Unveiling the mechanism of photothermal therapy in acne man-agement: targeting sebaceous gland ferroptosis via umbilical cord mesenchymal stem cell membrane-encapsulated Au-Ag-PDA.

Background: Branched gold and silver nanoparticles coated with polydopamine (Au-Ag-PDA) demonstrate high photothermal conversion efficiency. Utilizing umbilical cord mesenchymal stem cell membranes (MSCM) as an effective drug delivery system, our preliminary studies investigated the suppression of sebum secretion in sebaceous glands using MSCM-coated Au-Ag-PDA nano-particles (Au-Ag-PDA@MSCM) combined with 808 nm laser irradiation, showing potential for dermatological applications in acne treatment. Methods: This study employs proteomic analysis, complemented by subsequent techniques such as Western blotting (WB), small interfering RNA (siRNA), and transmission electron microscopy, to further investigate the differential mechanisms by which Au-Ag-PDA and Au-Ag-PDA@MSCM-mediated photothermal therapy (PTT) suppress sebum secretion. Results: Our proteomic analysis indicated mitochondrial respiratory chain damage in sebaceous gland tissues post-PTT, with further validation revealing ferroptosis in sebaceous cells and tissues. Acyl-CoA Synthetase Long-Chain Family Member 4 (Acsl4) has been identified as a critical target, with Au-Ag-PDA@MSCM demonstrating enhanced ferroptotic effects. Conclusion: These findings significantly advance our understanding of how PTT mediated by Au-Ag-PDA@MSCM nanoparticles reduces sebum secretion and underscore the pivotal role of MSCM in inducing ferroptosis in sebaceous glands, thus providing a robust theoretical foundation for employing PTT via specific molecular pathways in acne treatment.

Hyperosmotic cold shock mouse melanoma cells encapsulated with doxorubicin for targeted treatment of melanoma.

Background: The primary treatment strategies for melanoma include surgical excision, chemotherapy, and radiotherapy. However, the efficacy of these treatments is often limited by drug resistance, recurrence, and severe side effects. Therefore, we aimed to develop a targeted drug delivery system capable of selectively locating tumor sites to minimize systemic toxicity and enhance therapeutic efficacy. This cell drug delivery system can also deliver chemotherapeutic drugs to the tumor microenvironment. Methods: We treated B16F10 cells with hyperosmotic cold shock (HCS) to obtain and characterize HCS cells. We then investigated the anti-tumor effects and immune activation capabilities of these cells and explored their potential as a targeted drug delivery system. Results: HCS cells not only maintained an intact cellular structure and tumor antigens but also exhibited high expression of the homologous melanoma-associated antigen glycoprotein 100. These cells demonstrated an exceptional capacity for loading and releasing doxorubicin, which has chemotherapeutic anti-tumor effects. HCS cells can precisely target the tumor microenvironment to minimize systemic toxicity, inducing an immune response by activating CD3+ and CD4+ T cells. Conclusion: HCS cells are non-carcinogenic, with both cellular and tumor antigens intact; thus, they are suitable drug delivery carriers. Our findings highlight the potential of HCS cells for carrying doxorubicin because of their high drug-loading efficiency, effective tumor-targeting and anti-tumor effects. Therefore, our results will facilitate the development of melanoma treatments that have higher efficacy than those in the literature.

miR-206-3p Targets Brain-Derived Neurotrophic Factor and Affects Postoperative Cognitive Function in Aged Mice.

Postoperative cognitive dysfunction (POCD) occurs after surgery and severely impairs patients' quality of life. Finding POCD-associated variables can aid in its diagnosis and prognostication. POCD is associated with noncoding RNAs, such as microRNAs (miRNAs), involved in metabolic function, immune response alteration, and cognitive ability impairment; however, the underlying mechanisms remain unclear. The aim of this study was to investigate hub miRNAs (i.e., miRNAs that have an important regulatory role in diseases) regulating postoperative cognitive function and the associated mechanisms. Hub miRNAs were identified by bioinformatics, and their expression in mouse hippocampus tissues was determined using real-time quantitative polymerase chain reaction. Hub miRNAs were overexpressed or knocked down in cell and animal models to test their effects on neuroinflammation and postoperative cognitive function. Six differentially expressed hub miRNAs were identified. miR-206-3p was the only broadly conserved miRNA, and it was used in follow-up studies and animal experiments. Its inhibitors reduced the release of proinflammatory cytokines in BV-2 microglia by regulating its target gene, brain-derived neurotrophic factor (BDNF), and the downstream signaling pathways. miR-206-3p inhibition suppressed microglial activation in the hippocampi of mice and improved learning and cognitive decline. Therefore, miR-206-3p significantly affects POCD, implying its potential as a therapeutic target.

Host-microbiota interactions in collagen-induced arthritis rats treated with human umbilical cord mesenchymal stem cell exosome and ginsenoside Rh2.

Mesenchymal stem cell exosome (MSCs-exo) is a class of products secreted by mesenchymal stem cells (MSCs) that contain various biologically active substances. MSCs-exo is a promising alternative to MSCs due to their lower immunogenicity and lack of ethical constraints. Ginsenoside Rh2 (Rh2) is a hydrolyzed component of the primary active substance of ginsenosides. Rh2 has a variety of pharmacological functions, including anti-inflammatory, anti-tumor, and antioxidant. Studies have demonstrated that gut microbiota and metabolites are critical in developing rheumatoid arthritis (RA). In this study, we constructed a collagen-induced arthritis (CIA) model in rats. We used MSCs-exo combined with Rh2 to treat CIA rats. To observe the effect of MSCs-exo combined with Rh2 on joint inflammation, rat feces were collected for 16 rRNA amplicon sequencing and untargeted metabolomics analysis. The results showed that the arthritis index score and joint swelling of CIA rats treated with MSCs-exo in combination with Rh2 were significantly lower than those of the model and MSCs-exo alone groups. MSCs-exo and Rh2 significantly ameliorated the disturbed gut microbiota in CIA rats. The regulation of Candidatus_Saccharibacteria and Clostridium_XlVb regulation may be the most critical. Rh2 enhanced the therapeutic effect of MSCs-exo compared with the MSCs-exo -alone group. Furthermore, significant changes in gut metabolites were observed in the CIA rat group, and these differentially altered metabolites may act as messengers for host-microbiota interactions. These differential metabolites were enriched into relevant critical metabolic pathways, revealing possible pathways for host-microbiota interactions.

Identification of potential biomarkers for aging diagnosis of mesenchymal stem cells derived from the aged donors.

BACKGROUND: The clinical application of human bone-marrow derived mesenchymal stem cells (MSCs) for the treatment of refractory diseases has achieved remarkable results. However, there is a need for a systematic evaluation of the quality and safety of MSCs sourced from donors. In this study, we sought to assess one potential factor that might impact quality, namely the age of the donor. METHODS: We downloaded two data sets from each of two Gene Expression Omnibus (GEO), GSE39035 and GSE97311 databases, namely samples form young (< 65 years of age) and old (> 65) donor groups. Through, bioinformatics analysis and experimental validation to these retrieved data, we found that MSCs derived from aged donors can lead to differential expression of gene profiles compared with those from young donors, and potentially affect the function of MSCs, and may even induce malignant tumors. RESULTS: We identified a total of 337 differentially expressed genes (DEGs), including two upregulated and eight downregulated genes from the databases of both GSE39035 and GSE97311. We further identified 13 hub genes. Six of them, TBX15, IGF1, GATA2, PITX2, SNAI1 and VCAN, were highly expressed in many human malignancies in Human Protein Atlas database. In the MSCs in vitro senescent cell model, qPCR analysis validated that all six hub genes were highly expressed in senescent MSCs. Our findings confirm that aged donors of MSCs have a significant effect on gene expression profiles. The MSCs from old donors have the potential to cause a variety of malignancies. These TBX15, IGF1, GATA2, PITX2, SNAI1, VCAN genes could be used as potential biomarkers to diagnosis aging state of donor MSCs, and evaluate whether MSCs derived from an aged donor could be used for therapy in the clinic. Our findings provide a diagnostic basis for the clinical use of MSCs to treat a variety of diseases. CONCLUSIONS: Therefore, our findings not only provide guidance for the safe and standardized use of MSCs in the clinic for the treatment of various diseases, but also provide insights into the use of cell regeneration approaches to reverse aging and support rejuvenation.

Transcriptome Analysis Reveals Fruit Quality Formation in Actinidia eriantha Benth.

Actinidia chinensis Planch. is a fruit tree originating from China that is abundant in the wild. Actinidia eriantha Benth. is a type of A. chinensis that has emerged in recent years. The shape of A. eriantha is an elongated oval, and the skin is covered with dense, non-shedding milk-white hairs. The mature fruit has flesh that is bright green in colour, and the fruit has a strong flavour and a grass-like smell. It is appreciated for its rich nutrient content and unique flavour. Vitamin C, sugar, and organic acids are key factors in the quality and flavour composition of A. eriantha but have not yet been systematically analysed. Therefore, we sequenced the transcriptome of A. eriantha at three developmental stages and labelled them S1, S2, and S3, and comparisons of S1 vs. S2, S1 vs. S3, and S2 vs. S3 revealed 1218, 4019, and 3759 upregulated differentially expressed genes and 1823, 3415, and 2226 downregulated differentially expressed genes, respectively. Furthermore, the upregulated differentially expressed genes included 213 core genes, and Gene Ontology enrichment analysis showed that they were enriched in hormones, sugars, organic acids, and many organic metabolic pathways. The downregulated differentially expressed genes included 207 core genes, which were enriched in the light signalling pathway. We further constructed the metabolic pathways of sugars, organic acids, and vitamin C in A. eriantha and identified the genes involved in vitamin C, sugar, and organic acid synthesis in A. eriantha fruits at different stages. During fruit development, the vitamin C content decreased, the carbohydrate compound content increased, and the organic acid content decreased. The gene expression patterns were closely related to the accumulation patterns of vitamin C, sugars, and organic acids in A. eriantha. The above results lay the foundation for the accumulation of vitamin C, sugars, and organic acids in A. eriantha and for understanding flavour formation in A. eriantha.

TiO2 nanoparticles promote tumor metastasis by eliciting pro-metastatic extracellular vesicles.

The development of nanotechnology has provided numerous possibilities for the diagnosis and treatment of cancer. Paradoxically, some in vivo experimental studies have also shown that nanoparticles (NPs) could promote tumor progression, but the specific mechanism is not yet clear. Primary tumors can release extracellular vesicles (EVs) which can promote the inoculation and growth of tumor cells that have metastasized to distant organs. So, whether nanomaterials can promote tumor progression through tumor-derived EVs deserves further research. Here, we showed that TiO2 NPs, widely used in nanomedicine, could trigger tumor-derived EVs with enhanced pro-metastatic capacity in vitro and in vivo. Mechanically, miR-301a-3p derived from NPs-elicited EVs could be delivered into vascular endothelial cells, which inhibited the expression of VEGFR2 and VE-cadherin by targeting S1PR1, leading to disrupt the tight junctions of vascular endothelial cells, thus to promote vascular permeability and angiogenesis, and induce the formation of pre-metastasis niches in vivo. This study emphasizes that it is urgent to consider the effect of NPs on EVs under long-term use conditions when designing nanodrugs for cancer treatment.

Exosomes secreted by mesenchymal stem cells delay brain aging by upregulating SIRT1 expression.

The increase in the aging population has seriously affected our society. Neurodegenerative diseases caused by aging of the brain significantly impact the normal life of the elderly, and delaying brain aging is currently the focus of research. SIRT1 is a viable therapeutic target, and there is mounting evidence that it plays a significant role in the aging process. Mesenchymal stem cell-derived exosomes (MSC-Exos) have gained widespread interest as nanotherapeutic agents because of their ability to be injected at high doses to reduce the immune response. The present study focused on the ameliorative effect of MSC-Exos on aging mice and the potential mechanisms of this effect on cognitive impairment and brain aging. In this study, we first tested the neuroprotective effects of MSC-Exos in vitro on H2O2-induced oxidative damage in BV2 cells. An in vivo SAMP8 rapid senescence mouse model showed that MSC-Exos significantly increased SIRT1 gene expression in senescent mice. In addition, MSC-Exos also had an anti-apoptotic effect and reduced oxidative stress in the brains of SAMP8 senescent mice. In conclusion, MSC-Exos may exert neuroprotective effects and help prevent brain senescence in SAMP8 mice by activating the SIRT1 signaling pathway.

Combined surface functionalization of MSC membrane and PDA inhibits neurotoxicity induced by Fe3O4 in mice based on apoptosis and autophagy through the ASK1/JNK signaling pathway.

The extensive utilization of iron oxide nanoparticles in medical and life science domains has led to a substantial rise in both occupational and public exposure to these particles. The potential toxicity of nanoparticles to living organisms, their impact on the environment, and the associated risks to human health have garnered significant attention and come to be a prominent area in contemporary research. The comprehension of the potential toxicity of nanoparticles has emerged as a crucial concern to safeguard human health and facilitate the secure advancement of nanotechnology. As nanocarriers and targeting agents, the biocompatibility of them determines the use scope and application prospects, meanwhile surface modification becomes an important measure to improve the biocompatibility. Three different types of iron oxide nanoparticles (Fe3O4, Fe3O4@PDA and MSCM-Fe3O4@PDA) were injected into mice through the tail veins. The acute neurotoxicity of them in mice was evaluated by measuring the levels of autophagy and apoptosis in the brain tissues. Our data revealed that iron oxide nanoparticles could cause nervous system damage by regulating the ASK1/JNK signaling pathway. Apoptosis and autophagy may play potential roles in this process. Exposure to combined surface functionalization of mesenchymal stem cell membrane and polydopamine showed the neuroprotective effect and may alleviate brain nervous system disorders.

Review of the Pathogenesis, Diagnosis, and Management of Osteoradionecrosis of the Femoral Head.

Osteoradionecrosis (ORN) of the femoral head is an important issue for orthopedists and radiologists in clinical practice. With the rapid development of technological advances in radiation therapy and the improvement in cancer survival rates, the incidence of ORN is rising, and there is an unmet need for basic and clinical research. The pathogenesis of ORN is complex, and includes vascular injury, mesenchymal stem cell injury, bone loss, reactive oxygen species, radiation-induced fibrosis, and cell senescence. The diagnosis of ORN is challenging and requires multiple considerations, including exposure to ionizing radiation, clinical manifestations, and findings on physical examination and imaging. Differential diagnosis is essential, as clinical symptoms of ORN of the femoral head can resemble many other hip conditions. Hyperbaric oxygen therapy, total hip arthroplasty, and Girdlestone resection arthroplasty are effective treatments, each with their own advantages and disadvantages. The literature on ORN of the femoral head is incomplete and there is no criterion standard or clear consensus on management. Clinicians should gain a better and more comprehensive understanding on this disease to facilitate its early and better prevention, diagnosis, and treatment. This article aims to review the pathogenesis, diagnosis, and management of osteoradionecrosis of the femoral head.

Gap26 inhibited angiogenesis through the ß-catenin-VE-cadherin-VEGFR2-Erk signaling pathway.

PURPOSE: To investigate the effect of connexin 43 (Cx43) on corneal neovascularization and its regulation of VEGFR2 on vascular endothelial cells. METHODS: In vivo, we used mouse corneal suture model to induce corneal neovascularization and discovered the function of gap26 in corneal neovascularization. In vitro, the effect of gap26 on HUVEC was observed by cell proliferation, tube formation and scratch experiments. WB and PCR detected the changes in angiogenic protein and mRNA expression. Knockdown of key mRNA in neovascularization using siRNA confirmed that Cx43 regulates neovascularization through the ß-catenin-VE-cadherin-VEGFR2-Erk signaling pathway. RESULTS: In vivo, gap26 can reduce mouse corneal neovascularization. In vitro, we show that Cx43 expression is increased in the presence of VEGFA stimulation, and when we use gap26 to inhibit Cx43 can reduce vascular endothelial cell proliferation, tube formation and migration. We found that the expression of pVEGFR2 and pErk increased in response to VEGFA, while they decreased after using gap26. And the expression of ß-catenin and VE-cadherin decreased in response to VEGFA, while they increased after using gap26. Furthermore, we found that Cx43 regulates angiogenesis through the ß-catenin-VE-cadherin-VEGFR2-Erk pathway. CONCLUSIONS: Gap26 can downregulate VEGFR2 phosphorylation by stabilizing the expression of ß-catenin and VE-cadherin on the cell membrane, thereby inhibiting VEGFA-induced HUVECs proliferation, migration and tube formation and inhibiting corneal neovascularization.

Potential angiogenic, immunomodulatory, and antifibrotic effects of mesenchymal stem cell-derived extracellular vesicles in systemic sclerosis.

Systemic sclerosis (SSc) is an intricate systemic autoimmune disease with pathological features such as vascular injury, immune dysregulation, and extensive fibrosis of the skin and multiple organs. Treatment options are limited; however, recently, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been acknowledged in preclinical and clinical trials as being useful in treating autoimmune diseases and are likely superior to MSCs alone. Recent research has also shown that MSC-EVs can ameliorate SSc and the pathological changes in vasculopathy, immune dysfunction, and fibrosis. This review summarizes the therapeutic effects of MSC-EVs on SSc and the mechanisms that have been discovered to provide a theoretical basis for future studies on the role of MSC-EVs in treating SSc.

Depletion of gut microbiota resistance in 5×FAD mice enhances the therapeutic effect of mesenchymal stem cell-derived exosomes.

Mesenchymal stem cell-derived exosomes (MSCs-exo) can be used for treating Alzheimer's disease (AD) by promoting amyloid-ß (Aß) degradation, modulating immune responses, protecting neurology, promoting axonal growth, and improving cognitive impairment. Increasing evidence suggests that the alteration of gut microbiota is closely related to the occurrence and development of Alzheimer's disease. In this study, we hypothesized that dysbiosis of gut microbiota might limit the therapy of MSCs-exo, and the application of antibiotics would improve the therapy. METHODS: In this original research study, we used MSCs-exo to treat 5 ×FAD mice and fed them antibiotic cocktails for 1 week to detect cognitive ability and neuropathy. The mice's feces were collected to investigate alterations in the microbiota and metabolites. RESULTS: The results revealed that the AD gut microbiota eliminated the therapeutic effect of MSCs-exo, whereas antibiotic modulation of disordered gut microbiota and associated metabolites enhanced the therapeutic effect of MSCs-exo. CONCLUSIONS: These results encourage the research of novel therapeutics to enhance MSCs-exo treatment for AD, which could benefit a broader range of patients with AD.

Effects of magnetically targeted iron oxide@polydopamine-labeled human umbilical cord mesenchymal stem cells in cerebral infarction in mice.

Mesenchymal stem cells are a potential therapeutic candidate for cerebral infarction due to their anti-inflammatory proprieties. However, ensuring the engraftment of sufficient cells into the affected brain area remains a challenge. Herein, magnetic targeting techniques were used for the transplantation of a large number of cells noninvasively. Mice subjected to pMCAO surgery were administered MSCs labeled or not with iron oxide@polydopamine nanoparticles by tail vein injection. Iron oxide@polydopamine particles were characterized by transmission electron microscopy, and labeled MSCs were characterized by flow cytometry and their differentiation potential was assessed in vitro. Following the systemic injection of iron oxide@polydopamine-labeled MSCs into pMCAO-induced mices, magnetic navigation increased the MSCs localization to the brain lesion site and reduced the lesion volume. Treatment with iron oxide@polydopamine-labeled MSCs also significantly inhibited M1 microglia polarization and increased M2 microglia cell infiltration. Furthermore, western blotting and immunohistochemical analysis demonstrated that microtubule-associated protein 2 and NeuN levels were upregulated the brain tissue of mice treated with iron oxide@polydopamine-labeled MSCs. Thus, iron oxide@polydopamine-labeled MSCs attenuated brain injury and protected neurons by preventing pro-inflammatory microglia activation. Overall, the proposed iron oxide@polydopamine-labeled MSCs approach may overcome the major drawback of the conventional MSCs therapy for the treatment of cerebral infarction.

Synergistic treatment of osteosarcoma with biomimetic nanoparticles transporting doxorubicin and siRNA.

Introduction: Osteosarcoma tumors are the most common malignant bone tumors in children and adolescents. Their treatment usually requires surgical removal of all detectable cancerous tissue and multidrug chemotherapy; however, the prognosis for patients with unresectable or recurrent osteosarcoma is unfavorable. To make chemotherapy safer and more effective for osteosarcoma patients, biomimetic nanoparticles (NPs) camouflaged by mesenchymal stem cell membranes (MSCMs) were synthesized to induce osteosarcoma cell apoptosis by co-delivering the anticancer drug doxorubicin hydrochloride(DOX) and a small interfering RNA (siRNA). Importantly, these NPs have high biocompatibility and tumor-homing ability. This study aimed to improve the efficacy of osteosarcoma therapy by using the synergistic combination of DOX and an siRNA targeting the apoptosis suppressor gene survivin. Methods: Biomimetic NPs (DOX/siSUR-PLGA@MSCM NPs) were synthesized by coloading DOX and survivin siRNA (siSUR) into poly (lactide-co-glycolide acid) (PLGA) via a double-emulsion solvent evaporation method. The NPs were camouflaged by MSCMs to deliver both DOX and survivin-targeting siRNA and characterized and evaluated in terms of cellular uptake, in vitro release, in vitro and in vivo antitumor effects, and biosafety. Results: DOX/siSUR-PLGA@MSCM NPs had good tumor-homing ability due to the MSCMs modification. The drug-laden biomimetic NPs had good antitumor effects in homozygous MG63 tumor-bearing mice due to the synergistic effect of the drug combination. Conclusion: DOX/siSUR-PLGA@MSCM NPs can show improved therapeutic effects in osteosarcoma patients due to the combination of a chemotherapeutic drug and gene therapy based on their good tumor targeting and biosafety.

Systemic immune-inflammation index is associated with decreased bone mass density and osteoporosis in postmenopausal women but not in premenopausal women.

Purpose: This study aims to investigate the associations of the systemic immune-inflammation index (SII) with bone mineral density (BMD) and osteoporosis in adult females from a nationally representative sample. Methods: A cross-sectional study was performed among 4092 females aged ≥20 years from the National Health and Nutrition Examination Survey 2007-2010. Linear and logistic regressions were applied to explore the relationships of SII with BMD and the risk of osteoporosis, respectively. Results: Linear regression analyses found that a doubling of SII levels was significantly correlated with a 1.39% (95% CI: 0.57%, 2.20%) decrease in total femur BMD, a 1.16% (95% CI: 0.31%, 2.00%) decrease in femur neck BMD, a 1.73% (95% CI: 0.78%, 2.66%) decrease in trochanter BMD, and a 1.35% (95% CI: 0.50%, 2.20%) decrease in intertrochanteric BMD among postmenopausal women, after adjusting for covariates. Logistic regression analyses showed that compared with postmenopausal women in the lowest SII quartile, those in the highest quartile had higher risks of osteoporosis in the total femur (odds ratio (OR) = 1.70, 95% CI: 1.04, 2.76), trochanter (OR = 1.86, 95% CI: 1.07, 3.38), intertrochanter (OR = 2.01, 95% CI: 1.05, 4.04) as well as overall osteoporosis (OR = 1.57, 95% CI: 1.04, 2.37). In contrast, there was no significant association between SII and BMD in premenopausal women. Conclusions: SII levels were negatively associated with BMD levels in postmenopausal women but not in premenopausal women. Elevated SII levels could be a potential risk factor for osteoporosis in postmenopausal women.

Minoxidil delivered via a stem cell membrane delivery controlled release system promotes hair growth in C57BL/6J mice.

Objective: Umbilical cord-derived mesenchymal stem cell membrane-loaded minoxidil (MXD) nanoparticles (STCM-MXD-NPs) were prepared to investigate their effects on hair growth in C57BL/6J mice. Methods: STCM-MXD-NPs were obtained by freeze-thawing and differential centrifugation, and their effects on hair growth were evaluated using C57BL/6J mice. The mRNA and protein expression levels of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) were detected by real-time polymerase chain reaction and enzyme-linked immunosorbent assays, respectively. Protein expression levels of marker of proliferation Ki-67 (MKI67) and ß-catenin (CTNNB) in skin tissue were detected by immunohistochemistry. Results: STCM-MXD-NPs improved MXD solubility. They released the drug slowly, increasing its transdermal properties, accumulation in the skin, and content in the hair bulb tissues with a better efficacy than that of ordinary MXD. Moreover, STCM-MXD-NPs significantly upregulated the mRNA and protein levels of VEGF and IGF-1 and promoted the protein expression of MKI67 and CTNNB in mouse skin tissues, promoting mouse hair growth. Conclusion: Stem cell membrane-loaded MXD nanoparticles with slow-release properties increased MXD accumulation in the skin by improving its transdermal properties, increasing VEGF, IGF-1, MKI67, and CTNNB expression levels and promoting hair growth in C57BL/6J mice.