Abstract
After the discovery of endogenous dinitrosyl iron complexes (DNICs) as a potential biological equivalent of nitric oxide (NO), bioinorganic engineering of [Fe(NO)2] unit has emerged to develop biomimetic DNICs [(NO)2Fe(L)2] as a chemical biology tool for controlled delivery of NO. For example, water-soluble DNIC [Fe2(μ-SCH2CH2OH)2(NO)4] (DNIC-1) was explored for oral delivery of NO to the brain and for the activation of hippocampal neurogenesis. However, the kinetics and mechanism for cellular uptake and intracellular release of NO, as well as the biocompatibility of synthetic DNICs, remain elusive. Prompted by the potential application of NO to dermato-physiological regulations, in this study, cellular uptake and intracellular delivery of DNIC [Fe2(μ-SCH2CH2COOH)2(NO)4] (DNIC-2) and its regulatory effect/biocompatibility toward epidermal cells were investigated. Upon the treatment of DNIC-2 to human fibroblast cells, cellular uptake of DNIC-2 followed by transformation into protein-bound DNICs occur to trigger the intracellular release of NO with a half-life of 1.8 ± 0.2 h. As opposed to the burst release of extracellular NO from diethylamine NONOate (DEANO), the cell-penetrating nature of DNIC-2 rationalizes its overwhelming efficacy for intracellular delivery of NO. Moreover, NO-delivery DNIC-2 can regulate cell proliferation, accelerate wound healing, and enhance the deposition of collagen in human fibroblast cells. Based on the in vitro and in vivo biocompatibility evaluation, biocompatible DNIC-2 holds the potential to be a novel active ingredient for skincare products.
Highlights
Based on the distinctive electron paramagnetic resonance (EPR) signal at g ≈ 2.03 observed in the baker’s yeast cells (S. cerevisiae), biosynthesis of dinitrosyl iron complexes (DNICs) was first discovered by Prof
Sci. 2021, 22, 10101 biocompatibility evaluation using a 2-D culture of fibroblast/melanocyte/keratinocyte cells, 3-D culture of reconstructed human epidermis and human cornea-like epithelium models, and zebrafish embryo, DNIC [Fe2(μSCH2CH2COOH)2(NO)4] (DNIC-2) holds the potential for further development as a novel active ingredient for skincare products
A mechanistic and efficacy study of the cell-penetrating delivery of nitric oxide (NO) by DNIC-2 and its regulatory effect on dermato-physiology has led to the following results
Summary
Based on the distinctive electron paramagnetic resonance (EPR) signal at g ≈ 2.03 observed in the baker’s yeast cells (S. cerevisiae), biosynthesis of dinitrosyl iron complexes (DNICs) was first discovered by Prof. Biomimetic DNICs and their conjugates with drug delivery systems were explored for antiaging/anti-inflammatory/anti-viral effect, anti-cancer/anti-hypertensive therapy, diabetic angiogenesis/wound healing, penile erection, and treatment of mild cognitive impairment and neurodegenerative diseases [25,26,27,28,29,30,31,32,33,34,35]. Phase I and phase II clinical trials of glutathione-bound DNICs [Fe2 (μ-glutathione) (NO)4 ], a commercial medical product with the pharmacological name Oxacom® , was reported for application as a clinical medicine against hypertension [30,31]
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