Skin wounds are common in accidental injuries, and the intricacies of wound repair are closely linked to endogenous electric fields. Electrical stimulation plays a pivotal role in the restorative processes of skin injuries, encompassing collagen deposition, angiogenesis, inflammation, and re-epithelialization. Employing electrical stimulation therapy replicates and enhances the effects of endogenous wound electric fields by applying an external electric field to the wound site, thereby promoting skin wound healing. In this study, we developed a self-powered repetitive mechanical impacts-electrical stimulation (RMI-ES) system utilizing a BaTiO₃/polydimethylsiloxane (PDMS) piezoelectric composite film. Compared to conventional electrical stimulation devices, the fabricated piezoelectric composite film efficiently harvests energy from the pressure applied by the stimulation device and the tensile force occurring during natural rat activities. The results demonstrated that piezoelectric stimulation generated by the composite membrane expedited the cell cycle, promoting fibroblast proliferation. Additionally, piezoelectric stimulation induced favorable changes in fibroblast gene expression, including increased expression of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), collagen 1, collagen 3, vascular endothelial growth factor (VEGF), and alpha-smooth muscle actin (α-SMA), while reducing interleukin-6 (IL-6) expression. Transcriptome analysis revealed that piezoelectric stimulation may induce fibroblast migration, proliferation, and collagen expression by influencing PI3K/AKT serine/threonine kinase (AKT) pathways. Further confirmation through the addition of the PI3K inhibitor LY294002 validated that piezoelectric stimulation can regulate the repair process after skin injury through the pathway. Importantly, in vivo results demonstrated that the electric field at the wound site effectively promoted wound healing, reduced inflammation, and stimulated collagen deposition and neovascularization. This study emphasizes the role of the piezoelectric membrane as an effective, safe, and battery-free electrical stimulator crucial for skin wound healing.

TGFβ1 signaling is a critical driver of collagen accumulation in pulmonary fibrotic diseases and a well-characterized regulator of cancer associated fibroblasts (CAF) activation in lung cancer. Myofibroblasts induced by TGFβ1 and other factors are key players in the pathogenesis of lung fibrosis and tumor. Tremendous attention has been gained to targeting myofibroblasts in order to inhibit the progression of fibrosis and myofibroblast-induced tumor progression and metastasis. Here we determined the therapeutic efficacy of simultaneously targeting PI3K and HDAC pathways in lung myofibroblasts and CAF with a single agent and to evaluate biomarkers of treatment response. CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and PI3K/AKT pathway. We investigated its effects in counteracting the activity of TGFβ1-induced myofibroblasts/CAF in regard to cell proliferation, migration, invasion, apoptosis in vitro antifibrosis efficiency in vivo. We found that CUDC-907 inhibited myofibroblasts/CAF cell proliferation, migration and apoptosis in a dose-dependent manner and caused cell cycle arrest at G1-S phase. CUDC-907 not only inhibited myofibroblasts markers expression, but also significantly inhibited the phosphorylation level of AKT, mTOR, Smad2/3, and promoted acetylation of histones. Furthermore, the observed inhibitory effect was also confirmed in bleomycin-induced mice lung fibrosis and nude mouse transplanted tumor model. Overall, these data suggest that dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for TGFβ1-induced lung and tumor fibrosis.

A wide range of therapeutic options exists for the treatment of keloids, all of which have their own strengths; however, a high risk of side‑effects and frequent recurrence remains. Therefore, the present study aimed to identify improved therapeutic approaches or drugs for the treatment of keloids. Ginsenoside Rg3 (Rg3) has been reported to exert numerous antitumor effects, thus indicating that Rg3 may be a potential therapeutic agent that targets keloids. The present study determined the effects of Rg3 on human keloid fibroblasts (KFs) in vitro, and further explored the associated molecular and cellular mechanisms. Keloid scar specimens were obtained from patients, aged between 22 and 35 years, without systemic diseases and primary cells were isolated from keloid tissues. In each assay, KFs were divided into three groups and were cultured in medium with or without various concentrations of Rg3 (50 or 100 µg/ml). Cell viability assay, flow cytometry, quantitative polymerase chain reaction, cell migration assay, immunofluorescence staining, western blot analysis, Transwell cell invasion assay and immunohistochemical analysis were used to analyze the KFs and keloid explant cultures. The results of the present study demonstrated that Rg3 was able to exert an inhibitory effect on the transforming growth factor‑β/Smad and extracellular signal‑regulated kinase signaling pathways in KFs. The proliferation, migration, invasion, angiogenesis and collagen synthesis of KFs were markedly suppressed following treatment with Rg3. Furthermore, the results of an ex vivo assay indicated that Rg3 inhibited angiogenesis and reduced collagen accumulation in keloids. Significant statistical differences existed between the control and Rg3‑treated groups (P<0.05). All of these experimental results suggested that Rg3 may serve as a reliable drug for the treatment of patients with keloids.

Keloids are benign skin tumors with a high recurrence rate following surgical excision. Abnormal intracellular signaling is one of the key mechanisms involved in its pathogenesis. Over‑activated phosphoinositide 3‑kinase/RAC‑alpha serine/threonine‑protein kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway and overproduction of histone deacetylases 2 (HDAC2) have also been observed in keloid fibroblasts (KFs). The present study aimed to explore the possibility of reversing the KF pathological phenotype using CUDC‑907, a dual inhibitor of PI3K/Akt/mTOR pathway and HDACs. KFs and keloid xenografts were treated with CUDC‑907 to examine its inhibitory effects on the pathological activities of KFs in vitro and in vivo. CUDC‑907 inhibited cell proliferation, migration, invasion and extracellular matrix deposition of in vitro cultured KFs and also suppressed collagen accumulation and disrupted the capillaries of keloid explants ex vivo and in vivo. A mechanistic study of CUDC‑907 revealed the initiation of cell cycle arrest at G2/M phase along with the enhanced expression of cyclin‑dependent kinase inhibitor 1 and decreased expression of cyclin B in cells treated with CUDC‑907. CUDC‑907 not only inhibited AKT and mTOR phosphorylation and promoted the acetylation of histone H3, but also significantly inhibited the phosphorylation levels of Smad2/3 and Erk. These preclinical data demonstrating its anti‑keloid effects suggest that CUDC‑907 may represent a candidate drug for systemic keloid therapy.