scholarly journals Investigating the Role of VDR and Megalin in Semi-Selectivity of Side-Chain Modified 19-nor Analogs of Vitamin D

2019 ◽  
Vol 20 (17) ◽  
pp. 4183 ◽  
Author(s):  
Klaudia Berkowska ◽  
Aoife Corcoran ◽  
Małgorzata Grudzień ◽  
Agnieszka Jakuszak ◽  
Michał Chodyński ◽  
...  
Keyword(s):  
Vitamin D ◽  
Calcium Homeostasis ◽  
Minor Effect ◽  
Cellular Functions ◽  
Antitumor Effects ◽  
Dihydroxyvitamin D3 ◽  
Knock Out ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
A Minor

1,25-dihydroxyvitamin D3 (1,25D3) is implicated in many cellular functions, including cell proliferation and differentiation, thus exerting potential antitumor effects. A major limitation for therapeutic use of 1,25D3 are potent calcemic activities. Therefore, synthetic analogs of 1,25D3 for use in anticancer therapy should retain cell differentiating potential, with calcemic activity being reduced. To obtain this goal, the analogs should effectively activate transcription of genes responsible for cell differentiation, leaving the genes responsible for calcium homeostasis less active. In order to better understand this phenomenon, we selected a series of structurally related 19-nor analogs of 1,25D (PRI-5100, PRI-5101, PRI-5105, and PRI-5106) and tested their activities in blood cells and in cells connected to calcium homeostasis. Affinities of analogs to recombinant vitamin D receptor (VDR) protein were not correlated to their pro-differentiating activities. Moreover, the pattern of transcriptional activities of the analogs was different in cell lines originating from various vitamin D-responsive tissues. We thus hypothesized that receptors which participate in transport of the analogs to the cells might contribute to the observed differences. In order to study this hypothesis, we produced renal cells with knock-out of the megalin gene. Our results indicate that megalin has a minor effect on semi-selective activities of vitamin D analogs.

scholarly journals Transgenic Mice Overexpressing Human Fibroblast Growth Factor 23 (R176Q) Delineate a Putative Role for Parathyroid Hormone in Renal Phosphate Wasting Disorders

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5269-5279 ◽  
Author(s):  
Xiuying Bai ◽  
Dengshun Miao ◽  
Jiarong Li ◽  
David Goltzman ◽  
Andrew C. Karaplis
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Transgenic Mice ◽  
Fibroblast Growth Factor ◽  
Calcium Homeostasis ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism ◽  
Dihydroxyvitamin D3 ◽  
Circulating Levels

Abstract Fibroblast growth factor 23 (FGF23) is a recently characterized protein likely involved in the regulation of serum phosphate homeostasis. Increased circulating levels of FGF23 have been reported in patients with renal phosphate-wasting disorders, but it is unclear whether FGF23 is the direct mediator responsible for the decreased phosphate transport at the proximal renal tubules and the altered vitamin D metabolism associated with these states. To examine this question, we generated transgenic mice expressing and secreting from the liver human FGF23 (R176Q), a mutant form that fails to be degraded by furin proteases. At 1 and 2 months of age, mice carrying the transgene recapitulated the biochemical (decreased urinary phosphate reabsorption, hypophosphatemia, low serum 1,25-dihydroxyvitamin D3) and skeletal (rickets and osteomalacia) alterations associated with these disorders. Unexpectantly, marked changes in parameters of calcium homeostasis were also observed, consistent with secondary hyperparathyroidism. Moreover, in the kidney the anticipated alterations in the expression of hydroxylases associated with vitamin D metabolism were not observed despite the profound hypophosphatemia and increased circulating levels of PTH, both major physiological stimuli for 1,25-dihydroxyvitamin D3 production. Our findings strongly support the novel concept that high circulating levels of FGF23 are associated with profound disturbances in the regulation of phosphate and vitamin D metabolism as well as calcium homeostasis and that elevated PTH levels likely also contribute to the renal phosphate wasting associated with these disorders.

scholarly journals Non-apoptotic caspase activation sustains ovarian somatic stem cell functions by modulating Hedgehog-signalling and autophagy

2019 ◽  
Author(s):  
Alessia Galasso ◽  
Daria Iakovleva ◽  
Luis Alberto Baena-Lopez
Keyword(s):  
Stem Cell ◽  
Fine Tuning ◽  
Caspase Activation ◽  
Cellular Functions ◽  
Hedgehog Signalling ◽  
Cell Functions ◽  
Metabolic Defects ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Moderate Stress

ABSTRACTThere is increasing evidence associating the activity of caspases with the regulation of basic cellular functions beyond apoptosis. Accordingly, the dysregulation of these novel non-apoptotic functions often sits at the origin of neurological disorders, metabolic defects, autoimmunity, and cancer. However, the molecular interplay between caspases and the signalling networks active in non-apoptotic cellular scenarios remains largely unknown. Our work show that non-apoptotic caspase activation is critical to modulate Hedgehog-signalling and autophagy in ovarian somatic cells from both Drosophila and humans under moderate stress. We also demonstrate that these novel caspase functions are key to sustain stem cell proliferation and differentiation without inducing apoptosis. Finally, we molecularly link these caspase-dependent effects to the fine-tuning of the Hedgehog-receptor, Patched. Together, these findings confer a pro-survival role to the caspases, as opposed to the widely held apoptotic function assigned to these enzymes.

Independence of salt intake from the hormones regulating calcium homeostasis

1993 ◽  
Vol 264 (3) ◽  
pp. R500-R512 ◽  
Author(s):  
M. G. Tordoff ◽  
R. L. Hughes ◽  
D. M. Pilchak
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Calcium Homeostasis ◽  
Salt Intake ◽  
Calcium Content ◽  
Deficient Diet ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
Chronic Infusion ◽  
Intact Rats

Rats deprived of dietary calcium increase voluntary intake of NaCl solutions. We investigated whether the major hormones controlling calcium homeostasis are responsible for this increase in salt intake. Removing endogenous sources of calcitonin and parathyroid hormone by thyroidectomy and/or parathyroidectomy had no effect on NaCl intake. The surgically compromised rats and their intact controls drank similar amounts of NaCl in response to manipulations of diet calcium content. Despite normal NaCl intakes, rats with parathyroidectomy had low plasma calcium concentrations and a strong appetite for 50 mM CaCl2 solution. Chronic infusion of parathyroid hormone into rats with thyroparathyroidectomy decreased NaCl intake. Intact rats fed an American Institute of Nutrition (AIN)-76A-based vitamin D-deficient diet increased NaCl intake slightly and showed a strong appetite for CaCl2, but other rats maintained normocalcemic by the addition of calcium, phosphorus, and lactose to the vitamin D-deficient diet had normal NaCl and CaCl2 intakes. Chronic infusions of 1,25-dihydroxyvitamin D3 into intact rats had no effect on NaCl intake. Taken together, these results indicate that the increase in NaCl intake produced by calcium deprivation is not mediated by changes in circulating levels of calcium, calcitonin, parathyroid hormone, or 1,25-dihydroxyvitamin D3. Furthermore, the major calcium-regulating hormones are not involved in the control of "spontaneous" NaCl intake in the rat.

scholarly journals The Pleiotropic Effect of Vitamin D

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Yu-Hsien Lai ◽  
Te-Chao Fang
Keyword(s):  
Vitamin D ◽  
Cell Proliferation ◽  
Immune System ◽  
Hormone Secretion ◽  
Pleiotropic Effect ◽  
The Novel ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Calcium And Phosphorus ◽  
Pleiotropic Functions

The novel roles of vitamin D were discovered and valued in this century. In addition to the maintenance of calcium and phosphorus balance, vitamin D regulates the function of the kidneys, heart, and immune system. Moreover, its anti-inflammatory, antiapoptotic, and antifibrotic roles have gained considerable attention. Vitamin D is also important for the maintenance of homeostasis by regulation of hormone secretion, cell proliferation, and differentiation. This paper will review these pleiotropic functions of vitamin D.

A Systematic Screen for Dominant Second-Site Modifiers of Merlin/NF2 Phenotypes Reveals an Interaction With blistered/DSRF and scribbler

Genetics ◽  
2001 ◽  
Vol 158 (2) ◽  
pp. 667-679
Author(s):  
Dennis R LaJeunesse ◽  
Brooke M McCartney ◽  
Richard G Fehon
Keyword(s):  
Human Tumor ◽  
Suppressor Gene ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Genetic Screens ◽  
Cellular Functions ◽  
Cell Proliferation And Differentiation ◽  
Epithelial Development ◽  
Proliferation And Differentiation ◽  
Neuronal Tissues

Abstract Merlin, the Drosophila homologue of the human tumor suppressor gene Neurofibromatosis 2 (NF2), is required for the regulation of cell proliferation and differentiation. To better understand the cellular functions of the NF2 gene product, Merlin, recent work has concentrated on identifying proteins with which it interacts either physically or functionally. In this article, we describe genetic screens designed to isolate second-site modifiers of Merlin phenotypes from which we have identified five multiallelic complementation groups that modify both loss-of-function and dominant-negative Merlin phenotypes. Three of these groups, Group IIa/scribbler (also known as brakeless), Group IIc/blistered, and Group IId/net, are known genes, while two appear to be novel. In addition, two genes, Group IIa/scribbler and Group IIc/blistered, alter Merlin subcellular localization in epithelial and neuronal tissues, suggesting that they regulate Merlin trafficking or function. Furthermore, we show that mutations in scribbler and blistered display second-site noncomplementation with one another. These results suggest that Merlin, blistered, and scribbler function together in a common pathway to regulate Drosophila wing epithelial development.

scholarly journals Targeting cholesterol homeostasis in hematopoietic malignancies

Blood ◽  
2021 ◽  
Author(s):  
Andrea Brendolan ◽  
Vincenzo Russo
Keyword(s):  
Cholesterol Homeostasis ◽  
Cell Integrity ◽  
Cellular Functions ◽  
Hematopoietic Malignancies ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
X Receptors

Cholesterol is a vital lipid for cellular functions. It is necessary for membrane biogenesis, cell proliferation and differentiation. In addition to maintaining cell integrity and permeability, increasing evidence indicates a strict link between cholesterol homeostasis, inflammation and haematological tumors. This makes cholesterol homeostasis an optimal therapeutic target for hematopoietic malignancies. Manipulating cholesterol homeostasis either interfering with its synthesis or activating the reverse cholesterol transport via the engagement of liver X receptors (LXRs), affects the integrity of tumor cells both in vitro and in vivo. Cholesterol homeostasis has also been manipulated to restore antitumor immune responses in preclinical models. These observations have prompted clinical trials in acute myeloid leukemia (AML) to test the combination of chemotherapy with drugs interfering with cholesterol synthesis, i.e. statins. We review the role of cholesterol homeostasis in hematopoietic malignancies, as well as in cells of the tumor microenvironment, and discuss the potential use of lipid modulators for therapeutic purposes.

scholarly journals Removal of the phage-shock protein PspB causes reduction of virulence in Salmonella enterica serovar Typhimurium independently of NRAMP1

2014 ◽  
Vol 63 (6) ◽  
pp. 788-795 ◽  
Author(s):  
Inke Wallrodt ◽  
Lotte Jelsbak ◽  
Line E. Thomsen ◽  
Lena Brix ◽  
Sébastien Lemire ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Single Gene ◽  
Systemic Infection ◽  
Minor Effect ◽  
Membrane Stress ◽  
Knock Out ◽  
Serovar Typhimurium ◽  
A Minor

The phage-shock protein (Psp) system is believed to manage membrane stress in all Enterobacteriaceae and has recently emerged as being important for virulence in several pathogenic species of this phylum. The core of the Psp system consists of the pspA–D operon and the distantly located pspG gene. In Salmonella enterica serovar Typhimurium (S. Typhimurium), it has recently been reported that PspA is essential for systemic infection of mice, but only in NRAMP1+ mice, signifying that attenuation is related to coping with divalent cation starvation in the intracellular environment. In the present study, we investigated the contribution of individual psp genes to virulence of S. Typhimurium. Interestingly, deletion of the whole pspA–D set of genes caused attenuation in both NRAMP1+ and NRAMP1− mice, indicating that one or more of the psp genes contribute to virulence independently of NRAMP1 expression in the host. Investigations of single gene mutants showed that knock out of pspB reduced virulence in both types of mice, while deletion of pspA only caused attenuation in NRAMP1+ mice, and deletion of pspD had a minor effect in NRAMP1− mice, while deletions of either pspC or pspG did not affect virulence. Experiments addressed at elucidating the role of PspB in virulence revealed that PspB is dispensable for uptake to and intracellular replication in cultured macrophages and resistance to complement-induced killing. Furthermore, the Psp system of S. Typhimurium was dispensable during pIV-induced secretin stress. In conclusion, our results demonstrate that removal of PspB reduces virulence in S. Typhimurium independently of host NRAMP1 expression, demonstrating that PspB has roles in intra-host survival distinct from the reported contributions of PspA.

scholarly journals Impact of Vitamin D on Physical Efficiency and Exercise Performance—A Review

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2826 ◽  
Author(s):  
Michał Wiciński ◽  
Dawid Adamkiewicz ◽  
Monika Adamkiewicz ◽  
Maciej Śniegocki ◽  
Marta Podhorecka ◽  
...  
Keyword(s):  
Vitamin D ◽  
Exercise Performance ◽  
Strong Relationship ◽  
High Quality Research ◽  
Vitamin D Receptors ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Strongly Connected ◽  
The Impact

Vitamin D deficiency amongst athletes and the general population seems to be a prominent problem. The most recognized role of vitamin D is its regulation of calcium homeostasis; there is a strong relationship between vitamin D and bone health. Moreover, its concentrations are associated with muscle function and immune response in both the general and athletic populations. Vitamin D level is strongly connected with the presence of VDRs (vitamin D receptors) in most human extraskeletal cells. Expression of multiple myogenic transcription factors enhancing muscle cell proliferation and differentiation is caused by an exposure of skeletal muscles to vitamin D. The aim of this review is to summarize current understanding of the significance of vitamin D on exercise performance and physical efficiency, as well to analyze the impact of vitamin D on multiple potential mechanisms. More high-quality research studies, considering free 25(OH)D as a better marker of vitamin D status, the baseline level of 25(OH)D and multiple pathways of vitamin D acting and usage in athletes are required.

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