Antiproliferative activity of caged xanthones from the leaves of Garcinia wightii T. Anderson.

Two new caged xanthones, wightiic acid (1) 16-O-methyl wightiic acid (2), along with eight known compounds, gaudichaudic acid E (3), isogaudichaudic acid E (4), ursolic acid (5) stigmasterol (6), lupeol (7), glutinol (8), lupenone (9) and stigmasteryl linoleate (10) were isolated from Garcinia wightii T. Anderson. The structures of the compounds were elucidated by spectroscopic means, including 1D and 2D NMR, HR-ESIMS, and the absolute configuration of the new compounds 1 and 2 were determined by analysis of ECD data. Anti-proliferation activities of the four caged xanthones (1-4) were evaluated by MTT assay on MCF-7 and SKBR-3 human breast cancer cells and A-375 human melanoma cells by MTT assay. All the tested compounds exhibited dose dependent antiproliferative activity. Wightiic acid (1) showed remarkable activity with IC50 value of 4.7 µM and 5.2 µM respectively in A-375 and MCF-7 cells. The compound isogaudichaudic acid E (4) induced potent antiproliferation against SKBR-3 cells with an IC50 value of 6.1 µM.

Lichen Planopilaris and Frontal Fibrosing Alopecia as Model Epithelial Stem Cell Diseases.

Inflammation-associated, irreversible damage to epithelial stem cells (eSCs) of the hair follicle in their immunologically privileged niche lies at the heart of scarring alopecia, which causes permanent difficult-to-treat hair loss. We propose that the two most common and closely related forms, lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA), provide excellent model diseases for studying the biology and pathology of adult human eSCs in an easily accessible human mini-organ. Emphasising the critical roles for interferon (IFN)-γ and peroxisome proliferator-activated receptor (PPAR)-γ-mediated signalling in immune privilege (IP) collapse and epithelial-mesenchymal transition (EMT) of these eSCs respectively, we argue that these pathways deserve therapeutic targeting in the future management of LPP/FFA and other eSC diseases associated with IP collapse and EMT.

Epithelial-to-Mesenchymal Stem Cell Transition in a Human Organ: Lessons from Lichen Planopilaris.

Epithelial-to-mesenchymal transition (EMT) is critical for embryonic development and wound healing, and occurs in fibrotic disease and carcinoma. Here, we show that EMT also occurs within the bulge, the epithelial stem cell (eSC) niche of human scalp hair follicles, during the inflammatory permanent alopecia, lichen planopilaris. We show that a molecular EMT signature can be experimentally induced in healthy human eSCs in situ by antagonizing E-cadherin, combined with transforming growth factor-ß1, epidermal growth factor, and IFN-γ administration, which to our knowledge has not been reported previously. Moreover, induction of EMT within primary human eSCs can be prevented and even partially reversed ex vivo by peroxisome proliferator-activated receptor-γ agonists, likely through suppression of the transforming growth factor-ß signaling pathway. Furthermore, we show that peroxisome proliferator-activated receptor-γ agonists also attenuates the EMT signature even in lesional lichen planopilaris hair follicles ex vivo. We introduce lichen planopilaris as a model disease for pathological EMT in human adult eSCs, report a preclinical assay for therapeutically manipulating eSC EMT within a healthy human (mini-)organ, and show that peroxisome proliferator-activated receptor-γ agonists are promising agents for suppressing and partially reversing EMT in human hair follicles eSCs ex vivo, including in lichen planopilaris.