Publications by authors named "Dan-Dan Wang"

258 Publications

Discovery of pyrazolones as novel carboxylesterase 2 inhibitors that potently inhibit the adipogenesis in cells.

Bioorg Med Chem 2021 Apr 30;40:116187. Epub 2021 Apr 30.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address:

Carboxylesterase 2 (CES2) is one of the most important Phase I drug metabolizing enzymes in the carboxylesterase family. It plays crucial roles in the bioavailability of oral ester prodrugs and the therapeutic effect of some anticancer drugs such as irinotecan (CPT11) and capecitabine. In addition to the well-known roles of CES2 in xenobiotic metabolism, the enzyme also participates in endogenous metabolism and the production of lipids. In this study, we synthesized a series of pyrazolones and assayed their inhibitory effects against CES2 in vitro. Structure-activity relationship analysis of these pyrazolones reveals that the introduction of 4-methylphenyl unit (R), 4-methylbenzyl (R) and cyclohexyl (R) moieties are beneficial for CES2 inhibition. Guided by these SARs results, 1-cyclohexyl-4-(4-methylbenzyl)-3-p-tolyl-1H- pyrazol-5(4H)-one (27) was designed and synthesized. Further investigations demonstrated that the compound 27 exhibited stronger CES2 inhibition activity with a lower IC value (0.13 μM). The inhibition kinetic study demonstrated that compound 27 inhibited the hydrolysis of CES2-fluorescein diacetate (FD) through non-competitive inhibition. In addition, the molecular docking showed that the core of pyrazolone, the cyclohexane moiety, 4-methylbenzyl and 4-methylphenyl groups in compound 27 all played important roles with the amino acid residues of CSE2. Also, compound 27 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. In brief, we designed and synthesized a novel pyrazolone compound with a strong inhibitory ability on CES2 and could inhibit the adipogenesis induced by mouse preadipocytes, which can be served as a promising lead compound for the development of more potent pyrazolone-type CES2 inhibitors, and also used as a potential tool for exploring the biological functions of CES2 in human being.
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http://dx.doi.org/10.1016/j.bmc.2021.116187DOI Listing
April 2021

Frequency and phenotypic characteristics of RPE65 mutations in the Chinese population.

Orphanet J Rare Dis 2021 Apr 13;16(1):174. Epub 2021 Apr 13.

Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai, 200032, China.

Background: The retinoid isomerohydrolase RPE65 has received considerable attention worldwide since a successful clinical gene therapy was approved in 2017 as the first treatment for vision loss associated with RPE65-mediated inherited retinal disease. Identifying patients with RPE65 mutations is a prerequisite to assessing the patients' eligibility to receive RPE65-targeted gene therapies, and it is necessary to identify individuals who are most likely to benefit from gene therapies. This study aimed to investigate the RPE65 mutations frequency in the Chinese population and to determine the genetic and clinical characteristics of these patients.

Results: Only 20 patients with RPE65 mutations were identified, and RPE65 mutations were determined to be the 14th most common among all patients with genetic diagnoses. Ten novel variants and two hotspots associated with FAP were identified. A literature review revealed that a total of 57 patients of Chinese origin were identified with pathogenic mutations in the RPE65 gene. The mean best Snellen corrected visual acuity was worse (mean 1.3 ± 1.3 LogMAR) in patients older than 20 years old than in those younger than 15 years old (0.68 ± 0.92 LogMAR). Bone spicule-like pigment deposits (BSLPs) were observed in six patients; they were older than those without BSLP and those with white-yellow dots. Genotype-phenotype analysis revealed that truncating variants seem to lead to a more severe clinical presentation, while best corrected visual acuity testing and fundus changes did not correlate with specific RPE65 variants or mutation types.

Conclusions: This study provides a detailed clinical-genetic assessment of patients with RPE65 mutations of Chinese origin. These results may help to elucidate RPE65 mutations in the Chinese population and may facilitate genetic counseling and the implementation of gene therapy in China.
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http://dx.doi.org/10.1186/s13023-021-01807-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097799PMC
April 2021

The comparison analysis of Polyphyllin I and its analogues induced apoptosis of colon and lung cancer cells via mitochondrial dysfunction.

Basic Clin Pharmacol Toxicol 2021 Apr 29. Epub 2021 Apr 29.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.

Polyphyllin I (PPI) and its analogues, including polyphyllin II (PPII), polyphyllin VI (PPVI), and polyphyllin VII (PPVII), are major bioactive compounds isolated from the Chinese herb Chonglou. However, the susceptibilities of PPI and its analogues toward the different cell lines are diversified and the mechanisms are not fully clarified. Thus, the present study aimed to investigate the cytotoxicity of PPI and its analogues on two different cell lines, as well as to explore the underlying mechanisms of these agents via inducing mitochondrial dysfunction. The results showed that PPI and its analogues were cytotoxic agents towards both A549 and HT-29 cells, with IC values ranged from 1.0 to 4.5 μM. Further investigations demonstrated that they decreased the mitochondrial membrane potentials of both A549 and HT-29 cells in a dose-dependent manner. Among all tested compounds, PPVI and PPI induced the most obvious changes in Ca hemostasis in these two cell lines. In addition, they could induce the accumulation of ROS in cells and downregulated the Bcl-2 expression, upregulated the Bax expression, induced the activity of cleaved-caspase-3 in cells. Collectively, our findings clearly demonstrated the cytotoxic differences and mechanisms of PPI and its analogues induced cell apoptosis, and could partially explain the anti-cancer effects of these natural consitituents in Chonglou.
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http://dx.doi.org/10.1111/bcpt.13596DOI Listing
April 2021

Tumor-derived exosomal circPSMA1 facilitates the tumorigenesis, metastasis, and migration in triple-negative breast cancer (TNBC) through miR-637/Akt1/β-catenin (cyclin D1) axis.

Cell Death Dis 2021 Apr 28;12(5):420. Epub 2021 Apr 28.

Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, P.R. China.

Circular RNAs (circRNAs) are increasingly gaining importance and attention due to their diverse potential functions and their value as diagnostic biomarkers (disease specific). This study aims to explore the novel mechanisms by which exosome-contained circRNAs promote tumor development and metastasis in TNBC. We identified increased circRNA circPSMA1 in TNBC cells, their exosomes, and serum exosomes samples from TNBC patients. The overexpression of circPSMA1 promoted TNBC cell proliferation, migration, and metastasis both in vitro and in vivo. Moreover, we investigated the tumor-infiltrating immune cells (TICs) or stromal components in immune microenvironment (IME), and identified the significant differences in the immune cells between TNBC and non-TNBC samples. Mechanistically, circPSMA1 acted as a "miRNAs sponge" to absorb miR-637; miR-637 inhibited TNBC cell migration and metastasis by directly targeted Akt1, which recognized as a key immune-related gene and affected downstream genes β-catenin and cyclin D1. Subsequent co-culture experiments also demonstrated that exosomes from TNBC carrying large amounts of circPSMA1 could transmit migration and proliferation capacity to recipient cells. Kaplan-Meier plots showed that high expression of Akt1 and low expression of mir-637 are highly correlated with poor prognosis in patients with lymph node metastasis of TNBC. Collectively, all these results reveal that circPSMA1 functions as a tumor promoter through the circPSMA1/miR-637/Akt1-β-catenin (cyclin D1) regulatory axis, which can facilitate the tumorigenesis, metastasis, and immunosuppression of TNBC. Our research proposes a fresh perspective on novel potential biomarkers and immune treatment strategies for TNBC.
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http://dx.doi.org/10.1038/s41419-021-03680-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080849PMC
April 2021

circACTA2 mediates Ang II-induced VSMC senescence by modulation of the interaction of ILF3 with CDK4 mRNA.

Aging (Albany NY) 2021 Apr 22;13(8):11610-11628. Epub 2021 Apr 22.

Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China.

Chronic angiotensin II (Ang II) stimulation induces vascular smooth muscle cell (VSMC) senescence, and circRNAs and members of the ILF3 family are implicated in cellular senescence, but the mechanism underlying regulation of circRNAs and ILF3 by Ang II in VSMCs remains poorly understood. Here, a model of Ang II-induced VSMC senescence and the renal artery of hypertensive patients were used to investigate the roles and mechanisms of circACTA2 and ILF3 in VSMC senescence. We show that circACTA2 expression was elevated in Ang II-stimulated VSMCs and in the vascular walls of hypertensive patients. circACTA2 knockdown largely abrogated Ang II-induced VSMC senescence as shown by decreased p21 expression and increased CDK4 expression as well as by decreased SA β-gal-positive cells. Oligo pull-down and RIP assays revealed that both circACTA2 and CDK4 mRNA could bind with ILF3, and Ang II facilitated circACTA2 association with ILF3 and attenuated ILF3 interaction with CDK4 mRNA. Mechanistically, increased circACTA2 by Ang II reduced ILF3 association with CDK4 mRNA by competing with CDK4 mRNA to bind to ILF3, which decreases CDK4 mRNA stability and protein expression, thus leading to Ang II-induced VSMC senescence. Targeting the circACTA2-ILF3-CDK4 axis may provide a novel therapeutic strategy for VSMC senescence-associated cardiovascular diseases.
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http://dx.doi.org/10.18632/aging.202855DOI Listing
April 2021

Simple and robust differentiation of Ganoderma species by high performance thin-layer chromatography coupled with single quadrupole mass spectrometry QDa.

Chin J Nat Med 2021 Apr;19(4):295-304

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address:

In this study, a high performance thin-layer chromatography/single quadrupole mass spectrometry QDa (HPTLC-QDa) method for robust authentication of Ganoderma lucidum, a popular and valuable herbal medicine, has been developed. This method is simple and practical, which allows direct generation of characteristic mass spectra from the HPTLC plates automatically with the application of in situ solvent desorption interface. The HPTLC silica gel plates were developed with toluene-ethyl formate-formic acid (5 : 5 : 0.2, V/V) and all bands were transferred to QDa system directly in situ using 80% methanol with 0.1% formic acid as desorption solvent. The acquired HPTLC-QDa spectra showed that luminous yellow band b3, containing ganoderic acid B/G/H and ganodeneric acid B, the major active components of Ganoderma, could be found only in G. lucidum and G. lucidum (Antler-shaped), but not in G. sinense and G. applanatum. Moreover, bands b13 and b14 with m/z 475/477 and m/z 475/491/495, respectively, could be detected in G. lucidum (Antler-shaped), but not in G. lucidum, thus allowing simple and robust authentication of G. lucidum with confused species. This method is proved to be simple, practical and reproducible, which can be extended to analyze other herbal medicines.
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http://dx.doi.org/10.1016/S1875-5364(21)60030-4DOI Listing
April 2021

Hepatopulmonary syndrome delays postoperative recovery and increases pulmonary complications after hepatectomy.

Eur J Gastroenterol Hepatol 2021 Apr 9. Epub 2021 Apr 9.

Department of Anaesthesiology, Southwest Hospital, Army Medical University, Chongqing Department of Anesthesia, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France Department of Anaesthesiology, Renji Hospital affiliated to Shanghai Jiao Tong University, Shanghai Department of Anaesthesiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Background: This study attempted to investigate the impact of hepatopulmonary syndrome (HPS) on postoperative outcomes in hepatitis B virus-induced hepatocellular carcinoma (HBV-HCC) patients.

Methods: HBV-HCC patients undergoing primary curative hepatectomy for HCC in our hospital were diagnosed with HPS by contrast-enhanced echocardiography (CEE) and arterial blood gas analysis. Patients were divided into HPS, intrapulmonary vascular dilation (IPVD) (patients with positive CEE results and normal oxygenation) and control (patients with negative CEE results) groups. Baseline information, perioperative clinical data and postoperative pulmonary complications (PPCs) were compared among all groups. Cytokines in patient serums from each group (n = 8) were also assessed.

Results: Eighty-seven patients undergoing hepatectomy from October 2019 to January 2020 were analyzed. The average time in the postanaesthesia care unit (112.10 ± 38.57 min) and oxygen absorption after extubation [34.0 (14.5-54.5) min] in the HPS group was longer than in IPVD [81.81 ± 26.18 min and 16.0 (12.3-24.0) min] and control [93.70 ± 34.06 min and 20.5 (13.8-37.0) min] groups. There were no significant differences in oxygen absorption time after extubation between HPS and control groups. The incidence of PPCs, especially bi-lateral pleural effusions in the HPS group (61.9%), was higher than in IPVD (12.5%) and control (30.0%) groups. Increased serum levels of the growth-regulated oncogene, monocyte chemoattractant protein, soluble CD40 ligand and interleukin 8 might be related to delayed recovery in HPS patients.

Conclusions: HPS patients with HBV-HCC suffer delayed postoperative recovery and are at higher risk for PPCs, especially bi-lateral pleural effusions, which might be associated with changes in certain cytokines.
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http://dx.doi.org/10.1097/MEG.0000000000002134DOI Listing
April 2021

Systematic Characterization of Expression Profiles and Prognostic Values of the Eight Subunits of the Chaperonin TRiC in Breast Cancer.

Front Genet 2021 17;12:637887. Epub 2021 Mar 17.

Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Background: Chaperonin-containing TCP-1 (TRiC or CCT) was demonstrated to be involved in oncogenesis of cancers carcinogenesis and development of various malignancies. Increasing experimental evidence indicated that dysregulation of TRiC was implicated in the tumor progression of breast cancer (BCa). However, few definitive studies have addressed the diverse expression patterns and prognostic values of eight TRiC subunits. Thus, we aimed to investigate the clinical significance of TRiC subunit expression and prognostic values for their possible implications in diagnosis and treatment of BCa.

Methods: Based on updated public resources and comprehensive bioinformatics analysis, we used some online databases (e.g., UALCAN, GEPIA, cBioPortal, TIMER, BC-GenExMiner, metascape, and GeneMANIA) to comprehensively explore the expression levels and the prognostic effects of eight TRiC subunits in patients with BCa.

Results: The transcriptional levels of most subunits of the Chaperonin TRiC (CCT2, CCT3, CCT4, CCT5, CCT6A, and CCT7) were significantly elevated compared with normal breast tissues, whereas TCP1, CCT4, and CCT6B were lower in BCa tissues than in normal tissues. Besides, copy-number alterations (CNA) of eight TRiC subunits positively regulated their mRNA expressions. Furthermore, high mRNA expression of TCP1/CCT2/CCT4/CCT5/CCT6A/CCT7/CCT8 was significantly associated with poor overall survival (OS) in BCa patients. The eight subunits of the chaperonin TRiC was related to tumor purity and immune infiltration levels of BCa. Co-expression analysis showed CCT6B was negatively associated with other subunits of TRiC and other subunits of TRiC were positively correlated with each other. Additionally, TRiC and their interactive proteins were correlated with positive regulation of biological process, localization, and biological regulation.

Conclusion: This study systematically illustrated the expression profiles and distinct prognostic values of chaperonin TRiC in BCa, providing insights for further investigation of subunits of the chaperonin TRiC as novel therapeutic targets and potential prognostic biomarkers in BCa.
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http://dx.doi.org/10.3389/fgene.2021.637887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009990PMC
March 2021

Advances in receptor modulation strategies for flexible, efficient, and enhanced antitumor efficacy.

J Control Release 2021 Apr 1;333:418-447. Epub 2021 Apr 1.

Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China. Electronic address:

Tumor-sensitivity, effective transport, and precise delivery to tumor cells of nano drug delivery systems (NDDs) have been great challenges to cancer therapy in recent years. The conventional targeting approach involves actively installing the corresponding ligand on the nanocarriers, which is prone to recognize the antigen blasts overexpressed on the surface of tumor cells. However, there are some probable limitations for the active tumor-targeting systems in vivo as follows: a. the limited ligand amount of modifications; b. possible steric hindrance, which was likely to prevent ligand-receptor interaction during the delivery process. c. the restrained antigen saturation highly expressed on the cell membrane, will definitely decrease the specificity and often lead to "off-target" effects of NDDs; and d. water insolubility of nanocarriers due to excess of ligands modification. Obviously, any regulation of receptors on surface of tumor cells exerted an important influence on the delivery of targeting systems. Herein, receptor upregulation was mostly desired for enhancing targeted therapy from the cellular level. This technique with the amplification of receptors has the potential to enhance tumor sensitivity towards corresponding ligand-modified nanoparticles, and thereby increasing the effective therapeutic concentration as well as improving the efficacy of chemotherapy. The enhancement of positively expressed receptors on tumor cells and receptor-dependent therapeutic agents or NDDs with an assembled "self-promoting" effect contributes to increasing cell sensitivity to NPs, and will provide a basic platform for clinical therapeutic practice. In this review, we highlight the significance of modulating various receptors on different types of cancer cells for drug delivery and therapeutic benefits.
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http://dx.doi.org/10.1016/j.jconrel.2021.03.045DOI Listing
April 2021

Exosomal miR-222 from adriamycin-resistant MCF-7 breast cancer cells promote macrophages M2 polarization via PTEN/Akt to induce tumor progression.

Aging (Albany NY) 2021 Mar 22;13(7):10415-10430. Epub 2021 Mar 22.

Department of General Surgery, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou 213000, Jiangsu Province, China.

Exosome-mediated intercellular communication is considered to be an effective mode for malignant cells to transform biological behaviors in stromal cells. However, the mechanisms by which exosomes modulate macrophages within tumor microenvironment remain largely unclear. In this study, we found that both adriamycin-resistant breast cancer (BCa) cells and the corresponding exosomes (A/exo) were capable of inducing macrophages M2 polarization, which promoted the mobility, proliferation, migration and invasion of BCa cells. Since exosomes deliver microRNAs to affect cellular functions in recipient cells, we confirmed that miR-222 was significantly enriched in A/exo and could be successfully transferred to macrophages. Increased miR-222 level was also detected in exosomes derived from plasma and tissues of chemoresistant patients. Moreover, exosomal miR-222 from A/exo polarized M2 macrophages by targeting PTEN and activating Akt signaling pathway, which promoted BCa cells progression in a feed back loop. Co-culture of adriamycin-resistant BCa cells with macrophages in which miR-222 was upregulated or treated with A/exo facilitated tumor growth . Collectively, our data demonstrated that chemoresistant BCa cells could remodel macrophages within tumor microenvironment by secreting exosomal miR-222, which directly targeted PTEN and caused Akt cascade activation and macrophages M2 polarization. Our findings may provide a foundation for a promising strategy of BCa treatment by targeting exosomes or exosomal miR-222.
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http://dx.doi.org/10.18632/aging.202802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064228PMC
March 2021

Attenuated and delayed niacin skin flushing in schizophrenia and affective disorders: A potential clinical auxiliary diagnostic marker.

Schizophr Res 2021 Mar 4;230:53-60. Epub 2021 Mar 4.

Bio-X Institutes, Shanghai Mental Health Center, Shanghai Jiao Tong University, Shanghai, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China. Electronic address:

Aim: Schizophrenia and affective disorders all show high heterogeneity in clinical manifestations. A lack of objective biomarkers has long been a challenge in the clinical diagnosis of these diseases. In this study, we aimed to investigate the performance of niacin skin flushing in schizophrenia and affective disorders and determine its clinical potential as an auxiliary diagnostic marker.

Methods: In this case-control study, niacin skin-flushing tests were conducted in 613 patients (including 307 schizophrenia patients, 179 bipolar disorder patients, and 127 unipolar depression patients) and 148 healthy controls (HCs) with a modified method. Differences in niacin skin-flushing responses were compared with adjustment for gender, BMI, age, nicotine dependence, alcohol consumption and educational status. A diagnostic model was established based on a bivariate cut-off.

Results: Schizophrenia and affective disorders showed similar performance of niacin bluntness, characterized by attenuated flushing extent and reduced flushing rate. An innovative bivariate cut-off was established according to these two features, by which we could identify -patients with either schizophrenia or affective disorders from HCs with a sensitivity of 55.28%, a specificity of 83.56% and a positive predictive value of 93.66%.

Conclusions: The niacin-induced skin flushing was prevalently blunted in patients with schizophrenia or affective disorders, indicating a promising potential as an auxiliary diagnostic marker in risk prediction and clinical management of these disorders. Additionally, the niacin-blunted subgroup implies a common biological basis in the investigated disorders, which provokes new thoughts in elucidating the pathological mechanisms.
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http://dx.doi.org/10.1016/j.schres.2021.02.009DOI Listing
March 2021

Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ.

Front Pharmacol 2020 8;11:628314. Epub 2021 Feb 8.

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an essential enzyme in mammals that is responsible for detoxification and metabolic clearance of the endogenous toxin bilirubin and a variety of xenobiotics, including some crucial therapeutic drugs. Discovery of potent and safe UGT1A1 inducers will provide an alternative therapy for ameliorating hyperbilirubinaemia and drug-induced hepatoxicity. This study aims to find efficacious UGT1A1 inducer(s) from natural flavonoids, and to reveal the mechanism involved in up-regulating of this key conjugative enzyme by the flavonoid(s) with strong UGT1A1 induction activity. Among all the tested flavonoids, neobavaisoflavone (NBIF) displayed the most potent UGT1A1 induction activity, while its inductive effects were confirmed by both western blot and glucuronidation activity assays. A panel of nuclear receptor reporter assays demonstrated that NBIF activated PPARα and PPARγ in a dose-dependent manner. Meanwhile, we also found that NBIF could up-regulate the expression of PPARα and PPARγ in hepatic cells, suggesting that the induction of UGT1A1 by NBIF was mainly mediated by PPARs. In silico simulations showed that NBIF could stably bind on pocket II of PPARα and PPARγ. Collectively, our results demonstrated that NBIF is a natural inducer of UGT1A1, while this agent induced UGT1A1 mainly via activating and up-regulating PPARα and PPARγ. These findings suggested that NBIF can be used as a promising lead compound for the development of more efficacious UGT1A1 inducers to treat hyperbilirubinaemia and UGT1A1-associated drug toxicities.
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http://dx.doi.org/10.3389/fphar.2020.628314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897654PMC
February 2021

Mitochondrial DUT-M potentiates RLR-mediated antiviral signaling by enhancing VISA and TRAF2 association.

Mol Immunol 2021 04 11;132:117-125. Epub 2021 Feb 11.

Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Life Science, Jiangxi Normal University, Nanchang, Jiangxi, 330022, China. Electronic address:

Upon recognition of intracytoplasmic viral RNA, activated RIG-I is recruited to the mitochondrion-located adaptor protein VISA (also known as MAVS, CARDIF, and IPS-1). VISA then acts as a central signaling platform for linking RIG-I and downstream signaling components, such as TRAF2, 5, and 6, TBK1, and IKK, leading to activation of the kinases TBK1 and IKK. These activated kinases further phosphorylate the transcription factors IRF3/7 and NF-κB, leading to the induction of downstream antiviral genes. Here, we report a mitochondrial isoform, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), DUT-M, as a positive regulator in RLR-VISA-mediated antiviral signaling. DUT-M interacts with VISA and RIG-I to facilitate the assembly of the VISA-TRAF2 complex and to augment the polyubiquitination of TRAF2, leading to potentiated activation of IRF3 dimerization and phosphorylation of P65, and enhanced VISA-mediated innate immune response. RLR-VISA-mediated IRF3 dimerization and P65 phosphorylation, were inhibited in DUT-knockdown and DUT-deficient 293 cells. Thus, DUT-M is a positive regulator of the RIG-I-VISA-mediated innate immune response to RNA viruses.
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http://dx.doi.org/10.1016/j.molimm.2021.01.023DOI Listing
April 2021

[Review of classical prescription Ganjiang Lingzhu Decoction].

Zhongguo Zhong Yao Za Zhi 2020 Dec;45(24):5929-5943

Shanghai University of Traditional Chinese Medicine Shanghai 201203, China.

Ganjiang Lingzhu Decoction is one of the first 100 classical prescriptions published by China in 2018. According to the published literature, it was found that there is no review on the history, evolution and research progress of this prescription. In order to reflect the history, modifications, quality control and clinical applications, this paper focuses on the origination, evolution, current development and modern studies of Ganjiang Lingzhu Decoction, in the hope of providing a reference for the heritage and innovation of other classical prescriptions.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200904.602DOI Listing
December 2020

Glycosyltransformation of ginsenoside Rh2 into two novel ginsenosides using recombinant glycosyltransferase from and its applications.

J Ginseng Res 2021 Jan 15;45(1):48-57. Epub 2019 Nov 15.

Department of Oriental Medicinal Biotechnology, Ginseng Bank, College of Life Science, Kyung Hee University, Yongin, Republic of Korea.

Background: Ginsenoside Rh2 is well known for many pharmacological activities, such as anticancer, antidiabetes, antiinflammatory, and antiobesity properties. Glycosyltransferases (GTs) are ubiquitous enzymes present in nature and are widely used for the synthesis of oligosaccharides, polysaccharides, glycoconjugates, and novel derivatives. We aimed to synthesize new ginsenosides from Rh2 using the recombinant GT enzyme and investigate its cytotoxicity with diverse cell lines.

Methods: We have used a GT gene with 1,224-bp gene sequence cloned from (LRGT) and then expressed in BL21 (DE3). The recombinant GT protein was purified and demonstrated to transform Rh2 into two novel ginsenosides, and they were characterized by nuclear magnetic resonance (NMR) techniques and evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide assay.

Results: Two novel ginsenosides with an additional glucopyranosyl (6→1) and two additional glucopyranosyl (6→1) linked with the C-3 position of the substrate Rh2 were synthesized, respectively. Cell viability assay in the lung cancer (A549) cell line showed that glucosyl ginsenoside Rh2 inhibited cell viability more potently than ginsenoside Rg3 and Rh2 at a concentration of 10 μM. Furthermore, glucosyl ginsenoside Rh2 did not exhibit any cytotoxic effect in murine macrophage cells (RAW264.7), mouse embryo fibroblasts cells (3T3-L1), and skin cells (B16BL6) at a concentration of 10 μM compared with ginsenoside Rh2 and Rg3.

Conclusion: This is the first report on the synthesis of two novel ginsenosides, namely, glucosyl ginsenoside Rh2 and diglucosyl ginsenoside Rh2 from Rh2 by using recombinant GT isolated from . Moreover, diglucosyl ginsenoside Rh2 might be a new candidate for treatment of inflammation, obesity, and skin whiting, and especially for anticancer.
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http://dx.doi.org/10.1016/j.jgr.2019.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790896PMC
January 2021

An Integrative Pan-Cancer Analysis Revealing LCN2 as an Oncogenic Immune Protein in Tumor Microenvironment.

Front Oncol 2020 23;10:605097. Epub 2020 Dec 23.

Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Background: Lipocalin 2 (LCN2), an innate immune protein, plays a pivotal role in promoting sterile inflammation by regulating immune responses. However, the role of LCN2 in diverse cancers remains poorly defined. This research aimed to investigate the correlation between LCN2 expression and immunity and visualize its prognostic landscape in pan-cancer.

Methods: Raw data in regard to LCN2 expression in cancer patients were acquired from TCGA and GTEx databases. Besides, we investigated the genomic alterations, expression pattern, and survival analysis of LCN2 in pan-cancer across numerous databases, including cBioPortal and GEPIA database. The correlation between LCN2 expression and tumor immune infiltration was explored TIMER, and we utilized CIBERSORT and ESTIMATE computational methods to assess the proportion of tumor-infiltrating immune cells (TIICs) and the amount of stromal and immune components from TCGA database. Protein-Protein Interaction analysis was performed in GeneMANIA database, and gene functional enrichment was performed by Gene Set Enrichment Analysis (GSEA).

Results: On balance, tumor tissue had a higher LCN2 expression level compared with that in normal tissue. Elevated expression of LCN2 was related to poor clinical regimen with OS and RFS. There were significant positive correlations between LCN2 expression and TIICs, including CD8+ T cells, CD4+ T cells, B cells, neutrophils, macrophages, and dendritic cells. Moreover, markers of TIICs exhibited different LCN2-related immune infiltration patterns. GSEA analysis showed that the expression of LCN2 was related to retinol metabolism, drug metabolism cytochrome P450 and metabolism of xenobiotics by cytochrome P450.

Conclusions: These findings suggested that LCN2 might serve as a biomarker for immune infiltration and poor prognosis in cancers, shedding new light on therapeutics of cancers.
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http://dx.doi.org/10.3389/fonc.2020.605097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786136PMC
December 2020

Different roles of Numb-p72 and Numb-p65 on the trafficking of metabotropic glutamate receptor 5.

Mol Biol Rep 2021 Jan 4;48(1):595-600. Epub 2021 Jan 4.

Department of Physiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.

We previously reported that Numb, a protein localized to clathrin-coated vesicles, regulates the membrane expression of metabotropic glutamate receptor 5 (mGluR5) and is critical to social behaviors. However, the distinct actions of Numb isoforms on mGluR5 have not been investigated. Here, we showed that the expression patterns of Numb-p72 and Numb-p65, two important isoforms of Numb, were distinct in HEK293T cells. Numb-p72, but not Numb-p65, bound to mGluR5α, and enhanced mGluR5 membrane expression by inhibiting its internalization. Our results suggest that a complete structure is required for Numb to bind to mGluR5 and to modulate mGluR5 trafficking.
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http://dx.doi.org/10.1007/s11033-020-06103-0DOI Listing
January 2021

CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 contributes to prostate carcinogenesis.

J Exp Clin Cancer Res 2021 Jan 4;40(1). Epub 2021 Jan 4.

Department of Urology, The Second Hospital of Hebei Medical University, 215 Heping W Rd, Shijiazhuang, 050000, China.

Background: Both E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa.

Methods: The expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real-time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo.

Results: Here we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation.

Conclusions: These findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance.
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http://dx.doi.org/10.1186/s13046-020-01814-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780414PMC
January 2021

Effects of dietary n-3 PUFA levels in early life on susceptibility to high-fat-diet-induced metabolic syndrome in adult mice.

J Nutr Biochem 2021 03 31;89:108578. Epub 2020 Dec 31.

College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, China; Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, Shandong, China. Electronic address:

The maternal nutritional status during pregnancy and lactation was closely related to the growth and development of the fetus and infants, which had a profound impact on the health of the offspring. N-3 polyunsaturated fatty acid (PUFA) had been proved to have beneficial effects on glucolipid metabolism. However, the effects of dietary different n-3 PUFA levels for mother during pregnancy and lactation on susceptibility to high-fat-diet-induced metabolic syndrome for offspring in adulthood are still unclear. The maternal mice were fed with control, n-3 PUFA-deficient or fish oil-contained n-3 PUFA-rich diets during pregnancy and lactation, and the weaned offspring were fed with high-fat or low-fat diet for 13 weeks, then were subjected to oral glucose tolerance tests. The results showed that dietary n-3 PUFA-deficiency in early life could aggravate the high-fat-diet-induced glucolipid metabolism disorders, including glucose intolerance, insulin resistance, obesity, and dyslipidemia, thus increased the susceptibility to metabolic syndrome of adult mice. Notably, nutritional supplementation with n-3 PUFA in early life could significantly alleviate the glucose metabolism disorders by increasing insulin sensitivity, inhibiting gluconeogenesis and promoting glycogenesis. In addition, administration with n-3 PUFA in early life remarkably reduced serum and hepatic lipid profiles by mediating the expression of genes related to lipogenesis and β-oxidation of fatty acids. Dietary n-3 PUFA-deficiency in early life increases the susceptibility to metabolic syndrome of adult offspring, and nutritional supplementation with n-3 PUFA enhances the tolerance to a high-fat diet of adult offspring.
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http://dx.doi.org/10.1016/j.jnutbio.2020.108578DOI Listing
March 2021

[Chemical profiling and tissue distribution study of Jingyin Granules in rats using UHPLC-Q-Exactive Orbitrap HR-MS].

Zhongguo Zhong Yao Za Zhi 2020 Nov;45(22):5537-5554

Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine Shanghai 201203, China.

In this study, the chemical profiling of Jingyin Granules and the tissue distribution of nine major constituents in this Chinese medicine were performed after oral administration of Jingyin Granules to rats, by using UHPLC-Q-Exactive Orbitrap HR-MS. An Acquity UPLC BEH C_(18) chromatographic column(2.1 mm×100 mm, 1.7 μm) was used as solid phase, while the mobile phase was methanol and 0.1% formic acid water for gradient elution. The major constituents in this Chinese medicine were quickly and accurately identified, via comparison with the retention times and MS/MS spectra of the standards. A total of 106 chemicals were identified from Jingyin Granules, including 24 kinds of organic acids, 47 kinds of flavonoids, 10 kinds of iridoids, and 21 kinds of saponins and 4 kinds of other compounds. After oral administered Jingyin Granules to rats, 48, 30, 25, 23, 45, 34, 39, 26, 19 prototype compounds were identified in serum, heart, liver, spleen, lung, kidney, brain, fat, and testicles, respectively. Meanwhile, an LC-MS based analytical method was established for simultaneous determination of chlorogenic acid, swertiamarin, caffeic acid, sweroside, liquiritin, prim-O-glucosylcimifugin, arctiin, 5-O-methylvisammioside and arctigenin in biological samples. The tissue distribution(serum, liver and lung) of these nine aim constituents in rats after oral administration of Jingyin Granules were investigated. It was found that these nine constituents could be quickly absorbed into circulation system and then distributed to liver and lung tissues. Except arctigenin, the exposure of other eight aim constituents to serum and lung was peaked at 1 h. At 1 h, the exposure of these components to lung tissue were ranked as follows: swertiamarin [(75 191.0±3 483.21) ng·g~(-1)]>arctiin [(2 716.5±36.06) ng·g~(-1)]>5-O-methylvisammioside [(585.1±0.71) ng·g~(-1)]>arctigenin [(437.45±3.18) ng·g~(-1)]>chlorogenic acid [(308.1±5.66) ng·g~(-1)]>prim-O-glucosylcimifugin [(211.35±2.19) ng·g~(-1)]>sweroside [(184.3±9.05) ng·g~(-1)]>caffeic acid [(175.95±2.05) ng·g~(-1)]>liquiritin [(174.78±153.34) ng·g~(-1)]. In summary, an UHPLC-Q-Exactive Orbitrap HR-MS method has been established for rapid and accurate identification of the constituents in Jingyin Granules, while the tissue distribution of nine major absorpted constituents were investigated in rats following oral administration of Jingyin Granules. These findings provided key information and guidance for further studies on pharmacodynamic substances and clinical applications of Jingyin Granules.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200903.201DOI Listing
November 2020

Interpersonal psychotherapy-based psychological intervention for patient suffering from COVID-19: A case report.

World J Clin Cases 2020 Dec;8(23):6064-6070

Department of Mental Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China.

Background: Novel coronavirus disease 2019 (COVID-19) was first found in Wuhan, China, and it has rapidly spread worldwide since the end of 2019. There is an urgent need to treat the physical and psychological aspects of COVID-19. Interpersonal psychotherapy (IPT)-based psychological intervention is an evidence-based therapy for depression and post-traumatic stress disorder.

Case Summary: This report describes a case of COVID-19 in a patient who transmitted the disease to his entire family. The patient received four sessions of IPT-based psychological intervention. We used the Hamilton Rating Scale for Depression and Patient Health Questionnaire to measure depression level, and the Hamilton Anxiety Scale and Generalized Anxiety Disorder to measure anxiety among the patients.

Conclusion: This case shows that IPT-based therapy can reduce COVID-19 patient depression and anxiety and the advantage of IPT-based therapy.
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http://dx.doi.org/10.12998/wjcc.v8.i23.6064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723699PMC
December 2020

A better method for the dynamic, precise estimating of blood/haemoglobin loss based on deep learning of artificial intelligence.

Ann Transl Med 2020 Oct;8(19):1219

Department of Anaesthesiology, Southwest Hospital, Third Military Medical University (First Affiliated Hospital of Army Medical University), Chongqing, China.

Background: Dynamic and precise estimation of blood loss (EBL) is quite important for perioperative management. To date, the Triton System, based on feature extraction technology (FET), has been applied to estimate intra-operative haemoglobin (Hb) loss but is unable to directly assess the amount of blood loss. We aimed to develop a method for the dynamic and precise EBL and estimate Hb loss (EHL) based on artificial intelligence (AI).

Methods: We collected surgical patients' non-recycled blood to generate blood-soaked sponges at a set gradient of volume. After image acquisition and preprocessing, FET and densely connected convolutional networks (DenseNet) were applied for EBL and EHL. The accuracy was evaluated using R2, the mean absolute error (MAE), the mean square error (MSE), and the Bland-Altman analysis.

Results: For EBL, the R2, MAE and MSE for the method based on DenseNet were 0.966 (95% CI: 0.962-0.971), 0.186 (95% CI: 0.167-0.207) and 0.096 (95% CI: 0.084-0.109), respectively. For EHL, the R2, MAE and MSE for the method based on DenseNet were 0.941 (95% CI: 0.934-0.948), 0.325 (95% CI: 0.293-0.355) and 0.284 (95% CI: 0.251-0.317), respectively. The accuracies of EBL and EHL based on DenseNet were more satisfactory than that of FET. Bland-Altman analysis revealed a bias of 0.02 ml with narrow limits of agreement (LOA) (-0.47 to 0.52 mL) and of 0.05 g with narrow LOA (-0.87 to 0.97 g) between the methods based on DenseNet and actual blood loss and Hb loss.

Conclusions: We developed a simpler and more accurate AI-based method for EBL and EHL, which may be more fit for surgeries primarily using sponges and with a small to medium amount of blood loss.
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http://dx.doi.org/10.21037/atm-20-1806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607084PMC
October 2020

Novel variants of ABCA4 in Han Chinese families with Stargardt disease.

BMC Med Genet 2020 10 31;21(1):213. Epub 2020 Oct 31.

Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.

Background: Stargardt disease (STGD1) is a common recessive hereditary macular dystrophy in early adulthood or childhood, with an estimated prevalence of 1:8000 to 1:10,000. ABCA4 is the causative gene for STGD1. The current study aims at identifying the novel disease-related ABCA4 variants in Han Chinese families with STGD1 using next-generation sequencing (NGS).

Methods: In the present study, 12 unrelated Han Chinese families (19 males and 17 females) with STGD1 were tested by panel-based NGS. In order to capture the coding exons and the untranslated regions (UTRs) plus 30 bp of intronic flanking sequences of 792 genes, which were closely associated with usual ophthalmic genetic disease, we designed a customized panel, namely, Target_Eye_792_V2 chip. STGD1 patients were clinically diagnosed by experienced ophthalmologists. All the detected variants were filtered and analyzed through the public databases and in silico programs to assess potential pathogenicity.

Results: Twenty-one ABCA4 mutant variants were detected in 12 unrelated Han Chinese families with STGD1, containing 14 missense, three splicing, two frameshift, one small deletion, and one nonsense variants. Base on the American College of Medical Genetics (ACMG) guidelines, 8 likely pathogenic and 13 pathogenic variants were determined. The functional consequences of these mutant variants were predicted through in silico programs. Of the 21 mutant variants in ABCA4, two novel coding variants c.3017G > A and c.5167 T > C and one novel null variant c.3051-1G > A were detected in three unrelated probands.

Conclusions: By panel-based NGS, 21 ABCA4 variants were confirmed in 12 unrelated Han Chinese families. Among them, 3 novel mutant variants were found, which further expanded the ABCA4 mutation spectrum in STGD1 patients.
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http://dx.doi.org/10.1186/s12881-020-01152-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602306PMC
October 2020

Comprehensive analysis of genetic and clinical characteristics of 30 patients with X-linked juvenile retinoschisis in China.

Acta Ophthalmol 2020 Oct 30. Epub 2020 Oct 30.

Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai, China.

Purpose: To provides the clinical and genetic characteristics of a series of Chinese patients with X-linked juvenile retinoschisis (XLRS) through multimodal imaging and next-generation sequencing.

Methods: Thirty patients (60 eyes) from 29 unrelated families of Chinese origin with XLRS were screened using multigene panel testing, and underwent a complete clinical evaluation. All variants identified in this study and reported in the Human Gene Mutation Database were analysed.

Results: Twenty-five distinct variants in the retinoschisin gene were identified, of which eight were novel, and one was de novo. Missense mutations were the most prevalent type, and mutation hot spot was localized in the discoidin domain. The mean Snellen best-corrected visual acuity was 0.28 ± 0.17. Of all eyes presenting with schisis, 92.86% had lamellar schisis and 62.5% had peripheral schisis. Schisis changes mostly involved inner and outer nuclear layers. X-linked juvenile retinoschisis (XLRS) patients had a high incidence of complications, and peripheral schisis was a risk factor for it. No obvious genotype-phenotype association was observed.

Conclusion: This study provides comprehensive analyses of the genetic and clinical characteristics of XLRS in a cohort of Chinese patients. The fourth de novo mutation in RS1 was identified. And we show that XLRS has a wide spectrum of clinical characteristics; hence, molecular diagnosis is crucial for its diagnosis, differential diagnosis and genetic counselling. Peripheral schisis is a risk factor for the high incidence of complications, and no clear genotype-phenotype correlations were found.
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http://dx.doi.org/10.1111/aos.14642DOI Listing
October 2020

Epigenetic silencing of TET1 mediated hydroxymethylation of base excision repair pathway during lung carcinogenesis.

Environ Pollut 2021 Jan 15;268(Pt B):115860. Epub 2020 Oct 15.

Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China. Electronic address:

The methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is an important regulator for the balance of DNA methylation and hydroxymethylation through various pathways. Increasing evidence has suggested that TET1 probably involved in DNA methylation and demethylation dysregulation during chemical carcinogenesis. However, the role and mechanism of TET1 during lung cancer remains unclear. In this study, we found that TET1 expression was significantly down-regulated and the methylation level was significantly up-regulated in 3-methylcholanthrene (3-MCA) induced cell malignant transformation model, rat chemical carcinogenesis model, and human lung cancer tissues. Demethylation experiment further confirmed that DNA methylation negatively regulated TET1 gene expression. TET1 overexpression inhibited cell proliferation, migration and invasion in vitro and in vivo, while knockdown of TET1 resulted in an opposite phenotype. DNA hydroxymethylation level in the promoter region of base excision repair (BER) pathway key genes XRCC1, OGG1, APEX1 significantly decreased and the degree of methylation gradually increased in malignant transformed cells. After differential expression of TET1, the level of hydroxymethylation, methylation and expression of these genes also changed significantly. Furthermore, TET1 binds to XRCC1, OGG1, and APEX1 to maintain them hydroxymethylated. Blockade of BER pathway key gene alone or in combination significantly diminished the effect of TET1. Our study demonstrated for the first time that TET1 expression is regulated by DNA methylation and TET1-mediated hydroxymethylation regulates BER pathway to inhibit the proliferation, migration and invasion during 3-MCA-induced lung carcinogenesis. These results suggested that TET1 gene can be a potential biomarker and therapy target for lung cancer.
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http://dx.doi.org/10.1016/j.envpol.2020.115860DOI Listing
January 2021

Xanthones from antagonized the antirheumatic effects of methotrexate by promoting its secretion into urine.

Expert Opin Drug Metab Toxicol 2021 Feb 12;17(2):241-250. Epub 2020 Nov 12.

Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College , Wuhu, Anhui, China.

Background: This study was designed to characterize the interaction between Hassk. derived xanthones and methotrexate (MTX).

Methods: Collagen-induced arthritis (CIA) was induced in rats, which were treated with MTX, a xanthone-rich fraction (XRF), or MTX+XRF by gavage for 30 days. Clinical efficacy was assessed based on arthritis scores, serological analysis, and histological examination. Protein expression was investigated by either immunohistochemical or immunoblotting methods. MTX concentrations were determined by HPLC or LC-MS methods. Obtained results were further validated by assays using 1,7-dihydroxy-3,4-dimethoxyxanthone and HEK 293 T cells.

Results: XRF antagonized the antirheumatic effects of MTX , suggested by higher levels of proinflammatory cytokines, and severer swelling and deformation of joints in CIA rats in the MTX+XRF group compared with MTX monotherapy. XRF reduced MTX concentration in plasma and promoted its excretion into urine. As a result, XRF attenuated MTX-induced edema of the proximal tubule. Furthermore, XRF restored the decreased expression of organic anion transporter three (OAT3), which accounts for MTX secretion in the kidney. Consistently, 1,7-dihydroxy-3,4-dimethoxyxanthone promoted the cellular intake of MTX by increasing OTA3 expression.

Conclusion: It is suggested that the combined use of with MTX should be optimized to avoid the antagonistic effects and improve the safety of the MTX regimen.
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http://dx.doi.org/10.1080/17425255.2021.1843634DOI Listing
February 2021

The Separation of Antler Polypeptide and Its Effects on the Proliferation and Osteogenetic Differentiation of Bone Marrow Mesenchymal Stem Cells.

Evid Based Complement Alternat Med 2020 30;2020:1294151. Epub 2020 Sep 30.

State Key Laboratory of Precision Measurement Technology and Instruments, Tianjin University, Tianjin 300072, China.

Background: Colla Cornus Cervi (CCC) has been used as a traditional Chinese medicine in the treatment of osteoporosis and osteonecrosis of the femoral head. However, the bioavailability of CCC is seriously limited owing to its large molecular weight and complex ingredients. In the present study, antler polypeptide was separated from CCC, and the effects of antler polypeptide on rat bone marrow mesenchymal stem cells (BMSCs) were investigated.

Methods: Antler polypeptide was separated from Colla Cornus Cervi by ultrafiltration into different samples according to the molecular weight. The total peptide content of these samples was determined by the biuret method. The content of antler polypeptide in different samples was quantified by high-performance liquid chromatography (HPLC). The effects of antler polypeptide at different concentrations on the proliferation, cell cycle, alkaline phosphatase activity, and BMP7 expression of BMSCs were investigated.

Results: Antler polypeptide was separated by ultrafiltration into different samples: A (molecular weight <800 Da), B (molecular weight 800-1500 Da), and C (molecular weight >1500 Da). The total peptide contents of A, B, and C were 0.602 mg/mL, 8.976 mg/mL, and 38.88 mg/mL. Antler polypeptide B eluted at 14.279∼15.351 min showed that the content of antler polypeptide was significantly higher than that of A and C with a peak area of 933.80927. The BMSCs proliferation rate (84.66%) of polypeptide B was the highest at the concentration of 1.578 × 10 g/mL. Antler polypeptide B significantly promoted the proliferation of BMSCs with a proliferation index of 38.68%, which was significantly higher than that of the other groups. Antler polypeptide B significantly enhanced the activity of alkaline phosphatase in BMSCs compared to that of the blank group ( < 0.001). Antler polypeptide B increased the BMP7 protein expression in BMSCs.

Conclusions: Results suggested that antler polypeptide may promote the proliferation and osteogenic differentiation of BMSCs. Our study lays an experimental foundation for the further development and application of antler polypeptide in medicine.
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http://dx.doi.org/10.1155/2020/1294151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563042PMC
September 2020

Magnetic Polydopamine Modified with Choline-Based Deep Eutectic Solvent for the Magnetic Solid-Phase Extraction of Sulfonylurea Herbicides in Water Samples.

J Chromatogr Sci 2021 Jan;59(1):95-102

College of Plant Science and Technology, Department of Plant Protection, Huazhong Agriculture University, Shizishan Street 1, Wuhan 430070, China.

A novel magnetic solid-phase extraction technique coupled to ultraperformance liquid chromatography has been developed for separation and preconcentration of four sulfonylurea herbicides (sulfosulfuron, bensulfuron-methyl, pyrazosulfuron-ethyl and halosulfuro-methyl) in aqueous samples. The key point of this method was the application of a novel magnetic nanomaterial that composed of a low eutectic solvent as a shell coated on the magnetic core modified by polydopamine. The extensive active sites outside the low eutectic solvent can effectively adsorb the target herbicide in the extraction process. The obtained magnetic adsorbent was characterized with fourier transform infrared spectrometry, scanning electron microscopy and vibrating sample magnetometer. The influence parameters relevant to this method were optimized. Under the optimum conditions, good linearities could be obtained within the range of 1.0-200 μg L-1 for all analytes, with correlation coefficients ≥0.9908. The limit of detections of the method was between 0.0074 and 0.0100 μg L-1 and the relative standard deviations were 1.1-3.6%. The enrichment factor is 66.6. In the final experiment, the proposed method was successfully applied to the analysis of sulfonylurea herbicides residue in environment and drinking-water samples, and the obtained recoveries were between 70.6% and 109.4%.
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http://dx.doi.org/10.1093/chromsci/bmaa077DOI Listing
January 2021

Differential Transcription and Alternative Splicing in Cotton Underly Specialized Defense Responses Against Pests.

Front Plant Sci 2020 15;11:573131. Epub 2020 Sep 15.

CAS Key Laboratory of Insect Developmental and Evolutionary Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, University of CAS, Chinese Academy of Sciences, Shanghai, China.

The green mirid bug () and the cotton bollworm () are both preferred to live on cotton but cause different symptoms, suggesting specialized responses of cotton to the two insects. In this study, we investigated differential molecular mechanisms underlying cotton plant defenses against and transcriptomic analyses. At the transcription level, jasmonate (JA) signaling was dominated in defense against whereas salicylic acid (SA) signaling was more significant in defense against . A set of pathogenesis-related (PR) genes and protease inhibitor genes were differentially induced by the two insects. Insect infestations also had an impact on alternative splicing (AS), which was altered more significantly by the than . Interestingly, most differential AS (DAS) genes had no obvious change at the transcription level. GO analysis revealed that biological process termed "RNA splicing" and "cellular response to abiotic stimulus" were enriched only in DAS genes from the infested samples. Furthermore, insect infestations induced the retained intron of GhJAZs transcripts, which produced a truncated protein lacking the intact Jas motif. Taken together, our data demonstrate that the specialized cotton response to different insects is regulated by gene transcription and AS as well.
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http://dx.doi.org/10.3389/fpls.2020.573131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533563PMC
September 2020

Executive function and its relation to anatomical connectome in homosexual and heterosexual men.

Quant Imaging Med Surg 2020 Oct;10(10):1973-1983

Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: Sexual orientation has been suggested to affect executive function, of which the neurobiological basis is still largely unknown. In this study, we explored the interrelationship between neuropsychological characteristics in homosexual and heterosexual men and their anatomical connectome by graph theoretical analysis.

Methods: Fifty-three homosexual and 47 heterosexual males underwent diffusion tensor magnetic resonance imaging (MRI) and neuropsychological assessments. Whole-brain anatomical networks were constructed using white matter tractography, performed on the diffusion tensor imaging data. Neuropsychological tests included the Wisconsin Card Sorting Test (WCST), the Continuous Performance Test (CPT) and the Trail-Making Test (TMT).

Results: The cognitive performance of homosexual men was significantly poorer than their heterosexual counterparts in terms of WCST total correct responses. Anatomical connectome analysis revealed a lower (P=0.001) anatomical connectivity between left PoCG and left SMG (P=0.003) in homosexual men as compared to heterosexual men. Linear regression analyses showed that the WCST total correct responses score was significantly linked with sexual orientation (P=0.001). The anatomical connectivity strength between left PoCG and left SMG was also shown to be significantly correlated with sexual orientation (P=0.039) and education (P=0.047).

Conclusions: Our study demonstrated the differences in the performance of WCST and anatomical connectome of large-scale brain networks between homosexual and heterosexual men, extending our understanding of the brain's circuitry and the characteristics of executive function in men of different sexual orientation.
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http://dx.doi.org/10.21037/qims-19-821bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495316PMC
October 2020