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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 -
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 -
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 -
The Journal of Steroid Biochemistry and... Mar 2019Standard therapy for Acute Myeloid Leukemia (AML) is rarely curative, and several suggested improvements have had little success so far. We have reported that in an in...
Standard therapy for Acute Myeloid Leukemia (AML) is rarely curative, and several suggested improvements have had little success so far. We have reported that in an in vitro model of a potential therapeutic regimen for AML, the activity of cytarabine (AraC) is enhanced by a sequential treatment with a combination of the vitamin D2 analog Doxercalciferol (D2) and the plant-derived antioxidant carnosic acid (CA). Importantly, the enhancement occurred selectively in patient-derived AML blasts, but not in the normal bone marrow cells. We now demonstrate that TXNIP, previously known as Vitamin D up-regulated protein 1 (VDUP1) [PMID 808674] plays a part in signaling cell death (CD) in this regimen. This is shown by the reduced CD when TXNIP protein levels are decreased by the CRISPR/CAS9 or RNAi technology. Further, we show that direct activation of ASK1 kinase by TXNIP is required for the optimal transmission of the CD signal to apoptotic machinery, regulated by JNK and BIM. These studies provide a rationale for a projected clinical trial of this vitamin D-based new therapeutic regimen for AML.
Topics: Abietanes; Antineoplastic Agents; Antioxidants; Carrier Proteins; Cell Line, Tumor; Cell Survival; Cytarabine; Ergocalciferols; Humans; Leukemia, Myeloid, Acute; MAP Kinase Kinase Kinase 5; Mitogen-Activated Protein Kinase 8; Signal Transduction; Vitamins
PubMed: 30508644
DOI: 10.1016/j.jsbmb.2018.11.015 -
Experimental and Clinical Endocrinology... Aug 2020Age-related bone deteriorations are the common endocrine disorders in the elderly population, leading to an increased risk of fractures. Therefore, effective treatment...
BACKGROUND
Age-related bone deteriorations are the common endocrine disorders in the elderly population, leading to an increased risk of fractures. Therefore, effective treatment strategies provide a way to prevent bone loss and improve the quality of life in the elderly population. The present study aimed to investigate the anti-osteoporotic effects of doxercalciferol (DOX) in aging mice.
METHODS
Bone metabolism-related markers were measured by ELISA assay. The expression of bone formation and resorption-related genes was performed by RT-qPCR analysis. Hematoxylin and eosin (H&E) and Safranin O staining were performed to analyze the trabecular bone and cartilage degeneration.
RESULTS
Aging resulted in urine ca excretion, a decrease in bone ca content and reduction of biomechanical strength in mice. We also found that the level of PTH was increased in aging mice, while DOX administration markedly down-regulated serum PTH in aging mice. H&E and Safranin O staining showed that DOX protected against aging-induced bone loss and cartilage regeneration in the tibia from aging mice. Furthermore, DOX treatment resulted in an increase in and mRNA expression and a decrease in Ctsk, MMP-9 and mRNA expression in the tibia from aging mice.
CONCLUSION
These findings indicated that DOX had a beneficial effect on age-related bone deteriorations in aging mice by promoting osteoblast activity and cartilage regeneration and inhibiting osteoclast-specific genes expression.
Topics: Aging; Animals; Bone and Bones; Calcium; Cartilage; Cartilage Diseases; Ergocalciferols; Male; Mice; Mice, Inbred C57BL; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis
PubMed: 30380573
DOI: 10.1055/a-0754-1956 -
Mechanisms of Development Oct 2018Urodele amphibians such as the axolotl regenerate complete limbs as adults, and understanding how the "blueprint", or pattern, of the regenerate is established and...
Urodele amphibians such as the axolotl regenerate complete limbs as adults, and understanding how the "blueprint", or pattern, of the regenerate is established and manipulated are areas of intense interest. Nutrient signaling plays an important role in pattern formation during regeneration. Retinoic acid signaling is the most characterized pathway during this process. Exogenous retinoic acid (RA) reprograms the pattern information in regenerating cells to a more posterior, ventral, and proximal identity. Vitamin D signaling shares several molecular similarities with RA and has been shown to alter pattern formation during zebrafish pectoral fin regeneration. To determine if exogenous Vitamin D signaling is capable of reprograming pattern in the axolotl limb blastema, we treated regenerating limbs with a potent Vitamin D agonist. Under the studied conditions, exogenous Vitamin D did not act in a manner similar to RA and failed to proximalize the pattern of the resulting regenerates. The Vitamin D treatment did result in several skeletal defects during regeneration, including carpal fusions along the A/P axis; failure to integrate the newly regenerated tissue with the existing tissue, formation of ectopic nodules of cartilage at the site of amputation, and altered bone morphology in uninjured skeletal tissue.
Topics: Ambystoma mexicanum; Amputation, Surgical; Animals; Body Patterning; Bone and Bones; Cell Differentiation; Ergocalciferols; Extremities; Organogenesis; Phenotype; Regeneration; Signal Transduction; Vitamin D
PubMed: 30096415
DOI: 10.1016/j.mod.2018.08.004 -
American Journal of Kidney Diseases :... Aug 2018Medicare's 2011 prospective payment system (PPS) was introduced to curb overuse of separately billable injectable drugs. After epoietin, intravenous (IV) vitamin D...
BACKGROUND & RATIONALE
Medicare's 2011 prospective payment system (PPS) was introduced to curb overuse of separately billable injectable drugs. After epoietin, intravenous (IV) vitamin D analogues are the biggest drug cost drivers in hemodialysis (HD) patients, but the association between PPS introduction and vitamin D therapy has been scarcely investigated.
STUDY DESIGN
Interrupted time-series analyses.
SETTING & PARTICIPANTS
Adult US HD patients represented in the US Renal Data System between 2008 and 2013.
EXPOSURES
PPS implementation.
OUTCOMES
The cumulative dose of IV vitamin D analogues (paricalcitol equivalents) per patient per calendar quarter in prevalent HD patients. The average starting dose of IV vitamin D analogues and quarterly rates of new vitamin D use (initiations/100 person-months) in incident HD patients within 90 days of beginning HD therapy.
ANALYTICAL APPROACH
Segmented linear regression models of the immediate change and slope change over time of vitamin D use after PPS implementation.
RESULTS
Among 359,600 prevalent HD patients, IV vitamin D analogues accounted for 99% of the total use, and this trend was unchanged over time. PPS resulted in an immediate 7% decline in the average dose of IV vitamin D analogues (average baseline dose = 186.5 μg per quarter; immediate change = -13.5 μg [P < 0.001]; slope change = 0.43 per quarter [P = 0.3]) and in the starting dose of IV vitamin D analogues in incident HD patients (average baseline starting dose = 5.22 μg; immediate change = -0.40 μg [P < 0.001]; slope change = -0.03 per quarter [P = 0.03]). The baseline rate of vitamin D therapy initiation among 99,970 incident HD patients was 44.9/100 person-months and decreased over time, even before PPS implementation (pre-PPS β = -0.46/100 person-months [P < 0.001]; slope change = -0.19/100 person-months [P = 0.2]). PPS implementation was associated with an immediate change in initiation levels (by -4.5/100 person-months; P < 0.001).
LIMITATIONS
Incident HD patients were restricted to those 65 years or older.
CONCLUSION
PPS implementation was associated with a 7% reduction in the average dose and starting dose of IV vitamin D analogues and a 10% reduction in the rate of vitamin D therapy initiation.
Topics: Aged; Cohort Studies; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Interrupted Time Series Analysis; Kidney Failure, Chronic; Male; Medicare; Middle Aged; Prospective Payment System; Renal Dialysis; United States; Vitamin D
PubMed: 29891194
DOI: 10.1053/j.ajkd.2018.03.027 -
Asian Journal of Andrology 2018Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers.... (Review)
Review
Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers. Epidemiologic data also indicate that vitamin D signaling may be important in the cause and prognosis of prostate and other cancers. These data indicate that perturbation of vitamin D signaling may be a target for the prevention and treatment of prostate cancer. Large studies of vitamin D supplementation will be required to determine whether these observations can be translated into prevention strategies. This paper reviews the available data in the use of vitamin D compounds in the treatment of prostate cancer. Clinical data are limited which support the use of vitamin D compounds in the management of men with prostate cancer. However, clinical trials guided by existing preclinical data are limited.
Topics: Antineoplastic Combined Chemotherapy Protocols; Calcifediol; Calcitriol; Clinical Trials as Topic; Ergocalciferols; Humans; Male; Prostatic Neoplasms; Signal Transduction; Vitamin D; Vitamin D Deficiency
PubMed: 29667615
DOI: 10.4103/aja.aja_14_18 -
Nephrologie & Therapeutique Apr 2018Cyclophosphamide (CYP) has been used for over 40 years in patients with steroid-sensitive nephrotic syndrome (NSSS) presenting frequent relapses (NSRF) or steroid...
INTRODUCTION
Cyclophosphamide (CYP) has been used for over 40 years in patients with steroid-sensitive nephrotic syndrome (NSSS) presenting frequent relapses (NSRF) or steroid dependence (NSSD). However, the long-term success of treatment with cyclophosphamide is difficult to predict. The objectives of this study are to determine long-term outcomes of cyclophosphamide and identify the factors associated with sustained remission.
METHODS
We retrospectively studied the data from 50 patients with idiopathic nephrotic syndrome, treated by oral cyclophosphamide and followed at service of pediatric for more than 8 years for idiopathic nephrotic syndrome and related factors for survival without relapse were evaluated by univariate analysis.
RESULTS
The median age at the time of diagnosis was 4.3 years, and median follow-up time was 1.7 years with the median of 8 years at the first use of CYC. Patients had received a median cumulative dose of 168mg/kg. At the end of follow-up, 38% of patients entered into remission after using CYC while 62% failed to respond and further relapses then occur. The median time of stopping corticosteroid therapy was three month. The survival without relapse was respectively 56% (28 patients), 52% (26 patients), 48% (24 patients), and 38% (19 patients), at 6 months, one year, two years and more than two years. In univariate analysis, the survival without relapse was related to the age at the moment of starting the therapy par CYC (the median was 5 months for an age < 8 years and 41 months for an age≥8 years; P=0.049), the type of nephrotic syndrome [36 months for SNRF, 4 months for NSSD and nephrothic syndrome steroid resistant (NSSR); P=0.068], and the histological lesion (6 months for diffuse mesangial proliferation, 2 months for segmental glomerulosclerosis; P=0.009). The age at the moment of diagnosis, the sex and the cumulative dose of CYC did not have significant influence.
CONCLUSION
The results presented in this study suggest the use of oral cyclophosphamide for short period remain second line effective therapy. Further well-designed trials are required to evaluate the efficacy of other steroid-sparing agents.
Topics: Adolescent; Child; Child, Preschool; Cyclophosphamide; Female; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Male; Nephrotic Syndrome; Retrospective Studies; Survival Rate; Treatment Outcome
PubMed: 29631702
DOI: 10.1016/j.nephro.2017.03.004 -
Nephrologie & Therapeutique Jun 2018Secondary hyperparathyroidism (SHPT) is one of the most frequent and deleterious complication of chronic kidney disease (CKD). SHPT is also one of the principal... (Review)
Review
Secondary hyperparathyroidism (SHPT) is one of the most frequent and deleterious complication of chronic kidney disease (CKD). SHPT is also one of the principal components of the now called CKD-mineral and bone disorders (MBD) syndrome. It is usually prevented and treated by vitamin D derivatives. However, the rationale for the prescription of vitamin D sterols in those patients is still a matter of hotly debates, mainly because of unsatisfactory results from numerous observational and not well-controlled studies. Scanty clinical data on head-to-head comparisons between the multiple vitamin D sterols are currently available. Moreover, there is crescent expectations on nutritional vitamin D, as well as vitamin D receptor activators (VDRA), regarding their putative pleiotropic effects even in CKD patients, and the promising effects of VDRA against proteinuria and myocardial hypertrophy in diabetic CKD cohorts. Nevertheless, additional randomized controlled trials (RCT) are needed to answer to many open questions and incertitude considering the effect of nutritional vitamin D and VDRA on hard end points including the risk of skeletal fractures and of mortality in CKD patients. RCT comparing VDRA to calcimimetics in the control of SHPT are also needed in dialysis patients. The present review will visit these open questions that nephrologists should ask before starting a treatment by nutritional vitamin D or VDRA.
Topics: Bone Density; Bone Density Conservation Agents; Chronic Kidney Disease-Mineral and Bone Disorder; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Renal Insufficiency, Chronic; Vitamin D
PubMed: 29545131
DOI: 10.1016/j.nephro.2017.03.003