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HucMSC exosome-delivered 14-3-3ζ alleviates ultraviolet radiation-induced photodamage via SIRT1 pathway modulation.

ABSTRACT: Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) are nano-sized membrane-bound vesicles that have been reported to facilitate skin regeneration and repair. However, the roles played by hucMSC-ex in ultraviolet (UV) radiation-induced skin photodamage and the underlying mechanisms remain unknown. To investigate the functions of hucMSC-ex in a rat model of acute skin photodamage, immunofluorescence and immunohistochemical staining, quantitative real-time-polymerase chain reaction (qRT-PCR), western blot, and gene silencing assays were performed. We found that the in vivo subcutaneous injection of hucMSC-ex elicited antioxidant and anti-inflammatory effects against UV radiation-induced DNA damage and apoptosis. Further studies showed that the sirtuin 1 (SIRT1) expression level in skin keratinocytes (HaCaT) decreased in a time- and dose-dependent manner under in vitro UV radiation induced-oxidative stress conditions, which could be reversed by treatment with hucMSC-ex. The activation of SIRT1 significantly attenuated UV- and H₂O₂-induced cytotoxic damage by inhibiting oxidative stress and promoting the activation of autophagy. Our study found that 14-3-3ζ protein, which was delivered by hucMSC-ex, exerted a cytoprotective function via the modulation of a SIRT1-dependent antioxidant pathway. Collectively, our findings indicated that hucMSC-ex might represent a new potential agent for preventing or treating UV radiation-induced skin photodamage and aging.

SUBMITTER: Wu P

PROVIDER: S-EPMC8109102 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ultraviolet (UV) exposure to the skin causes photo-damage and acts as the primary etiological agent in photo-carcinogenesis. UV-B exposure induces cellular damage and is the major factor challenging skin homeostasis. Autophagy allows the fundamental adaptation of cells to metabolic and oxidative stress. Cellular dysfunction has been observed in aged tissues and in toxic insults to cells undergoing stress. Conversely, promising anti-aging strategies aimed at inhibiting the mTOR pathway have been found to significantly improve the aging-related disorders. Recently, autophagy has been found to positively regulate skin homeostasis by enhancing DNA damage recognition. Here, we investigated the geno-protective roles of autophagy in UV-B-exposed primary human dermal fibroblasts (HDFs). We found that UV-B irradiation to HDFs impairs the autophagy response in a time- and intensity-independent manner. However, improving autophagy levels in HDFs with pharmacological activators regulates the UV-B-induced cellular stress by decreasing the induction of DNA photo-adducts, promoting the DNA repair process, alleviating oxidative and ER stress responses, and regulating the expression levels of key cell cycle regulatory proteins. Autophagy also prevents HDFs from UV-B-induced nuclear damage as is evident in TUNEL assay and Acridine Orange/Ethidium Bromide co-staining. Salubrinal (an eIF2α phosphatase inhibitor) relieves ER stress response in cells and also significantly alleviates DNA damage and promotes the repair process in UV-B-exposed HDFs. P62-silenced HDFs show enhanced DNA damage response and also disturb the tumor suppressor PTEN/pAKT signaling axis in UV-B-exposed HDFs whereas Atg7-silenced HDFs reveal an unexpected consequence by decreasing the UV-B-induced DNA damage. Taken together, these results suggest that interventional autophagy offers significant protection against UV-B radiation-induced photo-damage and holds great promise in devising it as a suitable therapeutic strategy against skin pathological disorders.

Project description:Ultraviolet B (UVB) radiation leads to the excessive accumulation of reactive oxygen species (ROS), which subsequently promote inflammation, degradation of the extracellular matrix, and photoaging in skin. Thus antioxidant activity is particularly important when screening for active substances to prevent or repair photodamage. Marine fish-derived bioactive peptides have become a trend in cosmetics and functional food industries owing to their potential dermatological benefits. In this study, 1-diphenyl- 2-pycryl-hydrazyl (DPPH) scavenging activity was selected to optimize the hydrolysis conditions of sturgeon skin collagen peptides with antioxidant activity. The optimal hydrolysis conditions for sturgeon skin collagen hydrolysate (SSCH) were determined by response surface methodology, which comprised an enzyme dosage of flavorzyme at 6,068.4 U/g, temperature of 35.5°C, pH of 7, and hydrolysis time of 6 h. SSCH showed good radical-scavenging capacities with a DPPH scavenging efficiency of 95%. Then, the effect of low-molecular-weight SSCH fraction (SSCH-L) on UVB irradiation-induced photodamage was evaluated in mouse fibroblast L929 cells and zebrafish. SSCH-L reduced intracellular ROS levels and the malondialdehyde content, thereby alleviating the oxidative damage caused by UVB radiation. Moreover SSCH-L inhibited the mRNA expression of genes encoding the pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and Cox-2. SSCH-L treatment further increased the collagen Ⅰα1 content and had a significant inhibitory effect on matrix metalloproteinase expression. The phosphorylation level of JNK and the expression of c-Jun protein were significantly reduced by SSCH-L. Additionally, SSCH-L increased the tail fin area at 0.125 and 0.25 mg/ml in a zebrafish UVB radiation model, which highlighted the potential of SSCH-L to repair UVB-irradiated zebrafish skin damage. Peptide sequences of SSCH-L were identified by liquid chromatography-tandem mass spectrometry. Based on the 3D-QSAR modeling prediction, six total peptides were selected to test the UVB-protective activity. Among these peptides, DPFRHY showed good UVB-repair activity, ROS-scavenging activity, DNA damage-protective activity and apoptosis inhibition activity. These results suggested that DPFRHY has potential applications as a natural anti-photodamage material in cosmetic and functional food industries.

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HucMSC exosome-delivered 14-3-3ζ alleviates ultraviolet radiation-induced photodamage via SIRT1 pathway modulation.

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