Eldecalcitol ameliorates diabetic osteoporosis and glucolipid metabolic disorder by promoting Treg cell differentiation through SOCE
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ABSTRACT:
PROVIDER: PRJNA1113532 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29082263_1.fastq.gz | Fastqsanger.gz | |||
| SRR29082263_2.fastq.gz | Fastqsanger.gz | |||
| SRR29082264_1.fastq.gz | Fastqsanger.gz | |||
| SRR29082264_2.fastq.gz | Fastqsanger.gz | |||
| SRR29082265_1.fastq.gz | Fastqsanger.gz |
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Project description:Adaptive immunity plays a key role in osteoporosis in type 2 diabetes mellitus (T2DM); eldecalcitol (ED-71) is a novel active vitamin D analog, but its specific immunological mechanisms in ameliorating diabetic osteoporosis has not been well defined. In a T2DM mouse model, ED-71 attenuated bone loss and marrow adiposity. Simultaneously, it rectified imbalanced glucose homeostasis and dyslipidemia, ameliorated pancreatic β-cell damage and hepatic glycolipid metabolism disorder. Subsequently, in T2DM mice injected with CD25, we observed that the beneficial effects of ED-71 mentioned earlier were partially contingent on the Treg subsets ratio. Mechanistically, ED-71 promoted the differentiation of CD4+ T cells into Treg subsets, facilitating Ca2+ influx and the expression of ORAI1 and STIM1, pivotal proteins in store-operated Ca2+ entry (SOCE). The SOCE inhibitor, 2-APB, partially attenuated the positive effects of ED-71 observed in the above results. Together, these findings unveil ED-71 regulates SOCE-mediated Treg cell differentiation, accomplishing the dual purpose of simultaneously ameliorating diabetic osteoporosis and glucolipid metabolic disorders.
2024-11-06 | GSE267853 | GEO
Project description:Activated Foxp3+ regulatory T (Treg) cells differentiate into effector Treg (eTreg) cells to maintain peripheral immune homeostasis and tolerance. T cell receptor (TCR)-mediated induction and regulation of store-operated Ca2+ entry (SOCE) is essential for eTreg cell differentiation and function. However, SOCE regulation in Treg cells remains unclear. Here we show that inositol polyphosphate multikinase (IPMK), which generates inositol tetrakisphosphate and inositol pentakisphosphate, is a pivotal regulator of Treg cell differentiation downstream of TCR signaling. IPMK is highly expressed in TCR-stimulated Treg cells and promotes a TCR-induced Treg cell program. IPMK-deficient Treg cells display aberrant T cell activation and impaired differentiation into RORγt+ Treg cells, and tissue-resident Treg cells. Mechanistically, IPMK controls the generation of higher-order inositol phosphates, thereby promoting Ca2+ mobilization and Treg cell effector functions. Our findings identify IPMK as a critical regulator of TCR-mediated Ca2+ influx and highlight the importance of IPMK in Treg cell-mediated immune homeostasis.
2023-05-18 | GSE198960 | GEO
Project description:Postmenopausal osteoporosis is a prevalent clinical disorder in women. To elucidate the therapeutic mechanism underlying the combination of Juglans regia L. and Psoralea corylifolia Linn. for postmenopausal osteoporosis, we established bilateral ovariectomy-induced osteoporotic rat models and performed transcriptomic profiling. The results revealed that the anti-osteoporotic effects are predominantly mediated through ferroptosis-related pathways.
2026-04-30 | GSE293684 | GEO
Project description:Recent studies have shown that microRNAs (miRNAs) are implicated in the development of postmenopausal osteoporosis, implying potential biomarkers. We performed a microarray-based expression scanning to search for potential circulating miRNA biomarkers for postmenopausal osteoporosis as whole blood obtianed from patients was used. MiRNA expression in the whole blood of 23 Chinese postmenopausal women with osteopenia and that of 25 Chinese postmenopausal women with osteoporosis. After total RNA was extracted, all of the RNA extraction samples were seperately pooled into six subgroups according to the T-score measurement.
2014-12-23 | E-GEOD-64433 | biostudies-arrayexpress
Project description:Diabetic osteoporosis (DOP), as a typical representative of metabolic-immune cross-talk imbalance, has an unclear pathogenesis and lacks effective targeted intervention methods. This study aims to systematically analyze the molecular mechanism by which fecal microbiota transplantation (FMT) activates the TGF-β signaling axis through MOESIN lactic acid modification, reshapes the Treg/Th17 immune balance, and improves the pathological process of DOP based on multi-omics integrated analysis
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Project description:Sjogren’s Disease (SjD) is an autoimmune disorder characterized by progressive inflammation and destruction of both salivary and lacrimal gland leading to dysfunction, as well as extra glandular manifestations. The etiology and pathophysiology of SjD are incompletely understood. Regulatory T (Treg) cells are critical for immunological tolerance. Although Treg abnormalities have been implicated in the pathogenesis of several autoimmune diseases, their role in SjD remains ambiguous. We had previously shown that the function and development of Treg cells depend on store-operated Ca2+ entry (SOCE), which is mediated by ORAI1 Ca2+ channels and stromal interaction molecules (STIM) 1 and 2 following T cell receptor (TCR) stimulation. The ablation of SOCE in Treg cells causes SjD-like disease with increased Th1 and interferon gene expression signatures in the inflamed salivary glands of mice. Here we show enhanced Th1 gene expression signatures and type I and II interferon responses in the peripheral blood mononuclear cells (PBMCs) of human patients with SjD compared to non-SjD controls. We also identified attenuated gene expression in memory Treg cells of patients with SjD. These data from mice and human patients provide new evidence for a critical role of Treg cells and IFNγ producing Th1 cells in the pathogenesis of SjD.
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Project description:In the present study we analyzed the effect of primary osteoporosis on the transcriptome of human mesenchymal stem cells (hMSC; alternatively named mesenchymal stromal cells) from human bone marrow. Human MSC of elderly patients suffering from osteoporosis were isolated from femoral heads after low-energy fracture of the femoral neck. Bone marrow of age-matched, non-osteoporotic donors was obtained of femoral heads after total hip arthroplasty. Cells were isolated from human bone marrow according to the previously described protocol (Noth et al., 2002, J Orthop Res, 20/5, 1060-1069) under agreement of the local Ethics Committee of the University of Würzburg. Human MSC of elderly patients suffering from osteoporosis were isolated from femoral heads after low-energy fracture of the femoral neck. Additional criteria for confirming primary osteoporosis in these donors were vertebrae fractures and advanced age. Bone marrow of age-matched, non-osteoporotic donors was obtained of femoral heads after total hip arthroplasty due to osteoarthritis and/or hip dysplasia. RNA samples were taken from passage 1 or passage 2.
2012-02-22 | E-GEOD-35958 | biostudies-arrayexpress
Project description:Regulatory T (Treg) cells characterized by expression of the transcription factor forkhead box P3 (Foxp3) maintain immune homeostasis by suppressing self-destructive immune responses1-4. Foxp3 operates as a late acting differentiation factor controlling Treg cell homeostasis and function5, whereas the early Treg cell lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors6-10. However, whether Foxo proteins act beyond the Treg cell commitment stage to control Treg cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of Treg cell function. Treg cells express high amounts of Foxo1, and display reduced T-cell receptor-induced Akt activation, Foxo1 phosphorylation, and Foxo1 nuclear exclusion. Mice with Treg cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to Foxp3-deficient mice, but without the loss of Treg cells. Genome-wide analysis of Foxo1 binding sites reveals ~300 Foxo1-bound target genes, including the proinflammatory cytokine Ifng, that do not appear to be directly regulated by Foxp3. These findings demonstrate that the evolutionarily ancient Akt-Foxo1 signaling module controls a novel genetic program indispensable for Treg cell function. Treg cells were isolated from wild-type B6 mice or Foxo1tagBirA mice in which foxo1 is endogenously biotinylated. Foxo1 binding targets in Treg cells were identified by using Foxo1 antibody- and Streptavidin- ChIP-Seq approaches.
2012-09-07 | E-GEOD-40656 | biostudies-arrayexpress
Project description:Background: Osteoporosis and diabetes represent major global public health challenges. Neutrophil extracellular traps (NETs) serve as key components of the innate immune system by capturing bacteria, fungi, and parasites, thereby trapping them in local environments with high concentrations of antimicrobial agents leading to their elimination. This study aimed to identify biomarkers associated with NETs in osteoporosis with diabetes, and to explore the underlying molecular mechanisms. Methods: A transcriptomic sequencing dataset was obtained for osteoporosis combined with diabetes. The NETs-related genes (NETs-RGs) were obtained from previous literature. Biomarkers were identified through differential analysis, machine learning, and receiver operating characteristic (ROC). The identified biomarkers were further validated by qRT-PCR and ELISA. Subsequently, molecular regulatory network construction, immune infiltration analysis, enrichment analysis, and drug prediction were conducted. Results: S100A12 and SLC25A37 were identified as biomarkers. Their significant upregulation at the protein level was further confirmed by experimental validation in an independent cohort. Enrichment analysis indicated that S100A12 was significantly enriched in 68 pathways, including \"ECM receptor interaction\", \"maturity onset diabetes of the young\", and others. SLC25A37 was significantly enriched in 54 pathways, primarily including \"ribosome\", \"leishmania infection\", and \"Toll-like receptor signaling pathway\". A total of 7 immune cell types exhibited significant differences between the two groups, including neutrophils and regulatory T cells. A total of 59 miRNAs and 43 lncRNAs were predicted. Additionally, XIST-hsa-miR-146a-5p-S100A12 and XIST-hsa-miR-7-5-SLC25A37 were suggested to have potential regulatory roles in osteoporosis with diabetes. Drugs such as rimegepant and eptinezumab were associated with biomarkers. Conclusion: S100A12 and SLC25A37 were identified as biomarkers associated with NETs in osteoporosis with diabetes, providing a theoretical foundation for developing targeted treatments for osteoporosis with diabetes.
2026-01-11 | E-MTAB-16559 | biostudies-arrayexpress
Project description:Investigate genes expression profiles of postmenopausal osteoporosis in bone(femur)
2023-04-29 | GSE230665 | GEO