Publications by authors named "Yanzhao Zhou"

30 Publications

  • Page 1 of 1

A case report of an atypical hyper-dominant left anterior descending artery with a sac that misleads a stump-less chronic total occlusion.

Eur Heart J Case Rep 2021 Dec 23;5(12):ytab467. Epub 2021 Nov 23.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430000 Hubei, China.

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http://dx.doi.org/10.1093/ehjcr/ytab467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672655PMC
December 2021

Intermittent hypoxia treatment alleviates memory impairment in the 6-month-old APPswe/PS1dE9 mice and reduces amyloid beta accumulation and inflammation in the brain.

Alzheimers Res Ther 2021 Nov 29;13(1):194. Epub 2021 Nov 29.

Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.

Background: Alzheimer's disease (AD) is a progressive, degenerative, and terminal disease without cure. There is an urgent need for a new strategy to treat AD. The aim of this study was to investigate the effects of intermittent hypoxic treatment (IHT) on cognitive functions in a mouse model of AD and unravel the mechanism of action of IHT.

Methods: Six-month-old APPswe/PS1dE9 (APP/PS1) male mice were exposed to hypoxic environment (14.3% O) 4 h/day for 14 days or 28 days. Cognitive functions were measured by Morris water maze test after either 14 days or 42 days of interval. Thereafter the distribution of amyloid plaque and microglial activation were determined by mouse brain immunohistochemistry, while the amyloid beta (Aβ) and inflammatory cytokines were measured by ELISA and Western Blot. Microarray was used for studying gene expressions in the hippocampus.

Results: IHT for 14 days or 28 days significantly improved the spatial memory ability of the 6-month-old APP/PS1 mice. The memory improvement by 14 days IHT lasted to 14 days, but not to 42 days. The level of Aβ plaques and neurofilament accumulations was reduced markedly after the IHT exposure. IHT reduced the pro-inflammatory cytokines IL-1β, IL-6 levels, and β-secretase cleavage of APP processing which implies reduced Aβ production. Microarray analysis revealed a large number of genes in the hippocampus were significantly altered which are known to be metabolism-regulated genes.

Conclusions: This study provides evidence of the beneficial effect of IHT on the progression of AD by alleviating memory impairment, reducing Aβ accumulation and inflammation in the brain. IHT can be developed as a novel measure to relieve the progression of AD by targeting multiple pathways in the AD pathogenesis.
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http://dx.doi.org/10.1186/s13195-021-00935-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630860PMC
November 2021

Inhibition of microRNA-30a alleviates vascular remodeling in pulmonary arterial hypertension.

Mol Ther Nucleic Acids 2021 Dec 20;26:678-693. Epub 2021 Sep 20.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

The excessive and ectopic pulmonary artery smooth muscle cells (PASMCs) are crucial to the pathogenesis of pulmonary arteriole (PA) remodeling in pulmonary arterial hypertension (PAH). We previously found that microRNA (miR)-30a was significantly increased in acute myocardial infarction (AMI) patients and animals, as well as in cultured cardiomyocytes after hypoxia, suggesting that it might be strongly associated with hypoxia-related diseases. Here, we investigated the role of miR-30a in the PASMC remodeling of PAH. The expression of miR-30a was higher in the serum of PAH patients compared with healthy controls. miR-30a was mainly expressed in PAs and was increased in PASMCs after hypoxia, mediating the downregulation of p53 tumor suppressor protein (P53). Genetic knockout of miR-30a effectively decreased right ventricular (RV) systolic pressure (RVSP), PA, and RV remodeling in the Su5416/hypoxia-induced and monocrotaline (MCT)-induced PAH animals. Additionally, pharmacological inhibition of miR-30a via intratracheal liquid instillation (IT-L) delivery strategy showed high efficiency, which downregulated miR-30a to mitigate disease phenotype in the Su5416/hypoxia-induced PAH animals, and these beneficial effects could be partially reduced by simultaneous P53 inhibition. We demonstrate that inhibition of miR-30a could ameliorate experimental PAH through the miR-30a/P53 signaling pathway, and the IT-L delivery strategy shows good therapeutic outcomes, providing a novel and promising approach for the treatment of PAH.
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http://dx.doi.org/10.1016/j.omtn.2021.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517099PMC
December 2021

Using the aMAP Risk Score to Predict Late Recurrence Following Radiofrequency Ablation for Hepatocellular Carcinoma in Chinese Population: A Multicenter Study.

J Hepatocell Carcinoma 2021 28;8:837-850. Epub 2021 Jul 28.

Department of Hepatobiliary and Pancreatic Surgery, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, Henan Province, People's Republic of China.

Objective: This study was conducted to explore the application of age-male-ALBI-platelets (aMAP) score for predicting late recurrence of hepatocellular carcinoma (HCC) following radiofrequency ablation (RFA) and develop an aMAP score based-nomogram to predict prognosis in Chinese population.

Materials And Methods: HCC patients who developed late recurrence following RFA at National Cancer Center (NCC) of China, First Hospital of Shanxi Medical University and Beijing Hospital of Traditional Chinese Medicine from January 2011 to December 2016 were included as a training cohort, and patients who were treated at Affiliated Cancer Hospital of Zhengzhou University between January 2012 and December 2016 were included as an external validation cohort. The optimal cut-off value for aMAP score was determined using X-tile software to discriminate the performance of recurrence-free survival (RFS).

Results: A total of 339 eligible patients were included in this study. Patients were grouped into low-risk (aMAP score ≤64.2), medium-risk (64.3 ≤aMAP score ≤68.6) and high-risk (aMAP score ≥68.7) groups by X-tile plots. The prognostic factors that affected RFS were the number of lesions and aMAP score. A nomogram was constructed to predict the RFS with a C-index of 0.793 (95% CI: 0.744-0.842). The time-dependent receiver operating characteristic curves (t-AUCs) of the nomogram to predict 3, 4 and 5-year RFS were 0.808, 0.820 and 0.764, respectively. The model was then tested with data from an external validation cohort. The calibration curve confirmed the optimal agreement between the predicted and observed values.

Conclusion: The aMAP score provided a well-discriminated risk stratification and is an independent prognostic factor for the late recurrence of HCC following RFA. The aMAP score-based nomogram could help to strengthen prognosis-based decision making and formulate adjuvant therapeutic and preventive strategies.
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http://dx.doi.org/10.2147/JHC.S308587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327363PMC
July 2021

Challenges Facing Percutaneous Ablation in the Treatment of Hepatocellular Carcinoma: Extension of Ablation Criteria.

J Hepatocell Carcinoma 2021 21;8:625-644. Epub 2021 Jun 21.

Department of Hepatobiliary and Pancreatic Surgery, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450008, People's Republic of China.

As an emerging minimally invasive treatment method, percutaneous ablation is more and more widely used in the treatment of liver tumors. It has been recommended by guidelines for diagnosis and treatment of hepatocellular carcinoma (HCC) as a curative treatment alongside surgical resection and liver transplantation. In recent years, with the continuous advancement and innovation of percutaneous ablation technologies, their clinical efficacy and safety have been significantly improved, which has led to the expanded application of percutaneous ablation in the treatment of HCC-more and more patients who were previously considered unsuitable for ablation therapies are now being treated with percutaneous ablation. Obviously, percutaneous ablation can reduce the risk of treatment changes from curative strategies to palliative strategies. Based on clinical practice experience, this review enumerates the advantages and disadvantages of different ablative modalities and summarizes the existing combinations of ablation techniques, thus will help clinicians choose the most appropriate ablative modality for each patient and will provide scientific guidance for improving prognosis and making evidence-based treatment decisions. In addition, we point out the challenges and future prospects of the ablation therapies, thereby providing direction for future research.
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http://dx.doi.org/10.2147/JHC.S298709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232857PMC
June 2021

Sleep disturbance induces depressive behaviors and neuroinflammation by altering the circadian oscillations of clock genes in rats.

Neurosci Res 2021 Oct 27;171:124-132. Epub 2021 Mar 27.

Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, 27 Taiping Road, Beijing, 100850, China. Electronic address:

Sleep loss leads to a spectrum of mood disorders such as anxiety disorders, bipolar disorder and depression in many individuals. However, the underlying mechanisms are largely unknown. In this study, sleep-disturbed animals were tested for anxiety and depressive behaviors. We then studied the effects of SD on hypothalamic-pituitary-adrenal (HPA) axis function by measuring serum and CSF levels of corticosterone (CORT), and at the end of the experiment, brains were collected to measure the circadian oscillations of clock genes expression in the hypothalamus, glial cell activation and inflammatory cytokine alterations. Our results indicated that SD for 3 days resulted in anxiety- and depressive-like behaviors. SD exaggerated cortisol response to HPA axis, significantly altered the circadian oscillations of clock genes, decreased the expression of tight junction protein ZO-1 and Claudin 5 and increased the number of GFAP-positive cells and Iba-1-positive cells and caused subsequent elevation of pro-inflammatory cytokines IL-6, IL-1β and TNFα. These findings demonstrated that SD for 3 days induced anxiety- and depression-like behaviors in rats in company with altering the circadian oscillations of clock genes and inducing neuroinflammation, indicating the underlying mechanism of sleep loss induced neuronal dysfunction.
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http://dx.doi.org/10.1016/j.neures.2021.03.006DOI Listing
October 2021

A novel internal cold circulation radiofrequency-assisted device for liver transection.

Int J Hyperthermia 2021 ;38(1):308-315

Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Henan, People's Republic of China.

Purpose: To evaluate the safety and efficacy of a new internal cold circulation bipolar radiofrequency compared with Habib-4X bipolar radiofrequency device in the resection of liver tumors.

Methods: A total of 85 patients with hepatocellular carcinoma who received radiofrequency-assisted liver resection from February 2017 to January 2020 were retrospectively enrolled in our study, in which 45 patients received the new internal cold circulation bipolar radiofrequency (New-RF) and 40 patients received Habib-4X bipolar radiofrequency (Habib-4X). Primary outcome measures were the speed of liver transection, the width of coagulation tissue, hemorrhage volume, blood transfusion rate, and operation time.

Results: The baseline characteristics of patients in the New-RF and Habib-4X groups had no significant difference ( > 0.05). Compared to Habib-4X, the New-RF had a faster average speed of liver transection (4.81 ± 1.20 cm/min vs 3.64 ± 1.08 cm/min,  < 0.001), a narrower width of coagulation tissue (1.42 ± 0.23 cm vs 1.81 ± 0.20 cm,  < 0.001), a less operation time (55.04 ± 16.12 min vs 64.02 ± 15.09 min,  = 0.010), a lower rate of needle path bleeding (13.3% vs 35.0%,  = 0.019), and a lower carbonization rate of electrode needle (22.2% vs 77.8%,  < 0.001). Hemorrhage during the transection (85.0 ml vs 105.0 ml,  = 0.438) and hemorrhage per square centimeter (3.28 ± 0.86 ml/cm vs 3.60 ± 1.12 ml/cm,  = 0.141) in the New-RF group were smaller than those in Habib-4X group with no significant difference.

Conclusion: The new internal cold circulation bipolar radiofrequency was a safe and efficacious auxiliary device for liver resection with a faster speed of resection, lower carbonization rate of electrode needle, and more precise range of coagulation.
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http://dx.doi.org/10.1080/02656736.2021.1889046DOI Listing
July 2021

Anti-ATR001 monoclonal antibody ameliorates atherosclerosis through beta-arrestin2 pathway.

Biochem Biophys Res Commun 2021 03 28;544:1-7. Epub 2021 Jan 28.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address:

Background: Our previous study developed ATRQβ-001 vaccine, which targets peptide ATR001 from angiotensin Ⅱ (Ang Ⅱ) receptor type 1 (AT1R). The ATRQβ-001 vaccine could induce the production of anti-ATR001 monoclonal antibody (McAb-ATR) and inhibit atherosclerosis without feedback activation of the renin-angiotensin system (RAS). This study aims at investigating the underexploited mechanisms of McAb-ATR in ameliorating atherosclerosis.

Methods: AT1R-KO HEK293T cell lines were constructed to identify the specificity of McAb-ATR and key sites of ATRQβ-001 vaccine. Beta-arrestin1 knock-out (Arrb1) mice, Beta-arrestin2 knock-out (Arrb2) mice, and low-density lipoprotein receptor knock-out (LDLr) mice were used to detect potential signaling pathways affected by McAb-ATR. The role of McAb-ATR in beta-arrestin and G proteins (G or G) signal transduction events was also investigated.

Results: McAb-ATR could specifically bind to the Phe-His-Tyr site of AT1R second extracellular loop (ECL2). The anti-atherosclerotic effect of McAb-ATR disappeared in LDLr mice transplanted with Arrb2 mouse bone marrow (BM) and BM-derived macrophages (BMDMs) from Arrb2 mice. Furthermore, McAb-ATR inhibited beta-arrestin2-dependent extracellular signal regulated kinase1/2 (ERK1/2) phosphorylation, and promoted beta-arrestin2-mediated nuclear factor kappa B p65 (NFκB p65) inactivity. Compared with conventional AT1R blockers (ARBs), McAb-ATR did not inhibit Ang Ⅱ-induced uncoupling of heterotrimeric G proteins (G or G) and G-dependent intracellular Ca release, nor cause RAS feedback activation.

Conclusions: Through regulating beta-arrestin2, McAb-ATR ameliorates atherosclerosis without affecting G or G pathways. Due to high selectivity for AT1R and biased interaction with beta-arrestin2, McAb-ATR could serve as a novel strategy for treating atherosclerosis.
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http://dx.doi.org/10.1016/j.bbrc.2021.01.054DOI Listing
March 2021

PCSK9Qβ-003 Vaccine Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice.

Cardiovasc Drugs Ther 2021 02 28;35(1):141-151. Epub 2020 Jul 28.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, China.

Purpose: Our group has developed a therapeutic vaccine targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), named PCSK9Qβ-003. In this study, we investigated the potential effectiveness of the PCSK9Qβ-003 vaccine on atherosclerosis.

Methods: Male ApoE mice were randomly assigned to three groups: a phosphate-buffered saline (PBS) group, Qβ virus-like particles (VLP) group, and PCSK9Qβ-003 vaccine group. Mice in the PCSK9Qβ-003 group were injected with the PCSK9Qβ-003 vaccine four times (100 μg/time) over a period of 18 weeks. The effects of the vaccine on atherosclerotic plaque, cholesterol transport, inflammation and apoptosis were investigated.

Results: The PCSK9Qβ-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in ApoE mice. Compared with the other groups, the PCSK9Qβ-003 vaccine significantly reduced the lesion area and promoted the stability of atherosclerotic plaque. The vaccine regulated cholesterol transport in the aorta of ApoE mice by up-regulating the expression level of liver X receptor α and ATP binding cassette transporter A1. Additionally, macrophage infiltration and expression of monocyte chemoattractant protein-1 and tumor necrosis factor-α were significantly decreased in the mice administered the PCSK9Qβ-003 vaccine. The vaccine also markedly reduced apoptosis in the lesion area of the aorta in ApoE mice.

Conclusions: The results demonstrated that the PCSK9Qβ-003 vaccine attenuated the progression of atherosclerosis by modulating reverse cholesterol transport and inhibiting inflammation infiltration and apoptosis, which may provide a novel therapeutic approach for atherosclerosis and greatly improve treatment compliance among patients.
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http://dx.doi.org/10.1007/s10557-020-07041-6DOI Listing
February 2021

Vaccine Against PCSK9 Improved Renal Fibrosis by Regulating Fatty Acid β-Oxidation.

J Am Heart Assoc 2020 01 24;9(1):e014358. Epub 2019 Dec 24.

Department of Cardiology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China.

Background Defects in the renal fatty acid β-oxidation pathway have been implicated in the development of renal fibrosis. Our group has developed a therapeutic vaccine targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), named PCSK9Qβ-003. In this study, we investigated the potential effectiveness of the PCSK9Qβ-003 vaccine on hypercholesterolemia with renal fibrosis. Methods and Results The low-density lipoprotein receptor male mice fed with a high-cholesterol (1%) Western diet were randomly assigned into 4 groups: the sham group (or the control group), the phosphate-buffered saline group, the Qβ virus-like particles group and the PCSK9Qβ-003 vaccine group. Mice of the PCSK9Qβ-003 group were injected with the PCSK9Qβ-003 vaccine (100 μg/time) every 2 or 4 weeks. The mice were administered with either unilateral ureteral obstruction for 2 weeks or N-nitro-l-arginine methyl ester (50 mg/kg per day) for 6 weeks to establish a renal fibrosis model. Compared with the other 3 groups, the PCSK9Qβ-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in low-density lipoprotein receptor mice with hypercholesterolemia. Compared with the phosphate-buffered saline and Qβ virus-like particles groups, the PCSK9Qβ-003 vaccine improved hepatic steatosis and renal function. Histology analysis showed that the PCSK9Qβ-003 vaccine significantly ameliorated renal lipid accumulation and renal fibrosis. Moreover, the PCSK9Qβ-003 vaccine obviously upregulated the expression of low-density lipoprotein receptor, very-low-density lipoprotein receptor, sterol-regulatory element binding protein 2, and fatty acid β-oxidation-related factors, and ameliorated renal fibrosis-related molecules both in the unilateral ureteral obstruction and N-nitro-l-arginine methyl ester models. Conclusions This study suggested that the PCSK9Qβ-003 vaccine improved renal lipid accumulation and renal fibrosis by regulating fatty acid β-oxidation, which may provide a promising method for treating hypercholesterolemia with renal fibrosis.
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http://dx.doi.org/10.1161/JAHA.119.014358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988173PMC
January 2020

Vaccine Targeted Alpha 1D-Adrenergic Receptor for Hypertension.

Hypertension 2019 12 14;74(6):1551-1562. Epub 2019 Oct 14.

From the Department of Cardiology (C.L., X.Y., D.W., K.Z., Y.P., Y.Z., F.C., X.C., S.Y., Z.Z., Y.W., Y.L., Z.Q.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The α1-AR (α1 adrenergic receptor) blockers currently on the market cannot meet clinical needs because of low-selectivity for subtypes of α1-ARs, short half-life, and uncertain role in cardiovascular end point events. The study sought to find a vaccine specifically against α1D-AR (α1D-adrenergic receptor) for treating hypertension. A short peptide ADR-004 (cgiteeagy) belonging to α1D-AR was screened, and the ADRQβ-004 vaccine was produced and injected into spontaneously hypertensive rats model (including a short-term study, 10 weeks, and a long-term observation study, 39 weeks) and NG-nitro-l-arginine methyl ester + spontaneously hypertensive rats model (15 weeks). The antihypertensive effect and target organ protection of the ADRQβ-004 vaccine were carefully evaluated. The possible immune-mediated damage was detected in normal vaccinated Sprague Dawley rats. The ADR-004 peptide has perfect immunogenicity, and the ADRQβ-004 vaccine could induce strong antibody production. In the short-term study, the ADRQβ-004 vaccine averagely decreased the systolic blood pressure of spontaneously hypertensive rats up to 15 mm Hg and that of NG-nitro-l-arginine methyl ester+spontaneously hypertensive rats up to 29 mm Hg. In the long-term observation model, the antihypertensive effect of the ADRQβ-004 vaccine was quite stable, and the average decline of systolic blood pressure was 22 mm Hg. The ADRQβ-004 vaccine effectively prevented vascular structural remodeling, cardiac hypertrophy and fibrosis, and renal injury of hypertensive animals, superior to prazosin at renal level. Moreover, the ADRQβ-004 vaccine obviously downregulated the expression of α1D-AR, but not α1A-AR. Additionally, no significant immune-mediated damage was detected in immunized animals. The present results demonstrate that the ADRQβ-004 vaccine may provide a novel and promising method for the treatment of hypertension.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13700DOI Listing
December 2019

ATRQβ-001 Vaccine Prevents Experimental Abdominal Aortic Aneurysms.

J Am Heart Assoc 2019 09 12;8(18):e012341. Epub 2019 Sep 12.

Department of Cardiology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China.

Background We have developed a peptide vaccine named ATRQβ-001, which was proved to retard signal transduction initiated by angiotensin II (Ang II). Ang II was implicated in abdominal aortic aneurysm (AAA) progression, but whether the ATRQβ-001 vaccine would prevent AAA is unknown. Methods and Results Ang II-infused ApoE mice and calcium phosphate-induced AAA in C57BL/6 mice were used to verify the efficiency of ATRQβ-001 vaccine in AAA. Results demonstrated that the vaccine effectively restrained the aneurysmal dilation and vascular wall destruction of aorta in both animal models, beyond anti-hypertensive effects. In Ang II-induced AAA vascular sections, Immunohistochemical staining showed that the vaccine notably constrained vascular inflammation and vascular smooth muscle cell (VSMC) phenotypic transition, concurrently reduced macrophages infiltration. In cultured VSMC, the anti-ATR-001 antibody inhibited osteopontin secretion induced by Ang II, thereby impeded macrophage migration while co-culture. Furthermore, metalloproteinases and other matrix proteolytic enzymes were also found to be limited by the vaccine in vivo and in vitro. Conclusions ATRQβ-001 vaccine prevented AAA initiation and progression in both Ang II and calcium phosphate-induced AAA models. And the beneficial effects were played beyond decrease of blood pressure, which provided a novel and promising method to take precautions against AAA.
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http://dx.doi.org/10.1161/JAHA.119.012341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817999PMC
September 2019

Identification of heat-tolerance QTLs and high-temperature stress-responsive genes through conventional QTL mapping, QTL-seq and RNA-seq in tomato.

BMC Plant Biol 2019 Sep 11;19(1):398. Epub 2019 Sep 11.

College of Horticulture, Nanjing Agricultural University, Weigang NO 1, Nanjing, 210095, China.

Background: High temperature is one of the major abiotic stresses in tomato and greatly reduces fruit yield and quality. Identifying high-temperature stress-responsive (HSR) genes and breeding heat-tolerant varieties is an effective way to address this issue. However, there are few reports on the fine mapping of heat-tolerance quantitative trait locus (QTL) and the identification of HSR genes in tomato. Here, we applied three heat tolerance-related physiological indexes, namely, relative electrical conductivity (REC), chlorophyll content (CC) and maximum photochemical quantum efficiency (F/F) of PSII (photosystem II), as well as the phenotypic index, the heat injury index (HII), and conventional QTL analysis combined with QTL-seq technology to comprehensively detect heat-tolerance QTLs in tomato seedlings. In addition, we integrated the QTL mapping results with RNA-seq to identify key HSR genes within the major QTLs.

Results: A total of five major QTLs were detected: qHII-1-1, qHII-1-2, qHII-1-3, qHII-2-1 and qCC-1-5 (qREC-1-3). qHII-1-1, qHII-1-2 and qHII-1-3 were located, respectively, in the intervals of 1.43, 1.17 and 1.19 Mb on chromosome 1, while the interval of qHII-2-1 was located in the intervals of 1.87 Mb on chromosome 2. The locations observed with conventional QTL mapping and QTL-seq were consistent. qCC-1-5 and qREC-1-3 for CC and REC, respectively, were located at the same position by conventional QTL mapping. Although qCC-1-5 was not detected in QTL-seq analysis, its phenotypic variation (16.48%) and positive additive effect (0.22) were the highest among all heat tolerance QTLs. To investigate the genes involved in heat tolerance within the major QTLs in tomato, RNA-seq analysis was performed, and four candidate genes (SlCathB2, SlGST, SlUBC5, and SlARG1) associated with heat tolerance were finally detected within the major QTLs by DEG analysis, qRT-PCR screening and biological function analysis.

Conclusions: In conclusion, this study demonstrated that the combination of conventional QTL mapping, QTL-seq analysis and RNA-seq can rapidly identify candidate genes within major QTLs for a complex trait of interest to replace the fine-mapping process, thus greatly shortening the breeding process and improving breeding efficiency. The results have important applications for the fine mapping and identification of HSR genes and breeding for improved thermotolerance.
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http://dx.doi.org/10.1186/s12870-019-2008-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739936PMC
September 2019

Immunotherapy of Endothelin-1 Receptor Type A for Pulmonary Arterial Hypertension.

J Am Coll Cardiol 2019 05;73(20):2567-2580

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Background: Pulmonary arterial hypertension (PAH) is a chronic fatal disease. The treatment of PAH is less than ideal and the control is far from satisfactory worldwide. Vaccination provides a promising approach for treatment of PAH.

Objectives: This study sought to find a vaccine against endothelin-1 (ET-1) receptor type A (ETAR) for treating PAH.

Methods: The ETRQβ-002 vaccine was screened and the specific antibodies against epitope ETR-002 belonging to the second extracellular loop of ETAR (including the polyclonal and monoclonal antibody) were produced. The effect of the antibodies on Ca-dependent signal transduction events was investigated. In vivo, ETRQβ-002 vaccine was used to vaccinate monocrotaline (MCT)- and Sugen/hypoxia-induced pulmonary hypertension animals. The monoclonal antibody (mAb) against ETR-002 was also injected into the PAH animals. The effect of ETRQβ-002 vaccine on pulmonary hypertension and remodeling of pulmonary arterioles and right ventricle (RV) was carefully evaluated. Further, the possible immune-mediated damage was detected in normal vaccinated animals.

Results: ETR-002 peptide has perfect immunogenicity and ETRQβ-002 vaccine could induce strong antibody production. In vitro, the anti-ETR-002 antibody bound to ETAR and inhibited Ca-dependent signal transduction events, including extracellular signal-regulated kinase phosphorylation and elevation of intracellular Ca concentration induced by ET-1. In vivo, both ETRQβ-002 vaccine and the mAb significantly decreased the RV systolic pressure up to 20 mm Hg and 10 mm Hg in MCT-exposed rats and Sugen/hypoxia-exposed mice, respectively. Also, ETRQβ-002 vaccine/mAb obviously ameliorated pathological remodeling of pulmonary arterioles and hypertrophy of the RV in PAH animals. Additionally, no significant immune-mediated damage was detected in vaccinated animals.

Conclusions: ETRQβ-002 vaccine/mAb attenuated remodeling of pulmonary arterioles and RV in MCT- and Sugen/hypoxia-induced PAH animals and decreased RV systolic pressure effectively through diminishing the pressure response and inhibiting signal transduction initiated by ET-1. ETRQβ-002 vaccine/mAb may provide a novel and promising method for PAH treatment.
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http://dx.doi.org/10.1016/j.jacc.2019.02.067DOI Listing
May 2019

Metformin administration prevents memory impairment induced by hypobaric hypoxia in rats.

Behav Brain Res 2019 05 28;363:30-37. Epub 2019 Jan 28.

Institute of Military Cognition and Brain Sciences, Beijing, China; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China. Electronic address:

Metformin, an antidiabetic biguanide, reduces hyperglycemia by improving glucose utilization and reducing gluconeogenesis. Recently, an increasing number of studies have shown that metformin also led to a significant clinical improvement in memory and cognition in different clinical settings. In the present study, we investigated whether metformin administration protects against memory impairment and neuron damage caused by acute exposure to hypobaric hypoxia and screened the possible molecular mechanisms with a focused gene array. We found that metformin treatment obviously attenuated spatial memory and recognition memory impairment resulting from acute hypobaric hypoxia exposure but had no effect on general locomotor and behavioral activity. Moreover, the results of Nissl and TUNEL staining showed that neuron damage and cell apoptosis caused by hypobaric hypoxia exposure was also inhibited by metformin pretreatment. At the molecular level, we found that metformin pretreatment not only prevented the changes of FOS, JUNB and BDNF at both mRNA and protein levels, but also increased the expression of the postsynaptic scaffold genes HOMER and PSD95 after exposure to hypobaric hypoxia. These data suggested that metformin pretreatment is a feasible strategy for preventing memory impairment under hypobaric hypoxia.
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http://dx.doi.org/10.1016/j.bbr.2019.01.048DOI Listing
May 2019

The ATRQβ-001 vaccine improves cardiac function and prevents postinfarction cardiac remodeling in mice.

Hypertens Res 2019 03 26;42(3):329-340. Epub 2018 Dec 26.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

We invented the ATRQβ-001 hypertension vaccine, which targeted angiotensin II type 1 receptor (ATR) and showed a desirable blocking effect for ATR. The purpose of this study was to investigate whether the ATRQβ-001 vaccine could improve cardiac function and prevent cardiac remodeling after acute myocardial infarction (AMI). C57BL/6 male mice were randomly assigned into four groups: sham + VLP, MI + VLP, MI + ATRQβ-001, and MI + valsartan. Mice were administered Qβ virus-like particle (Qβ-VLP, 100 μg/time), ATRQβ-001 vaccine (100 μg/time), and valsartan (6 mg/kg/day) before AMI, which was induced by permanently ligating the left anterior descending coronary artery. The effect of the ATRQβ-001 vaccine on cardiac function and cardiac remodeling was observed by following up for 1 week, 4 weeks, and 12 weeks post MI. The ATRQβ-001 vaccine significantly reduced sudden cardiac death and increased survival rates (compared with MI + VLP, 80% versus 55% and mean estimate (days) 68.4 ± 7.0 versus 47.8 ± 8.9, respectively; p = 0.046) post MI. Echocardiography showed that the ATRQβ-001 vaccine remarkably improved cardiac function (left ventricular ejection fraction, 24.8 ± 7.0% versus 13.2 ± 3.8%, p = 0.005) post MI. Histological analysis revealed that the ATRQβ-001 vaccine obviously mitigated myocardial inflammation, apoptosis, and fibrosis after AMI. Further, the ATRQβ-001 vaccine significantly inhibited the TGF-β1/Smad2/3 signaling pathway. Assessment of the renin-angiotensin system (RAS) demonstrated that the ATRQβ-001 vaccine did not cause obvious feedback of circulating RAS, but prominently attenuated the expression of ATR, compared with the other groups at 4 and 12 weeks after AMI. In conclusion, the ATRQβ-001 vaccine decreased mortality and improved cardiac function and remodeling after AMI.
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http://dx.doi.org/10.1038/s41440-018-0185-3DOI Listing
March 2019

Respiratory burst oxidase homologue-dependent H O and chloroplast H O are essential for the maintenance of acquired thermotolerance during recovery after acclimation.

Plant Cell Environ 2018 10 3;41(10):2373-2389. Epub 2018 Jul 3.

College of Horticulture, Nanjing Agricultural University, Nanjing, China.

Thermotolerance is improved by heat stress (HS) acclimation, and the thermotolerance level is "remembered" by plants. However, the underlying signalling mechanisms remain largely unknown. Here, we showed NADPH oxidase-mediated H O (NADPH-H O ), and chloroplast-H O promoted the sustained expression of HS-responsive genes and programmed cell death (PCD) genes, respectively, during recovery after HS acclimation. When spraying the NADPH oxidase inhibitor, diphenylene iodonium, after HS acclimation, the NADPH-H O level significantly decreased, resulting in a decrease in the expression of HS-responsive genes and the loss of maintenance of acquired thermotolerance (MAT). In contrast, compared with HS acclimation, NADPH-H O declined but chloroplast-H O further enhanced during recovery after HS over-acclimation, resulting in the reduced expression of HS-responsive genes and substantial production of PCD. Notably, the further inhibition of NADPH-H O after HS over-acclimation also inhibited chloroplast-H O , alleviating the severe PCD and surpassing the MAT of HS over-acclimation treatment. Due to the change in subcellular H O after HS acclimation, the tomato seedlings maintained a constant H O level during recovery, resulting in stable and lower total H O levels during a tester HS challenge conducted after recovery. We conclude that tomato seedlings increase their MAT by enhancing NADPH-H O content and controlling chloroplast-H O production during recovery, which enhances the expression of HS-responsive genes and balances PCD levels, respectively.
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http://dx.doi.org/10.1111/pce.13351DOI Listing
October 2018

Immune Response of A Novel ATR-AP205-001 Conjugate Anti-hypertensive Vaccine.

Sci Rep 2017 10 3;7(1):12580. Epub 2017 Oct 3.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

We developed a virus-like particle (VLP)-based therapeutic vaccine against angiotensin II receptor type 1, ATR-AP205-001, which could significantly reduce the blood pressure and protect target organs of hypertensive animals. In this study, we focused on the immunological effect and safety of the VLP-based vaccine. By comparing to the depolymerized dimeric vaccine ATR-Dimer-001, we found that ATR-AP205-001 reached subcapsular sinus of lymph node shortly after administration, followed by accumulation on follicle dendritic cells via follicle B cell transportation, while ATR-Dimer-001 vaccine showed no association with FDCs. ATR-AP205-001 vaccine strongly activated dendritic cells, which promoted T cells differentiation to follicular helper T cells. ATR-AP205-001 vaccine induced powerful germinal center reaction, which was translated to a boost of specific antibody production and long-lasting B cell memory, far superior to ATR-Dimer-001 vaccine. Moreover, neither cytotoxic T cells, nor Th1/Th17 cell-mediated inflammation was observed in ATR-AP205-001 vaccine, similar to ATR-Dimer-001 vaccine. We concluded that ATR-AP205-001 vaccine quickly induced potent humoral immunity through collaboration of B cells, follicular dendritic cells and follicular helper T cells, providing an effective and safe intervention for hypertension in the future clinical application.
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http://dx.doi.org/10.1038/s41598-017-12996-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626684PMC
October 2017

A Therapeutic Peptide Vaccine Against PCSK9.

Sci Rep 2017 10 2;7(1):12534. Epub 2017 Oct 2.

Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Vaccination provides a promising approach for treatment of hypercholesterolemia and improvement in compliance. In this study, the appropriate virus-like particle (VLP)-peptide vaccines targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) were screened. The screening criteria of target peptides were as follows: (1) located in catalytic domain of PCSK9, or regulating the binding of PCSK9 and LDL receptors (LDLR); (2) having low/no-similarity when matched with the host proteome; (3) possessing ideal antigenicity and hydrophilicity; (4) including the functional mutation site of PCSK9. It was found that mice vaccinated with VLP -PCSK9 peptide vaccines, especially PCSK9Qβ-003 vaccine, developed high titer IgG antibodies against PCSK9. PCSK9Qβ-003 vaccine obviously decreased plasma total cholesterol in both Balb/c mice and LDLR mice. Also, PCSK9Qβ-003 vaccine decreased plasma PCSK9 level and up-regulated LDLR expression in liver. Additionally, PCSK9Qβ-003 vaccine injection was associated with significant up-regulation of sterol-regulatory element-binding protein-2 (SREBP-2), hepatocyte nuclear factor 1α (HNF-1α), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in LDLR mice. No obvious immune injury was detected in vaccinated animals. The PCSK9Qβ-003 vaccine, therefore, may be an attractive treatment approach for hypercholesterolemia through decreasing cholesterol and regulating lipid homeostasis.
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http://dx.doi.org/10.1038/s41598-017-13069-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624949PMC
October 2017

Hypoxia augments LPS-induced inflammation and triggers high altitude cerebral edema in mice.

Brain Behav Immun 2017 Aug 20;64:266-275. Epub 2017 Apr 20.

Department of Cognitive Sciences, Institute of Basic Medical Sciences, Beijing, China; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China. Electronic address:

High altitude cerebral edema (HACE) is a life-threatening illness that develops during the rapid ascent to high altitudes, but its underlying mechanisms remain unclear. Growing evidence has implicated inflammation in the susceptibility to and development of brain edema. In the present study, we investigated the inflammatory response and its roles in HACE in mice following high altitude hypoxic injury. We report that acute hypobaric hypoxia induced a slight inflammatory response or brain edema within 24h in mice. However, the lipopolysaccharide (LPS)-induced systemic inflammatory response rapidly aggravated brain edema upon acute hypobaric hypoxia exposure by disrupting blood-brain barrier integrity and activating microglia, increasing water permeability via the accumulation of aquaporin-4 (AQP4), and eventually leading to impaired cognitive and motor function. These findings demonstrate that hypoxia augments LPS-induced inflammation and induces the occurrence and development of cerebral edema in mice at high altitude. Here, we provide new information on the impact of systemic inflammation on the susceptibility to and outcomes of HACE.
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http://dx.doi.org/10.1016/j.bbi.2017.04.013DOI Listing
August 2017

ATRQβ-001 vaccine prevents atherosclerosis in apolipoprotein E-null mice.

J Hypertens 2016 Mar;34(3):474-85; discussion 485

Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China *Yanzhao Zhou, Shijia Wang and Zhihua Qiu contributed equally to the writing of this article. †Yuhua Liao and Xiao Chen contributed equally to this study.

Objective: Angiotensin II (AngII) type 1 receptor (AT1R) blockers have been proved to reduce atherosclerosis. Previously, we have invented ATRQβ-001 vaccine which showed a desirable blocking effect for AT1R. The purpose of this study was to investigate whether ATRQβ-001 vaccine would prevent atherosclerosis in apolipoprotein E-null (ApoE-/-) mice.

Methods: Male ApoE-/- mice were administered with ATRQβ-001 vaccine, Qβ virus-like particles, valsartan or vehicle over a period of 24 weeks. In vitro, human coronary artery endothelial cells preincubated with the anti-ATR-001 antibody, the neutralization antibody or valsartan for 2  h, were treated with AngII for 24  h. Histological stain and molecule biology methods were used to assess the atheroprotective effect of the vaccine.

Results: ATRQβ-001 vaccine significantly reduced the lesion area and promoted the stability of atherosclerotic plaque. Meanwhile, macrophage infiltration as well as the expressions of adhesion molecules and monocyte chemoattractant protein-1 was obviously decreased in the ATRQβ-001 vaccine group. Additionally, the vaccine markedly reduced the apoptosis in the lesions of the ApoE-/- mice. In vitro, the anti-ATR-001 antibody inhibited endothelial apoptosis induced by AngII. Furthermore, ATRQβ-001 vaccine exhibited a dramatical attenuation in the expressions of lectin-like oxidized low-density lipoprotein receptor-1 and AT1R in the aortic. More importantly, compared with the valsartan group, no obvious feedback of the plasma renin-angiotensin system was elicited in the vaccine group.

Conclusion: The results demonstrated that ATRQβ-001 vaccine reduced the progression of atherosclerosis in ApoE-/- mice without obvious feedback of renin-angiotensin system.
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http://dx.doi.org/10.1097/HJH.0000000000000835DOI Listing
March 2016

Dissolved oxygen concentration in the medium during cell culture: Defects and improvements.

Cell Biol Int 2016 Mar 3;40(3):354-60. Epub 2016 Jan 3.

Department of Brain Protection and Plasticity, Institute of Basic Medical Sciences, Beijing, 100850, China.

In vitro cell culture has provided a useful model to study the effects of oxygen on cellular behavior. However, it remains unknown whether the in vitro operations themselves affect the medium oxygen levels and the living states of cells. In addition, a prevailing controversy is whether reactive oxygen species (ROS) production is induced by continuous hypoxia or reoxygenation. In this study, we have measured the effects of different types of cell culture containers and the oxygen environment where medium replacement takes place on the actual oxygen tension in the medium. We found that the deviations of oxygen concentrations in the medium are much greater in 25-cm(2) flasks than in 24-well plates and 35-mm dishes. The dissolved oxygen concentrations in the medium were increased after medium replacement in normoxia, but remained unchanged in glove boxes in which the oxygen tension remained at a low level (11.4, 5.7, and 0.5% O2 ). We also found that medium replacement in normoxia increased the number of ROS-positive cells and reduced the cell viability; meanwhile, medium replacement in a glove box did not produce the above effects. Therefore, we conclude that the use of 25-cm(2) flasks should be avoided and demonstrate that continuous hypoxia does not produce ROS, whereas the reoxygenation that occurs during the harvesting of cells leads to ROS and induces cell death.
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http://dx.doi.org/10.1002/cbin.10570DOI Listing
March 2016

Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo.

PLoS One 2015 14;10(10):e0140035. Epub 2015 Oct 14.

Department of Brain Protection and Plasticity, Institute of Basic Medical Sciences, Beijing, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.

Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCs)in vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po2 values in the ventricles (45∼50 Torr) and DG (approximately 10 Torr) were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr). Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po2 levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140035PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605722PMC
June 2016

Vaccination against type 1 angiotensin receptor prevents streptozotocin-induced diabetic nephropathy.

J Mol Med (Berl) 2016 Feb 26;94(2):207-18. Epub 2015 Sep 26.

Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China.

Unlabelled: Recently, our group has developed a therapeutic hypertensive vaccine against angiotensin (Ang) II type 1 receptor (AT1R) named ATRQβ-001. To explore its potential effectiveness on streptozotocin-induced diabetic nephropathy, male Sprague Dawley rats were randomly divided into two groups: a control and a diabetic model. After 1 week, the diabetic rats were divided into four subgroups (each with 15 rats) for 14-week treatments with saline, olmesartan, ATRQβ-001, and Qβ virus-like particle (VLP), respectively. In addition to lower blood pressure, ATRQβ-001 vaccination ameliorated biochemical parameter changes of renal dysfunction, mesangial expansion, and fibrosis through inhibiting oxidative stress, macrophage infiltration, and proinflammatory factor expression. Furthermore, ATRQβ-001 vaccination suppressed renal Ang II-AT1R activation and abrogated the downregulation of angiotensin-converting enzyme 2-Ang (1-7), similar to olmesartan treatment, while no obvious feedback activation of circulating or local renin-angiotensin system (RAS) was only observed in vaccine group. In rat mesangial cells, the anti-ATR-001 antibody inhibited high glucose-induced transforming growth factor-β1 (TGF)-β1/Smad3 signal pathway. Additionally, no significant immune-mediated damage was detected in vaccinated animals. In conclusion, the ATRQβ-001 vaccine ameliorated streptozotocin-induced diabetic renal injury via modulating two RAS axes and inhibiting TGF-β1/Smad3 signal pathway, providing a novel, safe, and promising method to treat diabetic nephropathy.

Key Messages: Overactivation of RAS plays a crucial role in the development of the DN. Our aim was to verify the effectiveness of ATRQβ-001 vaccine in STZ-induced DN. The ATRQβ-001 modulated two RAS axes and inhibited TGF-β1/Smad3 signal pathway. The vaccine therapy may provide a novel, safe, and promising method to treat DN.
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http://dx.doi.org/10.1007/s00109-015-1343-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762923PMC
February 2016

Diagnostic Value of MicroRNAs for Urologic Cancers: A Systematic Review and Meta-Analysis.

Medicine (Baltimore) 2015 Sep;94(37):e1272

From Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (HO, LZ, GS); and Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China (YZ).

MicroRNAs (miRNAs), particularly those extracted from the blood or tissues, have become the focus of urologic cancers research. However, the literature reviews on the accuracy of miRNA detection in urologic cancers have been inconsistent, leading us to perform this meta-analysis. Eligible studies were searched in PubMed and other databases. To calculate the pooled detection accuracy estimates, we used a bivariate random-effects meta-analysis model. According to the exclusion and inclusion criteria, 41 studies were included. Overall, the results showed sensitivity of 0.77 (95% CI: 0.74-0.80) and specificity of 0.76 (95% CI: 0.72-0.79), with an area under the SROC curve (AUC) of 0.83 (95% CI: 0.80-0.86). In addition, further subgroup analyses were also conducted. Firstly, the multiple miRNAs subgroup has significantly better diagnostic specificity than single miRNA subgroup among all these cancer types, while only bladder cancer (BC) and prostate cancer (PC) group with significantly greater diagnostic sensitivity with their multiple miRNA detection. Secondly, none of these cancer types showed significant differences on diagnostic sensitivity and specificity in their specimen and sample size subgroups. Thirdly, the diagnostic sensitivity between Asian (0.791, 95% CI: 0.748-0.827) and Caucasian (0.713, 95% CI: 0.666-0.756) in BC type was shown significant different with the P-value of 0.011. The results of our study suggested that miRNAs, particularly the multiple miRNAs, may play an important role in diagnosis and monitoring of the urologic cancers as superior biomarkers.
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http://dx.doi.org/10.1097/MD.0000000000001272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635789PMC
September 2015

A method for establishing the high-altitude cerebral edema (HACE) model by acute hypobaric hypoxia in adult mice.

J Neurosci Methods 2015 Apr 19;245:178-81. Epub 2015 Feb 19.

Department of Brain Protection and Plasticity, Institute of Basic Medical Sciences, Beijing 100850, China; Co-innovation Center of Neuro-regeneration, Nantong University, Nantong, JS 226001, China; Beijing Institute for Brain Disorders, 10 Xitoutiao, You Anmen, Fengtai District, Beijing 100069, P.R. China. Electronic address:

Background: Exposure to acute hypobaric hypoxia (AHH) during ascent to high altitudes (>3500 m) is one of the main causes of acute mountain sickness (AMS) and high-altitude cerebral edema (HACE). Therefore, the aim of this study was to develop a model of HACE.

New Methods: We developed a model of HACE in mice using a decompression chamber with rapid ascent speed.

Results: Healthy male C57BL/6 mice were randomly divided into the control group and the AHH group. The AHH group was housed in a decompression chamber (at a velocity of 50 m/s within 5 min to 6000 m). Compared with the controls, brain water content was increased in the early stage (within 24 h) in the AHH group. After 72 h of exposure to AHH, there was a higher BBB permeability observed. In addition, the brain structure showed significant widening of the pericellular spaces and a dilatation of the cortical blood vessels after exposure to AHH, and some of the neurons appeared shrunken with darkly stained pyknotic nuclei, resulting in neuronal structural damage. Further, exposure to AHH also decreased cognitive function in the mice.

Comparison With Existing Methods: At present, there are no simple and rapid mouse models to study this syndrome in terms of its genetic basis, gene polymorphisms and susceptibility.

Conclusion: Our findings show that AHH can increase BBB permeability and lead to cerebral edema in mice; thus, we provide an effective and stable model of HACE in mice.
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http://dx.doi.org/10.1016/j.jneumeth.2015.02.004DOI Listing
April 2015

Inhibiting the Th17/IL-17A-related inflammatory responses with digoxin confers protection against experimental abdominal aortic aneurysm.

Arterioscler Thromb Vasc Biol 2014 Nov 18;34(11):2429-38. Epub 2014 Sep 18.

From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China.

Objective: T helper 17 cells and interleukin-17A have been implicated in the progression of abdominal aortic aneurysm (AAA). Retinoic acid-related orphan receptor gamma thymus, the master transcription factor of T helper 17 cell differentiation, is selectively antagonized by digoxin. However, the effect of antagonizing retinoic acid-related orphan receptor gamma thymus on AAA has not been investigated.

Approach And Results: We used human aortic sample analysis and 2 different experimental AAA models: (a) Angiotensin II (Ang II)-induced ApoE(-/-) male mice (Ang II/APOE model) and (b) porcine pancreatic elastase perfusion C57BL/6 mice (porcine pancreatic elastase/C57 model). In the Ang II/APOE model, all mice (n=80) were divided into 4 groups: sham group (saline+0.5% dimethyl sulfoxide treatment), control group (Ang II+0.5% dimethyl sulfoxide treatment), low-dose group (Ang II+low-dose digoxin, 20 μg/d per mouse), and high-dose group (Ang II+high-dose digoxin, 40 μg/d per mouse). All treatments began on day 0 after surgery. Efficacy was determined via aortic diameter and systolic blood pressure measurements, histopathology and protein expression, and flow cytometry analysis when euthenized. Human aortic tissue analysis showed that both interleukin-17A and retinoic acid-related orphan receptor gamma thymus increased in AAA tissues. The low-dose and high-dose groups had AAA incidences of 60% and 35%, respectively, compared with 70% in the control group. The T helper 17- and interleukin-17A-related inflammatory responses were dose-dependently attenuated by digoxin treatment. Digoxin was also highly effective in the porcine pancreatic elastase/C57 model.

Conclusions: Digoxin attenuates experimental AAA progression in a model-independent manner. Antagonizing retinoic acid-related orphan receptor gamma thymus activity by digoxin may become a novel strategy for nonsurgical AAA treatment.
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http://dx.doi.org/10.1161/ATVBAHA.114.304435DOI Listing
November 2014

Angiotensin II receptor type 1 autoantibodies promote endothelial microparticles formation through activating p38 MAPK pathway.

J Hypertens 2014 Apr;32(4):762-70

aLaboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology bDepartment of Cardiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China *These authors contributed to the work equally.

Background: Endothelial microparticles (EMPs) are small vesicular structures that serve as a marker of endothelial function. Angiotensin II receptor type 1 autoantibody (AT1-AA) can cause endothelial dysfunction. However, whether AT1-AA promotes EMPs formation and the mechanism remains obscure.

Methods: The titres of sera AT1-AA of 126 hypertensive patients and 30 normotensive individuals were evaluated by ELISA. EMPs in the sera and the supernatants of human umbilical vein endothelial cells (HUVECs) were measured by flow cytometry. The phosphorylation levels of mitogen-activated protein kinase (MAPK) pathways in HUVECs treated by AT1-AA were assessed and their correlation with microparticle formation was also analysed. Furthermore, the production of intracellular reactive oxygen species (ROS) and nitric oxide in HUVECs was examined after incubation with 'injured' endothelial microparticle (iEMPs) (EMPs derived from AT1-AA treated HUVECs).

Results: The positive rate of AT1-AA in 126 hypertensive patients was 21.4% (27/126), and higher than that in normotensive individuals [3.3% (1/30), P < 0.01]. Circulating EMP (CD31+/CD42b-) levels were corresponding to the AT1-AA titres in hypertensive group (r(2) = 0.3661, P < 0.01). AT1-AA promoted EMPs generation from HUVECs in a time and dose-dependent manner than the vehicle or nonspecific IgG. Meanwhile, AT1-AA significantly elevated phosphorylation level of P38 and ERK in HUVECs. Lorsartan and P38 inhibitor could suppress the AT1-AA's stimulation effect on EMPs generation. Moreover, the iEMP greatly increased ROS production and reduced nitric oxide synthesis in HUVECs.

Conclusion: Our findings showed that circulating EMPs levels positively correlate to the serum AT1-AA titres in essential hypertension patients. The AT1-AA could promote EMPs generation in HUVECs through activation of P38 MAPK signalling pathway, and this effect could be effectively inhibited by losartan or p38 inhibitor. Angiotensin receptor blockers (ARBs) may be more suitable for AT1-AA(+) hypertensive patients on account of suppressing the AT1-AA's stimulation effect on EMPs generation.
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http://dx.doi.org/10.1097/HJH.0000000000000083DOI Listing
April 2014

Therapeutic vaccines against human and rat renin in spontaneously hypertensive rats.

PLoS One 2013 25;8(6):e66420. Epub 2013 Jun 25.

Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.

Vaccination provides a promising approach for treatment of hypertension and improvement in compliance. As the initiation factor of renin-angiotensin system, renin plays a critical role in hypertension. In this study, we selected six peptides (rR32, rR72, rR215, hR32, hR72, and hR215) belonging to potential epitopes of rat and human renin. The main criteria were as follows: (1) include one of renin catalytic sites or the flap sequence; (2) low/no-similarity when matched with the host proteome; (3) ideal antigenicity and hydrophilicity. The peptides were coupled to keyhole limpet hemocyanin and injected into SpragueDawley (SD) rats, spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats. The antisera titers and the binding capacity with renin were detected. The effects of the anti-peptides antibodies on plasma renin activity (PRA) and blood pressure were also determined. All peptides elicited strong antibody responses. The antisera titers ranged from 1:32,000 to 1:80,000 in SD rats on day 63. All antisera could bind to renin in vitro. Compared with the control antibody, the antibodies against the rR32, hR32, rR72 and hR72 peptides inhibited PRA level by up to about 50%. Complete cross-reactivity of the anti-rR32 antibody and the anti-hR32 antibody was confirmed. The epitopes rR32 and hR32 vaccines significantly decreased systolic blood pressure (SBP) of SHRs up to 15mmHg (175±2 vesus 190±3 mmHg, P = 0.035; 180±2 vesus 195±3 mmHg, P = 0.039), while no obvious effect on SD rats. Additionally, no significant immune-mediated damage was detected in the vaccinated animals. In conclusion, the antigenic peptide hR32 vaccine mimicking the (32)Asp catalytic site of human renin may constitute a novel tool for the development of a renin vaccine.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066420PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692469PMC
February 2014

Effectiveness and safety of a therapeutic vaccine against angiotensin II receptor type 1 in hypertensive animals.

Hypertension 2013 Feb 26;61(2):408-16. Epub 2012 Nov 26.

Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China.

Primary hypertension is a chronic disease with high morbidity, and the rate of controlled blood pressure is far from satisfactory, worldwide. Vaccination provides a promising approach for treatment of hypertension and improvement in compliance. Here, the ATRQβ-001 vaccine, a peptide (ATR-001) derived from human angiotensin II (Ang II) receptor type 1 conjugated with Qβ bacteriophage virus-like particles, was developed and evaluated in animal models of hypertension. The ATRQβ-001 vaccine significantly decreased the blood pressure of Ang II-induced hypertensive mice up to 35 mm Hg (143 ± 4 versus 178 ± 6 mm Hg; P=0.005) and that of spontaneously hypertensive rats up to 19 mm Hg (173 ± 2 versus 192 ± 3 mm Hg; P=0.003) and prevented remodeling of vulnerable hypertensive target organs. No obvious feedback activation of circulating or local renin-angiotensin system was observed. Additionally, no significant immune-mediated damage was detected in vaccinated hypertensive and nonhypertensive animals. The half-life of the anti-ATR-001 antibody was 14.4 days, surpassing that of existing chemical drugs. In vitro, the anti-ATR-001 antibody specifically bound to Ang II receptor type 1 and inhibited Ca(2+)-dependent signal transduction events, including protein kinase C-α translocation, extracellular signal-regulated kinase 1/2 phosphorylation (72% decrease; P=0.013), and elevation of intracellular Ca(2+) (68% decrease; P=0.017) induced by Ang II, but without inhibiting Ang II binding to the receptor. In conclusion, the ATRQβ-001 vaccine decreased the blood pressure of Ang II-induced hypertensive mice and spontaneously hypertensive rats effectively through diminishing the pressure response and inhibiting signal transduction initiated by Ang II. Thus, the ATRQβ-001 vaccine may provide a novel and promising method for the treatment of primary hypertension.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.201020DOI Listing
February 2013
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