Publications by authors named "Yuhua Liao"

103 Publications

Genetic association analysis between IL9 and coronary artery disease in a Chinese Han population.

Cytokine 2021 Nov 20;150:155761. Epub 2021 Nov 20.

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

Interleukin-9 (IL-9) plays important role in coronary artery disease (CAD). However, the exact relationship between them is not explored yet. Here, four tag SNPs covering IL9 (rs31563, rs2069868, rs2069870 and rs31564) were selected to conduct case-control association analyses in a total of 3704 individuals from Chinese Han population (1863 CAD vs 1841 control). Results showed that: first, rs2069868 was associated with CAD combined with hypertension (P = 0.027); second, IL9 haplotype (CGAT) was associated with CAD (P = 0.035), and the combination genotype of "rs31563_CC/rs31564_TT" would remarkably decrease the risk of CAD (P = 0.001); third, significant associations were found between rs2069870 and decreased LDL-c levels and decreased total cholesterol levels, and between rs31563 and increased HDL-c levels (P < 0.05). Therefore, we conclude that IL9 might play a causal role in CAD by interacted with CAD traditional risk factors, which might confer a new way to improve the prevention and treatment of CAD.
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http://dx.doi.org/10.1016/j.cyto.2021.155761DOI Listing
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

Comparing mortality from covid-19 to mortality due to overdose: A micromort analysis.

J Affect Disord 2022 01 24;296:514-521. Epub 2021 Sep 24.

Mood Disorders Psychopharmacology Unit, Toronto Western Hospital, University Health Network, Toronto, ON, Canada, M5T 2S8; Institute of Medical Science, University of Toronto, Toronto, ON, Canada, M5S 1A8; Department of Psychiatry, University of Toronto, Toronto, ON, Canada, M5S 1A8; Department of Pharmacology, University of Toronto, Toronto, ON, Canada, M5S 1A8. Electronic address:

Objective: To compare the mortality risk due to covid-19 with death due to overdose in British Columbia, Canada. The opioid epidemic was declared a public health emergency in 2016.

Methods: Mortality risk was calculated in micromorts with covid-19 data for January-October 2020, derived from the BC center for Disease Control, and illicit drug toxicity deaths for January 2010-September 2020, derived from the BC Coroners Service. Age-stratified covid-19 incidence and deaths per 100,000 population and age-stratified illicit drug toxicity death rates per 100,000 population were calculated. A micromort is a unit of risk equivalent to a one-in-a-million chance of death.

Results: During the covid-19 pandemic, illicit drug toxicity deaths reached 1.0 micromorts per day, representing an increase of 0.5 micromorts per day relative to 2019 rates. In comparison, covid-19 mortality risk was 0.05 micromorts per day among individuals from the general population living in British Columbia and 21.1 micromorts per day among those infected with covid-19. Covid-related mortality risk was significantly lower among individuals aged <60 years, relative to older adults, whereas drug toxicity-related mortality was highest for individuals aged 30-59 years.

Conclusions: The mortality associated with covid-19 is apparent and distributed unevenly across subpopulations. The mortality due to overdose has increased during covid-19 and exceeds mortality due to covid-19. Our results instantiate the triple threat caused by covid-19 (i.e., public health crisis, economic crisis and mental health crisis) and quantitatively highlight the externality of increased mortality due to deaths of despair in response to public health efforts to reduce covid-related mortality.
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http://dx.doi.org/10.1016/j.jad.2021.09.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461265PMC
January 2022

Comparing mortality from covid-19 to mortality due to overdose: A micromort analysis.

J Affect Disord 2022 01 24;296:514-521. Epub 2021 Sep 24.

Mood Disorders Psychopharmacology Unit, Toronto Western Hospital, University Health Network, Toronto, ON, Canada, M5T 2S8; Institute of Medical Science, University of Toronto, Toronto, ON, Canada, M5S 1A8; Department of Psychiatry, University of Toronto, Toronto, ON, Canada, M5S 1A8; Department of Pharmacology, University of Toronto, Toronto, ON, Canada, M5S 1A8. Electronic address:

Objective: To compare the mortality risk due to covid-19 with death due to overdose in British Columbia, Canada. The opioid epidemic was declared a public health emergency in 2016.

Methods: Mortality risk was calculated in micromorts with covid-19 data for January-October 2020, derived from the BC center for Disease Control, and illicit drug toxicity deaths for January 2010-September 2020, derived from the BC Coroners Service. Age-stratified covid-19 incidence and deaths per 100,000 population and age-stratified illicit drug toxicity death rates per 100,000 population were calculated. A micromort is a unit of risk equivalent to a one-in-a-million chance of death.

Results: During the covid-19 pandemic, illicit drug toxicity deaths reached 1.0 micromorts per day, representing an increase of 0.5 micromorts per day relative to 2019 rates. In comparison, covid-19 mortality risk was 0.05 micromorts per day among individuals from the general population living in British Columbia and 21.1 micromorts per day among those infected with covid-19. Covid-related mortality risk was significantly lower among individuals aged <60 years, relative to older adults, whereas drug toxicity-related mortality was highest for individuals aged 30-59 years.

Conclusions: The mortality associated with covid-19 is apparent and distributed unevenly across subpopulations. The mortality due to overdose has increased during covid-19 and exceeds mortality due to covid-19. Our results instantiate the triple threat caused by covid-19 (i.e., public health crisis, economic crisis and mental health crisis) and quantitatively highlight the externality of increased mortality due to deaths of despair in response to public health efforts to reduce covid-related mortality.
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http://dx.doi.org/10.1016/j.jad.2021.09.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461265PMC
January 2022

Correction: Efficacy of omega-3 PUFAs in depression: A meta-analysis.

Transl Psychiatry 2021 Sep 7;11(1):465. Epub 2021 Sep 7.

Mood Disorders Psychopharmacology Unit, University Health Network; Department of Psychiatry, University of Toronto; Institute of Medical Science, University of Toronto; Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1038/s41398-021-01582-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423804PMC
September 2021

Long-Term Effect of a Vaccine Targeting Endothelin-1 Receptor Type A in Pulmonary Arterial Hypertension.

Front Cardiovasc Med 2021 17;8:683436. Epub 2021 Jun 17.

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

Previously, we invented a therapeutic vaccine targeting the endothelin-A receptor (termed ETRQβ-002). ETRQβ-002 successfully prevented the remodeling of pulmonary arterioles (PAs) and right ventricle (RV) without significant immune-mediated damage in experimental pulmonary arterial hypertension (PAH) mice models. Here, we aim to further evaluate the long-term effects of ETRQβ-002. PAH mice model was induced by a combination of subcutaneous injection with Sugen5416 and chronic hypoxic conditions (10% O). PAH mice were immunized with ETRQβ-002 at different time points, and the experiment lasted for 21 weeks. Hemodynamic, histological, and biochemical analyses were conducted to evaluate the long-term effects of ETRQβ-002. We demonstrated that the titer of the specific antibody against ETR-002 could be maintained chronically after periodic booster immunization in PAH mice. Long-term reduction of right ventricular systolic pressure and amelioration of PA remodeling by ETRQβ-002 were confirmed. Moreover, we found that ETRQβ-002 also exerted antiproliferation, anti-inflammation, and antifibrosis effects in PA remodeling. Besides, ETRQβ-002 durably limited pathological RV hypertrophy and fibrosis. Finally, no immune-mediated damage was observed in hepatic or renal function or by pathology in liver and kidney during the long-term administration of ETRQβ-002. Our findings indicate that ETRQβ-002 provides long-term therapeutic effects in Sugen/hypoxia-induced PAH animals and offers a promising clinical prospect for PAH treatment.
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http://dx.doi.org/10.3389/fcvm.2021.683436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247646PMC
June 2021

The Regulation of -Induced Inflammatory Responses in Bovine Mammary Epithelial Cells.

Front Vet Sci 2021 31;8:683886. Epub 2021 May 31.

College of Landscape Architecture and Life Science/Institute of Special Plants, Chongqing University of Arts and Sciences, Yongchuan, China.

Mastitis, an inflammatory disease, causes severe economic loss in the dairy industry, which is mainly infected by bacteria. (), the major pathogenic microorganism, derived from lipoteichoic acid (LTA) has been identified to activate inflammatory responses, but the cellular or intercellular regulatory mechanism is unclear. This study mainly focused on the effects of LTA in bovine mammary epithelial cells (Mac-T) and elaborated the regulation of microRNAs (miRNAs). The results showed that LTA enhanced the messenger RNA (mRNA) expression and production of tumor necrosis factor α (TNF-α) and interleukin (IL)-6. Furthermore, LTA could activate Toll-like receptor (TLR)2/MyD88-mediated phosphoinositide 3-kinase (PI3K)/AKT pathway, and TLR2 plays a pivotal role in LTA-induced inflammatory responses. The results of qRT-PCR showed that miRNA levels increased and reached the highest at 3 h and then gradually decreased over time in Mac-T cells. In exosomes, the levels of 11 and three miRNAs were upregulated and downregulated at 24 h, respectively. In addition, miR-23a showed the highest increase in Mac-T cells treated with LTA and targeted PI3K to regulate inflammatory responses. Furthermore, Mac-T cell-derived exosomes were identified to play a cell-cell communication by promoting M1 polarization of bovine macrophages. In summary, our study demonstrated that LTA could activate inflammatory responses via TLR2/MyD88/PI3K/AKT signaling pathway, and miR-23a inhibited it by targeting PI3K. Furthermore, we found that Mac-T cell-derived exosomes might be associated with inflammatory responses by promoting M1 polarization of bovine macrophages.
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http://dx.doi.org/10.3389/fvets.2021.683886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200483PMC
May 2021

Government response moderates the mental health impact of COVID-19: A systematic review and meta-analysis of depression outcomes across countries.

J Affect Disord 2021 07 27;290:364-377. Epub 2021 May 27.

Mood Disorders Psychopharmacology Unit, Toronto Western Hospital, University Health Network, Toronto, ON, Canada M5T 2S8; Institute of Medical Science, University of Toronto, Toronto, ON, Canada M5S 1A8; Department of Psychiatry, University of Toronto, Toronto, ON, Canada M5S 1A8; Department of Pharmacology, University of Toronto, Toronto, ON, Canada M5S 1A8.

Background: The COVID-19 pandemic represents a public health, economic and mental health crisis. We hypothesized that timely government implementation of stringent measures to reduce viral transmission would benefit mental health, as evidenced by reduced rates of depressive symptoms (i.e., Patient Health Questionnaire [PHQ]-9≥10, PHQ-2≥3).

Methods: The systematic review herein (PROSPERO CRD42020200647) evaluated to what extent differences in government-imposed stringency and timeliness of response to COVID-19 moderate the prevalence of depressive symptoms across 33 countries (k=114, N=640,037). We included data from six lower-middle-income countries, nine upper-middle-income countries, and 18 higher-income countries. Government-imposed stringency and timeliness in response were operationalized using the Oxford COVID-19 Government Response ("Stringency") Index.

Results: The overall proportion of study participants with clinically significant depressive symptoms was 21.39% (95% CI 19.37-23.47). The prevalence of clinically significant depressive symptoms was significantly lower in countries wherein governments implemented stringent policies promptly. The moderating effect of government response remained significant after including the national frequency of COVID cases at the time of study commencement, Healthcare Access and Quality index, and the inclusion of COVID patients in the study.

Limitations: Factors that may have confounded our results include, for example, differences in lockdown duration, lack of study participant and outcome assessor blinding, and retrospective assessment of depressive symptom severity.

Conclusions: Governments that enacted stringent measures to contain the spread of COVID-19 benefited not only the physical, but also the mental health of their population.
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http://dx.doi.org/10.1016/j.jad.2021.04.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159271PMC
July 2021

Association of FKBP5 gene variants with depression susceptibility: A comprehensive meta-analysis.

Asia Pac Psychiatry 2021 Jun 20;13(2):e12464. Epub 2021 Mar 20.

Department of Medical statistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, China.

Background: This comprehensive meta-analysis aimed to combine data from different studies and to estimate the association between FKBP5 polymorphisms and depression.

Methods: We performed a meta-analysis of observational studies. An electronic search was conducted on four databases for articles published before July 1, 2020.

Results: A total of 5125 patients with depression and 8399 controls from 16 independent studies were included in the analysis. The results showed that FKBP5 rs1360780 was associated with the risk of depression in the codominant model (CT vs. CC; OR = 1.10, 95% CI = 1.00-1.20, P = .04); rs4713916 polymorphism was associated with depression in the codominant model (AG vs. GG; OR = 1.19, 95% CI = 1.05-1.34, P = .008) and recessive model (AA vs. AG + GG; OR = 0.74, 95% CI = 0.56-0.99, P = .04); a significant association between rs3800373 and depression was found in the codominant genetic model (AC vs. AA; OR = 1.18, 95% CI = 1.05-1.34, P = .007) and dominant model (CC + AC vs. AA; OR = 1.15, 95% CI = 1.03-1.30, P = .02); there was no significant association of FKBP5 rs9470080 or rs9296158 with depression in any genetic model (P > .05). No publication bias was observed in our analysis. Moreover, sensitivity analyses demonstrated the Zobel's study significantly affected the heterogeneity for rs4713916 and rs3800373.

Conclusions: FKBP5 rs1360780 was associated with an increased risk of depression in the codominant model. We also found that rs4713916 and rs3800373 were involved in depression, rs4713916 was positively associated with depression in the codominant model and recessive model, and rs3800373 was related to an elevated risk of depression in the codominant model and dominant model.
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http://dx.doi.org/10.1111/appy.12464DOI Listing
June 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

Mental health conditions among the general population, healthcare workers and quarantined population during the coronavirus disease 2019 (COVID-19) pandemic.

Psychol Health Med 2020 Dec 30:1-13. Epub 2020 Dec 30.

Psychiatry and Pharmacology, University of Toronto, Toronto, Canada.

This study sought to assess the differences in mental health conditions among the general population, quarantined population and healthcare workers during the COVID-19 outbreak in China. An online rapid assessment captured depressive and anxiety symptoms, and sleep quality data. A total of 2689 participants (n=374 general population, n=403 healthcare workers, n=1912 quarantined population) were included in the final statistical analysis. The proportion of individuals with mild and/or serious depression and anxiety were higher in the general population when compared to the quarantined population and healthcare workers (58.6% vs. 25.1% 48.6%, <0.001; 41.2% 18.5%  35.7%, <0.001). The prevalence of sleep disturbance was higher among healthcare workers than the general population and quarantined population (29.8%  24.1%  22.7%, =0.013). Logistic regression analysis showed that, perceived effect on daily life was associated with depression, anxiety and sleep disturbance in the general population, quarantined population and the healthcare workers. The general population had a greater risk of developing psychological problems. The healthcare workers suffered the poorest sleep quality. Future research must further explorethe targeted measures for the general population and healthcare workers while combating COVID-19.
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http://dx.doi.org/10.1080/13548506.2020.1867320DOI Listing
December 2020

Targeting IL-1β in the Treatment of Atherosclerosis.

Front Immunol 2020 10;11:589654. Epub 2020 Dec 10.

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

The role of inflammation in atherosclerosis has been recognized several decades ago and existing treatments provide benefits in part through non-specific anti-inflammatory actions. Compared with other cytokines, interleukin-1β (IL-1β) is associated with acute and chronic inflammation. Anti-inflammatory therapy with canakinumab targeting the IL-1β innate immunity pathway could significantly reduce the rate of recurrent cardiovascular events than placebo. The results of CANTOS suggested an important role of IL-1β in atherosclerosis. However, there are numerous mechanisms that are to be clarified. We herein discussed the important immunomodulatory effect IL-1β exerts on atherosclerosis and the potential mechanisms underlying it. We also reviewed bench-to-bedside clinical translation of IL-1β neutralizing strategies associated with the use of IL-1β blockade in patients with atherosclerosis.
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http://dx.doi.org/10.3389/fimmu.2020.589654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758244PMC
July 2021

Immunotherapy against angiotensin II receptor ameliorated insulin resistance in a leptin receptor-dependent manner.

FASEB J 2021 01 6;35(1):e21157. Epub 2020 Nov 6.

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

The angiotensin II type 1 receptor (AT1R) signaling pathway is reported to modulate glucose metabolism. Targeting AT1R, our group invented ATRQβ-001 vaccine, a novel immunotherapeutic strategy to block the activation of AT1R. Here, we evaluated the therapeutic efficacy of ATRQβ-001 vaccine in insulin resistance, and investigated the mechanism. Our results showed that ATRQβ-001 vaccine and specific monoclonal antibody against epitope ATR-001 (McAb-ATR) decreased fasting serum insulin concentration and improved glucose and insulin tolerance in ob/ob mice. These beneficial effects were verified in high-fat diet-induced obese mice. McAb-ATR activated insulin signaling in skeletal muscle and insulin-resistant C2C12 myotubes without affecting liver or white adipose tissue of ob/ob mice. Mechanistically, the favorable impact of McAb-ATR on insulin resistance was abolished in db/db mice and in C2C12 myotubes with leptin receptor knockdown. AT1R knockdown also eradicated the effects of McAb-ATR in C2C12 myotubes. Furthermore, McAb-ATR treatment was able to activate the leptin receptor-mediated JAK2/STAT3 signaling in skeletal muscle of ob/ob mice and C2C12 myotubes. Additionally, angiotensin II downregulated the leptin signaling in skeletal muscle of ob/ob and diet-induced obese mice. We demonstrated that ATRQβ-001 vaccine and McAb-ATR improved whole-body insulin resistance and regulated glucose metabolism in skeletal muscle in a leptin receptor-dependent manner. Our data suggest that immunotherapy targeting AT1R is a novel strategy for treating insulin resistance.
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http://dx.doi.org/10.1096/fj.202000300RDOI Listing
January 2021

A Unique Population of Regulatory T Cells in Heart Potentiates Cardiac Protection From Myocardial Infarction.

Circulation 2020 11 28;142(20):1956-1973. Epub 2020 Sep 28.

Department of Cardiology, Union Hospital, and Key Laboratory of Biological Targeted Therapy of the Ministry of Education (N.X., Y. Lu, M.G., N.L., M.L., J.J., Z.Z., J.L., D.L., T.T., B.L., S.N., M.Z., M.L., Y. Liao, X.C.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Regulatory T cells (Tregs), traditionally recognized as potent suppressors of immune response, are increasingly attracting attention because of a second major function: residing in parenchymal tissues and maintaining local homeostasis. However, the existence, unique phenotype, and function of so-called tissue Tregs in the heart remain unclear.

Methods: In mouse models of myocardial infarction (MI), myocardial ischemia/reperfusion injury, or cardiac cryoinjury, the dynamic accumulation of Tregs in the injured myocardium was monitored. The bulk RNA sequencing was performed to analyze the transcriptomic characteristics of Tregs from the injured myocardium after MI or ischemia/reperfusion injury. Photoconversion, parabiosis, single-cell T-cell receptor sequencing, and adoptive transfer were applied to determine the source of heart Tregs. The involvement of the interleukin-33/suppression of tumorigenicity 2 axis and Sparc (secreted acidic cysteine-rich glycoprotein), a molecule upregulated in heart Tregs, was further evaluated in functional assays.

Results: We showed that Tregs were highly enriched in the myocardium of MI, ischemia/reperfusion injury, and cryoinjury mice. Transcriptomic data revealed that Tregs isolated from the injured hearts had plenty of differentially expressed transcripts in comparison with their lymphoid counterparts, including heart-draining lymphoid nodes, with a phenotype of promoting infarct repair, indicating a unique characteristic. The heart Tregs were accumulated mainly because of recruitment from the circulating Treg pool, whereas local proliferation also contributed to their expansion. Moreover, a remarkable case of repeatedly detected T-cell receptor of heart Tregs, more than that of spleen Tregs, suggests a model of clonal expansion. Besides, HeliosNrp-1 phenotype proved the mainly thymic origin of heart Tregs, with a small contribution of phenotypic conversion of conventional CD4 T cells, proved by the analysis of T-cell receptor repertoires and conventional CD4 T cells adoptive transfer experiments. The interleukin-33/suppression of tumorigenicity 2 axis was essential for sustaining heart Treg populations. Last, we demonstrated that Sparc, which was highly expressed by heart Tregs, acted as a critical factor to protect the heart against MI by increasing collagen content and boosting maturation in the infarct zone.

Conclusions: We identified and characterized a phenotypically and functionally unique population of heart Tregs that may lay the foundation to harness Tregs for cardioprotection in MI and other cardiac diseases.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046789DOI Listing
November 2020

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

Prognostic and Immunological Role of FUN14 Domain Containing 1 in Pan-Cancer: Friend or Foe?

Front Oncol 2019 10;9:1502. Epub 2020 Jan 10.

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

FUN14 domain containing 1 (FUNDC1) plays a pivotal role in mitochondrial autophagy (mitophagy), which is closely associated with human immunity. However, the role of FUNDC1 in cancers remains unclear. This study aimed to visualize the prognostic landscape of FUNDC1 in pan-cancer and investigate the relationship between FUNDC1 expression and immune infiltration. In this study, we explored the expression pattern and prognostic value of FUNDC1 in pan-cancer across multiple databases, including ONCOMINE, PrognoScan, GEPIA, and Kaplan-Meier Plotter. Then, using the GEPIA and TIMER databases, we investigated the correlations between FUNDC1 expression and immune infiltration in cancers, especially liver hepatocellular carcinoma (LIHC), and lung squamous cell carcinoma (LUSC). In general, compared with that in normal tissue, tumor tissue had a higher expression level of FUNDC1. Although FUNDC1 showed a protective effect on pan-cancer, a high expression level of FUNDC1 was detrimental to the survival of LIHC patients. Although different from what was found for LUSC, for LIHC, there were significant positive correlations between FUNDC1 expression and immune infiltrates, including B cells, CD8+ T cells, CD4+ T cells, neutrophils, macrophages, and dendritic cells. Furthermore, markers of infiltrating immune cells, such as tumor-associated-macrophages (TAMs), exhibited different FUNDC1-related immune infiltration patterns. The mitophagy regulator FUNDC1 can serve as a prognostic biomarker in pan-cancer and is correlated with immune infiltrates.
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http://dx.doi.org/10.3389/fonc.2019.01502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966411PMC
January 2020

Problematic Internet Use, Non-Medical Use of Prescription Drugs, and Depressive Symptoms among Adolescents: A Large-Scale Study in China.

Int J Environ Res Public Health 2020 01 26;17(3). Epub 2020 Jan 26.

Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.

This large-scale study aimed to test, among Chinese adolescents, the association between problematic Internet use (PIU), non-medical use of prescription drugs (NMUPD), and depressive symptoms, as well as the mediating effects of NMUPD on the associations above. This study used the data from the 2017 National School-based Chinese Adolescents Health Survey, and 24,345 students' questionnaires qualified for the analyses. Generalized linear mixed models and path models were performed. In the models without mediation, PIU was associated with depressive symptoms (unstandardized β estimate = 0.26, 95% CI = 0.25-0.27); frequent use of opioid or sedative was also related to depressive symptoms (unstandardized β estimate for opioid = 2.77, 95% CI = 1.90-3.63; unstandardized β estimate for sedative = 4.45, 95% CI = 3.02-5.88). Additionally, the results of the path models indicated that opioid misuse partially mediated the association between PIU and depressive symptoms. PIU and opioid/sedative misuse were related to the increased risk of depressive symptoms, respectively. The association above might be complicated, and PIU may elevate the risk of opioid or sedative misuse and depressive symptoms, which in turn could worsen the situation of PIU and vice versa. Multidisciplinary health intervention programs to prevent adolescents involving in PIU, as well as NMPUD, are recommended to be provided.
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http://dx.doi.org/10.3390/ijerph17030774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037924PMC
January 2020

Interleukin 35 ameliorates myocardial ischemia-reperfusion injury by activating the gp130-STAT3 axis.

FASEB J 2020 02 9;34(2):3224-3238. Epub 2020 Jan 9.

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

Myocardial ischemia-reperfusion injury (MIRI) is common clinical complication, which represents significant challenge in the treatment of acute myocardial infarction (AMI) diseases. Interleukin 35 (IL-35) exhibits anti-inflammatory properties via the engagement of the gp130, IL-12Rβ2 and IL-27Rα receptors. However, whether IL-35 plays a beneficial role in the treatment of MIRI and potential underling mechanism are unclear. We showed that IL-35 conferred protection from MIRI as demonstrated by reduced infarct size and cardiac troponin T, improved cardiac function and decreased cardiomyocyte apoptosis in a mouse model. Despite activation of both STAT3 and STAT5 phosphorylation in the heart by IL-35, signal transducers and activators of transcription 3 (STAT3) was essential for mediating the IL-35-mediated protective effect on MIRI using cardiomyocyte-specific STAT3 deficient mice. Furthermore, gp130 was required for the STAT3 activation and cardio-protection induced by IL-35. Interestingly, IL-35 induced gp130 homodimer and gp130/IL-12Rβ2 heterodimers in cardiomyocyte. Our results indicate that IL-35 can execute a protective role against MIRI through a novel signaling pathway, IL-35-gp130-STAT3 pathway, in cardiomyocytes, which may be beneficial for the development of novel and effective therapeutic approaches to treat the MIRI.
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http://dx.doi.org/10.1096/fj.201901718RRDOI Listing
February 2020

The efficacy of mind-body (Baduanjin) exercise on self-reported sleep quality and quality of life in elderly subjects with sleep disturbances: a randomized controlled trial.

Sleep Breath 2020 Jun 2;24(2):695-701. Epub 2020 Jan 2.

Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, Canada.

Objectives: To examine the efficacy of a 24-week Baduanjin exercise program on self-reported sleep quality and quality of life in community-dwelling elderly subjects with sleep disturbances.

Methods: Community-dwelling elderly men and women meeting criteria for sleep disturbances (i.e., Pittsburgh Sleep Quality of Index (PSQI) score ≥ 5) were recruited and randomized to a Baduanjin exercise intervention group or a control group. Participants in the intervention group completed five 45-min exercise sessions per week for 24 weeks, while those in control group were instructed to maintain their usual lifestyle behaviors.

Results: A total of 139 participants were enrolled and randomized. Sixty-two of 67 participants in the intervention group (response rate of 92.5%) and 57 of 72 participants (response rate of 79.6%) in the control group completed intervention and follow-up. The intervention group reported significant improvements in overall sleep quality after 24 weeks compared with those randomized to control (PSQI endpoint-to-baseline change = - 2.6 ± 4.0 vs. - 0.5 ± 4.2, time × group interaction p = 0.007). Intervention group participants had higher response rates at both week 12 (23.9% vs. 9.7%, p = 0.025) and week 24 (40.3% vs. 15.3%, p = 0.001) when compared with the control group. There was a trend that the intervention group had increased quality of life (The Short Form Health Survey [SF-36] endpoint=tobaseline change 6.3 ± 10.9 vs. 2.2 ± 10.9, time × group interaction p = 0.06) when compared with the control group.

Conclusions: Baduanjin exercise is an effective and feasible approach to improve self-reported sleep quality but less likely the quality of life in community-dwelling elderly men and women with sleep disturbances.

Trial Registration: Effect of Baduanjin Exercise on the Elderly's Sleep; http://www.chictr.org.cn/listbycreater.aspx; ChiCTR1800014706, registered 1 January 2018.
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http://dx.doi.org/10.1007/s11325-019-01999-wDOI Listing
June 2020

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

Association between habitual weekday sleep duration and depressive symptoms among Chinese adolescents:The role of mode of birth delivery.

J Affect Disord 2020 03 14;265:583-589. Epub 2019 Nov 14.

Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China; Guangdong Engineering Technology Research Center of Nutrition Translation, Guangzhou, 510080, China. Electronic address:

Background: Depressive symptoms among adolescents are common. This study aimed to assess, among Chinese adolescents, the associations of habitual weekday sleep duration with depressive symptoms and whether these associations varied with the mode of birth delivery.

Methods: Data were from the 2015 School-based Chinese Adolescents Health Survey, and 150,053 students' questionnaires were qualified for analysis. Multi-level logistic regression models were performed.

Results: A weekday sleep duration of ≤5 h/night was associated with depressive symptoms (adjusted odds ratio [aOR]=2.98, 95% CI=2.75-3.24), and adolescents who reported a weekday sleep duration of 5-7 h/night (aOR=1.69, 95% CI=1.60-1.79) and >9 h/night (aOR=1.28, 95% CI=1.11-1.45) were also at a higher risk of depressive symptoms. Stratification analyses showed that in both adolescents delivered by vaginal birth and cesarean section (CS), a weekday sleep duration of ≤5 h/night, 5-7 h/night, and >9 h/night were associated with the increased risk of depressive symptoms in the adjusted models, and the magnitudes of the aORs in adolescents delivered by CS were slightly higher than those in adolescents delivered by vaginal birth.

Limitations: The cross-sectional study design and self-reported sleep duration and depressive symptoms.

Conclusion: This study demonstrates a significant U-shaped association between weekday sleep duration and depressive symptoms among Chinese adolescents. In both adolescents delivered by vaginal birth and CS, those who reported having abnormal sleep duration were at a high risk of depressive symptoms. Based on the findings of this study, we suggest sleep duration and mode of delivery should be a matter of concern for public health authorities.
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http://dx.doi.org/10.1016/j.jad.2019.11.095DOI Listing
March 2020

A bivalent antihypertensive vaccine targeting L-type calcium channels and angiotensin AT receptors.

Br J Pharmacol 2020 01 12;177(2):402-419. Epub 2019 Dec 12.

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

Background And Purpose: Hypertension has been the leading preventable cause of premature death worldwide. The aim of this study was to design a more efficient vaccine against novel targets for the treatment of hypertension.

Experimental Approach: The epitope CE12, derived from the human L-type calcium channel (Ca 1.2), was designed and conjugated with Qβ bacteriophage virus-like particles to test the efficacy in hypertensive animals. Further, the hepatitis B core antigen (HBcAg)-CE12-CQ10 vaccine, a bivalent vaccine based on HBcAg virus-like particles and targeting both human angiotensin AT receptors and Ca 1.2 channels, was developed and evaluated in hypertensive rodents.

Key Results: The Qβ-CE12 vaccine effectively decreased the BP in hypertensive rodents. A monoclonal antibody against CE12 specifically bound to L-type calcium channels and inhibited channel activity. Injection with monoclonal antibody against CE12 effectively reduced the BP in angiotensin II-induced hypertensive mice. The HBcAg-CE12-CQ10 vaccine showed antihypertensive effects in hypertensive mice and relatively superior antihypertensive effects in spontaneously hypertensive rats and ameliorated L-NAME-induced renal injury. In addition, no obvious immune-mediated damage or electrophysiological adverse effects were detected.

Conclusion And Implications: Immunotherapy against both AT receptors and Ca 1.2 channels decreased the BP in hypertensive rodents effectively and provided protection against hypertensive target organ damage without obvious feedback activation of renin-angiotensin system or induction of dominant antibodies against the carrier protein. Thus, the HBcAg-CE12-CQ10 vaccine may provide a novel and promising therapeutic approach for hypertension.
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http://dx.doi.org/10.1111/bph.14875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989956PMC
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

Efficacy of omega-3 PUFAs in depression: A meta-analysis.

Transl Psychiatry 2019 08 5;9(1):190. Epub 2019 Aug 5.

Mood Disorders Psychopharmacology Unit, University Health Network; Department of Psychiatry, University of Toronto; Institute of Medical Science, University of Toronto; Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.

We conducted this meta-analysis of double-blind randomized placebo-controlled trials to estimate the efficacy of omega-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in the improvement of depression. We applied a systematic bibliographic search in PubMed and EMBASE for articles published prior to 20 December 2017. This meta-analysis was performed using RevMan 5.3 and R 3.4.3, and means and standard deviations were calculated in fixed- or random-effects models based on the results of the Q-test. A sensitivity analysis was also conducted to evaluate the stability of the results, and publication bias was evaluated by a funnel plot and Egger's linear regression analysis. Our search resulted in 180 articles; we analyzed 26 studies, which included 2160 participants. The meta-analysis showed an overall beneficial effect of omega-3 polyunsaturated fatty acids on depression symptoms (SMD = -0.28, P = 0.004). Compared with placebo, EPA-pure (=100% EPA) and EPA-major formulations (≥60% EPA) demonstrated clinical benefits with an EPA dosage ≤1 g/d (SMD = -0.50, P = 0.003, and SMD = -1.03, P = 0.03, respectively), whereas DHA-pure and DHA-major formulations did not exhibit such benefits.Current evidence supports the finding that omega-3 PUFAs with EPA ≥ 60% at a dosage of ≤1 g/d would have beneficial effects on depression. Further studies are warranted to examine supplementation with omega-3 PUFAs for specific subgroups of subjects with inflammation, severity of depression, and the dose response for both EPA and DHA supplementation.
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http://dx.doi.org/10.1038/s41398-019-0515-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683166PMC
August 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

Significant association of rare variant p.Gly8Ser in cardiac sodium channel β4-subunit SCN4B with atrial fibrillation.

Ann Hum Genet 2019 07 1;83(4):239-248. Epub 2019 Mar 1.

Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.

Atrial fibrillation (AF) affects 33.5 million individuals worldwide. It accounts for 15% of strokes and increases risk of heart failure and sudden death. The voltage-gated cardiac sodium channel complex is responsible for the generation and conduction of the cardiac action potential, and composed of the main pore-forming α-subunit Na 1.5 (encoded by the SCN5A gene) and one or more auxiliary β-subunits, including Na β1 to Na β4 encoded by SCN1B to SCN4B, respectively. We and others identified loss-of-function mutations in SCN1B and SCN2B and dominant-negative mutations in SCN3B in patients with AF. Three missense variants in SCN4B were identified in sporadic AF patients and small nuclear families; however, the association between SCN4B variants and AF remains to be further defined. In this study, we performed mutational analysis in SCN4B using a panel of 477 AF patients, and identified one nonsynonymous genomic variant p.Gly8Ser in four patients. To assess the association between the p.Gly8Ser variant and AF, we carried out case-control association studies with two independent populations (944 AF patients vs. 9,81 non-AF controls in the first discovery population and 732 cases and 1,291 controls in the second replication population). Significant association was identified in the two independent populations and in the combined population (p = 4.16 × 10 , odds ratio [OR] = 3.14) between p.Gly8Ser and common AF as well as lone AF (p = 0.018, OR = 2.85). These data suggest that rare variant p.Gly8Ser of SCN4B confers a significant risk of AF, and SCN4B is a candidate susceptibility gene for AF.
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http://dx.doi.org/10.1111/ahg.12305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815221PMC
July 2019

IL (Interleukin)-33 Suppresses Abdominal Aortic Aneurysm by Enhancing Regulatory T-Cell Expansion and Activity.

Arterioscler Thromb Vasc Biol 2019 03;39(3):446-458

From the Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, and Key Lab for Biological Targeted Therapy of Education Ministry and Hubei Province, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., N.X., S.W., D.L., Y.L., M.G., T.T., J.J., B.L., S.N., M.L.,Y.L., X.C.).

Objective- Inflammation occurs during the progression of abdominal aortic aneurysm (AAA). IL (interleukin)-33 is a pleiotropic cytokine with multiple immunomodulatory effects, yet its role in AAA remains unknown. Approach and Results- Immunoblot, immunohistochemistry, and immunofluorescent staining revealed increased IL-33 expression in adventitia fibroblasts from mouse AAA lesions. Daily intraperitoneal administration of recombinant IL-33 or transgenic IL-33 expression ameliorated periaorta CaPO injury- and aortic elastase exposure-induced AAA in mice, as demonstrated by blunted aortic expansion, reduced aortic wall elastica fragmentation, enhanced AAA lesion collagen deposition, attenuated T-cell and macrophage infiltration, reduced inflammatory cytokine production, skewed M2 macrophage polarization, and reduced lesion MMP (matrix metalloproteinase) expression and cell apoptosis. Flow cytometry analysis, immunostaining, and immunoblot analysis showed that exogenous IL-33 increased CD4Foxp3 regulatory T cells in spleens, blood, and aortas in periaorta CaPO-treated mice. Yet, ST2 deficiency muted these IL-33 activities. Regulatory T cells from IL-33-treated mice also showed significantly stronger activities in suppressing smooth muscle cell inflammatory cytokine and chemokine expression, macrophage MMP expression, and in increasing M2 macrophage polarization than those from vehicle-treated mice. In contrast, IL-33 failed to prevent AAA and lost its beneficial activities in CaPO-treated mice after selective depletion of regulatory T cells. Conclusions- Together, this study established a role of IL-33 in protecting mice from AAA formation by enhancing ST2-dependent aortic and systemic regulatory T-cell expansion and their immunosuppressive activities.
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http://dx.doi.org/10.1161/ATVBAHA.118.312023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393188PMC
March 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
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