Atp6v1h Deficiency Blocks Bone Loss in Simulated Microgravity Mice through the Fos-Jun-Src-Integrin Pathway.

The microgravity conditions in outer space are widely acknowledged to induce significant bone loss. Recent studies have implicated the close relationship between Atp6v1h gene and bone loss. Despite this, the role of Atp6v1h in bone remodeling and its molecular mechanisms in microgravity have not been fully elucidated. To address this, we used a mouse tail suspension model to simulate microgravity. We categorized both wild-type and Atp6v1h knockout (Atp6v1h+/-) mice into two groups: regular feeding and tail-suspension feeding, ensuring uniform feeding conditions across all cohorts. Analysis via micro-CT scanning, hematoxylin-eosin staining, and tartrate-resistant acid phosphatase assays indicated that wild-type mice underwent bone loss under simulated microgravity. Atp6v1h+/- mice exhibited bone loss due to Atp6v1h deficiency but did not present aggravated bone loss under the same simulated microgravity. Transcriptomic sequencing revealed the upregulation of genes, such as Fos, Src, Jun, and various integrin subunits in the context of simulated microgravity and Atp6v1h knockout. Real-time quantitative polymerase chain reaction (RT-qPCR) further validated the modulation of downstream osteoclast-related genes in response to interactions with ATP6V1H overexpression cell lines. Co-immunoprecipitation indicated potential interactions between ATP6V1H and integrin beta 1, beta 3, beta 5, alpha 2b, and alpha 5. Our results indicate that Atp6v1h level influences bone loss in simulated microgravity by modulating the Fos-Jun-Src-Integrin pathway, which, in turn, affects osteoclast activity and bone resorption, with implications for osteoporosis. Therefore, modulating Atp6v1h expression could mitigate bone loss in microgravity conditions. This study elucidates the molecular mechanism of Atp6v1h's role in osteoporosis and positions it as a potential therapeutic target against environmental bone loss. These findings open new possibilities for the treatment of multifactorial osteoporosis.

Hereditary dentin defects with systemic diseases.

OBJECTIVE: This review aimed to summarize recent progress on syndromic dentin defects, promoting a better understanding of systemic diseases with dentin malformations, the molecules involved, and related mechanisms. SUBJECTS AND METHODS: References on genetic diseases with dentin malformations were obtained from various sources, including PubMed, OMIM, NCBI, and other websites. The clinical phenotypes and genetic backgrounds of these diseases were then summarized, analyzed, and compared. RESULTS: Over 10 systemic diseases, including osteogenesis imperfecta, hypophosphatemic rickets, vitamin D-dependent rickets, familial tumoral calcinosis, Ehlers-Danlos syndrome, Schimke immuno-osseous dysplasia, hypophosphatasia, Elsahy-Waters syndrome, Singleton-Merten syndrome, odontochondrodysplasia, and microcephalic osteodysplastic primordial dwarfism type II were examined. Most of these are bone disorders, and their pathogenic genes may regulate both dentin and bone development, involving extracellular matrix, cell differentiation, and metabolism of calcium, phosphorus, and vitamin D. The phenotypes of these syndromic dentin defects various with the involved genes, part of them are similar to dentinogenesis imperfecta or dentin dysplasia, while others only present one or two types of dentin abnormalities such as discoloration, irregular enlarged or obliterated pulp and canal, or root malformation. CONCLUSION: Some specific dentin defects associated with systemic diseases may serve as important phenotypes for dentists to diagnose. Furthermore, mechanistic studies on syndromic dentin defects may provide valuable insights into isolated dentin defects and general dentin development or mineralization.

IGF2BP2 maybe a novel prognostic biomarker in oral squamous cell carcinoma.

AIM: The main of the present study was to investigate the role of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in oral squamous cell carcinoma (OSCC) with the overarching of providing new biomarkers or potential therapeutic targets for OSCC. METHODS: We combined datasets downloaded from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and samples collected from the clinic to evaluate the expression of IGF2BP2 in OSCC. IGF2BP2 survival analysis was respectively performed based on TCGA, GEO, and clinical samples. Correlations between IGF2BP2 expression and clinicopathological parameters were then analyzed, and signaling pathways associated with IGF2BP2 expression were identified using gene set enrichment analysis (GSEA 4.1.0). Moreover, an IGF2BP2 co-expressed gene network was constructed, followed by gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on IGF2BP2 co-expressed genes. Finally, TIMER and CIBERSORT were used to analyze the correlations among IGF2BP2, IGF2BP2-coexpressed genes, and tumor-infiltrating immune cells (TICs). RESULTS: IGF2BP2 was highly expressed in OSCC and significantly correlated with overall survival of OSCC patients (P<0.01). High IGF2BP2 expression correlated with poor overall survival. The GSEA results showed that cell apoptosis-, tumor-, and immune-related pathways were significantly enriched in samples with high IGF2BP2 expression. Furthermore, GO and KEGG enrichment analyses results of IGF2BP2 co-expressed genes indicated that these genes are mainly associated with immunity/inflammation and tumorigenesis. In addition, IGF2BP2 and its co-expressed genes are associated with TICs (P<0.01). CONCLUSION: IGF2BP2 may be a potential prognostic biomarker in OSCC and correlates with immune infiltrates.

Exploring the Molecular Mechanism of lncRNA-miRNA-mRNA Networks in Non-Syndromic Cleft Lip with or without Cleft Palate.

BACKGROUND: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common craniofacial birth defect. Growing evidence has demonstrated the competing endogenous RNA (ceRNA) hypothesis has played a role in the pathogenesis of NSCL/P. Here, we identified the important lncRNAs in NSCL/P and constructed a ceRNA regulatory network to predict their underlying functional mechanism. METHODS: Total RNA isolated from the peripheral blood samples were analyzed by the Human Clariom D Affymetrix platform and differentially expressed genes (DEGs) were identified. Using the limma package in R software, DEGs in the expression profile of GSE42589 were identified from Gene Expression Omnibus (GEO) database. Co-differentially expressed lncRNAs (co-DElncRNAs) were used to predict the microRNAs that may bind to them. Co-differentially expressed mRNAs (co-DEmRNAs) were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The hub genes were screened using the cytohubba plug-in in Cytoscape. A ceRNA network was built to investigate the molecular mechanism underlying the etiology of NSCL/P. The expression levels of lncRNAs, miRNAs, and mRNAs in the network were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: We found 116 DElncRNAs and 2955 DEmRNAs from the GSE42589 dataset, and 2626 DElncRNAs and 2771 DEmRNAs from the Human Clariom D gene chip. A network of co-DEmRNAs containing 3712 edges and 621 nodes were identified by PPI analysis. A ceRNA regulatory network comprising lncRNA USP17L6P, hsa-miR-449c-5p, and MYC was established. qRT-PCR results revealed significantly lower expression levels of lncRNA USP17L6P and c-Myc in NSCL/P tissues, while the expression level of hsa-miR-449c-5p was higher as compared to control samples (p < 0.05). CONCLUSION: The identified lncRNAs and the established ceRNA regulatory network provide novel insight into the pathogenesis of NSCL/P, therefore hold great promise in NSCL/P management in clinical practice.

LncRNA MALAT1 regulates inflammatory cytokine production in lipopolysaccharide-stimulated human gingival fibroblasts through sponging miR-20a and activating TLR4 pathway.

BACKGROUND AND OBJECTIVE: It has been reported that long non-coding RNAs (lncRNAs), such as metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), act as key regulators of the development of inflammatory diseases. However, it is unclear whether MALAT1 regulates the function of human gingival fibroblasts (HGFs) in periodontitis. This study is to explore the role of MALAT1 on inflammatory cytokine production of HGFs. MATERIAL AND METHODS: Primary HGFs were harvested from human gingiva. MALAT1 was detected in inflammatory and healthy gingival tissues via quantitative real-time PCR (qRT-PCR). Bioinformatics analysis, dual-luciferase reporter assay, and RNA-binding protein immunoprecipitation (RIP) were used to detect the relationship among MALAT1, toll-like receptor 4 (TLR4), and microRNA (miR) -20a. After transfection LPS-treated HGFs with MALAT1 siRNA (si-MALAT1), miR-20a mimic or overexpression MALAT1 plasmid (sno-MALAT1), the levels of MALAT1, miR-20a, TLR4, IL-6 and IL-8 were analyzed by qRT-PCR, enzyme-linked immunosorbent assay, or western blot assay. RESULTS: MALAT1 up-regulated in inflammatory gingival tissues of chronic periodontitis. MiR-20a was bound with MALAT1 and TLR4 3'-UTR in RNA-protein complex with Ago2, respectively. Moreover, MALAT1, TLR4, IL-6, and IL-8 increased while miR-20a decreased after 1 µg/mL Porphyromonas gingivalis lipopolysaccharide (LPS) or Escherichia coli LPS stimulation. MiR-20a inhibited the expression of proinflammatory cytokines via binding to TLR4 3'-UTR. In addition, MALAT1 increased TLR4 level and the secretion of inflammatory cytokines. CONCLUSION: MALAT1 enhances inflammatory cytokine production through sponging miR-20a and releasing TLR4, indicating a regulatory role of MALAT1 in periodontal inflammation.

FOXC2 promotes chemoresistance in nasopharyngeal carcinomas via induction of epithelial mesenchymal transition.

Paclitaxel (Taxol) is currently used as the front-line chemotherapeutic drug for many types of human cancers. However, the emergence of drug resistance has been a major obstacle to the effective treatment of cancers in clinical settings. The transcription factor Forkhead box protein C2 (FOXC2) was recently demonstrated to activate the epithelial-mesenchymal transition (EMT). In this article, we present a novel role of FOXC2 in regulating chemoresistance of nasopharyngeal carcinoma (NPC) through the EMT. Using an EMT PCR array based on the screening of 84 genes, the expression of FOXC2 was notably upregulated in paclitaxel-resistant NPC cells (CNE2/t). We observed that the paclitaxel-resistant cells exhibited characteristic EMT phenotypes. The silencing of FOXC2 expression in the resistant cells can reverse the EMT molecular markers and chemoresistant phenotypes, such as cellular morphology, proliferation and anoikis. In an NPC xenograft mouse model, the downregulation of FOXC2 expression in the resistant NPC cells increased their sensitivity to paclitaxel treatment, resulting in reduced tumor growth. Taken together, our results suggest that FOXC2-mediated EMT may be an alternative mechanism through which cancer cells can initiate and maintain drug resistance. Thus, targeting FOXC2 may provide a novel strategy for overcoming chemoresistance in NPC therapy.