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Alpha-Mangostin and its nano-conjugates induced programmed cell death in Acanthamoeba castellanii belonging to the T4 genotype

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Abstract

Acanthamoeba are free living amoebae that are the causative agent of keratitis and granulomatous amoebic encephalitis. Alpha-Mangostin (AMS) is a significant xanthone; that demonstrates a wide range of biological activities. Here, the anti-amoebic activity of α-Mangostin and its silver nano conjugates (AMS-AgNPs) were evaluated against pathogenic A. castellanii trophozoites and cysts in vitro. Amoebicidal assays showed that both AMS and AMS-AgNPs inhibited the viability of A. castellanii dose-dependently, with an IC50 of 88.5 ± 2.04 and 20.2 ± 2.17 μM, respectively. Both formulations inhibited A. castellanii-mediated human keratinocyte cell cytopathogenicity. Functional assays showed that both samples caused apoptosis through the mitochondrial pathway and reduced mitochondrial membrane potential and ATP production, while increasing reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) cytochrome-c reductase in the cytosol. Whole transcriptome sequencing of A. castellanii showed the expression of 826 genes, with 447 genes being up-regulated and 379 genes being down-regulated post treatment. The Kyoto Encyclopedia of Genes and Genomes analysis showed that the majority of genes were linked to apoptosis, autophagy, RAP1, AGE-RAGE and oxytocin signalling pathways. Seven genes (PTEN, H3, ARIH1, SDR16C5, PFN, glnA GLUL, and SRX1) were identified as the most significant (Log2 (FC) value 4) for molecular mode of action in vitro. Future in vivo studies with AMS and nanoconjugates are needed to realize the clinical potential of this work.

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References

  • Ahmed U, Anwar A, Ong SK, Anwar A, Khan NA (2022a) Applications of medicinal chemistry for drug discovery against Acanthamoeba infections. Med Res Rev 42(1):462–512

    Article  PubMed  Google Scholar 

  • Ahmed U, Ho KY, Simon SE, Saad SM, Ong SK, Anwar A, Tan KO, Sridewi N, Khan KM, Khan NA, Anwar A (2022b) Potential anti-acanthamoebic effects through inhibition of CYP51 by novel quinazolinones. Acta Trop 231:106440

    Article  CAS  PubMed  Google Scholar 

  • Ahmed U, Manzoor M, Qureshi S, Mazhar M, Fatima A, Aurangzeb S, Hamid M, Khan KM, Khan NA, Rashid Y, Anwar A, (2023) Anti-amoebic effects of synthetic acridine-9 (10H)-one against brain-eating amoebae. Acta Trop 239:106824. https://doi.org/10.1016/j.actatropica.2023.106824

  • Al-Massarani SM, El Gamal AA, Al-Musayeib NM, Mothana RA, Basudan OA, Al-Rehaily AJ, Farag M, Assaf MH, El Tahir KH, Maes L (2013) Phytochemical, antimicrobial and antiprotozoal evaluation of Garcinia mangostana pericarp and α-mangostin, its major xanthone derivative. Molecule 18(9):10599–10608

    Article  CAS  Google Scholar 

  • Anwar A, Khan NA, Siddiqui R (2018) Combating Acanthamoeba spp. cysts: what are the options? Parasit Vector 11(1):1–6

    Article  Google Scholar 

  • Anwar A, Ting EL, Anwar A, ul Ain N, Faizi S, Shah MR, Khan NA, Siddiqui R (2020) Antiamoebic activity of plant-based natural products and their conjugated silver nanoparticles against Acanthamoeba castellanii (ATCC 50492). AMB Express 10(1):1–10

    Article  Google Scholar 

  • Anwar A, Siddiqui R, Hussain MA, Ahmed D, Shah MR, Khan NA (2018b) Silver nanoparticle conjugation affects antiacanthamoebic activities of amphotericin B, nystatin, and fluconazole. Parasitol Res 117:265–271

    Article  PubMed  Google Scholar 

  • Anwar A, Numan A, Siddiqui R, Khalid M, Khan NA (2019) Cobalt nanoparticles as novel nanotherapeutics against Acanthamoeba castellanii. Parasit Vector 12(1):1–10

    Article  Google Scholar 

  • Baek MK, Kim MK, Cho HJ, Lee JA, Yu J, Chung HE, Choi SJ (2011) Factors influencing the cytotoxicity of zinc oxide nanoparticles: particle size and surface charge. J Phys: Conf Ser 304(1):012044

    Google Scholar 

  • Baig AM (2015) Pathogenesis of amoebic encephalitis: are the amoebae being credited to an ‘inside job’done by the host immune response? Acta Trop 148:72–76

    Article  PubMed  Google Scholar 

  • Chuprom J, Sangkanu S, Mitsuwan W, Boonhok R, Mahabusarakam W, Singh LR, Dumkliang E, Jitrangsri K, Paul AK, Surinkaew S, Wilairatana P (2022) Anti-Acanthamoeba activity of a semi-synthetic mangostin derivative and its ability in removal of Acanthamoeba triangularis WU19001 on contact lens. PeerJ 10:e14468

    Article  PubMed  PubMed Central  Google Scholar 

  • Cully M, You H, Levine AJ, Mak TW (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Canc 6(3):184–192

    Article  CAS  Google Scholar 

  • Damhorst GL, Watts A, Hernandez-Romieu A, Mel N, Palmore M, Ali IK, Neill SG, Kalapila A, Cope JR (2022) Acanthamoeba castellanii encephalitis in a patient with AIDS: a case report and literature review. Lanc Infect Dis 22(2):e59-65

    Article  Google Scholar 

  • Davey RJ, Moens PD (2020) Profilin: many facets of a small protein. Biophys Rev 12(4):827–849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Djoko KY, Phan MD, Peters KM, Walker MJ, Schembri MA, McEwan AG (2017) Interplay between tolerance mechanisms to copper and acid stress in Escherichia coli. Proc Natl Acad Sci 114 (26):6818-23

  • Ebert B, Kisiela M, Maser E (2016) Transcriptional regulation of human and murine short-chain dehydrogenase/reductases (SDRs)–an in silico approach. Drug Metab Rev 48(2):183–217

    Article  PubMed  Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang Y, Su T, Qiu X, Mao P, Xu Y, Hu Z, Zhang Y, Zheng X, Xie P, Liu Q (2016) Protective effect of alpha-mangostin against oxidative stress induced-retinal cell death. Sci Rep 6(1):1–5

    Google Scholar 

  • Fleury C, Mignotte B, Vayssiere JL (2002) Mitochondrial reactive oxygen species in cell death signaling. Biochim 84:131–141

    Article  CAS  Google Scholar 

  • Georgescu MM (2010) PTEN tumor suppressor network in PI3K-Akt pathway control. Gene Canc 1(12):1170–1177

    Article  CAS  Google Scholar 

  • González-Robles A, Salazar-Villatoro L, Omaña-Molina M, Reyes-Batlle M, Martín-Navarro CM, Lorenzo-Morales J (2014) Morphological features and in-vitro cytopathic effect of Acanthamoeba griffini trophozoites isolated from a clinical case. J Parasitol Res 256310:2014

    Google Scholar 

  • Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Gene Dev 13:1899–1911

    Article  CAS  PubMed  Google Scholar 

  • Gutiérrez-Escobedo G, Hernández-Carreón O, Morales-Rojano B, Revuelta-Rodríguez B, Vázquez-Franco N, Castaño I, De Las Peñas A (2020) Candida glabrata peroxiredoxins, Tsa1 and Tsa2, and sulfiredoxin, Srx1, protect against oxidative damage and are necessary for virulence. Fung Gen Biol 135:103287

    Article  Google Scholar 

  • Gutierrez-Orozco F, Chitchumroonchokchai C, Lesinski GB, Suksamrarn S, Failla ML (2013) α-Mangostin: anti-inflammatory activity and metabolism by human cells. J Agric Food Chem 61(16):3891–3900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herrera-Aco DR, Medina-Campos ON, Pedraza-Chaverri J, Sciutto-Conde E, Rosas-Salgado G, Fragoso-González G (2019) Alpha-mangostin: anti-inflammatory and antioxidant effects on established collagen-induced arthritis in DBA/1J mice. Food Chem Toxicol 124:300–315

    Article  CAS  PubMed  Google Scholar 

  • Hsieh SC, Huang MH, Cheng CW, Hung JH, Yang SF, Hsieh YH (2013) α-Mangostin induces mitochondrial dependent apoptosis in human hepatoma SK-Hep-1 cells through inhibition of p 38 MAPK pathway. Apop 18:1548–1560

    CAS  Google Scholar 

  • Ibrahim MY, Hashim NM, Mariod AA, Mohan S, Abdulla MA, Abdelwahab SI, Arbab IA (2016) α-Mangostin from Garcinia mangostana Linn: an updated review of its pharmacological properties. Arab J Chem 9(3):317–329

    Article  CAS  Google Scholar 

  • Jeyamogan S, Khan NA, Anwar A, Shah MR, Siddiqui R (2018) Cytotoxic effects of Benzodioxane, Naphthalene diimide, Porphyrin and Acetamol derivatives on HeLa cells. SAGE Open Med 6:2050312118781962

    Article  PubMed  PubMed Central  Google Scholar 

  • Jha BK, Jung HJ, Seo I, Suh SI, Suh MH, Baek WK (2015) Juglone induces cell death of Acanthamoeba through increased production of reactive oxygen species. Exp Parasitol 159:100–106

    Article  CAS  PubMed  Google Scholar 

  • Joshi DC, Bakowska JC (2011) Determination of mitochondrial membrane potential and reactive oxygen species in live rat cortical neurons. J vis Exp 23(51):e2704

    Google Scholar 

  • Kaomongkolgit R, Jamdee K, Pumklin J, Pavasant P (2013) Laboratory evaluation of the antibacterial and cytotoxic effect of alpha-mangostin when used as a root canal irrigant. Indian J Dent 4(1):12–17

    Article  Google Scholar 

  • Khan NA, Anwar A, Siddiqui R (2019) Acanthamoeba keratitis: current status and urgent research priorities. Curr Med Chem 26(30):5711–5726

    Article  CAS  PubMed  Google Scholar 

  • Kim D, Langmead B, Salzberg SL (2015) HISAT: a fast spliced aligner with low memory requirements. Nat Method 12(4):357–360

    Article  CAS  Google Scholar 

  • Koutsogiannis Z, MacLeod ET, Maciver SK (2019) G418 induces programmed cell death in Acanthamoeba through the elevation of intracellular calcium and cytochrome c translocation. Parasitol Res 118(2):641–651

    Article  PubMed  PubMed Central  Google Scholar 

  • Krishnan K, Moens PD (2009) Structure and functions of profilins. Biophys Rev 1(2):71–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li L, Brunner I, Han AR, Hamburger M, Kinghorn AD, Frye R, Butterweck V (2011) Pharmacokinetics of α-mangostin in rats after intravenous and oral application. Mol Nutri Food Res 55(S1):S67-74

    CAS  Google Scholar 

  • Lockman PR, Koziara JM, Mumper RJ, Allen DD (2004) Nanoparticle surface charges alter blood–brain barrier integrity and permeability. J Drug Target 12(9–10):635–641

    Article  CAS  PubMed  Google Scholar 

  • Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genom Biol 15(12):1–21

    Article  Google Scholar 

  • Loyola A, Almouzni G (2007) Marking histone H3 variants: how, when and why? Trend Biochem Sci 32(9):425–433

    Article  CAS  PubMed  Google Scholar 

  • Marciano-Cabral F, Cabral G (2003) Acanthamoeba spp. as agents of disease in humans. Clin Microbiol Rev 16(2):273–307

    Article  PubMed  PubMed Central  Google Scholar 

  • Márquez-Valadez B, Lugo-Huitrón R, Valdivia-Cerda V, Miranda-Ramírez LR, Pérez-De La Cruz V, González-Cuahutencos O, Rivero-Cruz I, Mata R, Santamaría A, Pedraza-Chaverrí J (2009) The natural xanthone α-mangostin reduces oxidative damage in rat brain tissue. Nutr Neurosci 12(1):35–42

    Article  PubMed  Google Scholar 

  • Masri A, Khan NA, Zoqratt MZ, Ayub Q, Anwar A, Rao K, Shah MR, Siddiqui R (2021) Transcriptome analysis of Escherichia coli K1 after therapy with hesperidin conjugated with silver nanoparticles. BMC Microbiol 21(1):1–1

    Article  Google Scholar 

  • Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B (2008) Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Method 5(7):621–628

    Article  CAS  Google Scholar 

  • Mungroo MR, Khan NA, Anwar A, Siddiqui R (2022) Nanovehicles in the improved treatment of infections due to brain-eating amoebae. Int Microbiol 25(2):225–235. https://doi.org/10.1007/s10123-021-00201-0

  • Myung J, Kim KB, Crews CM (2001) The ubiquitin-proteasome pathway and proteasome inhibitors. Med Res Rev 21(4):245–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orrenius S, Gogvadze V, Zhivotovsky B (2007) Mitochondrial oxidative stress: Implications for cell death. Ann Rev Pharmacol Toxicol 47:143–183

    Article  CAS  Google Scholar 

  • Pedraza-Chaverri J, Cardenas-Rodriguez N, Orozco-Ibarra M, Perez-Rojas JM (2008) Medicinal aproperties of mangosteen (Garcinia mangostana). Food Chem Toxicol 46:3227–3239

    Article  CAS  PubMed  Google Scholar 

  • Persson B, Kallberg Y (2013) Classification and nomenclature of the superfamily of short-chain dehydrogenases/reductases (SDRs). Chem Biol Interact 202(1–3):111–115

    Article  CAS  PubMed  Google Scholar 

  • Ramaiya A, Li G, Petiwala SM, Johnson JJ (2012) Single dose oral pharmacokinetic profile of α-mangostin in mice. Curr Drug Target 13(14):1698–1704

    Article  CAS  Google Scholar 

  • Rieger AM, Nelson KL, Konowalchuk JD, Barreda DR (2011) Modified annexin V/propidium iodide apoptosis assay for accurate assessment of cell death. J vis Exp 24(50):e2597

    Google Scholar 

  • Sangkanu S, Mitsuwan W, Mahabusarakam W, Jimoh TO, Wilairatana P, Girol AP, Verma AK, de Lourdes Pereira M, Rahmatullah M, Wiart C, Siyadatpanah A (2021) Anti-Acanthamoeba synergistic effect of chlorhexidine and Garcinia mangostana extract or α-mangostin against Acanthamoeba triangularis trophozoite and cyst forms. Sci Rep 11(1):1–1

    Article  Google Scholar 

  • Sato A, Fujiwara H, Oku H, Ishiguro K, Ohizumi Y (2004) α-Mangostin induces Ca2+-ATPase-dependent apoptosis via mitochondrial pathway in PC12 cells. J Pharmacol Sci 95(1):33–40

    Article  CAS  PubMed  Google Scholar 

  • Shimura H, Hattori N, Kubo SI, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25(3):302–305

    Article  CAS  PubMed  Google Scholar 

  • Siddiqui R, Rajendran K, Abdella B, Ayub Q, Lim SY, Khan NA (2020) Naegleria fowleri: differential genetic expression following treatment with Hesperidin conjugated with silver nanoparticles using RNA-Seq. Parasitol Res 119:2351–2358

    Article  PubMed  Google Scholar 

  • Sifaoui I, Rodríguez-Expósito RL, Reyes-Batlle M, Rizo-Liendo A, Piñero JE, Bazzocchi IL, Lorenzo-Morales J, Jiménez IA (2019) Ursolic acid derivatives as potential agents against Acanthamoeba spp. Pathogen 8(3):130

    Article  CAS  Google Scholar 

  • Sifaoui I, Lopez-Arencibia A, Martín-Navarro CM, Reyes-Batlle M, Wagner C, Chiboub O, Mejri M, Valladares B, Abderrabba M, Pinero JE, Lorenzo-Morales J (2017) Programmed cell death in Acanthamoeba castellanii Neff induced by several molecules present in olive leaf extracts. PLoS One 12(8):e0183795

    Article  PubMed  PubMed Central  Google Scholar 

  • Simon SE, Lim HS, Jayakumar FA, Tan EW, Tan KO (2022) Alpha-Mangostin activates MOAP-1 tumor suppressor and mitochondrial signaling in MCF-7 human breast cancer cells. Evid Based Compl Altern Med 2022:1–2

    Article  Google Scholar 

  • Tadtong S, Viriyaroj A, Vorarat S, Nimkulrat S, Suksamrarn S (2009) Antityrosinase and antibacterial activities of mangosteen pericarp extract. J Health Res 23(2):99–102

    CAS  Google Scholar 

  • Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, Van Baren MJ, Salzberg SL, Wold BJ, Pachter L (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 28(5):511–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trocha LK, Stobienia O (2007) Response of Acanthamoeba castellanii mitochondria to oxidative stress. Acta Biochim Pol 54(4):797–803

    Article  CAS  PubMed  Google Scholar 

  • Villa E, Ricci JE (2016) How does metabolism affect cell death in cancer? FEBS Lett 283(14):2653–2660

    Article  CAS  Google Scholar 

  • Villa E, Proïcs E, Rubio-Patiño C, Obba S, Zunino B, Bossowski JP, Rozier RM, Chiche J, Mondragón L, Riley JS, Marchetti S (2017) Parkin-independent mitophagy controls chemotherapeutic response in cancer cells. Cell Rep 20(12):2846–2859

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Zhu J, Liu M, Yang Q, Wu J, Li Z (2018) De novo sequencing and transcriptome assembly of Arisaema heterophyllum Blume and identification of genes involved in isoflavonoid biosynthesis. Sci Rep 8(1):1–2

    Article  Google Scholar 

  • Wei H, Liu L, Chen Q (2015) Selective removal of mitochondria via mitophagy: distinct pathways for different mitochondrial stresses. Biochim Biophys Acta Mol Cell Res 1853(10):2784–2790

    Article  CAS  Google Scholar 

  • Wingett SW, Andrews S (2018) FastQ Screen: A tool for multi-genome mapping and quality control. F1000Research 7:1338

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu Z, Lu Z, Ou J, Su X, Liu J (2020) Inflammatory response and oxidative stress attenuated by sulfiredoxin 1 in neuron like cells depends on nuclear factor erythroid 2 related factor 2. Mol Med Rep 22(6):4734–4742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang J, Yin Y (2020) PTEN in chromatin remodeling. Cold Spring Harbor Perspect Med 10(2):a036160

    Article  CAS  Google Scholar 

  • Young MD, Wakefield MJ, Smyth GK, Oshlack A (2010) Gene ontology analysis for RNA-seq: accounting for selection bias. Genom Biol 11(2):1–2

    Article  Google Scholar 

  • Zheng W, Rasmussen U, Zheng S, Bao X, Chen B, Gao Y, Guan X, Larsson J, Bergman B (2013) Multiple modes of cell death discovered in a prokaryotic (cyanobacterial) endosymbiont. PLoS ONE 8(6):e66147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang KJ, Gu QL, Yang K, Ming XJ, Wang JX (2017) Anticarcinogenic effects of α-mangostin: a review. Plant Med 83(03/04):188–202

    CAS  Google Scholar 

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Acknowledgements

This research work was supported by Sunway University, Malaysia, and University of Karachi, Pakistan.

Funding

This research work was supported by Sunway University, Malaysia (Individual research grant, GRTIN-IRG-10–2022). Ruqaiyyah Siddiqui and Naveed Ahmed Khan are supported by the Air Force Office of Scientific Research (AFOSR), USA.

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SKO, AA and NAK conceived the study. AA, RS and KMK designed experiments. UA carried out all experiments under the supervision of AA, KOT, KMK, NAK, SKO, BSA, and RS. UA and AA analyzed data and prepared the first draft of the manuscript. All authors read, corrected and approved the final manuscript.

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Correspondence to Naveed Ahmed Khan or Ayaz Anwar.

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Key points

• Alpha-Mangostin is a xanthone with biological activities.

• α-Mangostin (AMS) inhibited viability of A. castellanii.

• AMS caused apoptosis through the mitochondrial pathway.

• AMS inhibited A. castellanii-mediated human cells cytopathogenicity.

• Transcriptome analysis showed significant expression of 826 genes.

• KEGG analysis showed autophagy, RAP1, AGE-RAGE and oxytocin signalling.

PTEN,H3,ARIH1,SDR16C5,PFN,glnA GLUL, and SRX1) were found significant.

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Ahmed, U., Ong, SK., Tan, K.O. et al. Alpha-Mangostin and its nano-conjugates induced programmed cell death in Acanthamoeba castellanii belonging to the T4 genotype. Int Microbiol (2023). https://doi.org/10.1007/s10123-023-00450-1

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