Publications by authors named "Ziqing Li"

38 Publications

HO-1 nuclear accumulation and interaction with NPM1 protect against stress-induced endothelial senescence independent of its enzymatic activity.

Cell Death Dis 2021 Jul 26;12(8):738. Epub 2021 Jul 26.

Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou, China.

Heme oxygenase-1 (HO-1) has attracted accumulating attention for its antioxidant enzymatic activity. However, the exact regulatory role of its non-enzymatic activity in the cardiovascular system remains unaddressed. Here, we show that HO-1 was accumulated in the nuclei of stress-induced senescent endothelial cells, and conferred protection against endothelial senescence independent of its enzymatic activity. Overexpression of ΔHO-1, a truncated HO-1 without transmembrane segment (TMS), inhibited HO-induced endothelial senescence. Overexpression of ΔHO-1, the catalytically inactive form of ΔHO-1, also exhibited anti-senescent effect. In addition, infection of recombinant adenovirus encoding ΔHO-1 with three nuclear localization sequences (NLS), alleviated endothelial senescence induced by knockdown of endogenous HO-1 by CRISPR/Cas9. Moreover, repression of HO-1 nuclear translocation by silencing of signal peptide peptidase (SPP), which is responsible for enzymatic cleavage of the TMS of HO-1, exacerbated endothelial senescence. Mechanistically, nuclear HO-1 interacted with NPM1 N-terminal portion, prevented NPM1 translocation from nucleolus to nucleoplasm, thus disrupted NPM1/p53/MDM2 interactions and inhibited p53 activation by NPM1, finally resisted endothelial senescence. This study provides a novel understanding of HO-1 as a promising therapeutic strategy for vascular senescence-related cardiovascular diseases.
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http://dx.doi.org/10.1038/s41419-021-04035-6DOI Listing
July 2021

Synthesis, Electronic Structure, and Electrochemical Properties of the Cubic MgMnO Spinel with Porous-Spongy Structure.

Nanomaterials (Basel) 2021 Apr 27;11(5). Epub 2021 Apr 27.

State Key Laboratory of Crystal Materials, Institute of Crystal Materials, Shandong University, Jinan 250100, China.

MgMnO nanoparticles with cubic spinel structure were synthesized by the sol-gel method using polyvinyl alcohol (PVA) as a chelating agent. X-ray powder diffraction, infrared spectrum (IR), scanning electron microscope (SEM), and transmission electron microscope (TEM) were used to characterize the crystalline phase and particle size of as-synthesized nanoparticles. The electronic structure of MgMnO spinel was studied by X-ray photoelectron spectroscopy (XPS). The results showed that pure cubic MgMnO spinel nanoparticles were obtained when the annealing temperature was 500-700 °C. The samples had a porous-spongy structure assembled by nanoparticles. XPS studies indicated that MgMnO nanoparticles were mixed spinel structures and the degree of cation inversion decreased with increasing annealing temperature. Furthermore, the performance of MgMnO as lithium anode material was studied. The results showed that MgMnO samples had good cycle stability except for the slight decay in the capacity at 50 cycles. The coulombic efficiency (ratio of discharge and charge capacity) in most cycles was near 100%. The sample annealed at 600 °C exhibited good electrochemical properties, the first discharge capacity was 771.5 mAh/g, and the capacity remained 340 mAh/g after 100 cycles. The effect of calcination temperature on the charge-discharge performance of the samples was studied and discussed.
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http://dx.doi.org/10.3390/nano11051122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145627PMC
April 2021

Nano nickel embedded in N-doped CNTs-supported porous biochar for adsorption-reduction of hexavalent chromium.

J Hazard Mater 2021 Aug 20;416:125693. Epub 2021 Mar 20.

State Key Laboratory of Coal Combustion, School of Power and Energy Engineering, Huazhong University of Science and Technology, 430074 Wuhan, China; Department of New Energy Science and Engineering, School of Energy and Power Engineering, Huazhong University of Science and Technology, 430074 Wuhan, China.

Nitrogen-doped carbon coated transition metal hybrids for the removal of hazardous hexavalent chromium (Cr(VI)) has attracted increasing attention in wastewater treatment recently. In this study, three-dimensional nano-nickel particles embedded in N-doped carbon nanotubes supported on porous biochar ([email protected]) were synthesized by a two-stage strategy of KOH activation followed by annealing. The effect of KOH activation treatment on the doping process and Cr(VI) removal properties were investigated. The results indicate that KOH activation can improve the pore parameters and promote subsequent doping of Ni and N and the growth of carbon nanotubes (CNTs). After KOH pretreatment, the specific surface area of [email protected] increased significantly to 604.62 m/g. The improved pore structure accelerates the mass diffusion of Cr(VI) ions and provides an available surface for the adsorption and reduction of Cr(VI). Therefore, the [email protected] obtained at 900 °C showed a high removal capacity for Cr(VI) (824.4 mg/g) and a stronger ability to reduce to Cr(III).
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http://dx.doi.org/10.1016/j.jhazmat.2021.125693DOI Listing
August 2021

Longitudinal Expression of Testicular from Prepuberty to Sexual Maturity in Congjiang Xiang Pigs.

Animals (Basel) 2021 Feb 8;11(2). Epub 2021 Feb 8.

College of Animal Science, Guizhou University, Guiyang 550025, China.

Testicular expression of taste receptor type 1 subunit 3 (T1R3), a sweet/umami taste receptor, has been implicated in spermatogenesis and steroidogenesis in mice. We explored the role of testicular T1R3 in porcine postnatal development using the Congjiang Xiang pig, a rare Chinese miniature pig breed. Based on testicular weights, morphology, and testosterone levels, four key developmental stages were identified in the pig at postnatal days 15-180 (prepuberty: 30 day; early puberty: 60 day; late puberty: 90 day; sexual maturity: 120 day). During development, testicular T1R3 exhibited stage-dependent and cell-specific expression patterns. In particular, T1R3 levels increased significantly from prepuberty to puberty ( < 0.05), and expression remained high until sexual maturity ( < 0.05), similar to results for phospholipase Cβ2 (PLCβ2). The strong expressions of T1R3/PLCβ2 were observed at the cytoplasm of elongating/elongated spermatids and Leydig cells. In the eight-stage cycle of the seminiferous epithelium in pigs, T1R3/PLCβ2 levels were higher in the spermatogenic epithelium at stages II-VI than at the other stages, and the strong expressions were detected in elongating/elongated spermatids and residual bodies. The message RNA (mRNA) levels of taste receptor type 1 subunit 1 (T1R1) in the testis showed a similar trend to levels of T1R3. These data indicate a possible role of T1R3 in the regulation of spermatid differentiation and Leydig cell function.
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http://dx.doi.org/10.3390/ani11020437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916009PMC
February 2021

Pterostilbene and its nicotinate derivative ameliorated vascular endothelial senescence and elicited endothelium-dependent relaxations via activation of sirtuin 1.

Can J Physiol Pharmacol 2021 Feb 2:1-10. Epub 2021 Feb 2.

Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences; National and Local United Engineering Lab of Druggability and New Drugs Evaluation; Guangdong Engineering Laboratory of Druggability and New Drug Evaluation; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou, P.R. China.

Vascular endothelial cell senescence is a leading cause of age-associated diseases and cardiovascular diseases. Interventions and therapies targeting endothelial cell senescence and dysfunction would have important clinical implications. This study evaluated the effect of 10 resveratrol analogues, including pterostilbene (Pts) and its derivatives, against endothelial senescence and dysfunction. All the tested compounds at the concentrations from 10 M to 10 M did not show cytotoxicity in endothelial cells by MTT assay. Among the 10 resveratrol analogues, Pts and Pts nicotinate attenuated the expression of senescence-associated β-galactosidase, downregulated p21 and p53, and increased the production of nitric oxide (NO) in both angiotensin II - and hydrogen peroxide - induced endothelial senescence models. In addition, Pts and Pts nicotinate elicited endothelium-dependent relaxations, which were attenuated in the presence of endothelial NO synthase (eNOS) inhibitor L-NAME or sirtuin 1 (SIRT1) inhibitor sirtinol. Pts and Pts nicotinate did not alter SIRT1 expression but enhanced its activity. Both Pts and Pts nicotinate have high binding activities with SIRT1, according to surface plasmon resonance results and the molecular docking analysis. Inhibition of SIRT1 by sirtinol reversed the anti-senescent effects of Pts and Pts nicotinate. Moreover, Pts and Pts nicotinate shared similar ADME (absorption, distribution, metabolism, excretion) profiles and physiochemical properties. This study suggests that the Pts and Pts nicotinate ameliorate vascular endothelial senescence and elicit endothelium-dependent relaxations via activation of SIRT1. These two compounds may be potential drugs for the treatment of cardiovascular diseases related to endothelial senescence and dysfunction.
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http://dx.doi.org/10.1139/cjpp-2020-0583DOI Listing
February 2021

Bone marrow adipogenic lineage precursors promote osteoclastogenesis in bone remodeling and pathologic bone loss.

J Clin Invest 2021 Jan;131(2)

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Bone is maintained by coupled activities of bone-forming osteoblasts/osteocytes and bone-resorbing osteoclasts. Alterations in this relationship can lead to pathologic bone loss such as osteoporosis. It is well known that osteogenic cells support osteoclastogenesis via production of RANKL. Interestingly, our recently identified bone marrow mesenchymal cell population-marrow adipogenic lineage precursors (MALPs) that form a multidimensional cell network in bone-was computationally demonstrated to be the most interactive with monocyte-macrophage lineage cells through high and specific expression of several osteoclast regulatory factors, including RANKL. Using an adipocyte-specific Adipoq-Cre to label MALPs, we demonstrated that mice with RANKL deficiency in MALPs have a drastic increase in trabecular bone mass in long bones and vertebrae starting from 1 month of age, while their cortical bone appears normal. This phenotype was accompanied by diminished osteoclast number and attenuated bone formation at the trabecular bone surface. Reduced RANKL signaling in calvarial MALPs abolished osteolytic lesions after LPS injections. Furthermore, in ovariectomized mice, elevated bone resorption was partially attenuated by RANKL deficiency in MALPs. In summary, our studies identified MALPs as a critical player in controlling bone remodeling during normal bone metabolism and pathological bone loss in a RANKL-dependent fashion.
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http://dx.doi.org/10.1172/JCI140214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810488PMC
January 2021

Rhamnocitrin extracted from Nervilia fordii inhibited vascular endothelial activation via miR-185/STIM-1/SOCE/NFATc3.

Phytomedicine 2020 Dec 19;79:153350. Epub 2020 Sep 19.

Mathematical Engineering Academy of Chinese Medicine; Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China. Electronic address:

Background: Vascular endothelial activation is pivotal for the pathological development of various infectious and inflammatory diseases. Therapeutic interventions to prevent endothelial activation are of great clinical significance to achieve anti-inflammatory strategy. Previous studies indicate that the total flavonoids from the endemic herbal medicine Nervilia fordii (Hance) Schltr exerts potent anti-inflammatory effect and protective effect against endotoxin lipopolysaccharide (LPS)-induced acute lung injury, and shows clinical benefit in severe acute respiratory syndromes (SARS). However, the exact effective component of Nervilia fordii and its potential mechanism remain unknown.

Purpose: The aim of this study was to investigate the effect and mechanism of rhamnocitrin (RH), a flavonoid extracted from Nervilia fordii, on LPS-induced endothelial activation.

Methods: The in vitro endothelial cell activation model was induced by LPS in human umbilical vein endothelial cells (HUVECs). Cell viability was measured to determine the cytotoxicity of RH. RT-PCR, Western blot, fluorescent probe and immunofluorescence were conducted to evaluate the effect and mechanism of RH against endothelial activation.

Results: RH was extracted and isolated from Nervilia fordii. RH at the concentration from 10 M-10 M inhibited the expressions of interlukin-6 (IL-6) and -8 (IL-8), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) in response to LPS challenge. Mechanistically, RH repressed calcium store-operated Ca entry (SOCE) induced by LPS, which is due to downregulation of stromal interaction molecule-1 (STIM-1) following upregulating microRNA-185 (miR-185). Ultimately, RH abrogated LPS-induced activation of SOCE-mediated calcineurin/NFATc3 (nuclear factor of activated T cells, cytoplasmic 3) signaling pathway.

Conclusion: The present study identifies RH as a potent inhibitor of endothelial activation. Since vascular endothelial activation is a pivotal cause of excessive cytokine production, leading to cytokine storm and severe pathology in infectious diseases such as SARS and the ongoing COVID-19 pneumonia disease, RH might suggest promising therapeutic potential in the management of cytokine storm in these diseases.
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http://dx.doi.org/10.1016/j.phymed.2020.153350DOI Listing
December 2020

Prostacyclin facilitates vascular smooth muscle cell phenotypic transformation via activating TP receptors when IP receptors are deficient.

Acta Physiol (Oxf) 2021 02 20;231(2):e13555. Epub 2020 Sep 20.

Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drug Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangdong, PR China.

Aim: By activating prostacyclin receptors (IP receptors), prostacyclin (PGI ) exerts cardiovascular protective effects such as vasodilation and inhibition of vascular smooth muscle cell (VSMC) proliferation. However, IP receptors are dysfunctional under pathological conditions, and PGI produces detrimental effects that are opposite to its physiological protective effects via thromboxane-prostanoid (TP) receptors. This attempted to investigate whether or not IP receptor dysfunction facilitates the shift of PGI action.

Methods: The effects of PGI and its stable analog iloprost on VSMC phenotypic transformation and proliferation were examined in A10 cells silencing IP receptors, in human aortic VSMCs (HAVSMCs) knocked down IP receptor by CRISPR-Cas9, or in HAVSMCs transfected with a dysfunctional mutation of IP receptor IP .

Results: PGI /iloprost treatment stimulated cell proliferation, upregulated synthetic proteins and downregulated contractile proteins, suggesting that PGI /iloprost promotes VSMC phenotypic transformation in IP-deficient cells. The effect of PGI /iloprost was prevented by TP antagonist S18886 or TP knockdown, indicating that the VSMC detrimental effect of PGI is dependent on TP receptor. RNA sequencing and Western blotting results showed that RhoA/ROCKs, MEK1/2 and JNK signalling cascades were involved. Moreover, IP deficiency increased the distribution of TP receptors at the cell membrane.

Conclusion: PGI induces VSMC phenotypic transformation when IP receptors are impaired. This is attributed to the activation of TP receptor and its downstream signaling cascades, and to the increased membrane distribution of TP receptors. The VSMC detrimental effect of PGI medicated by IP dysfunction and TP activation might probably exacerbate vascular remodelling, accelerating cardiovascular diseases.
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http://dx.doi.org/10.1111/apha.13555DOI Listing
February 2021

Osteoimmunology in Bone Regeneration.

Biomed Res Int 2020 17;2020:6297356. Epub 2020 Jul 17.

Department of Medicine, Hematology & Oncology Division, University of Texas Health San Antonio, San Antonio, USA.

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http://dx.doi.org/10.1155/2020/6297356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387990PMC
April 2021

Efficacy of a small molecule inhibitor of the transcriptional cofactor PC4 in prevention and treatment of non-small cell lung cancer.

PLoS One 2020 31;15(3):e0230670. Epub 2020 Mar 31.

AscentGene, Inc., Gaithersburg, MD, United States of America.

The human positive coactivator 4 (PC4) was originally identified as a multi-functional cofactor capable of mediating transcription activation by diverse gene- and tissue-specific activators. Recent studies suggest that PC4 might also function as a novel cancer biomarker and therapeutic target for different types of cancers. siRNA knockdown studies indicated that down-regulation of PC4 expression could inhibit tumorigeneicity of A549 non-small cell lung cancer tumor model in nude mice. Here we show that AG-1031, a small molecule identified by high throughput screening, can inhibit the double-stranded DNA binding activity of PC4, more effectively than its single-stranded DNA binding activity. AG-1031 also specifically inhibited PC4-dependent transcriptional activation in vitro using purified transcription factors. AG-1031 inhibited proliferation of several cultured cell lines derived from non-small cell lung cancers (NSCLC) and growth of tumors that formed from A549 cell xenografts in immuno-compromised mice. Moreover, pre-injection of AG-1031 in these mice not only reduced tumor size, but also prevented tumor formation in 20% of the animals. AG-1031 treated A549 cells and tumors from AG-1031 treated animals showed a significant decrease in the levels of both PC4 and VEGFC, a key mediator of angiogenesis in cancer. On the other hand, all tested mice remained constant weight during animal trials. These results demonstrated that AG-1031 could be a potential therapy for PC4-positive NSCLC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230670PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108703PMC
June 2020

Friend or Foe? Essential Roles of Osteoclast in Maintaining Skeletal Health.

Biomed Res Int 2020 3;2020:4791786. Epub 2020 Mar 3.

Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Heightened activity of osteoclast is considered to be the culprit in breaking the balance during bone remodeling in pathological conditions, such as osteoporosis. As a "foe" of skeletal health, many antiosteoporosis therapies aim to inhibit osteoclastogenesis. However, bone remodeling is a dynamic process that requires the subtle coordination of osteoclasts and osteoblasts. Severe suppression of osteoclast differentiation will impair bone formation because of the coupling effect. Thus, understanding the complex roles of osteoclast in maintaining proper bone remodeling is highly warranted to develop better management of osteoporosis. This review aimed to determine the varied roles of osteoclasts in maintaining skeletal health and to highlight the positive roles of osteoclasts in maintaining normal bone remodeling. Generally, osteoclasts interact with osteocytes to initiate targeted bone remodeling and have crosstalk with mesenchymal stem cells and osteoblasts via secreted factors or cell-cell contact to promote bone formation. We believe that a better outcome of bone remodeling disorders will be achieved when proper strategies are made to coordinate osteoclasts and osteoblasts in managing such disorders.
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http://dx.doi.org/10.1155/2020/4791786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073503PMC
December 2020

Regulator of G protein signaling 12 enhances osteoclastogenesis by suppressing Nrf2-dependent antioxidant proteins to promote the generation of reactive oxygen species.

Elife 2019 09 6;8. Epub 2019 Sep 6.

Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, United States.

Regulators of G-protein Signaling are a conserved family of proteins required in various biological processes including cell differentiation. We previously demonstrated that Rgs12 is essential for osteoclast differentiation and its deletion in vivo protected mice against pathological bone loss. To characterize its mechanism in osteoclastogenesis, we selectively deleted Rgs12 in C57BL/6J mice targeting osteoclast precursors using -driven Cre mice or overexpressed Rgs12 in RAW264.7 cells. Rgs12 deletion in vivo led to an osteopetrotic phenotype evidenced by increased trabecular bone, decreased osteoclast number and activity but no change in osteoblast number and bone formation. Rgs12 overexpression increased osteoclast number and size, and bone resorption activity. Proteomics analysis of Rgs12-depleted osteoclasts identified an upregulation of antioxidant enzymes under the transcriptional regulation of Nrf2, the master regulator of oxidative stress. We confirmed an increase of Nrf2 activity and impaired reactive oxygen species production in Rgs12-deficient cells. Conversely, Rgs12 overexpression suppressed Nrf2 through a mechanism dependent on the 26S proteasome, and promoted RANKL-induced phosphorylation of ERK1/2 and NFκB, which was abrogated by antioxidant treatment. Our study therefore identified a novel role of Rgs12 in regulating Nrf2, thereby controlling cellular redox state and osteoclast differentiation.
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http://dx.doi.org/10.7554/eLife.42951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731062PMC
September 2019

Regulator of G Protein Signaling Protein 12 (Rgs12) Controls Mouse Osteoblast Differentiation via Calcium Channel/Oscillation and Gαi-ERK Signaling.

J Bone Miner Res 2019 04 28;34(4):752-764. Epub 2019 Jan 28.

Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Bone homeostasis intimately relies on the balance between osteoblasts (OBs) and osteoclasts (OCs). Our previous studies have revealed that regulator of G protein signaling protein 12 (Rgs12), the largest protein in the Rgs super family, is essential for osteoclastogenesis from hematopoietic cells and OC precursors. However, how Rgs12 regulates OB differentiation and function is still unknown. To understand that, we generated an OB-targeted Rgs12 conditional knockout (CKO) mice model by crossing Rgs12 mice with Osterix (Osx)-Cre transgenic mice. We found that Rgs12 was highly expressed in both OB precursor cells (OPCs) and OBs of wild-type (WT) mice, and gradually increased during OB differentiation, whereas Rgs12-CKO mice (Osx ; Rgs12 ) exhibited a dramatic decrease in both trabecular and cortical bone mass, with reduced numbers of OBs and increased apoptotic cell population. Loss of Rgs12 in OPCs in vitro significantly inhibited OB differentiation and the expression of OB marker genes, resulting in suppression of OB maturation and mineralization. Further mechanism study showed that deletion of Rgs12 in OPCs significantly inhibited guanosine triphosphatase (GTPase) activity and cyclic adenosine monophosphate (cAMP) level, and impaired Calcium (Ca ) oscillations via restraints of major Ca entry sources (extracellular Ca influx and intracellular Ca release from endoplasmic reticulum), partially contributed by the blockage of L-type Ca channel mediated Ca influx. Downstream mediator extracellular signal-related protein kinase (ERK) was found inactive in OBs of Osx ; Rgs12 mice and in OPCs after Rgs12 deletion, whereas application of pertussis toxin (PTX) or overexpression of Rgs12 could rescue the defective OB differentiation via restoration of ERK phosphorylation. Our findings reveal that Rgs12 is an important regulator during osteogenesis and highlight Rgs12 as a potential therapeutic target for bone disorders. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675783PMC
April 2019

Electroacupuncture for patients with irritable bowel syndrome: A systematic review and meta-analysis protocol.

Medicine (Baltimore) 2018 Aug;97(31):e11627

The Second Clinical School of Guangzhou University of Chinese Medicine The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.

Background: Irritable bowel syndrome (IBS) is a common functional intestinal disease characterized by chronic or recurrent abdominal pain, abdominal distension, constipation and diarrhea. Many IBS sufferers are usually present with poor quality of life for the abdominal discomfort, diarrhea, constipation, and other complaints. At present, the commonly used drug therapy for IBS in the Western clinic, such as antidiarrheal, laxative, gastrointestinal antispasmodic, often cannot get satisfying curative effect. Thus complementary therapies like electroacupuncture (EA) which may be effective to decrease patients' pain and fewer side-effects will be sought. EA, an innovative form of traditional acupuncture, is drawing more attention to the treatment of IBS due to its roles in symptom improvement. This systematic review protocol aims at describing a meta-analysis to critically evaluate the effectiveness and safety on EA for patients with IBS.

Methods: We search Ovid MEDLINE, Ovid Embase, PubMed, the Cochrane Central Register of Controlled Trials (Cochrane Library), the Allied and Complementary Medicine Databases (AMED), China National Knowledge Infrastructure (CNKI) for random controlled trials EA for IBS from their inception to April 1, 2018. Two reviewers will independently screen studies for data extraction and assess the quality and risk of bias. RevManV5. 3 will be applied to data extraction. Risk of bias for each RCT will be assessed according to criteria by the Cochrane Handbook to evaluate the methodological quality.

Results: This study will provide a high-quality synthesis of current evidence of effectiveness and safety on EA for patients with IBS.

Conclusion: The conclusion of our systematic review will provide evidence to judge whether EA is an effective intervention for patient with IBS.

Prospero Registration Number: PROSPERO CRD42018081610.
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http://dx.doi.org/10.1097/MD.0000000000011627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081165PMC
August 2018

Heme oxygenase-1 ameliorates oxidative stress-induced endothelial senescence via regulating endothelial nitric oxide synthase activation and coupling.

Aging (Albany NY) 2018 Jul;10(7):1722-1744

Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences; National and Local United Engineering Lab of Druggability and New Drugs Evaluation; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou, 510006, China.

Aim: Premature senescence of vascular endothelial cells is a leading cause of various cardiovascular diseases. Therapies targeting endothelial senescence would have important clinical implications. The present study was aimed to evaluate the potential of heme oxygenase-1 (HO-1) as a therapeutic target for endothelial senescence.

Methods And Results: Upregulation of HO-1 by Hemin or adenovirus infection reversed HO-induced senescence in human umbilical vein endothelial cells (HUVECs); whereas depletion of HO-1 by siRNA or HO-1 inhibitor protoporphyrin IX zinc (II) (ZnPP) triggered HUVEC senescence. Mechanistically, overexpression of HO-1 enhanced the interaction between HO-1 and endothelial nitric oxide synthase (eNOS), and promoted the interaction between eNOS and its upstream kinase Akt, thus resulting in an enhancement of eNOS phosphorylation at Ser1177 and a subsequent increase of nitric oxide (NO) production. Moreover, HO-1 induction prevented the decrease of eNOS dimer/monomer ratio stimulated by HO via its antioxidant properties. Contrarily, HO-1 silencing impaired eNOS phosphorylation and accelerated eNOS uncoupling. , Hemin treatment alleviated senescence of endothelial cells of the aorta from spontaneously hypertensive rats, through upregulating eNOS phosphorylation at Ser1177.

Conclusions: HO-1 ameliorated endothelial senescence through enhancing eNOS activation and defending eNOS uncoupling, suggesting that HO-1 is a potential target for treating endothelial senescence.
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http://dx.doi.org/10.18632/aging.101506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075439PMC
July 2018

Clinical efficacy and safety of nuanxin capsule for chronic heart failure: A systematic review and meta-analysis.

Medicine (Baltimore) 2018 Jul;97(27):e11339

The Second Clinical School of Guangzhou University of Chinese Medicine Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.

Background: Chronic heart failure (CHF), the final phase of various heart diseases, is a serious public health problem resulting in high hospitalization rates, mortality, and increasing health care costs. Nuanxin capsule (NXC), a Chinese herbal formula, has been widely used in the treatment of CHF. However, the safety and efficacy of NXC used in patients with CHF has been uncertain and there has been no standard clinical trial published to confirm this. Thus, we conduct a study to evaluate the safety and efficacy of NXC for CHF.

Methods: The reference lists of randomized controlled trials and 8 electronic databases will be independently and systematically searched by 2 review authors in May 2018. Four English databases (EMBASE, PubMed, Cumulative Index to Nursing and Allied Health Literature [CINAHL], and Cochrane Central Register of Controlled Trials [CENTRAL]) and 4 Chinese databases (Chinese Biomedical Literature Database [CBM], Chinese National Knowledge Infrastructure [CNKI], Wanfang Database, and VIP Database) will be included. The primary outcomes will be assessed according to the function classification of New York Heart Association (NYHA). Data synthesis will be precisely computed using the RevManV5.3 software when a data-analysis is allowed. Methodological quality will be assessed according to Cochrane Handbook.

Results: This study will provide a high-quality synthesis of current evidence of NXC for CHF from different aspects including the mortality, the function classification of NYHA.

Conclusion: The conclusion of this systematic review will provide evidence to prove whether NXC is an effective therapeutic intervention for patient with CHF.PROSPERO registration number: PROSPERO CRD42018090003.
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http://dx.doi.org/10.1097/MD.0000000000011339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076094PMC
July 2018

Electroacupuncture for primary insomnia: Protocol for a systematic review and meta-analysis.

Medicine (Baltimore) 2018 Jul;97(27):e11063

The Second Clinical School of Guangzhou University of Chinese Medicine Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical School of Guangzhou University of Chinese Medicine, Guangzhou, China.

Background: Insomnia is a highly widespread sleep disorder in the general population. Electroacupuncture (EA) has been widely received attention as a potential treatment for primary insomnia. However, few previous studies are available to report that EA is a beneficial therapeutic approach to primary insomnia. In addition, there is no critical systematic review or meta-analysis published regarding the effectiveness of this treatment. Here, we provide a protocol to systematically evaluate the efficacy and safety of EA for primary insomnia.

Methods: The reference lists of included studies for relevant randomized controlled trials and 8 electronic databases will be systematically searched by 2 review authors in January 2018, including 4 English databases (PubMed, EMBASE, Cochrane Central Register of Controlled Trials and Cumulative Index to Nursing and Allied Health Literature) and 4 Chinese databases (Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, VIP Database, and Wanfang Database). The primary outcomes will be assessed according to the Pittsburgh Sleep Quality Index. Data synthesis will be computed with the use of RevManV5.3 software when a data-analysis is allowed. Methodological quality will be evaluated with the risk of bias according to Cochrane Handbook.

Results: This study will provide a high-quality synthesis of current evidence of EA for primary insomnia.

Conclusion: The conclusion of this systematic review will provide evidence to judge whether EA is an effective therapeutic intervention for patient with primary insomnia.
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http://dx.doi.org/10.1097/MD.0000000000011063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076172PMC
July 2018

Interleukin‑1β‑mediated suppression of microRNA‑27a‑3p activity in human cartilage via MAPK and NF‑κB pathways: A potential mechanism of osteoarthritis pathogenesis.

Mol Med Rep 2018 Jul 4;18(1):541-549. Epub 2018 May 4.

Department of Orthopedics, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.

The aim of the present study was to investigate the role of microRNA (miR)‑27a‑3p in osteoarthritis (OA). Reverse transcription‑quantitative polymerase chain reaction and western blotting were performed to determine the expression of miR‑27a‑3p and aggrecanase‑2 (ADAMTS5) in cartilage tissues from patients with OA and healthy controls, and also in interleukin (IL)‑1β‑treated primary human chondrocytes. Primary human chondrocytes were transfected with miR‑27a‑3p. A luciferase reporter assay was used to validate the direct contact between miR‑27a‑3p and its putative binding site in the 3'‑untranslated region ADAMTS5 mRNA. Furthermore, the effects of IL‑1β‑induced activation of mitogen‑activated protein kinase (MAPK) and nuclear factor (NF)‑κB on miR‑27a‑3p were evaluated using specific inhibitors. The results revealed that the level of miR‑27a‑3p was reduced in OA cartilage tissues compared with those of normal controls. In addition, decreased miR‑27a‑3p and increased ADAMTS5 expression was observed in a time‑ and dose‑dependent manner in chondrocytes treated with IL‑1β. Furthermore, overexpression of miR‑27a‑3p suppressed the expression of ADAMTS5 in human chondrocytes induced by IL‑1β. miR‑27a‑3p overexpression also decreased the luciferase activity of the wild‑type ADAMTS5 reporter plasmid. Mutation of the miR‑27a‑3p binding site in the 3'‑untranslated region of ADAMTS5 mRNA abolished the miR‑27a‑3p‑mediated repression of reporter activity. Furthermore, the use of specific inhibitors demonstrated that IL‑1β may regulate miR‑27a‑3p expression via NF‑κB and MAPK signaling pathways in chondrocytes. The present study concluded that miR‑27a‑3p was downregulated in human OA and was suppressed by IL‑1β, and functions as a crucial regulator of ADAMTS5 in OA chondrocytes. In addition, IL‑1β‑mediated suppression of miR‑27a‑3p activity may occur via the MAPK and NF‑κB pathways. The present study may provide a novel strategy for clinical treatment of OA caused by upregulation of miR‑27a‑3p.
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http://dx.doi.org/10.3892/mmr.2018.8970DOI Listing
July 2018

SPHK-2 Promotes the Particle-Induced Inflammation of RAW264.7 by Maintaining Consistent Expression of TNF-α and IL-6.

Inflammation 2018 Aug;41(4):1498-1507

Department of Joint Surgery, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan Rd. 2, Guangzhou, 510080, China.

Aseptic implant loosening is a devastating long-term complication of total joint arthroplasty. It is mainly initiated by the interaction of wear debris and macrophages. However, how does the chronic inflammation persist and how to stop it is poorly understood. Sphingosine kinases (SPHKs) are an essential feature of immunosuppressive M2 polarisation in macrophages and a promoter for chronic inflammation. In this study, RAW 264.7 macrophages were exposed to stimulation with titanium particles (0.1 mg/ml), and the subsequent expression of SPHKs and pro-inflammatory cytokines was evaluated. The effect of inhibitors of SPHKs (FTY720, PF543, and ABC294640) on titanium particle-challenged macrophages was analysed. As for results, the amount of sphingosine kinase (SPHK)-1 and SPHK-2 in RAW264.7 macrophages increased in the presence of titanium particles in a time-dependent manner. Two inhibitors of SPHKs (FTY720 and ABC294640) suppressed titanium particle-induced tumour necrosis factor (TNF)-α and interleukin (IL)-6 production in RAW264.7 macrophages. These findings suggest that persistent stimulation with titanium particles may lead to a consistent release of TNF-α and IL-6 via SPHK-2 activity, which may lead to aseptic implant loosening. Appropriate regulation of SPHK-2 may serve as a potential new strategy in the treatment of aseptic implant loosening.
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http://dx.doi.org/10.1007/s10753-018-0795-6DOI Listing
August 2018

YiQiFuMai injection for chronic heart failure: Protocol for a systematic review and meta-analysis.

Medicine (Baltimore) 2018 Feb;97(8):e9957

The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou Shunde Hospital Affiliated of Guangzhou University of Chinese Medicine, Shunde, China.

Background: Chronic heart AQ4 failure (CHF) is the final stage of various heart diseases. YiQiFuMai injection (YQFMI) has been widely applied in the treatment of CHF. However, to our knowledge, there has been no systematic review or meta-analysis of randomized controlled trails (RCTs) regarding the effectiveness of this treatment. Here, we provide a protocol to evaluate the efficacy and safety of YQFMI for CHF.

Methods: To evaluate the clinical efficacy of YQFMI in treating CHF, 2 researcher members will independently search the RCTs in the following 8 Chinese and English databases, in which the data collection will be from the time when the respective databases were established to January 2018. The databases will include MEDLINE, EMBASE, Cochrane CENTRAL, CINAHL, the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, VIP Information and Wanfang Data. The therapeutic effects according to the mortality and the New York Heart Association (NYHA) function classification will be accepted as the primary outcomes. We will use RevMan V.5.3 software as well to compute the data synthesis carefully when a meta-analysis is allowed.

Results: This study will provide a high-quality synthesis of current evidence of YQFMI for CHF from several aspects including mortality, NYHA function classification.

Conclusion: The conclusion of our systematic review will provide evidence to judge whether YQFMI is an effective intervention for CHF.PROSPERO registration number: PROSPERO CRD42017079696.
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http://dx.doi.org/10.1097/MD.0000000000009957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842014PMC
February 2018

Acupuncture for vertebrobasilar insufficiency vertigo: Protocol for a systematic review and meta-analysis.

Medicine (Baltimore) 2017 Dec;96(50):e9261

Guangzhou University of Chinese Medicine The First Affiliated Hospital, Sun Yet-sen University The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.

Background: Vertebrobasilar insufficiency vertebrobasilar (VBIV) is a serious nerve disease and many old people suffer from it. Acupuncture has been widely applied in the treatment of VBIV. However, to our knowledge, there has been no systematic review or meta-analysis of randomized controlled trails regarding the effectiveness of this treatment. Here, we provide a protocol to evaluate the effectiveness and safety of acupuncture for VBIV.

Methods: Relevant randomized controlled trials in 5 databases (EMBASE, PubMed, the Cochrane Central Register of Controlled Trials [Cochrane Library], Chinese Biomedical Literature Database [CBM], China National Knowledge Infrastructure [CNKI]) will be comprehensively searched by 2 researchers in December 2017. The clinical efficacy will be accepted as the primary outcomes. We will also use RevMan V.5.3 software to compute the data synthesis carefully when a meta-analysis is allowed.

Results: This study will provide a high-quality synthesis of current evidence of acupuncture for VBIV from several aspects including clinical efficacy, the blood flow velocity of the left vertebral artery (LVA), the right vertebral artery (RVA), the basilar artery (BA)and adverse events.

Conclusion: The conclusion of our systematic review will provide evidence to judge whether acupuncture is an effective and safety intervention for patient with VBIV.
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http://dx.doi.org/10.1097/MD.0000000000009261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815781PMC
December 2017

Chinese herbal medicine for patients with atrial fibrillation: protocol for a systematic review and meta-analysis.

Medicine (Baltimore) 2017 Dec;96(50):e9228

Guangzhou University of Chinese Medicine The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, China.

Background: Atrial fibrillation (AF) is the most clinically common cardiac arrhythmia. Chinese herbal medicine (CHM) has been widely applied in the treatment of AF, However, to our knowledge, there has been no systematic review and meta-analysis of randomized controlled trails (RCTs) regarding the effectiveness of this treatment. Therefore, we provide a protocol to evaluate the effectiveness and safety of CHM for AF.

Methods: The databases reviewed to collect RCTs related to CHM treatment for AF will be as follows: 3 English literature databases, which are PubMed, Embase, and Cochrane Library, and 3 Chinese literature databases, which are CBM, CNKI, and Wanfang. The data collection in the above-mentioned databases will be from the time when the respective databases were established to December 2017. The maintenance of sinus rhythm and p-wave dispersion will be accepted as the primary outcomes. Quality of life (QOL), such as QOL scale embolic events, bleeding events, and symptom improvement (such as chest distress, palpitations, etc) will be measured as secondary outcomes. Two reviewers will independently screen the titles, abstracts, or even full texts, and extract data. Methodological quality will be evaluated according to the Cochrane risk of bias. All analyses will be applied by RevMan (version 5.3).

Results: The results of study will be disseminated via both international conference and peer-review journal.

Conclusion: The conclusion of our systematic review will provide evidence to judge whether CHM is an effective intervention for patient with AF.
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http://dx.doi.org/10.1097/MD.0000000000009228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815763PMC
December 2017

Role of Synthesis Method on Luminescence Properties of Europium(II, III) Ions in β-CaSiO: Probing Local Site and Structure.

Inorg Chem 2018 Feb 22;57(3):935-950. Epub 2018 Jan 22.

State Key Laboratory of Crystal Materials, Shandong University , Jinan, Shandong 250100, China.

The europium ion probes the symmetry disorder in the crystal structure, although the distortion due to charge compensation in the case of aliovalent dopant remains interesting, especially preparation involves low and high temperatures. This work studies the preparation of the β-CaSiO (from here on CS) particle from Pechini (CSP) and hydrothermal (CSH) methods, and its luminescence variance upon doping with Eu and Eu ions. The blue shift of the charge-transfer band (CTB) in the excitation spectra indicates a larger Eu-O distance in Eu doped CSH. The changes in vibrational frequencies due to stretching and bending vibrations in the FTIR and the Raman spectra and binding energy shift in the XPS analysis confirmed the distorted SiO tetrahedra in CSH. The high hydrothermal temperature and pressure produce distortion, which leads to symmetry lowering although doping of aliovalent ion may slightly change the position of the Ca atoms. The increasing asymmetry ratio value from CSP to CSH clearly indicates that the europium ion stabilized in a more distorted geometry. It is also supported by Judd-Ofelt analysis. The concentration quenching and site-occupancy of Eu ions in two nonequivalent sites of CS were discussed. The charge state and concentration of europium ions in CSP and CSH were determined using X-ray photoelectron spectroscopy measurements. The CS particles were studied by X-ray powder diffraction, FTIR, Raman, BET surface area, TGA/DTA, electron microscopy, XPS, and luminescence spectroscopy. The impact of citrate ion on the morphology and particle size of CSH has been hypothesized on the basis of the microscopy images. This study provides insights that are needed for further understanding the structure of CS and thereby improves the applications in optical and biomedical areas and cement hydration.
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http://dx.doi.org/10.1021/acs.inorgchem.7b01878DOI Listing
February 2018

Periodic microstructures of blood capillaries revealed by synchrotron X-ray multi-resolution microscopic analysis.

Biomed Opt Express 2017 Dec 30;8(12):5825-5833. Epub 2017 Nov 30.

School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China.

Cardiovascular diseases are closely related to structural blood capillaries lesions. Herein, microscopic investigations of mouse blood capillaries were performed at multiple spatial resolution by using synchrotron X-ray in-line phase contrast tomography and scanning transmission X-ray microscopy (STXM). The chemically fixed blood capillaries without any contrast agents were selected. For the first time, a periodic bamboo-shaped structure was observed at nanoscale resolution by STXM, and the three-dimensional tomographic slices at sub-micrometer resolution further confirmed the periodic wave profile of the blood capillaries. Then, a periodic microstructural model was suggested based on the microscopic images. By using high-performance imaging techniques, this work provides a better understanding of the relationship between the structure and function of blood capillaries, will be helpful in elucidating the causes of cardiovascular system diseases.
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http://dx.doi.org/10.1364/BOE.8.005825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745122PMC
December 2017

Protein Disulfide Isomerase Silence Inhibits Inflammatory Functions of Macrophages by Suppressing Reactive Oxygen Species and NF-κB Pathway.

Inflammation 2018 Mar;41(2):614-625

Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-Sen University, NO. 58 Zhongshan Rd. 2, Guangzhou, Guangdong, 510080, People's Republic of China.

Macrophages play an essential role in inflammation. Protein disulfide isomerase (PDI) is central to the redox system, which is closely linked with the inflammatory function of macrophages. However, the relationship between PDI and inflammation is still unknown. In this study, we tested the effects of PDI on inflammatory responses in RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS). Using CRISPR/Cas9 system, we found that PDI knockout suppressed migration, M1 polarization, and secretion of tumor necrosis factor-α (TNF-α) and interluekin-6 (IL-6). The repression of these inflammatory processes was accompanied by decreased production of reactive oxygen species (ROS). PDI ablation also inactivated the phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activated the phosphorylation of NF-κB inhibitor alpha (IκBα). These findings demonstrate that PDI knockout inhibits the inflammatory function of macrophages by decreasing ROS production and inactivating NF-κB pathway.
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http://dx.doi.org/10.1007/s10753-017-0717-zDOI Listing
March 2018

miRNA-140 inhibits C3H10T1/2 mesenchymal stem cell proliferation by targeting CXCL12 during transforming growth factor-β3-induced chondrogenic differentiation.

Mol Med Rep 2017 Aug 8;16(2):1389-1394. Epub 2017 Jun 8.

Department of Orthopedic Surgery, The First Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563003, P.R. China.

The aim of the present study was to investigate the role of microRNA (miRNA or miR)-140 in C3H10T1/2 mesenchymal stem cells (MSCs). Cluster analysis was used to evaluate the miRNA expression profile. The expression level of miRNA‑140 was validated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). TargetScan and microRNA.org databases were used to predict target miRNAs and cartilage‑associated target genes. Binding sites between miR‑140 and the target gene were predicted by bioinformatics software. A dual‑luciferase reporter assay was performed to determine whether miR‑140 could target C‑X‑C motif chemokine ligand 12 (CXCL12). Following the promotion/inhibition of miR‑140, 1, 7 and 14 days following transforming growth factor‑β3 (TGF‑β3)‑induction, western blotting was utilized to evaluate CXCL12 protein levels. MTT assays and alcian blue staining were applied to assess C3H10T1/2 MSC viability and chondrogenic differentiation, respectively. In the TGF‑β3‑induced group, RT‑qPCR verified that the mRNA level of Mus musculus (mmu)‑miR‑140 was significantly elevated when compared with the control group. miR‑140 was predicted to recognize and interact with CXCL12‑3'UTR and the dual luciferase reporter assay further validated that miR‑140 targeted the predicted region of CXCL12. CXCL12 was markedly decreased following miR‑140 overexpression and visibly increased following miR‑140 inhibition. In addition, the level of CXCL12 expression declined as the duration of induction increased. Following the promotion/inhibition of miR‑140, at 1 and 7 days following TGF‑β3‑induction, C3H10T1/2 MSCs inhibited or promoted cell viability, respectively, when compared with the control groups. In addition, in pellets achieved by chondrogenic differentiation following the induction of C3H10T1/2 MSCs for 7 days, alcian blue staining revealed no significant difference in characteristic extracellular matrix glycosaminoglycans between the miR‑140 up and downregulated groups, and their respective control groups. The present study concludes that miRNA‑140 inhibition promoted C3H10T1/2 MSC viability however, not C3H10T1/2 MSC differentiation by targeting and reducing CXCL12 protein levels during the process of TGF‑β3‑induced chondrogenic differentiation. In conclusion, the present study provided a potential target for the treatment of cartilage defection.
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http://dx.doi.org/10.3892/mmr.2017.6720DOI Listing
August 2017

Protein disulfide isomerase-mediated apoptosis and proliferation of vascular smooth muscle cells induced by mechanical stress and advanced glycosylation end products result in diabetic mouse vein graft atherosclerosis.

Cell Death Dis 2017 05 25;8(5):e2818. Epub 2017 May 25.

Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.

Protein disulfide isomerase (PDI) involves cell survival and death. Whether PDI mediates mechanical stretch stress (SS) and/or advanced glycosylation end products (AGEs) -triggered simultaneous increases in proliferation and apoptosis of vascular smooth muscle cells (VSMCs) is unknown. Here, we hypothesized that different expression levels of PDI trigger completely opposite cell fates among the different VSMC subtypes. Mouse veins were grafted into carotid arteries of non-diabetic and diabetic mice for 8 weeks; the grafted veins underwent simultaneous increases in proliferation and apoptosis, which triggered vein graft arterializations in non-diabetic or atherosclerosis in diabetic mice. A higher rate of proliferation and apoptosis was seen in the diabetic group. SS and/or AGEs stimulated the quiescent cultured VSMCs, resulting in simultaneous increases in proliferation and apoptosis; they could induce increased PDI activation and expression. Both in vivo and in vitro, the proliferating VSMCs indicated weak co-expression of PDI and SM-α-actin while apoptotic or dead cells showed strong co-expression of both. Either SS or AGEs rapidly upregulated the expression of PDI, NOX1 and ROS, and their combination had synergistic effects. Inhibiting PDI simultaneously suppressed the proliferation and apoptosis of VSMCs, while inhibition of SM-α-actin with cytochalasin D led to increased apoptosis and cleaved caspases-3 but had no effect on proliferation. In conclusion, different expression levels of PDI in VSMCs induced by SS and/or AGEs triggered a simultaneous increase in proliferation and apoptosis, accelerated vein graft arterializations or atherosclerosis, leading us to propose PDI as a novel target for the treatment of vascular remodeling and diseases.
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http://dx.doi.org/10.1038/cddis.2017.213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520728PMC
May 2017

Aromatic Hydrocarbon Receptor Suppresses Prostate Cancer Bone Metastasis Cells-Induced Vasculogenesis of Endothelial Progenitor Cells under Hypoxia.

Cell Physiol Biochem 2016 25;39(2):709-20. Epub 2016 Jul 25.

Department of Orthopaedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Background/aims: Hypoxia leads to the development of neovascularization in solid tumor by regulating VEGF expression. Aromatic hydrocarbon receptor (AHR), a receptor for dioxin-like compounds, functions as a transcription factor through dimerization with hypoxia-inducible factors 1β (HIF-1β) and inhibits the secretion of vascular endothelial growth factor (VEGF). The purpose of this study was to explore whether AHR can suppress hypoxia-induced VEGF production in prostate bone metastasis cells and repress neovascularization in endothelial progenitor cells (EPCs), and, if so, through what mechanisms.

Methods: PC-3 or LNCaP cells induced angiogenesis was detected by Matrigel-based tube formation assay, mRNA expression levels was measured by qRT-PCR, VEGF secretion level was determined by ELISA assay, respectively.

Results: AHR activation inhibits hypoxia-induced adhesiveness and vasculogenesis of EPCs induced by PC-3 or LNCaP cells under hypoxia. Moreover, AHR activation suppressed hypoxia-induced VEGF production in PC-3 and LNCaP cells (48 ± 14% in PC-3, p = 0.000; 41 ± 14% in LNCaP, p = 0.000) by attenuating HIF-1α and HIF-1β level that in turn diminished the angiogenic ability of EPCs in vitro. Furthermore, we found the mRNA level of hypoxia-inducible factors 1α (HIF-1α) (1.54 ± 0.13 fold in PC-3, p = 0.002, 1.62 ± 0.12 fold in LNCaP, p = 0.001) and HIF-1β (1.67 ± 0.23 fold in PC-3, p = 0.007; 1.75 ± 0.26 fold in LNCaP, p=0.008) were upregulated in prostate cancer bone metastasis PC-3 and LNCaP cell lines in response to hypoxia, and revealed that the regulation of VEGF by HIF-1α and HIF-1β was possibly mediated by the activation of phosphatidylinositol 3-kinase pathway.

Conclusion: By providing a mechanistic insight into the modulation of neovascularization by AHR ligand, we suggest that AHR ligand has a strong potential of being a new therapeutic agent with applications in the field of bone metastatic prostate cancer.
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http://dx.doi.org/10.1159/000445662DOI Listing
February 2017

Resveratrol Protects against Titanium Particle-Induced Aseptic Loosening Through Reduction of Oxidative Stress and Inactivation of NF-κB.

Inflammation 2016 Apr;39(2):775-85

Department of Joint Surgery, The First Affiliated Hospital, Sun Yat-sen University, NO. 58, Zhongshan Rd. 2, Guangzhou, 510080, People's Republic of China.

Aseptic implant loosening is closely associated with chronic inflammation induced by implant wear debris, and reactive oxygen species (ROS) play an important role in this process. Resveratrol, a plant compound, has been reported to act as an antioxidant in many inflammatory conditions; however, its protective effect and mechanism against wear particle-induced oxidative stress remain unknown. In this study, we evaluated resveratrol's protective effects against wear particle-induced oxidative stress in RAW 264.7 macrophages. At non-toxic concentrations, resveratrol showed dose-dependent inhibition of nitric oxide (NO) production, ROS generation, and lipid peroxidation. It also downregulated the gene expression of oxidative enzymes, including inducible nitric oxide synthase (iNOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-1 and NOX-2, and promoted the gene expression and activities of antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (GPx). This protective effect against wear particle-induced oxidative stress was accompanied by a reduction of gene expression and release of tumor necrosis factor-α (TNF-α), and decreased gene expression and phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These findings demonstrate that resveratrol can inhibit wear particle-induced oxidative stress in macrophages, and may exert its antioxidant effect and protect against aseptic implant loosening.
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http://dx.doi.org/10.1007/s10753-016-0306-6DOI Listing
April 2016

Advanced glycation end products biphasically modulate bone resorption in osteoclast-like cells.

Am J Physiol Endocrinol Metab 2016 Mar 15;310(5):E355-66. Epub 2015 Dec 15.

Department of Joint Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; and

Advanced glycation end products (AGEs) disturb bone remodeling during aging, and this process is accelerated in diabetes. However, their role in modulation of osteoclast-induced bone resorption is controversial, with some studies indicating that AGEs enhance bone resorption and others showing the opposite effect. We determined whether AGEs present at different stages of osteoclast differentiation affect bone resorption differently. Based on increased levels of tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CTSK), we identified day 4 of induction as the dividing time of cell fusion stage and mature stage in RAW264.7 cell-derived osteoclast-like cells (OCLs). AGE-modified BSA (50-400 μg/ml) or control BSA (100 μg/ml) was then added at the beginning of each stage. Results showed that the presence of AGEs at the cell fusion stage reduced pit numbers, resorption area, and CTSK expression. Moreover, expression of receptor activator of nuclear factor-κB (RANK) as well as the number of TRAP-positive cells, nuclei per OCL, actin rings, and podosomes also decreased. However, the presence of AGEs at the mature stage enlarged the resorption area markedly and increased pit numbers slightly. Intriguingly, only the number of nuclei per OCL and podosomes increased. These data indicate that AGEs biphasically modulate bone resorption activity of OCLs in a differentiation stage-dependent manner. AGEs at the cell fusion stage reduce bone resorption dramatically, mainly via suppression of RANK expression in osteoclast precursors, whereas AGEs at the mature stage enhance bone resorption slightly, most likely by increasing the number of podosomes in mature OCLs.
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http://dx.doi.org/10.1152/ajpendo.00309.2015DOI Listing
March 2016
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