Patient-derived organoids in human cancer: a platform for fundamental research and precision medicine.

Cancer is associated with a high degree of heterogeneity, encompassing both inter- and intra-tumor heterogeneity, along with considerable variability in clinical response to common treatments across patients. Conventional models for tumor research, such as in vitro cell cultures and in vivo animal models, demonstrate significant limitations that fall short of satisfying the research requisites. Patient-derived tumor organoids, which recapitulate the structures, specific functions, molecular characteristics, genomics alterations and expression profiles of primary tumors. They have been efficaciously implemented in illness portrayal, mechanism exploration, high-throughput drug screening and assessment, discovery of innovative therapeutic targets and potential compounds, and customized treatment regimen for cancer patients. In contrast to conventional models, tumor organoids offer an intuitive, dependable, and efficient in vitro research model by conserving the phenotypic, genetic diversity, and mutational attributes of the originating tumor. Nevertheless, the organoid technology also confronts the bottlenecks and challenges, such as how to comprehensively reflect intra-tumor heterogeneity, tumor microenvironment, tumor angiogenesis, reduce research costs, and establish standardized construction processes while retaining reliability. This review extensively examines the use of tumor organoid techniques in fundamental research and precision medicine. It emphasizes the importance of patient-derived tumor organoid biobanks for drug development, screening, safety evaluation, and personalized medicine. Additionally, it evaluates the application of organoid technology as an experimental tumor model to better understand the molecular mechanisms of tumor. The intent of this review is to explicate the significance of tumor organoids in cancer research and to present new avenues for the future of tumor research.

The antiferroptotic role of TRIM7: Molecular mechanism and synergistic effect with temozolomide.

Nuclear receptor coactivator 4 (NCOA4) protein is a selective cargo receptor that plays a crucial role in ferritinophagy by targeting and delivering the ferritin iron storage protein to lysosomes for degradation and releasing iron. TRIM7 overexpression inhibits ferroptosis in glioblastoma cells by ubiquitinating NCOA4 protein.

Targeting the ferroptosis crosstalk: novel alternative strategies for the treatment of major depressive disorder.

Depression is a major contributor to poor global health and disability, with a recently increasing incidence. Although drug therapy is commonly used to treat depression, conventional antidepressant drugs have several disadvantages, including slow onset, low response rates and severe adverse effects. Therefore, developing effective therapies for depression remains challenging. Although various aetiological theories of depression exist, the underlying mechanisms of depression are complex, and further research is crucial. Moreover, oxidative stress (OS)-induced lipid peroxidation has been demonstrated to trigger ferroptosis. Both OS and ferroptosis are pivotal mechanisms implicated in the pathogenesis of neurological disorders, and investigation of the mediators involved in these processes has emerged as a prominent and active research direction. One previous study revealed that regulatory proteins involved in ferroptosis are implicated in the pathogenesis of depression, and antidepressant drugs could reverse depressive symptoms by inhibiting ferroptosis in vivo, suggesting an important role of ferroptosis in the pathogenesis of depression. Hence, our current comprehensive review offers an up-to-date perspective on the intricate mechanisms involved, specifically concerning ferroptosis and OS in the context of depression, along with promising prospects for using molecular mediators to target ferroptosis. We delineate the key targets of molecular mediators involved in OS and ferroptosis implicated in depression, most notably reactive oxygen species and iron overload. Considering the pivotal role of OS-induced ferroptosis in the pathogenesis of neurological disorders, delving deeper into the underlying subsequent mechanisms will contribute significantly to the identification of novel therapeutic targets for depression.

Albumin-bound paclitaxel augment temozolomide treatment sensitivity of glioblastoma cells by disrupting DNA damage repair and promoting ferroptosis.

BACKGROUND: Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) patients has been limited by resistance in the clinic. Currently, there are no clinically proven therapeutic options available to restore TMZ treatment sensitivity. Here, we investigated the potential of albumin-bound paclitaxel (ABX), a novel microtubule targeting agent, in sensitizing GBM cells to TMZ and elucidated its underlying molecular mechanism. METHODS: A series of in vivo and in vitro experiments based on two GBM cell lines and two primary GBM cells were designed to evaluate the efficacy of ABX in sensitizing GBM cells to TMZ. Further proteomic analysis and validation experiments were performed to explore the underlying molecular mechanism. Finally, the efficacy and mechanism were validated in GBM patients derived organoids (PDOs) models. RESULTS: ABX exhibited a synergistic inhibitory effect on GBM cells when combined with TMZ in vitro. Combination treatment of TMZ and ABX was highly effective in suppressing GBM progression and significantly prolonged the survival oforthotopic xenograft nude mice, with negligible side effects. Further proteomic analysis and experimental validation demonstrated that the combined treatment of ABX and TMZ can induce sustained DNA damage by disrupting XPC and ERCC1 expression and nuclear localization. Additionally, the combination treatment can enhance ferroptosis through regulating HOXM1 and GPX4 expression. Preclinical drug-sensitivity testing based on GBM PDOs models confirmed that combination therapy was significantly more effective than conventional TMZ monotherapy. CONCLUSION: Our findings suggest that ABX has the potential to enhance TMZ treatment sensitivity in GBM, which provides a promising therapeutic strategy for GBM patients.

Transcription factor CASZ1 increases an oncogenic transcriptional process in tumorigenesis and progression of glioma cells.

As a transcription factor, the role of CASZ1 in different entities is inconsistent. Glioma is one of the leading causes of cancer death worldwide. Its prognostic relevance and biological functions in glioma remain obscure. We focused on the role, mechanism, and prognostic value of CASZ1 in glioma cells. Herein, CASZ1 was identified as a novel potential oncogene in glioma tissues from GEO and TCGA datasets. CASZ1 was highly expressed in glioma tissues, predicting poor prognosis in glioma patients. Knockdown of CASZ1 inhibited proliferation and invasion in vitro, whereas upregulation of CASZ1 presented opposite results. Overexpression of CASZ1 increased transcriptional process of target gene p75NTR. CASZ1 was the potential transcriptional regulators for p75NTR. In addition, the p75NTR expression is essential for CASZ1 to exert its function as an oncogene. Our findings indicate that highly expressed CASZ1 in glioma cells acts as a pro-oncogene factor in gliomas via regulating transcriptional process of target gene p75NTR, which was identified as an unfavorable prognostic marker in patients with gliomas. CASZ1 is expected to become a novel target for the treatment of gliomas.

An integrated analysis of C5AR2 related to malignant properties and immune infiltration of gliomas.

Background: C5AR2 is recognized as a proinflammatory molecule and activates the inflammatory response in multiple disorders. However, little has been reported on C5AR2 in glioma. This study sought to explore its expression, biological function, and association with clinical pathological indicators, prognosis, and immune infiltration levels in glioma through glioma cohorts. Methods: A cohort of 657 patients was screened from the Chinese Glioma Genome Atlas (CGGA). χ 2 test was performed to calculate the difference of classified variables. Cox proportional hazard regression modeling was used to identify independent prognostic indicators of glioma patients. A survival plot was generated by the Kaplan-Meier method. The immune cell infiltration score of glioma patients was calculated by TIMER algorithm. Results: We observed that high expression of C5AR2 was strongly associated with malignant clinical indicators in 657 patients with glioma, and patients with high C5AR2 expression had worse prognoses. Multivariate Cox analysis showed that C5AR2 could be a new independent prognostic indicator for glioma patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that C5AR2 overexpression correlated with multiple inflammatory and immune biological processes. Additionally, high C5AR2 expression was strongly associated with higher abundance and marker gene expression of multiple tumor immune cells in low-grade glioma. Finally, a model was constructed to improve the prognostic evaluation of glioma patients. Conclusions: The C5AR2 gene is highly expressed in gliomas and is significantly associated with clinical indicators of malignant progression in glioma patients. In glioma, patients with high C5AR2 expression displayed a worse outcome. In glioma tissues, the expression level of C5AR2 highly correlated with the abundance of tumor immune cell infiltration. Additionally, GO and KEGG enrichment analysis revealed that C5AR2 expression may be involved in a variety of immune and inflammatory biological processes.

Clinical Studies on Platelet-Rich Plasma Therapy for Chronic Cutaneous Ulcers: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Significance: Platelet-rich plasma (PRP) may be a potential drug for treatment of chronic refractory ulcers, which increase the risk of systemic infection and local canceration. However, the efficacy and safety of clinical application of PRP are still controversial. Thus, this study was aimed to assess the efficacy and safety of PRP in patients with chronic ulcers. Recent Advances: For this meta-analysis, Cochrane's Library, MEDLINE, EMBASE, PubMed, Web of Science, and CINAHL (Cumulate Index to Nursing and Allied Health Literature) databases were searched. Results were pooled using a random-effects model. The primary outcome was the proportion of completely healed chronic ulcers. Critical Issues: Seventeen randomized controlled trials were included. Compared with the control group, PRP significantly increased the fraction of healed ulcers (pooled risk ratio [RR] = 1.50; 95% confidence interval [CI] = 1.20 to 1.87; I2 = 47.8%). In autologous PRP (APRP) and homologous PRP (HPRP) subgroups, there were statistical differences between the control group versus treatment subgroup (pooled RR = 1.30, 95% CI = 1.10 to 1.54, I2 = 25.7%; pooled RR = 3.53, 95% CI = 1.94 to 6.43, I2 = 0.0%, respectively). In terms of percent of chronic ulcers area healed, there was a statistically significant difference between the PRP-treated group versus the control group (standard mean difference [SMD] = 1.37, 95% CI = 0.91 to 1.82, I2 = 22.1%). As for PRP safety, there existed a statistically significant difference between the APRP subgroup and the HPRP subgroup, respectively (pooled RR = 0.58; 95% CI = 0.35 to 0.98; I2 = 0.0%) and (pooled RR = 4.12; 95% CI = 1.55 to 10.96; I2 = 6.8%). Future Directions: Our findings shows that PRP may be a beneficial treatment of chronic skin ulcers and that APRP may be much safer than HPRP.

EVA1C Is a Potential Prognostic Biomarker and Correlated With Immune Infiltration Levels in WHO Grade II/III Glioma.

Background: Immunotherapy is an effective therapeutic approach for multiple human cancer types. However, the correlations between EVA1C and patients' prognosis as well as immune infiltration remain obscure. Herein, we employed transcriptomic and clinical data extracted from two independent databases to systematically investigate the role of EVA1C in the oncological context. Methods: The differential expression of EVA1C was analyzed via TCGA and Oncomine databases. We evaluated the influence of EVA1C on clinical prognosis using Kaplan-Meier plotter. We then used the expression profiler to calculate stromal score, immune score, and ESTIMATE score based on the ESTIMATE algorithm. The abundance of infiltrating immune cells was calculated via TIMER. The correlations between EVA1C expression and immune infiltration levels were analyzed in two independent cohorts. Results: In patients with World Health Organization (WHO) grade II/III glioma, high EVA1C expression was associated with malignant clinicopathological features and poor overall survival in both cohorts. EVA1C expression was positively associated with immune infiltration levels of B cell, CD4+ T cell, neutrophil, macrophage, and dendritic cells (DCs). Besides, EVA1C expression strongly correlated with diverse immune marker sets. And the predictive power of EVA1C was better than that of other indicators in predicting high immune infiltration levels in glioma. Conclusions: For the first time, we identified the overexpression of EVA1C in glioma, which was tightly correlated with the high infiltration levels of multiple immune cells as well as poor prognosis. Meanwhile, EVA1C might be a potential biomarker for predicting high immune infiltration in WHO grade II/III gliomas.

EVA1B to Evaluate the Tumor Immune Microenvironment and Clinical Prognosis in Glioma.

Background: Previous research indicated that the tumor cells and microenvironment interactions are critical for the immunotherapeutic response. However, predicting the clinical response to immunotherapy remains a dilemma for clinicians. Hence, this study aimed to investigate the associations between EVA1B expression and prognosis and tumor-infiltrating immune cells in glioma. Methods: Firstly, we detected the EVA1B expression in glioma tissues through biological databases. The chi-squared test, Kaplan-Meier, and univariate and multivariate Cox regression analyses were used to analyze the clinical significance of EVA1B expression. The correlation between EVA1B expression and levels of tumor-infiltrating immune cells in glioma tissues was investigated. Receiver operating characteristic (ROC) analysis was performed to compare the predictive power between EVA1B and other commonly immune-related markers. Results: In the CGGA cohort of 325 glioma patients, we found that EVA1B was upregulated in glioma, and increased with tumor grade. High EVA1B expression was prominently associated with unfavorable clinicopathological features, and poorer survival of patients, which were further confirmed by TCGA (n=609) and GEO (n=74) cohorts. Furthermore, multivariate analysis indicated that EVA1B is an independent prognostic biomarker for glioma. Importantly, EVA1B overexpression was associated with a higher infiltration level of CD4+ T cells, CD8+ T cells, B cells, macrophages, and neutrophils in glioma. ROC curves showed that, compared with PD-L1, CTLA-4, and Siglec15, EVA1B presented a higher area under the curve (AUC) value (AUC=0.824) for predicting high immune infiltration levels in glioma. Conclusions: We found that EVA1B was upregulated and could act as a poor prognostic biomarker in glioma. Importantly, EVA1B overexpression was associated with the immune infiltration levels of immune cells including B cells, CD4+ T cells, CD8+ T cells, macrophages, and neutrophils, and strongly with the overall immune infiltration levels of glioma. These findings suggested that EVA1B might be a potential biomarker for evaluating prognosis and immune infiltration in glioma.

Upregulation of hsa-miR-196a-5p is associated with MIR196A2 methylation and affects the malignant biological behaviors of glioma.

Hsa-miR-196a-5p is involved in tumorigenesis and progression. However, the driving factors for hsa-miR-196a-5p overexpression and its correlation with the clinicopathological features and prognosis of patients remain unclear in glioma. Thus, this study aimed to investigate the prognostic value of hsa-miR-196a-5p and its correlation with MIR196A2 methylation in glioma. We observed that hsa-miR-196a-5p expression was upregulated in glioma. Next, 112 patients were divided into high (n = 56) and low (n = 56) hsa-miR-196a-5p expression groups. The chi-square test showed that hsa-miR-196a-5p expression was significantly related to age, WHO grade, histopathology, IDH mutation status, and 1p/19q codeletion. Univariate and multivariate Cox regression analyses showed that hsa-miR-196a-5p expression was an independent prognostic factor. GO and KEGG enrichment analyses showed that hsa-miR-196a-5p may be involved in the MAPK signaling, focal adhesion and cancer-related pathways. Compared with the normal astrocyte cell line, glioma cell lines had an unregulated MIR196A2 methylation level, which was confirmed by TCGA data. The hypermethylated CpG sites of MIR196A2 were mainly concentrated in the gene body region, which was significantly associated with hsa-miR-196a-5p overexpression. Kaplan-Meier curves revealed that MIR196A2 hypermethylation was a poor prognostic factor. These findings suggest that hsa-miR-196a-5p overexpression may be involved in malignant biological behaviors, and MIR196A2 hypermethylation of the gene body was significantly associated with hsa-miR-196a-5p overexpression, which was a poor prognostic factor of glioma. Therefore, MIR196A2 hypermethylation may act as an early marker of prognosis of patients with glioma.

N6-methyladenine-related genes affect biological behavior and the prognosis of glioma.

BACKGROUND: Although aberrant expression of N6-methyladenine (m6 A) methylation-related genes contribute to tumorigenesis in many solid tumors, the prognostic value of the m6 A-related genes and their correlation with clinicopathological features in gliomas need advanced study. METHODS: The clinical and sequencing data of 288 patients with glioma were extracted from Chinese Glioma Genome Atlas database. By univariate and multivariable Cox regression analysis, the m6 A-related prognostic genes were identified, and their correlation with clinicopathological features was further analysis. A nomogram was constructed by R software and the performance of it was assessed by calibration and time-dependent receiver operating characteristic curve. RESULTS: Nine m6 A-related genes were identified as independent prognostic factors, which were mostly enriched in RNA splicing, regulation of immune response and vesicle-mediated transport. By expression value and regression coefficient of these genes, we constructed risk score of each patient, which was highly associated with clinicopathological features. Kaplan-Meier curve showed that the prognosis of patients with high-risk scores was significantly worse than that with low-risk scores (HR = 4.30, 95% CI = 3.16-5.85, p < 0.0001). A nomogram was constructed based on the nine m6 A-related genes signature and clinicopathological features with well-fitted calibration curves (c-index = 0.82), showing high specificity and sensitivity (area under the curve for 1-, 3-, and 5-years survival probability = 0.874, 0.918, and 0.934). CONCLUSIONS: A nine m6 A-related genes signature was identified in gliomas. The m6 A-related risk score is a novel prognostic factor for patients with glioma, and is associated with clinicopathological features. Moreover, the nomogram based on the nine m6 A-related genes signature and clinicopathological features had good efficacy in predicting the survival probability.

Upregulated Histone Deacetylase 6 Associates with Malignant Progression of Melanoma and Predicts the Prognosis of Patients.

BACKGROUND: Melanoma is the most malignant tumor among skin tumors, and its morbidity and mortality are increasing year by year. Although melanoma biology has been increasingly studied, no prognostic biomarkers have yet been incorporated into clinical protocols. Histone deacetylase 6 (HDAC6) has been shown to act as a prognostic biomarker in several cancers. Here, we aimed to investigate the predictive value of HDAC6 for the prognosis of cutaneous melanoma patients. METHODS: Eighty cutaneous melanoma patients were enrolled in this study. The protein and mRNA expression levels of HDAC6 were detected, and the clinical features and survival time of cutaneous melanoma patients with HDAC6 expression were analyzed. RESULTS: The results suggested that high HDAC6 expression was significantly associated with unfavorable clinicopathological features. High HDAC6 expression was related to melanoma metastasis and was also associated with a reduced survival time in melanoma patients, and this association remained significant in multivariate analysis adjusted for all other factors. CONCLUSION: These findings validate the utility of HDAC6 expression as an independent biomarker for the prognostication of patients with cutaneous melanoma.

Screening of autophagy genes as prognostic indicators for glioma patients.

Although autophagy is reported to be involved in tumorigenesis and cancer progression, its correlation with the prognosis of glioma patients remains unclear. Thus, the aim of this study was to identify prognostic autophagy-related genes, analyze their correlation with clinicopathological features of glioma, and further construct a prognostic model for glioma patients. After 139 autophagy-related genes were obtained from the GeneCards database, their expression data in glioma patients were extracted from the Chinese Glioma Genome Atlas database. Univariate and multivariate COX regression analyses were performed to identify prognostic autophagy-related genes. Ten hub autophagy-related genes associated with prognosis were identified. The autophagy risk score (ARS) was only positively correlated with histopathology (P = 0.000) and World Health Organization grade (P = 0.000). Kaplan-Meier analysis showed that the overall survival of patients with a high ARS was significantly worse than that of patients with a low ARS (hazard ratio = 1.59, 95% confidence interval = 1.25-2.03, P = 0.0001). In addition, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed several common biological processes and signaling pathways related to the 10 hub genes in glioblastoma. A prediction model was developed for glioma patients, which demonstrated high prediction efficiency on calibration. Moreover, the area under the receiver operating characteristic curve values for 1-, 3- and 5-year survival probabilities were 0.790, 0.861, and 0.853, respectively. In conclusion, we identified 10 autophagy-related genes that can serve as novel prognostic biomarkers for glioma patients. Our prediction model accurately predicted patient outcomes, and thus, may be a valuable tool in clinical practice.

Effect of Piezo1 Overexpression on Peritumoral Brain Edema in Glioblastomas.

BACKGROUND AND PURPOSE: Previous studies have suggested that increased mortality and disability in patients with brain tumor are associated with peritumoral brain edema. However, the mechanism of peritumoral brain edema in brain tumors is unknown. This study aimed to investigate the effect of Piezo1 overexpression on peritumoral brain edema in glioblastomas. MATERIALS AND METHODS: The Piezo1 expression in cell lines and paired samples was detected by quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry. Sixty-four patients with glioblastomas were analyzed retrospectively. The Piezo1 expression of tumor tissue was detected by immunohistochemistry. The diameters of tumor and edema were measured by preoperative MR imaging, and the edema index value was calculated. RESULTS: Western blot and quantitative reverse transcription polymerase chain reaction showed that Piezo1 expression was higher in 6 glioma cell lines than in the normal astrocyte cell line. Compared with peritumoral tissues, Piezo1 was up-regulated in tumor tissues. Sixty-four patients with glioblastomas were enrolled in further study. Piezo1 was higher in the moderate edema group than in the mild edema group (P < .001), higher in the severe edema group than in the moderate edema group (P < .001), and correlated with the edema index (r = 0.73; P < .001). Receiver operating characteristic curve analysis showed that the edema index yielded an area under the curve of 0.867 (95% CI, 0.76-0.97; P < .001), with a sensitivity of 100% and a specificity of 70%. CONCLUSIONS: Piezo1 overexpression is positively correlated with the degree of peritumoral brain edema in glioblastomas. Predicting high Piezo1 expression in tumor tissues based on the edema extent shows good sensitivity and specificity.

Upregulation of Piezo1 Is a Novel Prognostic Indicator in Glioma Patients.

PURPOSE: Previous study reported that Piezo1 was highly expressed in glioma and promoted the proliferation of glioma cells, suggesting that Piezo1 overexpression might contribute to the poor prognosis of patients. Thus, this study aimed to identify whether Piezo1 may become a new prognostic biomarker for glioma patients. PATIENTS AND METHODS: Firstly, Piezo1 expression of gliomas was analyzed through GEO and Oncomine dataset, and verified by qRT-PCR and immunohistochemistry (IHC) methods. A total of 183 glioma patients were included in this study between January 2010 and December 2014. Kaplan-Meier survival analyses, Cox regression analyses and ROC curve analyses were performed to assess the diagnostic and prognostic values of Piezo1 in glioma patients. RESULTS: In this study, Piezo1 was identified to be highly expressed in gliomas, and increased with WHO grade. Chi-square test results showed that Piezo1 expression was significantly related to age (P=0.00), WHO grade (P=0.00), Histopathology (P=0.00), IDH1 mutation (P=0.00) and chemotherapy (P=0.00). Kaplan-Meier analysis showed that the overall survival (OS) of patients with high Piezo1 expression was significantly worse than that of patients with low Piezo1 expression (HR=3.39, 95% CI=2.40-4.81, P<0.0001). A multivariate Cox regression analysis revealed that Piezo1 might be an independent prognostic factor for glioma patients (HR=1.34, 95% CI=1.23-1.47, P=0.000). The area under the ROC curve (AUC) of 1-, 3-, and 5-year overall survival for Piezo1 overexpression was 0.820 (P=0.000), 0.849 (P=0.000), and 0.861 (P=0.000), respectively. CONCLUSION: Piezo1 was overexpressed in glioma samples. Piezo1 overexpression as an independent prognostic factor adversely affects the prognosis of patients, which could be a new novel prognostic indicator in glioma patients.

Efficacy and Safety of Platelet-Rich Plasma for Patients with Diabetic Ulcers: A Systematic Review and Meta-analysis.

Significance: Autologous platelet-rich plasma (PRP) has been suggested to be effective for wound healing. However, clinical evidence for its use in patients with diabetic ulcer remains inconsistent. The aim of this systematic review and meta-analysis was to evaluate the efficacy and safety of PRP in patients with diabetic ulcer. Recent Advances: Relevant randomized controlled trials (RCTs) were identified via systematic search of PubMed, MEDLINE, EMBASE, the Cochrane Library, and Web of Knowledge databases. Results were pooled using a random-effects model. The primary outcome of the study was the healing rate of ulcers in patients with PRP, when compared with controls. Secondary outcomes included the percentage of ulcer area reduction, recurrence rate, and amputation rate. Critical Issues: Eight RCTs that involved 431 participants were included. Compared with controls, PRP was associated with a significantly increased ratio of complete ulcer healing (odds ratio [OR] = 3.77, 95% confidence interval [CI] = 1.91-7.45, I2 = 42.2%) and reduced areas of ulcers (standard mean difference = 0.86, 95% CI = 0.27-1.45, I2 = 0.0%). No differences were observed between patients allocated to PRP or controls, in terms of the outcomes of recurrence rate (OR = 3.32, 95% CI = 0.41-27.18, I2 = 66.3%) or amputation rate (OR = 0.15, 95% CI = 0.15-1.28). The results of the trial sequence analyses revealed that the cumulative Z-curve crossed both the traditional boundary (p = 0.05) and trial sequential monitoring boundary. Future Directions: Our findings suggest that PRP may improve ulcer healing without significant adverse effects for patients with diabetic ulcers.

Pleiotropic FTY720 Is a Specific and Potent Therapy for Hypertrophic Scars.

Hypertrophic scarring (HS) is a fibrotic skin condition characterized by aberrant fibroblast phenotypes and excessive deposition of extracellular matrix components. 2-Amino-2-[2-(4-octylphenyl)]-1, 3-propanediol hydrochloride (FTY720), an immunomodulator approved for treating multiple sclerosis, is reported to attenuate fibrosis in multiple disease models. Here we found that FTY720 could significantly attenuate the proliferation and fibrosis in HS fibroblasts (HSFs) and in an animal HS model. Upon treating HSFs or normal dermal fibroblasts with FTY720 at different concentrations for different time periods, we found that FTY720 presented a pleiotropic effect specifically on HSFs but not NFs, including reducing cell viability, arresting cell cycle progression at the G0/G1 phase, promoting apoptosis, inhibiting migration and contraction, and suppressing the expressions of α-smooth muscle actin, collagen I, and collagen III. Mechanistic studies showed that the antifibrotic activities of FTY720 were potentially mediated through sphingosine 1-phosphate receptor 5 to inhibit the protein kinase B/mTOR/p70S6K, but not the Smad, signaling pathway. The in vitro actions of FTY720 also translated into a rabbit ear HS model, stimulating the healing of HS. These findings collectively suggest that FTY720 targets multiple phenotypes of HSFs and is a promising therapeutic agent for HS.