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Nature Communications Jun 2024Veratramine and cyclopamine, two of the most representative members of the isosteroidal alkaloids, are valuable molecules in agricultural and medicinal chemistry. While...
Veratramine and cyclopamine, two of the most representative members of the isosteroidal alkaloids, are valuable molecules in agricultural and medicinal chemistry. While plant extraction of these compounds suffers from uncertain supply, efficient chemical synthesis approaches are in high demand. Here, we present concise, divergent, and scalable syntheses of veratramine and cyclopamine with 11% and 6.2% overall yield, respectively, from inexpensive dehydro-epi-androsterone. Our synthesis readily provides gram quantities of both target natural products by utilizing a biomimetic rearrangement to form the C-nor-D-homo steroid core and a stereoselective reductive coupling/(bis-)cyclization sequence to establish the (E)/F-ring moiety.
Topics: Veratrum Alkaloids; Stereoisomerism; Cyclization; Biological Products; Molecular Structure
PubMed: 38909052
DOI: 10.1038/s41467-024-49748-2 -
Frontiers in Cell and Developmental... 2024Polycystic ovary syndrome (PCOS) is characterized by excess androgens, ovulatory dysfunction, and polycystic ovaries. The mechanisms underlying ovulatory and metabolic...
Polycystic ovary syndrome (PCOS) is characterized by excess androgens, ovulatory dysfunction, and polycystic ovaries. The mechanisms underlying ovulatory and metabolic disorders in PCOS remain elusive, hampering therapeutic development. Enhanced metabolic health correlates with increased microbiota gene content and microbial diversity. We aimed to explore the impact of gut microbiota and serum steroids on PCOS regulation associated with androgen excess. The fecal samples of patients with hyperandrogenic PCOS ( = 14) and control group with PCOS ( = 14) were analyzed by 16S rRNA gene sequencing. The peripheral venous blood of all subjects was collected to detect serum hormones. The association between gut microbiota and serum hormones was analyzed with the R language. Our findings reveal that the hyperandrogenic PCOS group exhibits lower richness and diversity of gut microbiota compared to the control group. Characteristic genera in PCOS patients with hyperandrogenism include , and . Five hormones, including 5β-androsterone, deoxycorticosterone, corticosterone, 11-dehydrocorticosterone, and cortexolone, emerge as potential serum biomarkers for identifying patients with hyperandrogenic-PCOS (HA-PCOS). Furthermore, a lower vitamin D3 level may act as a susceptibility factor, suggesting that vitamin D3 supplementation could serve as a potential intervention for PCOS with hyperandrogenism. Specific fecal microbiota and serum steroids may be used as characteristic markers for clinical diagnosis of hyperandrogenic-PCOS. This research enhances our understanding of the intricate interplay among hormones, gut microbiota, and hyperandrogenemia in patients with PCOS.
PubMed: 38872933
DOI: 10.3389/fcell.2024.1384233 -
Molecular and Cellular Endocrinology Jun 2024Adrenarche is a normal developmental event in mid-childhood characterized by increasing adrenal androgen secretion. The role of the classic androgen pathway has been...
CONTEXT
Adrenarche is a normal developmental event in mid-childhood characterized by increasing adrenal androgen secretion. The role of the classic androgen pathway has been well described in adrenarche, but the role of newer active androgens and additional androgen pathways is less clear.
OBJECTIVE
To study the contribution of novel androgens and related steroid biosynthesis pathways to the development of adrenarche, and to identify additional steroid biomarkers of adrenarche.
DESIGN
A longitudinal study of children aged 6-8 years at baseline, followed up at ages 8-10 and 14-16 years. A total of 34 children (20 girls) with clinical and/or biochemical signs of adrenarche (cases) and 24 children (11 girls) without these signs (controls) at age 8-10 years were included. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry.
MAIN OUTCOME MEASURES
Thirty-two steroids compartmentalized in progestagens, gluco- and mineralocorticoid pathways, and four androgen related pathways, including the classic, backdoor, 11-oxy, and 11-oxy backdoor pathways.
RESULTS
The classic and 11-oxy androgen pathways were more active, and serum concentrations of main androgens in the classic (dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione and androsterone) and 11-oxy (11β-hydroxyandrostenedione, 11β-hydroxytestosterone, 11-ketoandrostenedione, and 11-ketotestosterone) pathways were higher in cases at ages 6-8 and 8-10 years. Pregnenolone concentrations at adrenarchal age (8-10 years) and cortisol concentrations at adolescence (14-16 years) were higher in cases. 11β-hydroxyandrosterone and 11-ketoandrosterone tended to be higher in cases with clinical signs compared to cases who had only biochemical evidence of adrenarche, albeit they were detected at low levels. In biomarker analyses, calculated steroid ratios with cortisol, cortisone, or 11-deoxycortisone as dividers were better classifiers for adrenarche than single steroids. Among these ratios, androstenedione/cortisone was the best.
CONCLUSIONS
The classic and 11-oxy androgen pathways are active in adrenarche. Children with earlier timing of adrenarche have higher serum cortisol levels at late pubertal age, suggesting that early adrenarche might have long-term effects on adrenal steroidogenesis by increasing the activity of the glucocorticoid pathway. Future studies should employ comprehensive steroid profiling to define novel classifiers and biomarkers for adrenarche and premature adrenarche.
PubMed: 38838762
DOI: 10.1016/j.mce.2024.112293 -
BMC Geriatrics Apr 2024Sarcopenia is a progressive loss of muscle mass and function. Since skeletal muscle plays a critical role in metabolic homeostasis, identifying the relationship of blood...
BACKGROUND
Sarcopenia is a progressive loss of muscle mass and function. Since skeletal muscle plays a critical role in metabolic homeostasis, identifying the relationship of blood metabolites with sarcopenia components would help understand the etiology of sarcopenia.
METHODS
A two-sample Mendelian randomization study was conducted to examine the causal relationship of blood metabolites with the components of sarcopenia. Summary genetic association data for 309 known metabolites were obtained from the Twins UK cohort and KORA F4 study (7824 participants). The summary statistics for sarcopenia components [hand grip strength (HGS), walking pace (WP), and appendicular lean mass (ALM)] were obtained from the IEU Open GWAS project (461,089 participants). The inverse variance weighted method was used, and the MR-Egger, weighted median, and MR-PRESSO were used for the sensitivity analyses. Metabolic pathways analysis was further performed.
RESULTS
Fifty-four metabolites associated with sarcopenia components were selected from 275 known metabolites pool. Metabolites that are causally linked to the sarcopenia components were mainly enriched in amino sugar and nucleotide sugar metabolism, galactose metabolism, fructose and mannose metabolism, carnitine synthesis, and biotin metabolism. The associations of pentadecanoate (15:0) with ALM, and 3-dehydrocarnitine and isovalerylcarnitine with HGS were significant after Bonferroni correction with a threshold of P < 1.82 × 10 (0.05/275). Meanwhile, the association of hyodeoxycholate and glycine with the right HGS, and androsterone sulfate with ALM were significant in the sensitivity analyses.
CONCLUSION
Blood metabolites from different metabolism pathways were causally related to the components of sarcopenia. These findings might benefit the understanding of the biological mechanisms of sarcopenia and targeted drugs development for muscle health.
Topics: Humans; Sarcopenia; Hand Strength; Mendelian Randomization Analysis; Muscle, Skeletal; Causality
PubMed: 38622574
DOI: 10.1186/s12877-024-04938-x -
Metabolites Feb 2024Adrenosterone (Androst-4-ene-3,11,17-trione, 11OXO) is forbidden in sports according to the Prohibited List of the World Anti-Doping Agency. The administration of 11OXO...
Adrenosterone (Androst-4-ene-3,11,17-trione, 11OXO) is forbidden in sports according to the Prohibited List of the World Anti-Doping Agency. The administration of 11OXO may be detected by monitoring the urinary concentrations of its main human metabolites 11β-hydroxy-androsterone and 11β-hydroxy-etiocholanolone. Preliminary urinary concentration and concentration ratio thresholds have been established for sports drug testing purposes, but adaptations are desirable as the suggested limits would result in numerous suspicious findings due to naturally elevated concentrations and ratios. Recently, the metabolism of 11-oxo-testosterone (KT) was investigated in the context of anti-doping research, resulting in a preliminary urinary concentration threshold and a confirmation procedure based on the determination of carbon isotope ratios (CIRs). Gas chromatography coupled to isotope ratio mass spectrometry was employed to investigate the CIRs of selected steroids. As KT is also a metabolite of 11OXO, the developed protocols for KT have been tested to elucidate their potential to detect the administration of 11OXO after a single oral dose of 100 mg. In order to further improve the analytical approach, the threshold for urinary concentrations of KT was re-investigated by employing a reference population of = 5232 routine doping control samples. Quantification of urinary steroids was conducted by employing gas chromatography coupled to triple quadrupole mass spectrometry. Derived from these, a subset of = 106 samples showing elevated concentrations of KT was investigated regarding their CIRs. By means of this, potentially positive samples due to the illicit administration of 11OXO or KT could be excluded, and the calculation of reference population-derived thresholds for the concentrations and CIR of KT was possible. Based on the results, the urinary concentration threshold for KT is suggested to be established at 130 ng/mL.
PubMed: 38535301
DOI: 10.3390/metabo14030141 -
Meat Science Jul 2024Mainly skatole and androstenone have so far been considered causative for boar taint. Using a mixed methods approach it is shown herein that 2-aminoacetophenone (AAP)...
Mainly skatole and androstenone have so far been considered causative for boar taint. Using a mixed methods approach it is shown herein that 2-aminoacetophenone (AAP) affects human perception of pork, too. We explored the importance of AAP in four trials: (1) chemical analyses of 221 fat samples from boar carcasses revealed that AAP occurs, on average, in similar quantities as skatole while the levels of androstenone being four-fold. (2) ranking tests with mixtures of androstenone and/or skatole with AAP presented on smell strips to trained sensory assessors showed that AAP amplifies boar odour. In order to study AAP's importance in meat products, four experimental variants of Lyon type sausage were then produced: a control, a product with added skatole (0.075 μg/g fat tissue), with added AAP (0.075 μg/g fat tissue), and with addition of both compounds. (3) results of a consumer discrimination test panel (n = 71) showed that, when added to a sausage system, APP causes a sensory difference of similar size as skatole while the methodology chosen affects the effect size: tetrad tests proved to be more sensitive than duo trio difference tests, in the tetrad test a sensory difference expressed as d' (d-prime) of 1.0 was reached. (4) a hedonic consumer test (n = 121) finally revealed that APP decreased consumer liking of the APP-spiked sausage - even to a stronger extent than skatole. APP caused significant drops in smell, taste, mouth-feel, after-taste and overall liking in Lyoner. Overall the findings suggest that, in the context of pork meat, AAP is of similar olfactory importance as skatole.
Topics: Animals; Meat Products; Humans; Skatole; Odorants; Consumer Behavior; Male; Adult; Female; Swine; Middle Aged; Acetophenones; Taste; Young Adult; Androsterone; Smell; Androstenes
PubMed: 38508078
DOI: 10.1016/j.meatsci.2024.109497 -
Frontiers in Genetics 2024Physical weakness and cardiovascular risk increase significantly with age, but the underlying biological mechanisms remain largely unknown. This study aims to reveal...
Physical weakness and cardiovascular risk increase significantly with age, but the underlying biological mechanisms remain largely unknown. This study aims to reveal the causal effect of circulating metabolites on frailty, sarcopenia and vascular aging related traits and diseases through a two-sample Mendelian Randomization (MR) analysis. Exposures were 486 metabolites analyzed in a genome-wide association study (GWAS), while outcomes included frailty, sarcopenia, arterial stiffness, atherosclerosis, peripheral vascular disease (PAD) and aortic aneurysm. Primary causal estimates were calculated using the inverse-variance weighted (IVW) method. Methods including MR Egger, weighted median, Q-test, and leave-one-out analysis were used for the sensitive analysis. A total of 125 suggestive causative associations between metabolites and outcomes were identified. Seven strong causal links were ultimately identified between six metabolites (kynurenine, pentadecanoate (15:0), 1-arachidonoylglycerophosphocholine, androsterone sulfate, glycine and mannose) and three diseases (sarcopenia, PAD and atherosclerosis). Besides, metabolic pathway analysis identified 13 significant metabolic pathways in 6 age-related diseases. Furthermore, the metabolite-gene interaction networks were constructed. Our research suggested new evidence of the relationship between identified metabolites and 6 age-related diseases, which may hold promise as valuable biomarkers.
PubMed: 38415056
DOI: 10.3389/fgene.2024.1353908 -
The Journal of Steroid Biochemistry and... May 2024Endometriosis is a complex gynecological pathology with a broad spectrum of symptoms, affecting around 10% of reproductive-aged women. Ovarian cancer (OC) is a...
Endometriosis is a complex gynecological pathology with a broad spectrum of symptoms, affecting around 10% of reproductive-aged women. Ovarian cancer (OC) is a heterogeneous disease for which we lack effective diagnostic and therapeutic strategies. The etiology and pathogenesis of both diseases remain ambiguous. Androgens in endometriosis could have a distinct role beyond serving as estrogen sources, whereas in the case of serous OC could be important in the formation of precursor lesions which ultimately lead to tumor formation. Here we performed two-sample Mendelian randomization (MR) analysis to examine the causal relationship between the androgen precursor - dehydroepiandrosterone sulphate (DHEAS), bioactive androgen - testosterone (T), androgen metabolite - androsterone sulphate, steroid hormone binding globulin (SHBG) and albumin and the risk of endometrioses of various sub-phenotypes and ovarian neoplasms across the benign-borderline-malignant spectrum. Stringent quality control procedures were followed to select eligible instrumental variables that were strongly associated with the selected exposures, sensitivity analyses were performed to assess the heterogeneities, horizontal pleiotropy, and stabilities of SNPs in endometriosis and ovarian neoplasms. We discovered an inverse association between genetically predicted levels of all androgens and risk of endometriosis, the same trend was most evident in the ovarian sub-phenotype. Total T levels were also inversely associated with peritoneal sub-phenotype of endometriosis. Likewise, T was causally associated with decreased risk of clear-cell OC, an endometriosis-associated OC subtype, and with malignant serous OC of both low- and high-grade, but with higher risk of their counterpart of low malignant potential. These findings support further investigation of androgen's action at a molecular level in ovary-associated endometriotic lesions, clear cell ovarian tumors and serous precursor lesions.
Topics: Female; Humans; Adult; Androgens; Endometriosis; Mendelian Randomization Analysis; Ovarian Neoplasms; Testosterone; Carcinoma, Ovarian Epithelial
PubMed: 38369034
DOI: 10.1016/j.jsbmb.2024.106482 -
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 -
BMC Genomics Jan 2024Current evidence suggests a significant association between metabolites and ovarian cancer (OC); however, the causal relationship between the two remains unclear. This...
BACKGROUND
Current evidence suggests a significant association between metabolites and ovarian cancer (OC); however, the causal relationship between the two remains unclear. This study employs Mendelian randomization (MR) to investigate the causal effects between different metabolites and OC.
METHODS
In this study, a total of 637 metabolites were selected as the exposure variables from the Genome-wide Association Study (GWAS) database ( http://gwas.mrcieu.ac.uk/datasets/ ). The OC related GWAS dataset (ieu-b-4963) was chosen as the outcome variable. R software and the TwoSampleMR package were utilized for the analysis in this study. MR analysis employed the inverse variance-weighted method (IVW), MR-Egger and weighted median (WM) for regression fitting, taking into consideration potential biases caused by linkage disequilibrium and weak instrument variables. Metabolites that did not pass the tests for heterogeneity and horizontal pleiotropy were considered to have no significant causal effect on the outcome. Steiger's upstream test was used to determine the causal direction between the exposure and outcome variables.
RESULTS
The results from IVW analysis revealed that a total of 31 human metabolites showed a significant causal effect on OC (P < 0.05). Among them, 9 metabolites exhibited consistent and stable causal effects, which were confirmed by Steiger's upstream test (P < 0.05). Among these 9 metabolites, Androsterone sulfate, Propionylcarnitine, 5alpha-androstan-3beta,17beta-diol disulfate, Total lipids in medium VLDL and Concentration of medium VLDL particles demonstrated a significant positive causal effect on OC, indicating that these metabolites promote the occurrence of OC. On the other hand, X-12,093, Octanoylcarnitine, N2,N2-dimethylguanosine, and Cis-4-decenoyl carnitine showed a significant negative causal association with OC, suggesting that these metabolites can inhibit the occurrence of OC.
CONCLUSIONS
The study revealed the complex effect of metabolites on OC through Mendelian randomization. As promising biomarkers, these metabolites are worthy of further clinical validation.
Topics: Humans; Female; Genome-Wide Association Study; Mendelian Randomization Analysis; Ovarian Neoplasms; Analysis of Variance; Databases, Factual
PubMed: 38262941
DOI: 10.1186/s12864-024-09997-3