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Li, Yixuan, Jiaqiang Huang, Jingxuan Wang, Mengjuan Ma, Yao Lu, Ran Wang i Huiyuan Guo. "Lactoferrin Is a Potential Activator of the Vitamin D Receptor in Its Regulation of Osteogenic Activities in C57BL/6J Mice and MC3T3-E1 Cells". Journal of Nutrition 151, nr 8 (12.05.2021): 2105–13. http://dx.doi.org/10.1093/jn/nxab105.
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ABSTRACT Background Lactoferrin (LF) has been shown to promote bone anabolism, and the vitamin D receptor (VDR) mediates the effects of vitamin D on bone. We hypothesized that LF improves bone health by increasing VDR expression. Objectives We sought to determine the role of VDR activation in LF-induced osteogenic activity in vivo and in vitro and the underlying molecular mechanisms. Methods Sixty male C57BL/6J mice (aged 4 wk) were randomly assigned into 6 groups and fed vitamin D–deficient (VDD; 0 IU/kg) or vitamin D–normal diet (VDN; 1000 IU cholecalciferol/kg) and administered placebo or LF (100 or 1000 mg/kg body weight) by gavage for 24 wk. Trabecular bone structure was analyzed using micro-CT, and VDR expression was assessed by immunohistochemistry. In vitro, MC3T3-E1 cells were treated with 100 μg LF/mL to evaluate its effect on VDR expression. Finally, the direct recruitment of LF to the Vdr promoter was confirmed by chromatin immunoprecipitation assay. In addition, cells were transfected with pGL3-basic Vdr vector for monitoring Vdr promoter activation using luciferase assays. Results LF supplementation at 100 and 1000 mg/kg revealed an ∼6.5% (P < 0.05) increase in bone mineral density in mice on VDD diet and exhibited an enhanced expression of VDR in bone compared with control. This increased expression of VDR was also observed in the bone of mice on the VDN diet, but the effect was more pronounced in VDD diet. In vitro, compared with the control group, Vdr mRNA expression was 18 times greater (P < 0.05) and peaked at 2 h posttreatment of LF. By cotransfection of the pGL3-basic Vdr vector, LF induced luciferase activity by 30% (P < 0.05) in MC3T3-E1 cells. Conclusions In vivo and in vitro, LF, a potential activator of VDR, promotes osteogenesis. This suggests that dairy products, which are rich in LF, may serve as a functional food to improve bone health.
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Kumar, Shaji, Ian W. Flinn, Parameswaran N. Hari, Natalie Callander, Stephen J. Noga, A. Keith Stewart, Jonathan Glass i in. "Novel Three– and Four–Drug Combinations of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Newly Diagnosed Multiple Myeloma: Encouraging Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study." Blood 114, nr 22 (20.11.2009): 127. http://dx.doi.org/10.1182/blood.v114.22.127.127.
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Abstract Abstract 127 Two- and three-drug regimens incorporating bortezomib (Velcade®, Vc), lenalidomide (Revlimid®, Rev), dexamethasone (Dex), and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC]), have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining Vc and Dex with Rev and Cy in a novel four-drug regimen (VDCR) may result in even greater activity with improved quality and duration of response. Results from the phase 1 dose-escalation portion of the multi-center EVOLUTION study showed that the VDCR regimen is a highly active and generally well-tolerated induction therapy in previously untreated MM patients (pts). Here we report the efficacy and safety of VDR, VDC, and VDCR from the non-comparative phase 2 portion of the study. Methods: Pts were randomized to receive up to eight 21-d cycles of VDR (Vc 1.3 mg/m2 d 1, 4, 8, 11; Dex 40 mg d 1, 8, 15; Rev 25 mg d 1–14) or VDC (VD as in VDR, plus Cy 500 mg/m2 d 1, 8) or VDCR (VDC plus Rev 15 mg d 1–14) as induction therapy, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles in all treatment arms. Pts received prophylactic antibiotics, acyclovir, transfusion support, and anticoagulants as required. Eligible pts wishing to undergo autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and undergo ASCT any time after cycle 4. Response categories were based on the IMWG Criteria with the addition of near complete response (nCR). Adverse events (AEs) were graded using the CTCAE v3.0. Results: In the VDR, VDC, and VDCR arms 42, 32, and 43 pts (including 6 pts treated at the maximum planned dose of Cy (500 mg/m2) from phase 1) have been treated, and 42, 31, and 33 are evaluable for response, respectively, as of data cut-off (31 July 2009). Median ages in the VDR, VDC, and VDCR arms were 60, 62, and 62 years, respectively; 62%, 63%, and 66% had International Staging System stage lI/III disease, and 38%, 25%, and 33% had Karnofsky Performance Status ≤80%, respectively. The median number of VDR, VDC, and VDCR cycles received is 4.5, 6, and 4, respectively (range 1–12). Best unconfirmed response rates are shown in the Table; patients categorized as very good partial response (VGPR) include those who have no measurable M-protein but have not yet had bone marrow assessments to confirm CR/nCR status. The overall rates of treatment-emergent AEs were 95%, 97%, and 88% for the VDR, VDC, and VDCR arms, respectively, with ≥grade 3 reported in 67%, 59%, and 65%. Peripheral neuropathy (PN) was reported as grade 2/3 in 12%/12% in the VDR, 31%/3% in the VDC, and 12%/9% in the VDCR arms; there was no grade 4 PN reported. Grade 3/4 neutropenia was reported in 5%/5%, 28%/13%, and 23%/9% of pts in the VDR, VDC, and VDCR arms, and grade 3/4 thrombocytopenia in 5%/2%, 9%/0%, and 5%/0% of pts, respectively. One case of grade 3 deep-vein thrombosis was reported in the VDCR arm. Overall rates of serious AEs were 24%, 13%, and 37% in the VDR, VDC, and VDCR arms, respectively. Two pts have died in the VDCR arm, both due to renal failure, considered possibly treatment-related. To date, 6 pts have undergone ASCT in the VDR arm, 5 in the VDC arm, and 3 in the VDCR arm. Median CD34+ yield was 4.7, 6.3, and 6.8 × 106/kg in the VDR, VDC, and VDCR arms, respectively. Conclusions: VDR, VDC, and VDCR are highly active and generally well-tolerated regimens in previously untreated MM. Response rates in the VDCR arm appeared somewhat higher than in the VDR and VDC arms at this early time point, although there also appeared to be higher rates of serious AEs, including possible treatment-related mortality in the VDCR arm. Following an interim analysis, dosing in the VDC arm was modified to include Cy on day 15 to examine if this will improve CR rates. Ten pts have been enrolled to date. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Milennium Pharmaceuticals Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Callander:Millenium: Research Funding. Noga:Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Raje:Celgene: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau. Shi:Millennium Pharmaceutical Inc.: Employment. Webb:Millennium: Employment, Equity Ownership. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Kumar, Shaji, Ian Flinn, Paul G. Richardson, Parameswaran Hari, Natalie Callander, Stephen J. Noga, A. Keith Stewart i in. "Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma". Blood 119, nr 19 (10.05.2012): 4375–82. http://dx.doi.org/10.1182/blood-2011-11-395749.
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Abstract Combinations of bortezomib (V) and dexamethasone (D) with either lenalidomide (R) or cyclophosphamide (C) have shown significant efficacy. This randomized phase 2 trial evaluated VDC, VDR, and VDCR in previously untreated multiple myeloma (MM). Patients received V 1.3 mg/m2 (days 1, 4, 8, 11) and D 40 mg (days 1, 8, 15), with either C 500 mg/m2 (days 1, 8) and R 15 mg (days 1-14; VDCR), R 25 mg (days 1-14; VDR), C 500 mg/m2 (days 1, 8; VDC) or C 500 mg/m2 (days 1, 8, 15; VDC-mod) in 3-week cycles (maximum 8 cycles), followed by maintenance with V 1.3 mg/m2 (days 1, 8, 15, 22) for four 6-week cycles (all arms) ≥ very good partial response was seen in 58%, 51%, 41%, and 53% (complete response rate of 25%, 24%, 22%, and 47%) of patients (VDCR, VDR, VCD, and VCD-mod, respectively); the corresponding 1-year progression-free survival was 86%, 83%, 93%, and 100%, respectively. Common adverse events included hematologic toxicities, peripheral neuropathy, fatigue, and gastrointestinal disturbances. All regimens were highly active and well tolerated in previously untreated MM, and, based on this trial, VDR and VCD-mod are preferred for clinical practice and further comparative testing. No substantial advantage was noted with VDCR over the 3-drug combinations. This trial is registered at www.clinicaltrials.gov (NCT00507442).
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Kumar, Shaji, Ian W. Flinn, Paul G. Richardson, Parameswaran Hari, Natalie Scott Callander, Stephen J. Noga, A. Keith Stewart i in. "Novel Three- and Four-Drug Combination Regimens of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Previously Untreated Multiple Myeloma: Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study". Blood 116, nr 21 (19.11.2010): 621. http://dx.doi.org/10.1182/blood.v116.21.621.621.
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Abstract Abstract 621 Background: Two- and three-drug regimens incorporating bortezomib (Velcade®, V), lenalidomide (Revlimid®, R), dexamethasone (D), or cyclophosphamide (C) have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining all four drugs in a single regimen (VDCR) may further enhance efficacy. Published results from the phase 1 dose-escalation portion of the non-comparative, multi-center EVOLUTION study showed that the VDCR regimen was highly active and generally well tolerated (Kumar et al Leukemia 2010). Here we present updated results from the phase 2 portion of the trial, focusing on efficacy and safety of the VDCR, VDR, and VDC regimens. Methods: Previously untreated patients with measurable disease were randomized to one of four treatment groups receiving up to eight 21-d cycles of VDCR (V 1.3 mg/m2 d 1, 4, 8, 11; D 40 mg d 1, 8, 15; R 15 mg d 1–14; C 500 mg/m2 d 1, 8), VDR (VD as in VDCR but with R 25 mg d 1–14), VDC (VDC as in VDCR), or VDC-mod (as for VDC but with an additional dose of C on d 15) as induction therapy, followed by four 42-d maintenance cycles of V 1.3 mg/m2 (d 1, 8, 15, 22) (all treatment arms). Patients eligible for autologous stem cell transplant (SCT) could undergo stem cell mobilization any time after cycle 2 and SCT any time after cycle 4. The primary endpoint was the combined complete response (CR) + very good partial response (VGPR) rate; secondary endpoints included safety/tolerability, time to response, duration of response, progression-free survival, and rate of minimal residual disease (MRD) negativity. Responses were assessed according to International Myeloma Working Group (IMWG) uniform criteria using an automated computer algorithm. Adverse events (AEs) were graded using the CTCAE v3.0. Results: Patient characteristics were similar among the groups with respect to age, performance status, ISS stage, and proportion of patients with high-risk cytogenetic features. Patients received a median of 5, 6, 6, and 6 treatment cycles in the VDCR, VDR, VDC, and VDC-mod arms, respectively; 65%, 60%, 52%, and 47% of patients had dose reductions of any drug. In the VDCR, VDR, VDC, and VDC-mod arms, respectively, 52%, 62%, 58%, and 65% of patients completed treatment; 31%, 43%, 24%, and 41%, respectively, underwent SCT. In the phase 2 response-evaluable patients (n=132), all treatment regimens showed substantial efficacy, with CR+VGPR rates of 59% (VDCR), 50% (VDR), 41% (VDC), and 59% (VDC-mod) (Table) (includes pre-transplant responses only in SCT patients). Of MRD-assessed patients, 46% (21/46) of those who achieved CR (including sCR) or nCR were MRD-negative; 48% (10/21), 75% (9/12), 0% (0/7) and 33% (2/6) in the VDCR, VDR, VDC and VDC-mod arms, respectively. Median time to first response was similar across arms (range 1.6–1.8 months); median time to best response of CR+VGPR was 4.0 months (VDCR), 3.4 months (VDR), 5.1 months (VDC), and 3.1 months (VDC-mod). Median duration of response has not been reached in any arm to date. All treatment regimens were generally well tolerated. In the VDCR, VDR, VDC, and VDC-mod arms, at least one grade ≥3 AE was observed in 81%, 76%, 79%, and 88% of enrolled patients, respectively; serious AEs were experienced by 42%, 40%, 21%, and 41% of patients, and AEs resulting in study discontinuation were reported for 19%, 17%, 12%, and 6% of patients. The five most common all-grade AEs across all treatment groups were fatigue (range 47–67%), nausea (36–67%), constipation (40–62%), diarrhea NOS (42–65%), and neutropenia (19–52%). The incidence of grade ≥3 (grade ≥2) peripheral neuropathy (PN) was 13% (40%) in the VDCR arm, 14% (45%) VDR, 9% (48%) VDC, and 18% (41%) VDC-mod; there was no grade 4 PN. Rates of grade ≥3 neutropenia/thrombocytopenia were 42%/10% for VDCR, 7%/7% VDR, 36%/12% VDC, and 65%/18% VDC-mod. Conclusions: All regimens appear highly active and generally well tolerated in previously untreated MM patients. The four-drug combination did not result in a substantial increase in response rate and was associated with a modest increase in the incidence of hematologic toxicities. Continuous weekly C in the VDC regimen was associated with high response rates and rapid responses, comparable to the VDR and VDCR arms. Outcome data will be presented following longer follow-up. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding; Bayer: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Richardson:Celgene, Millennium, Novartis, Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Hari:Celgene: Research Funding. Callander:Millennium Pharmaceuticals, Inc.: Research Funding. Noga:Amgen: Honoraria, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ortho-Centicor: Honoraria, Speakers Bureau; Cephalon: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Stewart:Millennium Pharmaceuticals, Inc.: Honoraria, Research Funding; Celgene: Honoraria. Rifkin:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Wolf:Millennium Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Genentech and Multiple Myeloma Research: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; OrthoBiotech: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Estevam:Millennium Pharmaceuticals: Employment. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Shi:Millennium Pharmaceuticals: Employment. Webb:Millennium Pharmaceuticals: Employment.
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Tsoumpra, Maria K., Shun Sawatsubashi, Michihiro Imamura, Seiji Fukumoto, Shin’ichi Takeda, Toshio Matsumoto i Yoshitsugu Aoki. "Dystrobrevin alpha gene is a direct target of the vitamin D receptor in muscle". Journal of Molecular Endocrinology 64, nr 3 (kwiecień 2020): 195–208. http://dx.doi.org/10.1530/jme-19-0229.
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The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (VD3), exerts its tissue-specific actions through binding to its intracellular vitamin D receptor (VDR) which functions as a heterodimer with retinoid X receptor (RXR) to recognize vitamin D response elements (VDRE) and activate target genes. Upregulation of VDR in murine skeletal muscle cells occurs concomitantly with transcriptional regulation of key myogenic factors upon VD3 administration, reinforcing the notion that VD3 exerts beneficial effects on muscle. Herein we elucidated the regulatory role of VD3/VDR axis on the expression of dystrobrevin alpha (DTNA), a member of dystrophin-associated protein complex (DAPC). In C2C12 cells, Dtna and VDR gene and protein expression were upregulated by 1–50 nM of VD3 during all stages of myogenic differentiation. In the dystrophic-derived H2K-mdx52 cells, upregulation of DTNA by VD3 occurred upon co-transfection of VDR and RXR expression vectors. Silencing of MyoD1, an E-box binding myogenic transcription factor, did not alter the VD3-mediated Dtna induction, but Vdr silencing abolished this effect. We also demonstrated that VD3 administration enhanced the muscle-specific Dtna promoter activity in presence of VDR/RXR only. Through site-directed mutagenesis and chromatin immunoprecipitation assays, we have validated a VDRE site in Dtna promoter in myogenic cells. We have thus proved that the positive regulation of Dtna by VD3 observed during in vitro murine myogenic differentiation is VDR mediated and specific. The current study reveals a novel mechanism of VDR-mediated regulation for Dtna, which may be positively explored in treatments aiming to stabilize the DAPC in musculoskeletal diseases.
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Kim, Mi-sun, Ryoji Fujiki, Akiko Murayama, Hirochika Kitagawa, Kazuyoshi Yamaoka, Yoko Yamamoto, Masatomo Mihara, Ken-ichi Takeyama i Shigeaki Kato. "1α,25(OH)2D3-Induced Transrepression by Vitamin D Receptor through E-Box-Type Elements in the Human Parathyroid Hormone Gene Promoter". Molecular Endocrinology 21, nr 2 (1.02.2007): 334–42. http://dx.doi.org/10.1210/me.2006-0231.
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Abstract Although transactivation by the liganded vitamin D receptor (VDR) is well described at the molecular level, the precise molecular mechanism of negative regulation by the liganded VDR remains to be elucidated. We have previously reported a novel class of negative vitamin D response element (nVDRE) called 1αnVDRE in the human 25(OH)D31α-hydroxylase [1α(OH)ase] gene by 1α,25(OH)2D3-bound VDR. This element was composed of two E-box-type motifs that bound to VDIR for transactivation, which was attenuated by liganded VDR. Here, we explore the possible functions of VDIR and E-box motifs in the human (h) PTH and hPTHrP gene promoters. Functional mapping of the hPTH and hPTHrP promoters identified E-box-type elements acting as nVDREs in both the hPTH promoter (hPTHnVDRE; −87 to −60 bp) and in the hPTHrP promoter (hPTHrPnVDRE; −850 to −600 bp; −463 to −104 bp) in a mouse renal tubule cell line. The hPTHnVDRE alone was enough to direct ligand-induced transrepression mediated through VDR/retinoid X receptor and VDIR. Direct DNA binding of hPTHnVDRE to VDIR, but not VDR/retinoid X receptor, was observed and ligand-induced transrepression was coupled with recruitment of VDR and histone deacetylase 2 (HDAC2) to the hPTH promoter. These results suggest that negative regulation of the hPTH gene by liganded VDR is mediated by VDIR directly binding to the E-box-type nVDRE at the promoter, together with recruitment of an HDAC corepressor for ligand-induced transrepression.
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Singh, Tejinder, Kamesh Ayasolla, Partab Rai, Nirupama Chandel, Shabirul Haque, Rivka Lederman, Mohammad Husain i in. "AT1R blockade in adverse milieus: role of SMRT and corepressor complexes". American Journal of Physiology-Renal Physiology 309, nr 3 (1.08.2015): F189—F203. http://dx.doi.org/10.1152/ajprenal.00476.2014.
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ANG II type 1 receptor blockade (AT1R-BLK) is used extensively to slow down the progression of proteinuric kidney diseases. We hypothesized that AT1R-BLK provides podocyte protection through regulation of silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and vitamin D receptor (VDR) expression under adverse milieus such as high glucose and human immunodeficiency virus infection. Both AT1R-BLK and VDR agonists (VDAs) stimulated VDR complex formation that differed not only in their composition but also in their functionality. AT1R-BLK-induced VDR complexes contained predominantly unliganded VDR, SMRT, and phosphorylated histone deacetylase 3, whereas VDA-VDR complexes were constituted by liganded VDR and CREB-binding protein/p300. AT1R-BLK-induced complexes attenuated podocyte acetyl-histone 3 levels as well as cytochrome P-450 family 24A1 expression, thus indicating their deacetylating and repressive properties. On the other hand, VDA-VDR complexes not only increased podocyte acetyl-histone 3 levels but also enhanced cytochrome P-450 family 24A1 expression, thus suggesting their acetylating and gene activation properties. AT1R-BLK- induced podocyte SMRT inhibited expression of the proapoptotic gene BAX through downregulation of Wip1 and phosphorylation of checkpoint kinase 2 in high-glucose milieu. Since SMRT-depleted podocytes lacked AT1R-BLK-mediated protection against DNA damage, it appears that SMRT is necessary for DNA repairs during AT1R-BLK. We conclude that AT1R-BLK provides podocyte protection in adverse milieus predominantly through SMRT expression and partly through unliganded VDR expression in 1,25(OH)2D-deficient states; on the other hand, AT1R-BLK contributes to liganded VDR expression in 1,25(OH)2D-sufficient states.
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Futawaka, Kumi, Tetsuya Tagami, Yuki Fukuda, Rie Koyama, Ayaka Nushida, Shoko Nezu, Hironori Yamamoto, Miyuki Imamoto, Masato Kasahara i Kenji Moriyama. "Transcriptional activation of the wild-type and mutant vitamin D receptors by vitamin D3 analogs". Journal of Molecular Endocrinology 57, nr 1 (lipiec 2016): 23–32. http://dx.doi.org/10.1530/jme-16-0048.
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The active form of vitamin D3 (1α,25(OH)2D3, also known as calcitriol) controls the expression of target genes via the vitamin D receptor (VDR). Vitamin D-dependent rickets type II (VDDRII) is a congenital disease caused by inactivating mutations in the VDR. The condition is treated with high doses of calcitriol, but the therapeutic effects of other synthetic VD3 analogs have not yet been investigated. In the present study, we analyzed the transcriptional activity of seven different VD3 analogs with VDRs carrying ligand-binding domain mutations identified in VDDRII patients. Wild-type VDR (WT-VDR) and seven mutant VDRs were expressed in TSA201 human embryonic kidney cells, HepG2 human liver cancer cells, and MC3T3-E1 mouse calvaria cells, and their transcriptional activation with VD3 analogs were analyzed by performing transient expression assays, western blotting, and quantitative real-time PCR. The results demonstrated that falecalcitriol stimulated significantly higher transcriptional activation of the WT-VDR and some mutant VDRs than did calcitriol. Calcitriol showed almost no transcriptional activation of the VDR with the I268T mutation identified in a severe case of VDDRII, whereas falecalcitriol caused a dose-dependent increase in the activation of this mutant VDR. Our findings demonstrate that falecalcitriol has a VDR activation profile distinct from that of calcitriol and may exhibit therapeutic effects even on difficult-to-treat VDDRII cases resistant to calcitriol. It is also possible that VDDRII patients responding to high doses of calcitriol could be appropriately treated with low doses of falecalcitriol.
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Sánchez-Martínez, Ruth, Alberto Zambrano, Ana I. Castillo i Ana Aranda. "Vitamin D-Dependent Recruitment of Corepressors to Vitamin D/Retinoid X Receptor Heterodimers". Molecular and Cellular Biology 28, nr 11 (24.03.2008): 3817–29. http://dx.doi.org/10.1128/mcb.01909-07.
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ABSTRACT Transcriptional regulation by nuclear receptors is mediated by recruitment of coactivators and corepressors. In the classical model, unliganded nonsteroidal receptors bind corepressors, such as the silencing mediator of thyroid and retinoid receptors (SMRT) or nuclear corepressor (NCoR), that are released upon ligand binding. We show here that, unlike other receptors, the heterodimer of the vitamin D receptor (VDR) with the retinoid X receptor (RXR) recruits NCoR and SMRT strictly in a VDR agonist-dependent manner. Binding of an agonist to VDR allows its partner receptor, RXR, to bind the corepressors. The RXR ligand has the opposite effect and induces corepressor release from the heterodimer. 1,25-Dihydroxy-vitamin D3 (VD3) causes recruitment of SMRT and NCoR to a VDR target promoter. Down-regulation of corepressors by means of small interfering RNA enhances transcriptional responses to VD3. These data reveal a new paradigm of SMRT and NCoR binding to nuclear receptors and demonstrate that these corepressors can function as physiological negative regulators of VD3-mediated transcription.
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Grzesiak, Malgorzata, Gabriela Burzawa, Patrycja Kurowska, Klaudia Blaszczyk, Agata Szlaga, Anna Blasiak, Andrzej Sechman i Agnieszka Rak. "Altered vitamin D3 metabolism in the ovary and periovarian adipose tissue of rats with letrozole-induced PCOS". Histochemistry and Cell Biology 155, nr 1 (23.10.2020): 101–16. http://dx.doi.org/10.1007/s00418-020-01928-z.
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AbstractVitamin D3 (VD3) plays an important role in the ovary and its deficiency is associated with ovarian pathologies, including polycystic ovary syndrome (PCOS). However, there is no data related to VD3 metabolism in the ovary during PCOS. Herein, we investigated differences in the expression of VD3 receptor (VDR) and key VD3 metabolic enzymes, 1α-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1), in the ovary and periovarian adipose tissue (POAT) of control (proestrus and diestrus) and PCOS induced by letrozole rats. Vdr, Cyp27b1 and Cyp24a1 mRNA expression was determined, their protein abundance was examined and immunolocalized. Furthermore, VD3 metabolite concentrations in plasma (25OHD) and tissues (ovary and POAT; 1,25(OH)2D3), and plasma calcium level were determined. 25OHD concentration decreased markedly in letrozole-treated rats in comparison with controls, whereas calcium concentration did not vary among the examined groups. The amount of 1,25(OH)2D3 decreased in both ovary and POAT of PCOS rats. In the ovary, we found decreased Cyp27b1 and increased Vdr mRNA expression in letrozole-treated and diestrus control group. Corresponding protein abundances were down-regulated and up-regulated, respectively but only following letrozole treatment. In POAT, only Cyp27b1 transcript level and CYP27B1 protein abundance were decreased in letrozole-treated rats. VDR was immunolocalized in healthy and cystic follicles, while CYP27B1 and CYP24A1 were found exclusively in healthy ones. Concluding, our results provide the first evidence of disrupted VD3 metabolism in the ovary and POAT of PCOS rats. The reduced 1,25(OH)2D3 concentration in those tissues suggests their contribution to VD3 deficiency observed in PCOS and might implicate in PCOS pathogenesis.
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Abdurahman, Ahmed Abdulahi, Leila Khorrami-nezhad i Khadijeh Mirzaei. "Vitamin D (FokI) Receptor Gene Polymorphism is associated with Vitamin D Deficiency and Chronic Musculoskeletal Pain. A meta-analysis". International Journal for Vitamin and Nutrition Research 87, nr 3-4 (1.05.2017): 219–32. http://dx.doi.org/10.1024/0300-9831/a000569.
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Abstract. Background: Musculoskeletal pain is the most common chronic pain experienced by older adults. The aim of this study is to explore the associations between vitamin D (FOKI) receptor gene polymorphism (VDR) and vitamin D deficiency (VDD) and chronic musculoskeletal pain. Methods: Cross-sectional studies published in English from January 2000 to January 2015which reported prevalence of chronic pain (CP) and chronic musculoskeletal pain (CMP) were included in this systematic review and meta-analysis. A heat map was used to visualize and observe the correlation between VDR and CMP, CP and VDD. Results: 20 studies (N = 216,365) were included in the analysis, which showed an overall pooled prevalence estimate of CMP and CP as 30.6 per 100 (95 % CI: 30.59, 30.69) and 27.9 per 100 (95 % CI: 27.68, 28.24) respectively. The heat map clustering analysis visualizes the similarity between CP and CMP. Moreover, a direct correlation was observed between the three disease conditions (namely CMP, CP, and VDD) and FokI VDR polymorphism (FF). Spearman’s correlation analyses with adjusted r2 revealed that there is a statistically significant interaction effect of the FF genotype and VDD on CMP (r2 = 0.19, p = 0.03), a marginally significant interaction effect of the ff genotype and VDD on CMP (r2 = 0.11, p = 0.08). VDD was also associated with increased CMP (r2 = 0.19, p = 0.028). The pooled estimates of the prevalence of CMP in this review were found to be high. Conclusion: FokI VDR gene polymorphism (FF) plays an important role in the relationship between VDD and CMP.
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Göbel, Florian, Sabine Taschner, Jennifer Jurkin, Sabine Konradi, Christine Vaculik, Susanne Richter, Doris Kneidinger i in. "Reciprocal role of GATA-1 and vitamin D receptor in human myeloid dendritic cell differentiation". Blood 114, nr 18 (29.10.2009): 3813–21. http://dx.doi.org/10.1182/blood-2009-03-210484.
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Abstract Two major pathways of human myeloid dendritic cell (DC) subset differentiation have previously been delineated. Langerhans cells (LCs) reside in epithelia in the steady state, whereas monocytes can provide dendritic cells (DCs) on demand in response to inflammatory signals. Both DC subset pathways arise from shared CD14+ monocyte precursors, which in turn develop from myeloid committed progenitor cells. However, the underlying hematopoietic mechanisms still remain poorly defined. Here, we demonstrate that the vitamin D3 receptor (VDR) is induced by transforming growth factor β1 during LC lineage commitment and exerts a positive role during LC generation. In contrast, VDR is repressed during interleukin-4 (IL-4)–dependent monocyte-derived DC (moDC) differentiation. We identified GATA-1 as a repressor of VDR. GATA-1 is induced by IL-4 in moDCs. Forced inducible expression of GATA-1 mimics IL-4 in redirecting moDC differentiation and vice versa, GATA-1 knockdown arrests moDC differentiation at the monocyte stage. Moreover, ectopic GATA-1 expression stabilizes the moDC phenotype under monocyte-promoting conditions in the presence of vitamin D3 (VD3). In summary, human myeloid DC subset differentiation is inversely regulated by GATA-1 and VDR. GATA-1 mediates the repression of VDR and enables IL-4–dependent moDC differentiation. Conversely, VDR is induced downstream of transforming growth factor β1 and is functionally involved in promoting LC differentiation.
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Han, Shuxin, Tiangang Li, Ewa Ellis, Steven Strom i John Y. L. Chiang. "A Novel Bile Acid-Activated Vitamin D Receptor Signaling in Human Hepatocytes". Endocrine Reviews 31, nr 2 (1.04.2010): 263. http://dx.doi.org/10.1210/edrv.31.2.9998.
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ABSTRACT Vitamin D receptor (VDR) is activated by natural ligands, 1α, 25-dihydroxy-vitamin D3 (1α, 25(OH)2-D3) and lithocholic acid (LCA). Our previous study shows that VDR is expressed in human hepatocytes, and VDR ligands inhibit bile acid synthesis and transcription of the gene encoding cholesterol 7α-hydroxylase (CYP7A1). Primary human hepatocytes were used to study LCA and 1α, 25(OH)2-D3 activation of VDR signaling. Confocal immunofluorescent microscopy imaging and immunoblot analysis showed that LCA and 1α, 25(OH)2-D3 induced intracellular translocation of VDR from the cytosol to the nucleus, and also plasma membrane where VDR co-localized with caveolin-1. VDR ligands induced tyrosine phosphorylation of c-Src and VDR, and their interaction. Inhibition of c-Src abrogated VDR ligand-dependent inhibition of CYP7A1 mRNA expression. Kinase assays showed that VDR ligands specifically activated the c-Raf/MEK1/2/ERK1/2 pathway, which stimulates serine phosphorylation of VDR and HNF4α, and their interaction. Mammalian two-hybrid assays showed a VDR ligand dependent interaction of nuclear receptor corepressor-1 (NCoR-1) and silencing mediator of retinoid and thyroid (SMRT) with VDR/RXRα. Chromatin immunoprecipitation assays revealed that an ERK1/2 inhibitor reversed VDR ligand-induced recruitment of VDR, RXRα and corepressors to human CYP7A1 promoter. In conclusion, VDR ligands activate membrane VDR signaling to activate the MEK1/2/ERK1/2 pathway, which stimulates nuclear VDR/RXRα recruitment of co-repressors to inhibit CYP7A1 gene transcription in human hepatocytes. This membrane VDR signaling pathway may be activated by bile acids to inhibit bile acid synthesis as a rapid response to protect hepatocytes from cholestatic liver injury.
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Arora, Juhi, i Margherita T. Cantorna. "Redefining the targets of the vitamin D receptor (VDR) utilizing a novel VDR reporter mouse." Journal of Immunology 206, nr 1_Supplement (1.05.2021): 24.10. http://dx.doi.org/10.4049/jimmunol.206.supp.24.10.
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Abstract The vitamin D receptor (VDR) is a ligand-activated nuclear protein that regulates gene transcription. Vitamin D target cells are identified by the expression of VDR. Kidney and colon epithelial cells constitutively express high levels of the VDR. Immune cells also express the VDR; however, at significantly lower levels. Western blots show very low expression of the VDR in spleen, and lymph nodes. Gene expression studies in macrophage, B cells and T cells showed that activation for 24–48 hours increased the VDR mRNA levels. We have developed transgenic mice that express Cre recombinase within the VDR locus (VDRcre) and crossed these with a reporter line (Tdtomatofl/fl). Cre expression in the VDR locus results in a VDR +/− mice. The frequencies of immune cells were similar between VDR−/− and VDR +/− mice. The VDRcre expressing offspring had pink skin. Kidneys, small intestine and colon were also distinctly pink suggesting high expression of the Tdtomato-VDR reporter. Splenic T cells, activated with CD3e antibody showed upregulation of VDR mRNA and protein. Regardless of activation status, naive, effector or memory T cells had similar and high levels of the VDR reporter. VDR expression was detected at various stages of T cell thymic development with a 80% in the CD4-CD8- cells and 90% of CD4+CD8+ cells, 84% CD4+ and 88% CD8+ thymocytes. High expression of the VDR reporter in multiple T cell types and precursors suggests that the VDR is expressed throughout the life of a T cell. Future work will identify immune cells negative for the VDR reporter and the kinetics of VDR expression following activation in various cell types.
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Wu, Shaoping, Sonia Yoon, Yong-Guo Zhang, Rong Lu, Yinglin Xia, Jiandi Wan, Elaine O. Petrof, Erika C. Claud, Di Chen i Jun Sun. "Vitamin D receptor pathway is required for probiotic protection in colitis". American Journal of Physiology-Gastrointestinal and Liver Physiology 309, nr 5 (1.09.2015): G341—G349. http://dx.doi.org/10.1152/ajpgi.00105.2015.
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Low expression of vitamin D receptor (VDR) and dysfunction of vitamin D/VDR signaling are reported in patients with inflammatory bowel disease (IBD); therefore, restoration of VDR function to control inflammation in IBD is desirable. Probiotics have been used in the treatment of IBD. However, the role of probiotics in the modulation of VDR signaling to effectively reduce inflammation is unknown. We identified a novel role of probiotics in activating VDR activity, thus inhibiting inflammation, using cell models and VDR knockout mice. We found that the probiotics Lactobacillus rhamnosus strain GG (LGG) and Lactobacillus plantarum (LP) increased VDR protein expression in both mouse and human intestinal epithelial cells. Using the VDR luciferase reporter vector, we detected increased transcriptional activity of VDR after probiotic treatment. Probiotics increased the expression of the VDR target genes, such as antimicrobial peptide cathelicidin, at the transcriptional level. Furthermore, the role of probiotics in regulating VDR signaling was tested in vivo using a Salmonella-colitis model in VDR knockout mice. Probiotic treatment conferred physiological and histologic protection from Salmonella-induced colitis in VDR+/+mice, whereas probiotics had no effects in the VDR−/−mice. Probiotic treatment also enhanced numbers of Paneth cells, which secrete AMPs for host defense. These data indicate that the VDR pathway is required for probiotic protection in colitis. Understanding how probiotics enhance VDR signaling and inhibit inflammation will allow probiotics to be used effectively, resulting in innovative approaches to the prevention and treatment of chronic inflammation.
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Yagishita, Naoko, Yoko Yamamoto, Tatsuya Yoshizawa, Keisuke Sekine, Yoshikatsu Uematsu, Hisashi Murayama, Yumiko Nagai i in. "Aberrant Growth Plate Development in VDR/RXRγ Double Null Mutant Mice". Endocrinology 142, nr 12 (1.12.2001): 5332–41. http://dx.doi.org/10.1210/endo.142.12.8544.
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Abstract VDR forms heterodimers with one of three RXRs, RXRα, RXRβ, and RXRγ, and it is thought that RXR ligands can also modulate the trans-activation function of VDR/RXR heterodimers. In the present study we generated VDR/RXRγ double null mutant mice to examine the convergent actions of vitamin D and vitamin A signaling and to explore the possibility of a functionally redundant VDR. Although RXRγ−/− mice exhibited no overt abnormalities, VDR−/−/RXRγ−/− mice appeared similar to VDR−/− mice, showing features typical of vitamin D-dependent rickets type II, including growth retardation, impaired bone formation, hypocalcemia, and alopecia. However, compared to VDR−/− mice, growth plate development in VDR−/−/RXRγ−/− mutant mice was more severely impaired. Normalizing mineral ion homeostasis through dietary supplementation with high calcium and phosphorous effectively prevented rachitic abnormalities, except for disarranged growth plates in VDR−/−/RXRγ−/− mutant mice, and alopecia in both VDR−/− and VDR−/−/RXRγ−/− mutant mice. Histological analysis of VDR−/−/RXRγ−/− growth plates revealed that development of the hypertrophic chondrocytes was selectively impaired. Thus, our findings indicated that the combined actions of VDR- and RXRγ-mediated signals are essential for the normal development of growth plate chondrocytes, and raised the possibility that a functionally redundant VDR is present on chondrocytes as a heterodimer with RXRγ.
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Segawa, Hiroko, Ichiro Kaneko, Setsuko Yamanaka, Mikiko Ito, Masahi Kuwahata, Yoshio Inoue, Shigeaki Kato i Ken-ichi Miyamoto. "Intestinal Na-Pi cotransporter adaptation to dietary Pi content in vitamin D receptor null mice". American Journal of Physiology-Renal Physiology 287, nr 1 (lipiec 2004): F39—F47. http://dx.doi.org/10.1152/ajprenal.00375.2003.
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Recent studies suggest that vitamin D may play a role in intestinal Na+-dependent phosphate transport adaptation to variable levels of dietary Pi. Therefore, the goal of the current study was to assess Na+-dependent Pi cotransport activity in transgenic mice to determine whether vitamin D is an essential mediator of this process. Intestinal brush-border membrane (BBM), Na+-dependent Pi cotransport activity was significantly decreased in vitamin D receptor (VDR) null [VDR (−/−)] mice compared with wild-type (VDR+/+) mice. While intestinal Na-Pi cotransporter (type IIb) mRNA levels were similar in VDR (−/−) and VDR (+/+) mice, type IIb Na-Pi cotransporter protein expression was markedly suppressed in VDR (−/−) mice compared with VDR (+/+) mice. Furthermore, Na-Pi cotransport activity in renal BBM was similar in VDR (−/−) and VDR (+/+) mice, but type IIa Na-Pi cotransporter protein expression was decreased in VDR (−/−) mice. After administration of a low-Pi diet, type IIb protein expression was significantly increased in VDR (+/+) and VDR (−/−) mice, and type IIb protein expression was present in the intestinal BBM of VDR (−/−) mice. These data demonstrate that intestinal Na-Pi cotransport adaptation to a low-Pi diet occurs independently of vitamin D.
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Takeshita, Akira, Yasunori Ozawa i William W. Chin. "Nuclear Receptor Coactivators Facilitate Vitamin D Receptor Homodimer Action on Direct Repeat Hormone Response Elements". Endocrinology 141, nr 3 (1.03.2000): 1281–84. http://dx.doi.org/10.1210/endo.141.3.7441.
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Abstract Vitamin D receptor (VDR) is a ligand-dependent transcription factor that regulates target gene expression. Although VDR forms stable heterodimer complex with retinoid X receptors (RXRs) on vitamin D-response elements (VDREs), it is still not clear whether VDR/RXR heterodimers are the only VDR complexes responsible for vitamin D-mediated gene transcription. In this report, we analyzed the effect of nuclear receptor coactivators (SRC-1 and TRAM-1) on VDR homodimer and VDR/RXR heterodimer formation by electrophoretic mobility shift assay. We found that VDR forms stable homodimers after interaction with the coactivators on a VDRE (DR+3). Of particular note, DR+4 and DR+5 hormone-response elements (HREs) may also support such interactions. Cotransfection experiments revealed further that the coactivators enhance ligand-induced VDR transcription on these elements. Our studies suggest the important role of VDR homodimers, in addition to VDR/RXR heterodimers, in vitamin D-induced transactivation. Thus, specific coactivator-VDR interactions on HREs may determine target gene transactivation.
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Meir, Tomer, Ronen Levi, Liesbet Lieben, Steven Libutti, Geert Carmeliet, Roger Bouillon, Justin Silver i Tally Naveh-Many. "Deletion of the vitamin D receptor specifically in the parathyroid demonstrates a limited role for the receptor in parathyroid physiology". American Journal of Physiology-Renal Physiology 297, nr 5 (listopad 2009): F1192—F1198. http://dx.doi.org/10.1152/ajprenal.00360.2009.
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1,25(OH)2D3 decreases parathyroid hormone (PTH) gene transcription through the vitamin D receptor (VDR). Total body VDR−/− mice have high PTH levels, hypocalcemia, hypophosphatemia, and bone malformations. To investigate PTH regulation by the VDR specifically in the parathyroid, we generated parathyroid-specific VDR knockout mice ( PT-VDR−/−). In both strains, there was a decrease in parathyroid calcium receptor (CaR) levels. The number of proliferating parathyroid cells was increased in the VDR−/− mice but not in the PT-VDR−/− mice. Serum PTH levels were moderately but significantly increased in the PT-VDR−/− mice with normal serum calcium levels. The sensitivity of the parathyroid glands of the PT-VDR−/− mice to calcium was intact as measured by serum PTH levels after changes in serum calcium. This indicates that the reduced CaR in the PT-VDR−/− mice enables a physiologic response to serum calcium. Serum C-terminal collagen crosslinks, a marker of bone resorption, were increased in the PT-VDR−/− mice with no change in the bone formation marker, serum osteocalcin, consistent with a resorptive effect due to the increased serum PTH levels in the PT-VDR−/− mice. Therefore, deletion of the VDR specifically in the parathyroid decreases parathyroid CaR expression and only moderately increases basal PTH levels, suggesting that the VDR has a limited role in parathyroid physiology.
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Kovacs, Christopher S., Mandy L. Woodland, Neva J. Fudge i James K. Friel. "The vitamin D receptor is not required for fetal mineral homeostasis or for the regulation of placental calcium transfer in mice". American Journal of Physiology-Endocrinology and Metabolism 289, nr 1 (lipiec 2005): E133—E144. http://dx.doi.org/10.1152/ajpendo.00354.2004.
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We utilized a vitamin D receptor (VDR) gene knockout model to study the effects of maternal and fetal absence of VDR on maternal fertility, fetal-placental calcium transfer, and fetal mineral homoeostasis. Vdr null mice were profoundly hypocalcemic, conceived infrequently, and had significantly fewer viable fetuses in utero that were also of lower body weight. Supplementation of a calcium-enriched diet increased the rate of conception in Vdr nulls but did not normalize the number or weight of viable fetuses. Among offspring of heterozygous ( Vdr+/−) mothers (wild type, Vdr+/−, and Vdr null fetuses), there was no alteration in serum Ca, P, or Mg, parathyroid hormone, placental 45Ca transfer, Ca and Mg content of the fetal skeleton, and morphology and gene expression in the fetal growth plates. Vdr null fetuses did have threefold increased 1,25-dihydroxyvitamin D levels accompanied by increased 1α-hydroxylase mRNA in kidney but not placenta; a small increase was also noted in placental expression of parathyroid hormone-related protein (PTHrP). Among offspring of Vdr null mothers, Vdr+/− and Vdr null fetuses had normal ionized calcium levels and a skeletal ash weight that was appropriate to the lower body weight. Thus our findings indicate that VDR is not required by fetal mice to regulate placental calcium transfer, circulating mineral levels, and skeletal mineralization. Absence of maternal VDR has global effects on fetal growth that were partly dependent on maternal calcium intake, but absence of maternal VDR did not specifically affect fetal mineral homeostasis.
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Sun, Jun, Juan Kong, Yingli Duan, Frances L. Szeto, Anne Liao, James L. Madara i Yan Chun Li. "Increased NF-κB activity in fibroblasts lacking the vitamin D receptor". American Journal of Physiology-Endocrinology and Metabolism 291, nr 2 (sierpień 2006): E315—E322. http://dx.doi.org/10.1152/ajpendo.00590.2005.
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1,25-Dihydroxyvitamin D [1,25(OH)2D3] is known to have anti-inflammatory activity; however, the molecular mechanism remains poorly defined. Here we show that the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-κB activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR−/− mice, the basal level of κB inhibitor (IκB) α protein was markedly decreased compared with VDR+/− MEFs; however, degradation of IκBα and its phosphorylation in response to TNF-α treatment or Salmonella infection were not altered in VDR−/− cells, neither were the levels of IκB kinase-α and IκB kinase-β proteins. Consistent with IκBα reduction, p65 accumulation in the nucleus was markedly increased in unstimulated VDR−/− cells. In addition, the physical interaction between VDR and p65 was absent in VDR−/− MEFs, which may free p65 and increase its activity. Consequently, these alterations combined led to a marked increase in nuclear p65 DNA binding and NF-κB transcriptional activity; consistently, induction of IL-6 by TNF-α or IL-1β was much more robust in VDR−/− than in VDR+/− cells, indicating that VDR−/− cells are more susceptible to inflammatory stimulation. Therefore, cells lacking VDR appear to be more proinflammatory due to the intrinsic high NF-κB activity. The reduction of IκBα in VDR−/− MEFs may be partially explained by the lack of VDR-mediated stabilization of IκBα by 1,25(OH)2D3. This is supported by the observation that IκBα degradation induced by TNF-α was inhibited by 1,25(OH)2D3 in VDR+/− cells, but not in VDR−/− cells. Taken together, these data suggest that VDR plays an inhibitory role in the regulation of NF-κB activation.
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James, Jamaal, i Margherita Cantorna. "B cell intrinsic effects of the vitamin D receptor on IgE responses. (IRC10P.417)". Journal of Immunology 194, nr 1_Supplement (1.05.2015): 196.15. http://dx.doi.org/10.4049/jimmunol.194.supp.196.15.
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Abstract B cells express the vitamin D receptor (VDR). VDR KO mice had higher levels of circulating total IgE than WT mice by 12 wks of age. Mice were sensitized using two OVA/alum injections. VDR KO mice mounted a significantly higher OVA-specific IgE response compared to WT mice. The data also showed that vitamin D deficient mice had higher OVA-specific IgE responses than vitamin D sufficient mice. IL-4, IL-5, IL-2, IFN-γ and IL-17 were not different in OVA re-stimulated spleen and mesenteric lymph nodes (MLN) in WT and VDR KO mice. However, VDR KO spleen and MLN produced significantly less IL-10 than WT. Furthermore B cells and not T cells were the major source of IL-10 in both the WT and VDR KO cultures. Experiments were done using T cell specific-VDR deletion (T-VDR KO), or B cell specific-VDR deletion (B-VDR KO). The serum IgE levels in T-VDR KO mice were comparable to that of WT mice. Conversely, B-VDR KO mice had higher total serum IgE levels than WT mice and, when immunized, produced significantly more OVA-IgE. In our current model, we propose that B cell-derived IL-10 is regulated by the VDR and that autocrine IL-10 is higher in WT mice, therefore inhibiting IgE production to a greater extent in WT than in VDR KO mice. The major finding of this work is that vitamin D receptor expression selectively regulates IgE levels in the serum via a direct effect of the VDR in B cells.
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Pilon, Catia, Andrea Rebellato, Riccardo Urbanet, Vincenza Guzzardo, Rocco Cappellesso, Hironobu Sasano, Ambrogio Fassina i Francesco Fallo. "Methylation Status of Vitamin D Receptor Gene Promoter in Benign and Malignant Adrenal Tumors". International Journal of Endocrinology 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/375349.
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We previously showed a decreased expression of vitamin D receptor (VDR) mRNA/protein in a small group of adrenocortical carcinoma (ACC) tissues, suggesting the loss of a protective role of VDR against malignant cell growth in this cancer type. Downregulation of VDR gene expression may result from epigenetics events, that is, methylation of cytosine nucleotide of CpG islands in VDR gene promoter. We analyzed methylation of CpG sites in the VDR gene promoter in normal adrenals and adrenocortical tumor samples. Methylation of CpG-rich 5′ regions was assessed by bisulfite sequencing PCR using bisulfite-treated DNA from archival microdissected paraffin-embedded adrenocortical tissues. Three normal adrenals and 23 various adrenocortical tumor samples (15 adenomas and 8 carcinomas) were studied. Methylation in the promoter region of VDR gene was found in 3/8 ACCs, while no VDR gene methylation was observed in normal adrenals and adrenocortical adenomas. VDR mRNA and protein levels were lower in ACCs than in benign tumors, and VDR immunostaining was weak or negative in ACCs, including all 3 methylated tissue samples. The association between VDR gene promoter methylation and reduced VDR gene expression is not a rare event in ACC, suggesting that VDR epigenetic inactivation may have a role in adrenocortical carcinogenesis.
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Zhang, Yunzhan, Jia-Zhong Cai, Lan Xiao, Hee K. Chung, Xiang-Xue Ma, Lin-Lin Chen, Jaladanki N. Rao i Jian-Ying Wang. "RNA-binding protein HuR regulates translation of vitamin D receptor modulating rapid epithelial restitution after wounding". American Journal of Physiology-Cell Physiology 319, nr 1 (1.07.2020): C208—C217. http://dx.doi.org/10.1152/ajpcell.00009.2020.
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Homeostasis of the intestinal epithelium is tightly regulated by numerous extracellular and intracellular factors including vitamin D and the vitamin D receptor (VDR). VDR is highly expressed in the intestinal epithelium and is implicated in many aspects of gut mucosal pathophysiology, but the exact mechanism that controls VDR expression remains largely unknown. The RNA-binding protein human antigen R (HuR) regulates the stability and translation of target mRNAs and thus modulates various cellular processes and functions. Here we report a novel role of HuR in the posttranscriptional control of VDR expression in the intestinal epithelium. The levels of VDR in the intestinal mucosa decreased significantly in mice with ablated HuR, compared with control mice. HuR silencing in cultured intestinal epithelial cells (IECs) also reduced VDR levels, whereas HuR overexpression increased VDR abundance; neither intervention changed cellular Vdr mRNA content. Mechanistically, HuR bound to Vdr mRNA via its 3′-untranslated region (UTR) and enhanced VDR translation in IECs. Moreover, VDR silencing not only inhibited IEC migration over the wounded area in control cells but also prevented the increased migration in cells overexpressing HuR, although it did not alter IEC proliferation in vitro and growth of intestinal organoids ex vivo. The human intestinal mucosa from patients with inflammatory bowel diseases exhibited decreased levels of both HuR and VDR. These results indicate that HuR enhances VDR translation by directly interacting with its mRNA via 3′-UTR and that induced VDR by HuR is crucial for rapid intestinal epithelial restitution after wounding.
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Arora, Juhi, Jinpeng Wang, Veronika Weaver i Margherita T. Cantorna. "Novel insight into the role of the vitamin D receptor in the development and function of the immune system". Journal of Immunology 208, nr 1_Supplement (1.05.2022): 107.01. http://dx.doi.org/10.4049/jimmunol.208.supp.107.01.
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Abstract Immune cells express the vitamin D receptor (VDR) and are therefore vitamin D targets. The VDR protein can be readily measured in the kidney using antibodies to the VDR and western blot. It is much more difficult to measure VDR protein in the spleen because of the low level of VDR expression in resting immune cells. In order to more sensitively measure VDR expression, the Cre enzyme was inserted in the 3rd exon of the VDR gene and a reporter mouse that irreversibly expresses tdTomato was made. Mice that express one copy of the VDRCre gene were confirmed to be VDR +/− and mice that express two copies were confirmed to be VDR −/−. Initial characterization of the immune cells from the VDR +/− VDRtdTomato+ compared to VDR+/+ wildtype (WT) littermates showed no effect of being hemizygous for the VDR on immune cell frequencies. Immune precursors from bone marrow and thymus showed high tdtomato expression. In the periphery, monocytes, neutrophils and macrophages had very high tdTomato+ (88–98%) expression while lymphocytes ranged from 60–70% tdTomato+. Tissue resident innate lymphoid cell (ILC) 1 and 3 cells were about 60–80% tdTomoto+, while ILC2 cells had very low tdTomato expression. Stimulation of VDRtdTomato+ splenocytes showed that the tdTomato− CD4+ and CD8+ T cells proliferated more than their tdTomato+ counterparts. Sorted tdTomato+ T cells expressed the VDR protein only after 72h post-activation and proliferated less than the tdtomato− T cells. Interestingly, activation of the tdTomato− T cells failed to induce new tdTomato expression. The data suggest that an early immune precursor expresses the VDR. In the periphery, neutrophils and monocytes are almost all tdTomato+, while some immune cells (ILC2 and some T cells) may never express the VDR. Supported by NIH R01AT005378 to MTC and T32GM108563 to JA, USDA NIFA award PEN04771 to MTC.
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Yamamoto, Yoko, Tatsuya Yoshizawa, Toru Fukuda, Yuko Shirode-Fukuda, Taiyong Yu, Keisuke Sekine, Takashi Sato i in. "Vitamin D Receptor in Osteoblasts Is a Negative Regulator of Bone Mass Control". Endocrinology 154, nr 3 (1.03.2013): 1008–20. http://dx.doi.org/10.1210/en.2012-1542.
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Abstract The physiological and beneficial actions of vitamin D in bone health have been experimentally and clinically proven in mammals. The active form of vitamin D [1α,25(OH)2D3] binds and activates its specific nuclear receptor, the vitamin D receptor (VDR). Activated VDR prevents the release of calcium from its storage in bone to serum by stimulating intestinal calcium absorption and renal reabsorption. However, the direct action of VDR in bone tissue is poorly understood because serum Ca2+ homeostasis is maintained through tightly regulated ion transport by the kidney, intestine, and bone. In addition, conventional genetic approaches using VDR knockout (VDR-KO, VDR−/−) mice could not identify VDR action in bone because of the animals' systemic defects in calcium metabolism. In this study, we report that systemic VDR heterozygous KO (VDR+/L−) mice generated with the Cre/loxP system as well as conventional VDR heterozygotes (VDR+/−) showed increased bone mass in radiological assessments. Because mineral metabolism parameters were unaltered in both types of mice, these bone phenotypes imply that skeletal VDR plays a role in bone mass regulation. To confirm this assumption, osteoblast-specific VDR-KO (VDRΔOb/ΔOb) mice were generated with 2.3 kb α1(I)-collagen promoter-Cre transgenic mice. They showed a bone mass increase without any dysregulation of mineral metabolism. Although bone formation parameters were not affected in bone histomorphometry, bone resorption was obviously reduced in VDRΔOb/ΔOb mice because of decreased expression of receptor activator of nuclear factor kappa-B ligand (an essential molecule in osteoclastogenesis) in VDRΔOb/ΔOb osteoblasts. These findings establish that VDR in osteoblasts is a negative regulator of bone mass control.
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Seoane, Samuel, Isabel Ben, Viviana Centeno i Roman Perez-Fernandez. "Cellular Expression Levels of the Vitamin D Receptor Are Critical to Its Transcriptional Regulation by the Pituitary Transcription Factor Pit-1". Molecular Endocrinology 21, nr 7 (1.07.2007): 1513–25. http://dx.doi.org/10.1210/me.2006-0554.
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Abstract The biological role of 1,25-dihydroxyvitamin D3 has generally been related to calcium homeostasis, but this hormone also has fundamental effects on processes of cellular proliferation and differentiation. The genomic actions of 1,25-dihydroxyvitamin D3 are mediated by the vitamin D receptor (VDR) present in target cells. However, VDR transcriptional regulation is not well understood, probably attributable to the complexity of the VDR gene and its promoter. In the present study, it is demonstrated that administration of the pituitary transcription factor Pit-1 (originally found in the pituitary gland but also present in other nonpituitary cell types and tissues) to the MCF-7 (human breast adenocarcinoma) cell line induces a significant increase in VDR mRNA and protein levels. Conversely, Pit-1-targeted small interference RNA markedly reduced expression of VDR in MCF-7 cells. Reporter gene assays demonstrated that the effect of Pit-1 is mediated by its binding to a region located between −254 and −246 bp from the VDR transcription start site. Selective mutations of this site completely abolished VDR transcription. Chromatin immunoprecipitation analysis showed that binding of Pit-1 to the VDR promoter leads additionally to recruitment of cAMP response element-binding protein binding protein, acetylated histone H4, and RNA polymerase II. Surprisingly, Pit-1 binding also recruits VDR protein to the VDR promoter. Using several cell lines with different levels of VDR expression, it was demonstrated that up-regulation of VDR transcription by Pit-1 is dependent on the presence of VDR protein, suggesting that transcriptional expression of VDR in a given cell type is dependent on, among other factors, its own expression levels.
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Nowak, Urszula, Sylwia Janik, Aleksandra Marchwicka, Agnieszka Łaszkiewicz, Agnieszka Jakuszak, Małgorzata Cebrat i Ewa Marcinkowska. "Investigating the Role of Methylation in Silencing of VDR Gene Expression in Normal Cells during Hematopoiesis and in Their Leukemic Counterparts". Cells 9, nr 9 (29.08.2020): 1991. http://dx.doi.org/10.3390/cells9091991.
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(1) Background: Vitamin D receptor (VDR) is present in multiple types of blood cells, and its ligand, 1,25-dihydroxyvitamin D (1,25D), is important for the proper functioning of the immune system. Activity of VDR is higher in hematopoietic stem and progenitor cells than in fully differentiated blood cells of mice and humans. In some human acute myeloid leukemia (AML) blasts, the expression of the VDR gene is also high. The mechanism of silencing the VDR gene expression during differentiation of blood cells has been addressed in this work. (2) Methods: The cells have been obtained using fluorescence activated sorting from murine tissues and from human umbilical cord blood (UCB). Then, the expression of the VDR gene and transcriptional activity of the VDR protein has been tested in real-time polymerase chain reaction (PCR). Eventually, the methylation of VDR promoter regions was tested using bisulfite sequencing. (3) Results: The CpG islands in VDR promoters were not methylated in the cells studied both in mice and in humans. The use of hypomethylating agents had no effect toward expression of human VDR transcripts, but it increased expression of the VDR-target gene, CYP24A1. (4) Conclusions: The expression of the VDR gene and transcriptional activity of the VDR protein varies at successive stages of hematopoietic differentiation in humans and mice, and in blasts from AML patients. The experiments presented in this case indicate that methylation of the promoter region of the VDR gene is not the major mechanism responsible for these differences.
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Shim, Yoo Jin, Yeon Hee Hong, Jaewang Lee i Byung Chul Jee. "Impact of vitamin D3 supplementation on the in vitro growth of mouse preantral follicles". Clinical and Experimental Reproductive Medicine 48, nr 4 (1.12.2021): 347–51. http://dx.doi.org/10.5653/cerm.2021.04735.
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Objective: We investigated the impact of vitamin D3 (VD3) supplementation during mouse preantral follicle culture in vitro and the mRNA expression of 25-hydroxylase (CYP2R1), 1-alpha-hydroxylase (CYP27B1), and vitamin D receptor (VDR) in mouse ovarian follicles at different stages.Methods: Preantral follicles were retrieved from 39 BDF1 mice (7–8 weeks old) and then cultured in vitro for 12 days under VD3 supplementation (0, 25, and 50 pg/mL). Follicular development and the final oocyte acquisition were assessed. Preantral follicles were retrieved from 15 other BDF1 mice (7–8 weeks old) and cultured without VD3 supplementation. Three stages of mouse ovarian follicles were obtained (preantral, antral, and ruptured follicles). Total RNA was extracted from the pooled cells (from 20 follicles at each stage), and then reverse transcriptase-polymerase chain reaction was performed to identify mRNA for CYP2R1, CYP27B1, and VDR.Results: The survival of preantral follicles, rates of antrum formation and ruptured follicles (per initiated follicle) and the number of total or mature oocytes were all comparable among the three groups. Both CYP2R1 and CYP27B1 were expressed in antral and ruptured follicles, but not in preantral follicles. VDR was expressed in all three follicular stages.Conclusion: VD3 supplementation in vitro (25 or 50 pg/mL) did not enhance mouse follicular development or final oocyte acquisition. Follicular stage-specific expression of CYP2R1, CYP27B1, and VDR was observed.
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Yi, Bin, Jing Huang, Wei Zhang, Ai Mei Li, Shi Kun Yang, Jian Sun, Jian Wen Wang, Yan Chun Li i Hao Zhang. "Vitamin D Receptor Down-Regulation Is Associated With Severity of Albuminuria in Type 2 Diabetes Patients". Journal of Clinical Endocrinology & Metabolism 101, nr 11 (23.08.2016): 4395–404. http://dx.doi.org/10.1210/jc.2016-1516.
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Context: Inflammation plays an important role in albuminuria in type 2 diabetes mellitus (T2DM). The vitamin D receptor (VDR) has potent anti-inflammatory activities. Objective: To investigate the correlation between VDR expression and albuminuria in T2DM. Design/Setting/Patients: Renal biopsies from T2DM patients with albuminuria (n = 8) and nondiabetic subjects (n = 4) were compared for VDR expression by immunohistochemistry. Recruited T2DM patients (n = 242; estimated glomerular filtration rate > 60 mL/min/1.73 m2) were divided into three groups based on urinary albumin-to-creatinine ratio (uACR): normal albuminuria (uACR < 30 mg/g; n = 85), microalbuminuria (30 mg/g ≤ uACR < 300 mg/g; n = 84), and macroalbuminuria (uACR ≥ 300 mg/g; n = 73), with healthy individuals (n = 72) as controls. Peripheral blood mononuclear cells (PBMCs) from these subjects were analyzed for VDR mRNA (n = 314), TNF-α mRNA (n = 314), microRNA (miR)-346 (n = 120; 30 for each group), and VDR protein (n = 80; 20 for each group). PBMCs from randomly selected subjects (n = 6 for each group) were cultured ex vivo to evaluate the effect of TNF-α on miR-346 and VDR, and miR-346-mediated VDR suppression was further explored in HK2 cells. Results: VDR expression was down-regulated in PBMCs and renal tubular epithelial cells from T2DM patients with albuminuria. VDR mRNA and protein levels were both negatively correlated with uACR, and VDR mRNA was inversely correlated with TNF-α and miR-346 in PBMCs from T2DM patients. TNF-α reduced VDR while inducing miR-346 in cultured PBMCs. TNF-α suppressed VDR by up-regulating miR-346 in HK2 cells. Conclusions: VDR down-regulation in PBMCs is independently associated with the severity of albuminuria in T2DM. TNF-α suppression of VDR in PBMCs and HK2 cells is mediated by miR-346.
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Song, Lige, Garyfallia Papaioannou, Hengguang Zhao, Hilary F. Luderer, Christine Miller, Claudia Dall’Osso, Rosalynn M. Nazarian, Amy J. Wagers i Marie B. Demay. "The Vitamin D Receptor Regulates Tissue Resident Macrophage Response to Injury". Endocrinology 157, nr 10 (15.08.2016): 4066–75. http://dx.doi.org/10.1210/en.2016-1474.
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Ligand-dependent actions of the vitamin D receptor (VDR) play a pleiotropic role in the regulation of innate and adaptive immunity. The liganded VDR is required for recruitment of macrophages during the inflammatory phase of cutaneous wound healing. Although the number of macrophages in the granulation tissue 2 days after wounding is markedly reduced in VDR knockout (KO) compared with wild-type mice, VDR ablation does not alter macrophage polarization. Parabiosis studies demonstrate that circulatory chimerism with wild-type mice is unable to rescue the macrophage defect in the wounds of VDR KO mice and reveal that wound macrophages are of local origin, regardless of VDR status. Wound cytokine analyses demonstrated a decrease in macrophage colony-stimulating factor (M-CSF) protein levels in VDR KO mice. Consistent with this, induction of M-CSF gene expression by TGFβ and 1,25-dihydroxyvitamin D was impaired in dermal fibroblasts isolated from VDR KO mice. Because M-CSF is important for macrophage self-renewal, studies were performed to evaluate the response of tissue resident macrophages to this cytokine. A decrease in M-CSF induced proliferation and cyclin D1 expression was observed in peritoneal resident macrophages isolated from VDR KO mice, suggesting an intrinsic macrophage abnormality. Consistent with this, wound-healing assays in mice with macrophage-specific VDR ablation demonstrate that a normal wound microenvironment cannot compensate for the absence of the VDR in macrophages and thus confirm a critical role for the macrophage VDR in the inflammatory response to injury.
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Soldati, Laura, Donatella Adamo, Cristiana Bianchin, Teresa Arcidiacono, Annalisa Terranegra, Maria Luisa Bianchi, Stefano Mora, Daniele Cusi i Giuseppe Vezzoli. "Vitamin D Receptor mRNA Measured in Leukocytes with the TaqMan Fluorogenic Detection System: Effect of Calcitriol Administration". Clinical Chemistry 50, nr 8 (1.08.2004): 1315–21. http://dx.doi.org/10.1373/clinchem.2004.033126.
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Abstract Background: The aim of the present study was to investigate the interactions between the circulating concentrations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and the mRNA concentration of its specific nuclear receptor in human leukocytes. Methods: We measured vitamin D receptor (VDR) mRNA extracted from leukocytes by use of TaqMan fluorescence analysis applied to the reverse transcription-PCR (RT-PCR) technique in 16 volunteers before and after calcitriol administration. VDR mRNA was also measured in leukocytes from calcium-stone-formers (37 hypercalciuric and 34 normocalciuric patients). The relationship between VDR mRNA concentrations and genetic VDR polymorphisms was analyzed in these patients. Results: Imprecision (CV) of RT-PCR was 1.3% within assay (n = 10) and 1.7% between assays (n = 4). Oral 1,25(OH)2D3 increased mean (SE) serum 1,25(OH)2D3 1.6 (0.3)-fold and VDR mRNA 1.6 (0.1)-fold 8 h after administration. The maximum VDR mRNA was reached 3.6 (1.3) h after 1,25(OH)2D3 ingestion. No differences in leukocyte VDR mRNA concentrations were found between normocalciuric and hypercalciuric stone-formers in the absence of stimulation. Finally, no association was found between VDR mRNA concentrations and genetic VDR polymorphisms in stone-formers. Conclusions: The TaqMan RT-PCR assay is a rapid and accurate method to measure VDR mRNA, and leukocytes are a useful model to study VDR and 1,25(OH)2D3 interactions. In humans, VDR mRNA is increased by agonist 1,25(OH)2D3, a finding resembling previously reported results obtained in cellular and animal models.
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Correa, Pamela, Jonas Rastad, Peter Schwarz, Gunnar Westin, Andreas Kindmark, Ewa Lundgren, Göran Åkerström i Tobias Carling. "The Vitamin D Receptor (VDR) Start Codon Polymorphism in Primary Hyperparathyroidism and Parathyroid VDR Messenger Ribonucleic Acid Levels1". Journal of Clinical Endocrinology & Metabolism 84, nr 5 (1.05.1999): 1690–94. http://dx.doi.org/10.1210/jcem.84.5.5707.
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Vitamin D regulates parathyroid cell proliferation and secretion of PTH. Increased prevalence of the polymorphic vitamin D receptor (VDR) alleles b, a, and T has been reported in sporadic primary hyperparathyroidism (PHPT), suggesting that these genetic variants may predispose to the disease. Recently, another polymorphism in the VDR gene was related to bone mineral density, and this VDR-FokI polymorphism causes different lengths of the VDR, implying possible functional consequences. The VDR-FokI polymorphism was studied in 182 postmenopausal women with sporadic PHPT and in matched controls. No significant differences in distribution of the VDR-FokI genotypes could be detected between the groups, although there was a tendency toward overrepresentation of the F allele in the PHPT patients (P = 0.05). There were no significant associations with age, serum calcium, serum PTH, bone mineral density, or parathyroid tumor weight. The VDR genotypes were unrelated to VDR and PTH messenger ribonucleic acid levels in the parathyroid adenomas of 42 PHPT patients. In 23 PHPT patients, the Ca2+-PTH set-points were determined in vivo and were unrelated to the VDR alleles. We suggest that the VDR-FokI polymorphism has at most a minor pathogenic importance in the development of PHPT.
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Favus, M. J. "Hypercalciuria: lessons from studies of genetic hypercalciuric rats." Journal of the American Society of Nephrology 5, nr 5 (listopad 1994): S54. http://dx.doi.org/10.1681/asn.v55s54.
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Human idiopathic hypercalciuria (IH) is a common cause of hypercalciuria that contributes to calcium oxalate nephrolithiasis. The disorder is characterized by normocalcemia, increased intestinal Ca absorption, and normal or elevated circulating 1,25(OH)2D3. Intestinal Ca hyperabsorption, which is a source of excess urine Ca excretion, may result from either a primary increase in renal 1,25(OH)2D3 production; a primary, vitamin D-independent defect in enterocyte regulation of Ca transport; or a secondary increase in 1,25(OH)2D3 production in response to a defect in renal tubular Ca reabsorption. Breeding male and female Sprague Dawley rats with spontaneous hypercalciuria has resulted in offspring with hypercalciuria, increased intestinal Ca absorption, and normal serum 1,25(OH)2D3. In male IH rats, vitamin D receptor (VDR) content measured by saturation binding and western blotting revealed a twofold increase in VDR number in the duodenum, kidney cortex, and splenic monocytes. The molecular basis for the increase in VDR appears not to be due to increased VDR gene expression, but may result from increased efficiency of translation of the VDR message or prolongation of the half-life of VDR. Comparable migration of normal and IH intestinal VDR on western blots and of intestinal VDR mRNA on northern blots suggests that the abundant VDR in IH rat intestine is not a mutation of the wild-type VDR. These observations strongly suggest that, in IH rats, normal serum 1,25(OH)2D3 and increased VDR results in increased VDR-1,25(OH)2D3 complexes and enhanced biologic actions of 1,25(OH)2D3, including increased intestinal Ca transport. IH in rats may be the first genetic disorder due to a pathologic increase in the VDR.
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Prüfer, Kirsten, i Julia Barsony. "Retinoid X Receptor Dominates the Nuclear Import and Export of the Unliganded Vitamin D Receptor". Molecular Endocrinology 16, nr 8 (1.08.2002): 1738–51. http://dx.doi.org/10.1210/me.2001-0345.
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Abstract Liganded and unliganded vitamin D receptors (VDRs) carry out distinct functions; both types of functions require heterodimerization with retinoid X receptors (RXRs). Our recent studies with fluorescent protein chimeras of VDR and RXR, termed GFP-VDR, YFP-RXR, and RXR-BFP, indicated that RXR regulates VDR functions in part by regulating subcellular localization. Here we explored the mechanisms of this regulation. Photobleaching experiments demonstrated that YFP-RXR and both unliganded and liganded GFP-VDR shuttle constantly between nucleus and cytoplasm. To characterize RXR import, we identified a nuclear localization sequence (NLS) in the DNA-binding domain. Mutations in this NLS caused predominant cytoplasmic localization of nlsYFP-RXR and prevented transcriptional activity. The nlsRXR-BFP retained unliganded GFP-VDR in the cytoplasm and reduced baseline transcriptional activity. After calcitriol exposure, however, both GFP-VDR and nlsRXR-BFP entered the nucleus. We characterized receptor export rates and mechanisms using permeabilization experiments. Mutations in the calreticulin binding region slowed both GFP-VDR and YFP-RXR export. Coexpression of RXR-BFP slowed the export of unliganded GFP-VDR, whereas calcitriol treatment tripled the rate of GFP-VDR export. Treatment with leptomycin B, an inhibitor of CRM-1 receptor-mediated export, inhibited export of unliganded GFP-VDR but did not influence export of liganded GFP-VDR or YFP-RXR. Leptomycin B added before calcitriol similarly decreased hormone-induced luciferase activity but was ineffective when added subsequent to calcitriol. These results indicate that the unliganded and liganded VDR interact differently with the import and export receptors and with RXR. Most likely, the regulation of VDR nuclear import by RXR is essential for ligand-independent functions.
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Fernandez Lahore, Gonzalo, Bruno Raposo, Marie Lagerquist, Claes Ohlsson, Pierre Sabatier, Bingze Xu, Mike Aoun i in. "Vitamin D3 receptor polymorphisms regulate T cells and T cell-dependent inflammatory diseases". Proceedings of the National Academy of Sciences 117, nr 40 (21.09.2020): 24986–97. http://dx.doi.org/10.1073/pnas.2001966117.
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It has proven difficult to identify the underlying genes in complex autoimmune diseases. Here, we use forward genetics to identify polymorphisms in the vitamin D receptor gene (Vdr) promoter, controlling Vdr expression and T cell activation. We isolated these polymorphisms in a congenic mouse line, allowing us to study the immunomodulatory properties of VDR in a physiological context. Congenic mice overexpressed VDR selectively in T cells, and thus did not suffer from calcemic effects. VDR overexpression resulted in an enhanced antigen-specific T cell response and more severe autoimmune phenotypes. In contrast, vitamin D3-deficiency inhibited T cell responses and protected mice from developing autoimmune arthritis. Our observations are likely translatable to humans, as Vdr is overexpressed in rheumatic joints. Genetic control of VDR availability codetermines the proinflammatory behavior of T cells, suggesting that increased presence of VDR at the site of inflammation might limit the antiinflammatory properties of its ligand.
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Fudge, Neva J., i Christopher S. Kovacs. "Pregnancy Up-Regulates Intestinal Calcium Absorption and Skeletal Mineralization Independently of the Vitamin D Receptor". Endocrinology 151, nr 3 (5.01.2010): 886–95. http://dx.doi.org/10.1210/en.2009-1010.
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Without the vitamin D receptor (VDR), adult mammals develop reduced intestinal calcium absorption, rickets, and osteomalacia. Intestinal calcium absorption normally increases during pregnancy so that the mother can supply sufficient calcium to her fetuses. The maternal skeleton is rapidly resorbed during lactation to provide calcium needed for milk; that lost bone mineral content (BMC) is completely restored after weaning. We studied Vdr null mice to determine whether these adaptations during pregnancy and lactation require the VDR. Vdr nulls were severely rachitic at 10 wk of age on a normal diet. Pregnancy induced a 158% increase in Vdr null BMC to equal the pregnant wild-type (WT) value. Lactation caused BMC losses that were equal in Vdr nulls and WT. Vdr nulls recovered after weaning to a BMC 50% higher than before pregnancy and equal to WT. Additional analyses showed that during pregnancy, duodenal 45Ca absorption increased in Vdr nulls, secondary hyperparathyroidism lessened, bone turnover markers decreased, and osteoid became fully mineralized. A genome-wide microarray analysis of duodenal RNA found marked reduction of Trpv6 in Vdr nulls at baseline but a 13.5-fold increase during pregnancy. Calbindin D-9K (S100g) and Ca2+-ATPase (Pmca1) were not altered by pregnancy. Several other solute transporters increased during pregnancy in Vdr nulls. In summary, Vdr nulls adapt to pregnancy by up-regulating duodenal Trpv6 and intestinal 45Ca absorption, thereby enabling rapid normalization of BMC during pregnancy. These mice lactate normally and fully restore BMC after weaning. Therefore, VDR is not required for the skeletal adaptations during pregnancy, lactation, and after weaning.
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Inoue, Yoshio, Hiroko Segawa, Ichiro Kaneko, Setsuko Yamanaka, Kenichiro Kusano, Eri Kawakami, Junya Furutani i in. "Role of the vitamin D receptor in FGF23 action on phosphate metabolism". Biochemical Journal 390, nr 1 (9.08.2005): 325–31. http://dx.doi.org/10.1042/bj20041799.
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FGF23 (fibroblast growth factor 23) is a novel phosphaturic factor that influences vitamin D metabolism and renal re-absorption of Pi. The goal of the present study was to characterize the role of the VDR (vitamin D receptor) in FGF23 action using VDR(−/−) (VDR null) mice. Injection of FGF23M (naked DNA encoding the R179Q mutant of human FGF23) into VDR(−/−) and wildtype VDR(+/+) mice resulted in an elevation in serum FGF23 levels, but had no effect on serum calcium or parathyroid hormone levels. In contrast, injection of FGF23M resulted in significant decreases in serum Pi levels, renal Na/Pi co-transport activity and type II transporter protein levels in both groups when compared with controls injected with mock vector or with FGFWT (naked DNA encoding wild-type human FGF23). Injection of FGF23M resulted in a decrease in 25-hydroxyvitamin D 1α-hydroxylase mRNA levels in VDR(−/−) and VDR(+/+) mice, while 25-hydroxyvitamin D 24-hydroxylase mRNA levels were significantly increased in FGF23M-treated animals compared with mock vector control- or FGF23WT-treated animals. The degree of 24-hydroxylase induction by FGF23M was dependent on the VDR, since FGF23M significantly reduced the levels of serum 1,25(OH)2D3 [1,25-hydroxyvitamin D3] in VDR(+/+) mice, but not in VDR(−/−) mice. We conclude that FGF23 reduces renal Pi transport and 25-hydroxyvitamin D 1α-hydroxylase levels by a mechanism that is independent of the VDR. In contrast, the induction of 25-hydroxyvitamin D 24-hydroxylase and the reduction of serum 1,25(OH)2D3 levels induced by FGF23 are dependent on the VDR.
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Zinser, Glendon M., i JoEllen Welsh. "Accelerated Mammary Gland Development during Pregnancy and Delayed Postlactational Involution in Vitamin D3 Receptor Null Mice". Molecular Endocrinology 18, nr 9 (1.09.2004): 2208–23. http://dx.doi.org/10.1210/me.2003-0469.
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Abstract The vitamin D receptor (VDR) is present in mammary gland, and VDR ablation is associated with accelerated glandular development during puberty. VDR is a nuclear receptor whose ligand, 1,25-dihydroxyvitamin D [1,25-(OH)2D] is generated after metabolic activation of vitamin D by specific vitamin D hydroxylases. In these studies, we demonstrate that both the VDR and the vitamin D 1-α hydroxylase (CYP27B1), which produces 1,25-(OH)2D are present in mammary gland and dynamically regulated during pregnancy, lactation, and involution. Furthermore, we show that mice lacking VDR exhibit accelerated lobuloalveolar development and premature casein expression during pregnancy and delayed postlactational involution compared with mice with functional VDR. The delay in mammary gland regression after weaning of VDR knockout mice is associated with impaired apoptosis as demonstrated by reductions in terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling staining, caspase-3 activation and Bax induction. Under the conditions used in this study, VDR ablation was not associated with hypocalcemia, suggesting that altered mammary gland development in the absence of the VDR is not related to disturbances in calcium homeostasis. Furthermore, in the setting of normocalcemia, VDR ablation does not affect milk protein or calcium content. These studies suggest that the VDR contributes to mammary cell turnover during the reproductive cycle, and its effects may be mediated via both endocrine and autocrine signaling pathways. Unlike many mammary regulatory factors that exert transient, stage-specific effects, VDR signaling impacts on mammary gland biology during all phases of the reproductive cycle.
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Choi, June Young, Jin Wook Yi, Jun Hyup Lee, Ra-Yeong Song, Hyeongwon Yu, Hyungju Kwon, Young Jun Chai, Su-jin Kim i Kyu Eun Lee. "VDR mRNA overexpression is associated with worse prognostic factors in papillary thyroid carcinoma". Endocrine Connections 6, nr 3 (kwiecień 2017): 172–78. http://dx.doi.org/10.1530/ec-17-0001.
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The purpose of this study was to assess the relationship between vitamin D receptor gene (VDR) expression and prognostic factors in papillary thyroid cancer (PTC). mRNA sequencing and somatic mutation data from The Cancer Genome Atlas (TCGA) were analyzed. VDR mRNA expression was compared to clinicopathologic variables by linear regression. Tree-based classification was applied to find cutoff and patients were split into low and high VDR group. Logistic regression, Kaplan–Meier analysis, differentially expressed gene (DEG) test and pathway analysis were performed to assess the differences between two VDR groups. VDR mRNA expression was elevated in PTC than that in normal thyroid tissue. VDR expressions were high in classic and tall-cell variant PTC and lateral neck node metastasis was present. High VDR group was also associated with classic and tall cell subtype, AJCC stage IV and lower recurrence-free survival. DEG test reveals that 545 genes were upregulated in high VDR group. Thyroid cancer-related pathways were enriched in high VDR group in pathway analyses. VDR mRNA overexpression was correlated with worse prognostic factors such as subtypes of papillary thyroid carcinoma that are known to be worse prognosis, lateral neck node metastasis, advanced stage and recurrence-free survival.
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Martínez-Sena, Teresa, Polina Soluyanova, Carla Guzmán, José Manuel Valdivielso, José Vicente Castell i Ramiro Jover. "The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes". Biomolecules 10, nr 3 (24.03.2020): 493. http://dx.doi.org/10.3390/biom10030493.
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The vitamin D receptor (VDR) must be relevant to liver lipid metabolism because VDR deficient mice are protected from hepatosteatosis. Therefore, our objective was to define the role of VDR on the overall lipid metabolism in human hepatocytes. We developed an adenoviral vector for human VDR and performed transcriptomic and metabolomic analyses of cultured human hepatocytes upon VDR activation by vitamin D (VitD). Twenty percent of the VDR responsive genes were related to lipid metabolism, including MOGAT1, LPGAT1, AGPAT2, and DGAT1 (glycerolipid metabolism); CDS1, PCTP, and MAT1A (phospholipid metabolism); and FATP2, SLC6A12, and AQP3 (uptake of fatty acids, betaine, and glycerol, respectively). They were rapidly induced (4–6 h) upon VDR activation by 10 nM VitD or 100 µM lithocholic acid (LCA). Most of these genes were also upregulated by VDR/VitD in mouse livers in vivo. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) metabolomics demonstrated intracellular accumulation of triglycerides, with concomitant decreases in diglycerides and phosphatidates, at 8 and 24 h upon VDR activation. Significant alterations in phosphatidylcholines, increases in lyso-phosphatidylcholines and decreases in phosphatidylethanolamines and phosphatidylethanolamine plasmalogens were also observed. In conclusion, active VitD/VDR signaling in hepatocytes triggers an unanticipated coordinated gene response leading to triglyceride synthesis and to important perturbations in glycerolipids and phospholipids.
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Malloy, Peter J., i David Feldman. "Inactivation of the Human Vitamin D Receptor by Caspase-3". Endocrinology 150, nr 2 (1.02.2009): 679–86. http://dx.doi.org/10.1210/en.2008-1217.
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Calcitriol actions are mediated by the vitamin D receptor (VDR), a nuclear transcription factor of the steroid-retinoid-thyroid nuclear receptor gene superfamily. Calcitriol inhibits the growth of many cells including cancer cells by inducing cell cycle arrest. In some cancer cell lines, calcitriol also induces apoptosis. In the LNCaP prostate cancer cell line, induction of apoptosis and caspase-3/7 activities by staurosporine (STS) abolished [3H]1,25-dihydroxy vitamin D3 binding and VDR protein, suggesting that the VDR may be targeted for inactivation by caspases during apoptosis. A potential caspase-3 site (D195MMD198S) was identified in the human VDR ligand-binding domain. Mutations D195A, D198A, and S199A were generated in the putative capase-3 cleavage site. In transfected COS-7 cells, STS treatment resulted in the cleavage of the wild-type (WT) VDR and S199A mutant VDR but not the D195A or D198A mutants. In in vitro assays, the WT VDR and S199A mutant VDR were cleaved by caspase-3, although the D195A and D198A mutants were resistant to caspase-3. In vitro, the WT VDR was also cleaved by caspase-6 and caspase-7 and in extracts of STS-treated LNCaP cells. In STS-treated LNCaP cells and human skin fibroblasts, the proteasome inhibitor MG-132 protected the VDR caspase cleavage fragment from further degradation by the 26S proteasome. The rat VDR that does not contain the caspase-3 cleavage site was not cleaved in STS-treated COS-7 cells. In conclusion, our results demonstrate that the human VDR is a target of caspase-3 and suggest that activation of caspase-3 may limit VDR activity. The vitamin D receptor contains a caspase-3 cleavage site in the ligand-binding domain that can be cleaved by caspase-3 in vitro and in intact cells.
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Syamsuddin, Fatmawati Annisa, Mochammad Hatta, Firdaus Hamid, Rosdiana Natzir, Ahyar Ahmad i Burhanuddin Bahar. "The Analysis of Vitamin D Receptor Protein on Salmonella typhi infection in acute recurrent cases in endemic area in Eastern Indonesia". Biomedika 14, nr 2 (31.12.2021): 83–91. http://dx.doi.org/10.31001/biomedika.v14i2.1298.
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The host susceptibility mechanisms such as Vitamin D Receptor (VDR) is involved in the modulation of macrophage function and may possibly correlate with immunity disease including the severity of typhoid fever symptoms. The study aimed to assess the VDR Protein expression in the serums of recurrent acute typhoid fever (RATF) patients and compares it with typhoid fever (TF) patients, and healthy persons (HP). The study employed 30 RATF patients and 30 TF patients selected from primary health centres and hospitals in Eastern Indonesia as the endemic area. All the samples were obtained from several health centers in South Sulawesi, Southeast Sulawesi, Central Sulawesi, East Kalimantan and Papua and then collected in the sample bank Biology Laboratory of Molecular Immunology, Faculty of Medicine, Hasanuddin University. As a comparison, 30 samples of healthy persons were also selected from the Blood Transfusion Unit in Makassar, South Sulwesi Indonesia. The profile of VDR Protein was analyzed with Enzyme-linked Immunosorbent Assay (ELISA). VDR protein content data on RATF and TF were designed according to completely randomized design T test. Subsequently, it correlated to Pearson correlation to determine the interaction between Widal titre and VDR protein levels. A comparison between Widal titre and VDR Protein level was also made to identify the correlation. It was found that the mean of VDR protein expression of RATF was 13,44 ng/mL, the mean of VDR protein expression of TF was 24,88 ng/mL, and the mean of VDR protein expression of HP was 43,49 ng/mL. The correlation results between RATF-TF Widal titre and VDR protein level indicated a negative correlation with p-value of 0,004. There were significant differences in the VDR expression in the RATF, TF, and HP. RATF VDR expression lower than TF and HP and there was also a correlation between Widal titre with VDR Protein expression.
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Lu, Rong, Mei Shang, Yong-Guo Zhang, Yang Jiao, Yinglin Xia, Shari Garrett, Danika Bakke i in. "Lactic Acid Bacteria Isolated From Korean Kimchi Activate the Vitamin D Receptor–autophagy Signaling Pathways". Inflammatory Bowel Diseases 26, nr 8 (14.03.2020): 1199–211. http://dx.doi.org/10.1093/ibd/izaa049.
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Abstract Background Probiotic lactic acid bacteria (LAB) have been used in the anti-inflammation and anti-infection process of various diseases, including inflammatory bowel disease (IBD). Vitamin D receptor (VDR) plays an essential role in pathogenesis of IBD and infectious diseases. Previous studies have demonstrated that the human VDR gene is a key host factor to shape gut microbiome. Furthermore, intestinal epithelial VDR conditional knockout (VDRΔIEC) leads to dysbiosis. Low expressions of VDR is associated with impaired autophagy, accompanied by a reduction of ATG16L1 and LC3B. The purpose of this study is to investigate probiotic effects and mechanism in modulating the VDR-autophagy pathways. Methods Five LAB strains were isolated from Korean kimchi. Conditional medium (CM) from these strains was used to treat a human cell line HCT116 or intestinal organoids to measure the expression of VDR and autophagy. Mouse embryonic fibroblast (MEF) cells with or without VDR were used to investigate the dependence on the VDR signaling. To test the role of LAB in anti-inflammation, VDR+/+ organoids were treated with 121-CM before infection with Salmonella enterica serovar Enteritidis. In vivo, the role of LAB in regulating VDR-autophagy signaling was examined using LAB 121-CM orally administrated to VDRLoxp and VDRΔIEC mice. Results The LAB-CM-treated groups showed higher mRNA expression of VDR and its target genes cathelicidin compared with the control group. LAB treatment also enhanced expressions of Beclin-1 and ATG16L1 and changed the ratio of LC3B I and II, indicating the activation of autophagic responses. Furthermore, 121-CM treatment before Salmonella enterica serovar Enteritidis infection dramatically increased VDR and ATG16L1 and inhibited the inflammation. Administration of 121-CM to VDRLoxp and VDRΔIEC mice for 12 and 24 hours resulted in an increase of VDR and LC3B II:I ratio. Furthermore, we identified that probiotic proteins P40 and P75 in the LAB-CM contributed to the anti-inflammatory function by increasing VDR. Conclusions Probiotic LAB exert anti-inflammation activity and induces autophagy. These effects depend on the VDR expression. Our data highlight the beneficial effects of these 5 LAB strains isolated from food in anti-infection and anti-inflammation.
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Lee, Seong Min, Kathleen A. Bishop, Joseph J. Goellner, Charles A. O'Brien i J. Wesley Pike. "Mouse and Human BAC Transgenes Recapitulate Tissue-Specific Expression of the Vitamin D Receptor in Mice and Rescue the VDR-Null Phenotype". Endocrinology 155, nr 6 (1.06.2014): 2064–76. http://dx.doi.org/10.1210/en.2014-1107.
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The biological actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) are mediated by the vitamin D receptor (VDR), which is expressed in numerous target tissues in a cell type-selective manner. Recent studies using genomic analyses and recombineered bacterial artificial chromosomes (BACs) have defined the specific features of mouse and human VDR gene loci in vitro. In the current study, we introduced recombineered mouse and human VDR BACs as transgenes into mice and explored their expression capabilities in vivo. Individual transgenic mouse strains selectively expressed BAC-derived mouse or human VDR proteins in appropriate vitamin D target tissues, thereby recapitulating the tissue-specific expression of endogenous mouse VDR. The mouse VDR transgene was also regulated by 1,25(OH)2D3 and dibutyryl-cAMP. When crossed into a VDR-null mouse background, both transgenes restored wild-type basal as well as 1,25(OH)2D3-inducible gene expression patterns in the appropriate tissues. This maneuver resulted in the complete rescue of the aberrant phenotype noted in the VDR-null mouse, including systemic features associated with altered calcium and phosphorus homeostasis and disrupted production of parathyroid hormone and fibroblast growth factor 23, and abnormalities associated with the skeleton, kidney, parathyroid gland, and the skin. This study suggests that both mouse and human VDR transgenes are capable of recapitulating basal and regulated expression of the VDR in the appropriate mouse tissues and restore 1,25(OH)2D3 function. These results provide a baseline for further dissection of mechanisms integral to mouse and human VDR gene expression and offer the potential to explore the consequence of selective mutations in VDR proteins in vivo.
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Yasuda, Kaori, Miyu Nishikawa, Hiroki Mano, Masashi Takano, Atsushi Kittaka, Shinichi Ikushiro i Toshiyuki Sakaki. "Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery". International Journal of Molecular Sciences 22, nr 21 (31.10.2021): 11839. http://dx.doi.org/10.3390/ijms222111839.
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We have developed an in vitro system to easily examine the affinity for vitamin D receptor (VDR) and CYP24A1-mediated metabolism as two methods of assessing vitamin D derivatives. Vitamin D derivatives with high VDR affinity and resistance to CYP24A1-mediated metabolism could be good therapeutic agents. This system can effectively select vitamin D derivatives with these useful properties. We have also developed an in vivo system including a Cyp27b1-gene-deficient rat (a type I rickets model), a Vdr-gene-deficient rat (a type II rickets model), and a rat with a mutant Vdr (R270L) (another type II rickets model) using a genome editing method. For Cyp27b1-gene-deficient and Vdr mutant (R270L) rats, amelioration of rickets symptoms can be used as an index of the efficacy of vitamin D derivatives. Vdr-gene-deficient rats can be used to assess the activities of vitamin D derivatives specialized for actions not mediated by VDR. One of our original vitamin D derivatives, which displays high affinity VDR binding and resistance to CYP24A1-dependent metabolism, has shown good therapeutic effects in Vdr (R270L) rats, although further analysis is needed.
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Seth, Nitin, Denise Johnson, Brian Allen i Hussein A. Abdullah. "Upper limb robotic assessment: Pilot study comparing velocity dependent resistance in individuals with acquired brain injury to healthy controls". Journal of Rehabilitation and Assistive Technologies Engineering 7 (styczeń 2020): 205566832092953. http://dx.doi.org/10.1177/2055668320929535.
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Introduction Assessment of velocity dependent resistance (VDR) can provide insights into spasticity in individuals with upper motor neuron syndrome. This study investigates the relationship between Modified Ashworth scores and a biomechanical based representation of VDR using a rehabilitation robot. Comparisons in VDR are made for the upper limb (UL) between individuals with acquired brain injury and healthy controls for the para-sagittal plane. Methods The system manipulates the individual’s limb through five flexion and extension motions at increasing speeds to obtain force profiles at different velocities. An approximation of VDR is calculated and analyzed statistically against clinical scales and tested for interactions. Results All individuals (aged 18–65), including healthy controls exhibited VDR greater than 0 (P < 0.05). MAS scores were found to be related to VDR (P < 0.05) with an interaction found between MAS Bicep and Tricep scores (P < 0.01). Considering this interaction, evidence of differences in VDR were found between several neighboring assessment score combinations. Conclusion The robot can detect and quantify VDR that captures information relevant to UL spasticity. Results suggests a better categorization of VDR is possible and supports further development of rehabilitation robotics for assisting spasticity assessment.
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Guo, Jia, Congqun Lu, Fangxing Zhang, Haixia Yu, Mengwen Zhou, Meixia He, Chunyan Wang, Zhanzheng Zhao i Zhangsuo Liu. "VDR Activation Reduces Proteinuria and High-Glucose-Induced Injury of Kidneys and Podocytes by Regulating Wnt Signaling Pathway". Cellular Physiology and Biochemistry 43, nr 1 (2017): 39–51. http://dx.doi.org/10.1159/000480315.
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Background: Diabetic nephropathy (DN) is a major cause of end-stage renal disease and proteinuria is one of the most prominent clinical manifestations. The expression of Vitamin D receptor (VDR) in patients with chronic kidney diseases was decreased, while VDR agonists could partially alleviate the proteinuria of DN in animal models. The present study was designed to determine the expression of VDR in renal tissues and its relationship with proteinuria the diabetic model db/db mice. Methods: The regulation effects of VDR on the Wnt signaling pathway were analyzed using RNA interference and VDR agonist paricalcitol. Results: With the increase in age of the db/db mice, the VDR protein and mRNA levels in renal tissues were decreased, proteinuria increased, and the protein and mRNA levels of GSK-3β of and β-catenin increased. Paricalcitol treatment resulted in the up-regulation of VDR and down-regulation of GSK-3β and β-catenin, indicating that VDR had a regulatory effect on the Wnt signaling pathway. Conclusion: VDR activation could reduce proteinuria of DN mice and alleviate high-glucose-induced injury of kidneys and podocytes by regulating the key molecules of Wnt signaling pathway.
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Belorusova, Anna Y., Daniela Rovito, Yassmine Chebaro, Stefanie Doms, Lieve Verlinden, Annemieke Verstuyf, Daniel Metzger, Natacha Rochel i Gilles Laverny. "Vitamin D Analogs Bearing C-20 Modifications Stabilize the Agonistic Conformation of Non-Responsive Vitamin D Receptor Variants". International Journal of Molecular Sciences 23, nr 15 (30.07.2022): 8445. http://dx.doi.org/10.3390/ijms23158445.
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The Vitamin D receptor (VDR) plays a key role in calcium homeostasis, as well as in cell proliferation and differentiation. Among the large number of VDR ligands that have been developed, we have previously shown that BXL-62 and Gemini-72, two C-20-modified vitamin D analogs are highly potent VDR agonists. In this study, we show that both VDR ligands restore the transcriptional activities of VDR variants unresponsive to the natural ligand and identified in patients with rickets. The elucidated mechanisms of action underlying the activities of these C-20-modified analogs emphasize the mutual adaptation of the ligand and the VDR ligand-binding pocket.
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Luderer, Hilary F., Rosalynn M. Nazarian, Eric D. Zhu i Marie B. Demay. "Ligand-Dependent Actions of the Vitamin D Receptor Are Required for Activation of TGF-β Signaling during the Inflammatory Response to Cutaneous Injury". Endocrinology 154, nr 1 (1.01.2013): 16–24. http://dx.doi.org/10.1210/en.2012-1579.
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The vitamin D receptor (VDR) has both 1,25-dihydroxyvitamin D-dependent and -independent actions in the epidermis. Ligand-dependent actions of the VDR have been shown to promote keratinocyte differentiation and to regulate formation of the epidermal barrier. In contrast, the actions of the VDR that regulate postmorphogenic hair cycling do not require 1,25-dihydroxyvitamin D. The VDR also has immunomodulatory actions that are dependent on its ligand, 1,25-dihydroxyvitamin D. To determine whether the ligand-dependent or -independent actions of the VDR regulate the inflammatory response to cutaneous injury, studies were performed in control, VDR knockout, and vitamin D-deficient mice. These investigations demonstrate that absence of receptor or ligand impairs the dermal response to cutaneous injury. Although neutrophil recruitment is not affected, the absence of VDR signaling leads to defects in macrophage recruitment and granulation tissue formation. Studies performed to identify the molecular basis for this phenotype demonstrate that absence of the VDR, or its ligand, impairs TGF-β signaling in the dermis, characterized by decreased expression of monocyte chemotactic protein-1 and reduced phosphorylation of phosphorylated Smad-3 as well as attenuated phosphorylated Smad-3 phosphorylation in response to TGF-β in primary dermal fibroblasts lacking the VDR. Thus, these data demonstrate that the liganded VDR interacts with the TGF-β signaling pathway to promote the normal inflammatory response to cutaneous injury.