The Mechanism of Traditional Chinese Medicine Based on Semi-Targeted Metabolomics to Improve IVF Outcomes in Senile Patients

Objective. To identify the biological function and metabolic pathway of differential metabolites in follicular fluid of senile patients with kidney qi deficiency undergoing in vitro fertilization-embryo transfer (IVF-ET) and observe the effect of kidney-invigorating herbs on IVF outcomes in senile patients. Methods. A total of 95 women undergoing IVF treatment were recruited and divided into three groups, including 34 cases in the treatment group (the senile patients with kidney qi deficiency after the intervention of Chinese medicine), 31 cases in the experiment group (the senile patients with kidney qi deficiency of no intervention of Chinese medicine), and 30 cases in the control group (young women with infertility due to male factor). The three groups of women were treated with long protocol ovarian hyperstimulation; the treatment group was given Qi-Zi-Yu-Si decoction on the day of HCG downregulation. Their IVF clinical outcomes were observed. The metabolites changes of kidney qi deficiency syndrome were analyzed in follicular fluid metabolomics using liquid chromatography-mass spectrometry (UPLC-MS/MS). Results. The syndrome score of kidney qi deficiency syndrome in the treatment group was significantly improved after treatment ( P < 0.01 ). Compared with the experiment group, the available embryo rate and implantation rate were increased, and the difference was statistically significant ( P < 0.05 ). Progesterone, indoleacrylic acid, 2-propenyl 1-(1-propenylsulfinyl) propyl disulfide, N-acetyltryptophan, decanoylcarnitine, 20a-dihydroprogesterone, testosterone acetate, eicosatrienoic acid, 1H-indole-3-carboxaldehyde, choline, phosphorylcholine, and tryptophan were downregulated in the treatment group. Through pathway analysis, glycerophospholipid metabolism and steroid hormone biosynthesis were regulated in senile patients with kidney qi deficiency after Qi-Zi-Yu-Si decoction intervention. Conclusion. Qi-Zi-Yu-Si decoction can effectively improve the IVF outcome and clinical symptoms of senile patients. Follicular fluid metabolites were significantly changed in senile infertile women with kidney qi deficiency, and the mechanism by which kidney-invigorating herbs improve IVF treatment outcomes may be related to glycerophospholipid metabolism and steroid hormone biosynthesis. This study was registered in the Chinese Clinical Trials Registry Platform (ChiCTR1800014422).

Steroid Hormone Biosynthesis Metabolism Is Associated With Fatigue Related to Androgen Deprivation Therapy for Prostate Cancer

BackgroundAndrogen deprivation therapy (ADT) is a cornerstone treatment for prostate cancer. Despite the clinical benefits, ADT is associated with multiple adverse effects including fatigue. The goal of the study was to examine metabolomic changes to better understand cancer-related fatigue specific to ADT treatment.MethodsA total of 160 plasma samples collected from participants with (+ADT, n = 58) or without neoadjuvant ADT (−ADT, n = 102) prior to radiation therapy for treatment of non-metastatic localized prostate cancer were included in the study. Fatigue and sleep-related impairment were measured using the Patient Reported Outcomes Measurement Information System. Plasma metabolites were identified and measured using untargeted ultrahigh-performance liquid chromatography/mass spectrometry metabolomics analyses. Partial least square discriminant analysis was used to identify discriminant metabolite features, and the diagnostic performance of selected classifiers was quantified using AUROC curve analysis. Pathway enrichment analysis was performed using metabolite sets enrichment analyses.FindingsSteroid hormone biosynthesis pathways, including androstenedione metabolism as well as androgen and estrogen metabolism, were overrepresented by metabolites that significantly discriminated samples in the +ADT from the −ADT group. Additional overrepresented metabolic pathways included amino acid metabolism, glutathione metabolism, and carnitine synthesis. Of the metabolites that were significantly different between the groups, steroid hormone biosynthesis metabolites were most significantly correlated with fatigue severity. Sleep-related impairment was strongly correlated with fatigue severity and inversely correlated with ADT-induced reduction in androsterone sulfate.ConclusionsPatients with non-metastatic prostate cancer receiving neoadjuvant ADT prior to radiation therapy reported relatively more severe fatigue. Increased fatigue in this population may be attributable to sleep-related impairment associated with alterations in steroid hormone biosynthesis. Findings in this study provide a basis for further research of changes in sleep patterns and their role in this specific subcategory of cancer-related fatigue caused by the treatment.

Genome-Wide DNA Methylation and Transcriptome Analyses Reveal Epigenetic and Genetic Mechanisms Underlying Sex Maintenance of Adult Chinese Alligator

The sexes of Chinese alligators are determined during embryonic development and remain fixed thereafter. In this study, we investigated the genetic and epigenetic mechanisms underlying sex maintenance in Chinese alligators through RNA sequencing and bisulfite sequencing data analyses of the adult gonads. We identified the genes and pathways (e. g., DMRT1-SOX9-AMH pathway for males and oocyte meiotic maturation pathway for females) involved in male and female sex maintenance and gonadal development of adult Chinese alligators. In contrast to their expression patterns in the embryo, both DMRT1 and the steroid hormone biosynthesis related genes showed a male-biased expression in adult gonads. The overall DNA methylation density and level were higher in testes than in ovaries. Hypermethylation in the gene bodies enhanced the expression of male-biased genes (such as DMRT1-SOX9-AMH and steroid hormone biosynthesis related genes) in the testis, as opposed to the normalization of gene expression. Our results provide insights into the genetic and epigenetic mechanisms underlying sex maintenance in adult Chinese alligators, and are expected to contribute to the development of scientific programs for the successful conservation of this endangered species.

Reduced concentrations of vaginal metabolites involved in steroid hormone biosynthesis are associated with increased vulvar vestibular pain and vaginal muscle tenderness in provoked vestibulodynia: An exploratory metabolomics study

Provoked vestibulodynia (PVD) is a chronic vulvar pain disorder characterized by hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Knowledge regarding pathophysiological mechanisms contributing to the etiology and production of symptoms in PVD remains incomplete but is considered multifactorial. Using a cross-sectional observational study design, data from untargeted metabolomic profiling of vaginal fluid and plasma in women with PVD and healthy women was combined with pain testing and brain imaging in women with PVD to test the hypotheses that women with PVD compared to healthy women show differences in vaginal and plasma metabolites involved in steroid hormone biosynthesis. Steroid hormone metabolites showing group differences were correlated with vulvar vestibular pain and vaginal muscle tenderness and functional connectivity of brain regions involved in pain processing in women with PVD to provide insight into the functional mechanisms linked to the identified alterations. Sensitivity analyses were also performed to determine the impact of hormonal contraceptive use on the study findings. Women with PVD compared to healthy controls had significant reductions primarily in vaginal fluid concentrations of androgenic, pregnenolone and progestin metabolites involved in steroidogenesis, suggesting localized rather than systemic effects in vagina and vulvar vestibule. The observed reductions in androgenic metabolite levels showed large effect size associations with increased vulvar vestibular pain and vulvar muscle tenderness and decreases in androgenic and progestin metabolites were associated with decreased connectivity strength in primary sensorimotor cortices. Women with PVD showed symptom-associated reductions in vaginal fluid concentrations of metabolites involved in the biosynthesis of steroid hormones previously shown to affect the integrity of vulvar and vaginal tissue and nociceptive processing. Deficiency of certain steroids may be an important mechanism contributing to the pathophysiology of symptoms in PVD may provide potential diagnostic markers that could lead to new targets for therapeutic intervention.

Metabolomic Signatures of High Red Blood Cell Distribution Width

Red blood cell distribution width (RDW) describes the amount of variation in blood cell volume and size and increases with age. Higher RDW predicts all-cause mortality, metabolic syndrome, diabetes, and markers of glycemic control, such as glycosylated hemoglobin. However, mechanisms that connect high RDW with these health outcomes are unknown. Thus, identification of high risk in these patients cannot be addressed. This study aims to identify metabolites and pathways that are associated with high levels of RDW in community-dwelling older adults. Using data from the Baltimore Longitudinal Study of Aging, we identified 1,004 cognitively normal participants (mean age: 67.1±13, 48% women, 26% black) with concurrent data on RDW and comprehensive targeted plasma metabolites by Biocrates p500. Participants were grouped into RDW quartiles (Q1:14%). Associations of metabolites with quartiles of RDW were examined using multivariable linear regression with Q1 being the reference group. Models were adjusted for age, sex, and race. Compared to Q1, Q4 had higher concentrations of SM(OH)C14:1, PC ae C30:2, and hypoxanthine, and lower concentrations of DHEAS, Cortisol, Tryptophan, and Hex2Cer(d/18:1/24:0) (all p&lt;0.01). These metabolites are critical components of sphingolipid metabolism and steroid hormone biosynthesis pathways. Elevated RDW was associated with metabolites derived from classes of hormones, amino acids, ceramides, sphingomyelins, PCs, and nucleobases. Individuals with elevated RDW (i.e. ≥14%) may have disrupted sphingolipid metabolism and steroid hormone biosynthesis. These pathways can be targeted for prevention.

METABOLIC PROFILE IN PLASMA AND CSF OF LEVODOPA-INDUCED DYSKINESIA OF PARKINSON’S DISEASE

Structured AbstractBackgroundThe existence of few biomarkers and the lack of a better understanding of the pathophysiology of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD) require new approaches, as the metabolomic analysis, for discoveries.ObjectivesWe aimed to identify a metabolic profile associated with LID in patients with PD in an original cohort, and to confirm the results in an external cohort (BioFIND).MethodsIn the original cohort, plasma and CSF were collected from 20 healthy controls, 23 patients with PD without LID, and 24 patients with PD with LID. LC-MS/MS and metabolomics data analysis were used to perform untargeted metabolomics. Untargeted metabolomics data from the BioFIND cohort were analyzed.ResultsWe identified a metabolic profile associated with LID in PD, composed of multiple metabolic pathways. In particular, the dysregulation of glycosphingolipids metabolic pathway was more related to LID and was strongly associated with the severity of dyskinetic movements. Further, bile acid biosynthesis and C21-steroid hormone biosynthesis metabolites simultaneously found in plasma and CSF have distinguished patients with LID from other participants. Levels of cortisol and cortisone were reduced in patients with PD and LID compared to patients with PD without LID. Data from the BioFIND cohort confirmed dysregulation in plasma metabolites from the bile acid biosynthesis and C21-steroid hormone biosynthesis pathways.ConclusionThere is a distinct metabolic profile associated with LID in PD, both in plasma and CSF, which may be associated with the dysregulation of lipid metabolism and neuroinflammation.

Detection of Vaginal Metabolite Changes in Premature Rupture of Membrane Patients in Third Trimester Pregnancy: a Prospective Cohort Study

Premature rupture of membranes (PROM) is usually associated with pregnant and neonatal complications. Most of the PROM cases are caused by ascending asymptomatic genital infection. In China, PROM (15.3%) is more common than spontaneous preterm labor (7.3%) and leads to more adverse pregnancy outcomes. Here, we designed a prospective cohort study to measure the metabolomics changes in vaginal swab samples and explored their potential contribution to PROM. A total of 260 differentially expressed metabolites were identified and further analyzed. In the PROM group, N-acetyl-d-galactosamine and sucrose were downregulated (P = 0.0025, P = 0.0195, respectively), both of which are the upstream metabolites of the glycolysis pathway. Furthermore, estriol 3-sulfate 16-glucuronide (P = 0.0154) and 2-methoxy-17beta-estradiol 3-glucosiduronic acid (P = 0.004), two final metabolites in steroid hormone biosynthesis, were both downregulated in the PROM group. Finally, we found two catechin metabolites (epigallocatechin-7-glucuronide, P = 0.0009; 4′-methyl-epigallocatechin-7-glucuronide, P = 0.01) as well as DL-citrulline (P = 0.0393) were also significantly downregulated in the PROM group compared with the healthy control (HC) group, which are related to important antioxidant and anti-inflammatory activities in the human body. Altogether, metabolite changes in glycolysis, steroid hormone biosynthesis, and antioxidant/anti-inflammatory pathways may contribute to (or be a consequence of) vaginal dysbiosis and PROM. Metabolite pathway analysis is a new and promising approach to further investigate the mechanism of PROM and help prevent its unfavorable pregnant outcomes at a functional level. Trial registration number: ChiCTR2000034721