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Pediatric Gastroenterology, Hepatology... Jan 2018Androgen therapy has proven efficacy in treating patients with bone marrow failure who are not candidates for bone marrow transplantation. Herein, we report on a case of...
Androgen therapy has proven efficacy in treating patients with bone marrow failure who are not candidates for bone marrow transplantation. Herein, we report on a case of colonic angioectasia secondary to oxymetholone use in an adolescent patient with Hoyeraal-Hreidarsson syndrome (HHS). A 13-year-old Caucasian male with HHS characterized by cerebellar hypoplasia, developmental delay, microcephaly, esophageal strictures and myelodysplasia presented with severe hematochezia from colonic angioectasia secondary to long-term oxymetholone therapy. These vascular lesions resolved spontaneously once this anabolic steroid was discontinued. While androgen therapy is often recommended for certain anemias and myelodysplastic syndromes, clinicians should be aware of the potential complication in developing these perceived uncommon colonic angioectasias. Moreover, pediatric gastroenterologists should familiarize themselves in identifying these vascular lesions by colonoscopy, especially among the high risk groups on long-term anabolic steroid therapy.
PubMed: 29383307
DOI: 10.5223/pghn.2018.21.1.68 -
Hematology. American Society of... Dec 2017Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure... (Review)
Review
Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.
Topics: Androgens; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Danazol; Female; Genetic Diseases, Inborn; Genetic Therapy; Humans; Leucine; Oxymetholone; Quercetin; Stem Cell Transplantation; Syndrome; Virilism
PubMed: 29222242
DOI: 10.1182/asheducation-2017.1.96 -
International Journal of Molecular... Mar 2018The present study assessed the beneficial skeletal muscle‑preserving effects of extracellular polysaccharides from Aureobasidium pullulans SM‑2001 (Polycan) (EAP) on...
The present study assessed the beneficial skeletal muscle‑preserving effects of extracellular polysaccharides from Aureobasidium pullulans SM‑2001 (Polycan) (EAP) on dexamethasone (DEXA)‑induced catabolic muscle atrophy in mice. To investigate whether EAP prevented catabolic DEXA‑induced muscle atrophy, and to examine its mechanisms of action, EAP (100, 200 and 400 mg/kg) was administered orally, once a day for 24 days. EAP treatment was initiated 2 weeks prior to DEXA treatment (1 mg/kg, once a day for 10 days) in mice. Body weight alterations, serum biochemistry, calf thickness, calf muscle strength, gastrocnemius muscle thickness and weight, gastrocnemius muscle antioxidant defense parameters, gastrocnemius muscle mRNA expression, histology and histomorphometry were subsequently assessed. After 24 days, DEXA control mice exhibited muscle atrophy according to all criteria indices. However, these muscle atrophy symptoms were significantly inhibited by oral treatment with all three doses of EAP. Regarding possible mechanisms of action, EAP exhibited favorable ameliorating effects on DEXA‑induced catabolic muscle atrophy via antioxidant and anti‑inflammatory effects; these effects were mediated by modulation of the expression of genes involved in muscle protein synthesis (AKT serine/threonine kinase 1, phosphatidylinositol 3‑kinase, adenosine A1 receptor and transient receptor potential cation channel subfamily V member 4) and degradation (atrogin‑1, muscle RING‑finger protein‑1, myostatin and sirtuin 1). Therefore, these results indicated that EAP may be helpful in improving muscle atrophies of various etiologies. EAP at 400 mg/kg exhibited favorable muscle protective effects against DEXA‑induced catabolic muscle atrophy, comparable with the effects of oxymetholone (50 mg/kg), which has been used to treat various muscle disorders.
Topics: Aldehydes; Animals; Antioxidants; Ascomycota; Body Weight; Catalase; Dexamethasone; Extracellular Space; Glutathione; Male; Malondialdehyde; Mice, Inbred ICR; Muscle Fibers, Skeletal; Muscle Strength; Muscle, Skeletal; Muscular Atrophy; Nitric Oxide Synthase Type II; Organ Size; Poly(ADP-ribose) Polymerases; Polysaccharides; RNA, Messenger; Reactive Oxygen Species; Superoxide Dismutase; Tyrosine
PubMed: 29138805
DOI: 10.3892/ijmm.2017.3251 -
Muscle-protective effects of Schisandrae Fructus extracts in old mice after chronic forced exercise.Journal of Ethnopharmacology Feb 2018Schisandrae Fructus (SF), the dried fruit of Schisandra chinensis (Turcz.) Baill., is a well-known traditional herb used in Asia for enhancing physical work capacity as...
ETHNOPHARMACOLOGICAL RELEVANCE
Schisandrae Fructus (SF), the dried fruit of Schisandra chinensis (Turcz.) Baill., is a well-known traditional herb used in Asia for enhancing physical work capacity as well as providing anti-stress and anti-inflammatory effects. Extracts of SF (SFe) have also been reported to increase skeletal muscle mass and inhibit muscle atrophy.
AIM OF THE STUDY
We examined whether SFe had muscle-protective effects in old mice after chronic forced exercises, and, if so, relevant mechanisms.
MATERIALS AND METHODS
Ten-month-old aged male mice were divided into six groups. One group received no forced swimming after oral administration of distilled water (Intact); the other groups received forced swimming after administration of distilled water (SW), oxymetholone (OXY), or SFe at 500, 250 and 125mg/kg (SFe500, SFe250, and SFe125, respectively). Forced swimming was conducted for 2min at 30min after oral administration; the treatment was repeated for 28 days. Muscle thickness, weight, lean proportion, and strength were examined. The sampled muscles were subjected to histopathological and biochemical analyses. Plasma was examined by biochemical analyses.
RESULTS
The thicknesses of the calf muscle and the sampled gastrocnemius and soleus, protein proportion and muscle strength increased significantly in the SW group versus Intact, and they were further increased in the SFe and OXY groups versus SW. The forced swimming in the SW group upregulated mRNA expression related to protein synthesis (Akt1, PI3K) and muscle growth (A1R, TRPV4), while it downregulated mRNAs related to protein degradation (atrogin-1, MuRF1) and muscle growth inhibitor (myostatin, SIRT1). The detected upregulation and downregulation were enhanced in the SFe groups. In addition, the SFe administration inhibited lipid peroxidation and reactive oxygen species, and accelerated activities of endogenous anti-oxidants and anti-oxidant enzymes. Plasma biochemistry showed decreases in creatine, creatine kinase and LDH in the SFe groups versus SW, suggesting muscle-protective effects of SFe. In the SFe groups versus SW, histopathological analyses revealed an increase in myofibre diameter, and immunohistochemistry showed increases in myofibres immunoreactive for ATPase and decreases in myofibres for apoptosis markers (caspase-3, PARP) and oxidative stress markers (NT, 4HNE, iNOS).
CONCLUSIONS
Oral administration of SFe, especially SFe500, enhanced exercise-induced adaptive muscle strengthening in aged mice after forced swimming through anti-apoptotic and anti-oxidant effects, mediated via modulation of gene expression related to muscle synthesis or degradation. These results suggest that SFe may be helpful in improvement various muscle disorders as an adjuvant therapy to exercise-based remedies.
Topics: Aging; Animals; Dose-Response Relationship, Drug; Fruit; Male; Mice; Motor Activity; Muscle, Skeletal; Muscular Diseases; Physical Conditioning, Animal; Plant Extracts; Schisandra
PubMed: 29107647
DOI: 10.1016/j.jep.2017.10.022 -
Leukemia Research Nov 2016Angiogenesis occurs in response to tissue ischemia and wound healing, and contributes to the pathogenesis of a variety of diseases, such as benign and malignant...
Angiogenesis occurs in response to tissue ischemia and wound healing, and contributes to the pathogenesis of a variety of diseases, such as benign and malignant neoplasia. Several studies have measured bone marrow microvessel density (MVD) in MDS patients and acute myeloid leukemia (AML) patients transformed from MDS, and MVD was higher in MDS patients than controls, but was lower than in AML patients. Vascular endothelial growth factor (VEGF) is expressed in bone marrow blast cells, and an autocrine VEGF signaling mechanism has been established in MDS. Increased bone marrow angiogenesis and VEGF concentrations are adverse prognostic features in all of these patients. In this study, 69 patients were treated in two groups: hypomethylating agents or supportive care with oxymetholone±pyridoxine. We evaluated the MVD and VEGF expression of paraffin-embedded bone marrow samples from patients. We also investigated the relationship between angiogenesis-related biomarkers including MVD, VEGF expression, and clinical factors. The patient median age was 65 years, and the median follow-up duration was 28 months. MVD assessment among subtypes of WHO MDS classification showed that the MVD of RCUD was significantly lower than in other types (p=0.02). However, there was no significant difference in VEGF expression according to the subtype of MDS. Although MVD and VEGF expression did not differ between risk groups based on the IPSS, the low risk group tended to have lower expression of angiogenesis-related biomarkers. MDS patients receiving hypomethylating agents had significantly lower MVD expression in responders than in non-responders (6.13±3.38 vs. 9.89±2.10, respectively, p=0.039). In a consecutive evaluation at the time of diagnosis and 3 months after the initial treatment, the group with a decrease or no change of MVD had a higher response rate compared to that in the group with an increase of MVD (92.9% vs. 58.8%, respectively, p=0.045). Adverse prognostic factors included older age, MDS type other than RCUD, a higher IPSS risk group, and abnormal cytogenetics. Although angiogenesis-related markers did not demonstrate any significant prognostic association with survival, MVD (≥10n/mm) and a strong expression of VEGF seemed to be associated with lower survival rate. These data suggested that the MVD value might be helpful in predicting responsiveness to treatment, especially in MDS patients treated with hypomethylating agents. Although angiogenesis-related markers including VEGF did not demonstrate a significant association with survival outcomes, we observed that high MVD and strong VEGF expression seemed to be associated with lower survival rate. Therefore, biologic markers related to angiogenesis might have a potential as prognostic factors for MDS patients.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Bone Marrow Examination; Humans; Immunosuppressive Agents; Microvessels; Middle Aged; Myelodysplastic Syndromes; Neovascularization, Pathologic; Oxymetholone; Prognosis; Pyridoxine; Retrospective Studies; Survival Rate; Vascular Endothelial Growth Factor A; Young Adult
PubMed: 27639703
DOI: 10.1016/j.leukres.2016.08.012 -
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 Biomedical Journal Sep 2016The present study was carried out to investigate the possible protective effects of royal jelly (RJ) on oxymetholone (OXM)-induced oxidative liver injuries in mice.
BACKGROUND
The present study was carried out to investigate the possible protective effects of royal jelly (RJ) on oxymetholone (OXM)-induced oxidative liver injuries in mice.
METHODS
In total, 32 adult male NMRI mice were divided into four groups of eight mice each. Mice in groups 1 and 2 were orally administered 5 mg/kg/day OXM for 30 days. At the same time, mice in group 3 received RJ at a dose of 100 mg/kg/day. Saline control and RJ control groups were also included in this study.
RESULTS
Administration of 5 mg/kg OXM resulted in a significant decrease in total antioxidant capacity and catalase activity, as well as a significant increase in malondialdehyde (P<0.05). In addition, OXM-administrated mice showed a slight increase in liver enzymes, including alanine amino transferase, aspartate amino transferase, and alkaline phosphatase. Although OXM caused histopathological changes in the liver, RJ could significantly improve all of the above-mentioned parameters at a dose of 100 mg/kg.
CONCLUSION
The results of the present study indicated that RJ has a partially protective effect on OXM-induced liver toxicity in mice.
Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antioxidants; Aspartate Aminotransferases; Catalase; Fatty Acids; Liver; Male; Malondialdehyde; Mice; Oxidative Stress; Oxymetholone
PubMed: 27178489
DOI: 10.7508/ibj.2016.04.007 -
The Journal of Laryngology and Otology Mar 2016Unilateral sudden sensorineural hearing loss due to an infarct in the vertebrobasilar system has been widely reported. Most patients have a background of traditional...
BACKGROUND
Unilateral sudden sensorineural hearing loss due to an infarct in the vertebrobasilar system has been widely reported. Most patients have a background of traditional coronary risk factors related to these cerebrovascular episodes.
CASE REPORT
A 32-year-old male, a regular user of anabolic steroids, presented to the emergency department with unilateral sensorineural hearing loss and symptoms suggestive of an infarct of the anterior inferior cerebellar artery but in the absence of risk factors for ischaemic stroke.
RESULTS
Magnetic resonance imaging confirmed the presence of infarction in the region supplied by the anterior inferior cerebellar artery. Polycythaemia was found on haematological analysis, which we believe was secondary to the use of anabolic steroids. The patient was commenced on aspirin as per the stroke management protocol. There was resolution of neurological symptomatology six weeks after the episode, but no improvement in hearing.
CONCLUSION
To our knowledge, this is the first case report of unilateral sensorineural hearing loss secondary to the use of anabolic steroids causing polycythaemia. This cause should be considered in the differential diagnosis of patients presenting with sensorineural hearing loss, especially in young males, when no other risk factors can be identified.
Topics: Adult; Anabolic Agents; Androgens; Audiometry, Pure-Tone; Hearing Loss, Sensorineural; Humans; Magnetic Resonance Imaging; Male; Oxymetholone; Polycythemia; Testosterone
PubMed: 26653249
DOI: 10.1017/S0022215115003187 -
Cell Journal 2015This study aimed to investigate the effects of royal jelly (RJ) on catalase, total antioxidant capacity and embryo development in adult mice treated with oxymetholone...
OBJECTIVE
This study aimed to investigate the effects of royal jelly (RJ) on catalase, total antioxidant capacity and embryo development in adult mice treated with oxymetholone (OXM).
MATERIALS AND METHODS
In this exprimental study, 32 male and 96 female adult Naval Medical Research Institute (NMRI) mice (7-9 weeks of age) with a ratio of 1:3 for fertili- zation purposes were randomly divided into 4 groups as follows: i. Control group (n=8) receiving 0.1 ml/mice saline daily by gavage for 30 day, ii. RJ group (n=8) treated with RJ at a dose of 100 mg/kg daily by gavage for 30 days, iii. OXM group (n=8) receiving OXM at the dose of 5 mg/kg daily by gavage for 30 days and iv. RJ+OXM group (n=8) receiving RJ at the dose of 100 mg/kg daily by gavage concomitant with 100 mg/kg OXM adminis- tration for 30 days.
RESULTS
Analysis revealed a significant reduction in catalase, total antioxidant, as well as embryo development in OXM group (P<0.05). However, RJ group showed a salient recovery in the all of the above mentioned parameters and embryo toxicity.
CONCLUSION
The results of this study indicated a partially protective effect of RJ against OXM-induced embryo toxicity.
PubMed: 26464831
DOI: 10.22074/cellj.2015.19 -
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