| Reference | [1]. J Virol. 2019 Aug 28;93(18):e00539-19. doi: 10.1128/JVI.00539-19. Print 2019 Sep 15.<br />
Pentagalloylglucose Inhibits the Replication of Rabies Virus via Mediation of the miR-455/SOCS3/STAT3/IL-6 Pathway.<br />
Tu Z(1), Xu M(1)(2), Zhang J(1)(3), Feng Y(1), Hao Z(1), Tu C(4), Liu Y(4).<br />
Author information: (1)Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Jilin, People's Republic of China. (2)College of Veterinary Medicine, Yangzhou University, Yangzhou, People's Republic of China. (3)Department of Hepatobiliary and Pancreas Surgery, the First Hospital, Jilin University, Changchun, People's Republic of China. (4)Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Jilin, People's Republic of China [email protected] [email protected].<br />
Our previous study showed that pentagalloylglucose (PGG), a naturally occurring hydrolyzable phenolic tannin, possesses significant anti-rabies virus (RABV) activity. In BHK-21 cells, RABV induced the overactivation of signal transducer and activator of transcription 3 (STAT3) by suppressing the expression of suppressor of cytokine signaling 3 (SOCS3). Inhibition of STAT3 by niclosamide, small interfering RNA, or exogenous expression of SOCS3 all significantly suppressed the replication of RABV. Additionally, RABV-induced upregulation of microRNA 455-5p (miR-455-5p) downregulated SOCS3 by directly binding to the 3' untranslated region (UTR) of SOCS3. Importantly, PGG effectively reversed the expression of miR-455-5p and its following SOCS3/STAT3 signaling pathway. Finally, activated STAT3 elicited the expression of interleukin-6 (IL-6), thereby contributing to RABV-associated encephalomyelitis; however, PGG restored the level of IL-6 in vitro and in vivo in a SOCS3/STAT3-dependent manner. Altogether, these data identify a new miR-455-5p/SOCS3/STAT3 signaling pathway that contributes to viral replication and IL-6 production in RABV-infected cells, with PGG exerting its antiviral effect by inhibiting the production of miR-455-5p and the activation of STAT3.IMPORTANCE Rabies virus causes lethal encephalitis in mammals and poses a serious public health threat in many parts of the world. Numerous strategies have been explored to combat rabies; however, their efficacy has always been unsatisfactory. We previously reported a new drug, PGG, which possesses a potent inhibitory activity on RABV replication. Herein, we describe the underlying mechanisms by which PGG exerts its anti-RABV activity. Our results show that RABV induces overactivation of STAT3 in BHK-21 cells, which facilitates viral replication. Importantly, PGG effectively inhibits the activity of STAT3 by disrupting the expression of miR-455-5p and increases the level of SOCS3 by directly targeting the 3' UTR of SOCS3. Furthermore, the downregulated STAT3 inhibits the production of IL-6, thereby contributing to a reduction in the inflammatory response in vivo Our study indicates that PGG effectively inhibits the replication of RABV by the miR-455-5p/SOCS3/STAT3/IL-6-dependent pathway.<br />
DOI: 10.1128/JVI.00539-19 PMCID: PMC6714789 PMID: 31243136 [Indexed for MEDLINE]<br />
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[2]. Int J Mol Sci. 2020 Dec 9;21(24):9369. doi: 10.3390/ijms21249369.<br />
High Capability of Pentagalloylglucose (PGG) in Inhibiting Multiple Types of Membrane Ionic Currents.<br />
Chang WT(1)(2)(3), Liu PY(1)(4), Wu SN(5)(6)(7).<br />
Author information: (1)Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. (2)Division of Cardiovascular Medicine, Chi-Mei Medical Center, Tainan 71004, Taiwan. (3)Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 71004, Taiwan. (4)Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan. (5)Department of Physiology, National Cheng Kung University Medical College, No. 1, University Road, Tainan 70101, Taiwan. (6)Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 70101, Taiwan. (7)Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan.<br />
Pentagalloyglucose (PGG, penta-O-galloyl-β-d-glucose; 1,2,3,4,6-pentagalloyl glucose), a pentagallic acid ester of glucose, is recognized to possess anti-bacterial, anti-oxidative and anti-neoplastic activities. However, to what extent PGG or other polyphenolic compounds can perturb the magnitude and/or gating of different types of plasmalemmal ionic currents remains largely uncertain. In pituitary tumor (GH3) cells, we found out that PGG was effective at suppressing the density of delayed-rectifier K+ current (IK(DR)) concentration-dependently. The addition of PGG could suppress the density of proton-activated Cl- current (IPAC) observed in GH3 cells. The IC50 value required for the inhibitory action of PGG on IK(DR) or IPAC observed in GH3 cells was estimated to be 3.6 or 12.2 μM, respectively, while PGG (10 μM) mildly inhibited the density of the erg-mediated K+ current or voltage-gated Na+ current. The presence of neither chlorotoxin, hesperetin, kaempferol, morin nor iberiotoxin had any effects on IPAC density, whereas hydroxychloroquine or 4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5yl)oxy] butanoic acid suppressed current density effectively. The application of PGG also led to a decrease in the area of voltage-dependent hysteresis of IPAC elicited by long-lasting isosceles-triangular ramp voltage command, suggesting that hysteretic strength was lessened in its presence. In human cardiac myocytes, the exposure to PGG also resulted in a reduction of ramp-induced IK(DR) density. Taken literally, PGG-perturbed adjustment of ionic currents could be direct and appears to be independent of its anti-oxidative property.<br />
DOI: 10.3390/ijms21249369 PMCID: PMC7763472 PMID: 33316951 [Indexed for MEDLINE]<br />
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[3]. J Biomol Struct Dyn. 2020 Jul 24:1-13. doi: 10.1080/07391102.2020.1797538. Online ahead of print.<br />
Polysaccharides like pentagalloylglucose, parishin a and stevioside inhibits the viral entry by binding the Zika virus envelope protein.<br />
Sharma N(1), Kumar P(1), Giri R(1).<br />
Author information: (1)Indian Institute of Technology Mandi, VPO Kamand, Himachal Pradesh, India.<br />
ZIKV belongs to a flavivirus family in which class II fusion proteins involve a low pH-dependent membrane fusion leading to infection of host cells. Envelope (E) protein is primarily responsible for the viral host membrane fusion and is the major target for inhibiting viral entry. Our findings reveal that compounds like PGG, Parishin A, and Stevioside have shown a high affinity for E protein and found to be active against various other viral infections. The binding of these molecules to E protein was found to decrease the RMSD and RMSF values of the ligand protein complex and restricted the Radius of Gyration in molecular dynamics simulation analysis. Further, the binding free energy calculations suggested the stability of complexes throughout simulations trajectory that could reduce the flexibility of the linker so as to block the folding back event of membrane fusion. A recent study has shown that PGG inhibits the early stages of viral entry in HCV and ZIKV. Therefore, we propose that PGG inhibits the entry of virion via binding the E protein and restricting the conformational rearrangement during membrane fusion.Communicated by Ramaswamy H. Sarma.<br />
DOI: 10.1080/07391102.2020.1797538 PMID: 32705969<br />
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[4]. Chem Biodivers. 2020 Feb;17(2):e1900414. doi: 10.1002/cbdv.201900414. Epub 2020 Jan 7.<br />
Identification of Vaccinia-H1 Related Phosphatase as an Anticancer Target for 1,2,3,4,6-O-Pentagalloylglucose.<br />
Yoon SY(1), Kim DH(1), Min Roh K(2), Ahn D(1), Jin Kang H(2), Chung SJ(1).<br />
Author information: (1)School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea. (2)Department of Chemistry, Dongguk University, Seoul, 100-715, Republic of Korea.<br />
Protein tyrosine phosphatases are involved in diverse human diseases, including cancer, diabetes and inflammatory disorders. Loss of Vaccinia-H1 related phosphatase (VHR) has been shown to arrest at the G1-S and G2-M transitions of the cell cycle, and to increases cell death of prostate cancer cells through JNK activation, suggesting that VHR can be considered as an anticancer target. In this study, 658 natural products were screened through in vitro enzyme assay to identify VHR inhibitor. Among the VHR-inhibitory compounds, 1,2,3,4,6-O-pentagalloylglucose (PGG) was selected for further study as it has been reported to show antitumor effects against tumor model mice, but its direct target has not been identified. PGG inhibited the catalytic activity of VHR (Ki =53 nm) in vitro. Furthermore, the incubation of HeLa cervical cancer cells with PGG dramatically decreased cell viability and markedly increased the protein levels of the cleaved PARP, a hallmark of apoptosis. In addition, treatment of HeLa cells with PGG significantly reduced the protein levels of cyclin D1, Bcl-2 and STAT3 phosphorylation. Taken together, these results suggest that PGG could be a potential therapeutic candidate for the treatment of cervical cancer through VHR inhibition.<br />
DOI: 10.1002/cbdv.201900414 PMID: 31797547 [Indexed for MEDLINE]
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