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Cell-Penetrating Delivery of Nitric Oxide by Biocompatible Dinitrosyl Iron Complex and Its Dermato-Physiological Implications.

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.

SUBMITTER: Chen YC

PROVIDER: S-EPMC8469893 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Nitric oxide (NO) is involved in all major environmental stresses. However, most of these understandings were mainly based on pharmacological study using NO modulator compounds. Recently, our studies together with others provided a new class of plant experimental system with specific in vivo NO release through constitutively overexpressing rat neuronal NO synthase (nNOS) in plants. In this study, we found that the nNOS transgenic Arabidopsis plants displayed lower level of H2O2 content, but higher levels of antioxidant enzyme activities and osmolytes under drought stress conditions. Transcriptomic analysis identified 490 and 20 genes that were differentially expressed in wild type (WT) and nNOS transgenic plants under control and drought stress conditions, respectively. Pathway analysis revealed that many genes involved in photosynthesis, cell, misc, co-factor and vitamin metabolism, major CHO metabolism, OPP and secondary metabolism were largely changed in nNOS vs. WT under control or drought stress conditions. Interestingly, CBF1/2 and 13 zinc finger family proteins, known as important family of transcription regulators in modulating several stress-responsive genes, were differentially expressed by nNOS transgenic effect. Additionally, some genes were commonly regulated by nNOS transgenic and abscisic acid (ABA) effects, indicating new insights to cross-talk between ABA and NO. Taken together, in vivo NO modulated antioxidant enzyme activities, osmolyte level, and the expression of genes involved in several pathways, thereby resulting in enhanced stress tolerance in nNOS transgenic plants. These observations might provide some insights to understand the physiological and molecular mechanisms of NO in response to drought stress in Arabidopsis. Two transgenic Arabidopsis lines (nNOS-2 and nNOS-25) with the nNOS gene under the control of the cauliflower mosaic virus (CaMV) 35S promoter, as well as Col-0 (WT), were used in this research. RNA samples from two nNOS transgenic lines were pooled for cRNA labelling and chip hybridization.

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Cell-Penetrating Delivery of Nitric Oxide by Biocompatible Dinitrosyl Iron Complex and Its Dermato-Physiological Implications.

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