Publications by authors named "Peiqing Liu"

201 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313700PMC
July 2021

Comparison of biological and transcriptomic effects of conventional cigarette and electronic cigarette smoke exposure at toxicological dose in BEAS-2B cells.

Ecotoxicol Environ Saf 2021 Oct 3;222:112472. Epub 2021 Jul 3.

School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, Guangdong 510006, China. Electronic address:

Cigarette seriously affects human health, and electronic cigarette (e-cigarette), considered as cigarette substitutes, become popular as its contribution to quit smoking. But scientific evidence about the absolute safety of e-cigarette is insufficient. Previous studies also have indicated that different dosages of cigarette can lead to different biological effects. Thus, the impact of cigarette at toxicological dose such as IC50 compared with that of e-cigarette are highly needed. In this study, we investigated the effects of cigarette smoke condensate (CSC) at toxicological dose compared with e-cigarette smoke condensate (ECSC) in equivalent nicotine level. Nicotine content of CSC and ECSC were determined by UPLC. Human lung epithelial cells (BEAS-2B) were exposed to 0-32 μg/ml of CSC and ECSC for 24 h to determine IC50 of cell viability and morphological assessment. Inflammation, apoptosis, cell cycle analysis and RNA-Seq transcriptome analysis were performed to characterize the differences between CSC and ECSC. We found that acute exposure of BEAS-2B cells to CSC at IC50 leaded to morphological change, inflammatory cytokines production and cell apoptosis, while ECSC did not exert such cell effects in equivalent nicotine level. The transcriptome analysis showed that differentially expressed genes in CSC were far more than that in ECSC, and mainly enriched in the category of cell cycle, DNA repair, cancer, and metabolic related pathways. Such cell cycle arrest was further experimentally confirmed. These results suggested that toxicological dose of ECSC might be much higher than that of CSC. Based on equivalent nicotine content, an acute exposure to CSC had significant impacts on cell effects and gene expression profile compared to ECSC. Our results provided a reference for the safety studies of conventional cigarette and e-cigarette.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112472DOI Listing
October 2021

PEX5 prevents cardiomyocyte hypertrophy via suppressing the redox-sensitive signaling pathways MAPKs and STAT3.

Eur J Pharmacol 2021 Sep 24;906:174283. Epub 2021 Jun 24.

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, China. Electronic address:

Peroxisomal biogenesis factor 5 (PEX5) is a member of peroxisome biogenesis protein family which serves as a shuttle receptor for the import of peroxisome matrix protein. The function of PEX5 on cardiomyocyte hypertrophy remained to be elucidated. Our study demonstrated that the protein expression level of PEX5 was declined in primary neonatal rat cardiomyocytes treated with phenylephrine (PE) and hearts from cardiac hypertrophic rats induced by abdominal aortic constriction (AAC). Overexpression of PEX5 alleviated cardiomyocyte hypertrophy induced by PE, while silencing of PEX5 exacerbated cardiomyocyte hypertrophy. PEX5 improved redox imbalance by decreasing cellular reactive oxygen species level and preserving peroxisomal catalase. Moreover, PEX5 knockdown aggravated PE-induced activation of redox-sensitive signaling pathways, including mitogen-activated protein kinase (MAPK) pathway and signal transducer and activator of transcription 3 (STAT3); whereas PEX5 overexpression suppressed activation of MAPK and STAT3. But PEX5 did not affect PE-induced phosphorylation of mammalian target of rapamycin (mTOR). In conclusion, the present study suggests that PEX5 protects cardiomyocyte against hypertrophy via regulating redox homeostasis and inhibiting redox-sensitive signaling pathways MAPK and STAT3.
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http://dx.doi.org/10.1016/j.ejphar.2021.174283DOI Listing
September 2021

The poly(ADP-ribosyl)ation of BRD4 mediated by PARP1 promoted pathological cardiac hypertrophy.

Acta Pharm Sin B 2021 May 14;11(5):1286-1299. Epub 2020 Dec 14.

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 510006, China.

The bromodomain and extraterminal (BET) family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy. BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin, facilitating the phosphorylation of RNA polymerases II (Pol II) and leading to transcription elongation. The present study identified a novel post-translational modification of BRD4: poly(ADP-ribosyl)ation (PARylation), that was mediated by poly(ADP-ribose)polymerase-1 (PARP1) in cardiac hypertrophy. BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol (ISO), whereas overexpression of BRD4 promoted cardiac hypertrophy, confirming the critical role of BRD4 in pathological cardiac hypertrophy. PARP1 was activated in ISO-induced cardiac hypertrophy and facilitated the development of cardiac hypertrophy. BRD4 was involved in the prohypertrophic effect of PARP1, as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses, and that BRD4 overexpression suppressed the anti-hypertrophic effect of PARP1 inhibitors. Interactions of BRD4 and PARP1 were observed by co-immunoprecipitation and immunofluorescence. PARylation of BRD4 induced by PARP1 was investigated by PARylation assays. In response to hypertrophic stimuli like ISO, PARylation level of BRD4 was elevated, along with enhanced interactions between BRD4 and PARP1. By investigating the PARylation of truncation mutants of BRD4, the C-terminal domain (CTD) was identified as the PARylation modification sites of BRD4. PARylation of BRD4 facilitated its binding to the transcription start sites (TSS) of hypertrophic genes, resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes. The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.
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http://dx.doi.org/10.1016/j.apsb.2020.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148063PMC
May 2021

Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies.

Pharmacol Rev 2021 07;73(3):924-967

Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)

The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1 monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.
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http://dx.doi.org/10.1124/pharmrev.120.000096DOI Listing
July 2021

Structure-based discovery of potent and selective small-molecule inhibitors targeting signal transducer and activator of transcription 3 (STAT3).

Eur J Med Chem 2021 Oct 7;221:113525. Epub 2021 May 7.

Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China. Electronic address:

STAT3 has been validated as an attractive anticancer target due to its important roles in cancer initiation and progression. However, discovery of potent and selective STAT3 small-molecule inhibitors with druglike properties is still challenging. In this study, two series of substituted 2-phenylquinolines and 2-arylimidazo[1,2-a]pyridines were designed through structure-based drug discovery approach by condensing the privileged structures of STX-119 and SH4-54. Our study has resulted in the discovery of a number of highly potent and selective STAT3 inhibitors, exemplified by compound 39 with the privileged structure of 2-phenylimidazo[1,2-a]pyridine, which selectively inhibits phosphorylation of STAT3 and suppresses subsequent signaling pathway. Moreover, 39 inhibits cell growth, migration and invasion of human triple negative breast cancer (TNBC) cells lines. Consistently, it achieves significant and dose-dependent tumor growth inhibition in both cell line-derived and patient-derived xenograft tumor models in mice. These results clearly indicate that 39 is a highly potent and selective STAT3 inhibitor.
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http://dx.doi.org/10.1016/j.ejmech.2021.113525DOI Listing
October 2021

Genome Sequence Resource of Phytophthora colocasiae from China Using Nanopore Sequencing Technology.

Plant Dis 2021 May 13. Epub 2021 May 13.

Hainan University, 74629, Plant Pathology, 58 Renmin Avenue, Haikou, China, 570288.

Phytophthora colocasiae is a destructive oomycete pathogen of taro (Colocasia esculenta), which causes taro leaf blight. To date, only one highly fragmented Illumina short-read-based genome assembly is available for this species. To address this problem, we sequenced strain Lyd2019 from China using Oxford Nanopore Technologies (ONT) long-read sequencing and Illumina short-read sequencing. We generated a 92.51-Mb genome assembly consisting of 105 contigs with an N50 of 1.70 Mb and a maximum length of 4.17 Mb. In the genome assembly, we identified 52.78% repeats and 18,322 protein-coding genes, of which 12,782 genes were annotated. We also identified 191 candidate RXLR effectors and 1 candidate CRN effectors. The updated near-chromosome genome assembly and annotation resources will provide a better understanding of the infection mechanisms of P. colocasiae.
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http://dx.doi.org/10.1094/PDIS-11-20-2327-ADOI Listing
May 2021

Sorting nexin 3 induces heart failure via promoting retromer-dependent nuclear trafficking of STAT3.

Cell Death Differ 2021 May 4. Epub 2021 May 4.

School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, P. R. China.

Sorting nexins (SNXs), the retromer-associated cargo binding proteins, have emerged as critical regulators of the trafficking of proteins involved in the pathogenesis of diverse diseases. However, studies of SNXs in the development of cardiovascular diseases, especially cardiac hypertrophy and heart failure, are lacking. Here, we ask whether SNX3, the simplest structured isoform in the SNXs family, may act as a key inducer of myocardial injury. An increased level of SNX3 was observed in failing hearts from human patients and mice. Cardiac-specific Snx3 knockout (Snx3-cKO) mice and Snx3 transgenic (Snx3-cTg) mice were generated to evaluate the role of Snx3 in myocardial hypertrophy, fibrosis, and heart function by morphology, echocardiography, histological staining, and hypertrophic biomarkers. We report that Snx3-cKO in mice significantly protected against isoproterenol (ISO)-induced cardiac hypertrophy at 12 weeks. Conversely, Snx3-cTg mice were more susceptible to ISO-induced cardiac hypertrophy at 12 weeks and showed aggravated cardiac injury even heart failure at 24 weeks. Immunoprecipitation-based mass spectrometry, immunofluorescent staining, co-immunoprecipitation, localized surface plasmon resonance, and proximity ligation assay were performed to examine the direct interaction of SNX3-retromer with signal transducer and activator of transcription 3 (STAT3). We discovered that STAT3 was a new interacting partner of SNX3-retromer, and SNX3-retromer served as an essential platform for assembling gp130/JAK2/STAT3 complexes and subsequent phosphorylation of STAT3 by direct combination at EE. SNX3-retromer and STAT3 complexes were transiently imported into the nucleus after hypertrophic stimuli. The pharmacological inhibition or knockdown of STAT3 reversed SNX3 overexpression-induced myocardial injury. STAT3 overexpression blunts the beneficial function of SNX3 knockdown on hypertrophic cardiomyocytes. We show that SNX3-retromer promoted importin α3-mediated STAT3 nuclear trafficking and ultimately leading to cardiac injury. Taken together, our study reveals that SNX3 plays a key role in cardiac function and implicates SNX3 as a potential therapeutic target for cardiac hypertrophy and heart failure.
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http://dx.doi.org/10.1038/s41418-021-00789-wDOI Listing
May 2021

Loss-of-function genetic screening identifies ALDOA as an essential driver for liver cancer cell growth under hypoxia.

Hepatology 2021 Apr 4. Epub 2021 Apr 4.

National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.

Hypoxia is a common feature of tumor microenvironment (TME), which promotes tumor progression, metastasis and therapeutic drug resistance via a myriad of cell activities in tumor and stroma cells. While targeting hypoxic TME is emerging as a promising strategy for treating solid tumors, preclinical development of this approach is lacking in the study of hepatocellular carcinoma (HCC). From a genome-wide CRISPR/Cas9 gene knockout screening, we identified aldolase A (ALDOA), a key enzyme in glycolysis and gluconeogenesis, as an essential driver for HCC cell growth under hypoxia. Knockdown of ALDOA in HCC cells leads to lactate depletion, and consequently inhibits tumor growth. Supplementation of lactate partly rescues the inhibitory effects mediated by ALDOA knockdown. Upon hypoxia, ALDOA is induced by HIF-1α and FTO-mediated m6A modification through transcriptional and post-transcriptional regulation, respectively. Analysis of TCGA shows that elevated levels of ALDOA are significantly correlated with poor prognosis of HCC patients. In a screen of FDA-approved drugs based on structured hierarchical virtual platforms, we identify sulfamonomethoxine derivative cpd-5 as a potential inhibitor to target ALDOA, evidenced by the anti-tumor activity of cpd-5 in preclinical patient-derived xenograft models of HCC. CONCLUSION: Our work identifies ALDOA as an essential driver for HCC cell growth under hypoxia, and we demonstrate that inhibition of ALDOA in hypoxic TME is a promising therapeutic strategy for treating HCC.
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http://dx.doi.org/10.1002/hep.31846DOI Listing
April 2021

Isorhapontigenin protects against doxorubicin-induced cardiotoxicity increasing YAP1 expression.

Acta Pharm Sin B 2021 Mar 1;11(3):680-693. Epub 2020 Nov 1.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

As an effective anticancer drug, the clinical limitation of doxorubicin (Dox) is the time- and dose-dependent cardiotoxicity. Yes-associated protein 1 (YAP1) interacts with transcription factor TEA domain 1 (TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced and cardiotoxic model. Ectopic expression of significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin (Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Dox-induced cardiomyocytes apoptosis in a dose-dependent manner . Administration with Isor (30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes and . Knockout or inhibition of blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.
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http://dx.doi.org/10.1016/j.apsb.2020.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982427PMC
March 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

Phosphite translocation in soybean and mechanisms of Phytophthora sojae inhibition.

Pestic Biochem Physiol 2021 Feb 13;172:104757. Epub 2020 Dec 13.

Fujian Key Laboratory for Monitoring and Integrated Management of Crop Pests, Institute of Plant Protection, Fujian Academy of Agricultural Sciences, Fuzhou 350003, China; Key Laboratory of Green Prevention and Control of Tropical Plant Diseases and Pests, Ministry of Education, College of Plant Protection, Hainan University, Haikou 570228, China. Electronic address:

Although phosphite (Phi)-based fertilizers are used in large quantities in agriculture, the use of Phi-based fungicides against soybean root rot caused by Phytophthora sojae are limited. While, their low toxicity are of high ecological and economic focus. Limited attention has been paid to Phi translocation efficiency in soybeans and the efficacy of Phi as a fungicide against P. sojae. In this study, we evaluated the efficiency of Phi translocation in the Williams soybean cultivar by determining the Phi concentrations in roots, stems, and leaves using high-performance ion chromatography after the application of Phi to the roots. Phi was translocated from roots to leaves within 1 h and its concentration increased significantly in leaves within 36 h after Phi application. Results of an in vitro growth inhibition assay and an in vivo infection assay showed that Phi inhibited P. sojae. Additionally, we examined the activation of the salicylic acid (SA) and ethylene (ET) defense pathways by Phi. The expression of SA and ET pathway-related genes was upregulated in most soybean tissues after Phi application. Our results provide evidence that Phi translocation suppresses root rot caused by P. sojae in soybean.
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http://dx.doi.org/10.1016/j.pestbp.2020.104757DOI Listing
February 2021

Genome Sequence Data of , an Oomycete Pathogen Causing Litchi Downy Blight.

Mol Plant Microbe Interact 2021 Jul 7:MPMI11200303A. Epub 2021 Jul 7.

Key Laboratory of Green Prevention and Control of Tropical Plant Diseases and Pests, Ministry of Education, College of Plant Protection, Hainan University, Haikou 570228, China.

is an oomycete pathogen that exclusively infects litchi, with infection stages affecting a broad range of tissues. In this study, we obtained a near chromosome-level genome assembly of ZL2018 from China using Oxford Nanopore Technologies long-read sequencing and Illumina short-read sequencing. The genome assembly was 64.15 Mb in size and consisted of 81 contigs with an N of 1.43 Mb and a maximum length of 4.74 Mb. Excluding 34.67% of repeat sequences, 14,857 protein-coding genes were identified, among which 14,447 genes were annotated. We also predicted 306 candidate RxLR effectors in the assembly. The high-quality genome assembly and annotation resources reported in this study will provide new insight into the infection mechanisms of . [Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 "No Rights Reserved" license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law. 2021.
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http://dx.doi.org/10.1094/MPMI-11-20-0303-ADOI Listing
July 2021

PRMT5 Prevents Cardiomyocyte Hypertrophy via Symmetric Dimethylating HoxA9 and Repressing HoxA9 Expression.

Front Pharmacol 2020 10;11:600627. Epub 2020 Dec 10.

Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratoty of Druggability and New Drug Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Higher Education Mega Center, Sun Yat-Sen University, Guangzhou, China.

The present study reveals a link between protein arginine methyltransferase 5 (PRMT5) and Homebox A9 (HoxA9) in the regulation of cardiomyocyte hypertrophy. In cardiomyocyte hypertrophy induced by β-adrenergic receptor agonist isoprenaline (ISO), PRMT5 expression was decreased while HoxA9 was upregulated. Silencing of PRMT5 or inhibition of PRMT5 by its pharmacological inhibitor EPZ augmented the expressions of cardiomyocyte hypertrophic genes brain natriuretic peptide (BNP) and β-Myosin Heavy Chain (β-MHC), whereas overexpression of PRMT5 inhibited ISO-induced cardiomyocyte hypertrophy, suggesting that PRMT5 ameliorates cardiomyocyte hypertrophy. On the contrary, HoxA9 promoted cardiomyocyte hypertrophy, as implied by the gain-of-function and loss-of-function experiments. HoxA9 was involved in the regulation of PRMT5 in cardiomyocyte hypertrophy, since HoxA9 knockdown prevented si-RPMT5-induced cardiomyocyte hypertrophy, and HoxA9 expression impaired the anti-hypertrophic effect of PRMT5. Co-immunoprecipitation experiments revealed that there were physical interactions between PRMT5 and HoxA9. The symmetric dimethylation level of HoxA9 was decreased by ISO or EPZ treatment, suggesting that HoxA9 is methylated by PRMT5. Additionally, PRMT5 repressed the expression of HoxA9. Chromatin immunoprecipitation (ChIP) assay demonstrated that HoxA9 could bind to the promoter of BNP, and that this binding affinity was further enhanced by ISO or EPZ. In conclusion, this study suggests that PRMT5 symmetric dimethylates HoxA9 and represses HoxA9 expression, thus impairing its binding to BNP promoter and ultimately protecting against cardiomyocyte hypertrophy. These findings provide a novel insight of the mechanism underlying the cardiac protective effect of PRMT5, and suggest potential therapeutic strategies of PRMT5 activation or HoxA9 inhibition in treatment of cardiac hypertrophy.
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http://dx.doi.org/10.3389/fphar.2020.600627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793800PMC
December 2020

A novel STAT3 inhibitor W2014-S regresses human non-small cell lung cancer xenografts and sensitizes EGFR-TKI acquired resistance.

Theranostics 2021 1;11(2):824-840. Epub 2021 Jan 1.

Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is a common feature in human non-small cell lung cancer (NSCLC). STAT3 plays an important role in cancer progression as a driver oncogene and acquired resistance of targeted therapies as an alternatively activated pathway. W2014-S with pharmacophore structure of imidazopyridine, which was firstly reported to be utilized in STAT3 inhibitor discovery, was screened out as a potent STAT3 inhibitor from a library of small molecules. The aim of this study is to investigate the antitumor activities and mechanisms of W2014-S in NSCLC and effect on epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) resistance and . SPR analysis, Co-immunoprecipitation, confocal microscope imaging, and luciferase report gene assays were utilized to determine the mechanisms. Cell viability, colonial survival, wound healing, cell invasion assay, human cancer cell xenografts and PDX tumor xenografts were used to determine antitumor activities. W2014-S disrupted STAT3 dimerization and selectively inhibited aberrant STAT3 signaling in NSCLC cell line. W2014-S strongly suppressed proliferation, survival, migration and invasion of lung cancer cells with aberrant STAT3 activation and inhibited the growth of human NSCLC cell xenografts and PDX tumor xenografts in mouse model. Furthermore, W2014-S significantly sensitized resistant NSCLC cell line to gefitinib and erlotinib and enhances the anti-tumor effect of gefitinib in TKI-resistant lung cancer xenografts . Our study has provided a novel STAT3 inhibitor with significant anti-tumor activities in NSCLC and suggests that combination of STAT3 inhibitor such as W2014-S with gefitinib could serve as a promising strategy to overcome EGFR-TKIs acquired resistance in NSCLC patients.
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http://dx.doi.org/10.7150/thno.49600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738869PMC
January 2021

Antifungal activity of liquiritin in Phytophthora capsici comprises not only membrane-damage-mediated autophagy, apoptosis, and Ca reduction but also an induced defense responses in pepper.

Ecotoxicol Environ Saf 2021 Feb 21;209:111813. Epub 2020 Dec 21.

Fujian Key Laboratory for Monitoring and Integrated Management of Crop Pests, Institute of Plant Protection, Fujian Academy of Agricultural Sciences, Fuzhou 350003, China; Key Laboratory of Green Prevention and Control of Tropical Plant Diseases and Pests, Ministry of Education, College of Plant Protection, Hainan University, Haikou 570228, China.

Phytophthora capsici causes a severe soil-borne disease in a wide variety of vegetables; to date, no effective strategies to control P. capsici have been developed. Liquiritin (LQ) is a natural flavonoid found in licorice (Glycyrrhiza spp.) root, and it is used in pharmaceuticals. However, the antifungal activity of LQ against P. capsici remains unknown. In the present study, we demonstrated that LQ inhibits P. capsici mycelial growth and sporangial development. In addition, the EC of LQ was 658.4 mg/L and LQ caused P. capsici sporangia to shrink and collapse. Next, LQ severely damaged the cell membrane integrity, leading to a 2.0-2.5-fold increase in relative electrical conductivity and malondialdehyde concentration, and a 65-70% decrease in sugar content. Additionally, the HO content was increased about 2.0-2.5 fold, but the total antioxidant activity, catalase activity and laccase activity were attenuated by 40-45%, 30-35% and 70-75%. LQ also induced autophagy, apoptosis, and reduction of intracellular Ca content. Furthermore, LQ inhibited P. capsici pathogenicity by reducing the expression of virulence genes PcCRN4 and Pc76RTF, and stimulating the plant defense (including the activated transcriptional expression of defense-related genes CaPR1, CaDEF1, and CaSAR82, and the increased antioxidant enzyme activity). Our results not only elucidate the antifungal mechanism of LQ but also suggest a promising alternative to commercial fungicides or a key compound in the development of new fungicides for the control of the Phytophthora disease.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111813DOI Listing
February 2021

Targeting castration-resistant prostate cancer with a novel ROR antagonist elaiophylin.

Acta Pharm Sin B 2020 Dec 12;10(12):2313-2322. Epub 2020 Jul 12.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

Prostate cancer (PCa) patients who progress to metastatic castration-resistant PCa (mCRPC) mostly have poor outcomes due to the lack of effective therapies. Our recent study established the orphan nuclear receptor ROR as a novel therapeutic target for CRPC. Here, we reveal that elaiophylin (Elai), an antibiotic from , is a novel ROR antagonist and showed potent antitumor activity against CRPC and . We demonstrated that Elai selectively binded to ROR protein and potently blocked ROR transcriptional regulation activities. Structure-activity relationship studies showed that Elai occupied the binding pocket with several key interactions. Furthermore, Elai markedly reduced the recruitment of ROR to its genomic DNA response element (RORE), suppressed the expression of ROR target genes and variants, and significantly inhibited PCa cell growth. Importantly, Elai strongly suppressed tumor growth in both cell line based and patient-derived PCa xenograft models. Taken together, these results suggest that Elai is novel therapeutic ROR inhibitor that can be used as a drug candidate for the treatment of human CRPC.
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http://dx.doi.org/10.1016/j.apsb.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745055PMC
December 2020

The regulatory factors and pathological roles of autophagy-related protein 4 in diverse diseases: Recent research advances.

Med Res Rev 2021 05 13;41(3):1644-1675. Epub 2020 Dec 13.

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

Macroautophagy (autophagy) is an evolutionarily conserved and dynamic degradation/recycling pathway in which portions of the cytoplasm, such as dysfunctional proteins and surplus organelles, are engulfed by double-membrane bound vesicles through a lysosome-dependent process. As the only proteolytic enzyme of the core mammalian autophagy proteins, autophagy-related protein 4 (ATG4) primes newly synthesized pro-light chain 3 (LC3) to form LC3-I that attaches to phosphatidylethanolamine and delipidates LC3-PE to LC3-I for recycling. Besides autophagy, ATG4 has been shown to be involved in regulating various biological and pathological processes. The roles of ATG4 in cancer therapy, a methodology for ATG4 activity detection, and the discovery of chemical modulators have been well-reviewed. However, a comprehensive summary on how ATG4 is regulated by multiple factors and, thereby, how ATG4 influences autophagy or other pathways remains lacking. In this paper, we summarize multiple processes and molecules that regulate the activity of ATG4, such as micro-RNAs, posttranslational modifications, and small molecules. Additionally, we focus on the relationship between ATG4 and diverse diseases, including cancer, neurodegeneration, microbial infection, and other diseases. It provides insight regarding potential ATG4-targeted therapeutic opportunities, which could be beneficial for future studies and human health.
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http://dx.doi.org/10.1002/med.21772DOI Listing
May 2021

CKIP-1 acts downstream to Cx43 on the activation of Nrf2 signaling pathway to protect from renal fibrosis in diabetes.

Pharmacol Res 2021 01 1;163:105333. Epub 2020 Dec 1.

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

We previously reported that both Cx43 and CKIP-1 attenuated diabetic renal fibrosis via the activation of Nrf2 signaling pathway. However, whether CKIP-1, a scaffold protein, participates in regulating the activation of Nrf2 signaling pathway by Cx43 remains to be elucidated. In this study, the effect of adenovirus-mediated Cx43 overexpression on renal fibrosis in CKIP-1 diabetic mice was investigated. We found that overexpression of Cx43 could significantly alleviate renal fibrosis by activating the Nrf2 pathway in diabetic mice, but have no obvious effect in CKIP-1 diabetic mice. Cx43 overexpressed plasmid and CKIP-1 small interfering RNA were simultaneously transfected into glomerular mesangial cells and the result demonstrated that the effect of activation of Nrf2 signaling pathway by Cx43 was blocked by CKIP-1 depletion. The interaction between Cx43 and CKIP-1 was analyzed by immunofluorescence and immunoprecipitation assays. We found that Cx43 interacted with CKIP-1, and the interaction was weakened by high glucose treatment. Moreover, Cx43 regulated the expression of CKIP-1 and the interaction of CKIP-1 with Nrf2 via Cx43 carboxyl terminus (CT) domain, thereby activating Nrf2 signaling pathway. According to the results, we preliminary infer that CKIP-1 acts downstream to CX43 on the activation of Nrf2 signaling pathway to protect from renal fibrosis in diabetes, the mechanism of which might be related to the interaction of CKIP-1 with Nrf2 through Cx43 CT. Our study provides further experimental basis for targeting the Cx43-CKIP-1-Nrf2 axis to resist diabetic renal fibrosis.
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http://dx.doi.org/10.1016/j.phrs.2020.105333DOI Listing
January 2021

Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression.

Front Cell Dev Biol 2020 29;8:548605. Epub 2020 Sep 29.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.

Jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, specifically catalyzes the demethylation of H3K27 (H3K27me3) and regulates gene expression. Sestrin2 (SESN2), a stress-inducible protein, protected against doxorubicin (DOX)-induced cardiomyopathy by regulating mitophagy and mitochondrial function. Here, the expression of JMJD3 was increased and that of SESN2 was decreased in both the heart samples from patients with dilated cardiomyopathy and chronic DOX-stimulation induced cardiomyopathy. Inhibition or knockdown of JMJD3 attenuated DOX-induced cardiomyocytes apoptosis, mitochondrial injury and cardiac dysfunction. However, JMJD3 overexpression aggravated DOX-induced cardiomyopathy, which were relieved by SESN2 overexpression. JMJD3 inhibited the transcription of SESN2 by reducing tri-methylation of H3K27 in the promoter region of SESN2. In conclusion, JMJD3 negatively regulated SESN2 via decreasing H3K27me3 enrichment in the promoter region of SESN2, subsequently inducing mitochondrial dysfunction and cardiomyocytes apoptosis. Targeting the JMJD3-SESN2 signaling axis may be a potential therapeutic strategy to protect against DOX-mediated cardiomyopathy.
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http://dx.doi.org/10.3389/fcell.2020.548605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552667PMC
September 2020

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

Editorial of Special Column "Research on Emerging COVID-19 (Target, Mechanism, and Therapeutics)".

Acta Pharm Sin B 2020 Jul 18;10(7):1146-1148. Epub 2020 Aug 18.

Laboratory of Pharmacology & Toxicology and New Drug R&D Center, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.

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http://dx.doi.org/10.1016/j.apsb.2020.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434428PMC
July 2020

Histone H4R3 symmetric di-methylation by Prmt5 protects against cardiac hypertrophy via regulation of Filip1L/β-catenin.

Pharmacol Res 2020 11 31;161:105104. Epub 2020 Jul 31.

Laboratory 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, No.132 East Wai-huan Road, Higher Education Mega Center, Guangzhou 510006, Guangdong, China. Electronic address:

Background And Purpose: Although histone lysine methylation has been extensively studied for their participation in pathological cardiac hypertrophy, the potential regulatory role of histone arginine methylation remains to be elucidated. The present study focused on H4R3 symmetric di-methylation (H4R3me2s) induced by protein arginine methyltransferase 5 (Prmt5), and explored its epigenetic regulation and underlying mechanisms in cardiomyocyte hypertrophy.

Methods And Results: 1. The expressions of Prmt5 and H4R3me2s were suppressed in cardiac hypertrophy models in vivo and in vitro; 2. Prmt5 silencing or its inhibitor EPZ, or knockdown of cooperator of Prmt5 (Copr5) to disrupt H4R3me2s, facilitated cardiomyocyte hypertrophy, whereas overexpression of wild type Prmt5 rather than the inactive mutant protected cardiomyocytes against hypertrophy; 3. ChIP-sequence analysis identified Filip1L as a target gene of Prmt5-induced H4R3me2s; 4. Knockdown or inhibition of Prmt5 impaired Filip1L transcription and subsequently prevented β-catenin degradation, thus augmenting cardiomyocyte hypertrophy.

Conclusions: The present study reveals that Prmt5-induced H4R3me2s ameliorates cardiomyocyte hypertrophy by transcriptional upregulation of Filip1L and subsequent enhancement of β-catenin degradation. Deficiency of Prmt5 and the resulting suppression of H4R3me2s might facilitate the development of pathological cardiac hypertrophy. Prmt5 might serve as a key epigenetic regulator in pathological cardiac hypertrophy.
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http://dx.doi.org/10.1016/j.phrs.2020.105104DOI Listing
November 2020

Connexin 43 prevents the progression of diabetic renal tubulointerstitial fibrosis by regulating the SIRT1-HIF-1α signaling pathway.

Clin Sci (Lond) 2020 07;134(13):1573-1592

Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

Hyperglycemia-induced renal epithelial-to-mesenchymal transition (EMT) is a key pathological factor in diabetic renal tubulointerstitial fibrosis (RIF). Our previous studies have shown that connexin 43 (Cx43) activation attenuated the development of diabetic renal fibrosis. However, whether Cx43 regulates the EMT of renal tubular epithelial cells (TECs) and the pathological process of RIF under the diabetic conditions remains to be elucidated. In the present study, we identified that Cx43 protein expression was down-regulated in the kidney tissues of db/db mice as well as in high glucose (HG)-induced NRK-52E cells. Overexpression of Cx43 improved renal function in db/db spontaneous diabetic model mice, increased SIRT1 levels, decreased hypoxia-inducible factor (HIF)-1α expression, and reduced production of EMT markers and extracellular matrix (ECM) components. Additionally, Cx43 overexpression inhibited the EMT process and reduced the expression of ECM components such as fibronectin (FN), Collagen I, and Collagen IV in HG-induced NRK-52E cells, whereas Cx43 deficiency had the opposite effects. Mechanistically, Cx43 in a carboxyl-terminal signal transduction-dependent manner could up-regulate SIRT1 expression and enhance SIRT1-dependent deacetylation of HIF-1α to reduce HIF-1α activity, which eventually ameliorated renal EMT and diabetic RIF. Our study indicates the essential role of Cx43 in regulating renal EMT and diabetic RIF via regulating the SIRT1-HIF-1α signaling pathway and provides an experimental basis for Cx43 as a potential target for diabetic nephropathy (DN).
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http://dx.doi.org/10.1042/CS20200171DOI Listing
July 2020

Flavine adenine dinucleotide inhibits pathological cardiac hypertrophy and fibrosis through activating short chain acyl-CoA dehydrogenase.

Biochem Pharmacol 2020 08 12;178:114100. Epub 2020 Jun 12.

Department of Clinical Pharmacy, GuangDong Pharmaceutical University, GuangZhou, China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China. Electronic address:

Short-chain acyl-CoA dehydrogenase (SCAD), the rate-limiting enzyme for fatty acid β-oxidation, has a negative regulatory effect on pathological cardiac hypertrophy and fibrosis. Furthermore, flavin adenine dinucleotide (FAD) can enhance the expression and enzyme activity of SCAD. However, whether FAD can inhibit pathological cardiac hypertrophy and fibrosis remains unclear. Therefore, we observed the effect of FAD on pathological cardiac hypertrophy and fibrosis. FAD significantly inhibited PE-induced cardiomyocyte hypertrophy and AngII-induced cardiac fibroblast proliferation. In addition, FAD ameliorated pathological cardiac hypertrophy and fibrosis in SHR. FAD significantly increased the expression and enzyme activity of SCAD. Meanwhile, ATP content was increased, the content of free fatty acids and reactive oxygen species were decreased by FAD in vivo and in vitro. In addition, molecular dynamics simulations were also used to provide insights into the structural stability and dynamic behavior of SCAD. The results demonstrated that FAD may play an important structural role on the SCAD dimer stability and maintenance of substrate catalytic pocket to increase the expression and enzyme activity of SCAD. In conclusion, FAD can inhibit pathological cardiac hypertrophy and fibrosis through activating SCAD, which may be a novel effective treatment for pathological cardiac hypertrophy and fibrosis, thus prevent them from developing into heart failure.
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http://dx.doi.org/10.1016/j.bcp.2020.114100DOI Listing
August 2020

S-adenosylhomocysteine (AdoHcy)-dependent methyltransferase inhibitor DZNep overcomes breast cancer tamoxifen resistance via induction of NSD2 degradation and suppression of NSD2-driven redox homeostasis.

Chem Biol Interact 2020 Feb 28;317:108965. Epub 2020 Jan 28.

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, PR China; National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, Guangdong, 510006, PR China. Electronic address:

Endocrine therapies (e.g. tamoxifen and aromatase inhibitors) targeting estrogen action are effective in decreasing mortality of breast cancer. However, their efficacy is limited by intrinsic and acquired resistance. Our previous study demonstrated that overexpression of a histone methyltransferase NSD2 drives tamoxifen resistance in breast cancer cells and that NSD2 is a potential biomarker of tamoxifen resistant breast cancer. Here, we found that DZNep, an indirect inhibitor of histone methyltransferases, potently induces the degradation of NSD2 protein and inhibits the expression of NSD2 target genes (HK2, G6PD, GLUT1 and TIGAR) involved in the pentose phosphate pathway (PPP). DZNep treatment of tamoxifen-resistant breast cancer cells and xenograft tumors also strongly inhibits tumor growth and the cancer cell survival through decreasing cell production of NADPH and glutathione (GSH) and invoking elevated ROS to cause apoptosis. These findings suggest that DZNep-like agents can be developed to target NSD2 histone methyltransferase for effective treatment of tamoxifen-resistant breast cancer.
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http://dx.doi.org/10.1016/j.cbi.2020.108965DOI Listing
February 2020

The protease activity of human ATG4B is regulated by reversible oxidative modification.

Autophagy 2020 10 3;16(10):1838-1850. Epub 2020 Jan 3.

School of Pharmaceutical Sciences, Sun Yat-Sen University, National-Local Joint Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drug Evaluation, Provincial Key Laboratory of New Drug Design and Evaluation , Guangzhou, Guangdong, China.

Macroautophagy/autophagy plays a pivotal role in cytoplasmic material recycling and metabolic turnover, in which ATG4B functions as a "scissor" for processing pro-LC3 and lipidated LC3 to drive the autophagy progress. Mounting evidence has demonstrated the tight connection between ROS and autophagy during various pathological situations. Coincidentally, several studies have shown that ATG4B is potentially regulated by redox modification, but the underlying molecular mechanism and its relationship with autophagy is ambiguous. In this study, we verified that ATG4B activity was definitely regulated in a reversible redox manner. We also determined that Cys292 and Cys361 are essential sites of ATG4B to form reversible intramolecular disulfide bonds that respond to oxidative stress. Interestingly, we unraveled a new phenomenon that ATG4B concurrently formed disulfide-linked oligomers at Cys292 and Cys361, and that both sites underwent redox modifications thereby modulating ATG4B activity. Finally, increased autophagic flux and decreased oxidation sensitivity were observed in Cys292 and Cys361 double site-mutated cells under normal growth conditions. In conclusion, our research reveals a novel molecular mechanism that oxidative modification at Cys292 and Cys361 sites regulates ATG4B function, which modulates autophagy.: Air-ox: air-oxidation; ATG4B: autophagy related 4B cysteine peptidase; BCNU: 1,3-bis(2-chloroethyl)-1-nitrosourea; CBB: Coomassie Brilliant Blue; CM: complete medium; CQ: chloroquine; DTT: dithiothreitol; GSH: reduced glutathione; GSNO: S-nitrosoglutathione; GSSG: oxidized glutathione; HMW: high molecular weight; HO: hydrogen peroxide; NAC: N-acetyl-L-cysteine; NEM: N-ethylmaleimide; PE: phosphatidylethanolamine; PTM: post-translational modification; ROS, reactive oxygen species; WT: wild type.
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http://dx.doi.org/10.1080/15548627.2019.1709763DOI Listing
October 2020

A one-step specific assay for continuous detection of sirtuin 2 activity.

Acta Pharm Sin B 2019 Nov 7;9(6):1183-1192. Epub 2019 Jun 7.

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

Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases with diverse physiological functions. A variety of small molecules have been developed to interrogate the physiological function of SIRTs. Therefore, it is desirable to establish efficient and convenient assays to screen SIRTs modulators. In this study, we designed a series of fluorescent nonapeptide probes derived from substrates of SIRT1-SIRT3. Fluorescence increment of these probes is based on SIRT-mediated removal of the acyl side chain with fluorophore, which makes this system free of lysine-recognizing protease. Comparing the reaction of these fluorescent nonapeptide substrates with SIRT1-SIRT3 and SIRT6, it was confirmed that this assessment system was the most suitable for SIRT2 activity detection. Thus, SIRT2 was used to modify substrates by truncating the amino acids or lysine side chain of nonapeptide. Finally, two specific and efficient fluorescent probes for SIRT2, ne-D9 and ne-K4a, were developed. Evaluation of the results revealed that ne-K4a based assay was more suitable for modulators screening , while the other specific substrate ne-D9 was stable in cell lysate and could detect the activity of SIRT2 in the same. In summary, this study presents a novel strategy for detecting SIRT2 activity and in cell lysate.
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http://dx.doi.org/10.1016/j.apsb.2019.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900550PMC
November 2019

Discovery of a novel niacin-lipoic acid dimer N2L attenuating atherosclerosis and dyslipidemia with non-flushing effects.

Eur J Pharmacol 2020 Feb 14;868:172871. Epub 2019 Dec 14.

School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China. Electronic address:

Niacin has been widely used as an antihyperlipidemic drug, but the flushing effect restricted its clinical application. Here, we developed novel niacin-lipoic acid dimers which lead to better lipid modulation, higher synergistic effects and less side effects. We utilized molecular docking simulation to design a novel series of niacin-lipoic acid dimers. The compound N-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)nicotinamide (N2L) was selected for the in vitro and in vivo evaluation, including the agonist activity in CHO-hGPR109A cells, cell protective effects in HT22 and HUVECs cells, flushing effect in guinea pigs and rats, lipid modulation in C57BL/6 mice and high fat diet-rats and atherosclerotic lesions regulation in apolipoprotein E null mice. N2L worked as potent and selective agonists for the high affinity niacin receptor GPR109A. N2L retained antioxidation and cytoprotection of lipoic acid. In addition, N2L displayed a good therapeutic index regarding lipid modulation and atherosclerotic lesions regulation, and minimized niacin-induced vasodilation (flushing) effect in vivo. N2L showed effective treatment regarding to lipid regulation and atherosclerosis inhibition effects, also with excellent antioxidant effects, safety profiles and non-flushing. All these results suggest N2L promising application prospects in the drug development for the treatment of atherosclerosis.
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http://dx.doi.org/10.1016/j.ejphar.2019.172871DOI Listing
February 2020
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