Publications by authors named "Zhimin Du"

119 Publications

The association between RGS4 and choline in cardiac fibrosis.

Cell Commun Signal 2021 Apr 23;19(1):46. Epub 2021 Apr 23.

Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin, 150086, People's Republic of China.

Background: Myocardial fibrosis is caused by the adverse and powerful remodeling of the heart secondary to the death of cardiomyocytes after myocardial infarction. Regulators of G protein Signaling (RGS) 4 is involved in cardiac diseases through regulating G protein-coupled receptors (GPCRs).

Methods: Cardiac fibrosis models were established through cardiac fibroblasts (CFs) treatment with transforming growth factor (TGF)-β1 in vitro and mice subjected to myocardial infarction in vivo. The mRNA expression of RGS4, collagen I/III and α-SMA detected by qRT-PCR. Protein level of RGS4, collagen I, CTGF and α-SMA detected by Western blot. The ejection fraction (EF%) and fractional shortening (FS%) of mice were measured by echocardiography. Collagen deposition of mice was tested by Masson staining.

Results: The expression of RGS4 increased in CFs treatment with TGF-β1 and in MI mice. The model of cardiac fibrosis detected by qRT-PCR and Western blot. It was demonstrated that inhibition of RGS4 expression improved cardiac fibrosis by transfection with small interfering RNA in CFs and injection with lentivirus shRNA in mice. The protective effect of choline against cardiac fibrosis was counteracted by overexpression of RGS4 in vitro and in vivo. Moreover, choline inhibited the protein level of TGF-β1, p-Smad2/3, p-p38 and p-ERK1/2 in CFs treated with TGF-β1, which were restored by RGS4 overexpression.

Conclusion: This study demonstrated that RGS4 promoted cardiac fibrosis and attenuated the anti-cardiac fibrosis of choline. RGS4 may weaken anti-cardiac fibrosis of choline through TGF-β1/Smad and MAPK signaling pathways. Video Abstract: Video Byte of this article.
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http://dx.doi.org/10.1186/s12964-020-00682-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063380PMC
April 2021

Endocytic pathway inhibition attenuates extracellular vesicle-induced reduction of chemosensitivity to bortezomib in multiple myeloma cells.

Theranostics 2021 1;11(5):2364-2380. Epub 2021 Jan 1.

Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China.

Extracellular vesicles (EVs), including exosomes and microvesicles, derived from bone marrow stromal cells (BMSCs) have been demonstrated as key factors in the progression and drug resistance of multiple myeloma (MM). EV uptake involves a variety of mechanisms which largely depend on the vesicle origin and recipient cell type. The aim of the present study was to identify the mechanisms involved in the uptake of BMSC-derived small EVs (sEVs) by MM cells, and to evaluate the anti-MM effect of targeting this process. Human BMSC-derived sEVs were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot. The effects of chemical inhibitors and shRNA-mediated knockdown of endocytosis-associated genes on sEV uptake and cell apoptosis were analyzed by flow cytometry. The anti-MM effect of blocking sEV uptake was evaluated and in a xenograft MM mouse model. sEVs derived from BMSC were taken up by MM cells in a time- and dose-dependent manner, and subsequently promoted MM cell cycling and reduced their chemosensitivity to bortezomib. Chemical endocytosis inhibitors targeting heparin sulphate proteoglycans, actin, tyrosine kinase, dynamin-2, sodium/proton exchangers, or phosphoinositide 3-kinases significantly reduced MM cell internalization of BMSC-derived sEVs. Moreover, shRNA-mediated knockdown of endocytosis-associated proteins, including caveolin-1, flotillin-1, clathrin heavy chain, and dynamin-2 in MM cells suppressed sEV uptake. Furthermore, an endocytosis inhibitor targeting dynamin-2 preferentially suppressed the uptake of sEV by primary MM cells and enhanced the anti-MM effects of bortezomib and in a mouse model. Clathrin- and caveolin-dependent endocytosis and macropinocytosis are the predominant routes of sEV-mediated communication between BMSCs and MM cells, and inhibiting endocytosis attenuates sEV-induced reduction of chemosensitivity to bortezomib, and thus enhances its anti-MM properties.
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http://dx.doi.org/10.7150/thno.47996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797667PMC
January 2021

Six-Year Change in QT Interval Duration and Risk of Incident Heart Failure - A Secondary Analysis of the Atherosclerosis Risk in Communities Study.

Circ J 2021 Apr 2;85(5):640-646. Epub 2020 Dec 2.

Cardiology Department, First Affiliated Hospital of Sun Yat-Sen University.

Background: Few studies have investigated the association between temporal change in QT interval and incident heart failure (HF). The aim of this study is to examine this association in the Atherosclerosis Risk in Communities (ARIC) study.Methods and Results:A secondary analysis was performed for the ARIC study. Overall, 10,274 participants (age 60.0±5.7 years, 45.7% male and 19.5% black) who obtained a 12-lead electrocardiography (ECG) at both Visit 1 (1987-1989) and Visit 3 (1993-1995) in the ARIC study were included. QT interval duration was corrected by using Bazett's formula (QTc). The change in corrected QT interval duration (∆QTc) was calculated by subtracting QTc at Visit 3 from Visit 1. The main outcome measure was incident HF. Multivariable Cox regression models were used to assess the association between ∆QTc and incident HF. During a median follow up of 19.5 years, 1,833 cases (17.8%) of incident HF occurred. ∆QTc was positively associated with incident HF (HR: 1.06, 95% CI 1.03, 1.08, per 10 ms increase, P<0.001; HR 1.22, 95% CI 1.08, 1.36, T3 vs. T1, P=0.002), after adjusting for traditional cardiovascular risk factor, QTc and QRS duration.

Conclusions: Temporal increases in QTc are independently associated with increased risk of HF.
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http://dx.doi.org/10.1253/circj.CJ-20-0719DOI Listing
April 2021

Multiple roles of Ca in the interaction of ciprofloxacin with activated sludge: Spectroscopic investigations of extracellular polymeric substances.

Sci Total Environ 2021 Jan 7;751:142246. Epub 2020 Sep 7.

Department of Environmental Engineering, Zhejiang University, Hangzhou 310058, China. Electronic address:

Calcium ion is an important cation influencing the binding of recalcitrant organic contaminants with activated sludge during wastewater treatment process, but there is still unknown about its role in amphoteric fluoroquinolones binding. Binding experiments show that Ca markedly inhibited binding of ciprofloxacin (CIP) onto sludge, causing 7-203 times of CIP release. Multi-spectroscopic examinations indicate that tryptophan-like and tyrosine-like proteins in extracellular polymeric substances (EPS) were dominant components for CIP binding by static quenching and forming CIP-proteins complexes. Addition of Ca into EPS and CIP binding systems induced increase of association constants (from 0.024-0.064 to 0.027-0.084 L/μmol) and binding constants (from 0.002-0.039 to 0.012-0.107) and decrease of binding sites number (from 0.893-2.007 to 0.721-1.386). Functional groups of EPS and secondary structure of proteins were remarkably changed upon reactions with CIP and Ca. Calcium ion interacted with EPS and CIP binding system in two distinct ways: Ca shielded CO in amide I in EPS for CIP binding, whereas strengthened binding between CIP and functional groups including CO in carboxyl groups in extra-microcolony polymers and OH in extra-cellular polymers by forming ternary complexes. Cation competition for CO in amide I is responsible for Ca induced CIP release from the sludge. Results suggest the highly potential release of CIP from high saline wastewater and cation-conditioned sludge which needs further monitoring and evaluation.
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http://dx.doi.org/10.1016/j.scitotenv.2020.142246DOI Listing
January 2021

Aloe-emodin relieves zidovudine-induced injury in neonatal rat ventricular myocytes by regulating the p90rsk/p-bad/bcl-2 signaling pathway.

Environ Toxicol Pharmacol 2021 Jan 5;81:103540. Epub 2020 Nov 5.

Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University Institute of Clinical Pharmacy, The University Key Laboratory of Drug Research, Heilongjiang Higher Education Institutions, Harbin, China; College of Pharmacy of Harbin Medical University, Harbin, China; State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China. Electronic address:

Background/aims: Zidovudine (3'-azido-2',3'-deoxythymidine; AZT) is a first-line drug for treatment of human immunodeficiency virus infection (HIV). However, its application is limited by cardiotoxicity due to cardiomyocyte injury. This study investigated whether Aloe-emodin (AE), an anthraquinone compound, protects against AZT-induced cardiomyocyte toxicity.

Methods: MTT, JC-1 assays and TUNEL were examined to verify the protective effect of AE against AZT-induced cardiomyocyte injury. Western blotting was performed to explore the anti-apoptotic effect of AE using anti-apoptotic proteins p90rsk, p-bad, and bcl-2 and pro-apoptotic proteins apaf-1, cleaved-caspase-3, and cytochrome c.

Results: We observed a protective effect of AE against cell viability decrease and TUNEL positive cells increase induced by AZT, which was counteracted by BI-D1870. Western blot analysis found that AE significantly inhibited cardiomyocyte apoptosis by activating p90rsk/p-bad/bcl-2 signaling pathway. Furthermore, BI-D1870 counteracted the anti-apoptotic effect of AE.

Conclusions: Taken together, these results indicate that AE attenuated AZT-induced cardiomyocyte apoptosis by activating p90rsk.
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http://dx.doi.org/10.1016/j.etap.2020.103540DOI Listing
January 2021

Notch pathway activation mediated the senescence of endothelial progenitor cells in hypercholesterolemic mice.

J Bioenerg Biomembr 2020 12 17;52(6):431-440. Epub 2020 Sep 17.

Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.

Hyperlipidemia is an important factor in the induction of cardiovascular diseases. However, the molecular mechanisms underlying the vascular injury involved in hyperlipidemia remains unclear. This study aimed to investigate the Notch pathway of endothelial progenitor cells (EPCs) in reendothelialization after vascular injury and to explore the involvement of Notch pathway in the senescence of EPCs. Our results demonstrated that high-fat diet (HFD) treatment inhibited reendothelialization after vascular injury in the mice model. In vitro studies showed that 7-ketocholesterol (7-keto) stimulation induced senescence in the isolated EPCs from mice. In addition, 7-keto markedly upregulated the protein expression of Notch1 and Delta-like ligand 4 and induced the transport of notch intracellular domain (NICD) to the nucleus. Mechanistically, treatment with NICD inhibitor reduced the senescence of the EPCs stimulated by cholesterol. In summary, our results showed that HFD treatment caused the disruption of reendothelialization after vascular injury in the mouse model. In vitro studies indicated that 7-keto-induced senescence of EPCs was at least via the activation of the Notch1 pathway. Mechanistic data suggested that 7-keto may activate the Notch1 pathway by regulating the generation and transport of NICD to the nucleus. Future investigations are warranted to confirm the role of Notch1 in the dysfunction of EPCs during obesity.
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http://dx.doi.org/10.1007/s10863-020-09853-5DOI Listing
December 2020

Efficacy and Safety of Triazavirin Therapy for Coronavirus Disease 2019: A Pilot Randomized Controlled Trial.

Engineering (Beijing) 2020 Oct 8;6(10):1185-1191. Epub 2020 Sep 8.

College of Pharmacology, Harbin Medical University, Harbin 150001, China.

No therapeutics have been proven effective yet for the treatment of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To assess the efficacy and safety of Triazavirin therapy for COVID-19, we conducted a randomized, double-blinded controlled trial involving hospitalized adult patients with COVID-19. Participants were enrolled from ten sites, and were randomized into two arms of the study with a ratio of 1:1. Patients were treated with Triazavirin 250 mg versus a placebo three or four times a day for 7 d. The primary outcome was set as the time to clinical improvement, defined as normalization of body temperature, respiratory rate, oxygen saturation, cough, and absorption of pulmonary infection by chest computed tomography (CT) until 28 d after randomization. Secondary outcomes included individual components of the primary outcome, the mean time and proportion of inflammatory absorption in the lung, and the conversion rate to a repeated negative SARS-CoV-2 nucleic acid test of throat swab sampling. Concomitant therapeutic treatments, adverse events, and serious adverse events were recorded. Our study was halted after the recruitment of 52 patients, since the number of new infections in the participating hospitals decreased greatly. We randomized 52 patients for treatment with Triazavirin ( = 26) or a placebo ( = 26). We found no differences in the time to clinical improvement (median, 7 d versus 12 d; risk ratio (RR), 2.0; 95% confidence interval (CI), 0.7-5.6;  = 0.2), with clinical improvement occurring in ten patients in the Triazavirin group and six patients in the placebo group (38.5% versus 23.1%; RR, 2.1; 95% CI, 0.6-7.0;  = 0.2). All components of the primary outcome normalized within 28 d, with the exception of absorption of pulmonary infection (Triazavirin 50.0%, placebo 26.1%). Patients in the Triazavirin group used less frequent concomitant therapies for respiratory, cardiac, renal, hepatic, or coagulation supports. Although no statistically significant evidence was found to indicate that Triazavirin benefits COVID-19 patients, our observations indicated possible benefits from its use to treat COVID-19 due to its antiviral effects. Further study is required for confirmation.
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http://dx.doi.org/10.1016/j.eng.2020.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476906PMC
October 2020

The Efficacy and Safety of Triazavirin for COVID-19: A Trial Protocol.

Engineering (Beijing) 2020 Oct 3;6(10):1199-1204. Epub 2020 Jul 3.

Department of Pharmacology & State-Province Key Laboratories of Biomedicine-Pharmaceutics of China & Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacology, Harbin Medical University, Harbin 150001, China.

The coronavirus disease 2019 (COVID-19), a pneumonia caused by a novel coronavirus, was reported in December 2019. COVID-19 is highly contagious and has rapidly developed from a regional epidemic into a global pandemic. As yet, no effective drugs have been found to treat this virus. This study, an ongoing multicenter and blind randomized controlled trial (RCT), is being conducted at ten study sites in Heilongjiang Province, China, to investigate the efficacy and safety of Triazavirin (TZV) versus its placebo in COVID-19 patients. A total of 240 participants with COVID-19 are scheduled to be enrolled in this trial. Participants with positive tests of throat swab virus nucleic acid are randomized (1:1) into two groups: standard therapy plus TZV or standard therapy plus placebo for a 7-day treatment with a 21-day follow-up. The primary outcome is the time to clinical improvement of the subjects. Secondary outcomes include clinical improvement rate, time to alleviation of fever, mean time and proportion of obvious inflammatory absorption in the lung, conversion rate of repeated negative virus nucleic acid tests, mortality rate, and conversion rate to severe and critically severe patients. Adverse events, serious adverse events, liver function, kidney function, and concurrent treatments will be monitored and recorded throughout the trial. The results of this trial should provide evidence-based recommendations to clinicians for the treatment of COVID-19.
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http://dx.doi.org/10.1016/j.eng.2020.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332434PMC
October 2020

Identification of spp. as Alternate Hosts for Under Controlled Conditions and Morphologic Observations of Sexual Stage Development of the Rust Fungus.

Front Microbiol 2020 25;11:1278. Epub 2020 Jun 25.

State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, China.

Gramineous grasses are a large group of species, many of which act as accessory (secondary) host for a large number of rust fungi, including devastating rust pathogens of cereals. Among the rust fungi, some are known to be heteroecious and have a complete macrocyclic life cycle with five types of spores on distinct plant species, but for many others the complete life cycle is unknown. , a rust fungus infecting grasses in the genus , has been known for only its uredinial and telial stages; however, the other (pycnial and aecial) stages have not been identified. In this study, we demonstrate that is a heteroecious, macrocyclic fungus with the sexual stage on barberry ( spp.) through inoculation. Pycnia and aecia were successively produced on the inoculated barberry plants. Inoculation of leaves with aeciospores produced yellow-orange uredinia with high infection types, whereas inoculation of wheat variety Mingxian 169, highly susceptible to f. sp. which causes stripe rust on wheat, produced chlorotic flecks but no uredinia. The ITS sequence analysis of did not match with any sequence in the NCBI database and had the highest homology with 94% compared to and . Observations of the uredinial, telial, and basidial stages on and pycnial and aecial stages on using light and scanning electron microscopes revealed its characteristics. Morphological characteristics of urediniospores and teliospores are most similar with those of described in the literature. This study proved (1) the life cycle of as heteroecious and macrocyclic and the alternate host as barberry; (2) the description of life stages in the sexual cycle, especially the morphologies of aecial, pycnial, and basidial stages; and (3) the expansion of knowledge on the rust flora on barberry.
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http://dx.doi.org/10.3389/fmicb.2020.01278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330019PMC
June 2020

'Prodrug-Like' Acetylmannosamine Modified Liposomes Loaded With Arsenic Trioxide for the Treatment of Orthotopic Glioma in Mice.

J Pharm Sci 2020 09 11;109(9):2861-2873. Epub 2020 Jun 11.

Department of Pharmacology, Harbin Medical University, 157 Baojian Road, Harbin, China. Electronic address:

Glioma is one of the fatal intracranial cancers that is a huge challenge to decrease the death rate currently. The deep penetration and high accumulation of therapeutic inorganic ions into the tumor site are extremely impeded due to the existence of physiological barriers, which limits to widen the indication of some drugs such as arsenic trioxide. The previous data have confirmed that the mannose substrate (MAN) without acetyl groups facilitates vesicles to go into the brain. Given that deacetylation of AcMAN groups on the surface of liposomes under the enzyme incubation occurred, namely 'prodrug-like' features of vesicles, the liposomes could more easily penetrate the BBB, target the glioma site, release arsenic trioxide, and inhibit the growth of glioma cells in the brain. Besides, the possibility of AcMAN binding to Gluts could be reduced due to the steric hindrance of acetyl groups, decreasing the off-target effects of vesicles. Here, we developed 'prodrug-like' arsenic trioxide (AsO, ATO)-loaded liposomes inserted with distearoyl phospho-ethanolamine-polyethylene glycol-1000-p-carboxylpheny-α-d-acetylmannosamine (DSPE-PEG-1000-AcMAN), which was named AcMAN-ATO-LIP. Cytotoxic experiments of liposomes indicated that the toxicity of AcMAN-ATO-LIP was lower than that of free ATO but stronger than that of ATO-LIP (without insertion of DSPE-PEG-1000-AcMAN). The uptake of vesicles by U87 glioma cells displayed that the cellular uptake of AcMAN-Rho-LIP (labeled by rhodamine) was remarkably improved, compared with Rho-LIP. The in vivo biodistribution results showed the superiority of AcMAN-Rho-LIP in enhanced intracranial accumulation. Furthermore, the treatment of orthotopic glioma in Balb/c nude mice with AcMAN-ATO-LIP elongated the survival time of the animals than that with physiological saline, free ATO, or ATO-LIP, respectively. All the results suggested that the AcMAN-ATO-LIP had stronger anti-glioma effects as well as lower toxicities, and may be a promising approach for the treatment of brain cancer.
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http://dx.doi.org/10.1016/j.xphs.2020.06.001DOI Listing
September 2020

Could the Novel Oral Anticoagulants Be Used for Coronary Artery Aneurysm?

Case Rep Med 2020 25;2020:5073814. Epub 2020 Apr 25.

Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

Coronary artery aneurysms (CAAs) are uncommon in coronary angiography, and left main coronary artery aneurysms are rare. There is no consensus for the treatment of CAAs. A young patient with left coronary artery aneurysm diagnosed by coronary angiography and with recurrent acute myocardial infarction was treated with rivaroxaban and aspirin. The patient had no angina for 6 months. Novel oral anticoagulants combined with antiplatelet agents may be appropriate for the treatment of CAAs.
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http://dx.doi.org/10.1155/2020/5073814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196985PMC
April 2020

Thioredoxin mitigates H O -induced inhibition of myogenic differentiation of rat bone marrow mesenchymal stem cells by enhancing AKT activation.

FEBS Open Bio 2020 05 2;10(5):835-846. Epub 2020 Apr 2.

Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, China.

Thioredoxin (Trx) is a hydrogen acceptor of ribonucleotide reductase and a regulator of some enzymes and receptors. It has been previously shown that significantly elevated levels of Trx expression are associated with the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), but it is not clear how Trx regulates the effects of hydrogen peroxide (H O ) on myogenic differentiation of BMSCs. Here, we report that rat BMSCs treated with a high dose (150 µm) of H O exhibited a significant reduction in viability, cell cycling, and superoxide dismutase and glutathione peroxidase levels, and an increase in reactive oxygen species and malondialdehyde levels, which was accompanied by reductions in protein kinase B activation and forkhead Box O1, myogenic differentiation 1 and myogenin expression during myogenic differentiation. Furthermore, treatment with recombinant human Trx significantly mitigated the effects of H O on the myogenic differentiation of BMSCs, and this was abrogated by cotreatment with wortmannin [a specific phosphatidylinositol 3-kinase inhibitor]. In summary, our results suggest that treatment with recombinant human Trx mitigates H O -induced oxidative stress and may promote myogenic differentiation of rat BMSCs by enhancing phosphatidylinositol 3-kinase/protein kinase B/forkhead Box O1 signaling.
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http://dx.doi.org/10.1002/2211-5463.12835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193161PMC
May 2020

Aloe Emodin Reduces Cardiac Inflammation Induced by a High-Fat Diet through the TLR4 Signaling Pathway.

Mediators Inflamm 2020 5;2020:6318520. Epub 2020 Feb 5.

Institute of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province, Harbin 150086, China.

Background: Aloe emodin (AE) is a lipid-lowering agent, which could be used to treat hyperlipidemia, thereby reducing the risk of cardiovascular disease. Recent evidence suggests that hyperlipidemia is associated with many cardiac pathological alterations and might worsen myocardial damages.

Purpose: The purpose of this study is to evaluate the potential roles and mechanisms of AE in hyperlipidemia-induced oxidative stress and inflammation in the heart. . We established a hyperlipidemia-induced cardiac inflammation model in rats and cells then administered AE and observed its effect on hyperlipidemia-induced cardiac inflammation.

Methods: We used a mouse model of hyperlipidemia caused by a high-fat diet (HFD) for 10 weeks and cell culture experimental models of inflammation in the heart stimulated by PA for 14 h. Inflammatory markers were detected by qRT-PCR, WB, and immunofluorescence.

Results: We demonstrated that the expression levels of proinflammatory cytokines IL-1, IL-6, and TNF- were increased in the HFD group compared to the normal diet (ND) group, whereas AE treatment significantly reduced their levels in the myocardium. In addition, vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM-1) protein expressions were also inhibited by AE. Our study showed AE treatment dose-dependently decreased the expression of IL-1, IL-6, and TNF- were increased in the HFD group compared to the normal diet (ND) group, whereas AE treatment significantly reduced their levels in the myocardium. In addition, vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM-1) protein expressions were also inhibited by AE. Our B, and p-P65l and study showed AE treatment dose-dependently decreased the expression of IL-1.

Conclusion: Taken together, our findings disclose that AE could alleviate HFD/PA-induced cardiac inflammation via inhibition of the TLR4/NF-B signaling pathway. Thus, AE may be a promising therapeutic strategy for preventing hyperlipidemia-induced myocardial injury.B, and p-P65l.
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http://dx.doi.org/10.1155/2020/6318520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025072PMC
November 2020

Choline Attenuates Cardiac Fibrosis by Inhibiting p38MAPK Signaling Possibly by Acting on M Muscarinic Acetylcholine Receptor.

Front Pharmacol 2019 21;10:1386. Epub 2019 Nov 21.

Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin, China.

Choline has been reported to produce a variety of cellular functions including cardioprotection activating M muscarinic acetylcholine receptor (MR) under various insults. However, whether choline offers similar beneficial effects the same mechanism in cardiac fibrosis remained unexplored. The present study aimed to investigate the effects of choline on cardiac fibrosis and the underlying signaling mechanisms, particularly the possible involvement of MR. Transverse aortic constriction (TAC) mouse model was established to simulate the cardiac fibrosis. Transforming growth factor (TGF)-β1 treatment was employed to induce proliferation of cardiac fibroblasts . Choline chloride and MR antagonist 4-diphenylacetoxy--methylpiperidine methiodide (4-DAMP) were used to unravel the potential role of MR. Cardiac function was assessed by echocardiography and interstitial fibrosis was quantified by Masson staining. Protein levels of collagens I and III were determined by Western blot analysis. The role of MR in the proliferation cardiac fibroblasts was validated by silencing MR with specific small interference RNA (siRNA). Furthermore, the mitogen-activated protein kinase (MAPK) signaling pathway including p38MAPK and ERK1/2 as well as the TGF-β1/Smad pathway were analyzed. MR protein was found abundantly in cardiac fibroblasts. MR protein level, as identified by Western blotting, was higher in mice with excessive cardiac fibrosis and in TGF-β1-induced cardiac fibrosis as well. Choline significantly inhibited interstitial fibrosis, and this beneficial action was reversed by 4-DAMP. Production of collagens I and III was reduced after choline treatment but restored by 4-DAMP. Expression silence of endogenous MR using siRNA increased the level of collagen I. Furthermore, the TGF-β1/Smad2/3 and the p38MAPK pathways were both suppressed by choline. In summary, choline produced an anti-fibrotic effect both and by regulating the TGF-β1/Smad2/3 and p38MAPK pathways. These findings unraveled a novel pharmacological property of choline linked to MR, suggesting that choline regulates cardiac fibrosis and the associated heart diseases possibly by acting on MR.
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http://dx.doi.org/10.3389/fphar.2019.01386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900736PMC
November 2019

Anthocyanidin attenuates myocardial ischemia induced injury via inhibition of ROS-JNK-Bcl-2 pathway: New mechanism of anthocyanidin action.

Phytother Res 2019 Dec 27;33(12):3129-3139. Epub 2019 Nov 27.

Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P. R. China.

Despite treatment options available to date, myocardial ischemia (MI) remains the leading cause of death worldwide. Studies are focused on finding effective therapeutic strategies against MI injury. Growing interest has been developed in natural compounds possessing medicinal properties with scarcer side effects. Here, we have evaluated the cardioprotective potential of anthocyanidin against MI injury and explored its underlying protective mechanism. Left anterior descending coronary artery was ligated to induce MI in mice. Neonatal mice cardiomyocytes were treated with H O to induce oxidative stress (a major contributor to MI injury) in vitro. Anthocyanidin pretreatment significantly reduced the infarct size, preserved the cell viability, and protected against ischemia-induced cardiac injury in treatment groups compared with the H O -treated group in vitro. Measurement of reactive oxygen species (ROS) validated the strong antioxidant potential of anthocyanidin, as significant reduction in oxidative stress was observed in anthocyanidin-pretreated groups. Mechanistically, pretreatment with anthocyanidin significantly subdued the activation of JNK (to p-JNK) and elevated Bcl-2 levels. Both in vivo and in vitro findings suggest that anthocyanidin can induce a state of myocardial resistance against ischemic insult. We have provided the experimental evidence for inhibition of ROS/p-JNK/Bcl-2 pathway being the underlying mechanism of action of anthocyanidin. Our results support the use of anthocyanidin as therapeutic strategy against MI injury.
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http://dx.doi.org/10.1002/ptr.6485DOI Listing
December 2019

Critical appraisal of guidelines for coronary artery disease on dual antiplatelet therapy: More consensus than controversies.

Clin Cardiol 2019 Dec 14;42(12):1170-1180. Epub 2019 Oct 14.

Cardiology Department, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background: Dual antiplatelet therapy (DAPT) in the form of aspirin plus a P Y inhibitor, when indicated, is one of the key treatments in coronary artery disease (CAD). Many recommendations on DAPT in patients with CAD based on current guidelines are largely inconsistent. In our current study, we aimed at systematically reviewing DAPT-relevant clinical practice guidelines, and highlighting their commonalities and differences for better informed decision-making.

Methods: Contemporary guidelines in English were searched in MEDLINE, Embase and websites of guideline organizations and professional societies. Guidelines with recommendations on DAPT for CAD patients were included. Guideline quality was appraised with the 6-domain Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. The reporting of conflicts of interest (COI) was assessed individually with supplementary items from the RIGHT (Reporting Item for Practice Guidelines in Healthcare) checklist. Meanwhile, extraction of recommendations was performed.

Results: A total of 18 guidelines fulfilled our inclusion criteria. Most of them were graded with relatively good scores averaging from 42% to 74%. Domains for lower scores were in "stakeholder involvement" and "application." The reporting of COI was satisfactory. For the recommendations on DAPT, most guidelines with high AGREE II scores included consistent recommendations on the timing and P Y inhibitor selection. Nonetheless, conflicts still exist on the duration of DAPT.

Conclusions: Quality of guidelines for DAPT in CAD was relatively high, though defects existed in "Applicability" and "Stakeholder Involvement." As these guidelines developed, DAPT recommendations gradually converged on a consensus. Clinical decision should be made on an individual basis.
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http://dx.doi.org/10.1002/clc.23275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906997PMC
December 2019

Lipid management for coronary heart disease patients: an appraisal of updated international guidelines applying Appraisal of Guidelines for Research and Evaluation II-clinical practice guideline appraisal for lipid management in coronary heart disease.

J Thorac Dis 2019 Aug;11(8):3534-3546

Cardiology Department, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.

Background: Clinical practice guidelines (CPGs) provide many recommendations for hyperlipidemia management, but some of them are still debatable.

Methods: We applied the six-domain Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument to evaluate the quality of guidelines with lipid management recommendations for coronary heart disease (CHD), including dyslipidemia and CHD guidelines published from 2009 to 2019. Meanwhile, we synthesized and compared major recommendations and present the consistency and controversy in current dyslipidemia management.

Results: Among 19 guidelines included, ten guidelines ("strongly recommended" with AGREE scores 61-94%) performed better than the other nine (38-65% as "recommended with some modification") For blood lipid tests, most CHD guidelines simply required fasting sample while dyslipidemia guidelines preferred non-fasting sample except in high triglycerides state. Most guidelines consistently chose low-density lipoprotein cholesterol (LDL-C) as the primary lipid-lowering target (LLT), while non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B were mainly selected as secondary LLTs. The specific goals of LDL-C lowering were either to lower than 70 mg/dL or with at least 50% reduction. All guidelines recommended high intensity or maximally tolerable doses of statins, while ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were recommended as second-line therapy.

Conclusions: The general quality of guidelines for lipid management is satisfactory. Consensus has been reached on the specific goal of lipid reduction and the intensity of statins therapy. Further research is needed to validate the application of non-fasting sample and non-HDL-C target, as well as the efficacy and safety of ezetimibe and PCSK9 inhibitors.
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http://dx.doi.org/10.21037/jtd.2019.07.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753419PMC
August 2019

LncRNA promotes ischemic myocardial injury by regulating autophagy through targeting .

Autophagy 2020 06 12;16(6):1077-1091. Epub 2019 Sep 12.

Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University , Harbin, Heilongjiang, P. R. China.

More evidence is emerging of the roles long non-coding RNAs (lncRNAs) play as regulatory factors in a variety of biological processes, but the mechanisms underlying the function of lncRNAs in acute myocardial infarction (AMI) have not been explicitly delineated. The present study identified the lncRNA , that inhibited macroautophagy/autophagy by modulating (microRNA 26a). Inhibition of led to cardiac injury both and , whereas overexpression of attenuated ischemic stress-induced cell death by activating autophagy through targeting (ubiquitin specific peptidase 15). More importantly, acted as a competitive endogenous RNA (ceRNA) of ; forced expression of downregulated to inhibit autophagy. In contrast, loss of resulted in upregulation of to promote autophagy and alleviate cardiac injury, which in turn improved cardiac function in MI mice. This study identified a lncRNA that functions as an anti-autophagic molecule via ceRNA activity toward . Our findings suggest that knockdown of might be a novel therapeutic approach for cardiac diseases associated with autophagy.

Abbreviations: 3-MA: 3-methyladenine; AAV-9: adenovirus associated virus-9; ago: cholesterol-conjugated mimic; AMI: acute myocardial infarction; inhibitor; ATG: autophagy related; BECN1: beclin 1; ceRNA: competitive endogenous RNAs; EF: ejection fraction; f-: fragment encompassing the binding site; FS: fraction shortening; GFP-mRFP: a plasmid expressing green fluorescent protein-monomeric red fluorescent protein; lncRNA: long non-coding RNA; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; : myocardial infarction-regulatory factor; miRNAs: microRNAs; : negative control; NMCMs: neonatal mice cardiomyocytes; shRNA: short hairpin RNA; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; : ubiquitin specific peptidase 15.
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http://dx.doi.org/10.1080/15548627.2019.1659610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469676PMC
June 2020

Aloe-emodin attenuates myocardial infarction and apoptosis via up-regulating miR-133 expression.

Pharmacol Res 2019 08 14;146:104315. Epub 2019 Jun 14.

Institute of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, China; Department of Clinical Pharmarcology, College of Pharmacy, Harbin Medical University, Harbin 150086, China; State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, PR China. Electronic address:

Aloe-emodin (AE) is an anthraquinone derived from rhubarb and has a variety of pharmacological actions. However, the role of AE in regulating ischemic heart diseases is still unclear. The present study investigated the effect of AE on cardiac injuries induced by myocardial infarction (MI) in vivo and oxidative insults in vitro and explored the mechanisms involved. TUNEL and Flow cytometry were performed to measure cell apoptosis. Western blot analysis was employed to detect expression of Bcl-2, Bax and Caspase-3 proteins. Real-time PCR was used to quantify the microRNAs levels. Our data showed that AE protected neonatal rat ventricular myocytes (NRVMs) from hydrogen peroxide (HO) induced apoptosis and significantly inhibited HO-induced reactive oxygen species (ROS) elevation. Furthermore, AE treatment significantly reversed HO-induced upregulation of Bax/Bcl-2 and the loss of mitochondrial membrane potential. In vivo, AE treatment significantly reduced infarct size, ameliorated impaired cardiac function and obviously decreased cardiac apoptosis and oxidative stress in MI mice heart. Meanwhile, AE restored HO-induced downregulation of miR-133, and transfection with miR-133 inhibitor abolished the anti-apoptotic and anti-oxidative effects of AE. Moreover, AE prevented HO-induced increase in caspase-3 activity, which was diminished by application of miR-133 inhibitor. Our results indicate that AE protectes against myocardial infarction via the upregulation of miR-133, inhibition of ROS production and suppression of caspase-3 apoptotic signaling pathway.
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http://dx.doi.org/10.1016/j.phrs.2019.104315DOI Listing
August 2019

A risk score to predict postdischarge bleeding among acute coronary syndrome patients undergoing percutaneous coronary intervention: BRIC-ACS study.

Catheter Cardiovasc Interv 2019 Jun 21;93(7):1194-1204. Epub 2019 May 21.

Department of Cardiology, Biomedical Research (Therapy) Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Background: Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) prevents ischemic events while increasing bleeding risk. Real-world-based metrics to accurately predict postdischarge bleeding (PDB) occurrence and its potential impact on postdischarge major cardiovascular event (MACE) remain undefined. This study sought to evaluate the impact of PDB on MACE occurrence, and to develop a score to predict PDB risk among Chinese acute coronary syndrome (ACS) patients after PCI.

Methods And Results: From May 2014 to January 2016, 2496 ACS patients who underwent PCI were recruited consecutively from 29 nationally representative Chinese tertiary hospitals. Among 2,381 patients (95.4%, 2,381/2,496) who completed 1-year follow-up, the cumulative incidence of PDB (bleeding academic research consortium type [BARC] ≥2) and postdischarge MACE (a composite of all-cause death, nonfatal myocardial infarction, ischemic stroke, or urgent revascularization) was 4.9% (n = 117) and 3.3% (n = 79), respectively. The association between PDB and MACE during 1-year follow-up, as well as the impact of DAPT with ticagrelor or clopidogrel on PDB were evaluated. PDB was associated with higher risk of postdischarge MACE (7.7 vs. 3.1%; adjusted hazard ratio: 2.59 [95% confidence interval: 1.17-5.74]; p = .02). For ticagrelor versus clopidogrel, PDB risk was higher (8.0 vs. 4.4%; 2.05 [1.17-3.60]; p = .01), while MACE risk was similar (2.0 vs. 3.4%; 0.70 [0.25-1.93]; p = .49). Based on identified PDB predictors, the constructed bleeding risk in real world Chinese acute coronary syndrome patients (BRIC-ACS) score for PDB was established. C-statistic for the score for PDB was 0.67 (95% CI: 0.62-0.73) in the overall cohort, and >0.70 in subgroups with non-ST- and ST-segment elevation myocardial infarction, diabetes and receiving more than two drug eluting stents.

Conclusions: In Chinese ACS patients, PDB with BARC ≥2 was associated with higher risk for MACE after PCI. The constructed BRIC-ACS risk score provides a useful tool for PDB discrimination, particularly among high ischemic and bleeding risk patients.
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http://dx.doi.org/10.1002/ccd.28325DOI Listing
June 2019

Low-Carbohydrate Diets and Risk of Incident Atrial Fibrillation: A Prospective Cohort Study.

J Am Heart Assoc 2019 05;8(9):e011955

1 Cardiology Department First Affiliated Hospital of Sun Yat-Sen University Guangzhou China.

Background The influences of low-carbohydrate diets in cardiovascular disease are controversial. Few studies have examined the relationship of carbohydrate intake and risk of incident atrial fibrillation ( AF ). We aimed to evaluate the association between carbohydrate intake and the risk of incident AF in the ARIC (Atherosclerosis Risk in Communities) Study. Methods and Results We included 13 385 participants (age, 54.2±5.8 years; 45.1% men and 74.7% white) who completed a dietary questionnaire at baseline (1987-1989) in the ARIC Study. The primary outcome was incident AF , which was identified by ECG performed during study examinations, hospital discharge codes, and death certificates. We used multivariable Cox hazard regression models to assess the association between carbohydrate intake and incident AF . We further explored the effects of specific food source (animal versus plant based) used to replace carbohydrate intake in the low-carbohydrate intake setting. During a median follow-up of 22.4 years, 1808 cases (13.5%) of AF occurred. The hazard ratio for incident AF associated with a 1- SD (9.4%) increase in carbohydrate intake as a percentage of energy intake was 0.82 (95% CI , 0.72-0.94), after adjustment for traditional AF risk factors and other diets factors. Results were similar when individuals were categorized by carbohydrate intake quartiles (hazard ratio, 0.64; 95% CI , 0.49-0.84; comparing extreme quartiles). No association was found between the type of protein or fat used to replace the carbohydrate and risk of incident AF . Conclusions Low-carbohydrate diets were associated with increased risk of incident AF , regardless of the type of protein or fat used to replace the carbohydrate.
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http://dx.doi.org/10.1161/JAHA.119.011955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512089PMC
May 2019

Inhibition of miR-23a attenuates doxorubicin-induced mitochondria-dependent cardiomyocyte apoptosis by targeting the PGC-1α/Drp1 pathway.

Toxicol Appl Pharmacol 2019 04 1;369:73-81. Epub 2019 Mar 1.

Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, PR China; State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, PR China; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, PR China. Electronic address:

Background And Purpose: Doxorubicin (Dox)-induced cardiotoxicity limits its clinical use. A number of microRNAs (miRs) have been found essential in Dox-induced cardiotoxicity. The aim of the present study was to elucidate the effects of miR-23a on Dox-induced cardiomyocyte apoptosis and underlying mechanisms.

Experimental Approach: Dox-induced cardiotoxicity model was established in primary neonatal rat ventricular myocytes (NRVMs). MTT assay, Live/Dead staining was employed to examine the viability and cell death of NRVMs. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were measured. Protein levels of mitochondria biogenesis and fission/fusion associated factors including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), dynamin-related protein-1 (Drp1) and mitofusin 2 (Mfn2) were detected. Meanwhile, apoptosis-related cytochrome c (Cyt c) and caspase-3 expression were examined by western blot. PGC-1α siRNA was employed to validate the role of miR-23a in Dox-induced cardiotoxicity.

Key Results: MiR-23a expression was significantly increased by Dox concentration-dependently. Inhibition of miR-23a markedly increased viability and MMP, reduced cell death and ROS production of NRVMs. MiR-23a mimic significantly inhibited expression of its target PGC-1α. MiR-23a inhibitor significantly diminished phosphorylation of Drp1 without affecting Mfn2 expression. Protein expression of Cyt c and cleaved caspase-3 were markedly inhibited by miR-23a inhibitor. The protective effects of miR-23a inhibitor were reversed by PGC-1α siRNA.

Conclusions And Implications: Increased miR-23a promoted mitochondrial injury in the Dox-induced cellular model. Inhibition of miR-23a attenuated cardiomyocyte damage by directly targeting PGC-1α/p-Drp1, thereby inhibiting mitochondria-dependent apoptosis. These findings may provide a new potential target for the treatment of Dox-induced cardiotoxicity.
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http://dx.doi.org/10.1016/j.taap.2019.02.016DOI Listing
April 2019

Anthocyanin is involved in the activation of pyroptosis in oral squamous cell carcinoma.

Phytomedicine 2019 Mar 26;56:286-294. Epub 2018 Sep 26.

Department of Pharmacology (State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, PR China; Chronic Disease Research Institute, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, PR China. Electronic address:

Background: The anti-carcinogenic effects of anthocyanin are well documented. Oral squamous cell carcinoma is one of the most common and lethal cancer types due to its high degree of malignancy and poor prognosis. The main purpose of the current study was to investigate the potential inhibitory effects of anthocyanin on oral squamous cell carcinoma and identify effective targets for therapy.

Methods: Cell viability was measured using cell counting kit-8 (CCK8). Cell migration and invasion abilities were determined using scratch-wound and Transwell invasion assays, respectively. mRNA and protein expression patterns of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3), caspase-1 and IL-1β were detected using qRT-PCR, immunofluorescence and western blot. The gasdermin D (GSDMD) level was determined via confocal microscopy and western blot.

Results: Anthocyanin reduced the viability of oral squamous cell carcinoma cells and inhibited migration and invasion abilities. Simultaneously, activation of pyroptosis was associated with enhanced expression of NLRP3, caspase-1, and IL-1β. Upon administration of caspase-1 inhibitors, anthocyanin-activated pyroptosis was suppressed and cell viability, migration, and invasion rates concomitantly enhanced.

Conclusion: Anthocyanin promotes the death of oral squamous cell carcinoma cells through activation of pyroptosis and inhibits tumor progression.
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http://dx.doi.org/10.1016/j.phymed.2018.09.223DOI Listing
March 2019

Serum magnesium and the prevalence of peripheral artery disease: The Atherosclerosis Risk in Communities (ARIC) study.

Atherosclerosis 2019 03 20;282:196-201. Epub 2018 Dec 20.

Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China. Electronic address:

Background And Aims: Peripheral arterial disease (PAD) is a clinical manifestation of extracoronary atherosclerosis. Many risk factors are involved in the process of PAD, but the association between serum magnesium (Mg) and PAD is not clear. Our study aimed to investigate whether serum Mg is associated with PAD incidence.

Methods: A total of 13,826 participants (aged 40-64 years) in the Atherosclerosis Risk in Communities (ARIC) study (1987-1989) without prior PAD were included in the final analysis. Serum Mg levels were measured at visits 1 and 2. PAD was defined as an ankle brachial index less than 0.9, or hospitalization with a PAD diagnosis. Cox regression was used to calculate hazard ratios (HRs) for incidence of PAD and serum Mg.

Results: During a median follow-up of 24.4 years, 1364 (48.4% female) PAD events were observed. After multiple adjustment, participants in the lowest (≤1.4 mEq/L) category of serum Mg compared with the highest (≥1.8 mEq/L) ones were at higher PAD risk (HR: 1.3; 95% confidence interval (CI): 1.06-1.58) (p value = 0.004). The HRs for PAD in 1.5, 1.6 and 1.7 mEq/L of serum Mg were 1.29 (95% CI: 1.08-1.54), 1.05 (95% CI: 0.89-1.24), and 1.0 (95% CI: 0.85-1.18), respectively.

Conclusions: Low serum Mg was independently associated with an increased prevalence of PAD in the large population-based study; further studies are needed to confirm our findings.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.12.004DOI Listing
March 2019

EGF/EGFR upregulates and cooperates with Netrin-4 to protect glioblastoma cells from DNA damage-induced senescence.

BMC Cancer 2018 Dec 4;18(1):1215. Epub 2018 Dec 4.

Department of pharmacy, the Second Clinical College, Harbin Medical University, Harbin, People's Republic of China.

Background: Glioblastoma multiforme (GBM) is the most malignant central nervous system tumor. Alkylating agent, temozolomide (TMZ), is currently the first-line chemotherapeutic agent for GBM. However, the sensitivity of GBM cells to TMZ is affected by many factors. And, several clinic trials, including co-administration of TMZ with other drugs, have failed in successful treatment of GBM. We have previously reported that Netrin-4 (NTN4), a laminin-like axon guidance protein, plays a protective role in GBM cell senescence upon TMZ-triggered DNA damage. However, the master regulator of NTN4 needs further elucidation. Epidermal growth factor/Epidermal growth factor receptor (EGF/EGFR) can modulate the expression of various extracellular matrix related molecules, and prevent DNA damage in GBM cells. In this study, we investigated the relationship between EGF/EGFR signaling and NTN4, and explored their effect on therapeutic efficacy in GBM cells upon TMZ treatment.

Methods: Co-expression analysis were performed by using the RNA sequencing data from NIH 934 cell lines and from single cell RNA sequencing data of GBM tumor. The co-expressing genes were used for GO enrichment and signaling pathway enrichment. mRNA expression of the target genes were quantified by qPCR, and cell senescence were investigated by Senescence-Associated Beta-Galactosidase Staining. Protein phosphorylation were observed and analyzed by immunoblotting. The RNA sequencing data and clinical information of TMZ treated patients were extracted from TCGA-glioblastoma project, and then used for Kaplan-Meier survival analysis.

Results: Analysis of RNA sequencing data revealed a potential co-expression relationship between NTN4 and EGFR. GO enrichment of EGFR-correlated genes indicated that EGFR regulates GBM cells in a manner similar to that in central nervous system development and neural cell differentiation. Pathway analysis suggested that EGFR and its related genes contribute to cell adhesion, extracellular matrix (ECM) organization and caspase related signaling. We also show that EGF stimulates NTN4 expression in GBM cells and cooperates with NTN4 to attenuate GBM cell senescence induced by DNA damage, possibly via AKT and ERK. Clinical analysis showed that co-expression of EGFR and NTN4 significantly predicts poor survival in TMZ-treated GBM patients.

Conclusions: This study indicates that EGF/EGFR regulates and cooperates with NTN4 in DNA damage resistance in GBM. Therefore, our findings provide a potential therapeutic target for GBM.
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http://dx.doi.org/10.1186/s12885-018-5056-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280426PMC
December 2018

Activation of cardiac TrkB receptor by its small molecular agonist 7,8-dihydroxyflavone inhibits doxorubicin-induced cardiotoxicity via enhancing mitochondrial oxidative phosphorylation.

Free Radic Biol Med 2019 01 22;130:557-567. Epub 2018 Nov 22.

Institute of Clinical Pharmacology, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, PR China; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, PR China. Electronic address:

Brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) pathway has been revealed as a novel therapeutic target for several neurological diseases. Recently, small-molecule TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) has received considerable attention as a novel potential candidate for the treatment of various BDNF-implicated human disorders. However, its roles in cardiac diseases are not fully understood. Here, the present study aimed to clarify the effects and mechanisms of 7,8-DHF on doxorubicin (Dox)-induced cardiotoxicity. Kunming mice and H9c2 cells were employed to investigate the functional role of 7,8-DHF both in vivo and in vitro. 7,8-DHF markedly increased cell viability and reduced cell death of Dox-treated cells. Meanwhile, 7,8-DHF significantly increased mitochondrial respiration, membrane potential, and optic atrophy 1 (OPA1) protein expression. 7,8-DHF improved cardiac function and attenuated cardiac injury in Dox mice model. Expression of AMP-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) was restored by 7,8-DHF. Furthermore, the protective role of 7,8-DHF was abolished by ANA-12 (a specific antagonist of TrkB). In elucidating the molecular mechanism, the phosphorylation of Akt was significantly increased while extracellular regulated protein kinase (ERK) was decreased after 7,8-DHF treatment. The regulatory effects of 7,8-DHF on STAT3 and AMPK was reversed by Akt inhibitor. In summary, 7,8-DHF attenuated Dox-induced cardiotoxicity by activating Akt and increasing mitochondrial oxidative phosphorylation and thereby regulating STAT3, AMPK, and ERK signals. The present study enhanced current understanding of TrkB receptor in the cardiovascular system and provided a novel target for prevention and treatment of heart diseases.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.11.024DOI Listing
January 2019

Inhibition of MicroRNA-124 Reduces Cardiomyocyte Apoptosis Following Myocardial Infarction via Targeting STAT3.

Cell Physiol Biochem 2018 15;51(1):186-200. Epub 2018 Nov 15.

Institute of Clinical Pharmacy, the Second Affiliated Hospital of Harbin Medical University, The University Key Laboratory of Drug Research, Heilongjiang Province, Harbin,

Background/aims: MicroRNAs play an important role in regulating myocardial infarction (MI)-induced cardiac injury. MicroRNA-124 (miR-124) plays a vital role in regulating cellular proliferation, differentiation and apoptosis. Although the alteration of miR-124 was confirmed in peripheral blood of MI patients, little is known regarding the biological functions of miR-124 in cardiomyocytes. This study was designed to explore the role of miR-124 in MI and its underlying mechanisms.

Methods: Real-time PCR was used to quantify the microRNAs levels. TUNEL and Flow cytometry were performed to measure cell apoptosis. Western blot analysis was employed to detect expression of Bcl-2, Bax, Caspase-3 and STAT3 proteins.

Results: We revealed that miR-124 was significantly up-regulated in a mice model of MI and in neonatal rat ventricular myocytes (NRVMs) with H2O2 treatment. H2O2 treatment induced cardiomyocyte injury with reduced cell viability and enhanced apoptotic cell death, whereas silencing expression of miR-124 by AMO-124 (antisense inhibitor oligodeoxyribonucleotides) alleviated these deleterious changes. AMO-124 decreased the expression of Bax and cleaved-caspase-3 and upregulated the expression of Bcl-2 in H2O2-treated NRVMs. Besides, AMO-124 improved mitochondrial dysfunction of NRVMs induced by H2O2 treatment. Moreover, antagomir-124 markedly decreased the infarct area and apoptotic cardiomyocytes and improved cardiac function in MI mice. Furthermore, we identified STAT3 as a direct target of miR-124, and downregulation of miR-124 ameliorated the diminished levels of STAT3 and p-STAT3 (Tyr705) in response to H2O2 or MI. STAT3 inhibitor, stattic, was shown to attenuate the elevation of p-STAT3 in NRVMs with AMO-124 transfection. Inhibiting of STAT3 activity by stattic abrogated protective effects of AMO-124 on H2O2-induced cardiomyocytes apoptosis.

Conclusion: Taken together, our data demonstrate that downregulation of miR-124 inhibits MI-induced apoptosis through upregulating STAT3, which suggests the therapeutic potential of miR-124 for myocardial infarction.
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http://dx.doi.org/10.1159/000495173DOI Listing
December 2018

Metformin Protects against HO-Induced Cardiomyocyte Injury by Inhibiting the miR-1a-3p/GRP94 Pathway.

Mol Ther Nucleic Acids 2018 Dec 6;13:189-197. Epub 2018 Sep 6.

Institute of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China. Electronic address:

Ischemia-reperfusion (I/R) injury is a major side effect of the reperfusion treatment of the ischemic heart. Few therapies are available for the effective prevention of this injury caused by the oxidative stress-induced cardiomyocyte apoptosis. Metformin was shown to have a potential cardiac protective effect and ability to reduce cardiac events, but the exact mechanism remains unclear. Here, we aimed to confirm and investigate the mechanisms underlying potential metformin activity against I/R injury in response to oxidative stress. We determined that the expression of miR-1a-3p was significantly increased in neonatal rat ventricular cells (NRVCs), which were exposed to HOin vitro and in the hearts of mice that underwent the I/R injury. MiR-1a-3p was shown to target the 3' UTR of GRP94, which results in the accumulation of un- or misfolded proteins, leading to the endoplasmic reticulum (ER) stress. The obtained results demonstrated that C/EBP β directly induces the upregulation of miR-1a-3p by binding to its promoter. Furthermore, as a direct allosteric AMPK activator, metformin was shown to activate AMPK and significantly reduce C/EBP β and miR-1a-3p levels compared with those in the control group. In conclusion, metformin protects cardiomyocytes against HO damage through the AMPK/C/EBP β/miR-1a-3p/GRP94 pathway, which indicates that metformin may be applied for the treatment of I/R injury.
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http://dx.doi.org/10.1016/j.omtn.2018.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172474PMC
December 2018

Influence of baseline systolic blood pressure on the relationship between intensive blood pressure control and cardiovascular outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT).

Clin Res Cardiol 2019 Mar 24;108(3):273-281. Epub 2018 Aug 24.

Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.

Objective: To determine whether the effects of intensive (< 120 mmHg) compared with standard (< 140 mmHg) systolic blood pressure (SBP) treatments are different among those with different baseline SBP.

Methods: De-identified SPRINT database was used for this post hoc analysis. SPRINT participants were categorized by baseline SBP status, defined as high-SBP (≥ 140 mmHg) group versus the low-SBP (< 140 mmHg) group. The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes. Treatment-related adverse events including hypotension, syncope, and bradycardia were also evaluated. Cox regression was used to calculate hazard ratios for study outcomes with intensive compared with standard SBP treatment between these two groups.

Results: Among 9361 participants randomized (age 67.9 ± 9.4 years; 35.5% female), 4964 and 4397 had baseline low SBP (< 140 mmHg) and high SBP (≥ 140 mmHg), respectively. After a median follow-up of 3.26 years, the hazard ratio for the primary outcome was 0.65 (95% CI 0.50, 0.83) and 0.84 (95% CI 0.66, 1.06) among those in the low-SBP group and high-SBP group, respectively (P value for interaction 0.15). For treatment-related adverse events, the hazard ratio with intensive SBP treatment was 2.03 (95% CI 1.44, 2.85) for the low-SBP group and 1.80 (95% CI 1.32, 2.47) for the high-SBP group (P value for interaction 0.28).

Conclusions: Hypertensive patients with low baseline SBP may benefit from intensive SBP lowering, whereas benefits were inconclusive among those with high baseline SBP.
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http://dx.doi.org/10.1007/s00392-018-1353-9DOI Listing
March 2019