Publications by authors named "Linlin Zhang"

527 Publications

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease.

Authors:
Sebastian Günther Patrick Y A Reinke Yaiza Fernández-García Julia Lieske Thomas J Lane Helen M Ginn Faisal H M Koua Christiane Ehrt Wiebke Ewert Dominik Oberthuer Oleksandr Yefanov Susanne Meier Kristina Lorenzen Boris Krichel Janine-Denise Kopicki Luca Gelisio Wolfgang Brehm Ilona Dunkel Brandon Seychell Henry Gieseler Brenna Norton-Baker Beatriz Escudero-Pérez Martin Domaracky Sofiane Saouane Alexandra Tolstikova Thomas A White Anna Hänle Michael Groessler Holger Fleckenstein Fabian Trost Marina Galchenkova Yaroslav Gevorkov Chufeng Li Salah Awel Ariana Peck Miriam Barthelmess Frank Schluenzen Paulraj Lourdu Xavier Nadine Werner Hina Andaleeb Najeeb Ullah Sven Falke Vasundara Srinivasan Bruno Alves França Martin Schwinzer Hévila Brognaro Cromarte Rogers Diogo Melo Joanna J Zaitseva-Doyle Juraj Knoska Gisel E Peña-Murillo Aida Rahmani Mashhour Vincent Hennicke Pontus Fischer Johanna Hakanpää Jan Meyer Philip Gribbon Bernhard Ellinger Maria Kuzikov Markus Wolf Andrea R Beccari Gleb Bourenkov David von Stetten Guillaume Pompidor Isabel Bento Saravanan Panneerselvam Ivars Karpics Thomas R Schneider Maria Marta Garcia-Alai Stephan Niebling Christian Günther Christina Schmidt Robin Schubert Huijong Han Juliane Boger Diana C F Monteiro Linlin Zhang Xinyuanyuan Sun Jonathan Pletzer-Zelgert Jan Wollenhaupt Christian G Feiler Manfred S Weiss Eike-Christian Schulz Pedram Mehrabi Katarina Karničar Aleksandra Usenik Jure Loboda Henning Tidow Ashwin Chari Rolf Hilgenfeld Charlotte Uetrecht Russell Cox Andrea Zaliani Tobias Beck Matthias Rarey Stephan Günther Dusan Turk Winfried Hinrichs Henry N Chapman Arwen R Pearson Christian Betzel Alke Meents

Science 2021 Apr 2. Epub 2021 Apr 2.

Center for Free-Electron Laser Science, DESY, Notkestr. 85, 22607 Hamburg, Germany.

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.
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http://dx.doi.org/10.1126/science.abf7945DOI Listing
April 2021

A Role for Transmembrane Protein 16C/Slack Impairment in Excitatory Nociceptive Synaptic Plasticity in the Pathogenesis of Remifentanil-induced Hyperalgesia in Rats.

Neurosci Bull 2021 Mar 29. Epub 2021 Mar 29.

Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China.

Remifentanil is widely used to control intraoperative pain. However, its analgesic effect is limited by the generation of postoperative hyperalgesia. In this study, we investigated whether the impairment of transmembrane protein 16C (TMEM16C)/Slack is required for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) activation in remifentanil-induced postoperative hyperalgesia. Remifentanil anesthesia reduced the paw withdrawal threshold from 2 h to 48 h postoperatively, with a decrease in the expression of TMEM16C and Slack in the dorsal root ganglia (DRG) and spinal cord. Knockdown of TMEM16C in the DRG reduced the expression of Slack and elevated the basal peripheral sensitivity and AMPAR expression and function. Overexpression of TMEM16C in the DRG impaired remifentanil-induced ERK1/2 phosphorylation and behavioral hyperalgesia. AMPAR-mediated current and neuronal excitability were downregulated by TMEM16C overexpression in the spinal cord. Taken together, these findings suggest that TMEM16C/Slack regulation of excitatory synaptic plasticity via GluA1-containing AMPARs is critical in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats.
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http://dx.doi.org/10.1007/s12264-021-00652-5DOI Listing
March 2021

Identification of non-covalent SARS-CoV-2 main protease inhibitors by a virtual screen of commercially available drug-like compounds.

Bioorg Med Chem Lett 2021 Mar 26;41:127990. Epub 2021 Mar 26.

Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, CA 93407, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bmcl.2021.127990DOI Listing
March 2021

Hydrogen enriched saline alleviates morphine tolerance via inhibiting neuroinflammation, GLT-1, GS nitration and NMDA receptor trafficking and functioning in the spinal cord of rats.

Neurosci Lett 2021 Mar 24:135847. Epub 2021 Mar 24.

Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin, 300052, PR China. Electronic address:

The development and maintenance of morphine tolerance showed association with neuroinflammation and dysfunction of central glutamatergic system (such as nitration of glutamate transporter). Recent evidence indicated that hydrogen could reduce the levels of neuroinflammation and oxidative stress, but its role in morphine tolerance has not been studied. The rats were intrathecally administered with morphine (10 µg/10 µl each time, twice/day for 5 days). Hydrogen enriched saline (HS) or saline was given intraperitoneally at 1, 3 and 10 ml/kg for 10 min before each dose of morphine administration. The tail-flick latency, mechanical threshold and thermal latency were assessed one day (baseline) before and daily for up to 5 days during morphine injection. The pro-inflammatory cytokine expressions [tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6)] (by western blotting), astrocyte activation (by immunofluorescence and western blotting), and nitration of glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) (by immunoprecipitation), membrane and total expression of N-methyl-D-aspartic acid (NMDA) receptor NR1 and NR2B subunits were carried out in the spinal dorsal horns. Chronic morphine administration induced antinociceptive tolerance, and together led to increased TNF-α, IL-1β and IL-6 expression, astrocyte activation, GLT-1 and GS nitration, increased membrane and total NR1, NR2B expression. Injection of HS attenuated morphine tolerance in a dose-dependent manner, decreased proinflammatory cytokine expression, inhibited astrocyte activation, decreased GLT-1 and GS nitration, and inhibited membrane trafficking of NMDA receptor. Our result showed that hydrogen pretreatment prevented morphine tolerance by reducing neuroinflammation, GLT-1, GS nitration, NMDA receptor trafficking in the spinal dorsal horn. Pretreatment with hydrogen might be considered as a novel therapeutic strategy for the prevention of morphine tolerance.
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http://dx.doi.org/10.1016/j.neulet.2021.135847DOI Listing
March 2021

Integrated analysis of miRNA and mRNA transcriptomic reveals antler growth regulatory network.

Mol Genet Genomics 2021 Mar 26. Epub 2021 Mar 26.

Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 1345 Pudong Road, Changchun, 130000, China.

The growth of antler is driven by endochondral ossification in the growth center of the apical region. Antler grows faster than cancer tissues, but it can be stably regulated and regenerated periodically. To elucidate the molecular mechanisms of how antler grows rapidly without carcinogenesis, in this study, we used RNA-seq technology to evaluate the changes of miRNA and mRNA profiles in antler at four different developmental stages, including 15, 60, 90, and 110 days. We identified a total of 55004 unigenes and 246 miRNAs of which, 10182, 13258, 10740 differentially expressed (DE) unigenes and 35, 53, 27 DE miRNAs were identified in 60-day vs. 15-day, 90-day vs. 60-day, and 110-day vs. 90-day. GO and KEGG pathway analysis indicated that DE unigenes and DE miRNA were mainly associated with chondrogenesis, osteogenesis and inhibition of oncogenesis, that were closely related to antler growth. The interaction networks of mRNA-mRNA and miRNA-mRNA related to chondrogenesis, osteogenesis and inhibition of oncogenesis of antler were constructed. The results indicated that mRNAs (COL2A1, SOX9, WWP2, FGFR1, SPARC, LOX, etc.) and miRNAs (miR-145, miR-199a-3p, miR-140, miR-199a-5p, etc.) might have key roles in chondrogenesis and osteogenesis of antler. As well as mRNA (TP53, Tpm3 and ATP1A1, etc.) and miRNA (miR-106a, miR-145, miR-1260b and miR-2898, etc.) might play important roles in inhibiting the carcinogenesis of antler. In summary, we constructed the mRNA-mRNA and miRNA-mRNA regulatory networks related to chondrogenesis, osteogenesis and inhibition of oncogenesis of antler, and identified key candidate mRNAs and miRNAs among them. Further developments and validations may provide a reference for in-depth analysis of the molecular mechanism of antler growth without carcinogenesis.
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http://dx.doi.org/10.1007/s00438-021-01776-zDOI Listing
March 2021

The Emerging Role of Neuropeptides in Parkinson's Disease.

Front Aging Neurosci 2021 8;13:646726. Epub 2021 Mar 8.

Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, School of Basic Medicine, Qingdao University, Qingdao, China.

Parkinson's disease (PD), the second most common age-related neurodegenerative disease, results from the loss of dopamine neurons in the substantia nigra. This disease is characterized by cardinal non-motor and motor symptoms. Several studies have demonstrated that neuropeptides, such as ghrelin, neuropeptide Y, pituitary adenylate cyclase-activating polypeptide, substance P, and neurotensin, are related to the onset of PD. This review mainly describes the changes in these neuropeptides and their receptors in the substantia nigra-striatum system as well as the other PD-related brain regions. Based on several and studies, most neuropeptides play a significant neuroprotective role in PD by preventing caspase-3 activation, decreasing mitochondrial-related oxidative stress, increasing mitochondrial biogenesis, inhibiting microglial activation, and anti-autophagic activity. Thus, neuropeptides may provide a new strategy for PD therapy.
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http://dx.doi.org/10.3389/fnagi.2021.646726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982480PMC
March 2021

SIRT2 ablation inhibits glucose-stimulated insulin secretion through decreasing glycolytic flux.

Theranostics 2021 4;11(10):4825-4838. Epub 2021 Mar 4.

Department of Endocrine and Metabolic Diseases/ Shanghai institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Sirtuins are NAD-dependent protein deacylases known to have protective effects against age-related diseases such as diabetes, cancer, and neurodegenerative disease. SIRT2 is the only primarily cytoplasmic isoform and its overall role in glucose homeostasis remains uncertain. SIRT2-knockout (KO) rats were constructed to evaluate the role of SIRT2 in glucose homeostasis. The effect of SIRT2 on β-cell function was detected by investigating the morphology, insulin secretion, and metabolomic state of islets. The deacetylation and stabilization of GKRP in β-cells by SIRT2 were determined by western blot, adenoviral infection, and immunoprecipitation. SIRT2-KO rats exhibited impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS), without change in insulin sensitivity. SIRT2 deficiency or inhibition by AGK2 decreased GSIS in isolated rat islets, with lowered oxygen consumption rate. Adenovirus-mediated overexpression of SIRT2 enhanced insulin secretion from rat islets. Metabolomics analysis revealed a decrease in metabolites of glycolysis and tricarboxylic acid cycle in SIRT2-KO islets compared with control islets. Our study further demonstrated that glucokinase regulatory protein (GKRP), an endogenous inhibitor of glucokinase (GCK), was expressed in rat islets. SIRT2 overexpression deacetylated GKRP in INS-1 β-cells. SIRT2 knockout or inhibition elevated GKRP protein stability in islet β-cells, leading to an increase in the interaction of GKRP and GCK. On the contrary, SIRT2 inhibition promoted the protein degradation of ALDOA, a glycolytic enzyme. SIRT2 ablation inhibits GSIS through blocking GKRP protein degradation and promoting ALDOA protein degradation, resulting in a decrease in glycolytic flux.
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http://dx.doi.org/10.7150/thno.55330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978320PMC
March 2021

Modified Alginate-Based Hydrogel as a Carrier of the CB2 Agonist JWH133 for Bone Engineering.

ACS Omega 2021 Mar 4;6(10):6861-6870. Epub 2021 Mar 4.

Department of Orthopedics, The First Affiliated Hospital of University of Science and Technology of China, 17, Lu Jiang Road, Hefei 230001, People's Republic of China.

Alginate hydrogels have been widely used as excellent scaffold materials for implantation in biological systems because of their good biocompatibility. However, it is difficult to repair bone defects with these materials because of their poor mechanical properties. The aim of the present study was to fabricate a novel degradable alginate/palygorskite (PAL) composite hydrogel with good mechanical properties and investigate its potential for application in bone defect repair. The modified alginate-based hydrogel with increasing PAL content exhibited better mechanical properties than the original alginate hydrogel. In addition, the resulting composite hydrogel was thoroughly characterized by scanning electron microscopy (SEM). With increasing PAL content, the swelling ratio of the hydrogel increased in PBS (pH = 7.4). cytocompatibility was evaluated using bone marrow-derived mesenchymal stem cells (BMSCs) to confirm that the developed composite hydrogel was cytocompatible after 1, 3, and 7 days. All these results suggest that the developed composite hydrogel has great potential for bone tissue engineering applications. JWH133 is a selective agonist of cannabinoid receptor type 2 (CB2), which exerts dual anti-inflammatory and anti-osteoclastogenic effects. We co-cultured BMSCs with composite hydrogels loaded with JWH133, and analysis of proliferation and osteogenic differentiation indicated that the composite hydrogel loaded with JWH133 may enhance the osteogenic differentiation of rat BMSCs. Furthermore, we found that the composite hydrogel loaded with JWH133 inhibited osteoclast formation and the mRNA expression of osteoclast-specific markers. In summary, the developed composite hydrogel has a high drug-loading capacity, good biocompatibility, and strong potential as a drug carrier for treating osteoporosis by promoting osteoblast and inhibiting osteoclast formation and function.
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http://dx.doi.org/10.1021/acsomega.0c06057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970551PMC
March 2021

Deficiency of mitochondrial glycerol 3-phosphate dehydrogenase exacerbates podocyte injury and the progression of diabetic kidney disease.

Diabetes 2021 Mar 19. Epub 2021 Mar 19.

Department of Endocrinology, Translational Research of Diabetes Key Laboratory of Chongqing Education Commission of China, the Second Affiliated Hospital of Army Medical University, Chongqing, China.

Mitochondrial function is essential for bioenergetics, metabolism and signaling and is compromised in diseases such as proteinuric kidney diseases, contributing to the global burden of kidney failure, cardiovascular morbidity and death. The key cell type that prevents proteinuria is the terminally differentiated glomerular podocyte. Here, we characterized the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated diabetes- or adriamycin-induced proteinuria, podocyte injury and glomerular pathology. RNA sequencing revealed that mGPDH regulated the RAGE signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased ROS generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury significantly improved their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.
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http://dx.doi.org/10.2337/db20-1157DOI Listing
March 2021

Assessing social-emotional development: Reliability and validity of the social-emotional responding task.

Psychol Assess 2021 Mar 18. Epub 2021 Mar 18.

Department of Psychology.

The Social-Emotional Responding Task (SERT) assesses children's anticipated emotions in the contexts of transgressions (Malti, . Unpublished tool by T. Malti, 2017.). We present a systematic psychometric evaluation of the SERT using data from two different samples of 4-8-year-old children from Canada ( = 291, = 6.55 years, = 2.02, 50% boys in Sample 1 and = 282, = 6.57 years, = 1.56, 49% boys in Sample 2). Children reported their anticipated emotions in six vignettes describing three domains of transgressions [aggressive acts (AA), prosocial omission (PO), and social exclusion (SE)]. Caregivers rated children's sympathy and prosocial and aggressive behaviors. Results supported a one-factor ("domain-general") model over a three-factor ("domain-specific") model, indicating convergence of anticipated emotions across vignettes and domains. Measurement invariance was established across gender and age groups, indicating the robustness of the assessment. Construct validity was supported by associations with sympathy and less robustly, with prosocial and aggressive behavior. We discuss the use of SERT as an assessment tool for children's social-emotional capacities in research and practice settings. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0000918DOI Listing
March 2021

Effects of sodium arsenite and dimethyl arsenic acid on Liaoning cashmere goat skin fibroblasts.

Environ Sci Pollut Res Int 2021 Mar 15. Epub 2021 Mar 15.

Liaoning Normal University, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Dalian, 116029, China.

The morphology and oxidation state of arsenic in its compounds affects the skin cell toxicity. Accordingly, the present study was conducted to explore the effects of two different arsenic compounds on the proliferation and survival of Liaoning cashmere goat skin fibroblasts. Based on MTT assay results, at 24 h, the proliferation concentration, critical concentration, and half inhibitory concentration (IC50) of sodium arsenite were 0.50, 5.00, and 45.66 μmol/L, respectively. The corresponding values for dimethyl arsenic acid were 0.85, 1.00, and 38.68 mmol/L. Immunofluorescence, transmission electron microscopy, and mitochondria membrane potential (MMP) assays showed that sodium arsenite promotes microtubule polymerization and increases MMP, while cells treated with dimethyl arsenic acid exhibited cytoskeletal collapse and decreased MMP. In the IC50 groups for both arsenic agents, the cytoskeletons collapsed, microtubules were gathered into bundles, and MMP was significantly decreased. Dimethyl arsenic acid had a stronger effect on MMP than sodium arsenite. Flow cytometry revealed a slightly lower occurrence of apoptosis in the sodium arsenite proliferation group, while it was slightly increased in the dimethyl arsenic acid proliferation group. Apoptosis was increased more significantly in the sodium arsenite IC50 group than in the dimethyl arsenic acid IC50 group. These results indicate that the differences in cell proliferation and cytotoxicity induced by inorganic and organic arsenic are related to their effects on cellular structures.
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http://dx.doi.org/10.1007/s11356-021-12457-0DOI Listing
March 2021

Serum Glycerophospholipid Profile in Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Front Physiol 2021 15;12:646010. Epub 2021 Feb 15.

Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China.

Studies have shown that glycerophospholipids are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). This study adopted targeted metabolomic analysis to investigate the changes in serum glycerophospholipids in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and their differential expression in patients with different inflammatory subtypes. Patients with AECOPD admitted between January 2015 and December 2017 were enrolled, and their clinical data were collected. The patients' gender, age, body mass index, and lung function were recorded. Routine blood and induced sputum tests were performed. Liquid chromatography-mass spectrometry was used to detect the serum glycerophospholipid metabolic profiles and to analyze the metabolic profile changes between the acute exacerbation and recovery stages as well as the differences between different inflammatory subtypes. A total of 58 patients were hospitalized for AECOPD, including 49 male patients with a mean age of 74.8 ± 10.0 years. In the metabolic profiles, the expression of lysophosphatidylcholine (LPC) 18:3, lysophosphatidylethanolamine (LPE) 16:1, and phosphatidylinositol (PI) 32:1 was significantly reduced in the acute exacerbation stage compared to the recovery stage ( < 0.05). The three glycerophospholipids were used to plot the receiver operating characteristic curves to predict the acute exacerbation/recovery stage, and the areas under the curves were all above 70%. There were no differential metabolites between the two groups of patients with blood eosinophil percentage (EOS%) ≥2% and <2% at exacerbation. The expression of LPC 18:3, LPE 16:1, and PI 32:1 was significantly reduced in the acute exacerbation stage compared to the recovery stage in the inflammatory subtype with blood EOS <2% ( < 0.05). Abnormalities in the metabolism of glycerophospholipids may be involved in the onset of AECOPD, especially in the non-eosinophilic subtype.
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http://dx.doi.org/10.3389/fphys.2021.646010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917046PMC
February 2021

P2X4 receptor in the dorsal horn contributes to BDNF/TrkB and AMPA receptor activation in the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats.

Neurosci Lett 2021 04 24;750:135773. Epub 2021 Feb 24.

Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anesthesiology, Tianjin, 300052, China. Electronic address:

The mechanism underlying the high incidence of remifentanil-induced postoperative hyperalgesia is unclear. Also, no effective prevention method exists. Inflammatory pain-related studies showed that P2X4 purinergic receptors (P2X4Rs) in the dorsal horn of the spinal cord and dorsal root ganglia are essential for maintaining allodynia caused by inflammation. However, little is known about its role in opioid-induced hyperalgesia. This study aimed to determine the role of P2X4R and related signaling pathways in the remifentanil-induced postoperative hyperalgesia (RIH) model. The study simulated the remifentanil infusion and surgical incision during general anesthesia. The mRNA and protein expression level of P2X4R in rats with RIH model increased from 2 h to 48 h after the surgery. The administration of P2X4R inhibitors prevented the occurrence of RIH, resulting in a reduction in mechanical and thermal pain. Moreover, P2X4R was involved in RIH in male and female rats, indicating no sex-specific difference. P2X4R also increased the expression of AMPA receptor subunit GluA1 in a brain-derived neurotrophic factor (BDNF) / tyrosine receptor kinase B (TrkB) dependent manner. The results from whole-cell patch-clamp recording suggested that P2X4R also regulated AMPA receptor-mediated miniature excitatory postsynaptic currents and participated in the synaptic plasticity of spinal dorsal horn neurons. In summary, P2X4R was involved in AMPAR expression, electrophysiological function, and synaptic plasticity of spinal dorsal horn neurons through BDNF/TrkB signaling. This might be the mechanism underlying RIH, and hence inhibition of P2X4R might be a potential treatment strategy.
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http://dx.doi.org/10.1016/j.neulet.2021.135773DOI Listing
April 2021

Dedicator of Cytokinesis 5 Regulates Keratinocyte Function and Promotes Diabetic Wound Healing.

Diabetes 2021 Feb 24. Epub 2021 Feb 24.

Department of Endocrinology, Translational Research of Diabetes Key Laboratory of Chongqing Education Commission of China, the Second Affiliated Hospital of Army Medical University, Chongqing, China.

Cutaneous wound healing is a fundamental biological and coordinated process, and failure to maintain this process contributes to the dysfunction of tissue homeostasis, increasing the global burden of diabetic foot ulcerations. However, the factors that mediate this process are not fully understood. Here, we identify dedicator of cytokinesis 5 (Dock5) a pivotal role in keratinocyte functions contributing to the process of skin wound healing. Specifically, Dock5 is highly upregulated during the proliferative phase of wound repair and is predominantly expressed in epidermal keratinocytes. It regulates keratinocyte adhesion, migration and proliferation, and influences the functions of extracellular matrix (ECM) deposition by facilitating the ubiquitination of transcription factor ZEB1 to activate laminin-332/integrin signaling. Genetic ablation of Dock5 in mice leads to attenuated re-epithelialization and granulation tissue formation, while Dock5 overexpression-improved skin repair can be abrogated by LAMA3 knockdown. Importantly, Dock5 expression in the skin edge is reduced in patients and animal models of diabetes, further suggesting a direct correlation between its abundance and healing capability. The rescue of Dock5 expression in diabetic mice causes a significant improvement in re-epithelialization, collagen deposition, ECM production and granulation. Our study provides a potential therapeutic target for wound healing impairment during diabetes.
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http://dx.doi.org/10.2337/db20-1008DOI Listing
February 2021

A gap existed between physicians' perceptions and performance of pain, agitation-sedation and delirium assessments in Chinese intensive care units.

BMC Anesthesiol 2021 Feb 25;21(1):61. Epub 2021 Feb 25.

Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, China.

Background: Pain, agitation-sedation and delirium management are crucial elements in the care of critically ill patients. In the present study, we aimed to present the current practice of pain, agitation-sedation and delirium assessments in Chinese intensive care units (ICUs) and investigate the gap between physicians' perception and actual clinical performance.

Methods: We sent invitations to the 33 members of the Neuro-Critical Care Committee affiliated with the Chinese Association of Critical Care Physicians. Finally, 24 ICUs (14 general-, 5 neuroscience-, 3 surgical-, and 2 emergency-ICUs) from 20 hospitals participated in this one-day point prevalence study combined with an on-site questionnaire survey. We enrolled adult ICU admitted patients with a length of stay ≥24 h, who were divided into the brain-injured group or non-brain-injured group. The hospital records and nursing records during the 24-h period prior to enrollment were reviewed. Actual evaluations of pain, agitation-sedation and delirium were documented. We invited physicians on-duty during the 24 h prior to the patients' enrollment to complete a survey questionnaire, which contained attitude for importance of pain, agitation-sedation and delirium assessments.

Results: We enrolled 387 patients including 261 (67.4%) brain-injured and 126 (32.6%) non-brain-injured patients. There were 19.9% (95% confidence interval [CI]: 15.9-23.9%) and 25.6% (95% CI: 21.2-29.9%) patients receiving the pain and agitation-sedation scale assessment, respectively. The rates of these two types of assessments were significantly lower in brain-injured patients than non-brain-injured patients (p = 0.003 and < 0.001). Delirium assessment was only performed in three patients (0.8, 95% CI: 0.1-1.7%). In questionnaires collected from 91 physicians, 70.3% (95% CI: 60.8-79.9%) and 82.4% (95% CI: 74.4-90.4%) reported routine use of pain and agitation-sedation scale assessments, respectively. More than half of the physicians (52.7, 95% CI: 42.3-63.2%) reported daily screening for delirium using an assessment scale.

Conclusions: The actual prevalence of pain, agitation-sedation and delirium assessment, especially delirium screening, was suboptimal in Chinese ICUs. There is a gap between physicians' perceptions and actual clinical practice in pain, agitation-sedation and delirium assessments. Our results will prompt further quality improvement projects to optimize the practice of pain, agitation-sedation and delirium management in China.

Trial Registration: ClinicalTrials.gov, identifier NCT03975751 . Retrospectively registered on 2 June 2019.
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http://dx.doi.org/10.1186/s12871-021-01286-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905610PMC
February 2021

Difficult differential diagnosis of bladder pedicled masses about metastasis from non-small cell lung cancer: A case report.

Cancer Biol Ther 2021 Feb 22;22(2):106-111. Epub 2021 Feb 22.

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

Differential diagnoses of primary bladder tumors from metastasis ones can be difficult, for the symptom and imaging findings are pretty similar. Here, we reported a case of bladder metastasis from lung adenocarcinoma. A 73-year-old female patient who was diagnosed with bladder metastasis from lung adenocarcinoma presented as gross hematuria and multiple pedicled masses in the bladder on MRI scan. Such clinical manifestations were easily misdiagnosed as primary bladder malignancy. Additionally, the tumor samples of this case were further harvested and processed for histopathological analysis and gene detections to confirm this case as a metastasis tumor that was refractory to the subsequent therapy. Diagnosis of bladder metastasis should be paid more consideration in patients with a history of cancer despite the fact that primary bladder malignancy accounts for the majority of bladder masses.
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http://dx.doi.org/10.1080/15384047.2020.1840885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928035PMC
February 2021

Serum sphingolipid profile in asthma.

J Leukoc Biol 2021 Feb 18. Epub 2021 Feb 18.

Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, China.

Sphingolipids metabolism is an important cell process and plays critical roles in asthma. However, the involvement of sphingolipids in the pathogenesis of asthma and its subtypes is unknown. The present study aimed to determine the role of sphingolipids in asthma and its subtypes. Clinical data from 51 asthma patients and 9 healthy individuals were collected and serum samples were performed to analyze the levels of serum sphingolipids by liquid chromatography-mass spectrometry-based targeted metabolomics. Results showed that the levels of sphingomyelin (SM) including SM34:2, SM38:1, and SM40:1 were significantly decreased in asthmatic patients compared to healthy controls. Moreover, serum SM levels were obviously decreased in the blood noneosinophilic asthma (bNEA) group compared with blood eosinophilic asthma group. Similar tendencies of serum SM level changes were observed in the early-onset group compared with late-onset group. Correlation analysis revealed that SM 40:1 was negatively related to sputum IL-17A (r = -0.621, P = 0.042). The present study presented that the SM may be a protective factor of asthma and contributes to the mechanism of asthma, especially bNEA. SM may be a potential biomarker and therapeutic target in asthma.
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http://dx.doi.org/10.1002/JLB.3MA1120-719RDOI Listing
February 2021

Transition-Metal-Free C(sp)-H Coupling of Cycloalkanes Enabled by Single-Electron Transfer and Hydrogen Atom Transfer.

Org Lett 2021 Mar 16;23(5):1714-1719. Epub 2021 Feb 16.

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, and School of Chemical Science and Technology, Yunnan University, Kunming 650091, P. R. China.

Here we report a unique transition-metal-free C(sp)-H/C(sp)-H coupling of cycloalkanes at room temperature. Unactivated cycloalkanes and 2-azaallyls underwent the combination process of single-electron transfer (SET) and hydrogen atom transfer (HAT) to deliver a wide variety of cycloalkane-functionalized products. This expedient approach enables C(sp)-H/C(sp)-H coupling of cycloalkanes under mild conditions without transition metals, initiators, and oxidants.
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http://dx.doi.org/10.1021/acs.orglett.1c00135DOI Listing
March 2021

promotes prostaglandin E synthesis by upregulating transcription in response to increasing estradiol levels in pregnant mice.

Am J Physiol Endocrinol Metab 2021 Apr 8;320(4):E747-E759. Epub 2021 Feb 8.

Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China.

Prostaglandin G/H synthase 2 (PTGS2) is a rate-limiting enzyme in prostaglandin synthesis. The present study assessed the role of the uterine circadian clock on transcription in response to steroid hormones during early pregnancy. We demonstrated that the core clock genes (, , , and ), , and and their encoded proteins, have rhythmic expression in the mouse uterus from to () of pregnancy. Progesterone (P) treatment of cultured uterus endometrial stromal cells (UESCs) isolated from reporter gene knock-in mice on D4 induced a phase shift in oscillations. This P-induced phase shift of oscillations was significantly attenuated by the P antagonist RU486. Additionally, the amplitude of oscillations was increased by estradiol (E) treatment in the presence of P. Consistently, the mRNA levels of clock genes ( and ), , and were markedly increased by E treatment of UESCs in the presence of P. Treatment with E also promoted prostaglandin E (PGE) synthesis by UESCs. Depletion of in UESCs by small-interfering RNA (siRNA) decreased the transcript levels of clock genes ( and ), , and compared with nonsilencing siRNA treatment. knockdown also inhibited PGE synthesis. Moreover, the mRNA expression levels of clock genes ( and ), , and , and their respective proteins were significantly decreased in the uterus of mice. Thus, these data suggest that in mice promotes PGE synthesis by upregulating in response to increases in E on D4 of pregnancy. Rhythmic expression of Bmal1 and Ptgs2 was observed in the uterus isolated from of pregnant mice. E increased the expression of Bmal1 and Ptg2 in UESCs isolated from mice on D4. The expression of Ptgs2 was significantly decreased in Bmal1-siRNA treated UESCs. knockdown also inhibited PGE synthesis. Thus, these data suggest that Bmal1 in mice promotes PGE synthesis by upregulating Ptgs2 in response to increases in E on D4 of pregnancy.
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http://dx.doi.org/10.1152/ajpendo.00466.2020DOI Listing
April 2021

Rapid and Specific Detection of the Poplar Black Spot Disease Caused by Using Loop-Mediated Isothermal Amplification Assay.

Plants (Basel) 2021 Jan 28;10(2). Epub 2021 Jan 28.

The Southern Modern Forestry Collaborative Innovation Center, Nanjing Forestry University, Nanjing 210037, China.

is the main pathogen that causes poplar black spot disease, which leads to the decrease of the photosynthetic efficiency and significantly affects the production and quality of timber. Currently, no in-field diagnostic exists for . Here, we described a loop-mediated isothermal amplification (LAMP) assay for the rapid and sensitive detection of . A set of six oligonucleotide primers was designed to recognize eight distinct sequences of the internal transcribed spacer () region of . The LAMP assay was optimized by the combination of high specificity, sensitivity, and rapidity for the detection of less than 10 pg/μL of target genomic DNA in 60 min per reaction at 65 °C, whereas with PCR, there was no amplification of DNA with concentration less than 1 ng/μL. Among the genomic DNA of 20 fungalisolates, only the samples containing the genomic DNA of changed from violet to sky blue (visible to the naked eye) by using hydroxynaphthol blue (HNB) dye. No DNA was amplified from the eight other fungus species, including two other pathogens, three other foliar fungi pathogens of poplar, and three common foliar fungal endophytes of poplar. Moreover, the detection rates of from artificially and naturally infected poplar leaves were 10/16 (62.5%) and 6/16 (37.5%) using PCR, respectively, while the positive-sample ratios were both 16/16 (100%) using the LAMP assay. Overall, the LAMP assay established here can be a better alternative to PCR-based techniques for the specific and sensitive detection of in poplar endemic areas with resource-limited settings.
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http://dx.doi.org/10.3390/plants10020253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912251PMC
January 2021

Hydrogen sulfide promotes flowering in heading Chinese cabbage by S-sulfhydration of BraFLCs.

Hortic Res 2021 Feb 1;8(1):19. Epub 2021 Feb 1.

School of Life Science and Shanxi Key Laboratory for Research and Development of Regional Plants, Shanxi University, Taiyuan, Shanxi Province, 030006, China.

Heading Chinese cabbage (Brassica rapa L. syn. B. campestris L. ssp. chinensis Makino var. pekinensis (Rupr.) J. Cao et Sh. Cao) is a cruciferous Brassica vegetable that has a triplicate genome, owing to an ancient genome duplication event. It is unclear whether the duplicated homologs have conserved or diversified functions. Hydrogen sulfide (HS) is a plant gasotransmitter that plays important physiological roles in growth, development, and responses to environmental stresses. The modification of cysteines through S-sulfhydration is an important mechanism of HS, which regulates protein functions. HS promotes flowering in Arabidopsis and heading Chinese cabbage. Here we investigated the molecular mechanisms of HS used to promote flowering in the latter. Four, five, and four BraFLC, BraSOC I, and BraFT homologs were identified in heading Chinese cabbage. Different BraFLC proteins were bound to different CArG boxes in the promoter regions of the BraSOC I and BraFT homologs, producing different binding patterns. Thus, there may be functionally diverse BraFLC homologs in heading Chinese cabbage. Exogenous HS at 100 μmol L significantly promoted flowering by compensating for insufficient vernalization. BraFLC 1 and BraFLC 3 underwent S-sulfhydration by HS, after which their abilities to bind most BraSOC I or BraFT promoter probes weakened or even disappeared. These changes in binding ability were consistent with the expression pattern of the BraFT and BraSOC I homologs in seedlings treated with HS. These results indicated that HS signaling regulates flowering time. In summary, HS signaling promoted plant flowering by weakening or eliminating the binding abilities of BraFLCs to downstream promoters through S-sulfhydration.
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http://dx.doi.org/10.1038/s41438-020-00453-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848000PMC
February 2021

Silencing long non-coding RNA HNF1A-AS1 inhibits growth and resistance to TAM of breast cancer cells via the microRNA-363/SERTAD3 axis.

J Drug Target 2021 Jan 21:1-31. Epub 2021 Jan 21.

Third Affiliated Hospital of Zhengzhou University(Henan Maternal and Child Health Care Hospital) , No. 7, Kangfuqian street, Erqi District, Zhengzhou, 450052, Henan,P.R. China.

Long non-coding RNAs (lncRNAs) can exert effects on drug resistance of cancer cells. This study investigated the role of lncRNA HNF1A-antisense 1 (HNF1A-AS1) in growth and Tamoxifen (TAM) sensitivity of breast cancer (BC) cells. HNF1A-AS1 expression was promoted in BC cells and tissues. BC cells with HNF1A-AS1 silencing were constructed to detect cell proliferation. TAM resistant cell line with HNF1A-AS1 silencing and parent cell line with overexpressed HNF1A-AS1 were constructed to measure drug resistance. Silencing HNF1A-AS1 reduced proliferation and TAM resistance of BC cells. The downstream microRNAs (miRs) of HNF1A-AS1 and its targets were figured out and their functions in TAM resistance of BC cells were identified. HNF1A-AS1 sponged miR-363 to promote SERTAD3 expression. Downregulation of miR-363 or upregulation of SERTAD3 stimulated TAM resistance of BC cells. The findings were reproduced in experiments. It could be concluded that silencing HNF1A-AS1 inhibited growth and drug resistance to TAM of BC cells through the miR-363/SERTAD3 axis and the inactivation of the TGF-β/Smad pathway.
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http://dx.doi.org/10.1080/1061186X.2021.1878362DOI Listing
January 2021

Confining Chainmail-Bearing Ni Nanoparticles in N-doped Carbon Nanotubes for Robust and Efficient Electroreduction of CO.

ChemSusChem 2021 Feb 19;14(4):1140-1154. Epub 2021 Jan 19.

Institute for New Energy Materials and Low-Carbon Technologies, School of Material Science and Engineering, Tianjin University of Technology, Tianjin, 300384, P. R. China.

It still remains challenging to simultaneously achieve high stability, selectivity, and activity in CO reduction. Herein, a dual chainmail-bearing nickel-based catalyst (Ni@NC@NCNT) was fabricated via a solvothermal-evaporation-calcination approach. In situ encapsulated N-doped carbon layers (NCs) and nanotubes (NCNTs) gave a dual protection to the metallic core. The confined space well maintained the local alkaline pH value and suppressed hydrogen evolution. Large surface area and abundant pyridinic N and Ni sites ensured high CO adsorption capacity and strength. Benefitting from these, it delivered a CO faradaic efficiency of 94.1 % and current density of 48.0 mA cm at -0.75 and -1.10 V, respectively. Moreover, the performance remained unchanged after continuous electrolysis for 43 h, far exceeding Ni@NC with single chainmail, Ni@NC/NCNT with Ni@NC sitting on the walls of NCNT, bare NCNT and most state-of-the-art catalysts, demonstrating structural superiority of Ni@NC@NCNT. This work sheds light on designing unique architectures to improve electrochemical performances.
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http://dx.doi.org/10.1002/cssc.202002596DOI Listing
February 2021

Spinal NR2B phosphorylation at Tyr1472 regulates IRE(-)DMT1-mediated iron accumulation and spine morphogenesis via kalirin-7 in tibial fracture-associated postoperative pain after orthopedic surgery in female mice.

Reg Anesth Pain Med 2021 Apr 18;46(4):363-373. Epub 2020 Dec 18.

Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China

Background: Prolonged postoperative pain is a major concern and occurs more frequently in women, but mechanisms remain elusive. NR2B-containging N-methyl-d-aspartate (NMDA) receptor is a key component of nociception transduction. Divalent metal transporter 1 (DMT1)-mediated iron overload involves NMDA-induced neurotoxicity in males. Kalirin-7 is vital in synaptic plasticity underlying pathological pain in males. Herein, the requirement for kalirin-7 in NR2B phosphorylation-dependent iron accumulation and spine plasticity in postoperative pain after tibial fracture in female mice has been examined.

Methods: Pain-related behavior, spinal NR2B phosphorylation at Tyr1472, kalirin-7 expression, DMT1 with/without iron-responsive element (IRE (+) DMT1 and IRE (-) DMT1) level, iron concentration and spine morphology were assessed in females. NR2B antagonist Ro25-6981, iron chelator deferoxamine and kalirin-7 knockdown by short hairpin RNA were employed to assess the potential cascade.

Results: Tibial fracture initiates long-term allodynia lasting at least 21 days postoperatively, and upregulates spinal NR2B phosphorylation, kalirin-7 and IRE (-) DMT1 expression, iron overload and spine density. Ro25-6981 reduces postoperative mechanical and cold allodynia, spinal NR2B phosphorylation, kalirin-7 level and IRE (-) DMT1-mediated iron overload. Kalirin-7 knockdown impairs fracture-associated allodynia, IRE (-) DMT1-mediated iron overload and spine plasticity. Deferoxamine also attenuates behavioral allodynia and spine plasticity. Spinal NMDA application elicits NR2B-dependent mechanical allodynia and iron overload, which is reversed by kalirin-7 knockdown or coadministration of deferoxamine.

Conclusion: Spinal NR2B phosphorylation at Tyr1472 upregulates kalirin-7 expression to facilitate IRE (-) DMT1-mediated iron accumulation and spine morphogenesis in the development of fracture-associated postoperative pain in female mice.
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http://dx.doi.org/10.1136/rapm-2020-101883DOI Listing
April 2021

Inhibition of autophagy by 3-methyladenine restricts murine cytomegalovirus replication.

J Med Virol 2021 Jan 9. Epub 2021 Jan 9.

Department of Pediatrics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China.

Cytomegalovirus (CMV) induced autophagy affects virus replication and survival of the infected cells. The purpose of this study was to investigate the role of autophagy inhibition by 3-methyladenine (3-MA) on murine cytomegalovirus (MCMV) replication and whether it is associated with caspase-3 dependent apoptosis. The eyecup isolated from adult C57BL/6J mice (6-8 weeks old) and mouse embryo fibroblast cells (MEFs) were infected with MCMV K181 strain, followed by the treatment of 3-methyladenine (3-MA), chloroquine, or rapamycin to block or stimulate autophagy. In cultured MEFs, the ratio of LC3I/II was reduced at 24 hours post infection (hpi), but was increased at 48 hpi In the eyecup culture, LC3I/II ratio was also decreased at 4 and 7 days post infection (dpi). In addition, caspase-3 cleavage was increased at 48 hpi in MEFs and also elevated in MCMV infected eyecups at 4, 7, 10, and 14 dpi. 3-MA treatment significantly inhibited the virus replication in MEFs and eyecups. The expression of early antigen (EA) of MCMV was also decreased in MEFs and eyecups. Meanwhile, cleaved caspase-3 dependent cell death was promoted with the presence of 3-MA in MCMV infected MEFs and eyecups, while RIPK1/RIPK3/MLKL pathway was inhibited by 3-MA in eyecups. Inhibition of autophagy by 3-MA restricts virus replication and promotes caspase-3 dependent apoptosis in the eyecup and MEFs with MCMV infection. It can be explained that during the early period of MCMV infection, the suppressed autophagy process directly reduced virus release, but later caspase-3 dependent apoptosis dominated and resulted in decreased virus replication.
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http://dx.doi.org/10.1002/jmv.26787DOI Listing
January 2021

Reply to: assessing risk factors of delirium and its effects on adverse outcomes in patients admitted to the ICU after craniotomy.

Eur J Anaesthesiol 2021 02;38(2):192-193

From the Department of Critical Care Medicine (LZ, J-XZ) and Clinical Trial and Research Centre (H-QG), Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

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http://dx.doi.org/10.1097/EJA.0000000000001309DOI Listing
February 2021

Self-Driven Reactive Oxygen Species Generation via Interfacial Oxygen Vacancies on Carbon-Coated TiO with Versatile Applications.

ACS Appl Mater Interfaces 2021 Jan 30;13(1):2033-2043. Epub 2020 Dec 30.

The Education Ministry Key Laboratory of Resource Chemistry, International Joint Laboratory of Resource Chemistry, College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234, P.R. China.

The effective activation and utilization of O have always been the focus of scientists because of its wide applications in catalysis, organic synthesis, life and medical science. Here, a novel method for activating O spontaneously via interfacial oxygen vacancies on carbon-coated TiO to generate reactive oxygen species (ROS) with versatile applications is reported. The interfacial oxygen vacancies can be stabilized by the carbon layer and hold its intrinsic properties for spontaneous oxygen activation without light irradiation, while common surface oxygen vacancies on TiO are always consumed by the capture of HO to form the surface hydroxyls. Thus, O absorbed at the interface of carbon and TiO can be directly activated into singlet oxygen (O) or superoxide radicals (·O), confirmed both experimentally and theoretically. These reactive oxygen species exhibit excellent performance in oxidation reactions and inhibition of MCF-7 cancer cells, providing new insight into the effective utilization of O via oxygen vacancies on metal oxides.
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http://dx.doi.org/10.1021/acsami.0c19414DOI Listing
January 2021

Common Salivary Protein 1 in Saliva of Diabetes Patients (II).

Clin Lab 2020 Dec;66(12)

Background: Human common salivary protein 1 (CSP1) is one of a variety of molecules in saliva but its function remains to be determined. The gold standard method for diagnosis of diabetes mellitus (DM) is to check levels of glucose or HbA1C in plasma or serum. The purpose of this study was to examine whether Salivary CSP1 concentration would be useful alternative for DM diagnosis.

Methods: The qualities of monoclonal antibodies (mAbs) to recombinant human CSP1 (rhCSP1) were tested by western blotting (WB) and immunohistochemistry. A sandwich ELISA was fabricated with the qualified capture and detector mAbs for measurement of CSP1 level in saliva. CSP1 levels of healthy adults and DM patients were measured by the sandwich ELISA and their results were statistically analyzed by Student's t-test. The receiver operating characteristic (ROC) curve was constructed and the area under the curve (AUC) was calculated.

Results: The tested mAbs recognized a 27-kDa CSP1 of saliva in WB and stained only a salivary gland in immunohistochemistry. Pearson's correlation coefficient with standard curve between OD450nm value vs. CSP level showed good linearity (r2 = 0.995). The median values (25th to 75th percentiles) of saliva CSP1 in 10 healthy adults and 18 DM patients using the sandwich ELISA were 3.92 µg/mL (3.15 - 4.02) and 4.35 µg/mL (3.94 - 5.11), respectively. Statistically, there was a significant difference of CSP1 level in two groups (p = 0.026). The sensitivity value of CSP1 was 64.71 while the specificity value was 88.89 with 0.784 of AUC (p = 0.003). These results suggested that the fabricated sandwich ELISA was a good diagnostic test tool for discriminating DM patients from healthy individuals.

Conclusions: The present data showed a significant increase of CSP1 levels for DM patients compared with control group, indicating that CSP1 level in saliva could be used as a potential biomarker of detection or screening of DM patients. However, further studies are necessary to provide scientific and clinical validation.
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http://dx.doi.org/10.7754/Clin.Lab.2020.200327DOI Listing
December 2020

Treacher Collins syndrome: Clinical report and retrospective analysis of Chinese patients.

Mol Genet Genomic Med 2020 Dec 17:e1573. Epub 2020 Dec 17.

Department of Otorhinolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: Treacher Collins syndrome-1 (TCS1; OMIM# 154500) is a rare autosomal dominant disease that is defined by congenital craniofacial dysplasia. Here, we report four sporadic and one familial case of TCS1 in Chinese patients with clinical features presenting as hypoplasia of the zygomatic complex and mandible, downslanting palpebral fissures, coloboma of the lower eyelids, and conductive hearing loss.

Materials And Methods: Audiological, radiological, and physical examinations were performed. Targeted next-generation sequencing (NGS) was performed to examine the genetics of this disease in five probands, and Sanger sequencing was used to confirm the identified variants. A literature review discusses the pathogenesis, treatment, and prevention of TCS1.

Results: We identified a novel insertion of c.939_940insA (p.Gly314Argfs*35; NM_001135243.1), a novel deletion of c.1766delC (p.Pro589Leufs*7), two previously reported insertions of c.1999_2000insC (p.Arg667Profs*31) and c.4218_4219insG (p.Ser1407Valfs*23), and one previously reported deletion of c.4369_4373delAAGAA (p.Lys1457Glufs*12) in the TCOF1 gene. All five cases exhibited a degree of interfamilial and intrafamilial phenotypic variability. A review of the literature revealed no clear evidence of a genotype-phenotype correlation in TCS1.

Conclusion: Our results expand the variant spectrum of TCOF1 and highlight that NGS is essential for the diagnosis of TCS and that genetic counseling is beneficial for guiding prevention.
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http://dx.doi.org/10.1002/mgg3.1573DOI Listing
December 2020

Co-Delivery of I and Prima-1 by Self-Assembled CD44-Targeted Nanoparticles for Anaplastic Thyroid Carcinoma Theranostics.

Adv Healthc Mater 2021 02 16;10(3):e2001029. Epub 2020 Dec 16.

Department of Nuclear Medicine, Xin Hua Hospital Affiliated To Shanghai Jiao Tong University School, 1665 Kongjiang Road, Shanghai, 200092, China.

New radionuclide-labeled targeting nanocarrier systems have generated new opportunities for tumor treatment and imaging. Nevertheless, such therapeutic strategy is clinically unfeasible on anaplastic thyroid carcinoma (ATC) patients, because of lacking suitable targets and resistance to radiation. In order to figure out a potential treatment, immuno-histochemical staining is performed in human ATC tissue species and high expression of cluster determinant 44 (CD44) is found. Therefore, a CD44-targeted delivery system is designed and constructed by self-assembly of tyrosine (Tyr)-hyaluronic acid (HA)-polyethyleneimine (PEI), which can radiolabel I and load a p53 mutant restoring regent, Prima-1. The I-labeled nanocomposites display an impressive tumor imaging as well as a long radiation treatment cycle. The I-labeled nanoparticles show remarkable anti ATC-tumor effects in vitro and in vivo, due to radiosensitization of Prima-1 by reactivation of the p53 mutants.
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http://dx.doi.org/10.1002/adhm.202001029DOI Listing
February 2021