Publications by authors named "Dan Du"

324 Publications

Stress Hyperglycemia Is Independently Associated with Persistent Organ Failure in Acute Pancreatitis.

Dig Dis Sci 2021 May 3. Epub 2021 May 3.

Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, No. 37 Wannan Guoxue Alley, Chengdu, 610041, Sichuan Province, China.

Background/aims: Stress hyperglycemia is common in critical illness but it has not been clearly studied in patients with acute pancreatitis (AP). This study aimed to investigate the specific blood glucose (BG) level that defines stress hyperglycemia and to determine the impact of stress hyperglycemia on clinical outcomes in AP patients.

Methods: AP patients admitted ≤ 48 h after abdominal pain onset were retrospectively analyzed. Patients were stratified by pre-existing diabetes and stress hyperglycemia was defined using stratified BG levels for non-diabetes and diabetes with clinical outcomes compared.

Results: There were 967 non-diabetic and 114 diabetic (10.5%) patients met the inclusion criteria and the clinical outcomes between these two groups were not significantly different. In non-diabetes, the cut-off BG level of ≥ 180 mg/dl was selected to define stress hyperglycemia with an 8.8-fold higher odds ratio for persistent organ failure (POF) (95% CI 5.4-14.3; P < 0.001). For diabetes, ≥ 300 mg/dl was selected with a 7.5-fold higher odds ratio for POF (95% CI 1.7-34.3; P = 0.009). In multivariable logistic regression, stress hyperglycemia was independently associated with POF, acute necrotic collection, major infection and mortality. The combination of BG and systemic inflammatory response syndrome (SIRS) score in predicting POF was better than SIRS or Glasgow score alone.

Conclusions: This study identifies a cut-off BG level of ≥ 180 mg/dl and ≥ 300 mg/dl was optimal to define stress hyperglycemia for non-diabetic and diabetic AP patients, respectively. There was a significant relationship between stress hyperglycemia and adverse clinical outcomes.
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http://dx.doi.org/10.1007/s10620-021-06982-8DOI Listing
May 2021

Nanomaterial-enhanced 3D-printed sensor platform for simultaneous detection of atrazine and acetochlor.

Biosens Bioelectron 2021 Apr 10;184:113238. Epub 2021 Apr 10.

School of Mechanical and Materials Engineering, Washington State University, Pullman, WA, 99164-2920, United States. Electronic address:

The widespread use of herbicides in agriculture and gardening causes environmental and safety issues such as water pollution. Thus, efficient and convenient analysis of the levels of herbicide residues is of significant importance. Here, we employed 3D-printing to design a multiplex immunosensor for simultaneous detection of two widely used herbicides, atrazine and acetochlor. Multiplexing was achieved through customization of a lateral flow immunoassay, and then integrated with an electrochemical analyzer for ultrasensitive detection. Quantification of herbicide residues was realized through the detection of a novel nanomaterial label, the mesoporous core-shell palladium@platium nanoparticle (Pd@Pt NP), for its outstanding peroxidase-like property. During the electrochemical analysis, the catalytic activity of Pd@Pt NPs on the redox reaction between thionin acetate and hydrogen peroxide provided an electrochemically driven signal that accurately indicated the level of herbicide residues. Using this Nanomaterial-enhanced multiplex electrochemical immunosensing (NEMEIS) system, simultaneous detection of atrazine and acetochlor was realized with a limit of detection of 0.24 ppb and 3.2 ppb, respectively. To further evaluate the feasibility, the optimized NEMEIS was employed for detection in atrazine and acetochlor residue-containing spiked samples, and an overall recovery with 90.8% - 117% range was obtained. The NEMEIS constructed with the aid of 3D-printing provides a rapid, precise, economical, and portable detection device for herbicides, and its success suggests potential broad applications in chemical analysis, biosensors and point-of-care monitoring.
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http://dx.doi.org/10.1016/j.bios.2021.113238DOI Listing
April 2021

Effects of camera viewing angles on tracking kinematic gait patterns using Azure Kinect, Kinect v2 and Orbbec Astra Pro v2.

Gait Posture 2021 Apr 5;87:19-26. Epub 2021 Apr 5.

Department of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong. Electronic address:

Background: Depth sensors could be a portable, affordable, marker-less alternative to three-dimension motion capture systems for gait analysis, but the effects of camera viewing angles on their joint angle tracking performance have not been fully investigated.

Research Questions: This study evaluated the accuracies of three depth sensors [Azure Kinect (AK); Kinect v2 (K2); Orbbec Astra (OA)] for tracking kinematic gait patterns during treadmill walking at five camera viewing angles (0°/22.5°/45°/67.5°/90°).

Methods: Ten healthy subjects performed fifteen treadmill walking trials (3 speeds × 5 viewing angles) using the three depth sensors to measure joint angles in sagittal hip, frontal hip, sagittal knee, and sagittal ankle. Ten walking steps were recorded and averaged for each walking trial. Range of motion in terms of maximum and minimum joint angles measured by the depth sensors were compared with the Vicon motion capture system as the gold standard. Depth sensors tracking accuracies were compared against the Vicon reference using root-mean-square error (RMSE) on the joint angle time series. Effects of different walking speeds, viewing angles, and depth sensors on the tracking accuracy were observed using three-way repeated-measure analysis of variance (ANOVA).

Results: ANOVA results on RMSE showed significant interaction effects between viewing angles and depth sensors for sagittal hip [F(8,72) = 4.404, p = 0.005] and for sagittal knee [F(8,72)=13.211, p < 0.001] joint angles. AK had better tracking performance when subjects walked at non-frontal camera viewing angles (22.5°/45°/67.5°/90°); while K2 performed better at frontal viewing angle (0°). The superior tracking performance of AK compared with K2/OA might be attributed to the improved depth sensor resolution and body tracking algorithm.

Significance: Researchers should be cautious about camera viewing angle when using depth sensors for kinematic gait measurements. Our results demonstrated Azure Kinect had good tracking performance of sagittal hip and sagittal knee joint angles during treadmill walking tests at non-frontal camera viewing angles.
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http://dx.doi.org/10.1016/j.gaitpost.2021.04.005DOI Listing
April 2021

The safety and immunogenicity of an inactivated SARS-CoV-2 vaccine in Chinese adults aged 18-59 years: A phase I randomized, double-blinded, controlled trial.

Vaccine 2021 05 9;39(20):2746-2754. Epub 2021 Apr 9.

Institute of Medical Biology, Chinese Academy of Medicine Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research and Development for Severe Infectious Diseases, Kunming 650118, China.

Background: This study examined the safety and immunogenicity of an inactivated SARS-CoV-2 vaccine.

Method: In a phase I randomized, double-blinded, placebo-controlled trial involving 192 healthy adults 18-59 years old, two injections of three doses (50 EU, 100 EU, 150 EU) of an inactivated SARS-CoV-2 vaccine or placebo were administered intramuscularly at a 2- or 4-week interval. The safety and immunogenicity of the vaccine were evaluated.

Results: Vaccination was completed in 191 subjects. Forty-four adverse reactions occurred within 28 days, most commonly mild pain and redness at the injection site or slight fatigue. At days 14 and 28, the seroconversion rates were 87.5% and 79.2% (50 EU), 100% and 95.8% (100 EU), and 95.8% and 87.5% (150 EU), respectively, with geometric mean titers (GMTs) of 18.1 and 10.6, 54.5 and 15.4, and 37.1 and 18.5, respectively, for the schedules with 2-week and 4-week intervals. Seroconversion was associated with synchronous upregulation of antibodies against the S protein, N protein and virion and a cytotoxic T lymphocyte (CTL) response. No cytokines and immune cells related to immunopathology were observed. Transcriptome analysis revealed the genetic diversity of immune responses induced by the vaccine.

Interpretation: In a population aged 18-59 years in this trial, this inactivated SARS-CoV-2 vaccine was safe and immunogenic.

Trial Registration: CTR20200943 and NCT04412538.
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http://dx.doi.org/10.1016/j.vaccine.2021.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040531PMC
May 2021

Design, synthesis and biological evaluation of novel pleuromutilin derivatives as potent anti-MRSA agents targeting the 50S ribosome.

Bioorg Med Chem 2021 May 2;38:116138. Epub 2021 Apr 2.

Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China. Electronic address:

A series of novel pleuromutilin derivatives were designed and synthesized with 1,2,4-triazole as the linker connected to benzoyl chloride analogues under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213, AD3 and 144) were tested by the broth dilution method. Most of the synthesized derivatives displayed potent activities, and 22-(3-amino-2-(4-methyl-benzoyl)-1,2,4-triazole-5-yl)-thioacetyl)-22-deoxypleuromutilin (compound 12) was found to be the most active antibacterial derivative against MRSA (MIC = 0.125 μg/mL). Furthermore, the time-kill curves showed compound 12 had a certain inhibitory effect against MRSA in vitro. The in vivo antibacterial activity of compound 12 was further evaluated using MRSA infected murine thigh model. Compound 12 exhibited superior antibacterial efficacy than tiamulin. It was also found that compound 12 had no significant inhibitory effect on the proliferation of RAW264.7 cells. Compound 12 was further evaluated in CYP450 inhibition assay and showed moderate inhibitory effect on CYP3A4 (IC = 3.95 μM). Moreover, seven candidate compounds showed different affinities with the 50S ribosome by SPR measurement. Subsequently, binding of compound 12 and 20 to the 50S ribosome was further investigated by molecular modeling. Three strong hydrogen bonds were formed through the interaction of compound 12 and 20 with 50S ribosome. The binding free energy of compound 12 and 20 with the ribosome was calculated to be -10.7 kcal/mol and -11.66 kcal/mol, respectively.
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http://dx.doi.org/10.1016/j.bmc.2021.116138DOI Listing
May 2021

Targeting Macrophage Migration Inhibitory Factor in Acute Pancreatitis and Pancreatic Cancer.

Front Pharmacol 2021 11;12:638950. Epub 2021 Mar 11.

Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in the pathogenesis of inflammation and cancer. It is produced by various cells and circulating MIF has been identified as a biomarker for a range of diseases. Extracellular MIF mainly binds to the cluster of differentiation 74 (CD74)/CD44 to activate downstream signaling pathways. These in turn activate immune responses, enhance inflammation and can promote cancer cell proliferation and invasion. Extracellular MIF also binds to the C-X-C chemokine receptors cooperating with or without CD74 to activate chemokine response. Intracellular MIF is involved in Toll-like receptor and inflammasome-mediated inflammatory response. Pharmacological inhibition of MIF has been shown to hold great promise in treating inflammatory diseases and cancer, including small molecule MIF inhibitors targeting the tautomerase active site of MIF and antibodies that neutralize MIF. In the current review, we discuss the role of MIF signaling pathways in inflammation and cancer and summarize the recent advances of the role of MIF in experimental and clinical exocrine pancreatic diseases. We expect to provide insights into clinical translation of MIF antagonism as a strategy for treating acute pancreatitis and pancreatic cancer.
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http://dx.doi.org/10.3389/fphar.2021.638950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992011PMC
March 2021

Metabolic Regulation of Hypoxia-Inducible Factors in Hypothalamus.

Front Endocrinol (Lausanne) 2021 8;12:650284. Epub 2021 Mar 8.

Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

The earliest hypoxia-inducible factor (HIF) function was to respond to hypoxia or hypoxic conditions as a transcription factor. Recent studies have expanded our understanding of HIF, and a large amount of evidence indicates that HIF has an essential effect on central regulation of metabolism. The central nervous system's response to glucose, inflammation, and hormones' main influence on systemic metabolism are all regulated by HIF to varying degrees. In the hypothalamus, HIF mostly plays a role in inhibiting energy uptake and promoting energy expenditure, which depends not only on the single effect of HIF or a single part of the hypothalamus. In this paper, we summarize the recent progress in the central regulation of metabolism, describe in detail the role of HIF in various functions of the hypothalamus and related molecular mechanisms, and reveal that HIF is deeply involved in hypothalamic-mediated metabolic regulation.
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http://dx.doi.org/10.3389/fendo.2021.650284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984363PMC
March 2021

Revealing the mechanism of SARS-CoV-2 spike protein binding with ACE2.

Comput Sci Eng 2020 Nov-Dec;22(6):21-29. Epub 2020 Aug 11.

Computational Science Program, University of Texas at El Paso, El Paso, TX.

A large population in the world has been infected by COVID-19. Understanding the mechanisms of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is important for management and treatment of the COVID-19. When it comes to the infection process, one of the most important proteins in SARS-CoV-2 is the spike (S) protein, which is able to bind to human Angiotensin-Converting Enzyme 2 (ACE2) and initializes the entry of the host cell. In this study, we implemented multi-scale computational approaches to study the electrostatic features of the interfaces of the SARS-CoV-2 S protein Receptor Binding Domain (RBD) and ACE2. The simulations and analyses were performed on high-performance computing resources in Texas Advanced Computing Center (TACC). Our study identified key residues on the SARS-CoV-2, which can be used as targets for future drug design. The results shed lights on future drug design and therapeutic targets for COVID-19.
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http://dx.doi.org/10.1109/MCSE.2020.3015511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983027PMC
August 2020

A multi-strategy platform for quality control and Q-markers screen of Chaiqin chengqi decoction.

Phytomedicine 2021 May 20;85:153525. Epub 2021 Feb 20.

Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address:

Background: Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that is associated with substantial morbidity and mortality. Chaiqin chengqi decoction (CQCQD) has been proven clinically to be an effective treatment for AP for decades in West China Hospital. Quality control for CQCQD containing many hundreds of characteristic phytochemicals poses a challenge for developing robust quality assessment metrics.

Purpose: To evaluate quality consistency of CQCQD with a multi-strategy based analytical method, identify potential quality-markers (Q-markers) based on drug properties and effect characteristics, and endeavor to establish CQCQD as a globally-accepted medicine.

Methods: A typical analysis of constitutive medicinal plant materials was performed following the Chinese Pharmacopoeia. The extraction process was optimized through an orthogonal array (L(3)) to evaluate three levels of liquid to solid ratio, soaking time, duration of extraction, and the number of extractions. An ultra-high-performance liquid chromatography (UHPLC) fingerprinting combined with absolute quantitation of multi chemical marker compounds, coupled with similarity, hierarchical clustering analysis (HCA), and principal component analyses (PCA) were performed to evaluate 10 batches of CQCQD. On the basis of systematic analysis of fundamental features of CQCQD in treating AP, the potential Q-marker screen was proposed through detection of quality transfer and efficacy for chemical markers. UHPLC coupled with quadrupole orbitrap mass spectrometry were used to determine compounds in medicinal materials, decoctions and plasma. Network pharmacology and taurolithocholic acid 3-sulfate induced pancreatic acinar cell death were used to evaluate the correlation between chemical markers and anti-pancreatitis activity. A cerulein induced AP murine model was used to validate quality assessed CQCQD batches at clinically-equivalent dose. The effective content of chemical markers was predicted using linear regression analysis on quantitative information between validated batches and the other batches.

Results: The chemical markers and other physical and chemical indices in the original materials met Chinese Pharmacopoeia standards. A total of 22 co-existing fingerprint peaks were selected and the similarity varied between 0.946 and 0.990. Batch D10 possessed the highest similarity index. HCA classified the 10 batches into 2 main groups: 7 batches represented by D10 and 3 batches represented by D1. During the initial Q-marker screen stage, 22 compounds were detected in both plant materials and decoctions, while 13 compounds were identified in plasma. Network pharmacology predicted the potential targets and pathway of AP related to the 22 compounds. All 10 batches showed reduced necrosis below 60% with the best effect achieved by D10 (~40%). The spectrum-efficacy relationship analyzed by Pearson correlation analysis indicated that emodin, rhein, aloe emodin, geniposide, hesperridin, chrysin, syringin, synephrine, geniposidic acid, magnolol, physcion, sinensetin, and baicalein showed positive correlation with pancreatic acinar cell death protection. Similar to the in vitro evaluation, batch D10 significantly reduced total histopathological scores and biochemical severity indices at a clinically-equivalent dose but batch D1 did not. The content of naringin, narirutin and baicalin in batches D1, D5 and D9 consistently exceeds the upper limit of the predicted value. Eight markers whose lower limit is predicted to be close to 0 contributed less to the material basis for AP protection.

Conclusion: Despite qualified materials used for CQCQD preparation, the clinical effect depends on appropriate content range of Q-markers. Emodin, rhein, aloe emodin, magnolol, hesperidin, synephrine, baicalein, and geniposide are considered as vital Q-markers in the primary screen. This study proposed a feasible platform for producing highly consistent batches of CQCQD in future study.
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http://dx.doi.org/10.1016/j.phymed.2021.153525DOI Listing
May 2021

Chaiqin chengqi decoction ameliorates acute pancreatitis in mice via inhibition of neuron activation-mediated acinar cell SP/NK1R signaling pathways.

J Ethnopharmacol 2021 Jun 14;274:114029. Epub 2021 Mar 14.

Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address:

Ethnopharmacological Relevance: Chaiqin chengqi decoction (CQCQD) and its derivatives have been widely used in China for the early management of patients with acute pancreatitis (AP). Numerous studies demonstrate the anti-inflammatory and anti-oxidative effects of CQCQD and derivatives, but whether these effects can be attributed to suppressing neurogenic inflammation, has never been studied.

Aim Of The Study: To investigate the effects of CQCQD on substance P (SP)-neurokinin 1 receptor (NK1R) based neurogenic inflammation in an experimental AP model.

Material And Methods: For AP patients on admission, pain score was accessed by visual analog scale (VAS); the levels of serum SP and expressions of pancreatic SP and NK1R were also determined. For in vivo study, mice received 7 intraperitoneal injections of cerulein (50 μg/kg) at hourly intervals to induce AP, whilst controls received normal saline injections. In the treatment groups, CQCQD (10 g/kg, 200 μl) was intragastrically given at the third, fifth, and seventh of the cerulein injection or the NK1R antagonist CP96345 (5 mg/kg) was intraperitoneally injected 30 min before the first cerulein administration. The von Frey test was performed to evaluate pain behavior. Animals were sacrificed at 12 h from the first cerulein/saline injection for severity assessment. Pharmacology network analysis was used to identify active ingredients of CQCQD for AP and pain. In vitro, freshly isolated pancreatic acinar cells were pre-treated with CQCQD (5 mg/ml), CP96345 (1 μM), or selected active compounds of CQCQD (12.5, 25, and 50 μM) for 30 min, followed by SP incubation for another 30 min.

Results: The VAS score as well as the levels of serum SP and expressions of pancreatic SP-NK1R were up-regulated in moderately severe and severe patients compared with those with mild disease. CQCQD, but not CP96345, consistently and significantly ameliorated pain, pancreatic necrosis, and systemic inflammation in cerulein-induced AP as well as inhibited NK1R internalization of pancreatic acinar cells. These effects of CQCQD were associated with reduction of pancreatic SP-NK1R and neuron activity in pancreas, dorsal root ganglia, and spinal cord. Baicalin, emodin, and magnolol, the top 3 active components of CQCQD identified via pharmacology network analysis, suppressed NK1R internalization and NF-κB signal pathway activation in isolated pancreatic acinar cells.

Conclusions: CQCQD ameliorated cerulein-induced AP and its associated pain via inhibiting neuron activation-mediated pancreatic acinar cell SP-NK1R signaling pathways and its active compounds baicalin, emodin, and magnolol contributed to this effect.
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http://dx.doi.org/10.1016/j.jep.2021.114029DOI Listing
June 2021

Metabolomic-based clinical studies and murine models for acute pancreatitis disease: A review.

Biochim Biophys Acta Mol Basis Dis 2021 Mar 11;1867(7):166123. Epub 2021 Mar 11.

West China-Washington Mitochondria and Metabolism Centre, Frontiers Science Center for Disease-related Molecular Network, West China Hospital/West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address:

Acute pancreatitis (AP) is one of the most common gastroenterological disorders requiring hospitalization and is associated with substantial morbidity and mortality. Metabolomics nowadays not only help us to understand cellular metabolism to a degree that was not previously obtainable, but also to reveal the importance of the metabolites in physiological control, disease onset and development. An in-depth understanding of metabolic phenotyping would be therefore crucial for accurate diagnosis, prognosis and precise treatment of AP. In this review, we summarized and addressed the metabolomics design and workflow in AP studies, as well as the results and analysis of the in-depth of research. Based on the metabolic profiling work in both clinical populations and experimental AP models, we described the metabolites with potential utility as biomarkers and the correlation between the altered metabolites and AP status. Moreover, the disturbed metabolic pathways correlated with biological function were discussed in the end. A practical understanding of current and emerging metabolomic approaches applicable to AP and use of the metabolite information presented will aid in designing robust metabolomics and biological experiments that result in identification of unique biomarkers and mechanisms, and ultimately enhanced clinical decision-making.
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http://dx.doi.org/10.1016/j.bbadis.2021.166123DOI Listing
March 2021

Fine-Tuning Pyridinic Nitrogen in Nitrogen-Doped Porous Carbon Nanostructures for Boosted Peroxidase-Like Activity and Sensitive Biosensing.

Research (Wash D C) 2020 6;2020:8202584. Epub 2020 Nov 6.

Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China.

Carbon materials have been widely used as nanozymes in bioapplications, attributing to their intrinsic enzyme-like activities. Nitrogen (N)-doping has been explored as a promising way to improve the activity of carbon material-based nanozymes (CMNs). However, hindered by the intricate N dopants, the real active site of N-doped CMNs (N-CMNs) has been rarely investigated, which subsequently retards the further progress of high-performance N-CMNs. Here, a series of porous N-CMNs with well-controlled N dopants were synthesized, of which the intrinsic peroxidase (POD)like activity has a positive correlation with the pyridinic N content. Density functional theory calculations also reveal that pyridinic N boosts the intrinsic POD-like activity of N-CMNs. Pyridinic-N dopant can effectively promote the first HO desorption process in comparison with the graphitic and pyrrolic N, which is the key endothermic reaction during the catalytic process. Then, utilizing the optimized nanozymes with high pyridinic N content (N-CMNs) and superior POD-like activity, a facile total antioxidant capacity (TAC) assay was developed, holding great promise in the quality assessment of medicine tablets and antioxidant food for healthcare and healthy diet.
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http://dx.doi.org/10.34133/2020/8202584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877393PMC
November 2020

Self-Assembling Allochroic Nanocatalyst for Improving Nanozyme-Based Immunochromatographic Assays.

ACS Sens 2021 01 12;6(1):220-228. Epub 2021 Jan 12.

School of Mechanical and Material Engineering, Washington State University, Pullman, Washington 99164, United States.

Paper-based rapid diagnostic tests, such as immunochromatographic assays, namely lateral flow immunoassay (LFA), are valuable alternatives for biomarker detection compared to traditional laboratory-based tests, but these assays need further refinement to consolidate their biosensing capabilities. Nanozyme integration into LFA systems may provide a reliable means of improving the analytic sensitivity of LFA tests. Due to the involvement of multiple liquid-handling steps, the quantitative accuracy is compromised, hence hindering the use of untrained personnel point-of-care use. Self-assembling allochroic nanocatalyst (SAN) assemblies satisfy these LFA quality measures by optimizing analyte-antibody reporting performance and by intrinsically catalyzing chromogen activation, thereby reducing the number of liquid handling steps involved during sample analysis. In SANs, the hydrophobic chromogens serve as peroxidase substrates that self-assemble into nanoparticles at high loading fractions. These features demonstrate the potential for SAN-LFAs to be a valuable patient point-of-care (POC) test. Herein, we describe the SAN fabrication process and employ SAN-LFAs to detect cardiac troponin I-troponin C (cTnI-TnC) and myoglobin (Myo) levels present in plasma samples. Using SAN-LFAs, the limits of detection for cTnI-TnC and Myo were 0.012 ng/mL and 0.2 ng/mL respectively. We also demonstrate SAN compatibility with blood samples and stability under long-term storage conditions. The successful utlization of SANs in LFA-based biomarker detection may inspire these nanocatalysts to be integrated into similar immunochromatographic testing methods.
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http://dx.doi.org/10.1021/acssensors.0c02148DOI Listing
January 2021

The CC-NB-LRR OsRLR1 mediates rice disease resistance through interaction with OsWRKY19.

Plant Biotechnol J 2020 Dec 26. Epub 2020 Dec 26.

Key Laboratory of Application and Safety Control of Genetically Modified Crops, Academy of Agricultural Sciences, Rice Research Institute, Southwest University, Chongqing, China.

Nucleotide-binding site-leucine-rich repeat (NB-LRR) resistance proteins are critical for plant resistance to pathogens; however, their mechanism of activation and signal transduction is still not well understood. We identified a mutation in an as yet uncharacterized rice coiled-coil (CC)-NB-LRR, Oryza sativa RPM1-like resistance gene 1 (OsRLR1), which leads to hypersensitive response (HR)-like lesions on the leaf blade and broad-range resistance to the fungal pathogen Pyricularia oryzae (syn. Magnaporthe oryzae) and the bacterial pathogen Xanthomonas oryzae pv. oryzae, together with strong growth reduction. Consistently, OsRLR1-overexpression lines showed enhanced resistance to both pathogens. Moreover, we found that OsRLR1 mediates the defence response through direct interaction in the nucleus with the transcription factor OsWRKY19. Down-regulation of OsWRKY19 in the rlr1 mutant compromised the HR-like phenotype and resistance response, and largely restored plant growth. OsWRKY19 binds to the promoter of OsPR10 to activate the defence response. Taken together, our data highlight the role of a new residue involved in the NB-LRR activation mechanism, allowing identification of a new NB-LRR downstream signalling pathway.
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http://dx.doi.org/10.1111/pbi.13530DOI Listing
December 2020

Spike Proteins of SARS-CoV and SARS-CoV-2 Utilize Different Mechanisms to Bind With Human ACE2.

Front Mol Biosci 2020 9;7:591873. Epub 2020 Dec 9.

Computational Science Program, University of Texas at El Paso, El Paso, TX, United States.

The ongoing outbreak of COVID-19 has been a serious threat to human health worldwide. The virus SARS-CoV-2 initiates its infection to the human body via the interaction of its spike (S) protein with the human Angiotensin-Converting Enzyme 2 (ACE2) of the host cells. Therefore, understanding the fundamental mechanisms of how SARS-CoV-2 S protein receptor binding domain (RBD) binds to ACE2 is highly demanded for developing treatments for COVID-19. Here we implemented multi-scale computational approaches to study the binding mechanisms of human ACE2 and S proteins of both SARS-CoV and SARS-CoV-2. Electrostatic features, including electrostatic potential, electric field lines, and electrostatic forces of SARS-CoV and SARS-CoV-2 were calculated and compared in detail. The results demonstrate that SARS-CoV and SARS-CoV-2 S proteins are both attractive to ACE2 by electrostatic forces even at different distances. However, the residues contributing to the electrostatic features are quite different due to the mutations between SARS-CoV S protein and SARS-CoV-2 S protein. Such differences are analyzed comprehensively. Compared to SARS-CoV, the SARS-CoV-2 binds with ACE2 using a more robust strategy: The electric field line related residues are distributed quite differently, which results in a more robust binding strategy of SARS-CoV-2. Also, SARS-CoV-2 has a higher electric field line density than that of SARS-CoV, which indicates stronger interaction between SARS-CoV-2 and ACE2, compared to that of SARS-CoV. Key residues involved in salt bridges and hydrogen bonds are identified in this study, which may help the future drug design against COVID-19.
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http://dx.doi.org/10.3389/fmolb.2020.591873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755986PMC
December 2020

Rapid detection of the New Delhi metallo-β-lactamase (NDM) gene by recombinase polymerase amplification.

Infect Genet Evol 2021 Jan 13;87:104678. Epub 2020 Dec 13.

Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China. Electronic address:

New Delhi metallo-β-lactamase (NDM) is a series of enzyme conferring resistance to β-lactam antibiotics including the carbapenems. The bla gene has been reported in a variety of Gram-negative bacilli, especially in the Enterobacteriaceae and Acinetobacter spp., which is deeply disconcerting for public health worldwide. In this study, recombinase polymerase amplification assays using a basic detection (Basic-RPA) and a real-time fluorescent detection (Exo-RPA) were established for detecting bla gene. The RPA reactions were performed at 39 °C and finished within 20 min. Using different copy numbers of pMD18T-NDM plasmid DNA as templates, we identified the detection limit of Basic-RPA assay (1.85 × 10 copies/μL), conventional PCR assay (1.85 × 10 copies/μL), Exo-RPA assay (1.85 × 10 copies/μL) and real-time PCR assay (1.85 × 10 copies/μL). Both Basic-RPA and Exo-RPA assays were highly specific for detecting bla, as there were no cross-reactions with the strains without bla gene. Examination of 62 clinical samples by RPA assays and PCR assays showed the same results, suggesting that RPA assays are reliable in clinical diagnosis. The amplification time of RPA is much shorter than that of other molecular techniques, it is easy to implement and has the potential for clinical application.
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http://dx.doi.org/10.1016/j.meegid.2020.104678DOI Listing
January 2021

Maximum chest CT score is associated with progression to severe illness in patients with COVID-19: a retrospective study from Wuhan, China.

BMC Infect Dis 2020 Dec 11;20(1):953. Epub 2020 Dec 11.

Department of Radiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 26 Shengli Avenue, Jiangan, Wuhan, 430014, Hubei, China.

Background: The Coronavirus Disease 2019 (COVID-19) pandemic is a world-wide health crisis. Limited information is available regarding which patients will experience more severe disease symptoms. We evaluated hospitalized patients who were initially diagnosed with moderate COVID-19 for clinical parameters and radiological feature that showed an association with progression to severe/critical symptoms.

Methods: This study, a retrospective single-center study at the Central Hospital of Wuhan, enrolled 243 patients with confirmed COVID-19 pneumonia. Forty of these patients progressed from moderate to severe/critical symptoms during follow up. Demographic, clinical, laboratory, and radiological data were extracted from electronic medical records and compared between moderate- and severe/critical-type symptoms. Univariable and multivariable logistic regressions were used to identify the risk factors associated with symptom progression.

Results: Patients with severe/critical symptoms were older (p < 0.001) and more often male (p = 0.046). A combination of chronic obstructive pulmonary disease (COPD) and high maximum chest computed tomography (CT) score was associated with disease progression. Maximum CT score (> 11) had the greatest predictive value for disease progression. The area under the receiver operating characteristic curve was 0.861 (95% confidence interval: 0.811-0.902).

Conclusions: Maximum CT score and COPD were associated with patient deterioration. Maximum CT score (> 11) was associated with severe illness.
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http://dx.doi.org/10.1186/s12879-020-05683-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729688PMC
December 2020

An Ion-Imprinting Derived Strategy to Synthesize Single-Atom Iron Electrocatalysts for Oxygen Reduction.

Small 2021 Apr 11;17(16):e2004454. Epub 2020 Dec 11.

School of Mechanical and Materials Engineering, Washington State University, Pullman, WA, 99164, USA.

Carbon-based single-atom catalysts (CSACs) have recently received extensive attention in catalysis research. However, the preparation process of CSACs involves a high-temperature treatment, during which metal atoms are mobile and aggregated into nanoparticles, detrimental to the catalytic performance. Herein, an ion-imprinting derived strategy is proposed to synthesize CSACs, in which isolated metal-nitrogen-carbon (Me-N -C ) moiety covalently binds oxygen atoms in Si-based molecular sieve frameworks. Such a feature makes Me-N -C moiety well protected/confined during the heat treatment, resulting in the final material enriched with single-atom metal active sites. As a proof of concept, a single-atom Fe-N-C catalyst is synthesized by using this ion-imprinting derived strategy. Experimental results and theoretical calculations demonstrate high concentration of single FeN active sites distributed in this catalyst, resulting in an outstanding oxygen reduction reaction (ORR) performance with a half-wave potential of 0.908 V in alkaline media.
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http://dx.doi.org/10.1002/smll.202004454DOI Listing
April 2021

Single-atom catalysts boost signal amplification for biosensing.

Chem Soc Rev 2021 Jan 11;50(2):750-765. Epub 2020 Dec 11.

Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan, 430079, P. R. China.

Development of highly sensitive biosensors has received ever-increasing attention over the years. Due to the unique physicochemical properties, the functional nanomaterial-enabled signal amplification strategy has made some great breakthroughs in biosensing. However, the sensitivity and selectivity still need further improvement. Single-atom catalysts (SACs) containing atomically dispersed metal active sites demonstrate distinctive advantages in catalytic activity and selectivity for various catalytic reactions. As a consequence, the SAC-enabled signal amplification strategy holds great promise in biosensors, demonstrating satisfactory sensitivity and selectivity with the assistance of tunable metal-support interactions, coordination environments and geometric/electronic structures of active sites. In this tutorial review, we briefly discuss the structural advantages of SACs. Then, the catalytic mechanism at the atomic scale and signal amplification effects of SACs in the colorimetric, electrochemical, chemiluminescence, electrochemiluminescence, and photoelectrochemical biosensing applications are highlighted in detail. Finally, opportunities and challenges to be faced in the future development of the SAC-enabled signal amplification strategy for biosensing are discussed and outlooked.
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http://dx.doi.org/10.1039/d0cs00367kDOI Listing
January 2021

SHORT-ROOT 1 is critical to cell division and tracheary element development in rice roots.

Plant J 2021 Mar 18;105(5):1179-1191. Epub 2020 Dec 18.

Rice Research Institute, Key Laboratory of Application and Safety Control of Genetically Modified Crops, Academy of Agricultural Sciences, Southwest University, Chongqing, 400715, China.

The exocyst is a key factor in vesicle transport and is involved in cell secretion, cell growth, cell division and other cytological processes in eukaryotes. EXO70 is the key exocyst subunit. We obtained a gene, SHORT-ROOT 1 (SR1), through map-based cloning and genetic complementation. SR1 is a conserved protein with an EXO70 domain in plants. SR1 mutation affected the whole root-development process: producing shorter radicles, adventitious roots and lateral roots, and demonstrating abnormal xylem development, resulting in dwarfing and reduced water potential and moisture content. SR1 was largely expressed in the roots, but only in developing root meristems and tracheary elements. The shortness of the sr1 mutant roots was caused by the presence of fewer meristem cells. The in situ histone H4 expression patterns confirmed that cell proliferation during root development was impaired. Tracheary element dysplasia was caused by marked decreases in the inner diameters of and distances between the perforations of adjacent tracheary elements. The membrane transport of sr1 mutants was blocked, affecting cell division in the root apical region and the development of root tracheary elements. The study of SR1 will deepen our understanding of the function of EXO70 genes in Oryza sativa (rice) and guide future studies on the molecular mechanisms involved in plant root development.
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http://dx.doi.org/10.1111/tpj.15095DOI Listing
March 2021

Targeting Mitochondria-Inflammation Circuit by β-Hydroxybutyrate Mitigates HFpEF.

Circ Res 2021 Jan 12;128(2):232-245. Epub 2020 Nov 12.

Laboratory of Mitochondrial and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics (Y.D., M.X., Q.L., W.O., Y. Zhang, H.Y., Y. Zheng, Y.L., C.J., G.C., D.D., W.Z., S.W., M.G., T.L.), West China Hospital of Sichuan University, Chengdu.

Rationale: Over 50% of patients with heart failure have preserved ejection fraction (HFpEF), rather than reduced ejection fraction. Complexity of its pathophysiology and the lack of animal models hamper the development of effective therapy for HFpEF.

Objective: This study was designed to investigate the metabolic mechanisms of HFpEF and test therapeutic interventions using a novel animal model.

Methods And Results: By combining the age, long-term high-fat diet, and desoxycorticosterone pivalate challenge in a mouse model, we were able to recapture the myriad features of HFpEF. In these mice, mitochondrial hyperacetylation exacerbated while increasing ketone body availability rescued the phenotypes. The HFpEF mice exhibited overproduction of IL (interleukin)-1β/IL-18 and tissue fibrosis due to increased assembly of NLPR3 inflammasome on hyperacetylated mitochondria. Increasing β-hydroxybutyrate level attenuated NLPR3 inflammasome formation and antagonized proinflammatory cytokine-triggered mitochondrial dysfunction and fibrosis. Moreover, β-hydroxybutyrate downregulated the acetyl-CoA pool and mitochondrial acetylation, partially via activation of CS (citrate synthase) and inhibition of fatty acid uptake.

Conclusions: Therefore, we identify the interplay of mitochondrial hyperacetylation and inflammation as a key driver in HFpEF pathogenesis, which can be ameliorated by promoting β-hydroxybutyrate abundance.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317933DOI Listing
January 2021

Noble Metal Aerogels.

ACS Appl Mater Interfaces 2020 Nov 11;12(47):52234-52250. Epub 2020 Nov 11.

College of Chemistry, Central China Normal University, Wuhan 430079, P.R. China.

Noble metal-based nanomaterials have been a hot research topic during the past few decades. Particularly, self-assembled porous architectures have triggered tremendous interest. At the forefront of porous nanostructures, there exists a research endeavor of noble metal aerogels (NMAs), which are unique in terms of macroscopic assembly systems and three-dimensional (3D) porous network nanostructures. Combining excellent features of noble metals and the unique structural traits of porous nanostructures, NMAs are of high interest in diverse fields, such as catalysis, sensors, and self-propulsion devices. Regardless of these achievements, it is still challenging to rationally design well-tailored NMAs in terms of ligament sizes, morphologies, and compositions and profoundly investigate the underlying gelation mechanisms. Herein, an elaborate overview of the recent progress on NMAs is given. First, a simple description of typical synthetic methods and some advanced design engineering are provided, and then, the gelation mechanism models of NMAs are discussed in detail. Furthermore, promising applications particularly focusing on electrocatalysis and biosensors are highlighted. In the final section, brief conclusions and an outlook on the existing challenges and future chances of NMAs are also proposed.
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http://dx.doi.org/10.1021/acsami.0c14007DOI Listing
November 2020

Single-Atom Nanozymes Linked Immunosorbent Assay for Sensitive Detection of A 1-40: A Biomarker of Alzheimer's Disease.

Research (Wash D C) 2020 19;2020:4724505. Epub 2020 Oct 19.

School of Mechanical and Materials Engineering, Washington State University, Pullman, WA 99164, USA.

Single-atom nanozymes (SANs) possess unique features of maximum atomic utilization and present highly assembled enzyme-like structure and remarkable enzyme-like activity. By introducing SANs into immunoassay, limitations of ELISA such as low stability of horseradish peroxidase (HRP) can be well addressed, thereby improving the performance of the immunoassays. In this work, we have developed novel Fe-N-C single-atom nanozymes (Fe-N SANs) derived from Fe-doped polypyrrole (PPy) nanotube and substituted the enzymes in ELISA kit for enhancing the detection sensitivity of amyloid beta 1-40. Results indicate that the Fe-N SANs contain high density of single-atom active sites and comparable enzyme-like properties as HRP, owing to the maximized utilization of Fe atoms and their abundant active sites, which could mimic natural metalloproteases structures. Further designed SAN-linked immunosorbent assay (SAN-LISA) demonstrates the ultralow limit of detection (LOD) of 0.88 pg/mL, much more sensitive than that of commercial ELISA (9.98 pg/mL). The results confirm that the Fe-N SANs can serve as a satisfactory replacement of enzyme labels, which show great potential as an ultrasensitive colorimetric immunoassay.
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http://dx.doi.org/10.34133/2020/4724505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592081PMC
October 2020

LncRNA PCAT6: A potential biomarker for diagnosis and prognosis of bladder cancer.

Ann Diagn Pathol 2020 Dec 16;49:151642. Epub 2020 Oct 16.

Second People's Hospital of China Three Gorges University, Yichang Second People's Hospital, Yichang, Hubei 443000, China. Electronic address:

Background: Many potential biomarkers have been identified and studied for bladder cancer diagnosis. In this study, we investigated the role of a new biomarker, long noncoding RNA (lncRNA) PCAT6, in bladder cancer diagnosis and prognosis.

Methods And Results: The lncRNA PCAT6 expression profile of BC is analyzed using the Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) data. PCAT6 expression level in 106 pairs of BC tissues and adjacent normal tissues was detected and compared using qRT-PCR. Then, the association between PCAT6 expression and clinicopathologic indicators of BC was evaluated. Meanwhile, the prognostic value of PCAT6 was tested using Kaplan-Meier analysis. Additionally, loss-of-function assays were used to explore the effect of PCAT6 on the biological function of BC cells. We identified that the expression level of PCAT6 in BC tissue was higher than that in adjacent normal tissues. And the BC patients have higher serum PCAT6 than that in healthy volunteers. In addition, the expression level of PCAT6 was correlated with tumor size (p = 0.005), differentiation (p = 0.018), TNM stage (p = 0.04), lymph nodes metastasis (p = 0.019), and distant metastasis (p = 0.028). Kaplan-Meier analysis showed that BC patients with high PCAT6 expression had shorter overall survival (OS) and progression-free survival (PFS). The loss-of-function results revealed that the proliferation and viability of BC cells in PCAT6 knockdown groups decreased significantly, compared with the negative control groups.

Conclusion: Our results demonstrated that PCAT6 might be a potential biomarker for diagnosis and prognosis of BC.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151642DOI Listing
December 2020

The small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome.

J Neurochem 2021 May 12;157(3):666-683. Epub 2020 Dec 12.

Neuroscience Research Center (NWFZ), Charité - Universitätsmedizin Berlin, Berlin, Germany.

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, results from silencing of the fragile X mental retardation gene 1 (FMR1). The analyses of FXS patients' brain autopsies revealed an increased density of immature dendritic spines in cortical areas. We hypothesize that the small GTPase Arf6, an actin regulator critical for the development of glutamatergic synapses and dendritic spines, is implicated in FXS. Here, we determined the fraction of active, GTP-bound Arf6 in cortical neuron cultures and synaptoneurosomes from Fmr1 knockout mice, measured actin polymerization in neurons expressing Arf6 mutants with variant GTP- or GDP-binding properties, and recorded hippocampal long-term depression induced by metabotropic glutamate receptors (mGluR-LTD) in acute brain slices. We detected a persistently elevated Arf6 activity, a loss of Arf6 sensitivity to synaptic stimulation and an increased Arf6-dependent dendritic actin polymerization in mature Fmr1 knockout neurons. Similar imbalances in Arf6-GTP levels and actin filament assembly were caused in wild-type neurons by RNAi-mediated depletion of the postsynaptic Arf6 guanylate exchange factors IQSEC1 (BRAG2) or IQSEC2 (BRAG1). Targeted deletion of Iqsec1 in hippocampal neurons of 3-week-old mice interfered with mGluR-LTD in wild-type, but not in Fmr1 knockout mice. Collectively, these data suggest an aberrant Arf6 regulation in Fmr1 knockout neurons with consequences for the actin cytoskeleton, spine morphology, and synaptic plasticity. Moreover, FXS and syndromes caused by genetic variants in IQSEC1 and IQSEC2 share intellectual disabilities and developmental delay as main symptoms. Therefore, dysregulation of Arf6 may contribute to the cognitive impairment in FXS.
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http://dx.doi.org/10.1111/jnc.15230DOI Listing
May 2021

Overcoming blood-brain barrier transport: Advances in nanoparticle-based drug delivery strategies.

Mater Today (Kidlington) 2020 Jul-Aug;37:112-125. Epub 2020 Mar 4.

School of Mechanical and Materials Engineering, Washington State University, PO Box 642920 Pullman, Washington 99164, United States.

The Blood-Brain Barrier (BBB), a unique structure in the central nervous system (CNS), protects the brain from bloodborne pathogens by its excellent barrier properties. Nevertheless, this barrier limits therapeutic efficacy and becomes one of the biggest challenges in new drug development for neurodegenerative disease and brain cancer. Recent breakthroughs in nanotechnology have resulted in various nanoparticles (NPs) as drug carriers to cross the BBB by different methods. This review presents the current understanding of advanced NP-mediated non-invasive drug delivery for the treatment of neurological disorders. Herein, the complex compositions and special characteristics of BBB are elucidated exhaustively. Moreover, versatile drug nanocarriers with their recent applications and their pathways on different drug delivery strategies to overcome the formidable BBB obstacle are briefly discussed. In terms of significance, this paper provides a general understanding of how various properties of nanoparticles aid in drug delivery through BBB and usher the development of novel nanotechnology-based nanomaterials for cerebral disease therapies.
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http://dx.doi.org/10.1016/j.mattod.2020.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575138PMC
March 2020

Site-specific N-glycosylation Characterization of Recombinant SARS-CoV-2 Spike Proteins.

Mol Cell Proteomics 2020 10 19:100058. Epub 2020 Oct 19.

Sichuan University, China

The glycoprotein spike (S) on the surface of SARS-CoV-2 is a determinant for viral invasion and host immune response. Herein, we characterized the site-specific N-glycosylation of S protein at the level of intact glycopeptides. All 22 potential N-glycosites were identified in the S-protein protomer and were found to be preserved among the 753 SARS-CoV-2 genome sequences. The glycosites exhibited glycoform heterogeneity as expected for a human cell-expressed protein subunit. We identified masses that correspond to 157 N-glycans, primarily of the complex type. In contrast, the insect cell-expressed S protein contained 38 N-glycans, completely of the high-mannose type. Our results revealed that the glycan types were highly determined by the differential processing of N-glycans among human and insect cells, regardless of the glycosites' location. Moreover, the N-glycan compositions were conserved among different sizes of subunits. Our study indicate that the S protein N-glycosylation occurs regularly at each site, albeit the occupied N-glycans were diverse and heterogenous. This N-glycosylation landscape and the differential N-glycan patterns among distinct host cells are expected to shed light on the infection mechanism and present a positive view for the development of vaccines and targeted drugs.
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http://dx.doi.org/10.1074/mcp.RA120.002295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876485PMC
October 2020

Chaiqin chengqi decoction alleviates severity of acute pancreatitis via inhibition of TLR4 and NLRP3 inflammasome: Identification of bioactive ingredients via pharmacological sub-network analysis and experimental validation.

Phytomedicine 2020 Dec 1;79:153328. Epub 2020 Sep 1.

Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address:

Background: Chaiqin chengqi decoction (CQCQD) is a Chinese herbal formula derived from dachengqi decoction. CQCQD has been used for the management of acute pancreatitis (AP) in the West China Hospital for more than 30 years. Although CQCQD has a well-established clinical efficacy, little is known about its bioactive ingredients, how they interact with different therapeutic targets and the pathways to produce anti-inflammatory effects.

Purpose: Toll-like receptor 4 (TLR4) and the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pro-inflammatory signaling pathways, play a central role in AP in determining the extent of pancreatic injury and systemic inflammation. In this study, we screened the bioactive ingredients using a pharmacological sub-network analysis based on the TLR4/NLRP3 signaling pathways followed by experimental validation.

Methods: The main CQCQD bioactive compounds were identified by UPLC-QTOF/MS. The TLR4/NLRP3 targets in AP for CQCQD active ingredients were confirmed through a pharmacological sub-network analysis. Mice received 7 intraperitoneal injections of cerulein (50 μg/kg; hourly) to induce AP (CER-AP), while oral gavage of CQCQD (5, 10, 15 and 20 g/kg; 3 doses, 2 hourly) was commenced at the 3rd injection of cerulein. Histopathology and biochemical indices were used for assessing AP severity, while polymerase chain reaction, Western blot and immunohistochemistry analyses were used to study the mechanisms. Identified active CQCQD compounds were further validated in freshly isolated mouse pancreatic acinar cells and cultured RAW264.7 macrophages.

Results: The main compounds from CQCQD belonged to flavonoids, iridoids, phenols, lignans, anthraquinones and corresponding glycosides. The sub-network analysis revealed that emodin, rhein, baicalin and chrysin were the compounds most relevant for directly regulating the TLR4/NLRP3-related proteins TLR4, RelA, NF-κB and TNF-α. In vivo, CQCQD attenuated the pancreatic injury and systemic inflammation of CER-AP and was associated with reduced expression of TLR4/NLRP3-related mRNAs and proteins. Emodin, rhein, baicalin and chrysin significantly diminished pancreatic acinar cell necrosis with varied effects on suppressing the expression of TLR4/NLRP3-related mRNAs. Emodin, rhein and chrysin also decreased nitric oxide production in macrophages and their combination had synergistic effects on alleviating cell death as well as expression of TLR4/NLRP3-related proteins.

Conclusions: CQCQD attenuated the severity of AP at least in part by inhibiting the TLR4/NLRP3 pro-inflammatory pathways. Its active ingredients, emodin, baicalin, rhein and chrysin contributed to these beneficial effects.
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http://dx.doi.org/10.1016/j.phymed.2020.153328DOI Listing
December 2020

Tri-functional Fe-Zr bi-metal-organic frameworks enable high-performance phosphate ion ratiometric fluorescent detection.

Nanoscale 2020 Oct;12(37):19383-19389

School of Mechanical and Materials Engineering, Washington State University, Pullman, WA 99164, USA.

Metal-organic frameworks (MOFs) featured with flexible design and versatile properties are finding increasing applications. In particular, integrating multiple functions into one framework can bring them improved detection efficiency towards various analytes. Herein, for the first time, a Fe-Zr bi-metal-organic framework (UiO-66(Fe/Zr)-NH2) with three functions (intrinsic fluorescence, peroxidase-mimicking activity, and specific recognition) is designed to establish a ratiometric fluorescent platform for high-performance phosphate ion (Pi) sensing. The use of a fluorescent organic ligand endows the MOF material with a strong intrinsic fluorescence at 435 nm. The presence of Fe3+/Fe2+ nodes offers good enzyme-like capacity to catalyze the o-phenylenediamine (OPD) substrate to fluorescent OPDox (555 nm), which then quenches the intrinsic fluorescence of UiO-66(Fe/Zr)-NH2 due to the inner filter effect. The Zr4+ nodes in the MOF material act as selective sites for Pi recognition. When Pi exists, it specifically adsorbs onto UiO-66(Fe/Zr)-NH2 and decreases the latter's peroxidase-mimetic activity, resulting in the less production of fluorescent OPDox. As a consequence, the intrinsic fluorescence of UiO-66(Fe/Zr)-NH2 at 435 nm is restored, and the signal from OPDox at 555 nm is reduced inversely. With the ratiometric strategy, efficient determination of Pi with outstanding sensitivity and selectivity was realized, giving a detection limit down to 85 nM in the concentration range of 0.2-266.7 μM. Accurate measurement of the target in practical water matrices was also validated, indicating its promising application for Pi analysis in environmental and other fields.
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http://dx.doi.org/10.1039/d0nr04531dDOI Listing
October 2020

Assessment of the Contrast-Enhanced Ultrasound in Percutaneous Nephrolithotomy for the Treatment of Patients with Nondilated Collecting System.

J Endourol 2021 Apr 30;35(4):436-443. Epub 2020 Oct 30.

Department of Urology, The Second People's Hospital of China Three Gorges University, The Second People's Hospital of Yichang, Yichang, China.

To investigate the clinical value of contrast-enhanced ultrasound (CEUS) in percutaneous nephrolithotomy (PCNL) for kidney stone patients without hydronephrosis. Patients with nondilated collecting system kidney stones who underwent PCNL between October 2018 and December 2019 at our hospital were enrolled in this study. Patients who met the inclusion criteria were randomized into two groups: a CEUS-guided PCNL group and a conventional ultrasound (US)-guided PCNL group. The operation results of the two groups were compared, including the number of attempts for effective puncture, duration to effective puncture, stone clearance rate, blood loss, postoperative complications, and hospital stay. Fifty-six patients with a nondilated collecting system who underwent PCNL for 60 kidneys were included in this study, including 4 patients who underwent bilateral PCNL due to bilateral renal stones. There were 30 kidneys in each group. All patients successfully underwent PCNL. The CEUS-guided PCNL group had more accurate punctures, with a higher effective rate of one puncture and shorter puncture time. There was no statistically significant difference in stone clearance rate between the two groups. Four cases of double channels were established in the conventional US-guided PCNL group, while there was only one case in the CEUS-guided PCNL group. In the CEUS-guided PCNL group, most cases (96.7%, 29/30) had no or only mild complications, which were significantly better than the conventional US-guided PCNL group (76.7%, 23/30). The mean postoperative hemoglobin loss in the CEUS-guided PCNL group was 9.5 (range 1-25) g/L, which was significantly lower than 15.5 (range 5-52) g/L in the conventional US-guided PCNL group. The CEUS technique can improve visibility of the nondilated renal collecting system, facilitate selection of suitable calix, and identify renal calix fornix. It also benefits needle placement in patients with a nondilated collecting system.
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http://dx.doi.org/10.1089/end.2020.0564DOI Listing
April 2021