Dataset Information

Dracunculin Inhibits Adipogenesis in Human Bone Marrow-Derived Mesenchymal Stromal Cells by Activating AMPK and Wnt/β-Catenin Signaling.

ABSTRACT: Increased bone marrow adiposity is widely observed in patients with obesity and osteoporosis and reported to have deleterious effects on bone formation. Dracunculin (DCC) is a coumarin isolated from Artemisia spp. but, until now, has not been studied for its bioactive potential except antitrypanosomal activity. In this context, current study has reported the anti-adipogenic effect of DCC in human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). DCC dose-dependently inhibited the lipid accumulation and expression of adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) in hBM-MSCs induced to undergo adipogenesis. To elucidate its action mechanism, the effect of DCC on Wnt/β-catenin and AMPK pathways was examined. Results showed that DCC treatment activated Wnt/β-catenin signaling pathway via AMPK evidenced by increased levels of AMPK phosphorylation and Wnt10b expression after DCC treatment. In addition, DCC treated adipo-induced hBM-MSCs exhibited significantly increased nuclear levels of β-catenin compared with diminished nuclear PPARγ levels. In conclusion, DCC was shown to be able to hinder adipogenesis by activating the β-catenin via AMPK, providing potential utilization of DCC as a nutraceutical against bone marrow adiposity.

SUBMITTER: Karadeniz F

PROVIDER: S-EPMC8776130 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dracunculin Inhibits Adipogenesis in Human Bone Marrow-Derived Mesenchymal Stromal Cells by Activating AMPK and Wnt/β-Catenin Signaling.

Karadeniz Fatih F Oh Jung Hwan JH Jo Hyun Jin HJ Yang Jiho J Lee Hyunjung H Seo Youngwan Y Kong Chang-Suk CS

International journal of molecular sciences 20220107 2

Increased bone marrow adiposity is widely observed in patients with obesity and osteoporosis and reported to have deleterious effects on bone formation. Dracunculin (DCC) is a coumarin isolated from <i>Artemisia</i> spp. but, until now, has not been studied for its bioactive potential except antitrypanosomal activity. In this context, current study has reported the anti-adipogenic effect of DCC in human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). DCC dose-dependently inhibited the ...[more]

PMID: 35054838

Similar Datasets

Project description:Environmental obesogens are a newly recognized category of endocrine disrupting chemicals that have been implicated in contributing to the rising rates of obesity in the United States. While obesity is typically regarded as an increase in visceral fat, adipocyte accumulation in the bone has been linked to increased fracture risk, lower bone density, and osteoporosis. Exposure to environmental toxicants that activate peroxisome proliferator activated receptor γ (PPARγ), a critical regulator of the balance of differentiation between adipogenesis and osteogenesis, may contribute to the increasing prevalence of osteoporosis. However, induction of adipogenesis and suppression of osteogenesis are separable activities of PPARγ, and ligands may selectively alter these activities. It currently is unknown whether suppression of osteogenesis is a common toxic endpoint of environmental PPARγ ligands. Using a primary mouse bone marrow culture model, we tested the hypothesis that environmental toxicants acting as PPARγ agonists divert the differentiation pathway of bone marrow-derived multipotent mesenchymal stromal cells towards adipogenesis and away from osteogenesis. The toxicants tested included the organotins tributyltin and triphenyltin, a ubiquitous phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). All of the compounds activated PPARγ1 and 2. All compounds increased adipogenesis (lipid accumulation, Fabp4 expression) and suppressed osteogenesis (alkaline phosphatase activity, Osx expression) in mouse primary bone marrow cultures, but with different potencies and efficacies. Despite structural dissimilarities, there was a strong negative correlation between efficacies to induce adipogenesis and suppress osteogenesis, with the organotins being distinct in their exceptional ability to suppress osteogenesis. As human exposure to a mixture of toxicants is likely, albeit at low doses, the fact that multiple toxicants are capable of suppressing bone formation supports the hypothesis that environmental PPARγ ligands represent an emerging threat to human bone health.

Project description:BackgroundPulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. Previous studies have shown that early intervention with bone marrow mesenchymal stem/stromal cells (BMSCs) has positive effect on anti-pulmonary fibrosis caused by silica dust. However, early intervention using BMSCs is not practical, and the therapeutic effects of BMSCs advanced intervention on pulmonary fibrosis have rarely been reported. In this study, we investigated the effects of advanced transplantation (on the 28th day after exposure to silica suspension) of BMSCs on an established rat model of pulmonary fibrosis.MethodsSprague Dawley (SD) rats were randomly divided into four groups including (1) control group (n = 6) which were normally fed, (2) silica model group (n = 6) which were exposed to silica suspension (1 mL of 50 mg/mL/rat), (3) BMSC transplantation group (n = 6) which received 1 mL BMSC suspension (2 × 106 cells/mL) by tail vein injection on the 28th day after exposure to silica suspension, and (4) BMSC-CM (conditioned medium) transplantation group (n = 6) which received CM from the same cell number by tail vein injection on the 28th day after exposure to silica suspension. On the 56th day after exposure to silica suspension, we used computed tomography (CT), hematoxylin and eosin (H&E), and Masson's trichrome staining to evaluate the changes in lung tissue. We examined the expression of epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathway-related proteins in lung tissue using immunohistochemistry and western blotting.ResultsSuccessful construction of a pulmonary fibrosis model was confirmed by H&E and Masson's trichrome staining on the 28th day after exposure to silica suspension. On the 56th day after exposure, pulmonary CT examination showed a relieving effect of BMSCs on silica-induced pulmonary fibrosis which was confirmed by H&E and Masson's trichrome staining. Treatment of BMSCs increased the expression of epithelial marker proteins including E-cadherin (E-cad) and cytokeratin19 (CK19) and reduced the expression of fibrosis marker proteins including Vimentin (Vim) and α-Smooth actin (α-SMA) after exposure to silica suspension. Furthermore, we found that Wnt/β-catenin signaling pathway is abnormally activated in silica-induced pulmonary fibrosis, and exogenous transplantation of BMSCs may attenuate their expression.ConclusionsBMSC transplantation inhibits the EMT to alleviate silica-induced pulmonary fibrosis in rats and the anti-fibrotic effect potentially by attenuating Wnt/β-catenin signaling. ᅟ: ᅟ.

Project description:Ruxolitinib is a JAK2/JAK1 inhibitor that blocks the inflammatory JAK-STAT signaling pathway. Ruxolitinib has been demonstrated to be effective in the treatment of steroid-resistant acute graft-versus-host disease (GVHD). Ruxolitinib's effect on inflammatory cells of hematopoietic origin is known. However, its effect on nonhematopoietic cell types with immune-modulating and antigen-presenting cell competency plausibly involved in pathogenesis of GVHD has not been explored. Mesenchymal stromal cells (MSCs) are CD45- nonhematopoietic cells of the bone marrow with immune modulatory functions in vivo. MSCs' immunobiology largely depends on their responsiveness to IFNγ. We aimed to define the effect of ruxolitinib on the immunobiology of MSCs that are modulated by IFNγ. Human bone marrow derived MSCs, peripheral blood mononuclear cells (PBMCs), and primary bone marrow aspirates were analyzed for their sensitivity to ruxolitinib-mediated blocking of IFNγ-induced STAT-1 phosphorylation and downstream effector molecules, utilizing Western blot, flow cytometry, secretome analysis, and phosflow techniques. IFNγ-induced cytostatic effects on MSCs are reversed by ruxolitinib. Ruxolitinib inhibits IFNγ and secretome of activated peripheral PBMC-induced STAT-1 phosphorylation on human bone marrow derived MSCs. In addition, ruxolitinib inhibits IFNγ-induced pro-GVHD pathways on MSCs, which includes HLAABC(MHCI), HLADR(MHCII), CX3CL1, and CCL2. IFNγ-induced immunosuppressive molecules IDO and PDL-1 were also inhibited by ruxolitinib on MSCs. Comparative analysis with PBMCs has demonstrated that MSCs are as equal as to HLADR+ PBMC populations in responding to ruxolitinib-mediated inhibition of IFNγ-induced STAT-1 phosphorylation. Ex vivo analysis of human marrow aspirates has demonstrated that ruxolitinib blocks IFNγ-induced STAT-1 phosphorylation in CD45+/-HLADR+/- populations at different levels, which is depending on their sensitivity to IFNγ responsiveness. These results inform the hypothesis that ruxolitinib's immune-modulatory effects in vivo may pharmacologically involve marrow and tissue-resident MSCs. Ruxolitinib affects the immunobiology of MSCs equivalent to professional HLADR+ antigen presenting cells, which collectively mitigate GVHD.

Dataset Information

Dracunculin Inhibits Adipogenesis in Human Bone Marrow-Derived Mesenchymal Stromal Cells by Activating AMPK and Wnt/β-Catenin Signaling.

Publications

Dracunculin Inhibits Adipogenesis in Human Bone Marrow-Derived Mesenchymal Stromal Cells by Activating AMPK and Wnt/β-Catenin Signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets