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Journal of Diabetes and Metabolic... Jun 2023The current study is aimed to perform structure-based screening of FDA-approved drugs that can act as novel inhibitor of the 11beta- hydroxysteroid dehydrogenase type 1...
PURPOSE
The current study is aimed to perform structure-based screening of FDA-approved drugs that can act as novel inhibitor of the 11beta- hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme.
METHODS
Structural analogs of carbenoxolone (CBX) were selected from DrugBank database and their Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) parameters were investigated by SwissADME. Molecular docking of CBX analogs against 11β-HSD1 was performed by AutoDock tool, their binding patterns were visualized using PyMOL and the interacting amino acids were determined by ProteinPlus tool. Molecular dynamics simulation was performed on the docked structure of 11β-HSD1 (Protein Data Bank (PDB) code: 2ILT) using GROMACS 2018.1.
RESULTS
The binding energies of hydrocortisone succinate, medroxyprogesterone acetate, testolactone, hydrocortisone cypionate, deoxycorticosterone acetate, and hydrocortisone probutate were lower than that of substrate corticosterone. The molecular dynamics simulation of 11β-HSD1 and hydrocortisone cypionate docked structure showed that it formed a stable complex with the inhibitor. The Root mean square deviation (RMSD) of the protein (0.37 ± 0.05 nm) and ligand (0.41 ± 0.06 nm) shows the stability of the ligand-protein interaction.
CONCLUSION
The docking study revealed that hydrocortisone cypionate has a higher binding affinity than carbenoxolone and its other analogs. The molecular dynamics simulation indicated the stability of the docked complex of 11β-HSD1 and hydrocortisone cypionate. These findings indicate the potential use of this FDA approved drug in the treatment of type 2 diabetes. However, validation by in vitro inhibitory studies and clinical trials on type 2 diabetes patients is essential to confirm the current findings.
PubMed: 37255841
DOI: 10.1007/s40200-023-01191-8 -
Biomedicine & Pharmacotherapy =... Aug 2022The quest for novel anti-diabetic medication from medicinal plants is very important since they contain bioactive phytochemicals that offer better activity and safety...
The quest for novel anti-diabetic medication from medicinal plants is very important since they contain bioactive phytochemicals that offer better activity and safety compared to conventional therapy. In the present study, in vitro, in vivo and in silico approaches were explored to evaluate the anti-inflammatory, antioxidants, and hypoglycemic activities of the crude methanol extract of Azanza garckeana pulp. Our in vitro analysis revealed that the extract contains total phenols (260.80 ± 2.23 mg/100 g) and total flavonoids (10.28 ± 1.29 mg/100 g) contents, and demonstrated dose-dependent in vitro antioxidants activities in; DPPH (IC =141.30 ± 1.64 µg/mL), FRAP (IC =155.07 ± 1.03 µg/mL), LPO (IC =184.96 ± 2.01 µg/mL), and ABTS (IC =162.56 ± 1.14 µg/mL) assays; anti-inflammatory activities in: membrane stabilization (IC =141.34 ± 0.46 µg/mL), protein denaturation (IC =203.61 ± 2.35 µg/mL) and proteinase activities (ICf 171.35 ± 1.56 µg/mL) assays; and hypoglycemic activities in: α- amylase (IC 277.85 ± 2.51 µg/mL), and glucose uptake by yeast cells assays. In vivo analysis revealed that the extract exhibited dose-dependent anti-inflammatory, hypoglycemic activities and improved the weight gain in STZ-induced diabetic rats. In addition, the extract attenuated oxidative stress and increased the activities of SOD, catalase, GSH while depleting the level of LPO in STZ induced diabetic rats. Consequently, the liquid chromatography mass spectrometry (LC-MS) characterization of A. garckeana pulp, revealed the presence of 2-Hexadecen-1-ol,3,7,11,15-tetramethyl-,(2E,7 R,11 R)-, nonyl flavanone, testolactone and 6-(Benzyloxy)- 4,4-Dimethyl-2-Chromanone. These compounds were subjected to pharmacoinformatics analysis among which testolactone and 6-(Benzyloxy)- 4,4-Dimethyl-2-Chromanone demonstrated the best drug-likeness, pharmacokinetics, and also exhibited potential hypoglycemic and anti-inflammatory properties. Altogether, the present study provides preclinical evidence of the antioxidant, anti-inflammatory and antidiabetic activities of A. garckeana extract suggesting its potential applications for the development of alternative therapy for diabetes and its associated inflammatory condition.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Blood Glucose; Diabetes Mellitus, Experimental; Hypoglycemic Agents; Malvaceae; Plant Extracts; Rats; Testolactone
PubMed: 35667233
DOI: 10.1016/j.biopha.2022.113196 -
Molecules (Basel, Switzerland) May 2022Androstenedione (AD) is a key intermediate in the body's steroid metabolism, used as a precursor for several steroid substances, such as testosterone, estradiol, ethinyl... (Review)
Review
Androstenedione (AD) is a key intermediate in the body's steroid metabolism, used as a precursor for several steroid substances, such as testosterone, estradiol, ethinyl estradiol, testolactone, progesterone, cortisone, cortisol, prednisone, and prednisolone. The world market for AD and ADD (androstadienedione) exceeds 1000 tons per year, which stimulates the pharmaceutical industry's search for newer and cheaper raw materials to produce steroidal compounds. In light of this interest, we aimed to investigate the progress of AD biosynthesis from phytosterols by prospecting scientific articles (Scopus, Web of Science, and Google Scholar databases) and patents (USPTO database). A wide variety of articles and patents involving AD and phytosterol were found in the last few decades, resulting in 108 relevant articles (from January 2000 to December 2021) and 23 patents of interest (from January 1976 to December 2021). The separation of these documents into macro, meso, and micro categories revealed that most studies (articles) are performed in China (54.8%) and in universities (76%), while patents are mostly granted to United States companies. It also highlights the fact that AD production studies are focused on "process improvement" techniques and on possible modifications of the "microorganism" involved in biosynthesis (64 and 62 documents, respectively). The most-reported "process improvement" technique is "chemical addition" (40%), which means that the addition of solvents, surfactants, cofactors, inducers, ionic liquids, etc., can significantly increase AD production. Microbial genetic modifications stand out in the "microorganism" category because this strategy improves AD yield considerably. These documents also revealed the main aspects of AD and ADD biosynthesis: sp. (basonym: sp.) (40%) and (known previously as ) (32%) are the most recurrent species studied. Microbial incubation temperatures can vary from 29 °C to 37 °C; incubation can last from 72 h to 14 days; the mixture is agitated at 140 to 220 rpm; vegetable oils, mainly soybean, can be used as the source of a mixture of phytosterols. In general, the results obtained in the present technological prospecting study are fundamental to mapping the possibilities of AD biosynthesis process optimization, as well as to identifying emerging technologies and methodologies in this scenario.
Topics: Androgens; Androstenedione; Biotransformation; Mycobacteriaceae; Phytosterols; Steroids
PubMed: 35630641
DOI: 10.3390/molecules27103164 -
Asian Journal of Andrology 2020Aromatase activity has commonly been associated with male infertility characterized by testicular dysfunction with low serum testosterone and/or testosterone to... (Meta-Analysis)
Meta-Analysis
Aromatase activity has commonly been associated with male infertility characterized by testicular dysfunction with low serum testosterone and/or testosterone to estradiol ratio. In this subset of patients, and particularly in those with hypogonadism, elevated levels of circulating estradiol may establish a negative feedback on the hypothalamic-pituitary-testicular axis by suppressing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production and impaired spermatogenesis. Hormonal manipulation via different agents such as selective estrogen modulators or aromatase inhibitors to increase endogenous testosterone production and improve spermatogenesis in the setting of infertility is an off-label option for treatment. We carried out a systematic review and meta-analysis of the literature of the past 30 years in order to evaluate the benefits of the use of aromatase inhibitors in the medical management of infertile/hypoandrogenic males. Overall, eight original articles were included and critically evaluated. Either steroidal (Testolactone) or nonsteroidal (Anastrozole and Letrozole) aromatase inhibitors were found to statistically improve all the evaluated hormonal and seminal outcomes with a safe tolerability profile. While the evidence is promising, future prospective randomized placebo-controlled multicenter trials are necessary to better define the efficacy of these medications.
Topics: Anastrozole; Aromatase Inhibitors; Clinical Trials as Topic; Estradiol; Humans; Hypogonadism; Infertility, Male; Letrozole; Male; Semen Analysis; Spermatogenesis; Testolactone; Testosterone; Treatment Outcome
PubMed: 31621654
DOI: 10.4103/aja.aja_101_19 -
The Journal of Pediatrics Nov 2017Antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone analog (GnRHa) treatment normalizes growth rate and bone maturation and increases predicted adult... (Clinical Trial)
Clinical Trial
OBJECTIVE
Antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone analog (GnRHa) treatment normalizes growth rate and bone maturation and increases predicted adult height (AH) in boys with familial male-limited precocious puberty (FMPP). To evaluate the effect of long-term antiandrogen, aromatase inhibitor, and GnRHa on AH, boys with FMPP who were treated were followed to AH.
STUDY DESIGN
Twenty-eight boys with FMPP, referred to the National Institutes of Health, were started on antiandrogen and aromatase inhibitor at 4.9 ± 1.5 years of age; GnRHa was added at 6.9 ± 1.5 years of age. Treatment was discontinued at 12.2 ± 0.5 years of age (bone age, 14.4 ± 1.3). AH was assessed at 16.4 ± 1.3 years of age (bone age, 18.5 ± 0.6).
RESULTS
AH (mean ± SD) for all treated subjects was 173.6 ± 6.8 cm (-0.4 ± 1.0 SD relative to adult US males). For 25 subjects with pretreatment predicted AH, AH significantly exceeded predicted AH at treatment onset (173.8 ± 6.9 vs 164.9 ± 10.7 cm; P < .001), but fell short of predicted AH at treatment discontinuation (177.3 ± 9.0 cm; P < .001). For 11 subjects with maternal or sporadic inheritance, the mean AH was 3.1 cm (0.4 SD score) below sex-adjusted midparental height (175.4 ± 5.8 vs 178.5 ± 3.1 cm [midparental height]; P = .10). For 16 subjects with affected and untreated fathers, AH was significantly greater than fathers' AH (172.8 ± 7.4 vs 168.8 ± 7.2 cm; P < .05).
CONCLUSIONS
Long-term treatment with antiandrogen, aromatase inhibitor, and GnRHa in boys with FMPP results in AH modestly below sex-adjusted midparental height and within the range for adult males in the general population.
Topics: Adult; Anastrozole; Androgen Antagonists; Aromatase Inhibitors; Body Height; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Nitriles; Puberty, Precocious; Spironolactone; Testolactone; Treatment Outcome; Triazoles; Triptorelin Pamoate
PubMed: 29144249
DOI: 10.1016/j.jpeds.2017.07.047 -
JBRA Assisted Reproduction May 2016The aim of this study as to analyze published evidence regarding the effectiveness of aromatase inhibitor therapy on improving spermatogenesis in infertile men. We... (Meta-Analysis)
Meta-Analysis Review
The aim of this study as to analyze published evidence regarding the effectiveness of aromatase inhibitor therapy on improving spermatogenesis in infertile men. We carried out a systematic review of randomized controlled trials. The date of the most recent search was October 4, 2015. Two authors independently selected relevant clinical trials, assessing their methodological quality and extracting data. Three studies were included in this review with a total of 100 participants; however, we were able to include data from only 54 participants in the analysis. In the representation of meta-analysis with a single study comparing testolactone versus placebo, related to the hormone concentrations, there was a statistically significance difference favoring the use of testolactone for Luteinizing Hormone (LH); Estrogen (E2); free Testosterone (free T); free Estrogen (free E2); 17-Hydroxyprogesterone (17OHP); prolactin (PRL). In another analysis from a single study comparing letrozole versus anastrozole, there was also a statistically significance difference favoring the use of letrozole for the increase in both the sperm count and LH. There is only low quality evidence regarding the effectiveness of aromatase inhibitor therapy in infertile men. Further trials are needed with standardized interventions and outcomes.
Topics: Aromatase Inhibitors; Azoospermia; Humans; Male; Oligospermia; Randomized Controlled Trials as Topic
PubMed: 27244767
DOI: 10.5935/1518-0557.20160019 -
Fertility and Sterility Dec 2012Some men with severely defective sperm production commonly have excess aromatase activity, reflected by low serum testosterone and relatively elevated estradiol levels.... (Review)
Review
Some men with severely defective sperm production commonly have excess aromatase activity, reflected by low serum testosterone and relatively elevated estradiol levels. Aromatase inhibitors can increase endogenous testosterone production and serum testosterone levels. Treatment of infertile males with the aromatase inhibitors testolactone, anastrazole, and letrozole has been associated with increased sperm production and return of sperm to the ejaculate in men with non-obstructive azoospermia. Use of the aromatase inhibitors anastrazole (1 mg/day) and letrozole (2.5 mg/day) represent off-label use of these agents for impaired spermatogenesis in men with excess aromatase activity (abnormal testosterone/estradiol [T/E] ratios). Side effects have rarely been reported. Randomized controlled trials are needed to define the magnitude of benefit of aromatase inhibitor treatment for infertile men.
Topics: Aromatase Inhibitors; Evidence-Based Medicine; Humans; Infertility, Male; Male; Prevalence; Risk Factors; Treatment Outcome
PubMed: 23103016
DOI: 10.1016/j.fertnstert.2012.10.023 -
Journal of Pharmaceutical Analysis Feb 2012A fast screening protocol was developed for the simultaneous determination of nine anti-estrogenic agents (aminoglutethimide, anastrozole, clomiphene, drostanolone,...
A fast screening protocol was developed for the simultaneous determination of nine anti-estrogenic agents (aminoglutethimide, anastrozole, clomiphene, drostanolone, formestane, letrozole, mesterolone, tamoxifen, testolactone) plus five of their metabolites in human urine. After an enzymatic hydrolysis, these compounds can be extracted simultaneously from urine with a simple liquid-liquid extraction at alkaline conditions. The analytes were subsequently analyzed by fast-gas chromatography/mass spectrometry (fast-GC/MS) after derivatization. The use of a short column, high-flow carrier gas velocity and fast temperature ramping produced an efficient separation of all analytes in about 4 min, allowing a processing rate of 10 samples/h. The present analytical method was validated according to UNI EN ISO/IEC 17025 guidelines for qualitative methods. The range of investigated parameters included the limit of detection, selectivity, linearity, repeatability, robustness and extraction efficiency. High MS-sampling rate, using a benchtop quadrupole mass analyzer, resulted in accurate peak shape definition under both scan and selected ion monitoring modes, and high sensitivity in the latter mode. Therefore, the performances of the method are comparable to the ones obtainable from traditional GC/MS analysis. The method was successfully tested on real samples arising from clinical treatments of hospitalized patients and could profitably be used for clinical studies on anti-estrogenic drug administration.
PubMed: 29403714
DOI: 10.1016/j.jpha.2011.09.011 -
The International Journal of... May 2011Major questions remain about how sex hormones influence human brain development and cognition. Studies in humans and animals suggest a strong impact of androgen on the...
Major questions remain about how sex hormones influence human brain development and cognition. Studies in humans and animals suggest a strong impact of androgen on the structure and function of the medial temporal lobe (MTL) and striatum. Using voxel-based morphometry (DARTEL), we compared MTL and striatal structures in 13 [mean age (±S.D.) 12.7±3.2 yr, mean bone age 14.8±3.2 yr] boys with familial male precocious puberty (FMPP), characterized by early excess androgen secretion, and 39 healthy age-matched boys (mean age 14.3±2.5 yr). The FMPP group showed significantly larger grey-matter volume (GMV) in parahippocampal and fusiform gyri as well as putamen relative to controls. By comparison, larger GMV for controls relative to patients was only apparent in the precentral gyrus. Exploratory regression analyses that examined the impact of age on the current findings revealed a significant increase of GMV in the putamen with age in patients suffering from excess androgen but not in controls. Finally, current levels of free testosterone were obtained in the patient group. Analyses revealed a significant negative association indicating that FMPP boys with low levels of bioavailable testosterone exhibited high GMV in the bilateral striatum. The findings suggest a critical influence of androgen on human brain development and are discussed in relation to male-dominant psychiatric childhood disorders.
Topics: Adolescent; Age Factors; Androgen Antagonists; Androgens; Aromatase Inhibitors; Attention Deficit Disorder with Hyperactivity; Child; Corpus Striatum; Humans; Male; Psychiatric Status Rating Scales; Puberty, Precocious; Spironolactone; Temporal Lobe; Testolactone; Testosterone
PubMed: 20860880
DOI: 10.1017/S1461145710001136 -
Hormones (Athens, Greece) 2006The McCune-Albright Syndrome (MAS) is a sporadic rare disease first described in 1936 by McCune and separately by Albright. MAS is characterized by a triad of physical...
The McCune-Albright Syndrome (MAS) is a sporadic rare disease first described in 1936 by McCune and separately by Albright. MAS is characterized by a triad of physical signs: café-au-lait spots, polyostotic fibrous dysplasia and autonomous endocrine hyperfunction. MAS is predominantly observed in girls and is rarely reported in males. We report the case of a 9-year old boy with gonadotropin independent precocious puberty, café-au-lait spots, polyostotic fibrous dysplasia and growth hormone hypersecretion.
Topics: Adenoma; Child; Facial Bones; Fibrous Dysplasia, Polyostotic; Glucagon; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Growth Hormone-Secreting Pituitary Adenoma; Humans; Male; Puberty, Precocious; Radionuclide Imaging; Skin Pigmentation; Somatostatin; Testolactone
PubMed: 16950755
DOI: 10.14310/horm.2002.11186