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Acta Neurobiologiae Experimentalis 2012The neurosteroids, dehydroepiandrosterone sulfate (DHEAS) and androsterone, are implicated in drug addictions. We examined their influence on locomotor activity and...
The neurosteroids, dehydroepiandrosterone sulfate (DHEAS) and androsterone, are implicated in drug addictions. We examined their influence on locomotor activity and reward in male Wistar rats, and on steroid and monoamine metabolism in the hippocampus and striatum. In the open field test, DHEAS injections (10, 40, 80 mg/kg, i.p.) 30 min prior the test had no significant effect on ambulation, but androsterone (10 mg/kg) increased general locomotion and at doses 1-10 mg/kg, increased central field activity, suggestive of an anxiolytic action. In the conditioned place preference test, both steroids had a biphasic effect: DHEAS was rewarding at doses of 10 and 40 mg/kg, but not at 80 mg/kg, while androsterone was rewarding at doses of 1 and 10 mg/kg, but aversive at 40 mg/kg. Monoamine and steroid concentrations were analyzed in homogenates from the hippocampus and striatum of DHEAS and androsterone injected rats. DHEAS reduced the hippocampal dopamine level, increased striatal homovanilic acid (HVA) and decreased the striatal serotonin concentrations. Androsterone did not affect dopamine levels or turnover, but increased noradrenaline concentration and serotonin turnover in the hippocampus. DHEAS administration augmented concentrations of DHEA, pregnenolone, androstendiol and androstentriol in both brain structures, while androsterone injections increased brain levels of androsterone, epiandrosterone, 5α-dihydrotestosterone, and androstandiol. Present data document that although psychobehavioral and neurochemical effects of DHEAS and androsterone differ in several aspects; both neurosteroids have rewarding properties at certain dose ranges, suggesting their likely involvement in addictions, which entail different mechanisms.
Topics: Androsterone; Animals; Basal Ganglia; Biogenic Amines; Dehydroepiandrosterone Sulfate; Dopamine; Hippocampus; Male; Pregnenolone; Psychomotor Performance; Rats; Rats, Wistar; Reward; Serotonin; Steroids
PubMed: 22508085
DOI: 10.55782/ane-2012-1881 -
Clinical and Experimental Immunology Aug 2021Tuberculosis (TB) is the leading cause of death from a single bacterial infectious agent and is one of the most relevant issues of public health. Another pandemic...
Tuberculosis (TB) is the leading cause of death from a single bacterial infectious agent and is one of the most relevant issues of public health. Another pandemic disease is type II diabetes mellitus (T2D) that is estimated to affect half a billion people in the world. T2D is directly associated with obesity and a sedentary lifestyle and is frequently associated with immunosuppression. Immune dysfunction induced by hyperglycemia increases infection frequency and severity. Thus, in developing countries the T2D/TB co-morbidity is frequent and represents one of the most significant challenges for the health-care systems. Several immunoendocrine abnormalities are occurring during the chronic phase of both diseases, such as high extra-adrenal production of active glucocorticoids (GCs) by the activity of 11-β-hydroxysteroid dehydrogenase type 1 (11-βHSD1). 11-βHSD1 catalyzes the conversion of inactive cortisone to active cortisol or corticosterone in lungs and liver, while 11-β-hydroxysteroid dehydrogenase type 2 (11-βHSD2) has the opposite effect. Active GCs have been related to insulin resistance and suppression of Th1 responses, which are deleterious factors in both T2D and TB. The anabolic adrenal hormone dehydroepiandrosterone (DHEA) exerts antagonistic effects on GC signaling in immune cells and metabolic tissues; however, its anabolic effects prohibit its use to treat immunoendocrine diseases. 16α-bromoepiandrosterone (BEA) is a water miscible synthetic sterol related to DHEA that lacks an anabolic effect while amplifying the immune and metabolic properties with important potential therapeutic uses. In this work, we compared the expression of 11-βHSD1 and the therapeutic efficacy of BEA in diabetic mice infected with tuberculosis (TB) (T2D/TB) with respect to non-diabetic TB-infected mice (TB). T2D was induced by feeding mice with a high-fat diet and administering a single low-dose of streptozotocin. After 4 weeks of T2D establishment, mice were infected intratracheally with a high-dose of Mycobacterium tuberculosis strain H37Rv. Then, mice were treated with BEA three times a week by subcutaneous and intratracheal routes. Infection with TB increased the expression of 11-βHSD1 and corticosterone in the lungs and liver of both T2D/TB and TB mice; however, T2D/TB mice developed a more severe lung disease than TB mice. In comparison with untreated animals, BEA decreased GC and 11-βHSD1 expression while increasing 11-βHSD2 expression. These molecular effects of BEA were associated with a reduction in hyperglycemia and liver steatosis, lower lung bacillary loads and pneumonia. These results uphold BEA as a promising effective therapy for the T2D/TB co-morbidity.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Androsterone; Animals; Antitubercular Agents; Comorbidity; Corticosterone; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Hydrocortisone; Hypoglycemic Agents; Lung; Male; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Tuberculosis
PubMed: 33866550
DOI: 10.1111/cei.13603 -
PLoS Biology Feb 2019Masculinization of the external genitalia in humans is dependent on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an...
Masculinization of the external genitalia in humans is dependent on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative (backdoor) pathway. The fetal testes are essential for canonical androgen production, but little is known about the synthesis of backdoor androgens, despite their known critical role in masculinization. In this study, we have measured plasma and tissue levels of endogenous steroids in second trimester human fetuses using multidimensional and high-resolution mass spectrometry. Results show that androsterone is the principal backdoor androgen in the male fetal circulation and that DHT is undetectable (<1 ng/mL), while in female fetuses, there are significantly lower levels of androsterone and testosterone. In the male, intermediates in the backdoor pathway are found primarily in the placenta and fetal liver, with significant androsterone levels also in the fetal adrenal. Backdoor intermediates, including androsterone, are only present at very low levels in the fetal testes. This is consistent with transcript levels of enzymes involved in the alternate pathway (steroid 5α-reductase type 1 [SRD5A1], aldo-keto reductase type 1C2 [AKR1C2], aldo-keto reductase type 1C4 [AKR1C4], cytochrome P450 17A1 [CYP17A1]), as measured by quantitative PCR (qPCR). These data identify androsterone as the predominant backdoor androgen in the human fetus and show that circulating levels are sex dependent, but also that there is little de novo synthesis in the testis. Instead, the data indicate that placental progesterone acts as substrate for synthesis of backdoor androgens, which occurs across several tissues. Masculinization of the human fetus depends, therefore, on testosterone and androsterone synthesis by both the fetal testes and nongonadal tissues, leading to DHT formation at the genital tubercle. Our findings also provide a solid basis to explain why placental insufficiency is associated with disorders of sex development in humans.
Topics: Androgens; Dihydrotestosterone; Female; Fetus; Humans; Male; Masculinity; Metabolic Networks and Pathways; Ovary; Pregnancy; Pregnancy Trimester, Second; RNA, Messenger; Testis
PubMed: 30763313
DOI: 10.1371/journal.pbio.3000002 -
Frontiers in Cellular and Infection... 2023Adenomyosis (AM) is a benign uterine disease characterized pathologically by the invasion of endometrial tissue into the myometrium. The pathogenesis of AM is still far...
BACKGROUND
Adenomyosis (AM) is a benign uterine disease characterized pathologically by the invasion of endometrial tissue into the myometrium. The pathogenesis of AM is still far from clear. Although the gut microbiome and metabolomics are thought to contribute to a variety of diseases, the role of them in AM has not been revealed.
OBJECTIVE
To investigate changes in the gut microbiota and derived metabolites in AM mice.
METHOD
Female ICR mice were randomly assigned to AM and control groups, and pituitary transplantation was employed to perform AM modeling. Then, the fecal samples were obtained for microbial (16S rRNA gene sequencing) and metabolomic (liquid chromatography mass spectrometry, LC-MS) analysis.
RESULT
The results of gut microbiota analysis showed that the intestinal microbiota composition of AM mice was altered. The ratio of and the relative abundance of in AM group increased compared with the control group. Sixty differential expressed metabolites were identified in intestinal metabolites, mainly involved in steroid hormone biosynthesis, cysteine and methionine metabolism, and alanine, aspartate, and glutamate metabolism. Further, correlation analysis verified that -methionine and -cystine were negatively correlated with and positively correlated with . The Pregnenolone, Androsterone glucuronide, and Testosterone glucuronide were negatively correlated with and , whereas they positively correlated with .
CONCLUSION
AM mice have a unique gut microbiome and intestinal metabolites.
Topics: Humans; Mice; Female; Animals; Gastrointestinal Microbiome; Metabolome; Adenomyosis; RNA, Ribosomal, 16S; Mice, Inbred ICR; Feces; Bacteroidetes
PubMed: 36923594
DOI: 10.3389/fcimb.2023.1075387 -
Nature Communications Jan 2022Non-heme iron and α-ketoglutarate-dependent (Fe/αKG) oxygenases catalyze various oxidative biotransformations. Due to their catalytic flexibility and high efficiency,...
Non-heme iron and α-ketoglutarate-dependent (Fe/αKG) oxygenases catalyze various oxidative biotransformations. Due to their catalytic flexibility and high efficiency, Fe/αKG oxygenases have attracted keen attention for their application as biocatalysts. Here, we report the biochemical and structural characterizations of the unusually promiscuous and catalytically versatile Fe/αKG oxygenase SptF, involved in the biosynthesis of fungal meroterpenoid emervaridones. The in vitro analysis revealed that SptF catalyzes several continuous oxidation reactions, including hydroxylation, desaturation, epoxidation, and skeletal rearrangement. SptF exhibits extremely broad substrate specificity toward various meroterpenoids, and efficiently produced unique cyclopropane-ring-fused 5/3/5/5/6/6 and 5/3/6/6/6 scaffolds from terretonins. Moreover, SptF also hydroxylates steroids, including androsterone, testosterone, and progesterone, with different regiospecificities. Crystallographic and structure-based mutagenesis studies of SptF revealed the molecular basis of the enzyme reactions, and suggested that the malleability of the loop region contributes to the remarkable substrate promiscuity. SptF exhibits great potential as a promising biocatalyst for oxidation reactions.
Topics: Androsterone; Binding Sites; Biocatalysis; Cations, Divalent; Crystallography, X-Ray; Fungal Proteins; Gene Expression; Humans; Hydroxylation; Iron; Ketoglutaric Acids; Kinetics; Models, Molecular; Mutation; Oxidation-Reduction; Oxidoreductases, N-Demethylating; Progesterone; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Recombinant Proteins; Saccharomyces cerevisiae; Substrate Specificity; Terpenes; Testosterone
PubMed: 35013177
DOI: 10.1038/s41467-021-27636-3 -
ChemPlusChem Jul 2021We report the synthesis and characterization of a fullerene-steroid hybrid that contains H @C and a dehydroepiandrosterone moiety synthesized by a cyclopropanation...
We report the synthesis and characterization of a fullerene-steroid hybrid that contains H @C and a dehydroepiandrosterone moiety synthesized by a cyclopropanation reaction with 76 % yield. Theoretical calculations at the DFT-D3(BJ)/PBE 6-311G(d,p) level predict the most stable conformation and that the saturation of a double bond is the main factor causing the upfield shielding of the signal appearing at -3.13 ppm, which corresponds to the H located inside the fullerene cage. Relevant stereoelectronic parameters were also investigated and reinforce the idea that electronic interactions must be considered to develop studies on chemical-biological interactions. A molecular docking simulation predicted that the binding energy values for the protease-hybrid complexes were -9.9 kcal/mol and -13.5 kcal/mol for PL and 3CL respectively, indicating the potential use of the synthesized steroid-H @C as anti-SARS-Cov-2 agent.
Topics: Androsterone; Antiviral Agents; Binding Sites; COVID-19; Coronavirus 3C Proteases; Coronavirus Papain-Like Proteases; Density Functional Theory; Fullerenes; Humans; Molecular Docking Simulation; Protein Binding; SARS-CoV-2; Static Electricity; Thermodynamics
PubMed: 33540487
DOI: 10.1002/cplu.202000770 -
Experimental and Therapeutic Medicine Dec 2018Osteoporosis is liable to affect patients with gonadal hormone deficiency, and a supplement of androgens may be used to increase bone density of patients with...
Osteoporosis is liable to affect patients with gonadal hormone deficiency, and a supplement of androgens may be used to increase bone density of patients with osteoporosis. Since the androgens currently used may cause severe side effects, it is useful to investigate the effect of other androgens and progestin on bone improvement. The aim of the current study was to investigate the effects of pregnenolone (Preg), androstenedione (AD), etiocholanolone (Etio), androsterone (An), nandrolone (NA) and testosterone (T) on the proliferation and differentiation of osteoblasts for potential clinical applications. Human osteoblasts were cultured and treated with androgens and progestin, including Preg, AD, Etio, An, NA, and T, at concentrations of 0, 10, 10, 10 and 10 mol/l. The levels of cell proliferation, alkaline phosphatase (ALP) activity and osteocalcin content were measured and assessed. Preg, AD, Etio, An, and T at concentrations of 10 and/or 10 mol/l significantly improved osteoblast proliferation. NA at concentrations of 10, 10, 10 and 10 mol/l also significantly improved osteoblast proliferation. Preg, AD, Etio, An, NA, and T significantly increased ALP activity and osteocalcin content. The present study demonstrated, for the first time, that Preg, AD, Etio, An, and NA could improve the proliferation and differentiation of osteoblasts .
PubMed: 30542427
DOI: 10.3892/etm.2018.6772 -
Journal of Hepatocellular Carcinoma 2022To clarify the underlying regulatory mechanisms of progression from liver cirrhosis to hepatocellular carcinoma (HCC), we analyzed the microbiomics, metabolomics, and...
PURPOSE
To clarify the underlying regulatory mechanisms of progression from liver cirrhosis to hepatocellular carcinoma (HCC), we analyzed the microbiomics, metabolomics, and proteomics in plasma and tissues from patients with HCC or decompensated liver cirrhosis (DC).
PATIENTS AND METHODS
Tissues and plasma from 44 HCC patients and 28 patients with DC were collected for metabolomic analysis. 16S rRNA sequencing was performed in nine HCC tissues (HCCT), four distal noncancerous tissues (HCCN), and 11 DC tissues (DCT). Five HCC tissues had liver cirrhosis (HCCT-LC). Five hepatocellular carcinoma tissues without liver cirrhosis (HCCT-NLC) and five DCT were selected for proteomic sequencing. After combining proteomic and metabolomic analysis, we constructed a mouse model of chronic liver injury using carbon tetrachloride (CCl4) and treated them with vitamin B6 (VB6).
RESULTS
16s rRNA sequence results showed that HCC tissues had higher alpha diversity. The highest LDA scores were detected for in HCCT, in DCT, and in HCCN. Metabolomics results demonstrated some metabolites, including capric acid, L-threonate, choline, alpha-D-Glucose, D-ribose, betaine, 2E-eicosenoic acid, linoleic acid, L-palmitoylcarnitine, taurodeoxycholic acid, L-pyroglutamic acid, androsterone sulfate, and phthalic acid mono-2-ethylhexyl ester (MEHP), had better diagnostic efficacy than AFP (AUC: 0.852; 95% CI: 0.749, 0.954). In a combined analysis of metabolomics and proteomics, we found that HCCT-LC had more obvious disorders of VB6 metabolism and pentose and glucuronate interconversions than DCT, and kynurenine metabolism disorder was more significant in HCCT-LC than in HCCT-NLC. In the CCl4-induced chronic liver injury model, after VB6 supplementation, inflammatory cell infiltration, hepatocyte edema, and degeneration were significantly improved.
CONCLUSION
We found significant differences in the flora distribution between HCCT and DC; MEHP was a new diagnostic biomarker of HCC, and VB6 ameliorated the inflammatory cell infiltration, hepatocyte edema, and degeneration in chronic liver injury.
PubMed: 35979344
DOI: 10.2147/JHC.S370255 -
Journal of the Endocrine Society Jul 2018To investigate the excretion and conjugation profile of testosterone (T), Epitestosterone (EpiT), and other androgen metabolites in different phases of pregnancy and...
OBJECTIVE
To investigate the excretion and conjugation profile of testosterone (T), Epitestosterone (EpiT), and other androgen metabolites in different phases of pregnancy and postpregnancy as a reflection of the "androgenic exposure."
DESIGN
Consecutive recruitment of pregnant women.
SETTING
Maternity outpatient low-risk pregnancy clinic.
PATIENTS
Seventy-seven pregnant women.
INTERVENTIONS
Collection of urine for analyses of sulfate (S) and glucuronide (G) conjugates and metabolic ratios of androgens and androgen metabolites using liquid chromatography-tandem mass spectrometry.
MAIN OUTCOME MEASURES
Excretion profiles and metabolic ratios of G and S conjugates of T, EpiT, dehydroepiandrosterone (DHEA), androsterone (A), etiocholanolone (Etio), and dihydrotestosterone in relation to trimester and postpartum, body mass index, fetal sex, and ethnicity.
RESULTS
T-S excretion increased significantly between the second and third trimester, whereas excretion of T-G did not change. In contrast, both conjugates of EpiT increased markedly, more so for the -(17-fold) than the G-conjugate (1.6-fold). The preference for S over G conjugation was conspicuous for EpiT and DHEA (S/G ratio 2.1 and 4.7, respectively, in the third trimester), whereas the reverse was true for T, A, and Etio (S/G 0.6, 0.13, and 0.11, respectively).
CONCLUSIONS
Pregnancy influences the androgen excretion profile, with the most profound change being an increase in EpiT excretion throughout the trimesters. EpiT may modulate the effect of T, but its exact role during pregnancy is not known. There were marked differences in the S/G conjugate ratios between androgens upstream and downstream from T in the metabolic network. These results are interesting to compare with the androgen disposition in women with endocrine disorders or abuse of steroids.
PubMed: 29942924
DOI: 10.1210/js.2018-00064 -
Frontiers in Genetics 2024Ischemic stroke (IS) is a major cause of death and disability worldwide. Previous studies have reported associations between metabolic disorders and IS. However,...
Ischemic stroke (IS) is a major cause of death and disability worldwide. Previous studies have reported associations between metabolic disorders and IS. However, evidence regarding the causal relationship between blood metabolites and IS lacking. A two-sample Mendelian randomization analysis (MR) was used to assess the causal relationship between 1,400 serum metabolites and IS. The inverse variance-weighted (IVW) method was employed to estimate the causal effect between exposure and outcome. Additionally, MR-Egger regression, weighted median, simple mode, and weighted mode approaches were employed as supplementary comprehensive evaluations of the causal effects between blood metabolites and IS. Tests for pleiotropy and heterogeneity were conducted. After rigorous selection, 23 known and 5 unknown metabolites were identified to be associated with IS. Among the 23 known metabolites, 13 showed significant causal effects with IS based on 2 MR methods, including 5-acetylamino-6-formylamino-3-methyluracil, 1-ribosyl-imidazoleacetate, Behenoylcarnitine (C22), N-acetyltyrosine, and N-acetylputrescine to (N (1) + N (8))-acetate,these five metabolites were positively associated with increased IS risk. Xanthurenate, Glycosyl-N-tricosanoyl-sphingadienine, Orotate, Bilirubin (E,E), Bilirubin degradation product, CHNO, Bilirubin (Z,Z) to androsterone glucuronide, Bilirubin (Z,Z) to etiocholanolone glucuronide, Biliverdin, and Uridine to pseudouridine ratio were associated with decreased IS risk. Among 1,400 blood metabolites, this study identified 23 known metabolites that are significantly associated with IS risk, with 13 being more prominent. The integration of genomics and metabolomics provides important insights for the screening and prevention of IS.
PubMed: 38313676
DOI: 10.3389/fgene.2024.1333454