NL13, a novel curcumin analogue and polo like kinase 4 inhibitor, induces cell cycle arrest and apoptosis in prostate cancer models.

BACKGROUND AND PURPOSE: Prostate cancer remains a major public health burden worldwide. Polo like kinase 4 (PLK4) has emerged as a promising therapeutic target in prostate cancer due to its key roles in cell cycle regulation and tumour progression. This study aims to develop and characterize the novel curcumin analogue NL13 as a potential therapeutic agent and PLK4 inhibitor against prostate cancer. EXPERIMENTAL APPROACH: NL13 was synthesized and its effects were evaluated in prostate cancer cells and mouse xenograft models. Kinome screening and molecular modelling identified PLK4 as the primary target. Antiproliferative and proapoptotic mechanisms were explored via cell cycle, apoptosis, gene and protein analyses. KEY RESULTS: Compared with curcumin, NL13 exhibited much greater potency in inhibiting PC3 (IC50, 3.51 µM vs. 35.45 µM) and DU145 (IC50, 2.53 µM vs. 29.35 µM) prostate cancer cells viability and PLK4 kinase activity (2.32 µM vs. 246.88 µM). NL13 induced G2/M cell cycle arrest through CCNB1/CDK1 down-regulation and triggered apoptosis via caspase-9/caspase-3 cleavage. These effects were mediated by PLK4 inhibition, which led to the inactivation of the AKT signalling pathway. In mice, NL13 significantly inhibited tumour growth and modulated molecular markers consistent with in vitro findings, including decreased p-AKT and increased cleaved caspase-9/3. CONCLUSION AND IMPLICATIONS: NL13, a novel PLK4-targeted curcumin analogue, exerts promising anticancer properties against prostate cancer by disrupting the PLK4-AKT-CCNB1/CDK1 and apoptosis pathways. NL13 represents a promising new agent for prostate cancer therapy.

Nanoarchitectonics of ultrafine molybdenum carbide nanocrystals into three-dimensional nitrogen-doped carbon framework for capacitive deionization.

Molybdenum carbide (MoC) has emerged as a promising material for capacitive deionization (CDI), but the poor electrochemical kinetics in conventional MoC owing to the bulk structure and low electric conductivity limit its CDI performance. To address this challenge, herein, we develop a novel strategy to synthesize ultrafine MoC nanocrystals that are embedded within a three-dimensional nitrogen-doped carbon framework (NC/MoC). This synthesis method involves the space-confined pyrolysis of molybdate precursors within metal-organic frameworks (MOFs). In this process, molybdates are confined into the MOF crystalline structure, where MOFs provide a confined reactor and carbon source. The resulting NC/MoC with the uniformly distributed MoC nanocrystals provides sufficient active sites for the electrosorption of salt ions, while the MOF-derived NC matrix facilitates charge transfer and provides the space-confined effect for preventing the possible aggregations of MoC nanocrystals during the CDI process. The NC/MoC exhibits an impressive salt adsorption capacity (SAC, 84.2 mg g-1, 1.2 V), rapid desalination rate, and high cycling stability (91.4% SAC retention after 200 cycles), better than those of most previously reported carbon-based CDI materials. Besides, the possible mechanisms are systematically investigated by ex situ characterization and density functional theory calculations. This study opens up new avenues for the construction of metal carbide-based nanocrystals for CDI and other electrochemical applications.

Short-term effects of temperature-related indices on emergency ambulance dispatches due to mental and behavioral disorders in Shenzhen, China.

Introduction: The precise associations between temperature-related indices and mental and behavioral disorders (MBDs) have yet to be fully elucidated. Our study aims to ascertain the most effective temperature-related index and assess its immediate impact on emergency ambulance dispatches (EADs) due to MBDs in Shenzhen, China. Methods: EADs data and meteorological data from January 1, 2013, to December 31, 2020, in Shenzhen were collected. Distributed lag non-linear models (DLNMs) were utilized to examine the non-linear and lagged effects of temperature-related indices on EADs due to MBDs. The Quasi Akaike Information criterion (QAIC) was used to determine the optimal index after standardizing temperature-related indices. After adjusting for confounding factors in the model, we estimated the immediate and cumulative effects of temperature on EADs due to MBDs. Results: The analysis of short-term temperature effects on EADs due to MBDs revealed Humidex as the most suitable index. Referring to the optimal Humidex (3.2th percentile, 12.00°C), we observed a significant effect of Humidex over the threshold (34.6th percentile, 26.80°C) on EADs due to MBDs at lag 0-5. The cumulative relative risks for high temperature (90th percentile, 41.90°C) and extreme high temperature (99th percentile, 44.20°C) at lag 0-5 were 1.318 (95% CI: 1.159-1.499) and 1.338 (95% CI: 1.153-1.553), respectively. No significant cold effect was observed on EADs due to MBDs. Conclusion: High Humidex was associated with more EADs due to MBDs in subtropical regions. Health authorities should implement effective measures to raise public awareness of risks related to high temperature and protect vulnerable populations.

Deoxynivalenol Inhibits Progenitor Leydig Cell Development by Stimulating Mitochondrial Fission in Rats.

Deoxynivalenol (DON) is a common food contaminant that can impair male reproductive function. This study investigated the effects and mechanisms of DON exposure on progenitor Leydig cell (PLC) development in prepubertal male rats. Rats were orally administrated DON (0-4 mg/kg) from postnatal days 21-28. DON increased PLC proliferation but inhibited PLC maturation and function, including reducing testosterone levels and downregulating biomarkers like HSD11B1 and INSL3 at ≥2 mg/kg. DON also stimulated mitochondrial fission via upregulating DRP1 and FIS1 protein levels and increased oxidative stress by reducing antioxidant capacity (including NRF2, SOD1, SOD2, and CAT) in PLCs in vivo. In vitro, DON (2-4 µM) inhibited PLC androgen biosynthesis, increased reactive oxygen species production and protein levels of DRP1, FIS1, MFF, and pAMPK, decreased mitochondrial membrane potential and MFN1 protein levels, and caused mitochondrial fragmentation. The mitochondrial fission inhibitor mdivi-1 attenuated DON-induced impairments in PLCs. DON inhibited PLC steroidogenesis, increased oxidative stress, perturbed mitochondrial homeostasis, and impaired maturation. In conclusion, DON disrupts PLC development in prepubertal rats by stimulating mitochondrial fission.

Prenatal diethylhexylphthalate exposure disturbs adult Leydig cell function via epigenetic downregulation of METTL4 expression in male rats.

Prenatal exposure to diethylhexyl phthalate (DEHP) has been linked with a decline in testosterone levels in adult male rats, but the underlying mechanism remains unclear. We investigated the potential epigenetic regulation, particularly focusing on N6-methyladenosine (m6A) modification, as a possible mechanism. Dams were gavaged with DEHP (0, 10, 100, and 750 mg/kg/day) from gestational day 14 to day 21. The male offspring were examined at the age of 56 days. Prenatal DEHP administration at 750 mg/kg/day caused a decline in testosterone concentrations, an elevation in follicle-stimulating hormone, a downregulated expression of CYP11A1 HSD3B2, without affecting Leydig cell numbers. Interestingly, Methyltransferase Like 4 (METTL4), an m6A methyltransferase, was downregulated, while there were no changes in METTL3 and METTL14. Moreover, CYP11A1 showed m6A reduction in response to prenatal DEHP exposure. Additionally, METTL4 expression increased postnatally, peaking in adulthood. Knockdown of METTL4 resulted in the downregulation of CYP11A1 and HSD3B2 and an increase in SCARB1 expression. Furthermore, the increase in autophagy protection in adult Leydig cells induced by prenatal DEHP exposure was not affected by 3-methyladenosine (3MA) treatment, indicating a potential protective role of autophagy in response to DEHP exposure. In conclusion, prenatal DEHP exposure reduces testosterone by downregulating CYP11A1 and HSD3B2 via m6A epigenetic regulation and induction of autophagy protection in adult Leydig cells as a response to DEHP exposure.

Linear semantic transformation for semi-supervised medical image segmentation.

Medical image segmentation is a focus research and foundation in developing intelligent medical systems. Recently, deep learning for medical image segmentation has become a standard process and succeeded significantly, promoting the development of reconstruction, and surgical planning of disease diagnosis. However, semantic learning is often inefficient owing to the lack of supervision of feature maps, resulting in that high-quality segmentation models always rely on numerous and accurate data annotations. Learning robust semantic representation in latent spaces remains a challenge. In this paper, we propose a novel semi-supervised learning framework to learn vital attributes in medical images, which constructs generalized representation from diverse semantics to realize medical image segmentation. We first build a self-supervised learning part that achieves context recovery by reconstructing space and intensity of medical images, which conduct semantic representation for feature maps. Subsequently, we combine semantic-rich feature maps and utilize simple linear semantic transformation to convert them into image segmentation. The proposed framework was tested using five medical segmentation datasets. Quantitative assessments indicate the highest scores of our method on IXI (73.78%), ScaF (47.50%), COVID-19-Seg (50.72%), PC-Seg (65.06%), and Brain-MR (72.63%) datasets. Finally, we compared our method with the latest semi-supervised learning methods and obtained 77.15% and 75.22% DSC values, respectively, ranking first on two representative datasets. The experimental results not only proved that the proposed linear semantic transformation was effectively applied to medical image segmentation, but also presented its simplicity and ease-of-use to pursue robust segmentation in semi-supervised learning. Our code is now open at: https://github.com/QingYunA/Linear-Semantic-Transformation-for-Semi-Supervised-Medical-Image-Segmentation.

Butorphanol inhibits androgen biosynthesis and metabolism in rat immature Leydig cells in vitro.

Butorphanol is a synthetic opioid analgesic medication that is primarily used for the management of pain. Butorphanol may have an inhibitory effect on androgen biosynthesis and metabolism in rat immature Leydig cells. The objective of this study was to investigate the influence of butorphanol on androgen secretion by rat Leydig cells isolated from the 35-day-old male rats. Rat Leydig cells were cultured with 0.5-50 µM butorphanol for 3 h in vitro. Butorphanol at 5 and 50 µM significantly inhibited androgen secretion in immature Leydig cells. At 50 µM, butorphanol also blocked the effects of luteinizing hormone (LH) and 8bromo-cAMP-stimulated androgen secretion and 22R-hydroxycholesterol- and pregnenolone-mediated androgen production. Further analysis of the results showed that butorphanol downregulated the expression of genes involved in androgen production, including Lhcgr (LH receptor), Cyp11a1 (cholesterol side-chain cleavage enzyme), Srd5a1 (5α-reductase 1), and Akr1c14 (3α-hydroxysteroid dehydrogenase). Additionally, butorphanol directly inhibited HSD3B1 (3ß-hydroxysteroid dehydrogenase 1) and SRD5A1 activity. In conclusion, butorphanol may have side effects of inhibiting androgen biosynthesis and metabolism in Leydig cells.

Structure-activity relationship and docking analysis of nature flavonoids as inhibitors of human and rat gonadal 3ß-hydroxysteroid dehydrogenases for therapeutic purposes.

The potential inhibitory effects of flavonoids on gonadal steroid biosynthesis have gained attention due to their widespread presence in natural plant sources. Specifically, our study focused on evaluating the inhibitory efficacy of these compounds on human 3ß-hydroxysteroid dehydrogenase 2 (h3ß-HSD2) and rat homolog r3ß-HSD1, enzymes responsible for the conversion of pregnenolone to progesterone. Through our investigations, we observed that the potency of flavonoids was silymarin (IC50, 1.31 µM) > luteolin (4.63 µM) > tectorigenin > (5.86 µM), and rutin (44.12 µM) in inhibiting human KGN cell microsomal h3ß-HSD2. Similarly, the potency of flavonoids was silymarin (9.50 µM) > luteolin (11.49 µM) > tectorigenin (14.06 µM), and rutin (145.71 µM) in inhibiting rat testicular r3ß-HSD1. Silymarin, luteolin, and tectorigenin acted as mixed inhibitors of both human and rat 3ß-HSDs. Luteolin and tectorigenin were able to penetrate human KGN cells to inhibit progesterone secretion. Furthermore, docking analysis and structure-activity relationship analysis highlighted the importance of hydrogen bond formation for the inhibitory efficacy of these compounds against h3ß-HSD2 and r3ß-HSD1. Overall, this study demonstrates that silymarin exhibits the most potent inhibition of human and rat gonadal 3ß-HSDs, and significant SAR differences exist among the tested compounds.

Enhanced inhibition of human and rat aromatase activity by benzene ring substitutions in bisphenol A: QSAR structure-activity relationship and in silico docking analysis.

Bisphenol A (BPA) is a widely used plastic material, but its potential endocrine disrupting effect has restricted its use. The BPA alternatives have raised concerns. This study aimed to compare inhibitory potencies of 11 BPA analogues on human and rat placental aromatase (CYP19A1). The inhibitory potency on human CYP19A1 ranged from bisphenol H (IC50, 0.93 µM) to tetramethyl BPA and tetrabromobisphenol S (ineffective at 100 µM) when compared to BPA (IC50, 73.48 µM). Most of them were mixed/competitive inhibitors and inhibited estradiol production in human BeWo cells. Molecular docking analysis showed all BPA analogues bind to steroid active site or in between steroid and heme of CYP19A1 and form a hydrogen bond with catalytic residue Met374. Pharmacophore analysis showed that there were 4 hydrophobic regions for BPA analogues, with bisphenol H occupying 4 regions. Bivariate correlation analysis showed that LogP (lipophilicity) and LogS (water solubility) of BPA analogues were correlated with their IC50 values. Computerized drug metabolism and pharmacokinetics analysis showed that bisphenol H, tetrabromobisphenol A, and tetrachlorobisphenol A had low solubility, which might explain their weaker inhibition on estradiol production on BeWo cells. In conclusion, BPA analogues mostly can inhibit CYP19A1 and the lipophilicity determines their inhibitory strength.

The impact of tetrachlorobisphenol A exposure during puberty: Altered Leydig cell development and induced endoplasmic reticulum stress in male mice.

Tetrachlorobisphenol A (TCBPA), a halogenated flame retardant and endocrine disruptor, has been detected in human urine and serum. While previous research has shown its impact on the reproductive system, investigations into its mechanisms during puberty remain limited. This study aims to explore the effects of TCBPA on Leydig cells in adolescent mice and potential underlying mechanisms. Male C57 mice of age 28 days were gavaged with 50, 100, and 200 mg/kg/day for 28 days. TCBPA did not alter body weight and testis weight but lowered testosterone levels at 100 and 200 mg/kg and reduced sperm count in the epididymis at 200 mg/kg. TCBPA lowered Leydig cell number at 200 mg/kg while it downregulated key Leydig cell gene (Lhcgr, Scarb1, Cyp11a1, Cyp17a1, Hsd3b6, Hsd17b3 and Insl3) as low as 50 mg/kg. Further study indicated that TCBPA induced reactive oxygen species and caused endoplasmic reticulum stress. In vitro study in TM3 mouse Leydig cells showed that TCBPA indeed induced reactive oxygen species and caused endoplasmic reticulum stress at 75 µM and inhibited testosterone production at this concentration and addition of antioxidant tocopherol can reverse it. These discoveries provide new insights and references for a deeper understanding of the toxic mechanisms of TCBPA on Leydig cells during puberty.

Establishment of a concise health index synthetic evaluation method for adolescents / 中国学校卫生

Objective@#The aim of this study was to establish a comprehensive concise health index (CHI) for evaluating adolescents, so as to provide a basis for determining the overall health status of adolescents in China.@*Methods@#On the basis of a literature review and consensus among core researchers, adolescent CHI indicators in the following five dimensions were assessed:physical growth, physical fitness, common diseases, mental health and behavioral health. A total of 24 experts used an analysis hierarcgy process (AHP) to calculate the indicators subjective weights. In addition, from October to December of 2021, two regions, A and B were selected to conduct empirical research, and the CRITIC method was used to calculate the objective weights of the indicators. Finally, the weight coefficients were determined through the AHP-CRITIC combination weight method, and comprehensive evaluation was performed with the TOPSIS method.@*Results@#Across academic period and genders, the combined weighted coefficients of the health indicators were as follows:BMI, 0.081-0.095; waist circumference, 0.070-0.081; relative grip strength, 0.101-0.108; myopia, 0.110-0.128; dental caries, 0.055-0.070; psychological symptoms, 0.240-0.262; physical exercise, 0.085-0.115; screen time, 0.097-0.111; and sleep duration, 0.086-0.103. The health index of middle school students in city A (0.626±0.065) was significantly higher than that in city B(0.613±0.066)( t=6.34, P <0.01).@*Conclusion@#The comprehensive adolescent CHI evaluation method has good consistency and application value, and may serve as a reference for adolescent health monitoring.

Association of vitamin D deficiency with anxiety and depressive symptoms among middle school students in Shenzhen / 中国学校卫生

Objective@#To explore the association of vitamin D deficiency with anxiety and depressive symptoms as well as their comorbidity, so as to provide references for improving the mental health of children and adolescents.@*Methods@#From October to December 2021, a total of 1 323 students from four middle schools in Shenzhen were selected by using convenience sampling method for a questionnaire survey and physical examination. Fasting blood samples were collected to detect vitamin D levels. The Chi square test and multiple Logistic regression model were used to analyze the association of vitamin D deficiency with anxiety and depressive symptoms and their comorbidity among middle school students.@*Results@#The detection rates of anxiety, depressive, and thier comorbidities in middle school students were 33.0%, 21.5% and 16.3%, respectively. After adjusting for confounding factors, vitamin D deficiency was positively associated with the risk of anxiety symptoms ( OR=1.59, 95%CI =1.02-2.46), depressive symptoms ( OR=1.94, 95%CI =1.22-3.09) and anxiety depressive comorbid symptoms ( OR=1.75, 95%CI =1.06-2.90) in secondary school students ( P ＜0.05).@*Conclusion@#Vitamin D deficiency is associated with an increased risk of anxiety, depressive and their co morbidity symptoms in middle school students, and the directionality of the association should be further studied.

Longitudinal study on the changes and correlation of height, weight and blood pressure among children in Shenzhen / 中国学校卫生

Objective@#To understand the changes of children s height, weight, blood pressure and gender differences, to explore the relationship between overweight, obesity and childhood hypertension, and to provide a scientific basis for childhood hypertension prevention.@*Methods@#Physical examination data during 2013 to 2018 of ten primary school students in Shenzhen were collected. Growth rate of height, weight and blood pressure by age and gender were calculated. The generalized estimating equation was used to analyze the association between overweight, obesity and hypertension.@*Results@#Weight, body mass index (BMI) and systolic pressure of boys and girls increased with age ( t/Z =3.89-31.52, P <0.05). The height growth rate of girls was higher than that of boys at the age of 8-11, and reaches the peak of height growth at the age of 10, while boys were two years later than girls(boys:7.68 cm, gilrs:7.42 cm). Weight and blood pressure growth rates were similar. At the same time, the growth rate of height and blood pressure had a synchronous trend, and the peak of the growth rate of blood pressure was also at the peak stage of height growth. The OR value of obesity on childhood hypertension was 1.62(1.48-1.81), and the OR value of overweight on childhood hypertension was 2.01(1.75-2.30), both P <0.01.@*Conclusion@#There are gender differences in children s height, weight, and blood pressure, and the growth rate of height and blood pressure shows a synchronous trend. Overweight and obesity in children can increase the risk of high blood pressure and hypertension.

Influencing factors of myopia among primary and secondary school students in Shenzhen / 中国学校卫生

Objective@#To investigate the associated factors of myopia among primary and secondary school students in Shenzhen, and to provide reference for the prevention and control of myopia.@*Methods@#By stratified cluster sampling, 3 073 students of 14 schools including primary,junior,regular and vocational senior schools from two districts in Shenzhen were selected and investigated.@*Results@#For primary school students, the time of using computer for 2-<3 hours per day (OR=2.23，95%CI=1.19-4.20) , and no physical education class(2 sections per week OR=0.34, 95%CI=0.13-0.91; 4 sections per week OR=0.23, 95%CI=0.08-0.62; 5 sections or more per week OR=0.33, 95%CI=0.11-0.97) were positively associated with myopia. Teachers finishing class on time at break (occasionally delaying OR=1.99, 95%CI=1.51-2.63; frequently delaying OR=2.07, 95%CI=1.29-3.30), taking 0.5-1 hour break when using eyes at close range (1-<2 hours OR=1.33，95%CI=1.03-1.70; ≥3 hours OR=1.87, 95%CI=1.17-3.00), no parents with myopia(one parent with myopia OR=1.69, 95%CI=1.32-2.17; two parents with myopia OR=2.13, 95%CI=1.50-3.02) were negatively associated with myopia. For junior high school students, without parents with myopia (one parent with myopia OR=3.27, 95%CI=2.17-4.94; two parents with myopia OR=5.38, 95%CI=2.78-10.42) was the protective factor of myopia. For senior high school students, male (female OR=1.52, 95%CI=1.07-2.14), doing eye exercises twice a day in school (OR=0.41, 95%CI=0.23-0.75), and accumulating outdoor activities for ≥2 hours a day (OR=0.70, 95%CI=0.49-1.00) were negatively associated with myopia.@*Conclusion@#There are different risk factors for myopia among different students in Shenzhen. Students with high risk factors are the key objects of prevention and control.

Parent-child cohesion and problematic mobile phone use of middle school students in Shenzhen / 中国学校卫生

Objective@#To understand parent-child cohesion and problematic mobile phone use among middle school students in Shenzhen, and to provide a refevence for conducting the relevant control and prevention work .@*Methods@#A total of 3 992 students from 5 junior high schools and 5 senior high schools in Shenzhen were selected by using stratified cluster sampling method. Problematic mobile phone use and parent-child cohesion were investigated, and their association was analyzed.@*Results@#The average score of father-child cohesion and mother-child cohesion was (34.34±9.67) and (38.14±8.35), respectively. Mother-child cohesion score was higher than father-child cohesion score in both junior and senior middle school students(t=12.07, 14.41, P<0.01). Father-child cohesion (r=-0.20, P<0.01) and mother-child cohesion (r=-0.17, P<0.01) was negatively correlated with problematic mobile phone use. The lower the score of parent-child cohesion, the higher the score of problematic mobile phone use.@*Conclusion@#Family plays an important role in the prevention and control of problematic mobile phone use among middle school students. Improving parent-child cohesion and building a good parent-child relationship may help prevent problematic mobile phone use.

Psychological sub-health status and its relationship with suicidal behaviors among middle school students in Shenzhen / 中国学校卫生

Objective@#To investigate psychological sub-health status and its correlation with suicidal behaviors among middle school students in Shenzhen, so as to provide reference for early prevention of suicide.@*Methods@#A total of 4 014 students from 5 junior high schools and 5 senior high schools in Shenzhen were selected as the subjects. The status of psychological sub-health and suicidal behaviors were assessed, and their correlation was analyzed.@*Results@#The detection rates of psychological sub-health, suicide ideation, suicide plan and suicide attempts were 21.38%, 24.66%, 11.81% and 3.64% respectively. The detection rates of suicidal ideation, suicide plan and suicide attempts among students with high level of psychological sub-health status were significantly higher than those without psychological sub-health status(P<0.01). Correlation analysis showed that the number of psychological sub-health symptoms was positively correlated with the number of suicidal ideations, suicide plans and suicide attempts(P<0.01).@*Conclusion@#Psychological health status of adolescents in Shenzhen is not optimistic. There is a correlation between psychological sub-health status and suicidal behaviors. More attention should be paid to suicide prevention among students with psychological sub-health status.