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Bouloukaki I, Christodoulakis A, Tsiligianni I. Vitamin D deficiency and its potential associations on the health status of older patients with chronic obstructive pulmonary disease in rural Crete, Greece: A cross-sectional study. Clin Nutr ESPEN 2025; 67:665-672. [PMID: 40287065 DOI: 10.1016/j.clnesp.2025.04.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 03/26/2025] [Accepted: 04/15/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND & AIMS While low vitamin D levels are common in Chronic Obstructive Pulmonary Disease (COPD) and have been associated with various adverse COPD-related outcomes, data on vitamin D status in rural COPD cohorts is limited. Therefore, the present study aimed to assess the prevalence of Vitamin D deficiency among patients with COPD living in rural areas and explore its potential association on the overall health status. METHODS This cross-sectional study included 138 participants >40 years with COPD from the prospective "COlaborative care vs usual CARE in primary care patients with COPD" (COCARE) study. Sociodemographic characteristics, medical history, patient's health-related quality of life (HRQoL) with the COPD Assessment Test (CAT), fatigue with the Fatigue Severity Scale (FSS), phycological parameters with Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7), sleep disorders with the COPD and Asthma Sleep Impact Scale (CASIS), Athens Insomnia Scale (AIS) and the Epworth Sleepiness Scale (ESS) were collected. Vitamin D deficiency was defined as levels of 25-hydroxy (OH)-Vitamin D below 20 ng/mL. Multiple logistic regression analysis was conducted to test for associations of Vitamin D deficiency with CAT, FSS, PHQ-9, GAD-7, CASIS, AIS, and ESS, adjusting for age, gender, smoking status, comorbidities, and seasonality. RESULTS Most of the participants were male (70 %) with a mean age of 68 ± 9 years and a mean Body Mass Index (BMI) of 30 ± 6 kg/m2. Moreover, 33 % of the participants had Vitamin D deficiency. Vitamin D deficiency increased the odds for worse HRQoL (CAT≥10 OR: 2.3, CI: 0.9-6.4, p = 0.008), greater fatigue severity (FSS, OR: 1.2, CI: 0.4-3.1, p = 0.756), more depressive (PHQ-9≥5, OR: 2.9, CI: 1.1-7.4, p = 0.024), anxiety (GAD-7, OR: 0.8, CI: 0.3-2.1, p = 0.592) and insomnia symptoms (AIS score OR: 1.1, CI: 0.7-5, p = 0.29), excessive daytime sleepiness (ESS, OR: 1.1, CI: 0.7-5, p = 0.29), and lower sleep quality (CASIS OR: 2.5, CI: 0.9-6.5, p = 0.006). CONCLUSION In conclusion, our findings indicate that Vitamin D deficiency is positively associated with numerous negative health outcomes of patients with COPD, including worse HRQoL, fatigue, depression, anxiety and sleep disorders. However, further research is needed to determine the role of Vitamin D in the health status of these patients.
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Affiliation(s)
- Izolde Bouloukaki
- Department of Social Medicine, School of Medicine, University of Crete, 71500 Heraklion, Greece.
| | - Antonios Christodoulakis
- Department of Social Medicine, School of Medicine, University of Crete, 71500 Heraklion, Greece; Department of Nursing, School of Health Sciences, Hellenic Mediterranean University, 71410 Heraklion, Greece.
| | - Ioanna Tsiligianni
- Department of Social Medicine, School of Medicine, University of Crete, 71500 Heraklion, Greece.
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Bartolomeo N, Pederzolli M, Palombella S, Fonteyne P, Suanno G, Tilaro G, de Pretis S, Borgo F, Bertuzzi F, Senni C, De Micheli M, Bandello F, Ferrari G. The effects of Vitamin D on Keratoconus progression. Am J Ophthalmol 2025:S0002-9394(25)00186-2. [PMID: 40245974 DOI: 10.1016/j.ajo.2025.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 04/03/2025] [Accepted: 04/07/2025] [Indexed: 04/19/2025]
Abstract
PURPOSE The aim of this study was to assess whether Vitamin D (Vit D) supplementation affects local disease progression, as well as systemic inflammation, collagen degradation, and oxidative stress in adolescents affected by Keratoconus (KC) and Vit D deficiency. DESIGN Prospective, interventional single-center study. SUBJECTS Forty patients (age range, 12.2-19.9) presenting with both KC and Vit D insufficiency (<30 ng/mL) were included in the study. METHODS Vit D was prescribed for 6 months as per standard of care. Follow-up visits were scheduled for 12 months. Each visit included the measurement of best spectacle-corrected visual acuity (BSCVA) , maximal keratometry (Kmax) , and thinnest corneal thickness (TCT) . Blood samples were collected at month 0 (M0) and month 6 (M6) to measure Vit D levels and systemic biomarkers of inflammation, collagen degradation, and oxidative stress by ELISA or RT-PCR; full RNA sequencing was performed on 20 patients at M0 and M6. MAIN OUTCOME MEASURES The primary outcome of the study was the percentage of patients with a Kmax progression less than 1 diopter (D) throughout the entire study (i.e.: stable patients) . RESULTS 65% of patients remained stable (75% of eyes) after 12 months. Specifically, BSCVA, Kmax, and TCT rates remained stable during the 12-month observational period. ELISA performed on blood plasma showed that Vit D upregulated the expression of VDBP. QPCR performed on peripheral leukocytes showed an increase in the expression of VDR and CD14 with no changes in the principal enzymes involved in Vit D activation/deactivation. ELISA and qPCR showed the modulation of collagen degradation and collagen crosslinking. Subgroup analysis with RNA sequencing showed differential response to Vit D treatment. Responder patients showed downregulation in inflammatory and platelet activation pathways, and upregulation of proteoglycan metabolism/biosynthesis enrichment. CONCLUSIONS Our findings support the hypothesis that Vit D supplementation can affect KC progression in adolescent patients with Vit D insufficiency possibly through the modulation of systemic inflammation, inhibition of collagen degradation and promotion of proteoglycan synthesis. Our results strongly suggest that KC may be the ocular manifestation of a systemic disorder.
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Affiliation(s)
- Nicolò Bartolomeo
- Eye Repair Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Matteo Pederzolli
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Silvia Palombella
- Eye Repair Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Philippe Fonteyne
- Eye Repair Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giuseppe Suanno
- Eye Repair Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Gianluca Tilaro
- Eye Repair Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano de Pretis
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Francesca Borgo
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Federico Bertuzzi
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Carlotta Senni
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Francesco Bandello
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Giulio Ferrari
- Eye Repair Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
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Gao F, Guan C, Cheng N, Liu Y, Wu Y, Shi B, Huang J, Li S, Tong Y, Gao Y, Liu J, Wang C, Zhang C. Design, synthesis, and anti-liver fibrosis activity of novel non-steroidal vitamin D receptor agonists based on open-ring steroid scaffold. Eur J Med Chem 2025; 286:117250. [PMID: 39827488 DOI: 10.1016/j.ejmech.2025.117250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 01/05/2025] [Accepted: 01/05/2025] [Indexed: 01/22/2025]
Abstract
Vitamin D receptor (VDR) has emerged as a crucial target for the treatment of hepatic fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) components leading to impaired liver function. Activation of VDR has been shown to inhibit the transformation of hepatic stellate cells (HSCs), which play a key role in the development of liver fibrosis, thus reducing ECM production. In this study, a series of 37 non-steroidal VDR agonists with novel scaffold were designed and synthesized utilizing the scaffold hopping strategy. Over one-third of these compounds demonstrated significant VDR affinity and agonistic activity. Among them, compound E15 exhibited the highest VDR agonistic activity, showing promising results in vitro by effectively inhibiting HSC activation. Further in vivo assessments of E15 in a carbon tetrachloride-induced murine model of liver fibrosis demonstrated significant anti-fibrotic activity. Histological analyses revealed a reduction in lesions, inflammatory cell infiltration, and collagen deposition. Concurrently, blood biochemical assays indicated decreased hepatic fibrosis markers and improved serum liver function indices. Notably, E15 achieved these therapeutic effects without inducing hypercalcemia, a common adverse effect associated with VDR agonists such as calcipotriol. These findings underscore the potential of E15 as a potent and safe therapeutic agent for the treatment of liver fibrosis.
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Affiliation(s)
- Fei Gao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Chun Guan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Nuo Cheng
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yichen Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yue Wu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Bingyue Shi
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Jiayi Huang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Sitong Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yu Tong
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yi Gao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Jiayi Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Cong Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China.
| | - Can Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, 211198, PR China.
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Yoon G, Puentes R, Tran J, Multani A, Cobo ER. The role of cathelicidins in neutrophil biology. J Leukoc Biol 2024; 116:689-705. [PMID: 38758953 DOI: 10.1093/jleuko/qiae112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/14/2024] [Accepted: 04/25/2024] [Indexed: 05/19/2024] Open
Abstract
Despite their relatively short lifespan, neutrophils are tasked with counteracting pathogens through various functions, including phagocytosis, production of reactive oxygen species, neutrophil extracellular traps (NETs), and host defense peptides. Regarding the latter, small cationic cathelicidins present a conundrum in neutrophil function. Although primarily recognized as microbicides with an ability to provoke pores in microbial cell walls, the ability of cathelicidin to modulate key neutrophil functions is also of great importance, including the release of chemoattractants, cytokines, and reactive oxygen species, plus prolonging neutrophil lifespan. Cumulative evidence indicates a less recognized role of cathelicidin as an "immunomodulator"; however, this term is not always explicit, and its relevance in neutrophil responses during infection and inflammation is seldom discussed. This review compiles and discusses studies of how neutrophils use cathelicidin to respond to infections, while also acknowledging immunomodulatory aspects of cathelicidin through potential crosstalk between sources of the peptide.
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Affiliation(s)
- Grace Yoon
- Faculty of Veterinary Medicine, University of Calgary, HSC 1871, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
| | - Rodrigo Puentes
- Faculty of Veterinary Medicine, University of Calgary, HSC 1871, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
| | - Jacquelyn Tran
- Faculty of Veterinary Medicine, University of Calgary, HSC 1871, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
| | - Anmol Multani
- Faculty of Veterinary Medicine, University of Calgary, HSC 1871, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
| | - Eduardo R Cobo
- Faculty of Veterinary Medicine, University of Calgary, HSC 1871, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
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Sarmadi F, Gao Z, Su J, Barbier C, Artusa P, Bijian K, Gleason JL, White JH. Bifunctionality and Antitumor Efficacy of ZG-126, a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule. J Med Chem 2024; 67:11182-11196. [PMID: 38906533 PMCID: PMC11249012 DOI: 10.1021/acs.jmedchem.4c00706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/23/2024]
Abstract
Analogues of hormonal vitamin D, 1,25-dihydroxyvitamin D (1,25D), signal through the nuclear vitamin D receptor (VDR). They have potential in combination therapies with other anticancer agents such as histone deacetylase inhibitors (HDACi's). Here, we characterize the ZG series of hybrid compounds that combine HDACi within the backbone of a VDR agonist. All display improved solubility, with ZG-126 being the most robustly bifunctional molecule in multiple cell lines. ZG-126 is well tolerated and strongly induces VDR target gene expression in vivo at therapeutic doses. Its antitumor efficacy is superior to 1,25D and the HDACi SAHA, separately or together, in mouse models of melanoma and triple-negative breast cancer (TNBC). Notably, ZG-126 treatment reduces metastases almost 4-fold in an aggressive TNBC model. ZG-126 also reduces total macrophage infiltration and the proportion of immunosuppressive M2-polarized macrophages in TNBC tumors by 2-fold. ZG-126 thus represents a bifunctional and efficacious anticancer agent with improved physicochemical properties.
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Affiliation(s)
- Fatemeh Sarmadi
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
| | - Zhizhong Gao
- Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC H3A 0B8, Canada
| | - Jie Su
- Segal Cancer Center and Lady Davis Institute for Medical Research, 3755 Cote Ste-Catherine, Montreal, QC H3T 1E2, Canada
| | - Camille Barbier
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
| | - Patricio Artusa
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
| | - Krikor Bijian
- Segal Cancer Center and Lady Davis Institute for Medical Research, 3755 Cote Ste-Catherine, Montreal, QC H3T 1E2, Canada
| | - James L Gleason
- Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC H3A 0B8, Canada
| | - John H White
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
- Department of Medicine, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada
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Figgins EL, Arora P, Gao D, Porcelli E, Ahmed R, Daep CA, Keele G, Ryan LK, Diamond G. Enhancement of innate immunity in gingival epithelial cells by vitamin D and HDAC inhibitors. FRONTIERS IN ORAL HEALTH 2024; 5:1378566. [PMID: 38567313 PMCID: PMC10986367 DOI: 10.3389/froh.2024.1378566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 03/05/2024] [Indexed: 04/04/2024] Open
Abstract
Introduction The human host defense peptide LL-37 is a component of the innate immune defense mechanisms of the oral cavity against colonization by microbes associated with periodontal disease. We have previously shown that the active form of vitamin D, 1,25(OH)2D3, can induce the expression of LL-37 in gingival epithelial cells (GEC), and prevent the invasion and growth of periopathogenic bacteria in these cells. Further, experimental vitamin D deficiency resulted in increased gingival inflammation and alveolar bone loss. Epidemiological studies have shown associations between vitamin D deficiency and periodontal disease in humans, suggesting application of vitamin D could be a useful therapeutic approach. Further, since we have shown the local activation of vitamin D by enzymes expressed in the GEC, we hypothesized that we could observe this enhancement with the stable, and inexpensive inactive form of vitamin D, which could be further increased with epigenetic regulators. Methods We treated 3-dimensional primary cultures of GEC topically with the inactive form of vitamin D, in the presence and absence of selected histone deacetylase (HDAC) inhibitors. LL-37 mRNA levels were quantified by quantitative RT-PCR, and inhibition of invasion of bacteria was measured by fluorescence microscopy. Results Vitamin D treatment led to an induction of LL-37 mRNA levels, as well as an inhibition of pro-inflammatory cytokine secretion. This effect was further enhanced by HDAC inhibitors, most strongly when the HDAC inhibitor, phenyl butyrate (PBA) was combined with Vitamin D3. This was observed both in solution and in a prototype gel formulation using sodium butyrate. Finally, this combination treatment led to an increase in the antimicrobial activity against infection by Porphyromonas gingivalis and Filifactor alocis, bacteria associated with periodontal lesions, as well as herpes simplex virus, which has also been shown to be associated with periodontal lesions. Conclusions Our results demonstrate that a combination of inactive vitamin D and sodium butyrate could be developed as a safe treatment for periodontal disease.
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Affiliation(s)
- Erika L. Figgins
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, FL, United States
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, United States
| | - Payal Arora
- Global Technology Center, Colgate Palmolive Company, Piscataway, NJ, United States
| | - Denny Gao
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, United States
| | - Emily Porcelli
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, FL, United States
| | - Rabab Ahmed
- Global Technology Center, Colgate Palmolive Company, Piscataway, NJ, United States
| | - Carlo Amorin Daep
- Global Technology Center, Colgate Palmolive Company, Piscataway, NJ, United States
| | - Garrett Keele
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, United States
| | - Lisa K. Ryan
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, United States
- Division of Infectious Disease and Global Medicine, Department of Medicine, University of Florida College of Medicine, Gainesville, FL, United States
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY, United States
| | - Gill Diamond
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, FL, United States
- Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, United States
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY, United States
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Kumar NB. Contemporary Strategies for Clinical Chemoprevention of Localized Prostate Cancer. Cancer Control 2024; 31:10732748241302863. [PMID: 39573923 PMCID: PMC11583501 DOI: 10.1177/10732748241302863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2024] Open
Abstract
Prostate cancer (PCa) is the most common cancer among men in the United States and the second leading cause of cancer-related deaths. Metastatic castration-resistant PCa is still a fatal disease. On the other hand, between 2016 and 2020, about 70% of PCa cases were diagnosed at a localized stage. Evolving data demonstrates that men with low-grade cancers treated with definitive therapies may now be exposed to morbidities of overtreatment and poor quality of life, with little or no benefit in terms of cancer specific mortality. Active surveillance (AS) is thus the recommended management strategy for men with low-grade disease. Although this subgroup of men have reported anxiety during the AS period, they account to be highly motivated to make positive lifestyle changes to further reduce their risk of PCa progression, underscoring the urgent need to identify novel strategies for preventing progression of localized PCa to metastatic disease through pharmacologic means, an approach termed chemoprevention. Although several promising agents and approaches have been examined over the past 2 decades, currently, there are several limitations in the approach used to systematically examine agents for chemoprevention targeting men on AS. The goal of this review is to summarize the current agents and approaches evaluated, targeting men on AS, recognize the gaps, and identify a contemporary and comprehensive path forward. Results of these studies may inform the development of phase III clinical trials and ultimately provide a strategy for clinical chemoprevention in men on AS, for whom, currently, there are no options for reducing the risk of progression to metastatic disease.
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Affiliation(s)
- Nagi B Kumar
- Cancer Epidemiology Program, Population Sciences Division, Genitourinary Oncology and Breast Oncology Departments, Department of Oncologic Sciences, Moffitt Cancer Center, University of South Florida College of Medicine, Tampa, FL, USA
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Wimalawansa SJ. Infections and Autoimmunity-The Immune System and Vitamin D: A Systematic Review. Nutrients 2023; 15:3842. [PMID: 37686873 PMCID: PMC10490553 DOI: 10.3390/nu15173842] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/24/2023] [Accepted: 08/29/2023] [Indexed: 09/10/2023] Open
Abstract
Both 25-autoimmunity and(25(OH)D: calcifediol) and its active form, 1,25-dihydroxyvitamin D (1,25(OH)2D: calcitriol), play critical roles in protecting humans from invasive pathogens, reducing risks of autoimmunity, and maintaining health. Conversely, low 25(OH)D status increases susceptibility to infections and developing autoimmunity. This systematic review examines vitamin D's mechanisms and effects on enhancing innate and acquired immunity against microbes and preventing autoimmunity. The study evaluated the quality of evidence regarding biology, physiology, and aspects of human health on vitamin D related to infections and autoimmunity in peer-reviewed journal articles published in English. The search and analyses followed PRISMA guidelines. Data strongly suggested that maintaining serum 25(OH)D concentrations of more than 50 ng/mL is associated with significant risk reduction from viral and bacterial infections, sepsis, and autoimmunity. Most adequately powered, well-designed, randomized controlled trials with sufficient duration supported substantial benefits of vitamin D. Virtually all studies that failed to conclude benefits or were ambiguous had major study design errors. Treatment of vitamin D deficiency costs less than 0.01% of the cost of investigation of worsening comorbidities associated with hypovitaminosis D. Despite cost-benefits, the prevalence of vitamin D deficiency remains high worldwide. This was clear among those who died from COVID-19 in 2020/21-most had severe vitamin D deficiency. Yet, the lack of direction from health agencies and insurance companies on using vitamin D as an adjunct therapy is astonishing. Data confirmed that keeping an individual's serum 25(OH)D concentrations above 50 ng/mL (125 nmol/L) (and above 40 ng/mL in the population) reduces risks from community outbreaks, sepsis, and autoimmune disorders. Maintaining such concentrations in 97.5% of people is achievable through daily safe sun exposure (except in countries far from the equator during winter) or taking between 5000 and 8000 IU vitamin D supplements daily (average dose, for non-obese adults, ~70 to 90 IU/kg body weight). Those with gastrointestinal malabsorption, obesity, or on medications that increase the catabolism of vitamin D and a few other specific disorders require much higher intake. This systematic review evaluates non-classical actions of vitamin D, with particular emphasis on infection and autoimmunity related to the immune system.
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Affiliation(s)
- Sunil J Wimalawansa
- Medicine, Endocrinology & Nutrition, Cardiometabolic & Endocrine Institute, North Brunswick, NJ 08902, USA
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Feng H, Chen Y, Xiong X, Xu Q, Zhang Z, Xi Q, Wu Y, Lu Y. Association of nutrients intake during pregnancy with the risk of allergic disease in offspring: a meta-analysis of prospective cohort studies. FOOD SCIENCE AND HUMAN WELLNESS 2023. [DOI: 10.1016/j.fshw.2022.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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10
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Lu EMC. The role of vitamin D in periodontal health and disease. J Periodontal Res 2023; 58:213-224. [PMID: 36537578 DOI: 10.1111/jre.13083] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/20/2022] [Accepted: 11/27/2022] [Indexed: 12/24/2022]
Abstract
Vitamin D plays an essential role in calcium and bone metabolism, immune regulation and possesses profound anti-inflammatory effects. Evidence suggests that low serum vitamin D is associated with increased severity of periodontitis, a chronic inflammatory condition characterised by destruction of the supporting tissues surrounding the tooth, which has several shared risk factors with other chronic non-communicable diseases. The biological functions of vitamin D are mediated by its strong anti-microbial, anti-inflammatory, and host modulatory properties. Experimental periodontitis models involving targeted deletion of 1α-hydroxylase, the enzyme responsible for the conversion of inactive substrate to active 1,25(OH)2 D3 (calcitriol), showed augmented alveolar bone loss and gingival inflammation. Vitamin D receptor (VDR) gene polymorphisms have also been associated with increased severity of periodontitis. Thus, the involvement of vitamin D in the pathogenesis of periodontitis is biological plausible. Clinical studies have consistently demonstrated an inverse relationship between serum 25OHD3 and periodontal disease inflammation. However, due to the paucity of well-designed longitudinal studies, there is less support for the impact of vitamin D status on periodontal disease progression and tooth loss. The evidence emphasises the importance of maintaining vitamin D sufficiency in supporting periodontal health. This review aims to first examine the biological mechanisms by which vitamin D might influence the pathogenesis of periodontal disease and second, discuss the clinical evidence which implicate the role of vitamin D in periodontal disease.
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Affiliation(s)
- Emily Ming-Chieh Lu
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, Guy's Hospital, London, UK
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Tang J, Gu L, Luo J, Luo H, Zeng Q, Jiang Y. 1,25(OH) 2D 3 promotes the elimination of Klebsiella pneumoniae infection by inducing autophagy through the VDR-ATG16L1 pathway. Int Immunopharmacol 2022; 112:109266. [PMID: 36174418 DOI: 10.1016/j.intimp.2022.109266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 09/08/2022] [Accepted: 09/16/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Previous studies have shown that vitamin D has regulatory functions in both innate and adaptive immune responses, indicating that it can perform essential roles in host resistance to pathogen infections. This study aimed to verify its effects on Klebsiella pneumoniae (Kp) infection and explore the underlying mechanisms. METHODS THP-1-derived macrophages were infected with Kp and then incubated with 1,25(OH)2D3. Autophagy induced by 1,25(OH)2D3 was investigated by western blotting and immunofluorescence. Real-time PCR (qPCR) was performed to determine the expression of inflammatory mediators. Baf A1 and 3-MA were used to inhibit autophagy. The intracellular killing of Kp was measured using qPCR and colony-forming unit assays. RNA interference assays were used to silence VDR or ATG16L1. The lungs of C57BL/6 mice were infected with Kp via intratracheal instillation, and the established pneumonia models were used for in vivo validation experiments. RESULTS Treatment with 1,25(OH)2D3 enhanced the bactericidal activity of macrophages and concomitantly reduced the expression of the pro-inflammatory mediators TNF-α and IL-6. Kp infection led to a lower expression level of VDR in macrophages than in the control, whereas co-treatment with 1,25(OH)2D3 up-regulated VDR expression and robustly induced autophagy via the VDR signaling pathway. Silencing ATG16L1 significantly counteracted autophagy induced by 1,25(OH)2D3 in Kp-infected macrophages. Furthermore, we found that when autophagy activity was diminished by ATG16L1 siRNA or blocked by Baf A1, the ability of 1,25(OH)2D3 to promote macrophages to eliminate Kp infection was obviously impaired, as were its anti-inflammatory effects. These protective efficacies of 1,25(OH)2D3 against Kp infection were also validated in vivo using a mouse model of pneumonia. CONCLUSIONS The present study demonstrated the protective features of 1,25(OH)2D3 in macrophages against Kp infection and may provide evidence for further exploration of its potential as an adjunctive therapy agent for the treatment of bacterial infections.
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Affiliation(s)
- Jinhui Tang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, and State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
| | - Liwen Gu
- Department of Emergency Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Jieyu Luo
- Department of Emergency Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Haihua Luo
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, and State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
| | - Qingli Zeng
- Department of Emergency Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
| | - Yong Jiang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, and State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China.
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12
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Barbier C, Mansour A, Ismailova A, Sarmadi F, Scarlata DA, Bouttier M, Zeitouni C, Wang C, Gleason JL, White JH. Molecular mechanisms of bifunctional vitamin D receptor agonist-histone deacetylase inhibitor hybrid molecules in triple-negative breast cancer. Sci Rep 2022; 12:6745. [PMID: 35468986 PMCID: PMC9038752 DOI: 10.1038/s41598-022-10740-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 03/29/2022] [Indexed: 11/24/2022] Open
Abstract
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), and its analogues signal through the nuclear vitamin D receptor (VDR), a ligand-regulated transcription factor, and have been extensively investigated as anticancer agents. 1,25D and its analogs have potential in combination therapies because they exhibit synergistic activities with other anticancer agents such as histone deacetylase inhibitors (HDACi). We have developed a series of hybrid molecules that combine HDACi within the backbone of a VDR agonist and thus represent fully integrated bifunctional molecules. They exhibit anti-tumor efficacy in reducing tumor growth and metastases in an aggressive model of triple-negative breast cancer. However, their solubility is limited by their hydrophobic diarylpentane cores. Our goals here were two-fold: (1) to improve the solubility of hybrids by introducing nitrogen into diarylpentane cores, and (2) to investigate the molecular mechanisms underlying their anti-tumor efficacy by performing comparative gene expression profiling studies with 1,25D and the potent HDACi suberoylanilide hydroxamic acid (SAHA). We found that substituting aryl with pyrydyl rings did not sacrifice bifunctionality and modestly improved solubility. Notably, one compound, AM-193, displayed enhanced potency as a VDR agonist and in cellular assays of cytotoxicity. RNAseq studies in triple negative breast cancer cells revealed that gene expression profiles of hybrids were very similar to that of 1,25D, as was that observed with 1,25D and SAHA combined. The effects of SAHA alone on gene expression were limited and distinct from those 1,25D or hybrids. The combined results suggest that efficacy of hybrids arises from targeting HDACs that do not have a direct role in gene regulation. Moreover, pathways analysis revealed that hybrids regulate numerous genes controlling immune cell infiltration into tumors and suppress the expression of several secreted molecules that promote breast cancer growth and metastasis.
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Affiliation(s)
- Camille Barbier
- Departments of Physiology, McGill University, Montreal, QC, Canada
| | - Ali Mansour
- Departments of Chemistry, McGill University, Montreal, QC, Canada
| | - Aiten Ismailova
- Departments of Physiology, McGill University, Montreal, QC, Canada
| | - Fatemeh Sarmadi
- Departments of Physiology, McGill University, Montreal, QC, Canada
| | - David A Scarlata
- Departments of Chemistry, McGill University, Montreal, QC, Canada
| | | | - Camille Zeitouni
- Departments of Physiology, McGill University, Montreal, QC, Canada
| | - Catherine Wang
- Departments of Physiology, McGill University, Montreal, QC, Canada
| | - James L Gleason
- Departments of Chemistry, McGill University, Montreal, QC, Canada.
| | - John H White
- Departments of Physiology, McGill University, Montreal, QC, Canada.
- Departments of Medicine, McGill University, Montreal, QC, Canada.
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13
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Gkotinakou IM, Mylonis I, Tsakalof A. Vitamin D and Hypoxia: Points of Interplay in Cancer. Cancers (Basel) 2022; 14:cancers14071791. [PMID: 35406562 PMCID: PMC8997790 DOI: 10.3390/cancers14071791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 11/16/2022] Open
Abstract
Vitamin D is a hormone that, through its action, elicits a broad spectrum of physiological responses ranging from classic to nonclassical actions such as bone morphogenesis and immune function. In parallel, many studies describe the antiproliferative, proapoptotic, antiangiogenic effects of calcitriol (the active hormonal form) that contribute to its anticancer activity. Additionally, epidemiological data signify the inverse correlation between vitamin D levels and cancer risk. On the contrary, tumors possess several adaptive mechanisms that enable them to evade the anticancer effects of calcitriol. Such maladaptive processes are often a characteristic of the cancer microenvironment, which in solid tumors is frequently hypoxic and elicits the overexpression of Hypoxia-Inducible Factors (HIFs). HIF-mediated signaling not only contributes to cancer cell survival and proliferation but also confers resistance to anticancer agents. Taking into consideration that calcitriol intertwines with signaling events elicited by the hypoxic status cells, this review examines their interplay in cellular signaling to give the opportunity to better understand their relationship in cancer development and their prospect for the treatment of cancer.
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Affiliation(s)
| | - Ilias Mylonis
- Correspondence: (I.M.); (A.T.); Tel.: +30-2410-685578 (I.M. & A.T)
| | - Andreas Tsakalof
- Correspondence: (I.M.); (A.T.); Tel.: +30-2410-685578 (I.M. & A.T)
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14
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Yu T, Ye DM. The epidemiologic factors associated with breast density: A review. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2022; 27:53. [PMID: 36092490 PMCID: PMC9450246 DOI: 10.4103/jrms.jrms_962_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/14/2022] [Accepted: 01/26/2022] [Indexed: 11/04/2022]
Abstract
In recent years, some studies have evaluated the epidemiologic factors associated with breast density. However, the variant and inconsistent results exist. In addition, breast density has been proved to be a significant risk factor associated with breast cancer. Our review summarized the published studies and emphasized the crucial factors including epidemiological factors associated with breast density. In addition, we also discussed the potential reasons for the discrepant results with risk factors. To decrease the incidence and mortality rates for breast cancer, in clinical practice, breast density should be included for clinical risk models in addition to epidemiological factors, and physicians should get more concentrate on those women with risk factors and provide risk-based breast cancer screening regimens.
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15
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Rahman KL, Akhter QS, Rahman MS, Rahman R, Rahman (Sami) S, Mukta FY, Sarker S. Genetic variations of CYP2R1 (rs10741657) in Bangladeshi adults with low serum 25(OH)D level-A pilot study. PLoS One 2021; 16:e0260298. [PMID: 34797893 PMCID: PMC8604301 DOI: 10.1371/journal.pone.0260298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 11/05/2021] [Indexed: 11/19/2022] Open
Abstract
Background Some studies revealed that despite having sufficient sun exposure and dietary supply, the level of serum 25(OH)D in Bangladeshi adults is lower than its normal range. Genetic pattern of an individual is also an essential factor that regulates the level of serum 25(OH)D. However, the genetic variations of CYP2R1 (rs10741657) and their association with low serum 25(OH)D level in Bangladeshi adults are yet to be explored. Objective This study was conducted to determine the frequency of variants of rs10741657 of CYP2R1 gene and its association with low serum 25(OH)D level among Bangladeshi adults. Method This pilot study was conducted among thirty individuals with low serum 25(OH)D level as the study population and ten subjects with sufficient serum 25(OH)D level as controls based on the inclusion and exclusion criteria. Genetic analysis of rs10741657 of CYP2R1 including primer designing, DNA extraction, PCR of target region with purification and Sanger sequencing of the PCR products were done accordingly. For statistical analysis, One-way ANOVA followed by LSD test, Freeman-Halton extension of Fisher’s exact test, Chi-square test (χ2) test and unpaired student t-test were performed. Results In this study, genetic variants of CYP2R1 (rs10741657) among the study population were genotype GG (63.30%), GA (30%) and AA (6.7%). Minor allele frequency of the study population was 0.217. The association between GG and GA genotypes of CYP2R1 (rs10741657) with low serum 25(OH)D level among the study population was found and it was statistically significant. Statistically significant differences were also observed between the genotypes and alleles of the study population and controls. Conclusions The presence of ‘GG’ and ‘GA’ genotypes of rs1041657 in CYP2R1 gene is associated with low serum 25(OH)D level among Bangladeshi adults in this pilot study.
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Affiliation(s)
- Kazi Lutfar Rahman
- Covid Dedicated RT-PCR Lab, Kurmitola General Hospital, Dhaka, Bangladesh
- * E-mail:
| | - Qazi Shamima Akhter
- Department of Physiology, Dhaka Medical College and Hospital, Dhaka, Bangladesh
| | - Md. Sayedur Rahman
- Department of Pharmacology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Ridwana Rahman
- Department of Physiology, Dhaka Medical College and Hospital, Dhaka, Bangladesh
| | | | | | - Sudipta Sarker
- Charbaria Union Health and Family Welfare Centre, Barishal Sadar, Barishal, Bangladesh
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Khriesha A, Bustanji Y, Abu Farha R, Al-Abbasi R, Abu-Irmaileh B. Evaluation of the potential anticancer activity of different vitamin D metabolites on colorectal and breast cancer cell lines. Horm Mol Biol Clin Investig 2021; 42:3-9. [PMID: 33544505 DOI: 10.1515/hmbci-2020-0045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 01/14/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Vitamin D is very important for calcium and mineral metabolism, and many hypotheses appear to link sunlight exposure with cancer risk and prognosis. As many studies supported the antitumor effect of vitamin D we wanted to investigate the potential effect of multiple vitamin D metabolites. METHODS This study compared the anticancer effect of three inactive forms of vitamin D3 which are; cholecalciferol, alfacalcidol, and calcifediol on two human cancer cell lines colorectal cancer (CaCo II) and breast cancer (MCF-7). All were examined after 24, 48, and 72 h continuous exposure using a colorimetric assay (MTT) seeded in 96-multiwell plates. Doxorubicin anticancer used as a standard agent for comparison, while normal skin fibroblast cells (HDFa) was used as our negative control. IC50 values were calculated as indication of antitumor effect. RESULTS Broad-spectrum of cytotoxicity with IC50 values ranging from 4 to 200 μM were found. Alfacalcidol was the most potent cytotoxic agents on colorectal cancer (CaCo II) and breast cancer (MCF-7) compared to cholecalciferol, and calcifediol. Both, alfacalcidol and calcifediol were more cytotoxic than cholecalciferol on the tested cell lines as they are partially active metabolites. Breast cancer (MCF-7) was the most sensitive to all metabolites at all-time intervals with the best IC50 values of 4.35 μM ± 1.06 after 72 h continuous exposure of alfacalcidol. CONCLUSIONS Vitamin D metabolites are a potential option for cancer treatment along with or an alternative to chemo-therapeutics although extensive preclinical studies are required to prove this effect.
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Affiliation(s)
- Abeer Khriesha
- Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan, Amman, Jordan
| | - Yasser Bustanji
- Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan, Amman, Jordan
| | - Rana Abu Farha
- Department of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Applied Science Private University, Amman, Jordan
| | - Reem Al-Abbasi
- Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan, Amman, Jordan
| | - Bashaer Abu-Irmaileh
- Hamdi Mango Center for Academic Research, The University of Jordan, Amman, Jordan
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17
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Dimitrov V, Barbier C, Ismailova A, Wang Y, Dmowski K, Salehi-Tabar R, Memari B, Groulx-Boivin E, White JH. Vitamin D-regulated Gene Expression Profiles: Species-specificity and Cell-specific Effects on Metabolism and Immunity. Endocrinology 2021; 162:bqaa218. [PMID: 33249469 PMCID: PMC7751191 DOI: 10.1210/endocr/bqaa218] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Indexed: 12/19/2022]
Abstract
Vitamin D has pleiotropic physiological actions including immune system regulation, in addition to its classical role in calcium homeostasis. Hormonal 1,25-dihydroxyvitamin D (1,25D) signals through the nuclear vitamin D receptor, and large-scale expression profiling has provided numerous insights into its diverse physiological roles. To obtain a comprehensive picture of vitamin D signaling, we analyzed raw data from 94 (80 human, 14 mouse) expression profiles of genes regulated by 1,25D or its analogs. This identified several thousand distinct genes directly or indirectly up- or downregulated in a highly cell-specific manner in human cells using a 1.5-fold cut-off. There was significant overlap of biological processes regulated in human and mouse but minimal intersection between genes regulated in each species. Disease ontology clustering confirmed roles for 1,25D in immune homeostasis in several human cell types, and analysis of canonical pathways revealed novel and cell-specific roles of vitamin D in innate immunity. This included cell-specific regulation of several components of Nucleotide-binding Oligomerization Domain-like (NOD-like) pattern recognition receptor signaling, and metabolic events controlling innate immune responses. Notably, 1,25D selectively enhanced catabolism of branched-chain amino acids (BCAAs) in monocytic cells. BCAA levels regulate the major metabolic kinase mammalian Target of Rapamycin (mTOR), and pretreatment with 1,25D suppressed BCAA-dependent activation of mTOR signaling. Furthermore, ablation of BCAT1 expression in monocytic cells blocked 1,25D-induced increases in autophagy marker LAMP1. In conclusion, the data generated represents a powerful tool to further understand the diverse physiological roles of vitamin D signaling and provides multiple insights into mechanisms of innate immune regulation by 1,25D.
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Affiliation(s)
- Vassil Dimitrov
- Department of Physiology, McGill University, Montreal QC, Canada
| | - Camille Barbier
- Department of Physiology, McGill University, Montreal QC, Canada
| | - Aiten Ismailova
- Department of Physiology, McGill University, Montreal QC, Canada
| | - Yifei Wang
- Department of Physiology, McGill University, Montreal QC, Canada
| | - Katy Dmowski
- Department of Physiology, McGill University, Montreal QC, Canada
| | | | - Babak Memari
- Department of Physiology, McGill University, Montreal QC, Canada
| | | | - John H White
- Department of Physiology, McGill University, Montreal QC, Canada
- Department of Medicine, McGill University, Montreal QC, Canada
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18
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Mäkitie A, Tuokkola I, Laurell G, Mäkitie O, Olsen K, Takes RP, Florek E, Szyfter K, Sier CFM, Ferlito A. Vitamin D in Head and Neck Cancer: a Systematic Review. Curr Oncol Rep 2020; 23:5. [PMID: 33216252 PMCID: PMC7679336 DOI: 10.1007/s11912-020-00996-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/05/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW Observational studies have shown that serum 25-OH vitamin D [25(OH)D] is inversely associated with overall cancer risk in many malignancies. We performed a systematic literature review to determine whether vitamin D deficiency is related to head and neck cancer (HNC) etiology and outcome. RECENT FINDINGS The search yielded five prospective studies reporting 25(OH)D levels prior to cancer diagnosis and their effect on the risk of HNC. Eight studies were cross-sectional or case-control studies, in which 25(OH)D levels were only measured after cancer diagnosis. Two studies found an inverse association between 25(OH)D level and HNC risk, while two other prospective cohort studies demonstrated no connection between 25(OH)D and HNC risk. Several studies reported cancer patients to have significantly lower 25(OH)D levels than controls. Associations between 25(OH)D and prognosis and mortality were variable. The link between vitamin D and HNC has so far only been investigated in a few observational, prospective, and case-control studies. Vitamin D deficiency may be more common in HNC patients than in the healthy population. There is no evidence for a causal relationship. Further studies are needed to evaluate whether low 25(OH)D concentrations play a role in the development or outcome of HNCs.
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Affiliation(s)
- Antti Mäkitie
- Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, University of Helsinki, P. O. Box 263, FI-00029 HUS, Helsinki, Finland. .,Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. .,Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet and Karolinska Hospital, Stockholm, Sweden.
| | - Iida Tuokkola
- Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, University of Helsinki, P. O. Box 263, FI-00029 HUS, Helsinki, Finland
| | - Göran Laurell
- Department of Surgical Sciences, ENT, Uppsala University, SE-75185, Uppsala, Sweden
| | - Outi Mäkitie
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Kerry Olsen
- Department of Otorhinolaryngology, Mayo Clinic, Rochester, MN, USA
| | - Robert P Takes
- Department of Otolaryngology-Head and Neck Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ewa Florek
- Laboratory of Environmental Research, Department of Toxicology, Poznan University of Medical Sciences, Poznan, Poland
| | - Krzysztof Szyfter
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Cornelis F M Sier
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Alfio Ferlito
- Coordinator of International Head and Neck Scientific Group, Padua, Italy
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Siddiqui M, Manansala JS, Abdulrahman HA, Nasrallah GK, Smatti MK, Younes N, Althani AA, Yassine HM. Immune Modulatory Effects of Vitamin D on Viral Infections. Nutrients 2020; 12:E2879. [PMID: 32967126 PMCID: PMC7551809 DOI: 10.3390/nu12092879] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/29/2020] [Accepted: 08/31/2020] [Indexed: 02/07/2023] Open
Abstract
Viral infections have been a cause of mortality for several centuries and continue to endanger the lives of many, specifically of the younger population. Vitamin D has long been recognized as a crucial element to the skeletal system in the human body. Recent evidence has indicated that vitamin D also plays an essential role in the immune response against viral infections and suggested that vitamin D deficiency increases susceptibility to viral infections as well as the risk of recurrent infections. For instance, low serum vitamin D levels were linked to increased occurrence of high burdens viral diseases such as hepatitis, influenza, Covid-19, and AIDS. As immune cells in infected patients are responsive to the ameliorative effects of vitamin D, the beneficial effects of supplementing vitamin D-deficient individuals with an infectious disease may extend beyond the impact on bone and calcium homeostasis. Even though numerous studies have highlighted the effect of vitamin D on the immune cells, vitamin D's antiviral mechanism has not been fully established. This paper reviews the recent mechanisms by which vitamin D regulates the immune system, both innate and adaptive systems, and reflects on the link between serum vitamin D levels and viral infections.
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Affiliation(s)
- Maheen Siddiqui
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
| | - Judhell S. Manansala
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
| | - Hana A. Abdulrahman
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
| | - Gheyath K. Nasrallah
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
| | - Maria K. Smatti
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
| | - Nadin Younes
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
| | - Asmaa A. Althani
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
| | - Hadi M. Yassine
- College of Health Science-QU Health, Qatar University, Doha 2713, Qatar; (M.S.); (J.S.M.); (G.K.N.); (N.Y.); (A.A.A.)
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (H.A.A.); (M.K.S.)
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Vaidya GN, Rana P, Venkatesh A, Chatterjee DR, Contractor D, Satpute DP, Nagpure M, Jain A, Kumar D. Paradigm shift of "classical" HDAC inhibitors to "hybrid" HDAC inhibitors in therapeutic interventions. Eur J Med Chem 2020; 209:112844. [PMID: 33143937 DOI: 10.1016/j.ejmech.2020.112844] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/10/2020] [Accepted: 09/10/2020] [Indexed: 02/07/2023]
Abstract
'Epigenetic' regulation of genes via post-translational modulation of proteins is the current mainstay approach for the disease therapies, particularly explored in the Histone Deacetylase (HDAC) class of enzymes. Mainly sight saw in cancer chemotherapeutics, HDAC inhibitors have also found a promising role in other diseases (neurodegenerative disorders, cardiovascular diseases, and viral infections) and successfully entered in various combination therapies (pre-clinical/clinical stages). The prevalent flexibility in the structural design of HDAC inhibitors makes them easily tuneable to merge with other pharmacophore modules for generating multi-targeted single hybrids as a novel tactic to overcome drawbacks of polypharmacy. Herein, we reviewed the putative role of prevalent HDAC hybrids inhibitors in the current and prospective stage as a translational approach to overcome the limitations of the existing conventional drug candidates (parent molecule) when used either alone (drug resistance, solubility issues, adverse side effects, selectivity profile) or in combination (pharmacokinetic interactions, patient compliance) for treating various diseases.
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Affiliation(s)
- Gargi Nikhil Vaidya
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Pooja Rana
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Ashwini Venkatesh
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Deep Rohan Chatterjee
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Darshan Contractor
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Dinesh Parshuram Satpute
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Mithilesh Nagpure
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India
| | - Alok Jain
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India; Department of Bio-Engineering, Birla Institute of Technology, Mesra, Ranchi, India.
| | - Dinesh Kumar
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, Gandhinagar, 382355, Gujarat, India.
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Bayirli BA, Öztürk A, Avci B. Serum vitamin D concentration is associated with antimicrobial peptide level in periodontal diseases. Arch Oral Biol 2020; 117:104827. [DOI: 10.1016/j.archoralbio.2020.104827] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/03/2020] [Accepted: 07/07/2020] [Indexed: 12/01/2022]
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Zhang J, Deng G. Protective effects of increased outdoor time against myopia: a review. J Int Med Res 2020; 48:300060519893866. [PMID: 31854216 PMCID: PMC7607527 DOI: 10.1177/0300060519893866] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/19/2019] [Indexed: 12/27/2022] Open
Abstract
Myopia has become a major cause for concern globally, particularly in East Asian countries. The increasing prevalence of myopia has been associated with a high socioeconomic burden owing to severe ocular complications that may occur with progressive myopia. There is an urgent need to identify effective and safe measures to address the growing number of people with myopia in the general population. Among the numerous strategies implemented to slow the progression of myopia, longer time spent outdoors has come to be recognized as a protective factor against this disorder. Although our understanding of the protective effects of outdoor time has increased in the past decade, considerably more research is needed to understand the mechanisms of action. Here, we summarize the main potential factors associated with the protective effects against myopia of increased outdoor time, namely, exposure to elevated levels and shorter wavelengths of light, and increased dopamine and vitamin D levels. In this review, we aimed to identify safe and effective therapeutic interventions to prevent myopia-related complications and vision loss.
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Affiliation(s)
- Jun Zhang
- Department of Ophthalmology, The Third People’s Hospital of Changzhou, Changzhou, Jiangsu, China
| | - Guohua Deng
- Department of Ophthalmology, The Third People’s Hospital of Changzhou, Changzhou, Jiangsu, China
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Malliaraki N, Lakiotaki K, Vamvoukaki R, Notas G, Tsamardinos I, Kampa M, Castanas E. Translating vitamin D transcriptomics to clinical evidence: Analysis of data in asthma and chronic obstructive pulmonary disease, followed by clinical data meta-analysis. J Steroid Biochem Mol Biol 2020; 197:105505. [PMID: 31669573 DOI: 10.1016/j.jsbmb.2019.105505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 09/29/2019] [Accepted: 10/22/2019] [Indexed: 12/29/2022]
Abstract
Vitamin D (VitD) continues to trigger intense scientific controversy, regarding both its bi ological targets and its supplementation doses and regimens. In an effort to resolve this dispute, we mapped VitD transcriptome-wide events in humans, in order to unveil shared patterns or mechanisms with diverse pathologies/tissue profiles and reveal causal effects between VitD actions and specific human diseases, using a recently developed bioinformatics methodology. Using the similarities in analyzed transcriptome data (c-SKL method), we validated our methodology with osteoporosis as an example and further analyzed two other strong hits, specifically chronic obstructive pulmonary disease (COPD) and asthma. The latter revealed no impact of VitD on known molecular pathways. In accordance to this finding, review and meta-analysis of published data, based on an objective measure (Forced Expiratory Volume at one second, FEV1%) did not further reveal any significant effect of VitD on the objective amelioration of either condition. This study may, therefore, be regarded as the first one to explore, in an objective, unbiased and unsupervised manner, the impact of VitD levels and/or interventions in a number of human pathologies.
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Affiliation(s)
- Niki Malliaraki
- Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, Heraklion, Greece; Laboratory of Clinical Chemistry/Biochemistry, University Hospital, Heraklion, Greece
| | - Kleanthi Lakiotaki
- Department of Computer Science, University of Crete, School of Sciences, Heraklion, Greece
| | - Rodanthi Vamvoukaki
- Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, Heraklion, Greece
| | - George Notas
- Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, Heraklion, Greece
| | - Ioannis Tsamardinos
- Department of Computer Science, University of Crete, School of Sciences, Heraklion, Greece; Gnosis Data Analysis PC, Heraklion, Greece
| | - Marilena Kampa
- Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, Heraklion, Greece
| | - Elias Castanas
- Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, Heraklion, Greece.
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Principi N, Esposito S. Vitamin D Deficiency During Pregnancy and Autism Spectrum Disorders Development. Front Psychiatry 2020; 10:987. [PMID: 32082196 PMCID: PMC7006052 DOI: 10.3389/fpsyt.2019.00987] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 12/12/2019] [Indexed: 12/18/2022] Open
Abstract
Autism spectrum disorder is a neurodevelopmental disorder characterized by reduced social interactions, impaired communications, and stereotypic and repetitive behavior with different degrees of severity. The etiology of autism spectrum disorder is unknown, although the interaction of genetic and environmental factors is believed to play a fundamental role in the process. The main aim of this narrative review is to discuss the current knowledge about the interrelationships between vitamin D deficiency during pregnancy and autism spectrum disorder development. Literature analysis showed that vitamin D supplementation during pregnancy plays a role in conditioning the development and function of the nervous system. Studies carried out in vitro and in experimental animals have shown that vitamin D deficiency can be associated with structural and functional abnormalities of the nervous system that can be observed in autism spectrum disorder patients. Moreover, it has been reported that vitamin D deficiency during pregnancy could be a risk factor for autism spectrum disorder development in the offspring, that children with autism spectrum disorder have significantly lower serum levels of vitamin D than normal children and that supplementation of vitamin D in autism spectrum disorder children is associated with a reduction in psychiatric manifestations. However, the data currently available do not adequately support the hypothesis that vitamin D may be a factor which contribute to the etiology of autism spectrum disorder. The effects of vitamin D supplementation during pregnancy should be better studied to establish whether and when fetal vulnerability is highest and if vitamin D supplementation is able to reduce the risk of structural and functional alterations of the nervous system and autism spectrum disorder development. The role of vitamin D after birth must be better defined to evaluate if vitamin D administration is potentially effective in reducing autism spectrum disorder manifestations.
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Affiliation(s)
| | - Susanna Esposito
- Pediatric Clinic, Pietro Barilla Children's Hospital, Department of Medicine and Surgery, University of Parma, Parma, Italy
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Munkhbayarlakh S, Kao HF, Hou YI, Tuvshintur N, Bayar-Ulzii B, Narantsetseg L, Wang JY, Hsin Wu LS. Vitamin D plasma concentration and vitamin D receptor genetic variants confer risk of asthma: A comparison study of Taiwanese and Mongolian populations. World Allergy Organ J 2019; 12:100076. [PMID: 31719947 PMCID: PMC6838943 DOI: 10.1016/j.waojou.2019.100076] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 09/08/2019] [Accepted: 09/23/2019] [Indexed: 01/16/2023] Open
Abstract
Background Recent reports have suggested that lower vitamin D serum levels are associated with susceptibility to and severity of asthma in different white populations, which may be due to a lack of sunlight exposure, genetic polymorphism of vitamin D pathway genes, and dietary intake. We investigated the associations between vitamin D concentration, genetic polymorphism of the vitamin D receptor (VDR), and asthma traits in Mongolian and Taiwanese populations that inhabited two different geographical areas. Methods In total, 328 Han Taiwanese subjects and 381 Mongolian subjects were enrolled, and their vitamin D serum levels assayed. Genomic DNA of 178 Han Taiwanese subjects and 90 Mongolian subjects was obtained from blood samples. Single-nucleotide polymorphisms (SNPs) of VDR, ApaI (rs7975232), TaqI (rs731236), BsmI (rs1544410) and FokI (rs2228570), were selected for genotyping. Logistic regression analyses were performed to detect an association between allergic asthma status and the interaction of the VDR SNP and serum vitamin D concentration in the case–control samples. Results We observed a significantly lower vitamin D level in the Mongolian subjects as compared with the Taiwanese population. In particular, in the population under 14 years of age, the serum vitamin D level was significantly higher in the Taiwanese population, in both non-asthmatic and asthmatic subjects, than in the Mongolian non-asthmatic and asthmatic subjects, respectively (P < 0.01). Moreover, the vitamin D level in the asthmatic children was significantly lower than that in the non-asthmatic children in both the Taiwanese and Mongolian populations (P < 0.01, respectively). Furthermore, we found that the rs2228570 genotype (OR, 3.763) of the VDR SNP and the vitamin D concentration (lower than 40 ng/ml, OR: 38.938) both contribute to increased susceptibility to bronchial asthma. Conclusion Our results demonstrated an association between vitamin D concentration and the risk of asthma in two populations of differing ethnicity living in different geographical areas. This information implies a potential role of vitamin D in the prevention and treatment of asthma worldwide.
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Affiliation(s)
- Sonomjamts Munkhbayarlakh
- Department of Pulmonology and Allergology, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Hui-Fang Kao
- Department of Nursing, National Tainan Junior College of Nursing, Tainan, Taiwan.,Allergy and Clinical Immunology Research (ACIR) Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yung-I Hou
- Allergy and Clinical Immunology Research (ACIR) Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Graduate Institute of Medical Sciences, China Medical University, Taichung, Taiwan
| | - Naidansuren Tuvshintur
- Department of Pulmonology and Allergology, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Batmunkh Bayar-Ulzii
- Department of Pulmonology and Allergology, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Logii Narantsetseg
- Department of Pulmonology and Allergology, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Jiu Yao Wang
- Graduate Institute of Medical Sciences, China Medical University, Taichung, Taiwan
| | - Lawrence Shih Hsin Wu
- Allergy and Clinical Immunology Research (ACIR) Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Graduate Institute of Medical Sciences, China Medical University, Taichung, Taiwan
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Bobek J, Oralova V, Lesot H, Kratochvilova A, Doubek J, Matalova E. Onset of calciotropic receptors during the initiation of mandibular/alveolar bone formation. Ann Anat 2019; 227:151427. [PMID: 31614180 DOI: 10.1016/j.aanat.2019.151427] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 09/23/2019] [Accepted: 09/25/2019] [Indexed: 12/11/2022]
Abstract
Mandibular/alveolar (m/a) bone, as a component of the periodontal apparatus, allows for the proper tooth anchorage and function of dentition. Bone formation around the tooth germs starts prenatally and, in the mouse model, the mesenchymal condensation turns into a complex vascularized bone (containing osteo-blasts, -cytes, -clasts) within only two days. This very short but critical period is characterized by synchronized cellular and molecular events. The m/a bone, as others, is subjected to endocrine regulations. This not only requires vasculature to allow the circulation of active molecules (ligands), but also the expression of corresponding cell receptors to define target tissues. This contribution aimed at following the dynamics of calciotropic receptors´ expression during morphological transformation of a mesenchymal condensation into the initial m/a bone structure. Receptors for all three calciotropic systemic regulators: parathormone, calcitonin and activated vitamin D (calcitriol), were localized on serial histological sections using immunochemistry and their relative expression was quantified by q-PCR. The onset of calciotropic receptors was followed along with bone cell differentiation (as checked using osteocalcin, sclerostin, RANK and TRAP) and vascularization (CD31) during mouse prenatal/embryonic (E) days 13-15 and 18. Additionally, the timing of calciotropic receptor appearance was compared with that of estrogen receptors (ESR1, ESR2). PTH receptor (PTH1r) appeared in the bone already at E13, when the first osteocalcin-positive cells were detected within the mesenchymal condensation forming the bone anlage. At this stage, blood vessels were only lining the condensation. At E14, the osteoblasts started to express the receptor for activated vitamin D (VDR). At this stage, the vasculature just penetrated the forming bone. On the same day, the first TRAP-positive (but not yet multinucleated) osteoclastic cells were identified. However, calcitonin receptor was detected only one day later. The first Sost-positive osteocytes, present at E15, were PTH1r and VDR positive. ESR1 almost copied the expression pattern of PTH1r, and ESR2 appearance was similar with VDR with a significant increase between E15 and E18. This report focuses on the in vivo situation and links morphological transformation of the mesenchymal cell condensation into a bone structure with dynamics of cell differentiation/maturation, vascularization and onset of receptors for calciotropic endocrine signalling in developing m/a bone.
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Affiliation(s)
- Jan Bobek
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetics, Academy of Sciences, Brno, Czech Republic
| | - Veronika Oralova
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetics, Academy of Sciences, Brno, Czech Republic
| | - Herve Lesot
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetics, Academy of Sciences, Brno, Czech Republic; Department of Biology, University of Ghent, Ghent, Belgium
| | - Adela Kratochvilova
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetics, Academy of Sciences, Brno, Czech Republic
| | - Jaroslav Doubek
- Department of Physiology, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
| | - Eva Matalova
- Laboratory of Odontogenesis and Osteogenesis, Institute of Animal Physiology and Genetics, Academy of Sciences, Brno, Czech Republic; Department of Physiology, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic.
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Vitamin D treatment of peripheral blood mononuclear cells modulated immune activation and reduced susceptibility to HIV-1 infection of CD4+ T lymphocytes. PLoS One 2019; 14:e0222878. [PMID: 31550271 PMCID: PMC6759150 DOI: 10.1371/journal.pone.0222878] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 09/09/2019] [Indexed: 01/16/2023] Open
Abstract
INTRODUCTION Mucosal immune activation, in the context of sexual transmission of HIV-1 infection, is crucial, as the increased presence of activated T cells enhance susceptibility to infection. In this regard, it has been proposed that immunomodulatory compounds capable of modulating immune activation, such as Vitamin D (VitD) may reduce HIV-1 transmission and might be used as a safe and cost-effective strategy for prevention. Considering this, we examined the in vitro effect of the treatment of peripheral blood mononuclear cells (PBMCs) with the active form of VitD, calcitriol, on cellular activation, function and susceptibility of CD4+ T cells to HIV-1 infection. METHODS We treated PBMCs from healthy HIV unexposed individuals (Co-HC) and frequently exposed, HIV-1 seronegative individuals (HESNs) from Colombia and from healthy non-exposed individuals from Canada (Ca-HC) with calcitriol and performed in vitro HIV-1 infection assays using X4- and R5-tropic HIV-1 strains respectively. In addition, we evaluated the activation and function of T cells and the expression of viral co-receptors, and select antiviral genes following calcitriol treatment. RESULTS Calcitriol reduced the frequency of infected CD4+ T cells and the number of viral particles per cell, for both, X4- and R5-tropic viruses tested in the Co-HC and the Ca-HC, respectively, but not in HESNs. Furthermore, in the Co-HC, calcitriol reduced the frequency of polyclonally activated T cells expressing the activation markers HLA-DR and CD38, and those HLA-DR+CD38-, whereas increased the subpopulation HLA-DR-CD38+. Calcitriol treatment also decreased production of granzyme, IL-2 and MIP-1β by T cells and increased the transcriptional expression of the inhibitor of NF-kB and the antiviral genes cathelicidin (CAMP) and APOBEC3G in PBMCs from Co-HC. CONCLUSION Our in vitro findings suggest that VitD treatment could reduce HIV-1 transmission through a specific modulation of the activation levels and function of T cells, and the production of antiviral factors. In conclusion, VitD remains as an interesting potential strategy to prevent HIV-1 transmission that should be further explored.
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Kaykhaei MA, Khodadoost M, Dashipour AR, Haidari Z, Karimkoshteh A, Sandoughi M. Baseline levels determine magnitude of increment in 25 hydroxy vitamin D following vitamin D3 prescription in healthy subjects. Endocrine 2019; 64:378-383. [PMID: 30877526 DOI: 10.1007/s12020-019-01881-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 02/22/2019] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Vitamin D deficiency is a major health problem which affects about one billion people in the world. Although, vitamin D supplementation is recommended as standard treatment of vitamin D deficiency, there are controversies on dose response relationship. In this regard, the present study aimed to determine the impact of vitamin D3 supplement on raising of serum 25 hydroxyvitamin D[25(OH)D] in healthy subjects with varying degrees of vitamin D deficiency. MATERIALS AND METHODS In this clinical trial 114 subjects with varying degrees of vitamin D deficiency were entered and divided into three groups: serum levels of 25(OH) D less than 10 ng/ml, 10-20 ng/ml, and 20-30 ng/ml. All of the participants were given 50,000 units vitamin D3 per week for 8 weeks, thereafter, changes in serum levels of vitamin D and PTH were evaluated at week twelve. The results were analyzed using SPSS version 16 and P < 0.05 was considered to be significant. RESULTS Of the 114 vitamin D deficient subjects, serum level of vitamin D was below 10 ng/ml in 22 persons (19.3%), 10-20 ng/ml in 52 persons (45.6%) and 20-30 ng/ml in 40 persons (35.1%). Following vitamin D prescription all people with varying degrees of vitamin D deficiency obtained a favorable serum level. The increase in vitamin D levels were 26.4, 18.5, and 8.3 ng/ml, in individuals with baseline vitamin D levels below 10 ng/ml, 10-20 ng/ml and 20-30 ng/ml, respectively. The changes in 25(OH) vitamin D in all three groups were significant (P < 0.05), nonetheless no significant alterations in serum levels of PTH were observed (P > 0.05). CONCLUSION Our results indicated an inverse relationship between baseline serum levels of 25(OH) D and its increment following treatment with vitamin D3. Therefore, the magnitude of increments in serum 25(OH) D is greater in subjects with lower baseline levels of 25(OH) D.
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Affiliation(s)
- Mahmoud Ali Kaykhaei
- Department of Internal Medicine, Ali-EbneAbitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
- Genetics of non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mahdieh Khodadoost
- Department of Internal Medicine, Ali-EbneAbitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Ali Reza Dashipour
- Department of Food Sciences and Nutrition, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Zahra Haidari
- Department of Internal Medicine, Ali-EbneAbitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Azra Karimkoshteh
- Department of Internal Medicine, Ali-EbneAbitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mahnaz Sandoughi
- Department of Internal Medicine, Ali-EbneAbitaleb Hospital, Zahedan University of Medical Sciences, Zahedan, Iran.
- Clinical Immunology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.
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Lactoferrin stimulates the expression of vitamin D receptor in vitamin D deficient mice. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.02.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
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Menzel LP, Ruddick W, Chowdhury MH, Brice DC, Clance R, Porcelli E, Ryan LK, Lee J, Yilmaz Ö, Kirkwood KL, McMahon L, Tran A, Diamond G. Activation of vitamin D in the gingival epithelium and its role in gingival inflammation and alveolar bone loss. J Periodontal Res 2019; 54:444-452. [PMID: 30802957 DOI: 10.1111/jre.12646] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 01/15/2019] [Accepted: 02/06/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE Both chronic and aggressive periodontal disease are associated with vitamin D deficiency. The active form of vitamin D, 1,25(OH)2 D3 , induces the expression of the antimicrobial peptide LL-37 and innate immune mediators in cultured human gingival epithelial cells (GECs). The aim of this study was to further delineate the mechanism by which vitamin D enhances the innate defense against the development of periodontal disease (PD). MATERIALS AND METHODS Wild-type C57Bl/6 mice were made deficient in vitamin D by dietary restriction. Cultured primary and immortalized GEC were stimulated with 1,25(OH)2 D3 , followed by infection with Porphyromonas gingivalis, and viable intracellular bacteria were quantified. Conversion of vitamin D3 to 25(OH)D3 and 1,25(OH)2 D3 was quantified by ELISA. Effect of vitamin D on basal IL-1α expression in mice was determined by topical administration to the gingiva of wild-type mice, followed by qRT-PCR. RESULTS Dietary restriction of vitamin D led to alveolar bone loss and increased inflammation in the gingiva in the mouse model. In primary human GEC and established human cell lines, treatment of GEC with 1,25(OH)2 D3 inhibited the intracellular growth of P. gingivalis. Cultured GEC expressed two 25-hydroxylases (CYP27A1 and CYP2R1), as well as 1-α hydroxylase, enabling conversion of vitamin D to both 25(OH)D3 and 1,25(OH)2 D3 . Topical application of both vitamin D3 and 1,25(OH)2 D3 to the gingiva of mice led to rapid inhibition of IL-1α expression, a prominent pro-inflammatory cytokine associated with inflammation, which also exhibited more than a 2-fold decrease from basal levels in OKF6/TERT1 cells upon 1,25(OH)2 D3 treatment, as determined by RNA-seq. CONCLUSION Vitamin D deficiency in mice contributes to PD, recapitulating the association seen in humans, and provides a unique model to study the development of PD. Vitamin D increases the activity of GEC against the invasion of periodontal pathogens and inhibits the inflammatory response, both in vitro and in vivo. GEC can convert inactive vitamin D to the active form in situ, supporting the hypothesis that vitamin D can be applied directly to the gingiva to prevent or treat periodontal disease.
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Affiliation(s)
- Lorenzo P Menzel
- Department of Oral Biology, University of Florida, Gainesville, Florida
| | - Willam Ruddick
- Department of Oral Biology, University of Florida, Gainesville, Florida
| | | | - David C Brice
- Department of Oral Biology, University of Florida, Gainesville, Florida
| | - Ryan Clance
- Department of Oral Biology, University of Florida, Gainesville, Florida
| | - Emily Porcelli
- Department of Oral Biology, University of Florida, Gainesville, Florida
| | - Lisa K Ryan
- Division of Infectious Diseases and Global Medicine, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida
| | - Jungnam Lee
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida
| | - Özlem Yilmaz
- Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina.,Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Keith L Kirkwood
- Department of Oral Biology, State University of New York at Buffalo, Buffalo, New York
| | - Laura McMahon
- Department of Oral Biology, Rutgers New Jersey Dental School, Newark, New Jersey
| | - Amy Tran
- Department of Oral Biology, Rutgers New Jersey Dental School, Newark, New Jersey
| | - Gill Diamond
- Department of Oral Biology, University of Florida, Gainesville, Florida
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Şahin S, Gürgen SG, Yazar U, İnce İ, Kamaşak T, Acar Arslan E, Diler Durgut B, Dilber B, Cansu A. Vitamin D protects against hippocampal apoptosis related with seizures induced by kainic acid and pentylenetetrazol in rats. Epilepsy Res 2019; 149:107-116. [DOI: 10.1016/j.eplepsyres.2018.12.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 12/04/2018] [Accepted: 12/14/2018] [Indexed: 11/26/2022]
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Gong A, Chen J, Wu J, Li J, Wang L, Goltzman D, Miao D. 1,25-dihydroxyvitamin D deficiency accelerates alveolar bone loss independent of aging and extracellular calcium and phosphorus. J Periodontol 2018; 89:983-994. [DOI: 10.1002/jper.17-0542] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 01/27/2018] [Accepted: 02/03/2018] [Indexed: 01/08/2023]
Affiliation(s)
- Aixiu Gong
- Department of Stomatology; Children's Hospital of Nanjing Medical University; Nanjing PR China
| | - Jie Chen
- State Key Laboratory of Reproductive Medicine; Center for Bone and Stem Cells; Department of Anatomy; Histology and Embryology, Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University; Nanjing PR China
| | - Jun Wu
- State Key Laboratory of Reproductive Medicine; Center for Bone and Stem Cells; Department of Anatomy; Histology and Embryology, Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University; Nanjing PR China
| | - Jing Li
- Department of Stomatology; Children's Hospital of Nanjing Medical University; Nanjing PR China
| | - Lin Wang
- Jiangsu Key Laboratory of Oral Diseases; Department of Orthodontics; School of Stomatology; Nanjing Medical University; Nanjing PR China
| | - David Goltzman
- Calcium Research Laboratory; McGill University Health Centre and Department of Medicine; McGill University; Montreal Canada
| | - Dengshun Miao
- State Key Laboratory of Reproductive Medicine; Center for Bone and Stem Cells; Department of Anatomy; Histology and Embryology, Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University; Nanjing PR China
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Silva ON, Porto WF, Ribeiro SM, Batista I, Franco OL. Host-defense peptides and their potential use as biomarkers in human diseases. Drug Discov Today 2018; 23:1666-1671. [PMID: 29803935 DOI: 10.1016/j.drudis.2018.05.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 05/06/2018] [Accepted: 05/21/2018] [Indexed: 02/07/2023]
Abstract
Since the early 19th century, host-defense peptides (HDPs) have been known to play a crucial role in innate host defense. Subsequent work has demonstrated their role in adaptive immunity as well as their involvement in cancer and also a number of inflammatory and/or autoimmune diseases. In addition to these multiple functional activities, several studies have shown that HDP accumulation might be correlated with various human diseases and, therefore, could be used as a biomarkers for such. Thus, research has aimed to validate the clinical use of HDPs for diagnosis, prognosis, and further treatment. In this review, we outline the most recent findings related to the use of HDPs as biomarkers, their clinical and epidemiological value, and the techniques used to determine the levels of HDPs.
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Affiliation(s)
- Osmar N Silva
- S-Inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil
| | - William F Porto
- S-Inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil; Porto Reports, 70790-160, Brasília, DF, Brazil
| | - Suzana M Ribeiro
- S-Inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil; Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal da Grande Dourados, Dourados-MS
| | - Ingrid Batista
- S-Inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil
| | - Octavio Luiz Franco
- S-Inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil; Centro de Análises Proteômicas e Bioquímicas, Universidade Católica de Brasília, Brasília, DF, Brazil; Departamento de Patologia Molecular, Universidade de Brasília, Brasília, DF, Brazil.
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Bossé Y, Amos CI. A Decade of GWAS Results in Lung Cancer. Cancer Epidemiol Biomarkers Prev 2018; 27:363-379. [PMID: 28615365 PMCID: PMC6464125 DOI: 10.1158/1055-9965.epi-16-0794] [Citation(s) in RCA: 152] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Revised: 12/06/2016] [Accepted: 04/20/2017] [Indexed: 01/03/2023] Open
Abstract
Genome-wide association studies (GWAS) were successful to identify genetic factors robustly associated with lung cancer. This review aims to synthesize the literature in this field and accelerate the translation of GWAS discoveries into results that are closer to clinical applications. A chronologic presentation of published GWAS on lung cancer susceptibility, survival, and response to treatment is presented. The most important results are tabulated to provide a concise overview in one read. GWAS have reported 45 lung cancer susceptibility loci with varying strength of evidence and highlighted suspected causal genes at each locus. Some genetic risk loci have been refined to more homogeneous subgroups of lung cancer patients in terms of histologic subtypes, smoking status, gender, and ethnicity. Overall, these discoveries are an important step for future development of new therapeutic targets and biomarkers to personalize and improve the quality of care for patients. GWAS results are on the edge of offering new tools for targeted screening in high-risk individuals, but more research is needed if GWAS are to pay off the investment. Complementary genomic datasets and functional studies are needed to refine the underlying molecular mechanisms of lung cancer preliminarily revealed by GWAS and reach results that are medically actionable. Cancer Epidemiol Biomarkers Prev; 27(4); 363-79. ©2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer."
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Affiliation(s)
- Yohan Bossé
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, Canada.
- Department of Molecular Medicine, Laval University, Quebec, Canada
| | - Christopher I Amos
- Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
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Broadgate S, Kiire C, Halford S, Chong V. Diabetic macular oedema: under-represented in the genetic analysis of diabetic retinopathy. Acta Ophthalmol 2018; 96 Suppl A111:1-51. [PMID: 29682912 DOI: 10.1111/aos.13678] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 11/21/2017] [Indexed: 12/15/2022]
Abstract
Diabetic retinopathy, a complication of both type 1 and type 2 diabetes, is a complex disease and is one of the leading causes of blindness in adults worldwide. It can be divided into distinct subclasses, one of which is diabetic macular oedema. Diabetic macular oedema can occur at any time in diabetic retinopathy and is the most common cause of vision loss in patients with type 2 diabetes. The purpose of this review is to summarize the large number of genetic association studies that have been performed in cohorts of patients with type 2 diabetes and published in English-language journals up to February 2017. Many of these studies have produced positive associations with gene polymorphisms and diabetic retinopathy. However, this review highlights that within this large body of work, studies specifically addressing a genetic association with diabetic macular oedema, although present, are vastly under-represented. We also highlight that many of the studies have small patient numbers and that meta-analyses often inappropriately combine patient data sets. We conclude that there will continue to be conflicting results and no meaningful findings will be achieved if the historical approach of combining all diabetic retinopathy disease states within patient cohorts continues in future studies. This review also identifies several genes that would be interesting to analyse in large, well-defined cohorts of patients with diabetic macular oedema in future candidate gene association studies.
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Affiliation(s)
- Suzanne Broadgate
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
| | - Christine Kiire
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
- Oxford Eye Hospital; John Radcliffe Hospital; Oxford University NHS Foundation Trust; Oxford UK
| | - Stephanie Halford
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
| | - Victor Chong
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
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Iqbal MUN, Maqbool SA, Khan TA. Association of low penetrance vitamin D receptor Tru9I (rs757343) gene polymorphism with risk of premenopausal breast cancer. J Int Med Res 2018. [PMID: 29529900 PMCID: PMC5991241 DOI: 10.1177/0300060518761304] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective The aim of this study was to determine whether a novel polymorphism ( Tru9I) in the low penetrance vitamin D receptor (VDR) gene is associated with risk of premenopausal breast cancer (BC). Methods This case-control study included 228 patients with BC and 503 healthy women living in Pakistan who were analyzed for the VDR Tru9I (rs757343) single nucleotide polymorphism. BC cases were histopathologically confirmed, and all healthy controls were age-matched with patients (age range, 20-45 years). DNA was extracted, and the polymerase chain reaction and restriction fragment length polymorphism assays were performed. Results The VDR Tru9I polymorphism was not significantly associated with premenopausal BC. However, the risk of BC was associated with the 'uu' genotype (odds ratio [OR], 1.141; 95% confidence interval [95% CI], 0.206-6.317). Further, mutant Tru9I was significantly associated with Grade IV carcinoma (OR, 5.36; 95% CI, 1.181-24.338). Conclusion The VDR Tru9I 'uu' genotype may increase the risk of premenopausal BC.
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Affiliation(s)
| | - Syed Amir Maqbool
- 2 Department of Clinical Oncology, Karachi Institute of Radiotherapy and Nuclear Medicine (KIRAN) hospital, Karachi, Pakistan
| | - Taseer Ahmed Khan
- 3 Department of Physiology, 63596 University of Karachi , Karachi, Pakistan
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Trivedi T, Zheng Y, Fournier PGJ, Murthy S, John S, Schillo S, Dunstan CR, Mohammad KS, Zhou H, Seibel MJ, Guise TA. The vitamin D receptor is involved in the regulation of human breast cancer cell growth via a ligand-independent function in cytoplasm. Oncotarget 2018; 8:26687-26701. [PMID: 28460457 PMCID: PMC5432290 DOI: 10.18632/oncotarget.15803] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 02/15/2017] [Indexed: 12/31/2022] Open
Abstract
Vitamin D has pleiotropic effects on multiple tissues, including malignant tumors. Vitamin D inhibits breast cancer growth through activation of the vitamin D receptor (VDR) and via classical nuclear signaling pathways. Here, we demonstrate that the VDR can also function in the absence of its ligand to control behaviour of human breast cancer cells both outside and within the bone microenvironment. Stable shRNA expression was used to knock down VDR expression in MCF-7 cells, generating two VDR knockdown clonal lines. In ligand-free culture, knockdown of VDR in MCF-7 cells significantly reduced proliferation and increased apoptosis, suggesting that the VDR plays a ligand-independent role in cancer cell growth. Implantation of these VDR knockdown cells into the mammary fat pad of nude mice resulted in reduced tumor growth in vivo compared with controls. In the intra-tibial xenograft model, VDR knockdown greatly reduced the ability of the cells to form tumors in the bone microenvironment. The in vitro growth of VDR knockdown cells was rescued by the expression of a mutant form of VDR which is unable to translocate to the nucleus and hence accumulates in the cytoplasm. Thus, our data indicate that in the absence of ligand, the VDR promotes breast cancer growth both in vitro and in vivo and that cytoplasmic accumulation of VDR is sufficient to produce this effect in vitro. This new mechanism of VDR action in breast cancer cells contrasts the known anti-proliferative nuclear actions of the VDR-vitamin D ligand complex.
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Affiliation(s)
- Trupti Trivedi
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia.,Division of Endocrinology, Department of Medicine, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana, USA
| | - Yu Zheng
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
| | - Pierrick G J Fournier
- Division of Endocrinology, Department of Medicine, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana, USA.,Biomedical Innovation Department, Scientific Research and High Education Center from Ensenada (CICESE), Ensenada, Baja California, Mexico
| | - Sreemala Murthy
- Division of Endocrinology, Department of Medicine, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana, USA
| | - Sutha John
- Division of Endocrinology, Department of Medicine, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana, USA
| | - Suzanne Schillo
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
| | - Colin R Dunstan
- Department of Biomedical Engineering, University of Sydney, Sydney, Australia
| | - Khalid S Mohammad
- Division of Endocrinology, Department of Medicine, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana, USA
| | - Hong Zhou
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia
| | - Markus J Seibel
- Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia.,Department of Endocrinology and Metabolism, Concord Hospital, Concord, Sydney, Australia
| | - Theresa A Guise
- Division of Endocrinology, Department of Medicine, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana, USA
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Bijian K, Kaldre D, Wang TT, Su J, Bouttier M, Boucher A, Alaoui-Jamali M, White JH, Gleason JL. Efficacy of hybrid vitamin D receptor agonist/histone deacetylase inhibitors in vitamin D-resistant triple-negative 4T1 breast cancer. J Steroid Biochem Mol Biol 2018; 177:135-139. [PMID: 28847749 DOI: 10.1016/j.jsbmb.2017.08.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 08/15/2017] [Accepted: 08/21/2017] [Indexed: 11/24/2022]
Abstract
Hormonal 1,25-dihydroxyvitamin D (1,25D) and its analogues have shown efficacy in some preclinical models of cancer. However, many models are resistant to the antiproliferative effects of 1,25D or its analogues in vitro or in vivo, and such compounds have failed in the clinic as monotherapies because of tumor resistance. Given the observed synergism between 1,25D analogues and histone deacetylase inhibitors (HDACi) in 1,25D-resistant cells, we previously developed a series of hybrid secosteroidal and easily assembled non-secosteroidal analogues that combined agonism for the vitamin D receptor and HDACi in a single backbone. These compounds displayed enhanced efficacy against 1,25D-resistant malignant cells in vitro. Structure/function studies led to synthesis of several non-secosteroidal variants in which HDACi potency was optimized without substantially sacrificing VDR agonism. Here, we present the first studies of efficacy in vivo of two of these compounds, DK-366 and DK-406, in the aggressive mouse 4T1 model of triple-negative breast cancer, a form of the disease for which treatment options are limited. 4T1 cells are resistant in vitro to the cytostatic and cytotoxic effects of 1,25D and the potent HDACi SAHA individually up to concentrations of 1μM and 50μM, respectively, whereas combinations of the two are efficacious. In vitro, DK-366 or -406 induced dose-dependent arrest of cell proliferation and cytotoxicity at 10-20μM. In vivo, the maximum tolerated dose (MTD) of DK-366 and DK-406 were 2.5 and 5.0mg/kg, respectively. Although the compounds induced hypercalcemia at elevated doses, consistent with VDR agonism in vivo, they both reduced tumor burden at doses below their MTD's. Moreover, in a separate experiment, DK-406 at 5mg/kg reduced 4T1 lung metastases by at least 50%. Under the same conditions, 1,25D (0.25μg/kg) and SAHA (25mg/kg) combined had no effect on tumor burden or on lung metastases. These experiments show that hybrid compounds are bioavailable and efficacious against a particularly aggressive model of metastatic breast cancer, providing strong support for the therapeutic potential of the hybrid concept.
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Affiliation(s)
- Krikor Bijian
- Segal Cancer Center and Lady Davis Institute for Medical Research, 3755 Cote Ste-Catherine, Montreal, QC, H3T 1E2, Canada
| | - Dainis Kaldre
- Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC, H3A 0B8, Canada
| | - Tian-Tian Wang
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada
| | - Jie Su
- Segal Cancer Center and Lady Davis Institute for Medical Research, 3755 Cote Ste-Catherine, Montreal, QC, H3T 1E2, Canada
| | - Manuella Bouttier
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada
| | - Annie Boucher
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada
| | - Moulay Alaoui-Jamali
- Segal Cancer Center and Lady Davis Institute for Medical Research, 3755 Cote Ste-Catherine, Montreal, QC, H3T 1E2, Canada.
| | - John H White
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada; Department of Medicine, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada.
| | - James L Gleason
- Department of Chemistry, McGill University, 801 Sherbrooke W., Montreal, QC, H3A 0B8, Canada.
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Gayam V, Mandal AK, Khalid M, Mukhtar O, Gill A, Garlapati P, Tiongson B, Sherigar J, Mansour M, Mohanty S. Association Between Vitamin D Levels and Treatment Response to Direct-Acting Antivirals in Chronic Hepatitis C: A Real-World Study. Gastroenterology Res 2018; 11:309-316. [PMID: 30116431 PMCID: PMC6089592 DOI: 10.14740/gr1072w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 07/23/2018] [Indexed: 12/11/2022] Open
Abstract
Background Low serum vitamin D levels in chronic hepatitis C (CHC) is associated with advanced liver fibrosis; and there remains an imprecise relationship with the treatment response based on the vitamin D levels. Previous studies have shown conflicting results on the vitamin D levels, and association with treatment response in CHC treated with interferon-based regimens. Methods Patients with CHC treated with direct-acting antivirals (DAAs) between January 2016 and December 2017 in the community clinic setting were retrospectively analyzed. Pretreatment baseline patient characteristics, treatment efficacy with the sustained virologic response at 12 weeks post-treatment (SVR 12) were assessed in CHC patients with deficient, insufficient, and normal levels of vitamin D measured before the initiation of DAA therapy. Results Two hundred and ninety-one patients were included in the study. Direct-acting antivirals included in the study were ledipasvir/sofosbuvir ± ribavirin, ombitasvir + paritaprevir + ritonavir + dasabuvir ± ribavirin, and sofosbuvir/velpatasvir. An overall sustained virologic response was achieved in 95% (n = 276) of patients. SVR 12 rates among patients with vitamin D deficiency, vitamin D insufficiency and normal vitamin D levels were 92%, 96.2%, and 97.2% respectively and was not statically significant (P = 0.214). A total of 71 patients were cirrhotic. The prevalence of vitamin D insufficiency (20 - 29.9 ng/mL) and deficiency (< 20 ng/mL) was significantly higher in cirrhotic patients (P = 0.01). Despite this, pretreatment vitamin D levels did not show any impact on the virologic response. The most common adverse effect observed was fatigue. None of the patients had to discontinue the treatment due to adverse events. Conclusions DAAs are safe and effective with a high overall SVR 12 in CHC and treatment response does not depend on the pretreatment vitamin D levels. The prevalence of both vitamin D insufficiency and deficiency was observed to be higher in cirrhotic cohorts compared to non-cirrhotic counterparts.
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Affiliation(s)
- Vijay Gayam
- Department of Medicine and Gastroenterology, Interfaith Medical Center, 1545 Atlantic Avenue. Brooklyn, NY 11213, USA
| | - Amrendra Kumar Mandal
- Department of Medicine and Gastroenterology, Interfaith Medical Center, 1545 Atlantic Avenue. Brooklyn, NY 11213, USA
| | - Mazin Khalid
- Department of Medicine and Gastroenterology, Interfaith Medical Center, 1545 Atlantic Avenue. Brooklyn, NY 11213, USA
| | - Osama Mukhtar
- Department of Medicine and Gastroenterology, Interfaith Medical Center, 1545 Atlantic Avenue. Brooklyn, NY 11213, USA
| | - Arshpal Gill
- Department of Medicine and Gastroenterology, Interfaith Medical Center, 1545 Atlantic Avenue. Brooklyn, NY 11213, USA
| | - Pavani Garlapati
- Department of Medicine and Gastroenterology, Interfaith Medical Center, 1545 Atlantic Avenue. Brooklyn, NY 11213, USA
| | - Benjamin Tiongson
- Department of Medicine and Gastroenterology, Interfaith Medical Center, 1545 Atlantic Avenue. Brooklyn, NY 11213, USA
| | - Jagannath Sherigar
- Department of Medicine and Division of Gastroenterology and Hepatology, New York-Presbyterian Brooklyn Methodist Hospital, 506, 6th St, Brooklyn, NY 11215, USA
| | - Mohammed Mansour
- Department of Medicine and Gastroenterology, Interfaith Medical Center, 1545 Atlantic Avenue. Brooklyn, NY 11213, USA
| | - Smruti Mohanty
- Department of Medicine and Division of Gastroenterology and Hepatology, New York-Presbyterian Brooklyn Methodist Hospital, 506, 6th St, Brooklyn, NY 11215, USA
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Gallieni M, Cozzolino M, Fallabrino G, Pasho S, Olivi L, Brancaccio D. Vitamin D: Physiology and Pathophysiology. Int J Artif Organs 2018; 32:87-94. [DOI: 10.1177/039139880903200205] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Although vitamin D was initially considered a nutrient, it has been recognized that the molecules derived from vitamin D metabolism are best considered as a complex endocrine system. In this review article we summarize the basic concepts regarding vitamin D metabolism, transport, and genomic activity through the vitamin D receptor, facilitating activation or suppression of target genes. We also examine non-genomic actions, biological responses to vitamin D in classic target organs (intestine, bone, kidneys, and parathyroid glands), and in organs and tissues not related to mineral homeostasis.
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Affiliation(s)
- Maurizio Gallieni
- Nephrology and Dialysis Unit, San Paolo Hospital, University of Milan, Milan
| | - Mario Cozzolino
- Nephrology and Dialysis Unit, San Paolo Hospital, University of Milan, Milan
- Chair of Nephrology, Department of Medicine, Surgery and Dentistry, University of Milan - Italy
| | - Giuditta Fallabrino
- Nephrology and Dialysis Unit, San Paolo Hospital, University of Milan, Milan
| | - Sabina Pasho
- Nephrology and Dialysis Unit, San Paolo Hospital, University of Milan, Milan
| | - Laura Olivi
- Nephrology and Dialysis Unit, San Paolo Hospital, University of Milan, Milan
| | - Diego Brancaccio
- Nephrology and Dialysis Unit, San Paolo Hospital, University of Milan, Milan
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White JH. Vitamin D deficiency and the pathogenesis of Crohn's disease. J Steroid Biochem Mol Biol 2018; 175:23-28. [PMID: 28025175 DOI: 10.1016/j.jsbmb.2016.12.015] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 11/07/2016] [Accepted: 12/23/2016] [Indexed: 12/14/2022]
Abstract
Vitamin D has emerged as a key regulator of innate immune responses to pathogen threat. The hormonal form of vitamin D signals through a nuclear receptor transcription factor and regulates gene transcription. Several papers have shown that vitamin D signaling is active both upstream and downstream of pattern recognition receptors, vanguards of innate immune responses. Crohn's disease (CD) is a relapsing-recurring inflammatory bowel disease (IBD) that arises from dysregulated intestinal innate immunity. Indeed, genetic studies have identified several CD susceptibility markers linked to mechanisms of innate immune responses to infection. Interest in links between vitamin D deficiency and CD has grown substantially, particularly in the last five years. While a number of studies have consistently revealed an association between CD and vitamin D deficiency, recent experimental work has uncovered a compelling mechanistic basis for the contribution of vitamin D deficiency to the pathogenesis of the disease. Moreover, a number of intervention trials have provided generally solid evidence that robust vitamin D supplementation may be of therapeutic benefit to patients with CD. This review summarizes these laboratory and clinical findings.
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Affiliation(s)
- John H White
- Departments of Physiology and Medicine, McGill University, Montreal, Quebec, Canada.
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Wimalawansa SJ. Non-musculoskeletal benefits of vitamin D. J Steroid Biochem Mol Biol 2018; 175:60-81. [PMID: 27662817 DOI: 10.1016/j.jsbmb.2016.09.016] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 09/15/2016] [Accepted: 09/19/2016] [Indexed: 02/06/2023]
Abstract
The aim of this study is to determine and critically evaluate the plausible relationships of vitamin D with extra-skeletal tissues in humans. Severe vitamin D deficiency results in rickets in children and osteomalacia in adults; these beneficial effects in the musculoskeletal system and certain physiological functions are well understood. Nevertheless, mounting reports support additional beneficial effects of vitamin D, outside the musculoskeletal system. This review explores the recent advances in knowledge about the non-skeletal effects of vitamin D. Peer-reviewed papers were extracted from research databases using key words, to assess correlations between vitamin D and extra-skeletal diseases and conditions. As per the guidelines of the Preferred Reporting Items for Systematic Reviews (PRISMA); general interpretations of results are included; taking into consideration the broader evidence and implications. This review summarizes current knowledge of the effects of vitamin D status on extra-skeletal tissues with special attention given to relationships between vitamin D status and various diseases commonly affecting adults; the effects of intervention with vitamin D and exposure to sunlight. Evidence suggests that vitamin D facilitates the regulation of blood pressure; and cardiac; endothelial; and smooth muscle cell functions; playing an important role in cardiovascular protection. In addition; 1,25(OH)2D improves immunity; subdues inflammation; and reduces the incidence and severity of common cancers; autoimmune diseases and infectious diseases. Almost all adequately powered; epidemiological and biological studies that use; adequate doses of vitamin D supplementation in D-deficient populations have reported favorable outcomes. These studies have concluded that optimizing 25(OH)D status improves the functionality of bodily systems; reduces comorbidities; improves the quality of life; and increases survival. Although accumulating evidence supports biological associations of vitamin D sufficiency with improved physical and mental functions; no definitive evidence exists from well-designed; statistically powered; randomized controlled clinical trials. Nevertheless, most studies point to significant protective effects of vitamin D in humans when the minimum 25(OH)D serum level exceeds 30ng/mL and is maintained throughout the year.
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Affiliation(s)
- Sunil J Wimalawansa
- Endocrinology & Nutrition, Cardio Metabolic Institute, 661 Darmody Avenue, North Brunswick, NJ, USA.
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Mohammed I, Said DG, Dua HS. Human antimicrobial peptides in ocular surface defense. Prog Retin Eye Res 2017; 61:1-22. [DOI: 10.1016/j.preteyeres.2017.03.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 03/22/2017] [Accepted: 03/27/2017] [Indexed: 01/17/2023]
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Donate-Correa J, Henríquez-Palop F, Martín-Núñez E, Hernández-Carballo C, Ferri C, Pérez-Delgado N, Muros-de-Fuentes M, Mora-Fernández C, Navarro-González JF. Anti-inflammatory profile of paricalcitol in kidney transplant recipients. Nefrologia 2017; 37:622-629. [PMID: 28623033 DOI: 10.1016/j.nefroe.2017.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 03/15/2017] [Accepted: 03/27/2017] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Paricalcitol, a selective vitamin D receptor activator, is used to treat secondary hyperparathyroidism in kidney transplant patients. Experimental and clinical studies in non-transplant kidney disease patients have found this molecule to have anti-inflammatory properties. In this exploratory study, we evaluated the anti-inflammatory profile of paricalcitol in kidney-transplant recipients. METHODS Thirty one kidney transplant recipients with secondary hyperparathyroidism completed 3 months of treatment with oral paricalcitol (1μg/day). Serum concentrations and gene expression levels of inflammatory cytokines in peripheral blood mononuclear cells were analysed at the beginning and end of the study. RESULTS Paricalcitol significantly decreased parathyroid hormone levels with no changes in calcium and phosphorous. It also reduced serum concentrations of interleukin (IL)-6 and tumour necrosis factor-alpha (TNF-α) by 29% (P<0.05) and 9.5% (P<0.05) compared to baseline, respectively. Furthermore, gene expression levels of IL-6 and TNF-α in peripheral blood mononuclear cells decreased by 14.1% (P<0.001) and 34.1% (P<0.001), respectively. The ratios between pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory cytokines (IL-10), both regarding serum concentrations and gene expression, also experienced a significant reduction. CONCLUSIONS Paricalcitol administration to kidney transplant recipients has been found to have beneficial effects on inflammation, which may be associated with potential clinical benefits.
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Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España; Unidad de Investigación, Hospital Universitario de Canarias, Santa Cruz de Tenerife, España.
| | - Fernando Henríquez-Palop
- Servicio de Nefrología, Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, España
| | - Ernesto Martín-Núñez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Carolina Hernández-Carballo
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Carla Ferri
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Nayra Pérez-Delgado
- Servicio de Análisis Clínicos, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Mercedes Muros-de-Fuentes
- Servicio de Análisis Clínicos, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Juan F Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España; Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España.
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Dimitrov V, Bouttier M, Boukhaled G, Salehi-Tabar R, Avramescu RG, Memari B, Hasaj B, Lukacs GL, Krawczyk CM, White JH. Hormonal vitamin D up-regulates tissue-specific PD-L1 and PD-L2 surface glycoprotein expression in humans but not mice. J Biol Chem 2017; 292:20657-20668. [PMID: 29061851 DOI: 10.1074/jbc.m117.793885] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 09/28/2017] [Indexed: 12/14/2022] Open
Abstract
PD-L1 (programmed death ligand 1) and PD-L2 are cell-surface glycoproteins that interact with programmed death 1 (PD-1) on T cells to attenuate inflammation. PD-1 signaling has attracted intense interest for its role in a pathophysiological context: suppression of anti-tumor immunity. Similarly, vitamin D signaling has been increasingly investigated for its non-classical actions in stimulation of innate immunity and suppression of inflammatory responses. Here, we show that hormonal 1,25-dihydroxyvitamin D (1,25D) is a direct transcriptional inducer of the human genes encoding PD-L1 and PD-L2 through the vitamin D receptor, a ligand-regulated transcription factor. 1,25D stimulated transcription of the gene encoding PD-L1 in epithelial and myeloid cells, whereas the gene encoding the more tissue-restricted PD-L2 was regulated only in myeloid cells. We identified and characterized vitamin D response elements (VDREs) located in both genes and showed that 1,25D treatment induces cell-surface expression of PD-L1 in epithelial and myeloid cells. In co-culture experiments with primary human T cells, epithelial cells pretreated with 1,25D suppressed activation of CD4+ and CD8+ cells and inhibited inflammatory cytokine production in a manner that was abrogated by anti-PD-L1 blocking antibody. Consistent with previous observations of species-specific regulation of immunity by vitamin D, the VDREs are present in primate genes, but neither the VDREs nor the regulation by 1,25D is present in mice. These findings reinforce the physiological role of 1,25D in controlling inflammatory immune responses but may represent a double-edged sword, as they suggest that elevated vitamin D signaling in humans could suppress anti-tumor immunity.
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Affiliation(s)
| | | | | | | | | | | | - Benedeta Hasaj
- Microbiology and Immunology, McGill University, Montreal, Quebec H3G 1Y6, Canada
| | | | - Connie M Krawczyk
- From the Departments of Physiology, .,Microbiology and Immunology, McGill University, Montreal, Quebec H3G 1Y6, Canada
| | - John H White
- From the Departments of Physiology, .,Medicine, and
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47
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Dimitrov V, White JH. Vitamin D signaling in intestinal innate immunity and homeostasis. Mol Cell Endocrinol 2017; 453:68-78. [PMID: 28412519 DOI: 10.1016/j.mce.2017.04.010] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 04/10/2017] [Accepted: 04/10/2017] [Indexed: 12/14/2022]
Abstract
The lumen of the gut hosts a plethora of microorganisms that participate in food assimilation, inactivation of harmful particles and in vitamin synthesis. On the other hand, enteric flora, a number of food antigens, and toxins are capable of triggering immune responses causing inflammation, which, when unresolved, may lead to chronic conditions such as inflammatory bowel disease (IBD). It is important, therefore, to contain the gut bacteria within the lumen, control microbial load and composition, as well as ensure adequate innate and adaptive immune responses to pathogenic threats. There is growing evidence that vitamin D signaling has impacts on all these aspects of intestinal physiology, contributing to healthy enteric homeostasis. VD was first discovered as the curative agent for nutritional rickets, and its classical actions are associated with calcium absorption and bone health. However, vitamin D exhibits a number of extra-skeletal effects, particularly in innate immunity. Notably, it stimulates production of pattern recognition receptors, anti-microbial peptides, and cytokines, which are at the forefront of innate immune responses. They play a role in sensing the microbiota, in preventing excessive bacterial overgrowth, and complement the actions of vitamin D signaling in enhancing intestinal barrier function. Vitamin D also favours tolerogenic rather than inflammogenic T cell differentiation and function. Compromised innate immune function and overactive adaptive immunity, as well as defective intestinal barrier function, have been associated with IBD. Importantly, observational and intervention studies support a beneficial role of vitamin D supplementation in patients with Crohn's disease, a form of IBD. This review summarizes the effects of vitamin D signaling on barrier integrity and innate and adaptive immunity in the gut, as well as on microbial load and composition. Collectively, studies to date reveal that vitamin D signaling has widespread effects on gut homeostasis, and provide a mechanistic basis for potential therapeutic benefit of vitamin D supplementation in IBD.
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Affiliation(s)
- Vassil Dimitrov
- Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - John H White
- Department of Physiology, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.
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48
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Donate-Correa J, Henríquez-Palop F, Martín-Núñez E, Hernández-Carballo C, Ferri C, Pérez-Delgado N, Muros-de-Fuentes M, Mora-Fernández C, Navarro-González JF. Anti-inflammatory profile of paricalcitol in kidney transplant recipients. Nefrologia 2017. [PMID: 28623033 DOI: 10.1016/j.nefro.2017.03.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Paricalcitol, a selective vitamin D receptor activator, is used to treat secondary hyperparathyroidism in kidney transplant patients. Experimental and clinical studies in non-transplant kidney disease patients have found this molecule to have anti-inflammatory properties. In this exploratory study, we evaluated the anti-inflammatory profile of paricalcitol in kidney-transplant recipients. METHODS Thirty one kidney transplant recipients with secondary hyperparathyroidism completed 3 months of treatment with oral paricalcitol (1μg/day). Serum concentrations and gene expression levels of inflammatory cytokines in peripheral blood mononuclear cells were analysed at the beginning and end of the study. RESULTS Paricalcitol significantly decreased parathyroid hormone levels with no changes in calcium and phosphorous. It also reduced serum concentrations of interleukin (IL)-6 and tumour necrosis factor-alpha (TNF-α) by 29% (P<0.05) and 9.5% (P<0.05) compared to baseline, respectively. Furthermore, gene expression levels of IL-6 and TNF-α in peripheral blood mononuclear cells decreased by 14.1% (P<0.001) and 34.1% (P<0.001), respectively. The ratios between pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory cytokines (IL-10), both regarding serum concentrations and gene expression, also experienced a significant reduction. CONCLUSIONS Paricalcitol administration to kidney transplant recipients has been found to have beneficial effects on inflammation, which may be associated with potential clinical benefits.
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Affiliation(s)
- Javier Donate-Correa
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España; Unidad de Investigación, Hospital Universitario de Canarias, Santa Cruz de Tenerife, España.
| | - Fernando Henríquez-Palop
- Servicio de Nefrología, Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, España
| | - Ernesto Martín-Núñez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Carolina Hernández-Carballo
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Carla Ferri
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Nayra Pérez-Delgado
- Servicio de Análisis Clínicos, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Mercedes Muros-de-Fuentes
- Servicio de Análisis Clínicos, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Carmen Mora-Fernández
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Juan F Navarro-González
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España; Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España.
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49
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De Filippis A, Fiorentino M, Guida L, Annunziata M, Nastri L, Rizzo A. Vitamin D reduces the inflammatory response by Porphyromonas gingivalis infection by modulating human β-defensin-3 in human gingival epithelium and periodontal ligament cells. Int Immunopharmacol 2017; 47:106-117. [DOI: 10.1016/j.intimp.2017.03.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 03/07/2017] [Accepted: 03/22/2017] [Indexed: 10/19/2022]
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50
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Liu ZQ, Li MG, Geng XR, Liu J, Yang G, Qiu SQ, Liu ZG, Yang PC. Vitamin D regulates immunoglobulin mucin domain molecule-4 expression in dendritic cells. Clin Exp Allergy 2017; 47:656-664. [PMID: 28160341 DOI: 10.1111/cea.12894] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 12/10/2016] [Accepted: 01/15/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Dendritic cell (DC)-derived immunoglobulin domain molecule (TIM)4 plays a critical role in the initiation of T helper (Th)2 polarization. Vitamin D (VitD) involves the regulation of a number of immune responses. OBJECTIVES This study tests a hypothesis that VitD regulates TIM4 expression in DCs. METHODS Peripheral blood samples were collected from patients with allergic rhinitis (AR) and healthy subjects. DCs were isolated from the samples and analyzed for the expression of TIM4. RESULTS We observed that the levels of calcitriol, the active form of VitD3, in the sera of AR patients were lower than that in healthy subjects. The peripheral DC expressed higher levels of TIM4 and lower levels of VDR. A negative correlation was identified between the data of serum calcitriol and TIM4 in DCs. Exposure DCs to calcitriol in the culture increased the expression of VDR. We also found that VDR bound to the TIM4 promoter locus in DCs to repress the TIM4 gene transcription and expression. CONCLUSIONS AND CLINICAL RELEVANCE VitD deficiency may contribute to the pathogenesis of AR by increasing the TIM4 expression. The results suggest that to regulate the serum calcitriol levels and the expression of VDR in DCs may be necessary to be taken into account in the treatment of AR.
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Affiliation(s)
- Z-Q Liu
- ENT Institute of the Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.,Longgang ENT Hospital and Shenzhen ENT Institute, Shenzhen, China.,The Brain Body Institute, McMaster University, Hamilton, ON, Canada
| | - M-G Li
- ENT Institute of the Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - X-R Geng
- ENT Institute of the Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.,Longgang ENT Hospital and Shenzhen ENT Institute, Shenzhen, China.,The Brain Body Institute, McMaster University, Hamilton, ON, Canada
| | - J Liu
- Shenzhen Maternity & Child Health Hospital, Shenzhen, China
| | - G Yang
- ENT Institute of the Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.,Longgang ENT Hospital and Shenzhen ENT Institute, Shenzhen, China.,The Brain Body Institute, McMaster University, Hamilton, ON, Canada
| | - S-Q Qiu
- Longgang ENT Hospital and Shenzhen ENT Institute, Shenzhen, China
| | - Z-G Liu
- ENT Institute of the Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - P-C Yang
- ENT Institute of the Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
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