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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 -
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 -
International Journal of Molecular... Dec 2017Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-β (Aβ), as derived from sequential cleavage of the...
Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-β (Aβ), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aβ-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D₂ and D₃ analogues decreased Aβ-production and increased Aβ-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aβ-producing enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased β-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention.
Topics: Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Brain; Cell Line, Tumor; Female; Humans; Mice; Mice, Inbred C57BL; Plaque, Amyloid; Proteolysis; Vitamin D; Vitamins
PubMed: 29257109
DOI: 10.3390/ijms18122764 -
Endocrinology and Metabolism Clinics of... Dec 2017Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with abnormalities in bone and mineral metabolism, known as CKD-bone mineral disorder. CKD... (Review)
Review
Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with abnormalities in bone and mineral metabolism, known as CKD-bone mineral disorder. CKD and ESRD cause skeletal abnormalities characterized by hyperparathyroidism, mixed uremic osteodystrophy, osteomalacia, adynamic bone disease, and frequently enhanced vascular and ectopic calcification. Hyperparathyroidism and mixed uremic osteodystrophy are the most common manifestations due to phosphate retention, reduced concentrations of 1,25-dihydroxyvitamin D, intestinal calcium absorption, and negative calcium balance. Treatment with 1-hydroxylated vitamin D analogues is useful.
Topics: Calcitriol; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Treatment Outcome
PubMed: 29080646
DOI: 10.1016/j.ecl.2017.07.008 -
Antimicrobial Agents and Chemotherapy Jan 2018Vitamin D analogs were identified as compounds that induced lysis of planktonic cultures of in a high-throughput screen of FDA-approved drugs. Previous studies have...
Vitamin D analogs were identified as compounds that induced lysis of planktonic cultures of in a high-throughput screen of FDA-approved drugs. Previous studies have demonstrated that certain derivatives of vitamin D possess lytic activity against other bacteria, though the mechanism has not yet been established. Through the use of a combinatorial approach, the vitamin D derivative doxercalciferol was shown to act synergistically with bacitracin, a polypeptide-type drug that is known to interfere with cell wall synthesis, suggesting that doxercalciferol may act in a bacitracin-related pathway. Innate resistance to bacitracin is attributed to efflux by a conserved ABC-type transporter, which in is encoded by the operon. possesses two characterized mechanisms of resistance to bacitracin, the ABC transporter, bacitracin resistance (Mbr) cassette, consisting of MbrABCD, and the rhamnose-glucose polysaccharide (Rgp) system, RgpABCDEFGHI. Loss of function of the transporter in and mutants exacerbated the effect of the combination of doxercalciferol and bacitracin. Despite conservation of a transporter homologous to , the combination of doxercalciferol and bacitracin appeared to be synergistic only in streptococcal species. We conclude that vitamin D derivatives possess lytic activity against and act through a mechanism dependent on the bacitracin resistance mechanism of MbrABCD.
Topics: ATP-Binding Cassette Transporters; Anti-Bacterial Agents; Bacitracin; Bacterial Proteins; Drug Resistance, Bacterial; Drug Synergism; Ergocalciferols; Gene Expression Regulation, Bacterial; High-Throughput Screening Assays; Microbial Sensitivity Tests; Streptococcus mutans; Vitamin D; Vitamins
PubMed: 29061743
DOI: 10.1128/AAC.01675-17 -
The Journal of Steroid Biochemistry and... Mar 2018Numerous clinical studies of vitamin D, its derivatives or analogs, have failed to clearly demonstrate sustained benefits when used for the treatment of human malignant...
Numerous clinical studies of vitamin D, its derivatives or analogs, have failed to clearly demonstrate sustained benefits when used for the treatment of human malignant diseases. However, given the strong preclinical evidence of anti-neoplastic activity and the epidemiological associations suggesting that vitamin D compounds may have a place in cancer therapy, attempts are continuing to devise new approaches to their therapeutic use. This laboratory has developed a strategy to enhance the effectiveness of the currently standard therapy of Acute Myeloid Leukemia (AML) by the immediate addition of the vitamin D2 analog Doxercalciferol combined with the plant polyphenol-derived Carnosic acid to AML cells previously treated with Cytarabine (AraC). Enhancement of AML cell death was noted to be dependent on VDR and BRAF kinase. Here we document that the stress-related kinase JNK is an important additional component of cell death enhancement in this protocol. Either the Knock-down or the inhibition of JNK activity reduced the enhancement of AraC-induced cell death, and we show that JNK signaling to the apoptosis regulator BIM and Caspase executioners of cell death are downstream of VDR and BRAF. A clear understanding of the molecular basis for the increased efficacy of AraC in the therapy of AML is expected to bring this regimen to a clinical trial.
Topics: Antimetabolites, Antineoplastic; Cell Death; Cytarabine; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase 9; Proto-Oncogene Proteins B-raf; RNA, Messenger; RNA, Small Interfering; Receptors, Calcitriol; Signal Transduction
PubMed: 28765039
DOI: 10.1016/j.jsbmb.2017.07.005 -
British Journal of Pharmacology Aug 2017Pathological growth of ocular vasculature networks can underpin visual impairment in neovascular age-related macular degeneration, proliferative diabetic retinopathy and...
BACKGROUND AND PURPOSE
Pathological growth of ocular vasculature networks can underpin visual impairment in neovascular age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity. Our aim was to uncover novel pharmacological regulators of ocular angiogenesis by phenotype-based screening in zebrafish.
EXPERIMENTAL APPROACH
A bioactive chemical library of 465 drugs was screened to identify small molecule inhibitors of ocular hyaloid vasculature (HV) angiogenesis in zebrafish larvae. Selectivity was assessed by evaluation of non-ocular intersegmental vasculature development. Safety pharmacology examined visual behaviour and retinal histology in larvae. Molecular mechanisms of action were scrutinized using expression profiling of target mRNAs and miRNAs in larval eyes.
KEY RESULTS
Library screening identified 10 compounds which significantly inhibited HV developmental angiogenesis. The validated hit calcitriol selectively demonstrated dose-dependent attenuation of HV development. In agreement, vitamin D receptor (VDR) agonists paricalcitol, doxercalciferol, maxacalcitol, calcipotriol, seocalcitol, calcifediol and tacalcitol significantly and selectively attenuated HV development. VDR agonists induced minor ocular morphology abnormalities and affected normal visual function. Calcitriol induced a three to sevenfold increase in ocular dre-miR-21 expression. Consistently, all-trans-retinoic acid attenuated HV development and increased ocular dre-miR-21 expression. Interestingly, zebrafish ocular vegfaa and vegfab expression was significantly increased while, vegfc, flt1 and kdrl expression was unchanged by calcitriol.
CONCLUSION AND IMPLICATIONS
These studies identified VDR agonists as significant and selective anti-angiogenics in the developing vertebrate eye and miR21 as a key downstream regulated miRNA. These targets should be further evaluated as molecular hallmarks of, and therapeutic targets for pathological ocular neovascularization.
Topics: Angiogenesis Inhibitors; Animals; Animals, Genetically Modified; Calcitriol; Eye; Larva; MicroRNAs; Neovascularization, Physiologic; Receptors, Calcitriol; Tretinoin; Vascular Endothelial Growth Factor A; Zebrafish; Zebrafish Proteins
PubMed: 28547797
DOI: 10.1111/bph.13875 -
The Journal of Steroid Biochemistry and... Oct 2017Vitamin D has so far not fulfilled its early promise as an antineoplastic agent, in spite of compelling in vitro data. With the aim of bringing vitamin D or its...
Vitamin D has so far not fulfilled its early promise as an antineoplastic agent, in spite of compelling in vitro data. With the aim of bringing vitamin D or its derivatives (VDDs) effectively to the clinic, we developed a two-pronged approach. First, by adding the plant-derived Carnosic Acid (CA) to a vitamin D2 derivative Doxercalciferol we increased its differentiation potency without increasing it hypercalcemic properties. Second, we added these two agents together to AML cells already treated with Cytarabine (AraC), the standard drug for the treatment of patients with AML. We now report that BRAF, a part of the MAPK signaling pathway, is required for the optimally increased cell death in this system and acts upstream of BIM, the regulator of the caspase cascade that leads to cell death by apoptosis. It is proposed that this therapeutic regimen should be tested in a clinical trial.
Topics: Antineoplastic Agents; Apoptosis; Bcl-2-Like Protein 11; Cell Differentiation; Cell Line, Tumor; Cells, Cultured; Cytarabine; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins B-raf; Signal Transduction; Vitamin D
PubMed: 27637326
DOI: 10.1016/j.jsbmb.2016.09.009 -
Oncotarget Jun 2016Acute Myeloid Leukemia (AML) has grave prognosis due to aggressive nature of the disease, the toxicity of standard treatment, and overall low cure rates. We recently...
Acute Myeloid Leukemia (AML) has grave prognosis due to aggressive nature of the disease, the toxicity of standard treatment, and overall low cure rates. We recently showed that AML cells in established culture treated with Cytarabine (AraC) and a differentiation agent combination show enhancement of AraC cytotoxicity. Here we elucidate molecular changes which underlie this observation with focus on AML blasts in primary culture. The cells were treated with AraC at concentrations achievable in clinical settings, and followed by the addition of Doxercalciferol, a vitamin D2 derivative (D2), together with Carnosic acid (CA), a plant-derived antioxidant. Importantly, although AraC is also toxic to normal bone marrow cell population, the enhanced cell kill by D2/CA was limited to malignant blasts. This enhancement of cell death was associated with activation of the monocytic differentiation program as shown by molecular markers, and the increased expression of vitamin D receptor (VDR). Apoptosis elicited by this treatment is caspase-dependent, and the optimal blast killing required the increased expression of the apoptosis regulator Bim. These data suggest that testing of this regimen in the clinic is warranted.
Topics: Abietanes; Adult; Aged; Aged, 80 and over; Apoptosis; Bcl-2-Like Protein 11; Cytarabine; Drug Synergism; Ergocalciferols; Female; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; RNA Interference; Receptors, Calcitriol; Tumor Cells, Cultured; U937 Cells
PubMed: 27144333
DOI: 10.18632/oncotarget.8998 -
PloS One 2016Vitamin D receptor activators (VDRAs) can protect against mineral bone disease, but they are reported to elevate serum creatinine (SCr) and may also reduce glomerular... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Vitamin D receptor activators (VDRAs) can protect against mineral bone disease, but they are reported to elevate serum creatinine (SCr) and may also reduce glomerular filtration rate (GFR).
METHODS
We conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) to evaluate the effect of VDRAs on kidney function and adverse events. MEDLINE, EMBASE, the Cochrane Controlled Trials Register were searched for RCTs that evaluate vitamin D receptor activators (alfacalcidol, calcitriol, doxercalciferol, falecalcitriol, maxacalcitol and paricalcitol) up to March 2015.
RESULTS
We included 31 studies, all of which were performed between 1976 and 2015, which enrolled 2621 patients. Patients receiving VDRAs had lower eGFR (weighted mean difference WMD -1.29 mL/min /1.73 m2, 95% CI -2.42 to -0.17) and elevated serum creatinine (WMD 7.03 μmol/L, 95% CI 0.61 to 13.46) in sensitivity analysis excluding studies with dropout rate more than 30%. Subgroup analysis of the 5 studies that not use SCr-based measures did not indicated lower GFR in the VDRAs group(WMD -0.97 mL/min/1.73 m2, 95% CI -4.85 to 2.92). Compared with control groups, there was no difference in all-cause mortality (relative risk RR 1.41, 95% CI 0.58 to 3.80), cardiovascular disease (RR 0.84, 95% CI 0.42 to 1.71), and severe adverse events (RR 1.15, 95% CI 0.75 to 1.77) for the VDRAs groups. Episodes of hypercalcemia (RR 3.29, 95% CI 2.02 to 5.38) were more common in the VDRAs group than in the control group.
CONCLUSIONS
Administration of VDRAs increased serum creatinine levels. Subgroup analysis of studies that did not use SCr-based measures did not indicate a lower GFR in the VDRA group. Future studies with non-SCr-based measures are needed to assess whether the mild elevations of serum creatinine are of clinical significance.
Topics: Bone Density Conservation Agents; Bone Diseases; Cardiovascular Diseases; Creatinine; Databases, Factual; Glomerular Filtration Rate; Humans; Hypercalcemia; Receptors, Calcitriol
PubMed: 26812502
DOI: 10.1371/journal.pone.0147347