Publications by authors named "Wenwei Luo"

16 Publications

  • Page 1 of 1

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313700PMC
July 2021

Effects of Strain and Electric Field on Molecular Doping in MoSSe.

ACS Omega 2021 Jun 25;6(22):14639-14647. Epub 2021 May 25.

College of Physics and Communication Electronics, Laboratory of Computational Material Physics, Jiangxi Normal University, Nanchang 330022, China.

Recently, synthesized Janus MoSSe monolayers have attracted tremendous attention in science and technology due to their novel properties and promising applications. In this work, we investigate their molecular adsorption-induced structural and electronic properties and tunable doping effects under biaxial strain and external electric field by first-principles calculations. We find an effective n-type or p-type doping in the MoSSe monolayer caused by noncovalent tetrathiafulvalene (TTF) or tetracyanoquinodimethane (TCNQ) molecular adsorption. Moreover, the concentration of doping carrier with respect to the S or Se side also exhibits Janus characteristics because of the electronegativity difference between S and Se atoms and the intrinsic dipole moment in the MoSSe monolayer. In particular, this n-type or p-type molecular doping effect can be flexibly tuned by biaxial strain or under external electric field. By analyzing the valence band maximum (VBM) and conduction band minimum (CBM) in the band structure of MoSSe/TTF under strain, the strain-tunable band gap of MoSSe and the n-type molecular doping effect is revealed. Further explanation of charge transfer between TTF or TCNQ and the MoSSe monolayer by an equivalent capacitor model shows that the superimposition of external electric field and molecular adsorption-induced internal electric field plays a crucial role in achieving a controllable doping concentration in the MoSSe monolayer.
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http://dx.doi.org/10.1021/acsomega.1c01747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190909PMC
June 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 Sep 2;99(9):900-909. 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
September 2021

Clinical Characteristics of Patients With Papilloma in the External Auditory Canal.

Laryngoscope 2021 05 8;131(5):1132-1137. Epub 2020 Oct 8.

ENT institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200031, China.

Objectives: To determine the clinical characteristics of papilloma involving the external auditory canal (PEAC) in a region of China.

Study Design: A retrospective study.

Methods: Demographics, manifestations, imaging results, histopathology, and treatment of 67 patients diagnosed with PEAC in a period of 6 years were analyzed at Shanghai Eye, Ear, Nose and Throat Hospital in China.

Results: PEAC were encountered in patients between the ages of 12 and 82 years (mean 53.8 years). It was more prevalent in men (82%) than in women (18%) (P < .05). The clinical presentation was usually a mass in EAC, aural fullness, and hearing loss. Otoscopic and radiological examination were used together for initial diagnosis and pretreatment planning. Unilateral involvement was more common than bilateral involvement (P < .05). The average time between onset of first symptom and surgical resection and/or biopsy was 6.5 months (range, 0.25-60 months). All patients underwent gross total resection. In 5 patients, (7.5%) carcinoma was detected in the specimen. Fifteen patients (22%) had recurrence; recurrent tumors were detected after an average period of 10 months after surgery (range, 4-24 months).

Conclusion: PEAC is largely a benign lesion with a low risk of malignancy. Optimal management is via gross total resection. However, the risk of recurrence is high, which motivates a need for long-term monitoring.

Level Of Evidence: 4 Laryngoscope, 131:1132-1137, 2021.
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http://dx.doi.org/10.1002/lary.29113DOI Listing
May 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

Sequence-Defined Peptoids with -OH and -COOH Groups As Binders to Reduce Cracks of Si Nanoparticles of Lithium-Ion Batteries.

Adv Sci (Weinh) 2020 Sep 5;7(18):2000749. Epub 2020 Aug 5.

Institute for Sustainable Energy/College of Sciences Shanghai University Shanghai 200444 China.

Silicone (Si) is one type of anode materials with intriguingly high theoretical capacity. However, the severe volume change associated with the repeated lithiation and delithiation processes hampers the mechanical/electrical integrity of Si anodes and hence reduces the battery's cycle-life. To address this issue, sequence-defined peptoids are designed and fabricated with two tailored functional groups, "-OH" and "-COOH", as cross-linkable polymeric binders for Si anodes of LIBs. Experimental results show that both the capacity and stability of such peptoids-bound Si anodes can be significantly improved due to the decreased cracks of Si nanoparticles. Particularly, the 15-mer peptoid binder in Si anode can result in a much higher reversible capacity (ca. 3110 mAh g) after 500 cycles at 1.0 A g compared to other reported binders in literature. According to the density functional theory (DFT) calculations, it is the functional groups presented on the side chains of peptoids that facilitate the formation of Si-O binding efficiency and robustness, and then maintain the integrity of the Si anode. The sequence-designed polymers can act as a new platform for understanding the interactions between binders and Si anode materials, and promote the realization of high-performance batteries.
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http://dx.doi.org/10.1002/advs.202000749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509666PMC
September 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

Improving the Interfacial Stability between Lithium and Solid-State Electrolyte via Dipole-Structured Lithium Layer Deposited on Graphene Oxide.

Adv Sci (Weinh) 2020 Jul 18;7(13):2000237. Epub 2020 May 18.

Ningbo Institute of Materials Technology and Engineering Chinese Academy of Sciences Ningbo 315201 China.

Utilization of lithium (Li) metal anode in solid-state batteries (SSBs) with sulfide solid-state electrolyte (SSE) is hindered by the instable Li/SSE interface. A general solution to solve this problem is to place an expensive indium (In) foil between the SSE and Li, while it decreases the output voltage and thus the energy density of the battery. In this work, an alternative strategy is demonstrated to boost the cycling performances of SSB by wrapping a graphene oxide (GO) layer on the anode. According to density functional theory results, initial deposition of a thin Li layer on the defective GO sheets leads to the formation of a dipole structure, due to the electron-withdrawing ability of GO acting on Li. By incorporating GO sheets in a nanocomposite of copper-cuprous oxide-GO (Cu-CuO-GO, CCG), a composite Li anode enables a high coulombic efficiency above 99.5% over 120 cycles for an SSB using LiGePS SSE and LiCoO cathode, and the sulfide SSE is not chemically decomposed after cycling. The highest occupied molecule orbital/lowest unoccupied molecular orbital energy gap of this Li/GO dipole structure likely stretches over those of Li and sulfide SSE, enabling stabilized Li/SSE interface that can replace the expensive In layer as Li protective structure in SSBs.
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http://dx.doi.org/10.1002/advs.202000237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341093PMC
July 2020

First-principles study of χ-borophene for charge-modulated switchable CO capture.

Phys Chem Chem Phys 2020 Apr;22(16):8864-8869

Department of Physics, Laboratory of Computational Materials Physics, Jiangxi Normal University, Nanchang, 330022, China.

A first-principles calculation was performed to investigate the switchable CO2 capture on χ3-borophene by injecting/removing the extra electrons. The results show that the CO2 adsorption energy on the neutral χ3-borophene is 0.150 eV. After extra 2.5 e are injected, the adsorption energy is raised up to 0.802 eV, showing a significant enhancement with the change from the physical adsorption to chemical adsorption. Furthermore, both the CO2 capture and release processes are exothermic reactions involving injecting/removing extra electrons. χ3-borophene possesses a metallic electronic structure, which is conducive to the injection of extra electrons. The minimum charge density for CO2 capture on the negatively charged χ3-borophene is 1.6 × 1014 e cm-2. The CO2 capture capacity of χ3-borophene is 4.09 × 1014 cm-2. Finally, we study the selectivity of negatively charged χ3-borophene. The results show that the negatively-charged χ3-borophene possesses a high selectivity for CO2 from its mixtures with CO, CH4, NH3, N2, H2S, and H2. χ3-borophene is a new promising charge-modulated switchable CO2 capture material with good stability, high CO2 capture capacity, high selectivity, and excellent electrical conductivity.
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http://dx.doi.org/10.1039/d0cp01020kDOI Listing
April 2020

The Atoh1 expression levels are correlated with the arrangement, ciliary morphology, and electrophysiological characteristics of ectopic hair cell-like cells.

Neurosci Lett 2020 02 13;720:134758. Epub 2020 Jan 13.

Department of Otology and Skull Base Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai 200031, China; Shanghai Clinical Medical Center of Hearing Medicine, Shanghai 200031, China; Key Laboratory of Hearing Medicine of National Health Commission of the People's Republic of China, Shanghai 20031, China; Research Institute of Otolaryngology, Fudan University, Shanghai 200031, China. Electronic address:

Previous reports have suggested that the level and duration of Atoh1 expression are correlated with the survival, arrangement and stereociliary bundle-related morphology of hair cells during development, but whether Atoh1 expression levels are correlated with the arrangement, bundle formation and electrophysiological characteristics of newly formed hair cells is unknown. To address this question, cultured cochlear explants obtained from neonatal rats were treated with different titers of a human adenovirus serotype 5 (Ad5) vector encoding Atoh1 and/or EGFP (EGFP-Atoh1+/-). The results showed that higher EGFP-Atoh1 concentrations led to higher initial Atoh1 mRNA expression levels and induced greater numbers of ectopic hair cell-like cells (EHCLCs) in the lesser epithelial ridge (LER). Furthermore, gradual increases in the number of EHCLCs were associated with the progressive conversion of the LER region similarly to that of hair cells during development. Some of the cilia on EHCLCs with higher Atoh1 expression were regularly arranged in a manner similar to that of normal hair bundles. As demonstrated through patch clamp recordings, high Atoh1 expression was associated with significantly decreased proportions of cells with I currents, significantly reduced proportions of transient potassium channel currents, and potassium channel currents with a greatly increased mean amplitude, which indicated that EHCLCs with high Atoh1 expression were more mature than those with low Atoh1 expression. Overall, the evidence suggests that the Atoh1 expression levels affect not only the arrangement and ciliary morphology of hair cells but also the electrophysiological characteristics of Atoh1-induced EHCLCs, and these findings provide important guidance for future therapies aimed at treating deafness.
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http://dx.doi.org/10.1016/j.neulet.2020.134758DOI Listing
February 2020

Sirtuin 1 represses PKC-ζ activity through regulating interplay of acetylation and phosphorylation in cardiac hypertrophy.

Br J Pharmacol 2019 02 9;176(3):416-435. Epub 2018 Dec 9.

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

Background And Purpose: Activation of PKC-ζ is closely linked to the pathogenesis of cardiac hypertrophy. PKC-ζ can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)-trisphosphate and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of the sirtuin1-PKC-ζ signalling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy.

Experimental Approach: Cellular hypertrophy in cultures of cardiac myocytes, from neonatal Sprague-Dawley rats, was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Interaction between sirtuin1 and PKC-ζ was investigated by co-immunoprecipitation and confocal immunofluorescence microscopy. Sirtuin1 activation was enhanced by resveratrol treatment or Ad-sirtuin1 transfection. A model of cardiac hypertrophy in Sprague-Dawley rats was established by abdominal aortic constriction surgery or induced by isoprenaline in vivo.

Key Results: Overexpression of PKC-ζ led to cardiac hypertrophy and increased activity of NF-κB, ERK1/2 and ERK5, which was ameliorated by sirtuin1 overexpression. Enhancement of sirtuin1 activity suppressed acetylation of PKC-ζ, hindered its binding to phosphoinositide-dependent kinase 1 and inhibited PKC-ζ phosphorylation in cardiac hypertrophy. Consequently, the downstream pathways of PKC-ζ' were suppressed in cardiac hypertrophy. This regulation loop suggests a new role for sirtuin1 in mediation of cardiac hypertrophy.

Conclusions And Implications: Sirtuin1 is an endogenous negative regulator for PKC-ζ and mediates its activity via regulating the acetylation and phosphorylation in the pathogenesis of cardiac hypertrophy. Targeting the sirtuin1-PKC-ζ signalling axis may suggest a novel therapeutic approach against cardiac hypertrophy.
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http://dx.doi.org/10.1111/bph.14538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329629PMC
February 2019

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

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

Cilia distribution and polarity in the epithelial lining of the mouse middle ear cavity.

Sci Rep 2017 03 30;7:45870. Epub 2017 Mar 30.

Department of Cell Biology Emory University, Atlanta, USA.

The middle ear conducts sound to the cochlea for hearing. Otitis media (OM) is the most common illness in childhood. Moreover, chronic OM with effusion (COME) is the leading cause of conductive hearing loss. Clinically, COME is highly associated with Primary Ciliary Dyskinesia, implicating significant contributions of cilia dysfunction to COME. The understanding of middle ear cilia properties that are critical to OM susceptibility, however, is limited. Here, we confirmed the presence of a ciliated region near the Eustachian tube orifice at the ventral region of the middle ear cavity, consisting mostly of a lumen layer of multi-ciliated and a layer of Keratin-5-positive basal cells. We also found that the motile cilia are polarized coordinately and display a planar cell polarity. Surprisingly, we also found a region of multi-ciliated cells that line the posterior dorsal pole of the middle ear cavity which was previously thought to contain only non-ciliated cells. Our study provided a more complete understanding of cilia distribution and revealed for the first time coordinated polarity of cilia in the epithelium of the mammalian middle ear, thus illustrating novel structural features that are likely critical for middle ear functions and related to OM susceptibility.
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http://dx.doi.org/10.1038/srep45870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372464PMC
March 2017

Establishment of planar cell polarity is coupled to regional cell cycle exit and cell differentiation in the mouse utricle.

Sci Rep 2017 02 23;7:43021. Epub 2017 Feb 23.

Department of Otology and Skull Base Surgery, Eye &ENT Hospital of Fudan University, Shanghai 200031, China.

Sensory hair cells are coordinately oriented within each inner ear sensory organ to exhibit a particular form of planar cell polarity (PCP) necessary for mechanotransduction. However, the developmental events associated with establishing PCP in the vestibule are unclear, hindering data interpretation and employment of the vestibule for PCP studies. Herein, we investigated PCP of the mouse vestibular organs. We further characterised cell cycle exit, cell differentiation, and PCP establishment in the utricle. We found that hair cells formed first in the striolar and medial extrastriolar (MES) regions of the utricle at embryonic day 11.5 (E11.5), while cells in the lateral extrastriolar region (LES) mostly formed at E13.5. Cell differentiation was initiated in the striolar region, which expanded first toward the MES, then to the LES by E15.5. The polarity of hair cells was established at birth along a putative line of polarity reversal (LPR), lateral to the striolar region. Core PCP protein Vangl2 emerged in the cell boundaries since E11.5, while cell intrinsic polarity protein Gαi3 appeared at E12.5, then polarized to the bare zone of individual hair cell at E13.5. These findings provide a blueprint of the developmental events associated with establishing PCP in the utricle.
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http://dx.doi.org/10.1038/srep43021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322371PMC
February 2017

PKCζ interacts with STAT3 and promotes its activation in cardiomyocyte hypertrophy.

J Pharmacol Sci 2016 Sep 29;132(1):15-23. Epub 2016 Mar 29.

Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou 510006, PR China. Electronic address:

This study was aimed to investigate the crosstalk between protein kinase C ζ (PKCζ) and signal transducer and activator of transcription 3 (STAT3) in cardiomyocyte hypertrophy. In neonatal rat cardiomyocyte hypertrophic model induced by phenylephrine (PE), the levels of phosphorylated PKCζ and phosphorylated STAT3 were significantly increased, suggesting the activation of both PKCζ and STAT3 in cardiomyocyte hypertrophy. Overexpression of PKCζ by adenovirus infection elevated the expressions of hypertrophic markers atrial natriuretic factor (ANF) and brains natriuretic polypeptide (BNP), as well as the cell surface area; while genetic silencing of PKCζ inhibited PE-induced cardiomyocyte hypertrophy. An interaction between PKCζ and STAT3 in cardiomyocytes was shown by co-immunoprecipitation experiments. Overexpression of PKCζ increased the phosphorylated level of STAT3 at both Ser727 and Tyr705, promoted the nuclear translocation of STAT3, and enhanced the expression of STAT3 downstream target genes c-fos and angiotensinogen (aGT); whereas PKCζ knockdown prevented PE-induced STAT3 activation, nuclear shuttling and transcriptional activation. In conclusion, PKCζ interacts with STAT3 and promotes its activation in cardiomyocyte hypertrophy. Strategies targeting inhibition of PKCζ-STAT3 signaling pathway suggest a therapeutic potential for cardiac hypertrophy.
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http://dx.doi.org/10.1016/j.jphs.2016.03.010DOI Listing
September 2016
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