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image of The Punicalagin Compound Mitigates Bronchial Epithelial Cell Senescence Induced by Cigarette Smoke Extractthrough the PAR2/mTOR Pathway

Abstract

Background

Tobacco smoke is an important inducer of airway epithelial cell aging. Punicalagin(PCG) is a natural anti-aging compound. The effect of PCG on tobacco smoke-induced airway epithelial cell senescence is unknown.

Objective

Our study investigated whether PCG can treat the human bronchial epithelial cell line (BEAS-2B) aging by inhibiting the protease-activated receptor 2 (PAR2)/mTOR pathway.

Methods

Bioinformatics techniques were used to analyze the potential biological functions of PAR2. Molecular dynamics evaluated the binding ability of PCG and PAR2. The CCK8 assay was used to detect the cytotoxicity of CSE and PCG. The activity of the PAR2/mTOR pathway and the expression of the characteristic aging markers p16, p21, and SIRT1 are detected by qRT-PCR and Western blotting. Cell senescence was observed by Senescence-associated β-galactosidase (SA-β-gal) staining. The senescence-associated secretory phenotype (SASP): concentrations of interleukin IL-6, IL-8, and TNF-α were detected by ELISA.

Results

The GSE57148 bioinformatics analysis dataset showed that PAR2 regulates lung senescence through the mTOR signaling pathway. Molecular dynamics results found that PCG and PAR2 had a strong and stable binding force. CSE induces BEAS-2B cell senescence and activates the PAR2/mTOR pathway. Inhibition of PAR2 mitigated the senescence changes. In addition, PCG's pretreatment can significantly alleviate CSE-induced BEAS-2B cell senescence while inhibiting the PAR2/mTOR pathway.

Conclusion

PCG has a therapeutic effect on the senescence of airway epithelial cells.

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/content/journals/cmc/10.2174/0109298673346794241001110826
2024-10-03
2024-11-26
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References

  1. Reitsma M.B. Kendrick P.J. Ababneh E. Abbafati C. Abbasi-Kangevari M. Abdoli A. Abedi A. Abhilash E.S. Abila D.B. Aboyans V. Abu-Rmeileh N.M.E. Adebayo O.M. Advani S.M. Aghaali M. Ahinkorah B.O. Ahmad S. Ahmadi K. Ahmed H. Aji B. Akunna C.J. Al-Aly Z. Alanzi T.M. Alhabib K.F. Ali L. Alif S.M. Alipour V. Aljunid S.M. Alla F. Allebeck P. Alvis-Guzman N. Amin T.T. Amini S. Amu H. Amul G.G.H. Ancuceanu R. Anderson J.A. Ansari-Moghaddam A. Antonio C.A.T. Antony B. Anvari D. Arabloo J. Arian N.D. Arora M. Asaad M. Ausloos M. Awan A.T. Ayano G. Aynalem G.L. Azari S. B D.B. Badiye A.D. Baig A.A. Bakhshaei M.H. Banach M. Banik P.C. Barker-Collo S.L. Bärnighausen T.W. Barqawi H.J. Basu S. Bayati M. Bazargan-Hejazi S. Behzadifar M. Bekuma T.T. Bennett D.A. Bensenor I.M. Berfield K.S.S. Bhagavathula A.S. Bhardwaj N. Bhardwaj P. Bhattacharyya K. Bibi S. Bijani A. Bintoro B.S. Biondi A. Birara S. Braithwaite D. Brenner H. Brunoni A.R. Burkart K. Butt Z.A. Caetano dos Santos F.L. Cámera L.A. Car J. Cárdenas R. Carreras G. Carrero J.J. Castaldelli-Maia J.M. Cattaruzza M.S.S. Chang J-C. Chen S. Chu D-T. Chung S-C. Cirillo M. Costa V.M. Couto R.A.S. Dadras O. Dai X. Damasceno A.A.M. Damiani G. Dandona L. Dandona R. Daneshpajouhnejad P. Darega Gela J. Davletov K. Derbew Molla M. Dessie G.A. Desta A.A. Dharmaratne S.D. Dianatinasab M. Diaz D. Do H.T. Douiri A. Duncan B.B. Duraes A.R. Eagan A.W. Ebrahimi Kalan M. Edvardsson K. Elbarazi I. El Tantawi M. Esmaeilnejad S. Fadhil I. Faraon E.J.A. Farinha C.S.S. Farwati M. Farzadfar F. Fazlzadeh M. Feigin V.L. Feldman R. Fernandez Prendes C. Ferrara P. Filip I. Filippidis F. Fischer F. Flor L.S. Foigt N.A. Folayan M.O. Foroutan M. Gad M.M. Gaidhane A.M. Gallus S. Geberemariyam B.S. Ghafourifard M. Ghajar A. Ghashghaee A. Giampaoli S. Gill P.S. Glozah F.N. Gnedovskaya E.V. Golechha M. Gopalani S.V. Gorini G. Goudarzi H. Goulart A.C. Greaves F. Guha A. Guo Y. Gupta B. Gupta R.D. Gupta R. Gupta T. Gupta V. Hafezi-Nejad N. Haider M.R. Hamadeh R.R. Hankey G.J. Hargono A. Hartono R.K. Hassankhani H. Hay S.I. Heidari G. Herteliu C. Hezam K. Hird T.R. Hole M.K. Holla R. Hosseinzadeh M. Hostiuc S. Househ M. Hsiao T. Huang J. Iannucci V.C. Ibitoye S.E. Idrisov B. Ilesanmi O.S. Ilic I.M. Ilic M.D. Inbaraj L.R. Irvani S.S.N. Islam J.Y. Islam R.M. Islam S.M.S. Islami F. Iso H. Itumalla R. Iwagami M. Jaafari J. Jain V. Jakovljevic M. Jang S-I. Janjani H. Jayaram S. Jeemon P. Jha R.P. Jonas J.B. Joo T. Jürisson M. Kabir A. Kabir Z. Kalankesh L.R. Kanchan T. Kandel H. Kapoor N. Karimi S.E. Katikireddi S.V. Kebede H.K. Kelkay B. Kennedy R.D. Khoja A.T. Khubchandani J. Kim G.R. Kim Y-E. Kimokoti R.W. Kivimäki M. Kosen S. Koulmane Laxminarayana S.L. Koyanagi A. Krishan K. Kugbey N. Kumar G.A. Kumar N. Kurmi O.P. Kusuma D. Lacey B. Lam J.O. Landires I. Lasrado S. Lauriola P. Lee D.W. Lee Y.H. Leung J. Li S. Lin H. Linn S. Liu W. Lopez A.D. Lopukhov P.D. Lorkowski S. Lugo A. Majeed A. Maleki A. Malekzadeh R. Malta D.C. Mamun A.A. Manjunatha N. Mansouri B. Mansournia M.A. Martinez-Raga J. Martini S. Mathur M.R. Medina-Solís C.E. Mehata S. Mendoza W. Menezes R.G. Meretoja A. Meretoja T.J. Miazgowski B. Michalek I.M. Miller T.R. Mirrakhimov E.M. Mirzaei H. Mirzaei-Alavijeh M. Misra S. Moghadaszadeh M. Mohammad Y. Mohammadian-Hafshejani A. Mohammed S. Mokdad A.H. Monasta L. Moni M.A. Moradi G. Moradi-Lakeh M. Moradzadeh R. Morrison S.D. Mossie T.B. Mubarik S. Mullany E.C. Murray C.J.L. Naghavi M. Naghshtabrizi B. Nair S. Nalini M. Nangia V. Naqvi A.A. Narasimha Swamy S. Naveed M. Nayak S. Nayak V.C. Nazari J. Nduaguba S.O. Neupane Kandel S. Nguyen C.T. Nguyen H.L.T. Nguyen S.H. Nguyen T.H. Nixon M.R. Nnaji C.A. Norrving B. Noubiap J.J. Nowak C. Ogbo F.A. Oguntade A.S. Oh I-H. Olagunju A.T. Oren E. Otstavnov N. Otstavnov S.S. Owolabi M.O. P A M. Pakhale S. Pakshir K. Palladino R. Pana A. Panda-Jonas S. Pandey A. Parekh U. Park E-C. Park E-K. Pashazadeh Kan F. Patton G.C. Pawar S. Pestell R.G. Pinheiro M. Piradov M.A. Pirouzpanah S. Pokhrel K.N. Polibin R.V. Prashant A. Pribadi D.R.A. Radfar A. Rahimi-Movaghar V. Rahman A. Rahman M.H.U. Rahman M.A. Rahmani A.M. Rajai N. Ram P. Ranabhat C.L. Rathi P. Rawal L. Renzaho A.M.N. Reynales-Shigematsu L.M. Rezapour A. Riahi S.M. Riaz M.A. Roever L. Ronfani L. Roshandel G. Roy A. Roy B. Sacco S. Saddik B. Sahebkar A. Salehi S. Salimzadeh H. Samaei M. Samy A.M. Santos I.S. Santric-Milicevic M.M. Sarrafzadegan N. Sathian B. Sawhney M. Saylan M. Schaub M.P. Schmidt M.I. Schneider I.J.C. Schutte A.E. Schwendicke F. Seidu A-A. Senthil Kumar N. Sepanlou S.G. Seylani A. Shafaat O. Shah S.M. Shaikh M.A. Shalash A.S. Shannawaz M. Sharafi K. Sheikh A. Sheikhbahaei S. Shigematsu M. Shiri R. Shishani K. Shivakumar K.M. Shivalli S. Shrestha R. Siabani S. Sidemo N.B. Sigfusdottir I.D. Sigurvinsdottir R. Silva D.A.S. Silva J.P. Singh A. Singh J.A. Singh V. Sinha D.N. Sitas F. Skryabin V.Y. Skryabina A.A. Soboka M. Soriano J.B. Soroush A. Soshnikov S. Soyiri I.N. Spurlock E.E. Sreeramareddy C.T. Stein D.J. Steiropoulos P. Stortecky S. Straif K. Suliankatchi Abdulkader R. Sulo G. Sundström J. Tabuchi T. Tadakamadla S.K. Taddele B.W. Tadesse E.G. Tamiru A.T. Tareke M. Tareque M.I. Tarigan I.U. Temsah M-H. Thankappan K.R. Thapar R. Tichopad A. Tolani M.A. Topouzis F. Tovani-Palone M.R. Tran B.X. Tripathy J.P. Tsegaye G.W. Tsilimparis N. Tymeson H.D. Ullah A. Ullah S. Unim B. Updike R.L. Vacante M. Valdez P.R. Vardavas C. Varona Pérez P. Vasankari T.J. Venketasubramanian N. Verma M. Vetrova M.V. Vo B. Vu G.T. Waheed Y. Wang Y. Welding K. Werdecker A. Whisnant J.L. Wickramasinghe N.D. Yamagishi K. Yandrapalli S. Yatsuya H. Yazdi-Feyzabadi V. Yeshaw Y. Yimmer M.Z. Yonemoto N. Yu C. Yunusa I. Yusefzadeh H. Zahirian Moghadam T. Zaman M.S. Zamanian M. Zandian H. Zar H.J. Zastrozhin M.S. Zastrozhina A. Zavala-Arciniega L. Zhang J. Zhang Z-J. Zhong C. Zuniga Y.M.H. Gakidou E. Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990–2019: A systematic analysis from the Global Burden of Disease Study 2019. Lancet 2021 397 10292 2337 2360 10.1016/S0140‑6736(21)01169‑7 34051883
    [Google Scholar]
  2. World Health Organization WHO report on the global tobacco epidemic, 2017: Monitoring tobacco use and prevention policies. 2017 Available From: https://www.who.int/publications/i/item/9789241512824
    [Google Scholar]
  3. St Sauver J.L. Weston S.A. Atkinson E.J. Mc Gree M.E. Mielke M.M. White T.A. Heeren A.A. Olson J.E. Rocca W.A. Palmer A.K. Cummings S.R. Fielding R.A. Bielinski S.J. LeBrasseur N.K. Biomarkers of cellular senescence and risk of death in humans. Aging Cell 2023 22 12 e14006 10.1111/acel.14006 37803875
    [Google Scholar]
  4. Wu Q. Jiang D. Matsuda J.L. Ternyak K. Zhang B. Chu H.W. Cigarette smoke induces human airway epithelial senescence via growth differentiation factor 15 production. Am. J. Respir. Cell Mol. Biol. 2016 55 3 429 438 10.1165/rcmb.2015‑0143OC 27093475
    [Google Scholar]
  5. Vij N. Chandramani-Shivalingappa P. Van Westphal C. Hole R. Bodas M. Cigarette smoke-induced autophagy impairment accelerates lung aging, COPD-emphysema exacerbations and pathogenesis. Am. J. Physiol. Cell Physiol. 2018 314 1 C73 C87 10.1152/ajpcell.00110.2016 27413169
    [Google Scholar]
  6. Mohamad Kamal N.S. Safuan S. Shamsuddin S. Foroozandeh P. Aging of the cells: Insight into cellular senescence and detection Methods. Eur. J. Cell Biol. 2020 99 6 151108 10.1016/j.ejcb.2020.151108 32800277
    [Google Scholar]
  7. Lehmann M. Hu Q. Hu Y. Hafner K. Costa R. van den Berg A. Königshoff M. Chronic WNT/β-catenin signaling induces cellular senescence in lung epithelial cells. Cell. Signal. 2020 70 109588 10.1016/j.cellsig.2020.109588 32109549
    [Google Scholar]
  8. Miotto D. Hollenberg M.D. Bunnett N.W. Papi A. Braccioni F. Boschetto P. Rea F. Zuin A. Geppetti P. Saetta M. Maestrelli P. Fabbri L.M. Mapp C.E. Expression of protease activated receptor-2 (PAR-2) in central airways of smokers and non-smokers. Thorax 2002 57 2 146 151 10.1136/thorax.57.2.146 11828045
    [Google Scholar]
  9. Valencia I. Vallejo S. Dongil P. Romero A. San Hipólito-Luengo Á. Shamoon L. Posada M. García-Olmo D. Carraro R. Erusalimsky J.D. Romacho T. Peiró C. Sánchez-Ferrer C.F. DPP4 Promotes Human Endothelial Cell Senescence and Dysfunction via the PAR2–COX-2–TP Axis and NLRP3 Inflammasome Activation. Hypertension 2022 79 7 1361 1373 10.1161/HYPERTENSIONAHA.121.18477 35477273
    [Google Scholar]
  10. Mannick J.B. Teo G. Bernardo P. Quinn D. Russell K. Klickstein L. Marshall W. Shergill S. Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: Phase 2b and phase 3 randomised trials. Lancet Healthy Longev. 2021 2 5 e250 e262 10.1016/S2666‑7568(21)00062‑3 33977284
    [Google Scholar]
  11. Bang E. Kim D.H. Chung H.Y. Protease-activated receptor 2 induces ROS-mediated inflammation through Akt-mediated NF-κB and FoxO6 modulation during skin photoaging. Redox Biol. 2021 44 102022 10.1016/j.redox.2021.102022 34082382
    [Google Scholar]
  12. Jiang X. Zhu S. Panetti T.S. Bromberg M.E. Formation of tissue factor-factor VIIa-factor Xa complex induces activation of the mTOR pathway which regulates migration of human breast cancer cells. Thromb. Haemost. 2008 100 7 127 133 10.1160/TH07‑12‑0722 18612547
    [Google Scholar]
  13. Chen K-D. Wang C-C. Tsai M-C. Wu C-H. Yang H-J. Chen L-Y. Nakano T. Goto S. Huang K-T. Hu T-H. Chen C-L. Lin C-C. Interconnections between autophagy and the coagulation cascade in hepatocellular carcinoma. Cell Death Dis. 2014 5 5 e1244 e1244 10.1038/cddis.2014.212 24853422
    [Google Scholar]
  14. Kim B.M. Kim D.H. Park Y.J. Ha S. Choi Y.J. Yu H.S. Chung K.W. Chung H.Y. PAR2 promotes high-fat diet-induced hepatic steatosis by inhibiting AMPK-mediated autophagy. J. Nutr. Biochem. 2021 95 108769 10.1016/j.jnutbio.2021.108769 34000413
    [Google Scholar]
  15. Liu B. Yang M.Q. Yu T.Y. Yin Y.Y. Liu Y. Wang X.D. He Z.G. Yin L. Chen C.Q. Li J.Y. Mast cell tryptase promotes inflammatory bowel disease–induced intestinal fibrosis. Inflamm. Bowel Dis. 2021 27 2 242 255 10.1093/ibd/izaa125 32507895
    [Google Scholar]
  16. Du C. Zhang T. Xiao X. Shi Y. Duan H. Ren Y. Protease-activated receptor-2 promotes kidney tubular epithelial inflammation by inhibiting autophagy via the PI3K/Akt/mTOR signalling pathway. Biochem. J. 2017 474 16 2733 2747 10.1042/BCJ20170272 28694352
    [Google Scholar]
  17. Lee K.H. Lee J. Jeong J. Woo J. Lee C.H. Yoo C.G. Cigarette smoke extract enhances neutrophil elastase-induced IL-8 production via proteinase-activated receptor-2 upregulation in human bronchial epithelial cells. Exp. Mol. Med. 2018 50 7 1 9 10.1038/s12276‑018‑0114‑1 29980681
    [Google Scholar]
  18. Sumere B.R. de Souza M.C. dos Santos M.P. Bezerra R.M.N. da Cunha D.T. Martinez J. Rostagno M.A. Combining pressurized liquids with ultrasound to improve the extraction of phenolic compounds from pomegranate peel (Punica granatum L.). Ultrason. Sonochem. 2018 48 151 162 10.1016/j.ultsonch.2018.05.028 30080537
    [Google Scholar]
  19. Seeram N. Adams L. Henning S. Niu Y. Zhang Y. Nair M. Heber D. In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J. Nutr. Biochem. 2005 16 6 360 367 10.1016/j.jnutbio.2005.01.006 15936648
    [Google Scholar]
  20. Ganesan T. Sinniah A. Chik Z. Alshawsh M.A. Punicalagin Regulates Apoptosis-Autophagy Switch via Modulation of Annexin A1 in Colorectal Cancer. Nutrients 2020 12 8 2430 10.3390/nu12082430 32823596
    [Google Scholar]
  21. Luo J. Long Y. Ren G. Zhang Y. Chen J. Huang R. Yang L. Punicalagin Reversed the Hepatic Injury of Tetrachloromethane by Antioxidation and Enhancement of Autophagy. J. Med. Food 2019 22 12 1271 1279 10.1089/jmf.2019.4411 31718395
    [Google Scholar]
  22. Suručić R. Tubić B. Stojiljković M.P. Djuric D.M. Travar M. Grabež M. Šavikin K. Škrbić R. Computational study of pomegranate peel extract polyphenols as potential inhibitors of SARS-CoV-2 virus internalization. Mol. Cell. Biochem. 2021 476 2 1179 1193 10.1007/s11010‑020‑03981‑7 33200379
    [Google Scholar]
  23. Xu Y. Shi C. Wu Q. Zheng Z. Liu P. Li G. Peng X. Xia X. Antimicrobial Activity of Punicalagin Against Staphylococcus aureus and Its Effect on Biofilm Formation. Foodborne Pathog. Dis. 2017 14 5 282 287 10.1089/fpd.2016.2226 28128637
    [Google Scholar]
  24. Chen P. Chen F. Lei J. Zhou B. Pomegranate polyphenol punicalagin improves learning memory deficits, redox homeostasis, and neuroinflammation in aging mice. Phytother. Res. 2023 37 9 3655 3674 10.1002/ptr.7848 37092799
    [Google Scholar]
  25. Cheng X. Yao X. Xu S. Pan J. Yu H. Bao J. Guan H. Lu R. Zhang L. Punicalagin induces senescent growth arrest in human papillary thyroid carcinoma BCPAP cells via NF-κB signaling pathway. Biomed. Pharmacother. 2018 103 490 498 10.1016/j.biopha.2018.04.074 29677534
    [Google Scholar]
  26. Subkorn P. Norkaew C. Deesrisak K. Tanyong D. Punicalagin, a pomegranate compound, induces apoptosis and autophagy in acute leukemia. PeerJ 2021 9 e12303 10.7717/peerj.12303 34760363
    [Google Scholar]
  27. Zhang L. Cheng X. Gao Y. Zheng J. Xu Q. Sun Y. Guan H. Yu H. Sun Z. Apigenin induces autophagic cell death in human papillary thyroid carcinoma BCPAP cells. Food Funct. 2015 6 11 3464 3472 10.1039/C5FO00671F 26292725
    [Google Scholar]
  28. Wang Y. Chen B. Longtine M.S. Nelson D.M. Punicalagin promotes autophagy to protect primary human syncytiotrophoblasts from apoptosis. Reproduction 2016 151 2 97 104 10.1530/REP‑15‑0287 26659860
    [Google Scholar]
  29. Seo Y. Mun C.H. Park S.H. Jeon D. Kim S.J. Yoon T. Ko E. Jo S. Park Y.B. Namkung W. Lee S.W. Punicalagin ameliorates lupus nephritis via inhibition of PAR2. Int. J. Mol. Sci. 2020 21 14 4975 10.3390/ijms21144975 32674502
    [Google Scholar]
  30. Zeng X. Yang X. Liu X. Resveratrol attenuates cigarette smoke extract induced cellular senescence in human airway epithelial cells by regulating the miR-34a/SIRT1/NF-κB pathway. Medicine (Baltimore) 2022 101 46 e31944 10.1097/MD.0000000000031944 36401446
    [Google Scholar]
  31. Ahmad T. Sundar I.K. Tormos A.M. Lerner C.A. Gerloff J. Yao H. Rahman I. Shelterin Telomere Protection Protein 1 Reduction Causes Telomere Attrition and Cellular Senescence via Sirtuin 1 Deacetylase in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Cell Mol. Biol. 2017 56 1 38 49 10.1165/rcmb.2016‑0198OC 27559927
    [Google Scholar]
  32. Davalli P. Marverti G. Lauriola A. D’Arca D. Targeting Oxidatively Induced DNA Damage Response in Cancer: Opportunities for Novel Cancer Therapies. Oxid. Med. Cell. Longev. 2018 2018 1 2389523 10.1155/2018/2389523 29770165
    [Google Scholar]
  33. Voic H. Li X. Jang J.H. Zou C. Sundd P. Alder J. Rojas M. Chandra D. Randell S. Mallampalli R.K. Tesfaigzi Y. Ryba T. Nyunoya T. RNA sequencing identifies common pathways between cigarette smoke exposure and replicative senescence in human airway epithelia. BMC Genomics 2019 20 1 22 10.1186/s12864‑018‑5409‑z 30626320
    [Google Scholar]
  34. Huang W. Hickson L.J. Eirin A. Kirkland J.L. Lerman L.O. Cellular senescence: The good, the bad and the unknown. Nat. Rev. Nephrol. 2022 18 10 611 627 10.1038/s41581‑022‑00601‑z 35922662
    [Google Scholar]
  35. Nascimento M. Gombault A. Lacerda-Queiroz N. Panek C. Savigny F. Sbeity M. Bourinet M. Le Bert M. Riteau N. Ryffel B. Quesniaux V.F.J. Couillin I. Self-DNA release and STING-dependent sensing drives inflammation to cigarette smoke in mice. Sci. Rep. 2019 9 1 14848 10.1038/s41598‑019‑51427‑y 31619733
    [Google Scholar]
  36. Pando-Sandoval A. Ruano-Ravina A. Candal-Pedreira C. Rodríguez-García C. Represas-Represas C. Golpe R. Fernández-Villar A. Pérez-Ríos M. Risk factors for chronic obstructive pulmonary disease in never-smokers: A systematic review. Clin. Respir. J. 2022 16 4 261 275 10.1111/crj.13479 35142054
    [Google Scholar]
  37. Barnes P.J. Oxidative Stress in Chronic Obstructive Pulmonary Disease. Antioxidants 2022 11 5 965 10.3390/antiox11050965 35624831
    [Google Scholar]
  38. Baker R.R. Pereira da Silva J.R. Smith G. The effect of tobacco ingredients on smoke chemistry. Part I: Flavourings and additives. Food Chem. Toxicol. 2004 42 Suppl. 3 37 10.1016/S0278‑6915(03)00189‑3 15072836
    [Google Scholar]
  39. Li J. Tang L.Y. Fu W.W. Yuan J. Sheng Y.Y. Yang Q.P. Low-concentration hydrogen peroxide can upregulate keratinocyte intracellular calcium and PAR-2 expression in a human keratinocyte–melanocyte co-culture system. Arch. Dermatol. Res. 2016 308 10 723 731 10.1007/s00403‑016‑1692‑1 27722782
    [Google Scholar]
  40. Tian T. Li X. Zhang J. mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy. Int. J. Mol. Sci. 2019 20 3 755 10.3390/ijms20030755 30754640
    [Google Scholar]
  41. Zou Z. Tao T. Li H. Zhu X. mTOR signaling pathway and mTOR inhibitors in cancer: Progress and challenges. Cell Biosci. 2020 10 1 31 10.1186/s13578‑020‑00396‑1 32175074
    [Google Scholar]
  42. Houssaini A. Breau M. Kebe K. Abid S. Marcos E. Lipskaia L. Rideau D. Parpaleix A. Huang J. Amsellem V. Vienney N. Validire P. Maitre B. Attwe A. Lukas C. Vindrieux D. Boczkowski J. Derumeaux G. Pende M. Bernard D. Meiners S. Adnot S. mTOR pathway activation drives lung cell senescence and emphysema. JCI Insight 2018 3 3 e93203 10.1172/jci.insight.93203 29415880
    [Google Scholar]
  43. Tang K.L. Tang H.Y. Du Y. Tian T. Xiong S.J. PAR-2 promotes cell proliferation, migration, and invasion through activating PI3K/AKT signaling pathway in oral squamous cell carcinoma. Biosci. Rep. 2019 39 7 BSR20182476 10.1042/BSR20182476 31213575
    [Google Scholar]
  44. Shah H. Hill T.A. Lim J. Fairlie D.P. Protease-activated receptor 2 attenuates doxorubicin-induced apoptosis in colon cancer cells. J. Cell Commun. Signal. 2023 17 4 1293 1307 10.1007/s12079‑023‑00791‑6 37991681
    [Google Scholar]
  45. Jiang Y. Zhuo X. Fu X. Wu Y. Mao C. Targeting PAR2 Overcomes Gefitinib Resistance in Non-Small-Cell Lung Cancer Cells Through Inhibition of EGFR Transactivation. Front. Pharmacol. 2021 12 625289 10.3389/fphar.2021.625289 33967759
    [Google Scholar]
  46. Jiang Y. Zhuo X. Wu Y. Fu X. Mao C. PAR2 blockade reverses osimertinib resistance in non-small-cell lung cancer cells via attenuating ERK-mediated EMT and PD-L1 expression. Biochim. Biophys. Acta Mol. Cell Res. 2022 1869 1 119144 10.1016/j.bbamcr.2021.119144 34599981
    [Google Scholar]
  47. Huang X. Ni B. Xi Y. Chu X. Zhang R. You H. Protease-activated receptor 2 (PAR-2) antagonist AZ3451 as a novel therapeutic agent for osteoarthritis. Aging (Albany NY) 2019 11 24 12532 12545 10.18632/aging.102586 31841119
    [Google Scholar]
  48. Ge S. Duo L. Wang J. GegenZhula Yang J. Li Z. Tu Y. A unique understanding of traditional medicine of pomegranate, Punica granatum L. and its current research status. J. Ethnopharmacol. 2021 271 113877 10.1016/j.jep.2021.113877 33515685
    [Google Scholar]
  49. Singh B. Singh J.P. Kaur A. Singh N. Phenolic compounds as beneficial phytochemicals in pomegranate ( Punica granatum L.) peel: A review. Food Chem. 2018 261 75 86 10.1016/j.foodchem.2018.04.039 29739608
    [Google Scholar]
  50. Babbar N. Biotransformation of waste biomass into high value biochemicals. Cham Springer 2013 261 295
    [Google Scholar]
  51. Akhtar S. Ismail T. Fraternale D. Sestili P. Pomegranate peel and peel extracts: Chemistry and food features. Food Chem. 2015 174 417 425 10.1016/j.foodchem.2014.11.035 25529700
    [Google Scholar]
  52. Ismail T. Sestili P. Akhtar S. Pomegranate peel and fruit extracts: A review of potential anti-inflammatory and anti-infective effects. J. Ethnopharmacol. 2012 143 2 397 405 10.1016/j.jep.2012.07.004 22820239
    [Google Scholar]
  53. Rice-Evans C. Miller N. Paganga G. Antioxidant properties of phenolic compounds. Trends Plant Sci. 1997 2 4 152 159 10.1016/S1360‑1385(97)01018‑2
    [Google Scholar]
  54. Balasundram N. Sundram K. Samman S. Phenolic compounds in plants and agri-industrial by-products: Antioxidant activity, occurrence, and potential uses. Food Chem. 2006 99 1 191 203 10.1016/j.foodchem.2005.07.042
    [Google Scholar]
  55. Elfalleh W. Tlili N. Nasri N. Yahia Y. Hannachi H. Chaira N. Ying M. Ferchichi A. Antioxidant capacities of phenolic compounds and tocopherols from Tunisian pomegranate (Punica granatum) fruits. J. Food Sci. 2011 76 5 C707 C713 10.1111/j.1750‑3841.2011.02179.x 22417416
    [Google Scholar]
  56. Sanchez-Maldonado A.F. Mode of action, interaction and recovery of plant secondary metabolites for potential applications as food preservatives. 2014 Available From: https://era.library.ualberta.ca/items/5bf7180c-2581-492d-925e-ad1a07f65fab
  57. López-Marcos M.C. Bailina C. Viuda-Martos M. Pérez-Alvarez J.A. Fernández-López J. Properties of dietary fibers from agroindustrial coproducts as source for fiber-enriched foods. Food Bioprocess Technol. 2015 8 12 2400 2408 10.1007/s11947‑015‑1591‑z
    [Google Scholar]
  58. Choi M.E. Jung C.J. Won C.H. Chang S.E. Lee M.W. Choi J.H. Lee W.J. Case report of cutaneous nodule caused by Gordonia bronchialis in an immunocompetent patient after receiving acupuncture. J. Dermatol. 2019 46 4 343 346 10.1111/1346‑8138.14785 30710379
    [Google Scholar]
  59. Moilanen J. Karonen M. Tähtinen P. Jacquet R. Quideau S. Salminen J.P. Biological activity of ellagitannins: Effects as anti-oxidants, pro-oxidants and metal chelators. Phytochemistry 2016 125 65 72 10.1016/j.phytochem.2016.02.008 26899362
    [Google Scholar]
  60. Kulkarni A.P. Mahal H.S. Kapoor S. Aradhya S.M. In vitro studies on the binding, antioxidant, and cytotoxic actions of punicalagin. J. Agric. Food Chem. 2007 55 4 1491 1500 10.1021/jf0626720 17243704
    [Google Scholar]
  61. González-Sarrías A. García-Villalba R. Núñez-Sánchez M.Á. Tomé-Carneiro J. Zafrilla P. Mulero J. Tomás-Barberán F.A. Espín J.C. Identifying the limits for ellagic acid bioavailability: A crossover pharmacokinetic study in healthy volunteers after consumption of pomegranate extracts. J. Funct. Foods 2015 19 225 235 10.1016/j.jff.2015.09.019
    [Google Scholar]
  62. Xu X. Yin P. Wan C. Chong X. Liu M. Cheng P. Chen J. Liu F. Xu J. Punicalagin inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4-mediated MAPKs and NF-κB activation. Inflammation 2014 37 3 956 965 10.1007/s10753‑014‑9816‑2 24473904
    [Google Scholar]
  63. Cao Y. Chen J. Ren G. Zhang Y. Tan X. Yang L. Punicalagin Prevents Inflammation in LPS- Induced RAW264.7 Macrophages by Inhibiting FoxO3a/Autophagy Signaling Pathway. Nutrients 2019 11 11 2794 10.3390/nu11112794 31731808
    [Google Scholar]
  64. Zhang L. Chinnathambi A. Alharbi S.A. Veeraraghavan V.P. Mohan S.K. Zhang G. Punicalagin promotes the apoptosis in human cervical cancer (ME-180) cells through mitochondrial pathway and by inhibiting the NF-kB signaling pathway. Saudi J. Biol. Sci. 2020 27 4 1100 1106 10.1016/j.sjbs.2020.02.015 32256171
    [Google Scholar]
  65. Carneiro C.C. da Costa Santos S. de Souza Lino R. Jr Bara M.T.F. Chaibub B.A. de Melo Reis P.R. Chaves D.A. da Silva A.J.R. Silva L.S. de Melo e Silva D. Chen-Chen L. Chemopreventive effect and angiogenic activity of punicalagin isolated from leaves of Lafoensia pacari A. St.-Hil. Toxicol. Appl. Pharmacol. 2016 310 1 8 10.1016/j.taap.2016.08.015 27546523
    [Google Scholar]
  66. Tang J. Li B. Hong S. Liu C. Min J. Hu M. Li Y. Liu Y. Hong L. Punicalagin suppresses the proliferation and invasion of cervical cancer cells through inhibition of the β-catenin pathway. Mol. Med. Rep. 2017 16 2 1439 1444 10.3892/mmr.2017.6687 28586031
    [Google Scholar]
  67. Wang S. Huang M. Li J. Lai F. Lee H. Hsu Y. Punicalagin induces apoptotic and autophagic cell death in human U87MG glioma cells. Acta Pharmacol. Sin. 2013 34 11 1411 1419 10.1038/aps.2013.98 24077634
    [Google Scholar]
  68. Ammar O. Urolithins and their antimicrobial activity: A short review. EMU J. Pharmaceut. Sci. 2019 3 2 117 124
    [Google Scholar]
  69. Lin L.T. Chen T.Y. Lin S.C. Chung C.Y. Lin T.C. Wang G.H. Anderson R. Lin C.C. Richardson C.D. Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry. BMC Microbiol. 2013 13 1 187 10.1186/1471‑2180‑13‑187 23924316
    [Google Scholar]
  70. Liu F. Smith A.D. Wang T.T.Y. Pham Q. Yang H. Li R.W. Ellagitannin Punicalagin Disrupts the Pathways Related to Bacterial Growth and Affects Multiple Pattern Recognition Receptor Signaling by Acting as a Selective Histone Deacetylase Inhibitor. J. Agric. Food Chem. 2023 71 12 5016 5026 10.1021/acs.jafc.2c08738 36917202
    [Google Scholar]
  71. Lu L. Peng Y. Yao H. Wang Y. Li J. Yang Y. Lin Z. Punicalagin as an allosteric NSP13 helicase inhibitor potently suppresses SARS-CoV-2 replication in vitro. Antiviral Res. 2022 206 105389 10.1016/j.antiviral.2022.105389 35985407
    [Google Scholar]
  72. Wang Y. Zhang H. Liang H. Yuan Q. Purification, antioxidant activity and protein-precipitating capacity of punicalin from pomegranate husk. Food Chem. 2013 138 1 437 443 10.1016/j.foodchem.2012.10.092 23265509
    [Google Scholar]
  73. Yu L. Li J. Punicalagin attenuated allergic airway inflammation via regulating IL4/IL-4Rα/STAT6 and Notch- GATA3 pathways. Acta Pharm. 2022 72 4 561 573 10.2478/acph‑2022‑0038 36651367
    [Google Scholar]
  74. Ohanyan N. Abelyan N. Manukyan A. Hayrapetyan V. Chailyan S. Tiratsuyan S. Danielyan K. Tannin-albumin particles as stable carriers of medicines. Nanomedicine (Lond.) 2024 19 8 689 708 10.2217/nnm‑2023‑0275 38348681
    [Google Scholar]
  75. Cheng R.K.Y. Fiez-Vandal C. Schlenker O. Edman K. Aggeler B. Brown D.G. Brown G.A. Cooke R.M. Dumelin C.E. Doré A.S. Geschwindner S. Grebner C. Hermansson N.O. Jazayeri A. Johansson P. Leong L. Prihandoko R. Rappas M. Soutter H. Snijder A. Sundström L. Tehan B. Thornton P. Troast D. Wiggin G. Zhukov A. Marshall F.H. Dekker N. Structural insight into allosteric modulation of protease-activated receptor 2. Nature 2017 545 7652 112 115 10.1038/nature22309 28445455
    [Google Scholar]
  76. Seo Y. Mun C.H. Park Y.B. Lee S.W. Namkung W. Novel PAR2 antagonist ameliorates progression of lupus nephritis in NZB/Z F1 mice. FASEB J. 2020 34 S1 1 1 10.1096/fasebj.2020.34.s1.03867
    [Google Scholar]
  77. Zhang W. Zhu Q. Punicalagin suppresses inflammation in ventilator-induced lung injury through protease-activated receptor-2 inhibition-induced inhibition of NLR family pyrin domain containing-3 inflammasome activation. Chem. Biol. Drug Des. 2022 100 2 218 229 10.1111/cbdd.14059 35434894
    [Google Scholar]
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  • Article Type:
    Research Article
Keywords: punicalagin ; PAR2 ; mTOR ; cellular senescence ; airway ; Cigarette smoke
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