Ultraviolet radiations have many detrimental effects in living organisms that challenge the stability and function of cellular structures. UV exposure also alters the properties and durability of materials and affects their lifetime. It is becoming increasingly important to develop new biocompatible and environmentally friendly materials to address these issues. Inspired by the strategy developed by fish, algae, and microorganisms exposed to UV radiations in confined ecosystems, we have constructed novel UV-protective materials that exclusively consist of natural compounds. Chitosan was chosen as the matrix for grafting mycosporines and mycosporine-like amino acids as the functional components of the active materials. Here, we show that these materials are biocompatible, photoresistant, and thermoresistant, and exhibit a highly efficient absorption of both UV-A and UV-B radiations. Thus, they have the potential to provide an efficient protection against both types of UV radiations and overcome several shortfalls of the current UV-protective products. In practice, the same concept can be applied to other biopolymers than chitosan and used to produce multifunctional materials. Therefore, it has a great potential to be exploited in a broad range of applications in living organisms and nonliving systems.
Articular cartilage degeneration is one of the most common causes of pain and disability in middle-aged and older people. Tissue engineering (TE) has shown great therapeutic promise for this condition. The design of cartilage regeneration constructs must take into account the specific characteristics of the cartilaginous matrix, as well as the avascular nature of cartilage and its cells’ peculiar arrangement in isogenic groups. Keeping these factors in mind, we have designed a 3D porous scaffold based on genipin-crosslinked chitosan/chitin nanocrystals for spheroid chondral differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) induced in hypoxic conditions. First, we demonstrated that, under low oxygen conditions, the chondrospheroids obtained express cartilage-specific markers including collagen type II (COL2A1) and aggrecan, lacking expression of osteogenic differentiation marker collagen type I (COL1A2). These results were associated with an increased expression of hypoxia-inducible factor 1α, which positively directs COL2A1 and aggrecan expression. Finally, we determined the most suitable chondrogenic differentiation pattern when hASC spheroids were seeded in the 3D porous scaffold under hypoxia and obtained a chondral extracellular matrix with a high sulphated glycosaminoglycan content, which is characteristic of articular cartilage. These findings highlight the potential use of such templates in cartilage tissue engineering.
The precise role and value of incorporating nanoforms in biologically active matrices for medical applications is not known. In our current work, we incorporate two chitin nanoforms (i.e., nanocrystals or nanofibers) into Genipin-chitosan crosslinked matrices. These materials were studied as 2D films and 3D porous scaffolds to assess their potential as primary support and guidance for stem cells in tissue engineering and regenerative medicine applications. The incorporation of either nanoforms in these 2D and 3D materials reveals significantly better swelling properties and robust mechanical performance in contrast to nanoform-free chitosan matrices. Furthermore, our data shows that these materials, in particular, incorporation of low concentration chitin nanoforms provide specific topological cues to guide the survival, adhesion, and proliferation of human adipose-derived stem cells. These findings demonstrate the potential of Genipin-chitosan crosslinked matrices impregnated with chitin nanoforms as value added materials for stem cell-based biomedical applications.
Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using Induced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carrying a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, enhanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we demonstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression and to identify putative targets.
Infiltration of tumor-promoting immune cells is a strong driver of tumor progression. Especially the accumulation of macrophages in the tumor microenvironment is known to facilitate tumor growth and to correlate with poor prognosis in many tumor types. TAp73, a member of the p53/p63/p73 family, acts as a tumor suppressor and has been shown to suppress tumor angiogenesis. However, what role TAp73 has in regulating immune cell infiltration is unknown. Here, we report that low levels of TAp73 correlate with an increased NF-κB–regulated inflammatory signature in breast cancer. Furthermore, we show that loss of TAp73 results in NF-κB hyperactivation and secretion of Ccl2, a known NF-κB target and chemoattractant for monocytes and macrophages. Importantly, TAp73-deficient tumors display an increased accumulation of protumoral macrophages that express the mannose receptor (CD206) and scavenger receptor A (CD204) compared to controls. The relevance of TAp73 expression in human breast carcinoma was further accentuated by revealing that TAp73 expression correlates negatively with the accumulation of protumoral CD163+ macrophages in breast cancer patient samples. Taken together, our findings suggest that TAp73 regulates macrophage accumulation and phenotype in breast cancer through inhibition of the NF-κB pathway.
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