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Bone Oct 2019Impaired osteoblast and osteocyte maturation contribute to mineralization defects and excess FGF23 expression in CKD bone. Vitamin D sterols decrease osteoid...
Impaired osteoblast and osteocyte maturation contribute to mineralization defects and excess FGF23 expression in CKD bone. Vitamin D sterols decrease osteoid accumulation and increase FGF23 expression; these agents also increase osteoblast maturation in vitro but a link between changes in bone cell maturation, bone mineralization, and FGF23 expression in response to vitamin D sterols has not been established. We evaluated unmineralized osteoid accumulation, osteocyte maturity markers (FGF23: early osteocytes; sclerostin: late osteocytes), and osteocyte apoptosis in iliac crest of 11 pediatric dialysis patients before and after 8 months of doxercalciferol therapy. We then evaluated the effect of 1,25(OH)vitamin D on in vitro maturation and mineralization of primary osteoblasts from dialysis patients. Unmineralized osteoid accumulation decreased while numbers of early (FGF23-expressing) increased in response to doxercalciferol. Osteocyte apoptosis was low but increased with doxercalciferol. Bone FGF23 expression correlated with numbers of early, FGF23-expressing, osteocytes (r = 0.83, p < 0.001). In vitro, 1,25(OH)vitamin D increased expression of the mature osteoblast marker osteocalcin (BGLAP) but only very high (100 nM) concentrations affected in vitro osteoblast mineralization. High doses (10 and 100 nM) of 1,25(OH)vitamin D also increased the ratio of RANKL/OPG expression in CKD osteoblasts. Vitamin D sterols directly stimulate osteoblast maturation. They also increase osteocyte turnover and increase osteoblast expression of osteoclast differentiation factors, thus likely modulating osteoblast/osteoclast/osteocyte coupling. By increasing numbers of early osteocytes, vitamin D sterols increase FGF23 expression in CKD bone.
Topics: Adolescent; Apoptosis; Bone and Bones; Calcification, Physiologic; Cell Count; Cell Differentiation; Cells, Cultured; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Male; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Renal Insufficiency, Chronic; Sterols; Vitamin D
PubMed: 31377240
DOI: 10.1016/j.bone.2019.07.026 -
The Journal of Steroid Biochemistry and... Mar 2020Hepatocellular carcinoma (HCC) is the most common form of liver cancer and it is the third leading cause of global cancer mortality. Sorafenib (Sf) is the first oral...
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and it is the third leading cause of global cancer mortality. Sorafenib (Sf) is the first oral multi-kinase inhibitor approved for systemic treatment of advanced HCC, and can prolong survival, although only for three months longer than placebo treated patients. Preclinical studies showed that active forms of vitamin D can induce cell differentiation and regulate cell survival in several cell types, and epidemiological data link vitamin D insufficiency to an increased risk of neoplastic diseases, suggesting a potentially important role of vitamin D in cancer therapy. Other studies showed that the effect of vitamin D analogs on human neoplastic cells is potentiated by carnosic acid (CA), a plant polyphenol with anti-oxidant properties. Here we tested if the addition of the vitamin D2 analog Doxercalciferol (D2) together with CA can enhance the cytotoxic effect of Sf on HCC cell lines Huh7 (Sf-sensitive) and HCO2 (Sf-resistant). Indeed, this combination increased HCC cell death in cell lines, enhancing autophagy as well as apoptosis. Autophagy was confirmed by increased cytoplasmic vacuolation, perinuclear aggregation of LC3, and elevated protein levels of autophagy markers Beclin1, Atg3, and LC3. These results suggest that a regimen which combines a vitamin D2 analog/CA mixture with Sf can be a novel and promising therapeutic option for the treatment of HCC.
Topics: Abietanes; Antineoplastic Agents; Antioxidants; Apoptosis; Autophagy; Bone Density Conservation Agents; Carcinoma, Hepatocellular; Cell Proliferation; Drug Synergism; Drug Therapy, Combination; Ergocalciferols; Humans; Liver Neoplasms; Signal Transduction; Sorafenib; Tumor Cells, Cultured
PubMed: 31704246
DOI: 10.1016/j.jsbmb.2019.105524 -
Journal of Oral Microbiology 2024is a virulent microorganism associated with dental caries. This study aimed to investigate the antimicrobial effects of Cholecalciferol (D3) and Doxercalciferol (D2),...
BACKGROUND
is a virulent microorganism associated with dental caries. This study aimed to investigate the antimicrobial effects of Cholecalciferol (D3) and Doxercalciferol (D2), against and on glycosyltransferase gene expression.
METHODS
Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of D3 and D2 for were determined according to the Clinical Laboratory Standards Institute guidelines. The effect of the compounds on environmental pH in 1% w/v and 5% w/v sucrose broth cultures after 24 hours were assessed colorimetrically. Additionally, their impact on glycosyltransferases gene expression () in 5% w/v sucrose culture was evaluated using quantitative real-time PCR.
RESULTS
The MBCs of D3 and D2 were 83 µg/ml and 166 µg/ml respectively. Both compounds were effective in preventing the local pH drop <5.5 at ≥166 µg/ml in sucrose supplemented cultures. However, the compounds did not inhibit pH drop at MIC values. Notably, D2 upregulated expression significantly ( < 0.05) and downregulated and .
CONCLUSION
Vitamin D2 and D3 inhibited mediated pH drop in sucrose supplemented cultures and altered glycosyltransferase expression, suggesting potential therapeutic roles in dental caries prevention. Further research is needed to assess their full impact on survival under environmental stresses.
PubMed: 38550660
DOI: 10.1080/20002297.2024.2327758 -
Journal of Cellular Physiology Jan 2020Acute myeloid leukemia (AML) has a poor prognosis and requires new approaches for treatment. We have reported that a combination of vitamin D-based cell differentiation...
Acute myeloid leukemia (AML) has a poor prognosis and requires new approaches for treatment. We have reported that a combination of vitamin D-based cell differentiation agents (doxercalciferol/carnosic acid [D2/CA]) added following the cytotoxic drug arabinocytosine (AraC) increases AML cell death (CD), a model for improved therapy of this disease. Because AraC-induced CD is known to involve reactive oxygen species (ROS) generation, here we investigated if the modulation of cellular REDOX status plays a role in the enhancement of cell death (ECD) by D2/CA. Using thiol antioxidants, such as N-acetyl cysteine (NAC), we found a significant inhibition of ECD, yet this occurred in the absence of any detectable change in cellular ROS levels. In contrast, NAC reduced the vitamin D receptor (VDR) abundance and its signaling of ECD. Importantly, VDR knockdown and NAC similarly inhibited ECD without producing an additive effect. Thus, the proposed post-AraC therapy may be compromised by agents that reduce VDR levels in AML blasts.
Topics: Abietanes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antioxidants; Apoptosis; Cell Line, Tumor; Cytarabine; Ergocalciferols; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; RNA Interference; RNA, Small Interfering; Reactive Oxygen Species; Receptors, Calcitriol; U937 Cells; Vitamin D
PubMed: 31245853
DOI: 10.1002/jcp.28996