A Biomimetic Multifunctional Scaffold for Infectious Vertical Bone Augmentation.

The regenerative treatment of infectious vertical bone defects remains difficult and challenging today. Current clinical treatments are limited in their ability to control bacteria and infection, which is unfavorable for new bone formation and calls for a new type of material with excellent osteogenic and antibacterial properties. Here a multifunctional scaffold is synthesized that mimics natural bone nanostructures by incorporating silver nanowires into a hierarchical, intrafibrillar mineralized collagen matrix (IMC/AgNWs), to achieve the therapeutic goals of inhibiting bacterial activity and promoting infectious alveolar bone augmentation in rats and beagle dogs. An appropriate concentration of 0.5 mg mL-1 AgNWs is selected to balance biocompatibility and antibacterial properties. The achieved IMC/AgNWs exhibit a broad spectrum of antimicrobial properties against Gram-negative Porphyromonas gingivalis and Gram-positive Streptococcus mutans. When the IMC/AgNWs are cocultured with periodontal ligament stem cells, it possesses excellent osteoinductive activities under both non-inflammatory and inflammatory conditions. By constructing a rat mandibular infected periodontal defect model, the IMC/AgNWs achieve a near-complete healing through the canonical BMP/Smad signaling. Moreover, the IMC/AgNWs enhance vertical bone height and osseointegration in peri-implantitis in beagle dogs, indicating the clinical translational potential of IMC/AgNWs for infectious vertical bone augmentation.

Quantitative evaluation of vertical control in orthodontic camouflage treatment for skeletal class II with hyperdivergent facial type.

BACKGROUND: In this study, we sought to quantify the influence of vertical control assisted by a temporary anchorage device (TAD) on orthodontic treatment efficacy for skeletal class II patients with a hyperdivergent facial type and probe into the critical factors of profile improvement. METHODS: A total of 36 adult patients with skeletal class II and a hyperdivergent facial type were included in this retrospective case-control study. To exclude the effect of sagittal anchorage reinforcement, the patients were divided into two groups: a maxillary maximum anchorage (MMA) group (N = 17), in which TADs were only used to help with anterior tooth retraction, and the MMA with vertical control (MMA + VC) group (N = 19), for which TADs were also used to intrude the maxillary molars and incisors. The treatment outcome was evaluated using dental, skeletal, and soft-tissue-related parameters via a cephalometric analysis and cast superimposition. RESULTS: A significant decrease in ANB (P < 0.05 for both groups), the retraction and uprighting of the maxillary and mandibular incisors, and the retraction of protruded upper and lower lips were observed in both groups. Moreover, a significant intrusion of the maxillary molars was observed via the cephalometric analysis (- 1.56 ± 1.52 mm, P < 0.05) and cast superimposition (- 2.25 ± 1.03 mm, P < 0.05) of the MMA + VC group but not the MMA group, which resulted in a remarkable decrease in the mandibular plane angle (- 1.82 ± 1.38°, P < 0.05). The Z angle (15.25 ± 5.30°, P < 0.05) and Chin thickness (- 0.97 ± 0.45°, P < 0.05) also improved dramatically in the MMA + VC group, indicating a better profile and a relaxed mentalis. Multivariate regression showed that the improvement in the soft tissue was closely related to the counterclockwise rotation of the mandible plane (P < 0.05). CONCLUSIONS: TAD-assisted vertical control can achieve intrusion of approximately 2 mm for the upper first molars and induce mandibular counterclockwise rotation of approximately 1.8°. Moreover, it is especially important for patients without sufficient retraction of the upper incisors or a satisfactory chin shape.

Analysis of oral microbiome on temporary anchorage devices under different periodontal conditions.

BACKGROUND: Temporary anchorage devices (TADs) are maximum anchorages that have been widely used in orthodontic treatment. The aim of the study was to uncover whether a history of periodontitis would influence microbiome colonization on the TAD surface. RESULTS: Patients were grouped by periodontal evaluations before the orthodontic treatment. Patients with healthy periodontal conditions were classified as the healthy group, and patients diagnosed with periodontitis stage II or even worse were classified as the periodontitis group. Scanning electron microscopy (SEM) was used to analyze the existence of biofilm on the surface of 4 TADs from the healthy group and 4 TADs from the periodontitis group. Fifteen TADs from the healthy group and 12 TADs from the periodontitis group were collected. The microorganisms on the surface of TADs were harvested and analyzed by 16S rRNA gene sequencing. α-diversity indices and ß-diversity indices were calculated. Wilcoxon's test was used to determine differences between genera, species as well as KEGG functions. SEM analysis revealed bacteria colonization on the surface of TADs from both groups. Principal coordinate analysis (PCoA) based on ß diversity revealed differential sample clusters depending on periodontal conditions (P < 0.01). When comparing specific genera, Fusobacterium, Porphyromonas, Saccharibacteria_(TM7)_[G-1], Dialister, Parvimonas, Fretibacterium, Treponema were more enriched in TADs in the periodontitis group. In the KEGG analysis, TADs in the periodontitis group demonstrated enriched microbial activities involved with translation, genetic information processing, metabolism, and cell motility. CONCLUSIONS: This analysis elucidated the difference in total composition and function of TADs oral microorganisms between patients periodontally healthy and with periodontitis.

Mechanical overload induces TMJ disc degeneration via TRPV4 activation.

OBJECTIVE: The temporomandibular joint (TMJ) disc cushions intraarticular stress during mandibular movements. While mechanical overloading is related to cartilage degeneration, the pathogenesis of TMJ disc degeneration is unclear. Here, we determined the regulatory role of mechanoinductive transient receptor potential vanilloid 4 (TRPV4) in mechanical overload-induced TMJ disc degeneration. METHODS: We explored the effect of mechanical overload on the TMJ discs in a rat occlusal interference model in vivo, and by applying sustained compressive force in vitro. TRPV4 inhibition was delivered by small interfering RNA or GSK2193874; TRPV4 activation was delivered by GSK1016790A. The protective effect of TRPV4 inhibition was validated in the rat occlusal interference model. RESULTS: Occlusal interference induced TMJ disc degeneration with enhanced extracellular matrix degradation in vivo and mechanical overload promoted inflammatory responses in the TMJ disc cells via Ca2+ influx with significantly upregulated TRPV4. TRPV4 inhibition reversed mechanical overload-induced inflammatory responses; TRPV4 activation simulated mechanical overload-induced inflammatory responses. Moreover, TRPV4 inhibition alleviated TMJ disc degeneration in the rat occlusal interference model. CONCLUSION: Our findings suggest TRPV4 plays a pivotal role in the pathogenesis of mechanical overload-induced TMJ disc degeneration and may be a promising target for the treatment of degenerative changes of the TMJ disc.

Effects of orthodontic camouflage treatment vs orthodontic-orthognathic surgical treatment on condylar stability in Class II hyperdivergent patients with severe temporomandibular joint osteoarthrosis: a retrospective observational study.

OBJECTIVES: To investigate the differences in profile changes and stability of the condyles between orthodontic camouflage treatment assisted by vertical control and that accomplished via orthognathic surgery in Class II hyperdivergent patients with TMJ osteoarthrosis (TMJOA). MATERIALS AND METHODS: This study included 27 Class II hyperdivergent TMJOA patients (54 condyles) who received orthodontic camouflage treatment (13 patients) or orthognathic surgery (14 patients) Cone-beam computerized tomography (CBCT) scans were taken before treatment (T1) and 1 year after treatment (T2). Cephalometric and TMJ measurement analyses were conducted to evaluate the change in profile and condyles from T1 to T2 using independent samples t-test and paired t-test. Three-dimensional (3D) deviation analysis was also performed to evaluate the stability of condyles from T1 to T2. RESULTS: Both groups showed significant profile improvement from T1 to T2. The changes in Z angle and ANB angle were larger in the surgical group than in the orthodontic group. Condylar width, length, and height remained stable after treatment in the orthodontic group (P > .05), while they reduced by 0.67 ± 0.85 mm, 1.14 ± 1.10 mm, and 1.07 ± 1.34 mm, respectively, in the surgical group (P < .05). Superior, posterior, medial, and lateral joint spaces were significantly reduced in the orthodontic group (P < .05). 3D deviations intuitively showed that condylar bone in the orthodontic group was more stable than that in the surgical group. CONCLUSIONS: For Class II hyperdivergent patients with severe TMJOA, orthodontic camouflage treatment with vertical control can effectively maintain the stability of condyles while significantly improving the profile. Surgical treatment yields a better profile but may increase the risk of condyle resorption.

Dental Pulp Stem Cell-Derived Exosomes Alleviate Mice Knee Osteoarthritis by Inhibiting TRPV4-Mediated Osteoclast Activation.

Osteoarthritis (OA) is a degenerative disease that causes chronic pain and joint swelling and even disables millions of patients. However, current non-surgical treatment for OA can only relieve pain without obvious cartilage and subchondral bone repair. Mesenchymal stem cell (MSC)-secreted exosomes have promising therapeutic effects on knee OA, but the efficacy of MSC-exosome therapy is not well determined, and the mechanisms involved are still unclear. In this study, we isolated dental pulp stem cell (DPSC)-derived exosomes by ultracentrifugation and determined the therapeutic effects of a single intra-articular injection of DPSC-derived exosomes in a mice knee OA model. The results showed that the DPSC-derived exosomes effectively improved abnormal subchondral bone remodeling, inhibited the occurrence of bone sclerosis and osteophytes, and alleviated cartilage degradation and synovial inflammation in vivo. Moreover, transient receptor potential vanilloid 4 (TRPV4) was activated during the progression of OA. Enhanced TRPV4 activation facilitated osteoclast differentiation, and TRPV4 inhibition blocked this process in vitro. DPSC-derived exosomes repressed osteoclast activation in vivo by inhibiting TRPV4 activation. Our findings demonstrated that a topical, single injection of DPSC-derived exosomes is a potential strategy for knee OA treatment, and that the exosomes regulated osteoclast activation by TRPV4 inhibition, which may act as a promising target for clinical OA treatment.

Oral microbiome contributes to the failure of orthodontic temporary anchorage devices (TADs).

BACKGROUND: The stability of temporary anchorage devices (TADs) is critical in orthodontic clinics. The failure of TADs is multifactorial, and the role of the oral microbiome has not been clearly defined. Herein, we attempted to analyze the contribution of the oral microbiome to the failure of TADs. METHODS: Next-generation sequencing was adopted for analyzing the microbiome on the TADs from orthodontic patients. 29 TADs (15 failed TADs and 14 successful TADs) were used for 16S rRNA gene sequencing. A total of 135 TADs (62 failed TADs and 73 successful TADs) were collected to conduct metagenomic sequencing. Additionally, 34 verified samples (18 failed TADs and 16 successful TADs) were collected for quantitative real-time polymerase chain reaction analysis (qRT-PCR). RESULTS: Successful and failed TADs demonstrated discrepancies in microbiome structure, composition, and function. Clear separations were found in ß-diversity in 16S rRNA gene sequencing as well as metagenomic sequencing (p < 0.05). Metagenomic sequencing showed that Prevotella intermedia, Eikenella corrodens, Parvimonas spp., Neisseria elongata, and Catonella morbi were enriched in the failed groups. qRT-PCR also demonstrated that the absolute bacteria load of Prevotella intermedia was higher in failed TADs (p < 0.05). Considering functional aspects, the failed group showed enriched genes involved in flagellar assembly, bacterial chemotaxis, and oxidative phosphorylation. CONCLUSIONS: This study illustrated the compositional and functional differences of microorganisms found on successful and failed TADs, indicating that controlling bacterial adhesion on the surface of TADs is essential for their success rate.

Microbiological Advances in Orthodontics: An Overview and Detailed Analysis of Temporary Anchorage Devices.

Dental biofilm is the initiating factor of oral diseases, such as periodontitis and caries. Orthodontic treatment could alter the microbiome structure balance, and increase the risk of such diseases. Furthermore, fixed appliances can induce temporary changes in the microbiome community, and the changes that clear aligners bring are smaller by comparison. Temporary anchorage devices (TADs) are skeletal anchorages that are widely used in orthodontic treatment. Microorganisms affect the occurrence and development of inflammation surrounding TADs. At present, existing researches have verified the existence of plaque biofilm on the surface of TADs, but the formation of plaque biofilm and plaque composition under different stable conditions have not been fully understood. The development of high-throughput sequencing, molecular biology experiments, and metabonomics have provided new research ideas to solve this problem. They can become an effective means to explore the microbiome surrounding TADs.

Mechanical force-promoted osteoclastic differentiation via periodontal ligament stem cell exosomal protein ANXA3.

Exosomes play a critical role in intracellular communication. The biogenesis and function of exosomes are regulated by multiple biochemical factors. In the present study, we find that mechanical force promotes the biogenesis of exosomes derived from periodontal ligament stem cells (PDLSCs) and alters the exosomal proteome profile to induce osteoclastic differentiation. Mechanistically, mechanical force increases the level of exosomal proteins, especially annexin A3 (ANXA3), which facilitates exosome internalization to activate extracellular signal-regulated kinase (ERK), thus inducing osteoclast differentiation. Moreover, the infusion of exosomes derived from PDLSCs into mice promotes mechanical force-induced tooth movement and increases osteoclasts in the periodontal ligament. Collectively, this study demonstrates that mechanical force treatment promotes the biogenesis of exosomes from PDLSCs and increases exosomal protein ANXA3 to facilitate exosome internalization, which activates ERK phosphorylation, thus inducing osteoclast differentiation. Our findings shed light on new mechanisms for how mechanical force regulates the biology of exosomes and bone metabolism.

Similarities and differences of estrogen in the regulation of temporomandibular joint osteoarthritis and knee osteoarthritis.

BACKGROUND: Temporomandibular joint osteoarthritis (TMJOA) and knee osteoarthritis (knee OA) are two kinds of common osteoarthritis (OA) that are characterized by chronic degeneration of soft and hard tissues around joints. Their gender and age differences suggest that there are similarities and differences between the pathogenic mechanisms of TMJOA and knee OA. OBJECTIVE: To review recent studies on the effect of estrogen on TMJOA and knee OA, and summarize their possible pathogenesis and molecular mechanisms. SOURCES: Articles up to present reporting the relationship of estrogen and TMJOA or knee OA are included. An extensive electronic search was conducted of databases including PubMed, Web of science core collection. CONCLUSION: According to epidemiological investigations, TMJOA primarily happens to females of puberty and childbearing age, while knee OA mainly affects postmenopausal women. Epidemiological investigation and experimental research suggest that estrogen may have a different effect on TMJ and on knee. Though estrogen regulates TMJOA and knee OA via estrogen-related receptors (ERR), their pathogenesis and pathway of estrogen regulation are different. To find out the accurate regulation of estrogen on TMJOA and knee OA, specific pathways and molecular mechanisms still need further exploration.

A hierarchical bilayer architecture for complex tissue regeneration.

Engineering a complete, physiologically functional, periodontal complex structure remains a great clinical challenge due to the highly hierarchical architecture of the periodontium and coordinated regulation of multiple growth factors required to induce stem cell multilineage differentiation. Using biomimetic self-assembly and microstamping techniques, we construct a hierarchical bilayer architecture consisting of intrafibrillarly mineralized collagen resembling bone and cementum, and unmineralized parallel-aligned fibrils mimicking periodontal ligament. The prepared biphasic scaffold possesses unique micro/nano structure, differential mechanical properties, and growth factor-rich microenvironment between the two phases, realizing a perfect simulation of natural periodontal hard/soft tissue interface. The interconnected porous hard compartment with a Young's modulus of 1409.00 ± 160.83 MPa could induce cross-arrangement and osteogenic differentiation of stem cells in vitro, whereas the micropatterned soft compartment with a Young's modulus of 42.62 ± 4.58 MPa containing abundant endogenous growth factors, could guide parallel arrangement and fibrogenic differentiation of stem cells in vitro. After implantation in critical-sized complete periodontal tissue defect, the biomimetic bilayer architecture potently reconstructs native periodontium with the insertion of periodontal ligament fibers into newly formed cementum and alveolar bone by recruiting host mesenchymal stem cells and activating the transforming growth factor beta 1/Smad3 signaling pathway. Taken together, integration of self-assembly and microstamping strategies could successfully fabricate a hierarchical bilayer architecture, which exhibits great potential for recruiting and regulating host stem cells to promote synergistic regeneration of hard/soft tissues.

Recurrent Adult Sacrococcygeal Teratoma Developing Adenocarcinoma: A Case Report and Review of Literatures.

Sacrococcygeal teratomas (SCT) are most commonly seen in infants and children but are rare in adults. Most adult SCT are benign and mature with a minority of tumors having immature components or overt malignancy. Here, we report a 65-year-old female with a SCT developing adenocarcinoma. The patient was diagnosed with benign sacrococcygeal cystic teratoma on her initial hospital visit and was treated with surgical resection. She was followed up postoperatively and was noted to have a markedly elevated CA 19-9 level 13 months after the surgery. Radiological and clinical examination revealed thickening of the perirectal soft tissues, located near the inferior portion of her previous incision site. Histological evaluation of the lesion showed invasive, moderately differentiated adenocarcinoma. Immunohistochemical staining results were suggestive, but not diagnostic, of anal gland adenocarcinoma. This case report expands the knowledge regarding an adenocarcinoma arising from a previously benign, adult SCT.

Clinicopathological characteristics and aetiological factors of granulomatous gastritis.

AIMS: To examine the clinicopathological characteristics of granulomatous gastritis (GG) among different aetiologies, particularly Crohn disease (CD), and determine the contribution of Helicobacter pylori and the clinical significance of isolated GG. METHODS AND RESULTS: We identified 269 GG cases overall (0.19% prevalence): 220 had an underlying granulomatous disease (CD, sarcoidosis, tuberculosis) and only eight of these (3.6%) had H. pylori, fewer than the 10.3% rate among non-GG biopsies (P < 0.001). Conversely, among 49 GG cases without known cause (foreign body, undetermined, idiopathic), 13 (26.5%) had H. pylori more than background (P = 0.001). Most patients (n = 185/68.8%) had CD and these were more probably male (P < 0.001), younger (P < 0.001), white (P < 0.001) and had single (P = 0.010), smaller (P = 0.005) and antral (P = 0.027) granulomas amid inflammation (P = 0.005) compared to non-CD GG cases; younger age was independently associated with CD [P = 0.003; odds ratio (OR) = 1.13, 95% confidence interval (CI) = 1.04-1.22]. Among CD patients, younger age (P = 0.003; OR = 1.04, 95% CI = 1.01-1.07) and upper gastrointestinal (GI) symptoms (P = 0.017; OR = 2.53, 95% CI = 1.18-5.43) were associated with new (versus established) diagnosis, whereas multiple gastric granulomas (P = 0.003; OR = 4.67, 95% CI = 1.67-13.04) and lack of upper GI symptoms (P < 0.001; OR = 6.75, 95% CI = 2.94-15.49) were associated with lower GI granulomas. Of 86 isolated GG cases (i.e. no prior diagnosis or lower GI granulomas), 51 (59.3%) were eventually diagnosed with CD, and this was independently associated with younger age (P = 0.014; OR = 1.11, 95% CI = 1.02-1.21) and upper GI symptoms (P = 0.033; OR = 19.27, 95% CI = 1.27-293.31). The positive predictive value of finding isolated GG towards a CD diagnosis in patients aged <30 years was 91%, increasing in males (93%), with single (94%), antral (97%) granulomas or upper GI symptoms (94%). CONCLUSIONS: GG does not correlate with H. pylori in patients with granulomatous disease, but may be associated with the organism when such diagnosis is lacking. In CD patients with GG, younger age and upper GI symptoms are associated with a new CD diagnosis, whereas multiple gastric granulomas and lack of upper GI symptoms correlate with lower GI granulomas. GG, including in isolated cases with no prior clinical history or granuloma, probably signifies CD, particularly in younger, male patients or those with single, antral granulomas or upper GI symptoms.

An Overview of Anterior Repositioning Splint Therapy for Disc Displacement-related Temporomandibular Disorders.

Anterior repositioning splint (ARS) therapy is considered one of the most effective therapies for treating disc displacement-related temporomandibular disorders (TMDs), which account for a large proportion of TMD cases. Owing to the wide application of this therapy, the exact mechanism of remission has increasingly drawn attention. Given that practitioners have different views on ARS therapy, its indications are broadened, and operating methods diverged. This review attempts to provide an overview of ARS therapy and helps practitioners establish indications and suitable operating methods. Representative views in the past 10 years were summarised, and conclusions were drawn as follows: The mechanism of ARS therapy is mainly attributed to internal derangement correction, improvement of stress distribution and recently reported joint remodeling. It has an evident effect in the short term, and the most prevalent operating methods are protruding the mandible to the edge-to-edge position and wearing the ARS for 24 hours daily for 3-6 months. However, long-term stability is not optimal, and thus indications should be selected carefully. Notably, most of the clinical studies in this field are case analyses with low-quality evidence. Well-designed RCTs are required to further validate relevant theories.

Force-Induced Autophagy in Periodontal Ligament Stem Cells Modulates M1 Macrophage Polarization via AKT Signaling.

Autophagy, a lysosomal degradation pathway, serves as a protective cellular mechanism in maintaining cell and tissue homeostasis under mechanical stimulation. As the mechanosensitive cells, periodontal ligament stem cells (PDLSCs) play an important role in the force-induced inflammatory bone remodeling and tooth movement process. However, whether and how autophagy in PDLSCs influences the inflammatory bone remodeling process under mechanical force stimuli is still unknown. In this study, we found that mechanical force stimuli increased the expression of the autophagy protein LC3, the number of M1 macrophages and osteoclasts, as well as the ratio of M1/M2 macrophages in the compression side of the periodontal ligament in vivo. These biological changes induced by mechanical force were repressed by the application of an autophagy inhibitor 3-methyladenine. Moreover, autophagy was activated in the force-loaded PDLSCs, and force-stimulated PDLSC autophagy further induced M1 macrophage polarization in vitro. The macrophage polarization could be partially blocked by the administration of autophagy inhibitor 3-methyladenine or enhanced by the administration of autophagy activator rapamycin in PDLSCs. Mechanistically, force-induced PDLSC autophagy promoted M1 macrophage polarization via the inhibition of the AKT signaling pathway. These data suggest a novel mechanism that force-stimulated PDLSC autophagy steers macrophages into the M1 phenotype via the AKT signaling pathway, which contributes to the inflammatory bone remodeling and tooth movement process.

Novel Inorganic Nanomaterial-Based Therapy for Bone Tissue Regeneration.

Extensive bone defect repair remains a clinical challenge, since ideal implantable scaffolds require the integration of excellent biocompatibility, sufficient mechanical strength and high biological activity to support bone regeneration. The inorganic nanomaterial-based therapy is of great significance due to their excellent mechanical properties, adjustable biological interface and diversified functions. Calcium-phosphorus compounds, silica and metal-based materials are the most common categories of inorganic nanomaterials for bone defect repairing. Nano hydroxyapatites, similar to natural bone apatite minerals in terms of physiochemical and biological activities, are the most widely studied in the field of biomineralization. Nano silica could realize the bone-like hierarchical structure through biosilica mineralization process, and biomimetic silicifications could stimulate osteoblast activity for bone formation and also inhibit osteoclast differentiation. Novel metallic nanomaterials, including Ti, Mg, Zn and alloys, possess remarkable strength and stress absorption capacity, which could overcome the drawbacks of low mechanical properties of polymer-based materials and the brittleness of bioceramics. Moreover, the biodegradability, antibacterial activity and stem cell inducibility of metal nanomaterials can promote bone regeneration. In this review, the advantages of the novel inorganic nanomaterial-based therapy are summarized, laying the foundation for the development of novel bone regeneration strategies in future.

Hidradenocarcinoma: a rare but challenging diagnosis.

Hidradenocarcinoma is a rare, aggressive cancer arising from sweat glands. Hidradenocarcinoma has no definitive histologic features compared to its benign hidradenoma, thereby posing a diagnostic challenge for clinicians and pathologists. This novel case report demonstrates specific MRI signs that suggested malignant degeneration of hidradenoma.

Mechanical penetration of ß-lactam-resistant Gram-negative bacteria by programmable nanowires.

ß-Lactam-resistant (BLR) Gram-negative bacteria that are difficult or impossible to treat are causing a global health threat. However, the development of effective nanoantibiotics is limited by the poor understanding of changes in the physical nature of BLR Gram-negative bacteria. Here, we systematically explored the nanomechanical properties of a range of Gram-negative bacteria (Salmonella, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae) with different degrees of ß-lactam resistance. Our observations indicated that the BLR bacteria had cell stiffness values almost 10× lower than that of ß-lactam-susceptible bacteria, caused by reduced peptidoglycan biosynthesis. With the aid of numerical modeling and experimental measurements, we demonstrated that these stiffness findings can be used to develop programmable, stiffness-mediated antimicrobial nanowires that mechanically penetrate the BLR bacterial cell envelope. We anticipate that these stiffness-related findings will aid in the discovery and development of novel treatment strategies for BLR Gram-negative bacterial infections.

IFN-γ promoted exosomes from mesenchymal stem cells to attenuate colitis via miR-125a and miR-125b.

Bone marrow mesenchymal stem cells (MSCs) have demonstrated therapeutic effects for colitis through immunomodulation and anti-inflammation. However, whether MSC-derived exosomes possessed the similar function remains unclear. In present study, exosomes were isolated from control and IFN-γ-primed MSCs and was verified by transmission electron microscope (TEM) and immunofluorescence staining. Administration of exosomes to mice significantly improved the disease activity index and histological score of colitis, and decreased the ratio of Th17 cells with elevated Treg cells ratio in mice colitis model. Exosomes from IFN-γ-primed MSCs showed superior therapeutic effects to colitis. Exosomes treatment inhibited Th17 differentiation in vitro, and exosomes from IFN-γ-primed MSCs showed higher inhibition efficacy. Mechanistically, exosomes treatment significantly decreased the expression of Stat3 and p-Stat3 to inhibit Th17 cells differentiation. IFN-γ pretreatment increased the level of miR-125a and miR-125b of exosomes, which directly targeted on Stat3, to repress Th17 cell differentiation. Moreover, combination of miR-125a and miR-125b agmior infusion also showed therapeutic effects for colitis, accompanied by decreased Th17 cell ratio. Collectively, this study demonstrates that IFN-γ treatment promoted exosomes from MSCs to attenuate colitis through increasing the level of miR-125a and miR-125b, which binding on 3'-UTR of Stat3 to repress Th17 cell differentiation. This study provides a new approach of exocytosis on the treatment of colitis.

Mechanical load-induced H2S production by periodontal ligament stem cells activates M1 macrophages to promote bone remodeling and tooth movement via STAT1.

BACKGROUND: Tooth movement is a unique bone remodeling process induced by mechanical stimulation. Macrophages are important in mediating inflammatory processes during mechanical load-induced tooth movement. However, how macrophages are regulated under mechanical stimulation remains unclear. Mesenchymal stem cells (MSCs) can modulate macrophage polarization during bone remodeling. Hydrogen sulfide (H2S) can be produced by MSCs and have been linked to bone homeostasis. Therefore, this study aimed to investigate whether H2S contributed to periodontal ligament stem cell (PDLSC)-regulated macrophage polarization and bone remodeling under mechanical stimulation. METHODS: An experimental mechanical load-induced tooth movement animal model was established. Changes in cystathionine-ß-synthase (CBS), markers of M1/M2 macrophages, tooth movement distance, and the number of osteoclasts were examined. The conditioned medium of PDLSCs with or without mechanical loading was utilized to treat THP-1 derived macrophages for 24 h to further investigate the effect of PDLSCs on macrophage polarization. Different treatments with H2S donor, CBS inhibitor, or the inhibitor of STAT1 were used to investigate the related mechanism. Markers of M1/M2 polarization and STAT1 pathway expression were evaluated in macrophages. RESULTS: Mechanical load promoted tooth movement and increased the number of M1-like macrophages, M1-associated pro-inflammatory cytokines, and the expression of CBS on the compression side of the periodontal ligament. The injection of CBS inhibitor or H2S donor could further repress or increase the number of M1-like macrophages, tartrate-resistant acid phosphatase-positive osteoclasts and the distance of tooth movement. Mechanistically, load-induced PDLSCs enhanced H2S production, which increased the expression of M1-associated cytokines in macrophages. These effects could be blocked by the administration of CBS inhibitor. Moreover, load-induced H2S steered M1 macrophage polarization via the STAT1 signaling pathway. CONCLUSIONS: These data suggest a novel mechanism indicating that mechanical load-stimulated PDLSCs produce H2S to polarize macrophages toward the M1 phenotype via the STAT1 signaling pathway, which contributes to bone remodeling and tooth movement process. These results provide new insights into the role of PDLSCs in regulating macrophage polarization and mediating bone remodeling under mechanical stimulation, and indicate that appropriate H2S supplementation may accelerate tooth movement.