α-Catenin promotes dermal fibroblasts proliferation and migration during wound healing via FAK/YAP activation.

Skin wound healing is a complex and organized biological process, and the dermal fibroblasts play a crucial role. α-Catenin is known to be involved in regulating various cellular signals, and its role in wound healing remains unclear. Here, we have identified the pivotal role of the α-catenin/FAK/YAP signaling axis in the proliferation and migration of dermal fibroblasts, which contributes to the process of skin wound healing. Briefly, when α-catenin was knocked down specifically in dermal fibroblasts, the wound healing rate is significantly delayed. Moreover, interfering with α-catenin can impede the proliferation and migration of dermal fibroblasts both in vitro and in vivo. Mechanistically, the overexpression of α-catenin upregulates the nuclear accumulation of YAP and transcription of downstream target genes, resulting in enhanced the proliferation and migration of dermal fibroblasts. Furthermore, the FAK Tyr397 phosphorylation inhibitor blocked the promoting effects of α-catenin on YAP activation. Importantly, the continuous phosphorylation mutation of FAK Tyr397 reversed the retardatory effects of α-catenin knockdown on wound healing, by increasing the vitality of fibroblasts. Likewise, α-catenin/FAK was validated as a therapeutic target for wound healing in the db/db chronic trauma model. In summary, our findings have revealed a novel mechanism by which α-catenin facilitates the function of fibroblasts through the activity of the FAK/YAP signaling axis. These findings define a promising therapeutic strategy for accelerating the wound healing process.

Fibroblast growth factor 10 protects against UVB-induced skin injury by activating the ERK/YAP signalling pathway.

OBJECTIVES: Ultraviolet light B (UVB) irradiation can induce skin injury and result in keratinocytes proliferation inhibition. However, the molecular understanding of the repair during UVB-induced cell proliferation inhibition remains poorly understood. The purpose of this study was to explore the role and potential mechanism of FGF10 in promoting keratinocytes cell cycle and proliferation after UVB injury. MATERIALS AND METHODS: Expression of FGF10 protein was analysed in skin treated with UVB radiation by immunohistochemistry. The proliferation potential was examined by Immunofluorescence, Western Blot and RT-PCR under UVB radiation, treated with FGF10 protein or overexpression of FGF10 using adeno-associated virus. CCK8 kit was used to further detect cell proliferation ability. RESULTS: We found that FGF10 is highly expressed in skin treated with UVB. Overexpression of FGF10 has a protective effect against UVB-induced skin damage by balancing epidermal thickness and enhancing epidermal keratinocytes proliferation. Importantly, FGF10 is found to alleviate UVB-induced downregulation of YAP activity, then promoting keratinocytes proliferation. Disruption of YAP function, either with the small molecule YAP inhibitor Verteporfin (VP) or YAP small-interfering RNA (siRNA), largely abolishes the protective activity of FGF10 on epidermal keratinocytes proliferation. Meanwhile, disruption of ERK kinase (MEK) activity with U0126 or ERK siRNA hinder the positive influence of FGF10 on UVB-induced skin injury. CONCLUSION: FGF10 promotes epidermal keratinocytes proliferation during UVB-induced skin injury in an ERK/YAP-dependent manner.

Suppression of Cutibacterium acnes-Mediated Inflammatory Reactions by Fibroblast Growth Factor 21 in Skin.

Cutibacterium acnes (C. acnes) is a common commensal bacterium that is closely associated with the pathogenesis of acne. Fibroblast growth factor 21 (FGF21), as a favorable regulator of glucose and lipid metabolism and insulin sensitivity, was recently shown to exert anti-inflammatory effects. The role and mechanism of FGF21 in the inflammatory reactions induced by C. acnes, however, have not been determined. The present study shows that FGF21 in the dermis inhibits epidermal C. acnes-induced inflammation in a paracrine manner while it functions on the epidermal layer through a receptor complex consisting of FGF receptor 1 (FGFR1) and ß-Klotho (KLB). The effects of FGF21 in heat-killed C. acnes-induced HaCaT cells and living C. acnes-injected mouse ears were examined. In the presence of C. acnes, FGF21 largely counteracted the activation of Toll-like receptor 2 (TLR2), the downstream nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways induced by C. acnes. FGF21 also significantly reduced the expression of proinflammatory cytokines, including interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor (TNF)-α. Taken together, these findings indicate that FGF21 suppresses C. acnes-induced inflammation and might be used clinically in the management and treatment of acne.

Modulation of phase transition of thermosensitive liposomes with leucine zipper-structured lipopeptides.

Targeted therapy for cancer requires thermosensitive components in drug carriers for controlled drug release against viral cells. The conformational transition characteristic of leucine zipper-structured lipopeptides is utilized in our lab to modulate the phase transition temperature of liposomes, thus achieving temperature-responsive control. In this study, we computationally examined the conformational transition behaviors of leucine zipper-structured lipopeptides that were modified at the N-terminus by distinct functional groups. The conformational transition temperatures of these lipopeptides were determined by structural analysis of the implicit-solvent replica exchange molecular dynamics simulation trajectories using the dihedral angle principal component analysis and the dictionary of protein secondary structure method. Our calculations revealed that the computed transition temperatures of the lipopeptides are in good agreement with the experimental measurements. The effect of hydrogen bonds on the conformational stability of the lipopeptide dimers was examined in conventional explicit-solvent molecular dynamics simulations. A quantitative correlation of the degree of structural dissociation of the dimers and their binding strength is well described by an exponential fit of the binding free energies to the conformation transition temperatures of the lipopeptides.

Computational insights into the destabilization of α-helical conformations formed by leucine zipper peptides in response to temperature.

Recent experiments in our lab (Phys. Chem. Chem. Phys., 2016, 18, 10129-10137) suggested using leucine zipper peptides to enhance the thermosensitivity of liposomes. To understand the mechanisms of temperature-responsive control by the leucine zipper peptide in liposomes, we firstly performed quantum mechanics calculations and implicit-solvent replica exchange molecular dynamics simulations to study the thermo-stability of two leucine zipper peptides, CH3(CH2)4-CO-[VAQLEVK-VAQLESK-VSKLESK-VSSLESK] (termed the capped peptide) and A-[VAQLEVK-VAQLESK-VSKLESK-VSSLESK] (termed the ALA peptide). The analysis of dihedral angle principal components and protein secondary structures was conducted to determine the temperature-dependence conformation transition of the two peptides. Simulation results revealed that our computed transition temperature of the capped peptide is 319.1 K that accords with experimental measurement, 321.1 K. Later, explicit-solvent conventional molecular dynamics simulations were carried out to examine the process of folding and unfolding of the ALA and capped peptides complexed with a lipid bilayer and water in the vicinity of their transition temperatures. A further analysis of conformation and energy of the folded peptides showed that the increase of temperature gives rise to a notable decrease in the number of intra-chain hydrogen bonds and a significant increase in the potential energy of the peptides, thereby reducing the folding stability of the two peptides. As compared to the ALA peptide, a lower transition temperature caused by less intra-chain hydrogen bonds was observed in the capped peptide, which is closer to the temperature of tumor cells. This fact suggests that the capped peptide is more suitable to produce highly sensitive liposomes for the delivery of cancer drugs.