Blocking Metallothionein-2 Expression by Copper-Doped Carbon Dots Induces Cellular Antioxidant System Collapse for Antitumor Therapy.

The insufficient antioxidant reserves in tumor cells play a critical role in reactive oxygen species (ROS)-mediated therapeutics. Metallothionein-2 (MT-2), an intracellular cysteine-rich protein renowned for its potent antioxidant properties, is intricately involved in tumor development and correlates with a poor prognosis. Consequently, MT-2 emerges as a promising target for tumor therapy. Herein, we present the development of copper-doped carbon dots (Cu-CDs) to target MT-2 to compromise the delicate antioxidant reserves in tumor cells. These Cu-CDs with high tumor accumulation and prolonged body retention can effectively suppress tumor growth by inducing oxidative stress. Transcriptome sequencing unveils a significant decrease in MT-2 expression within the in vivo tumor samples. Further mechanical investigations demonstrate that the antitumor effect of Cu-CDs is intricately linked to apolipoprotein E (ApoE)-mediated downregulation of MT-2 expression and the collapse of the antioxidant system. The robust antitumor efficacy of Cu-CDs provides invaluable insights into developing MT-2-targeted nanomedicine for cancer therapies.

Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice.

BACKGROUND: Extracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA. MATERIALS AND METHODS: To determine whether Dspp+/- mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/-, and Dspp homozygous (Dspp-/-) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/- mice over time, condyles of Dspp+/- and WT mice were analyzed radiologically, histologically, and immunohistochemically. RESULTS: Micro-CT and histomorphometric analyses revealed that Dspp+/- and Dspp-/- mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp-/- mice which exhibited tooth loss, Dspp+/- mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/- mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/- mice showed increased distribution of osteoclasts in the subchondral bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage. CONCLUSIONS: Dspp+/- mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

Carbon Dots as Potential Therapeutic Agents for Treating Non-Alcoholic Fatty Liver Disease and Associated Inflammatory Bone Loss.

Nonalcoholic fatty liver disease (NAFLD) has emerged as one of the most significant metabolic diseases worldwide and is associated with heightened systemic inflammation, which has been shown to foster the development of extrahepatic complications. So far, there is no definitive, effective, and safe treatment for NAFLD. Although antidiabetic agents show potential for treating NAFLD, their efficacy is significantly limited by inadequate liver accumulation at safe doses and unwanted side effects. Herein, we demonstrate that pharmacologically active carbon dots (MCDs) derived from metformin can selectively accumulate in the liver and ameliorate NAFLD by activating hepatic PPARα expression while maintaining an excellent biosafety. Interestingly, MCDs can also improve the function of extrahepatic organs and tissues, such as alleviating alveolar inflammatory bone loss, in the process of treating NAFLD. This study proposes a feasible and safe strategy for designing pharmacologically active MCDs to target the liver, which regulates lipid metabolism and systemic inflammation, thereby treating NAFLD and its related extrahepatic complications.

Mannose-doped metal-organic frameworks induce tumor cell pyroptosis via the PERK pathway.

BACKGROUND: The implementation of pyroptosis exhibits significant potential as a tactic to enhance tumor immune microenvironments. Previous applications of pyroptosis inducers have encountered various limitations, such as the development of drug resistance, manifestation of toxic side effects, and a deficiency in targeting capabilities. As a result, there is a growing demand for tumor therapeutic molecules that can overcome these obstacles. Therefore, the objective of this study is to develop a multifunctional nanospheres that addresses these challenges by enabling high-precision targeting of tumor cells and inducing effective pyroptosis. RESULTS: We prepared a mannose-modified MOF called mannose-doped Fe3O4@NH2-MIL-100 (M-FNM). M-FNM could enter CAL27 cells through MR-mediated endocytosis, which caused in a significant increase in the level of intracellular ROS. This increase subsequently triggered ER stress and activated the PERK-eIF2α-ATF4-CHOP signaling pathway. CHOP then mediated the downstream cascade of Caspase-1, inducing pyroptosis. In in vivo experiments, M-FNM demonstrated excellent targeting ability and exhibited anti-tumor effects. Additionally, M-FNM reshaped the immune microenvironment by promoting the infiltration of anti-tumor immune cells, primarily T lymphocytes. CONCLUSIONS: M-FNM significantly decreased tumor growth. This novel approach to induce pyroptosis in tumor cells using M-FNM may offer new avenues for the development of effective immunotherapies against cancer.

Fe-doped carbon dots: a novel biocompatible nanoplatform for multi-level cancer therapy.

BACKGROUND: Tumor treatment still remains a clinical challenge, requiring the development of biocompatible and efficient anti-tumor nanodrugs. Carbon dots (CDs) has become promising nanomedicines for cancer therapy due to its low cytotoxicity and easy customization. RESULTS: Herein, we introduced a novel type of "green" nanodrug for multi-level cancer therapy utilizing Fe-doped carbon dots (Fe-CDs) derived from iron nutrient supplement. With no requirement for target moieties or external stimuli, the sole intravenous administration of Fe-CDs demonstrated unexpected anti-tumor activity, completely suppressing tumor growth in mice. Continuous administration of Fe-CDs for several weeks showed no toxic effects in vivo, highlighting its exceptional biocompatibility. The as-synthesized Fe-CDs could selectively induce tumor cells apoptosis by BAX/Caspase 9/Caspase 3/PARP signal pathways and activate antitumoral macrophages by inhibiting the IL-10/Arg-1 axis, contributing to its significant tumor immunotherapy effect. Additionally, the epithelial-mesenchymal transition (EMT) process was inhibited under the treatment of Fe-CDs by MAPK/Snail pathways, indicating the capacity of Fe-CDs to inhibit tumor recurrence and metastasis. CONCLUSIONS: A three-level tumor treatment strategy from direct killing to activating immunity to inhibiting metastasis was achieved based on "green" Fe-CDs. Our findings reveal the broad clinical potential of Fe-CDs as a novel candidate for anti-tumor nanodrugs and nanoplatform.

Piezo1 mediates the degradation of cartilage extracellular matrix in malocclusion-induced TMJOA.

OBJECTIVES: To evaluate the role of Piezo1 in the malocclusion-induced osteoarthritic cartilage of the temporomandibular joint. METHODS: A temporomandibular joint osteoarthritis model was established using a unilateral anterior crossbite in vivo, and cartilage degeneration and Piezo1 expression were observed by histological and immunohistochemical staining. ATDC5 cells were loaded with 24 dyn/cm2 fluid flow shear stress using the Flexcell device in vitro and expression and function of Piezo1 were evaluated. After identifying the function of Piezo1 in YAP translocation under FFSS conditions, the influence of Piezo1 and YAP on metabolism-related enzymes under FFSS was detected through a real-time polymerase chain reaction analysis and western blotting. A UAC-TMJ injection model was established to observe the therapeutic effect of intra-articular injection of a Piezo1 inhibitor on osteoarthritic cartilage matrix loss. RESULTS: Piezo1 was overexpressed in the osteoarthritic cartilage and cultured chondrocytes under shear stress. Piezo1 Silencing inhibited the nuclear translocation of YAP and subsequently downregulated the expression of MMP13 and ADAMTS5. Intra-articular injection of the Piezo1 inhibitor, GsMTx4, could ameliorate proteoglycan degradation in malocclusion-induced TMJOA and suppressed MMP13 and ADAMTS5 expression. CONCLUSIONS: Our results revealed that the activation of Piezo1 promotes mechanical-induced cartilage degradation through the YAP-MMP13/ADAMTS5 signaling pathway.

[Oral Squamous Cell Carcinoma-Derived Cell-Free DNA Modulates Stemness and Migration of Oral Squamous Cell Carcinoma Cell Line by Inducing M2 Macrophage Polarization].

Objective: To investigate the effect of oral squamous cell carcinoma (OSCC)-derived cell-free DNA (cfDNA) on the polarization of macrophages and the regulatory effect of polarized macrophages on the stemness and migration of OSCC cells. Methods: A total of 30 OSCC tissue samples, 10 dysplastic oral tissue samples, and 10 normal oral tissue samples were collected. The status of all tissue samples was confirmed by pathology analysis. Immunohistochemical (IHC) staining and immunofluorescence (IF) staining were performed to examine the cell count and location of M2 macrophages in different types of oral tissue samples. The conditioned medium (CM) of OSCC cell line CAL-27 from the human tongue was collected and the cfDNA was concentrated and isolated for identification. The macrophages were treated by cfDNA and their morphological characteristics were observed under microscope. The expression levels of polarization-related indicators were determined by RT-qPCR. CAL-27 cell line was treated with macrophage CM induced by cfDNA and the expression levels of stemness-related genes were determined by RT-qPCR. Scratch-wound assay was conducted to verify that the migration ability of CAL-27 was modulated by macrophages induced by cfDNA. Results: There were more M2 macrophages in the deep connective tissue of dysplastic oral epithelium and the stroma of OSCC compared with those in the normal oral tissues ( P<0.05). OSCC cell line CAL-27 could secret cfDNA of 10000-15000 bp in length. cfDNA secreted by CAL-27 could induced in macrophages significantly higher expression of M2-macrophage-related genes ( P<0.05). cfDNA-treated macrophages induced significantly increased expression of stemness-related genes in CAL-27 cell line ( P<0.05) and promoted the migration ability of CAL-27 cell line ( P<0.05). Conclusion: OSCC-derived cfDNA promotes stemness and migration of OSCC cell line by inducing M2 macrophage polarization.

Arginine methylation of R81 in Smad6 confines BMP-induced Smad1 signaling.

Bone morphogenetic proteins (BMPs) secreted by a variety of cell types are known to play essential roles in cell differentiation and matrix formation in the bone, cartilage, muscle, blood vessel, and neuronal tissue. BMPs activate intracellular effectors via C-terminal phosphorylation of Smad1, Smad5, and Smad9, which relay the signaling by forming a complex with Smad4 and translocate to the nucleus for transcriptional activation. Smad6 inhibits BMP signaling through diverse mechanisms operative at the membrane, cytosolic, and nuclear levels. However, the mechanistic underpinnings of Smad6 functional diversity remain unclear. Here, using a biochemical approach and cell differentiation systems, we report a cytosolic mechanism of action for Smad6 that requires arginine methylation at arginine 81 (R81) and functions through association with Smad1 and interference with the formation of Smad1-Smad4 complexes. By mutating the methylated arginine residue, R81, and by silencing the expression of protein arginine methyltransferase 1, we show that protein arginine methyltransferase 1 catalyzes R81 methylation of Smad6 upon BMP treatment, R81 methylation subsequently facilitates Smad6 interaction with the phosphorylated active Smad1, and R81 methylation facilitates Smad6-mediated interruption of Smad1-Smad4 complex formation and nuclear translocation. Furthermore, Smad6 WT but not the methylation-deficient R81A mutant inhibited BMP-responsive transcription, attenuated BMP-mediated osteogenic differentiation, and antagonized BMP-mediated inhibition of cell invasion. Taken together, our results suggest that R81 methylation plays an essential role in Smad6-mediated inhibition of BMP responses.

Acvr1 deletion in osteoblasts impaired mandibular bone mass through compromised osteoblast differentiation and enhanced sRANKL-induced osteoclastogenesis.

Bone morphogenetic protein (BMP) signaling is well known in bone homeostasis. However, the physiological effects of BMP signaling on mandibles are largely unknown, as the mandible has distinct functions and characteristics from other bones. In this study, we investigated the roles of BMP signaling in bone homeostasis of the mandibles by deleting BMP type I receptor Acvr1 in osteoblast lineage cells with Osterix-Cre. We found mandibular bone loss in conditional knockout mice at the ages of postnatal day 21 and 42 in an age-dependent manner. The decreased bone mass was related to compromised osteoblast differentiation together with enhanced osteoclastogenesis, which was secondary to the changes in osteoblasts in vivo. In vitro study revealed that deletion of Acvr1 in the mandibular bone marrow stromal cells (BMSCs) significantly compromised osteoblast differentiation. When wild type bone marrow macrophages were cocultured with BMSCs lacking Acvr1 both directly and indirectly, both proliferation and differentiation of osteoclasts were induced as evidenced by an increase of multinucleated cells, compared with cocultured with control BMSCs. Furthermore, we demonstrated that the increased osteoclastogenesis in vitro was at least partially due to the secretion of soluble receptor activator of nuclear factor-κB ligand (sRANKL), which is probably the reason for the mandibular bone loss in vivo. Overall, our results proposed that ACVR1 played essential roles in maintaining mandibular bone homeostasis through osteoblast differentiation and osteoblast-osteoclast communication via sRANKL.

Mussel-Inspired Biocoating for Improving the Adhesion of Dental Pulp Stem Cells in Dental Pulp Regeneration.

Dental pulp engineering possesses a promising perspective to replacing lost pulp in the root canal and restoring its functions. Stable adhesion of dental pulp stem cells (DPSCs) on the root canal dentin wall is a key element required for reconstruction of a functional odontoblast layer in dental pulp regeneration. To address this challenge, dopamine-modified hyaluronic acid (DA-HA) is coated on dentin to obtain a stable adhesion of DPSCs. The dopamine segment provides adhesion ability to the coating, and the hyaluronic acid increases the biocompatibility. The results show that DPSCs can adhere on the DA-HA coated dentin slice better than those without coating. Simultaneously, DPSCs proliferation can be further promoted on the prepared coating. Therefore, the DA-HA coating may provide a possible way to immobilize odontoblast cell onto dentin surface for pulp regeneration.

CXCL12/CXCR4 pathway orchestrates CSC-like properties by CAF recruited tumor associated macrophage in OSCC.

Tumor-associated macrophage (TAM), a crucial component of immune cell infiltrated in tumor microenvironment, is associated with progression of oral squamous cell carcinoma (OSCC). However, it is still unclear how TAM is induced/accumulated and activated around/in OSCC. In the study herein, we tried to understand how TAM accumulates and activates in the OSCC and how TAM promotes OSCC to convert cancer stem cell (CSC). In this study, first important finding was that the M2 macrophages significantly increased in all twenty human OSCC samples in vivo. Cancer-associated fibroblast (CAF)-derived CXCL12 effectively attracted monocytes, which displayed M2 macrophage phenotype. Blocking CXCL12 receptor (CXCR4) significantly reduced chemotaxis of M2 macrophage. Polarized M2 macrophage promoted CSC-like transition in OSCC cell line, Cal27 cells. These CSC-like cells significantly expressed higher Sox2, Oct4, and Nanog genes, were stronger positive for CD44 and CD105, increased cell proliferation with less apoptosis, enhanced cell migration, and were resistant to chemotherapy drug, vineristine. These results indicate that CAF effectively attracts monocytes via the CXCL12/CXCR4 pathway and induces their differentiation to M2 macrophages. Interestingly, these polarized M2 macrophages promote formation of CSC-like cells from the OSCC lead to enhance OSCC proliferation with less apoptosis. Therefore, our findings have potential to lead to novel therapy for the OSCC to target CXCL12-mediated TAM recruitment.

Dexamethasone-loaded hollow hydroxyapatite microsphere promotes odontogenic differentiation of human dental pulp cells in vitro.

A sustained-release system was established by synthesis of dexamethasone-loaded hollow hydroxyapatite microspheres (DHHAM). The in vitro effect of DHHAM on odontogenic differentiation of human dental pulp cells (hDPCs) was evaluated. Hollow hydroxyapatite microspheres (HHAM) are successfully manufactured using simple biomimetic one-step strategy in the presence of glycine and sodium dodecyl sulfonate. Dexamethasone (DEX) was loaded to the system after the formation of HHAM. The drug encapsulation capacity of DEX in HHAM is 40.3% and its loading efficiency is 16.7%. The cumulative release of DEX in vitro is 55% up to 35 days. Results of Real-time Polymerase Chain Reaction (Real-time PCR), alkaline phosphatase (ALP) activity and Alizarin Red S staining revealed that DHHAM can obviously promote bio-mineralization of hDPCs in the absence of osteogenic medium and enhance the gene expression of ALP, Runt-related transcription factor 2 (RUNX2), osteocalcin, dentin sialophosphoprotein (DSPP) and dentin matrix protein 1 (DMP1). The data suggest that sustained release of DEX from DHHAM could efficiently enhance odontogenic differentiation of hDPCs.

Compound mutations in Bmpr1a and Tak1 synergize facial deformities via increased cell death.

BMP signaling plays a critical role in craniofacial development. Augmentation of BMPR1A signaling through neural crest-specific expression of constitutively active Bmpr1a (caBmpr1a) results in craniofacial deformities in mice. To investigate whether deletion of Tak1 may rescue the craniofacial deformities caused by enhanced Smad-dependent signaling through caBMPR1A, we generated embryos to activate transcription of caBmpr1a transgene and ablate Tak1 in neural crest derivatives at the same time. We found that deformities of the double mutant mice showed more severe than those with each single mutation, including median facial cleft and cleft palate. We found higher levels of cell death in the medial nasal and the lateral nasal processes at E10.5 in association with higher levels of p53 in the double mutant embryos. We also found higher levels of pSmad1/5/9 in the lateral nasal processes at E10.5 in the double mutant embryos. Western analyses revealed that double mutant embryos showed similar degrees of upregulation of pSmad1/5/9 with caBmpr1a or Tak1-cKO embryos while the double mutant embryos showed higher levels of phospho-p38 than caBmpr1a or Tak1-cKO embryos at E17.5, but not at E10.5. It suggested that deletion of Tak1 aggravates the craniofacial deformities of the caBmpr1a mutants by increasing p53 and phospho-p38 at different stage of embryogenesis.

Bone morphogenetic protein signaling through ACVR1 and BMPR1A negatively regulates bone mass along with alterations in bone composition.

Bone quantity and bone quality are important factors in determining the properties and the mechanical functions of bone. This study examined the effects of disrupting bone morphogenetic protein (BMP) signaling through BMP receptors on bone quantity and bone quality. More specifically, we disrupted two BMP receptors, Acvr1 and Bmpr1a, respectively, in Osterix-expressing osteogenic progenitor cells in mice. We examined the structural changes to the femora from 3-month old male and female conditional knockout (cKO) mice using micro-computed tomography (micro-CT) and histology, as well as compositional changes to both cortical and trabecular compartments of bone using Raman spectroscopy. We found that the deletion of Acvr1 and Bmpr1a, respectively, in an osteoblast-specific manner resulted in higher bone mass in the trabecular compartment. Disruption of Bmpr1a resulted in a more significantly increased bone mass in the trabecular compartment. We also found that these cKO mice showed lower mineral-to-matrix ratio, while tissue mineral density was lower in the cortical compartment. Collagen crosslink ratio was higher in both cortical and trabecular compartments of male cKO mice. Our study suggested that BMP signaling in osteoblast mediated by BMP receptors, namely ACVR1 and BMPR1A, is critical in regulating bone quantity and bone quality.

One-Step Hydrothermal Synthesis of Nitrogen-Doped Conjugated Carbonized Polymer Dots with 31% Efficient Red Emission for In Vivo Imaging.

Carbon dots with long-wavelength emissions, high quantum yield (QY) and good biocompatibility are highly desirable for biomedical applications. Herein, a green, facile hydrothermal synthesis of highly efficient red emissive nitrogen-doped carbonized polymer dots (CPDs) with optimal emission at around 630 nm are reported. The red emissive CPDs possess a variety of superior properties including excellent water dispersibility, good biocompatibility, narrow bandwidth emission, an excitation-independent emission, and high QY (10.83% (in water) and 31.54% (in ethanol)). Further studies prove that such strong red fluorescence is ascribed to the efficient conjugated aromatic π systems and hydrogen bonds of CPDs. And the fluorescence properties of CPDs can be regulated by adjusting the dosage of HNO3 before the reaction. Additionally, the as-prepared CPDs are successfully used as a fluorescent probe for bioimaging, both in vitro and in vivo. More importantly, biodistribution results demonstrate that most CPDs and their metabolites are not only excreted in urine but also excreted by hepatobiliary system in a rapid manner. Besides, the CPDs could easily cross the blood brain barrier, which may provide a valuable strategy for the theranostics of some brain diseases through real-time tracking.

BMP Signaling Mediated by BMPR1A in Osteoclasts Negatively Regulates Osteoblast Mineralization Through Suppression of Cx43.

Osteoblasts and osteoclasts are well orchestrated through different mechanisms of communication during bone remodeling. Previously, we found that osteoclast-specific disruption of one of the BMP receptors, Bmpr1a, results in increased osteoblastic bone formation in mice. We hypothesized that BMPR1A signaling in osteoclasts regulates production of either membrane bound proteins or secreted molecules that regulated osteoblast differentiation. In our current study, we co-cultured wild-type osteoblasts with either control osteoclasts or osteoclasts lacking BMPR1A signaling activity. We found that loss of Bmpr1a in osteoclasts promoted osteoblast mineralization in vitro. Further, we found that the expression of Cx43/Gja1 in the mutant osteoclasts was increased, which encoded for one of the gap junction proteins connexin 43/gap junction alpha 1. Knockdown of Gja1 in the mutant osteoclasts for Bmpr1a reduced osteoblastic mineralization when co-cultured. Our findings suggest that GJA1 may be one of the downstream targets of BMPR1A signaling in osteoclasts that mediates osteoclast-osteoblast communication during bone remodeling. J. Cell. Biochem. 118: 605-614, 2017. © 2016 Wiley Periodicals, Inc.

The Influence of Surface Modification on the Photoluminescence of CdTe Quantum Dots: Realization of Bio-Imaging via Cost-Effective Polymer.

To impart biocompatibility, stability, and specificity to quantum dots (QDs)-and to reduce their toxicity-it is essential to carry out surface modification. However, most surface-modification processes are costly, complicated, and time-consuming. In addition, the modified QDs often have a large size, which leads to easy aggregation in biological environments, making it difficult to excrete them from in vivo systems. To solve these problems, three kinds of conventional polymers, namely, polyvinyl alcohol (PVA, neutral), sodium polystyrene sulfonate (PSS, negative charged), and poly(diallyl dimethyl ammonium chloride) (PDDA, positive charged) were selected to modify the surface of QDs at low cost via a simple process in which the size of the QDs was kept small after modification. The effect of polymer modification on the photoluminescence (PL) properties of the QDs was systematically investigated. High quantum yields (QYs) of 65 % were reached, which is important for the realization of bio-imaging. Then, the cytotoxicity of CdTe QD-polymer composites was systematically investigated via MTT assay using the Cal27 and HeLa cell lines, especially for high concentrations of QD-polymer composites in vitro. The experimental results showed that the cytotoxicity decreased in the order CdTe-PDDA>CdTe>CdTe-PSS>CdTe-PVA, indicating that PSS and PVA can reduce the toxicity of the QDs. An obvious cytotoxicity of CdTe-PVA and CdTe-PSS was present until 120 h for the Cal27 cell line and until 168 h for the HeLa cell line. At last, the Cal27 cell line was selected to realize bio-imaging using CdTe-PSS and CdTe-PVA composites with different emission colors under one excitation wavelength.

Advancing dentin remineralization: Exploring amorphous calcium phosphate and its stabilizers in biomimetic approaches.

OBJECTIVE: This review elucidates the mechanisms underpinning intrafibrillar mineralization, examines various amorphous calcium phosphate (ACP) stabilizers employed in dentin's intrafibrillar mineralization, and addresses the challenges encountered in clinical applications of ACP-based bioactive materials. METHODS: The literature search for this review was conducted using three electronic databases: PubMed, Web of Science, and Google Scholar, with specific keywords. Articles were selected based on inclusion and exclusion criteria, allowing for a detailed examination and summary of current research on dentin remineralization facilitated by ACP under the influence of various types of stabilizers. RESULTS: This review underscores the latest advancements in the role of ACP in promoting dentin remineralization, particularly intrafibrillar mineralization, under the regulation of various stabilizers. These stabilizers predominantly comprise non-collagenous proteins, their analogs, and polymers. Despite the diversity of stabilizers, the mechanisms they employ to enhance intrafibrillar remineralization are found to be interrelated, indicating multiple driving forces behind this process. However, challenges remain in effectively designing clinically viable products using stabilized ACP and maximizing intrafibrillar mineralization with limited materials in practical applications. SIGNIFICANCE: The role of ACP in remineralization has gained significant attention in dental research, with substantial progress made in the study of dentin biomimetic mineralization. Given ACP's instability without additives, the presence of ACP stabilizers is crucial for achieving in vitro intrafibrillar mineralization. However, there is a lack of comprehensive and exhaustive reviews on ACP bioactive materials under the regulation of stabilizers. A detailed summary of these stabilizers is also instrumental in better understanding the complex process of intrafibrillar mineralization. Compared to traditional remineralization methods, bioactive materials capable of regulating ACP stability and controlling release demonstrate immense potential in enhancing clinical treatment standards.

Adhesive hydrogel releases protocatechualdehyde-Fe3+ complex to promote three healing stages for accelerated therapy of oral ulcers.

Oral ulcers can significantly reduce the life quality of patients and even lead to malignant transformations. Local treatments using topical agents are often ineffective because of the wet and dynamic environment of the oral cavity. Current clinical treatments for oral ulcers, such as corticosteroids, have limitations and side effects for long-term usage. Here, we develop adhesive hydrogel patches (AHPs) that effectively promote the healing of oral ulcers in a rat model. The AHPs are comprised of the quaternary ammonium salt of chitosan, aldehyde-functionalized hyaluronic acid, and a tridentate complex of protocatechualdehyde and Fe3+ (PF). The AHPs exhibit tunable mechanical properties, self-healing ability, and wet adhesion on the oral mucosa. Through controlling the formula of the AHPs, PF released from the AHPs in a temporal manner. We further show that the AHPs have good biocompatibility and the capability to heal oral ulcers rapidly. Both in vitro and in vivo experiments indicate that the PF released from AHPs facilitated ulcer healing by suppressing inflammation, promoting macrophage polarization, enhancing cell proliferation, and inducing epithelial-mesenchymal transition involving inflammation, proliferation, and maturation stages. This study provides insights into the healing of oral ulcers and presents an effective therapeutic biomaterial for the treatment of oral ulcers. STATEMENT OF SIGNIFICANCE: By addressing the challenges associated with current clinical treatments for oral ulcers, the development of adhesive hydrogel patches (AHPs) presents an effective approach. These AHPs possess unique properties, such as tunable mechanical characteristics, self-healing ability, and strong adhesion to the mucosa. Through controlled release of protocatechualdehyde-Fe3+ complex, the AHPs facilitate the healing process by suppressing inflammation, promoting cell proliferation, and inducing epithelial-mesenchymal transition. The study not only provides valuable insights into the healing mechanisms of oral ulcers but also introduces a promising therapeutic biomaterial. This work holds significant scientific interest and demonstrates the potential to greatly improve the treatment outcomes and quality of life for individuals suffering from oral ulcers.

Ultrahigh Energy Storage Density and Efficiency in Orthorhombic PLZST Antiferroelectric Ceramics via Composition Regulation.

PbZrO3-based antiferroelectric (AFE) ceramic materials have emerged as potential candidates for the next generation of high-energy multilayer ceramic capacitors (MLCCs) because of their distinctive characteristics of double hysteresis loops. The energy storage efficiency of orthorhombic AFE ceramics with ultrahigh storage density is relatively low, which hinders their practical application. In this study, the low efficiency limit of PLZST-based orthorhombic ceramics was overcome by precisely adjusting the Sn4+ content in the (Pb0.95Ca0.02La0.02)(Zr0.99-xSnxTi0.01)O3 AFE ceramics. On one hand, the addition of Sn4+ disrupts the original long-range dipole and improves the rapid response of polarization reversal under the applied voltage. As a result, the difference in electric hysteresis under an electric field is reduced, leading to a significant improvement in energy storage efficiency. On the other hand, increasing the Sn4+ content suppresses the formation of oxygen vacancies, inhibiting grain growth and strengthening grain bonding. This results in ceramics with a high breakdown field strength. Ultimately, the resulting PLCZST ceramics reveal an expressively improved recoverable energy density of 10.2 J cm-3 together with a high energy efficiency of 91.4% under a high applied electric field of 560 kV cm-1. The present study demonstrates the tunability of performance in orthorhombic PLZST AFE ceramics, thereby introducing a ceramic material with exceptional energy storage capabilities for MLCC applications.