ABSTRACT
Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid clonal diseases with diverse clinical courses, and immune dysregulation plays an important role in the pathogenesis of MDS. However, immune dysregulation is complex and heterogeneous in the development of MDS. Lower-risk MDS (LR-MDS) is mainly characterized by immune hyperfunction and increased apoptosis, and the immunosuppressive therapy shows a good response. Instead, higher-risk MDS (HR-MDS) is characterized by immune suppression and immune escape, and the immune activation therapy may improve the survival of HR-MDS. Furthermore, the immune dysregulation of some MDS changes dynamically which is characterized by the coexistence and mutual transformation of immune hyperfunction and immune suppression. Taken together, the authors think that the immune dysregulation in MDS with different risk stratification can be summarized by an advanced philosophical thought "Yin-Yang theory" in ancient China, meaning that the opposing forces may actually be interdependent and interconvertible. Clarifying the mechanism of immune dysregulation in MDS with different risk stratification can provide the new basis for diagnosis and clinical treatment. This review focuses on the manifestations and roles of immune dysregulation in the different risk MDS, and summarizes the latest progress of immunotherapy in MDS.
Subject(s)
Myelodysplastic Syndromes , Yin-Yang , Humans , Immunosuppression Therapy , Immunotherapy/adverse effects , Myelodysplastic Syndromes/therapy , Risk AssessmentABSTRACT
Intervertebral disc degeneration (IVDD) is a main cause of low back pain that is associated with extracellular matrix (ECM) degradation and inflammation. This study aims to investigate the role of DNMT3B and its regulatory mechanisms in IVDD. IVDD rat models were constructed followed by transfections with oe-DNMT3B or oe-YAP in order to explore the role of DNMT3B in the development of IVDD. After that transfection, nucleus pulposus (NP) cells were isolated and transfected with oe-DNMT3B, oe-TRPA1, si-YAP, oe-YAP or oe-COX2 in order to investigate the functions of DNMT3B in NP cells. DNMT3B was poorly expressed in IVDD tissues and NP cells whereas TRPA1, COX2, and YAP were highly expressed. The proliferation or apoptosis of NP cells was detected through CCK-8 assay or flow cytometry, respectively. Overexpression of DNMT3B promoted the proliferation of NP cells, inhibited their apoptosis, as well as increasing the expression of collagen II and aggrecan and decreasing expression of MMP3 and MMP9. Besides, DNMT3B suppressed inflammation and alleviated IVDD. Mechanistically, DNMT3B modified the TRPA1 promoter by methylation to inhibit the expression of COX2. Overexpression of COX2 promoted the apoptosis of NP cells and decreased the expression of YAP, which was reversed by upregulating DNMT3B. DNMT3B may promote the proliferation of NP cells and prevent their ECM degradation through the TRPA1/COX2/YAP axis, thereby alleviating IVDD in rats.
Subject(s)
Cyclooxygenase 2/metabolism , DNA (Cytosine-5-)-Methyltransferases/metabolism , Extracellular Matrix/metabolism , TRPA1 Cation Channel/metabolism , YAP-Signaling Proteins/metabolism , Animals , Cyclooxygenase 2/genetics , DNA (Cytosine-5-)-Methyltransferases/genetics , Extracellular Matrix/enzymology , Extracellular Matrix/genetics , Humans , Intervertebral Disc/metabolism , Intervertebral Disc/physiopathology , Intervertebral Disc Degeneration/metabolism , Male , Methylation , Rats , Rats, Sprague-Dawley , TRPA1 Cation Channel/genetics , YAP-Signaling Proteins/genetics , DNA Methyltransferase 3BABSTRACT
BACKGROUND: Calcium polyphosphate (CPP) is a commonly used biomaterial in bone tissue engineering, but CPP is insufficient in osteoinduction. This study aimed to fabricate lithium doped CPP (LiCPP) scaffolds and assess their characterization, degradation, biocompatibility and osteogenesis behavior for bone tissue engineering. METHODS: The novel scaffold was characterized by XRD, FTIR and SEM. The porosity, cell mediated degradation behavior and mechanical properties were also investigated. Meanwhile, cell proliferation activity and adhesion in vitro was exploited. Finally, osteogenesis the LiCPP scaffolds in vitro and in vivo was researched. RESULTS: The outcomes revealed that low-content Li doping had no significant influence on the structure of CPP. The results of cells mediated degradation experiments from the weight loss and the release of ions indicated that Li doped CPP improved biological degradation. The compressive strength of CPP with 66% porosity was improved to 7 MPa. Cells proliferation experiment and adhesion experiment demonstrated 2.0%LiCPP scaffold was most beneficial to cell growth and attachment. Furthermore, Li doped CPP up-regulated Wnt signal pathway when co-cultured with MG63 and increased osteogenic marker ALP expression and calcium phosphate deposition in vitro. At the same time, new bone formation in vivo was also enhanced by using LiCPP scaffolds and the 2.0%LiCPP scaffolds obtained best osteogenesis outcomes. CONCLUSION: The results obtained in our study suggest that 2.0%LiCPP scaffold could benefit from improving the osteogenesis behavior and is a promising biomaterial for bone repairing applications.
