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International Journal of Molecular... Sep 2020Dyskeratosis congenita (DKC) is a rare inherited disease of impaired telomere maintenance that progressively leads to multi-organ failure, including the bone marrow. By...
Comparable Effects of the Androgen Derivatives Danazol, Oxymetholone and Nandrolone on Telomerase Activity in Human Primary Hematopoietic Cells from Patients with Dyskeratosis Congenita.
Dyskeratosis congenita (DKC) is a rare inherited disease of impaired telomere maintenance that progressively leads to multi-organ failure, including the bone marrow. By enhancing telomerase activity, androgen derivatives (ADs) are a potential therapeutic option able to re-elongate previously shortened telomeres. Danazol, oxymetholone, and nandrolone are ADs most frequently used to treat DKC. However, no direct in vitro analyses comparing the efficacy of these ADs have been conducted so far. We therefore treated mononuclear cells derived from peripheral blood and bone marrow of four patients with mutations in telomerase reverse transcriptase (, = 1),in the telomerase RNA component (TERC, = 2) and in dyskerin pseudouridine synthase 1 (, = 1) and found no substantial differences in the activity of these three agents in patients with mutations. All AD studied produced comparable improvements of proliferation rates as well as degrees of telomere elongation. Increased expression levels were shown with danazol and oxymetholone. The beneficial effects of all ADs on proliferation of bone marrow progenitors could be reversed by tamoxifen, an estrogen antagonist abolishing estrogen receptor-mediated expression, thereby underscoring the involvement of in AD mechanism of action. In conclusion, no significant differences in the ability to functionally enhance telomerase activity could be observed for the three AD studied in vitro. Physicians therefore might choose treatment based on patients' individual co-morbidities, e.g., pre-existing liver disease and expected side-effects.
Topics: Androgens; Cell Cycle Proteins; Danazol; Dyskeratosis Congenita; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Mutation; Nandrolone; Nuclear Proteins; Oxymetholone; Primary Cell Culture; RNA; Telomerase; Telomere
PubMed: 33003434
DOI: 10.3390/ijms21197196 -
International Journal of Molecular... Jul 2015In the present study, we aimed to determine whether ethanol extracts of Fructus Schisandrae (FS), the dried fruit of Schizandra chinensis Baillon, mitigates the...
In the present study, we aimed to determine whether ethanol extracts of Fructus Schisandrae (FS), the dried fruit of Schizandra chinensis Baillon, mitigates the development of dexamethasone-induced muscle atrophy. Adult SPF/VAT outbred CrljOri:CD1 (ICR) mice were either treated with dexamethasone to induce muscle atrophy. Some mice were treated with various concentrations of FS or oxymetholone, a 17α-alkylated anabolic-androgenic steroid. Muscle thickness and weight, calf muscle strength, and serum creatine and creatine kinase (CK) levels were then measured. The administration of FS attenuated the decrease in calf thickness, gastrocnemius muscle thickness, muscle strength and weight, fiber diameter and serum lactate dehydrogenase levels in the gastrocnemius muscle bundles which was induced by dexamethasone in a dose-dependent manner. Treatment with FS also prevented the dexamethasone-induced increase in serum creatine and creatine kinase levels, histopathological muscle fiber microvacuolation and fibrosis, and the immunoreactivity of muscle fibers for nitrotyrosine, 4-hydroxynonenal, inducible nitric oxide synthase and myostatin. In addition, the destruction of the gastrocnemius antioxidant defense system was also inhibited by the administration of FS in a dose-dependent manner. FS downregulated the mRNA expression of atrogin-1 and muscle ring-finger protein-1 (involved in muscle protein degradation), myostatin (a potent negative regulator of muscle growth) and sirtuin 1 (a representative inhibitor of muscle regeneration), but upregulated the mRNA expression of phosphatidylinositol 3-kinase, Akt1, adenosine A1 receptor and transient receptor potential cation channel subfamily V member 4, involved in muscle growth and the activation of protein synthesis. The overall effects of treatment with 500 mg/kg FS were comparable to those observed following treatment with 50 mg/kg oxymetholone. The results from the present study support the hypothesis that FS has a favorable ameliorating effect on muscle atrophy induced by dexamethasone, by exerting anti-inflammatory and antioxidant effects on muscle fibers, which may be due to an increase in protein synthesis and a decrease in protein degradation.
Topics: Aldehydes; Animals; Anti-Inflammatory Agents; Antioxidants; Creatine; Creatine Kinase; Dexamethasone; Drugs, Chinese Herbal; Fibrosis; L-Lactate Dehydrogenase; Mice; Mice, Inbred ICR; Muscle Proteins; Muscle Strength; Muscle Tonus; Muscle, Skeletal; Muscular Atrophy; Myostatin; Nitric Oxide Synthase Type II; Oxymetholone; Phosphatidylinositol 3-Kinase; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; RNA, Messenger; Receptor, Adenosine A1; SKP Cullin F-Box Protein Ligases; Schisandra; Sirtuin 1; TRPV Cation Channels; Tripartite Motif Proteins; Tyrosine; Ubiquitin-Protein Ligases
PubMed: 25955031
DOI: 10.3892/ijmm.2015.2200 -
Blood Dec 2016Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently...
Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2 mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2Trp53 mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells.
Topics: Aldehydes; Animals; Blood Cell Count; Bone Marrow Cells; Carcinogenesis; Cell Cycle; Chromosome Breakage; DNA Damage; Diet; Fanconi Anemia; Fanconi Anemia Complementation Group D2 Protein; Guanidines; Hematopoiesis; Hematopoietic Stem Cells; Humans; Inactivation, Metabolic; Metformin; Mice; Poly I-C
PubMed: 27756748
DOI: 10.1182/blood-2015-11-683490 -
Iranian Journal of Pharmaceutical... Dec 2022Using sports supplements is common among athletes. The presence of anabolic steroids in sports supplements as a hormonal contaminant can increase production efficiency....
BACKGROUND
Using sports supplements is common among athletes. The presence of anabolic steroids in sports supplements as a hormonal contaminant can increase production efficiency. Since anabolic steroids cause health problems and result in positive doping tests in athletes, it is important to investigate their presence in the supplement preparations consumed by athletes.
OBJECTIVES
This paper aims to simultaneously determine ten anabolic steroids by high-performance thin-layer chromatography (HPTLC) method in sports supplements.
METHODS
Chromatographic analysis was conducted on glass silica gel 60F254 plates. The extracts loaded on silica gel plates are subjected to programed multiple development (PMD) to separate anabolic androgenic steroids (AASs). Densitometric scanning is carried out at the wavelength of 245 and 366nm. The method was validated according to the ICH guidelines.
RESULTS
Spots at retardation factor (Rf) 0.72 (elution system 1), 0.4 (elution system 1), 0.29 (elution system 2), 0.25 (elution system 2), 0.1 (elution system 1), 0.65 (elution system 2), 0.59 (elution system 1), 0.44 (elution system 1), 0.8 (elution system 3), and 0.82 (elution system 3) values were recognized as 19-nor androstenedione, 19-nortestosterone, methyl testosterone, clostebol, stanozolol, trenbolone enanthate, oxymetholone, oxandrolone, testosterone enanthate, and nandrolone decanoate, respectively. The linear ranges were 25 - 250 μg/mL for oxymetholone, 7 - 50 μg/mL for 19-nor androstenedione, 19-nortestosterone, and oxandrolone, and 3 - 20 μg/mL for methyl testosterone, clostebol, stanozolol, trenbolone enanthate, testosterone enanthate, and nandrolone decanoate. The developed method is validated by acceptable precision (CV < 20%) and good accuracy (94% < R < 114%). The value of limit of detection (LOD) for all derivatives was in the range of 0.02 - 0.16 μg/spot (20-160 μg/g of supplement), while limit of quantitation (LOQ) was found to be in the range of 0.06 - 0.5 μg/spot (60 - 500 μg/g of supplement). Fifty sports supplement samples as real sample were collected and analyzed. None of the samples screened positive using the HPTLC method.
CONCLUSIONS
In the present study, the fast, cheap, and simple HPTLC method could be used for the multi-residue analysis of ten anabolic androgenic steroids in sports supplements.
PubMed: 36942061
DOI: 10.5812/ijpr-127444 -
Foods (Basel, Switzerland) Apr 2021In recent years, the undeclared presence of various anabolic androgenic steroids (AAS) in commercial supplements has been confirmed. This fact can be a potential threat...
In recent years, the undeclared presence of various anabolic androgenic steroids (AAS) in commercial supplements has been confirmed. This fact can be a potential threat to all athletes using these supplements, and therefore, there is of increased interest in the implementation of rapid methods for the detection of AAS. The presented study describes the development of an immunostrip test for the detection of multiple 17α-methylated AAS based on direct and indirect competitive principle using gold nanoparticles as a label. As a capture reagent on test lines conjugated stanazolol to rabbit serum albumin (RSA/ST-3) was used, the intensity of color formed in the test line of the AAS-positive sample was visually distinguishable from that of negative sample within 10 min. The optimized closed direct and indirect format of the test provided a similar visual detection limit (0.7 and 0.9 ng/mL, respectively). The most commonly orally abused AAS (17α-methyltestosterone, methandienone, methyldihydrotestosterone, oxandrolone and oxymetholone) showed a strong cross-reaction. Developed immunostrips were successfully applied to analysis of artificially contaminated dietary supplements with 17α-methylated AASs. The developed immunostrips offer potential as a useful user-friendly method for capturing suspicious dietary supplement samples with different contents of AAS at levels far below the usually used concentrations of AAS.
PubMed: 33915816
DOI: 10.3390/foods10040741 -
British Medical Journal Jun 1971Four patients developed acute myeloblastic leukaemia after treatment of aplastic anaemia with oxymetholone. Two had previously shown an excellent clinical response to...
Four patients developed acute myeloblastic leukaemia after treatment of aplastic anaemia with oxymetholone. Two had previously shown an excellent clinical response to the drug and a third some improvement. Though no definite causal relationship between therapy and the onset of leukaemia has been established, the number of cases is greater than might have been expected by chance. The association of the two diseases is discussed.
Topics: Adult; Aged; Anemia, Aplastic; Bone Marrow; Bone Marrow Cells; Erythrocytes; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitosis; Oxymetholone; Stimulation, Chemical
PubMed: 5282950
DOI: 10.1136/bmj.2.5764.743 -
Journal of Korean Medical Science Jun 2005Androgens remain a common treatment for certain type of anemia, based upon its myelostimulating effects; however, it has not been established whether androgens affect...
Androgens remain a common treatment for certain type of anemia, based upon its myelostimulating effects; however, it has not been established whether androgens affect apoptosis of hematopoietic progenitor cells (HPCs). We investigated the effects of the androgens, such as testosterone, 5beta-dihydrotestosterone (5-DHT), and oxymetholone, on apoptosis of normal hematopoietic progenitor cells in vitro. Androgens did not rescue normal bone marrow (BM) CD34+ cells and colony-forming cells (CFCs), other than mature erythroid CFCs, from apoptosis induced by serum- and growth factor deprivation. Oxymetholone did not affect growth factor-mediated survival of normal CD34+ cells or its inhibition by interferon-gamma (IFN-gamma). In a standard methylcellulose clonogenic assay, low concentrations of oxymetholone and 5-DHT stimulated the clonal growth of colony-forming unit (CFU)-erythroid, but did not affect growth of CFU-granulocyte/macrophage or burst-forming unit-erythroid. Oxymetholone and 5-DHT stimulated the production of stem cell factor in normal bone marrow stromal cells (BMSCs) via transcriptional regulation. In agreement with this, oxymetholone-treated BMSCs better supported the survival of HPCs. These data indicate that survival-enhancing or growth-stimulatory effects of androgens on hematopoietic progenitor cells are minimal and mostly restricted to mature erythroid progenitors, and its myelostimulating effects could be attributed, at least in part, to the stimulation of production of hematopoietic growth factors in BMSCs.
Topics: Androgens; Antigens, CD34; Apoptosis; Blotting, Northern; Blotting, Western; Bone Marrow Cells; Cell Survival; Cells, Cultured; Chemokine CXCL12; Chemokines, CXC; Colony-Forming Units Assay; Cytokines; Dihydrotestosterone; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression; Hematopoietic Stem Cells; Humans; Oxymetholone; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Testosterone; Time Factors
PubMed: 15953861
DOI: 10.3346/jkms.2005.20.3.409 -
Physiology & Behavior Jan 1998Anabolic-androgenic steroid (AAS) effects on the estrous cycle of adult Long-Evans rats were examined in four different experiments. Sexual receptivity, vaginal... (Comparative Study)
Comparative Study
Anabolic-androgenic steroid (AAS) effects on the estrous cycle of adult Long-Evans rats were examined in four different experiments. Sexual receptivity, vaginal cytology, and body weight were monitored throughout two-week baseline, AAS treatment, and recovery periods. In Experiments 1-3, rats were administered stanozolol, oxymetholone, or testosterone cypionate within dose ranges selected to mimic the human abuse levels of each compound. In these studies, the highest doses of stanozolol (5 mg/kg), oxymetholone (12 mg/kg), or testosterone cypionate (7.5 mg/kg) disrupted the cyclical display of sexual receptivity and vaginal estrus. To compare effects on estrous cyclicity across AAS compounds, rats in Experiment 4 received a single dose (7.5 mg/kg) of each compound for 2 weeks. At the 7.5 mg/kg dose, all AAS compounds interfered with the cyclical display of vaginal estrus, although effects on sexual receptivity were not uniform. No striking AAS effects on body weight were seen in any experiment. The short-term administration of AAS compounds at high doses disrupts female neuroendocrine function in rats.
Topics: Anabolic Agents; Animals; Body Weight; Estrus; Female; Oxymetholone; Posture; Rats; Sexual Behavior, Animal; Stanozolol; Testosterone
PubMed: 9423971
DOI: 10.1016/s0031-9384(97)00443-5 -
Oxidative Medicine and Cellular... 2015The objective of this study was to assess the possible beneficial skeletal muscle preserving effects of ethanol extract of Schisandrae Fructus (EESF) on sciatic...
The objective of this study was to assess the possible beneficial skeletal muscle preserving effects of ethanol extract of Schisandrae Fructus (EESF) on sciatic neurectomy- (NTX-) induced hindlimb muscle atrophy in mice. Here, calf muscle atrophy was induced by unilateral right sciatic NTX. In order to investigate whether administration of EESF prevents or improves sciatic NTX-induced muscle atrophy, EESF was administered orally. Our results indicated that EESF dose-dependently diminished the decreases in markers of muscle mass and activity levels, and the increases in markers of muscle damage and fibrosis, inflammatory cell infiltration, cytokines, and apoptotic events in the gastrocnemius muscle bundles are induced by NTX. Additionally, destruction of gastrocnemius antioxidant defense systems after NTX was dose-dependently protected by treatment with EESF. EESF also upregulated muscle-specific mRNAs involved in muscle protein synthesis but downregulated those involved in protein degradation. The overall effects of 500 mg/kg EESF were similar to those of 50 mg/kg oxymetholone, but it showed more favorable antioxidant effects. The present results suggested that EESF exerts a favorable ameliorating effect on muscle atrophy induced by NTX, through anti-inflammatory and antioxidant effects related to muscle fiber protective effects and via an increase in protein synthesis and a decrease in protein degradation.
Topics: Animals; Antioxidants; Body Weight; Creatine Kinase; Cytokines; Dietary Supplements; Ethanol; Fruit; Immunohistochemistry; L-Lactate Dehydrogenase; Male; Mice; Mice, Inbred ICR; Muscle Strength; Muscle, Skeletal; Muscular Atrophy; Plant Extracts; Schisandra; Sciatic Nerve
PubMed: 26064425
DOI: 10.1155/2015/872428 -
British Medical Journal (Clinical... Jun 1986
Topics: Adolescent; Adult; Anemia, Aplastic; Female; Glucagon; Humans; Male; Oxymetholone
PubMed: 3087554
DOI: 10.1136/bmj.292.6536.1637