Publications by authors named "Quan Fang"

249 Publications

Author Correction: Astaxanthin protects against early acute kidney injury in severely burned rats by inactivating the TLR4/MyD88/NF-κB axis and upregulating heme oxygenase-1.

Sci Rep 2022 Jan 12;12(1):921. Epub 2022 Jan 12.

Department of Burns, The Second Affiliated Hospital Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.

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http://dx.doi.org/10.1038/s41598-022-05213-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755776PMC
January 2022

Hypoxia-induced Fascin-1 upregulation is regulated by Akt/Rac1 axis and enhances malignant properties of liver cancer cells via mediating actin cytoskeleton rearrangement and Hippo/YAP activation.

Cell Death Discov 2021 Dec 11;7(1):385. Epub 2021 Dec 11.

Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China.

In solid tumors, hypoxia facilitates malignant progression of cancer cells by triggering epithelial-mesenchymal transition (EMT) and cancer stemness. Fascin-1, an actin-bundling protein, takes part in the formation of many actin-based cellular structures. In the present study, we explored the potential functions of hypoxia-induced upregulation of Fascin-1 in liver cancer. Transcriptome RNA-sequencing was conducted to identify hypoxia-related genes. The potential functions of Fascin-1 were evaluated by western blot, transwell migration and invasion assays, sphere-formation assay, tumor xenograft growth, gelatin zymography analysis, immunofluorescence, cell viability assay, soft agar assay, and flow cytometry. We found that Fascin-1 was upregulated by hypoxia in liver cancer cell lines, elevated in liver cancer patients and correlated with larger tumor size, lymph node metastasis, distant metastasis, and shorter overall survival. Knockdown of Fascin-1 suppressed migration, invasion, EMT, stemness, and tumor xenograft growth of liver cancer cells under both normoxia and hypoxia conditions, while forced Fascin-1 expression showed opposite effects. Moreover, hypoxia-induced upregulation of Fascin-1 was regulated by the Akt/Rac1 signaling, and inhibition of Akt/Rac1 signaling by EHop-016 and MK-2206 restrained migration, invasion, EMT, and stemness of liver cancer cells under hypoxia. Furthermore, Fascin-1 knockdown suppressed MMP-2 and MMP-9 expression, impaired actin cytoskeleton rearrangement, inactivated Hippo/YAP signaling, and increased Sorafenib sensitivity in liver cancer cells. Our study provided a novel insight of Fascin-1 in regulating migration, invasion, EMT, and stemness of liver cancer cells under normoxia and hypoxia conditions.
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http://dx.doi.org/10.1038/s41420-021-00778-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8665929PMC
December 2021

Mitral valve regurgitation is associated with left atrial fibrosis in patients with atrial fibrillation.

J Electrocardiol 2022 Jan-Feb;70:24-29. Epub 2021 Nov 23.

Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Low voltage zones (LVZ) are associated with poor outcomes in patients with atrial fibrillation (AF). The APPLE and DR-FLASH scores predict LVZ in patients undergoing catheter ablation. This study aimed to assess the relationship of mitral valve regurgitation (MR) and LVZ after adjusting for APPLE or DR-FLASH scores.

Methods: This was a retrospective study on patients with AF who underwent their first catheter ablation. All patients underwent a transthoracic echocardiographic examination before ablation. The APPLE and DR-FLASH scores were calculated at baseline. LVZ determined by high-density mapping was defined as bipolar voltage amplitude <0.5 mV. LVZ presence was defined as LVZ covering >5% of the left atrial surface area.

Results: Altogether, 152 patients (mean age 62.0 ± 10.8 years, 65.8% men, and 36.2% with persistent AF) were included. Of the 152 patients, 47 (30.9%) had LVZ. The patients with LVZ had more moderate-to-severe MR (17.0% vs. 3.8%, P = 0.014) and higher APPLE scores (1.7 ± 1.1 vs. 1.2 ± 1.1, P = 0.009) and DR-FLASH scores (3.0 ± 1.5 vs. 2.4 ± 1.4, P = 0.010). Using multivariate logistic regression analysis, we found moderate-to-severe MR was related to LVZ presence after adjusting for the APPLE (OR 4.040, P = 0.034) or DR-FLASH (OR 4.487, P = 0.020) scores. Furthermore, moderate-to-severe MR had an incremental predictive value for LVZ presence in addition to the APPLE (P = 0.03) or DR-FLASH (P = 0.02) scores.

Conclusion: In patients with AF, MR severity was related to LVZ after adjusting the APPLE score or DR-FLASH score.
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http://dx.doi.org/10.1016/j.jelectrocard.2021.11.031DOI Listing
November 2021

NOP01, a NOP receptor agonist, produced potent and peripherally restricted antinociception in a formalin-induced mouse orofacial pain model.

Neuropeptides 2022 Feb 20;91:102212. Epub 2021 Nov 20.

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China. Electronic address:

Orofacial pain is one of the most common medical challenges. A preliminary report indicates that the NOP receptor may act as a therapeutic target in orofacial pain. Previous studies have shown that [(pF)Phe, Aib, Aib, Arg, Lys]N/OFQ-NH (NOP01) functions as a potent NOP receptor peptide agonist. This work aims to investigate the antinociception of NOP01 and its possible action mechanisms in a formalin-induced mouse orofacial pain model at different levels. Our results demonstrated that local, intraperitoneal (i.p.) or intrathecal (i.t.) injection of NOP01 produced dose-related antinociception in both phases of the formalin pain, which could be inhibited by the NOP receptor antagonist but not the classical opioid receptor antagonist. Furthermore, the antinociception induced by systemic NOP01 was blocked by local but not spinal pretreatment with the NOP receptor antagonist, suggesting the involvement of the peripheral NOP receptor in NOP01-induced systemic antinociception. Moreover, local injection of NOP01 markedly suppressed the expression of c-Fos protein induced by formalin in ipsilateral trigeminal ganglion (TG) neurons. In conclusion, this work suggests that NOP01 exerts significant antinociception on orofacial pain at both peripheral and spinal levels via the NOP receptor. Notably, NOP01 cannot readily penetrate the blood-brain barrier. Thus, NOP01 may behave as a potential compound for developing peripherally restricted analgesics.
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http://dx.doi.org/10.1016/j.npep.2021.102212DOI Listing
February 2022

Proteomic analysis of pulmonary arterial hypertension.

Ther Adv Chronic Dis 2021 26;12:20406223211047304. Epub 2021 Sep 26.

Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing Dongcheng District, Beijing 100730, China.

Pulmonary arterial hypertension (PAH) is a rare but fatal cardiovascular disorder with high morbidity and mortality. Diagnosis and treatment of this disease at an early stage would greatly improve outcomes. The molecular indicators of PAH are mostly nonspecific, and diagnostic and prognostic biomarkers are urgently needed. A more comprehensive understanding of the molecular mechanisms underlying this complex disease is crucial for the development of new and more effective therapeutics to improve patient outcomes. In this article, we review published literature on proteomic biomarkers and underlying molecular mechanisms in PAH and their value for disease management, aiming to deepen our understanding of the disease and, ultimately, pave the way for clinical application.
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http://dx.doi.org/10.1177/20406223211047304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482352PMC
September 2021

Response to ibutilide and the long-term outcome after catheter ablation for non-paroxysmal atrial fibrillation.

Cardiovasc J Afr 2021 Oct 15;32:1-6. Epub 2021 Oct 15.

Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Email:

Purpose: This study aimed to assess the relationship between the cardiac rhythm response to ibutilide infusion after pulmonary vein isolation and the recurrence of long-term atrial arrhythmias.

Methods: One hundred and thirty-eight patients with non-paroxysmal atrial fibrillation who had had their first catheter ablation were retrospectively included. All patients whose atrial fibrillation did not terminate after pulmonary vein isolation were administered intravenous ibutilide (1.0 mg). Those with termination of atrial fibrillation after ibutilide administration were defined as responders ( = 86); those without termination of atrial fibrillation, as non-responders ( = 52). The primary endpoint was any documented recurrence of atrial arrhythmia lasting more than 30 seconds after the initial catheter ablation.

Results: Conversion of atrial fibrillation to sinus rhythm, directly or via atrial flutter, with ibutilide administration was achieved in 62.3% of patients. A longer duration of atrial fibrillation was associated with failed termination of atrial fibrillation (odds ratio 1.009, 95% confidence interval 1.002-1.017, = 0.011). During a median follow-up period of 610 days (interquartile range 475-1 106) post ablation, non-responders ( = 24, 46.2%) had a higher recurrence rate of atrial arrhythmia than the responders ( = 26, 30.2%; log-rank, = 0.011) after the initial catheter ablation. Multivariate Cox regression analysis revealed that non-responders (hazard ratio 1.994, 95% confidence interval 1.117-3.561, = 0.020) was significantly correlated with recurrence of atrial arrhythmias.

Conclusions: In patients whose atrial fibrillation persisted after pulmonary vein isolation, the response to ibutilide administration could predict the recurrence of atrial arrhythmias after catheter ablation, which may be useful for risk stratification for recurrence of atrial fibrillation and individualised management of atrial fibrillation.
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http://dx.doi.org/10.5830/CVJA-2021-044DOI Listing
October 2021

Will the zero-margin drug policy reduce the economic burden of stroke patients in China?

J Glob Health 2021 30;11:08007. Epub 2021 Sep 30.

College of Health Management, China Medical University, Shenyang, Liaoning, China.

Background: China is facing a more severe stroke challenge. In 2017, China fully implemented the zero-margin drug policy (ZMDP), cancelling 15% of drug markups in public hospitals. Based on the "System of Health Accounts 2011" (SHA 2011), this paper explores the changes in the economic burden of stroke in China after implementing ZMDP to provide an accurate reference for policymakers.

Methods: Stroke patients from 2016 to 2018 were selected by multistage stratification probability-proportional random sampling in Shanxi Province. A total of 223 187 samples were included. Regression discontinuity design (RDD) was used to measure the change of drug proportion and cost. Sensitivity analysis and subgroup analysis were implied to determine the stability of the results.

Results: The current curative expenditure on stroke from 2016 to 2018 was 4374.69, 3727.22, and 3752.52 million Chinese Yuan (CNY). About 90% of the cost occurred during hospitalization, and 60% in general hospitals. After the implementation of ZMDP, the drug proportion from 46.54% (interquartile range (IQR) = 37.10%, 55.14%) in 2016 to 36.40% (IQR = 25.82%, 48.58%) in 2018, and average hospitalization cost per stay was from 7950.02 (IQR = 4938.76, 12 639.90) CNY in 2016 to 7362.08 (IQR = 4892.82, 11 501.40) CNY in 2018. RDD showed the drug proportion decreased by 2.76% (95% confidence interval (CI) = 1.17%, 4.35%,  = 0.001), and the expense decreased by 4698.34 (95% CI = 3047.59, 6349.09,  < 0.001) CNY.

Conclusions: The economic burden of stroke patients in China was severe. ZMDP played a noticeable effect in reducing drug proportion and hospitalization costs. The Chinese government should continue to implement relevant policies to control stroke costs according to regional and population characteristics.
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http://dx.doi.org/10.7189/jogh.11.08007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501452PMC
October 2021

FERM domain-containing protein 6 exerts a tumor-inhibiting role in thyroid cancer by antagonizing oncogenic YAP1.

Biofactors 2021 Oct 20. Epub 2021 Oct 20.

Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

The emerging role of FERM domain-containing protein 6 (FRMD6) in cancer progression has been revealed in several malignancies. However, its relevance on thyroid cancer is not well understood. This work evaluated the possible role and mechanism of FRMD6 in thyroid cancer. We demonstrated that FRMD6 expression was downregulated in thyroid cancer by analyzing the Cancer Genome Atlas data. Remarkable reductions in FRMD6 expression were also confirmed in the clinical specimens and cell lines of thyroid cancer. The upregulation of FRMD6 restrained the proliferation, epithelial-mesenchymal transition, and invasion of thyroid cancer. Moreover, FRMD6 overexpression significantly increased the apoptosis and cell cycle arrest. Further molecular research demonstrated that the overexpression of FRMD6 increased the phosphorylation levels of mammalian STE20-like protein kinase 1, large tumor suppressor 1, and Yes-associated protein 1 (YAP1) and prohibited the activation of YAP1. The re-expression of constitutively active YAP1 strikingly reversed FRMD6-induced tumor-inhibiting effects. Thyroid cancer cells overexpressing FRMD6 had a weakened ability to form xenograft tumors in vivo in nude mice. Overall, the overexpression of FRMD6 produces remarkable tumor-inhibiting effects in thyroid cancer by inhibiting oncogenic YAP1.
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http://dx.doi.org/10.1002/biof.1791DOI Listing
October 2021

Development of Multifunctional and Orally Active Cyclic Peptide Agonists of Opioid/Neuropeptide FF Receptors that Produce Potent, Long-Lasting, and Peripherally Restricted Antinociception with Diminished Side Effects.

J Med Chem 2021 09 31;64(18):13394-13409. Epub 2021 Aug 31.

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, Gansu Province 730000, PR China.

We previously reported that a multifunctional opioid/neuropeptide FF receptor agonist, DN-9, achieved peripherally restricted analgesia with reduced side effects. To develop stable and orally bioavailable analogues of DN-9, eight lactam-bridged cyclic analogues of DN-9 between positions 2 and 5 were designed, synthesized, and biologically evaluated. cAMP assays revealed that these analogues, except , were multifunctional ligands that activated opioid and neuropeptide FF receptors. Analogue exhibited improved potency for κ-opioid and NPFF receptors. All analogues exhibited potent, long-lasting, and peripherally restricted antinociception in the tail-flick test without tolerance development after subcutaneous administration and produced oral analgesia. Oral administration of the optimized compound analogue exhibited powerful, peripherally restricted antinociceptive effects in mouse models of acute, inflammatory, and neuropathic pain. Remarkably, orally administered analogue had no significant side effects, such as tolerance, dependence, constipation, or respiratory depression, at effective analgesic doses.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00694DOI Listing
September 2021

Long non-coding RNA SNHG16, binding with miR-106b-5p, promoted cell apoptosis and inflammation in allergic rhinitis by up-regulating leukemia inhibitory factor to activate the JAK1/STAT3 signaling pathway.

Hum Exp Toxicol 2021 Dec 18;40(12_suppl):S233-S245. Epub 2021 Aug 18.

Otorhinolaryngology and Head and Neck Surgery Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Allergic rhinitis (AR) is a type I hypersensitive disease. Long non-coding RNA (lncRNA) SNHG16 acts as an oncogene in a variety of tumors and promotes the occurrence of inflammation in many inflammatory diseases. The study aims to investigate the expression of SNHG16 and its potential biological functions in AR. RT-qPCR results showed that the expression of SNHG16 in AR was up-regulated. The AR cell model was constructed by stimulating primary nasal mucosal epithelial cells from AR patients with IL-13. After knocking down the expression of lncRNA SNHG16, cell apoptosis was detected by flow cytometry, and the expression of inflammatory factors was detected by ELISA. The results showed that SNHG16 promoted cell apoptosis and inflammation. Then, bioinformatics analysis was used to screen miRNAs bound with SNHG16. Luciferase reporter gene assay and RNA pull-down experiment were used to verify the relationship. We found that the expression of miR-106b-5p was down-regulated and leukemia inhibitory factor (LIF) expression was up-regulated in the AR cell model. The expression of phospho-Janus kinase 1 and p-signal transducer and activator of transcription 3 (STAT3) were detected by Western blotting. Silencing the expression of LIF could inhibit the activity of JAK1/STAT3 pathway and further inhibit cell apoptosis and the occurrence of inflammation. Then transfected SNHG16 shRNA alone or together with miR-106b-5p antagomir into the AR cell model, we found that silencing the expression of SNHG16 down-regulated the expression of LIF and inhibited the activity of the JAK1/STAT3 pathway, cell apoptosis, and inflammation. However, miR-106b-5p antagomir weakened its inhibitory effects. The role of SNHG16 in AR was further verified by the ovalbumin-induced AR mouse model . In conclusion, SNHG16 up-regulates LIF expression by binding with miR-106b-5p, thus promoting the activity of JAK1/STAT3 pathway, and promoting the development of AR. These results provide new targets for the treatment of AR and may help reduce the damage caused by AR.
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http://dx.doi.org/10.1177/09603271211035665DOI Listing
December 2021

Non-RBM Mutations Impaired SARS-CoV-2 Spike Protein Regulated to the ACE2 Receptor Based on Molecular Dynamic Simulation.

Front Mol Biosci 2021 27;8:614443. Epub 2021 Jul 27.

Allergy Center, Department of Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.

The emergence of novel coronavirus mutants is a main factor behind the deterioration of the epidemic situation. Further studies into the pathogenicity of these mutants are thus urgently needed. Binding of the spinous protein receptor binding domain (RBD) of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor was shown to initiate coronavirus entry into host cells and lead to their infection. The receptor-binding motif (RBM, 438-506) is a region that directly interacts with ACE2 receptor in the RBD and plays a crucial role in determining affinity. To unravel how mutations in the non-RBM regions impact the interaction between RBD and ACE2, we selected three non-RBM mutant systems (N354D, D364Y, and V367F) from the documented clinical cases, and the Q498A mutant system located in the RBM region served as the control. Molecular dynamics simulation was conducted on the mutant systems and the wild-type (WT) system, and verified experiments also performed. Non-RBM mutations have been shown not only to change conformation of the RBM region but also to significantly influence its hydrogen bonding and hydrophobic interactions. In particular, the D364Y and V367F systems showed a higher affinity for ACE2 owing to their electrostatic interactions and polar solvation energy changes. In addition, although the binding free energy at this point increased after the mutation of N354D, the conformation of the random coil (Pro384-Asp389) was looser than that of other systems, and the combined effect weakened the binding free energy between RBD and ACE2. Interestingly, we also found a random coil (Ala475-Gly485). This random coil is very sensitive to mutations, and both types of mutations increase the binding free energy of residues in this region. We found that the binding loop (Tyr495-Tyr505) in the RBD domain strongly binds to Lys353, an important residue of the ACE2 domain previously identified. The binding free energy of the non-RBM mutant group at the binding loop had positive and negative changes, and these changes were more obvious than that of the Q498A system. The results of this study elucidate the effect of non-RBM mutation on ACE2-RBD binding, and provide new insights for SARS-CoV-2 mutation research.
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http://dx.doi.org/10.3389/fmolb.2021.614443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353372PMC
July 2021

FBP1 enhances the radiosensitivity by suppressing glycolysis via the FBXW7/mTOR axis in nasopharyngeal carcinoma cells.

Life Sci 2021 Oct 20;283:119840. Epub 2021 Jul 20.

Department of Oncology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address:

Aims: The high glycolysis state of tumor cells is closely related to radioresistance. Fructose-1,6-bisphosphatase (FBP1) can regulate aerobic glycolysis and exerts tumor suppressor effects in many cancers, but its role in nasopharyngeal carcinoma (NPC) remains to be investigated.

Materials And Methods: RT-qPCR was used to measure FBP1 mRNA level. Glucose consumption, lactic acid production and ATP level was determined to evaluate glycolysis. The sensitivity of NPC cells to radiation was analyzed by MTT assay. Apoptosis was performed using flow cytometry. Gain- and loss-of function assays were carried out to explore the specific role of FBP1 and FBXW7 (F-box and WD repeat domain-containing 7) in NPC cell functions. The interactions between FBXW7 and FBP1 or mTOR were validated with co-immunoprecipitation assay. The in vivo experiments with xenografts were used to evaluate the role of FBP1 in tumor growth.

Key Findings: FBP1 expression was lower in NPC tissues and cells than in normal controls and nasopharyngeal epithelial cells. Human recombinant FBP1 (rh-FBP1) treatment suppressed glycolysis in NPC cells. Besides, silencing FBP1 weakened the radiosensitivity and alleviated radiation-induced apoptosis and DNA damage by promoting glycolysis. Mechanism exploration found that FBP1 promoted FBXW7 protein level through suppressing the autoubiquitination of FBXW7. Then, FBXW7 restrained mTOR level by facilitating mTOR ubiquitination, thereby suppressing glycolysis and promoting radiation-induced apoptosis and DNA damage. Furthermore, overexpressing FBP1 in vivo hindered tumor growth and enhanced the antitumor activity of radiation.

Significance: FBP1 promoted the radiosensitivity in NPC cells by inhibiting glycolysis through the FBXW7/mTOR axis.
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http://dx.doi.org/10.1016/j.lfs.2021.119840DOI Listing
October 2021

M2 macrophage-derived extracellular vesicles facilitate CD8+T cell exhaustion in hepatocellular carcinoma via the miR-21-5p/YOD1/YAP/β-catenin pathway.

Cell Death Discov 2021 Jul 16;7(1):182. Epub 2021 Jul 16.

Graduate College of Youjiang Medical University for Nationalities, Guangxi Zhuang, China.

Hepatocellular carcinoma (HCC) is a common malignancy. CD8 T cell-mediated immune response is critical for the inhibition of HCC progression. M2 macrophages participate in HCC progression. This study set out to investigate the effect of M2 macrophage-derived extracellular vesicles (EVs) on CD8 T cell exhaustion in HCC. M2 macrophage-derived EVs were isolated and identified. The murine model of primary HCC was established through DEN/CCl induction, and model mice were injected with EVs. Peripheral blood mononuclear cells (PBMCs) were isolated from the mouse liver and CD8 T cells were sorted. The expressions of immune checkpoint inhibitory receptors and effector cytokines on CD8 T cells were detected, followed by the evaluation of CD8 T cell proliferation and killing function. miR-21-5p expression in M2 macrophage-derived EVs was detected. The binding relationship between miR-21-5p and YOD1 was verified. The activation of the YAP/β-catenin pathway was detected. Consequently, M2 macrophage-derived EVs promoted CD8 T cell exhaustion in HCC mice. miR-21-5p expression was upregulated in M2 macrophage-derived EVs, and EVs carried miR-21-5p into HCC tissues. miR-21-5p targeted YOD1. Inhibition of miR-21-5p or overexpression of YOD1 annulled the promoting effect of EVs on CD8 T cell exhaustion. YOD1 inactivated the YAP/β-catenin pathway. In conclusion, M2 macrophage-derived EVs facilitated CD8 T cell exhaustion via the miR-21-5p/YOD1/YAP/β-catenin axis. This study may confer novel insights into the immunotherapy of HCC.
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http://dx.doi.org/10.1038/s41420-021-00556-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289864PMC
July 2021

MRI Features of Hepatic Sarcomatoid Carcinoma Different From Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma.

Front Oncol 2021 17;11:611738. Epub 2021 Jun 17.

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

Introduction: Hepatic sarcomatoid carcinoma (HSC) is a rare type of liver cancer with a high malignant grade and poor prognosis. This study compared the clinical characteristics and magnetic resonance imaging (MRI) features of HSCs with those of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), aiming to identify valuable features for HSC diagnosis.

Methods: In total, 17 pathologically confirmed HSC cases, 50 HCC cases and 50 common ICC cases were enrolled from two hospitals. The clinical characteristics and MRI features of all cases were summarized and statistically analyzed.

Results: On the one hand, the incidence rates of elevated carbohydrate antigen (CA) 19-9 and elevated carcinoembryonic antigen (CEA) were significantly higher in the HSC cases than in the HCC cases (29.4% 0%; 17.6% 0%). The HSC enhancement patterns, primarily including progressive enhancement, were also significantly different from HCC cases. The incidence rates of heterogeneous signals on T2-weighted imaging and during the arterial phase were significantly higher in the HSC cases than in the HCC cases (94.1% 66.0%; 100.0% 72.0%). The diameter of HSCs was significantly larger than that in the HCC cases (6.12 cm 4.21 cm), and the incidence rates of adjacent cholangiectasis, intrahepatic metastasis and lymph node enlargement were considerably higher in the HSC cases than in the HCC cases (52.9% 6.0%; 47.1% 12.0%; 41.2% 2.0%). On the other hand, the incidence rate of elevated CA199 was significantly lower in the HSC cases than in the ICC cases (29.4% 60.0%). The incidence rates of intratumoral necrosis and pseudocapsules were significantly higher in the HSC cases than in the HCC cases (35.3% 8.0%; 47.1% 12.0%). However, the incidence rates of target signs were significantly lower in the HSC cases than in the HCC cases (11.8% 42.0%). In addition, there was no significant difference in the enhancement patterns between HSC cases and ICC cases.

Conclusions: HSCs were frequently seen in elderly men with clinical symptoms and elevated CA199 levels. The MRI features, including large size, obvious heterogeneity, hemorrhage, progressive enhancement, pseudocapsule and lymph node enlargement, contributed to the diagnosis of HSC.
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http://dx.doi.org/10.3389/fonc.2021.611738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247642PMC
June 2021

Interventricular systolic asynchrony predicts prognosis in patients with systemic sclerosis-associated pulmonary arterial hypertension.

Rheumatology (Oxford) 2021 May 31. Epub 2021 May 31.

Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, China.

Objective: Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc) with high mortality. Interventricular systolic asynchrony (IVSA) is observed in PAH patients, but the effect of IVSA and its association with long-term mortality and clinical events in SSc-associated PAH are unclear. This study aimed to investigate the impact of IVSA on the prognosis of SSc-associated PAH.

Methods: Between March 2010 and July 2018, a total of 60 consecutive patients with SSc-associated PAH were enrolled. The end point was a composite of all-cause mortality and clinical worsening. Asynchrony was assessed by colour-coded tissue Doppler imaging (TDI) echocardiography. The myocardial sustained systole curves (Sm) of the basal portion of the right ventricular (RV) free wall and left ventricular (LV) lateral wall were obtained. IVSA was defined as the time difference from the onset of the QRS complex to the end of Sm between LV and RV.

Results: Patients with greater IVSA time differences presented with advanced pulmonary vascular resistance (PVR). The IVSA time difference was an independent predictive factor (HR = 1.018, 95% CI 1.005-1.031, p = 0.005) for the composite end point and was significantly associated with PVR (r = 0.399, R2=0.092, p = 0.002). Kaplan-Meier survival curves showed that patients with greater IVSA had worse prognoses (log-rank p = 0.001).

Conclusion: In conclusion, IVSA analyzed by colour-coded TDI echocardiography provided added value as a noninvasive, easy-to-use approach for assessing the prognosis of patients with SSc-associated PAH. A significant IVSA time difference identifies the subgroup of patients at high risk of a poor prognosis.
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http://dx.doi.org/10.1093/rheumatology/keab465DOI Listing
May 2021

The prognostic significance of electrocardiography findings in patients with coronavirus disease 2019: A retrospective study.

Clin Cardiol 2021 Jul 11;44(7):963-970. Epub 2021 May 11.

Department of Cardiology, Intervention Cardiology Center, Wuhan No.1 Hospital, No.215 Zhongshan Avenue, QiaoKou District, Wuhan, China.

Background: Coronavirus disease 2019 (COVID-19) has reached a pandemic level. Cardiac injury is not uncommon among COVID-19 patients. We sought to describe the electrocardiographic characteristics and to identify the prognostic significance of electrocardiography (ECG) findings of patients with COVID-19.

Hypothesis: ECG abnormality was associated with higher risk of death.

Methods: Consecutive patients with laboratory-confirmed COVID-19 and definite in-hospital outcome were retrospectively included. Demographic characteristics and clinical data were extracted from medical record. Initial ECGs at admission or during hospitalization were reviewed. A point-based scoring system of abnormal ECG findings was formed, in which 1 point each was assigned for the presence of axis deviation, arrhythmias, atrioventricular block, conduction tissue disease, QTc interval prolongation, pathological Q wave, ST-segment change, and T-wave change. The association between abnormal ECG scores and in-hospital mortality was assessed in multivariable Cox regression models.

Results: A total of 306 patients (mean 62.84 ± 14.69 years old, 48.0% male) were included. T-wave change (31.7%), QTc interval prolongation (30.1%), and arrhythmias (16.3%) were three most common found ECG abnormalities. 30 (9.80%) patients died during hospitalization. Abnormal ECG scores were significantly higher among non-survivors (median 2 points vs 1 point, p < 0.001). The risk of in-hospital death increased by a factor of 1.478 (HR 1.478, 95% CI 1.131-1.933, p = 0.004) after adjusted by age, comorbidities, cardiac injury and treatments.

Conclusions: ECG abnormality was common in patients admitted for COVID-19 and was associated with adverse in-hospital outcome. In-hospital mortality risk increased with increasing abnormal ECG scores.
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http://dx.doi.org/10.1002/clc.23628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237010PMC
July 2021

Heme oxygenase-1 induction mitigates burn-associated early acute kidney injury via the TLR4 signaling pathway.

Burns 2022 Feb 24;48(1):156-167. Epub 2021 Apr 24.

Department of Burns, The Second Affiliated Hospital Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou 310009, Zhejiang, China. Electronic address:

Objectives: Early acute kidney injury (AKI) after burn contributes to disastrous prognoses for severely burned patients. Burn-induced renal oxidative stress and secondary proinflammatory mediator release contribute to early AKI development, and Toll-like receptor (TLR) 4 regulates inflammation. Heme oxygenase-1 (HO-1) is a stress-responsive enzyme that plays a vital role in protecting against ischemia-induced organ injury via its antioxidant properties and regulation of inflammation. We investigated the potential effect of HO-1 induction in preventing burn-induced early AKI and its related mechanism.

Methods: A classic major-burn rat model was established using a 100 °C water bath, and hemin was injected intraperitoneally immediately after the injury to induce HO-1. Histological staining and blood tests were used to assess AKI progression based on structural changes and function. Renal levels of HO-1, oxidative stress, proinflammatory mediators and TLR4-related signals were detected using ELISA, immunostaining, qRT-PCR, and western blotting. The selective TLR4 inhibitor TAK242 and TLR4 inducer LPS were introduced to determine the roles of HO-1 in burn-related renal inflammation and the TLR4 pathway.

Results: Hemin improved burn-induced renal histological damage and dysfunction, and this beneficial effect was related to reduced renal oxidative stress and the release of proinflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and intracellular adhesion molecule-1 (ICAM-1). Hemin downregulated the expression of TLR4 and the subsequent phosphorylation of IKKα/β, IκBα, and NF-κB p65;. TAK242 exerted an effect similar to but weaker than hemin; and LPS reversed the antiinflammatory effect of hemin and the regulation of TLR4 signals. These results suggested that the TLR4 signaling pathway mediated the HO-1-facilitated regulation of renal inflammation after burn.

Conclusion: The present study demonstrated that HO-1 induction prevented burn-induced early AKI by targeting renal inflammation, which was mediated via regulation of the TLR4/NF-κB signaling pathway.
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http://dx.doi.org/10.1016/j.burns.2021.04.013DOI Listing
February 2022

Spinal endomorphins attenuate burn-injury pain in male mice by inhibiting p38 MAPK signaling pathway through the mu-opioid receptor.

Eur J Pharmacol 2021 Jul 30;903:174139. Epub 2021 Apr 30.

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, Gansu, 730000, China. Electronic address:

Burn injury is one of the main causes of mortality worldwide and frequently associated with severe and long-lasting pain that compromises the quality of patient life. Several studies have shown that the mu-opioid system plays an important role in burn pain relief. In this study, we investigated the spinal antinociception induced by the endogenous mu-opioid receptor (MOR) agonists endomorphins and explored their mechanisms of actions in burn injury-induced pain model. Our results showed that intrathecal injection of endomorphin-1 and -2 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia via the mu-opioid receptor in mice on day 3 after burn injury, which was consistent with the data obtained from the mu-opioid receptor knockout mice. Western blot showed that the phosphorylation levels of extracellular signal-regulated kinase1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) in ipsilateral spinal cord tissues were significantly up-regulated after burn injury. Intrathecal injection of endomorphins selectively inhibited the activation of p38 MAPK on day 3 after burn injury via the mu-opioid receptor. Further studies found that repeated application of the specific p38 MAPK inhibitor SB203580 dose-dependently inhibited burn-injury pain, as well as the activation of spinal p38 MAPK. Taken together, our present study demonstrates that intrathecal injection of endomorphins attenuates burn-injury pain in male mice by affecting the spinal activation of p38 MAPK via the mu-opioid receptor.
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http://dx.doi.org/10.1016/j.ejphar.2021.174139DOI Listing
July 2021

ASMq protects against early burn wound progression in rats by alleviating oxidative stress and secondary mitochondria‑associated apoptosis via the Erk/p90RSK/Bad pathway.

Mol Med Rep 2021 05 24;23(5). Epub 2021 Mar 24.

Department of Plastic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China.

Burn wounds present an evolutionary progression, in which the initial wound tissue deepens and expands following thermal injury. Progressive tissue damage in the zone of stasis may worsen burn injury, which is associated with oxidative stress and secondary apoptosis, and worsen the prognosis of patients with burn wounds. The mitochondrial apoptotic pathway is involved in receiving oxidative signals and regulating tissue apoptosis. Previously, Abnormal Savda Munziq (ASMq), a natural compound of traditional Uyghur Medicine, which includes ten types of herb, has been reported to exhibit a number of effects, including anti‑inflammatory, antioxidative and anti‑apoptotic activities. The present study demonstrated that ASMq protected against early burn wound progression following thermal injury in rats; this effect may be mediated by its ability to attenuate oxidative stress‑induced mitochondria‑associated apoptosis. The present study may provide a novel therapeutic method to prevent early burn wound progression following burn injury.
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http://dx.doi.org/10.3892/mmr.2021.12029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008225PMC
May 2021

Astaxanthin protects against early acute kidney injury in severely burned rats by inactivating the TLR4/MyD88/NF-κB axis and upregulating heme oxygenase-1.

Sci Rep 2021 03 23;11(1):6679. Epub 2021 Mar 23.

Department of Burns, The Second Affiliated Hospital Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.

Early acute kidney injury (AKI) contributes to severe morbidity and mortality in critically burned patients. Renal inflammation plays a vital role in the progression of early AKI, acting as a therapeutic target. Astaxanthin (ATX) is a strong antioxidant widely distributed in marine organisms that exerts many biological effects in trauma and disease. ATX is also suggested to have anti-inflammatory activity. Hence, we attempted to explore the role of ATX in protecting against early postburn AKI via its anti-inflammatory effects and the related mechanisms. A severely burned model was established for histological and biochemical assessments based on adult male rats. We found that oxidative stress-induced tissue inflammation participated in the development of early AKI after burn injury and that the MyD88-dependent TLR4/NF-κB pathway was activated to regulate renal inflammation. The TLR4 and NF-κB inhibitors TAK242 and PDTC showed similar effects in attenuating burn-induced renal inflammation and early AKI. Upon ATX treatment, the release of inflammatory mediators in the kidneys was downregulated, while the TLR4/MyD88/NF-κB axis was inhibited in a dose-related manner. TAK242 and PDTC could enhance the anti-inflammatory effect of high-dose ATX, whereas lipopolysaccharide (LPS) reversed its action. Furthermore, the expression of heme oxygenase (HO)-1 was upregulated by ATX in a dose-related manner. Collectively, the above data suggest that ATX protects against renal inflammation in a dose-related manner by regulating the TLR4/MyD88/NF-κB axis and HO-1 and ultimately prevents early AKI following severe burns.
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http://dx.doi.org/10.1038/s41598-021-86146-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988001PMC
March 2021

Long non-coding RNA AGAP2-AS1 promotes proliferation and metastasis in papillary thyroid cancer by miR-628-5p/KLF12 axis.

J Bioenerg Biomembr 2021 04 18;53(2):235-245. Epub 2021 Feb 18.

Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xi 'an Jiaotong University, NO.277 of Yanta West Road, Shaanxi, 710061, Xi'an, China.

Long non-coding RNA (lncRNA) AGAP2-AS1 acts as an oncogene in several types of cancers. However, the role and mechanism of AGAP2-AS1 in papillary thyroid carcinoma (PTC) remain unclear. Thus, in this study, we aimed to explore the role of AGAP2-AS1 in PTC. Our results showed that AGAP2-AS1 was significantly upregulated in PTC tissues. Knockdown of AGAP2-AS1 inhibited the proliferation, migration and invasion of PTC cells. In vivo experiment showed that AGAP2-AS1 knockdown inhibited the tumorigenesis of PTC. MiR-628-5p was found to act as a target miRNA of AGAP2-AS1 in PTC. The expression level of miR-628-5p in PTC tissues was negatively associated with that of AGAP2-AS1. Inhibition of miR-628-5p attenuated the effects of AGAP2-AS1 knockdown on PTC. Moreover, miR-628-5p directly bound to the 3'UTR of KLF12 and inhibited the expression of KLF12. Knockdown of KLF12 enhanced the inhibitory effects of miR-628-5p on PTC cell proliferation and metastasis. In conclusion, these findings indicated that AGAP2-AS1 exerted an oncogenic role in PTC progression and metastasis. The effects of AGAP2-AS1 might be mediated by the regulation of miR-628-5p/KLF12 axis.
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http://dx.doi.org/10.1007/s10863-021-09879-3DOI Listing
April 2021

Prognostic Value of Circulating sST2 for the Prediction of Mortality in Patients With Cardiac Light-Chain Amyloidosis.

Front Cardiovasc Med 2020 20;7:597472. Epub 2021 Jan 20.

Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Systemic light-chain (AL) amyloidosis is a multisystemic disorder leading to multiple organ dysfunction and mortality that is often caused by cardiac involvement. Soluble suppression of tumorigenicity 2 (sST2) is a novel biomarker identified for risk stratification of heart disease. The aim of this study was to investigate the value of circulating sST2 levels in prognosis and mortality risk assessments for the AL amyloidosis population. A total of 56 patients diagnosed with AL amyloidosis were enrolled in Peking Union Medical College Hospital (PUMCH) from January 2015 to May 2018. The relationships between the clinical parameters and overall survival (OS) and risk factors for disease progression were assessed. Additionally, receiver operating characteristic (ROC) curves, Kaplan-Meier analysis, and Cox hazard models were performed to explore the predictive value of sST2 in mortality rates. We found that the median OS of all patients was 7.3 [interquartile range (IQR) 4.4, 15.9] months. The median baseline sST2 level was 12.2 (IQR 5.1, 31.1) ng/ml, and the sST2 high group had more severe patients with a higher Mayo stage. In the ROC analysis, the area under the curve (AUC) was 0.728 [95% confidence interval (CI) 0.603-0.853] for sST2 to predict the outcomes of AL amyloidosis patients, and the optimal cutoff value was 12.34 ng/ml (sensitivity 80.2%, specificity 61.1%). Moreover, in multivariate Cox proportional hazards regression analysis, sST2 acted as an independent predictor of poor functional outcome in patients with AL amyloidosis. In AL amyloidosis patients, sST2 was a strong and independent prognostic biomarker for all-cause mortality, providing complementary prognostic information of a novel scoring system for risk stratification.
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http://dx.doi.org/10.3389/fcvm.2020.597472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855859PMC
January 2021

Locally activated mitophagy contributes to a "built-in" protection against early burn-wound progression in rats.

Life Sci 2021 Jul 23;276:119095. Epub 2021 Jan 23.

Department of Plastic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China. Electronic address:

Aims: Deep burn-wounds undergo a dynamic progression in the initial or periburn area after insults, and the zone of stasis is the crucial region suffering the deterioration, considered as salvageable. Few studies explored the role of mitochondria in this process. This study is to clarify a possible "built-in" protection of mitophagy.

Main Methods: A classic "comb" scald rat model was established. Histological and blood-flow observation were processed based on hematoxylin-eosin staining and laser analysis. Oxidative and apoptotic status were analyzed by commercial kits. Transmission-electron microscope, immunofluorescence staining, and western blot were applied to detect the mitophagy in the zone of stasis and potential regulators. Adenovirus-based gene-silence contributed to determine the role of HIF-1α as a regulatory mediator.

Key Findings: We found that burn-caused typical ischemia and histological deterioration in the zone of stasis, in parallel with increases in oxidative stress and apoptosis. Mitochondrial damage was involved in the aforementioned changes. Furthermore, we detected mitophagy in burn-wounds, which was contradictory to the burn-wound conversion. HIF-1α expression was closely related to the level of mitophagy, while BNIP3 and PARKIN are involved downstream.

Significance: We demonstrate that burn-induced mitochondrial impairment contributes to the mobilization of injurious mechanisms in the zone of stasis and that mitophagy provides a beneficial way to protect against burn-wound progression via the elimination of damaged mitochondria. Our findings offer insights into mitochondrial quality control in burn-wound progression and suggest the novel concept that HIF-1α may be a therapeutic target due to its possible regulation on BNIP3- or PARKIN-mediated mitophagy.
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http://dx.doi.org/10.1016/j.lfs.2021.119095DOI Listing
July 2021

Ventricular arrhythmia predicts poor outcome in polymyositis/dermatomyositis with myocardial involvement.

Rheumatology (Oxford) 2021 08;60(8):3809-3816

Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Objective: Myocardial involvement (MCI) is known to increase morbidity and mortality in polymyositis (PM) and dermatomyositis (DM). This study aims to investigate whether complicating with ventricular arrhythmia (VA) predicts poor outcomes in patients with PM/DM-related myocardial involvement (PM/DM-MCI).

Methods: We reviewed all PM/DM-MCI patients admitted to Peking Union Medical College Hospital from October 1997 to April 2019. VA and the other possible risk factors for the composite endpoint, including death from any cause and rehospitalization for cardiac causes, were analyzed.

Results: A total of 75 PM/DM-MCI patients (44 PM and 31 DM) were enrolled, of which 27 (36%) met the composite endpoint during a median follow-up of 24 months. Independent prognostic factors for the composite endpoint include VA [HR 4.215, 95% CI (1.737, 10.230)], NT-proBNP > 3415 pg/ml [HR 2.606, 95% CI (1.203, 5.646)], interstitial lung disease [HR 2.688, 95% CI (1.209, 5.978)], and anti-cardiac remodelling therapy [HR 0.302, 95% CI (0.115, 0.792)]. The 3-year event-free survival rate of patients without VA was significantly higher than that of patients with VA (63.3% vs 40.7%, P = 0.034). Skin lesions [OR 0.163, 95% CI (0.051, 0.523)] and positive antimitochondrial antibody [OR 3.484, 95% CI (1.192, 10.183)] were independent predictors of VA.

Conclusion: VA provides prognostic insights for PM/DM-MCI patients and predicts poor outcome. Polymyositis and positive antimitochondrial antibody are closely associated with the presence of VA in PM/DM-MCI.
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http://dx.doi.org/10.1093/rheumatology/keaa872DOI Listing
August 2021

Synthesis and Biological Characterization of Cyclic Disulfide-Containing Peptide Analogs of the Multifunctional Opioid/Neuropeptide FF Receptor Agonists That Produce Long-Lasting and Nontolerant Antinociception.

J Med Chem 2020 12 3;63(24):15709-15725. Epub 2020 Dec 3.

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.

In a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing l- and/or d-type cysteine at positions 2 and 5 were synthesized. The cyclized analogs and their linear counterparts behaved as multifunctional agonists at both opioid and NPFF receptors and produced potent analgesia without tolerance development. In comparison to , cyclized peptide exhibited sevenfold more potent μ-opioid receptor agonistic activity . Interestingly, the cyclized analog possessed an improved stability in the brain and an increased blood-brain barrier permeability compared to the parent peptide and produced more potent analgesia after supraspinal or subcutaneous administration with improved duration of action of 4 h. In addition, antinociceptive tolerance of analog was greatly reduced after subcutaneous injection compared to fentanyl, as was the rewarding effect, withdrawal reaction, and gastrointestinal inhibition.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01367DOI Listing
December 2020

Oxidation of Ryanodine Receptors Promotes Ca Leakage and Contributes to Right Ventricular Dysfunction in Pulmonary Hypertension.

Hypertension 2021 01 30;77(1):59-71. Epub 2020 Nov 30.

From the Department of Cardiology, Peking Union Medical College Hospital (Y.H., C.L., Z.W., X.Y., X.Q., Q.F., L.F., X.G.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Right ventricular (RV) failure is a major cause of death in patients with pulmonary arterial hypertension, and the mechanism of RV failure remains unclear. While the malfunction of RyR2 (ryanodine receptor type 2) on sarcoplasmic reticulum (SR) and aberrant Ca cycling in cardiomyocytes have been recognized in some cardiovascular diseases, their roles in RV failure secondary to pulmonary arterial hypertension require further investigation. In a monocrotaline-induced rat model of pulmonary arterial hypertension, the RV remodeling process was divided into normal, compensated, and decompensated stages according to the hemodynamic and morphological parameters. In both compensated and decompensated stages, significant diastolic SR Ca leakage was detected along with reduced intracellular Ca transient amplitude and SR Ca contents in RV myocytes. RyR2 protein levels decreased progressively during the process, and the thiol oxidation proportions of RyR2 were higher in compensated and decompensated stages than in normal stage. Inhibition of RyR2 oxidation by dithiothreitol or repairing RyR2 directly by dantrolene could restore Ca homeostasis in RV myocytes. Daily intraperitoneal injection of dantrolene delayed decompensation progression and significantly improved the survival rate of pulmonary hypertension rats in decompensated stage (79.3% versus 55.9%; =0.026). Our findings suggest that diastolic SR Ca leakage via oxidized RyR2 facilitates the development of RV failure. Dantrolene can inhibit diastolic SR Ca leakage in RV cardiomyocytes, delay right cardiac dysfunction, and improve the survival of rats with pulmonary arterial hypertension.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15561DOI Listing
January 2021

Biventricular pacemaker and defibrillator implantation in patients with chronic heart failure in China.

ESC Heart Fail 2021 02 9;8(1):546-554. Epub 2020 Nov 9.

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

Aims: This study aims to investigate the current status of biventricular pacemaker and defibrillator implantation in chronic heart failure (CHF) patients with indications for primary prevention of sudden cardiac death (SCD) in China and the effects of cardiac resynchronization therapy (CRT)-pacemaker (P) and CRT-defibrillator (D) implantation on the clinical prognosis of CHF among patients undergoing CRT.

Methods And Results: Overall, 798 consecutive patients who had devices implanted (implantable cardioverter defibrillator: 199, CRT-D: 362, and CRT-P: 237) from May 2012 to July 2013 in POSCD-China, a multicentric prospective cohort study, were enrolled. The primary endpoint was all-cause death, and the secondary endpoint was SCD. In total, 71.3% of patients had non-ischaemic CHF. The mean follow-up time was 27.7 ± 12.0 months, and death occurred in 158 cases, with 35 cases of SCD. CHF was the main cause of death (68.4%), followed by sudden death (22.2%). In the CRT-P group, the SCD rate was 8.0%, which was much higher than that in the CRT-D (3.3%) and implantable cardioverter defibrillator (2.0%) groups. No significant differences were identified in the all-cause death rate between the CRT-D and CRT-P groups (CRT-D vs. CRT-P, 20.4% vs. 19.4%, P = 0.840).

Conclusions: In China, among CHF patients with indications for primary prevention of SCD who received device implantation, non-ischaemic CHF was the main aetiology, and the most important cause of death was heart failure. No differences in all-cause death were observed between the CRT-D and CRT-P groups, but the CRT-D group had a lower SCD rate than the CRT-P group.
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http://dx.doi.org/10.1002/ehf2.13114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835594PMC
February 2021

Predictive Value of Pulmonary Arterial Compliance in Systemic Lupus Erythematosus Patients With Pulmonary Arterial Hypertension.

Hypertension 2020 10 10;76(4):1161-1168. Epub 2020 Aug 10.

Department of Rheumatology (J.Z., M.L., X.Z.), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Pulmonary arterial hypertension is a serious complication of systemic lupus erythematosus. It is characterized by increased right ventricular afterload which mainly comprises pulmonary arterial compliance (PAC) and pulmonary vascular resistance. The role of PAC in predicting the outcome of systemic lupus erythematosus-associated pulmonary arterial hypertension has not been investigated yet. Between February 2012 to December 2016, 120 consecutive patients diagnosed with systemic lupus erythematosus-associated pulmonary arterial hypertension based on right heart catheterization were enrolled, prospectively. Baseline clinical characteristics and hemodynamic assessment were analyzed. Baseline right ventricular afterload was stratified according to the PAC and pulmonary vascular resistance. The end point was a composite of all-cause mortality and clinical worsening. Among them, end points occurred in 49 (41%) patients after 15 months (interquartile range, 8.5-24.0). Patients with a PAC <1.39 mL/mm Hg had a 3.09-fold higher risk (95% CI, 1.54-6.20, =0.001) of the end point events than the patients with a PAC ≥1.39 mL/mm Hg. Multivariable Cox regression analysis showed that stratified right ventricular afterload was the only independent predictor for the end point (hazard ratio, 2.009 [95% CI, 1.390-2.904], <0.001). A 3-group prediction risk was created. The patients with the highest right ventricular afterload (PAC <1.39 mL/mm Hg and pulmonary vascular resistance ≥10.3Wood Unit) had the highest risk (χ, 6.10; <0.014) of experiencing the end point. Our results suggest that PAC is a good predictor of mortality and clinical worsening in systemic lupus erythematosus-associated pulmonary arterial hypertension. PAC, in addition to pulmonary vascular resistance, may be an attractive tool for screening high-risk populations in these patients.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15682DOI Listing
October 2020

Noninvasive electrocardiography monitoring for very early recurrence predicts long-term outcome in patients after atrial fibrillation ablation.

Ann Noninvasive Electrocardiol 2020 11 25;25(6):e12785. Epub 2020 Jun 25.

Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia, and catheter ablation has been shown to be a highly effective treatment for patients with symptomatic AF. Very early recurrence (VER) of AF within 7 days after catheter ablation is common, but the clinical significance of VER remains unclear. We have examined the usefulness of the noninvasive electrocardiography monitor for the detection of VER and the relationship between VER and late recurrence (LR).

Methods: Eighty-eight patients with paroxysmal or persistent atrial fibrillation were retrospectively included. All patients underwent primary catheter ablation at a large general hospital between March 2016 and August 2018. All patients were followed up in atrial fibrillation clinic at an interval of every 3 months for late recurrence of AF. VER was evaluated by one-lead continuous noninvasive electrocardiography monitoring device for 7 days after ablation. The association between VER and LR was analyzed by univariate and multivariate Cox regression model.

Results: Mean age was 62.9 ± 9.7 years, and 39.8% were female. Thirty-two patients (36.4%) experienced VER. After a mean follow-up of 539.36 ± 211.66 days, 17 patients (19.3%) experienced LR. Multivariate Cox regression analysis revealed VER was an independent predictor of LR: HR 3.6 (95% CI, 1.2-10.8), p = .020. In addition, diabetes was also associated with LR of atrial fibrillation.

Conclusions: Noninvasive electrocardiography monitoring was a useful tool for detecting VER and VER after catheter ablation was associated with LR.
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http://dx.doi.org/10.1111/anec.12785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679836PMC
November 2020

VF-13, a chimeric peptide of VD-hemopressin(α) and neuropeptide VF, produces potent antinociception with reduced cannabinoid-related side effects.

Neuropharmacology 2020 09 13;175:108178. Epub 2020 Jun 13.

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China. Electronic address:

Pharmacological evidence indicated a functional interaction between neuropeptide FF (NPFF) and cannabinoid systems, and the cannabinoids combined with the NPFF receptor agonist neuropeptide VF (NPVF) produced antinociception without tolerance. In the present study, VF-13, a chimeric peptide containing the pharmacophores of the endogenous cannabinoid peptide VD-hemopressin(α) (VD-Hpα) and NPVF, was synthesized and pharmacologically evaluated. In vitro, VF-13 significantly upregulated the phosphorylated level of extracellular signal-regulated kinase 1/2 (ERK1/2) in CHO cells stably expressing CB1 receptors and inhibited forskolin-induced cAMP accumulation in HEK293 cells stably expressing NPFF or NPFF receptors. Moreover, VF-13 induced neurite outgrowth in Neuro 2A cells via CB1 and NPFF receptors. These results suggest that VF-13 exhibits multifunctional agonism at CB1, NPFF and NPFF receptors in vitro. Interestingly, intracerebroventricular VF-13 produced dose-dependent antinociception in mouse models of tail-flick and carrageenan-induced inflammatory pain via the TRPV1 receptor. In contrast, the reference compound (m)VD-Hpα-NH induced CB1 receptor-mediated supraspinal antinociception. Additionally, subcutaneous injection of (m)VD-Hpα-NH and VF-13 produced significant antinociception in carrageenan-induced inflammatory pain model. In the tetrad assay, our data demonstrated that VF-13 elicited hypothermia, but not catalepsy and hypoactivity after intracerebroventricular injection. Notably, VF-13 produced non-tolerance forming antinociception over 6 days treatment in both acute and inflammatory pain models. Furthermore, VF-13 had no apparent effects on gastrointestinal transit, pentobarbitone-induced sedation, food intake, and motor coordination at the supraspinal level. In summary, VF-13, a novel chimeric peptide of VD-Hpα and NPVF, produced non-tolerance forming antinociception in preclinical pain models with reduced cannabinoid-related side effects.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108178DOI Listing
September 2020
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