Hypovitaminosis D exacerbates the DNA damage load in human uterine fibroids, which is ameliorated by vitamin D3 treatment.
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SUBMITTER: Ali M
PROVIDER: S-EPMC6786389 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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Hypovitaminosis D exacerbates the DNA damage load in human uterine fibroids, which is ameliorated by vitamin D3 treatment.
Ali Mohamed M Shahin Sara Mahmoud SM Sabri Nagwa Ali NA Al-Hendy Ayman A Yang Qiwei Q
Acta pharmacologica Sinica 20181126 7
Uterine fibroids (UFs) are the most common benign neoplastic threat to women's health and associated with DNA damage and genomic instability. Hypovitaminosis D is a known risk factor for UFs, especially among African Americans. Vitamin D3 has been shown to effectively inhibit UF phenotype, but its mechanisms remain unclear. We hypothesize that Vitamin D3 ameliorates UFs by recovering the damaged DNA repair system, thus inhibits tumor progression. We compared the DNA damage status and Vitamin D r ...[more]
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Project description:AIM:To prospectively evaluate the effects of vitamin D3 on disease activity and quality of life in ulcerative colitis (UC) patients with hypovitaminosis D. METHODS:The study was a prospective double-blinded, randomized trial conducted at Community Regional Medical Center, Fresno, CA from 2012-2013. Patients with UC and a serum 25(OH)D level <30 ng/ml were eligible for the study. Enrolled subjects were randomized to receive either 2,000 IU or 4,000 IU of oral vitamin D3 daily for a total of 90 days. The Short IBD Questionnaire (SIBDQ) for quality of life, the Partial Mayo Score for UC disease activity and serum lab tests were compared between the two treatment groups. Matched pair t-tests were computed to assess differences between the vitamin D levels, CRP, UC disease activity and SIBDQ scores before and after vitamin D3 therapy using SPSS version 21. RESULTS:Eight UC patients received 2,000 IU/daily and ten UC patients received 4,000 IU/daily of vitamin D3 for 90 days. Vitamin D levels increased after 90 days of oral vitamin D3 in both dose groups. However, the increase in vitamin D levels after 90 days of oral vitamin D3, in the 4,000 IU group was significantly higher 16.80 ± 9.15 (p < 0.001) compared to the 2,000 IU group of vitamin D 5.00 ± 3.12 (p = 0.008). Normal vitamin D levels (>30 ng/dl) were achieved in four out of the ten UC patients (40%) in the 4,000 IU group and in one out of the eight UC patients (12%) in the 2,000 IU group. In the group receiving 4,000 IU/day of vitamin D3 the increase in quality life scores (SIBDQ) was significant 1.0 ± 1.0 (p = 0.017) but not in the 2,000 IU vitamin D3 group 0.1 ± 1.0 (p = 0.87). In the 2,000 IU of vitamin D3 group the mean decrease in the Partial Mayo UC Score was -0.5 ± 1.5 (p = 0.38) compared to -1.3 ± 2.9 (p = 0.19) in the 4,000 IU vitamin D3 group but this was not statistically significant. CRP levels decreased after 90 days of daily vitamin D3 in both the 2,000 IU group and 4,000 IU group by -3.0 ± 9.4 (p = 0.4) and -10.8 ± 35.0 (p = 0.36) respectively. CONCLUSION:Vitamin D3 at 4,000 IU/day is more effective than 2,000 IU/day in increasing vitamin D to sufficient levels in UC patients with hypovitaminosis D, however higher doses or treatment beyond ninety days may be required. Vitamin D3 may improve the quality of life in UC patients but clinically significant improvement is not yet established. The effect of vitamin D3 on UC disease activity is still unclear. Further larger studies are needed to investigate the effects of vitamin D in ulcerative colitis.
| S-EPMC5545112 | biostudies-literature
Project description:Early-life exposure of the myometrium to endocrine-disrupting chemicals (EDCs) has been shown to increase the risk of uterine fibroid (UF) prevalence in adulthood. Vitamin D3 (VitD3) is a unique, natural compound that may reduce the risk of developing UFs. However, little is known about the role and molecular mechanism of VitD3 on exposed myometrial stem cells (MMSCs). We investigated the role of, and molecular mechanism behind, VitD3 action on DNA damage response (DDR) defects in rat MMSCs due to developmental exposure to diethylstilbestrol (DES), with the additional goal of understanding how VitD3 decreases the incidence of UFs later in life. Female newborn Eker rats were exposed to DES or a vehicle early in life; they were then sacrificed at 5 months of age (pro-fibroid stage) and subjected to myometrial Stro1+/CD44+ stem cell isolation. Several techniques were performed to determine the effect of VitD3 treatment on the DNA repair pathway in DES-exposed MMSCs (DES-MMSCs). Results showed that there was a significantly reduced expression of RAD50 and MRE11, key DNA repair proteins in DES-exposed myometrial tissues, compared to vehicle (VEH)-exposed tissues (p < 0.01). VitD3 treatment significantly decreased the DNA damage levels in DES-MMSCs. Concomitantly, the levels of key DNA damage repair members, including the MRN complex, increased in DES-MMSCs following treatment with VitD3 (p < 0.01). VitD3 acts on DNA repair via the MRN complex/ATM axis, restores the DNA repair signaling network, and enhances DDR. This study demonstrates, for the first time, that VitD3 treatment attenuated the DNA damage load in MMSCs exposed to DES and classic DNA damage inducers. Moreover, VitD3 targets primed MMSCs, suggesting a novel therapeutic approach for the prevention of UF development.
| S-EPMC7349254 | biostudies-literature
Project description:Uterine fibroids (UFs) are the most common benign gynecological tumors. It was estimated that fifty percent of women presenting with UFs has symptomatology that negatively influences their quality of life. Pharmacological and/or surgical treatments are frequently required, depending on the woman's desire to preserve fertility, with a high impact on healthcare costs. Generally, the use of currently available pharmacological treatments may lead to side effects. Therefore, there is a growing interest in a natural and safe approach for UFs. In recent years, epidemiological studies reported a vitamin D deficiency in patients with UFs raised interest in the potential biological effects of vitamin D supplementation. In vitro studies proved vitamin D efficacy in inhibiting UFs growth by targeting pathways involved in the regulation of various biological processes, including proliferation, extracellular matrix (ECM) remodeling, DNA repair, signaling and apoptosis. However, clinical studies supported only in part the beneficial effects of vitamin D supplementation in reducing UFs growth and tumor volume. Randomized controlled trials and large population studies are mandatory as the potential clinical benefits are likely to be substantial.
| S-EPMC7917888 | biostudies-literature
Project description:RationalePatients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be vitamin D3 (VD3) deficient, which is associated with more severe disease and increased polyp size. To gain mechanistic insights into these observational studies, we examined the impact of VD3 deficiency on inflammation and VD3 metabolism in an Aspergillus fumigatus (Af) mouse model of chronic rhinosinusitis (Af-CRS).MethodsBalb/c mice were fed control or VD3 deficient diet for 4 weeks. Mice were then sensitized with intraperitoneal Af, and one week later given Af intranasally every three days for four weeks while being maintained on control or VD3 deficient diet. Airway function, sinonasal immune cell infiltrate and sinonasal VD3 metabolism profiles were then examined.ResultsMice with VD3 deficiency had increased Penh and sRaw values as compared to controls as well as exacerbated changes in sRaw when coupled with Af-CRS. As compared to controls, VD3 deficient and Af-CRS mice had reduced sinonasal 1α-hydroxylase and the active VD3 metabolite, 1,25(OH)2D3. Differential analysis of nasal lavage samples showed that VD3 deficiency alone and in combination with Af-CRS profoundly upregulated eosinophil, neutrophil and lymphocyte numbers. VD3 deficiency exacerbated increases in monocyte-derived dendritic cell (DC) associated with Af-CRS. Conversely, T-regulatory cells were decreased in both Af-CRS mice and VD3 deficient mice, though coupling VD3 deficiency with Af-CRS did not exacerbate CD4 or T-regulatory cells numbers. Lastly, VD3 deficiency had a modifying or exacerbating impact on nasal lavage levels of IFN-γ, IL-6, IL-10 and TNF-α, but had no impact on IL-17A.ConclusionsVD3 deficiency causes changes in sinonasal immunity, which in many ways mirrors the changes observed in Af-CRS mice, while selectively exacerbating inflammation. Furthermore, both VD3 deficiency and Af-CRS were associated with altered sinonasal VD3 metabolism causing reductions in local levels of the active VD3 metabolite, 1,25(OH)2D3, even with adequate circulating levels.
| S-EPMC5646812 | biostudies-literature
Project description:This article provides a detailed review of current knowledge on the role of vitamin D and its receptor in the biology and management of uterine fibroids (UFs). Authors present ideas for future steps in this area. A literature search was conducted in PubMed using the following key words: "uterine fibroid" and "vitamin D". The results of the available studies, published in English from January 2002 up to April 2018, have been discussed. Vitamin D is a group of steroid compounds with a powerful impact on many parts of the human body. This vitamin is believed to regulate cell proliferation and differentiation, inhibit angiogenesis, and stimulate apoptosis. Nowadays, hypovitaminosis D is believed to be a major risk factor in the development of UFs. In many studies vitamin D appears to be a powerful factor against UFs, resulting in inhibition of tumor cell division and a significant reduction in its size, however, the exact role of this compound and its receptor in the pathophysiology of UFs is not fully understood. According to available studies, vitamin D and its analogs seem to be promising, effective, and low-cost compounds in the management of UFs and their clinical symptoms, and the anti-tumor activities of vitamin D play an important role in UF biology. The synergy between vitamin D and selected anti-UF drugs is a very interesting issue which requires further research. Further studies about the biological effect of vitamin D on UF biology are essential. Vitamin D preparations (alone or as a co-drugs) could become new tools in the fight with UFs, with the additional beneficial pleiotropic effect.
| S-EPMC6073230 | biostudies-literature
Project description:Uterine fibroids are a major cause of morbidity in women of a reproductive age (and sometimes even after menopause). There are several factors that are attributed to underlie the development and incidence of these common tumors, but this further corroborates their relatively unknown etiology. The most likely presentation of fibroids is by their effect on the woman's menstrual cycle or pelvic pressure symptoms. Leiomyosarcoma is a very rare entity that should be suspected in postmenopausal women with fibroid growth (and no concurrent hormone replacement therapy). The gold standard diagnostic modality for uterine fibroids appears to be gray-scale ultrasonography, with magnetic resonance imaging being a close second option in complex clinical circumstances. The management of uterine fibroids can be approached medically, surgically, and even by minimal access techniques. The recent introduction of selective progesterone receptor modulators (SPRMs) and aromatase inhibitors has added more armamentarium to the medical options of treatment. Uterine artery embolization (UAE) has now been well-recognized as a uterine-sparing (fertility-preserving) method of treating fibroids. More recently, the introduction of ultrasound waves (MRgFUS) or radiofrequency (VizAblate™ and Acessa™) for uterine fibroid ablation has added to the options of minimal access treatment. More definite surgery in the form of myomectomy or hysterectomy can be performed via the minimal access or open route methods. Our article seeks to review the already established information on uterine fibroids with added emphasis on contemporary knowledge.
| S-EPMC3914832 | biostudies-other
Project description:BackgroundUterine fibroids are the most common benign uterine tumours present in women of reproductive age. Mifepristone (RU-486) competitively binds and inhibits progesterone receptors. Studies have suggested that fibroid growth depends on the sexual steroids. Mifepristone has been shown to decrease fibroid size. This review summarises the effects of mifepristone treatment on fibroids and the associated adverse effects as described in randomised controlled trials.ObjectivesTo determine the efficacy and safety of mifepristone for the management of uterine fibroids in pre-menopausal women.Search methodsWe searched the specialised register of the Cochrane Menstrual Disorders and Subfertility (Cochrane Menstrual Disorders and subfertility Review Group), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), MEDLINE, EMBASE, PsycINFO, and CINAHL (to November 2011). We handsearched a number of journals, and searched reference lists, databases of ongoing trials and the Internet. There were no language restrictions.Selection criteriaOnly truly randomised controlled trials of mifepristone versus other forms of medical therapy or placebo in pre-menopausal women with confirmed uterine fibroids were included.Data collection and analysisFour authors independently extracted data and assessed trial quality. Data were analysed using the Peto odds ratios (OR) for dichotomous data and the weighted mean differences for continuous data, with 95% confidence intervals (CI). Meta-analyses were performed using the fixed-effect model.Main resultsThree studies involving 112 participants were included. Comparison interventions included different dosages of mifepristone, placebo and vitamin B tablets. There is evidence that treatment with mifepristone relieves heavy menstrual bleeding compared with placebo (Peto OR 17.84; 95% CI 6.72 to 47.38; 2 RCTs, 77 women, I(2) = 0%). Three studies (Bagaria 2009; Engman 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on the fibroid volume (standardised mean difference (SMD) -0.02; 95% CI -0.38 to 0.41; 99 women). Two studies (Bagaria 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on uterine volume (mean difference (MD) -77.24; 95% CI -240.62 to 86.14; 72 women). The pooled data suggest an increased adverse event (abnormal endometrial histology) in the mifepristone group compared to placebo (OR 31.65; 95% CI 4.83 to 207.35; 2 RCTs; 54 women; I(2) = 0%). Only one study (Bagaria 2009) reported endometrial hyperplasia at the end of the therapy (12/19 women in the mifepristone group versus 0/16 in the placebo group; OR 55.0; 95% CI 2.86 to 105.67). Engman 2009 found a significantly higher rate of cystic glandular dilatation in women in the mifepristone group (5/8 women biopsied) compared with the placebo group (1/11 women biopsied) (OR 16.67; 95% CI 1.36 to 204.03). One study (Fiscella 2006) suggested significant improvements (P < 0.001) for specific quality of life outcomes.Authors' conclusionsMifepristone reduced heavy menstrual bleeding and improved fibroid-specific quality of life. However, it was not found to reduce fibroid volume. Further well-designed, adequately powered RCTs are needed before a recommendation can be made on the use of mifepristone for the treatment of uterine fibroids.
| S-EPMC8212859 | biostudies-literature
Project description:BackgroundUterine fibroids are the most common non-malignant growths in women of childbearing age. They are associated with heavy menstrual bleeding and subfertility. Herbal preparations are commonly used as alternatives to surgical procedures.ObjectivesTo assess the benefits and risks of herbal preparations for uterine fibroids.Search strategyAuthors searched following electronic databases: the Trials Registers of the Cochrane Menstrual Disorders and Subfertility Group and the Cochrane Complementary Medicine Field, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, the Chinese Biomedical Database, the Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), AMED, and LILACS. The searches ended on 31st December 2008.Selection criteriaRandomised controlled trials comparing herbal preparations with no intervention, placebo, medical treatment or surgical procedures in women with uterine fibroids. We also included trials of herbal preparations with or without conventional therapy.Data collection and analysisTwo review authors collected data independently. We assessed trial risk of bias according to our methodological criteria . We presented dichotomous data as risk ratios (RR) and continuous outcomes as mean difference (MD), both with 95% confidence intervals (CI).Main resultsWe included two randomised trials (involved 150 women) with clear description of randomisation methods. The methodological risk of bias of the trials varied. There were variations in the tested herbal preparations, and the treatment duration was six months. The outcomes available were not the primary outcomes selected for this review, such as symptom relief or the need for surgical treatment; trials mainly reported outcomes in terms of shrinkage of the fibroids.Compared with mifepristone, Huoxue Sanjie decoction showed no significant difference in the disappearance of uterine fibroids, number of patients with shrinking of uterine fibroids or average volume of uterine fibroids, but less effective than mifepristone on reducing average size of uterus (mean difference 23.23 cm(3),95% confidence interval 17.85 to 28.61). There was no significant difference between Nona Roguy herbal product and GnRH agonist in average volume of uterine fibroids or size of uterus. No serious adverse effects from herbal preparations was reported.Authors' conclusionsCurrent evidence does not support or refute the use of herbal preparations for treatment of uterine fibroids due to insufficient studies of large sample and high quality. Further high quality trials evaluating clinically relevant outcomes are warranted.
| S-EPMC3155698 | biostudies-literature
Project description:We review recent studies dealing with the molecular genetics and basic results of omics analysis of uterine leiomyoma (LM)-a common benign muscle tumor of the uterus. Whole genome studies of LM resulted in the discovery of many new gene nets and biological pathways, including its origin, transcriptomic, and epigenetic profiles, as well as the impact of the inter-cell matrix in LM growth and involvement of microRNA in its regulation. New data on somatic cell mutations ultimately involved in the origin, distribution and growth of LM are reviewed. Putative identification of LM progenitor SC (stem cells) giving rise to maternal fibroid nodes and junctional zones provide a new clue for hypotheses on the pathogenomics of LM. The reviewed data are consistent with at least two different but probably intimately interacted molecular mechanisms of LM. One of them (the genetic hypothesis) is focused primarily on the MED12 gene mutations and suggests its onset in the side population of embryonic myoblasts of the female reproductive system, which later gave rise to multiple small and medium fibroids. The single and usually large-size fibroids are induced by predominantly epigenetic disorders in LM SC, provoked by enhanced expression of the HMGA2 gene caused by its hypomethylation and epigenetic deregulation enhanced by hypoxia, muscle tension, or chromosome instability/aberrations. The pathogenomics of both genetic and epigenetic programs of LM with many peculiarities at the beginning later became rather similar and partly overlapped due to the proximity of their gene nets and epigenetic landscape. Pathogenomic studies of LM open ways for elaboration of novel strategies of prevention and treatment of this common disease.
| S-EPMC6940759 | biostudies-literature
Project description:Uterine fibroids (UFs) are benign tumors that arise from a single genetically altered mesenchymal stem cell under the influence of gonadal hormones. UFs are the most common benign gynecologic tumors in premenopausal women worldwide. It is estimated that nearly 70% to 80% of women will develop UFs at some point during their lifetime. UFs often present with abnormal uterine bleeding (AUB), pelvic fullness, and may have deleterious effects on fertility. The natural regression of UFs begins in menopause. This is, however, a generality as this pathology may still be present in this age group. Many clinicians are concerned about hormone therapy (HT) because of UFs regrowth; nevertheless, research of this subject remains inconclusive. If UFs are present in perimenopause or menopause, they typically manifest as AUB, which represents up to 70% of all gynecological consultations in perimenopausal and postmenopausal women. As AUB is a broad symptom and may not be specific to UFs, a thorough evaluation is required for correct diagnosis and proper treatment accordingly. Understanding the unique characteristics of the available treatment modalities is crucial in deciding the appropriate treatment approach. Decision on treatment modality should be made based on selection of the least morbidity and lowest risk for each patient. Multiple modalities are available; however, surgery remains the method of choice, with the best cure rates. Various attempts to create an inexpensive, safe, and effective drug for the treatments of UFs are still in the early stages of the clinical trials with some showing great promise. Treatment options include tibolone, aromatase inhibitors, selective estrogen receptor modulators, uterine artery embolization, and selective progesterone receptor modulators.
| S-EPMC6994343 | biostudies-literature