Identification of kukoamine a as an anti-osteoporosis drug target using network pharmacology and experiment verification

Luo, Liying; Guan, Zhiyuan; Jin, Xiao; Guan, Zhiqiang; Jiang, Yanyun

doi:10.1186/s10020-023-00625-6

Cited by 10 publications

(3 citation statements)

References 74 publications

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“…These BMSCs were subsequently cultured in an osteogenic medium, concomitant with the administration of either Wnt3a recombinant protein or DKK1 recombinant protein. In contrast to untreated BMSCs and those treated with DKK1 recombinant protein, BMSCs treated with Wnt3a recombinant protein displayed heightened transcription levels of four selected osteogenesis-related genes, comprising collagen 1α1, osteocalcin, runx2, and osterix (Geng et al 2024 ; Zhou et al 2024 ; Luo et al 2023 ). Furthermore, compared to untreated BMSCs, DKK1 recombinant protein-treated BMSCs demonstrated even lower expression of collagen 1α1 and osteocalcin (p < 0.001 for collagen 1α1, osteocalcin, and runx2; p = 0.016 for osterix) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease

Ko,

Wang,

Lian

et al. 2024

Mol Med

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Background The current treatment of osteogenesis imperfecta (OI) is imperfect. Our study thus delves into the potential of using Dickkopf-1 antisense (DKK1-AS) to treat OI. Methods We analysed serum DKK1 levels and their correlation with lumbar spine and hip T-scores in OI patients. Comparative analyses were conducted involving bone marrow stromal cells (BMSCs) and bone tissues from wild-type mice, untreated OI mice, and OI mice treated with DKK1-ASor DKK1-sense (DKK1-S). Results Significant inverse correlations were noted between serum DKK1 levels and lumbar spine (correlation coefficient = − 0.679, p = 0.043) as well as hip T-scores (correlation coefficient = − 0.689, p = 0.042) in OI patients. DKK1-AS improved bone mineral density (p = 0.002), trabecular bone volume/total volume fraction (p < 0.001), trabecular separation (p = 0.010), trabecular thickness (p = 0.001), trabecular number (p < 0.001), and cortical thickness (p < 0.001) in OI mice. DKK1-AS enhanced the transcription of collagen 1α1, osteocalcin, runx2, and osterix in BMSC from OI mice (all p < 0.001), resulting in a higher von Kossa-stained matrix area (p < 0.001) in ex vivo osteogenesis assays. DKK1-AS also reduced osteoclast numbers (p < 0.001), increased β-catenin and T-cell factor 4 immunostaining reactivity (both p < 0.001), enhanced mineral apposition rate and bone formation rate per bone surface (both p < 0.001), and decreased osteoclast area (p < 0.001) in OI mice. DKK1-AS upregulated osteoprotegerin and downregulated nuclear factor-kappa B ligand transcription (both p < 0.001). Bone tissues from OI mice treated with DKK1-AS exhibited significantly higher breaking force compared to untreated OI mice (p < 0.001). Conclusions Our study elucidates that DKK1-AS has the capability to enhance bone mechanical properties, restore the transcription of osteogenic genes, promote osteogenesis, and inhibit osteoclastogenesis in OI mice.

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Section: Resultsmentioning

confidence: 99%

Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease

Ko,

Wang,

Lian

et al. 2024

Mol Med

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“…KuA can reduce nerve cell damage by inhibiting oxidative stress and cell apoptosis [18,19] . KuA can protect neuronal cells [20] , and had neuroprotective effects in the animal model of neurotoxin-induced Parkinson [21] .…”

Section: Resultsmentioning

confidence: 99%

Study on the Mechanism of Kukoamine A Attenuating Interleukin-1 Beta Induced Chondrocyte Damage by Downregulating microRNA-302b-3p

Li,

Wang,

Zhang

et al. 2024

IJPS

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For probing the influence of kukoamine A on interleukin-1 beta-evoked damage of chondrocytes and its possible mechanism. Interleukin-1 beta was used to induce human knee joint chondrocytes to establish a cell injury model, and different concentrations of kukoamine A were used to treat chondrocytes. Following anti-microRNA-302b-3p introduction into chondrocytes, interleukin-1 beta (10 ng/ml) was employed for treating cells for 24 h. microRNA-NC and microRNA-302b-3p mimics were respectively transfected into chondrocytes and treated with kukoamine A (40 μmol/l) and interleukin-1 beta (10 ng/ml) for 24 h. Enzymelinked immunosorbent assay method was used for detecting the levels of interleukin-6, tumour necrosis factor alpha, and interferon gamma. Flow cytometry was used for detecting the rate of cell apoptosis. The quantitative reverse transcription polymerase chain reaction was utilized for detecting microRNA-302b-3p level. Western blot was employed for detecting Bcl-2 associated X, apoptosis and B-cell lymphoma 2 protein levels. Kukoamine A could reduce interleukin-6, tumour necrosis factor alpha, and interferon gamma levels in chondrocytes induced by interleukin-1 beta, and could reduce the rate of apoptosis and the protein level of Bcl-2 associated X, apoptosis, and could also reduce the level of micoRNA-302b-3p, whereas it promoted B-cell lymphoma 2 level dose-dependently. After anti-microRNA-302b-3p introduction, interleukin-6, tumour necrosis factor alpha, and interferon gamma were downregulated, the rate of apoptosis and the protein level of Bcl-2 associated X, apoptosis were declined, whereas B-cell lymphoma 2 level was elevated. Transfection of microRNA-302b-3p mimics reversed kukoamine A impact on inflammation and apoptosis in interleukin-1 betaevoked chondrocytes. Kukoamine A could inhibit cell inflammatory reaction and apoptosis by downregulating microRNA-302b-3p level, thereby reducing interleukin-1 beta induced chondrocyte damage.

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“…PYGM is the target gene with the strongest correlation with the active components of LC and is regulated by KuA. [ 53 ]…”

Section: Discussionmentioning

confidence: 99%

Analysis and validation of biomarkers of immune cell-related genes in postmenopausal osteoporosis: An observational study

Chen,

Zhao,

Qiu

et al. 2024

Medicine

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Postmenopausal osteoporosis (PMOP) is a common metabolic inflammatory disease. In conditions of estrogen deficiency, chronic activation of the immune system leads to a hypo-inflammatory phenotype and alterations in its cytokine and immune cell profile, although immune cells play an important role in the pathology of osteoporosis, studies on this have been rare. Therefore, it is important to investigate the role of immune cell-related genes in PMOP. PMOP-related datasets were downloaded from the Gene Expression Omnibus database. Immune cells scores between high bone mineral density (BMD) and low BMD samples were assessed based on the single sample gene set enrichment analysis method. Subsequently, weighted gene co-expression network analysis was performed to identify modules highly associated with immune cells and obtain module genes. Differential analysis between high BMD and low BMD was also performed to obtain differentially expressed genes. Module genes are intersected with differentially expressed genes to obtain candidate genes, and functional enrichment analysis was performed. Machine learning methods were used to filter out the signature genes. The receiver operating characteristic (ROC) curves of the signature genes and the nomogram were plotted to determine whether the signature genes can be used as a molecular marker. Gene set enrichment analysis was also performed to explore the potential mechanism of the signature genes. Finally, RNA expression of signature genes was validated in blood samples from PMOP patients and normal control by real-time quantitative polymerase chain reaction. Our study of PMOP patients identified differences in immune cells (activated dendritic cell, CD56 bright natural killer cell, Central memory CD4 T cell, Effector memory CD4 T cell, Mast cell, Natural killer T cell, T follicular helper cell, Type 1 T-helper cell, and Type 17 T-helper cell) between high and low BMD patients. We obtained a total of 73 candidate genes based on modular genes and differential genes, and obtained 5 signature genes by least absolute shrinkage and selection operator and random forest model screening. ROC, principal component analysis, and t-distributed stochastic neighbor embedding down scaling analysis revealed that the 5 signature genes had good discriminatory ability between high and low BMD samples. A logistic regression model was constructed based on 5 signature genes, and both ROC and column line plots indicated that the model accuracy and applicability were good. Five signature genes were found to be associated with proteasome, mitochondria, and lysosome by gene set enrichment analysis. The real-time quantitative polymerase chain reaction results showed that the expression of the signature genes was significantly different between the 2 groups. HIST1H2AG, PYGM, NCKAP1, POMP, and LYPLA1 might play key roles in PMOP and be served as the biomarkers of PMOP.

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Identification of kukoamine a as an anti-osteoporosis drug target using network pharmacology and experiment verification

Cited by 10 publications

References 74 publications

Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease

Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease

Study on the Mechanism of Kukoamine A Attenuating Interleukin-1 Beta Induced Chondrocyte Damage by Downregulating microRNA-302b-3p

Analysis and validation of biomarkers of immune cell-related genes in postmenopausal osteoporosis: An observational study

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