Publications by authors named "Xiaoqiang Yao"

176 Publications

Ang II Promotes Cardiac Autophagy and Hypertrophy via Orai1/STIM1.

Front Pharmacol 2021 17;12:622774. Epub 2021 May 17.

School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, China.

The pathophysiology of cardiac hypertrophy is complex and multifactorial. Both the store-operated Ca entry (SOCE) and excessive autophagy are the major causative factors for pathological cardiac hypertrophy. However, it is unclear whether these two causative factors are interdependent. In this study, we examined the functional role of SOCE and Orai1 in angiotensin II (Ang II)-induced autophagy and hypertrophy using neonatal rat cardiomyocytes (NRCMs) and mouse model, respectively. We show that YM-58483 or SKF-96365 mediated pharmacological inhibition of SOCE, or silencing of Orai1 with Orail-siRNA inhibited Ang II-induced cardiomyocyte autophagy both and . Also, the knockdown of Orai1 attenuated Ang II-induced pathological cardiac hypertrophy. Together, these data suggest that Ang II promotes excessive cardiomyocyte autophagy through SOCE/Orai1 which can be the prime contributing factors in cardiac hypertrophy.
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http://dx.doi.org/10.3389/fphar.2021.622774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165566PMC
May 2021

TRPC7 regulates the electrophysiological functions of embryonic stem cell-derived cardiomyocytes.

Stem Cell Res Ther 2021 May 3;12(1):262. Epub 2021 May 3.

School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.

Background: Biological pacemakers consisting of pluripotent stem cell-derived cardiomyocytes are potentially useful for treating bradycardia. However, tachyarrhythmia caused by derived cardiomyocytes themselves is one of main barriers hampering their clinical translation. An in-depth understanding of the mechanisms underlying the spontaneous action potential (a.k.a. automaticity) might provide potential approaches to solve this problem. The aim of this project is to study the role of canonical transient receptor potential isoform 7 (TRPC7) channels in regulating the automaticity of embryonic stem cell-derived cardiomyocytes (ESC-CMs).

Methods And Results: By Western blotting, the expression of TRPC7 was found to be increased during the differentiation of mouse ESC-CMs (mESC-CMs). Adenovirus-mediated TRPC7 knockdown decreased while overexpression increased the frequency of Ca transients (CaTs), local Ca releases (LCRs), and action potentials (APs) as detected by confocal microscopy and whole-cell patch-clamping. TRPC7 was found to be positively associated with the activity of ryanodine receptor 2 (RyR2), sarco/endoplasmic reticulum Ca-ATPase (SERCA), and sodium-calcium exchanger (NCX) but not hyperpolarization-activated, cyclic nucleotide-gated channel (HCN), and inositol trisphosphate receptor (IP3R). Knockdown or overexpression of TRPC7 did not alter the expression of HCN4, Cav1.3, Cav3.1, Cav3.2, IP3R1, RyR2, and SERCA but positively regulated the phosphorylation of RyR2 at S2814 and phospholamban (PLN) at T17. Moreover, the positive regulation of APs by TRPC7 was Ca-dependent, as overexpression of N-terminus of TRPC7 (dominant negative of TRPC7) which diminished the Ca permeability of TRPC7 decreased the AP frequency.

Conclusions: TRPC7 regulates the automaticity of mESC-CMs through two mechanisms. On the one hand, TRPC7 positively regulates the intracellular Ca clock through the regulation of activities of both RyR2 and SERCA; on the other hand, TRPC7 also positively regulates the membrane clock via its influence on NCX activity. Altogether, our study reveals that TRPC7 is a potential drug target to manipulate the action potential firing rate of pluripotent stem cell-derived cardiomyocyte-based biological pacemakers to prevent tachyarrhythmia, a condition that might be encountered after transplantation.
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http://dx.doi.org/10.1186/s13287-021-02308-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091699PMC
May 2021

Nanostructured Lateral Boryl Substitution Conjugated Donor-Acceptor Oligomers for Visible-Light-Driven Hydrogen Production.

Small 2021 Jun 23;17(23):e2100132. Epub 2021 Apr 23.

State Key Laboratory of Applied Organic Chemistry (Lanzhou University), Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China.

Poor charge separation is the main factor that limits the photocatalytic hydrogen generation efficiency of organic conjugated polymers. In this work, a series of linear donor-acceptor (D-A) type oligomers are synthesized by a palladium-catalyzed Sonogashira-Hagihara coupling of electron-deficient diborane unit and different dihalide substitution sulfur functionalized monomers. Such diborane-based A unit exerts great impact on the resulting oligomers, including distinct semiconductor characters with isolated lowest unoccupied molecular orbital (LUMO) orbits locating in diborane-containing fragment, and elevated LUMO level higher than water reduction potential. Relative to A-A type counterpart, the enhanced dipole polarization effect in D-A oligomers facilitates separation of photogenerated charge carriers, as evidenced by notably prolonged electron lifetime. Owing to π-π stacking of rigid backbone, the oligomers can aggregate into an interesting 2D semicrystalline nanosheet (≈2.74 nm), which is rarely reported in linear polymeric photocatalysts prepared by similar carbon-carbon coupling reaction. Despite low surface area (30.3 m g ), such ultrathin nanosheet D-A oligomer offers outstanding visible light (λ > 420 nm) hydrogen evolution rate of 833 µmol g h , 14 times greater than its A-A analogue (61 µmol g h ). The study highlights the great potential of using boron element to construct D-A type oligomers for efficient photocatalytic hydrogen generation.
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http://dx.doi.org/10.1002/smll.202100132DOI Listing
June 2021

TRPV1 channels regulate the automaticity of embryonic stem cell-derived cardiomyocytes through stimulating the Na /Ca exchanger current.

J Cell Physiol 2021 Mar 30. Epub 2021 Mar 30.

School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Calcium controls the excitation-contraction coupling in cardiomyocytes. Embryonic stem cell-derived cardiomyocytes (ESC-CMs) are an important cardiomyocyte source for regenerative medicine and drug screening. Transient receptor potential vanilloid 1 (TRPV1) channels are nonselective cation channels that permeate sodium and calcium. This study aimed to investigate whether TRPV1 channels regulate the electrophysiological characteristics of ESC-CMs. If yes, what is the mechanism behind? By immunostaining and subcellular fractionation, followed by western blotting, TRPV1 was found to locate intracellularly. The staining pattern of TRPV1 was found to largely overlap with that of the sarco/endoplasmic reticulum Ca -ATPase, the sarcoplasmic reticulum (SR) marker. By electrophysiology and calcium imaging, pharmacological blocker of TRPV1 and the molecular tool TRPV1β (which could functionally knockdown TRPV1) were found to decrease the rate and diastolic depolarization slope of spontaneous action potentials, and the amplitude and frequency of global calcium transients. By calcium imaging, in the absence of external calcium, TRPV1-specific opener increased intracellular calcium; this increase was abolished by preincubation with caffeine, which could deplete SR calcium store. The results suggest that TRPV1 controls calcium release from the SR. By electrophysiology, TRPV1 blockade and functional knockdown of TRPV1 decreased the Na /Ca2 exchanger (NCX) currents from both the forward and reverse modes, suggesting that sodium and calcium through TRPV1 stimulate the NCX activity. Our novel findings suggest that TRPV1 activity is important for regulating the spontaneous activity of ESC-CMs and reveal a novel interplay between TRPV1 and NCX in regulating the physiological functions of ESC-CMs.
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http://dx.doi.org/10.1002/jcp.30369DOI Listing
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

TRPM2 promotes autophagic degradation in vascular smooth muscle cells.

Sci Rep 2020 11 26;10(1):20719. Epub 2020 Nov 26.

School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, People's Republic of China.

Transient receptor potential channel M2 (TRPM2) is a Ca-permeable channel that is activated by reactive oxygen species (ROS). In many cell types, ROS activate TRPM2 to induce excessive Ca influx, resulting in Ca overload and consequent cell death. Recent studies suggest that TRPM2 may also regulate autophagy in pericytes and cancer cells by acting on the early step of autophagy, i.e. autophagic induction. However, there is no report on the role of TRPM2 in autophagic degradation, which is the late stage of autophagy. In the present study, we found abundant TRPM2 expression in lysosomes/autolysosomes in the primary cultured mouse aortic smooth muscle cells (mASMCs). Nutrient starvation stimulated autophagic flux in mASMCs mainly by promoting autophagic degradation. This starvation-induced autophagic degradation was reduced by TRPM2 knockout. Importantly, starvation-induced lysosomal/autolysosomal acidification and cell death were also substantially reduced by TRPM2 knockout. Taken together, the present study uncovered a novel mechanism that lysosomal TRPM2 facilitates lysosomal acidification to stimulate excessive autolysosome degradation and consequent cell death.
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http://dx.doi.org/10.1038/s41598-020-77620-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693237PMC
November 2020

TRPP2 and STIM1 form a microdomain to regulate store-operated Ca entry and blood vessel tone.

Cell Commun Signal 2020 08 31;18(1):138. Epub 2020 Aug 31.

School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.

Background: Polycystin-2 (TRPP2) is a Ca permeable nonselective cationic channel essential for maintaining physiological function in live cells. Stromal interaction molecule 1 (STIM1) is an important Ca sensor in store-operated Ca entry (SOCE). Both TRPP2 and STIM1 are expressed in endoplasmic reticular membrane and participate in Ca signaling, suggesting a physical interaction and functional synergism.

Methods: We performed co-localization, co-immunoprecipitation, and fluorescence resonance energy transfer assay to identify the interactions of TRPP2 and STIM1 in transfected HEK293 cells and native vascular smooth muscle cells (VSMCs). The function of the TRPP2-STIM1 complex in thapsigargin (TG) or adenosine triphosphate (ATP)-induced SOCE was explored using specific small interfering RNA (siRNA). Further, we created TRPP2 conditional knockout (CKO) mouse to investigate the functional role of TRPP2 in agonist-induced vessel contraction.

Results: TRPP2 and STIM1 form a complex in transfected HEK293 cells and native VSMCs. Genetic manipulations with TRPP2 siRNA, dominant negative TRPP2 or STIM1 siRNA significantly suppressed ATP and TG-induced intracellular Ca release and SOCE in HEK293 cells. Inositol triphosphate receptor inhibitor 2-aminoethyl diphenylborinate (2APB) abolished ATP-induced Ca release and SOCE in HEK293 cells. In addition, TRPP2 and STIM1 knockdown significantly inhibited ATP- and TG-induced STIM1 puncta formation and SOCE in VSMCs. Importantly, knockdown of TRPP2 and STIM1 or conditional knockout TRPP2 markedly suppressed agonist-induced mouse aorta contraction.

Conclusions: Our data indicate that TRPP2 and STIM1 are physically associated and form a functional complex to regulate agonist-induced intracellular Ca mobilization, SOCE and blood vessel tone. Video abstract.
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http://dx.doi.org/10.1186/s12964-020-00560-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457527PMC
August 2020

Resveratrol Stimulates the Na+-Ca2+ Exchanger on the Plasma Membrane to Reduce Cytosolic Ca2+ in Rat Aortic Smooth Muscle Cells.

J Cardiovasc Pharmacol 2020 11;76(5):610-616

Li Ka Shing Institute of Health Sciences and School of Biomedical Sciences, the Chinese University of Hong Kong, Hong Kong, China.

Resveratrol is well known to exhibit vascular relaxant and antihypertensive effects. In this study, we determined the effects of resveratrol on the modulation of cytosolic [Ca] level and adenosine 5'-triphosphate-induced Ca release from the sarcoplasmic reticulum (SR) in rat aortic smooth muscle cells (ASMCs) and explored its underlying mechanisms. In this article, cytosolic [Ca] and SR [Ca] in ASMCs were determined by Fluo-4/acetoxymethyl and Mag-Fluo-4/acetoxymethyl respectively. Resveratrol (20, 50, and 100 µM) caused a rapid and substantial reduction in cytosolic [Ca] in ASMCs bathed in normal Hank's Balanced Salt Solution or Ca-free Hank's Balanced Salt Solution. Pretreatment with resveratrol reduced adenosine 5'-triphosphate-induced SR Ca release and SR Ca content. In the cells bathed in Na-free physiological saline, which favors the reverse mode of the Na-Ca exchanger (NCX), resveratrol induced an increase in cytosolic [Ca] and SR [Ca]. However, its effect on cytosolic [Ca] was inhibited by the selective NCX inhibitor, SEA0400. Our findings suggest that resveratrol reduces cytosolic [Ca] and SR [Ca] in ASMCs in normal physiological saline, which might be, at least in part, mediated by the NCX.
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http://dx.doi.org/10.1097/FJC.0000000000000897DOI Listing
November 2020

Comparison of Chest CT Manifestations of Coronavirus Disease 2019 (COVID-19) and Pneumonia Associated with Lymphoma.

Int J Med Sci 2020 19;17(13):1909-1915. Epub 2020 Jul 19.

Department of Radiology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Rd, Zhengzhou 450008, China.

To retrospectively compare the clinical features and chest computed tomography (CT) characteristics of coronavirus disease 2019 (COVID-19) and pneumonia in lymphoma patients. Ten lymphoma patients with pneumonia and 12 patients with COVID-19 infections were enrolled from January 15 to March 14, 2020. The clinical features were recorded. All pulmonary lesions on chest CT were assessed for location, shape, density and diffusion degree. Other typical CT features were also evaluated. The most commonly observed patchy lesions were ground-glass opacities (GGOs) and mixed GGOs in both groups. Regarding the diffusion degree, 82% (92/112) of the lesions in the COVID-19 group were relatively limited, while 69% (52/75) of those in the lymphoma group were diffuse ( < 0.001). The proportions of interlobular septal thickening, vascular thickening, pleural involvement and fibrous stripes observed in the lymphoma cases were statistically compatible with those observed in the COVID-19 cases ( 0.05). Air bronchograms were observed more frequently in COVID-19 patients (45%, 50/112) than in lymphoma patients with pneumonia (5%, 4/75) ( < 0.001). Halo sign (6%) and reversed halo sign (1%) were observed in several COVID-19 patients but not in lymphoma-associated pneumonia patients. Both lymphoma-associated pneumonia and COVID-19 generally manifested as patchy GGOs and mixed GGOs in more than one lobe. Compared to COVID-19, lymphoma-associated pneumonia tended to be relatively diffuse, with fewer air bronchograms, and no halo or reversed halo signs observed on chest CT.
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http://dx.doi.org/10.7150/ijms.46688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415398PMC
August 2020

TRPC1 participates in the HSV-1 infection process by facilitating viral entry.

Sci Adv 2020 03 18;6(12):eaaz3367. Epub 2020 Mar 18.

Wuxi School of Medicine and School of Food Science and Technology, Jiangnan University, Jiangsu, China.

Mammalian transient receptor potential (TRP) channels are major components of Ca signaling pathways and control a diversity of physiological functions. Here, we report a specific role for TRPC1 in the entry of herpes simplex virus type 1 (HSV-1) into cells. HSV-1-induced Ca release and entry were dependent on Orai1, STIM1, and TRPC1. Inhibition of Ca entry or knockdown of these proteins attenuated viral entry and infection. HSV-1 glycoprotein D interacted with the third ectodomain of TRPC1, and this interaction facilitated viral entry. Knockout of TRPC1 attenuated HSV-1-induced ocular abnormality and morbidity in vivo in TRPC1 mice. There was a strong correlation between HSV-1 infection and plasma membrane localization of TRPC1 in epithelial cells within oral lesions in buccal biopsies from HSV-1-infected patients. Together, our findings demonstrate a critical role for TRPC1 in HSV-1 infection and suggest the channel as a potential target for anti-HSV therapy.
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http://dx.doi.org/10.1126/sciadv.aaz3367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080438PMC
March 2020

Transient Receptor Potential Canonical 5-Scramblase Signaling Complex Mediates Neuronal Phosphatidylserine Externalization and Apoptosis.

Cells 2020 02 26;9(3). Epub 2020 Feb 26.

School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China.

Phospholipid scramblase 1 (PLSCR1), a lipid-binding and Ca-sensitive protein located on plasma membranes, is critically involved in phosphatidylserine (PS) externalization, an important process in cell apoptosis. Transient receptor potential canonical 5 (TRPC5), is a nonselective Ca channel in neurons that interacts with many downstream molecules, participating in diverse physiological functions including temperature or mechanical sensation. The interaction between TRPC5 and PLSCR1 has never been reported. Here, we showed that PLSCR1 interacts with TRPC5 through their C-termini in HEK293 cells and mouse cortical neurons. Formation of TRPC5-PLSCR1 complex stimulates PS externalization and promotes cell apoptosis in HEK293 cells and mouse cerebral neurons. Furthermore, in vivo studies showed that PS externalization in cortical neurons induced by artificial cerebral ischemia-reperfusion was reduced in TRPC5 knockout mice compared to wild-type mice, and that the percentage of apoptotic neurons was also lower in TRPC5 knockout mice than in wild-type mice. Collectively, the present study suggested that TRPC5-PLSCR1 is a signaling complex mediating PS externalization and apoptosis in neurons and that TRPC5 plays a pathological role in cerebral-ischemia reperfusion injury.
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http://dx.doi.org/10.3390/cells9030547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140530PMC
February 2020

Post-Translational Modification and Natural Mutation of TRPC Channels.

Cells 2020 01 7;9(1). Epub 2020 Jan 7.

School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Transient Receptor Potential Canonical (TRPC) channels are homologues of Drosophila TRP channel first cloned in mammalian cells. TRPC family consists of seven members which are nonselective cation channels with a high Ca permeability and are activated by a wide spectrum of stimuli. These channels are ubiquitously expressed in different tissues and organs in mammals and exert a variety of physiological functions. Post-translational modifications (PTMs) including phosphorylation, N-glycosylation, disulfide bond formation, ubiquitination, S-nitrosylation, S-glutathionylation, and acetylation play important roles in the modulation of channel gating, subcellular trafficking, protein-protein interaction, recycling, and protein architecture. PTMs also contribute to the polymodal activation of TRPCs and their subtle regulation in diverse physiological contexts and in pathological situations. Owing to their roles in the motor coordination and regulation of kidney podocyte structure, mutations of TRPCs have been implicated in diseases like cerebellar ataxia (moonwalker mice) and focal and segmental glomerulosclerosis (FSGS). The aim of this review is to comprehensively integrate all reported PTMs of TRPCs, to discuss their physiological/pathophysiological roles if available, and to summarize diseases linked to the natural mutations of TRPCs.
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http://dx.doi.org/10.3390/cells9010135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016788PMC
January 2020

Trust Game Database: Behavioral and EEG Data From Two Trust Games.

Front Psychol 2019 12;10:2656. Epub 2019 Dec 12.

School of Economics and Management, Fuzhou University, Fuzhou, China.

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http://dx.doi.org/10.3389/fpsyg.2019.02656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920181PMC
December 2019

Knockdown of TM9SF4 boosts ER stress to trigger cell death of chemoresistant breast cancer cells.

Oncogene 2019 07 27;38(29):5778-5791. Epub 2019 Jun 27.

School of Biomedical Sciences and Li Ka Shing Institute of Health Science, the Chinese University of Hong Kong, Hong Kong, China.

Drug resistance is one of the major obstacles to breast cancer therapy. However, the mechanisms of how cancer cells develop chemoresistance are still not fully understood. In the present study, we found that expression of TM9SF4 proteins was much higher in adriamycin (ADM)-resistant breast cancer cells MCF-7/ADM than in its parental line wild-type breast cancer cells MCF-7/WT. shRNA-mediated knockdown of TM9SF4 preferentially reduced cell growth and triggered cell death in chemoresistant MCF-7/ADM cells compared with MCF-7/WT cells. Knockdown of TM9SF4 also reduced cell growth and triggered cell death in chemoresistant MDA-MB-231/GEM cells. Mechanistic studies showed that TM9SF4 knockdown increased protein misfolding and elevated endoplasmic reticulum (ER) stress level in MCF-7/ADM cells, as indicated by aggresome formation and upregulated expression of ER stress markers, the effect of which was reversed by a small molecule chaperone 4-phenybutyric acid. In an athymic nude mouse model of ADM-resistant human breast xenograft tumor, knockdown of TM9SF4 decreased the growth of tumor xenografts. In chemoresistant breast cancer patients, chemotherapy increased the expression of TM9SF4 proteins in breast tumor samples. Taken together, these results uncovered a novel role of TM9SF4 proteins in alleviating ER stress and protecting chemoresistant breast cancer cells from apoptotic/necrotic cell death. These results highlight a possible strategy of targeting TM9SF4 to overcome breast cancer chemoresistance.
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http://dx.doi.org/10.1038/s41388-019-0846-yDOI Listing
July 2019

Arabidopsis ENDOMEMBRANE PROTEIN 12 contributes to the endoplasmic reticulum stress response by regulating K/HDEL receptor trafficking.

Plant Cell 2019 May 23. Epub 2019 May 23.

The Chinese University of Hong Kong CITY: Hong Kong China [CN]

ENDOMEMBRANE PROTEIN 70 (EMP70) proteins constitute a 12-member superfamily in Arabidopsis thaliana, and are the most abundant protein species in plant Golgi proteomes. However, the physiological functions of EMPs in plants remain largely unknown. Here we have demonstrated that two AtEMP12 T-DNA insertion mutants are sensitive to ER (endoplasmic reticulum) stress as induced by tunicamycin and dithiothreitol treatments. Interestingly, the unfolded protein response (UPR) is constitutively activated in the knockout mutant emp12-1 under normal growth conditions, suggesting that the activation is a result of insufficient chaperones in the ER to aid protein folding. Indeed, we have further shown that BiP is secreted into the apoplast in emp12-1, while the K/HDEL receptor ERD2a, which regulates BiP trafficking, is exclusively localized in the ER in emp12-1, instead of its known ER-Golgi dual-localization. Given an enhanced retrograde transport of ERD2a, along with less dimerized receptor formed in the absence of EMP12, ERD2a may be prematurely returned to the ER without its bound ligands. Therefore, we propose that EMP12 may act as a novel regulator of the K/HDEL receptor to ensure an effective retrograde transport of K/HDEL ligands.
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http://dx.doi.org/10.1105/tpc.18.00913DOI Listing
May 2019

The activity of transient receptor potential channel C-6 modulates the differentiation of fat cells.

FASEB J 2019 05 20;33(5):6526-6538. Epub 2019 Feb 20.

School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, China.

Previously, the V1-3 isoforms of the transient receptor potential channel (TRP) have been shown to promote or prevent adipocyte differentiation. In the current study, the C isoforms were screened for blocking adipogenesis. The hypothesis that the TRP classic or canonical (TRPC) deters adipocyte differentiation was investigated in 3T3-L1 cells employing the channel-specific activator and antagonist, silencing, and overexpression techniques. Fat accumulation in cells was visualized by Oil Red O staining. Intracellular calcium inflow was estimated by confocal microscopy. A high-fat (HF) feeding study was also performed on C57BL/6J mice to verify the findings in the cell model. Among the 6 C isoforms tested, only TRPC-6 inhibited the differentiation of fat cells. The phytochemical quercetin induced the channel protein expression. Calcium-imaging results also revealed that the flavonoid could trigger calcium inflow. Coadministration of quercetin (1 or 20 mg/kg body weight) in an HF diet prevented TRPC-6 from declining and attenuated phosphorylated (p)-PKB and PI3k, as well as the proliferation of visceral fat cells. The present study illustrated that TRPC-6 activation could perturb adipocyte differentiation. The food flavonoid quercetin was a TRPC-6 inducer and activator and it could prevent adipogenesis in mice.-Tan, Y. Q., Kwan, H. Y., Yao, X., Leung, L. K. The activity of transient receptor potential channel C-6 modulates the differentiation of fat cells.
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http://dx.doi.org/10.1096/fj.201801518RRDOI Listing
May 2019

Focal TLR4 activation mediates disturbed flow-induced endothelial inflammation.

Cardiovasc Res 2020 01;116(1):226-236

Shenzhen Research Institute, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.

Aims: Disturbed blood flow at arterial branches and curvatures modulates endothelial function and predisposes the region to endothelial inflammation and subsequent development of atherosclerotic lesions. Activation of the endothelial Toll-like receptors (TLRs), in particular TLR4, contributes to vascular inflammation. Therefore, we investigate whether TLR4 can sense disturbed flow (DF) to mediate the subsequent endothelial inflammation.

Methods And Results: En face staining of endothelium revealed that TLR4 expression, activation, and its downstream inflammatory markers were elevated in mouse aortic arch compared with thoracic aorta, which were absent in Tlr4mut mice. Similar results were observed in the partial carotid ligation model where TLR4 signalling was activated in response to ligation-induced flow disturbance in mouse carotid arteries, and such effect was attenuated in Tlr4mut mice. DF in vitro increased TLR4 expression and activation in human endothelial cells (ECs) and promoted monocyte-EC adhesion, which were inhibited in TLR4-knockdown ECs. Among endogenous TLR4 ligands examined as candidate mediators of DF-induced TLR4 activation, fibronectin containing the extra domain A (FN-EDA) expressed by ECs was increased by DF and was revealed to directly interact with and activate TLR4.

Conclusion: Our findings demonstrate the indispensable role of TLR4 in DF-induced endothelial inflammation and pinpoint FN-EDA as the endogenous TLR4 activator in this scenario. This novel mechanism of vascular inflammation under DF condition may serve as a critical initiating step in atherogenesis.
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http://dx.doi.org/10.1093/cvr/cvz046DOI Listing
January 2020

Psychopathy and Decision-Making: Antisocial Factor Associated With Risky Decision-Making in Offenders.

Front Psychol 2019 1;10:166. Epub 2019 Feb 1.

School of Psychology, Jiangxi Normal University, Nanchang, China.

Psychopathy is a personality development disorder increasing the risk of antisocial behavior. Studies on the relationship between psychopathy and decision-making have received limited attention and the result of studies is mixed. A present study examines whether or not the different factors of psychopathy are related to decision-making under risk and ambiguity in offenders and how they are related. Also, the study investigates whether general intelligence is associated with decision-making or moderates the relationship between psychopathy and decision-making. The results showed that only antisocial factor of psychopathy significantly correlates with Game of Dice Task (GDT) risky selections, but there no general relation between psychopathy and Iowa Gambling Task (IGT) performance. Lastly, general intelligence neither is related to decision-making under risk and ambiguity nor moderates the relationship between decision-making and psychopathy. The study results show that antisocial factor of psychopathy was associated with decision-making under risk rather than ambiguity. Our results also suggest that the antisocial factor of psychopathy was more related to executive dysfunction in offenders.
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http://dx.doi.org/10.3389/fpsyg.2019.00166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367264PMC
February 2019

Endothelial cell transient receptor potential channel C5 (TRPC5) is essential for endothelium-dependent contraction in mouse carotid arteries.

Biochem Pharmacol 2019 01 7;159:11-24. Epub 2018 Nov 7.

School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. Electronic address:

Augmented endothelium-dependent contractions (EDC) contributes to endothelial dysfunction and vascular disease progression. An early signal in EDC is cytosolic [Ca] rise in endothelial cells, which stimulates the production of contractile prostanoids, leading to vascular contraction. In this study, the molecular identity of Ca-permeable channels in endothelial cells and its function were investigated. Vascular tension was measured by wire myograph. EDCs were elicited by acetylcholine (ACH) in the presence of N-nitro-l-arginine methyl ester (L-NAME). [Ca] was measured using a Ca-sensitive fluorescence dye. Enzyme Immunoassay (EIA) was used for prostaglandin measurement. Immunohistochemical staining found the expression of transient receptor potential channel C5 (TRPC5) in endothelial and smooth muscle cells of mouse carotid arteries. ACH-induced EDC in male mouse carotid arteries was found to be substantially reduced in TRPC5 knockout (KO) mice than in wild-type (WT) mice. TRPC5 inhibitors clemizole and ML204 also reduced the EDC. Furthermore, ACH-induced Ca entry in endothelial cells was lower in TRPC5 KO mice than in WT mice. Moreover, the EDC was abolished by a cyclooxygenase-2 (COX-2) inhibitor NS-398, but not affected by a COX-1 inhibitor valeryl salicylate (VAS). Enzyme immunoassay results showed that TRPC5 stimulated the COX-2-linked production of prostaglandin F (PGF), prostaglandin E (PGE), and prostaglandin D (PGD). Exogeneous PGF, PGE, and PGD could induce contractions in carotid arteries. Our present study demonstrated that TRPC5 in endothelial cells contributes to EDC by stimulating the production of COX-2-linked prostanoids. The finding extends our knowledge about EDC.
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http://dx.doi.org/10.1016/j.bcp.2018.11.002DOI Listing
January 2019

The TRPC5 channel regulates angiogenesis and promotes recovery from ischemic injury in mice.

J Biol Chem 2019 01 9;294(1):28-37. Epub 2018 Nov 9.

Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214000, China. Electronic address:

Ischemia-related diseases are a leading cause of death worldwide, and promoting therapeutic angiogenesis is key for effective recovery from hypoxia-ischemia. Given the limited success of angiogenic factors, such as vascular endothelial growth factor, in clinical trials, it is important to find more promising angiogenic targets. Here, using both cell- and tissue-based assays and a mouse model of injury-induced ischemia, we investigated the involvement of the transient receptor potential canonical 5 (TRPC5) ion channel in angiogenesis and the effects of a TRPC5 activator, the Food and Drug Administration-approved drug riluzole, on recovery from ischemic injury. We demonstrate that TRPC5 is involved in endothelial cell sprouting, angiogenesis, and blood perfusion in an oxygen-induced retinopathy model and a hind limb ischemia model. We found a potential regulatory link between nuclear factor of activated T cell isoform c3 and angiopoietin-1 that could provide the mechanistic basis for the angiogenic function of TRPC5. Importantly, treatment with riluzole, which can activate TRPC5 in endothelial cells, improved recovery from ischemia in mice. Our study reveals TRPC5 as a potential angiogenic target and suggests riluzole as a promising drug for managing ischemic diseases.
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http://dx.doi.org/10.1074/jbc.RA118.005392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322878PMC
January 2019

Pyrolysis of metal-organic framework (CuBTC) decorated filter paper as a low-cost and highly active catalyst for the reduction of 4-nitrophenol.

Dalton Trans 2018 Nov 18;47(43):15458-15464. Epub 2018 Oct 18.

Key Laboratory of Eco-Environment-Related Polymer Materials of Ministry of Education, Key Laboratory of Polymer Materials of Gansu Province, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. China.

The fabrication of noble metal free catalysts with excellent performance and high stability by a simple, efficient, general and low-cost approach remains an urgent task for solving the problem of resource shortage. Herein, Cu-based metal organic frameworks (MOFs) immobilized on commercial filter papers were used as pyrolysis precursors to synthesize [email protected] at various calcination temperatures. Notably, the resultant [email protected] exhibits an excellent catalytic performance toward the reaction of reducing 4-nitrophenol (4-NP) to 4-aminophenol (4-AP). By virtue of the large specific surface area, well-developed porosity, good stability and high dispersity of CuO nanoparticles, the obtained [email protected] could complete the reduction reaction within 11 min with a large apparent rate constant κ value (4.8 × 10 s). Our strategy therefore opens a new avenue for the preparation of low-cost and high-performance noble metal free catalysts.
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http://dx.doi.org/10.1039/c8dt03327gDOI Listing
November 2018

Serum exosomes mediate delivery of arginase 1 as a novel mechanism for endothelial dysfunction in diabetes.

Proc Natl Acad Sci U S A 2018 07 2;115(29):E6927-E6936. Epub 2018 Jul 2.

Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong, China;

Exosomes, abundant in blood, deliver various molecules to recipient cells. Endothelial cells are directly exposed to circulating substances. However, how endothelial cells respond to serum exosomes (SExos) and the implications in diabetes-associated vasculopathy have never been explored. In the present study, we showed that SExos from diabetic mice ( SExos) were taken up by aortic endothelial cells, which severely impaired endothelial function in nondiabetic mice. The exosomal proteins, rather than RNAs, mostly account for SExos-induced endothelial dysfunction. Comparative proteomics analysis showed significant increase of arginase 1 in SExos. Silence or overexpression of arginase 1 confirmed its essential role in SExos-induced endothelial dysfunction. This study is a demonstration that SExos deliver arginase 1 protein to endothelial cells, representing a cellular mechanism during development of diabetic endothelial dysfunction. The results expand the scope of blood-borne substances that monitor vascular homeostasis.
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http://dx.doi.org/10.1073/pnas.1721521115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055191PMC
July 2018

Auto-oxidation promoted sp C-H arylation of glycine derivatives.

Org Biomol Chem 2018 07;16(27):4985-4989

College of Chemistry and Chemical Engineering, Northwest Normal University Lanzhou, Gansu 730070, China.

An auto-oxidation promoted sp3 C-H arylation reaction between N-aryl glycine derivatives and electron-rich arenes, leading to the formation of N-aryl α-aryl α-amino acid derivatives, is described. This atom-economical and environmentally benign reaction proceeds smoothly under mild reaction conditions and requires only Brønsted acid and oxygen (balloon). A plausible radical involved mechanism is proposed.
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http://dx.doi.org/10.1039/c8ob01068dDOI Listing
July 2018

TRPV6 protects ER stress-induced apoptosis via ATF6α-TRPV6-JNK pathway in human embryonic stem cell-derived cardiomyocytes.

J Mol Cell Cardiol 2018 07 16;120:1-11. Epub 2018 May 16.

School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Hong Kong, China. Electronic address:

Human pluripotent stem cell-derived cardiomyocytes have potential applications in disease modeling and drug screening. Therefore, it is important to understand the mechanisms and signaling pathways underlying the survival and death of these cells. Endoplasmic reticulum (ER) stress is triggered by various cellular stresses that disturb protein folding in the ER. Cells cope with ER stress by activating the unfolded protein response (UPR), a homeostatic signaling network that orchestrates the recovery of ER function. In the present study, we hypothesized that ER stress may upregulate the expression of transient receptor potential channel TRPV6, which in turn serves to protect human embryonic stem cell-derived cardiomyocytes (hESC-CMs) from ER stress-induced apoptotic cell death. Indeed, we found that ER stress induced by thapsigargin and tunicamycin led to increased expression of TRPV6 via ATF6α signaling branch. siRNA-mediated knockdown of TRPV6 aggravated ER stress-induced apoptotic cell death, whereas overexpression of TRPV6 attenuated ER stress-induced apoptosis in hESC-CMs. Furthermore, the signaling pathway downstream of TRPV6 was MAPK-JNK. Taken together, these results provide strong evidence that, under ER stress, TRPV6 is upregulated to protect hESC-CMs from apoptotic cell death via ATF6α-TRPV6-JNK pathway.
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http://dx.doi.org/10.1016/j.yjmcc.2018.05.008DOI Listing
July 2018

Positively Charged Hyperbranched Polymers with Tunable Fluorescence and Cell Imaging Application.

ACS Appl Mater Interfaces 2018 Jun 29;10(23):20064-20072. Epub 2018 May 29.

Key Laboratory of Polymer Materials of Gansu Province, Key Laboratory of Eco-Environment-Related Polymer Materials Ministry of Education, College of Chemistry and Chemical Engineering , Northwest Normal University , Lanzhou 730070 , PR China.

Fluorescence-tunable materials are becoming increasingly attractive because of their potential applications in optics, electronics, and biomedical technology. Herein, a multicolor molecular pixel system is realized using a simple copolymerization method. Bleeding of two complementary colors from blue and yellow fluorescence segments reproduced serious multicolor fluorescence materials. Interestingly, the emission colors of the polymers can be fine-tuned in the solid state, solution phase, and in hydrogel state. More importantly, the positive fluorescent polymers exhibited cell-membrane permeable ability and were found to accumulate on the cell nucleus, exhibiting remarkable selectivity to give bright fluorescence. The DNA/RNA selectivity experiments in vitro and in vivo verified that [tris(4-(pyridin-4-yl)phenyl)amine]-[1,8-dibromooctane] has prominent selectivity to DNA over RNA inside cells.
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http://dx.doi.org/10.1021/acsami.8b05073DOI Listing
June 2018

Correspondence: Reply to 'Challenging a proposed role for TRPC5 in aortic baroreceptor pressure-sensing'.

Nat Commun 2018 03 23;9(1):1244. Epub 2018 Mar 23.

School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.

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http://dx.doi.org/10.1038/s41467-017-02704-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865186PMC
March 2018

Integrated transcriptomic and regulatory network analyses identify microRNA-200c as a novel repressor of human pluripotent stem cell-derived cardiomyocyte differentiation and maturation.

Cardiovasc Res 2018 05;114(6):894-906

School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Aims: MicroRNAs (miRNAs) are crucial for the post-transcriptional control of protein-encoding genes and together with transcription factors (TFs) regulate gene expression; however, the regulatory activities of miRNAs during cardiac development are only partially understood. In this study, we tested the hypothesis that integrative computational approaches could identify miRNAs that experimentally could be shown to regulate cardiomyogenesis.

Methods And Results: We integrated expression profiles with bioinformatics analyses of miRNA and TF regulatory programs to identify candidate miRNAs involved with cardiac development. Expression profiling showed that miR-200c, which is not normally detected in adult heart, is progressively down-regulated both during cardiac development and in vitro differentiation of human embryonic stem cells (hESCs) to cardiomyocytes (CMs). We employed computational methodologies to predict target genes of both miR-200c and five key cardiac TFs to identify co-regulated gene networks. The inferred cardiac networks revealed that the cooperative action of miR-200c with these five key TFs, including three (GATA4, SRF and TBX5) targeted by miR-200c, should modulate key processes and pathways necessary for CM development and function. Experimentally, over-expression (OE) of miR-200c in hESC-CMs reduced the mRNA levels of GATA4, SRF and TBX5. Cardiac expression of Ca2+, K+ and Na+ ion channel genes (CACNA1C, KCNJ2 and SCN5A) were also significantly altered by knockdown or OE of miR-200c. Luciferase reporter assays validated miR-200c binding sites on the 3' untranslated region of CACNA1C. In hESC-CMs, elevated miR-200c increased beating frequency, and repressed both Ca2+ influx, mediated by the L-type Ca2+ channel and Ca2+ transients.

Conclusions: Our analyses demonstrate that miR-200c represses hESC-CM differentiation and maturation. The integrative computation and experimental approaches described here, when applied more broadly, will enhance our understanding of the interplays between miRNAs and TFs in controlling cardiac development and disease processes.
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http://dx.doi.org/10.1093/cvr/cvy019DOI Listing
May 2018

Orai1 is critical for Notch-driven aggressiveness under hypoxic conditions in triple-negative breast cancers.

Biochim Biophys Acta Mol Basis Dis 2018 Apr 5;1864(4 Pt A):975-986. Epub 2018 Jan 5.

School of Medicine, Jiangnan University, Wuxi, China. Electronic address:

It is believed that hypoxia stimulates triple-negative breast cancers (TNBCs) metastasis, which is associated with a poor prognosis. However, the underlying mechanism remains unclear. Here, we demonstrated that hypoxia up-regulates both the levels of Orai1 and Notch1, and the increase in Orai1 is mediated by Notch1 signaling in TNBCs. Functionally, Orai1 caused a sustained elevation of intracellular Ca via Store-operated Ca entry (SOCE), then activated the calcineurin-nuclear factor of activated T-cell 4 (NFAT4, also named NFATc3) in hypoxic TNBCs. Furthermore, pharmacologic inhibition or gene-silencing studies showed that the aggressiveness mediated by Orai1 during hypoxia is dependent on the Notch1/Orai1/SOCE/NFAT4 signaling. Moreover, Orai1 signaling also mediated hypoxia-induced angiogenesis in TNBCs. Thus, our results revealed a novel role of Orai1 as an inducer of aggression and angiogenesis under hypoxic conditions, and this suggests a novel mechanism of hypoxia-induced invasion. It may be worthwhile to further explore the potential of using Orai1 signaling as new target for anti-tumor therapy in TNBCs.
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http://dx.doi.org/10.1016/j.bbadis.2018.01.003DOI Listing
April 2018

Polycystin-2 Plays an Essential Role in Glucose Starvation-Induced Autophagy in Human Embryonic Stem Cell-Derived Cardiomyocytes.

Stem Cells 2018 04 3;36(4):501-513. Epub 2018 Jan 3.

School of Biomedical Sciences and Li Ka Shing Institute of Health Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, People's Republic of China.

Autophagy is a process essential for cell survival under stress condition. The patients with autosomal dominant polycystic kidney disease, which is caused by polycystin-1 or polycystin-2 (PKD2) mutation, display cardiovascular abnormalities and dysregulation in autophagy. However, it is unclear whether PKD2 plays a role in autophagy. In the present study, we explored the functional role of PKD2 in autophagy and apoptosis in human embryonic stem cell-derived cardiomyocytes. HES2 hESC line-derived cardiomyocytes (HES2-CMs) were transduced with adenoviral-based PKD2-shRNAs (Ad-PKD2-shRNAs), and then cultured with normal or glucose-free medium for 3 hours. Autophagy was upregulated in HES2-CMs under glucose starvation, as indicated by increased microtubule-associated protein 1 light chain 3-II level in immunoblots and increased autophagosome and autolysosome formation. Knockdown of PKD2 reduced the autophagic flux and increased apoptosis under glucose starvation. In Ca measurement, Ad-PKD2-shRNAs reduced caffeine-induced cytosolic Ca rise. Co-immunoprecipitation and in situ proximity ligation assay demonstrated an increased physical interaction of PKD2 with ryanodine receptor 2 (RyR2) under glucose starvation condition. Furthermore, Ad-PKD2-shRNAs substantially attenuated the starvation-induced activation of AMP-activated protein kinase (AMPK) and inactivation of mammalian target of rapamycin (mTOR). The present study for the first time demonstrates that PKD2 functions to promote autophagy under glucose starvation, thereby protects cardiomyocytes from apoptotic cell death. The mechanism may involve PKD2 interaction with RyR2 to alter Ca release from sarcoplasmic reticulum, consequently modulating the activity of AMPK and mTOR, resulting in alteration of autophagy and apoptosis. Stem Cells 2018;36:501-513.
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http://dx.doi.org/10.1002/stem.2764DOI Listing
April 2018