The interplay between oral microbiota, gut microbiota and systematic diseases.

Over the past two decades, the importance of microbiota in health and disease has become evident. The human gut microbiota and oral microbiota are the largest and second-largest microbiome in the human body, respectively, and they are physically connected as the oral cavity is the beginning of the digestive system. Emerging and exciting evidence has shown complex and important connections between gut microbiota and oral microbiota. The interplay of the two microbiomes may contribute to the pathological processes of many diseases, including diabetes, rheumatoid arthritis, nonalcoholic fatty liver disease, inflammatory bowel disease, pancreatic cancer, colorectal cancer, and so on. In this review, we discuss possible routes and factors of oral microbiota to affect gut microbiota, and the contribution of this interplay between oral and gut microbiota to systemic diseases. Although most studies are association studies, recently, there have been increasing mechanistic investigations. This review aims to enhance the interest in the connection between oral and gut microbiota, and shows the tangible impact of this connection on human health.

Multiscale design of stiffening and ROS scavenging hydrogels for the augmentation of mandibular bone regeneration.

Although biomimetic hydrogels play an essential role in guiding bone remodeling, reconstructing large bone defects is still a significant challenge since bioinspired gels often lack osteoconductive capacity, robust mechanical properties and suitable antioxidant ability for bone regeneration. To address these challenges, we first engineered molecular design of hydrogels (gelatin/polyethylene glycol diacrylate/2-(dimethylamino)ethyl methacrylate, GPEGD), where their mechanical properties were significantly enhanced via introducing trace amounts of additives (0.5 wt%). The novel hybrid hydrogels show high compressive strength (>700 kPa), stiff modulus (>170 kPa) and strong ROS-scavenging ability. Furthermore, to endow the GPEGD hydrogels excellent osteoinductions, novel biocompatible, antioxidant and BMP-2 loaded polydopamine/heparin nanoparticles (BPDAH) were developed for functionalization of the GPEGD gels (BPDAH-GPEGD). In vitro results indicate that the antioxidant BPDAH-GPEGD is able to deplete elevated ROS levels to protect cells viability against ROS damage. More importantly, the BPDAH-GPEGD hydrogels have good biocompatibility and promote the osteo differentiation of preosteoblasts and bone regenerations. At 4 and 8 weeks after implantation of the hydrogels in a mandibular bone defect, Micro-computed tomography and histology results show greater bone volume and enhancements in the quality and rate of bone regeneration in the BPDAH-GPEGD hydrogels. Thus, the multiscale design of stiffening and ROS scavenging hydrogels could serve as a promising material for bone regeneration applications.

PgC3Mg metal-organic cages functionalized hydrogels with enhanced bioactive and ROS scavenging capabilities for accelerated bone regeneration.

The repair of large bone defects is an urgent problem in the clinic. Note that the disruption of redox homeostasis around bone defect sites might hinder the new bone reconstruction. The rational design of hydrogels for bone regeneration still faces the challenges of insufficient antioxidant capability and weak osteogenesis performance. Here, motivated by the versatile therapeutic functions of metal-organic cages, magnesium-seamed C-propylpyrogallol[4]arene (PgC3Mg) functionalized biodegradable and porous gelatin methacrylate (GelMA) hydrogels are constructed. The novel metal-organic cages endow hydrogels with highly bioactive characteristics and strong reactive oxygen species (ROS)-scavenging ability owing to the simultaneous release of bioactive Mg2+ ions and antioxidant phenolic hydroxyl-rich moieties. The in vitro results reveal that the PgC3Mg modified biocompatible hydrogels show higher expression of osteo-related genes and significantly eliminate the intracellular ROS levels of bone marrow-derived mesenchymal stem cells (BMSCs) against oxidative damage. Meanwhile, the bioactive and ROS scavenging hydrogels can accelerate bone regeneration in large cranial defects. Overall, this study may provide new insights into the designing of regenerative bone grafts with simultaneously enhanced osteogenic and antioxidant capabilities.

The glycoprotein Wnt6 regulates human dental papilla cells differentiation by canonical Wnt signaling pathway.

OBJECTIVE: The aim of this study was to test the hypothesis in vitro and in vivo, that the glycoprotein Wnt6 can regulate human dental papilla cell differentiation by ß-catenin signaling. DESIGN: The expression of Wnt6 was detected by quantitative polymerase chain reaction (qPCR). Wnt6 stealth RNA was used to knockdown the expression of Wnt6. The Wnt canonical signaling was detected by immunofluorescence staining, qPCR, and TOPflash/FOPflash dual-luciferase reporter assay. The differentiation was investigated by alkaline phosphatase staining or Alizarin Red staining after osteo/odontogenic medium culture and by Masson trichrome staining after subcutaneous transplantation. There are at least three samples in one group for each experiment. RESULTS: Wnt6 protein and mRNA were high expressed in dental mesenchyme tissue and cells. In human dental papilla cells, Wnt6 over-expression could activate ß-catenin dependent pathway, including ß-catenin accumulation in cell nuclei, lymphoid enhancer factor 1 mRNA up-regulation, and enhanced ß-catenin transcriptional activity. Wnt6 activated ß-catenin pathway in a similar way to Wnt3a but at a lower level. Wnt6 inhibited human dental papilla cells differentiation as alkaline phosphatase activity in vitro, and promoted differentiation as mineralization after subcutaneous transplantation in vivo, as same trend as Wnt3a but at a lower level. The Wnt/ß-catenin inhibitor XAV939 treatment attenuated Wnt6- or Wnt3a-induced human dental papilla cells mineralization. CONCLUSIONS: Wnt6 activated ß-catenin dependent pathway and regulated human dental papilla cells differentiation. Potential mechanism of Wnt6-regulated cell differentiation is the activation of Wnt/ß-catenin signaling pathway.

C-Jun N-terminal kinase (JNK) pathway activation is essential for dental papilla cells polarization.

During tooth development, dental papilla cells differentiate into odontoblasts with polarized morphology and cell function. Our previous study indicated that the C-Jun N-terminal kinase (JNK) pathway regulates human dental papilla cell adhesion, migration, and formation of focal adhesion complexes. The aim of this study was to further examine the role of the JNK pathway in dental papilla cell polarity formation. Histological staining, qPCR, and Western Blot suggested the activation of JNK signaling in polarized mouse dental papilla tissue. After performing an in vitro tooth germ organ culture and cell culture, we found that JNK inhibitor SP600125 postponed tooth germ development and reduced the polarization, migration and differentiation of mouse dental papilla cells (mDPCs). Next, we screened up-regulated polarity-related genes during dental papilla development and mDPCs or A11 differentiation. We found that Prickle3, Golga2, Golga5, and RhoA were all up-regulated, which is consistent with JNK signaling activation. Further, constitutively active RhoA mutant (RhoA Q63L) partly rescued the inhibition of SP600125 on cell differentiation and polarity formation of mDPCs. To sum up, this study suggests that JNK signaling has a positive role in the formation of dental papilla cell polarization.