Notopterol Inhibits the NF-κB Pathway and Activates the PI3K/Akt/Nrf2 Pathway in Periodontal Tissue.

Notopterol, an active component isolated from the traditional Chinese medicine Notopterygium incisum Ting ex H.T. Chang, exerts anti-inflammatory activity in rheumatoid arthritis. However, its roles in suppression of inflammatory insults and halting progression of tissue destruction in periodontitis remain elusive. In this study, we reveal that notopterol can inhibit osteoclastogenesis, thereby limiting alveolar bone loss in vivo. In vitro results demonstrated that notopterol administration inhibited synthesis of inflammatory mediators such as IL-1ß, IL-32, and IL-8 in LPS-stimulated human gingival fibroblasts. Mechanistically, notopterol inhibits activation of the NF-κB signaling pathway, which is considered a prototypical proinflammatory signaling pathway. RNA sequencing data revealed that notopterol activates the PI3K/protein kinase B (Akt)/NF-E2-related factor 2 (Nrf2) signaling pathway in LPS-stimulated human gingival fibroblasts, a phenomenon validated via Western blot assay. Additionally, notopterol treatment suppressed reactive oxygen species levels by upregulating the expression of antioxidant genes, including heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), catalase (CAT), and glutathione reductase (GSR), indicating that notopterol confers protection against oxidative stress. Notably, inhibition of Akt activity by the potent inhibitor, MK-2206, partially attenuated both anti-inflammatory and antioxidant effects of notopterol. Collectively, these results raise the possibility that notopterol relieves periodontal inflammation by suppressing and activating the NF-κB and PI3K/AKT/Nrf2 signaling pathways in periodontal tissue, respectively, suggesting its potential as an efficacious treatment therapy for periodontitis.

Development of Novel ß-Carboline/Furylmalononitrile Hybrids as Type I/II Photosensitizers with Chemo-Photodynamic Therapy and Minimal Toxicity.

Chemo-photodynamic therapy is a treatment method that combines chemotherapy and photodynamic therapy and has demonstrated significant potential in cancer treatment. However, the development of chemo-photodynamic therapeutic agents with fewer side effects still poses a challenge. Herein, we designed and synthesized a novel series of ß-carboline/furylmalononitrile hybrids 10a-i and evaluated their chemo-photodynamic therapeutic effects. Most of the compounds were photodynamically active and exhibited cytotoxic effects in four cancer cells. In particular, 10f possessed type-I/II photodynamic characteristics, and its 1O2 quantum yield increased by 3-fold from pH 7.4 to 4.5. Most interestingly, 10f exhibited robust antiproliferative effects by tumor-selective cytotoxicities and hypoxic-overcoming phototoxicities. In addition, 10f generated intracellular ROS and induced hepatocellular apoptosis, mitochondrial damage, and autophagy. Finally, 10f demonstrated extremely low acute toxicity (LD50 = 1415 mg/kg) and a high tumor-inhibitory rate of 80.5% through chemo-photodynamic dual therapy. Our findings may provide a promising framework for the design of new photosensitizers for chemo-photodynamic therapy.

miR-378a-5p represses Barrett's esophagus cells proliferation, migration and invasion through targeting TSPAN8.

Barrett's esophagus (BE) belongs to a pathological phenomenon occurring in the esophagus, this paper intended to unveil the underlying function of miR-378a-5p and its target TSPAN8 in BE progression. GEO analysis was conducted to determine differentially expressed genes in BE samples. Non-dysplastic metaplasia BE samples, high-grade dysplastic BE samples and controls were collected from subjects. CP-A and CP-B cells were exposed to bile acids (BA) to mimic gastroesophageal reflux in BE cells. RT-qPCR as well as western blot were applied for verifying expressions of miR-378a-5p, TSPAN8, CDX2 and SOX9. CCK-8, wound scratch together with Transwell assays were exploited for ascertaining cell proliferation, migration as well as invasion. The targeted relationship of miR-378a-5p and TSPAN8 could be verified by correlation analysis, dual-luciferase reporter experiment, and rescue experiments. Through analyzing GSE26886 dataset, we screened the most abundantly expressed gene TSPAN8 in BE samples. miR-378a-5p was reduced whereas TSPAN8 was elevated in CP-A as well as CP-B cells after triggering with BA. Knocking down TSPAN8 could counteract BA-triggered enhancement in BE cell proliferation, migration along with invasion. miR-378a-5p could suppress BE cell proliferation, and migration along with invasion via targeting TSPAN8. In BE, miR-378a-5p targeted TSPAN8 to inhibit BE cell proliferation, and migration along invasion. miR-378a-5p deletion or elevation of TSPAN8 may be key point in regulating CDX2 and SOX9 levels, thereby promoting BE formation.

Loss of ß-catenin causes cementum hypoplasia by hampering cementogenic differentiation of Axin2-expressing cells.

BACKGROUND AND OBJECTIVE: Although cementum plays an essential role in tooth attachment and adaptation to occlusal force, the regulatory mechanisms of cementogenesis remain largely unknown. We have previously reported that Axin2-expressing (Axin2+ ) mesenchymal cells in periodontal ligament (PDL) are the main cell source for cementum growth, and constitutive activation of Wnt/ß-catenin signaling in Axin2+ cells results in hypercementosis. Therefore, the aim of the present study was to further evaluate the effects of ß-catenin deletion in Axin2+ cells on cementogenesis. MATERIALS AND METHODS: We generated triple transgenic mice to conditionally delete ß-catenin in Axin2-lineage cells by crossing Axin2CreERT2/+ ; R26RtdTomato/+ mice with ß-cateninflox/flox mice. Multiple approaches, including X-ray analysis, micro-CT, histological stainings, and immunostaining assays, were used to analyze cementum phenotypes and molecular mechanisms. RESULTS: Our data revealed that loss of ß-catenin in Axin2+ cells led to a cementum hypoplasia phenotype characterized by a sharp reduction in the formation of both acellular and cellular cementum. Mechanistically, we found that conditional removal of ß-catenin in Axin2+ cells severely impaired the secretion of cementum matrix proteins, for example, bone sialoprotein (BSP), dentin matrix protein 1 (DMP1) and osteopontin (OPN), and markedly inhibited the differentiation of Axin2+ mesenchymal cells into osterix+ cementoblasts. CONCLUSIONS: Our findings confirm the vital role of Axin2+ mesenchymal PDL cells in cementum growth and demonstrate that Wnt/ß-catenin signaling shows a positive correlation with cementogenic differentiation of Axin2+ cells.

Design, synthesis and pharmacological characterization of aminopyrimidine derivatives as BTK/FLT3 dual-target inhibitors against acute myeloid leukemia.

A novel class of aminopyrimidine-based Bruton's tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) dual-target inhibitors based on the BTK inhibitor spebrutinib was designed for the treatment of acute myeloid leukemia. Representative compounds 14d, 14g, 14j and 14m effectively inhibited BTK, FLT3, and FLT3(D835Y) mutant activities with low nanomolar IC50's. These compounds displayed potent antiproliferative activities against leukemia cells with IC50's of 0.29-950 nM. In particular, 14m had IC50 values 101-1045 times lower than those of spebrutinib against all cancer cell lines tested. Compound 14m effectively induced autophagy and apoptosis in MV-4-11 cells through regulating related proteins in a dose-dependent manner. Finally, intraperitoneal administration of 14m at 20 mg/kg significantly repressed the growth of MV-4-11 cells with a TGI value of 95.68% with no apparent toxicity. These BTK/FLT3 dual-target inhibitors represent promising leads for further structural optimization and antitumor mechanism studies.

Rational design of ß-carboline as an efficient type I/II photosensitizer to enable hypoxia-tolerant chemo-photodynamic therapy.

Photodynamic therapy (PDT) is a clinically approved treatment for cancer due to its high spatiotemporal selectivity and non-invasive modality. However, its therapeutic outcomes are always limited to the severe hypoxia environment of the solid tumor. Herein, two novel photosensitizers HY and HYM based on naturally antitumor alkaloids ß-carboline were designed and synthesized. Through a series of experiments, we found HY and HYM can produce type II ROS (singlet oxygen) after light irradiation. HYM had higher singlet oxygen quantum yield and molar extinction coefficient than HY, as well as type I PDT behavior, which further let us find that HYM could exhibit robust phototoxicity activities in both normoxia and hypoxia. Meanwhile, HYM showed tumor-selective cytotoxicity with minimal toxicity toward normal cells. Notably, thanks to HYM's hypoxia-tolerant type I/II PDT and tumor selective chemotherapy, HYM showed synergistic inhibitory effect on tumor growth (inhibition rate > 91%). Our research provides a promising photosensitizer for hypoxia-tolerant chemo-photodynamic therapy, and may also give a novel molecular skeleton for photosensitizer design.

Effect of lipoxin A4 on the osteogenic differentiation of periodontal ligament stem cells under lipopolysaccharide-induced inflammatory conditions.

Lipoxin A4 (LXA4) has been identified as the braking signal of inflammation, but the specific role of LXA4 in regulating the regenerative potential of periodontal ligament stem cells (PDLSCs) remains unclear. The aim of this study was to investigate whether and, if so, how LXA4 improves the osteogenic differentiation of PDLSCs in a lipopolysaccharide (LPS)-induced inflammatory environment. We detected the effects of LXA4 on the osteogenic differentiation of PDLSCs in vitro and explored the bone regenerative potential of LXA4-treated inflammatory PDLSCs in vivo using a calvarial critical sized defect model in male rats. RNA sequencing, real-time PCR and western blot were performed to elucidate the relevant potential mechanisms. Results showed that LXA4 promoted the proliferation, migration and osteogenic differentiation of PDLSCs in vitro, and effectively improved the impaired osteogenic capacity of PDLSCs induced by LPS both in vitro and in vivo. Mechanistically, LXA4 significantly promoted the PI3K/AKT phosphorylation under inflammatory conditions. Additionally, LY294002 (a PI3K inhibitor) blocked the effect of LXA4, suggesting that the PI3K/AKT pathway is a key signaling pathway that mediates the effect of LXA4 on the osteogenesis of inflammatory PDLSCs. These findings indicate LXA4 may be a promising strategy for periodontal regeneration using inflammatory PDLSCs.

Activation of Wnt signaling in Axin2+ cells leads to osteodentin formation and cementum overgrowth.

OBJECTIVES: In this study, we used the mouse incisor model to investigate the regulatory mechanisms of Wnt/ß-catenin signaling on Axin2+ cells in tooth development. MATERIALS AND METHODS: Axin2lacZ/+ reporter mice were used to define the expression pattern of Axin2 in mouse incisors. We traced the fate of Axin2+ cells from postnatal Day 21 (P21) to P56 using Axin2CreERT2/+ and R26RtdTomato/+ reporter mice. For constitutive activation of Wnt signaling, Axin2CreERT2/+ , ß-cateninflox(Ex3)/+ , and R26RtdTomato/+ (CA-ß-cat) mice were generated to investigate the gain of function (GOF) of ß-catenin in mouse incisor growth. RESULTS: The X-gal staining of Axin2lacZ/+ reporter mice and lineage tracing showed that Axin2 was widely expressed in dental mesenchyme of mouse incisors, and Axin2+ cells were essential cell sources for odontoblasts, pulp cells, and periodontal ligament cells. The constitutive activation of Wnt signaling in Axin2+ cells resulted in the formation of osteodentin featured with increased DMP1 and dispersed DSP expression and overgrowth of cementum. CONCLUSION: Wnt signaling plays a key role in the differentiation and maturation of Axin2+ cells in mouse incisors.

Osteogenic mesenchymal stem cells/progenitors in the periodontium.

Periodontitis is the major cause of tooth loss in adults and is mainly characterized by alveolar bone destruction. Elucidating the mesenchymal stem cell (MSC)/progenitor populations of alveolar bone formation will provide valuable insights into regenerative approaches to clinical practice, such as endogenous regeneration and stem-cell-based tissue engineering therapies. Classically, MSCs residing in the bone marrow, periosteum, periodontal ligament (PDL), and even the gingiva are considered to be osteogenic progenitors. Furthermore, the contributions of MSCs expressing specific markers, including Gli1, Axin2, PTHrP, LepR, and α-SMA, to alveolar bone formation have been studied using cell lineage tracing and gene knockout models. In this review, we describe the MSCs/progenitors of alveolar bone and the biological properties of different subpopulations of MSCs involved in alveolar bone development, remodeling, injury repair, and regeneration.

Axin2-CreERT2 mediated knockout of bone morphogenetic protein receptor type 1A caused abnormal secondary dentine and altered cell fate of Axin2-expressing odontogenic cells.

AIM: Inducing odontogenic differentiation and tubular dentine formation is extremely important in dentine repair and tooth regeneration. Bone morphogenic proteins (BMPs) signalling plays a critical role in dentine development and tertiary dentine formation, whilst how BMPR1A-mediated signalling affects odontoblastic differentiation of Axin2-expressing (Axin2+ ) odontogenic cells and tubular dentine formation remains largely unknown. This study aims to reveal the cellular and molecular mechanisms involved in the formation of secondary dentine. METHODOLOGY: Axin2lacZ/+ mice harvested at post-natal 21 (P21) were used to map Axin2+ mesenchymal cells. Axin2CreERT2/+ ; R26RtdTomato/+ mice and Axin2CreERT2/+ ; R26RDTA/+ ; R26RtdTomato/+ mice were generated to observe the tempo-spatial distribution pattern of Axin2-lineage cells and the effect of ablation of Axin2+ cells on dentinogenesis, respectively. A loss-of-function model was established with Axin2CreERT2/+ ; Bmpr1afl/fl ; R26RtdTomato/+ (cKO) mice to study the role of BMP signalling in regulating Axin2+ cells. Micro-computed tomography, histologic and immunostainings, and other approaches were used to examine biological functions, including dentine formation, mineralization and cell differentiation in cKO mice. RESULTS: The results showed rich expression of Axin2 in odontoblasts at P21. Lineage tracing assay confirmed the wide distribution of Axin2 lineage cells in odontoblast layer and dental pulp during secondary dentine formation (P23 to P56), suggesting that Axin2+ cells are important cell source of primary odontoblasts. Ablation of Axin2+ cells (DTA mice) significantly impaired secondary dentine formation characterized with notably reduced dentine thickness (Mean of control: 54.11 µm, Mean of DTA: 27.79 µm, p = .0101). Furthermore, malformed osteo-dentine replaced the tubular secondary dentine in the absence of Bmpr1a with irregular cell morphology, abnormal cellular process formation and lack of cell-cell tight conjunction. Remarkably increased expression of osteogenic markers like Runx2 and DMP1 was detected, whilst DSP expression was observed in a dispersed manner, indicating an impaired odontogenic cell fate and failure in producing tubular dentine in cKO mice. CONCLUSIONS: Axin2+ cells are a critical population of primary odontoblasts which contribute to tubular secondary dentine formation, and BMP signalling pathway plays a vital role in maintaining the odontogenic fate of Axin2+ cells.

The Effects of Auditory Working Memory Task on Situation Awareness in Complex Dynamic Environments: An Eye-movement Study.

OBJECTIVE: This study investigated the effect of auditory working memory task on situation awareness (SA) and eye-movement patterns in complex dynamic environments. BACKGROUND: Many human errors in aviation are caused by a lack of SA, and distraction from auditory secondary tasks is a serious threat to SA. However, it remains unclear how auditory working memory tasks affect SA and eye-movement patterns. METHOD: Participants (n = 28) were randomly allocated to two groups and received different periods of visual search training (short versus long). They subsequently completed a situation awareness measurement task in three auditory secondary task conditions (without secondary task, auditory calculation task, and auditory 2-back task). Eye-movement data were collected during the situation awareness measurement task. RESULTS: The auditory 2-back task significantly reduced overall SA, Level 1 SA, dwell times, and total percentage of fixation time on task-related areas of interests in the SA measurement task. Overall SA and Level 3 SA were not reduced by the auditory 2-back task in individuals in the longer visual search training time condition. CONCLUSION: Auditory working memory load impairs SA in the perception and projection stage; however, greater experience can overcome impairment of SA in the projection stage. APPLICATION: This study provided possible approaches to preventing loss of SA: (1) improving crew members' communication skills to ensure the accurate and clear transmission of information, reducing the difficulty of processing information, and (2) providing targeted cognitive training tailored to each pilot's level of experience.

Proto-Oncogene FAM50A Can Regulate the Immune Microenvironment and Development of Hepatocellular Carcinoma In Vitro and In Vivo.

Hepatocellular carcinoma (HCC) is a vital global health problem. The characteristics are high morbidity, high mortality, difficulty in early diagnosis and insensitivity to chemotherapy. The main therapeutic schemes for treating HCC mainly include Tyrosine kinase inhibitors represented by sorafenib and lenvatinib. In recent years, immunotherapy for HCC has also achieved certain results. However, a great number of patients failed to benefit from systemic therapies. FAM50A belongs to the FAM50 family and can be used as a DNA-binding protein or transcription factor. It may take part in the splicing of RNA precursors. In studies of cancer, FAM50A has been demonstrated to participate in the progression of myeloid breast cancer and chronic lymphocytic leukemia. However, the effect of FAM50A on HCC is still unknown. In this study, we have demonstrated the cancer-promoting effects and diagnostic value of FAM50A in HCC using multiple databases and surgical samples. We identified the role of FAM50A in the tumor immune microenvironment (TIME) and immunotherapy efficacy in HCC. We also proved the effects of FAM50A on the malignancy of HCC in vitro and in vivo. In conclusion, we confirmed that FAM50A is an important proto-oncogene in HCC. FAM50A acts as a diagnostic marker, immunomodulator and therapeutic target for HCC.

Discoidin domain receptors (DDRs): Potential implications in periodontitis.

Periodontitis is a chronic inflammatory disease leading to the destruction of periodontal tissues associated with high prevalence and significant economic burden. As special collagen-binding tyrosine kinase receptors, the discoidin domain receptors (DDRs) can control cell migration, adhesion, proliferation, and extracellular matrix remodeling. DDRs are constitutively expressed and widely distributed in periodontal tissues which are rich in collagen. Ddr1/2 knockout mice showed significant periodontal defects including connective tissue destruction, alveolar bone loss, and even tooth loss. It has been demonstrated that bone homeostasis, inflammation, matrix metalloproteinases, and autophagy are crucial characteristics involved in the pathogenesis of periodontitis. Of note, DDRs have been reported to participate in the above pathophysiological processes, implicating the potential roles of DDRs in periodontitis. In this review article, we aim to illustrate the possible roles of DDRs in periodontitis in an attempt to explore their potential value as therapeutic targets for periodontitis.

All-in-One: Multifunctional Hydrogel Accelerates Oxidative Diabetic Wound Healing through Timed-Release of Exosome and Fibroblast Growth Factor.

The treatment of diabetic wounds remains a major challenge in clinical practice, with chronic wounds characterized by multiple drug-resistant bacterial infections, angiopathy, and oxidative damage to the microenvironment. Herein, a novel in situ injectable HA@MnO2 /FGF-2/Exos hydrogel is introduced for improving diabetic wound healing. Through a simple local injection, this hydrogel is able to form a protective barrier covering the wound, providing rapid hemostasis and long-term antibacterial protection. The MnO2 /ε-PL nanosheet is able to catalyze the excess H2 O2 produced in the wound, converting it to O2 , thus not only eliminating the harmful effects of H2 O2 but also providing O2 for wound healing. Moreover, the release of M2-derived Exosomes (M2 Exos) and FGF-2 growth factor stimulates angiogenesis and epithelization, respectively. These in vivo and in vitro results demonstrate accelerated healing of diabetic wounds with the use of the HA@MnO2 /FGF-2/Exos hydrogel, presenting a viable strategy for chronic diabetic wound repair.

Metformin alleviates bone loss in ovariectomized mice through inhibition of autophagy of osteoclast precursors mediated by E2F1.

BACKGROUND: Postmenopausal bone loss, mainly caused by excessive bone resorption mediated by osteoclasts, has become a global public health burden. Metformin, a hypoglycemic drug, has been reported to have beneficial effects on maintaining bone health. However, the role and underlying mechanism of metformin in ovariectomized (OVX)-induced bone loss is still vague. RESULTS: In this study, we demonstrated for the first time that metformin administration alleviated bone loss in postmenopausal women and ovariectomized mice, based on reduced bone resorption markers, increased bone mineral density (BMD) and improvement of bone microstructure. Then, osteoclast precursors administered metformin in vitro and in vivo were collected to examine the differentiation potential and autophagical level. The mechanism was investigated by infection with lentivirus-mediated BNIP3 or E2F1 overexpression. We observed a dramatical inhibition of autophagosome synthesis and osteoclast formation and activity. Treatment with RAPA, an autophagy activator, abrogated the metformin-mediated autophagy downregulation and inhibition of osteoclastogenesis. Additionally, overexpression of E2F1 demonstrated that reduction of OVX-upregulated autophagy mediated by metformin was E2F1 dependent. Mechanistically, metformin-mediated downregulation of E2F1 in ovariectomized mice could downregulate BECN1 and BNIP3 levels, which subsequently perturbed the binding of BECN1 to BCL2. Furthermore, the disconnect between BECN1 and BCL2 was shown by BNIP3 overexpression. CONCLUSION: In summary, we demonstrated the effect and underlying mechanism of metformin on OVX-induced bone loss, which could be, at least in part, ascribed to its role in downregulating autophagy during osteoclastogenesis via E2F1-dependent BECN1 and BCL2 downregulation, suggesting that metformin or E2F1 inhibitor is a potential agent against postmenopausal bone loss. Video abstract.

Axin2-expressing cells in the periodontal ligament are regulated by bone morphogenetic protein signalling and play a pivotal role in periodontium development.

AIM: To date, controversies still exist regarding the exact cellular origin and regulatory mechanisms of periodontium development, which hinders efforts to achieve ideal periodontal tissue regeneration. Axin2-expressing cells in the periodontal ligament (PDL) have been shown to be a novel progenitor cell population that is essential for periodontal homeostasis. In the current study, we aimed to elucidate the regulatory role of bone morphogenetic protein receptor type 1A (BMPR1A)-mediated BMP signalling in Axin2-expressing cells during periodontium development. MATERIALS AND METHODS: Two strains of Axin2 gene reporter mice, Axin2lacZ/+ and Axin2CreERT2/+ ; R26RtdTomato/+ mice, were used. We next generated Axin2CreERT2/+ ; R26RDTA/+ ; R26RtdTomato/+ mice to genetically ablate of Axin2-lineage cells. Axin2CreERT2/+ ; Bmpr1afl/fl ; R26RtdTomato/+ mice were established to conditionally knock out Bmpr1a in Axin2-lineage cells. Multiple approaches, including micro-computed tomography, calcein green, and alizarin red double-labelling, scanning electron microscopy, and histological and immunostaining assays, were used to analyse periodontal phenotypes and molecular mechanisms. RESULTS: X-gal staining revealed that Axin2-expressing cells in the PDL were mainly distributed along the alveolar bone and cementum surface. Cell lineage tracing and cell ablation assays further demonstrated the indispensable role of Axin2-expressing cells in periodontium development. Next, we found that conditional knockout of Bmpr1a in Axin2-lineage cells led to periodontal defects, which were characterized by alveolar bone loss, impaired cementogenesis, and abnormal Sharpey's fibres. CONCLUSIONS: Our findings suggest that Axin2-expressing cells in the PDL are essential for periodontium development, which is regulated by BMP signalling.

The critical role of nuclear factor I-C in tooth development.

OBJECTIVES: Nuclear factor I-C (NFIC) plays a critical role in regulating epithelial-mesenchymal crosstalk during tooth development. However, it remains largely unknown about how NFIC functions in dentin and enamel formation. In the present review, we aim to summarize the most recent discoveries in the field and gain a better understanding of the roles NFIC performs during tooth formation. SUBJECTS AND METHODS: Nfic-/- mice exhibit human dentin dysplasia type I (DDI)-like phenotypes signified by enlarged pulp chambers, the presence of short-root anomaly, and failure of odontoblast differentiation. Although loss of NFIC has little effect on molar crown morphology, researchers have detected aberrant microstructures of enamel in the incisors. Recently, accumulating evidence has further uncovered the novel function of NFIC in the process of enamel and dentin formation. RESULTS: During epithelial-mesenchyme crosstalk, the expression of NFIC is under the control of SHH-PTCH-SMO-GLI1 pathway. NFIC is closely involved in odontoblast lineage cells proliferation and differentiation, and the maintenance of NFIC protein level in cytoplasm is negatively regulated by TGF-ß signaling pathway. In addition, NFIC has mild effect on ameloblast differentiation, enamel mineralization and cementum formation. CONCLUSIONS: NFIC plays an important role in tooth development and is required for the formation of dentin, enamel as well as cementum.

The identification of critical time windows of postnatal root elongation in response to Wnt/ß-catenin signaling.

OBJECTIVES: In this study, we attempted to define the precise window of time for molar root elongation using a gain-of-function mutation of ß-catenin model. MATERIALS AND METHODS: Both the control and constitutively activated ß-catenin (CA-ß-cat) mice received a one-time tamoxifen administration (for activation of ß-catenin at newborn, postnatal day 3, or 5, or 7, or 9) and were harvested at the same stage of P21. Multiple approaches were used to define the window of time of postnatal tooth root formation. RESULTS: In the early activation groups (tamoxifen induction at newborn, or P3 or P5), there was a lack of molar root elongation in the CA-ß-cat mice. When induced at P7, the root length was slightly reduced at P21. However, the root length was essentially the same as that in the control when ß-cat activated at P9. This study indicates that root elongation occurs in a narrow time of window, which is highly sensitive to a change of ß-catenin levels. Molecular studies showed a drastic decrease in the levels of nuclear factor I-C (NFIC) and osterix (OSX), plus sharp reductions of odontoblast differentiation markers, including Nestin, dentin sialoprotein (DSP), and dentin matrix protein 1 (DMP1) at both mRNA and protein levels. CONCLUSIONS: Murine molar root elongation is precisely regulated by the Wnt/ß-catenin signaling within a narrow window of time (newborn to day 5).

Operative treatment outcomes of anterior sternoclavicular joint dislocation using two experimental methods - an acromioclavicular joint hook plate versus a locking plate: a retrospective study.

BACKGROUND: We aimed to compare the intraoperative and early postoperative clinical outcomes of using an acromioclavicular joint hook plate (AJHP) versus a locking plate (LP) in the treatment of anterior sternoclavicular joint dislocation. METHODS: Seventeen patients with anterior sternoclavicular joint dislocation were retrospectively analyzed from May 2014 to September 2019. Six patients were surgically treated with an AJHP, and 11 were surgically treated with an LP. Five male and one female patients composed the AJHP group, and nine male and two female patients composed the LP group. The mean age of all patients was 49.5 years. RESULTS: Reduction and fixation were performed with AJHP or LP in all 17 patients. The mean operative blood loss, operative time, and length of incision in the AJHP group were significantly better than those in the LP group. Shoulder girdle movement of the AJHP group was significantly better than that of the LP group. CONCLUSIONS: This study revealed that AJHP facilitated glenohumeral joint motion, reduced the risk of rupture of mediastinal structures, required a shorter incision, and had lesser blood loss and a shorter duration of operation compared with LP. However, some deficiencies require further improvement.

The vital role of Gli1+ mesenchymal stem cells in tissue development and homeostasis.

The hedgehog (Hh) signaling pathway plays an essential role in both tissue development and homeostasis. Glioma-associated oncogene homolog 1 (Gli1) is one of the vital transcriptional factors as well as the direct target gene in the Hh signaling pathway. The cells expressing the Gli1 gene (Gli1+ cells) have been identified as mesenchymal stem cells (MSCs) that are responsible for various tissue developments, homeostasis, and injury repair. This review outlines some recent discoveries on the crucial roles of Gli1+ MSCs in the development and homeostasis of varieties of hard and soft tissues.