Plumbagin Inhibits Fungal Growth, HMGB1/LOX-1 Pathway and Inflammatory Factors in Keratitis

Overview

Journal Front Microbiol

Specialty Microbiology

Date 2024 Apr 24

PMID 38655086

Authors

Fan Cong

Lingwen Gu

Jing Lin

Guibo Liu

Qian Wang

Lina Zhang

Menghui Chi

Qiang Xu

Guiqiu Zhao

Cui Li

Affiliations

Soon will be listed here.

Abstract

To investigate the anti-inflammatory and antifungal effects of plumbagin (PL) in () keratitis, the minimum inhibitory concentration (MIC), time-killing curve, spore adhesion, crystal violet staining, calcium fluoride white staining, and Propidium Iodide (PI) staining were employed to assess the antifungal activity of PL against . The cytotoxicity of PL was assessed using the Cell Counting Kit-8 (CCK8). The impact of PL on the expression of HMGB1, LOX-1, TNF-α, IL-1β, IL-6, IL-10 and ROS in keratitis was investigated using RT-PCR, ELISA, Western blot, and Reactive oxygen species (ROS) assay. The therapeutic efficacy of PL against keratitis was assessed through clinical scoring, plate counting, Immunofluorescence and Hematoxylin-Eosin (HE) staining. Finally, we found that PL inhibited the growth, spore adhesion, and biofilm formation of and disrupted the integrity of its cell membrane and cell wall. PL decreased IL-6, TNF-α, and IL-1β levels while increasing IL-10 expression in fungi-infected mice corneas and peritoneal macrophages. Additionally, PL significantly attenuated the HMGB1/LOX-1 pathway while reversing the promoting effect of Boxb (an HMGB1 agonist) on HMGB1/LOX-1. Moreover, PL decreased the level of ROS. , clinical scores, neutrophil recruitment, and fungal burden were all significantly reduced in infected corneas treated with PL. In summary, the inflammatory process can be inhibited by PL through the regulation of the HMGB-1/LOX-1 pathway. Simultaneously, PL can exert antifungal effects by limiting fungal spore adhesion and biofilm formation, as well as causing destruction of cell membranes and walls.

References

J Hoffman J, Arunga S, H A Mohamed Ahmed A, Hu V, Burton M . Management of Filamentous Fungal Keratitis: A Pragmatic Approach. J Fungi (Basel). 2022; 8(10). PMC: 9605596. DOI: 10.3390/jof8101067. View

Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y . ROS and ROS-Mediated Cellular Signaling. Oxid Med Cell Longev. 2016; 2016:4350965. PMC: 4779832. DOI: 10.1155/2016/4350965. View

Brown L, Leck A, Gichangi M, Burton M, Denning D . The global incidence and diagnosis of fungal keratitis. Lancet Infect Dis. 2021; 21(3):e49-e57. DOI: 10.1016/S1473-3099(20)30448-5. View

Min H, Kim J, Yoo J, Oh J, Kim K, Yoon J . ROS-dependent HMGB1 secretion upregulates IL-8 in upper airway epithelial cells under hypoxic condition. Mucosal Immunol. 2016; 10(3):685-694. DOI: 10.1038/mi.2016.82. View

Yang X, Zhang B, Yu P, Liu M, Zhang C, Su E . HMGB1 in macrophage nucleus protects against pressure overload induced cardiac remodeling via regulation of macrophage differentiation and inflammatory response. Biochem Biophys Res Commun. 2022; 611:91-98. DOI: 10.1016/j.bbrc.2022.04.053. View

Kim Y, Kim J . ROS-Scavenging Therapeutic Hydrogels for Modulation of the Inflammatory Response. ACS Appl Mater Interfaces. 2021; . DOI: 10.1021/acsami.1c18261. View

Yin M, Li C, Zhang L, Zhang L, Lin J, Jiang N . Mechanism of antifungal activity and therapeutic action of β-ionone on Aspergillus fumigatus keratitis via suppressing LOX1 and JNK/p38 MAPK activation. Int Immunopharmacol. 2022; 110:108992. DOI: 10.1016/j.intimp.2022.108992. View

Zheng X, Mao C, Qiao H, Zhang X, Yu L, Wang T . Plumbagin suppresses chronic periodontitis in rats via down-regulation of TNF-α, IL-1β and IL-6 expression. Acta Pharmacol Sin. 2017; 38(8):1150-1160. PMC: 5547554. DOI: 10.1038/aps.2017.19. View

Sha X, Shi Q, Liu L, Zhong J . Update on the management of fungal keratitis. Int Ophthalmol. 2021; 41(9):3249-3256. DOI: 10.1007/s10792-021-01873-3. View

10.

Peiro T, Patel D, Akthar S, Gregory L, Pyle C, Harker J . Neutrophils drive alveolar macrophage IL-1β release during respiratory viral infection. Thorax. 2017; 73(6):546-556. PMC: 5969338. DOI: 10.1136/thoraxjnl-2017-210010. View

11.

Periasamy H, Iswarya S, Pavithra N, Senthilnathan S, Gnanamani A . In vitro antibacterial activity of plumbagin isolated from Plumbago zeylanica L. against methicillin-resistant Staphylococcus aureus. Lett Appl Microbiol. 2019; 69(1):41-49. DOI: 10.1111/lam.13160. View

12.

Pan P, Wang Y, Lin S, Liao S, Chen Y, Huang W . Plumbagin ameliorates bile duct ligation-induced cholestatic liver injury in rats. Biomed Pharmacother. 2022; 151:113133. DOI: 10.1016/j.biopha.2022.113133. View

13.

Ung L, Bispo P, Shanbhag S, Gilmore M, Chodosh J . The persistent dilemma of microbial keratitis: Global burden, diagnosis, and antimicrobial resistance. Surv Ophthalmol. 2018; 64(3):255-271. PMC: 7021355. DOI: 10.1016/j.survophthal.2018.12.003. View

14.

Bernardino P, Smith W, Conrad P, Packham A, Tamez-Trevino E, Barnum S . Molecular detection of Sarcocystis neurona in cerebrospinal fluid from 210 horses with suspected neurologic disease. Vet Parasitol. 2021; 291:109372. DOI: 10.1016/j.vetpar.2021.109372. View

15.

Niu L, Liu X, Ma Z, Yin Y, Sun L, Yang L . Fungal keratitis: Pathogenesis, diagnosis and prevention. Microb Pathog. 2019; 138:103802. DOI: 10.1016/j.micpath.2019.103802. View

16.

Chen H, Wang H, An J, Shang Q, Ma J . Inhibitory Effects of Plumbagin on Retinal Pigment Epithelial Cell Epithelial-Mesenchymal Transition In Vitro and In Vivo. Med Sci Monit. 2018; 24:1502-1510. PMC: 5861765. DOI: 10.12659/msm.906265. View

17.

Shu C, Chen J, Lv M, Xi Y, Zheng J, Xu X . Plumbagin relieves rheumatoid arthritis through nuclear factor kappa-B (NF-κB) pathway. Bioengineered. 2022; 13(5):13632-13642. PMC: 9276045. DOI: 10.1080/21655979.2022.2081756. View

18.

Kohli V, Sharma D, Sandur S, Suryavanshi S, Sainis K . Immune responses to novel allergens and modulation of inflammation by vitamin K3 analogue: a ROS dependent mechanism. Int Immunopharmacol. 2010; 11(2):233-43. DOI: 10.1016/j.intimp.2010.11.027. View

19.

Zaki A, El-Tanbouly D, Abdelsalam R, Zaki H . Plumbagin ameliorates hepatic ischemia-reperfusion injury in rats: Role of high mobility group box 1 in inflammation, oxidative stress and apoptosis. Biomed Pharmacother. 2018; 106:785-793. DOI: 10.1016/j.biopha.2018.07.004. View

20.

Ratitong B, Pearlman E . Pathogenic Aspergillus and Fusarium as important causes of blinding corneal infections - the role of neutrophils in fungal killing, tissue damage and cytokine production. Curr Opin Microbiol. 2021; 63:195-203. PMC: 10492570. DOI: 10.1016/j.mib.2021.07.018. View