ATPR induces acute promyelocytic leukemia cells differentiation and cycle arrest via the lncRNA CONCR/DDX11/PML-RARα signaling axis.

Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) with a high mortality rate, and the production of PML-RARα fusion protein is the cause of its pathogenesis. Our group has synthesized a novel compound, 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), by structural modification of All-trans retinoic acid (ATRA), which has strong cell differentiation-inducing effects and inhibits the expression of PML-RARα. In this study, acute promyelocytic leukemia NB4 cells before and after ATPR induction were analyzed by whole transcriptome microarray, and the expression of lncRNA CONCR was found to be significantly downregulated. The role of CONCR in ATPR-induced cell differentiation and cycle arrest was explored through overexpression and silencing of CONCR. And then the database was used to predict that CONCR may bind to DEAD/H-Box Helicase 11 (DDX11) protein to further explore the role of CONCR binding to DDX11. The results showed that ATPR could reduce the expression of CONCR, and overexpression of CONCR could reverse the ATPR-induced cell differentiation and cycle blocking effect, and conversely silencing of CONCR could promote this effect. RNA immunoprecipitation (RIP) experiments showed that CONCR could bind to DDX11, the protein expression levels of DDX11 and PML-RARα were elevated after overexpression of CONCR. These results suggest that ATPR can regulate the expression of DDX11 through CONCR to affect the expression of PML-RARα fusion protein, which in turn induces the differentiation and maturation of APL cells.

A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice.

We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and that most of these TP53 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in NrasG12D/+ p53-/- (NP-/-) mice, NrasG12D/+ p53R172H/+ (NPmut) mice rapidly developed inflammation-associated AML. Under the inflammatory conditions, NPmut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and mostly normal cell proliferation despite MEK/ERK hyperactivation. RNA-Seq analysis revealed that oncogenic NRAS signaling and mutant p53 synergized to establish an NPmut-AML transcriptome distinct from that of NP-/- cells. The NPmut-AML transcriptome showed GATA2 downregulation and elevated the expression of inflammatory genes, including those linked to NF-κB signaling. NF-κB was also upregulated in human NRAS TP53 AML. Exogenous expression of GATA2 in human NPmut KY821 AML cells downregulated inflammatory gene expression. Mouse and human NPmut AML cells were sensitive to MEK and NF-κB inhibition in vitro. The proteasome inhibitor bortezomib stabilized the NF-κB-inhibitory protein IκBα, reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NPmut mice. Our study demonstrates that a p53 structural mutant synergized with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss.

Molecular characterization stratifies VQ myeloma cells into two clusters with distinct risk signatures and drug responses.

Multiple myeloma (MM) is a cancer of malignant plasma cells in the bone marrow and extramedullary sites. We previously characterized a VQ model for human high-risk MM. The various VQ lines display different disease phenotypes and survival rates, suggesting significant intra-model variation. Here, we use whole-exome sequencing and copy number variation (CNV) analysis coupled with RNA-Seq to stratify the VQ lines into corresponding clusters: Group A cells had monosomy chromosome (chr) 5 and overexpressed genes and pathways associated with sensitivity to bortezomib (Btz) treatment in human MM patients. By contrast, Group B VQ cells carried recurrent amplification (Amp) of chr3 and displayed high-risk MM features, including downregulation of Fam46c, upregulation of cancer growth pathways associated with functional high-risk MM, and expression of Amp1q and high-risk UAMS-70 and EMC-92 gene signatures. Consistently, in sharp contrast to Group A VQ cells that showed short-term response to Btz, Group B VQ cells were de novo resistant to Btz in vivo. Our study highlights Group B VQ lines as highly representative of the human MM subset with ultrahigh risk.

An Electroconductive Hydrogel Scaffold with Injectability and Biodegradability to Manipulate Neural Stem Cells for Enhancing Spinal Cord Injury Repair.

Spinal cord injury (SCI) generally leads to long-term functional deficits and is difficult to repair spontaneously. Many biological scaffold materials and stem cell treatment strategies have been explored, but very little research focused on the method of combining exogenous neural stem cells (NSCs) with a biodegradable conductive hydrogel scaffold. Here, a NSC loaded conductive hydrogel scaffold (named ICH/NSCs) was assembled by amino-modified gelatin (NH2-Gelatin) and aniline tetramer grafted oxidized hyaluronic acid (AT-OHA). Desirably, the well-conducting ICH/NSCs can be simply injected into the target site of SCI for establishing a good electrical signal pathway of cells, and the proper degradation cycle facilitates new nerve growth. In vitro experiments indicated that the inherent electroactive microenvironment of the hydrogel could better manipulate the differentiation of NSCs into neurons and inhibit the formation of glial cells and scars. Collectively, the ICH/NSC scaffold has successfully stimulated the recovery of SCI and may provide a promising treatment strategy for SCI repair.

A smart hydrogel patch with high transparency, adhesiveness and hemostasis for all-round treatment and glucose monitoring of diabetic foot ulcers.

The treatment and management of diabetic foot ulcers (DFUs) is a pretty intractable problem for clinical nursing. Urgently, the "Black Box" status of the healing process prevents surgeons from providing timely analysis for more effective diagnosis and therapy of the wound. Herein, we designed a transparent monitoring system to treat and manage the DFUs with blood oozing and hard-healing, which resolved the problem of blind management for the other conductive patches. This system was prepared from a conductive hydrogel patch with ultra-high transparence (up to 93.6%), adhesiveness and hemostasis, which is engineered by assembling in situ formed poly(tannic acid) (PTA)-doped polypyrrole (PPy) nanofibrils in the poly(acrylamide-acrylated adenine) (P(AM-Aa)) polymer networks. Significantly, the high transparent conductive hydrogel patch can monitor the wound-healing status visually and effectively promote the healing of DFUs by accelerating hemostasis, improving communication between cells, preventing wound infection, facilitating collagen deposition, and promoting angiogenesis. In addition, the versatile hydrogel patch could realize indirect blood glucose monitoring by detecting the glucose levels on wounds, and further sense the movements with different magnitudes of human body timely. This research may provide a novel strategy in the design of chronic wound dressings for monitoring and treating the wounds synergistically.

ATPR regulates human mantle cell lymphoma cells differentiation via SOX11/CyclinD1/Rb/E2F1.

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder that lacks reliable therapeutic options. Therefore, new treatment approaches for targeting novel biological pathways are required. 4-amino-2-trifluoromethyl-phenyl retinate (ATPR) synthesized by our group previously has been proven to have higher solubility and superior differentiation effects compared to those of conventional all-trans retinoic acid in acute myeloid leukemia. ATPR induces differentiation and inhibits the proliferation of acute promyelocytic leukemia. However, whether ATPR induces differentiation of MCL cells to normal immune cells has not been investigated. In this study, the proliferation of JEKO-1 cells was completely repressed, and differentiation was activated after ATPR treatment. The neural transcription factor SOX11 was further found to be highly expressed in MCL, but was downregulated by ATPR. After silencing SOX11 in vitro and in vivo, the malignant proliferation and inhibited differentiation of JEKO-1 cells were reversed, whereas the overexpression of SOX11 exacerbated the malignant phenotype of JEKO-1 cells. We also have added additional MCL cell lines (MINO) to complete the key pilot experiments. In addition, the CyclinD1/Rb/E2F1 axis was involved in MCL and was regulated by ATPR. In conclusion, ATPR promoted JEKO-1 cell differentiation via SOX11/CyclinD1/Rb/E2F1. This study provides experimental foundation for developing differentiation therapy for MCL with ATPR.

The role of E2A in ATPR-induced cell differentiation and cycle arrest in acute myeloid leukaemia cells.

Acute myeloid leukaemia (AML) is a biologically heterogeneous disease with an overall poor prognosis; thus, novel therapeutic approaches are needed. Our previous studies showed that 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), a new derivative of all-trans retinoic acid (ATRA), could induce AML cell differentiation and cycle arrest. The current study aimed to determine the potential pharmacological mechanisms of ATPR therapies against AML. Our findings showed that E2A was overexpressed in AML specimens and cell lines, and mediate AML development by inactivating the P53 pathway. The findings indicated that E2A expression and activity decreased with ATPR treatment. Furthermore, we determined that E2A inhibition could enhance the effect of ATPR-induced AML cell differentiation and cycle arrest, whereas E2A overexpression could reverse this effect, suggesting that the E2A gene plays a crucial role in AML. We identified P53 and c-Myc were downstream pathways and targets for silencing E2A cells using RNA sequencing, which are involved in the progression of AML. Taken together, these results confirmed that ATPR inhibited the expression of E2A/c-Myc, which led to the activation of the P53 pathway, and induced cell differentiation and cycle arrest in AML.

Novel Diabetic Foot Wound Dressing Based on Multifunctional Hydrogels with Extensive Temperature-Tolerant, Durable, Adhesive, and Intrinsic Antibacterial Properties.

Diabetic foot ulcers (DFUs) are hard-healing chronic wounds and susceptible to bacterial infection. Conventional hydrogel dressings easily lose water at high temperature or freeze at low temperature, making them unsuitable for long-term use or in extreme environments. Herein, a temperature-tolerant (-20 to 60 °C) antibacterial hydrogel dressing is fabricated by the assembly of polyacrylamide, gelatin, and ε-polylysine. Owing to the water/glycerin (Gly) binary solvent system, the resultant hydrogel (G-PAGL) displayed good heat resistance and antifreezing properties. Within the wide temperature range (-20 to 60 °C), all the desirable features of the hydrogel, including superstretchability (>1400%), enduring water retention, adhesiveness, and persistent antibacterial property, are quite stable. Remarkably, the hydrogel wound dressing displayed lasting and broad antibacterial activity against Gram-positive and Gram-negative bacteria. Satisfactorily, the double-network (DN) G-PAGL hydrogel dressing could effectively promote the healing of DFUs by accelerating collagen deposition, promoting angiogenesis, and inhibiting bacterial breed. As far as we know, this is the first time that the extensive temperature-tolerant DN hydrogel with antibacterial ability is developed to use as DFU wound dressing. The G-PAGL hydrogel provides more choices for DFU wound dressings that could be used in extreme environments.

ZEB1 serves as an oncogene in acute myeloid leukaemia via regulating the PTEN/PI3K/AKT signalling pathway by combining with P53.

Acute myeloid leukaemia is a complex, highly aggressive hematopoietic disorder. Currently, in spite of great advances in radiotherapy and chemotherapy, the prognosis for AML patients with initial treatment failure is still poor. Therefore, the need for novel and efficient therapies to improve AML treatment outcome has become desperately urgent. In this study, we identified the expression of ZEB1 (a transcription factor) and focused on its possible role and mechanisms in the progression of AML. According to the data provided by the Gene Expression Profiling Interactive Analysis (GEPIA), high expression of ZEB1 closely correlates with poor prognosis in AML patients. Additionally, the overexpression of ZEB1 was observed in both AML patients and cell lines. Further functional experiments showed that ZEB1 depletion can induce AML differentiation and inhibit AML proliferation in vitro and in vivo. Moreover, ZEB1 expression was negatively correlated with tumour suppressor P53 expression and ZEB1 can directly bind to P53. Our results also revealed that ZEB1 can regulate PTEN/PI3K/AKT signalling pathway. The inhibitory effect of ZEB1 silencing on PTEN/PI3K/AKT signalling pathway could be significantly reversed by P53 small interfering RNA treatment. Overall, the present data indicated that ZEB1 may be a promising therapeutic target for AML treatment or a potential biomarker for diagnosis and prognosis.

Infliximab-based self-healing hydrogel composite scaffold enhances stem cell survival, engraftment, and function in rheumatoid arthritis treatment.

Rheumatoid arthritis (RA) is a severe inflammatory autoimmune disease, but its treatment has been very difficult. Recently, stem cell-based therapies have opened up possibilities for the treatment of RA. However, the hostile RA pathological conditions impede the survival and differentiation of transplanted cells, and it remains challenging to fabricate a suitable biomaterial for the improvement of stem cells survival, engraftment, and function. Here we construct an optimal scaffold for RA management through the integration of 3D printed porous metal scaffolds (3DPMS) and infliximab-based hydrogels. The presence of rigid 3DPMS is appropriate for repairing large-scale bone defects caused by RA, while the designed infliximab-based hydrogels are introduced because of their self-healable, anti-inflammatory, biocompatible, and biodegradable properties. We demonstrate that the bioengineered composite scaffolds support adipose-derived mesenchymal stem cells (ADSCs) proliferation, differentiation, and extracellular matrix production in vitro. The composite scaffolds, along with ADSCs, are then implanted into the critical-sized bone defect in the RA rabbit model. In vivo results prove that the bioengineered composite scaffolds are able to down-regulate inflammatory cytokines, rebuild damaged cartilage, as well as improve subchondral bone repair. To the best of the authors' knowledge, this is the first time that using the antirheumatic drug to construct hydrogels for stem cell-based therapies, and this inorganic-organic hybrid system has the potential to alter the landscape of RA study.

Long noncoding RNA HOXA-AS2 functions as an oncogene by binding to EZH2 and suppressing LATS2 in acute myeloid leukemia (AML).

Acute myeloid leukemia (AML) is the most common hematological malignancy in the world. Long noncoding RNAs (lncRNAs) play an important role in the development of physiology and pathology. Many reports have shown that lncRNA HOXA cluster antisense RNA 2 (HOXA-AS2) is a carcinogen and plays an important role in many tumors, but little is known about its role in AML. The aim of this study was to explore the potential mechanism and role of HOXA-AS2 in AML. HOXA-AS2 was upregulated in AML cell lines and tissues, and the overexpression of HOXA-AS2 is negatively correlated with the survival of patients. Silencing HOXA-AS2 can inhibit the proliferation and induce differentiation of AML cells in vitro and in vivo. Overexpressing HOXA-AS2 showed the opposite result. Moreover, more in-depth mechanism studies showed that carcinogenicity of HOXA-AS2 exerted mainly through binding with the epigenetic inhibitor Enhancer of zeste homolog 2 (EZH2) and then inhibiting the expression of Large Tumor Suppressor 2 (LATS2). Taken together, our findings highlight the important role of HOXA-AS2 in AML, suggesting that HOXA-AS2 may be an effective therapeutic target for patients with AML.

Regulation of inflammatory microenvironment using a self-healing hydrogel loaded with BM-MSCs for advanced wound healing in rat diabetic foot ulcers.

A diabetic foot ulcer (DFUs) is a state of prolonged chronic inflammation, which can result in amputation. Different from normal skin wounds, various commercially available dressings have not sufficiently improved the healing of DFUs. In this study, a novel self-healing hydrogel was prepared by in situ crosslinking of N-carboxyethyl chitosan (N-chitosan) and adipic acid dihydrazide (ADH) with hyaluronic acid-aldehyde (HA-ALD), to provide a moist and inflammatory relief environment to promote stem cell proliferation or secretion of growth factors, thus accelerating wound healing. The results demonstrated that this injectable and self-healing hydrogel has excellent swelling properties, stability, and mechanical properties. This biocompatible hydrogel stimulated secretion of growth factors from bone marrow mesenchymal stem cells (BM-MSCs) and regulated the inflammatory environment by inhibiting the expression of M1 macrophages and promoting the expression of M2 macrophages, resulting in granulation tissue formation, collagen deposition, nucleated cell proliferation, neovascularization, and enhanced diabetic wound healing. This study showed that N-chitosan/HA-ALD hydrogel could be used as a multifunctional injectable wound dressing to regulate chronic inflammation and provide an optimal environment for BM-MSCs to promote diabetic wound healing.

LncRNA DDX11-AS1: a novel oncogene in human cancer.

Long noncoding RNA (lncRNA) is a newly identified type of noncoding RNA with a length of more than 200 nucleotides. The latest research shows that lncRNAs play important roles in the occurrence and development of human tumours by acting both as carcinogenic genes and as tumour suppressor genes. LncRNAs plays a role in various biological processes, such as cell growth, apoptosis, migration and invasion. The newly discovered lncRNA DDX11-AS1 is abnormally highly expressed in various malignant tumours, such as hepatocellular carcinoma, colorectal cancer, osteosarcoma, bladder cancer, NSCLC and gastric cancer. DDX11-AS1 mainly regulates the expression of related genes through direct or indirect ways to perform its functions in carcinogenicity. These results indicate that DDX11-AS1 may be a marker or therapeutic target of tumours. This review summarizes the biological function and mechanism of DDX11-AS1 in the process of tumour development.

Acid-sensing ion channel 1a mediates acid-induced pyroptosis through calpain-2/calcineurin pathway in rat articular chondrocytes.

The pyroptosis is a causative agent of rheumatoid arthritis, a systemic autoimmune disease merged with degenerative articular cartilage. Nevertheless, the precise mechanism of extracellular acidosis on chondrocyte pyroptosis is largely unclear. Acid-sensing ion channels (ASICs) belong to an extracellular H+ -activated cation channel family. Accumulating evidence has highlighted activation of ASICs induced by extracellular acidosis upregulate calpain and calcineurin expression in arthritis. In the present study, to investigate the expression and the role of acid-sensing ion channel 1a (ASIC1a), calpain, calcineurin, and NLRP3 inflammasome proteins in regulating acid-induced articular chondrocyte pyroptosis, primary rat articular chondrocytes were subjected to different pH, different time, and different treatments with or without ASIC1a, calpain-2, and calcineurin, respectively. Initially, the research results showed that extracellular acidosis-induced the protein expression of ASIC1a in a pH- and time-dependent manner, and the messenger RNA and protein expressions of calpain, calcineurin, NLRP3, apoptosis-associated speck-like protein, and caspase-1 were significantly increased in a time-dependent manner. Furthermore, the inhibition of ASIC1a, calpain-2, or calcineurin, respectively, could decrease the cell death accompanied with the decreased interleukin-1ß level, and the decreased expression of ASIC1a, calpain-2, calcineurin, and NLRP3 inflammasome proteins. Taken together, these results indicated the activation of ASIC1a induced by extracellular acidosis could trigger pyroptosis of rat articular chondrocytes, the mechanism of which might partly be involved with the activation of calpain-2/calcineurin pathway.

Targeting ferroptosis contributes to ATPR-induced AML differentiation via ROS-autophagy-lysosomal pathway.

Ferroptosis, a newly discovered form of non-apoptotic cell death, is induced by an excessive degree of iron-dependent lipid peroxide. ATPR, a novel all-trans retinoic acid (ATRA) derivative, has been extensively developed to show superior anticancer effect than ATRA in acute myeloid leukemia (AML). However, whether ferroptosis exists during ATPR treatment of AML remains unclear. Herein, we found that ferroptosis occurred in an AML xenograft mouse model of ATPR treatment. In vitro, ATPR was verified to induce ferroptosis in a dose-dependent manner by proferroptotic protein marker, lipid peroxidation, and lipid ROS, which could be significantly reversed by ferrostatin-1. Using lysosomal inhibitor chloroquine and iron chelator desferrioxamine, we further revealed that ATPR-induced ferroptosis was regulated by autophagy via iron homeostasis, especially Nrf2. Furthermore, targeting ferroptosis contributes to ATPR-induced AML differentiation. In conclusion, these results indicated that ferroptosis play an important role in ATPR-induced differentiation, and suggested that ATPR would provide a potential therapeutic value for AML treatment.

Bioinspired mineral hydrogels as nanocomposite scaffolds for the promotion of osteogenic marker expression and the induction of bone regeneration in osteoporosis.

Osteoporosis is one of the most prevalent age-related diseases worldwide and is characterized by a systemic deterioration of bone strength (bone mineral density and bone quality) with a resulting increase in fragility fractures. Due to the complex osteoporotic pathological environment, it is a huge challenge to induce bone regeneration under osteoporosis conditions. In this study, we successfully nanoengineer a bioinspired mineralized hydrogel from the supramolecular assembly of nano-hydroxyapatite, sodium carbonate, and polyacrylic acid, termed as CHAp-PAA. The resultant nanocomposite hydrogels can maintain their initial morphology and mechanical properties under physiological conditions, while exhibiting good primary stability, biocompatibility, bioactivity, and osteoconductivity. We demonstrate that this optimized hydrogel scaffold has shown superior performance for bone marrow stem cells (BMSCs) proliferation, differentiation, and extracellular matrix production in vitro. Remarkably, the mineralized CHAp-PAA hydrogels could be used as scaffolds for the critical-sized bone defect (6.0 mm diameter and 10.0 mm depth) in the osteoporotic rabbit model. Without the delivery of additional therapeutic agents or stem cells, these CHAp-PAA hydrogel scaffolds can improve bone ingrowth and accelerate new bone formation even in complex osteoporotic pathological environments. Therefore, this work presents a type of bioinspired multifunctional mineral hydrogel that offers an alternative strategy to manage osteoporosis. STATEMENT OF SIGNIFICANCE.

ATPR triggers acute myeloid leukaemia cells differentiation and cycle arrest via the RARα/LDHB/ERK-glycolysis signalling axis.

Acute myeloid leukaemia (AML) remains a therapeutic challenge and improvements in chemotherapy are needed. 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, has been proven to show superior anticancer effect compared with ATRA on various cancers. However, its potential effect on AML remains largely unknown. Lactate dehydrogenase B (LDHB) is the key glycolytic enzyme that catalyses the interconversion between pyruvate and lactate. Currently, little is known about the role of LDHB in AML. In this study, we found that ATPR showed antileukaemic effects with RARα dependent in AML cells. LDHB was aberrantly overexpressed in human AML peripheral blood mononuclear cell (PBMC) and AML cell lines. A lentiviral vector expressing LDHB-targeting shRNA was constructed to generate a stable AML cells with low expression of LDHB. The effect of LDHB knockdown on differentiation and cycle arrest of AML cells was assessed in vitro and vivo, including involvement of Raf/MEK/ERK signalling. Finally, these data suggested that ATPR showed antileukaemic effects by RARα/LDHB/ ERK-glycolysis signalling axis. Further studies should focus on the underlying leukaemia-promoting mechanisms and investigate LDHB as a therapeutic target.

ATPR induces acute promyelocytic leukemia cells differentiation and growth arrest by blockade of SHP2/Rho/ROCK1 pathway.

Acute promyelocytic leukemia (APL) is a form of acute myeloid leukemia with a unique chromosome translocation t (15;17), commonly complicated by a complex coagulopathy. 4-Amino-2-trifuoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, was synthesized by our group and known to possess obvious biological anti-tumor activities. It has previously been shown that ATPR could induce differentiation and inhibit proliferation of APL cells, although the mechanism responsible for this effect was not well understood. In this study, we demonstrated that ATPR remarkably inhibited the expression and activity of SHP2. Further experiments showed silencing SHP2 or using SHP2 inhibition (SHP099) enhanced the effect of ATPR on cell proliferation and maturation. In addition, we also demonstrated that Rho/ROCK1 might be regulated by SHP2. Using Y-27632, a ROCK inhibitor, further proved that ROCK1 played an important role in ATPR-induced differentiation and proliferation suppression. In conclusion, the results from this study revealed that ATPR induced APL cells terminal differentiation and growth arrest by blockade of SHP2/Rho/ ROCK1 pathway.

LncRNA NR-104098 Inhibits AML Proliferation and Induces Differentiation Through Repressing EZH2 Transcription by Interacting With E2F1.

Abundant evidence has illustrated that long non-coding RNA (lncRNA) plays a vital role in the regulation of tumor development and progression. Most lncRNAs have been proven to have biological and clinical significance in acute myeloid leukemia (AML), but further investigation remains necessary. In this study, we investigated lncRNA NR-104098 in AML and its specific mechanism. The microarray analysis was performed on NB4 cells. Based on the related analysis results, we identified that lncRNA NR-104098 is a suppressor gene that is significantly upregulated in AML cells. LncRNA NR-104098 could inhibit proliferation and induce differentiation in AML cells in vitro and also play main role in the mouse xenografts. Mechanically, it was confirmed that lncRNA NR-104098 may effectively inhibit EZH2 transcription by directly binding to E2F1 and recruiting E2F1 to the EZH2 promoter. In addition, ATPR can significantly increase the expression of lncRNA NR-104098, whereas knocking down NR104098 can inhibit the inhibitory effect of ATPR on the proliferation and induction differentiation of AML cells. Taken together, these results lead to deeper insight into the mechanism of ATPR-induced AML differentiation and prevent proliferation by inhibiting EZH2 on the transcriptional level.

Enhanced osseointegration of three-dimensional supramolecular bioactive interface through osteoporotic microenvironment regulation.

Purpose: Osteoporosis is more likely to cause serious complications after joint replacement, mainly due to physiological defects of endogenous osteogenic cells and the pathological osteoclast activity. It is a feasible solution to design a prosthetic surface interface that specifically addresses this troublesome situation. Methods: A novel "three-dimensional (3D) inorganic-organic supramolecular bioactive interface" was constructed consisting of stiff 3D printing porous metal scaffold and soft multifunctional, self-healable, injectable, and biodegradable supramolecular polysaccharide hydrogel. Apart from mimicking the bone extracellular matrix, the bioactive interface could also encapsulate bioactive substances, namely bone marrow mesenchymal stem cells (BMSCs) and bone morphogenetic protein-2 (BMP-2). A series of in vitro characterizations, such as topography and mechanical characterization, in vitro release of BMP-2, biocompatibility analysis, and osteogenic induction of BMSCs were carried out. After that, the in vivo osseointegration effect of the bioactive interface was investigated in detail using an osteoporotic model. Results: The administration of injectable supramolecular hydrogel into the inner pores of 3D printing porous metal scaffold could obviously change the morphology of BMSCs and facilitate its cell proliferation. Meanwhile, BMP-2 was capable of being sustained released from supramolecular hydrogel, and subsequently induced osteogenic differentiation of BMSCs and promoted the integration of the metal microspores-bone interface in vitro and in vivo. Moreover, the osteoporosis condition of bone around the bioactive interface was significantly ameliorated. Conclusion: This study demonstrates that the 3D inorganic-organic supramolecular bioactive interface can serve as a novel artificial prosthesis interface for various osteogenesis-deficient patients, such as osteoporosis and rheumatoid arthritis.