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  • Bifidobacterium pseudolongum reduces triglycerides by modulating gut microbiota in mice fed high-fat food
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-24
    Tingbei Bo; Jing Wen; Yuanchun Zhao; Shuangjie Tian; Xueying Zhang; Dehua Wang

    Obesity has become a growing concern around the world. The purpose of this study was to investigate the potential benefit of Bifidobacterium pseudolongum (B. pseudolongum) on obesity, gut microbiota, and its physiological mechanism. The obese mice model was established with a high-fat diet (HFD), and the treatment were used the strain B. pseudolongum. We investigated the changes in fat content, plasma metabolites and gut microbiota on obese mice and B. pseudolongum treated obese mice. We found that B. pseudolongum treatment significantly decreased the body mass (about 12%), plasma triglycerides (about 12.4%), gross energy intake (about 12.8%), and visceral fat (about 26.5%) in obese mice. Further, High-throughput pyrosequencing of the 16S rRNA demonstrated that B. pseudolongum treatment markedly recovered the gut microbiota dysbiosis in obese mice, including the diversity of microbiota and the ratio of Firmicutes to Bacteroidetes. B. pseudolongum treatment increased the abundance of the bacterial genus Butyricimonas and Bifidobacterium. Therefore, B. pseudolongum may have therapeutic potential for the treatment of diet-induced obesity (DIO). B. pseudolongum treatment could change host gut microbiota and provide benefits to host digestive processes that mitigate metabolic diseases.

    更新日期:2020-01-24
  • Molecular docking, anti-proliferative activity and induction of apoptosis in human liver cancer cells treated with androstane derivatives: Implication of PI3K/AKT/mTOR pathway
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-23
    Shahad W. Kattan; Mohamed S. Nafie; Gamal A. Elmgeed; Walla Alelwani; Muhammad Badar; Mohamed A. Tantawy
    更新日期:2020-01-23
  • Molecular mechanisms of posaconazole- and itraconazole-induced pseudohyperaldosteronism and assessment of other systemically used azole antifungals
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-23
    Katharina R. Beck; Lucija Telisman; Chris J. van Koppen; George R. Thompson; Alex Odermatt
    更新日期:2020-01-23
  • Impact of Dietary Vitamin D on Initiation and Progression of Oral Cancer
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-22
    Aparajita Verma; Vui King Vincent-Chong; Hendrik DeJong; Pamela A. Hershberger; Mukund Seshadri

    Calcitriol, the active metabolite of vitamin D, has been widely studied for its preventive and therapeutic activity against several cancers including oral squamous cell carcinoma (OSCC). However, the impact of dietary vitamin D supplementation on initiation and progression of OSCC is unclear. To address this gap in knowledge, we conducted preclinical trials using the 4-nitroquinoline-1-oxide (4NQO) carcinogen model of oral carcinogenesis. Female C57BL/6 mice were maintained on one of three vitamin D diets [25 IU, 100 IU, 10,000 IU] and exposed to 4NQO in drinking water for 16 weeks followed by regular water for 10 weeks. Body weight measurements obtained through the study duration did not reveal any differences between the three diets. Animals on 100 IU diet showed lower incidence of high-grade dysplasia/OSCC and higher CD3 + T cells compared to animals on 25 IU and 10000 IU diets. Serum 25(OH)D3 levels were highest in animals on 10000 IU diet at week 0 (prior to carcinogen exposure) but showed ∼50% reduction at week 26. Histologic evaluation revealed highest incidence of OSCC in animals maintained on 10000 IU diet. Animals on 100 IU and 10000 IU diets showed higher vitamin D receptor (VDR) and CYP24A1 immunostaining in high-grade dysplastic lesions and OSCC compared to normal tongue. Validation studies performed in a 4NQO-derived OSCC model showed that short-term treatment of animals on a 25 IU diet with calcitriol significantly inhibited tumor growth compared to controls but did not affect tumor growth in animals on reference diet (1000 IU). Collectively, our results highlight the complex dynamics between vitamin D status and oral carcinogenesis. Our observations also suggest that therapeutic benefits of short-term calcitriol treatment may be more pronounced in vitamin D deficient hosts.

    更新日期:2020-01-22
  • Canadian Recommendations for Vitamin D Intake for Persons Affected by Multiple Sclerosis
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-22
    Stephanie A. Atkinson; James C. Fleet

    In 2016, the Multiple Sclerosis (MS) Society of Canada convened a panel of expert scientists, clinicians and patient advocate to review the evidence for an association between vitamin D status and MS prevention and/or disease modification. The goal was to develop clear and accurate recommendations on optimal vitamin D intake and status for people affected by MS for use in clinical practice and public health policy. The final consensus report was based on a review and grading of existing published papers combined with expert opinions of panel members. The report led to recommendations published in November of 2018 on the website of the MS Society of Canada, one in a format for use by health professionals and another in a question and answer format that was targeted to persons affected by MS and the general public. For people at risk of developing MS, the vitamin D recommendations are similar to those for the general public following the Dietary Reference Intakes (DRI) for Canada and the United States. Adults should achieve and maintain a normal vitamin D status with monitoring by physicians (serum 25-hydroxyvitamin D (25(OH)D) = 50-125 nmol/L, requiring 600-4000 IU vitamin D/d intake). For pregnant women, newborn infants, and all youth at risk of MS, vitamin D intakes should also follow DRI recommendations but additionally their serum 25-(OH)D should be monitored. For persons living with MS, existing evidence did not allow prediction of a vitamin D intake that might modify MS disease course. For this group the recommendations included: (1) serum 25-(OH)D should be maintained in the range of 50–125 nmol/L (600-4000 IU/d intake).; and (2) vitamin D should not be used as a standalone treatment for MS. For children and adolescents, serum 25OHD status was recommended to be measured upon diagnosis of a first clinical demyelinating event, and monitored every 6 months to achieve a target of 75 nmol/L Since people living with MS are at increased risk of osteoporosis, falls, and bone fractures, it was recommended to achieve a minimum serum 25OHD concentration that is protective for bone health in the general population. The revision of the MS Society recommendations on vitamin D awaits future clinical trial evidence.

    更新日期:2020-01-22
  • Expression of estrogen receptor α variants and c-Fos in rat mammary gland and tumors
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-20
    Alicia Gutiérrez; Lorena Sambuco; Laura Álvarez; Mariel Núñez; Rosa Bergoc; Elsa Zotta; Gabriela Martín; Andrea Randi

    Breast cancer is currently the leading cause of cancer death among women worldwide. AP-1 (c-Fos/c-Jun) is associated with proliferation and survival, while cytoplasmic c-Fos activates phospholipid synthesis in cells induced to differentiate or grow. Estrogen receptor α 46 (ERα46) is a splice variant of full-length ERα66 and it is known that it has an inhibitory role in cancer cell growth. We investigated c-Fos localization, its relationship to AP-1, the non genomic pathway of phospho-Tyr537-ERα66, as well as ERα46 and ERα66 isoforms in rat mammary gland development and carcinogenic transformation, and in mammary tumors. Female rats were injected: a) saline solution (Control mammary gland, CMG) or b) N-Nitroso-N-methyl urea (NMU), and samples were taken at 60, 90, 120 and 150 days of life. In addition, we analyzed hormone-dependent (HD) and independent (HI) tumors in ovariectomized rats, and intact tumors (IT) in non-ovariectomized ones. Our results show that, in CMG, nuclear c-Fos and proliferation decreased with age, AP-1 content was low, and nuclear ERα46/ERα66 ratio was higher than 1. In NMU, nuclear c-Fos and proliferation increased with carcinogenic transformation, AP-1 content was high, and nuclear ERα46/ERα66 was below 1. As tumor grade increased, proliferation, nuclear c-Fos and AP-1 expression were negatively associated to nuclear ERα46/ERα66 in IT. In HD, nuclear ERα46/ERα66, nuclear c-Fos expression, AP-1 levels and proliferation were lower than in HI, whose growth is estrogen-independent. Phospho-Tyr537-ERα66 content and ERK1/2 activation were associated with AP-1 levels and cell proliferation. Collectively, our findings support the notion that variant detection and ERα46/ERα66 ratio could shed light on the role of ERα isoforms in mammary gland transformation and the behavior of ERα positive mammary tumors.

    更新日期:2020-01-21
  • Development and application of a LC-MS/MS assay for simultaneous analysis of 25-hydroxyvitamin-D and 3-epi-25-hydroxyvitamin-D metabolites in canine serum
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-17
    Emma A. Hurst; Natalie Z. Homer; Scott G. Denham; Emma MacFarlane; Susan Campbell; Maaike Boswinkel; Richard J. Mellanby

    Hypovitaminosis D and hypervitaminosis D are well recognised disorders in dogs. Hypovitaminosis D can occur following consumption of a diet inadequately supplemented with vitamin D or as a sequelae of severe intestinal disease. Hypervitaminosis D may occur as a result of consuming proprietary dog foods over-supplemented with vitamin D or through ingestion of vitamin D containing medicinal products or rodenticides. Consequently, there is a clear need to establish a methodology that can accurately quantify vitamin D metabolites across a broad dynamic range in dogs. The existence of C3-epimers of vitamin D metabolites has yet to be elucidated in dogs, yet are known to interfere with the analysis of vitamin D and have unknown biological activity in other species. Here, we describe the development and validation of a sensitive, specific and robust analytical liquid chromatography tandem mass spectrometry (LC-MS/MS) assay capable of separating and accurately measuring 25-hydroxyvitamin-D2/3 (25(OH)D2/3) and 3-epi-25-hydroxyvitamin-D2/3 (3-epi-25(OH)D2/3). We describe a simplified workflow utilising supported liquid extraction (SLE) without derivatization that provides good linearity (mean r > 0.996) and accuracy across a broad dynamic range of 4 - 500 nmol/L for D3 metabolites and 7.8 – 500 nmol/L for D2 metabolites. Upon application of this assay to 117 canine serum samples, 25(OH)D3 was detectable in all samples with a median concentration of 82.1 nmol/L (inter-quartile range (IQR) 59.7 – 101.8 nmol/L). 3-epi-25(OH)D3 could be detected in 87.2% of the study population, with a median concentration of 5.2 nmol/L (2.4 – 8.1 nmol/L). However, 3-epi-25(OH)D3 was quantified below the LLOQ in 40.2% of these samples. 3-epi-25(OH)D3 contributed on average 6.3% to 25(OH)D3 status (contribution ranges from 0 – 23.8%) and a positive correlation was detected between 25(OH)D3 and 3-epi-25(OH)D3 concentrations. Free 25(OH)D was also measured using an immunoassay with a median concentration of 15.2 pmol/L (12.5 – 23.2 pmol/L), and this metabolite was also positively correlated to both 3-epi-25(OH)D3 and 25(OH)D3 concentrations. D2 metabolites were not detected in canine serum as expected. Vitamin D metabolite concentrations were variable between individuals, and research into the causes of this variation should include factors such as breed, age, sex and neuter status to determine the impact of genetic and hormonal factors. Given the clinical importance of vitamin D in dogs, and the immense potential for utilising this species as a model for human disease, further elucidation of the vitamin D pathway in this species would provide immense clinical and research benefit.

    更新日期:2020-01-17
  • Sex dimorphism in an animal model of multiple sclerosis: focus on pregnenolone synthesis
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-17
    S. Giatti; R. Rigolio; S. Diviccaro; E. Falvo; D. Caruso; L.M. Garcia-Segura; G. Cavaletti; R.C. Melcangi

    Neuroactive steroids, molecules produced from cholesterol in steroidogenic cells (i.e., peripheral glands and nervous system) are physiological modulators and protective agents of nervous function. A possible role for neuroactive steroids in the sex-dimorphic clinical manifestation, onset and progression of Multiple Sclerosis (MS) has been recently suggested. To explore this possibility, we assessed the synthesis of the first steroidogenic product (pregnenolone; PREG) in the spinal cord of experimental autoimmune encephalomyelitis rats, a MS model. Data obtained indicate that the synthesis of PREG in the spinal cord is altered by the pathology in a sex dimorphic way and depending on the pathological progression. Indeed, in male spinal cord the synthesis was already decreased at the acute phase of the disease (i.e., 14 days post induction - dpi) and maintained low during the chronic phase (i.e., 45 dpi), while in females this effect was observed only at the chronic phase. Substrate availability had also a role in the sex dimorphic kinetics. Indeed, at the chronic phase, male animals showed a reduction in the levels of free cholesterol coupled to alteration of cholesterol metabolism into oxysterols; these effects were not observed in female animals. These findings suggest that the comprehension of the neurosteroidogenic processes could be relevant to better understand the sexual dimorphism of MS and to possibly design sex-oriented therapeutic strategies based on neuroactive steroids.

    更新日期:2020-01-17
  • VDR in Salivary Gland Homeostasis and Cancer
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-17
    Kara A. DeSantis; Samantha L. Robilotto; Mark Matson; Noor M. Kotb; Cathryn M. Lapierre; Zenab Minhas; Alana A. Leder; Khushbakht Abdul; Emily M. Facteau; JoEllen Welsh

    The vitamin D receptor (VDR) and its ligand 1,25(OH)2D3 (1,25D) impact differentiation and exert anti-tumor effects in many tissues, but its role in salivary gland has yet to be defined. Using immunohistochemistry (IHC), we have detected strong VDR expression in murine and human salivary gland ducts. Compared to normal gland, VDR protein expression was retained in differentiated human pleomorphic adenoma (PA) but was undetectable in undifferentiated PA and in carcinomas, suggesting deregulation of VDR during salivary cancer progression. To gain insight into the potential role of VDR in salivary cancer, we assessed the effects of vitamin D in vivo and in vitro. Despite the presence of VDR in salivary gland, chronic dietary vitamin D restriction did not alter morphology of the salivary epithelium in C57/Bl6 mice. The localization of VDR in ductal epithelium prompted us to examine the effects of 1,25D in an established cell line (mSGc) derived from normal murine submandibular gland (SMG). This previously characterized cell line consists of multiple stem, progenitor and differentiated cell types as determined by mutually exclusive cellular expression of basal, ductal and myoepithelial markers. We demonstrated VDR expression and regulation of VDR target genes Vdr and Postn by 1,25D in mSGc, indicating functional ligand-mediated transcriptional activity. The effect of VDR signaling on epithelial differentiation markers was assessed by qPCR and IHC in mSGc cells treated with 1,25D. We found that 1,25D reduced mRNA expression of the basal cell progenitor marker keratin 5 (K5) and increased expression of the differentiated ductal cell marker keratin 7 (K7). Further, we found that 1,25D significantly decreased the number of proliferating cells, including proliferating K5+ cells. Characterization of cell cycle by Muse cytometry indicated 1,25D treatment decreased cells in S, G2, and M phase. The inhibition of K5+ cell proliferation by 1,25D is of particular interest because K5+ basal cells contribute to a wide variety of salivary tumor types. Our studies suggest that 1,25D alters cancer-relevant progenitor and differentiation markers in the salivary gland.

    更新日期:2020-01-17
  • Characteristics and sex dimorphism of 17β-hydroxysteroid dehydrogenase family genes in the olive flounder Paralichthys olivaceus
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-17
    Congcong Zou; Lijuan Wang; Yuxia Zou; Zhihao Wu; Wenxiang Wang; Shaoshuai Liang; Ling Wang; Feng You

    Sex steroid hormones play important roles in fish sex differentiation, gonadal development and secondary sexual characteristics. Olive flounder Paralichthys olivaceus is a valuable commercial marine fish species and has marked sexual dimorphism. However, the mechanisms of action of sex hormones in flounder sex are still unclear. In this study, a total of ten Hsd17b family genes, including Hsd17b3, -4, -7, -8, -9, -10, -12a, -12b, -14 and -15, were identified in the flounder, which encoded critical enzymes acting on sex steroid synthesis and metabolism. Hsd17b genes were distributed on eight chromosomes. Hsd17b12a and -12b were located on chromosomes 19 and 7, respectively. It was speculated that these two genes were just highly similar rather than different transcripts derived from the same gene. According to the results of domain and motif analyses, they all belonged to the SDR superfamily and contained conserved Hsd17b motifs TGxxxGxG, PGxxxT, NNAG and YxxxK. Analysis of amino acid sequences predicted that Hsd17b1, -4, -7, -12a and -14 were hydrophilic proteins. The stability of Hsd17b1, -3 and -12b proteins was predicted to be low. The various Hsd17b family genes differed in tissue expression pattern, and Hsd17b10, -12a and -12b were highly expressed in the flounder ovary. Moreover, throughout gonadal development, Hsd17b3 was highly expressed in the testis, and Hsd17b1, -12a and -12b were highly expressed in the ovary, suggesting that they might play an important role in testosterone synthesis in the testis or estrogen synthesis in the ovary. Activities of Hsd17b3 at stages I-V were all significantly higher in the testis than in the ovary (P < 0.05, P < 0.01). Transfection analysis in HEK293 T cells showed that Hsd17b1 and -3 were located in both the cytoplasm and nucleus. Additionally, after challenging fish with tamoxifen, Hsd17b3 expression level in the testis decreased significantly (P < 0.01), and in the ovary no significant change was observed. Moreover, the expression of Hsd17b1 in the ovary was significantly upregulated after injection with flutamide (P < 0.05). These findings introduce the characteristics of the flounder Hsd17b in subfamily, which contribute to our understanding of the regulation of sex steroid hormone synthesis in fish gonadal development.

    更新日期:2020-01-17
  • DAILY AND SEASONAL MITOCHONDRIAL PROTECTION: UNRAVELING COMMON POSSIBLE MECHANISMS INVOLVING VITAMIN D AND MELATONIN
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-16
    Feres José Mocayar Marón; León Ferder; Russel J. Reiter; Walter Manucha

    From an evolutionary point of view, vitamin D and melatonin appeared very early and share functions related to defense mechanisms. In the current clinical setting, vitamin D is exclusively associated with phosphocalcic metabolism. Meanwhile, melatonin has chronobiological effects and influences the sleep-wake cycle. Scientific evidence, however, has identified new actions of both molecules in different physiological and pathological settings. The biosynthetic pathways of vitamin D and melatonin are inversely related relative to sun exposure. A deficiency of these molecules has been associated with the pathogenesis of cardiovascular diseases, including arterial hypertension, neurodegenerative diseases, sleep disorders, kidney diseases, cancer, psychiatric disorders, bone diseases, metabolic syndrome, and diabetes, among others. During aging, the intake and cutaneous synthesis of vitamin D, as well as the endogenous synthesis of melatonin are remarkably depleted, therefore, producing a state characterized by an increase of oxidative stress, inflammation, and mitochondrial dysfunction. Both molecules are involved in the homeostatic functioning of the mitochondria. Given the presence of specific receptors in the organelle, the antagonism of the renin-angiotensin-aldosterone system (RAAS), the decrease of reactive species of oxygen (ROS), in conjunction with modifications in autophagy and apoptosis, anti-inflammatory properties inter alia, mitochondria emerge as the final common target for melatonin and vitamin D. The primary purpose of this review is to elucidate the common molecular mechanisms by which vitamin D and melatonin might share a synergistic effect in the protection of proper mitochondrial functioning.

    更新日期:2020-01-17
  • Impact of Maternal Smoking Associated Lyso-phosphatidylcholine 20:3 on Offspring Brain Development
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-15
    Lu Yong-Ping; Christoph Reichetzeder; Cornelia Prehn; Liang-Hong Yin; Chang Chu; Saban Elitok; Bernhard K. Krämer; Jerzy Adamski; Berthold Hocher

    Maternal smoking during pregnancy affects fetal neurological development. Metabolomic studies in the general population suggest that smoking is associated with characteristic metabolic alterations. We investigated the association between the maternal smoking status, the fetal metabolome and head circumference at birth, as a surrogate parameter of brain development. 320 mother/newborn pairs of the Berlin Birth Cohort were investigated. Anthropometric parameters, including head circumference, of newborns of smoking mothers, former smoking mothers, and never smoking mothers were compared to assess the impact of maternal smoking behavior. Associations between maternal smoking behavior and 163 cord blood metabolites and associations between newborn head circumference and concentrations of smoking behavior related metabolites were analyzed. Male newborns of smoking mothers had a reduced head circumference when compared with newborns from former smoking and never smoking mothers (p < 0.05). Using linear regression models corrected for established confounding factors, maternal smoking during pregnancy showed an independent association with head circumference (95% CI: -0.75~-0.41 cm, p = 2.45×10-11). In a stepwise linear regression model corrected for known confounding factors of brain growth lyso-phosphatidylcholine 20:3 (95% CI: 6.68~39.88 cm, p = 4.62×10-4) was associated with head circumference in male offspring only. None of the metabolites were associated with head circumference of female newborns. In conclusion, maternal smoking during pregnancy impacted on male offspring’s development including brain development. The smoking related metabolite lyso-phosphatidylcholine 20:3 was associated with head circumference of male offspring.

    更新日期:2020-01-15
  • Vitamin D and sex steroid production in men with normal or impaired Leydig cell function
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-15
    Rune Holt; Li Juel Mortensen; Katrine Harpelunde Poulsen; John Erik Nielsen; Hanne Frederiksen; Niels Jørgensen; Anne Jørgensen; Anders Juul; Martin Blomberg Jensen

    Production of testosterone is under tight control by human chorion gonadotropin (hCG) during fetal life and luteinizing hormone (LH) in adulthood. Several animal and human studies have linked vitamin D status with sex steroid production although it is not clear whether there exist a direct or indirect involvement in androgen production. Few studies have investigated this crosslink in young healthy men and putative direct or synergistic effect of activated vitamin D (1,25(OH)2D3) and LH/hCG on sex steroid production in vitro. Here, we present cross-sectional data from 300 young men and 41 hCG-stimulated men with impaired Leydig cell function combined with data from an ex vivo culture of human testicular tissue exposed to 1,25(OH)2D3 alone or in combination with hCG. Serum 25-OHD was positively associated with SHBG (β:0.002; p = 0.023) and testosterone/estradiol-ratio (β:0.001; p = 0.039), and inversely associated with free testosterone (%) (free testosterone/total testosterone) (β:-0.002; p = 0.016) in young men. Vitamin D deficient men had higher total and free estradiol concentrations than men with higher vitamin D status (19% and 18%, respectively; p < 0.01). Interestingly, men with impaired Leydig cell function and vitamin D deficiency had a significantly lower hCG-mediated increase in total and free testosterone compared with vitamin D sufficient men (p < 0.05). Accordingly, testicular tissue exposed to 0.1 µM 1,25(OH)2D3 had a 15% higher testosterone release into the media compared with vehicle treated specimens (p = 0.030). In conclusion, vitamin D deficiency is associated with lower testosterone/estradiol ratio in young men and lower Leydig cell sensitivity after hCG-stimulation in men with impaired gonadal function. The significant effect of 1,25(OH)2D3 on testosterone production in a human testis model supports that the stimulatory effect at least in part may be direct. Larger placebo-controlled studies are needed to determine whether vitamin D supplementation can influence testosterone production.

    更新日期:2020-01-15
  • 更新日期:2020-01-15
  • 25(OH)D3 stimulates the expression of vitamin D target genes in renal tubular cells when Cyp27b1 is abrogated
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-13
    Takahiro Kikuyama; Takao Susa; Mimi Tamamori-Adachi; Masayoshi Iizuka; Miho Akimoto; Hiroko Okinaga; Yoshihide Fujigaki; Shunya Uchida; Shigeru Shibata; Tomoki Okazaki

    Recently, it was reported that 25(OH)D3 (25D3) has physiological bioactivity in certain tissues derived from Cyp27b1 knockout mice. To investigate the function of 25D3 in the kidney as an informational crossroad of various calciotropic substances, we employed the CRISPR-Cas9 system to knock out Cyp27b1 in the mouse renal distal tubular mDCT cell line. Unlike the previously reported mice in which Cyp27b1 was targeted systemically, Cyp27b1 knockout mDCT cells did not produce any measurable 1α,25(OH)2D3 (1,25D3) after 25D3 administration. As was seen with treatment of Cyp27b1 knockout mDCT cells with ≥10-8 M of 1,25D3, the administration of 10-7 M of 25D3 translocated the vitamin D3 receptor (VDR) into the nucleus and promoted the expression of the representative 1,25D3-responsive gene Cyp24a1. The exhaustive target gene profiles of 25D3 were similar to those of 1,25D3. Subsequently, we confirmed that 25D3 induced the expression of the calcium reabsorption-related gene calbindin-D9K, in a way similar to 1,25D3. We also found that 1,25D3 and 25D3 induced the expression of the megalin gene. A chromatin immunoprecipitation assay identified two vitamin D response elements in the upstream region of the megalin gene that seemed to contribute to its expression. Together, we surmise that the ability of 25D3 to stimulate VDR target genes may provide a novel perspective for its role in certain tissues.

    更新日期:2020-01-14
  • Cholestenoic Acid Analogues as Inverse Agonists of the Liver X Receptors
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-10
    Lautaro D. Alvarez; María V. Dansey; María F. Ogara; Carina I. Peña; René Houtman; Adriana S. Veleiro; Adali Pecci; Gerardo Burton
    更新日期:2020-01-11
  • 更新日期:2020-01-09
  • Chemotherapy and vitamin D supplement use are determinants of serum 25-hydroxyvitamin D levels during the first six months after colorectal cancer diagnosis
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-07
    Evertine Wesselink; Martijn J.L. Bours; Johannes H.W. de Wilt; Michiel Aquarius; Stephanie O. Breukink; Bibi Hansson; Eric T.P. Keulen; Dieuwertje E. Kok; Jody van den Ouweland; Eline H. van Roekel; Merel Snellen; Renate Winkels; Renger F. Witkamp; Moniek van Zutphen; Matty P. Weijenberg; Ellen Kampman; Fränzel van Duijnhoven

    Vitamin D metabolites, including 25-hydroxyvitamin D3 (25(OH)D3), may inhibit colorectal cancer (CRC) progression. Here we investigated cross-sectional and longitudinal associations of demographic, lifestyle and clinical characteristics with 25(OH)D3 serum concentrations in CRC patients at diagnosis and six months later. In 1,201 newly-diagnosed stage I-III CRC patients, 25(OH)D3 levels were analysed twice. Multivariable linear regression was used to assess demographic, lifestyle and clinical determinants of 25(OH)D3 levels at diagnosis and six months later. Linear mixed models were used to assess characteristics associated with changes in 25(OH)D3 levels over time. Results of our study showed that vitamin D intake from diet or supplements, use of calcium supplements, BMI and disease stage were associated with 25(OH)D3 levels at both time points. Six months after diagnosis, gender and having received chemo- and/or radiotherapy were also associated with 25(OH)D3 levels. A stronger decrease in 25(OH)D3 levels was observed in patients who underwent chemotherapy, compared to surgery only (β-6.9 nmol/L 95%CI -9.8; -4.0). Levels of 25(OH)D3 levels increased in patients using vitamin D supplements compared to non-users (β 4.0 nmol/L 95%CI 1.2; 6.8). In conclusion, vitamin D supplement use and treatment appear to be important determinants of 25(OH)D3 levels during the first six months after CRC diagnosis, although the difference in 25(OH)D3 levels was minor. ClinicalTrials.gov Identifier: NCT03191110

    更新日期:2020-01-07
  • Investigating a suitable model for the study of vitamin D mediated regulation of human placental gene expression
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2020-01-02
    Claire L Simner; Brogan Ashley; Cyrus Cooper; Nicholas C Harvey; Rohan M Lewis; Jane K Cleal

    Transfer and metabolism of vitamin D across the human placenta is required for fetal development. However, these fundamental mechanisms are not well understood and model systems are required to help understand them. The BeWo choriocarcinoma cell line is derived from extravillous trophoblast but is used as a model for villous syncytiotrophoblast and the placental barrier. Questions have been raised about the suitability of the BeWo cell line as a model for villous trophoblast. This study compares the expression of amino acid transporters and vitamin D related genes in human term placenta with the BeWo and human embryonic kidney (HEK)293 cell lines. HEK293 cells, as transporting epithelium may be more similar to placenta. Gene expression in term placenta was much more similar to HEK293 than BeWo. This study provides further evidence that the BeWo cell line is not an appropriate model for villous trophoblast and a model that more closely represents the human placenta is now required to investigate the effects of vitamin D on the placenta ex-vivo.

    更新日期:2020-01-02
  • The role of diosgenin in diabetes and diabetic complications
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-30
    Qingxia Gan; Jin Wang; Ju Hu; Guanhua Lou; Haijun Xiong; Chengyi Peng; Song Zheng; Qinwan Huang

    Diabetes mellitus is a chronic and common metabolic disease that seriously endangers human health. Hyperglycemia and long-term metabolic disorders in diabetes will cause damage to the whole body tissues and organs, resulting in serious complications. Nowadays, drugs for treating diabetes on the market has strong side effects, new treatments thus are urgently needed. Natural therapy of natural ingredients is a promising avenue, this is because natural ingredients are safer and they also show strong activity in the treatment of diabetes. Diosgenin is such a very biologically active natural steroidal sapogenin. The research of diosgenin in the treatment of diabetes and its complications has been widely reported. This article reviews the effects of diosgenin through multiple targets and multiple pathways in diabetes and its complications which including diabetic nephropathy, diabetic liver disease, diabetic neuropathy, diabetic vascular disease, diabetic cardiomyopathy, diabetic reproductive dysfunction, and diabetic eye disease.

    更新日期:2019-12-30
  • Association of nonalcoholic fatty liver disease with serum vitamin D levels in combination of physical fitness in Korean older adults
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-28
    Inhwan Lee; Eunmi Park; Jinkyung Cho

    The prevalence of non-alcoholic fatty liver disease (NAFLD) tends to increase with age, but little is known regarding relations between the risk of NAFLD in older adults and serum vitamin D (25-hydroxyvitamin D) and physical fitness levels. The aim of this study was to investigate the relationship between NAFLD risk and serum vitamin D levels combined with physical fitness in elderly adults using a non-invasive diagnostic approach. We enrolled 533 Korean older adults (80.8% women), aged 65 years or older in this cross-sectional study. NAFLD in absence of another cause of liver disease was defined according to the ZJU and NAFLD liver fat (LFS) score. Physical fitness was assessed using a senior fitness test protocol. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of NAFLD for different combinations of serum vitamin D and physical fitness levels. According to the ZJU (OR: 3.073, CI: 1.285-7.350, p = 0.012) and LFS (OR = 2.443, CI = 1.071-5.572, p = 0.034), individuals with serum vitamin D < 30 ng/ml and poor physical fitness had a significantly higher risk of NAFLD than individuals with serum vitamin D ≥ 30 ng/ml and high fitness (reference, OR = 1), even after adjustments for age, sex, smoking, alcohol consumption and physical inactivity. However, there was no significant association after adjustment for additional metabolic diseases. Our findings suggest that the maintenance of appropriate levels of serum vitamin D and/or high physical fitness and the monitoring metabolic diseases can help reduce the risk of NAFLD in older adults.

    更新日期:2019-12-29
  • Structure-dependent retention of steroid hormones by common laboratory materials
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-26
    Jeffrey M. McManus; Nima Sharifi

    The tendency of steroid molecules to adsorb to various materials, particularly plastics, has been known of for decades but has not received widespread attention in the scientific community, and a modern, systematic study is lacking. This adsorption is an important consideration for researchers working with steroid hormones as it could skew the results of various experiments. Here we show that steroids adsorb to various vessels used in experiments, including microcentrifuge tubes, glass vials, and cell culture plates, in a manner that depends on the steroid’s molecular structure and on the type of vessel. The lipophilicity of steroids is a strong predictor of the degree of adsorption, with nearly 50% of the most lipophilic steroid tested, pregnenolone, retained in a high-adsorbing microcentrifuge tube after one hour incubation of an aqueous pregnenolone solution followed by removal of the aqueous solvent. We also show the effects of other factors such as incubation time, centrifugation, and temperature on adsorption, and show that adsorption can be mostly prevented by the presence of serum proteins in steroid solutions and/or by the use of low-adsorbing tubes.

    更新日期:2019-12-27
  • The implications of vitamin content in the plasma in reference to the parameters of carbohydrate metabolism and hormone and lipid profiles in PCOS
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-26
    Małgorzata Szczuko; Viktoria Hawryłkowicz; Justyna Kikut; Arleta Drozd

    So far, there have been no analyses of correlations between the level of water-soluble vitamins in women with polycystic ovary syndrome (PCOS) and hormone and lipid profiles as well as carbohydrate metabolism. The unpopular concept that PCOS may also be conditioned by a chronic infection leads to a suspicion that water-soluble vitamins may be involved in the struggle against PCOS. This is why the aim of this research was to determine whether there are any indications that could confirm this hypothesis. The study included 64 women of Caucasian race: 50 patients aged 29.52 ± 7.01 years with PCOS, diagnosed according to the Rotterdam criteria. The control group consisted of 14 women aged 30.23 ± 6.3 years with correct BMI. HPLC Infinity1260 Binary LC (Agilent Technologies, Waldbronn, Germany) was used to analyze nine vitamins. The vitamins were separated using the gradient method, a buffer of 25 mM HK2PO4 with pH equal to 7.0, and 100% methanol buffer. The acquired results were compared using Statistica 12.0 (Statsoft, Tulsa, Oklahoma, USA). Non-parametric tests were used: Mann–Whitney tests for comparisons between groups (PCOS and control group, CG), in which p < 0.05 was considered statistically significant. Subsequently, we performed a correlation matrix of the biochemical parameters of blood with vitamins at p ≤ 0.05. Higher concentrations of ascorbic acid were observed in PCOS. The content of the remaining vitamins was higher in the control group, and the statistical differences were significant in reference to thiamine, riboflavin, pyridoxine and folic acid in comparison to the control group. A significant positive correlation was observed between vitamin C and testosterone/insulin, another between riboflavin and androstenedione/testosterone, next between biotin and thyrotropic hormone (TSH), between pantothenic acid and dehydroepiandrosteron (DHEA-SO4), and finally between pyridoxine and androstenedione. A negative correlation was observed in the case of niacin with sex hormone binding protein (SHBG) and high density lipoprotein (HDL). Water-soluble vitamins play an important role in the therapy of women with PCOS through the reduction of antioxidative stress and low-intensity inflammation caused by various factors, including chronic infection.

    更新日期:2019-12-27
  • Targeting 1,25(OH)2D-Mediated Calcium Absorption Machinery in Proximal Colon with Calcitriol Glycosides and Glucuronides
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-24
    H. Jiang; R.L. Horst; N.J. Koszewski; J.P. Goff; S. Christakos; J.C. Fleet

    High intestinal calcium (Ca) absorption efficiency is associated with high peak bone mass in adolescents and reduced bone loss in adulthood. Transepithelial intestinal Ca absorption is mediated by 1,25-dihydroxyvitamin D (1,25(OH)2D, calcitriol) through the vitamin D receptor (VDR). Most research on Ca absorption focuses on the proximal small intestine but evidence shows that large intestine plays a crucial role in whole body Ca homeostasis. We directly assessed and compared Ca absorption capacity at the proximal colon and duodenum using in situ ligated loops (2 mM Ca, 10 min). In C57BL/6 J mice, the proximal colon (26.2 ± 3.7%) had comparable ability to absorb Ca as the duodenum (30.0 ± 6.7%). In VDR knockout (KO) mice, Ca absorption efficiency was reduced by 67% in duodenum and 48% in proximal colon. These data suggest that large intestine could be targeted to improve Ca absorption and protect bone in at risk-groups (e.g. bariatric patients). Glycoside forms of calcitriol found in Solanum Glaucophyllum (Sg) leaf are biologically inert but can be activated in the colon upon bacterial cleavage of the glycosides. We conducted a study to test whether Sg leaf, as well as a novel, synthetic 1,3-diglucuronide form of calcitriol (1,3-diG) could target the proximal colon and upregulate genes involved in Ca absorption (i.e. Trpv6, S100 g). 13-week-old female C57BL6/J mice were fed AIN93 G diet containing increasing levels of one of the two compounds for 2 weeks (delivering 0, 0.25, 0.5, 1, or 2 ng calcitriol equivalent per day). Both compounds induced a dose-dependent upregulation of Cyp24a1 and Trpv6 gene expression in the proximal colon. 1,3-diG also induced S100 g gene expression in the proximal colon. Duodenal expression of Trpv6 was upregulated at higher doses of 1,3-diG but not Sg leaf. These data suggest that both glycosylated and glucuronidated calcitriol could be used to target the proximal colon but that dosing must be optimized to limit systemic effects that could cause hypercalcemia. Future studies will test the translational potential of these compounds to determine if they can increase Ca absorption at proximal colon and whether this can help protect bone.

    更新日期:2019-12-25
  • Ordered structure-forming properties of the intrinsically disordered AB region of hRXRγ and its ability to promote liquid-liquid phase separation
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-24
    Katarzyna Sołtys; Andrzej Ożyhar

    The retinoid X receptor (RXR) is a member of the nuclear receptor (NR) superfamily that occupies the central position among other NRs by forming both homodimers and heterodimers with other representatives of the family. RXR shares similar structural domains with other members of NRs. The major differences in the subtypes and isoforms of RXR are in the AB region. To date, there have been no data concerning the molecular properties of the AB region of hRXRγ (AB_hRXG). Here, we describe the biochemical and biophysical properties of the recombinant AB_hRXG. The results indicate that AB_hRXG shows the structural and functional characteristics of the pre-molten globule-like (PMG-like) group of intrinsically disordered proteins (IDPs) and also has a significant propensity for folding. We also present the first experimental evidence showing that the AB region of NRs promotes the formation of liquid–liquid phase separation (LLPS).

    更新日期:2019-12-25
  • Plasma oxysterol levels in luminal subtype breast cancer patients are associated with clinical data
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-23
    Alzbeta Kloudova-Spalenkova; Yune-Fang Ueng; Shouzou Wei; Katerina Kopeckova; F. Peter Guengerich; Pavel Soucek

    Oxygenated metabolites of cholesterol (oxysterols) have been previously demonstrated to contribute to progression of various cancers and to modulate resistance to breast cancer endocrine therapy in vitro. We measured prognostic roles of circulating levels of seven major oxysterols in the progression of luminal subtype breast carcinoma. Liquid chromatography coupled with tandem mass spectrometry was used for determination of levels of non-esterified 25-hydroxycholesterol, 27-hydroxycholesterol, 7α-hydroxycholesterol, 7-ketocholesterol, cholesterol-5α,6α-epoxide, cholesterol-5β,6β-epoxide, and cholestane-3β,5α,6β-triol in plasma samples collected from patients (n = 58) before surgical removal of tumors. Oxysterol levels were then associated with clinical data of patients. All oxysterols except cholesterol-5α,6α-epoxide were detected in patient plasma samples. Circulating levels of 7α-hydroxycholesterol and 27-hydroxycholesterol were significantly lower in patients with small tumors (pT1) and cholesterol-5β,6β-epoxide and cholestane-3β,5α,6β-triol were lower in patients with stage IA disease compared to larger tumors or more advanced stages. Patients with higher than median cholestane-3β,5α,6β-triol levels had significantly worse disease-free survival than patients with lower levels (p = 0.037 for all patients and p = 0.015 for subgroup treated only with tamoxifen). In conclusion, this study shows, for the first time, that circulating levels of oxysterols, especially cholestane-3β,5α,6β-triol, may have prognostic roles in patients with luminal subtype breast cancer.

    更新日期:2019-12-23
  • Vitamin D Receptor Fokl polymorphism is a determinant of both maternal and neonatal Vitamin D concentrations at birth
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-20
    Spyridon N. Karras; Theocharis Koufakis; Vasiliki Antonopoulou; Dimitrios G. Goulis; Merve Alaylıoğlu; Erdinc Dursun; Diugy Gezen-Ak; Cedric Annweiler; Stefan Pilz; Hana Fakhoury; Fatme Al Anouti; Vikentia Harizopoulou; Declan P. Naughton; Pantelis Zebekakis; Kalliopi Kotsa

    Maternal vitamin D deficiency is considered to be the key determinant of the development of neonatal vitamin D deficiency at birth and during early infancy. Specific vitamin D receptor (VDR) gene polymorphisms have been associated with adverse pregnancy and offspring outcomes. The aim of this study was to evaluate the effect of maternal and neonatal VDR polymorphisms (ApaI, TaqI, BsmI, FokI, Tru9I) on maternal and neonatal vitamin D status. VDR polymorphisms were genotyped in 70 mother-neonate pairs of Greek origin, and classified according to international thresholds for Vitamin D status. Mean neonatal and maternal 25-hydroxy-vitamin D [25(OH)D] concentrations were 35 ± 20 and 47 ± 26 nmol/l, respectively. Neonatal VDR polymorphisms were not associated with neonatal 25(OH)D concentrations. In contrast, mothers with the Fokl FF polymorphism had a 70% lower risk of vitamin D deficiency [25(OH)D <30 nmol/l] compared with ff ones, after adjustment for several confounders. They were also in 73% and 88% lower risk of giving birth to vitamin D deficient [25(OH)D <30 nmol/l] neonates compared with Ff and ff mothers, respectively. These results suggest a protective role of maternal Fokl FF genotype against both maternal and neonatal vitamin D deficiency. Further studies are needed to clarify the complex gene-gene and gene-environment interactions that determine vitamin D status at birth.

    更新日期:2019-12-21
  • Bacterial steroid-17,20-desmolase is a taxonomically rare enzymatic pathway that converts prednisone to 1,4-androstanediene-3,11,17-trione, a metabolite that causes proliferation of prostate cancer cells
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-20
    Lindsey K. Ly; Joe L. Rowles; Hans Müller Paul; João M.P. Alves; Camdon Yemm; Patricia M. Wolf; Saravanan Devendran; Matthew E. Hudson; David J. Morris; John W. Erdman; Jason M. Ridlon

    The adrenal gland has traditionally been viewed as a source of “weak androgens”; however, emerging evidence indicates 11-oxy-androgens of adrenal origin are metabolized in peripheral tissues to potent androgens. Also emerging is the role of gut bacteria in the conversion of C21 glucocorticoids to 11-oxygenated C19 androgens. Clostridium scindens ATCC 35704 is a gut microbe capable of converting cortisol into 11-oxy-androgens by cleaving the side-chain. The desA and desB genes encode steroid-17,20-desmolase. Our prior study indicated that the urinary tract bacterium, Propionimicrobium lymphophilum ACS-093-V-SCH5 encodes desAB and converts cortisol to 11β-hydroxyandrostenedione. We wanted to determine how widespread this function occurs in the human microbiome. Phylogenetic and sequence similarity network analyses indicated that the steroid-17,20-desmolase pathway is taxonomically rare and located in gut and urogenital microbiomes. Two microbes from each of these niches, C. scindens and Propionimicrobium lymphophilum, respectively, were screened for activity against endogenous (cortisol, cortisone, and allotetrahydrocortisol) and exogenous (prednisone, prednisolone, dexamethasone, and 9-fluorocortisol) glucocorticoids. LC/MS analysis showed that both microbes were able to side-chain cleave all glucocorticoids, forming 11-oxy-androgens. Pure recombinant DesAB from C. scindens showed the highest activity against prednisone, a commonly prescribed glucocorticoid. In addition, 0.1 nM 1,4-androstadiene-3,11,17-trione, bacterial side-chain cleavage product of prednisone, showed significant proliferation relative to vehicle in androgen-dependent growth LNCaP prostate cancer cells after 24 hours (2.3 fold; P < 0.01) and 72 hours (1.6 fold; P < 0.01). Taken together, DesAB-expressing microbes may be an overlooked source of androgens in the body, potentially contributing to various disease states, such as prostate cancer.

    更新日期:2019-12-21
  • Vitamin D deficiency in Kazakhstan: cross-sectional study
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-05
    Olga Gromova, Aikerm Doschanova, Vyacheslav Lokshin, Ainur Tuletova, Galina Grebennikova, Laura Daniyarova, Gulnaz Kaishibayeva, Tair Nurpeissov, Viktoriya Khan, Yuliya Semenova, Albina Chibisova, Natalia Suzdalskaya, Zhanara Aitaly, Natalia Glushkova

    Vitamin D deficiency (VDD) is one of the serious and highly debatable public health problems affecting at least one billion of world population. This study objected to evaluate Vitamin D status in adult population of both sexes residing in different geographical areas of Kazakhstan and to elucidate the possible contributing factors related to VDD. This cross-sectional study covered 6 regions of Kazakhstan and applied the systematic random sampling to recruit 1,347 healthy adults (of whom 819 were females) with mean age 44 ± 14 years. The concentration of 25-hydroxy vitamin D (25-OHD) was measured from May 2018 to August 2018 with Architect 25OH Vitamin D assay (Abbott Ireland Diagnostics Division Lisnamuck, Longford Co. Longford Ireland). Vitamin D deficiency was defined as 25-OHD values not exceeding 20 ng/mL as a reference threshold in healthy population. The median serum 25(OH)D concentrations in all studied regions of Kazakhstan were below the reference threshold (20 ng/mL). The lowest range of vitamin D (<10 ng/mL) was observed more commonly in females (34.6 % – 283) as compared to males (16.7 % – 88) and was significantly higher in Asians (33.2 % – 352) in contrast with Caucasians (6.7 % – 19) (χ2 = 177,939; D.f. = 3; p-value=<0,001). The proportion of severe VDD was higher in individuals with low body mass index (31.1 % – 188) vs. individuals with high body mass index (18.7 % – 50). In this study individuals aged 60 years and older had the most favorable situation with 25-OHD concentrations since these were normal in 14.4 % of observations (χ2 = 26,589; D.f. = 6; p-value=<0,001). Studying the prevalence of VDD is an important public health task. Further research is needed to understand the epidemiology of VDD in more details to tailor intervention programs.

    更新日期:2019-12-05
  • Differential Quantitative Proteomics Reveals Key Proteins Related to Phenotypic Changes of Breast Cancer Cells Expressing Progesterone Receptor A
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-03
    Prangwan Pateetin, Trairak Pisitkun, Eileen McGowan, Viroj Boonyaratanakornkit

    Progesterone receptor isoforms A and B exert different biological effects in breast cancer cells. Alteration of PRA/PRB ratio is often observed during breast cancer progression. High PRA/PRB ratios in breast cancer patients are associated with resistance to chemotherapy and poor prognosis. While it is well accepted that PRA and PRB regulate different sets of genes, how the expression of PRA and PRB alters breast cancer proteomes has not been fully investigated. To directly investigate the effects of PR isoform expression on the breast cancer proteome, both in the presence and absence of progestin, PRA and PRB were independently stably expressed in T47DC42 PR-null breast cancer cells using a doxycycline (Dox)-regulated promoter. Dox induction dose-dependently increased PRA and PRB expression. Dox-induced PRA and PRB showed normal receptor localization and were transcriptionally active. Differential quantitative proteomic analysis by stable isotope dimethyl labeling was performed to quantitatively examine how PR isoforms altered global breast cancer proteomes. Cells expressing PRA in the absence of progestin were enriched in proteins involved in the TCA cycle and enriched in proteins involved in glycolysis and Heat shock factor -1 (HSF-1) activation in the presence of progestin, whilst cells expressing PRB in the absence and presence progestin were significantly enriched in proteins involved in the cell cycle and cell apoptosis pathways. This proteomic data revealed a link between PR isoform expression and alteration in cell metabolism, cell proliferation, and apoptosis. The enrichment of proteins involved in the glycolytic pathway in breast cancer cells expressing PRA is consistent with stem cell-like properties, previously reported in PRA-rich breast cancer cells. Moreover, compared to liganded PRB, liganded PRA differentially upregulated proteins involved in chromatin remodeling, such as linker histone H1.2. Silencing H1.2 gene expression suppressed PRA-mediated cell proliferation and promoted G2/M and S phase entry of the cell cycle. Additionally, liganded PRA upregulated the expression of cathepsin D (CTSD) protease, whose expression is associated with poor prognosis in breast cancer patients. Together, our data demonstrated that the expression of PRA or PRB dramatically and differentially altered breast cancer cell proteomes. These isoform-specific changes in the breast cancer proteome will help to explain the distinct phenotypic properties of breast cancer cells expressing different levels of PRA and PRB.

    更新日期:2019-12-04
  • Obesity and Leptin Influence Vitamin D Metabolism and Action in Human Marrow Stromal Cells
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-03
    Jing Li, Yuan Gao, Tao Yu, Jeffrey K. Lange, Meryl S. LeBoff, Anna Gorska, Simon Luu, Shuanhu Zhou, Julie Glowacki

    Obesity is associated with low serum 25-hydroxyvitamin D [s25(OH)D], high serum leptin, and generally high bone mineral density (BMD). Human Marrow Stromal Cells (hMSCs) differentiate to osteoblasts and are both a target and source of vitamin D metabolites in bone marrow. There is no information about the influence of obesity on vitamin D metabolism and osteoblastogenesis in hMSCs and little about direct effects of leptin on hMSCs. In this study, we tested the hypotheses that 1) obesity has an influence on the ex vivo constitutive expression of vitamin D-hydroxylase genes in hMSCs, and 2) recombinant human (rh) Leptin regulates the D-hydroxylases and promotes osteoblastogenesis in hMSCs. In a cohort of female subjects undergoing joint replacement surgery, the effects of Body Mass Index (BMI) and Fat Mass Index (FMI) on BMD T-scores and s25(OH)D were evaluated. hMSCs were isolated from bone tissues discarded during surgery. The direct effects of rh-Leptin on osteoblast differentiation and D-related genes in hMSCs were examined in vitro. There were positive correlations for BMD T-score of femoral neck and spine with BMI and FMI. Serum 25(OH)D levels in obese subjects were 71% of that in non-obese counterparts (p = 0.001). hMSCs from obese women had higher constitutive expression of CYP27A1/25-hydroxylase and vitamin D receptor. Those findings raised the mechanistic question of how obesity could influence vitamin D metabolism and osteoblast differentiation in hMSCs. Treating hMSCs with rh-Leptin in vitro significantly stimulated osteoblastogenesis. In addition, leptin downregulated CYP24A1 and upregulated CYP27B1, CYP27A1 and VDR, which play vital roles in vitamin D metabolism. Furthermore, co-treatment with leptin and vitamin D3 metabolites promoted ALP activity compared with either alone. This research demonstrates links between obesity, vitamin D metabolism, and osteoblastogenesis by which leptin's direct effects on D-metabolism and osteoblast differentiation in hMSCs may protect bone from low s25(OH)D in obese subjects.

    更新日期:2019-12-04
  • Nutritional rickets: Historic overview and plan for worldwide eradication
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-03
    Roger Bouillon, Leen Antonio

    Rickets was first described in great detail in the mid 17th century and was affecting a great number of children in major European cities. The disease, however, existed already in the Roman times. The etiology of this disease remained enigmatic until the 1920s when two different mechanisms, lack of exposure to sunlight and lack of a dietary factor were finally solved by the discovery of vitamin D and its dual origin. Soon thereafter, the implementation of vitamin D supplementation for all infants and small children largely eliminated nutritional rickets in Europe and North America. It took nearly a century to elucidate the complex chemistry, metabolism, mode and spectrum of activity of the vitamin D endocrine system. Nutritional rickets, whether due to simple vitamin D or calcium deficiency or both, remains widely ravaging many infants and children around the world. Asian countries and the Middle East are mainly confronted with vitamin D deficiency whereas many African and some Asian countries face calcium deficiency rickets. Immigrants and refugees or in general people with a darker skin living in moderate climate zone are also confronted with this disease. There is great consensus how this disease could be prevented or cured. In collaboration with most international professional societies, we prepare a memorandum, in line with the successful battle against iodine deficiency disorders, to convince the World Health Organization and its member states to start an implementation program to eradicate nutritional rickets by 2030.

    更新日期:2019-12-03
  • THE VITAMIN D ASSESSMENT (ViDA) STUDY – DESIGN AND MAIN FINDINGS
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-03
    Robert Scragg

    Accumulating evidence from observational studies indicates that vitamin D status is inversely associated with a many non-skeletal diseases. This has initiated the conduct of several large clinical trials to determine if high dose vitamin D supplementation (≥ 2000 IU/day or monthly equivalent) prevents non-skeletal disease including cardiovascular disease, cancer and mortality. One of these trials is the Vitamin D Assessment (ViDA) Study which recruited 5,110 participants, aged 50-84 years, mostly from primary care practices in Auckland, New Zealand. The intervention was a capsule that contained either 100,000 IU vitamin D3 or placebo, two of which were taken by each participant soon after randomization, and then monthly up to 31 July 2015 (median follow-up 3.3 years). Information on study outcomes came from self-completed questionnaires and health data collected routinely by the Ministry of Health. There was no effect of vitamin D on the main outcomes: cardiovascular disease, acute respiratory infections, non-vertebral fractures, falls and all cancer. In contrast, vitamin D increased persistence with taking statins among participants on long term statin therapy. Beneficial effects were seen also for lung function among ever smokers (especially if vitamin D deficient), and in participants with low 25-hydroxyvitamin D levels for bone mineral density and arterial function. The findings support future research being carried out mainly in people who are vitamin D deficient, although there are practical and ethical issues in recruiting such people into future vitamin D supplementation trials.

    更新日期:2019-12-03
  • The Effects of Correction of Vitamin D Deficiency on Arterial stiffness: A Systematic Review and Updated Meta-analysis of Randomized Controlled Trials
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-03
    Nai-Ching Chen, Chih-Yang Hsu, Pili Chi-Ming Mao, Gavin Dreyer, Fu-Zong Wu, Chien-Liang Chen

    It is unclear whether nutritional vitamin D supplementation in vitamin D-deficient persons improves arterial stiffness. To conduct a meta-analysis of the effects of the nutritional vitamin D therapy on arterial stiffness in adults with vitamin D deficiency, the Scopus, PUBMED, EMBASE, and Cochrane databases were searched for systematic reviews conducted up to October 5, 2018. Randomized clinical trials that compared nutritional vitamin D therapy with placebo in adults with vitamin D deficiency were eligible. Two reviewers independently evaluated eligibility of all retrieved studies based on titles and abstracts. Meta-analysis was performed using random effect or fixed effects model and inverse variance method was used to calculate the effect using standardized mean difference (SMD) and weighted mean difference. A leave-one-out method was used for sensitivity analysis. The main outcome was arterial stiffness, indicated by the carotid-femoral pulse wave velocity (PWV). We identified 237 records, of which 9 satisfied the inclusion criteria of the study. Our meta-analysis included relatively high-quality placebo-controlled randomized trials. In a random-effects model, nutritional vitamin D was associated with significant reductions in the pooled difference of PWV [(SMD: -0.29; 95% CI: -0.51 to -0.06), p = 0.01; Cochran's Q test: chi2 = 21.85; df = 9; p = 0.009; I2 = 59%; n = 909 from 9 studies]. All sensitivity analyses yielded similar results. Nutritional vitamin D supplementation significantly improved arterial stiffness (PWV) in several subgroups by correcting vitamin D deficiency, for a study duration of ≥4 months and a daily dose of vitamin D3 ≥ 2000 IU. The study indicated that the correction of vitamin D deficiency by nutritional vitamin D supplementation may improve arterial stiffness in vitamin D-deficient persons, especially by the correction of vitamin D deficiency with a daily dose of vitamin D3 ≥ 2000 IU. However, further studies are required to confirm this.

    更新日期:2019-12-03
  • Clinical and hormonal characteristics in heterozygote carriers of congenital adrenal hyperplasia
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-02
    Valentina Guarnotta, Marcello Niceta, Marianna Bono, Serena Marchese, Carmelo Fabiano, Serena Indelicato, Francesca Di Gaudio, Piernicola Garofalo, Carla Giordano

    Non-classical congenital adrenal hyperplasia (NC-CAH) includes a group of genetic disorders due to a broad class of CYP21A2 variants identifying a disease-causing ‘C’ genotype. The heterozygous carriers of CYP21 mutations are at increased risk of developing clinically evident hyperandrogenism, even though clinical and laboratory characteristics are still underestimated. With the aim of obtaining a more accurate delineation of the phenotype of heterozygous carrier of CAH, we analyzed clinical, biochemical and molecular characteristics in a cohort of Sicilian subjects. Fifty-seven females with biallelic and monoallelic CYP21A2 variants classifying NC-CAH (24) and heterozygous carriers of CAH (33), respectively were selected. Forty-four females age-matched healthy controls were also enrolled and genotyped for CYP21A2. Clinical, hormonal and genetic data were collected. CYP21A2 monoallelic mutations, defining the heterozygous carriers state, were identified in subjects with clinical features including hirsutism, oligomenorrhoea, overweight and a PCO-like phenotype, particularly occurring in the age of adolescence. Consistently, levels of 17OHP and cortisol were found to be significantly different from NC-CAH. Overall, some clinical and laboratory findings including oligomenorrhea and 17OHP/cortisol ratio were observed as independent markers associated with carriers of CAH. Here we report a high prevalence of late-onset signs of polycystic ovary syndrome (PCOS) and hyperandrogenism in heterozygous carriers. The 17OHP/cortisol ratio may be a predictive tool to identify the carriers of CAH, even though specific cut-off values have not yet been identified.

    更新日期:2019-12-02
  • ANTI-proliferative transcriptional effects of medroxyprogesterone acetate in Estrogen receptor positive breast cancer cells are predominantly mediated by ThE progesterone receptor
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-12-02
    Nicole L. Moore, Adrienne R. Hanson, Esmaeil Ebrahimie, Theresa E. Hickey, Wayne D. Tilley

    Medroxyprogesterone acetate (MPA) is a first generation progestin that has been in clinical use for various hormonal conditions in women since the 1960s. Although developed as a progesterone receptor (PR) agonist, MPA also has strong binding affinity for other steroid receptors. This promiscuity confounds the mechanistic action of MPA in target cells that express multiple steroid receptors. This study is the first to assess the relative contribution of progesterone, androgen and glucocorticoid receptors in mediating the transcriptional activity of MPA on endogenous targets in breast cancer cells that endogenously express all three receptors at comparable levels. Gene expression profiling in estrogen receptor positive (ER+) ZR-75-1 breast cancer cells demonstrated that although the MPA-regulated transcriptome strongly overlapped with that of Progesterone (PROG), 5α-dihydrotestosterone (DHT) and Dexamethasone (DEX), it clustered most strongly with that of PROG, suggesting that MPA predominantly acts via the progesterone receptor (PR) rather than androgen receptor (AR) or glucocorticoid receptor (GR). Subsequent experiments manipulating levels of these receptors, either through specific culture conditions or with lentiviral shRNAs targeting individual receptors, also revealed a stronger contribution of PR compared to AR and GR on the expression of endogenous target genes that are either commonly regulated by all ligands or specifically regulated only by MPA. A predominant contribution of PR to MPA action in ER + T-47D breast cancer cells was also observed, although a stronger role for AR was evident in T-47D compared to that observed in ZR-75-1 cells. Network analysis of ligand-specific and commonly regulated genes demonstrated that MPA utilises different transcription factors and signalling pathways to inhibit proliferation compared with PROG. This study reaffirms the importance of PR in mediating MPA action in an endogenous breast cancer context where multiple steroid receptors are co-expressed and has potential implications for PR-targeting therapeutic strategies in ER + breast cancer.

    更新日期:2019-12-02
  • SerpinB1 promotes the proliferation of porcine pancreatic stem cells through the STAT3 signaling pathway
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-27
    Shuanshuan Xu, Dezhe Qin, Hong Yang, Chen He, Wenqing Liu, Na Tian, Yudong Wei, Xin He, Jinlian Hua, Sha Peng

    Porcine pancreatic stem cells (pPSCs) can be induced to insulin-secreting cells and therefore considered the most promising seeding cells for curing human diabetes in future. However, insufficient pPSCs number is one of the bottleneck problems before its clinical application. SerpinB1 is a serine protease inhibitor in neutrophils and can directly promote the proliferation of β cells. Whether SerpinB1 is involved in pPSC proliferation and differentiation remains unknown. The effects of SerpinB1 on pPSCs proliferation were measured by Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, qRT-PCR, western blot, and flow cytometry assays. We found that pPSCs did not efficiently reach the S phase when SerpinB1 expression was knocked down with short hairpin RNA (sh-SerpinB1), the expression of Cyclin D1, CDK-2, and PCNA also decreased. Meanwhile, cell viability and proliferation ability were both declined. Further analyses showed that the expression level of phosphorylated STAT3/STAT3was downregulated, along with an upregulation of p53 and p21. We used a two-step induction method to induce pPSCs to insulin-secreting cells and found that SerpinB1 expression in insulin-secreting cells was higher than in pPSCs. Meanwhile, the protein expression level of phosphorylated STAT3/STAT3 was increased while p53 and p21 was decreased in induced insulin-secreting cells in comparison with control cells. The insulin-secreting cells derived from the sh-SerpinB1 cells secreted less insulin and showed poor sensitivity to high glucose than control group. However, the insulin-secreting cells derived from the ov-SerpinB1 cells has a quite contrary tendency. In conclusion, this study demonstrates that SerpinB1 promotes the proliferation of pPSCs through the STAT3 signaling pathway, and SerpinB1 is a key factor for maintaining the viability of pPSCs during the transition to insulin-secreting cells.

    更新日期:2019-11-28
  • Characterizing neonatal vitamin D deficiency in the modern era: a maternal-neonatal birth cohort from Southern Europe
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-26
    Spyridon N. Karras, Theocharis Koufakis, Vasiliki Antonopoulou, Dimitrios G. Goulis, Cedric Annweiler, Stefan Pilz, Helen Bili, Declan P. Naughton, Iltaf Shah, Vikentia Harizopoulou, Pantelis Zebekakis, Alkiviadis Bais, Kalliopi Kotsa

    Absence of adequate maternal vitamin D supplementation and decreased maternal ultraviolet exposure during pregnancy are key determinants for the manifestation of neonatal hypovitaminosis D at birth. These parameters may vary, according to country-specific dietary patterns, health policies and sunshine exposure. We aimed to investigate differences in calcium metabolism and anthropometric profiles according to neonatal vitamin D status at birth, in a sunny region of Northern Greece. A secondary aim was to identify maternal parameters as risk factors for developing neonatal vitamin D deficiency at birth. A total of 129 mother-neonate pairs were included in the study and classified into three groups, according to neonatal 25-hydroxy-D [25(OH)D)] concentrations at birth [deficiency (<30 nmol/l), insufficiency (30-50 nmol/l) and sufficiency (>50 nmol/l)]. Neonatal biochemical and anthropometric profiles and maternal demographic, social, dietary and biochemical profiles were comparatively evaluated between the three groups. Univariate and multivariate logistic regression was performed to identify independent associations of maternal factors with neonatal vitamin D status. Vitamin D deficient-neonates manifested higher parathyroid hormone (7.20 ± 2.60 vs 5.50 ± 1.50 pg/ml, p = 0.01) and lower corrected calcium (10.70 ± 0.70 vs 11.30 ± 1.30 mg/dl, p = 0.02) concentrations compared with vitamin D-insufficient neonates. Mothers of vitamin D deficient and insufficient neonates had a lower total of 25(OH)D (31.7 ± 19.2 and 36.5 ± 22.3 vs 53.3 ± 39.0 nmol/l, p < 0.01) and 25(OH)D3 (27.4 ± 17.5 and 33.3 ± 19.9 vs 47.3 ± 36.7 nmol/l, p < 0.01 and p = 0.04, respectively) concentrations respectively, compared with those of vitamin D-sufficient neonates. Maternal use of alcohol during pregnancy was associated with a 5.57-fold higher risk for neonatal vitamin D deficiency at birth (OR 5.57, 95% CI1.17-26.56, p = 0.03). Newborns with vitamin D deficiency presented a 6.89-fold higher risk of having been given birth by vitamin D deficient mothers (OR 6.89, 95% CI 3.09-15.38, p < 0.01). In conclusion, neonatal vitamin D deficiency is associated with maternal 25(OH)D concentrations at birth and maternal alcohol use. Further studies are required to replicate these findings in other regions and populations.

    更新日期:2019-11-27
  • Vitamin D and the nutritional environment in functions of intestinal stem cells: implications for tumorigenesis and prevention
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-26
    Wenge Li, Karina Peregrina, Michele Houston, Leonard H. Augenlicht

    Sporadic colon cancer accounts for ∼80% of CRC, with high incidence in western societies strongly linked to dietary patterns. The only mouse model for sporadic CRC results from feeding mice a purified rodent western-style diet (NWD1), establishing mouse intake of several common nutrients that mimic for each its level consumed in western populations at higher risk for colon cancer (higher fat, lower vitamin D3, calcium, methyl donors and fiber). This causes sporadic colon and small intestinal tumors at an incidence and frequency similar to that of humans. NWD1 perturbs intestinal cell maturation and Wnt signaling throughout villi and colonic crypts before tumors are detected. Surprisingly, feeding NWD1 decreases mouse Lgr5hi intestinal stem cell contribution to homeostasis and tumorigenesis, associated with extensive Lgr5hi cell transcriptional reprogramming, with nutrient levels interactive in these effects. There is a key impact of the lower vitamin D3 in NWD1 and its signaling through the Vdr. The DNA mismatch repair pathway is elevated in Lgr5hi cells by lower vitamin D3 and/or calcium in NWD1, reducing accumulation of relevant somatic mutations detected by single cell exome sequencing. There are also alterations in metabolic pathways, including down-regulation of oxidative phosphorylation. In compensation for compromise of Lgr5hi cells, NWD1 also reprograms cells derived from the Bmi1+ population, defined as those cells marked in Bmi1creERT2, Rosa26tom mice following tamoxifen injection, and at least a portion of these cells then function and persist as stem-like cells in mucosal homeostasis and tumorigenesis. The data establish a key role of the nutrient environment, and vitamin D signaling, in defining contribution of at least two different stem cell populations to mucosal homeostasis and tumorigenesis. This raises significant questions regarding impact of variable human diets on which and how multiple potential intestinal stem cell populations function in the human and give rise to tumors. Moreover, genetic and epigenetic changes in long-lived stem cells have important implications for understanding the effects of vitamin D and other nutrients on intestinal homeostasis and on intervention strategies for altering probability of tumor development.

    更新日期:2019-11-27
  • 1α, 25 Dihydroxyvitamin D (1,25(OH)2D) Inhibits the T cell Suppressive Function of Myeloid Derived Suppressor Cells (MDSC)
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-26
    J.C. Fleet, G.N. Burcham, R.D. Calvert, B.D. Elzey, T.L. Ratliff

    Myeloid derived suppressor cells (MDSC) suppress the ability of cytotoxic T cells to attack and clear tumor cells from the body. The active form of vitamin D, 1,25 dihydroxyvitamin D (1,25(OH)2D), regulates myeloid cell biology and previous research showed that in mouse models 1,25(OH)2D reduced the tumor level of CD34+ cells, an MDSC precursor, and reduced metastasis. We tested whether MDSC are vitamin D target cells by examining granulocytic- (G-MDSC) and monocytic (M-MDSC) MDSC from tumors (TU), spleen (SP), and bone marrow (BM). Vitamin D receptor (VDR) mRNA levels are low in MDSC from bone marrow and SP but are 20-fold higher in TU MDSC. At all sites, M-MDSC have 4-fold higher VDR mRNA expression than G-MDSC. Bone marrow MDSC were induced to differentiate in vitro into tumor MDSC-like cells by treating with IFN-γ, IL-13, and GM-CSF for 48 h. This treatment significantly elevated Arg1 and Nos2 levels, activated the T cell-suppressive function of MDSC, increased VDR expression 50-fold, and made the MDSC responsive to 1,25(OH)2D treatment. Importantly, 1,25(OH)2D treatment reduced the T cell suppressive capacity of cytokine-induced total MDSC and M-MDSC by ≥70% and tumor-derived M-MDSC by 30-50%. Consistent with this finding, VDR deletion (KO) increased T cell suppressive function of in vitro M-MDSC by 30% and of tumor-derived M-MDSC by 50% and G-MDSC by 400%. VDR KO did not alter Nos2 mRNA levels but significantly increased Arg1 mRNA levels in Tu M-MDSC by 100%. In contrast, 1,25(OH)2D treatment reduced nitric oxide production in both in vitro derived M- and G- MDSC. The major finding of this study is that 1,25(OH)2D signaling through the VDR decreases the immunosuppressive capability of MDSC. Collectively, our data suggest that activation of vitamin D signaling could be used to suppress MDSC function and release a constraint on T-cell mediated clearance of TU cells.

    更新日期:2019-11-27
  • Meta-Analysis of steroid-converting enzymes and related receptors in prostate cancer suggesting novel combined therapies
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-26
    Wen-Fa Zhang, Tang Li, Sheng-Xiang Lin

    Androgen receptor (AR) signaling is essential for prostate cancer (PC) progression and treatment. Experiments have demonstrated that the intratumoral androgen levels are not affected by circulating androgen levels, but rather modulated by local steroid-converting enzyme activities. The expression modulation status of human steroid-converting enzymes and nuclear receptors are of great promise to identify novel therapeutic targets. Meta-analysis was performed with 9 cohorts (1093 specimens) from Gene Expression Omnibus, 16 cohorts (933 specimens) from Oncomine and the TCGA cohort (550 specimens). We found significant up regulation of 5α-reductase type 1 and type 3 in both primary and metastatic PC, together with the down regulation of AKR1C2 in primary PC, contributing to the high intratumoral DHT levels. The expression of AR in metastatic PC was up regulated, indicating the importance of AR signaling in the progression of this cancer. The down regulations of HSD11B1 and NR3C1 in primary and metastatic PC may diminish the anti-inflammation and anti-proliferation effects of glucocorticoids signaling. Furthermore, the decrease of progesterone receptor (PGR) expression in primary and metastatic PC was also observed, relieving the suppression effect of PGR on PC proliferation. The clinical evidences of the remarkable expression modulation of steroid-converting enzymes and receptors in PC may indicate novel combined treatment against this highly incident cancer.

    更新日期:2019-11-27
  • Lipidomic analysis of human primary hepatocytes following LXR activation with GW3965 identifies AGXT2L1 as a main target associated to changes in phosphatidylethanolamine
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-26
    Deolinda Santinha, Anna Klopot, Igor Marques, Ewa Ellis, Carl Jorns, Helene Johansson, Tânia Melo, Per Antonson, Tomas Jakobsson, Vítor Félix, Jan-Åke Gustafsson, Maria Rosário Domingues, Agneta Mode, Luisa A. Helguero

    Liver X receptor (LXR) agonists have the potential to alleviate obesity related diseases, particularly atherosclerosis. However, LXRs are transcriptional regulators that induce de novo lipogenesis and lipid accumulation in hepatocytes which represents a serious adverse effect. In this work, we sought to characterize the LXR agonist GW3965 effects on fatty acid (FA) and phospholipid (PL) remodelling and the correlation with gene expression in order to better understand the underlying effects leading to hepatic pathology upon LXR activation. Human primary hepatocytes treated for 48 h with GW3965 were analysed for changes in lipid metabolism gene expression by qPCR, variations in the FA profile was evaluated by GC-FID and in PL profiles using thin layer chromatography, ESI-MS and MS/MS analysis. Changes in cell membrane biochemical properties were studied using bilayer models generated with CHARMM-GUI. ELOLV6 and SCD1 mRNA increase was consistent with higher C16:1 and C18:1n9 at the expense of C16:0 and C18:0. The reduction of C18:2n6 and increase in C20:2n6 was in agreement with ELOVL5 upregulation. Phosphatydilethanolamine (PE) levels tended to decrease and phosphatidylinositol to increase; although differences did not reach significance, they correlated with changes in AGXT2L1, CDS1 and LPIN1 mRNA levels that were increased. The overall effect of GW3965 on PEs molecular profiles was an increase of long-chain polyunsaturated FA chains and a decrease of C16/C18 saturated and monounsaturated FAs chains. Additionally, PC (32:1) and PC (34:2) were decreased, and PC (36:1) and PC (34:1) were increased. AGXT2L1 is an enzyme with strict substrate specificity for phosphoethanolamine, which is converted into ammonia in GW3965-treated hepatocytes and could explain the PE reduction. In summary, LXR activation by GW3965 targets PE biosynthesis and FA elongation/desaturation, which tends to decrease PE in relation to total PL levels, and remodelling of PC and PE molecular species. We identified the human AGXT2L1 gene as induced by LXR activation by both synthetic and endogenous agonist treatment. The increase in acetaldehyde-induced oxidative stress, and in the lipid species identified have the potential to enhance the inflammatory process and impair membrane function. Future studies should focus on inhibition of AGXT2L1 activity with the aim of reverting the steatosis induced by LXR activation.

    更新日期:2019-11-27
  • A mouse model for vitamin D-induced human cathelicidin antimicrobial peptide gene expression
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-26
    Malcolm B. Lowry, Chunxiao Guo, Yang Zhang, Mary L. Fantacone, Isabelle E. Logan, Yan Campbell, Weijian Zhang, Mai Le, Arup K. Indra, Gitali Ganguli-Indra, Jingwei Xie, Richard L. Gallo, H. Phillip Koeffler, Adrian F. Gombart

    In humans and other primates, 1,25(OH)2vitamin D3 regulates the expression of the cathelicidin antimicrobial peptide (CAMP) gene via toll-like receptor (TLR) signaling that activates the vitamin D pathway. Mice and other mammals lack the vitamin D response element (VDRE) in their CAMP promoters. To elucidate the biological importance of this pathway, we generated transgenic mice that carry a genomic DNA fragment encompassing the entire human CAMP gene and crossed them with Camp knockout (KO) mice. We observed expression of the human transgene in various tissues and innate immune cells. However, in mouse CAMP transgenic macrophages, TLR activation in the presence of 25(OH)D3 did not induce expression of either CAMP or CYP27B1 as would normally occur in human macrophages, reinforcing important species differences in the actions of vitamin D. Transgenic mice did show increased resistance to colonization by Salmonella typhimurium in the gut. Furthermore, the human CAMP gene restored wound healing in the skin of Camp KO mice. Topical application of 1,25(OH)2vitamin D3 to the skin of CAMP transgenic mice induced CAMP expression and increased killing of Staphylococcus aureus in a wound infection model. Our model can help elucidate the biological importance of the vitamin D-cathelicidin pathway in both pathogenic and non-pathogenic states.

    更新日期:2019-11-27
  • Urinary Steroidomic Profiles by LC-MS/MS to monitor Classic 21-Hydroxylase Deficiency
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-26
    Eric Pussard, Simon Travers, Claire Bouvattier, Qiong-Yao Xue, Claudine Cosson, Say Viengchareun, Laetitia Martinerie, Marc Lombès

    21-hydroxylase deficiency, the most common enzyme defect associated with congenital adrenal hyperplasia (CAH) is characterized by an impairment of both aldosterone and cortisol biosynthesis. Close clinical and biological monitoring of Hydrocortisone (HC) and 9α-Fludrocortisone (FDR) replacement therapies is required to achieve an optimal treatment. As frequent and repeated reassessments of plasma steroids, 17-hydroxyprogesterone (17-OHP), androstenedione (Δ4-A) and testosterone (TESTO) is needed in childhood, urine steroid profiling could represent an interesting non-invasive alternative. We developed and validated a LC-MS/MS method for the measurement of 23-urinary mineralocorticoids, glucocorticoids and adrenal androgens. The usefulness of steroid profiling was investigated on single 08h00 am-collected spot urine for discriminating between 61 CAH patients and their age- and sex-matched controls. CAH patients were split into two groups according to their 08h00 am-plasma concentrations of 17-OHP: below (controlled patients, n = 26) and above 20 ng/mL (uncontrolled patients, n = 35). The lower limit of quantification and the wide analytical range allows to assay both free and total concentrations of the main urinary adreno-corticoids and their tetra-hydrometabolites. Extraction recoveries higher than 75% and intra-assay precision below 20% were found for most steroids. Urinary steroids upstream of the 21-hydroxylase defect were higher in uncontrolled CAH patients. Among CAH patients, plasma and urinary 17-OHP were closely correlated. As compared to controls, steroids downstream of the enzyme defect collapsed in CAH patients. This fall was more pronounced in controlled than in uncontrolled patients. Androgens (Δ4-A, TESTO and the sum etiocholanolone + androsterone) accumulated in uncontrolled CAH patients. A strong relationship was observed between plasma and urinary levels of androstenedione. Daily doses and urinary excretion of both FDR and HC were similar in both CAH groups. Urinary FDR was inversely related to the sodium-to-potassium ratio in urine. A partial least squares discriminant analysis model allowed to classify the patient’s classes unaffected, controlled and un-controlled CAH patients based on urinary steroidomic profiles. Our LC-MS/MS method successfully established steroid profiling in urine and represents a useful and non-invasive tool for discriminating CAH patients according to treatment efficiency.

    更新日期:2019-11-26
  • 17β-hydroxysteroid dehydrogenase type 12a responsible for testicular 11-ketotestosterone synthesis in the Japanese eel, Anguilla japonica
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-25
    Hiroshi Suzuki, Yuichi Ozaki, Shigeho Ijiri, Koichiro Gen, Yukinori Kazeto

    The production of 11-ketotestosterone (11KT), an important steroid hormone in piscine spermatogenesis, is regulated by the pituitary gonadotropins [Gths: follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh)] and it is synthesized by catalytic reactions involving several steroidogenic enzymes. Among these enzymes, the role of 17β-hydroxysteroid dehydrogenases (Hsd17bs) that exhibited 17-ketosteroid reducing activity (17KSR activity) responsible for 11KT synthesis is still poorly understood. In the present study, for the deeper understanding of testicular 11KT biosynthesis, we first investigated the steroidogenic pathway to produce 11KT in Japanese eel testis. In vitro incubation of the testis with androstenedione (A4) and the subsequent analysis of the metabolites by thin-layer chromatography indicated that 11KT was synthesized from A4 via 11β-hydroxyandrostenedione (11OHA4) and 11-ketoandrostenedione (11KA4), which indicated that the steroidogenic enzyme exhibiting the 17KSR activity responsible for converting 11KA4 to 11KT is crucial for 11KT production. Subsequently, cDNAs encoding three candidate enzymes, Hsd17b type3 (Hsd17b3), Hsd17b type12a (Hsd17b12a), and 20β-hydroxysteroid dehydrogenase type2 (Hsd20b2), potentially with the 17KSR activity were isolated and characterized in the Japanese eel. The isolated hsd17b3, hsd17b12a, and hsd20b2 cDNAs putatively encoded 308, 314, and 327 amino acid residues with high homology to those of other vertebrate counterparts, respectively. The Hsd17b3, Hsd17b12a, and Hsd20b2 expressed either in HEK293 T or in Hepa-E1 converted 11KA4 to 11KT. Tissue-distribution analysis by quantitative real time PCR revealed that hsd17b12a and hsd20b2 mRNAs were detected in the testis, while hsd17b3 mRNA was not detectable. Furthermore, we examined the effects of Gths on the 17KSR activity and the expression of the candidate genes in the immature testis. The 17KSR activity was upregulated by administration of Gths. Furthermore, only expression of hsd17b12a among three candidates was upregulated by Gths as well as the 17KSR activity. These findings strongly suggested that Hsd17b12a is one of the enzymes with 17KSR activity responsible for 11KT synthesis in the testis of Japanese eel.

    更新日期:2019-11-26
  • Association between CUBN gene variants, type 2 diabetes and vitamin D concentrations in an elderly Greek population
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-23
    Xanthippi Tsekmekidou, Fotis Tsetsos, Theocharis Koufakis, Spyridon N. Karras, Marianthi Georgitsi, Nikolaos Papanas, Dimitrios Papazoglou, Athanasios Roumeliotis, Stylianos Panagoutsos, Elias Thodis, Marios Theodoridis, Ploumis Pasadakis, Eustratios Maltezos, Peristera Paschou, Kalliopi Kotsa

    Accumulating evidence suggests a potential implication of vitamin D biological network in the pathogenesis of diabetes mellitus. The megalin-cubilin endocytotic system constitutes a key transport structure, with a modulating role in vitamin D metabolism. We aimed to assess the contribution of variants in the CUBN gene to the genetic risk of Type 2 Diabetes Mellitus (T2DM). 95 polymorphisms within CUBN were genotyped in 716 patients with T2DM and 542 controls of Greek origin. Samples were analyzed on Illumina Human PsychArray. Permutation test analysis was implemented to determine statistical significance. Twenty-five-hydroxy-vitamin-D [25(OH)D)] levels were measured in a sub-group of participants (n = 276). Permutation analysis associated rs11254375_G/T (pemp = 0.00049, OR = 1.482), rs6602175_G/T (pemp = 0.016, OR = 0.822), rs1801224_G/T (pemp = 0.025, OR = 0.830), rs4366393_A/G (pemp = 0.028, OR = 0.829) and rs7071576_A/G (pemp = 0.04, OR = 1.219) with T2DM. Mean 25(OH)D concentrations were significantly lower in patients with T2DM compared to controls (16.70 ± 6.69 ng/ml vs 18.51 ± 6.71 ng/ml, p < 0.001), although both groups were vitamin D deficient. In a further quantitative analysis, rs41301097 was strongly associated with higher 25(OH)D concentrations (p = 5.233e-6, beta = 15.95). Our results indicate a potential role of CUBN gene in T2DM genetic susceptibility in the Greek population. These findings may also denote an indirect effect of vitamin D metabolism dysregulation on the pathogenesis of T2DM. Further studies are required to replicate our findings and clarify the complex underlying mechanisms.

    更新日期:2019-11-26
  • Increasing telomerase enhanced steroidogenic genes expression and steroid hormones production in rat and human granulosa cells and in mouse ovary
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-22
    Amitai Mordechai, Michal Wasserman, Marina Abramov, David Ben-Menahem, Iris Har-Vardi, Eliahu Levitas, Esther Priel

    Telomerase, a ribonucleoprotein responsible for telomere re-elongation, is important for male and female fertility. Several factors, including the steroid hormone estrogen, regulate the expression of Telomerase Reverse Transcriptase (TERT), which one of its non-canonical functions is gene expression regulation. The steroidogenesis process is regulated principally by transcription of genes encoding steroidogenic enzymes, but it is not clear if TERT non-canonical functions affect the expression of steroidogenic genes. Here we investigated this new notion by increasing TERT expression and activity in granulosa cells (GCs) derived from rat and from women that underwent in vitro fertilization (IVF) procedures and in vivo in mouse ovary. We show that gonadotropin enhanced the expression of TERT in rat GCs. Overexpression of human- TERT enhanced the expression of steroidogenesis genes in gonadotropin-stimulated rat GCs. Moreover, treatment with TERT increasing compounds (AGS) alone enhanced the expression of the steroidogenic genes in both rat and human GCs and in vivo in mouse ovary, while telomerase inhibitor reduced their expression. Treatment with AGS compounds, together with gonadotropin stimulation, additively increased steroidogenic gene expression. Enhancing TERT expression and activity increased the level of progesterone in mouse blood and in the medium of rat GCs and estrogen in women derived pre-ovulatory luteinized GCs. These data suggest that increasing TERT in GCs by pharmaceutical compounds enhanced steroidogenesis and the production of steroid hormones that are essential processes in human and animal reproduction. These data also suggest a novel possible strategy for the enhancement of the production of steroid hormones.

    更新日期:2019-11-22
  • Higher risk of Vitamin D insufficiency/deficiency for rural than urban dwellers
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-19
    Tomás P Griffin, Deirdre Wall, Liam Blake, Damian G Griffin, Stephanie Robinson, Marcia Bell, Eamon C Mulkerrin, Paula O’Shea

    There are many risk factors for Vitamin D deficiency. This study aimed to compare the Vitamin D status and serum 25(OH)D concentrations of adults living in an urban area to adults living in a rural area in the West of Ireland (latitude 53.27 °North). A cross-sectional retrospective analysis of clinical records was performed. Following interrogation of the electronic laboratory information system, individuals who had Vitamin D samples analysed at Galway University Hospitals between January 2011 and December 2015 were identified. Clinical demographics, setting and date of sampling were recorded. In total, 17,590 patients (urban n = 4,824; rural n = 12,766) were eligible for inclusion. Serum 25(OH)D concentrations were lower among rural compared to urban dwellers irrespective of season (spring p < 0.001, summer p = 0.009, autumn p = 0.002, winter p < 0.001). There was a significant difference in Vitamin D status between urban and rural dwellers in three of the four seasons: spring- deficiency: 16%-v-23%, insufficiency: 39%-v-43%, sufficiency: 45%-v-35% (p < 0.001); autumn- deficiency: 11%-v-10%, insufficiency: 30%-v-35%, sufficiency: 59%-v-56% (p = 0.01); winter- deficiency: 23%-v-25%, insufficiency: 35%-v-42%, sufficiency: 41%-v-33% (p < 0.001). Serum 25(OH)D concentrations were higher and the prevalence of deficiency lower in urban/rural females compared to urban/rural males (p < 0.001). Serum 25(OH)D concentrations increased sequentially from the 18-39 year age group to the 60-69 year age group in both urban (p < 0.001) and rural (p < 0.001) dwellers and then decreased progressively as age increased to >90 years. The odds of Vitamin D deficiency increased with age, lower daily sunshine hours, male gender, rural address and season.

    更新日期:2019-11-20
  • The relationship of 25-hydroxyvitamin D concentrations and individual-level socioeconomic status
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-18
    Tom D Thacher, Daniel V Dudenkov, Kristin C Mara, Julie A Maxson, Chung-Il Wi, Young J Juhn

    Socioeconomic status (SES), defined as the ability to access desired resources, is associated with behaviors that may affect vitamin D status. Most studies of the effect of vitamin D status on outcomes do not account for individual-level SES. The ability to adjust for SES in epidemiologic studies, when data on conventional SES measures have not been obtained, would be advantageous. We identified all serum 25(OH)D measurements in adults age 18 years and older residing in Olmsted County, MN, a mixed urban-rural setting, between January 1, 2005 and December 31, 2011, through the Rochester Epidemiology Project. The first 25(OH)D measurement was considered the index measurement for each subject. SES was determined for each subject by the HOUsing-based SocioEconomic Status (HOUSES) index, derived from real property data. The HOUSES index is an aggregated z-score of assessed housing value, area of living space, number of bedrooms, and number of bathrooms, with higher scores indicating higher SES. Multivariable analyses were adjusted for age, BMI, sex, race, season of 25(OH)D measurement, and Charlson comorbidity index. HOUSES was matched for 10,378 of 11,002 subjects (94%) with 25(OH)D measurements available. The mean (SD) age was 54.3 (17.1) years with 26.9% ≥65 years; 77.3% were women, and 12.1% were non-white. The mean 25(OH)D concentration was 30.0 (12.9) ng/mL, and 598 (5.8%) had a 25(OH)D value <12 ng/mL. The mean (SD) HOUSES was -1.55 (3.09),-0.97 (3.34), 0.14 (3.52), 0.24 (3.51) for serum 25(OH)D categories of <12, 12-19, 20-50, and >50 ng/mL, respectively (P = 0.12 for trend). 25(OH)D increased by 0.43 (95% CI 0.36-0.50) ng/mL for each unit increase in HOUSES in univariate analysis and by 0.28 (0.21-0.35; P < 0.001) ng/mL in multivariable analysis. This represents a change of 4 ng/mL across the entire range of observed HOUSES, an effect similar in magnitude to the seasonal variation of 25(OH)D values. SES was independently associated with serum 25(OH)D concentrations in a dose-response manner after adjustment for important covariates. HOUSES is a useful tool to assess the role of individual-level SES in health outcomes when other SES measures are unavailable and to control for confounding by SES in examining the effect of 25(OH)D on clinical and metabolic outcomes.

    更新日期:2019-11-18
  • Risk factors for reporting adverse events and for study withdrawal in a population-based trial of vitamin D supplementation
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-18
    Z Malihi, Z Wu, CMM Lawes, J Sluyter, D Waayer, L Toop, K-T Khaw, CA Camargo, R Scragg

    With increasing numbers of randomized controlled trials (RCTs) investigating potential health events of vitamin D supplementation, a better understanding is required of the risk factors for adverse events and for study withdrawals. This analysis aimed to identify baseline risk factors of reporting an adverse event in a multi-year randomized double-blinded placebo-controlled trial of vitamin D supplementation. The secondary aim was to investigate if adverse events were associated with study withdrawals. We analyzed data from the Vitamin D Assessment (ViDA) study: 5,110 adults, aged 50-84 years, living in Auckland, New Zealand. Monthly doses of 100,000 IU vitamin D3 or placebo were mailed to participants homes, with a questionnaire to collect data on adverse events and adherence to the study capsule (initially monthly, then 4-monthly). Median follow-up was 3.3 years. Data were analysed using multivariable log-binomial regression and Cox-regression. During the follow-up period, 818 people reported adverse events and 412 withdrew or stopped returning questionnaires. Vitamin D was not associated with reporting of adverse events. Of sociodemographic factors, ethnicity was associated with reporting adverse events: compared to European participants, Maori and Pacific Islander people were more likely to report an adverse event. Non-smokers were more likely to report an adverse event, compared to smokers (adjusted hazard ratio (HR) = 1.80; 95%CI = 1.24, 2.62); as were those who had reported a history of depression (adjusted HR = 1.27; 95%CI = 1.01, 1.60) or a recent cough or cold (adjusted HR = 1.22; 95%CI = 1.03, 1.44) at baseline. Reporting of adverse events was not associated with withdrawals (adjusted HR = 1.12; 95%CI 0.86, 1.46). These data did not identify any clear pattern in the factors associated with self-reported adverse events, which themselves did not increase risk of withdrawals.

    更新日期:2019-11-18
  • The role of adrenal derived androgens in castration resistant prostate cancer
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-10-28
    Monique Barnard, Elahe A. Mostaghel, Richard J. Auchus, Karl-Heinz Storbeck
    更新日期:2019-11-18
  • Female and male serum reference intervals for challenging sex and precursor steroids by liquid chromatography tandem mass spectrometry
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-15
    Marco Mezzullo, Carla Pelusi, Alessia Fazzini, Andrea Repaci, Guido Di Dalmazi, Alessandra Gambineri, Uberto Pagotto, Flaminia Fanelli

    Measuring some sex and precursor steroids is still challenging even by liquid chromatography – tandem mass spectrometry (LC-MS/MS), and few normal values are available. We developed a LC-MS/MS method for estradiol, estrone, dihydrotestosterone and 17-hydroxypregnenolone measurement, compared it with direct immunoassays, and generated sex, age, menopausal and menstrual status specific reference intervals. Liquid-liquid extraction was optimized on 300 µL serum spiked with isotopic internal standards. A 2D-LC system allowed on-line purification and separation in 11 min run. Electrospray ionization was enhanced by ammonium fluoride. MS-detection was obtained by multiple reaction monitoring. Direct ECLIA for estradiol (n = 80) and RIA for estrone (n = 41) were compared with LC-MS/MS. Reference values were estimated in healthy, lean women in reproductive age (n = 118), menopausal women (n = 33) and men (n = 159). The assay showed satisfying imprecision, trueness, recovery and selectivity. Adequate functional sensitivity was achieved for measuring estrone (18.1 pmol/L) and 17-hydroxypregnenolone (117 pmol/L) in all subjects, and estradiol (35.9 pmol/L) and dihydrotestosterone (134 pmol/L) in women in reproductive age and men, but not in menopausal women. Compared with LC-MS/MS, immunoassays showed good agreement for estradiol but severe disagreement for estrone. Estrogens exhibited sex, menopausal and menstrual variations. Dihydrotestosterone and 17-hydroxypregnenolone depended on sex and menopause, the latter also declining with age in men. Strictly defined reference intervals in the adult female and male population were generated for challenging steroids such as estrogens, dihydrotestosterone and 17-hydroxypregnenolone by a novel LC-MS/MS method. Our achievement can be used to deepen the comprehension of several endocrine diseases.

    更新日期:2019-11-15
  • Intraocular Calcidiol: Uncovering a role for vitamin D in the eye
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-14
    Jacob Rullo, Tracie Pennimpede, Parsa Mehraban Far, Yi Ning Strube, Isabella Irrcher, Todd Urton, Mark Bona, Tom Gonder, Robert Campbell, Martin ten Hove, Sanjay Sharma, James Farmer, Martin Petkovich

    Vitamin D has emerged as a potentially important molecule in ophthalmology. To date, all ophthalmic data pertaining to vitamin D has been restricted primarily to tear and serum analysis in human patients. Considering the isolated nature of the eye, we sought to determine the presence of intraocular vitamin D in ocular disease. Methods 25-hydroxyvitamin D3 (25(OH)D3) concentrations were measured in the eye and blood of 120 participants undergoing ophthalmic procedures. Ocular localization of the 1,25-dihydroxyvitamin D3-generating (CYP27B1) and deactivating (CYP24A1) hydroxylases was performed by immunohistochemistry. Gene expression of CYP27B1, CYP24A1 and VEGF-A was measured in eyes from patients with and without disease. Results 25(OH)D3 was quantified in 112 ocular samples. In 40 cataract patient samples, the average 25(OH)D3 concentration was 0.057 ng/mL, compared to 72 retinal disease patient samples, average of 0.502 ng/mL (p < 0.001). Intraocular 25(OH)D3 did not correlate with serum levels of 25(OH)D3. There was no difference between the level of 25(OH)D3 measured in the aqueous and vitreous humour. The vitamin D-specific CYPs 27B1 and 24A1, strongly localized to complementary regions of the ciliary body, retinal pigment epithelium and neural retina. Gene expression analysis confirmed retinal CYP27B1 correlated strongly with VEGF-A in eyes from diabetic patients (r = 0.92, p < 0.001). Conclusions Our data confirms that vitamin D is present in the humours of the human eye and that local synthesis/degradation is possible via the ocular CYP27B1 and CYP24A1. This argues for a functional role for local vitamin D production and signaling in the eye and suggests that vitamin D may be an important intraocular mediator in disease pathogenesis.

    更新日期:2019-11-14
  • Role of human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C3) in the extrahepatic metabolism of the steroidal aromatase inactivator Formestane
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-13
    Runlan Wan, Xi Kong, Youzhe Yang, Siwen Tao, Youyou Chen, Alexander Tobias Teichmann, Frank Heinrich Wieland

    The clinical use of the steroidal aromatase inhibitor Formestane (4-hydroxandrostenedione, 4-OHA) in the treatment of advanced ER+ breast cancer has been discontinued, and therefore, interest in this remarkable drug has vanished. As a C-19 sterol, 4-OHA can undergo extensive intracellular metabolism depending on the expression of specific enzymes in the corresponding cells. We used the metabolites 4β-hydroxyandrosterone, 4β-hydroxyepiandrosterone and its 17β-reduced derivative as standards for the proof of catalytic activity present in the cell culture medium and expressed by the isolated enzymes. All of the aldo-keto reductases AKR1C1, AKR1C2, AKR1C3 and AKR1C4 catalysed the reduction of the 3-keto-group and the Δ4,5 double bond of 4-OHA at the same time. Molecular docking experiments using microscale thermophoresis and the examination of the kinetic behaviour of the isolated enzymes with the substrate 4-OHA proved that AKR1C3 had the highest affinity for the substrate, whereas AKR1C1 was the most efficient enzyme. Both enzymes (AKR1C1and AKR1C3) are highly expressed in adipose tissue and lungs, exhibiting 3β-HSD activity. The possibility that 4-OHA generates biologically active derivatives such as the androgen 4-hydroxytestosterone or some 17β-hydroxy derivatives of the 5α-reduced metabolites may reawaken interest in Formestane, provided that a suitable method of administration can be developed, avoiding oral or intramuscular depot-injection administration.

    更新日期:2019-11-13
  • Principal Results of the VITamin D and OmegA-3 TriaL (VITAL) and Updated Meta-analyses of Relevant Vitamin D Trials
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-13
    JoAnn E. Manson, Shari S. Bassuk, Julie E. Buring

    Whether supplemental vitamin D reduces risk of cancer or cardiovascular disease (CVD) is relatively unexplored in randomized trial settings. The VITamin D and OmegA-3 TriaL (VITAL) was a nationwide, randomized, placebo-controlled, 2 × 2 factorial trial of daily vitamin D3 (2000 IU) and marine omega-3 fatty acids (1 g) in the primary prevention of cancer and CVD among 25,871 U.S. men aged ≥50 and women aged ≥55, including 5,106 African Americans. Median treatment duration was 5.3 years. Vitamin D did not significantly reduce the primary endpoint of total invasive cancer incidence (hazard ratio [HR] = 0.96 [95% confidence interval 0.88-1.06]) but showed a promising signal for reduction in total cancer mortality (HR = 0.83 [0.67-1.02]), especially in analyses that accounted for latency by excluding the first year (HR = 0.79 [0.63-0.99]) or first 2 years (HR = 0.75 [0.59-0.96]) of follow-up. Vitamin D did not significantly reduce the co-primary endpoint of major CVD events (HR = 0.97 [0.85-1.12]), other cardiovascular endpoints, or all-cause mortality (HR = 0.99 [0.87-1.12]). Updated meta-analyses that include VITAL and other recent vitamin D trials indicate a significant reduction in cancer mortality but not in cancer incidence or CVD endpoints. Additional research is needed to determine which individuals may be most likely to derive a net benefit from vitamin D supplementation. (VITAL clinicaltrials.gov identifier: NCT01169259)

    更新日期:2019-11-13
  • Effect of androgen excess and glucocorticoid exposure on metabolic risk profiles in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-12
    Luisa Paizoni, Matthias K. Auer, Heinrich Schmidt, Angela Hübner, Martin Bidlingmaier, Nicole Reisch

    Data on cardiovascular morbidity in adults with congenital adrenal hyperplasia (CAH) is sparse. We therefore aimed to determine the role of androgen control and glucocorticoid therapy on metabolic health. For that purpose, we included 90 patients (N = 39 men, N = 51 women) with classic CAH due to 21-hydroxylase deficiency (N = 61 salt wasting, N = 29 simple virilizing) and an equal number of controls matched for age, sex, BMI and smoking-habits. We could show that there was no difference in intima-media-thickness between patients and controls and only one patient fulfilled all criteria of the metabolic syndrome. CAH men presented with an increased relative body fat mass in comparison to controls (25.6% vs. 22.1%; p = 0.011) while this was not true for CAH women. Body fat was lower in those taking hydrocortisone instead of synthetic glucocorticoids (B = -3.27; p = 0.048). While arterial hypertension was rare, 54 % of patients had an impaired systolic drop at night or were classified as non-dippers (17%). Impaired dipping was not associated with evening glucocorticoid and fludrocortisone intake but mediated by sodium levels. Insulin resistance was more common in CAH women (B = 1.689; p = 0.036) and in those with poor androgen control (B = 0.823; p = 0.046). In summary, we could show that good cardiovascular health outcome in adult CAH patients can be achieved. Hydrocortisone is superior in terms of body composition. It is yet unclear how non-dipping will translate into cardiovascular morbidity in the long-term.

    更新日期:2019-11-13
  • Assessing the progression of gastric cancer via profiling of histamine, histidine, and bile acids in gastric juice using LC-MS/MS
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-12
    Wonwoong Lee, Jinhee Um, Boram Hwang, Yong Chan Lee, Bong Chul Chung, Jongki Hong

    Bile acid (BA) imbalance may be directly associated with gastric cancer and indirectly influence stomach carcinogenesis via overexpression of histidine decarboxylase (HDC), which converts histidine (His) into histamine (HIST). Moreover, the progression of gastric cancer, could change the gut microbiome, including bacteria spp. that produce secondary BAs. Gastric juice has various metabolites that could indicate gastric cancer-related stomach conditions. Therefore, profiling of HIST, His, and BAs in gastric juice is crucial for understanding the etiological mechanisms of gastric cancer. We used a profiling method to simultaneously determine targeted metabolites in gastric juice using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We successfully analyzed 70 human gastric juice samples from patients with chronic superficial gastritis (CSG, n = 20), intestinal metaplasia (IM, n = 12), and gastric cancer (n = 38). Furthermore, we investigated the relevance between BA metabolism and gastric cancer. There were statistical differences in the metabolism of cholic acid (CA) into deoxycholic acid (DCA) based on the progression of CSG into IM and gastric cancer. Hence, the progression of gastric cancer might be related to the alterations in gut microbiome composition. We provide insight into the etiological mechanisms of the progression of gastric cancer and biomarkers to diagnose and treat gastric cancer.

    更新日期:2019-11-13
  • Utilizing cooled liquid chromatography and chemical derivatization to separate and quantify C3-epimers of 25-hydroxy vitamin D and low abundant 1α,25(OH)2D3: application in a pediatric population
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-10
    Brian C. DeFelice, Theresa L. Pedersen, Hanan Shorrosh, Randi K. Johnson, Jennifer A. Seifert, Jill M. Norris, Oliver Fiehn

    There is need for a single assay able to quantify the most biologically active metabolite, 1α,25-dihydroxy-vitamin-D3, and the recently discovered biologically distinct C3-epimers of 25OHD, in addition to traditional vitamin D metabolites. We developed a method of chromatographic separation and absolute quantification of the following ten forms of vitamin D: 3-epi-25OHD3, 25OHD3, 3-epi-25OHD2, 25OHD2, 1α,25(OH)2D3, 24R,25(OH)2D3, 23R,25(OH)2D3, 1a,25(OH)2D2, D3, and D2 by single extraction and injection. Chemical derivatization followed by liquid chromatography using a charged surface hybrid C18 column and subsequent tandem mass spectrometry was utilized to detect and quantify each metabolite. This method is remarkable as a cooled column was required to achieve chromatographic resolution of epimers. Validation of each metabolite was performed at four concentrations and revealed inter- and intra-day precision and accuracy below 15% across three consecutive days of analysis. After validation, this method was applied to analyze the blood plasma from 739 samples from 352 subjects (8mo to 20 yr), 79 pooled plasma samples, and 10 NIST SRM972a samples. Healthy control samples (n = 357) were used to investigate developmentally associated changes in vitamin D metabolite concentrations during early life. This method yields excellent linearity (R2 ≥0.99) across concentrations encompassing the biological range of many metabolites including 1α,25(OH)2D3. Concentrations of 25OHD2 and 24R,25(OH)2D3 were significantly (q ≤0.05) lower in infants compared to both children and adolescents. The percentage of 3-epi-25OHD3 in total 25OHD3 was significantly lower (q ≤0.009) in post-puberty subjects. Here we present a single assay capable of separating and quantifying ten vitamin D metabolites including C3-epimers of 25OHD, and quantifying 1α,25-dihydroxy-vitamin-D3 at and below concentrations observed in human plasma (LLOQ < 10 pM).

    更新日期:2019-11-11
  • Deterioration of neuroregenerative plasticity in association with testicular atrophy and dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis in Huntington’s disease: A putative role of the Huntingtin gene in steroidogenesis
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-09
    Kaviya Selvaraj, Nivethitha Manickam, Elamathi Kumaran, Kayalvizhi Thangadurai, Gokul Elumalai, Aravinthan Sekar, Risna Kanjirassery Radhakrishnan, Mahesh Kandasamy

    Huntington’s disease (HD) is an autosomal dominant progressive neurodegenerative disorder mainly affecting the structure and functions of the striatum, cerebral cortex and hippocampus leading to movement disorders, cognitive dysfunctions and emotional disturbances. The onset of HD has been linked to a pathogenic CAG repeat expansion in the huntingtin (HTT) gene that encodes for the polyglutamine (polyQ) stretches in the huntingtin (Htt) protein. Notably, the neuropathogenic events of the mutant HTT gene appear to be primed during adulthood and magnified along the ageing process. While normal Htt protein is vital for the neuronal differentiation and neuroprotection, experimental HD models and postmortem human HD brains have been characterized by neurodegeneration and defects in neuroregenerative plasticity in the basal ganglia and limbic system including the hippocampus. Besides gonadal dysfunctions, reduced androgen levels and abnormal hypothalamic–pituitary–gonadal (HPG) axis have increasingly been evident in HD. Recently, ageing-related changes in levels of steroid sex hormones have been proposed to play a detrimental effect on the regulation of hippocampal neurogenesis in the adult brain. Considering its adult-onset nature, a potential relationship between dysregulation in synthesis of sex steroid hormones and the pathogenesis of the mutant HTT gene appears to be an important clinical issues in HD. While the hippocampus and testis are the major sites of steroidogenesis, the presence of Htt in both the areas is conclusively evident. Hence, the expression of the normal HTT gene may take part in the steroidogenic events in both organs in the physiological state, whereas the mutant HTT gene may cause defects in steroidogenesis in HD. Therefore, this review article comprehends the potential relationship between the gonadal dysfunction and abnormal hippocampal plasticity in HD and represents a hypothesis for the putative role of the HTT gene in the regulation of steroidogenesis in gonads and in the brain.

    更新日期:2019-11-11
  • Circulating Sex Steroid Measurements of Men by Mass Spectrometry Are Highly Reproducible after Prolonged Frozen Storage
    J. Steroid Biochem. Mol. Biol. (IF 3.785) Pub Date : 2019-11-09
    D.J. Handelsman, R. Desai, M.J. Seibel, D.G. Le Couteur, R.G. Cumming
    更新日期:2019-11-11
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