Publications by authors named "Yue Zhong"

109 Publications

An efficient strategy for digging protein-protein interactions for rational drug design - A case study with HIF-1α/VHL.

Eur J Med Chem 2021 Sep 28;227:113871. Epub 2021 Sep 28.

National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address:

The ubiquitination of the hypoxia-inducible factor-1α (HIF-1α) is mediated by interacting with the von Hippel-Lindau protein (VHL), and is associated with cancer, chronic anemia, and ischemia. VHL, an E3 ligase, has been reported to degrade HIF-1 for decades, however, there are few successful inhibitors currently. Poor understanding of the binding pocket and a lack of in-depth exploration of the interactions between two proteins are the main reasons. Hence, we developed an effective strategy to identify and design new inhibitors for protein-protein interaction targets. The hydroxyproline (Hyp564) of HIF-1α contributed the key interaction between HIF-1α and VHL. In this study, detailed information of the binding pocket were explored by alanine scanning, site-directed mutagenesis and molecular dynamics simulations. Interestingly, we found the interaction(s) between Y565 and H110 played a key role in the binding of VHL/HIF-1α. Based on the interactions, 8 derivates of VH032, 16a-h, were synthesized by introducing various groups bounded to H110. Further assay on protein and cellular level exhibited that 16a-h accessed higher binding affinity to VHL and markable or modest improvement in stabilization of HIF-1α or HIF-1α-OH in HeLa cells. Our work provides a new orientation for the modification or design of VHL/HIF-1α protein-protein interaction inhibitors.
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http://dx.doi.org/10.1016/j.ejmech.2021.113871DOI Listing
September 2021

Overexpression of MAL2 Correlates with Immune Infiltration and Poor Prognosis in Breast Cancer.

Evid Based Complement Alternat Med 2021 9;2021:5557873. Epub 2021 Sep 9.

Department of Breast Diseases, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.

Background: Myelin and lymphocyte, T cell differentiation protein 2 (MAL2) is highly expressed in various cancers and associated with the development and prognosis of cancer. However, the relationship between MAL2 and breast cancer requires further investigation. This study aimed to explore the prognostic significance of MAL2 in breast cancer.

Methods: MAL2 expression was initially assessed using the Oncomine database and The Cancer Genome Atlas (TCGA) database and verified by quantitative real-time polymerase chain reaction (RT-qPCR). The chi-square test or Fisher's exact test was used to explore the association between clinical characteristics and MAL2 expression. The prognostic value of MAL2 in breast cancer was assessed by the Kaplan-Meier method and Cox regression analysis. Gene set enrichment analysis (GSEA) was performed to identify the biological pathways correlated with MAL2 expression in breast cancer. Besides, a single-sample GSEA (ssGSEA) was used to assess the relationship between the level of immune infiltration and MAL2 in breast cancer.

Results: Both bioinformatics and RT-qPCR results showed that MAL2 was expressed at high levels in breast cancer tissues compared with the adjacent tissues. The chi-square test or Fisher's exact test indicated that MAL2 expression was related to stage, classification, and vital status. Kaplan-Meier curves implicated that high MAL2 expression was significantly associated with the poor prognosis. Cox regression models showed that high MAL2 expression could be an independent risk factor for breast cancer. GSEA showed that 14 signaling pathways were enriched in the high-MAL2-expression group. Besides, the MAL2 expression level negatively correlated with infiltrating levels of eosinophils and plasmacytoid dendritic cells in breast cancer.

Conclusion: Overexpression of MAL2 correlates with poor prognosis and lower immune infiltrating levels of eosinophils and plasmacytoid dendritic cells in breast cancer and may become a biomarker for breast cancer prognosis.
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http://dx.doi.org/10.1155/2021/5557873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457941PMC
September 2021

A Network Pharmacology and Molecular Docking Strategy to Explore Potential Targets and Mechanisms Underlying the Effect of Curcumin on Osteonecrosis of the Femoral Head in Systemic Lupus Erythematosus.

Biomed Res Int 2021 13;2021:5538643. Epub 2021 Sep 13.

Department of Orthopaedic Surgery, First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.

Background: Systemic lupus erythematosus (SLE) is a refractory immune disease, which is often complicated with osteonecrosis of the femoral head (ONFH). Curcumin, the most active ingredient of Curcuma longa with a variety of biological activities, has wide effects on the body system. The study is aimed at exploring the potential therapeutic targets underlying the effect of curcumin on SLE-ONFH by utilizing a network pharmacology approach and molecular docking strategy.

Methods: Curcumin and its drug targets were identified using network analysis. First, the Swiss target prediction, GeneCards, and OMIM databases were mined for information relevant to the prediction of curcumin targets and SLE-ONFH-related targets. Second, the curcumin target gene, SLE-ONFH shared gene, and curcumin-SLE-ONFH target gene networks were created in Cytoscape software followed by collecting the candidate targets of each component by R software. Third, the targets and enriched pathways were examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Eventually, a gene-pathway network was constructed and visualized by Cytoscape software; key potential central targets were verified and checked by molecular docking and literature review.

Results: 201 potential targets of curcumin and 170 related targets involved in SLE-ONFH were subjected to network analysis, and the 36 intersection targets indicated the potential targets of curcumin for the treatment of SLE-ONFH. Additionally, for getting more comprehensive and accurate candidate genes, the 36 potential targets were determined to be analyzed by network topology and 285 candidate genes were obtained finally. The top 20 biological processes, cellular components, and molecular functions were identified, when corrected by a value ≤ 0.05. 20 related signaling pathways were identified by KEGG analysis, when corrected according to a Bonferroni value ≤ 0.05. Molecular docking showed that the top three genes (TP53, IL6, VEGFA) have good binding force with curcumin; combined with literature review, some other genes such as TNF, CCND1, CASP3, and MMP9 were also identified.

Conclusion: The present study explored the potential targets and signaling pathways of curcumin against SLE-ONFH, which could provide a better understanding of its effects in terms of regulating cell cycle, angiogenesis, immunosuppression, inflammation, and bone destruction.
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http://dx.doi.org/10.1155/2021/5538643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455200PMC
September 2021

α-Mangostin Induces Apoptosis and Inhibits Metastasis of Breast Cancer Cells via Regulating RXRα-AKT Signaling Pathway.

Front Pharmacol 2021 30;12:739658. Epub 2021 Aug 30.

School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.

Mangostin, which has the function of anti-inflammatory, antioxidant, and anticancer, etc, is one of the main active ingredients of the hull of the mangosteen. The main objective of the study was to elucidate its anti-cancer function and possible mechanism. α-Mangostin was separated and structurally confirmed. MTT method was used to check the effect of mangostin on breast cancer cell proliferation. Then the effect of α-Mangostin on the transcriptional activity of RXRα was tested by dual-luciferase reporter gene assay. And Western blot (WB) was used to detect the expression of apoptosis-related proteins or cell cycle-associated proteins after treatment. Also, this study was to observe the effects of α-Mangostin on the invasion of breast cancer cell line MDA-MB-231. α-Mangostin regulates the downstream effectors of the PI3K/AKT signaling pathway by degrading RXRα/tRXRα. α-Mangostin can trigger PARP cleavage and induce apoptosis, which may be related to the induction of upregulated BAX expression and downregulation of BAD and cleaved caspase-3 expression in MDA-MB-231 cells through blockade of AKT signaling. The experiments verify that α-Mangostin have evident inhibition effects of invasion and metastasis of MDA-MB-231 cells. Cyclin D1 was involved in the anticancer effects of α-Mangostin on the cell cycle in MDA-MB-231 cells. α-Mangostin induces apoptosis, suppresses the migration and invasion of breast cancer cells through the PI3K/AKT signaling pathway by targeting RXRα, and cyclin D1 has involved in this process.
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http://dx.doi.org/10.3389/fphar.2021.739658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444262PMC
August 2021

Can N3 Period Duration Serve as a Predictor of Cognitive Dysfunction?

Am J Respir Crit Care Med 2021 Sep 3. Epub 2021 Sep 3.

Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Respiratory, Guangzhou, China.

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http://dx.doi.org/10.1164/rccm.202105-1231LEDOI Listing
September 2021

Pulmonary Hypertension: A Predictor of Lung Cancer Prognosis?

Am J Respir Crit Care Med 2021 Sep 2. Epub 2021 Sep 2.

Guangzhou Medical University The First Associated Hospital, Guangzhou Institute of Respiratory Diseases, Guangzhou, China;

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http://dx.doi.org/10.1164/rccm.202105-1256LEDOI Listing
September 2021

miRNA-451 regulates the NF-κB signaling pathway by targeting IKKβ to inhibit glioma cell growth.

Cell Cycle 2021 Aug 31:1-11. Epub 2021 Aug 31.

Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.

Glioblastoma multiforme (GBM) is associated with a poor prognosis, and effective treatments are lacking. Our previous studies have shown that miRNA-451 is closely related to the development and progression of glioma. miRNA-451 is a tumor suppressor whose expression is negatively correlated with the WHO grades of gliomas, but its specific mechanism is still unclear. Research shows that NF-κB is highly expressed in early malignant glioma, and thus, the NF-κB signaling pathway has become an important target for the treatment of malignant glioma. Activation of IKK is a critical step in the activation of the classical NF-κB pathway. By performing a bioinformatics analysis, we found that IKKβ is a potential direct target of miRNA-451 in glioma. In this study, we transfected lentivirus expressing miRNA-451 to test the effect of miRNA-451 overexpression on malignant glioma cell lines and confirmed that IKKβ is a target gene of miRNA-451 by luciferase assay. By targeting IKKβ, MTT, cell invasion and wound-healing assays showed that cell proliferation, cell invasion and migration were significantly suppressed in the LV-miRNA-451 group. Western blotting results showed that the expression levels of IKKβ, p-p65, MMP-2, MMP-9, Cyclin D1, p16 and PCNA were significantly decreased in the LV-miRNA-451 group. In vivo, miRNA-451 significantly decreased glioma cell growth, and the survival of BALB/c-A nude mice was significantly prolonged. Immunohistochemistry showed that p-p65, Cyclin D1 and Ki67 expression was significantly reduced in the LV-miRNA-451 group. Taken together, these results suggest that miRNA-451 could regulate the NF-κB signaling pathway by targeting IKKβ, which inhibits glioma cell growth in vitro and in vivo. Therefore, this study may provide novel insight into miRNA-451-targeted therapy for glioma.
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http://dx.doi.org/10.1080/15384101.2021.1969496DOI Listing
August 2021

Is the Atrial Reverse Remodeling after Ablation of Atrial Fibrillation Associated with Reduced Rehospitalization Rate?

Authors:
Yue Zhong Li Rao

J Am Soc Echocardiogr 2021 Aug 27. Epub 2021 Aug 27.

Department of Cardiology, Sichuan University West China Hospital, Chengdu, Sichuan, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.echo.2021.08.012DOI Listing
August 2021

The Role and Function of Regulatory T Cells in -Induced Adverse Pregnancy Outcomes.

J Immunol Res 2021 18;2021:8782672. Epub 2021 Aug 18.

Department of Pathogen Biology, School of Medicine, Nantong University, Nantong, 226001 Jiangsu, China.

Infection with () during the pregnant period and its potentially miserable outcomes for the fetus, newborn, and even adult offspring continuously occur worldwide. People acquire infection through the consumption of infected and undercooked meat or contaminated food or water. infection in pregnant women primarily during the gestation causes microcephaly, mental and psychomotor retardation, or death. Abnormal pregnancy outcomes are mainly associated with regulatory T cell (Treg) dysfunction. Tregs, a special subpopulation of T cells, function as a vital regulator in maintaining immune homeostasis. Tregs exert a critical effect on forming and maintaining maternal-fetal tolerance and promoting fetal development during the pregnancy period. Forkhead box P3 (Foxp3), a significant functional factor of Tregs, determines the status of Tregs. In this review, we summarize the effects of infection on host Tregs and its critical transcriptional factor, Foxp3.
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http://dx.doi.org/10.1155/2021/8782672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390175PMC
August 2021

Left ventricular diastolic pressure gradient and outcome in advanced chronic kidney disease patients with preserved ejection fraction.

Int J Cardiovasc Imaging 2021 Sep 20;37(9):2663-2673. Epub 2021 Jul 20.

Department of Cardiology, West China Hospital of Sichuan University, 37 Guoxue Alley, Chengdu, 610041, Sichuan, China.

Assessment of left ventricular (LV) diastolic dysfunction is important in patients with chronic kidney disease (CKD). The early diastolic peak intraventricular pressure gradient (IVPG) has a vital role in diastolic function. Relative pressure imaging (RPI) is a new echocardiographic method to quantify IVPG. The purpose of this study was to analyze RPI-derived IVPG in advanced CKD patients with preserved LV ejection fraction. The study population consisted of 51 advanced CKD patients and 39 healthy controls. Patients were stratified by the evidence of heart failure with preserved ejection fraction (HFpEF) into HFpEF group (32 patients) and non-HFpEF group (19 patients). RPI analysis was used to determine the early diastolic LV relative pressure and pressure distribution. The total IVPG and segmental IVPGs corresponding to basal, mid, and apical part of the LV were calculated. Total IVPG, along with apical and mid IVPGs were all significantly reduced in HFpEF Group compared with non-HFpEF Group and controls (all P < 0.05). But no significant difference of total or segmental IVPGs was found between non-HFpEF Group and the controls. Additionally, apical IVPG < 0.02 mmHg/cm (Hazard ratio 9.82, 95 % confidence interval 2.01-48.01, P = 0.005) was the independent risk factor for the composite outcome (mortality and cardiovascular hospitalization) during a median follow-up of 24 months. Advanced CKD patients with HFpEF exhibited decreased apical and mid IVPG of the LV, and the severity of apical IVPG reduction correlated with poor outcome.
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http://dx.doi.org/10.1007/s10554-021-02339-4DOI Listing
September 2021

Metabolic Remodeling in Glioma Immune Microenvironment: Intercellular Interactions Distinct From Peripheral Tumors.

Front Cell Dev Biol 2021 11;9:693215. Epub 2021 Jun 11.

Department of Clinical Pharmacology Lab, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.

During metabolic reprogramming, glioma cells and their initiating cells efficiently utilized carbohydrates, lipids and amino acids in the hypoxic lesions, which not only ensured sufficient energy for rapid growth and improved the migration to normal brain tissues, but also altered the role of immune cells in tumor microenvironment. Glioma cells secreted interferential metabolites or depriving nutrients to injure the tumor recognition, phagocytosis and lysis of glioma-associated microglia/macrophages (GAMs), cytotoxic T lymphocytes, natural killer cells and dendritic cells, promoted the expansion and infiltration of immunosuppressive regulatory T cells and myeloid-derived suppressor cells, and conferred immune silencing phenotypes on GAMs and dendritic cells. The overexpressed metabolic enzymes also increased the secretion of chemokines to attract neutrophils, regulatory T cells, GAMs, and dendritic cells, while weakening the recruitment of cytotoxic T lymphocytes and natural killer cells, which activated anti-inflammatory and tolerant mechanisms and hindered anti-tumor responses. Therefore, brain-targeted metabolic therapy may improve glioma immunity. This review will clarify the metabolic properties of glioma cells and their interactions with tumor microenvironment immunity, and discuss the application strategies of metabolic therapy in glioma immune silence and escape.
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http://dx.doi.org/10.3389/fcell.2021.693215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239469PMC
June 2021

Oxygenation: An important indicator for evaluating the effect of treating pulmonary hypertension.

Int J Cardiol 2021 09 9;338:239-240. Epub 2021 Jun 9.

Department of Respiration, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2021.06.005DOI Listing
September 2021

A meta-analysis of the diagnostic value of NoSAS in patients with sleep apnea syndrome.

Sleep Breath 2021 Jun 9. Epub 2021 Jun 9.

China State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Objective: The NoSAS score is a new tool widely used in recent years to screen for obstructive sleep apnea. A number of studies have shown that the NoSAS score is more accurate than previous tools, such as the Berlin, STOP-Bang, and STOP questionnaires. Therefore, this meta-analysis assessed the diagnostic value of the NoSAS score for sleep apnea syndrome in comparison to polysomnography.

Methods: Two researchers searched the PubMed, EMBASE, Cochrane, and Web of Science databases through November 13, 2020. This paper used Endnote9.3 software to manage the literature and RevMan 5.3 and STATA12.0 software to perform the meta-analysis.

Results: A total of 10 studies were included in this meta-analysis, including 14,510 patients. The meta-analysis showed that the pooled sensitivity was 0.798 (95% CI 0.757, 0.833), the pooled specificity was 0.582 (95% CI 0.510, 0.651), the positive likelihood ratio was 1.909 (95% CI 1.652, 2.206), the negative likelihood ratio was 0.347 (95% CI 0.300, 0.403), the diagnostic OR was 5.495 (95% CI 4.348, 6.945), and the area under the SROC curve was 0.77 (95% CI 0.73, 0.80). The NoSAS score has good efficacy in identifying patients likely to have obstructive sleep apnea.

Conclusion: The NoSAS score can accurately identify patients likely to have obstructive sleep apnea. Therefore, in the absence of polysomnography, one should use the NoSAS score to evaluate patients with suspected sleep apnea syndrome.
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http://dx.doi.org/10.1007/s11325-021-02410-3DOI Listing
June 2021

Gut microbiota mediates the effects of curcumin on enhancing Ucp1-dependent thermogenesis and improving high-fat diet-induced obesity.

Food Funct 2021 Jul 7;12(14):6558-6575. Epub 2021 Jun 7.

College of Pharmacy, Jilin Medical University, Jilin, Jilin, China.

Due to extremely poor systemic bioavailability, the mechanism by which curcumin increases energy expenditure remains unelucidated. Accumulating evidence suggests a strong association between the gut microbiota (GM) and energy metabolism. We investigated whether the GM mediates the effects of curcumin on improving energy homeostasis. High-fat diet (HFD)-fed wild type, uncoupling protein 1 (Ucp1) knockout and G protein-coupled membrane receptor 5 (TGR5) knockout mice were treated with curcumin (100 mg kg d, p.o.). Curcumin-treated HFD-fed mice displayed decreased body weight gain and augmented cold tolerance due to enhanced adaptive thermogenesis as compared with that in control mice. The anti-obesity effects of curcumin were abolished by Ucp1 knockout. 16S ribosomal DNA sequencing analysis revealed that curcumin restructured the GM in HFD-fed mice. Fecal microbiota transplantation (FMT) and endogenous GM depletion indicated that the GM mediated the enhanced effect of curcumin on Ucp1-dependent thermogenesis. Curcumin altered bile acid (BA) metabolism with increased fractions of circulating deoxycholic acid (DCA) and lithocholic acid (LCA), which are the two most potent ligands for TGR5. Consistently, the enhanced effect of curcumin on Ucp1-dependent thermogenesis was eliminated by TGR5 knockout. Curcumin requires the GM and TGR5 to activate the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway in thermogenic adipose tissue. Here, we demonstrated that the GM mediates the effects of curcumin on enhancing Ucp1-dependent thermogenesis and ameliorating HFD-induced obesity by influencing BA metabolism. We disclosed the potential of nutritional and pharmacologic manipulations of the GM to enhance Ucp1-dependent thermogenesis in the prevention and treatment of obesity.
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http://dx.doi.org/10.1039/d1fo00671aDOI Listing
July 2021

Bufotenine and its derivatives: synthesis, analgesic effects identification and computational target prediction.

Chin J Nat Med 2021 Jun;19(6):454-463

National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address:

Natural product bufotenine (5) which could be isolated from Venenum Bufonis, has been widely used as a tool in central nervous system (CNS) studies. We present here its quaternary ammonium salt (6) which was synthesized with high yields using 5-benzyloxyindole as raw materials, and we firstly discover its analgesic effects in vivo. The analgesic evaluation showed that compounds 5 and 6 had stronger effects on the behavior of formalin induced pain in mice. Moreover, the combination of compound 6 and morphine has a synergistic effect. We intended to explain the molecular mechanism of this effect. Therefore, 36 analgesic-related targets (including 15 G protein-coupled receptors, 6 enzymes, 13 ion channels, and 2 others) were systemically evaluated using reverse docking. The results indicate that bufotenine and its derivatives are closely related to acetyl cholinesterase (AChE) or αβ nicotinic acetylcholine receptor (nAChR). This study provides practitioners a new insight of analgesic effects.
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http://dx.doi.org/10.1016/S1875-5364(21)60044-4DOI Listing
June 2021

o-Vanillin, a promising antifungal agent, inhibits Aspergillus flavus by disrupting the integrity of cell walls and cell membranes.

Appl Microbiol Biotechnol 2021 Jun 4;105(12):5147-5158. Epub 2021 Jun 4.

Henan Key Laboratory of Cereal and Oil Food Safety Inspection and Control, College of Food Science and Engineering, Henan University of Technology, Zhengzhou, 450001, Henan, People's Republic of China.

o-Vanillin is a natural product that has been widely applied in the food and pharmaceutical industries. In this study, we determined that o-vanillin can strongly inhibit the growth of Aspergillus flavus mycelia. However, the inhibition mechanism of o-vanillin is still elusive. The ultrastructural morphology of mycelia was injured, and the cell walls were destroyed. The OH functional groups on cell walls were altered, and the content of protein in mycelial cell walls was reduced by o-vanillin. The content of β-1,3-glucan in cell walls was significantly (P < 0.05) reduced by o-vanillin in a dose-dependent manner, while chitin was not markedly affected. Moreover, o-vanillin led to an increase in the permeability of cell membranes. o-Vanillin also exhibited a promising antifungal effect on contaminated corn kernels. Therefore, o-vanillin inhibited the growth of mycelia by disrupting the integrity of cell walls and cell membranes. This study not only sheds light on the antifungal mechanism of o-vanillin but also indicates that it is a promising agent for the control of A. flavus infection. KEY POINTS: • o-Vanillin has strong inhibitory effects on A. flavus. • o-Vanillin destroyed the integrity of cell walls and cell membranes. • o-Vanillin could effectively inhibit the growth of A. flavus on corn kernels.
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http://dx.doi.org/10.1007/s00253-021-11371-2DOI Listing
June 2021

miR-451 suppresses EMT and metastasis in glioma cells.

Cell Cycle 2021 Jul 28;20(13):1270-1278. Epub 2021 May 28.

Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.

The metastasis of tumor cells is a challenge for the clinical treatment of glioma. Epithelial-mesenchymal transition (EMT) contributes to glioma cell invasiveness. Our previous study confirmed that the expression of miRNA-451, which inhibits the PI3K/Akt signaling pathway by directly targeting CAB39 and plays a repressive role in glioma, is downregulated in glioma. However, the specific mechanism of miRNA-451 regulation in glioma is unclear. In this study, we investigated whether miRNA-451 blocks the processes of EMT and metastasis in glioma cells in vivo and in vitro. By targeting CAB39, miRNA-451 likely triggers the PI3K/Akt/Snail signaling pathway to reduce glioma proliferation, invasion, migration and EMT. We used Western blotting experiments to demonstrate that overexpression of miRNA-451 significantly reduced p-AKT(Ser473), N-cadherin, Vimentin, Twist, Snail and Cyclin D1 expression and increased E-cadherin expression. We demonstrated that overexpression of miR-451 suppressed glioma cell proliferation, invasion, migration and EMT by MTT and colony formation assays, Transwell assays, wound healing assays and animal experiments. Taken together, these results suggest that miRNA-451 can reduce EMT and metastasis in glioma cells through the suppression of the PI3K/Akt/Snail signaling pathway by targeting CAB39 in vitro and in vivo. miR-451 may be a new target for glioma treatment.
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http://dx.doi.org/10.1080/15384101.2021.1933303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331032PMC
July 2021

Development of Prognostic Evaluation Model to Predict the Overall Survival and Early Recurrence of Hepatocellular Carcinoma.

J Hepatocell Carcinoma 2021 29;8:301-312. Epub 2021 Apr 29.

The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350025, People's Republic of China.

Background: The aberrant expressions of lncRNAs have been frequently demonstrated to be closely associated with the prognosis of patients in many cancer types including hepatocellular carcinoma (HCC). Integration of these lncRNAs might provide accurate evaluation of HCC. Therefore, this study aims to develop a novel prognostic evaluation model based on the expression of lncRNAs to predict the survival of HCC patients, postoperatively.

Patients And Methods: RNA sequencing (RNA-seq) analysis was performed for 61 HCC patients (training cohort) to screen prognosis-associated lncRNAs with univariate Cox regression and Log rank test analyses. Multivariate Cox regression analysis was then applied to establish the final model, which was further verified in a validation cohort (n=191). Moreover, performance of the mode was assessed with time-dependent receiver operating characteristic curve (tdROC), Harrell's c-index, and Gönen & Heller's K.

Results: After a serial statistical computation, a novel risk scoring model consisting of four lncRNAs and TNM staging was established, which could successfully divide the HCC patients into low-risk and high-risk groups with significantly different OS and RFS in both training and validation cohorts. tdROC analysis showed that this model achieved a high performance in predicting OS and 2-year RFS in both cohorts. Gene Set Enrichment Analysis revealed that HCC tumor tissues with high-risk score have stronger capacities in immune escape and resistance to treatment.

Conclusion: We successfully established a novel prognostic evaluation model, which exhibited reliable capacity in predicting the OS and early recurrence of HCC patients with relatively higher accuracy.
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http://dx.doi.org/10.2147/JHC.S303330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092946PMC
April 2021

A dissecting aneurysm of the sinus of Valsalva involving the inter-ventricsular septum in a patient with syphilis and a quadricuspid aortic valve.

Echocardiography 2021 06 30;38(6):1061-1063. Epub 2021 Apr 30.

Cardiology Department, West China Hospital, Sichuan University, China.

Aneurysms of the sinus of Valsalva are rare, with dissecting aneurysms of the sinus of Valsalva that extend into the inter-ventricular septum being even more rare. This report describes a young patient with syphilis and a quadricuspid aortic valve who experienced a spontaneously dissecting aneurysm of the sinus of Valsalva and the basal inter-ventricular septum.
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http://dx.doi.org/10.1111/echo.15055DOI Listing
June 2021

[The preliminary value of vector flow mapping on assessment of left intraventricular pressure difference in patients with paroxysmal atrial fibrillation].

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2021 Apr;38(2):310-316

Department of Cardiology, West China Hospital, Sichuan University, Chengdu 610041, P.R.China.

This study aims to explore the intraventricular pressure difference (IVPD) within left ventricle in patients with paroxysmal atrial fibrillation (PAF) by using the relative pressure imaging (RPI) of vector flow mapping (VFM). Twenty patients with paroxysmal atrial fibrillation (PAF) and thirty control subjects were enrolled in the study. Systolic and diastolic IVPD derived from VFM within left ventricle and conventional echocardiographic parameters were analyzed. It was found that the B-A IVPD of left ventricle in PAF patients showed the same pattern as controls-single peak and single valley during systole and double peaks and double valleys during diastole. Basal IVPD was the main component of base to apex IVPD (B-A IVPD). The isovolumetric systolic IVPD was associated with early systolic IVPD, early systolic IVPD was associated with late systolic IVPD, and late systolic IVPD was associated with isovolumic diastolic IVPD (all < 0.05). The B-A IVPD and basal IVPD during isovolumetric systole, early systole, late systole and isovolumetric diastole in PAF patients significantly decreased (all < 0.05). The study shows that the B-A IVPD pattern of the PAF group is the same as controls, but systolic B-A IVPD and basal IVPD are significantly reduced in PAF patients. VFM-derived RPI can evaluate left ventricular IVPD in PAF patients, providing a visually quantitative method for evaluating left ventricular hemodynamic mechanics in the patients with PAF.
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http://dx.doi.org/10.7507/1001-5515.202011004DOI Listing
April 2021

A Deep Ensemble Predictor for Identifying Anti-Hypertensive Peptides Using Pre-trained Protein Embedding.

IEEE/ACM Trans Comput Biol Bioinform 2021 Mar 24;PP. Epub 2021 Mar 24.

Hypertension (HT), or high blood pressure is one of the most common and main causes in cardiovascular diseases, which is also related to a series of detrimental diseases in humans. Deficiencies in effective treatment in HT are often associated with a series of diseases including multi-infarct dementia, amputation, and renal failure. Therefore, identifying anti-hypertension peptides has the vital realistic significance. Although many bioactive peptides have been developed to reduce blood pressure, they are time-consuming and laborious. In views of the obstacles of the intrinsic methods in antihypertensive peptide (AHTP) classification, computational methods are suggested as a supplement to identify AHTPs. In this study, we develop a comprehensive feature rep-resentation algorithm based on pretrained model and convolutional neural network and apply the deep ensemble model to construct the prediction model. The new predictor is used to identify AHTPs in benchmark and independent datasets. It has been shown in the independent test set that the performance is better than the recent methods. Comparative results indicate that our model can shed some light on hypertension therapy and gains more insights of classifying AHTPs. The implements and codes can be found in https://github.com/yuanying566/AHPred-DE.
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http://dx.doi.org/10.1109/TCBB.2021.3068381DOI Listing
March 2021

SE-OnionNet: A Convolution Neural Network for Protein-Ligand Binding Affinity Prediction.

Front Genet 2020 19;11:607824. Epub 2021 Feb 19.

Trinity Earth Technology Co. Ltd, Beijing, China.

Deep learning methods, which can predict the binding affinity of a drug-target protein interaction, reduce the time and cost of drug discovery. In this study, we propose a novel deep convolutional neural network called SE-OnionNet, with two squeeze-and-excitation (SE) modules, to computationally predict the binding affinity of a protein-ligand complex. The OnionNet is used to extract a feature map from the three-dimensional structure of a protein-drug molecular complex. The SE module is added to the second and third convolutional layers to improve the non-linear expression of the network to improve model performance. Three different optimizers, stochastic gradient descent (SGD), Adam, and Adagrad, were also used to improve the performance of the model. A majority of protein-molecule complexes were used for training, and the comparative assessment of scoring functions (CASF-2016) was used as the benchmark. Experimental results show that our model performs better than OnionNet, Pafnucy, and AutoDock Vina. Finally, we chose the macrophage migration inhibitor factor (PDB ID: 6cbg) to test the stability and robustness of the model. We found that the prediction results were not affected by the docking position, and thus, our model is of acceptable robustness.
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http://dx.doi.org/10.3389/fgene.2020.607824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962986PMC
February 2021

Impact of concomitant tricuspid annuloplasty on right ventricular remodeling in patients with rheumatic mitral valve disease.

Cardiovasc Ultrasound 2021 Mar 4;19(1):16. Epub 2021 Mar 4.

Department of Cardiology, West China Hospital of Sichuan University, 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, China.

Background: Studies on the management of functional tricuspid regurgitation (TR) during mitral valve operations have drawn inconsistent conclusions. This study was designed to compare the treatment strategy of concomitant tricuspid annuloplasty (TAP) against isolated mitral valve replacement (MVR) in rheumatic mitral valve disease patients, and to assess the effect of concomitant TAP on postoperative right ventricular (RV) remodeling and function.

Methods: One hundred-seventy patients with rheumatic mitral valve disease receiving MVR were categorized into TAP group (n = 124) and non-TAP group (n = 46). Clinical and echocardiographic data were collected preoperatively and at 1-year follow-up. Three-dimensional echocardiographic indices of RV geometry and function were analyzed.

Results: At baseline, concomitant TAP group had larger RV end-diastolic volume, more decreased RV ejection fraction and RV longitudinal strain than non-TAP group (all P <  0.001). At 1-year follow-up, TAP group had improved RV geometry and function. While adverse changes were observed in non-TAP group. In analysis of variance, the above indices demonstrated significant interaction with different treatment group (all P <  0.001). In multivariate regression analysis, independent of age and Maze procedure, concomitant TAP was associated with postoperative RV volume reduction (P <  0.001), improvement of RV ejection fraction (P <  0.001), and relieved postoperative functional TR severity (P = 0.025).

Conclusions: Our results suggest that concomitant TAP could improve RV remodeling and function for rheumatic mitral valve disease patients, while those with mild preoperative functional TR who had isolated MVR might experience RV dilation and deterioration of RV function at follow-up. Concomitant surgery for functional TR could be considered for patients undergoing MVR with rheumatic mitral valve disease.
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http://dx.doi.org/10.1186/s12947-021-00245-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934510PMC
March 2021

Repositioning Drugs to the Mitochondrial Fusion Protein 2 by Three-Tunnel Deep Neural Network for Alzheimer's Disease.

Front Genet 2021 15;12:638330. Epub 2021 Feb 15.

Department of Neurology Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Alzheimer's disease (AD) is a common neurodegenerative dementia in the elderly. Although there is no effective drug to treat AD, proteins associated with AD have been discovered in related studies. One of the proteins is mitochondrial fusion protein 2 (Mfn2), and its regulation presumably be related to AD. However, there is no specific drug for Mfn2 regulation. In this study, a three-tunnel deep neural network (3-Tunnel DNN) model is constructed and trained on the extended Davis dataset. In the prediction of drug-target binding affinity values, the accuracy of the model is up to 88.82% and the loss value is 0.172. By ranking the binding affinity values of 1,063 approved drugs and small molecular compounds in the DrugBank database, the top 15 drug molecules are recommended by the 3-Tunnel DNN model. After removing molecular weight <200 and topical drugs, a total of 11 drug molecules are selected for literature mining. The results show that six drugs have effect on AD, which are reported in references. Meanwhile, molecular docking experiments are implemented on the 11 drugs. The results show that all of the 11 drug molecules could dock with Mfn2 successfully, and 5 of them have great binding effect.
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http://dx.doi.org/10.3389/fgene.2021.638330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917248PMC
February 2021

Predicting drug-target affinity based on recurrent neural networks and graph convolutional neural networks.

Comb Chem High Throughput Screen 2021 Feb 14. Epub 2021 Feb 14.

College of Computer Science and Technology, China University of Petroleum, Qingdao 266580, Shandong. China.

Background: Drug development requires a lot of money and time, and the outcome of the challenge is unknown. So, there is an urgent need for researchers to find a new approach that can reduce costs. Therefore, the identification of drug-target interactions (DTIs) has been a critical step in the early stages of drug discovery. These computational methods aim to narrow the search space for novel DTIs and to elucidate the functional background of drugs. Most of the methods developed so far use binary classification to predict the presence or absence of interactions between the drug and the target. However, it is more informative, but also more challenging, to predict the strength of the binding between a drug and its target. If the strength is not strong enough, such a DTI may not be useful. Hence, the development of methods to predict drug-target affinity (DTA) is of significant importance.

Method: We have improved the Graph DTA model from a dual-channel model to a triple-channel model. We interpreted the target/protein sequences as time series and extracted their features using the LSTM network. For the drug, we considered both the molecular structure and the local chemical background, retaining the four variant networks used in Graph DTA to extract the topological features of the drug and capturing the local chemical background of the atoms in the drug by using BiGRU. Thus, we obtained the latent features of the target and two latent features of the drug. The connection of these three feature vectors is then input into a 2-layer FC network, and a valuable binding affinity is output.

Result: We use the Davis and Kiba datasets, using 80% of the data for training and 20% of the data for validation. Our model shows better performance by comparing it with the experimental results of Graph DTA.

Conclusion: In this paper, we altered the Graph DTA model to predict drug-target affinity. It represents the drug as a graph, and extracts the two-dimensional drug information using a graph convolutional neural network. Simultaneously, the drug and protein targets are represented as a word vector, and the convolutional neural network is used to extract the time series information of the drug and the target. We demonstrate that our improved method has better performance than the original method. In particular, our model has better performance in the evaluation of benchmark databases.
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http://dx.doi.org/10.2174/1386207324666210215101825DOI Listing
February 2021

Screening and identifying hepatobiliary diseases through deep learning using ocular images: a prospective, multicentre study.

Lancet Digit Health 2021 02;3(2):e88-e97

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, Sun Yat-sen University, Guangzhou, China; Centre for Precision Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address:

Background: Ocular changes are traditionally associated with only a few hepatobiliary diseases. These changes are non-specific and have a low detection rate, limiting their potential use as clinically independent diagnostic features. Therefore, we aimed to engineer deep learning models to establish associations between ocular features and major hepatobiliary diseases and to advance automated screening and identification of hepatobiliary diseases from ocular images.

Methods: We did a multicentre, prospective study to develop models using slit-lamp or retinal fundus images from participants in three hepatobiliary departments and two medical examination centres. Included participants were older than 18 years and had complete clinical information; participants diagnosed with acute hepatobiliary diseases were excluded. We trained seven slit-lamp models and seven fundus models (with or without hepatobiliary disease [screening model] or one specific disease type within six categories [identifying model]) using a development dataset, and we tested the models with an external test dataset. Additionally, we did a visual explanation and occlusion test. Model performances were evaluated using the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, and F1* score.

Findings: Between Dec 16, 2018, and July 31, 2019, we collected data from 1252 participants (from the Department of Hepatobiliary Surgery of the Third Affiliated Hospital of Sun Yat-sen University, the Department of Infectious Diseases of the Affiliated Huadu Hospital of Southern Medical University, and the Nantian Medical Centre of Aikang Health Care [Guangzhou, China]) for the development dataset; between Aug 14, 2019, and Jan 31, 2020, we collected data from 537 participants (from the Department of Infectious Diseases of the Third Affiliated Hospital of Sun Yat-sen University and the Huanshidong Medical Centre of Aikang Health Care [Guangzhou, China]) for the test dataset. The AUROC for screening for hepatobiliary diseases of the slit-lamp model was 0·74 (95% CI 0·71-0·76), whereas that of the fundus model was 0·68 (0·65-0·71). For the identification of hepatobiliary diseases, the AUROCs were 0·93 (0·91-0·94; slit-lamp) and 0·84 (0·81-0·86; fundus) for liver cancer, 0·90 (0·88-0·91; slit-lamp) and 0·83 (0·81-0·86; fundus) for liver cirrhosis, and ranged 0·58-0·69 (0·55-0·71; slit-lamp) and 0·62-0·70 (0·58-0·73; fundus) for other hepatobiliary diseases, including chronic viral hepatitis, non-alcoholic fatty liver disease, cholelithiasis, and hepatic cyst. In addition to the conjunctiva and sclera, our deep learning model revealed that the structures of the iris and fundus also contributed to the classification.

Interpretation: Our study established qualitative associations between ocular features and major hepatobiliary diseases, providing a non-invasive, convenient, and complementary method for hepatobiliary disease screening and identification, which could be applied as an opportunistic screening tool.

Funding: Science and Technology Planning Projects of Guangdong Province; National Key R&D Program of China; Guangzhou Key Laboratory Project; National Natural Science Foundation of China.
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http://dx.doi.org/10.1016/S2589-7500(20)30288-0DOI Listing
February 2021

Predicting the Disease Risk of Protein Mutation Sequences With Pre-training Model.

Front Genet 2020 21;11:605620. Epub 2020 Dec 21.

College of Information Science and Engineering, Hunan University, Changsha, China.

Accurately identifying the missense mutations is of great help to alleviate the loss of protein function and structural changes, which might greatly reduce the risk of disease for tumor suppressor genes (e.g., BRCA1 and PTEN). In this paper, we propose a hybrid framework, called BertVS, that predicts the disease risk for the missense mutation of proteins. Our framework is able to learn sequence representations from the protein domain through pre-training BERT models, and also integrates with the hydrophilic properties of amino acids to obtain the sequence representations of biochemical characteristics. The concatenation of two learned representations are then sent to the classifier to predict the missense mutations of protein sequences. Specifically, we use the protein family database (Pfam) as a corpus to train the BERT model to learn the contextual information of protein sequences, and our pre-training BERT model achieves a value of 0.984 on accuracy in the masked language model prediction task. We conduct extensive experiments on BRCA1 and PTEN datasets. With comparison to the baselines, results show that BertVS achieves higher performance of 0.920 on AUROC and 0.915 on AUPR in the functionally critical domain of the BRCA1 gene. Additionally, the extended experiment on the ClinVar dataset can illustrate that gene variants with known clinical significance can also be efficiently classified by our method. Therefore, BertVS can learn the functional information of the protein sequences and effectively predict the disease risk of variants with an uncertain clinical significance.
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http://dx.doi.org/10.3389/fgene.2020.605620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780924PMC
December 2020

The long noncoding RNA HCG18 participates in PM2.5-mediated vascular endothelial barrier dysfunction.

Aging (Albany NY) 2020 11 16;12(23):23960-23973. Epub 2020 Nov 16.

GMU-GIBH Joint School of Life Sciences, Center of Reproductive Medicine, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510182, China.

Increased vascular endothelial permeability can disrupt vascular barrier function and further lead to multiple human diseases. Our previous reports indicated that particulate matter 2.5 (PM2.5) can enhance the permeability of vascular endothelial cells. However, the regulatory mechanism was not comprehensively demonstrated. Therefore, this work elucidated this mechanism by demonstrating that PM2.5 can increase the permeability of HUVECs by inhibiting the expression of Hickson compact group 18 (HCG18). Moreover, we demonstrated that lncRNA HCG18 functioned as a ceRNA for miR-21-5p and led to the derepression of its target SOX7, which could further transcriptionally activate the expression of VE-cadherin to regulate the permeability of HUVECs. In this study, we provide evidence that HCG18/miR-21-5p/SOX7/VE-cadherin signaling is involved in PM2.5-induced vascular endothelial barrier dysfunction.
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http://dx.doi.org/10.18632/aging.104073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762519PMC
November 2020

[Study on molecular target of Taohong Siwu Decoction in delaying growth of fibroblasts based on network pharmacology].

Zhongguo Zhong Yao Za Zhi 2020 Sep;45(17):4120-4128

the First Clinical Medical College of Guangzhou University of Chinese Medicine Guangzhou 510405, China.

As a prescription for promoting blood circulation and removing blood stasis, Taohong Siwu Decoction(THSWD) has certain effects in delaying the progression of renal fibrosis. However, as a traditional Chinese medicine compound containing many monomer components, it has been a research hotspot in the field of exploring the research methods and targets for the complex pathological process. The method of activating blood circulation and removing blood stasis has certain clinical effect in retarding the process of IgA nephropathy(IgAN) fibrosis, but the mechanism of action is still unclear. In this study, the network pharmacology method was used to investigate the active ingredients, targets and molecular mechanisms of THSWD in the intervention of IgAN fibrosis. On this basis, in vitro experiments were conducted to verify the effect of THSWD on the expression of ERK factor in BALB/c 3 T3 cells. The active ingredients and targets in THSWD were collected through the TCMSP. Sixty-one active ingredients and 240 targets including luteolin and quercetin were screened, and 185 targets were obtained by intersecting with CTD database to search IgAN related targets. Cytoscape software and STRING database were used to construct "THSWD-active ingredients-targets" network and protein-protein interaction network, and 69 core targets were screened. In DAVID's GO enrichment analysis and KEGG pathway analysis of the core targets and cell experiments, the results showed that ERK was an important factor for THSWD to interfere with IgAN fibrosis, and THSWD intervention could significantly decrease cell activity, ERK1/2 mRNA expression, and p-ERK1/2 protein expression. This study preliminarily revealed that THSWD may delay the growth of fibroblasts by affecting ERK factor and its phosphorylation level.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200615.401DOI Listing
September 2020

4-Hydroxy Pyridones from Heterologous Expression and Cultivation of the Native Host.

J Nat Prod 2020 11 23;83(11):3338-3346. Epub 2020 Oct 23.

Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drug Research, Jinan University, Guangzhou 510632, People's Republic of China.

4-Hydroxy pyridones are a class of fungi-derived polyketide-nonribosomal peptide products featuring a core of 4-hydroxy-2-pyridone which have a wide range of biological activities. Genome mining of in-house strains using polyketide synthase-nonribosomal peptide synthase as a query identified an endophyte sp. 49Y, which possesses a potential 4-hydroxy pyridone biosynthetic gene cluster. Heterologous expression in NSAR1 revealed that this gene cluster is functional and able to produce a rare type of 4-hydroxy pyridones called tolypyridones (compounds and ). sp. 49Y was grown in a variety of media which led to the isolation of six 4-hydroxy pyridones (-) and one pyrrolidone () from a rice culture, and compounds and showed antifungal activity. These latter compounds are different from those obtained by heterologous expression. This study shows that both heterologous expression and cultivation of the native host are complementary approaches to discover new natural products.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00675DOI Listing
November 2020
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