β-Estradiol antagonizes the inhibitory effects of caffeine in BMMSCs via the ERβ-mediated cAMP-dependent PKA pathway

Wang, Chaowei; Zhou, Yi; Guan, Xiaoxu; Yu, Mengfei; Wang, Huiming

doi:10.1016/j.tox.2017.11.015

Cited by 9 publications

(8 citation statements)

References 33 publications

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“…The gene expression levels were detected by quantitative real‐time RT‐PCR as described previously (Wang, Zhou, Guan, Yu, & Wang, ). Briefly, the total RNA of milled bone tissues or cells was extracted using the RNAiso Plus (TaKaRa Biotechnology, Kusatsu, Japan) and reverse transcribed using the PrimeScript RT Reagent Kit (TaKaRa Biotechnology, Kusatsu, Japan).…”

Section: Methodsmentioning

confidence: 99%

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Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT₂‐inactivated NF‐κB pathway

Zhou

Wang

et al. 2020

British J Pharmacology

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Background and Purpose: Melatonin is a neurohormone involved in bone homeostasis. Melatonin directs bone remodelling and the role of bone marrow mesenchymal stem cells (BMMSCs) in the regulating melatonin-mediated bone formationresorption balance remains undefined. Experimental Approach: Osteoporosis models were established and bone tissue and serum were collected to test the effects of melatonin on bone homeostasis. Melatonin receptors were knocked down, the NF-κB signalling pathway and receptor activator of NF-κB ligand (RANKL) expression were investigated. Communication between bone marrow mesenchymal stem cells and osteoclasts was detected with directcontact or indirect-contact system. Key Results: Bone loss and microstructure disorder in mice were reversed after melatonin treatment, as a result of anabolic and anti-resorptive effects. In vitro, a physiological (low) concentration of melatonin promoted the bone marrow mesenchymal stem cells, osteogenic lineage commitment and extracellular mineralization but had no impact on extracellular matrix synthesis. After MT knockdown, especially MT 2 , the positive effects of melatonin on osteogenesis were attenuated. The canonical NF-κB signalling pathway was the first discovered downstream signalling pathway after MT receptor activation and was found to be down-regulated by melatonin during osteogenesis. Melatonin suppressed BMMSC-mediated osteoclastogenesis by inhibiting RANKL production in BMMSCs and this effect only occurred when BMMSCs and osteoclast precursors were co-cultured in an indirect-contact manner. Conclusion and Implications: Our work suggests that melatonin plays a crucial role in bone balance, significantly accelerates the osteogenic differentiation of bone marrow mesenchymal stem cells by suppressing the MT 2 -dependent NF-κB signalling pathway, and down-regulates osteoclastogenesis via RANKL paracrine secretion. Abbreviations: ALP, alkaline phosphatase; BMD, bone mineral density; BMMs, bone marrow monocytes; BMMSCs, bone marrow mesenchymal stem cells; BV/TV, trabecular bone volume per total volume; Col-I, collagen I; CTX-I, C-terminal telopeptide α1 chain of type I collagen; H&E, haematoxylin and eosin; Mel, melatonin; OCN, osteocalcin; OPG, osteoprotegerin; OVX, ovariectomy; PINP, N-terminal propeptide of type I procollagen; RANK, receptor activator of NF-κB; RANKL, receptor activator of NF-κB ligand; TRAP, tartrate-resistant acid phosphatase; Tb. N, trabecular bone number; Tb. Sp, trabecular bone separation; Tb. Th, trabecular bone thickness; μCT, micro-CT.

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Section: Methodsmentioning

confidence: 99%

“…Protein expression levels of cells were detected by western blotting as described previously (Wang et al, ). Cells were lysed in RIPA mixed with protease and phosphatase inhibitors and incubated for half an hour at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT₂‐inactivated NF‐κB pathway

Zhou

Wang

et al. 2020

British J Pharmacology

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“…A subtle difference of 2 amino acid residues within the ligand-binding receptor cavities of estrogen receptor subtypes ERα and ERβ limits the design of selective ligands (Paterni et al 2014). A cAMP template is used for fitting ERβ agonist structures, as their effects are associated with the cAMP/PKA pathway (Wang et al 2018). The agonists of ERα (13-16) and ERβ (17-20) provide two patterns of fit to the nucleotide structures.…”

Section: Tumour Initiators and Modulatorsmentioning

confidence: 99%

Tumour initiation, store-operated calcium entry (SOCE) and apoptosis: cyclic nucleotide dependence

Williams

2020

gpb

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Chemical instigators and modulators of tumourigenesis influence cell signal transduction pathways. Cyclic nucleotides and steroid hormones may contribute to the process of carcinogenesis or provide protection via apoptotic mechanisms. Although several pharmacologic classes of compounds influence cyclic nucleotide levels markedly, less is known about the class effects of promoters and blockers of tumourigenesis and apoptosis. This molecular modeling study uses cyclic nucleotide templates to investigate relative molecular similarity within compounds modulating tumourigenesis and apoptosis. Findings, in respect of superimposition and molecular fit of the investigated compounds, are related to their individual effects on cyclic nucleotide pharmacology. Modulators of tumourigenesis and estrogen receptor sub-type ligands relate to cyclic nucleotide structure. Estradiol and GPER ligands provide a similar pattern of fit to adenine nucleotide. Chemically diverse modulators of apoptosis, including K + channel ligands, fit to different components of cyclic nucleotide structure. Compounds modulating Ca 2+ entry and IP3 receptors relate structurally to the nucleotide dioxaphosphinin moiety. Relative molecular similarity within the structures of apoptosis and tumourigenesis modulators identifies a unifying property within chemically disparate compounds. The ubiquitous generation of oxidative stress and ROS in cells by apoptosis modulating compounds may relate to the disruption of cyclic nucleotide regulated homeostasis mechanisms.

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“…As an antagonist to adenosine receptor (AdoR), caffeine competitively binds to AdorR, which affects activities of downstream signaling molecules such as cyclic adenosine monophosphate (cAMP)‐response element‐binding protein (CREB) by a second messenger Camp 17 . It has been reported that caffeine could induce the fibrosis of hepatic stellate cells by inhibiting the cAMP/PKA/CREB pathway through adenosine receptor 2A (A2AR), 18 which could also affect bone metabolism and induce osteoporosis 19 . Our previous study found that PCE could inhibit the cAMP pathway and placental leptin expression by inhibiting A2AR 20 .…”

Section: Introductionmentioning

confidence: 99%

“…17 It has been reported that caffeine could induce the fibrosis of hepatic stellate cells by inhibiting the cAMP/PKA/CREB pathway through adenosine receptor 2A (A2AR), 18 which could also affect bone metabolism and induce osteoporosis. 19 Our previous study found that PCE could inhibit the cAMP pathway and placental leptin expression by inhibiting A2AR. 20 Brain-derived neurotrophic factor (BDNF) is one of the essential neurotrophic factors in the brain, which is involved in neuronal growth, neuronal development, neuronal differentiation, synaptic plasticity, and synaptic regeneration.…”

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confidence: 95%

The upregulation of glutamate decarboxylase 67 against hippocampal excitability damage in male fetal rats by prenatal caffeine exposure

Jiao

et al. 2022

Environmental Toxicology

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As a kind of xanthine alkaloid, caffeine is widely present in beverages, food, and analgesic drugs. Our previous studies have shown that prenatal caffeine exposure (PCE) can induce programmed hypersensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in offspring rats, which is involved in developing many chronic adult diseases. The present study further examined the potential molecular mechanism and toxicity targets of hippocampal dysfunction, which might mediate the programmed hypersensitivity of the HPA axis in offspring. Pregnant rats were intragastrically administered with 0, 30, and 120 mg/kg/day caffeine from gestational days (GD) 9-20, and the fetal rats were extracted at GD20. Rat fetal hippocampal H19-7/IGF1R cell line was treated with caffeine, adenosine A2A receptor (A2AR) agonist (CGS-21680) or adenylate cyclase agonist (forskolin) plus caffeine. Compared with the control group, hippocampal neurons of male fetal rats by PCE displayed increased apoptosis and reduced synaptic plasticity, whereas glutamate decarboxylase 67 (GAD67) expression was increased. Moreover, the expression of A2AR was down-regulated, PCE inhibited the cAMP/PKA/CREB/BDNF/TrkB pathway. Furthermore, the results in vitro were consistent with the in vivo study. Both CGS21680 and forskolin could reverse the above alteration caused by caffeine. These results indicated that PCE inhibits the BDNF pathway and mediates the hippocampus's glutamate (Glu) excitotoxicity. The compensatory up-regulation of GAD67 unbalanced the Glu/gammaaminobutyric acid (GABA)ergic output, leading to the impaired negative feedback to the hypothalamus and hypersensitivity of the HPA axis.

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β-Estradiol antagonizes the inhibitory effects of caffeine in BMMSCs via the ERβ-mediated cAMP-dependent PKA pathway

Cited by 9 publications

References 33 publications

Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT₂‐inactivated NF‐κB pathway

Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT₂‐inactivated NF‐κB pathway

Tumour initiation, store-operated calcium entry (SOCE) and apoptosis: cyclic nucleotide dependence

The upregulation of glutamate decarboxylase 67 against hippocampal excitability damage in male fetal rats by prenatal caffeine exposure

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β-Estradiol antagonizes the inhibitory effects of caffeine in BMMSCs via the ERβ-mediated cAMP-dependent PKA pathway

Cited by 9 publications

References 33 publications

Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT2‐inactivated NF‐κB pathway

Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT2‐inactivated NF‐κB pathway

Tumour initiation, store-operated calcium entry (SOCE) and apoptosis: cyclic nucleotide dependence

The upregulation of glutamate decarboxylase 67 against hippocampal excitability damage in male fetal rats by prenatal caffeine exposure

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Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT₂‐inactivated NF‐κB pathway

Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT₂‐inactivated NF‐κB pathway