Publications by authors named "Guoshuai Feng"

4 Publications

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Ferroptotic cell death and TLR4/Trif signaling initiate neutrophil recruitment after heart transplantation.

J Clin Invest 2019 02 26;129(6):2293-2304. Epub 2019 Feb 26.

Department of Surgery and.

Non-apoptotic forms of cell death can trigger sterile inflammation through the release of danger-associated molecular patterns, which are recognized by innate immune receptors. However, despite years of investigation the mechanisms which initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation. Inhibition of necroptosis had no effect on neutrophil trafficking in cardiac grafts. We extend these observations to a model of coronary artery ligation-induced myocardial ischemia reperfusion injury where inhibition of ferroptosis resulted in reduced infarct size, improved left ventricular systolic function, and reduced left ventricular remodeling. Using intravital imaging of cardiac transplants, we uncover that ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through a TLR4/TRIF/type I IFN signaling pathway. Thus, we have discovered that inflammatory responses after cardiac transplantation are initiated through ferroptotic cell death and TLR4/Trif-dependent signaling in graft endothelial cells. These findings provide a platform for the development of therapeutic strategies for heart transplant recipients and patients, who are vulnerable to ischemia reperfusion injury following restoration of coronary blood flow.
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http://dx.doi.org/10.1172/JCI126428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546457PMC
February 2019

Molecular Imaging Visualizes Recruitment of Inflammatory Monocytes and Macrophages to the Injured Heart.

Circ Res 2019 03;124(6):881-890

Department of Medicine (B.K., G.F., G.B., S.L.B., K.J.L.), Washington University School of Medicine, St. Louis, MO.

Rationale: Paradigm shifting studies have revealed that the heart contains functionally diverse populations of macrophages derived from distinct embryonic and adult hematopoietic progenitors. Under steady-state conditions, the heart is largely populated by CCR2- (C-C chemokine receptor type 2) macrophages of embryonic descent. After tissue injury, a dramatic shift in macrophage composition occurs whereby CCR2+ monocytes are recruited to the heart and differentiate into inflammatory CCR2+ macrophages that contribute to heart failure progression. Currently, there are no techniques to noninvasively detect CCR2+ monocyte recruitment into the heart and thus identify patients who may be candidates for immunomodulatory therapy.

Objective: To develop a noninvasive molecular imaging strategy with high sensitivity and specificity to visualize inflammatory monocyte and macrophage accumulation in the heart.

Methods And Results: We synthesized and tested the performance of a positron emission tomography radiotracer (Ga-DOTA [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-ECL1i [extracellular loop 1 inverso]) that allosterically binds to CCR2. In naive mice, the radiotracer was quickly cleared from the blood and displayed minimal retention in major organs. In contrast, biodistribution and positron emission tomography demonstrated strong myocardial tracer uptake in 2 models of cardiac injury (diphtheria toxin induced cardiomyocyte ablation and reperfused myocardial infarction). Ga-DOTA-ECL1i signal localized to sites of tissue injury and was independent of blood pool activity as assessed by quantitative positron emission tomography and ex vivo autoradiography. Ga-DOTA-ECL1i uptake was associated with CCR2+ monocyte and CCR2+ macrophage infiltration into the heart and was abrogated in CCR2 mice, demonstrating target specificity. Autoradiography demonstrated that Ga-DOTA-ECL1i specifically binds human heart failure specimens and with signal intensity associated with CCR2+ macrophage abundance.

Conclusions: These findings demonstrate the sensitivity and specificity of Ga-DOTA-ECL1i in the mouse heart and highlight the translational potential of this agent to noninvasively visualize CCR2+ monocyte recruitment and inflammatory macrophage accumulation in patients.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.314030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435034PMC
March 2019

SIRT3 prevents angiotensin II-induced renal tubular epithelial-mesenchymal transition by ameliorating oxidative stress and mitochondrial dysfunction.

Mol Cell Endocrinol 2018 01 1;460:1-13. Epub 2017 Jun 1.

Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, People's Republic of China; National and Local Joint Engineering Laboratory of Druggabilitiy Assessment and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, People's Republic of China. Electronic address:

Silent mating type information regulation 2 homolog 3 (SIRT3) is a major protective mediator that ameliorates oxidative stress and mitochondrial dysfunction, which are associated with the pathogenesis of epithelial-mesenchymal transition (EMT). The present study was aimed to investigate the potential role of SIRT3 in renal tubular EMT both in vitro and in vivo. Firstly, we showed that the expression of SIRT3 was repressed in angiotensin II-induced EMT. SIRT3 deficiency triggered EMT response, while over-expression of SIRT3 attenuated EMT response. In addition, over-expression of SIRT3 repressed AngⅡ-induced excessive production of mitochondrial superoxide, as well as mitochondrial dysfunction evidenced by the maintenance of mitochondrial number and morphology, and the stabilization of mitochondrial membrane potential. In conclusion, these findings identify a protective role of SIRT3 against angiotensin II-induced EMT in the kidney, and suggest SIRT3 upregulation is a potential therapeutic strategy for the treatment of renal tubulointerstitial fibrosis.
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http://dx.doi.org/10.1016/j.mce.2017.04.027DOI Listing
January 2018

Protective effect of chinonin in MPTP-induced C57BL/6 mouse model of Parkinson's disease.

Biol Pharm Bull 2014 28;37(8):1301-7. Epub 2014 May 28.

College of Pharmacy, Jinan University.

The aims of this study were to investigate the effect of chinonin in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration in C57BL/6 mice and to examine the possible mechanisms. The neurotoxin MPTP was employed to create a subacute Parkinson's disease (PD)-like model in C57BL/6 mice. Chinonin (10, 20, 40 mg/kg body weight) was intraperitoneally administered 0.5 h after MPTP (30 mg/kg) injection for 7 d consecutively. Chinonin showed neuroprotective effects in the MPTP-treated mice PD model by ameliorating motor impairment in the catwalk and open-field tests. Consistently, chinonin reduced loss of dopaminergic neurons in the substantia nigra and prevented depletion of dopamine and its metabolites 3-methoxy-4-hydroxy-phenylacetic acid and homovanillic acid in the striatum of mice. Compared with the MPTP group, in the chinonin plus MPTP groups significant increases of superoxide dismutase activity and glutathione levels were observed as well as a distinct reduction of lipid peroxidation product malondialdehyde in the striatum. Taken together, we propose that chinonin exerts neuroprotective effects in C57BL/6 mouse model of PD and these effects may be due to chinonin's antioxidative property.
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http://dx.doi.org/10.1248/bpb.b14-00128DOI Listing
April 2015