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Abstract This study aims to explore the coding sequence (CDS) of the putative DUS gene in Eimeria media and assess its potential biological functions during the parasite's lifecycle. Initially, oocysts were isolated from fecal samples of rabbits infected with E. media, from which DNA and RNA were extracted. These extractions were used as templates for PCR to successfully amplify the CDS of the DUS gene, confirming its presence within the E. media genome. Further analysis using quantitative PCR (qPCR) demonstrated significantly higher expression of the DUS gene in the precocious line (PL) compared to the wild type (WT). This differential expression highlights a potential functional role for the DUS gene in influencing the development and sporulation processes of E. media, which may contribute to the precocious phenotype. Additionally, bioinformatics analysis provided insights into the evolutionary trends and structural characteristics of the DUS gene across different species, suggesting a broader biological significance. The elevated expression of the DUS gene in the PL suggests its critical involvement in the growth and reproductive processes of the parasite. This finding opens new avenues for research aimed at controlling E. media infection through targeted interventions in the DUS gene expression pathways.

The current study aims to explore the representative and typical female body shapes through in-depth observation and analysis of the diversity in Malaysian female body shape characteristics across different ethnic and age groups, which assists in facilitating the establishment of accurate apparel size standards. This study was conducted in Selangor, which is the most populous and developed Malaysian state. The data were collected via a highly systematic approach. The K-mean clustering method was applied to synthesise and analyse the collected data, which classified the body types into five major clusters. The results not only revealed significant differences in the distribution of body shapes across ethnic and age groups but also highlighted the limitations of the various sizing systems currently employed by the Malaysian apparel industry to fulfil the requirements of the diverse Malaysian market. The findings provided practical implications for apparel manufacturers and retailers with concrete evidence to support improved product design and enhance customer satisfaction. A deeper understanding and categorisation of Malaysian females’ body types could also assist the apparel industry in developing more tailored sizing systems. Resultantly, an improved system minimises return rates, optimises inventory management, and supports environmental and sustainability goals by reducing overproduction.

As an alternative compound of bisphenol A (BPA), bisphenol B (BPB) was widely used in plastic materials. The potential actions of BPB on the function of Leydig cells through the regulation of H3K27me3 and H3K9me3 remains unclear. Our goal was to assess how BPB influences Leydig cell function via histone modifications mediated by H3K27me3 and H3K9me3. Male 56-day-old Sprague-Dawley rats were given with 0, 50, 100, and 200 mg/kg/day of BPB by the oral administration for 14 days to study the impact of BPB on the function of Leydig cells in rats. The findings indicated that BPB significantly reduced the serum testosterone levels at the dose of 100 mg/kg and 200 mg/kg and follicle-stimulating hormone levels at the doses of 50, 100, and 200 mg/kg, while increasing estradiol levels at the dose of 200 mg/kg. BPB did not alter the numbers of CYP11A1+ Leydig cells and SOX9+ Sertoli cells, but it downregulated the expression of key genes in testosterone synthesis pathway (Lhcgr, Scarb1, Star, Cyp11a1, Cyp17a1, Hsd11b1, Hsd17b3, and Insl3) and their corresponding protein levels. Notably, BPB significantly boosted the expressions of histone methylation markers like EEF1A1, SUZ12, EED, EZH2, H3K27me3, and H3K9me3 in vivo. H3K27me3 and H3K9me3 levels were enhanced at the proximal promoters of Lhcgr, Cyp11a1, and Star through ChIP and PCR analyses. Furthermore, adult Leydig cells were extracted and cultured with BPB (0, 10, 50, 100, and 200 μM) alone or in combination with H3K27me3 antagonist GSK-J4. The results demonstrated that BPB significantly decreased testosterone output, which was counteracted by GSK-J4 to reverse BPB-mediated testosterone suppression. Additionally, BPB significantly elevated the levels of EEF1A1, EEF1A2, EED, H3K27me3, and H3K9me3 in vitro. BPB could potentially hinder the growth and function of Leydig cells by modulating H3K27me3 and H3K9me3. The findings of the study indicate the involvement of histone methylation (H3K27me3) in BPB-induced steroidogenic dysfunction, emphasizing the correlation between histone modifications and male reproductive toxicity.

Dicarboximide fungicides, including captafol, captan, cyclohexylthiophthalimide, folpet, and procymidone, represent a distinct category of fungicides. 17β-Hydroxysteroid dehydrogenase 1 (17β-HSD1) catalyzes the conversion of estrone to estradiol in mammals. Yet, the impact of these fungicides on 17β-HSD1 activity remains unknown. In this study, we investigated their inhibition using human placental cytosols, rat and pig ovarian cytosols. Our observations revealed that dicarboximide fungicides significantly inhibited human 17β-HSD1 activity. Among them, captan showed the strongest potency, with its IC50 of 1.28 μM, whereas procymidone had an IC50 of 100.71 μM. However, both rat and pig 17β-HSD1 enzymes were less sensitive to the inhibition of these fungicides compared to the human enzyme, with captan displaying an IC50 of 5.65 μM for the rat enzyme and 7.36 μM for the pig enzyme. Correlation analysis indicated a positive correlation between IC50 values and LogP. Docking analysis revealed that these fungicides bound to cofactor or between the steroid and cofactor binding sites. The dithiothreitol treatment demonstrated that the formation of irreversible bonds between dicarboximide fungicides and the cysteine residues played a key role in the inhibition of 17β-HSD1 activity. In conclusion, dicarboximide fungicides inhibit 17β-HSD1 depending on lipophilicity, species, and cysteine residue interactions.

This research investigated the impact of cyclopiazonic acid (CPA), a mycotoxin, on the function of progenitor Leydig cells (PLCs) in prepubertal male rats, focusing on its potential disruption of mitochondrial integrity through mitofusin 1 (MFN1) modulation. In vivo, Sprague Dawley rats received CPA (0.2, 1, 5 mg/kg/day) via gavage from postnatal days 21–28 to evaluate PLC function and mitochondrial morphology using serum hormone levels, histology, qPCR, and Western blot analyses. In vitro, rat R2C cells were treated with CPA (0.1, 1, 10 μM) alone or in combination with 100 μM leflunomide to assess PLC development through testosterone measurements, Western blotting, flow cytometry, and Mito-Tracker Green Staining. The findings from in vivo experiments showed that CPA reduced serum testosterone and progesterone levels at 1 mg/kg/day. The qPCR and Western blotting analyses revealed significant alterations in the expression of genes and proteins pertinent to PLC function, such as Scarb1, Star, Cyp11a1, and Cyp17a1. Immunofluorescence staining further revealed a reduction in MFN1 expression following exposure to CPA. In vitro experiments corroborated these observations, demonstrating that CPA induced mitochondrial fragmentation by downregulating SIRT1, PGC1-α, MFN1, and OPA1, increase reactive oxygen species, and inhibit testosterone synthesis in R2C cells. The administration of leflunomide was shown to mitigate the detrimental effects of CPA on PLCs. In conclusion, this research sheds new light on the deleterious effects of CPA on the reproductive development of prepubertal males.

Background: Macular hole (MH) formation after rhegmatogenous retinal detachment (RRD) surgery is rare, and in most cases, additional surgical procedures are required to repair MH. Spontaneous closure of the MH is even rarer. In this study, we aimed to report a series of cases of spontaneous closure of the secondary MH and provide a review of the literature. Methods: We retrospectively collected the cases of secondary MH formation following vitrectomy in RRD patients followed by spontaneous closure. Ophthalmological data at presentation and during follow-up were collected and analyzed. Results: We reported a total of three RRD patients aged 31,67,12 years, including two females and one male. The three patients underwent pars plana vitrectomy (PPV) with either silicone oil tamponade or air tamponade. Optical coherence tomography (OCT) revealed a second full-thickness MH formation with remnant vitreous cortex bridging in the macular region during early follow-up. Observations of the cases revealed subsequent remnant vitreous cortex traction remission and spontaneous closure of MH during follow-up, although with subsequent thin macular and abnormal macular structure. Conclusion: The progression of secondary MH formation in the cases may be related to vitreomacular traction (VMT) by the posterior vitreous cortex remnant after PPV, and the release of VMT may help the spontaneous closure of the MH after PPV for RRD.

Abstract Background Although research has explored the association between atherogenic index of plasma (AIP) and prediabetes and diabetes, there is still not sufficient available evidence the role of physical activity (PA) in this relationship. Our purpose is to examine the complex connections between AIP, PA, and prediabetes and diabetes in a young and middle‐aged population. Methods This study included 2220 individuals from the general population, aged 20–60 years. AIP was calculated from the logarithm of the triglyceride (TG) to high‐density lipoprotein cholesterol (HDL‐C) ratio. PA was assessed depending to the American Heart Association (AHA) criteria and categorized into medium‐high and low PA levels. We used binary logistic regression to explore associations and subsequently performed sensitivity and subgroup analyses. Results The 2220 participants had a mean age of 38 years, with a mean AIP of −0.1185, and a prediabetes and diabetes prevalence of 7.2%. After adjusting for auxiliary variables, AIP was positively correlated with prediabetes and diabetes (odds ratio [OR]: 3.447, 95% confidence interval [CI]: 1.829–6.497). In the low PA population, the prevalence of prediabetes and diabetes raised significantly with higher AIP (OR: 3.678, 95% CI: 1.819–7.434). This association was not meaningful in the medium to high PA population (OR: 1.925, 95% CI: 0.411–9.007). Joint and sensitivity analyze results also showed agreement. Restricted cubic spline identified a linear relationship between AIP and the prevalence of prediabetes and diabetes. Notably, the prevalence significantly increases when AIP values exceed −0.16 (p for linearity

Triclosan is a potent antibacterial compound widely used in everyday products. Whether triclosan affects Leydig cell function in adult male rats remains unknown. In this study, 0, 50, 100, or 200 mg/kg/day triclosan was gavaged to Sprague-Dawley male rats from 56 to 63 days postpartum. Triclosan significantly reduced serum testosterone levels at ≥ 50 mg/kg/day via downregulating the expression of Leydig cell gene Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Hsd17b3 and regulatory transcription factor Nr3c2 at 100–200 mg/kg. Further analysis showed that triclosan markedly increased autophagy as shown by increasing LC3II and BECN1 and decreasing SQSTM1. The mRNA m6A modification analysis revealed that triclosan significantly downregulated Fto expression at 200 mg/kg while upregulating Ythdf1 expression at 100 and 200 mg/kg, leading to methylation of Becn1 mRNA as shown by MeRIP assay. Triclosan significantly inhibited testosterone output in rat R2C Leydig cells at ≥ 5 μM via downregulating Fto and upregulating Ythdf1. SiRNA Ythdf1 knockdown can reverse triclosan-mediated mitophagy in R2C cells, thereby reversing the reduction of testosterone output. In summary, triclosan caused Becn1 m6A methylation by downregulating Fto and upregulating Ythdf1, which accelerated Becn1 translation, thus leading to the occurrence of autophagy and the decrease of testosterone biosynthesis.

A series of CeO2–TiO2 mixed oxides supports with various Ce/Ti molar ratio were synthesized by modified coprecipitation method. The corresponding Pt loaded (0.5 wt% Pt) catalysts were prepared by electronless deposition method and evaluated for the deep oxidation of n-hexane as a model VOCs. The results show that the CeO2 and TiOx nanoparticles can highly disperse into each other and form Ce2Ti2O7 solid solution with appropriate Ce/Ti molar ratio, which significantly improves their redox ability by enhancing the interaction between CeO2 and TiOx. The dispersibility of Pt species can also be adjusted by altering the Ce/Ti molar ratio, and Pt/CeTi-2/1 catalyst with Ce/Ti molar ratio of 2:1 exhibits the best Pt dispersibility that Pt species mainly exist as Pt single atoms. The high dispersion of Pt species in the Pt/CeO2–TiO2 catalysts would promote the catalytic activity of VOCs oxidation with low T90% values (1000 ppm, GHSV = 15,000 h−1), such as for n-hexane degradation with T90% of 139 °C. The characterizations reveal that the superior activity is mainly related to possessing the more Pt2+ species, adsorbed oxygen species and higher low-temperature reducibility owing to the strong interaction between highly dispersed Pt species and CeO2–TiO2 as well as the promoted migration of lattice oxygen by the formation of more Ce2Ti2O7 species. Furthermore, the Pt/CeTi-2/1 catalyst also exhibits excellent stability for chlorinated and other non-chlorinated VOCs oxidation, making it very promising for real application under various operating conditions.

Abstract Background The global prevalence of chronic kidney disease (CKD) in the general population is relatively clear. Our previous study showed that elderly individuals who are physically disabled are more likely to experience kidney function impairment, and the main purpose of this study was to determine the prevalence and risk factors associated with CKD in elderly patients with physical disabilities. Methods A total of 2679 elderly individuals with physical disabilities from the 2018 Shanghai Disability Health Survey were screened to calculate the prevalence of CKD. Multiple logistic regression was performed to identify the factors associated with CKD. Detailed subgroup analyses of disability level were also conducted. Results We confirmed CKD in 287 of 2679 (10.7%) participants. Female sex, age, history of hypertension, red blood cell count, albumin, urea, and uric acid (UA) were independently correlated with CKD. Age and UA abnormalities were common risk factors for different levels of disabilities. Conclusion The prevalence of CKD is higher in the mild level of older physically handicapped individuals. Age and the level of UA should also be considered in this population. The preventive strategies for patients with two levels of elderly disability should have different focuses.

BackgroundT cell exhaustion in the tumor microenvironment has been demonstrated as a substantial contributor to tumor immunosuppression and progression. However, the correlation between T cell exhaustion and osteosarcoma (OS) remains unclear.MethodsIn our present study, single-cell RNA-seq data for OS from the GEO database was analysed to identify CD8+ T cells and discern CD8+ T cell subsets objectively. Subgroup differentiation trajectory was then used to pinpoint genes altered in response to T cell exhaustion. Subsequently, six machine learning algorithms were applied to develop a prognostic model linked with T cell exhaustion. This model was subsequently validated in the TARGETs and Meta cohorts. Finally, we examined disparities in immune cell infiltration, immune checkpoints, immune-related pathways, and the efficacy of immunotherapy between high and low TEX score groups.ResultsThe findings unveiled differential exhaustion in CD8+ T cells within the OS microenvironment. Three genes related to T cell exhaustion (RAD23A, SAC3D1, PSIP1) were identified and employed to formulate a T cell exhaustion model. This model exhibited robust predictive capabilities for OS prognosis, with patients in the low TEX score group demonstrating a more favorable prognosis, increased immune cell infiltration, and heightened responsiveness to treatment compared to those in the high TEX score group.ConclusionIn summary, our research elucidates the role of T cell exhaustion in the immunotherapy and progression of OS, the prognostic model constructed based on T cell exhaustion-related genes holds promise as a potential method for prognostication in the management and treatment of OS patients.

Abstract Background Much less is known about the importance of blood pressure (BP) trajectories concerning the incidence of coronary heart disease (CHD) in people with disabilities. Our aim was to evaluate this association. Methods This cohort study surveyed 5711 adults from the Shanghai Disability Health Survey from June 2012 to June 2019. The latent class growth mixture model was used to examine distinct BP trajectories. We evaluated the association of BP trajectories with the risk of CHD by Cox proportional hazard models. The model for CHD risk fitted to BP trajectories was compared with models fitted to other BP-related indicators by goodness-of-fit, discrimination, and calibration. Results During a median follow-up of 71.74 months, 686 cases (median age was 49.03 (54.49, 58.55) years, 51.90% female) with CHD were identified, with a cumulative incidence of 12.01%. Systolic BP (SBP) and diastolic BP (DBP) were categorized into three classes, respectively. A statistically significant association was only observed between SBP trajectories and CHD. Compared with the normotensive stable SBP group (n = 1956), the prehypertension-stable group (n = 3268) had a higher risk (adjust hazards ratio (aHR) = 1.266, 95% confidence interval (CI) 1.014–1.581), and the stage 1 hypertension-decreasing group (n = 487) had the highest risk (aHR = 1.609, 95%CI 1.157–2.238). Among the BP-related indicators, the SBP trajectory was the strongest predictor of new-onset CHD. Findings were similar when sensitivity analyses were conducted. Conclusions SBP trajectory was a more important risk factor for CHD than other BP-related indicators and stringent BP control strategies may be effective for primary CHD prevention in the disabled population.

Abstract Objective Previous studies had demonstrated that disability increases mortality in patients with coronary heart disease (CHD). However, for people who had been disabled but do not have baseline cardiovascular disease, there is still limited data on how they might develop CHD. This study aimed to investigate the incidence and predictors of CHD in people with disabilities. Methods We conducted a 7-year retrospective study utilizing data from the Shanghai Comprehensive Information Platform for Persons with Disabilities Rehabilitation. Subjects aged over 18 years with at least four annual complete electronic health records were included. The primary outcome was CHD, defined as ischemic heart disease or myocardial infarction. Kaplan–Meier analysis and log-rank tests were used to compare cumulative CHD for sub-populations, stratified by age, gender, and the classification of disabilities. Cox regression was used to identify the potentially important factors. Results Out of 6419 persons with disabilities, 688 CHD cases (mean age 52.95 ± 7.17 years, male 52.2%) were identified, with a cumulative incidence of 10.72% and an incidence density of 15.15/1000 person-years. The incidence density of CHD is higher in the male gender, people over 45 years, and those with physical disabilities. Male (HR = 1.294, 95% CI, 1.111–1.506), hypertension (HR = 1.683, 95% CI, 1.405–2.009), diabetes mellitus (HR = 1.488, 95% CI, 1.140–1.934), total cholesterol (HR = 1.110, 95% CI, 1.023–1.204), and physical disabilities (HR = 1.122, 95% CI, 1.019–1.414) were independently associated with CHD. Conclusion The findings indicate that the incidence of CHD differs across disability categories rather than the severity of disability. People with physical disabilities had significantly higher risks for the development of CHD. The underlying physiological and pathological factors need to be further studied.

Objective: This study aimed to analyze associations between body mass index (BMI) and vascular measurements (brachial ankle pulse wave velocity [baPWV] and ankle-brachial index [ABI]), whether blood pressure (BP) was involved in the relationship, and implications for nursing. Methods: A cross-sectional study was conducted, including 1,894 middle-aged and older adults who underwent routine health screening at a community medical center in the Zhangjiang community in Shanghai, China. Participants were divided into three groups based on BMI: normal weight (n = 1,202), overweight (n = 480), and obese (n = 212). Multivariate linear regression models and smooth curve fittings were used to evaluate the associations between BMI and indices of vascular stiffness. Mediation analysis examined whether blood pressure mediate the association between BMI and vascular stiffness. Results: Multiple linear regression analysis showed that BMI to be significantly and negatively associated with baPWV (β = −0.06 [−0.10, −0.03]) and ABI (β = −0.004 [−0.005, −0.003]), respectively. The interaction test results of systolic blood pressure (SBP) in the relationship between BMI and baPWV were significant (P for interaction = 0.01). After adjusting for age and sex, mediation analyses showed that BMI and baPWV were correlated (β = 0.090, P

Abstract Aims The activation of cardiac fibroblasts (CFs) leads to overproduction of collagens and subsequently cardiac fibrosis. However, the regulatory mechanism of CF function in the process of cardiac fibrosis remains unclear. This work investigated the function of polypyrimidine tract binding protein 1 (PTBP1)/nuclear receptor NR4A1 (Nur77)/fatty acid‐binding protein 5 (FABP5) axis in myocardial fibrosis. Methods and results Cardiac fibrosis was induced in mice suffered left anterior descending ligation. In parallel, neonatal mouse CFs were isolated and stimulated with transforming growth factor‐β1 (TGF‐β1). Cardiac fibrosis was evaluated by Masson's trichrome staining. Expression of PTBP1, Nur77, FABP5, collagen I, and collagen III was measured by quantitative real‐time PCR and western blotting. Proliferation of CFs was assessed by 5‐ethynyl‐2′‐deoxyuridine assay. Molecular interaction was validated by RNA‐binding protein immunoprecipitation, chromatin immunoprecipitation, and dual luciferase reporter assay. PTBP1 was up‐regulated (P

Curcuminoids are functional food additives, and the effect on gonadal hormone biosynthesis remains unclear. Gonads contain 3β-hydroxysteroid dehydrogenase isoforms, h3β-HSD2 (humans) and r3β-HSD1 (rats), which catalyse pregnenolone into progesterone. The potency and mechanisms of curcuminoids to inhibit 3β-HSD activity were explored. The inhibitory potency was bisdemethoxycurcumin (IC50, 1.68 µM) >demethoxycurcumin (3.27 µM) > curcumin (13.87 µM) > tetrahydrocurcumin (109.0 µM) > dihydrocurcumin and octahydrocurcumin on KGN cell h3β-HSD2, while that was bisdemethoxycurcumin (1.22 µM) >demethoxycurcumin (2.18 µM) > curcumin (4.12 µM) > tetrahydrocurcumin (102.61 µM) > dihydrocurcumin and octahydrocurcumin on testicular r3β-HSD1. All curcuminoids inhibited progesterone secretion by KGN cells under basal and forskolin-stimulated conditions at >10 µM. Docking analysis showed that curcuminoids bind steroid-active site with mixed or competitive mode. In conclusion, curcuminoids inhibit gonadal 3β-HSD activity and de-methoxylation of curcumin increases inhibitory potency and metabolism of curcumin by saturation of carbon chain losses inhibitory potency.

Abstract Background Exercise tolerance plays a vital role in the process of cardiac rehabilitation in patients undergoing percutaneous coronary intervention (PCI). The study sought to determine the characteristics, risks and correlates of post-PCI exercise tolerance in patients with coronary artery disease (CAD). Methods We analyzed clinical data of 299 CAD patients undergoing elective PCI and completing cardiopulmonary exercise testing (CPET). According to the Weber classification, post-PCI exercise tolerance was evaluated by peak oxygen uptake (VO2 peak). We assessed the impact of 34 predefined clinical features, cardiac functional parameters, and blood biochemistry data on exercise tolerance by univariate analysis and logistics regression analysis. Results Of 299 patients, 74.92% were men and average age was 60.90 ± 10.68 years. VO2 peak in the entire population was 17.54 ± 3.38 ml/kg/min, and 24.41% (n = 73) were less than 16 ml/kg/min, who were considered to have exercise intolerance. Multivariate logistics regression results showed that sex, diabetes mellitus, number of stents, left atrial diameter (LAD), end-diastolic volume (EDV), and hemoglobin influenced the peak oxygen uptake of CAD patients undergoing elective PCI. (All p

Abstract Bone morphogenetic protein 4 (BMP4) is an important member of the transforming growth factor-β superfamily. BMP4 is expressed in the Leydig cell lineage. We hypothesized that BMP4 might regulate the development of stem/progenitor Leydig cells. The BMP4 receptors, BMPR1A, BMPR1B, and BMPR2 were found to be expressed in progenitor Leydig cells of prepubertal testis and isolated cells. BMP4 at 1 and 10 ng/mL significantly reduced androgen production and down-regulated steroidogenesis-related gene and protein expression possibly by activating the SMAD signaling pathway (increasing SMAD1/5 phosphorylation and SMAD4) at 24 h treatment. BMP4 at 0.1 ng/mL and higher concentrations markedly reduced the EdU labeling index of CD90+ stem Leydig cells after 24 h treatment and significantly reduced the number of EdU+ stem Leydig cells on the surface of seminiferous tubules after 7 days of culture. BMP4 at 0.01 ng/mL and higher concentrations significantly blocked the differentiation of stem Leydig cells into adult cells, as shown by the reduction of testosterone secretion and the downregulation of Lhcgr, Scarb1, Cyp11a1, Hsd11b1, and Insl3 and their function after 3D seminiferous tubule culture for 3 weeks, and this effect was reversed by co-treatment with the BMP4 antagonists noggin and doxomorphine. In addition, BMP4 also blocked stem Leydig cell differentiation through SMAD-independent signaling pathways (ERK1/2 and AMPK). Ethanedimethane sulfonate (EDS) single injection can result in reduction of testosterone, restoration can happen post treatment. In an in vivo model of Leydig cell regeneration following EDS treatment, intratesticular injection of BMP4 from day 14 to day 28 post-elimination significantly reduced serum testosterone levels and down-regulated the expression of Scarb1, Star, Hsd11b1, and Insl3 and its proteins, possibly through SMAD-dependent and SMAD-independent (ERK1/2 and AMPK) signaling pathways. In conclusion, BMP4 is expressed in cells of the Leydig cell lineage and blocks entry of stem/progenitor Leydig cells into adult Leydig cells through SMAD-dependent and SMAD-independent signaling pathways.

Exposure to 4-nonyl phenol (4-NP) on Leydig cell (LC) development and function remains poorly understood. We explored the effects of 4-NP on LC development and elucidate the underlying mechanisms. Male (28-day-old) mice received orally 4-NP (0.125, 0.25, and 0.5 mg/kg/day) for 28 days. We found that 4-NP at ≥ 0.125 mg/kg markedly compromised serum testosterone levels and LC numbers. Gene and protein expression analysis demonstrated downregulation of key genes and their proteins involved in LC steroidogenesis, including Star, Cyp11a1, Cyp17a1, Hsd17b3, Hsd3b6, and Scarb1. Furthermore, exposure to 4-NP induced oxidative stress, as evidenced by elevated reactive oxygen species (ROS) and malondialdehyde (MDA), as well as reduced superoxide dismutase 1/2 and catalase (CAT). Apoptosis was also observed in LCs following exposure to 4-NP, as shown by an increased BAX/BCL2 ratio and caspase-3. A TM3 mouse LC line further confirmed that 4-NP induced ROS and the expression of apoptosis-related genes and proteins. In conclusion, this study demonstrates that 4-NP exposure compromises LC development through multiple mechanisms.

Bisphenol A (BPA) is a chemical used in the production of certain plastics and resins. Recent research has found that BPA can inhibit the activity of 3β-hydroxysteroid dehydrogenase/Δ5,4-isomerases (3β-HSDs). Whether benzene ring BPA substitutes can inhibit human, rat, and mouse gonadal 3β-HSDs, the structure-activity relationship and the underlying mechanism remain unclear. In this study, we compared 6 benzene ring BPA substitutes to BPA in the inhibition of human, rat, and mouse gonadal 3β-HSDs and conducted structure-activity relationship and in silico docking analysis. The inhibitory activity (IC50) of human 3β-HSD2 in KGN cells ranged from about 0.02 μM for bisphenol H to 8.75 μM for BPA, that of rat 3β-HSD1 in testicular microsomes ranged from 0.099 μM for bisphenol H to 31.32 μM for BPA, and that of mouse 3β-HSD6 ranged from 0.021 μM for BPH to ineffectiveness for 100 μM BPA. These compounds acted as mixed inhibitors with LogP inversely correlated with IC50 and ΔG positively correlated with IC50 value. Docking analysis showed that these compounds bind to the steroid active site of the 3β-HSD enzymes. In conclusion, some benzene ring BPA substitutes potently inhibit gonadal 3β-HSD in various species, and lipophilicity and binding affinity determine their inhibitory strength.

Abstract An efficient and economical electrocatalyst as kinetic support is key to electrochemical reactions. For this reason, chemists have been working to investigate the basic changing of chemical principles when the system is confined in limited space with nanometer‐scale dimensions or sub‐microliter volumes. Inspired by biological research, the design and construction of a closed reaction environment, namely the reactor, has attracted more and more interest in chemistry, biology, and materials science. In particular, nanoreactors became a high‐profile rising star and different types of nanoreactors have been fabricated. Compared with the traditional particle nanoreactor, the one‐dimensional (1D) carbon‐based nanoreactor prepared by the electrospinning process has better electrolyte diffusion, charge transfer capabilities, and outstanding catalytic activity and selectivity than the traditional particle catalyst which has great application potential in various electrochemical catalytic reactions.

Bisphenols (BPs) as endocrine-disrupting compounds have drawn attention to their health hazards. Whether a BP interferes with glucocorticoid metabolism remains unclear. 11β-Hydroxysteroid dehydrogenase 2 (11β-HSD2) is a key glucocorticoid-metabolizing enzyme that controls fetal glucocorticoid levels across the placental barrier and mineralocorticoid receptor specificity in the kidney. In this study, 11 BPs were tested to inhibit human placental and rat renal 11β-HSD2 and were analyzed for inhibitory potency, mode action, and docking parameters. BPs had inhibitory potency against human 11β-HSD2: BPFL>BPAP>BPZ>BPB>BPC>BPAF>BPA>TDP and the IC10 values were 0.21, 0.55, 1.04, 2.04, 2.43, 2.57, 14.43, and 22.18 μM, respectively. All BPs are mixed inhibitors except BPAP, which is a competitive inhibitor for human 11β-HSD2. Some BPs also inhibited rat renal 11β-HSD2, with BPB (IC50, 27.74 ± 0.95) > BPZ (42.14 ± 0.59) > BPAF (54.87 ± 1.73) > BPA (77.32 ± 1.20) > other BPs (about 100 μM). Docking analysis showed that all BPs bound to the steroid-binding site, interacting with the catalytic residue Tyr232 of both enzymes and the most potent human 11β-HSD2 inhibitor BPFL acts possibly due to its large fluorene ring that has hydrophobic interaction with residues Glu172 and Val270 and π-stacking interaction with catalytic residue Tyr232. The increase in the size of substituted alkanes and halogenated groups in the methane moiety of the bridge of BPs increases its inhibitory potency. Regressions of the lowest binding energy with inhibition constant indicated that there was an inverse regression. These results indicated that BPs significantly inhibited human and rat 11β-HSD2 activity and that there were species-dependent differences.

Citrinin, a mycotoxin existing in fruits, has nephrotoxicity, hepatotoxicity and embryotoxicity. The effects of citrinin on Leydig cell development in prepuberty remains unclear. Male Sprague-Dawley rats were gavaged with 0, 1, 2.5, and 5 mg/kg citrinin from postnatal days 21–28. Citrinin at 5 mg/kg significantly decreased serum testosterone levels, while increasing serum LH and FSH levels. Citrinin at 1–5 mg/kg markedly downregulated Hsd17b3 and HSD17B3 expression, while upregulating Srd5a1 (SRD5A1) and Akr1c14 (AKR1C14) expression at 2.5 and/or 5 mg/kg. Citrinin at 5 mg/kg also significantly increased PCNA-labeling index in Leydig cells. Citrinin at 5 mg/kg significantly raised testicular MDA amount, whiling at 2.5 and 5 mg/kg downregulating SOD1 and SOD2 expression. Citrinin at 5 mg/kg markedly decreased the ratio of Bcl2 to Bax, in consistent with the increased apoptosis in Leydig cells judged by TUNEL assay. Enzymatic assay revealed that citrinin inhibited rat testicular HSD3B1 activity at 100 µM and HSD17B3 activity at 10–100 μM. Citrinin at 50 μM and higher also induced reactive oxygen species (ROS) and apoptosis of R2C cell line. In conclusion, citrinin inhibits Leydig cell development at multiple levels via different mechanisms and oxidative stress partially plays a role.

In order to reduce the membrane pollution of ultrafiltration caused by natural organic matter and improve the treatment efficiency, electroflocculation/oxidation is used as the premembrane treatment method. The membrane specific flux attenuation characteristics was compared and analyzed under the conditions of direct ultrafiltration and electroflocculation/oxidation-ultrafiltration. Combined with the analysis of the reversibility of membrane fouling, the mechanism of electroflocculation/oxidation pretreatment to alleviate ultrafiltration membrane fouling was evaluated, and the membrane pore clogging model was used to fit the fouling law. The results show that, in the continuously fed filtration experiment, the electroflocculation/oxidation process involved in the pretreatment and the direct ultrafiltration membrane filtration decreased the ultrafiltration membrane flux to 79.1% and 28.5%, respectively. The reversible resistance generated by ultrafiltration and electroflocculation/oxidation-ultrafiltration processes accounted for 37.70% and 62.26% of their total pollution resistance, whereas the irreversible resistance generated accounted for 47.30% and 12.40%, respectively. Meanwhile, the direct correlation between the the flux dropped and complete clogging became less than that of the ultrafiltration process. The pretreatment significantly strengthened irreversible fouling resistance of the membrane pores. The membrane permeation flux was significantly increased after the electroflocculation/oxidation pretreatment. HIGHLIGHTS The proportion of reversible pollution via EC/O-UF dropped from 62.26% to 37.70%.; The proportion of irreversible pollution via EC/O-UF dropped from 47.30% to 12.40%.; With EC/O, the membrane flux increased from 28.5% to 79.1% after 3 h operation.;

Background: At present, simple reminiscence has been widely used in the field of neurocognitive disorders, life review/life review therapy has been widely used in the field of cancer, and both simple reminiscence and life review/life review therapy are suitable for psychological disorders such as depression and anxiety. However, the efficacy of reminiscence in treating cancer-related symptom has not been fully assessed. Objectives: To evaluate the effect of reminiscence therapy (RT) on relieving cancer-related symptoms such as anxiety and depression in cancer survivals. Methods: China National Knowledge Infrastructure (CNKI), VIP database, Wanfang Data Knowledge Service Platform, China Biomedical Database, PubMed, Cochrane Library, Embase, EBSCO, Scopus, and Ovid databases were searched. To collect clinical randomized controlled trials (RCT) on RT and cancer-related studies published from the establishment of the database to October 05, 2021. Two researchers independently evaluated the articles that met the inclusion criteria, meta-analysis was performed using RevMan5.4 software. Results: A total of 20 RCTs published in 2010 to 2021 were included, with a total of 1853 cancer patients. Meta-analysis results showed that the anxiety scale (HADS-A and HAMA and SAS) and depression scale (HADS-D and HAMD and SDS) scores of the RT group were significantly lower than those of the control group (HADS-A: P = .0002; HAMA: P

Abstract Background Patients with nasopharyngeal cancer (NPC) differ in prognosis, even at the same stage; therefore, new biomarkers are urgently required to identify early-stage NPC patients at high risk of poor prognosis. Although Epstein–Barr virus (EBV) DNA has been used for prognosis, the value of many other biomarkers expressed during the infection cycle of EBV remains unclarified. This study aimed to evaluate the prognostic potential of EA-IgA, VCA-IgA and d-dimer in patients with NPC. Methods Electronic databases, including PubMed, Embase and Web of Science, were searched up to February 1, 2021. Pooled data were extracted from studies that evaluated the relationship between NPC and overall survival (OS), distant metastasis-free survival (DMFS) or disease-free survival (DFS) and then were subjected to a meta-analysis. Results Nine studies with 5729 patients were included in this meta-analysis. In patients with NPC, EA-IgA levels significantly predicted OS (HR = 1.63, 95% CI 1.07–2.48). d-Dimer levels significantly predicted OS (HR = 1.75, 95% CI 1.24–2.47) and DMFS (HR = 1.91, 95% CI 1.31–2.79). However, high levels of VCA-IgA were not associated with OS (HR = 1.24, 95% CI 0.95–1.60), DMFS (HR = 1.41, 95% CI 0.92–2.17) or DFS (HR = 2.39, 95% CI 0.78–7.26). Conclusions The present findings reveal that EA-IgA and d-dimer, but not VCA-IgA, can be used as prognostic biomarkers in NPC.

Abstract Background The cylindromatosis (CYLD) tumor suppressor is a microtubule‐associated deubiquitinase that plays a critical role in the regulation of cell signaling and contributes to a variety of physiological and pathological processes. However, the functions of CYLD in zebrafish are less well known, particularly with regard to their development and physiology. In this context, we investigated the loss of function of CYLD in zebrafish via transcription activator‐like effector nuclease (TALEN)‐based gene deletion. Methods Semi‐quantitative RT‐PCR was used to quantify CYLD mRNA expression in zebrafish embryos at various developmental stages. We also performed whole‐mount in situ hybridization to further assess the dynamic expression and distribution of CYLD in the entire zebrafish embryos at different stages. In addition, we deleted CYLD in zebrafish with TALENs to investigate its potential impact on embryonic development. Results The expression of CYLD mRNA varied during early embryonic development. The CYLD mRNA localized to the brain and notochord of developing zebrafish embryos. Homozygous deletion of CYLD resulted in embryonic death before 8 h post‐fertilization. Conclusions CYLD appears to play an important role in central nervous system development in zebrafish. Although severe embryonic death restricted analysis of homozygous mutants, further research into the role of CYLD in central nervous system development is warranted.

Bisphenol A (BPA) analogues substituted on the benzene ring are widely used in a variety of industrial and consumer materials. However, their effects on the glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) remain unclear. The inhibitory effects of 6 BPA analogues on the inhibition of human and rat 11β-HSD1 were investigated. The potencies of inhibition on human 11β-HSD1 were bisphenol H (IC50, 0.75 µM) > bisphenol G (IC50, 5.06 µM) > diallyl bisphenol A (IC50, 13.36 µM) > dimethyl bisphenol A (IC50, 30.18 µM) > bisphenol A dimethyl ether (IC50, 33.08 µM) > tetramethyl bisphenol A (>100 µM). The inhibitory strength of these chemicals on rat 11β-HSD1 was much weaker than that on the human enzyme, ranging from 74.22 to 205.7 µM. All BPA analogues are mixed/competitive inhibitors of both human and rat enzymes. Molecular docking studies predict that bisphenol H and bisphenol G both bind to the active site of human 11β-HSD1, forming a hydrogen bond with catalytic residue Ser170. The bivariate correlation of IC50 values with LogP (lipophilicity), molecular weight, heavy atoms, and molecular volume revealed a significant inverse regression and the correlation of IC50 values with ΔG (low binding energy) revealed a positive regression. In conclusion, the lipophilicity, molecular weight, heavy atoms, molecular volume, and binding affinity of a BPA analogue determine the inhibitory strength of human and rat 11β-HSD isoforms.

Introduction Most patients with coronary heart disease experience sleep disturbances and low cardiorespiratory fitness (CRF), but their relationship during cardiac rehabilitation (CR) is still unclear. This article details a protocol for the study of sleep trajectory in patients with coronary heart disease during CR and the relationship between sleep and CRF. A better understanding of the relationship between sleep and CRF on patient outcomes can improve sleep management strategies.Methods and analysis This is a longitudinal study with a recruitment target of 101 patients after percutaneous cardiac intervention from the Seventh People’s Hospital of Shanghai, China. Data collection will include demographic characteristics, medical history, physical examination, blood sampling, echocardiography and the results of cardiopulmonary exercise tests. The information provided by a 6-min walk test will be used to supplement the CPET. The Pittsburgh Sleep Quality Index will be used to understand the sleep conditions of the participants in the past month. The Patient Health Questionnaire and General Anxiety Disorder Scale will be used to assess depression and anxiety, respectively. All participants will be required to wear an actigraphy on their wrists for 72 hours to monitor objective sleep conditions. This information will be collected four times within 6 months of CR, and patients will be followed up for 1 year. The growth mixture model will be used to analyse the longitudinal sleep data. The generalised estimating equation will be used to examine the associations between sleep and CRF during CR.Ethics and dissemination Ethical approval for this observational longitudinal study was granted by the Shanghai Seventh People’s Hospital Ethics Committee on 23 April 2021 (2021-7th-HIRB-012). Study results will be disseminated in peer-reviewed journal articles.

Abstract Background With a shift in the healthcare paradigm towards a more patient-centered approach, data on inflammatory bowel disease (IBD) needs to be further explored. This study aimed to determine patient perspectives on the effect of IBD and features of patients with lower satisfaction level and compare patient and physician perception of IBD-related Quality of Care (QoC). Methods A previously developed pre-standardised set of questions regarding patient-centered outcome (PRO) measures for IBD, comprising 36 items, was administered in five centers, and a concomitant questionnaire for specialised physicians was adapted and administered. Results Overall, 1005 patients with IBD met the inclusion criteria. Sixty-five questionnaires were administered to specialised physicians. Both patients and physicians perceived the IBD-related QoC as being satisfactory. Furthermore, this study revealed areas of shortcomings where it comes to patient perceptions. Female sex and the presence of negatively impacting disease characteristics (presence of significant pain or discomfort, lack of energy, feeling fatigued most of the time, experiencing anxiety or depression in the last 2 weeks) were associated with lower satisfaction levels. Conclusions Our findings can be used in establishing strategies aimed at improving patient QoC and defining strategic priorities. These data can aid in improving the communication of the pressing needs of IBD patients, to both the public payers and health authorities.

Tetramethyl bisphenol A (TMBPA) is a commonly used bisphenol analog, used as a fire retardant. However, whether it inhibits the function of Leydig cells in late puberty remains unclear. In this study, 35-day-old male Sprague-Dawley rats were gavaged with 0, 10, 100, and 200 mg/kg body weight TMBPA for 21 days. TMBPA significantly reduced serum testosterone levels at 10 mg/kg and higher doses without altering serum luteinizing hormone and follicle-stimulating hormone levels. TMBPA significantly increased serum iron concentraion while reducing the ratio of serum glutathione (GSH) and GSH/GSSG (oxidized glutathione disulfide). In addition, TMBPA significantly increased testicular iron amount at 10 mg/kg and higher doses and malondialdehyde level at 200 mg/kg. TMBPA down-regulated the expression of Leydig cell genes, including Nr5a1, Star, Scarb1, Insl3, Cyp11a1, Cyp17a1, Hsd17b3, and Hsd11b1, and their proteins. In addition, TMBPA markedly down-regulated the expression of genes in the ferroptosis pathway (Tp53, Slc7a11, Sod1, Sod2, Cat, Sqstm1, Keap1, and Hmox1). TMBPA significantly reduced the levels of ferroptosis pathway proteins (TP53, SLC7A11, GPX4, SQSTM1, KEAP1, NRF2, and HMOX1) in Leydig cells in vivo. Immature and adult Leydig cell culture in vitro also showed that TMBPA significantly reduced testosterone concentrations in the medium, which can be reversed by a ferroptosis inhibitor. After 24 h of culture in primary Leydig cells at 10 and 50 μM, TMBPA significantly induced reactive oxygen species and lowered the mitochondrial membrane potential. TMBPA also altered protein levels in the ferroptosis pathway in Leydig cells in vitro. In conclusion, TMBPA directly inhibits the activity of rat Leydig cell steroidogenic enzymes and induces the ferroptosis of Leydig cells, thereby inhibiting the testosterone synthesis of Leydig cells in the late puberty.

Decision-making is an advanced cognitive function that promotes information processes in complex motor situations. In recent years, many neuroimaging studies have assessed the effects of long-term motor training on athletes’ brain activity while performing decision-making tasks, but the findings have been inconsistent and a large amount of data has not been quantitatively summarized until now. Therefore, this study aimed to identify the neural mechanism of long-term motor training affecting the decision-making function of athletes by using activation likelihood estimation (ALE) meta-analysis. Altogether, 10 studies were included and comprised a total of 350 people (168 motor experts and 182 novices, 411 activation foci). The ALE meta-analysis showed that more brain regions were activated for novices including the bilateral occipital lobe, left posterior cerebellar lobe, and left middle temporal gyrus (MTG) in decision-making tasks compared to motor experts. Our results possibly suggested the association between long-term motor training and neural efficiency in athletes, which provided a reference for further understanding the neural mechanisms of motor decision-making.

National identity is an important national conscience and plays a key spiritual role in maintaining national unity, stability and promoting the healthy and rapid development of the country. As an essential driver of education, the discipline must assume a major responsibility for national identity education. This study integrates national identity education into high school geography teaching, combines the latest geography teaching theory system with literature research method, text analysis method to analyze the components and specific content of national identity in high school geography teaching, and establishes a new teaching model. Simultaneously, the theme of "maritime rights and interests and ocean development strategy" was selected for teaching experiment, and the impact of the teaching mode proposed in this paper on the students' learning efficiency in geography is investigated by questionnaire. The results of the teaching experiment show that the proposed teaching model can improve students' awareness of national identity and serve as a reference for the teaching of national identity in subject subjects.

Glucocorticoid hormone might cause intrauterine growth restriction. The glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) in the placenta eliminates excess levels of glucocorticoids during pregnancy. The aim of the current study was to define the effects of diethylstilbestrol (DES) on HS D11B2 activity in the mammalian placentas and identify its mode of action. Rat and human placental microsomal HSD11B2 were incubated with different concentrations of DES, and IC50 values were determined. The mode of action was analyzed by incubation of DES together with substrates, glucocorticoid and NAD+. DES suppressed rat and human HSD11B2 with IC50 values of 5.33 and 12.62 μM, respectively. DES was a competitive inhibitor of rat and human HSD11B2 when steroid substrates were added, while it was an uncompetitive inhibitor when cofactor NAD+ was exposed. Oral administration of DES (0.5 mg/kg) to the rat delayed the cortisol metabolism in adult female Sprague–Daw ley rats, as indicated by the increases in cortisol’s elimination half-life, maximum concentration and area under the curve. In conclusion, DES is a potent HSD11B2 inhibitor, possibly contributing to the intrauterine growth restriction.

Many endocrine disruptors may interfere with sperm motility, hyperactivation, and capacitation, thereby leading to male infertility. In the current study, we screened 14 endocrine disruptors, including plant ingredients, cigarette ingredients, minerals, insecticides and fungicides, plastics, and plasticizers, to inhibit human sperm motility and forward motility. Only ziram, a dithiocarbamate fungicide, can effectively inhibit sperm motility, forward motility, hyperactivation, capacitation, and spontaneous acrosome reaction of normal human spermatozoa. Its half maximum inhibitory concentration (IC50) values were less than 4 μM. Ziram also inhibited sperm motility and forward motility of asthenozoospermia spermatozoa and IC50 values were about 6–8 μM. In addition, ziram inhibited normal sperm motility, calcium influx, reactive oxygen species, and mitochondrial membrane potential at 2.5 and/or 5 μM, with IC50 values ​​exceeding 100 μM, although it did not affect sperm DNA fragmentation up to 5 μM. Ziram-mediated inhibition of sperm motility and forward motility was irreversible. Forskolin, 8Br-cAMP, pentoxifylline, progesterone, vitamin E, and A23187 cannot prevent ziram-mediated inhibition of sperm motility and forward motility. Further studies have shown that ziram inhibited the level of tyrosine protein kinase with an IC50 value of about 10 μM, without affecting p21-activated kinase 4, and it caused damage to the mitochondrial structure of normal spermatozoa at 2.5 and 5 μM. In conclusion, ziram irreversibly inhibits human sperm motility, forward motility, and capacitation by reducing the level of tyrosine protein kinase and damaging the ultrastructure of mitochondria.

Perfluorooctane sulfonate is related to male reproductive dysfunction in rats and humans. However, the underlying mechanism remains unknown. Here, we reported the effects of short-term exposure to perfluorooctane sulfonate on the regeneration of Leydig cells in vivo and investigated possible mechanisms in vitro. After adult male Sprague-Dawley rats were gavaged perfluorooctane sulfonate (0, 5 or 10 mg/kg/day) for 7 days and then injected intraperitoneally ethane dimethane sulfonate next day to eliminate Leydig cells, the Leydig cell regeneration process was monitored. Perfluorooctane sulfonate significantly lowered serum testosterone levels, reduced the number of regenerated Leydig cells, down-regulated the expression of Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Dhh) and their proteins at doses of 5 and 10 mg/kg 35 and 56 days after ethane dimethane sulfonate. Using a 3D seminiferous tubule culture system to study the development of stem Leydig cells, we found that perfluorooctane sulfonate inhibited stem Leydig cell proliferation and differentiation and hedgehog signaling pathway. In conclusion, a short-term exposure to perfluorooctane sulfonate can inhibit the development of stem Leydig cells into the Leydig cell lineage via direct suppression of hedgehog signaling pathway and indirect inhibition of desert hedgehog section by Sertoli cells.

Background: 11β-Hydroxysteroid dehydrogenase one is responsible for activating inert glucocorticoid cortisone into biologically active cortisol in humans and may be a novel target for the treatment of nonalcoholic fatty liver disease.Methods: A series of benzylidene cyclopentanone derivatives were synthesized, and the selective inhibitory effects on rat, mouse and human 11β-hydroxysteroid dehydrogenase one and two were screened. The most potent compound [5-bis-(2,6-difluoro-benzylidene)-cyclopentanone] (WZS08), was used to treat nonalcoholic fatty liver disease in mice fed a high-fat-diet for 100 days.Results: WZS08 was the most potent inhibitor of rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, with half maximum inhibitory concentrations of 378.0, 244.1, and 621.1 nM, respectively, and it did not affect 11β-hydroxysteroid dehydrogenase two at 100 μM. When mice were fed WZS08 (1, 2, and 4 mg/kg) for 100 days, WZS08 significantly lowered the serum insulin levels and insulin index at 4 mg/kg. WZS08 significantly reduced the levels of serum triglycerides, cholesterol, low-density lipoprotein, and hepatic fat ratio at low concentration of 1 mg/kg. It down-regulated Plin2 expression and up-regulated Fabp4 expression at low concentration of 1 mg/kg. It significantly improved the morphology of the non-alcoholic fatty liver.Conclusion: WZS08 selectively inhibits rat, mouse, and human 11β-hydroxysteroid dehydrogenase 1, and can treat non-alcoholic fatty liver disease in a mouse model.

Background: Diisoheptyl phthalate (DIHP) is a phthalate plasticizer, which is a branched phthalate. Here, we reported the effects of gestational exposure to DIHP on testis development in male rats.Methods: Pregnant Sprague-Dawley rats were orally fed with vehicle (corn oil, control) or DIHP (10, 100, 500, and 1,000 mg/kg) from gestational day (GD) 12–21. At GD21, serum testosterone levels, the number and distribution of fetal Leydig cells, and testicular mRNA and protein levels, the incidence of multinucleated gonocytes, and focal testicular hypoplasia in the neonatal testis were measured.Results: DIHP increased the fetal Leydig cell cluster size and decreased the fetal Leydig cell size with LOAEL of 10 mg/kg. DIHP did not affect the fetal Leydig cell number. DIHP significantly lowered serum testosterone levels, down-regulated the expression of steroidogenesis-related genes (Lhcgr, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Hsd17b3) and testis descent-related gene (Insl3) as well as protein levels of cholesterol side-chain cleavage enzyme (CYP11A1) and insulin-like 3 (INSL3). DIHP dose-dependently increased the percentage of multinucleated gonocytes with the low observed adverse-effect level (LOAEL) of 100 mg/kg. DIHP induced focal testicular hypoplasia.Conclusion: Gestational exposure to DIHP causes testis dysgenesis in rats.

The function of immature Leydig cells is regulated by hormones, such as androgen and luteinizing hormone (LH). However, the regulation of this process is still unclear. The objective of this study was to determine whether luteinizing hormone (LH) or androgens contribute to this process. Immature Leydig cells were purified from 35-day-old male Sprague Dawley rats and cultured with LH (1 ng/ml) or androgen (7α-methyl-19- nortestosterone, MENT, 100 nM) for 2 days. LH or MENT treatment significantly increased the androgens produced by immature Leydig cells in rats. Microarray and qPCR and enzymatic tests showed that LH up-regulated the expression of Scarb1, Cyp11a1, Cyp17a1, and Srd5a1 while down-regulated the expression of Sult2a1 and Akr1c14. On the contrary, the expression of Cyp17a1 was up-regulated by MENT. LH and MENT regulate Leydig cell function through different sets of transcription factors. We conclude that LH and androgens participate in the regulation of rat immature Leydig cell function through different transcriptional pathways.

The discussion of collective agency involves the reduction problem of the concept of a collective. Individualism and Cartesian internalism have long restricted orthodox theories and made them face the tension between an irreducible concept of a collective and ontological reductionism. Heterodox theories as functionalism and interpretationism reinterpret the concept of agency and accept it as realized on the level of a collective. In order to adequately explain social phenomena that have relations as their essence, in this paper we propose a relational, holistic account of collective agency and argue that functionalism and interpretationism can be integrated into such an account.

The characteristics of the benthic community structure can effectively reflect the health status of the river ecosystem and the quality of the river ecological environment. It is of great significance to identify the limiting factors of benthic community structure for the maintenance of river ecosystem health. As a typical semi-arid ecological fragile area, the eco-environmental problems in the Wei River basin have become increasingly prominent. The benthic community structure is affected by multiple stresses such as habitat degradation and water quality deterioration. In this study, 18 national monitoring stations were selected to investigate the ecological environment and benthic invertebrate community characteristics in the Wei River basin in October 2019. W-statistics, Shannon-Winer index, Pielou index, Margalef index, and B-IBI index were selected to evaluate the community characteristics of benthic macroinvertebrates from three aspects of the community stability, community diversity, and community integrity. Principal component analysis, Pearson correlation analysis, and canonical correspondence analysis were used to analyze the correlation and variability between zoobenthos community index and environmental factors. The results showed that the spatial difference of benthic community structure in the Wei River basin was not significant, and the Sal, NH3-N, Tub, DO in water environment and heavy metals in sediment were the main environmental factors affecting the community structure of benthos. Improving water quality and controlling pollution were the main strategies to improve benthic biodiversity and promote sustainable development in the Wei River basin.

As the largest tributary of the Yellow River and a large semi-arid area, the ecological status of the Wei River Basin, China, has become an important issue of concern. Habitat, water quality and biological pressure are the factors affecting the structure and function of rivers. However, it is a challenging task to determine the joint rather than isolated influence of factors on the watershed. Plankton is sensitive to the status of water system, so it is used to analyze the interaction between habitat indexes and physic-chemical parameters of water body. In this study, plankton and water samples were collected from 21 sampling sites in the whole Wei River Basin in October 2019. The planktonic index of biotic integrity (P-IBI), biomass, abundance, diversity index and trophic status were established. The integrity of plankton in the basin was evaluated. Redundancy analysis (RDA) was used to assess the correlation and variability between 23 physicochemical factors and habitat indexes of planktonic community. The results show that the applicability and accuracy of P-IBI are good. The planktonic integrity of the ecosystem in the basin is “critical”. The upper and lower reaches of the main stream are better than those of the middle reaches, while the upper reaches of the two major tributaries are in poor condition due to the influence of cities and industries. Wei River system is better than Jing River and Beiluo River system. Physical and chemical factors, including dissolved oxygen, turbidity, phycocyanin and chlorophyll, are the main driving forces affecting the integrity of plankton in the study area. Relatively speaking, the contribution of physicochemical parameters to P-IBI was greater than that of habitat indexes, and there was a shared explanatory variance between them. The abundance level can best reflect the isolation effect of two aspects of the environment. The results show that the planktonic index of biotic integrity is a potential tool to reflect the interaction of habitat conditions and physical and chemical factors. The whole basin scale research is helpful to promote habitat restoration and water conservation.

Humans are exposed to phthalates ubiquitously, which may threaten health. However, whether di-n-octyl phthalate can prevent pubertal sexual maturity is still elusive. In this study, male Sprague Dawley rats (age 35 days) were treated daily by gavage with 0, 10, 100, and 1000 mg/kg body weight of di-n-octyl phthalate from day 35 to day 49 after birth. Di-n-octyl phthalate significantly reduced serum testosterone levels at doses of 100 and 1000 mg/kg, but increased serum luteinizing hormone levels of 1000 mg/kg and decreased testosterone/luteinizing hormone ratio at ≥10 mg/kg, without affecting serum follicle-stimulating hormone levels. Di-n-octyl phthalate significantly induced Leydig cell hyperplasia (increased number of CYP11A1-positive Leydig cells) at 100 and 1000 mg/kg. Di-n-octyl phthalate down-regulates the gene expression of Cyp11a1, Hsd3b1 and Insl3 in individual Leydig cells. Di-n-octyl phthalate can also reduce the number of sperm in the epididymis. Di-n-octyl phthalate increased phosphorylated AKT1/AKT2 without affecting their total proteins, but increased the total protein and phosphorylated protein of ERK1/2 and GSK-3β. Primary immature Leydig cells isolated from 35-day-old rats were treated with 0–50 μM di-n-octyl phthalate for 3 h. This phthalate inhibited androgen production under basal, LH-stimulated, and cAMP-stimulated conditions by 5 and 50 μM in vitro via down-regulating Cyp11a1 expression but up-regulating Srd5a1 expression in vitro. In conclusion, di-n-octyl phthalate induces hypergonadotropic hypogonadism caused by Leydig cell hyperplasia but reduced steroidogenic function and prevents sperm production.

Bisphenol A (BPA) is a ubiquitous environmental pollutant, mainly from the production and use of plastics and the degradation of wastes related to industrial plastics. Evidence from laboratory animal and human studies supports the view that BPA has an endocrine disrupting effect on Leydig cell development and function. To better understand the adverse effects of BPA, we reviewed its role and mechanism by analyzing rodent data in vivo and in vitro and human epidemiological evidence. BPA has estrogen and anti-androgen effects, thereby destroying the development and function of Leydig cells and causing related reproductive diseases such as testicular dysgenesis syndrome, delayed puberty, and subfertility/infertility. Due to the limitation of BPA production, the increased use of BPA analogs has also attracted attention to these new chemicals. They may share actions and mechanisms similar to or different from BPA.

11β-Hydroxysteroid dehydrogenase 1 (HSD11B1) is an NADPH-dependent oxidoreductase that elevates cortisol (in human beings) or corticosterone (in rats) locally via metabolically activating 11 keto-glucocorticoids. Taxifolin is a flavonoid in food plants. The present study investigated the effects of taxifolin on rat and human liver microsomal HSD11B1. Taxifolin competitively inhibited rat and human HSD11B1 against steroid cortisone or 11-dehydrocorticosterone, with IC50 values of 37,833 and 4981 nM, respectively. Oral administration of 5 and 10 mg/kg taxifolin for 30 min significantly inhibited rat liver HSD11B1 ex vivo and suppressed cortisone metabolism as shown by the significant increase of T1/2, Cmax, Tmax, and the area under curve (AUC) after exogenous injection of cortisone in vivo. This result shows that taxifolin is a potent inhibitor of both rat and human HSD11B1, being a possible supplement to treat the metabolic syndrome.

Previous studies have examined the association between elevated serum uric acid (SUA) level and hypertension; however, the association in the Chinese elderly is still uncertain. A cross-sectional study was performed in a rural district of Beijing. A total of 2,397 participants (967 men and 1,430 women) completed the survey. The SUA levels of participants were categorized into four levels using the quartiles (P25, P50, and P75) as cutoff values. Participant was diagnosed as hyperuricemia if the SUA level was ≥417 μmol/L (male) or ≥357 μmol/L (female). Hypertension was defined as systolic blood pressure (BP) ≥140 mmHg and/or diastolic BP ≥90 mmHg and/or receiving antihypertensive drug treatment. Multiple logistic regression was used to estimate the association between SUA and hypertension. We found that higher SUA level was associated with the increased risk of hypertension in both sexes, even after adjusting for potential confounding variables. In total, the risk for having hypertension increased by 0.3% per 1 μmol/L increment in SUA level, increased by 95% for the highest vs. lowest quartile of SUA level, and increased by 111% in the hyperuricemia patients. Moreover, we found that the association was more pronounced in the male participants. There were approximately J-shaped relationships between SUA level (quartiles) and hypertension in all age groups. Higher SUA levels are positively associated with hypertension among the Chinese rural elderly. Further studies are still required to determine the relationship between SUA level and hypertension and to explore its potential biological mechanisms underlying the gender-related association in the elderly population. Abbreviations: CVD; cardiovascular disease; BMI: body mass index; BP: blood pressure; SUA: serum uric acid; TC: total cholesterol; TG: triglycerides; HDL-C: high-density lipoprotein; LDL-C: low-density lipoprotein; FPG: fasting blood glucose; OR: odds ratio; CI: confidence interval; SD: standard deviation

Male fetal Leydig cells in the testis secrete androgen and insulin-like 3, determining the sexual differentiation. The abnormal development of fetal Leydig cells could lead to the reduction of androgen and insulin-like 3, thus causing the male reproductive tract anomalies in male neonates, including cryptorchidism and hypospadias. Environmental pollutants, such as phthalic acid esters (phthalates), can perturb the development and differentiated function of Leydig cells, thereby contributing to the reproductive toxicity in the male. Here, we review the epidemiological studies in humans and experimental investigations in rodents of various phthalates. Most of phthalates disturb the expression of various genes encoded for steroidogenesis-related proteins and insulin-like 3 in fetal Leydig cells and the dose-additive effects are exerted after exposure in a mixture.

Background: Propofol is a widely used anesthetic. Whether propofol inhibits androgen production by rat Leydig cells and the underlying mechanism remains unclear. The objective of the current study was to examine the effects of propofol exposure to rat primary immature Leydig cells and to define propofol-induced inhibition of steroidogenic enzymes in both rat and human testes in vitro.Methods: Immature Leydig cells were purified from 35-day-old male Sprague–Dawley rats and were exposed to propofol for 3 h. The androgen production by Leydig cells under basal, luteinizing hormone, 8bromo-cAMP, and steroid-substrate stimulated conditions and gene expression of Leydig cells after exposure to propofol were measured. Immature Leydig cells were treated with propofol for 3 h and switched to propofol-free medium for additional 3 and 9 h to test whether propofol-induced inhibition is reversible. 3H-Steroids were used to evaluate the direct action of propofol on cytochrome P450 cholesterol side chain cleavage (CYP11A1), 3β-hydroxysteroid dehydrogenase (HSD3B), cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1), and 17β-hydroxysteroid dehydrogenase 3 (HSD17B3) activities in rat and human testes in vitro.Results: Propofol significantly lowered luteinizing hormone and 8bromo-cAMP stimulated androgen production by Leydig cells after 3-h exposure. Further investigation showed that propofol down-regulated the expression of Cyp11a1 and Cyp17a1 and their proteins at 5 and 50 µM, although it up-regulated Lhcgr expression at 50 µM. Propofol significantly suppressed phosphorylation of ERK1/2 and induced ROS production in immature Leydig cells at 5 and 50 µM. Propofol significantly induced apoptosis of immature Leydig cells at 50 µM. Propofol specifically inhibited rat and human testis HSD3B activities in vitro. The half maximal inhibitory concentrations of propofol for rat and human HSD3B enzymes were 1.011 ± 0.065 and 3.498 ± 0.067 µM, respectively. The mode of action of propofol of inhibiting HSD3B was competitive when pregnenolone was added. At 50 µM, propofol did not directly inhibit rat and human testis CYP11A1, CYP17A1, and HSD17B3 activities in vitro.Conclusion: Propofol inhibits androgen production via both directly inhibiting HSD3B activity and down-regulating Cyp11a1 and Cyp17a1 expression in Leydig cells. Suppression of steroidogenic enzymes is presumably associated with the lower production of androgen by Leydig cells after propofol treatment. However, propofol-induced inhibition on androgen production is reversible.

Fibroblast growth factor 1 (FGF1) is reported to be expressed in the testis. How FGF1 affects stem Leydig cell development remains unclear. Here, we report the effects of FGF1 on rat stem Leydig cell development in an ethane dimethane sulfonate (EDS)-treated model. FGF1 (100 ng/testis) significantly increased serum testosterone level, increased PCNA-positive Leydig cell percentage and Leydig cell number, but down-regulated the expression of Lhcgr, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Hsd11b1 in Leydig cells per se, after its daily intratesticular injection from post-EDS day 14 for 14 days. Primary culture of the seminiferous tubules showed that FGF1 stimulated EdU incorporation to stem Leydig cells but blocked the differentiation into the Leydig cell lineage, possibly via FGFR1-mediated mechanism. In conclusion, FGF1 promotes stem Leydig cell proliferation but blocks its differentiation.