ESR1 Gene Variants Are Predictive of Osteoporosis in Female Patients with Crohn’s Disease

Krela‐Kaźmierczak, Iwona; Skrzypczak-Zielińska, Marzena; Kaczmarek-Ryś, Marta; Michalak, Michał; Szymczak-Tomczak, Aleksandra; Hryhorowicz, Szymon; Szalata, Marlena; Łykowska‐Szuber, Liliana; Eder, Piotr; Stawczyk‐Eder, Kamila; Tomczak, Maciej; Słomski, Ryszard; Dobrowolska, Agnieszka

doi:10.3390/jcm8091306

Cited by 16 publications

(10 citation statements)

References 50 publications

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“…84 Besides, the methylation of ESR1 was related to dysplasia/cancer and inflammatory status in UC patients, suggesting the involvement of the methylation of ESR1 in UC carcinogenesis due to chronic active inflammation. 85,86 These data further support our findings on the great significance of TP53 and ESR1 in HHS for UC.…”

Section: Discussionsupporting

confidence: 88%

Network Pharmacology Prediction and Molecular Docking-Based Strategy to Discover the Potential Pharmacological Mechanism of Huai Hua San Against Ulcerative Colitis

Liu¹,

Liu²,

Tong³

et al. 2021

DDDT

145

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Background: Huai Hua San (HHS), a famous Traditional Chinese Medicine (TCM) formula, has been widely applied in treating ulcerative colitis (UC). However, the interaction of bioactives from HHS with the targets involved in UC has not been elucidated yet. Aim: A network pharmacology-based approach combined with molecular docking and in vitro validation was performed to determine the bioactives, key targets, and potential pharmacological mechanism of HHS against UC. Materials and Methods: Bioactives and potential targets of HHS, as well as UC-related targets, were retrieved from public databases. Crucial bioactive ingredients, potential targets, and signaling pathways were acquired through bioinformatics analysis, including protein-protein interaction (PPI), as well as the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Subsequently, molecular docking was carried out to predict the combination of active compounds with core targets. Lastly, in vitro experiments were conducted to further verify the findings. Results: A total of 28 bioactive ingredients of HHS and 421 HHS-UC-related targets were screened. Bioinformatics analysis revealed that quercetin, luteolin, and nobiletin may be potential candidate agents. JUN, TP53, and ESR1 could become potential therapeutic targets. PI3K-AKT signaling pathway might play an important role in HHS against UC. Moreover, molecular docking suggested that quercetin, luteolin, and nobiletin combined well with JUN, TP53, and ESR1, respectively. Cell experiments showed that the most important ingredient of HHS, quercetin, could inhibit the levels of inflammatory factors and phosphorylated c-Jun, as well as PI3K-Akt signaling pathway in LPS-induced RAW264.7 cells, which further confirmed the prediction by network pharmacology strategy and molecular docking. Conclusion:Our results comprehensively illustrated the bioactives, potential targets, and molecular mechanism of HHS against UC. It also provided a promising strategy to uncover the scientific basis and therapeutic mechanism of TCM formulae in treating diseases.

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Section: Discussionsupporting

confidence: 88%

Network Pharmacology Prediction and Molecular Docking-Based Strategy to Discover the Potential Pharmacological Mechanism of Huai Hua San Against Ulcerative Colitis

Liu¹,

Liu²,

Tong³

et al. 2021

DDDT

145

View full text Add to dashboard Cite

show abstract

“…For example, LRP5 had the highest OP “relevance scores,” and its pathogenic risk for OP has been identified in different races [ 64 ]. The ESR1 gene polymorphism leads to decreased bone mineral density in postmenopausal women [ 51 ] and predicts OP occurrence in women with Crohn's disease [ 65 ]. The single nucleotide polymorphisms, 245T > G and 1181G > C in TNFRSF11B, were associated with lumbar spine bone mineral density in OP postmenopausal women and possibly altered susceptibility to OP [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

“…By analyzing EXD targets, we hypothesize that EXD acts synergistically to mediate OP via calcium regulation and apoptosis, e.g., several studies have shown that ESR1 variants are related to postmenopausal OP [ 97 – 99 ], and ESR1 gene polymorphisms may be predictive of OP in female patients with Crohn's disease [ 65 ]. ESR2 variants have been shown to increase fracture risks in postmenopausal women [ 100 ] and could affect renal calcium oxalate crystal deposition [ 101 ].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Molecular Mechanism of Erxian Decoction in Treating Osteoporosis Based on Formula Optimization Model

Yang

Fan

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Osteoporosis (OP) is a highly prevalent orthopedic condition in postmenopausal women and the elderly. Currently, OP treatments mainly include bisphosphonates, receptor activator of nuclear factor kappa-B ligand (RANKL) antibody therapy, selective estrogen receptor modulators, teriparatide (PTH1-34), and menopausal hormone therapy. However, increasing evidence has indicated these treatments may exert serious side effects. In recent years, Traditional Chinese Medicine (TCM) has become popular for treating orthopedic disorders. Erxian Decoction (EXD) is widely used for the clinical treatment of OP, but its underlying molecular mechanisms are unclear thanks to its multiple components and multiple target features. In this research, we designed a network pharmacology method, which used a novel node importance calculation model to identify critical response networks (CRNs) and effective proteins. Based on these proteins, a target coverage contribution (TCC) model was designed to infer a core active component group (CACG). This approach decoded the mechanisms underpinning EXD’s role in OP therapy. Our data indicated that the drug response network mediated by the CACG effectively retained information of the component-target (C-T) network of pathogenic genes. Functional pathway enrichment analysis showed that EXD exerted therapeutic effects toward OP by targeting PI3K-Akt signaling (hsa04151), calcium signaling (hsa04020), apoptosis (hsa04210), estrogen signaling (hsa04915), and osteoclast differentiation (hsa04380) via JNK, AKT, and ERK. Our method furnishes a feasible methodological strategy for formula optimization and mechanism analysis and also supplies a reference scheme for the secondary development of the TCM formula.

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“…ESR1 is one of the two subtypes of estrogen receptor, which resident in bone and participates in bone metabolism ( Krela-Kaźmierczak et al, 2019 ). ESR1 expression was found to be down-regulated in OVX-induced PMOP rats, this could be viewed as the result of OVX-induced estrogen deficiency.…”

Section: Discussionmentioning

confidence: 99%

Integrated Strategy of Network Pharmacological Prediction and Experimental Validation Elucidate Possible Mechanism of Bu-Yang Herbs in Treating Postmenopausal Osteoporosis via ESR1

et al. 2021

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Postmenopausal osteoporosis (PMOP) is a type of bone metabolism disease-related to estrogen deficiency with an increasing incidence. Traditional Chinese (TCM) has always been used and showed effectiveness in treating PMOP. In the current study, Bu-Yang herbs were considered to be the most frequently used and efficient TCM herbs in PMOP treatment. However, chemical and pharmacological profiles were not elucidated. Network pharmacology was conducted on representative Bu-Yang herbs (Yin-Yang-Huo. Du-Zhong, Bu-Gu-Zhi, Tu-Si-Zi) to investigate the mechanism of Bu-Yang herbs on PMOP. Chemical compounds, potential targets, and disease related genes were available from the corresponding database. Results showed that Bu-Yang herbs could interact with ESR1 and estrogen signaling pathways. For further validation, the Bu-Yang decoction (BYD), formula consisted of the above-mentioned 4 Bu-Yang herbs was presented for experimental validation. In vivo, BYD significantly reversed ovariectomy (OVX)-induced osteoporosis progress in a dose-dependent manner by up-regulation of bone mineral density and amelioration of bone microarchitecture. In vitro, BYD dramatically improved the proliferation and mineral nodules formation of osteoblasts. Both in vitro and in vivo results illustrated that the phenotype change induced by BYD is correlated with up-regulated of ESR1 and activation of the β-catenin pathway. Meanwhile, inhibition of ESR1 by ICI182, 780 blocked the osteogenic phenotype and β-catenin pathway activation induced by BYD. In conclusion, the current study suggested that Bu-Yang herbs are the most useful TCM herbs in treating PMOP. Furthermore, the integrated strategy of network pharmacology prediction with experimental validation suggested that BYD exerted its anti-PMOP via ESR1 and the downstream mechanism might be activation of the β-catenin signaling pathway.

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ESR1 Gene Variants Are Predictive of Osteoporosis in Female Patients with Crohn’s Disease

Cited by 16 publications

References 50 publications

Network Pharmacology Prediction and Molecular Docking-Based Strategy to Discover the Potential Pharmacological Mechanism of Huai Hua San Against Ulcerative Colitis

Network Pharmacology Prediction and Molecular Docking-Based Strategy to Discover the Potential Pharmacological Mechanism of Huai Hua San Against Ulcerative Colitis

Analysis of Molecular Mechanism of Erxian Decoction in Treating Osteoporosis Based on Formula Optimization Model

Integrated Strategy of Network Pharmacological Prediction and Experimental Validation Elucidate Possible Mechanism of Bu-Yang Herbs in Treating Postmenopausal Osteoporosis via ESR1

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