MEG3 shuttled by exosomes released from human bone marrow mesenchymal stem cells promotes TP53 stability to regulate MCM5 transcription in keloid fibroblasts.

BACKGROUND: Despite the interest in mesenchymal stem cells (MSC), their potential to treat abnormal scarring, especially keloids, is yet to be described. The present study aimed to investigate the therapeutic potential of exosomes derived from human bone marrow MSCs (hBMSC-Exos) in alleviating keloid formation. METHODS: Exosomes were isolated from hBMSC, and keloid fibroblasts (KFs) were treated with hBMSC-Exos. Cell counting kit-8, wound healing, transwell invasion, immunofluorescence, and western blot assays were conducted to study the malignant phenotype of KFs. Mice were induced with keloids and treated with hBMSC-Exos. The effect of hBMSC-Exos on keloid formation in vivo was evaluated by hematoxylin and eosin staining, Masson staining, immunohistochemistry, and western blotting. The GSE182192 dataset was screened for differentially expressed long non-coding RNA during keloid formation. Next, maternally expressed gene 3 (MEG3) was knocked down in hBMSC to obtain hBMSC-Exossh-MEG3. The molecular mechanism of MEG3 was investigated by bioinformatic screening, and the relationship between MEG3 and TP53 or MCM5 was verified. RESULTS: hBMSC-Exos inhibited the malignant proliferation, migration, and invasion of KFs at same time as promoting their apoptosis, Moreover, hBMSC-Exos reduced the expression of fibrosis- and collagen-related proteins in the cells and the formation of keloids caused by KFs. The reduction in MEG3 enrichment in hBMSC-Exos weakened the inhibitory effect of hBMSC-Exos on KF activity. hBMSC-Exos delivered MEG3 to promote MCM5 transcription by TP53 in KFs. Overexpression of MCM5 in KFs reversed the effects of hBMSC-Exossh-MEG3, leading to reduced KF activity. CONCLUSIONS: hBMSC-Exos delivered MEG3 to promote the protein stability of TP53, thereby activating MCM5 and promoting KF activity.

Advanced glycation end products promote meniscal calcification by activating the mTOR-ATF4 positive feedback loop.

The meniscus is vital for maintaining knee homeostasis and function. Meniscal calcification is one of the earliest radiological indicators of knee osteoarthritis (KOA), and meniscal calcification is associated with alterations in biomechanical properties. Meniscal calcification originates from a biochemical process similar to vascular calcification. Advanced glycation end products (AGEs) and their receptors (RAGEs) reportedly play critical roles in vascular calcification. Herein, we investigated whether targeting AGE-RAGE is a potential treatment for meniscal calcification. In our study, we demonstrated that AGE-RAGE promotes the osteogenesis of meniscal cells and exacerbates meniscal calcification. Mechanistically, AGE-RAGE activates mTOR and simultaneously promotes ATF4 accumulation, thereby facilitating the ATF4-mTOR positive feedback loop that enhances the osteogenic capacity of meniscal cells. In this regard, mTOR inhibits ATF4 degradation by reducing its ubiquitination, while ATF4 activates mTOR by increasing arginine uptake. Our findings substantiate the unique role of AGE-RAGE in the meniscus and reveal the role of the ATF4-mTOR positive feedback loop during the osteogenesis of meniscal cells; these results provide potential therapeutic targets for KOA.

Unraveling the distribution characteristic of cyclic volatile methylsiloxanes in various environmental media of a wastewater treatment plant.

Cyclic volatile methylsiloxane (cVMS) is extensively used in consumer products and frequently detected in various environmental media, including water and air. In this study, we developed reliable and convenient methods to sample three cVMS compounds: octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6) in water and air samples collected from different tanks within a wastewater treatment plant (WWTP). The concentrations of D4, D5, and D6 in the water samples ranged from 0.40 to 8.0 µg L-1, 0.35 to 91 µg L-1, and 0.54 to 17 µg L-1, respectively. In the air samples, these concentrations varied from 0.34 to 20 µg m-3, 0.34 to 128 µg m-3, and 0.08 to 12 µg m-3, respectively. It is worth noting that the air-water distribution coefficient (Kaw) for these three cVMS exhibited a strong correlation with their water solubility. Moreover, fugacity fractions indicated a net evaporation process from water to the atmosphere. Furthermore, we investigated the distribution of cVMS between the gaseous and particulate phases. The results revealed a significant fraction, exceeding 72 %, of cVMS resided in the gas phase. D4 and D5 predominate in the gaseous phase, while D5 and D6 are the principal constituents within the particulate phase. The distribution coefficient characterizing the partitioning of cVMS compounds between the gaseous and particulate (Kp) exhibited a strong correlation with their corresponding octanol-air partitioning coefficients (Koa). These findings contribute to a better understanding of the distribution of cVMS in diverse environmental media and the underlying mechanism governing their dispersion.

Reactive Oxygen Species Scavenging Hydrogel Regulates Stem Cell Behavior and Promotes Bone Healing in Osteoporosis.

BACKGROUND: Implantation of bone marrow mesenchymal stem cells (BMSCs) is a potential alternative for promoting bone defects healing or osseointegration in osteoporosis. However, the reactive oxygen species (ROS) accumulated and excessive inflammation in the osteoporotic microenvironment could weaken the self-replication and multi-directional differentiation of transplanted BMSCs. METHODS: In this study, to improve the hostile microenvironment in osteoporosis, Poloxamer 407 and hyaluronic acid (HA) was crosslinked to synthetize a thermos-responsive and injectable hydrogel to load MnO2 nanoparticles as a protective carrier (MnO2@Pol/HA hydrogel) for delivering BMSCs. RESULTS: The resulting MnO2@Pol/HA hydrogel processed excellent biocompatibility and durable retention time, and can eliminate accumulated ROS effectively, thereby protecting BMSCs from ROS-mediated inhibition of cell viability, including survival, proliferation, and osteogenic differentiation. In osteoporotic bone defects, implanting of this BMSCs incorporated MnO2@Pol/HA hydrogel significantly eliminated ROS level in bone marrow and bone tissue, induced macrophages polarization from M1 to M2 phenotype, decreased the expression of pro-inflammatory cytokines (e.g., TNF-α, IL-1ß, and IL-6) and osteogenic related factors (e.g., TGF-ß and PDGF). CONCLUSION: This hydrogel-based BMSCs protected delivery strategy indicated better bone repair effect than BMSCs delivering or MnO2@Pol/HA hydrogel implantation singly, which providing a potential alternative strategy for enhancing osteoporotic bone defects healing.

Exploring the release of hazardous volatile organic compounds from face masks and their potential health risk.

Hazardous chemicals released from the petroleum-derived face mask can be inhaled by wearers and cause adverse health effects. Here, we first used headspace solid-phase microextraction coupled with GC-MS to comprehensively analyze the volatile organic compounds (VOCs) released from 26 types of face masks. The results showed that total concentrations and peak numbers ranged from 3.28 to 197 µg/mask and 81 to 162, respectively, for different types of mask. Also, light exposure could affect the chemical composition of VOCs, particularly increasing the concentrations of aldehydes, ketones, organic acids and esters. Of these detected VOCs, 142 substances were matched to a reported database of chemicals associated with plastic packaging; 30 substances were identified by the International Agency for Research on Cancer (IARC) as potential carcinogenic to humans; 6 substances were classified in the European Union as persistent, bioaccumulative, and toxic, or very persistent, very bioaccumulative substance. Reactive carbonyls were ubiquitous in masks, especially after exposure to light. The potential risk of VOCs released from the face masks were then accessed by assuming the extreme scenario that all the VOC residues were released into the breathing air within 3 h. The result showed that the average total concentration of VOCs (17 µg/m3) was below the criterion for hygienic air, but seven substances, 2-ethylhexan-1-ol, benzene, isophorone, heptanal, naphthalene, benzyl chloride, and 1,2-dichloropropane exceeded the non-cancer health guidelines for lifetime exposure. This finding suggested that specific regulations should be adopted to improve the chemical safety of face masks.