Exosomes from Adipose-Derived Stem Cells Can Prevent Medication-Related Osteonecrosis of the Jaw.

The treatment measures of medication-related osteonecrosis of the jaw (MRONJ) is a worldwide challenge in oral and maxillofacial surgery because of its unclear pathogenesis. Previous studies suggested that mesenchymal stem cells played important roles in promoting MRONJ lesion healing, but the detailed mechanisms were unknown. Increasing numbers of studies have demonstrated that exosomes derived from mesenchymal stem cells, especially adipose-derived stem cells, have key roles in stem cell-based therapies by accelerating bone remodeling, facilitating angiogenesis, and promoting wound healing. We hypothesized that exosomes derived from adipose-derived stem cells can prevent MRONJ by accelerating gingival healing and enhancing bone remodeling processes. Our results may provide a promising therapeutic option for MRONJ clinical therapy.

Brief reports: TRPM7 Senses mechanical stimulation inducing osteogenesis in human bone marrow mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are multipotential stem cells residing in the bone marrow. Several studies have shown that mechanical stimulation modulates MSC differentiation through mobilization of second messengers, but the mechanism of mechanotransduction remains poorly understood. In this study, using fluorescence and laser confocal microcopy as well as patch-clamp techniques, we identified the transient receptor potential melastatin type 7 (TRPM7) channel as the key channel involved in mechanotransduction in bone marrow MSCs. TRPM7 knockdown completely abolished the pressure-induced cytosolic Ca(2+) increase and pressure-induced osteogenesis. TRPM7 directly sensed membrane tension, independent of the cytoplasm and the integrity of cytoskeleton. Ca(2+) influx through TRPM7 further triggered Ca(2+) release from the inositol trisphosphate receptor type 2 on the endoplasmic reticulum and promoted NFATc1 nuclear localization and osteogenesis. These results identified a central role of TRPM7 in MSC mechanical stimulation-induced osteogenesis.

Hydrogen-rich water alleviates constipation by attenuating oxidative stress through the sirtuin1/nuclear factor-erythroid-2-related factor 2/heme oxygenase-1 signaling pathway.

BACKGROUND: Constipation, a highly prevalent functional gastrointestinal disorder, induces a significant burden on the quality of patients' life and is associated with substantial healthcare expenditures. Therefore, identifying efficient therapeutic modalities for constipation is of paramount importance. Oxidative stress is a pivotal contributor to colonic dysmotility and is the underlying pathology responsible for constipation symptoms. Consequently, we postulate that hydrogen therapy, an emerging and promising intervention, can serve as a safe and efficacious treatment for constipation. AIM: To determine whether hydrogen-rich water (HRW) alleviates constipation and its potential mechanism. METHODS: Constipation models were established by orally loperamide to Sprague-Dawley rats. Rats freely consumed HRW, and were recorded their 24 h total stool weight, fecal water content, and charcoal propulsion rate. Fecal samples were subjected to 16S rDNA gene sequencing. Serum non-targeted metabolomic analysis, malondialdehyde, and superoxide dismutase levels were determined. Colonic tissues were stained with hematoxylin and eosin, Alcian blue-periodic acid-Schiff, reactive oxygen species (ROS) immunofluorescence, and immunohistochemistry for cell growth factor receptor kit (c-kit), PGP 9.5, sirtuin1 (SIRT1), nuclear factor-erythroid-2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Quantitative real-time PCR and western blot analysis were conducted to determine the expression level of SIRT1, Nrf2 and HO-1. A rescue experiment was conducted by intraperitoneally injecting the SIRT1 inhibitor, EX527, into constipated rats. NCM460 cells were induced with H2O2 and treated with the metabolites to evaluate ROS and SIRT1 expression. RESULTS: HRW alleviated constipation symptoms by improving the total amount of stool over 24 h, fecal water content, charcoal propulsion rate, thickness of the intestinal mucus layer, c-kit expression, and the number of intestinal neurons. HRW modulated intestinal microbiota imbalance and abnormalities in serum metabolism. HRW could also reduce intestinal oxidative stress through the SIRT1/Nrf2/HO-1 signaling pathway. This regulatory effect on oxidative stress was confirmed via an intraperitoneal injection of a SIRT1 inhibitor to constipated rats. The serum metabolites, ß-leucine (ß-Leu) and traumatic acid, were also found to attenuate H2O2-induced oxidative stress in NCM460 cells by up-regulating SIRT1. CONCLUSION: HRW attenuates constipation-associated intestinal oxidative stress via SIRT1/Nrf2/HO-1 signaling pathway, modulating gut microbiota and serum metabolites. ß-Leu and traumatic acid are potential metabolites that upregulate SIRT1 expression and reduce oxidative stress.

Osteoclasts may contribute bone substitute materials remodeling and bone formation in bone augmentation.

Bone augmentation is increasingly important in implantology. Bone substitute materials exert essential roles during bone augmentation process. However, accelerating bone substitute materials remodeling and acquiring high bone architecture quality was still the challenges of bone augmentation. Accumulated studies had suggested osteoclasts is the key cell type to resorb bone or bone substitute materials. Our previous study and other studies suggested osteoclasts contributed to bone formation by promoting osteoblast function and facilitate angiogenesis. We hypothesized that bone substitute materials loaded osteoclastogenic cytokines or osteoclast progenitors will help to bone substitute materials rapid remodeling and subsequent bone formation. Our hypothesis could help to lessen long-term post-bone augmentation period and acquire better bone quality for osseointegration.

Effects of articular disc or condylar cartilage resection on mandibular growth in young rats.

OBJECTIVE: This study was aimed to compare the effects of articular disc and condylar cartilage resection on mandibular growth in Sprague Dawley rats. DESIGN: Eighty-four male Sprague Dawley rats (age = 4 weeks) were grouped according to the following procedures: group A (n = 21), exclusive surgical exposure of articular disc and condylar cartilage; group B (n = 21), exclusive surgical resection of articular disc; group C (n = 21), exclusive surgical resection of condylar cartilage; group D (n = 21), surgical resection of both articular disc and condylar cartilage. All surgery was performed in unilateral. One rat was killed in each group immediately after the surgery. Hematoxylin and eosin (H&E) staining was used to confirm the completely removal of the disc or cartilage. Five rats in the four groups were sacrificed in 1, 3, 6, and 9 weeks post-operation. The heights and lengths of the mandibles were measured and analyzed statistically. RESULTS: The mandibular height of group D (5.01 ± 0.25 mm) was statistically lower than group A (5.59 ± 0.17 mm) at 1 week post-operation. The height of group C (5.62 ± 0.26 mm) was significantly lower than group A (6.27 ± 0.31 mm) 3 weeks after surgery. The height of group B (6.38 ± 0.36 mm) was significantly lower than group A (6.95 ± 0.10 mm) 6 weeks after surgery. At 9 weeks post-operation, the mandibular heights in groups B, C, and D were lower than group A, group D was lower than group C, and group C was lower than group B. The lengths of the mandibles were not significantly decreased until 9 weeks post-operation in group D. CONCLUSIONS: The increase in mandibular height was interfered after either articular disc or condylar cartilage was resected, and mandibular height deficiency likely occurred earlier and more severely when cartilage was resected. However, the increase in mandibular length was barely interfered when either articular disc or condylar cartilage was resected.

TRPV1 deletion impaired fracture healing and inhibited osteoclast and osteoblast differentiation.

Fracture healing, in which osteoclasts and osteoblasts play important roles, has drawn much clinical attention. Osteoclast deficiency or decreased osteoblast activity will impair fracture healing. TRPV1 is a member of the Ca2+ permeable cation channel subfamily, and pharmacological inhibition of TRPV1 prevents ovariectomy-induced bone loss, which makes TRPV1 a potential target for osteoporosis. However, whether long term TRPV1 inhibition or TRPV1 deletion will affect the fracture healing process is unclear. In this study, we found that the wild-type mice showed a well-remodeled fracture callus, whereas TRPV1 knockout mice still had an obvious fracture gap with unresorbed soft-callus 4 weeks post-fracture. The number of osteoclasts was reduced in the TRPV1 knockout fracture callus, and osteoclast formation and resorption activity were also impaired in vitro. TRPV1 deletion decreased the calcium oscillation frequency and peak cytoplasmic concentration in osteoclast precursors, subsequently reducing the expression and nuclear translocation of NFATc1 and downregulating DC-stamp, cathepsin K, and ATP6V. In addition, TRPV1 deletion caused reduced mRNA and protein expression of Runx2 and ALP in bone marrow stromal cells (BMSCs) and reduced calcium deposition in vitro. Our results suggest that TRPV1 deletion impairs fracture healing, and inhibited osteoclastogenesis and osteogenesis.

A six-microRNA set as prognostic indicators for bile duct cancer.

MicroRNAs (miRNAs) play important roles in cancer progression by altering transcriptional control. The purpose of this study is to identify and explore specific miRNAs as prognostic and predictive biomarkers for bile duct cancer (BDC) by analyzing Next-generation data. miRNA expression profiles and corresponding clinical information of BDC samples were extracted from The Cancer Genome Atlas (TCGA). The differentially expressed miRNAs were determined by SAMR package in R software. Target genes of those miRNAs were predicted by Targetscan. Functional enrichment analysis and hypergeometric test analysis of target genes were performed. Then, diagnosis accuracy of miRNAs was judged by ROC Curves analysis. Total 120 differentially expressed miRNAs were obtained, of which six important miRNAs were selected and predicted as prognosis and predicting biomarkers in BDC. Besides, functional analysis showed that both enriched pathways were significantly related with ion binding, which might involve in the carcinogenesis of BDC. Moreover, top 3 important pathways sharing the most influence were noted. Our results demonstrated that hsa-miR-483-5p, hsa-miR-675, hsa-miR-139-3p, hsa-miR-598, hsa-miR-625 and hsa-miR-187 could serve as prognostic and predictive markers for survival of BDC patients and could potentially be provided as targets for future therapy.