation of MtRopGEF2 by LYK3 mediates MtROP activity to regulate rhizobial infection in Medicago truncatula.

J Integr Plant Biol 2021 Jul 8. Epub 2021 Jul 8.

College of Life and Environment Sciences, Shanghai Normal University, Shanghai, 200234, China.

The formation of nitrogen-fixing nodules on legume roots requires the coordination of infection by rhizobia at the root epidermis with the initiation of cell divisions in the root cortex. During infection, rhizobia attach to the tip of elongating root hairs which then curl to entrap the rhizobia. However, the mechanism of root hair deformation and curling in response to symbiotic signals is still elusive. Here, we found that small GTPases (MtRac1/MtROP9 and its homologs) are required for root hair development and rhizobial infection in Medicago truncatula. Our results show that the Nod factor receptor LYK3 phosphorylates the guanine nucleotide exchange factor MtRopGEF2 at S73 which is critical for the polar growth of root hairs. In turn, phosphorylated MtRopGEF2 can activate MtRac1. Activated MtRac1 was found to localize at the tips of root hairs and to strongly interact with LYK3 and NFP. Taken together, our results support the hypothesis that MtRac1, LYK3, and NFP form a polarly localized receptor complex that regulates root hair deformation during rhizobial infection. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/jipb.13148DOI Listing
July 2021

HIF-1α Affects the Neural Stem Cell Differentiation of Human Induced Pluripotent Stem Cells via MFN2-Mediated Wnt/β-Catenin Signaling.

Front Cell Dev Biol 2021 21;9:671704. Epub 2021 Jun 21.

Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, China.

Hypoxia-inducible factor 1α (HIF-1α) plays pivotal roles in maintaining pluripotency, and the developmental potential of pluripotent stem cells (PSCs). However, the mechanisms underlying HIF-1α regulation of neural stem cell (NSC) differentiation of human induced pluripotent stem cells (hiPSCs) remains unclear. In this study, we demonstrated that HIF-1α knockdown significantly inhibits the pluripotency and self-renewal potential of hiPSCs. We further uncovered that the disruption of HIF-1α promotes the NSC differentiation and development potential and . Mechanistically, HIF-1α knockdown significantly enhances mitofusin2 (MFN2)-mediated Wnt/β-catenin signaling, and excessive mitochondrial fusion could also promote the NSC differentiation potential of hiPSCs via activating the β-catenin signaling. Additionally, MFN2 significantly reverses the effects of HIF-1α overexpression on the NSC differentiation potential and β-catenin activity of hiPSCs. Furthermore, Wnt/β-catenin signaling inhibition could also reverse the effects of HIF-1α knockdown on the NSC differentiation potential of hiPSCs. This study provided a novel strategy for improving the directed differentiation efficiency of functional NSCs. These findings are important for the development of potential clinical interventions for neurological diseases caused by metabolic disorders.
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http://dx.doi.org/10.3389/fcell.2021.671704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256873PMC
June 2021

MicroRNA-126a-5p Exerts Neuroprotective Effects on Ischemic Stroke via Targeting NADPH Oxidase 2.

Neuropsychiatr Dis Treat 2021 25;17:2089-2103. Epub 2021 Jun 25.

Department of Neurology, The Third Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, 330008, People's Republic of China.

Background: Ischemic stroke is a destructive cerebrovascular disorder related to oxidative stress; NOX2 is a major source for ROS production; and miR-126a-5p is involved in several diseases, such as abdominal aortic aneurysm. We investigated the role of miR-126a-5p in regulating NOX2 in ischemic stroke.

Methods: MiR-126a-5p and NOX2 were examined in the brains of rats subjected to cerebral ischemia/reperfusion (I/R) by RT-PCR and Western blot. MiR-126a-5p agomir was delivered to examine the effects of miR-126a-5p on I/R injury. The neurological deficit, infarct volume, and brain water content were evaluated. NOX activity, ROS production, and MDA and SOD levels were detected to assess oxidative stress. H&E staining was used to examine cell state. Apoptosis was evaluated by TUNEL, caspase-3 activity, and cleaved-caspase-3 protein level. The relationship between miR-126a-5p and NOX2 was analyzed by bioinformatics and luciferase reporter assay. MiR-126a-5p mimic, miR-126a-5p inhibitor, or pcDNA-NOX2 were transfected in SH-SY5Y cells to further assess the effects of miR-126a-5p on OGD/R-induced cells injury.

Results: NOX2 was upregulated and miR-126a-5p was down-regulated in the brains of I/R rats. MiR-126a-5p agomir obviously reduced the neurological deficit, infarct volume, brain water content, oxidative stress, and apoptosis in I/R rats. MiR-126a-5p targeted NOX2 directly and regulated NOX2 negatively. Moreover, miR-126a-5p mimic elevated cell viability and inhibited oxidative stress and apoptosis in OGD/R-treated SH-SY5Y cells, while miR-126a-5p inhibitor had the opposite effects. NOX2 overexpression antagonized the protective effects of miR-126a-5p mimic on OGD/R-induced cell injury.

Conclusion: MiR-126a-5p is a novel potential target for ischemic stroke therapy due to its protection against cerebral I/R injury via directly targeting NOX2.
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http://dx.doi.org/10.2147/NDT.S293611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242150PMC
June 2021

Nod factor receptor complex phosphorylates GmGEF2 to stimulate ROP signaling during nodulation.

Curr Biol 2021 Jun 29. Epub 2021 Jun 29.

National Key Laboratory of Plant Molecular Genetics, Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai 200032, China. Electronic address:

The establishment of the symbiotic interaction between rhizobia and legumes involves the Nod factor signaling pathway. Nod factor recognition occurs through two plant receptors, NFR1 and NFR5. However, the signal transduction mechanisms downstream of NFR1-NFR5-mediated Nod factor perception remain largely unknown. Here, we report that a small guanosine triphosphatase (GTPase), GmROP9, and a guanine nucleotide exchange factor, GmGEF2, are involved in the soybean-rhizobium symbiosis. We show that GmNFR1α phosphorylates GmGEF2a at its N-terminal S86, which stimulates guanosine diphosphate (GDP)-to-GTP exchange to activate GmROP9 and that the active form of GmROP9 can associate with both GmNFR1α and GmNFR5α. We further show that a scaffold protein, GmRACK1, interacts with active GmROP9 and contributes to root nodule symbiosis. Collectively, our results highlight the symbiotic role of GmROP9-GmRACK1 and support the hypothesis that rhizobial signals promote the formation of a protein complex comprising GmNFR1, GmNFR5, GmROP9, and GmRACK1 for symbiotic signal transduction in soybean.
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http://dx.doi.org/10.1016/j.cub.2021.06.011DOI Listing
June 2021

eDNA metabarcoding revealed differential structures of aquatic communities in a dynamic freshwater ecosystem shaped by habitat heterogeneity.

Environ Res 2021 Jun 29;201:111602. Epub 2021 Jun 29.

State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.

Freshwater ecosystems have been threatened by complicated disturbances from both natural and anthropogenic variables, especially in dynamic and complex river basins. The environmental DNA (eDNA)-based approach provides a broader spectrum and higher throughput way of biomonitoring for biodiversity assessment compared with traditional morphological survey. Most eDNA metabarcoding studies have been limited to a few specific taxa/groups and habitat scopes. Here we applied the eDNA metabarcoding to characterize the structures and spatial variations of zooplankton and fish communities among different habitat types in a highly dynamic and complex freshwater ecosystem of the Daqing River basin (DRB). The results showed that varied species spectra of zooplankton and fish communities were identified and unique dominant species occurred across habitats. Additionally, markedly spatial distributions of biotic community structures were observed in areas with different habitat characteristics. Natural variables, including geographic distances and gradient ratio, as well as anthropogenic factors of chemical oxygen demand (COD) and organic chemicals demonstrated significant effects but different outcomes on the structures of zooplankton and fish communities. Moreover, the relative abundances of specific aquatic taxa were associated with the gradient of particular environmental variables. This case study verified the distribution patterns and differentiation mechanisms of biotic communities under habitat heterogeneity could be captured by application of eDNA biomonitoring. And habitat-specific and even species-specific environmental stressors would be diagnosed for improving management of complex river basins.
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http://dx.doi.org/10.1016/j.envres.2021.111602DOI Listing
June 2021

Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway.

Front Pharmacol 2021 14;12:658362. Epub 2021 Jun 14.

Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China.

Oxidative stress contributes to adverse atrial remodeling in diabetes mellitus. This remodeling can be prevented by the PPAR-γ agonist pioglitazone its antioxidant and anti-inflammatory effects. In this study, we examined the molecular mechanisms underlying the protective effects of pioglitazone on atrial remodeling in a rabbit model of diabetes. Rabbits were randomly divided into control, diabetic, and pioglitazone-treated diabetic groups. Echocardiographic, hemodynamic, and electrophysiological parameters were measured. Serum PPAR-γ levels, serum and tissue oxidative stress and inflammatory markers, mitochondrial morphology, reactive oxygen species (ROS) production rate, respiratory function, and mitochondrial membrane potential (MMP) levels were measured. Protein expression of the pro-fibrotic marker TGF-β1, the PPAR-γ coactivator-1α (PGC-1α), and the mitochondrial proteins (biogenesis-, fusion-, and fission-related proteins) was measured. HL-1 cells were transfected with PGC-1α small interfering RNA (siRNA) to determine the underlying mechanisms of pioglitazone improvement of mitochondrial function under oxidative stress. The diabetic group demonstrated a larger left atrial diameter and fibrosis area than the controls, which were associated with a higher incidence of inducible atrial fibrillation (AF). The lower serum PPAR-γ level was associated with lower PGC-1α and higher NF-κB and TGF-β1 expression. Lower mitochondrial biogenesis (PGC-1α, NRF1, and TFAM)-, fusion (Opa1 and Mfn1)-, and fission (Drp1)-related proteins were detected. Mitochondrial swelling, higher mitochondrial ROS, lower respiratory control rate, and lower MMP were observed. The pioglitazone group showed a reversal of structural remodeling and a lower incidence of inducible AF, which were associated with higher PPAR-γ and PGC-1α. The pioglitazone group had lower NF-κB and TGF-β1 expression levels, whereas biogenesis-, fusion-, and fission-related protein expression was higher. Further, mitochondrial structure and function were improved. In HL-1 cells, PGC-1α siRNA transfection blunted the effect of pioglitazone on Mn-SOD protein expression and MMP collapse in HO-treated cells. Diabetes mellitus induces adverse atrial structural, electrophysiological remodeling, and mitochondrial damage and dysfunction. Pioglitazone prevented these abnormalities through the PPAR-γ/PGC-1α pathway.
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http://dx.doi.org/10.3389/fphar.2021.658362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237088PMC
June 2021

Recovery of a Far-Eastern Strain of Tick-Borne Encephalitis Virus with a Full-Length Infectious cDNA Clone.

Virol Sin 2021 Jun 30. Epub 2021 Jun 30.

CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.

Tick-borne encephalitis virus (TBEV) is a pathogenic virus known to cause central nervous system (CNS) diseases in humans, and has become an increasing public health threat nowadays. The rates of TBEV infection in the endemic countries are increasing. However, there is no effective antiviral against the disease. This underscores the urgent need for tools to study the emergence and pathogenesis of TBEV and to accelerate the development of vaccines and antivirals. In this study, we reported an infectious cDNA clone of TBEV that was isolated in China (the WH2012 strain). A beta-globin intron was inserted in the coding region of nonstructural protein 1 (NS1) gene to improve the stability of viral genome in bacteria. In mammalian cells, the inserted intron was excised and spliced precisely, which did not lead to the generation of inserted mutants. High titers of infectious progeny viruses were generated after the transfection of the infectious clone. The cDNA-derived TBEV replicated efficiently, and caused typical cytopathic effect (CPE) and plaques in BHK-21 cells. In addition, the CPE and growth curve of cDNA-derived virus were similar to that of its parental isolate in cells. Together, we have constructed the first infectious TBEV cDNA clone in China, and the clone can be used to investigate the genetic determinants of TBEV virulence and disease pathogenesis, and to develop countermeasures against the virus.
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http://dx.doi.org/10.1007/s12250-021-00396-6DOI Listing
June 2021

AKP and GGT level can provide an early prediction of first-line treatment efficacy in colorectal cancer patients with hepatic metastases.

Biomark Med 2021 Jun 25;15(10):697-713. Epub 2021 Jun 25.

Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, PR China.

It is important to early evaluate or predict the efficacy to avoid ineffective treatment for most colorectal cancer (CRC) patients with liver metastases. The medical records of 440 patients with histologically confirmed primary CRC admitted to the Fudan University Shanghai Cancer Center were reviewed. High baseline serum alkaline phosphatase (AKP) and γ-glutamyl transferase (GGT) is associated with worse overall survival. In patients with a high serum AKP and GGT a decreased percentage had high objective response rate and better progression-free survival. Measuring the changes of serum AKP or GGT in CRC patients with hepatic metastases before and after the first cycle of treatment is a convenient, fast and economical way to early predict antitumor treatment efficacy.
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http://dx.doi.org/10.2217/bmm-2020-0667DOI Listing
June 2021

An SNP Mutation of Gene Converts Petal Color From Purple to White in Radish ( L.).

Front Plant Sci 2021 3;12:643579. Epub 2021 Jun 3.

Institute of Horticulture, Henan Academy of Agricultural Sciences, Zhengzhou, China.

Along with being important pigments that determining the flower color in many plants, anthocyanins also perform crucial functions that attract pollinators and reduce abiotic stresses. Purple and white are two different colors of radish petals. In this study, two cDNA libraries constructed with purple and white petal plants were sequenced for transcriptome profiling. Transcriptome results implied that the expression level of the genes participating in the anthocyanin biosynthetic pathway was commonly higher in the purple petals than that in the white petals. In particular, two genes, F3'H and DFR, had a significantly higher expression pattern in the purple petals, suggesting the important roles these genes playing in radish petal coloration. BSA-seq aided-Next Generation Sequencing of two DNA pools revealed that the radish purple petal gene () was located on chromosome 7. With additional genotyping of 617 F population plants, the was further confined within a region of 93.23 kb. Transcriptome and Sanger sequencing analysis further helped identify the target gene, . is a homologous gene to F3'H, a key gene in the anthocyanin biosynthetic pathway. These results will aid in elucidating the molecular mechanism of plant petal coloration and developing strategies to modify flower color through genetic transformation.
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http://dx.doi.org/10.3389/fpls.2021.643579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210830PMC
June 2021

Vpr counteracts the restriction of LAPTM5 to promote HIV-1 infection in macrophages.

Nat Commun 2021 06 17;12(1):3691. Epub 2021 Jun 17.

Department of Laboratory Medicine, Key Laboratory of AIDS Immunology of Ministry of Health, The First Affiliated Hospital, China Medical University, Shenyang, China.

The HIV-1 accessory proteins Vif, Vpu, and Nef can promote infection by overcoming the inhibitory effects of the host cell restriction factors APOBEC3G, Tetherin, and SERINC5, respectively. However, how the HIV-1 accessory protein Vpr enhances infection in macrophages but not in CD4 T cells remains elusive. Here, we report that Vpr counteracts lysosomal-associated transmembrane protein 5 (LAPTM5), a potent inhibitor of HIV-1 particle infectivity, to enhance HIV-1 infection in macrophages. LAPTM5 transports HIV-1 envelope glycoproteins to lysosomes for degradation, thereby inhibiting virion infectivity. Vpr counteracts the restrictive effects of LAPTM5 by triggering its degradation via DCAF1. In the absence of Vpr, the silencing of LAPTM5 precisely phenocopied the effect of Vpr on HIV-1 infection. In contrast, Vpr did not enhance HIV-1 infection in the absence of LAPTM5. Moreover, LAPTM5 was highly expressed in macrophages but not in CD4 T lymphocytes. Re-expressing LAPTM5 reconstituted the Vpr-dependent promotion of HIV-1 infection in primary CD4 T cells, as observed in macrophages. Herein, we demonstrate the molecular mechanism used by Vpr to overcome LAPTM5 restriction in macrophages, providing a potential strategy for anti-HIV/AIDS therapeutics.
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http://dx.doi.org/10.1038/s41467-021-24087-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211709PMC
June 2021

Life History Recorded in the Vagino-cervical Microbiome Along with Multi-omics.

Genomics Proteomics Bioinformatics 2021 Jun 9. Epub 2021 Jun 9.

BGI-Shenzhen, Shenzhen 518083, China.

The vagina contains at least a billion microbial cells, dominated by lactobacilli. Here we perform metagenomic shotgun sequencing on cervical and fecal samples from a cohort of 516 Chinese women of reproductive age, and cervical, fecal, and salivary samples from a second cohort of 632 women. Factors such as pregnancy, delivery histories, cesarean section, and breast-feeding were all more important than menstrual cycle in shaping the microbiome, and such information would be necessary before trying to interpret differences between vagino-cervical microbiome data. Greater proportion of Bifidobacterium breve was seen with older age at sexual debut. The relative abundance of lactobacilli especially Lactobacillus crispatus was negatively associated with pregnancy history. Potential markers for lack of menstrual regularity, heavy flow, dysmenorrhea, and contraceptives were also identified. Lactobacilli were rare during breast-feeding or post-menopause. Other features such as mood fluctuations and facial speckles could potentially be predicted from the vagino-cervical microbiome. Gut and salivary microbiome, plasma vitamins, metals, amino acids, and hormones showed associations with the vagino-cervical microbiome. Our results offer an unprecedented glimpse into the microbiota of the female reproductive tract and call for international collaborations to better understand its long-term health impact other than in the settings of infection or pre-term birth.
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http://dx.doi.org/10.1016/j.gpb.2021.01.005DOI Listing
June 2021

A Low-Field Magnetic Resonance Imaging Aptasensor for the Rapid and Visual Sensing of in Food, Juice, and Water.

Anal Chem 2021 06 9;93(24):8631-8637. Epub 2021 Jun 9.

Department of Food Science, Purdue University, West Lafayette, Indiana 47906, United States.

In this work, we present a low-field magnetic resonance imaging (LF-MRI) aptasensor based on the difference in magnetic behavior of two magnetic nanoparticles with diameters of 10 (MN) and 400 nm (MN) for the rapid detection of (). First, specific anti- aptamers were covalently immobilized onto magnetic nanoparticles via 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/-hydroxysuccinimide chemistry for the capture of the target bacteria. In the presence of , an MN-bacteria-MN (MBM) complex was formed after binding between the aptamers on magnetic nanoparticles and cells. When a magnetic field was applied, the MBM complex and free MN were rapidly magnetically separated, and free MN left in the solution worked as a (transverse relaxation time) single readout in MRI measurement. Under optimum conditions, the LF-MRI platform provides both image analysis and quantitative detection of , with a detection limit of 100 cfu/mL. The feasibility and specificity of the aptasensor were demonstrated in detecting real food, orange juice, and drinking water samples and validated using plate counting methods.
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http://dx.doi.org/10.1021/acs.analchem.1c01669DOI Listing
June 2021

Different muscle mass indices of the Global Leadership Initiative on Malnutrition in diagnosing malnutrition and predicting survival of patients with gastric cancer.

Nutrition 2021 Apr 24;89:111286. Epub 2021 Apr 24.

Department of Gastrointestinal Surgery/Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; Department of Oncology, Capital Medical University, Beijing, China; Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China. Electronic address:

Objective: Malnutrition is common and related to negative prognosis in patients with gastric cancer (GC). The Global Leadership Initiative on Malnutrition (GLIM), a novel consensus for the diagnosis of malnutrition, was proposed recently. However, the roles of GLIM in diagnosing malnutrition and predicting overall survival (OS) in patients with GC have been unclear.

Method: We conducted a multicenter, observational cohort study including 877 hospitalized patients with GC 2013 through 2018. Different anthropometric measurements were compared to assess reduced muscle mass. Kaplan-Meier curves and multivariate Cox regression were used to analyze the relationship between GLIM-defined malnutrition and the OS of patients with GC. Independent prognostic variables were incorporated to develop a nomogram for individualized survival prediction. The calibration curve was used to determine the predictive accuracy and discriminatory capacity of the nomogram. In addition, 219 patients with GC were enrolled for external validation.

Results: A total of 464 (53%) patients with GC were diagnosed with malnutrition. Patients diagnosed with severe malnutrition based on either midarm circumference or body weight-standardized hand grip strength had a shorter median survival time (16.7 mo; interquartile range, 8.4-32.7 mo) and a higher hazard ratio (HR, 1.49; 95% CI, 1.15-1.92; P = 0.002). Severe malnutrition was an independent risk factor for OS (HR, 1.32; 95% CI, 1.02-1.71; P = 0.038). The GLIM nomogram showed good performance in predicting 3-y survival in patients with GC.

Conclusions: Our findings support the effectiveness of GLIM in diagnosing malnutrition and predicting OS in patients with GC.
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http://dx.doi.org/10.1016/j.nut.2021.111286DOI Listing
April 2021

Cross-Model Comparison of Transcriptomic Dose-Response of Short-Chain Chlorinated Paraffins.

Environ Sci Technol 2021 06 26;55(12):8149-8158. Epub 2021 May 26.

State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, P. R. China.

Short-chain chlorinated paraffins (SCCPs) have attracted attention because of their toxicological potential in humans and wildlife at environmentally relevant doses. However, limited information is available regarding mechanistic differences across species in terms of the biological pathways that are impacted by SCCP exposure. Here, a concentration-dependent reduced human transcriptome (RHT) approach was conducted to evaluate 15 SCCPs in HepG2 cells and compared with our previous results using a reduced zebrafish transcriptome (RZT) approach in zebrafish embryos (ZFEs). Generally, SCCPs induced a broader suite of biological pathways in ZFEs than HepG2 cells, and all of the 15 SCCPs were more potent in HepG2 cells compared to ZFEs. Despite these general differences, the transcriptional potency of SCCPs in both model systems showed a significant linear relationship ( = 0.0017, = 0.57), and the average ratios of transcriptional potency for each SCCP in RZT to that in RHT were ∼100,000. CHCl was the most potent SCCP, while CHCl was the least potent in both ZFEs and HepG2 cells. An adverse outcome pathway network-based analysis demonstrated model-specific responses, such as xenobiotic metabolism that may be mediated by different nuclear receptor-mediated pathways between HepG2 cells (, CAR and AhR activation) and ZFEs (, PXR activation). Moreover, induced transcriptional changes in ZFEs associated with pathways and molecular initiating events (, activation of nicotinic acetylcholine receptor) suggest that SCCPs may disrupt neural development processes. The cross-model comparison of concentration-dependent transcriptomics represents a promising approach to assess and prioritize SCCPs.
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http://dx.doi.org/10.1021/acs.est.1c00975DOI Listing
June 2021

Correction to: TAK1 is involved in sodium L‑lactate‑stimulated p38 signaling and promotes apoptosis.

Mol Cell Biochem 2021 Jul;476(7):2889-2890

Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University, The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, China.

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http://dx.doi.org/10.1007/s11010-021-04184-4DOI Listing
July 2021

Predictive value of vitamin A and E levels in pre-eclampsia and postpartum kidney injury.

Am J Transl Res 2021 15;13(4):3427-3434. Epub 2021 Apr 15.

Department of Gynaecology and Obstetrics, Civil Aviation General Hospital Beijing 100123, China.

Objective: This research aimed to explore the predictive value of levels of vitamin A and E in pre-eclampsia and postpartum kidney injury.

Methods: A total of 106 pregnant women with severe pre-eclampsia diagnosed in our hospital from May 2015 to December 2018 were selected as the research subjects. There from, 75 pregnant women with severe pre-eclampsia were enrolled into the severe PE group (SPE) and 31 with acute kidney injury were divided into the severe PE and AKI group (SPE and AKI). Serum vitamin A and E content was determined by high-performance liquid chromatography (HPLC), and the correlation between vitamins A and E and disease was analyzed. The expression levels of kidney injury markers in both groups were detected, and the correlation between markers and vitamin A and E levels was analyzed.

Results: The expression level of vitamins A and E decreased in the pre-eclampsia and postpartum kidney injury, and it was negatively correlated with disease severity. The expression of the two decreased further in the severe pre-eclampsia patients with kidney injury. In addition, the expression of kidney injury markers in the severe pre-eclampsia patients with postpartum kidney injury was higher than that in severe pre-eclampsia patients, and it was negatively correlated with vitamin A and E levels.

Conclusion: Vitamins A and E are expressed in low levels in pre-eclampsia and postpartum kidney injury, and the latter has a higher sensitivity and specificity than the former. It is negatively correlated with kidney injury markers KIM-1, NGAL, UA and Scr, which can be used as a physical and chemical indexes for clinical prediction.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129214PMC
April 2021

FERONIA receptor kinase-regulated reactive oxygen species mediate self-incompatibility in Brassica rapa.

Curr Biol 2021 Jul 19;31(14):3004-3016.e4. Epub 2021 May 19.

State Key Laboratory of Crop Biology, Shandong Agricultural University, Tai'an, 271018 Shandong, China; College of Horticulture Science and Engineering, Shandong Agricultural University, Tai'an, 271018 Shandong, China. Electronic address:

Most plants in the Brassicaceae evolve self-incompatibility (SI) to avoid inbreeding and generate hybrid vigor. Self-pollen is recognized by the S-haplotype-specific interaction of the pollen ligand S-locus protein 11 (SP11) (also known as S-locus cysteine-rich protein [SCR]) and its stigma-specific S-locus receptor kinase (SRK). However, mechanistically much remains unknown about the signaling events that culminate in self-pollen rejection. Here, we show that self-pollen triggers high levels of reactive oxygen species (ROS) in stigma papilla cells to mediate SI in heading Chinese cabbage (Brassica rapa L. ssp. pekinensis). We found that stigmatic ROS increased after self-pollination but decreased after compatible(CP)- pollination. Reducing stigmatic ROS by scavengers or suppressing the expression of respiratory burst oxidase homologs (Rbohs), which encode plant NADPH oxidases that produce ROS, both broke down SI. On the other hand, increasing the level of ROS inhibited the germination and penetration of compatible pollen on the stigma, mimicking an incompatible response. Furthermore, suppressing a B. rapa FERONIA (FER) receptor kinase homolog or Rac/Rop guanosine triphosphatase (GTPase) signaling effectively reduced stigmatic ROS and interfered with SI. Our results suggest that FER-Rac/Rop signaling-regulated, NADPH oxidase-produced ROS is an essential SI response leading to self-pollen rejection.
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http://dx.doi.org/10.1016/j.cub.2021.04.060DOI Listing
July 2021

Nanoscale Imaging of RNA-Protein Interactions with a Photoactivatable Trimolecular Fluorescence Complementation System.

ACS Chem Biol 2021 06 19;16(6):1003-1010. Epub 2021 May 19.

State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.

Imaging RNA-protein interaction in the cellular space with single molecule sensitivity is attractive for studying gene expression and regulation, but remains a challenge. In this study, we reported a photoactivatable trimolecular fluorescence complementation (TriFC) system based on fluorescent protein, mIrisFP, to identify and visualize RNA-protein interactions in living mammalian cells. We also combined this TriFC system with photoactivated localization microscopy (PALM), named the TriFC-PALM technique, which allowed us to image the RNA-protein interactions with single molecule sensitivity. Using this TriFC-PALM technique, we identified the actin-bundling protein, FSCN1, specifically interacting with the HOX Transcript Antisense RNA (HOTAIR). The TriFC-PALM imaging acquired a higher resolution compared with the traditional method of total internal reflection (TIRF) imaging. The TriFC-PALM thus provides a useful tool for imaging and identifying the RNA-protein interactions inside cells at the nanometer scale.
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http://dx.doi.org/10.1021/acschembio.0c00945DOI Listing
June 2021

Polychlorinated Diphenyl Sulfides: An Emerging Class of Persistent, Bioaccumulative, and Toxic Substances in the Environment.

Environ Toxicol Chem 2021 May 18. Epub 2021 May 18.

State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University, Nanjing, China.

Polychlorinated diphenyl sulfides (PCDPSs) have recently attracted increasing attention due to their potential adverse effects on human and ecosystem health. We present a review regarding their environmental occurrence, persistence, bioaccumulation, toxicity, and biotransformation. The existing literature demonstrates that PCDPSs are ubiquitous in various environmental matrices, are persistent in the environment, and have long-range transport potential. In addition, the high bioaccumulation potential of these emerging pollutants, especially the low chlorinated PCDPS congeners, has been confirmed based on both theoretical calculations and experimental investigations. Moreover, a spectrum of adverse effects, such as acute liver injury, retardation of development, reproductive disorders, and increased mortality have been widely reported in vertebrates. These adverse outcomes were associated with oxidative stress and activation of aryl hydrocarbon receptors. Given these findings, PCDPSs represent candidate persistent, bioaccumulative, and toxic substances and thus deserve further research to fully elucidate their environmental behavior and fate, and evaluate the risks to human and ecosystem health. Environ Toxicol Chem 2021;00:1-10. © 2021 SETAC.
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http://dx.doi.org/10.1002/etc.5120DOI Listing
May 2021

Microwave treatment enhances human gut microbiota fermentability of isolated insoluble dietary fibers.

Food Res Int 2021 05 9;143:110293. Epub 2021 Mar 9.

Departamento de Bioquímica e Biologia Molecular, Universidade Federal do Paraná, CP 19.046, CEP 81.531-980, Curitiba, PR, Brazil. Electronic address:

Most insoluble dietary fibers are known to be relatively poorly fermented by the human gut microbiota. Here, the potential of microwave (MW) treatment to enhance the susceptibility of insoluble fruit polysaccharides to fermentation by the human gut microbiota was evaluated. Insoluble fruits dietary fibers before (xylan A, xylan T, and arabinan) and after MW (xylan A-MW, xylan T-MW, and arabinan-MW) treatment were fermented using an in vitro fermentation model. Gas production, shifts in pH, and short chain fatty acids (SCFAs) production showed an increase in fermentability of all tested dietary fibers, with an average 4-fold increase in SCFAs production after microwaving with total SCFAs ranging from 17.1 mM in the arabinan-MW to 40.4 mM in the xylan T-MW. While arabinan-MW and xylan T-MW promoted all three SCFAs proportionally (acetate:propionate:butyrate), xylan A-MW led to a marked and slow increase in butyrate reaching 28.1% of total SCFAs at 24 h. Rearrangements in three-dimensional structure that potentially facilitate bacterial accessibility to the dietary fiber were observed by scanning electron microscopy in xylan A-MW, forming coin-like particles with ~1.1 µm diameter. 16S rRNA gene sequencing indicated that microbiota shifts were related to both treatment (native versus MW) and dietary fiber type with many butyrogenic species being promoted by xylan A-MW. Overall, MW treatment enhanced insoluble dietary fiber fermentability promoting increased SCFAs production and bacterial shifts which are related to health benefits.
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http://dx.doi.org/10.1016/j.foodres.2021.110293DOI Listing
May 2021

Upregulation of miR-20b Protects Against Cerebral Ischemic Stroke by Targeting Thioredoxin Interacting Protein (TXNIP).

Exp Neurobiol 2021 Apr;30(2):170-182

Department of Neurology, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, PR. China.

Dysregulation of microRNAs (miRNAs) is involved in abnormal development and pathophysiology in the brain. Although miR-20b plays essential roles in various human diseases, its function in cerebral ischemic stroke remains unclear. A cell model of oxygen glucose deprivation/reoxygenation (OGD/R) and A rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) were constructed. qRT-PCR and western blot were used to evaluate the expression of miR-20b and TXNIP. Cell viability was detected by MTT assay, and cell apoptosis was evaluated by flow cytometry. Targetscan and Starbase were used to predict the potential targets of miR-20b. Luciferase reporter assay was applied to determine the interaction between miR-20b and TXNIP. Rescue experiments were conducted to confirm the functions of miR-20b/TXNIP axis in cerebral ischemic stroke. MiR-20b was significantly downregulated after I/R both and . Upregulation of miR-20b inhibited OGD/R-induced neurons apoptosis and attenuated ischemic brain injury in rat model. Bioinformatic prediction suggested that TXNIP might be a target of miR-20b, and luciferase reporter assay revealed that miR-20b negatively regulated TXNIP expression by directly binding to the 3'-UTR of TXNIP. Downregulation of TXNIP inhibited OGD/R-induced neurons apoptosis and ischemic brain injury . Rescue experiments indicated that downregulation of TXNIP effectively reversed the effect of miR-20b inhibitor in neurons apoptosis after OGD/R-treatment and ischemic brain injury in a mouse model after MCAO/R-treatment. Our study demonstrated that upregulation of miR-20b protected the brain from ischemic brain injury by targeting TXNIP, extending our understanding of miRNAs in cerebral ischemic stroke.
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http://dx.doi.org/10.5607/en20046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118756PMC
April 2021

Psychological Burden and Experiences Following Exposure to COVID-19: A Qualitative and Quantitative Study of Chinese Medical Student Volunteers.

Int J Environ Res Public Health 2021 04 13;18(8). Epub 2021 Apr 13.

Injury Prevention Research Center, Shantou University Medical College, Shantou 515041, China.

: During the COVID-19 pandemic, some medical students devoted themselves to volunteer activities, but it was the first time that they had been exposed to such an infectious disease and they might have experienced fear in the face of the epidemic. We aimed to conduct a timely assessment of the psychological burden and experience on medical student volunteers during the COVID-19 pandemic. : We used the 21-item Depression Anxiety Stress Scales to survey the psychology burden of students in April 2020. Semi-structured interviews were conducted with nine medical students who signed up for volunteer activities in Chinese from February to April 2020. Quantitative and qualitative methods were used to analyze the data. : The detection of depression, anxiety and stress of medical student volunteers were 26.8%, 20.2% and 11.1%, respectively. The volunteer's negative emotions were more pronounced before work and diminished gradually. Most participants expressed no concern about being infected themselves, but worry about family infection. Participant's motivations for volunteering were primarily their duties as medical students and encouragement from their families/teachers. The vast majority of medical students said they would be willing to work as medical assistants again and this experience would not affect their career choice. : Chinese medical student volunteers tended to show negative emotions at the beginning of their work, and then gradually declined, while positive emotions emerged. Most medical students were willing to volunteer as medical assistants when their country needed them due to their sense of responsibility as medical students. This study on the psychological and experiential aspects were derived from Chinese medical student volunteers and might have a significant impact on future public health emergencies in similar settings.
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http://dx.doi.org/10.3390/ijerph18084089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069905PMC
April 2021

CD36+/CD61+ Microparticles Correlate with the Risk of Percutaneous Cardiac Interventions in Coronary Artery Disease Patients and the Effects of Ticagrelor.

Cardiovasc Drugs Ther 2021 Apr 24. Epub 2021 Apr 24.

Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, China.

Purpose: The CD36 scavenger receptor is a mediator of both atherogenesis and thrombosis. We aimed to investigate the prognostic value of CD36+ microparticles (MPs) released from platelets for cardiovascular event presentation in coronary artery disease (CAD) patients and the effects of different antiplatelet drugs on MPs.

Methods: A total of 101 aspirin-treated CAD patients, who were planned to undergo coronary angiography (CAG), were randomized to either a standard clopidogrel regimen or ticagrelor treatment. Total Annexin V-(AV)+ MPs, CD61+/AV+ MPs, and CD36+/CD61+/AV+ MPs were quantified by flow cytometry at baseline, before and immediately after the operation. The ADP-induced platelet inhibition rate was measured by thromboelastogram (TEG) examination 1 h before the operation.

Results: The baseline levels of CD36+/CD61+/AV+ MPs were significantly increased in percutaneous coronary intervention (PCI) patients (n = 52) compared to no-PCI patients (n = 49) (p < 0.05). A ROC-curve clustered model for CD36+/CD61+/AV+ MPs at baseline predicted an increased risk of PCI [p = 0.009, AUC = 0.761 (95%CI: 0.601 to 0.922)]. Moreover, TEG examination showed that the preoperative proportion of CD36+/CD61+/AV+ MPs was significantly negatively correlated with R time and K time (r = - 0.236, p = 00.026; r = - 0.288, p = 0.006), and positively correlated with MA (r = 0.226, p = 0.045). Subgroup analysis of PCI group showed that the platelet inhibition rate of ticagrelor was significantly higher (66.05% ± 28.76% vs.31.01% ± 27.33%, p < 0.001), and the number of AV+ MPs, CD61+/AV+ MPs, and CD36+/CD61+/AV+ MPs before the operation was significantly lower than clopidogrel (p < 0.05, all).

Conclusion: The high levels of CD36+ MPs derived from activated platelets are related to an increased risk of PCI in CAD patients. Ticagrelor significantly reduced the number of CD61+/AV+ MPs and CD36+/CD61+/AV+ MPs. This trial registration number is ChiCTR1800014908 and the date of registration is 2018.05.01.
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http://dx.doi.org/10.1007/s10557-021-07184-0DOI Listing
April 2021

Discriminating symbiosis and immunity signals by receptor competition in rice.

Proc Natl Acad Sci U S A 2021 Apr;118(16)

National Key Laboratory of Plant Molecular Genetics, Chinese Academy of Sciences Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200032 Shanghai, China;

Plants encounter various microbes in nature and must respond appropriately to symbiotic or pathogenic ones. In rice, the receptor-like kinase OsCERK1 is involved in recognizing both symbiotic and immune signals. However, how these opposing signals are discerned via OsCERK1 remains unknown. Here, we found that receptor competition enables the discrimination of symbiosis and immunity signals in rice. On the one hand, the symbiotic receptor OsMYR1 and its short-length chitooligosaccharide ligand inhibit complex formation between OsCERK1 and OsCEBiP and suppress OsCERK1 phosphorylating the downstream substrate OsGEF1, which reduces the sensitivity of rice to microbe-associated molecular patterns. Indeed, OsMYR1 overexpression lines are more susceptible to the fungal pathogen , whereas mutants show higher resistance. On the other hand, OsCEBiP can bind OsCERK1 and thus block OsMYR1-OsCERK1 heteromer formation. Consistently, the mutant displayed a higher rate of mycorrhizal colonization at early stages of infection. Our results indicate that OsMYR1 and OsCEBiP receptors compete for OsCERK1 to determine the outcome of symbiosis and immunity signals.
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http://dx.doi.org/10.1073/pnas.2023738118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072404PMC
April 2021

The responses of Salmonella enterica serovar Typhimurium to vanillin in apple juice through global transcriptomics.

Int J Food Microbiol 2021 Jun 31;347:109189. Epub 2021 Mar 31.

School of Food Science and Engineering, South China University of Technology, Guangzhou City, Guangdong Province 510640, China. Electronic address:

Salmonella enterica serovar Typhimurium can survive some extreme environment in food processing, and vanillin generally recognized as safe is bactericidal to pathogens. Thus, we need to explore the responses of S. Typhimurium to vanillin in order to apply this antimicrobial agent in food processing. In this study, we exposed S. Typhimurium to commercial apple juice with/without vanillin (3.2 mg/mL) at 45 °C for 75 min to determine the survival rate. Subsequently, the 10-min cultures were selected for transcriptomic analysis. Using high-throughput RNA sequencing, genes related to vanillin resistance and their expression changes of S. Typhimurium were identified. The survival curve showed that S. Typhimurium treated with vanillin were inactivated by 5.5 log after 75 min, while the control group only decreased by 2.3 log. Such a discrepancy showed the significant antibacterial effect of vanillin on S. Typhimurium. As a result, 265 differentially expressed genes (DEGs) were found when coping with vanillin, among which, 225 showed up-regulation and 40 DEGs were down-regulated. Treated with vanillin, S. Typhimurium significantly up-regulated genes involved in cell membrane, acid tolerance response (ATR) and oxidative stress response, cold shock cross-protection, DNA repair, virulence factors and some key regulators. Firstly, membrane-related genes, including outer membrane (bamE, mepS, ygdI, lolB), inner membrane (yaiY, yicS) and other proteins (yciC, yjcH), were significantly up-regulated because of the damaged cell membrane. Then, up-regulated proteins associated with arginine synthesis (ArgABCDIG) and inward transportation (ArtI, ArtJ, ArtP and HisP), participated in ATR to pump out the protons inside the cell in this scenario. Next, superoxide stress response triggered by vanillin was found to have a significant up-regulation as well, which was controlled by SoxRS regulon. Besides, NADH-associated (nuoA, nuoB, nuoK, nadE, fre and STM3021), thioredoxin (trxA, trxC, tpx and bcp) and glutaredoxin (grxC and grxD) DEGs led to the increase of the oxidative stress response. Cold shock proteins such as CspA and CspC showed an up-regulation, suggesting it might play a role in cross-protecting S. Typhimurium from vanillin stress. Furthermore, DEGs in DNA repair and virulence factors, including flagellar assembly, adhesins and type III secretion system were up-regulated. Some regulators like fur, rpoE and csrA played a pivotal role in response to the stress caused by vanillin. Therefore, this study sounds an alarm for the risks caused by stress tolerance of S. Typhimurium in food industry.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2021.109189DOI Listing
June 2021

HBP1-mediated transcriptional repression of AFP inhibits hepatoma progression.

J Exp Clin Cancer Res 2021 Apr 1;40(1):118. Epub 2021 Apr 1.

Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Xueyuan Road 38, Beijing, 100191, People's Republic of China.

Background: Hepatoma is a common malignancy of the liver. The abnormal high expression of alpha-fetoprotein (AFP) is intimately associated with hepatoma progress, but the mechanism of transcriptional regulation and singularly activation of AFP gene in hepatoma is not clear.

Methods: The expression of transcription factor HBP1 and AFP and clinical significance were further analyzed in hepatoma tissues from the patients who received surgery or TACE and then monitored for relapse for up 10 years. HBP1-mediated transcriptional regulation of AFP was analyzed by Western blotting, Luciferase assay, Realtime-PCR, ChIP and EMSA. After verified the axis of HBP-AFP, its impact on hepatoma was measured by MTT, Transwell and FACS in hepatoma cells and by tumorigenesis in HBP1 mice.

Results: The relative expressions of HBP1 and AFP correlated with survival and prognosis in hepatoma patients. HBP1 repressed the expression of AFP gene by directly binding to the AFP gene promoter. Hepatitis B Virus (HBV)-encoded protein HBx promoted malignancy in hepatoma cells through binding to HBP1 directly. Icaritin, an active ingredient of Chinese herb epimedium, inhibited malignancy in hepatoma cells through enhancing HBP1 transrepression of AFP. The repression of AFP by HBP1 attenuated AFP effect on PTEN, MMP9 and caspase-3, thus inhibited proliferation and migration, and induced apoptosis in hepatoma cells. The deregulation of AFP by HBP1 contributed to hepatoma progression in mice.

Conclusions: Our data clarify the mechanism of HBP1 in inhibiting the expression of AFP and its suppression in malignancy of hepatoma cells, providing a more comprehensive theoretical basis and potential solutions for the diagnosis and treatment of hepatoma.
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http://dx.doi.org/10.1186/s13046-021-01881-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015059PMC
April 2021

Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma.

BMC Cancer 2021 Mar 25;21(1):318. Epub 2021 Mar 25.

Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, 100191, Beijing, People's Republic of China.

Background: Icaritin, an active ingredient of the Chinese herb Epimedium, plays an anti-tumor role in liver cancer by inhibiting the proliferation of hepatocellular cells and promoting their apoptosis. In China, phase II and a large phase III clinical trial of icaritin reagent for the treatment of hepatocellular cancer is under-going, but the specific mechanism of icaritin action was unclear. Alpha-fetoprotein (AFP), an oncofetal protein, produced in the healthy fetal liver and yolk sac. Intracellular AFP promoted cellular proliferation and inhibited cellular apoptosis in hepatocellular carcinoma (HCC). The study was aimed to investigate the effect of icaritin on HCC through p53/AFP pathway.

Methods: Real-time RT PCR and western blot were used to detect p53 and AFP expression levels in HCC cells treated with icaritin. The mechanism of icaritin affecting p53 expression was verified by ubiquitination experiment, and the binding activity of icaritin on p53 in AFP promoter region was verified by luciferase experiment. EdU, MTT and flow cytometry were used to determine whether icaritin affected HCC cellular proliferation and apoptosis through p53/ AFP pathway. Expression levels of p53 and AFP in xenograft mouse model were determined by western blotting.

Results: Our results showed icaritin inhibited AFP expression at mRNA and protein level. AFP was also identified as the target gene of the p53 transcription factor. Icaritin abrogated murine double minute (Mdm) 2-mediated p53 ubiquitination degradation to improve the stability of p53. Up-regulated p53 protein levels then transcriptionally inhibited the AFP promoter. Icaritin-mediated decrease of AFP through Mdm2/p53 pathways inhibited HCC cellular proliferation and promoted HCC cellular apoptosis.

Conclusion: Our findings revealed the mechanism of icaritin in promoting apoptosis and inhibiting proliferation in liver cancer cells. The regulatory mechanism of icaritin in AFP protein down-regulation provides a theoretical and experimental basis for further research into new drugs for the treatment of liver cancer.
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http://dx.doi.org/10.1186/s12885-021-08043-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992931PMC
March 2021
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