Landscape of the gut mycobiome dynamics during pregnancy and its relationship with host metabolism and pregnancy health.

OBJECTIVE: The remodelling of gut mycobiome (ie, fungi) during pregnancy and its potential influence on host metabolism and pregnancy health remains largely unexplored. Here, we aim to examine the characteristics of gut fungi in pregnant women, and reveal the associations between gut mycobiome, host metabolome and pregnancy health. DESIGN: Based on a prospective birth cohort in central China (2017 to 2020): Tongji-Huaxi-Shuangliu Birth Cohort, we included 4800 participants who had available ITS2 sequencing data, dietary information and clinical records during their pregnancy. Additionally, we established a subcohort of 1059 participants, which included 514 women who gave birth to preterm, low birthweight or macrosomia infants, as well as 545 randomly selected controls. In this subcohort, a total of 750, 748 and 709 participants had ITS2 sequencing data, 16S sequencing data and serum metabolome data available, respectively, across all trimesters. RESULTS: The composition of gut fungi changes dramatically from early to late pregnancy, exhibiting a greater degree of variability and individuality compared with changes observed in gut bacteria. The multiomics data provide a landscape of the networks among gut mycobiome, biological functionality, serum metabolites and pregnancy health, pinpointing the link between Mucor and adverse pregnancy outcomes. The prepregnancy overweight status is a key factor influencing both gut mycobiome compositional alteration and the pattern of metabolic remodelling during pregnancy. CONCLUSION: This study provides a landscape of gut mycobiome dynamics during pregnancy and its relationship with host metabolism and pregnancy health, which lays the foundation of the future gut mycobiome investigation for healthy pregnancy.

A modified flexible GnRH antagonist protocol using antagonist early cessation and a gonadotropin step-down approach improves live birth rates in fresh cycles: a randomized controlled trial.

STUDY QUESTION: Can pregnancy outcomes following fresh elective single embryo transfer (eSET) in gonadotropin-releasing hormone (GnRH) antagonist protocols increase using a gonadotropin (Gn) step-down approach with cessation of GnRH antagonist on the day of hCG administration (hCG day) in patients with normal ovarian response? SUMMARY ANSWER: The modified GnRH antagonist protocol using the Gn step-down approach and cessation of GnRH antagonist on the hCG day is effective in improving live birth rates (LBRs) per fresh eSET cycle. WHAT IS KNOWN ALREADY: Currently, there is no consensus on optimal GnRH antagonist regimens. Studies have shown that fresh GnRH antagonist cycles result in poorer pregnancy outcomes than the long GnRH agonist (GnRHa) protocol. Endometrial receptivity is a key factor that contributes to this phenomenon. STUDY DESIGN, SIZE, DURATION: An open label randomized controlled trial (RCT) was performed between November 2021 and August 2022. There were 546 patients allocated to either the modified GnRH antagonist or the conventional antagonist protocol at a 1:1 ratio. PARTICIPANTS/MATERIALS, SETTING, METHODS: Both IVF and ICSI cycles were included, and the sperm samples used were either fresh or frozen from the partner, or from frozen donor ejaculates. The primary outcome was the LBRs per fresh SET cycle. Secondary outcomes included rates of implantation, clinical and ongoing pregnancy, miscarriage, and ovarian hyperstimulation syndrome (OHSS), as well as clinical outcomes of ovarian stimulation. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline demographic features were not significantly different between the two ovarian stimulation groups. However, in the intention-to-treat (ITT) population, the LBRs in the modified antagonist group were significantly higher than in the conventional group (38.1% [104/273] vs. 27.5% [75/273], relative risk 1.39 [95% CI, 1.09-1.77], P = 0.008). Using a per-protocol (PP) analysis which included all the patients who received an embryo transfer, the LBRs in the modified antagonist group were also significantly higher than in the conventional group (48.6% [103/212] vs. 36.8% [74/201], relative risk 1.32 [95% CI, 1.05-1.66], P = 0.016). The modified antagonist group achieved significantly higher implantation rates, and clinical and ongoing pregnancy rates than the conventional group in both the ITT and PP analyses (P < 0.05). The two groups did not show significant differences between the number of oocytes retrieved or mature oocytes, two-pronuclear zygote (2PN) rates, the number of embryos obtained, blastocyst progression and good-quality embryo rates, early miscarriage rates, or OHSS incidence rates (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: A limitation of our study was that the subjects were not blinded to the treatment allocation in the RCT trial. Only women under 40 years of age who had a good prognosis were included in the analysis. Therefore, use of the modified antagonist protocol in older patients with a low ovarian reserve remains to be investigated. In addition, the sample size for Day 5 elective SET was small, so larger trials will be required to strengthen these findings. WIDER IMPLICATIONS OF THE FINDINGS: The modified GnRH antagonist protocol using the Gn step-down approach and cessation of GnRH antagonist on hCG day improved the LBRs per fresh eSET cycle in normal responders. STUDY FUNDING/COMPETING INTEREST(S): This project was funded by grant 2022YFC2702503 from the National Key Research & Development Program of China and grant 2021140 from the Beijing Health Promotion Association. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: The RCT was registered in the Chinese Clinical Trial Registry; Study Number: ChiCTR2100053453. TRIAL REGISTRATION DATE: 21 November 2021. DATE OF FIRST PATIENT'S ENROLLMENT: 23 November 2021.

Maternal overweight and obesity modify the association of serum fibroblast growth factor 21 levels with gestational diabetes mellitus: A nested case-control study.

AIMS: To examine the prospective association between fibroblast growth factor 21 (FGF21) and risk of gestational diabetes mellitus (GDM) and the modifying effect of overweight/obesity for this association. METHODS: Serum FGF21 levels were measured at 6-15 weeks of gestation among 332 GDM cases and 664 matched controls. Conditional logistic regression was used to evaluate its association with GDM risk. Interaction analyses on multiplicative and additive scales were conducted to investigate the modifying effect of overweight/obesity. RESULTS: Elevated FGF21 levels were associated with a higher risk of GDM in multivariable models, but the positive association was attenuated after further adjustment for pre-pregnancy body mass index (BMI). A significant multiplicative interaction was noted between FGF21 (both continuous and dichotomous) and pre-pregnancy BMI (p for interaction = 0.049 and 0.03), and the association was only significant in participants with pre-pregnancy BMI ≥24 kg/m2 . When participants were grouped based on pre-pregnancy BMI (≥24 and <24 kg/m2 ) and FGF21 levels (≥median and

Neural functional network of early Parkinson's disease based on independent component analysis.

This work explored neural network changes in early Parkinson's disease: Resting-state functional magnetic resonance imaging was used to investigate functional alterations in different stages of Parkinson's disease (PD). Ninety-five PD patients (50 early/mild and 45 early/moderate) and 37 healthy controls (HCs) were included. Independent component analysis revealed significant differences in intra-network connectivity, specifically in the default mode network (DMN) and right frontoparietal network (RFPN), in both PD groups compared to HCs. Inter-network connectivity analysis showed reduced connectivity between the executive control network (ECN) and DMN, as well as ECN-left frontoparietal network (LFPN), in early/mild PD. Early/moderate PD exhibited decreased connectivity in ECN-LFPN, ECN-RFPN, ECN-DMN, and DMN-auditory network, along with increased connectivity in LFPN-cerebellar network. Correlations were found between ECN-DMN and ECN-LFPN connections with UPDRS-III scores in early/mild PD. These findings suggest that PD progression involves dysfunction in multiple intra- and inter-networks, particularly implicating the ECN, and a wider range of abnormal functional networks may mark the progression of the disease.

Genetic insights into the dissolution of dioecy in diploid persimmon Diospyros oleifera Cheng.

BACKGROUND: Dioecy, a sexual system of single-sexual (gynoecious/androecious) individuals, is rare in flowering plants. This rarity may be a result of the frequent transition from dioecy into systems with co-sexual individuals. RESULTS: In this study, co-sexual expression (monoecy and hermaphroditic development), previously thought to be polyploid-specific in Diospyros species, was identified in the diploid D. oleifeara historically. We characterized potential genetic mechanisms that underlie the dissolution of dioecy to monoecy and andro(gyno)monoecy, based on multiscale genome-wide investigations of 150 accessions of Diospyros oleifera. We found all co-sexual plants, including monoecious and andro(gyno)monoecious individuals, possessed the male determinant gene OGI, implying the presence of genetic factors controlling gynoecia development in genetically male D. oleifera. Importantly, discrepancies in the OGI/MeGI module were found in diploid monoecious D. oleifera compared with polyploid monoecious D. kaki, including no Kali insertion on the promoter of OGI, no different abundance of smRNAs targeting MeGI (a counterpart of OGI), and no different expression of MeGI between female and male floral buds. On the contrary, in both single- and co-sexual plants, female function was expressed in the presence of a genome-wide decrease in methylation levels, along with sexually distinct regulatory networks of smRNAs and their targets. Furthermore, a genome-wide association study (GWAS) identified a genomic region and a DUF247 gene cluster strongly associated with the monoecious phenotype and several regions that may contribute to andromonoecy. CONCLUSIONS: Collectively, our findings demonstrate stable breakdown of the dioecious system in D. oleifera, presumably also a result of genomic features of the Y-linked region.

Liver biomarkers, lipid metabolites, and risk of gestational diabetes mellitus in a prospective study among Chinese pregnant women.

BACKGROUND: Liver plays an important role in maintaining glucose homeostasis. We aimed to examine the associations of liver enzymes and hepatic steatosis index (HSI, a reliable biomarker for non-alcoholic fatty liver disease) in early pregnancy with subsequent GDM risk, as well as the potential mediation effects of lipid metabolites on the association between HSI and GDM. METHODS: In a birth cohort, liver enzymes were measured in early pregnancy (6-15 gestational weeks, mean 10) among 6,860 Chinese women. Multivariable logistic regression was performed to examine the association between liver biomarkers and risk of GDM. Pearson partial correlation and least absolute shrinkage and selection operator (LASSO) regression were conducted to identify lipid metabolites that were significantly associated with HSI in a subset of 948 women. Mediation analyses were performed to estimate the mediating roles of lipid metabolites on the association of HSI with GDM. RESULTS: Liver enzymes and HSI were associated with higher risks of GDM after adjustment for potential confounders, with ORs ranging from 1.42 to 2.24 for extreme-quartile comparisons (false discovery rate-adjusted P-trend ≤0.005). On the natural log scale, each SD increment of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and HSI was associated with a 1.15-fold (95% CI: 1.05, 1.26), 1.10-fold (1.01, 1.20), 1.21-fold (1.10, 1.32), 1.15-fold (1.04, 1.27), and 1.33-fold (1.18, 1.51) increased risk of GDM, respectively. Pearson partial correlation and LASSO regression identified 15 specific lipid metabolites in relation to HSI. Up to 52.6% of the association between HSI and GDM risk was attributed to the indirect effect of the HSI-related lipid score composed of lipid metabolites predominantly from phospholipids (e.g., lysophosphatidylcholine and ceramides) and triacylglycerol. CONCLUSIONS: Elevated liver enzymes and HSI in early pregnancy, even within a normal range, were associated with higher risks of GDM among Chinese pregnant women. The association of HSI with GDM was largely mediated by altered lipid metabolism.

Detection of chromosome aberrations in 17 054 individuals with fertility problems and their subsequent assisted reproductive technology treatments in Central China.

STUDY QUESTION: How do the types and frequency of chromosome aberrations in couples in central China affect fertility and ART treatment? SUMMARY ANSWER: Men with chromosome aberrations or polymorphisms have an increased risk of semen quality impairment and infertility, and couples affected by reciprocal translocations had a lower pregnancy rate compared with other chromosome aberrations. WHAT IS KNOWN ALREADY: Karyotyping is crucial for patients affected by infertility as chromosome aberrations play an important role in the etiology of male infertility. However, the influence of chromosome aberrations and polymorphisms on sperm motility and morphology remains controversial. Data on ART treatment outcomes in infertile couples affected by chromosome aberrations are insufficient. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective study involving 17 054 patients affected by infertility who underwent karyotyping in our center between January 2020 and May 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Karyotyping was performed on 17 054 patients with reproductive failure. All patients were from the central regions of China. The following data were collected from a medical records system using patient identification numbers: couples' ages, history of pregnancy and childbirth, type of infertility, years of infertility, cause of infertility, chromosome karyotypes, semen analysis results, assisted reproductive techniques performed, and treatment outcomes of ART. MAIN RESULTS AND THE ROLE OF CHANCE: The incidence of chromosome aberrations was 2.04%; 2.49% in men and 1.57% in women. By analyzing the relationships between chromosome aberrations/polymorphisms and abnormal semen parameters, we found that there were significantly higher rates of asthenozoospermia, oligospermia, and teratozoospermia among men with Robertsonian translocations and sex chromosomal structural aberrations compared with those with normal karyotypes. Higher rates of asthenozoospermia and teratozoospermia were also observed among men with autosomal reciprocal translocations. The incidence of chromosome aberrations in azoospermic men (13.75%), and in men with cryptozoospermia or severe oligospermia (6.97%) was significantly higher than that in men with mild oligospermia or normospermia (0.88-2.12%). In addition, we found that the progressive movement of sperm is impaired in men with Chromosome 21 polymorphisms compared with men with normal karyotypes (39.46% ± 20.51% vs 48.61% ± 18.76%, P = 0.026). The percentage of morphologically normal forms was lower in the chromosomal polymorphism group than in the normal karyotype group (5.01% ± 2.41% vs 5.59% ± 2.14%, P = 0.001), especially in men with polymorphisms on Chromosome 9 (enlarged Chromosome 9 heterochromatin [9qh+]: 4.48% ± 2.22% vs 5.59% ± 2.14%, P = 0.006; pericentric inversion of Chromosome 9 [inv(9)]: 5.09% ± 3.11% vs 5.59% ± 2.14%, P = 0.008). ART treatment was successful in 36.00% of couples affected by chromosome aberrations. However, couples affected by reciprocal translocations achieved a lower pregnancy rate (24.07%), which may be due to the lower euploidy rates (27.31%) when compared with that in other chromosome aberrations. LIMITATIONS, REASONS FOR CAUTION: First, although the initial cohort was large, chromosome aberrations were identified in a small number of patients. Second, the observational nature of the study design is limiting. Third, the couples affected by infertility in this study were all outpatients that did not undergo identical comprehensive examinations except for karyotyping, leading to the incomplete collection of medical records. Also, the population included in this study mainly focused on couples affected by infertility, which may not be included in the European Association of Urology (EAU) recommendation on male infertility. WIDER IMPLICATIONS OF THE FINDINGS: Men with chromosome aberrations or polymorphisms have an increased risk of semen quality impairment and infertility. Constitutional chromosome analysis is recommended for men affected by infertility and severe oligospermia or azoospermia to facilitate early and appropriate guidance for the most suitable treatment. Carriers of chromosome aberrations can achieve acceptable pregnancy outcomes through IVF. However, couples affected by reciprocal translocations have lower pregnancy rates, and more treatment cycles are needed before a successful pregnancy. A possible explanation may be the fewer euploid embryos obtained. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Grant 2021YFC2700603 from the National Key Research & Development Program of China. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Target Exposome for Characterizing Early Gestational Exposure to Contaminants of Emerging Concern and Association with Gestational Diabetes Mellitus.

Characterization of gestational exposure to complex contaminants of emerging concern (CECs) is critical to the identification of environmental risk factors for pregnancy complications. However, determination of various CECs with diverse physicochemical properties in biological fluids is technically challenging. In the present study, we developed a target exposome protocol, consisting of simple liquid-liquid extraction-based sample preparation and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, to determine 325 CECs covering 11 subclasses, including poly- and perfluoroalkyl substances, organophosphate esters, ultraviolet (UV) stabilizers, synthetic antioxidants, phthalate esters, and several others. The protocol exhibits exceptional advantages over traditional approaches in the coverage of chemicals, sample volume demand, and time and financial cost. The protocol was applied in a prospective nested gestational diabetes mellitus (GDM) study including 120 cases and 240 matched healthy controls. Thirty-three CECs were detected in >70% of the samples, with a combined concentration of 17.0-484.7 ng/mL. Bayesian kernel machine regression analysis showed that exposure to the CEC mixture was significantly associated with a higher GDM risk. For example, when increasing all CECs in the mixture from 50th percentile to 75th percentile, the estimated probit of GDM incidence had an increase of 92% (95% CI: 56%, 127%). Meanwhile, perfluorohexanesulfonic acid, 1,3-diphenylguanidine, and dibutyl fumarate were identified as the key CECs driving the joint effect. This work demonstrates great potential of our target exposome protocol for environmental risk factor identification in large-scale epidemiology or biomonitoring studies.

Metal Exposure during Early Pregnancy and Risk of Gestational Diabetes Mellitus: Mixture Effect and Mediation by Phospholipid Fatty Acids.

Despite existing studies exploring the association between metal exposure and gestational diabetes mellitus (GDM), most of them have focused on a single metal or a small mixture of metals. Our prospective work investigated the joint and independent effects of early gestational exposure to 17 essential and nonessential metals on the GDM risk and potential mediation by plasma phospholipid fatty acids (PLFAs) based on a nested case-control study established with 335 GDM cases and 670 randomly matched healthy controls. The Bayesian kernel machine regression (BKMR) and quantile g-computation analyses demonstrated a joint effect from metal co-exposure on GDM risk. BKMR with hierarchical variable selection indicated that the group of essential metals was more strongly associated with GDM than the group of nonessential metals with group posterior inclusion probabilities (PIPs) of 0.979 and 0.672, respectively. Cu (0.988) and Ga (0.570) had the largest conditional PIPs within each group. We also observed significant mediation effects of selected unsaturated PLFAs on Cu-GDM and Ga-GDM associations. KEGG enrichment analysis further revealed significant enrichment in the biosynthesis of unsaturated PLFAs. C18:1 n-7 exhibited the largest proportion of mediation in both associations (23.8 and 22.9%). Collectively, our work demonstrated the joint effect of early gestational metal exposure on GDM risk and identified Cu and Ga as the key species to the joint effect. The findings lay a solid ground for further validation through multicenter investigations and mechanism exploration via laboratory studies.

Combined healthy lifestyle in early pregnancy and risk of gestational diabetes mellitus: A prospective cohort study.

OBJECTIVE: To examine the association of a combined healthy lifestyle in early pregnancy with gestational diabetes mellitus (GDM) risk. DESIGN, SETTING AND POPULATION: A Chinese prospective cohort study with 6980 pregnant women. METHODS: Individual modifiable lifestyle factors were assessed in early pregnancy and a combined lifestyle score was derived from the sum of the lifestyle factors, with a higher score indicating a healthier lifestyle. The association of a combined healthy lifestyle with GDM risk was examined. MAIN OUTCOME MEASURES: Gestational diabetes mellitus was diagnosed in middle pregnancy according to the International Association of Diabetes and Pregnancy Study Group criteria or diagnoses in medical records. RESULTS: Overall, 501 (7.2%) pregnant women were diagnosed with GDM. Being physically active (total energy expenditure in upper three quintiles, i.e. ≥100.1 metabolic equivalent of task [MET]-hours/week; odds ratio [OR] 0.76, 95% confidence interval [CI] 0.63-0.92), healthy diet (total intake of vegetables and fruits ≥5 times/day; OR 0.74, 95% CI 0.59-0.94), sufficient sleep (night-time sleep duration ≥7 hours/night; OR 0.66, 95% CI 0.48-0.90) and healthy weight (early-pregnancy BMI <24.0 kg/m2 ; OR 0.57, 95% CI 0.46-0.71) were associated with lower GDM risk. The GDM risk decreased linearly across the combined lifestyle score (Ptrend <0.001): women with 2, 3 and 4 lifestyle factors compared with those with 0-1 factor had 38% (OR 0.62, 95% CI 0.46-0.84), 57% (OR 0.43, 95% CI 0.31-0.58) and 66% (OR 0.34, 95% CI 0.22-0.52) lower risks of GDM, respectively. CONCLUSION: A healthy lifestyle in early pregnancy was associated with a substantially lower GDM risk.

Prognosis of lung cancer with simple brain metastasis patients and establishment of survival prediction models: a study based on real events.

OBJECTIVES: The aim of this study was to explore risk factors for the prognosis of lung cancer with simple brain metastasis (LCSBM) patients and to establish a prognostic predictive nomogram for LCSBM patients. MATERIALS AND METHODS: Three thousand eight hundred and six cases of LCSBM were extracted from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015 using SEER Stat 8.3.5. Lung cancer patients only had brain metastasis with no other organ metastasis were defined as LCSBM patients. Prognostic factors of LCSBM were analyzed with log-rank method and Cox proportional hazards model. Independent risk and protective prognostic factors were used to construct nomogram with accelerated failure time model. C-index was used to evaluate the prediction effect of nomogram. RESULTS AND CONCLUSION: The younger patients (18-65 years old) accounted for 54.41%, while patients aged over 65 accounted for 45.59%.The ratio of male: female was 1:1. Lung cancer in the main bronchus, upper lobe, middle lobe and lower lobe were accounted for 4.91%, 62.80%, 4.47% and 27.82% respectively; and adenocarcinoma accounted for 57.83% of all lung cancer types. The overall median survival time was 12.2 months. Survival rates for 1-, 3- and 5-years were 28.2%, 8.7% and 4.7% respectively. We found female (HR = 0.81, 95% CI 0.75-0.87), the married (HR = 0.80; 95% CI 0.75-0.86), the White (HR = 0.90, 95% CI 0.84-0.95) and primary site (HR = 0.45, 95% CI 0.39-0.52) were independent protective factors while higher age (HR = 1.51, 95% CI 1.40-1.62), advanced grade (HR = 1.19, 95% CI 1.12-1.25) and advanced T stage (HR = 1.09, 95% CI 1.05-1.13) were independent risk prognostic factors affecting the survival of LCSBM patients. We constructed the nomogram with above independent factors, and the C-index value was 0.634 (95% CI 0.622-0.646). We developed a nomogram with seven significant LCSBM independent prognostic factors to provide prognosis prediction.

Research progress on icariin, a traditional Chinese medicine extract, in the treatment of asthma.

Bronchial asthma is a common chronic airway disease, and long-term management of asthma is the focus and challenge of clinical treatment. Glucocorticoids are often used as the first choice for the treatment of asthma. However, the occurrence of hormone dependence, hormone resistance, and local and systemic adverse reactions caused by hormone application also creates problems for the treatment of asthma. Finding new, safe, and effective therapeutic drugs is an important research direction at present. Icariin is an effective ingredient of the traditional Chinese medicine, Epimedium. It has various biological attributes such as anti-inflammatory and antioxidative activities, and immune regulation. It has high safety and a wide range of clinical applications. Icariin has the characteristics of multitargeted intervention in the treatment of asthma. Here, we review the specific mechanisms of icariin in treating asthma, and icariin is considered a novel therapy in controlling asthma; however, the mechanism is still worth further investigation.

Curcumin Can Improve Spinal Cord Injury by Inhibiting TGF-ß-SOX9 Signaling Pathway.

Spinal cord injury (SCI) is a severe nervous system disease with high morbidity and disability rate. Signaling pathways play a key role in the neuronal restorative mechanism following SCI. SRY-related high mobility group (HMG)-box gene 9 (SOX9) affects glial scar formation via Transforming growth factor beta (TGF-ß) signaling pathway. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is transferred into nucleus to upregulate TGF-ß-SOX9. Curcumin exhibits potent anti-inflammatory and anti-oxidant properties. Curcumin can play an important role in SCI recovery by inhibiting the expression of NF-κB and TGF-ß-SOX9. Herein, we review the potential mechanism of curcumin-inhibiting SOX9 signaling pathway in SCI treatment. The inhibition of NF-κB and SOX9 signaling pathway by curcumin has the potentiality of serving as neuronal regenerative mechanism following SCI.

Bioactive sphingolipids as emerging targets for signal transduction in cancer development.

Sphingolipids, crucial components of cellular membranes, play a vital role in maintaining cellular structure and signaling integrity. Disruptions in sphingolipid metabolism are increasingly implicated in cancer development. Key bioactive sphingolipids, such as ceramides, sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glycosphingolipids, profoundly impact tumor biology. They influence the behavior of tumor cells, stromal cells, and immune cells, affecting tumor aggressiveness, angiogenesis, immune modulation, and extracellular matrix remodeling. Furthermore, abnormal expression of sphingolipids and their metabolizing enzymes modulates the secretion of tumor-derived extracellular vesicles (TDEs), which are key players in creating an immunosuppressive tumor microenvironment, remodeling the extracellular matrix, and facilitating oncogenic signaling within in situ tumors and distant pre-metastatic niches (PMNs). Understanding the role of sphingolipids in the biogenesis of tumor-derived extracellular vesicles (TDEs) and their bioactive contents can pave the way for new biomarkers in cancer diagnosis and prognosis, ultimately enhancing comprehensive tumor treatment strategies.

Alterations in cortical volume and complexity in Parkinson's disease with depression.

AIMS: The aim of this study is to investigate differences in gray matter volume and cortical complexity between Parkinson's disease with depression (PDD) patients and Parkinson's disease without depression (PDND) patients. METHODS: A total of 41 PDND patients, 36 PDD patients, and 38 healthy controls (HC) were recruited and analyzed by Voxel-based morphometry (VBM) and surface-based morphometry (SBM). Differences in gray matter volume and cortical complexity were compared using the one-way analysis of variance (ANOVA) and correlated with the Hamilton Depression Scale-17 (HAMD-17) scores. RESULTS: PDD patients exhibited significant cortical atrophy in various regions, including bilateral medial parietal-occipital-temporal lobes, right dorsolateral temporal lobes, bilateral parahippocampal gyrus, and bilateral hippocampus, compared to HC and PDND groups. A negative correlation between the GMV of left precuneus and HAMD-17 scores in the PDD group tended to be significant (r = -0.318, p = 0.059). Decreased gyrification index was observed in the bilateral insular and dorsolateral temporal cortex. However, there were no significant differences found in fractal dimension and sulcal depth. CONCLUSION: Our research shows extensive cortical structural changes in the insular cortex, parietal-occipital-temporal lobes, and hippocampal regions in PDD. This provides a morphological perspective for understanding the pathophysiological mechanism underlying depression in Parkinson's disease.

Metal exposure and blood lipid biomarkers in early pregnancy: A cross-sectional study.

Recognizing the risk factors for dyslipidemia during pregnancy is crucial for safeguarding the health of both the mothers and the offspring. Growing evidence emerged and suggested links between environmental factors, including metals, and alteration in lipid levels or dyslipidemia in general populations. However, knowledge of the associations during pregnancy remains extremely lacking. Herein, we aimed to explore whether elevated metal exposure constitutes a risk factor for dyslipidemia in pregnant women. Based on the Tongji-Shuangliu Birth Cohort (TSBC), a total of 663 pregnant women were recruited and their urinary levels of 17 metals and blood lipid biomarkers in early pregnancy were measured, namely triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). The multivariable linear regression models revealed that exposure to selected metals during early pregnancy was significantly associated with some important biomarkers. In particular, after natural log-transformed for the levels of lipid biomarkers and metals, copper (Cu) exposure was positively associated with HDL-C (ß = 0.024, 95% CI: 0.001, 0.046), while zinc (Zn) was associated with TG (ß = 0.062, 95% CI: 0.013, 0.110) and selenium with TC (ß = 0.028, 95% CI: 0.004, 0.054). Exposure to rubidium (Rb) was positively associated with multiple lipid biomarkers, including HDL-C (ß = 0.020, 95% CI: 0.002, 0.037) and LDL-C (ß = 0.022, 95% CI: 0.001, 0.042). Mixture exposure analysis further identified significant associations between Cu and HDL-C, Zn and TG, Rb and HDL-C, when multiple metal exposures were considered in the Bayesian kernel machine regression model simultaneously. Our findings showed that exposure to several metals during early pregnancy was associated with an increased prevalence of blood lipid abnormalities in pregnant women. These findings underscore the potential impact of metal combinations on lipid metabolism and increase our understanding of the risk factors associated with abnormal lipid metabolism during pregnancy.

Gut antibiotic resistome during pregnancy associates with the risk of gestational diabetes mellitus: New evidence from a prospective nested case-control study.

Antibiotic resistome has emerged as a global threat to public health. However, gestational antibiotic resistome and potential link with adverse pregnancy outcomes remains poorly understood. Our study reports for the first time an association between gut antibiotic resistome during early pregnancy and the risk of gestational diabetes mellitus (GDM) based on a prospective nested case-control cohort including 120 cases and 120 matched controls. A total of 214 antibiotic resistance gene (ARG) subtypes belonging to 17 ARG types were identified in > 10 % fecal samples collected during each trimester. The data revealed dynamic profiles of gut antibiotic resistome through pregnancy, and significant positive associations between selected features (i.e., ARG abundances and a GDM-ARG score which is a new feature characterizing the association between ARGs and GDM) of gut antibiotic resistome during early pregnancy and GDM risk as well as selected endogenous metabolites. The findings demonstrate ubiquitous presence of ARGs in pregnant women and suggest it could constitute an important risk factor for the development of GDM.

FUNDC1 mediated mitochondria-dependent ferroptosis of epithelial cells in model of asthma by FBXL2/ar/GPX4 signaling pathway of SUMO1 at K136.

This study aimed to explore the critical role of FUNDC1 on epithelial cells in model of asthma. Patients with asthma and normal healthy volunteers were obtained from our hospital. The serum of FUNDC1 mRNA expression was down-regulated in patients with asthma. Meanwhile, the serum of FUNDC1 mRNA expression was positive correlation with IgE and anti-HDM IgE protein. FUNDC1 expression in lung tissue of mice model was decreased in mice model of asthma. Sh-FUNDC1 enhanced asthma in mice model of asthma. FUNDC1 up-regulation reduced IL-4, IL-5, IL-10 and IL-13 activity levels in vitro model of asthma.FUNDC1 down-regulation promoted IL-4, IL-5, IL-10 and IL-13 activity levels in vitro model of asthma. FUNDC1 reduced ferroptosis of epithelial cells in model of asthma through the inhibition of mitochondrial damage. FUNDC1 induced FBXL2 and AR protein expression in model of asthma. FUNDC1 interlinked with FBXL2 is modified by SUMO1 at K136. FBXL2, ASN-205, GLN-204, ARG-235, and GLN-237 form hydrogen bonds with FUNDC1's ASP-15, ASP-16, GLU-25, and ARG-29, with lengths of 2.3, 3.1, 2.9, 2.3, and 2.9 Å, respectively. The induction of FBXL2 reduced the effects of Sh-FUNDC1 on asthma in mice model of asthma. The inhibition of AR reduced the effects of Sh-FUNDC1 on asthma in mice model of asthma Overall, FUNDC1 prevents ferroptosis of airway epithelial cells of asthma through FBXL2/AR/GPX4 signaling pathway of SUMO1 at K136. FUNDC1 might benefit the treatment of asthma or other pulmonary disease.

FUNDC1 prevents ferroptosis of airway epithelial cells of asthma through FBXL2/AR/GPX4 signaling pathway of SUMO1 at K136. FUNDC1 might benefit the treatment of asthma or other pulmonary disease.

Oleanolic acid inhibits hypoxic tumor-derived exosomes-induced premetastatic niche formation in hepatocellular carcinoma by targeting ERK1/2-NFκB signaling.

BACKGROUND: Pulmonary premetastatic niche (PMN) formation plays a key role in the lung metastasis of hepatocellular carcinoma (HCC). Hypoxia promotes the secretion of tumor-derived exosomes (TDEs) and facilitates the formation of PMN. However, the mechanisms remain unexplored. METHODS: TDEs from normoxic (N-TDEs) or hypoxic (H-TDEs) HCC cells were used to induce fibroblast activation in vitro and PMN formation in vivo. Oleanolic acid (OA) was intragastrically administered to TDEs-preconditioned mice. Bioinformatics analysis and drug affinity responsive target stability (DARTS) assays were performed to identify targets of OA in fibroblasts. RESULTS: H-TDEs induced activation of pulmonary fibroblasts, promoted formation of pulmonary PMN and subsequently facilitated lung metastasis of HCC. OA inhibited TDEs-induced PMN formation and lung metastasis and suppressed TDEs-mediated fibroblast activation. MAPK1 and MAPK3 (ERK1/2) were the potential targets of OA. Furthermore, H-TDEs enhanced ERK1/2 phosphorylation in fibroblasts in vitro and in vivo, which was suppressed by OA treatment. Blocking ERK1/2 signaling with its inhibitor abated H-TDEs-induced activation of fibroblasts and PMN formation. H-TDEs-induced phosphorylation of ERK1/2 in fibroblasts touched off the activation NF-κB p65, which was mitigated by OA. In addition, the ERK activator C16-PAF recovered the activation of ERK1/2 and NF-κB p65 in H-TDEs-stimulated MRC5 cells upon OA treatment. CONCLUSION: The present study offers insights into the prevention of TDEs-induced PMN, which has been insufficiently investigated. OA suppresses the activation of inflammatory fibroblasts and the development of pulmonary PMN by targeting ERK1/2 and thereby has therapeutic potential in the prevention of lung metastasis of HCC.

Exploring brain asymmetry in early-stage Parkinson's disease through functional and structural MRI.

OBJECTIVE: This study explores the correlation between asymmetrical brain functional activity, gray matter asymmetry, and the severity of early-stage Parkinson's disease (PD). METHODS: Ninety-three early-stage PD patients (ePD, H-Y stages 1-2.5) were recruited, divided into 47 mild (ePD-mild, H-Y stages 1-1.5) and 46 moderate (ePD-moderate, H-Y stages 2-2.5) cases, alongside 43 matched healthy controls (HCs). The study employed the Hoehn and Yahr (H-Y) staging system for disease severity assessment and utilized voxel-mirrored homotopic connectivity (VMHC) for analyzing brain functional activity asymmetry. Asymmetry voxel-based morphometry analysis (VBM) was applied to evaluate gray matter asymmetry. RESULTS: The study found that, relative to HCs, both PD subgroups demonstrated reduced VMHC values in regions including the amygdala, putamen, inferior and middle temporal gyrus, and cerebellum Crus I. The ePD-moderate group also showed decreased VMHC in additional regions such as the postcentral gyrus, lingual gyrus, and superior frontal gyrus, with notably lower VMHC in the superior frontal gyrus compared to the ePD-mild group. A negative correlation was observed between the mean VMHC values in the superior frontal gyrus and H-Y stages, UPDRS, and UPDRS-III scores. No significant asymmetry in gray matter was detected. CONCLUSIONS: Asymmetrical brain functional activity is a significant characteristic of PD, which exacerbates as the disease severity increases, resembling the dissemination of Lewy bodies across the PD neurological framework. VMHC emerges as a potent tool for characterizing disease severity in early-stage PD.