Publications by authors named "Yongzhen Guo"

10 Publications

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FNDC5/Irisin attenuates diabetic cardiomyopathy in a type 2 diabetes mouse model by activation of integrin αV/β5-AKT signaling and reduction of oxidative/nitrosative stress.

J Mol Cell Cardiol 2021 Jul 3;160:27-41. Epub 2021 Jul 3.

Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address:

Irisin, the cleaved form of the fibronectin type III domain containing 5 (FNDC5) protein, is involved in metabolism and inflammation. Recent findings indicated that irisin participated in cardiovascular physiology and pathology. In this study, we investigated the effects of FNDC5/irisin on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice. Downregulation of myocardial FNDC5/irisin protein expression and plasma irisin levels was observed in db/db mice compared to db/+ controls. Moreover, echocardiography revealed that db/db mice exhibited normal cardiac systolic function and impaired diastolic function. Adverse structural remodeling, including cardiomyocyte apoptosis, myocardial fibrosis, and cardiac hypertrophy were observed in the hearts of db/db mice. Sixteen-week-old db/db mice were intramyocardially injected with adenovirus encoding FNDC5 or treated with recombinant human irisin via a peritoneal implant osmotic pump for 4 weeks. Both overexpression of myocardial FNDC5 and exogenous irisin administration attenuated diastolic dysfunction and cardiac structural remodeling in db/db mice. Results from in vitro studies revealed that FNDC5/irisin protein expression was decreased in high glucose (HG)/high fat (HF)-treated cardiomyocytes. Increased levels of inducible nitric oxide synthase (iNOS), NADPH oxidase 2 (NOX2), 3-nitrotyrosine (3-NT), reactive oxygen species (ROS), and peroxynitrite (ONOO) in HG/HF-treated H9C2 cells provided evidence of oxidative/nitrosative stress, which was alleviated by treatment with FNDC5/irisin. Moreover, the mitochondria membrane potential (ΔΨm) was decreased and cytochrome C was released from mitochondria with increased levels of cleaved caspase-3 in HG/HF-treated H9C2 cells, indicating the presence of mitochondria-dependent apoptosis, which was partially reversed by FNDC5/irisin treatment. Mechanistic studies showed that activation of integrin αVβ5-AKT signaling and attenuation of oxidative/nitrosative stress were responsible for the cardioprotective effects of FNDC5/irisin. Therefore, FNDC5/irisin mediates cardioprotection in DCM by inhibiting myocardial apoptosis, myocardial fibrosis, and cardiac hypertrophy. These findings implicate that FNDC5/irisin as a potential therapeutic intervention for DCM, especially in type 2 diabetes mellitus (T2DM).
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http://dx.doi.org/10.1016/j.yjmcc.2021.06.013DOI Listing
July 2021

Damage to the blood‑brain barrier and activation of neuroinflammation by focal cerebral ischemia under hyperglycemic condition.

Int J Mol Med 2021 07 3;48(1). Epub 2021 Jun 3.

Department of Pathology, School of Basic Medical Science, Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Incubation Base of National Key Laboratory, Yinchuan, Ningxia 750004, P.R. China.

Hyperglycemia aggravates brain damage caused by cerebral ischemia/reperfusion (I/R) and increases the permeability of the blood‑brain barrier (BBB). However, there are relatively few studies on morphological changes of the BBB. The present study aimed to investigate the effect of hyperglycemia on BBB morphological changes following cerebral I/R injury. Streptozotocin‑induced hyperglycemic and citrate‑buffered saline‑injected normoglycemic rats were subjected to 30 min middle cerebral artery occlusion. Neurological deficits were evaluated. Brain infarct volume was assessed by 2,3,5‑triphenyltetrazolium chloride staining and BBB integrity was evaluated by Evans blue and IgG extravasation following 24 h reperfusion. Changes in tight junctions (TJ) and basement membrane (BM) proteins (claudin, occludin and zonula occludens‑1) were examined using immunohistochemistry and western blotting. Astrocytes, microglial cells and neutrophils were labeled with specific antibodies for immunohistochemistry after 1, 3 and 7 days of reperfusion. Hyperglycemia increased extravasations of Evan's blue and IgG and aggravated damage to TJ and BM proteins following I/R injury. Furthermore, hyperglycemia suppressed astrocyte activation and damaged astrocytic endfeet surrounding cerebral blood vessels following I/R. Hyperglycemia inhibited microglia activation and proliferation and increased neutrophil infiltration in the brain. It was concluded that hyperglycemia‑induced BBB leakage following I/R might be caused by damage to TJ and BM proteins and astrocytic endfeet. Furthermore, suppression of microglial cells and increased neutrophil infiltration to the brain may contribute to the detrimental effects of pre‑ischemic hyperglycemia on the outcome of cerebral ischemic stroke.
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http://dx.doi.org/10.3892/ijmm.2021.4975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175066PMC
July 2021

Self-Triggered Consensus of Vehicle Platoon System With Time-Varying Topology.

Front Neurorobot 2020 14;14:53. Epub 2020 Oct 14.

China Information Technology Security Evaluation Center, Beijing, China.

This paper focuses on the consensus problem of a vehicle platoon system with time-varying topology via self-triggered control. Unlike traditional control methods, a more secure event-triggered controller considering the safe distance was designed for the vehicle platoon system. Then, a Lyapunov function was designed to prove the stability of the platoon system. Furthermore, based on the new event-triggered function, a more energy efficient self-triggered control strategy was designed by using the Taylor formula. The new self-triggered control strategy can directly calculate the next trigger according to the state information of the last trigger. It avoids continuous calculation and measurement of vehicles. Finally, the effectiveness of the proposed two self-triggered control strategies were verified by numerical simulation experiments.
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http://dx.doi.org/10.3389/fnbot.2020.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591777PMC
October 2020

Recent Applications of Benzimidazole as a Privileged Scaffold in Drug Discovery.

Mini Rev Med Chem 2021 ;21(11):1367-1379

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 Wenhuaxi Road, 250012, Jinan, Shandong, China.

Benzimidazole is an aromatic bicyclic heterocycle that is regarded as a valuable privileged scaffold in medicinal chemistry. Many marketed drugs and natural products containing benzimidazole scaffolds exert great influence in fighting various diseases, such as hypertension, peptic ulcers, parasitic infections, and cancer. In this review, we introduce the pharmacological applications of some marketed drugs and lead compounds with a focus on anticancer agents, reporting the corresponding data to show the biological activities at their targets. The publications in this review encompass those from 2014 to 2019.
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http://dx.doi.org/10.2174/1389557520666200804124924DOI Listing
January 2021

Polycomb-like 2 regulates PRC2 components to affect proliferation in glioma cells.

J Neurooncol 2020 Jun 21;148(2):259-271. Epub 2020 May 21.

Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technological Enterprise (BRITE), North Carolina Central University, Durham, NC, USA.

Introduction: The Polycomb group (PcG) is an important family of transcriptional regulators that controls growth and tumorigenesis. The PcG mainly consists of two complexes, PRC1 and Polycomb Repressive Complex 2 (PRC2). Polycomb-like 2 (PCL2) is known to interact with the PRC2 protein. The role of PCL2 in the development and progression of glioma is unclear.

Methods: We use The Cancer Genome Atlas (TCGA) database to detect the expression of PCL2 in various tumors. 117 cases of clinical glioma (WHOI-IV) were collected, and PCL2 expression and localization were detected by immunohistochemical staining. Glioma cells U87/U251 were infected with overexpressed and interfered PCL2. CCK8 assay, colony formation assay, EdU method, cell cycle and apoptosis were used to detect cell proliferation and apoptosis. Western blot was used to detect the expression of PRC2-related core proteins. After DZNeP intervention, PRC2 protein expression was again measured to discuss the mechanism of PCL2 action.

Results: TCGA database results and immunohistochemical staining results suggest that PCL2 is highly expressed in gliomas. We found that the PCL2 gene promoted tumor cell proliferation, enhanced the colony formation ability, and increased S phase in the cell cycle. The overexpression of PCL2 upregulated the expression levels of EZH2 and EED (two core members of PRC2), decreased the expression of SUZ12, increased the level of H3K27 trimethylation (H3K27me3), H3K4 dimethylation (H3K4me2), and decreased H3K9 dimethylation (H3K9me2). The result after interfering with PCL2 was the opposite.

Conclusions: As an important accessory protein of PRC2, PCL2 can not only change the expression of PRC2 components, but also affect the expression level of Histone methylation. Therefore, PCL2 may be an important hub for regulating the synergy among PRC2 members. This study revealed PCL2 as a new target for tumor research and open up a new avenue for future research in glioma.
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http://dx.doi.org/10.1007/s11060-020-03538-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316845PMC
June 2020

N-Cadherin Overexpression Mobilizes the Protective Effects of Mesenchymal Stromal Cells Against Ischemic Heart Injury Through a β-Catenin-Dependent Manner.

Circ Res 2020 03 21;126(7):857-874. Epub 2020 Feb 21.

From the Department of Cardiology, Xijing Hospital (W.Y., C. Lin, Y.G., Y.C., Y.X., F.Z., R.S., C. Li, L.T.), Fourth Military Medical University, China.

Rationale: Mesenchymal stromal cell-based therapy is promising against ischemic heart failure. However, its efficacy is limited due to low cell retention and poor paracrine function. A transmembrane protein capable of enhancing cell-cell adhesion, N-cadherin garnered attention in the field of stem cell biology only recently.

Objective: The current study investigates whether and how N-cadherin may regulate mesenchymal stromal cells retention and cardioprotective capability against ischemic heart failure.

Methods And Results: Adult mice-derived adipose tissue-derived mesenchymal stromal cells (ADSC) were transfected with adenovirus harboring N-cadherin, T-cadherin, or control adenovirus. CM-DiI-labeled ADSC were intramyocardially injected into the infarct border zone at 3 sites immediately after myocardial infarction (MI) or myocardial ischemia/reperfusion. ADSC retention/survival, cardiomyocyte apoptosis/proliferation, capillary density, cardiac fibrosis, and cardiac function were determined. Discovery-driven/cause-effect analysis was used to determine the molecular mechanisms. Compared with ADSC transfected with adenovirus-control, N-cadherin overexpression (but not T-cadherin) markedly increased engrafted ADSC survival/retention up to 7 days post-MI. Histological analysis revealed that ADSC transfected with adenovirus-N-cadherin significantly preserved capillary density and increased cardiomyocyte proliferation and moderately reduced cardiomyocyte apoptosis 3 days post-MI. More importantly, ADSC transfected with adenovirus-N-cadherin (but not ADSC transfected with adenovirus-T-cadherin) significantly increased left ventricular ejection fraction and reduced fibrosis in both MI and myocardial ischemia/reperfusion mice. In vitro experiments demonstrated that N-cadherin overexpression promoted ADSC-cardiomyocyte adhesion and ADSC migration, enhancing their capability to increase angiogenesis and cardiomyocyte proliferation. MMP (matrix metallopeptidases)-10/13 and HGF (hepatocyte growth factor) upregulation is responsible for N-cadherin's effect upon ADSC migration and paracrine angiogenesis. N-cadherin overexpression promotes cardiomyocyte proliferation by HGF release. Mechanistically, N-cadherin overexpression significantly increased N-cadherin/β-catenin complex formation and active β-catenin levels in the nucleus. β-catenin knockdown abolished N-cadherin overexpression-induced MMP-10, MMP-13, and HGF expression and blocked the cellular actions and cardioprotective effects of ADSC overexpressing N-cadherin.

Conclusions: We demonstrate for the first time that N-cadherin overexpression enhances mesenchymal stromal cells-protective effects against ischemic heart failure via β-catenin-mediated MMP-10/MMP-13/HGF expression and production, promoting ADSC/cardiomyocyte adhesion and ADSC retention.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315806DOI Listing
March 2020

Tailorable Hydrogel Improves Retention and Cardioprotection of Intramyocardial Transplanted Mesenchymal Stem Cells for the Treatment of Acute Myocardial Infarction in Mice.

J Am Heart Assoc 2020 01 18;9(2):e013784. Epub 2020 Jan 18.

Department of Cardiology Xijing Hospital Fourth Military Medical University Xi'an China.

Background Poor engraftment of intramyocardial stem cells limits their therapeutic efficiency against myocardial infarction (MI)-induced cardiac injury. Transglutaminase cross-linked Gelatin (Col-Tgel) is a tailorable collagen-based hydrogel that is becoming an excellent biomaterial scaffold for cellular delivery in vivo. Here, we tested the hypothesis that Col-Tgel increases retention of intramyocardially-injected stem cells, and thereby reduces post-MI cardiac injury. Methods and Results Adipose-derived mesenchymal stem cells (ADSCs) were co-cultured with Col-Tgel in a 3-dimensional system in vitro, and Col-Tgel encapsulated ADSCs were observed using scanning electron microscopy and confocal microscopy. Vitality, proliferation, and migration of co-cultured ADSCs were evaluated. In addition, mice were subjected to MI and were intramyocardially injected with ADSCs, Col-Tgel, or a combination thereof. ADSCs engraftment, survival, cardiac function, and fibrosis were assessed. In vitro MTT and Cell Counting Kit-8 assays demonstrated that ADSCs survive and proliferate up to 4 weeks in the Col-Tgel. In addition, MTT and transwell assays showed that ADSCs migrate outside the edge of the Col-Tgel sphere. Furthermore, when compared with ADSCs alone, Col-Tgel-encapsulated ADSCs significantly enhanced the long-term retention and cardioprotective effect of ADSCs against MI-induced cardiac injury. Conclusions In the current study, we successfully established a 3-dimensional co-culture system using ADSCs and Col-Tgel. The Col-Tgel creates a suitable microenvironment for long-term retention of ADSCs in an ischemic area, and thereby enhances their cardioprotective effects. Taken together, this study may provide an alternative biomaterial for stem cell-based therapy to treat ischemic heart diseases.
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http://dx.doi.org/10.1161/JAHA.119.013784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033822PMC
January 2020

TXNIP/Redd1 signalling and excessive autophagy: a novel mechanism of myocardial ischaemia/reperfusion injury in mice.

Cardiovasc Res 2020 03;116(3):645-657

Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Rd, Xi'an 710032, China.

Aims: Either insufficient or excessive autophagy causes cellular death and contributes to myocardial ischaemia/reperfusion (I/R) injury. However, mechanisms controlling the 'right-level' of autophagy in the heart remains unidentified. Thioredoxin-interacting protein (TXNIP) is a pro-oxidative molecule knowing to contribute to I/R injury. However, whether and how TXNIP may further inhibit suppressed autophagy or promote excessive cardiac autophagy in I/R heart has not been previously investigated.

Methods And Results: Wild type or gene-manipulated adult male mice were subjected to myocardial I/R. TXNIP was increased in myocardium during I/R. Cardiac-specific TXNIP overexpression increased cardiomyocytes apoptosis and cardiac dysfunction, whereas cardiac-specific TXNIP knock-out significantly mitigated I/R-induced apoptosis and improved cardiac function. Importantly, TXNIP overexpression significantly promoted cardiac autophagy and TXNIP knock-out significantly inhibited cardiac autophagy. In vitro studies demonstrated that TXNIP increased autophagosome formation but inhibited autophagosome clearance during myocardial reperfusion. Atg5 siRNA significantly decreased hypoxia/reoxygenation induced apoptosis in cardiomyocytes with TXNIP overexpression. Mechanistically, TXNIP suppressed autophagosome clearance via increasing reactive oxygen species (ROS) level. However, TXNIP-increased autophagosome formation was not mediated by ROS as a ROS scavenger failed to block increased autophagosome formation in TXNIP overexpression heart. Finally, TXNIP directly interacted and stabilized Redd1 (an autophagy regulator), resulting in mTOR inhibition and autophagy activation. Redd1 knock-down significantly reduced autophagy formation and ameliorated I/R injury in TXNIP overexpression hearts.

Conclusions: Our results demonstrated that increased TXNIP-Redd1 expression is a novel signalling pathway that contributes to I/R injury by exaggerating excessive autophagy during reperfusion. These observations advance our understanding of the mechanisms of myocardial I/R injury.
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http://dx.doi.org/10.1093/cvr/cvz152DOI Listing
March 2020

Resistin promotes cardiac homing of mesenchymal stem cells and functional recovery after myocardial ischemia-reperfusion via the ERK1/2-MMP-9 pathway.

Am J Physiol Heart Circ Physiol 2019 01 9;316(1):H233-H244. Epub 2018 Nov 9.

Department of Cardiology, Xijing Hospital, Fourth Military Medical University , Xi'an , China.

Stem cell therapy is a potentially effective and promising treatment for ischemic heart disease. Resistin, a type of adipokine, has been found to bind to adipose-derived mesenchymal stem cells (ADSCs). However, the effects of resistin on cardiac homing by ADSCs and on ADSC-mediated cardioprotective effects have not been investigated. ADSCs were obtained from enhanced green fluorescent protein transgenic mice. C57BL/6J mice were subjected to myocardial ischemia-reperfusion (I/R) or sham operations. Six hours after the I/R operation, mice were intravenously injected with resistin-treated ADSCs (ADSC-resistin) or vehicle-treated ADSCs (ADSC-vehicle). Cardiac homing by ADSCs and cardiomyocyte apoptosis were investigated 3 days after I/R. Cardiac function, fibrosis, and angiogenesis were evaluated 4 wk after I/R. Cellular and molecular mechanisms were investigated in vitro using cultured ADSCs. Both immunostaining and flow cytometric experiments showed that resistin treatment promoted ADSC myocardial homing 3 days after intravenous injection. Echocardiographic experiments showed that ADSC-resistin, but not ADSC-vehicle, significantly improved left ventricular ejection fraction. ADSC-resistin transplantation significantly mitigated I/R-induced fibrosis and reduced atrial natriuretic peptide/brain natriuretic peptide mRNA expression. In addition, cardiomyocyte apoptosis was reduced, whereas angiogenesis was increased by ADSC-resistin treatment. At the cellular level, resistin promoted ADSC proliferation and migration but did not affect HO-induced apoptosis. Molecular experiments identified the ERK1/2-matrix metalloproteinase-9 pathway as a key component mediating the effects of resistin on ADSC proliferation and migration. These results demonstrate that resistin can promote homing of injected ADSCs into damaged heart tissue and stimulate functional recovery, an effect mediated through the ERK1/2 signaling pathway and matrix metalloproteinase-9. NEW & NOTEWORTHY First, intravenous injection of adipose-derived mesenchymal stem cells (ADSCs) treated with resistin significantly increased angiogenesis and reduced myocardial apoptosis and fibrosis in a murine model of ischemia-reperfusion, resulting in improved cardiac performance. Second, resistin treatment significantly increased myocardial homing of intravenously delivered ADSCs. Finally, the ERK1/2-matrix metalloproteinase 9 pathway contributed to the higher proliferative and migratory capacities of ADSCs treated with resistin.
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http://dx.doi.org/10.1152/ajpheart.00457.2018DOI Listing
January 2019

C1q/Tumor Necrosis Factor-Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways.

Circulation 2017 Nov 4;136(22):2162-2177. Epub 2017 Oct 4.

Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.Y., Y.G., W.B.L., L.G., Z.Y., R.G., Y.W., X.-L.M.).

Background: Cell therapy remains the most promising approach against ischemic heart injury. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for cardiac repair after myocardial infarction. CTRP9 (C1q/tumor necrosis factor-related protein-9) is a novel prosurvival cardiokine with significantly downregulated expression after myocardial infarction. Here we tested a hypothesis that CTRP9 might be a cardiokine required for a healthy microenvironment promoting implanted stem cell survival and cardioprotection.

Methods: Mice were subjected to myocardial infarction and treated with adipose-derived mesenchymal stem cells (ADSCs, intramyocardial transplantation), CTRP9, or their combination. Survival, cardiac remodeling and function, cardiomyocytes apoptosis, and ADSCs engraftment were evaluated. Whether CTRP9 directly regulates ADSCs function was determined in vitro. Discovery-drive approaches followed by cause-effect analysis were used to uncover the molecular mechanisms of CTRP9.

Results: Administration of ADSCs alone failed to exert significant cardioprotection. However, administration of ADSCs in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9 (<0.05 or <0.01 versus CTRP9 alone), suggesting a synergistic effect. Administration of CTRP9 at a dose recovering physiological CTRP9 levels significantly prolonged ADSCs retention/survival after implantation. Conversely, the number of engrafted ADSCs was significantly reduced in the CTRP9 knockout heart. In vitro study demonstrated that CTRP9 promoted ADSCs proliferation and migration, and it protected ADSCs against hydrogen peroxide-induced cellular death. CTRP9 enhances ADSCs proliferation/migration by extracellular regulated protein kinases (ERK)1/2-matrix metallopeptidase 9 signaling and promotes antiapoptotic/cell survival via ERK-nuclear factor erythroid-derived 2-like 2/antioxidative protein expression. N-cadherin was identified as a novel CTRP9 receptor mediating ADSCs signaling. Blockade of either N-cadherin or ERK1/2 completely abolished the previously noted CTRP9 effects. Although CTRP9 failed to promote ADSCs cardiogenic differentiation, CTRP9 promotes superoxide dismutase 3 expression and secretion from ADSCs, protecting cardiomyocytes against oxidative stress-induced cell death.

Conclusions: We provide the first evidence that CTRP9 promotes ADSCs proliferation/survival, stimulates ADSCs migration, and attenuates cardiomyocyte cell death by previously unrecognized signaling mechanisms. These include binding with N-cadherin, activation of ERK-matrix metallopeptidase 9 and ERK-nuclear factor erythroid-derived 2-like 2 signaling, and upregulation/secretion of antioxidative proteins. These results suggest that CTRP9 is a cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue, thereby enhancing stem cell therapeutic efficacy.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.029557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705403PMC
November 2017