The Lysosome in Malignant Melanoma: Biology, Function and Therapeutic Applications.

Lysosomes are membrane-bound vesicles that play roles in the degradation and recycling of cellular waste and homeostasis maintenance within cells. False alterations of lysosomal functions can lead to broad detrimental effects and cause various diseases, including cancers. Cancer cells that are rapidly proliferative and invasive are highly dependent on effective lysosomal function. Malignant melanoma is the most lethal form of skin cancer, with high metastasis characteristics, drug resistance, and aggressiveness. It is critical to understand the role of lysosomes in melanoma pathogenesis in order to improve the outcomes of melanoma patients. In this mini-review, we compile our current knowledge of lysosomes' role in tumorigenesis, progression, therapy resistance, and the current treatment strategies related to lysosomes in melanoma.

Surfactin induces ER stress-mediated apoptosis via IRE1-ASK1-JNK signaling in human osteosarcoma.

Osteosarcoma, one of primary bone tumor in children and young adults, has poor prognosis and drug resistances to chemotherapy. In order to reinforce the conventional therapies and antagonize the osteosarcoma in patients, a novel strategy is required for developing a new treatment. In this study, surfactin, a natural product from Bacillus subtilis, showed the efficiency of cell death in osteosarcoma, but not in normal cells. Surfactin triggers ER stress mechanism by promoting the aberrant Ca2+ release from ER lumen and ER-signaling to mitochondrial dysfunction following caspases activation mediating cell apoptosis. Surfactin-induced ER stress not only upregulated of glucose-regulated protein 78/94 and IRE1-ASK1-JNK pathway but also leading to calpains and Bcl-2 proteins family involving the release of cytochrome c. The releases into cytosol trigger the cleavage of caspase-9 and caspase-3 to induce cell apoptosis. In this study, surfactin demonstrated the potential functions to trigger the ER stress, ER stress-associated IRE1-ASK1-JNK signaling pathway, mitochondrial dysfunction, and caspase activations leading to programmed cell apoptosis. Importantly, implicating the signaling pathway that regulates the connection between ER stress and mitochondrial dysfunction causing apoptosis associated with surfactin. These results indicated a potential application of surfactin strengthen current conventional therapies.

Concurrence of Pigmented Villonodular Synovitis with Calcium Pyrophosphate Deposition in a Postacute Stroke Patient.

Pigmented villonodular synovitis (PVNS) is a rare synovial proliferative disease featuring hemosiderin deposits. Calcium pyrophosphate deposition (CPPD) is a crystal-induced inflammatory arthritis common in the elderly. We reported the case of a 78-year-old male who was under stroke rehabilitation when acute inflammatory and hemorrhagic knee arthritis of his paretic lower limb occurred. CPPD was proven by synovial analysis. Ultrasonography showed widespread synovial nodular lesions in the affected knee and helped guiding difficult arthrocentesis. These led to a rapid diagnosis of PVNS with magnetic resonance imaging. In elderly stroke patients, knee pain, being a common complaint, warrants a careful diagnosis including adequate imaging. This case demonstrates that ultrasonography is an accessible and useful diagnostic tool.

A study of the differentiation of stem cells from human exfoliated deciduous teeth on 3D silk fibroin scaffolds using static and dynamic culture paradigms.

Stem cells from human exfoliated deciduous teeth (SHED) are considered the best current source of human stem cells due to their ability to differentiate into multiple cell lineages. Dynamic co-culture systems can improve the culture environment, as they provide cells with signaling factors, extracellular matrixes, and cellular shear force, as well as enable the formation of heterotypic clusters. We seeded SHED in 3D silk fibroin porous scaffolds under static and dynamic cultures for 28 days, using the NIH3T3 cultivated medium as an induction agent. Many hepatospheres formed in these porous scaffolds, and cellular viability was shown to continually increase by MTT assays. Hepatic AFP and ALB gene expression, as well as glycogen storage, albumin secretion, and urea synthesis, were greater in cells in the 3D porous scaffold under a dynamic culture than in those cultured under 3D static culture and petri dish conditions. However, the 3D static culture is still superior to the traditional petri dish culture. The NIH3T3 cultivated medium can significantly induce hepatic differentiation of SHED, while the 3D dynamic culture system significantly enhances hepatic differentiation of SHED. This study provides alternative sources of hepatocytes for liver disease treatment.

ZnO Nanoparticles Induced Caspase-Dependent Apoptosis in Gingival Squamous Cell Carcinoma through Mitochondrial Dysfunction and p70S6K Signaling Pathway.

Zinc oxide nanoparticles (ZnO-NPs) are increasingly used in sunscreens, food additives, pigments, rubber manufacture, and electronic materials. Several studies have shown that ZnO-NPs inhibit cell growth and induce apoptosis by the production of oxidative stress in a variety of human cancer cells. However, the anti-cancer property and molecular mechanism of ZnO-NPs in human gingival squamous cell carcinoma (GSCC) are not fully understood. In this study, we found that ZnO-NPs induced growth inhibition of GSCC (Ca9-22 and OECM-1 cells), but no damage in human normal keratinocytes (HaCaT cells) and gingival fibroblasts (HGF-1 cells). ZnO-NPs caused apoptotic cell death of GSCC in a concentration-dependent manner by the quantitative assessment of oligonucleosomal DNA fragmentation. Flow cytometric analysis of cell cycle progression revealed that sub-G1 phase accumulation was dramatically induced by ZnO-NPs. In addition, ZnO-NPs increased the intracellular reactive oxygen species and specifically superoxide levels, and also decreased the mitochondrial membrane potential. ZnO-NPs further activated apoptotic cell death via the caspase cascades. Importantly, anti-oxidant and caspase inhibitor clearly prevented ZnO-NP-induced cell death, indicating the fact that superoxide-induced mitochondrial dysfunction is associated with the ZnO-NP-mediated caspase-dependent apoptosis in human GSCC. Moreover, ZnO-NPs significantly inhibited the phosphorylation of ribosomal protein S6 kinase (p70S6K kinase). In a corollary in vivo study, our results demonstrated that ZnO-NPs possessed an anti-cancer effect in a zebrafish xenograft model. Collectively, these results suggest that ZnO-NPs induce apoptosis through the mitochondrial oxidative damage and p70S6K signaling pathway in human GSCC. The present study may provide an experimental basis for ZnO-NPs to be considered as a promising novel anti­tumor agent for the treatment of gingival cancer.

Epidermal cells differentiated from stem cells from human exfoliated deciduous teeth and seeded onto polyvinyl alcohol/silk fibroin nanofiber dressings accelerate wound repair.

Mesenchymal stem cells (MSCs) or epidermal stem cells (ESCs) may be used as a source of cells for skin wound repair in order to preserve the patient's remaining autologous skin and reduce the wound area and pain. Many studies use MSCs as therapeutic cells for wound healing, but treatment with ESCs instead can speed up wound repair. In additional to therapeutic cells, the biomechanical properties and surface topography of the dressing also affect the speed of wound healing. Silk fibroin (SF) has the property of promoting collagen regeneration to accelerate wound healing. It has made into nanofibers as a wound healing dressing with hydrophilic polyvinyl alcohol (PVA). Methanol-treated PVA-SF dressing (PFSM) is a beadless nanofiber that can mimic the structure of endogenous extracellular matrix. In this study, SHED was first differentiated into ESCs and then effects of SHED and ESCs on wound closure were compared. Differentiation of SHED into ESCs was shown to induce growth factors that reached a maximum on the third day. In vivo, PFSM/ESC showed regeneration of granulation tissue on the third day, and the wound closure percent was 53.49%, which was 1.18-fold higher than PFSM/SHED. Therefore, the differentiation of stem cells into ESCs in advance combined with PFSM dressing can effectively accelerate wound healing in vivo. These findings can be applied to clinical treatment in the future.

Senescence Induces Dysfunctions in Endothelial Progenitor Cells and Osteoblasts by Interfering Translational Machinery and Bioenergetic Homeostasis.

Age-related bone diseases are partly caused by impaired bone integrity, which are closely related to osteoblasts' activity and angiogenesis. Endothelial progenitor cells (EPCs) are the initiators of angiogenesis and found to have senescent-induced dysfunctions. The aim of this study is to investigate the effects of senescence in EPCs on osteogenesis and angiogenesis. Human primary EPCs and a murine osteoblast cell line (MC3T3-E1) are utilized in this study. The senescence of EPCs are induced by serial passages. When co-cultured with senescent EPCs, the osteoblasts demonstrate weakened alkaline phosphatase (ALP) activity and mineral deposition. On the other hand, osteoblast-induced migration decreases in senescent EPCs. As for the intracellular alterations of senescent EPCs, the activation of Akt/mTOR/p70S6K pathway, MnSOD and catalase are diminished. In contrast, the level of reactive oxygen species are significantly higher in senescent EPCs. Furthermore, senescent EPCs has decreased level intracellular ATP level and coupling efficiency for oxidative phosphorylation while the non-mitochondrial respiration and glycolysis are elevated. The senescence of EPCs impairs the functions of both osteoblasts and EPCs, suggesting EPCs' role in the pathophysiology of age-related bone diseases. Targeting the alterations found in this study could be potential treatments.

BMP-2 induces angiogenesis by provoking integrin α6 expression in human endothelial progenitor cells.

Bone morphogenetic protein-2 (BMP-2) is a multifunctional cytokine, capable of governing several cellular functions, including proliferation, motility, differentiation, and angiogenesis. Circulating endothelial progenitor cells (EPCs) have been shown to facilitate tissue repair, postnatal neovascularization, and tumor associated angiogenesis. Nevertheless, the impact of BMP-2 on angiogenesis of human EPCs has largely remained a mystery. In this study, we found that BMP-2 promoted cell migration and tube formation of EPCs in a concentration-dependent manner, indicating BMP-2 induced in vitro angiogenesis in human EPCs. Furthermore, BMP-2 significantly increased microvessel formation in Matrigel plug assay, and BMP-2 antagonist noggin prevented BMP-2-induced in vivo angiogenesis. Mechanistic investigations showed BMP-2 profoundly induced the expression of Id-1 and integrin α6 as well as EPCs angiogenesis by activating PI3K/Akt and MEK/ERK signaling pathways. Moreover, knockdown of Id-1 and integrin α6 by siRNA transfection obviously attenuated BMP-2-indueced tube formation of EPCs. These results suggest that BMP-2 promotes angiogenesis in human EPCs through the activation of PI3K/Akt, MEK/ERK, and Id-1/integrin α6 signaling cascades. This is the first demonstration that BMP-2 exhibits the angiogenesis property on human EPCs. BMP-2 might serve as the potential therapeutic target for treatment of angiogenesis-related diseases.