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Marizé Cuyler,1 Danielle Twilley,1 Velaphi C Thipe,2 Vusani Mandiwana,3 Michel L Kalombo,3 Suprakas S Ray,4 Rirhandzu Shamaine Rikhotso-Mbungela,4 Arno Janse van Vuuren,5 Will Coetsee,6 Kattesh V Katti,2,&ast; Namrita Lall1,7– 9,&ast; 1Department of Plant and Soil Sciences, University of Pretoria, Pretoria, Gauteng, 0002, South Africa; 2Department of Radiology, Institute of Green Nanotechnology, University of Missouri, Columbia, MO, 65212, USA; 3Chemical Cluster Centre for Nanostructures and Advanced Materials, Council for Scientific and Industrial Research, Pretoria, 0001, South Africa; 4DST/CSIR National Centre for Nanostructured Materials, Council for Scientific and Industrial Research, Pretoria, 0001, South Africa; 5Centre for High Transmission Electron Microscopy, Nelson Mandela University, Port Elizabeth, 6031, South Africa; 6Botanica Natural Products Pty (Ltd), Canterbury Farm MR 254, Alldays, Limpopo, 0909, South Africa; 7School of Natural Resources, University of Missouri, Columbia, MO, 65211, USA; 8College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, 570015, India; 9Bio-Tech Research and Development Institute, University of the West Indies 770, Kingston, Jamaica&ast;These authors contributed equally to this workCorrespondence: Kattesh V Katti, Department of Radiology, Institute of Green Nanotechnology, University of Missouri, Columbia, MO 65212, USA, Tel +1 (573) 882-5656, Fax +1 (573) 884-5679, Email kattik@health.missouri.edu Namrita Lall, Department of Plant and Soil Sciences, University of Pretoria, Pretoria, Gauteng, South Africa, Tel/Fax +27 (012) 420 2524, Email namrita.lall@up.ac.zaBackground: Atopic dermatitis (eczema) is an inflammatory skin condition with synthetic treatments that induce adverse effects and are ineffective. One of the proposed causes for the development of the condition is the outside-in hypothesis, which states that eczema is caused by a disruption in the skin barrier. These disruptions include developing dry cracked skin, which promotes the production of histamine. Bulbine frutescens (BF) is traditionally used to treat wounds and eczema; however, limited research has been conducted to scientifically validate this. Furthermore, gold nanoparticles (AuNPs) have been used to repair damaged skin; however, no research has been conducted on AuNPs synthesized using BF.Purpose: The study aimed to determine whether BF alleviated skin damage through wound healing, reducing the production of histamine and investigate whether AuNPs synthesized using BF would enhance biological activity.Methods: Four extracts and four synthesized AuNPs were prepared using BF and their antiproliferative and wound healing properties against human keratinocyte cells (HaCaT) were evaluated. Thereafter, the selected samples antiproliferative activity and antihistamine activity against phorbol 12-myristate 13-acetate (PMA) stimulated granulocytes were evaluated.Results: Of the eight samples, the freeze-dried leaf juice (BFE; p < 0.01) extract and its AuNPs (BFEAuNPs; p < 0.05) displayed significant wound closure at 100 μg/mL and were further evaluated. The selected samples displayed a fifty percent inhibitory concentration (IC50) of > 200 μg/mL against PMA stimulated granulocytes. Compared to the untreated (media with PMA) control (0.30 ± 0.02 ng/mL), BFEAuNPs significantly inhibited histamine production at a concentration of 100 (p < 0.01) and 50 μg/mL (p < 0.001).Conclusion: BFE and BFEAuNPs stimulated wound closure, while BFEAuNPs significantly inhibited histamine production. Further investigation into BFEAuNPs in vivo wound healing activity and whether it can target histamine-associated receptors on mast cells as a potential mechanism of action should be considered. Keywords: atopic dermatitis, histamine production, outside-in hypothesis, scratch assay