Publications by authors named "Hongyun Wang"

194 Publications

Negative Emotion Arousal and Altruism Promoting of Online Public Stigmatization on COVID-19 Pandemic.

Front Psychol 2021 26;12:652140. Epub 2021 May 26.

School of Business Administration and Tourism Management, Yunnan University, Kunming, China.

The outbreak of COVID-19 is a public health crisis that has had a profound impact on society. Stigma is a common phenomenon in the prevalence and spread of infectious diseases. In the crisis caused by the pandemic, widespread public stigma has influenced social groups. This study explores the negative emotions arousal effect from online public stigmatization during the COVID-19 pandemic and the impact on social cooperation. We constructed a model based on the literature and tested it on a sample of 313 participants from the group being stigmatized. The results demonstrate: (1) relevance and stigma perception promote negative emotions, including anxiety, anger, and grief; (2) the arousal of anger and grief leads to a rise in the altruistic tendency within the stigmatized group; and (3) stigmatization-induced negative emotions have a complete mediating effect between perceived relevance and altruistic tendency, as well as perceived stigma and altruistic tendency. For a country and nation, external stigma will promote the group becoming more united and mutual help. One wish to pass the buck but end up helping others unintentionally. We should not simply blame others, including countries, regions, and groups under the outbreak of COVID-19, and everyone should be cautious with the words and actions in the Internet public sphere.
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http://dx.doi.org/10.3389/fpsyg.2021.652140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187574PMC
May 2021

Transient behavior of compressed magnetorheological brake excited by step currents.

Sci Rep 2021 Jun 9;11(1):12193. Epub 2021 Jun 9.

College of Aeronautics, Taizhou University, Taizhou, 318000, Zhejiang, China.

Transient behavior of a magnetorheological brake excited by step currents under compression-shear mode has been experimentally studied. The results show that the amplitude of the applied current had little effect on the rising time of transient torque, while the rising time was significantly affected by the rotational speed, the compressive speed and the compressive strain position. The falling time of transient torque was independent of the amplitude of the applied current, the compressive speed and the compressive strain position, and it was affected by the rotational speed. The falling time of the transient torque was much shorter than the rising time by a step current. The transient process of MR brake applied as a step current was different from a stable process pre-applied at constant current in different particle chain structure forming processes. In addition, the compressive processes applied in one step current and randomly on/off current were compared and experimentally verified: the particle chains in two processes both experienced the same evolutionary of transient torque. The results achieved in this study should be properly considered in the design and control of magnetorheological brake under compression-shear mode.
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http://dx.doi.org/10.1038/s41598-021-91836-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190152PMC
June 2021

The progress of chemokines and chemokine receptors in autism spectrum disorders.

Brain Res Bull 2021 May 30. Epub 2021 May 30.

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica and Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address:

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders and the main symptoms of ASD are impairments in social communication and abnormal behavioral patterns. Studies have shown that immune dysfunction and neuroinflammation play a key role in ASD patients and experimental models. Chemokines are groups of small proteins that regulate cell migration and mediate inflammation responses via binding to chemokine receptors. Thus, chemokines/chemokine receptors may be involved in neurodevelopmental disorders and associated with ASD. In this review, we summarize the research progress of chemokine aberrations in ASD and also review the recent progress of clinical treatment of ASD and pharmacological research related to chemokines/chemokine receptors. This review highlights the possible connection between chemokines/chemokine receptors and ASD, and provides novel potential targets for drug discovery of ASD.
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http://dx.doi.org/10.1016/j.brainresbull.2021.05.024DOI Listing
May 2021

The effects of S-nitrosylation-induced PPARγ/SFRP5 pathway inhibition on the conversion of non-alcoholic fatty liver to non-alcoholic steatohepatitis.

Ann Transl Med 2021 Apr;9(8):684

Gastroenterology Department, Shanxi Provincial People's Hospital, Taiyuan, China.

Background: Peroxisome proliferators-activated receptors γ (PPARγ) and secreted frizzled related protein 5 (SFRP5) are abnormally expressed in liver cells. But their role in the transformation of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) remains to be studied. We aimed to explore the role of S-nitrosylation (SNO) in the conversion of NAFL to NASH via the peroxisome PPARγ/SFRP5 pathway.

Methods: A normal diet and methionine-choline deficient diet were used to construct the NAFL and NASH mouse models, respectively. The differences between the SNO of PPARγ in both models were measured by irreversible biotinylation. Quantitative reverse transcription PCR (qRT-PCR) and Western blotting were used to detect the effect of SNO on the expression of PPARγ messageRNA (mRNA) and protein in L02 hepatocytes. Nubiscan software, luciferase reporter gene, and chromatin immunoprecipitation assay (CHIP) were used to verify the targeting relationship between PPAR and SFRP5. The expression of tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and interleukin-6 (IL-6), which are indicators for the activation of Kupffer cells, were determined by enzyme linked immunosorbent assay (ELISA) after co-cultivation of L02 hepatocytes and Kupffer macrophages, as well as the exogenous regulation of SNO, PPARγ, and SFRP5 in hepatic L02 cells.

Results: The NAFL and NASH mouse models were successfully constructed, and the level of PPARγ SNO in the NAFL model was significantly lower than the NASH model (P<0.05). The level of PPARγ was significantly downregulated after increasing the SNO of L02 cells, respectively (P<0.05). Nubiscan software and CHIP confirmed that PPARγ could bind to the promoter region of SFRP5 (P<0.05). Overexpression of PPARγ and SFRP5 could significantly downregulate the expression of TNFα, IL-1β, and IL-6 (P<0.05) correspondingly, while increasing the SNO level of L02 cells could restore the expression levels of TNFα, IL-1β, and IL-6.

Conclusions: SNO promoted the activation of macrophage Kupffer cells by inhibiting the PPARγ/SFRP5 pathway in L02 hepatocytes, thereby promoting the conversion of NAFL into NASH.
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http://dx.doi.org/10.21037/atm-21-1070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106108PMC
April 2021

Preparation of loratadine nanocrystal tablets to improve the solubility and dissolution for enhanced oral bioavailability.

J Pharm Pharmacol 2021 Jun;73(7):937-946

State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.

Objectives: Loratadine is a selective H1 receptor inhibitor that has been widely used in the clinical treatment of allergic diseases. Here we aimed to develop a novel solid loratadine nanocrystal to increase the low and pH-dependent water solubility for bioavailability enhancement.

Methods: Loratadine solid nanocrystal was developed through high-speed shear-high pressure homogenization followed by freeze-drying, which was further prepared into tablets through direct compression. The formulation and process parameter were screened. Furthermore, the characterization and oral bioavailability of loratadine nanocrystal were studied.

Key Findings: The loratadine nanocrystal had the satisfactory particle size of 425.9 nm and great redispersibility, which was mainly attributed to the addition of Pluronic F127 and polyvinylpyrrolidone K17 as the stabilizer. The saturation solubility of the loratadine nanocrystal was increased to 3.81, 3.22 and 2.57-fold that of the crude drug in water, pH 6.8 and pH 4.5 buffer respectively. Furthermore, the pharmacokinetic studies in rats revealed that the AUC (0-∞) of the nanocrystal tablets was 2.38-fold that of raw tablets and 1.94-fold that of commercial tablets, respectively.

Conclusions: The nanocrystal tablets could significantly improve the oral bioavailability of loratadine, which would also be a promising approach to enhance the solubility of insoluble drugs.
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http://dx.doi.org/10.1093/jpp/rgab043DOI Listing
June 2021

Compressions of magnetorheological fluids under instantaneous magnetic field and constant area.

Sci Rep 2021 Apr 26;11(1):8887. Epub 2021 Apr 26.

College of Aeronautics, Taizhou University, Taizhou, 318000, Zhejiang, China.

Compressions of magnetorheological (MR) fluids have been carried out under instantaneous magnetic fields. The yield strength of the MR fluid in compressive mode has been derived by assuming that it was a transformed shear flow in Bi-visous model. The compressive stresses have experimentally studied under different magnetic fields, different initial gap distances and different compressive velocities. The nominal yield shear stresses of the compressed MR fluid under different influential factors have been calculated. The compressive stress increased in a power law as the applied magnetic field increased, while it decreased as the initial gap distance and the compressive velocity increased. With the increase of magnetic field, the difference between the nominal yield shear stress curves increased, and the exponents of the power law increased with the increase of the magnetic field strengths. A larger initial gap distance and a lower compressive velocity resulted in a higher nominal yield shear stress under the same instantaneous magnetic field. The achieved results of the nominal yield shear stress with magnetic field seemed to deviate from the prediction of dipole model, and the chain structure aggregation effect, the sealing effect and the friction effect by compression should be considered.
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http://dx.doi.org/10.1038/s41598-021-88407-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076221PMC
April 2021

An evaluation of mental health and emotion regulation experienced by undergraduate nursing students in China during the COVID-19 pandemic: A cross-sectional study.

Int J Ment Health Nurs 2021 Apr 13. Epub 2021 Apr 13.

School of Nursing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.

The COVID-19 outbreak negatively impacted the mental health and emotions of many individuals. The study presented here explores the mental health and emotion regulation experienced by undergraduate nursing students in China during the pandemic. Potential risk factors related to negative mental health symptoms were identified in this study. An online cross-sectional study including 342 respondents was performed from March 6, 2020, to April 1, 2020, at a University in China. A Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Emotion Regulation Questionnaire (ERQ) were used to evaluate mental health and emotions. The statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) version 22. The prevalence of anxiety, depression, or comorbid anxiety and depression were 55.0%, 56.4%, and 31.6%, respectively. The mean score of cognitive reappraisal and expressive suppression was 29.36 ± 8.00 and 15.55 ± 5.14. Lower scores for cognitive reappraisal and higher scores for expressive suppression were susceptible to symptoms of anxiety, depression, or comorbid anxiety and depression. Issues with mental health occurred in nursing students during the COVID-19 pandemic. Findings from this study provide a better understanding of the association between mental health and emotion regulation, which will help direct psychological intervention that relieves these issues during the pandemic.
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http://dx.doi.org/10.1111/inm.12867DOI Listing
April 2021

Targets identified from exercised heart: killing multiple birds with one stone.

NPJ Regen Med 2021 Apr 9;6(1):23. Epub 2021 Apr 9.

Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong, China.

Cardiovascular diseases (CVDs) are a major cause of mortality worldwide, which are mainly driven by factors such as aging, sedentary lifestyle, and excess alcohol use. Exercise targets several molecules and protects hearts against many of these physiological and pathological stimuli. Accordingly, it is widely recognized as an effective therapeutic strategy for CVD. To investigate the molecular mechanism of exercise in cardiac protection, we identify and describe several crucial targets identified from exercised hearts. These targets include insulin-like growth factor 1 (IGF1)-phosphatidylinositol 3 phosphate kinase (PI3K)/protein kinase B (AKT), transcription factor CCAAT/enhancer-binding protein β (C/EBPβ), cardiac microRNAs (miRNAs, miR-222 and miR-17-3p etc.), exosomal-miRNAs (miR-342, miR-29, etc.), Sirtuin 1 (SIRT1), and nuclear factor erythroid 2‑related factor/metallothioneins (Nrf2/Mts). Targets identified from exercised hearts can alleviate injury via multiple avenues, including: (1) promoting cardiomyocyte proliferation; (2) facilitating cardiomyocyte growth and physiologic hypertrophy; (3) elevating the anti-apoptotic capacity of cardiomyocytes; (4) improving vascular endothelial function; (5) inhibiting pathological remodeling and fibrosis; (6) promoting extracellular vesicles (EVs) production and exosomal-molecules transfer. Exercise is one treatment ('stone'), which is cardioprotective via multiple avenues ('birds'), and is considered 'killing multiple birds with one stone' in this review. Further, we discuss the potential application of EV cargos in CVD treatment. We provide an outline of targets identified from the exercised heart and their mechanisms, as well as novel ideas for CVD treatment, which may provide novel direction for preclinical trials in cardiac rehabilitation.
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http://dx.doi.org/10.1038/s41536-021-00128-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035363PMC
April 2021

Accelerating Development of Benziamidazole-Class Proton Pump Inhibitors: A Mechanism-Based PK/PD Model to Optimize Study Design with Ilaprazole as a Case Drug.

Pharmaceutics 2021 Mar 15;13(3). Epub 2021 Mar 15.

Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100032, China.

Proton pump inhibitors (PPIs) are the mainstay for treatment of acid-related diseases. This study developed a mechanism-based pharmacokinetic (PK) and pharmacodynamics (PD) model with ilaprazole as case drug, so as to support and accelerate the development of novel PPIs. The model was established and verified using the PK and PD data from 26 subjects receiving 5 to 30 mg of ilaprazole and 22 subjects receiving the loading dose of ilaprazole 20 mg followed by 10 mg once daily for 2 days. The nonlinear mixed-effects modeling approach was performed for the PK/PD model. A two-compartment model with linear elimination and covariates (body weight and gender) described the observed data well. The relationship between plasma concentrations of ilaprazole and gastric acid pH was well quantified with individual variability, in which the synthesis and degradation of H/K-ATPase, the food effect, the circular rhythms of gastric acid secretion, and the irreversible inhibition of H/K-ATPase by ilaprazole were integrated. This PK/PD model well predicted the PK and PD profile of ilaprazole in healthy subjects and patients with duodenal ulcers receiving wide range dose regimens. The mechanism-based PK/PD model provided a potential strategy to accelerate the development of novel PPIs by waiving the unnecessary clinical trials.
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http://dx.doi.org/10.3390/pharmaceutics13030392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998456PMC
March 2021

Analysis of Glycemic Improvement in Hemodialysis Patients Based on Time in Range, Assessed by Flash Glucose Monitoring.

Blood Purif 2021 Mar 26:1-8. Epub 2021 Mar 26.

The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China.

Introduction: This study aimed to investigate the application value of "time in ranges (TIRs)" in dialysis patients with diabetes and summarize the experience of optimizing glycemic control by flash glucose monitoring (FGM) system.

Methods: In this monocentric 2-week pilot study, FGM was applied for 14 days in 57 type 2 diabetes mellitus medically stable patients under maintenance hemodialysis to determine their glycemic improvement. The diagnostic value of TIR versus HbA1c in detecting glucose fluctuations and levels was evaluated using receiver operating characteristic analysis.

Results: Average glucose exhibited stronger association with TIR (r = -0.785, p < 0.001) than HbA1c (r = 0.644, p < 0.001), and mean amplitude of glycemic excursion (MAGE) had the same conclusion (r = -0.568, p < 0.001 for TIR vs. r = 0.423, p = 0.016 for HbA1c). TIR exhibited a higher area under curve than HbA1c in detecting significant derangements in glucose fluctuation, using a 14-day average FGM-derived coefficient of variation >36% as the reference standard (difference between areas: 0.237; 95% CI 0.092-0.383, p = 0.001). We found a significant improvement in TIR (58.38 ± 19.42 vs. 46.45 ± 24.42 mmol/L, p < 0.001) and a significant decline in MAGE (median 5.64 vs.7.42 mmol/L, p < 0.001) compared to the baseline without deterioration of time spent in hypoglycemia.

Conclusion: TIR seems to be feasible and clinically useful for AGP analysis in dialysis patients with diabetes, and FGM can be used to improve glycemic control.
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http://dx.doi.org/10.1159/000513162DOI Listing
March 2021

Development of a rapid and sensitive UPLC-MS/MS assay for simultaneous quantitation of Vorolanib and its metabolite in human plasma and application to a pharmacokinetics study.

J Pharm Biomed Anal 2021 May 22;199:114034. Epub 2021 Mar 22.

Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China. Electronic address:

Vorolanib is an oral tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). A sensitive and specific LC-MS/MS assay was developed and fully validated for simultaneous quantification of vorolanib and its main metabolite X297 in human plasma. The two analytes were extracted from K2-EDTA plasma samples by protein precipitation (PP) with acetonitrile, and chromatographically separated on a C18 reverse-phase column using a gradient elution. A SCIEX 5500 QTRAP® mass spectrometer system was operated in multiple-reaction monitoring mode (MRM) and all components were detected using positive electrospray ionization (ESI). The results successfully demonstrated that the method had satisfactory linearity, sensitivity, and selectivity in the concentration ranges of vorolanib (1.00-1000 ng/mL) and X297 (0.500-500 ng/mL). In this study, two concentration related peaks in the vorolanib and X297 detection channels were observed, which were speculated to be isomers of vorolanib and X297. In order to standardize the sample pretreatment process, the effect of lamp light and pH on the isomer reconversion was evaluated. The results indicated, that the exposure of samples to lamp light during the handling procedures, did not cause the conversion of the isomers. For the first time a robust and specific ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for the high-throughput quantification of vorolanib and X297 in human plasma was established and validated following bioanalytical validation guidelines. The proposed method was successfully applied to clinical trials evaluating the pharmacokinetics of vorolanib tablets in Chinese advanced solid tumor patients.
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http://dx.doi.org/10.1016/j.jpba.2021.114034DOI Listing
May 2021

Gualou Guizhi Granule Protects against OGD/R-Induced Injury by Inhibiting Cell Pyroptosis via the PI3K/Akt Signaling Pathway.

Evid Based Complement Alternat Med 2021 8;2021:6613572. Epub 2021 Mar 8.

Pharmacy College, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China.

Pyroptosis is a proinflammatory form of regulated cell death that plays an important role in ischemic stroke. Gualou Guizhi granule (GLGZG) is a classic prescription that has been shown to exert neuroprotective effects against cerebral ischemia reperfusion injury. In the present study, we examined the involvement of pyroptosis and its associated mechanism in protecting nerve function. . Primary neurons were exposed to oxygen-glucose deprivation and reperfusion (OGD/R) conditions in the presence or absence of GLGZG. Cellular viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide (MTT) assay. The number of apoptoic cells was detected by NeuN and NSE protein expression. The expression levels of the pyroptosis markers, namely, NOD-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, interleukin-18 (IL-18), and IL-1 were determined by quantitative real-time PCR analysis, western blot, and ELISA analyses as appropriate. Moreover, the expression levels of the PI3K/Akt pathway key proteins were determined by quantitative real-time PCR analysis and western blot assays. To determine the PI3K/Akt pathway involvement in GLGZG-mediated neuroprotection, the PI3K inhibitor LY294002 (LY, 10 M) was added. The expression levels of NeuN, Akt, and p-Akt were evaluated. . It was found that GLGZG could inhibit OGD/R-induced cell apoptosis, increase neuronal cell viability, decrease the production of IL-18 and IL-1, and downregulate the expression levels of pyroptosis markers (NLRP3, ASC, and caspase-1). Furthermore, GLGZG could modulate the PI3K/Akt signaling pathway. Pharmacological inhibition of the PI3K pathway not only abrogated the effects of GLGZG on Akt but also neutralized its prosurvival and antipyroptotic actions. . The findings indicated that GLGZG pretreatment effectively reduced OGD/R-induced injury by inhibiting cell pyroptosis and activating the PI3K/Akt pathway. These data provide important evidence for the therapeutic applications of this regimen in ischemic stroke.
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http://dx.doi.org/10.1155/2021/6613572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960020PMC
March 2021

Simultaneous determination of indapamide, perindopril and its active metabolite perindoprilat in human plasma using UPLC-MS/MS method.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Apr 4;1169:122585. Epub 2021 Mar 4.

Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Beijing 100032, China. Electronic address:

Lots of studies showed the combination therapy of perindopril, indapamide and amlodipine could increase BP lowering efficacy and the benefits of high-risk patients. To evaluate potential pharmacokinetic interaction, a simultaneous UPLC-MS/MS quantification method of perindopril, perindoprilat and indapamide in human plasma was developed and validated. The plasma samples were prepared by solid phase extraction, and then separated on an X-terra MS C (2.1 mm × 150 mm, 3.5 μm) with isocratic elution. The ion transitions at m/z 369.165 → 172.000 (perindopril), m/z 341.146 → 170.112 (perindoprilat), m/z 366.010 → 132.100 (indapamide), m/z 389.120 → 206.200 (S10211-1, IS1) and m/z 394.080 → 160.200 (S1641, IS2) were monitored under the positive ion mode of electrospray ionization with multiple reaction monitoring. This method exhibited great sensitivity, linearity, accuracy, and precision for the determination of perindopril, perindoprilat and indapamide over the range of 0.250-50.0 ng/mL. The average extraction recovery of perindopril, perindoprilat and indapamide samples at low, medium, and high concentration levels were between 85.9% and 93.6%, respectively. The stability of analytes over different storage and processing conditions in the whole study was also validated. The method is fast, accurate, sensitive and reproducible, which is suitable for the detection of the concentration of perindopril, perindoprilat and indapamide in human plasma.
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http://dx.doi.org/10.1016/j.jchromb.2021.122585DOI Listing
April 2021

Pharmacokinetics and safety evaluation of oral Palonosetron in Chinese healthy volunteers: A phase 1, open-label, randomized, cross-over study.

Eur J Pharm Sci 2021 May 10;160:105752. Epub 2021 Feb 10.

Clinical Pharmacology Research Center, Peking Union Medical College Hospital. Electronic address:

Purpose: Palonosetron hydrochloride is a specific 5-HT3 receptor antagonist, used to prevent chemotherapy-induced nausea and vomiting (CINV), and is a known chemical entity currently registered in the oral and IV forms in several countries worldwide.

Methods: Single-center, single-dose, 3-treatment, open-label, randomized, 3-period, phase-I cross-over study, conducted in 18 individuals (16 males and 2 females). The primary objective was to assess the pharmacokinetic profile of Palonosetron 0.25, 0.5 and 0.75mg, after a single, oral administration in Chinese male and female healthy volunteers.

Results: After administration of a single oral dose of 0.25mg, 0.5mg, or 0.75mg palonosetron in Chinese male and female healthy subjects, plasma palonosetron concentrations reached maximum values (C) of 673 ± 151 pg/mL, 1330 ± 258 pg/mL, and 1990 ± 490 pg/mL, respectively, at 3-5 h (t). The plasma elimination half-life for 0.25, 0.5 and 0.75 mg of palonosetron was 41.8±9.72 hours, 44.6±8.59 hours and 42.3±8.51 hours, respectively. Single oral doses of 0.25mg, 0.5mg, or 0.75mg palonosetron were safe and well tolerated among all the 18 subjects involved.

Conclusions: The PK of palonosetron was found to be linear in the dose range of 0.25 to 0.75 mg. Oral palonosetron in doses up to 0.75 mg was well tolerated in healthy Chinese subjects. The PK and safety data obtained from this study were similar to previous phase I studies with IV palonosetron.
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http://dx.doi.org/10.1016/j.ejps.2021.105752DOI Listing
May 2021

SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms.

Sci Rep 2021 Jan 14;11(1):1399. Epub 2021 Jan 14.

Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.

SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.
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http://dx.doi.org/10.1038/s41598-021-80999-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809281PMC
January 2021

CDKN2A (p16INK4A) affects the anti‑tumor effect of CDK inhibitor in somatotroph adenomas.

Int J Mol Med 2021 02 2;47(2):500-510. Epub 2020 Dec 2.

Department of Cell Biology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, P.R. China.

The altered cell cycle is associated with aberrant growth factor signaling in somatotroph adenoma, which is the primary cause of acromegaly. The aim of the present study was to investigate the pathological role of the INK4 family and evaluate the effectiveness of CDK4 inhibitor, palbociclib, in somatotroph adenoma. RNA‑Seq, RT‑PCR, and immunohistochemistry were applied to measure the levels and correlations of the INK4 family with angiogenesis, CDKs, EMT, and therapeutic targets. MTS, flow cytometry, and ELISA were used to investigate the bio‑activity in GH3 and GT1‑1 cell lines after palbociclib treatment. Compared with lactotroph adenoma, gonadotroph adenoma, and corticotroph adenoma, somatotroph samples demonstrated higher expression of CDKN2A and SSTR2 but a lower expression of EGFR, CDK4, and CDH2 (P<0.05). CDKN2A positively correlates with SSTR2, and negatively with CDK4, EGFR, and CDH2. Patients with lower CDKN2A had larger tumor size (P=0.016) and more invasive potential (P=0.023). Palbociclib inhibited cell proliferation, induced G1 phase arrest, reduced GH/IGF‑1 secretion of GH3 and GT1‑1 cell lines (P<0.05), and had a more prominent role in GH3 cells (P<0.05). CDKN2A inhibited the bio‑activity by modulating CDK4, and high CDKN2A predicted the insensitivity to CDK4 inhibitor, palbociclib, in somatotroph adenoma patients. In summary, the present study shows CDKN2A inhibited the bio‑activity by modulating CDK4, and high CDKN2A predicts the insensitivity to CDK4 inhibitor, Palbociclib, in somatotroph adenoma patients.
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http://dx.doi.org/10.3892/ijmm.2020.4807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797444PMC
February 2021

LncRNA PCAT6 regulates the progression of pituitary adenomas by regulating the miR-139-3p/BRD4 axis.

Cancer Cell Int 2021 Jan 6;21(1):14. Epub 2021 Jan 6.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No.119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, People's Republic of China.

Background: Dysregulated lncRNA PCAT6 was discovered in many cancers excluding pituitary adenomas (PA). Therefore, we explored the role of PCAT6 in PA in this research.

Methods: Abnormally expressed miRNAs were analyzed by bioinformatics and RT-qPCR. The target and regulator of miR-139-3p were determined by bioinformatics, dual-luciferase reporter assay, or RIP. The correlation among PCAT6, miR-139-3p, and BRD4 was further analyzed. The viability, apoptosis, cell cycle distribution of PA cells, as well as their ability to invade, migrate, and proliferate, were tested after transfection through CCK-8, flow cytometry, transwell, wound healing, and colony formation assays. After construction of transplanted-tumor model in nude mice, cell apoptosis in the tumor was detected by TUNEL. The expressions of PCAT6, BRD4, miR-139-3p, and apoptosis-related factors in PA tissues, cells, or tumor tissues were detected by RT-qPCR, Western blot, or IHC.

Results: PCAT6 and BRD4 were high-expressed but miR-139-3p was low-expressed in PA. Both the 3'-untranslated regions of PCAT6 and BRD4 mRNAs were demonstrated to contain a potential binding site for miR-139-3p. PCAT6 was positively correlated to BRD4, and miR-139-3p was negatively correlated to PCAT6 and BRD4. MiR-139-3p mimic, shPCAT6 and siBRD4 inhibited the viability, migration, invasion, and proliferation of PA cells while inducing apoptosis. MiR-139-3p mimic and shPCAT6 inhibited the cell cycle progression of PA cells, decreased the weight and volume of the xenotransplanted tumor, and reduced the levels of Bcl-2 and BRD4 while enhancing the levels of Bax, miR-139-3p, and Cleaved caspase-3. MiR-139-3p inhibitor caused the opposite effect of miR-139-3p mimic and further reversed the effect of shPCAT6 on on PA cells.

Conclusion: PCAT6 regulated the progression of PA via modulating the miR-139-3p/BRD4 axis, which might provide a novel biomarker for the prevention, diagnosis, and treatment of PA.
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http://dx.doi.org/10.1186/s12935-020-01698-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789787PMC
January 2021

Up-regulation of the expressions of MiR-149-5p and MiR-99a-3p in exosome inhibits the progress of pituitary adenomas.

Cell Biol Toxicol 2021 Jan 5. Epub 2021 Jan 5.

Department of Cell Biology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.

This study explored the function of microRNAs (miRNAs) in invasive pituitary adenomas (IPA), and developed a microRNA-exosome strategy for the disease treatment. Differentially expressed miRNAs and tumor-associated markers in IPA, non-invasive pituitary adenoma (NIPA), and rat pituitary adenoma cells were identified by bioinformatics analysis and qRT-PCR. Then, the cells were treated by miR-149-5p and miR-99a-3p mimics or inhibitors, or incubated with modified exosome with overexpressed or silenced miRNAs. The cell behaviors were analyzed by molecular experiments. Xenograft assays were constructed by injection of pituitary adenoma cells and exosome into NU/NU nude mice. Tumor size, weight, and expressions of markers related to miRNAs and angiogenesis were determined. Target genes for miR-99a-3p and miR-149 were predicted and verified by bioinformatics analysis and molecular experiments. Twenty differentially expressed miRNAs were identified, among which miR-99a-3p and miR-149 were inhibited in both pituitary adenoma cells and tissues significantly. Expressions of E-cadherin and p53 were down-regulated, while those of MMP-2, MMP-9, N-cadherin, Vimentin, and VEGF were up-regulated in pituitary adenoma cells and tissues, especially in IPA. Further experiments revealed that overexpressed miR-149 and miR-99a-3p inhibited the growth and metastasis of pituitary adenoma cells and tube formation of endothelial cells. MiR-149 and miR-99a-3p overexpressed by exosome showed similar suppressive effects on cell viability, metastasis, tube formation ability, in vivo tumor growth, and expressions of angiogenesis-related markers. Further analysis showed that NOVA1, DTL, and RAB27B were targeted by miR-99a-3p. This study found that overexpressed miR-149-5p and miR-99a-3p induced by exosome could suppress the progression of IPA. 1. MiR-149-5p and miR-99a-3p affect the expression of EMT- and ECM-related markers and tumor-related genes in rat pituitary adenoma cells treated with exosomes. 2. Exosome inhibited the tumor growth. 3. Overexpressed miR-149-5p and miR-99a-3p induced by exosome.
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http://dx.doi.org/10.1007/s10565-020-09570-0DOI Listing
January 2021

A phase 1 pharmacokinetic study of oral NEPA, the fixed combination of netupitant and palonosetron, in Chinese healthy volunteers.

Cancer Chemother Pharmacol 2021 03 2;87(3):387-396. Epub 2021 Jan 2.

Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China.

Purpose: Oral NEPA, the only fixed-combination antiemetic, is composed of the neurokinin-1 receptor antagonist netupitant (300 mg) and the 5-hydroxytryptamine-3 receptor antagonist palonosetron (0.50 mg). This study was conducted to evaluate the pharmacokinetic profile of netupitant and its main metabolites M1 and M3, and palonosetron in Chinese subjects. Oral NEPA tolerability and safety were also analyzed.

Methods: This was a single-center, single-dose phase 1 study in healthy, adult Chinese volunteers. Eligible subjects received oral NEPA, and blood samples were collected on day 1 predose and at various time points up until day 10 postdose. Pharmacokinetic parameters were analyzed using noncompartmental methods. For safety assessments, adverse events (AEs) were monitored during the study.

Results: In total 18 Chinese healthy volunteers received oral NEPA. Netupitant mean maximum plasma concentration (C) [± standard deviation] of 698 ± 217 ng/mL was reached at 3-6 h, with a mean total exposure (AUC) of 22,000 ± 4410 h·ng/mL. For palonosetron, a mean C of 1.8 ± 0.252 ng/mL was reached at 2-6 h postadministration, with a mean AUC of 81.0 ± 14.0 h·ng/mL. The most common treatment-related AEs in > 2 subjects were constipation (n = 9) and tiredness (n = 3). No severe AEs were observed, and no subject withdrew due to AEs.

Conclusion: Following single-dose administration of oral NEPA in Chinese subjects, the pharmacokinetic profiles of the NEPA components were mostly similar to those reported previously in Caucasians. NEPA was well tolerated with a safety profile in line with that observed in pivotal trials in Caucasians.
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http://dx.doi.org/10.1007/s00280-020-04200-2DOI Listing
March 2021

Smart-ORF: a single-molecule method for accessing ribosome dynamics in both upstream and main open reading frames.

Nucleic Acids Res 2021 03;49(5):e26

Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Upstream open reading frame (uORF) translation disrupts scanning 43S flux on mRNA and modulates main open reading frame (mORF) translation efficiency. Current tools, however, have limited access to ribosome dynamics in both upstream and main ORFs of an mRNA. Here, we develop a new two-color in vitro fluorescence assay, Smart-ORF, that monitors individual uORF and mORF translation events in real-time with single-molecule resolution. We demonstrate the utility of Smart-ORF by applying it to uORF-encoded arginine attenuator peptide (AAP)-mediated translational regulation. The method enabled quantification of uORF and mORF initiation efficiencies, 80S dwell time, polysome formation, and the correlation between uORF and mORF translation dynamics. Smart-ORF revealed that AAP-mediated 80S stalling in the uORF stimulates the uORF initiation efficiency and promotes clustering of slower uORF-translating ribosomes. This technology provides a new tool that can reveal previously uncharacterized dynamics of uORF-containing mRNA translation.
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http://dx.doi.org/10.1093/nar/gkaa1185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969011PMC
March 2021

Nuclear cGAS Functions Non-canonically to Enhance Antiviral Immunity via Recruiting Methyltransferase Prmt5.

Cell Rep 2020 12;33(10):108490

State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing 211198, China. Electronic address:

Cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS), upon sensing cytosolic DNA, catalyzes the production of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which activates STING-TBK1-IRF3 signaling. cGAS is also present in the nucleus, but the relevant nuclear function or mechanism remains largely unknown. Here, we report that nuclear cGAS is indispensable for inducing cytokines and chemokines triggered by RNA/DNA viruses. Unexpectedly, the DNA-binding/nucleotidyltransferase activity of cGAS is dispensable for RNA-virus-induced genes expression. cGAS deficiency does not affect the phosphorylation, dimerization, or nuclear translocation of IRF3 induced by double-stranded RNA (dsRNA). Mechanistically, nuclear-localized cGAS interacts with protein arginine methyltransferase 5 (Prmt5), which catalyzes the symmetric dimethylation of histone H3 arginine 2 at Ifnb and Ifna4 promoters, thus facilitating the access of IRF3. Deficiency of Prmt5 or disrupting its catalytic activity suppresses the production of type I interferons (IFNs), impairing the host defenses against RNA/DNA virus infections. Taken together, our study uncovers a non-canonical function of nuclear-localized cGAS in innate immunity via regulating histone arginine modification.
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http://dx.doi.org/10.1016/j.celrep.2020.108490DOI Listing
December 2020

How Could In Vitro Antiviral Activity Be Applied to Optimize the Dosing Regimens of Candidates for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)?

Clin Infect Dis 2020 Nov 27. Epub 2020 Nov 27.

Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Damucang Hutong, Xicheng District, Beijing, China.

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http://dx.doi.org/10.1093/cid/ciaa1325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717149PMC
November 2020

In silico prediction of bioequivalence of Isosorbide Mononitrate tablets with different dissolution profiles using PBPK modeling and simulation.

Eur J Pharm Sci 2021 Feb 26;157:105618. Epub 2020 Oct 26.

Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China. Electronic address:

Aim: The waiver of bioequivalence (BE) studies is well accepted for Biopharmaceutics Classification System (BCS) class I drugs in form of immediate-release solid oral products. This study aimed to assess whether the rapid dissolution profiles (≥85% in 30 min) was crucial to guarantee bioequivalence of isosorbide mononitrate (ISMN) and then established a clinically relevant dissolution specification (CRDS) for screening BE or non-BE batches.

Method: A physiologically based pharmacokinetic (PBPK) model was constructed by integrating clinical and non-clinical data by BO simulator. The model was verified by an actual clinical study (NMPA registration number: CTR20191360) with 28 healthy Chinese subjects. Then a virtual BE study was simulated to evaluate the bioequivalence of 7 virtual batches of ISMN tablets with different dissolution profiles, and the CRDS was established by integrating the results.

Result: The simulated PK behavior of ISMN was comparable to the observed. Even though the batches with slower dissolution were not equivalent to a rapid dissolution profile (≥85% in 30 min), it was demonstrated these batches would exhibit the similar in vivo performance. Meanwhile, the in vitro dissolution specification time point and the percentage of drug release (75% in 45 min) proved to have clinical relevance.

Conclusion: The virtual BE simulation by integrating in vitro dissolution profiles into the PBPK model provided a powerful tool for screening formulations, contributing to gaining time and reducing costs in BE evaluations.
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http://dx.doi.org/10.1016/j.ejps.2020.105618DOI Listing
February 2021

Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling.

Clin Cancer Res 2021 Jan 12;27(1):342-354. Epub 2020 Oct 12.

Oncology Disease Area, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.

Purpose: SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development.

Experimental Design: The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASi, CDK4/6i, and anti-programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models and , and their effects on downstream signaling were examined.

Results: In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAF colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRAS cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASi and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient-derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti-PD-1 antibody.

Conclusions: Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2718DOI Listing
January 2021

An In Vitro Single-Molecule Imaging Assay for the Analysis of Cap-Dependent Translation Kinetics.

J Vis Exp 2020 09 15(163). Epub 2020 Sep 15.

Molecular Biology Program, Memorial Sloan Kettering Cancer Center;

Cap-dependent protein synthesis is the predominant translation pathway in eukaryotic cells. While various biochemical and genetic approaches have allowed extensive studies of cap-dependent translation and its regulation, high resolution kinetic characterization of this translation pathway is still lacking. Recently, we developed an in vitro assay to measure cap-dependent translation kinetics with single-molecule resolution. The assay is based on fluorescently labeled antibody binding to nascent epitope-tagged polypeptide. By imaging the binding and dissociation of antibodies to and from nascent peptide-ribosome-mRNA complexes, the translation progression on individual mRNAs can be tracked. Here, we present a protocol for establishing this assay, including mRNA and PEGylated slide preparations, real-time imaging of translation, and analysis of single molecule trajectories. This assay enables tracking of individual cap-dependent translation events and resolves key translation kinetics, such as initiation and elongation rates. The assay can be widely applied to distinct translation systems and should broadly benefit in vitro studies of cap-dependent translation kinetics and translational control mechanisms.
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http://dx.doi.org/10.3791/61648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040289PMC
September 2020

Comparison of gut microbiota in exclusively breast-fed and formula-fed babies: a study of 91 term infants.

Sci Rep 2020 09 25;10(1):15792. Epub 2020 Sep 25.

Department of Neonatology, Inner Mongolia People's Hospital, Hohhot, 010010, China.

To compare gut microbiota of healthy infants that were exclusively breast-fed or formula-fed, we recruited 91 infants, who were assigned into three different groups and fed by breast milk (30 babies), formula A (30 babies) or formula B (31 babies) exclusively for more than 4 months after birth. Faecal bacterial composition was tested. Among different groups, α diversity was lower in breast-fed group than formula-fed groups in 40 days of age, but increased significantly in 6 months of age. The Bifidobacterium represented the most predominant genus and Enterobacteriaceae the second in all groups. In 40 days of age, Bifidobacterium and Bacteroides were significantly higher, while Streptococcus and Enterococcus were significantly lower in breast-fed group than they were in formula A-fed group. Lachnospiraceae was lower in breast-fed than formula B-fed group. Veillonella and Clostridioides were lower in breast-fed than formula-fed groups. In 3 months of age there were less Lachnospiraceae and Clostridioides in breast-fed group than formula-fed groups. There were also significant differences of microbiota between formula A-fed and formula B-fed groups. Those differences may have impacts on their long-term health.
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http://dx.doi.org/10.1038/s41598-020-72635-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519658PMC
September 2020

Qualitative study of the psychological experience of COVID-19 patients during hospitalization.

J Affect Disord 2021 01 24;278:15-22. Epub 2020 Aug 24.

Department of Infection, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China. Electronic address:

Background: Coronavirus disease 2019 (COVID-19) continues to spread across the globe, but patient experiences are rarely documented.

Objective: To explore the psychology of COVID-19 patients during hospitalization.

Methods: A phenomenological and robust sampling approach was employed. Sixteen patients admitted to the First Affiliated Hospital of Henan University of Science and Technology with COVID-19 from 20th January to 1st March 2020 were selected. Data were collected through semi-structured interviews, phone calls, or face-to-face interviews using quarantine measures. Data were analyzed using the Colaizzi method.

Results: The psychological experience of COVID-19 patients during hospitalization could be summarized into five themes. Firstly, attitudes toward the disease included fear, denial, and stigma during the early stages, which gradually developed into acceptance in the later stages. Secondly, the major source of stress included the viral nature of the disease, quarantine measures, and concerns regarding the health of family members. Thirdly, reactions of body and mind included disease stage-dependent emotional responses, excessive attention to symptoms, rumination, and changes in diet, sleep, and behavior. Fourthly, supportive factors included psychological adjustments, medical care, and family and social support. Finally, the disease resulted in psychological growth and patients viewed problems with gratitude through the cherishing of life, family, bravery, and tenacity.

Conclusion: COVID-19 patients gradually changed their attitude toward the disease and displayed emotional responses dependent on the stage of the disease. Negative emotions dominated during the early stages but gradually gave way to mixed positive and negative emotions. Active guidance of psychological growth may therefore promote physical and mental recovery in COVID-19 patients.
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http://dx.doi.org/10.1016/j.jad.2020.08.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444461PMC
January 2021

Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.

J Med Chem 2020 11 24;63(22):13578-13594. Epub 2020 Sep 24.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent antitumor activity. These studies culminated in the discovery of TNO155, (3,4)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01170DOI Listing
November 2020

Efficacy and safety of Ginkgo biloba for patients with early diabetic nephropathy: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2020 Aug;99(35):e21959

Department of Nephrology, Hubei Provincial Hospital of Traditional Chinese Medicine.

Background: Diabetic nephropathy (DN) is not only an important microvascular complication of diabetes but also the main cause of end-stage renal disease. Ginkgo biloba has a variety of biological activities and has been widely used in China to treat kidney diseases such as DN. This article aimed to evaluate the efficacy and safety of G biloba in patients affected with DN in the early stage.

Methods: This protocol follows the preferred reporting items for systematic review and meta-analysis protocols and the recommendations of the Cochrane Collaboration Handbook. Seven electronic databases will be searched from inception to July 31, 2020. Two investigators will independently identify relevant randomized controlled trials, fetch data, and assess the risk of bias with tools provided by Cochrane. A comprehensive meta-analysis will be conducted with the Cochrane Collaboration software (Review Manager 5.3) for eligible and appropriate studies. Further, the evidence will be assessed with the Grading of Recommendations Assessment, Development, and Evaluation approach.

Results: The results will be published in academic peer-reviewed journals, and the evidence gathered by this project will be dedicated to assessing the efficacy and safety of G biloba for DN patients in the early stage.

Conclusion: This systematic review and meta-analysis will synthesize the available evidence to demonstrate the efficacy of G biloba in delaying the progression of patients with early DN.

Trial Registration Number: PROSPERO CRD42020166805.
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http://dx.doi.org/10.1097/MD.0000000000021959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458229PMC
August 2020

Exosomes: Multifaceted Messengers in Atherosclerosis.

Curr Atheroscler Rep 2020 08 9;22(10):57. Epub 2020 Aug 9.

Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, 333 Nan Chen Road, Shanghai, 200444, China.

Purpose Of Review: Atherosclerosis (AS) is a chronic inflammatory disease that contributes to the development of coronary artery disease, which has become a leading health burden worldwide. Though several strategies such as pharmacological treatment, exercise intervention, and surgery have been used in clinical practice, there is still no effective strategy to cure AS. Exosomes are extensively studied both as diagnostic markers as well as for therapeutic purposes due to their role in pathological processes related to AS. To elucidate the role of exosomes in AS and thus provide a new insight into AS therapy, we review recent advances concerning exosome targets and their function in mediating intercellular communication in AS, and expect to provide a reference for novel effective strategies to cure AS.

Recent Findings: Exosomes exert important roles in the diagnosis, development, and potential therapy of AS. For AS development, (1) activation of CD-137 in endothelial cells represses exosomal-TET2 production, causing a phenotypic switch of vascular smooth muscle cells (VSMC) and promoting plaque formation; (2) exosomal-MALTA1 derived from endothelial cells causes neutrophil extracellular traps (NETs) and M2 macrophage polarization, which aggravates AS; and (3) exosomal-miR-21-3p derived from macrophages inhibits PTEN expression and further promotes VSMC migration/proliferation, leading to AS development. For AS diagnosis, plasma exosomal-miR30e and miR-92a are considered to be potential diagnostic markers. For AS therapy, adipose mesenchymal stem cell-derived exosomes protect endothelial cells from AS aggravation, via inhibiting miR-342-5p. Exosome-mediated cross-talk between different cells within the vasculature exerts crucial roles in regulating endothelial function, proliferation and differentiation of vascular smooth muscle cells, and platelet activation as well as macrophage activation, collectively leading to the development and progression of AS. Exosomes can potentially be used as diagnostic biomarkers and constitute as a new therapeutic strategy for AS.
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http://dx.doi.org/10.1007/s11883-020-00871-7DOI Listing
August 2020