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1.
Nutrients ; 14(16)2022 Aug 16.
Article in English | MEDLINE | ID: mdl-36014862

ABSTRACT

Female pattern hair loss (FPHL) is a non-scarring alopecia resulting from the progressive conversion of the terminal (t) scalp hair follicles (HFs) into intermediate/miniaturized (i/m) HFs. Although data supporting nutrient deficiency in FPHL HFs are lacking, therapeutic strategies are often associated with nutritional supplementation. Here, we show by metabolic analysis that selected nutrients important for hair growth such as essential amino acids and vitamins are indeed decreased in affected iHFs compared to tHFs in FPHL scalp skin, confirming nutrient insufficiency. iHFs also displayed a more quiescent metabolic phenotype, as indicated by altered metabolite abundance in freshly collected HFs and release/consumption during organ culture of products/substrates of TCA cycle, aerobic glycolysis, and glutaminolysis. Yet, as assessed by exogenous nutrient supplementation ex vivo, nutrient uptake mechanisms are not impaired in affected FPHL iHFs. Moreover, blood vessel density is not diminished in iHFs versus tHFs, despite differences in tHFs from different FPHL scalp locations or versus healthy scalp or changes in the expression of angiogenesis-associated growth factors. Thus, our data reveal that affected iHFs in FPHL display a relative nutrient insufficiency and dormant metabolism, but are still capable of absorbing nutrients, supporting the potential of nutritional supplementation as an adjunct therapy for FPHL.


Subject(s)
Alopecia , Hair Follicle , Alopecia/drug therapy , Female , Humans , Nutrients , Phenotype , Scalp
2.
Life Sci ; 138: 35-40, 2015 Oct 01.
Article in English | MEDLINE | ID: mdl-25921771

ABSTRACT

AIM: Cannabinoids (CB) like ∆(9)-tetrahydrocannabinol (THC) can induce cancer cell apoptosis and inhibit angiogenesis. However, the use of cannabinoids for the treatment of malignant diseases is discussed controversially because of their immunomodulatory effects which can suppress anti-tumor immunity. Here we investigated the role of exogenous and endogenous cannabinoids in mouse skin cancer. MAIN METHODS: First we examined the effect of THC, which binds to CB receptors (CB1, CB2), on the growth of the mouse melanoma cell lines B16 and HCmel12 in vitro and in vivo in wild type (WT) and CB1/CB2-receptor deficient mice (Cnr1/2(-/-)). Next we evaluated the role of the endogenous cannabinoid system by studying the growth of chemically induced melanomas, fibrosarcoma and papillomas in WT and Cnr1/2(-/-) mice. KEY FINDINGS: THC significantly inhibited tumor growth of transplanted HCmel12 melanomas in a CB receptor-dependent manner in vivo through antagonistic effects on its characteristic pro-inflammatory microenvironment. Chemically induced skin tumors developed in a similar manner in Cnr1/2(-/-) mice when compared to WT mice. SIGNIFICANCE: Our results confirm the value of exogenous cannabinoids for the treatment of melanoma but do not support a role for the endogenous cannabinoid system in the pathogenesis of skin cancer.


Subject(s)
Cannabinoids/pharmacology , Skin Neoplasms/pathology , Animals , Cell Line, Tumor , Dronabinol/pharmacology , Fibrosarcoma/pathology , Melanoma/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasm Transplantation , Papilloma/pathology , Receptor, Cannabinoid, CB1/genetics , Receptor, Cannabinoid, CB2/genetics , Skin Neoplasms/chemically induced , Skin Neoplasms/etiology
3.
Exp Dermatol ; 23(6): 401-6, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24750433

ABSTRACT

Atopic dermatitis is a chronic inflammatory disease characterized by an impaired epidermal barrier function combined with a chronic Th2-type inflammatory response and an intense pruritus. Here, we used an experimental mouse model for Th2-type contact hypersensitivity (CHS) to fluorescein isothiocyanate (FITC) to investigate the potential role of cannabinoid 1 receptors (CB1) in the pathophysiology of mouse atopic-like dermatitis. Mice lacking CB1 receptors globally (Cnr1(-/-) ) or specifically in keratinocytes (KC-Cnr1(-/-) ) as well as wild-type (WT) control mice were sensitized and challenged with FITC. We examined ear swelling responses, transepidermal water loss, Th2-type skin inflammatory responses and serum IgE levels. Both Cnr1(-/-) and KC-Cnr1(-/-) showed enhanced CHS responses to FITC and a delayed epidermal barrier repair when compared with WT mice. mRNA levels for IL-4, thymic stromal lymphopoietin (TSLP) and CCL8, as well as eosinophil activity, were significantly increased in inflamed ear tissue of FITC-challenged Cnr1(-/-) and KC-Cnr1(-/-) mice. Importantly, CB1 receptor-deficient keratinocytes secreted increased levels of TSLP, a proinflammatory mediator that drives Th2-type skin inflammation in atopic dermatitis, under basal and Th2-type inflammatory conditions. Taken together, our results demonstrate that CB1 receptors in keratinocytes help to maintain epidermal barrier homoeostasis and attenuate Th2-type allergic inflammatory responses. Based on our work, we propose that enhanced epidermal allergen penetrance cooperates with increased production of TSLP and CCL8 by epidermal keratinocytes for the induction of type 2 CD4+ T helper cells. Our results place keratinocytes at the cross-roads of outside-in and inside-out pathophysiologic mechanisms of atopic dermatitis.


Subject(s)
Dermatitis, Atopic/metabolism , Dermatitis, Atopic/prevention & control , Keratinocytes/metabolism , Receptor, Cannabinoid, CB1/metabolism , Animals , Cells, Cultured , Chemokine CCL8/metabolism , Cytokines/metabolism , Dermatitis, Atopic/chemically induced , Disease Models, Animal , Fluorescein-5-isothiocyanate/adverse effects , Homeostasis/physiology , Interleukin-4/metabolism , Keratinocytes/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptor, Cannabinoid, CB1/deficiency , Receptor, Cannabinoid, CB1/genetics , Th2 Cells/pathology , Thymic Stromal Lymphopoietin
4.
J Invest Dermatol ; 134(8): 2131-2137, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24577407

ABSTRACT

ß-Arrestins participate in G-protein receptor signaling and act as adapter proteins that direct the recruitment, activation, and scaffolding of various cytoplasmic signaling complexes. ß-Arrestin 2-deficient (Arrb2(-/-)) mice show decreased T-cell recruitment into allergic lung tissue but increased neutrophil infiltration into wounded skin. Given these opposing effects in different immune cell subsets, we investigated the role of ß-arrestin 2 in the regulation of contact hypersensitivity responses. We observed significantly increased allergic ear swelling to the obligate contact sensitizers DNFB and FITC in Arrb2(-/-) compared with wild-type mice. Immunohistological analyses revealed strikingly increased neutrophil infiltration with abundant subcorneal pustules in inflamed ear tissue of DNFB-allergic Arrb2(-/-) mice. Experiments involving adoptive transfers of sensitized lymphocytes and bone marrow chimeric mice indicated that ß-arrestin 2 exerts its anti-inflammatory effects predominantly through radioresistant, skin-resident cells in the challenge phase of contact hypersensitivity. As a potential mechanism, we found that primary cultures of ß-arrestin 2-deficient keratinocytes secreted higher levels of neutrophil-attracting chemokines including CXCL1/KC in response to T cell-derived cytokines in vitro. These experimental results support a model in which ß-arrestin 2 inhibits the production of proinflammatory chemokines, which limits the recruitment of myeloid immune cells and thereby attenuates allergic skin inflammation.


Subject(s)
Arrestins/physiology , Chemokines/biosynthesis , Dermatitis, Allergic Contact/immunology , Animals , Chemokine CXCL2/biosynthesis , Dermatitis, Allergic Contact/prevention & control , Dinitrofluorobenzene , Keratinocytes/immunology , Mice , Mice, Inbred C57BL , Neutrophils/physiology , Radiation Tolerance , beta-Arrestin 2 , beta-Arrestins
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