Mitochondrial dysfunction is associated with cardiovascular diseases and diabetes. Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, and the abnormal proliferation, apoptosis and migration of pulmonary arterial smooth muscle cells (PASMCs). The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, has been shown to prevent pulmonary hypertension in monocrotaline-exposed rats. The aim of this study was to investigate the effect of liraglutide on autophagy, mitochondrial stress and apoptosis induced by platelet-derived growth factor BB (PDGF-BB). PASMCs were exposed to PDGF-BB, and changes in mitochondrial morphology, fusion-associated protein markers, and reactive oxygen species (ROS) production were examined. Autophagy was assessed according to the expressions of microtubule-associated protein light chain 3 (LC3)-II, LC3 puncta and Beclin-1. Western blot analysis was used to assess apoptosis, mitochondrial stress and autophagy markers. Liraglutide significantly inhibited PDGF-BB proliferation, migration and motility in PASMCs. PDGF-BB-induced ROS production was mitigated by liraglutide. Liraglutide increased the expression of α-smooth muscle actin (α-SMA) and decreased the expression of p-Yes-associated protein (p-YAP), inhibited autophagy-related protein (Atg)-5, Atg-7, Beclin-1 and the formation of LC3-β and mitochondrial fusion protein dynamin-related (Drp)1. Therefore, liraglutide can mitigate the proliferation of PASMCs via inhibiting cellular Drp1/nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) pathways and Atg-5/Atg-7/Beclin-1/LC3β-dependent pathways of autophagy in PAH.

The primary cause of breast cancer mortality is the metastatic invasion of cancerous stem cells (CSC). Cluster of differentiation 44 (CD44) is a well-known CSC marker in various cancers, as well as a key role player in metastasis and relapse of breast cancer. CD44 is a cell-membrane embedded protein, and it interacts with different proteins to regulate cancer cell behavior. Transcription factor forkhead box protein A2 (FOXA2) acts as an important regulator in multiple cancers, including breast cancer. However, the biological significance of CD44-FOXA2 association in breast cancer metastasis remains unclear. Herein, we observed that CD44 expression was higher in metastatic lymph nodes compared to primary tumors using a flow cytometric analysis. CD44 overexpression in breast cancer cell lines significantly promoted cell migration and invasion abilities, whereas the opposite effects occurred upon the knockdown of CD44. The stem cell array analysis revealed that FOXA2 expression was upregulated in CD44 knockdown cells. However, the knockdown of FOXA2 in CD44 knockdown cells reversed the effects on cell migration and invasion. Furthermore, we found that CD44 mediated FOXA2 localization in breast cancer cells through the AKT pathway. Moreover, the immunofluorescence assay demonstrated that AKT inhibitor wortmannin and AKT activator SC79 treatment in breast cancer cells impacted FOXA2 localization. Collectively, this study highlights that CD44 promotes breast cancer metastasis by downregulating nuclear FOXA2.

Impaired wound healing and especially the “all-too-common” occurrence of associated diabetic foot ulcers (DFU) are becoming an increasingly urgent and deteriorating healthcare issue, which drastically impact the quality of life and further heighten the risks of infection and amputation in patients with diabetes mellitus. Amongst the multifactorial wound healing determinants, glycemic dysregulation has been identified to be the primary casual factor of poor wound healing. Unfortunately, current therapeutic modalities merely serve as moderate symptomatic relieves but often fail to completely restore the wound site to its pre-injury state and prevent further recurrence. Stem cell-based therapeutics have been employed for its promising potential to address the root of the problem as they not only exhibit the capacity for self-renewal and differentiation towards multiple lineages, but also have been disclosed to participate in mediating variant growth factors and cytokines. Herein we review the current literatures on the therapeutic benefits of using various kinds of stem cells, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and adipose-derived stem cells (ASCs) in diabetic wound healing by searching on the PubMed^® Database for publications. This study shall serve as an overview of the current body of research with particular focus on autologous ASCs and the laboratory expandable iPSCs in hope of shedding more light on this attractive therapy so as to elevate the efficacy of wound healing that is almost always compromised in diabetic patients.

Adipose-derived stem cells (ADSCs) have been implicated in tumor growth and metastasis in breast cancer. ADSCs exhibit tumor tropism, and are of increasing clinical relevance due to the autologous fat grafting for breast reconstruction. Although we have previously shown that a high level of the adipocytokine visfatin in human breast cancer tissues correlated with tumor progression mediated by cAbl and STAT3, the effects of visfatin in the tumor microenvironment are unclear. To understand how visfatin modulates breast cancer within the tumor-stromal environment, we examined determinants of breast cancer progression using a visfatin-primed ADSCs-tumor co-culture model. ADSCs were isolated from tumor-free adipose tissue adjacent to breast tumors. ADSCs were treated with or without visfatin for 48 h and then collected for co-culture with breast cancer cell line MDA-MB-231 for 72 h in a transwell system. We found that the MDA-MB-231 cells co-cultured with visfatin-treated ADSCs (vADSCs) had higher levels of cell viability, anchorage independent growth, migration, invasion, and tumorsphere formation than that co-cultured with untreated ADSCs (uADSCs). Growth differentiation factor 15 (GDF15) upregulation was found in the co-culture conditioned medium, with GDF15 neutralizing antibody blocking the promoting effect on MDA-MB-231 in co-culture. In addition, a GDF15-induced AKT pathway was found in MDA-MB-231 and treatment with PI3K/AKT inhibitor also reversed the promoting effect. In an orthotopic xenograft mouse model, MDA-MB-231 co-injected with vADSCs formed a larger tumor mass than with uADSCs. Positive correlations were noted between visfatin, GDF15, and phosphor-AKT expressions in human breast cancer specimens. In conclusion, visfatin activated GDF15-AKT pathway mediated via ADSCs to facilitate breast cancer progression.

Exosomal microRNAs (miRNAs) are novel, non-invasive biomarkers for facilitating communication and diagnosing cancer. However, only a few studies have investigated their function and role in the clinical diagnosis of breast cancer. To address this gap, we established a stable cell line, MDA-MB-231-CD63-RFP, and recruited 112 female participants for serum collection. We screened 88 exosomal miRNAs identified through microarray analysis of 231-CD63 and literature screening using real-time PCR; only exosomal miR-92b-5p was significantly increased in patients with breast cancer. It had a significant correlation with stage and discriminated patients from the control with an AUC of 0.787. Exosomal miR-92b-5p impacted the migration, adhesion, and spreading ability of normal human mammary epithelial recipient cells through the downregulation of the actin dynamics regulator MTSS1L. In clinical breast cancer tissue, the expression of MTSS1L was significantly inversely correlated with tissue miR-92b-5p, and high expression of MTSS1L was associated with better 10-year overall survival rates in patients undergoing hormone therapy. In summary, our studies demonstrated that exosomal miR-92b-5p might function as a non-invasive body fluid biomarker for breast cancer detection and provide a novel therapeutic strategy in the axis of miR-92b-5p to MTSS1L for controlling metastasis and improving patient survival.

Clinically available materials, including allogeneic irradiated costal cartilage and fibrin glue polymer, were used as scaffolds for in vivo chondrogenic differentiation of human adipose-derived stem/stromal cells (hASCs) in the attempt to develop a more efficient treatment over current methods. Current studies include the use of growth-factor stimulation, tissue engineering, and biocompatible materials; however, most methods involve complicated processes and pose clinical limitations. In this report, the xenografts in the experimental group composed of a diced decellularized cartilage extracellular matrix (ECM), hASCs, and fibrin glue polymer were implanted into the subcutaneous layer of nude mice, and the results were compared with two groups of controls; one control group received implantation of decellularized cartilage ECM and fibrin glue polymer, and the other control group received implantation of hASCs mixed with fibrin glue polymer. To evaluate whether hASCs had in vivo chondrogenesis in the xenografts, hASCs were labeled with fluorescent nanodiamonds (FNDs), a biocompatible and photostable nanomaterial, to allow for long-term detection and histological analysis. Increased cellularity, glycosaminoglycan, and collagen deposition were found by the histological examination in the experimental group compared with control groups. With the background-free detection technique and time-gated fluorescence imaging, the numbers and locations of the FND-labeled hASCs could be detected by confocal microscopy. The chondrocyte-specific markers, such as aggrecan and type II collagen, were colocalized with cells containing signals of FNDs which indicated in vivo chondrogenesis of hASCs. Taken together, functional in vivo chondrogenesis of the hASCs could be achieved by clinically available decellularized cartilage ECM and fibrin glue polymer in the nude mice model without in vitro chondrogenic induction. The fluorescent signals of FNDs in hASCs can be detected in histological analysis, such as hematoxylin and eosin staining (H&E staining) without the interference of the autofluorescence. Our study may warrant future clinical applications of the combination of decellular cartilage ECM, fibrin glue polymer, and hASCs for cartilage repair.