Hydroxysafflor Yellow A Promoted Bone Mineralization and Inhibited Bone Resorption Which Reversed Glucocorticoids-Induced Osteoporosis

Glucocorticoids intake is the most common cause of secondary osteoporosis. Clinical studies have shown that 50% patients develop glucocorticoids-induced osteoporosis (GCIOP) after taking glucocorticoids for more than 6 months. Hydroxysafflor yellow A (HYA) is one main active ingredient in Carthamus tinctorius L. Previous studies have shown that HYA promoted bone marrow mesenchymal stem cells to differentiate into osteoblasts which promoted bone formation. Therefore, we speculated that HYA has a therapeutic effect on GCIOP. However, there is no in vivo evidence about the anti-GCIOP effect of HYA. In this paper, the effect of HYA (0.1, 1.0, and 10.0 μM) on bone formation in normal zebrafish was investigated firstly. Secondly, the reversal effect of HYA on GCIOP was also evaluated by zebrafish model. It is demonstrated that HYA not only promoted bone formation in normal zebrafish (compared to Control group), but also reversed glucocorticoid induced bone loss (compared to Prednisolone group) according to the intervention of HYA in upregulating the area of mineralized bones (p < 0.01), increasing cumulative optical density (p < 0.01), promoting bone formation related gene expression (AKP, Type I, Runx2, OPG, and OCN, p < 0.01), inhibiting bone resorption related gene expression (TRACP, p < 0.01), and elevating whole-body trace mineral elements (Ca, P, K, Mg, Zn, and Fe) levels (p < 0.01). In conclusion, HYA had the potential to prevent and heal GCIOP by promoting bone mineralization, osteoblasts viability, and bone collagen expression and inhibiting bone resorption.

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The Effect of the Combination of Vitamin K2 and Genistein, Coumestrol and Daidzein on the Osteoblast Differentiation and Bone Matrix Formation

Journal of Biotechnology Research Center ◽

10.24126/jobrc.2016.10.2.474 ◽

2016 ◽

Vol 10 (2) ◽

pp. 12-19

Author(s):

Sahar S. Karieb ◽

Mohammed M. Jawad ◽

Hanady S. Al-Shmgani ◽

Zahraa H.M. Kadri

Keyword(s):

Bone Formation ◽

Osteoblast Differentiation ◽

Nuclear Factor Kappa B ◽

Type I Collagen ◽

Bone Mineralization ◽

Bone Matrix ◽

Vitamin K2 ◽

Type I ◽

Nuclear Factor ◽

Effective Factor

Multiple studies have been reported the stimulatory effect of the combinations of nutrients factors on bone formation. One such factor is vitamin K2 which can be associated with bone protective activities. The effect of vitamin K2 alone and in combination with genistein, coumestrol and daidzein on osteoblast differentiation and mineralization were tested. Significantly, vitamin K2 increased bone mineralization in combination with genistein (10-5M), coumestrol (10-7M) and daidzein (10-5M). However, there is no additive effect of this vitamin on alkaline phosphatase (ALP) levels in osteoblasts. By contrast, vitamin K2 enhanced the stimulatory effect of type I collagen and osteocalcin expression. Vitamin K2 alone increased RUNX and OSX expression while there is no synergistic effect with tested compound; this vitamin also did not modulate nuclear factor kappa B ligand (RANKL)/ osteoprotegerin (OPG) ratio expression. These results suggested that vitamin K2 can be more effective factor in the presence of phytoestrogens on the improvement of bone formation after menopause.

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Impact of mutant IDH (mIDH) inhibition on DNA hydroxymethylation, tumor cell function, and tumor immune microenvironment (TIME) in resected mIDH1 lower-grade glioma (LGG).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2008 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2008-2008

Author(s):

Min Lu ◽

Timothy Francis Cloughesy ◽

Patrick Y. Wen ◽

Ania Tassinari ◽

Sung Choe ◽

...

Keyword(s):

Gene Expression ◽

Tumor Cell ◽

Antigen Presentation ◽

Post Treatment ◽

Type I ◽

Interferon Signaling ◽

Related Gene ◽

Ki 67 ◽

Dual Inhibitor ◽

Upper Limit

2008 Background: Somatic mutations in IDH1 and IDH2 occur in ̃80% and ̃4% of LGGs, respectively, promoting tumorigenesis via increased levels of the oncometabolite D-2-hydroxyglutarate (2-HG). Vorasidenib (VOR; AG-881) is an oral, brain-penetrant, dual inhibitor of mIDH1/2; ivosidenib (IVO; AG-120) is a first-in-class oral inhibitor of mIDH1. In this ongoing perioperative study, treatment with IVO/VOR reduced 2-HG levels in resected tumors vs untreated control tumors in patients (pts) with LGG (NCT03343197; Mellinghoff SNO 2019). We assessed the biological impact of 2-HG suppression on tumors and TIME. Methods: Pts (n = 49) with recurrent, non-enhancing, mIDH1-R132H LGG eligible for resection were randomized to IVO (500 mg QD/250 mg BID), VOR (10/50 mg QD), or no treatment, for 4 weeks preoperatively. Tumor tissue samples collected at surgery were assessed in genomic (n = 42), transcriptomic (n = 42), and immunohistochemistry (IHC; n = 43) analyses. Unpaired t-test was used for statistical comparisons. Results: Optimal 2-HG suppression (post-treatment 2-HG below the upper limit of 2-HG levels in a reference set of 15 wild-type [wt] IDH samples) was observed in 23 of 40 pts, including 9 (90%) pts receiving VOR 50 mg QD and 6 (50%) receiving IVO 500 mg QD. Of samples with valid biomarker data, those with optimal 2-HG suppression (n = 21) showed upregulation of neural differentiation-related gene expression, but downregulation of stemness-related gene expression, vs those with suboptimal 2-HG suppression (post-treatment 2-HG above upper limit of wt IDH 2-HG levels; n = 17; p < 0.01). IHC analysis of the proliferation marker Ki-67 showed a ̃2-fold decrease in Ki-67–positive cells in samples with optimal 2-HG suppression (mean 2.7%; n = 22) vs those with suboptimal suppression (5.8%; n = 16; p < 0.05). Epigenetic analysis revealed a ̃2-fold increase in mean 5-hydroxymethylcytosine (5hmC) levels in samples with optimal (0.36%; n = 17) vs suboptimal 2-HG suppression (0.2%; n = 15; p < 0.05), suggesting reversal of TET2 inhibition. IHC analysis of TIME revealed increases in mean CD3+ and CD8+ tumor-infiltrating lymphocyte levels in samples with optimal (1.05% [CD3]/0.22% [CD8]; n = 22) vs suboptimal 2-HG suppression (0.44% [CD3]/0.07% [CD8]; n = 16; p < 0.05). Optimal 2-HG suppression was associated with upregulation of gene expression related to type I interferon signaling and antigen presentation (p < 0.01). Conclusions: These data suggest that both tumor-intrinsic and -extrinsic mechanisms underlie 2-HG suppression by VOR and IVO. VOR, and IVO to a lesser extent, increased 5hmC, promoted cellular differentiation, and inhibited tumor cell proliferation; both also increased T-cell infiltration, activated interferon signaling, and increased antigen presentation capability. These data support development of VOR in combination with immunotherapy. Clinical trial information: NCT03343197.

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Dietary lysine affects growth performance, whole‐body composition and growth‐related gene expression in the yellow drum Nibea albiflora

Aquaculture Nutrition ◽

10.1111/anu.13139 ◽

2020 ◽

Vol 26 (6) ◽

pp. 1970-1980

Author(s):

Ligai Wang ◽

Dan Zhao ◽

Peng Tan ◽

Ruiyi Chen ◽

Dongdong Xu

Keyword(s):

Gene Expression ◽

Body Composition ◽

Growth Performance ◽

Whole Body ◽

Related Gene ◽

Nibea Albiflora

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Novel Metabolic Pathways Associated with Serum Bone Turnover Markers in Healthy Young Adults

Current Developments in Nutrition ◽

10.1093/cdn/nzaa040_071 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 71-71

Author(s):

Joseph Roberts ◽

Moriah Bellissimo ◽

Kaitlin Taibl ◽

Karan Uppal ◽

Dean Jones ◽

...

Keyword(s):

Young Adults ◽

Fatty Acid ◽

Amino Acid ◽

High Resolution ◽

Bone Resorption ◽

Bone Formation ◽

Bone Turnover ◽

Metabolic Pathways ◽

Type I ◽

Turnover Markers

Abstract Objectives Optimal bone health is maintained through a remodeling cycle consisting of resorption followed by formation. Procollagen type I N-terminal propeptide (P1NP) and C-terminal telopeptides of type I collagen (CTX) are biomarkers of bone metabolism that capture changes in bone formation and bone resorption, respectively. This study aimed to identify unique metabolic pathways related to bone turnover markers (BTMs) in healthy young adults. Methods This cross-sectional study included 34 healthy, young adults (19 females, average age 27.8 years). Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry. Fasting plasma was analyzed using dual column liquid chromatography and ultra-high-resolution mass spectrometry for metabolomics. Serum levels of P1NP and CTX were measured with ELISA. Linear regression and pathway enrichment analyses were used to identify metabolic pathways related to the BTMs. Results All participants had a normal whole-body BMD T-score. Metabolites significantly associated with P1NP (at P < 0.05) were significantly enriched in pathways linked to the TCA cycle, pyruvate metabolism, and metabolism of B-vitamins important for energy production (e.g., niacin, thiamin). Other nutrition-related metabolic pathways associated with P1NP were amino acid (proline, arginine, glutamate) and vitamin C metabolism, which are important for collagen formation. Metabolites were associated with CTX levels (at P < 0.05), which were enriched within lipid and fatty acid beta-oxidation metabolic pathways, as well as fat soluble micronutrients pathways including, vitamin D metabolism, vitamin E metabolism, and bile acid biosynthesis. Conclusions High-resolution metabolomics identified several distinct plasma metabolic pathways, including energy-yielding metabolic pathways and pathways related to fatty acid, amino acid, and micronutrient metabolism that were associated with markers of bone formation and bone resorption. Characterizing these metabolism-related pathways associated with BTMs in healthy adults is an important step towards understanding the metabolic perturbations that lead to low bone mass in older and clinical populations. Funding Sources National Institutes of Health and Emory University.

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The assessment of bone formation and bone resorption in osteoporosis: A comparison between tetracycline-based iliac histomorphometry and whole body 85Sr kinetics

Journal of Bone and Mineral Research ◽

10.1002/jbmr.5650020604 ◽

2009 ◽

Vol 2 (6) ◽

pp. 479-489 ◽

Cited By ~ 29

Author(s):

J. Reeve ◽

Monique E. Arlot ◽

Pascale M. Chavassieux ◽

Claude Edouard ◽

J.R. Green ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Whole Body

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Bortezomib Reduces Serum Dickkopf-1 and RANKL Concentrations and Normalizes Indices of Bone Remodeling in Patients with Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.506.506 ◽

2006 ◽

Vol 108 (11) ◽

pp. 506-506

Author(s):

Evangelos Terpos ◽

Deborah Heath ◽

Amin Rahemtulla ◽

Kostas Zervas ◽

Andrew Chantry ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Bone Remodeling ◽

Serum Levels ◽

Response To Therapy ◽

Tartrate Resistant Acid Phosphatase ◽

Type I ◽

Lytic Lesions ◽

Tracp 5B ◽

Dickkopf 1

Abstract Bortezomib is a proteasome inhibitor, which is currently indicated for the treatment of relapsed/refractory myeloma (MM). Although the anti-myeloma effect of bortezomib has been clearly demonstrated, its effect on bone metabolism is still unclear. There are recent reports that bortezomib increases serum alkaline phosphatase (ALP) activity, which is consistent with enhanced osteoblast function. The aim of this study was to evaluate the effect of bortezomib on bone turnover in 34 patients with relapsed MM. Bortezomib was given alone at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of a 3-week cycle for 4 cycles. Responders could continue for 4 more cycles, while non-responders could continue therapy with the addition of dexamethasone. The following serum indices were measured on day 1 of cycle 1, and then on day 21 of cycles 4 and 8: osteoblast inhibitor dickkopf-1 (DKK-1); osteoclast regulators: soluble RANKL (sRANKL) and osteoprotegerin (OPG); bone resorption markers: C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase type-5b (TRACP-5b); and bone formation markers: bone-specific ALP (bALP) and osteocalcin (OC). We also studied 33 healthy controls of similar gender and age. The objective response rate after 4 cycles of therapy was 66%: CR 8% and PR 58%. Sixteen responders and 3 non-responders continued on therapy for 4 more cycles. Myeloma patients at baseline had increased values of DKK-1 (p=0.007), sRANKL, sRANKL/OPG ratio, and both markers of bone resorption (p<0.0001) when compared to controls. In contrast, bone formation as assessed by serum bALP and OC was significantly reduced (p<0.001). There was a strong correlation between bone lytic disease and serum CTX (r=0.59, p<0.01), and sRANKL (r=0.4, p=0.03). Patients with severe bone disease (>9 lytic lesions, n=7) had elevated values of DKK-1 compared with all others (mean±SD: 223.4±264.4 ng/mL vs. 84±62.4 ng/mL; p=0.01). Moreover, serum levels of DKK-1 correlated with CTX levels (r=0.39, p=0.04), and weakly with bALP concentrations (r=−0.32, p=0.09). The administration of bortezomib produced a significant reduction of DKK-1 (p=0.035), sRANKL (p=0.01), CTX and TRACP-5b (p<0.001) after 4 cycles, which was still seen after 8 cycles of treatment (p<0.01). Bortezomib also produced a dramatic increase in both markers of bone formation, bALP and OC, after 4 and 8 cycles of therapy (p<0.01). Responders tended to have lower initial levels of DKK-1 compared with non-responders. Patients who achieved a CR or vgPR after 4 cycles of bortezomib had greater elevation of bALP than all others: mean±SD of increase: 306.3%±556.9% vs. 45.8%±56.5%; p=0.02. It is of interest that 3/4 non responders also had an increase in bALP (mean: 39.6%) after 4 cycles of bortezomib. There was no other correlation between response to therapy and alteration of bone markers. No healing of the lytic lesions was observed even in CR patients. This study suggests that bortezomib reduces serum levels of DKK-1 and RANKL, irrespective of response to therapy, in patients with relapsed myeloma and thus leads to normalization of abnormal bone remodeling through the increase of bone formation and reduction of bone resorption.

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Altered skeletal pattern of gene expression in response to spaceflight and hindlimb elevation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.267.6.e822 ◽

1994 ◽

Vol 267 (6) ◽

pp. E822-E827 ◽

Cited By ~ 18

Author(s):

D. D. Bikle ◽

J. Harris ◽

B. P. Halloran ◽

E. Morey-Holton

Keyword(s):

Gene Expression ◽

Alkaline Phosphatase ◽

Bone Formation ◽

Bone Mineralization ◽

Mrna Levels ◽

Skeletal Unloading ◽

Compensatory Response ◽

Factor I ◽

Igf I ◽

Skeletal Pattern

Spaceflight leads to osteopenia, in part by inhibiting bone formation. Using an animal model (hindlimb elevation) that simulates the weightlessness of spaceflight, we and others showed a reversible inhibition of bone formation and bone mineralization. In this study, we have measured the mRNA levels of insulin-like growth factor I (IGF-I), IGF-I receptor (IGF-IR), alkaline phosphatase, and osteocalcin in the tibiae of rats flown aboard National Aeronautics and Space Administration Shuttle Flight STS-54 and compared the results with those obtained from their ground-based controls and from the bones of hindlimb-elevated animals. Spaceflight and hindlimb elevation transiently increase the mRNA levels for IGF-I, IGF-IR, and alkaline phosphatase but decrease the mRNA levels for osteocalcin. The changes in osteocalcin and alkaline phosphatase mRNA levels are consistent with a shift toward decreased maturation, whereas the rise in IGF-I and IGF-IR mRNA levels may indicate a compensatory response to the fall in bone formation. We conclude that skeletal unloading during spaceflight or hindlimb elevation resets the pattern of gene expression in the osteoblast, giving it a less mature profile.

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Markers of Bone Formation and Resorption Identify Subgroups of Patients with Clinical Knee Osteoarthritis Who Have Reduced Rates of Cartilage Loss

The Journal of Rheumatology ◽

10.3899/jrheum.091055 ◽

2010 ◽

Vol 37 (6) ◽

pp. 1252-1259 ◽

Cited By ~ 23

Author(s):

PATRICIA A. BERRY ◽

ROSE A. MACIEWICZ ◽

FLAVIA M. CICUTTINI ◽

MARK D. JONES ◽

CAROLINE J. HELLAWELL ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Type I Collagen ◽

Serum Markers ◽

Cartilage Volume ◽

Cartilage Loss ◽

Type I ◽

Bone Formation Markers ◽

Markers Of Bone Formation ◽

Markers Of Bone Resorption

Objective.To determine whether serum markers of bone formation and resorption, used individually or in combination, can be used to identify subgroups who lose cartilage volume at different rates over 2 years within a knee osteoarthritis (OA) population.Methods.Changes in cartilage volume over 2 years were measured in 117 subjects with knee OA using magnetic resonance imaging. We examined relationships between change in cartilage volume and baseline serum markers of bone formation [intact N-terminal propeptide of type I procollagen (PINP) and osteocalcin] and resorption [N-telopeptide of type I collagen (NTX-I), C-telopeptide of type I collagen (CTX-I), and C-telopeptide of type I collagen (ICTP).Results.The baseline markers of bone formation, PINP and osteocalcin (p = 0.02, p = 0.01, respectively), and the baseline markers of bone resorption, CTX-I and NTX-I (p = 0.02 for both), were significantly associated with reduced cartilage loss. There were no significant associations between baseline ratios of bone formation to resorption markers and cartilage loss. However, when subjects were divided into subgroups with high or low bone formation markers (based on levels of marker ≥ mean or < mean for the population, respectively), in the subgroup with high PINP there was a significant association between increasing bone resorption markers CTX-I and NTX-I and reduced cartilage loss (p = 0.02, p = 0.001, respectively). Similarly, in the subgroup with high osteocalcin, there was a significant association between increasing CTX-I and NTX-I and reduced cartilage loss (p = 0.02, p = 0.003, respectively). In contrast, in subgroups with low bone formation markers, no significant associations were obtained between markers of bone resorption and cartilage loss.Conclusion.Overall, the results suggest that higher bone remodeling (i.e., higher serum levels of bone formation and resorption) is associated with reduced cartilage loss. Considering markers of bone formation and resorption together, it is possible to identify subgroups within the OA population who have reduced rates of cartilage loss.

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Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases

Scientific Reports ◽

10.1038/srep15145 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 98

Author(s):

Jialiang Yang ◽

◽

Tao Huang ◽

Francesca Petralia ◽

Quan Long ◽

...

Keyword(s):

Gene Expression ◽

Complex Disease ◽

Principal Component ◽

Tissue Expression ◽

Whole Body ◽

Disease Genes ◽

Related Gene ◽

Tissue Specific ◽

Age Related ◽

Holistic Understanding

Abstract Aging is one of the most important biological processes and is a known risk factor for many age-related diseases in human. Studying age-related transcriptomic changes in tissues across the whole body can provide valuable information for a holistic understanding of this fundamental process. In this work, we catalogue age-related gene expression changes in nine tissues from nearly two hundred individuals collected by the Genotype-Tissue Expression (GTEx) project. In general, we find the aging gene expression signatures are very tissue specific. However, enrichment for some well-known aging components such as mitochondria biology is observed in many tissues. Different levels of cross-tissue synchronization of age-related gene expression changes are observed and some essential tissues (e.g., heart and lung) show much stronger “co-aging” than other tissues based on a principal component analysis. The aging gene signatures and complex disease genes show a complex overlapping pattern and only in some cases, we see that they are significantly overlapped in the tissues affected by the corresponding diseases. In summary, our analyses provide novel insights to the co-regulation of age-related gene expression in multiple tissues; it also presents a tissue-specific view of the link between aging and age-related diseases.

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