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Chang-Shou She,1 Yue-Lin Deng,1 Guo-Qing Huang,1 Chao Cheng,2 Fang-Jie Zhang1,3 1Department of Emergency Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Clinical Laboratory, Lixian People’s Hospital, Changde, Hunan, People’s Republic of China; 3National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, Hunan, People’s Republic of ChinaCorrespondence: Fang-Jie Zhang, Department of Emergency Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China, Tel +86 15116256248, Email zhangfj@csu.edu.cnPurpose: This study’s goal was to explore risk factors affecting short-term prognosis of cardiorenal syndrome type 1 (CRS1) in acute myocardial infarction (AMI) patients.Methods: In this retrospective analysis of CRS1 in AMI patients hospitalized from January 2011 to December 2014, the patients were classified into deceased or survivor groups. Clinical data, including demographics, laboratory results, and 28-day outcomes, were collected.Results: The incidence rate of CRS1 in AMI patients was 15.2% (274 in 1801). Ultimately, 88 patients were enrolled and 25 (28.4%) were classified into the deceased group, while 63 were classified into the survivor group. There were statistically significant differences between the groups for hypertension, mechanical ventilation, KIDGO stage, NT-proBNP, Hb, ALB, PCI, decreased LVEF, 7th-day SCr value, and the highest SCr value recorded within 7 days (all P < 0.05). Multivariate logistic regression showed that the following factors were significantly related to whether a patient died: requiring mechanical ventilation, increased NT-proBNP levels and 7th-day SCr values, and decreased LVEFs. The APACHE II, SOFA, and SASP II scores on the 7th day were significantly higher in the deceased group (all P < 0.05). The accuracy of APACHE II, SOFA, and SASP II scores on the 7th day for predicting death were 84.1%, 78.4% and 79.5%, respectively. The AUC of 7th-day APACHE II, SOFA, and SASP II scores was 0.844, 0.803, and 0.827, respectively, with no statistically significant differences between the three scores (P > 0.05).Conclusion: The mortality rate of CRS1 in AMI patients was 28.4% (25 in 88) within 28 days. Mechanical ventilation, increased NT-proBNP levels, the 7th-day SCr value, and decreased LVEF were related to death in AMI patients with CRS1. APACHE II, SOFA, and SAPS II scores on the 7th day were satisfactorily accurate in predicting death within 28 days.Keywords: acute myocardial infarction, cardiorenal syndrome type 1, APACHE II, SOFA, SAPS II, mortality

Xiang Wang,1 Lisha Dai,1 Meng Yin,1 Yunlong Deng1,2 1Department of Clinical Psychology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; 2Psychosomatic Health Institute, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China Background/purpose: Dream emotions and contents are associated with psychological well-being. Dream disturbances, such as frequent nightmares and dream anxiety, are associated with a variety of psychopathological conditions. Therefore, it is important to consider nightmares and the resulting dream anxiety. To address this issue, the Van Dream Anxiety Scale (VDAS) was designed especially for measuring nightmare frequency and dream anxiety caused by frightening dreams. As a Chinese version of VDAS may be helpful in promoting study of nightmare and dream anxiety among Chinese population, in the current study, we sought to develop a Chinese version of the VDAS (CVDAS). Methods: We translated the VDAS into Chinese. To evaluate its validity and reliability, a sample of 1,081 Chinese college students from two universities answered the CVDAS, GAD-7, PHQ-9 and EPQ-R-N. Ninety of them answered the CVDAS twice. We also conducted exploratory factor analysis (EFA) to explore the structure of CVDAS. Results: Excellent internal consistency (Cronbach’s alpha coefficient was 0.926), split-half reliability (equal-length Spearman–Brown coefficient was 0.938) and good test–retest reliability (the intraclass correlation coefficient was 0.942 and t=-1.478, P=0.143) of the CVDAS was presented. Exploratory factor analyses indicated a two-factor structure: sleep-related disturbances caused by nightmares and dysfunction caused by nightmares. Convergent and divergent validities were acceptable. Conclusion: The CVDAS shows promise for the measurement of nightmare frequency and specific dream anxiety in Chinese population. Future study should confirm the reliability and validity in the clinical population and further improve this scale. Keywords: nightmare, dream anxiety, assessment, Chinese population

Yunbin Xiao,1,* Zuan Tao Lin,2,* Yanmei Chen,1 He Wang,1 Ya Li Deng,2 D Elizabeth Le,3 Jianguo Bin,1 Meiyu Li,1 Yulin Liao,1 Yili Liu,1 Gangbiao Jiang,2 Jianping Bin1 1State Key Laboratory of Organ Failure Research, Division of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Pharmaceutical Engineering, South China Agricultural University, Guangzhou, People’s Republic of China; 3Cardiovascular Division, Oregon Health and Science University, Portland, OR, USA *These authors contributed equally to this work Abstract: Magnetic resonance imaging (MRI) contrast agents based on chitosan derivatives have great potential for diagnosing diseases. However, stable tumor-targeted MRI contrast agents using micelles prepared from high molecular weight chitosan derivatives are seldom reported. In this study, we developed a novel tumor-targeted MRI vehicle via superparamagnetic iron oxide nanoparticles (SPIONs) encapsulated in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan (FAPLCS) micelles. The tumor-targeting ability of FAPLCS/SPIONs was demonstrated in vitro and in vivo. The results of dynamic light scattering experiments showed that the micelles had a relatively narrow size distribution (136.60±3.90 nm) and excellent stability. FAPLCS/SPIONs showed low cytotoxicity and excellent biocompatibility in cellular toxicity tests. Both in vitro and in vivo studies demonstrated that FAPLCS/SPIONs bound specifically to folate receptor-positive HeLa cells, and that FAPLCS/SPIONs accumulated predominantly in established HeLa-derived tumors in mice. The signal intensities of T2-weighted images in established HeLa-derived tumors were reduced dramatically after intravenous micelle administration. Our study indicates that FAPLCS/SPION micelles can potentially serve as safe and effective MRI contrast agents for detecting tumors that overexpress folate receptors. Keywords: superparamagnetic iron oxide, magnetic resonance imaging, polymeric micelles, folate receptors, tumor-targeted MRI, N-palmitoyl chitosan

Boran Cheng,1,* Zhaobo He,2,* Libo Zhao,2,* Yuan Fang,1 Yuanyuan Chen,1 Rongxiang He,2 Fangfang Chen,1 Haibin Song,1 Yuliang Deng,2 Xingzhong Zhao,2 Bin Xiong1 1Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Wuhan, Hubei, People’s Republic of China; 2Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Abstract: Circulating tumor cells (CTCs) in the blood which have detached from both the primary tumor and any metastases may be considered as a “liquid biopsy” and are expected to replace tumor biopsies in the monitoring of treatment response and determining patient prognosis. Here, we introduce a facile and efficient CTC detection material made of hydroxyapatite/chitosan (HA/CTS), which is beneficial because of its transparency and excellent biological compatibility. Atomic force microscopy images show that the roughness of the HA/CTS nanofilm (HA/CTSNF) substrates can be controlled by changing the HA:CTS ratio. Enhanced local topographic interactions between nano-components on cancer cell membranes, and the antibody coated nanostructured substrate lead to improved CTC capture and separation. This remarkable nanostructured substrate has the potential for CTC culture in situ and merits further analysis. CTCs captured from artificial blood samples were observed in culture on HA/CTSNF substrates over a period of 14 days by using conventional staining methods (hematoxylin eosin and Wright’s stain). We conclude that these substrates are multifunctional materials capable of isolating and culturing CTCs for subsequent studies. Keywords: cell capture, cell culture, nanofilms, hydroxyapatite/chitosan

The main objective of this study was to assess the economic cost of Alzheimer's disease (AD) in Shanghai, China, as a pilot study for future evaluations. Sixty-seven patients with AD were interviewed, and the information of the AD-related cost and resources used was collected from October 2005 to September 2006. By retrospective analysis, annual costs were calculated and expressed in Chinese renminbi (RMB). Direct cost per patient per year averaged approximately 8,432 RMB (1,058 USD), indirect cost per patient per year was 10,568 RMB (1,326 USD), and annual costs were 19,001 RMB (2,384 USD) per patient per year in this investigation. Total cost was significantly associated with the degree of severity including cognitive function (MMSE) and activity of daily living (ADL). With the increase in the number of persons at risk for developing AD, the economic burden of AD patients in China is significantly heavy. [ABSTRACT FROM AUTHOR]

A new triterpenoid saponin ( 1 ), along with five known compounds ( 2-6 ), was isolated from Bupleurum marginatum Wall. ex DC, of which compounds 2-4 were obtained for the first time from this plant. The structures were confirmed by the analysis of 1D, 2D NMR, and HR-ESIMS data, and comparison with previous spectral data. Anti-liver fibrotic activities of the isolates were determined as proliferation inhibition of LPS-induced activation of HSC-T6 in vitro .

Over the past decades, the immune responses have been suspected of participating in the mechanisms for epilepsy. To assess the immune related pathway in temporal lobe epilepsy (TLE), we explored the altered immune pathways in TLE patients with and without hippocampal sclerosis (HS). We analyzed RNA-seq data from 3 TLE-HS and 3 TLE-nonHS patients, including identification of differentially expressed RNA, function pathway enrichment, the protein-protein interaction network and construction of ceRNA regulatory network. We illustrated the immune related landscape of molecules and pathways on human TLE-HS. Also, we identified several differential immune related genes like HSP90AA1 and SOD1 in TLE-HS patients. Further ceRNA regulatory network analysis found SOX2-OT connected to miR-671-5p and upregulated the target gene SPP1 in TLE-HS patients. Also, we identified both SOX2-OT and SPP1 were significantly upregulated in five different databases including TLE-HS patients and animal models. Our findings established the first immune related genes and possible regulatory pathways in TLE-HS patients and animal models, which provided a novel insight into disease pathogenesis in both patients and animal models. The immune related SOX2-OT/miR-671-5p/SPP1 axis may be the potential therapeutic target for TLE-HS., (© 2024. The Author(s).)

Background: Disinfection byproducts (DBPs) have been shown to impair thyroid function in experimental models. However, epidemiological evidence is scarce., Methods: This study included 1190 women undergoing assisted reproductive technology (ART) treatment from the Tongji Reproductive and Environmental (TREE) cohort from December 2018 to August 2021. Serum thyrotropin (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were measured as indicators of thyroid function. FT4/FT3 and TSH/FT4 ratios were calculated as markers of thyroid hormone homeostasis. Dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA), the two most abundant HAAs, in urine were detected to assess individual DBP exposures., Results: After adjusting for relevant covariates, positive associations were observed between urinary TCAA concentrations and serum TSH and TSH/FT4 levels (e.g., percent change = 5.82 %, 95 % CI: 0.70 %, 11.21 % for TSH), whereas inverse associations were found for serum FT3 and FT4 (e.g., percent change = -1.29 %, 95 % CI: -2.49 %, -0.07 % for FT3). There also was a negative association between urinary DCAA concentration and serum FT4/FT3 (percent change = -2.49 %, 95 % CI: -4.71 %, -0.23 %). These associations were further confirmed in the restricted cubic spline and generalized additive models with linear or U-shaped dose-response relationships., Conclusion: Urinary HAAs were associated with altered thyroid hormone homeostasis among women undergoing ART treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Context: Low bone mineral density (BMD) has been linked to elevated risks of mortality and infections in the general population; however, its association with these outcomes in stroke patients remains unclear., Objective: This study aims to investigate the correlation between low BMD and risks of mortality and infections among stroke patients in a Taiwanese cohort., Methods: In this single-centered retrospective cohort study, 905 stroke patients from a Taiwanese database (2000-2022) were analyzed. Patients were divided based on BMD measurements of the femur and spine. The primary outcome was all-cause mortality, and secondary outcomes included urinary tract infection (UTI) and pneumonia. Accelerated failure time regression model analyses evaluated the association between BMD and these outcomes, while the Kaplan-Meier method and log-rank test assessed survival differences between groups., Results: Among the participants (average age 76.1 years, 70.5% female), 33.82% had osteopenia and 55.25% had osteoporosis. Stroke patients with lower spine and right femur BMD had significantly reduced survival rates, especially when the BMD value fell below 0.842 g/cm2 (spine), and 0.624 g/cm2 (right femur), respectively. Regarding secondary outcomes, lower spine BMD was significantly associated with an increased risk of UTI., Conclusion: Low BMD, particularly in the femur and spine, is a significant predictor of mortality and UTI in stroke patients. These findings highlight the importance of assessing and managing BMD in stroke patients to improve outcomes and reduce complications., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To investigate the genetic and expression characteristics of transcription factor IIH (TFIIH) in pre-initiationcomplex in prostate cancer (PCa) and its relationship with prostate cancer progression. Methods: Analyzing the expression characteristics and clinical signification of TFIIH subunits about 495 cases of PCa and 52 cases of adjacent cancer in The Cancer Genome Atlas-Prostate adenocarcinoma (TCGA-PRAD) database. PCa microarray chip was used to verify the correlation between the key factor General Transcription Factor IIH Subunit 4 (GTF2H4) in TFIIH and clinical features. Results: The 495 patients with PCa were (61.01±6.82) years old.The mRNA expression of ERCC3、GTF2H4 and MNAT1 were high in PCa tissues with GS≥8( P <0.05). The expression of GTF2H4 and MNAT1 were relevant to the pathological stages( P <0.05). High expression of GTF2H4 has higher biochemical recurrence (BCR) rate in PCa patients( HR =2.47, 95% CI :1.62-3.77, P <0.001), which has better predictive effect of BCR in PCa patients(The 3rd, 5th, and 7th year AUC all>0.7) than other subunits, and it has been verified in four additional databases. Single-factor Cox regression analysis showed that GTF2H4 were risk factors for BCR ( HR =2.470, 95% CI :1.620-3.767, P <0.001) and GTF2H5 were protective factors( HR =0.506,95% CI : 0.336-0.762, P =0.001). The results of immunohistochemical staining showed that the protein expression of GTF2H4 was correlated with the clinical features of PCa patients.The differences of the above results were statistically significant. Conclusion: GTF2H4, the key factor of TFIIH, is highly expressed in PCa and indicates a poor prognosis.

Two templated borates, [Co(1-EI) 2 ]·[B 5 O 7 (OH) 3 ] (1) and [Ga(1-MI) 2 ·B 6 O 9 (OH) 4 ]·[H 3 BO 3 ]·H[1-MI] (2), have been synthesized using a mild method. Notably, they exhibit an excellent ORR performance with an E 1/2 value of 0.84 V and are the first to be used as the positive electrode catalyst for a zinc-air battery, which opens a pathway for the application of borate-based oxide catalysts.

Background: Disinfection byproducts (DBPs), the ubiquitous contaminants in drinking water, have been shown to impair renal function in experimental studies. However, epidemiological evidence is sparse., Objective: To investigate exposures to DBPs in associations with renal function among women., Methods: A total of 920 women from December 2018 to January 2020 were abstracted from the Tongji Reproductive and Environmental (TREE) Study, an ongoing cohort study in Wuhan, China. Urine samples were gathered at baseline recruitment and analyzed for dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) as biomarkers of DBP exposures. Serum uric acid (UA), creatinine, and estimated glomerular filtration rate (eGFR) were measured as indicators of renal function. Multivariate linear regression and restricted cubic spline (RCS) models were conducted to assess urinary DCAA and TCAA concentrations in associations with renal function indicators. Stratified analyses by age and body mass index (BMI) were also performed., Results: We found null evidence of urinary TCAA in associations with renal function indicators. However, elevated urinary DCAA tertiles were related to decreased eGFR (β = -1.78%, 95% CI: 3.21%, -0.36%, comparing the upper vs. lower tertile; P for trend = 0.01). This inverse association still existed when urinary DCAA concentration was treated as a continuous variable, and the dose-response relationship was linear based on the RCS model (P for overall association = 0.002 and P for non-linear associations = 0.44). In the stratified analyses, we found an association of urinary DCAA concentration with decreased UA level among women <30 years but an association with increased UA level among women ≥30 years (P for interaction = 0.04)., Conclusion: Urinary DCAA but not TCAA was associated with impaired renal function among women undergoing assisted reproductive technology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In vitro fertilization (IVF) is a highly effective treatment for infertility; however, it poses challenges for women with decreased ovarian reserve (DOR). Despite the importance of understanding the impact of DOR on IVF outcomes, limited research has explored this relationship, particularly using omics approaches. Hence, we conducted a study to investigate the association between DOR and IVF outcomes, employing a metabolomic approach. We analyzed serum samples from 207 women undergoing IVF treatment, including 89 with DOR and 118 with normal ovarian reserve (NOR). Our findings revealed that DOR was significantly associated with unfavorable IVF outcomes, characterized by a reduced oocyte count, lower embryo quality, and decreased rates of pregnancy and live births. Furthermore, we identified 82 metabolites that displayed significant alterations in DOR patients, impacting diverse metabolic pathways. Notably, a distinct panel of metabolites, including palmitic acid, stearic acid, LysoPC(9:0(CHO)/0:0), PC(18:0/9:0(CHO)), and PC(16:0/9:0(CHO)), exhibited discriminatory power between the DOR and NOR groups, showcasing a strong correlation with IVF outcomes. These findings emphasize the crucial role of metabolomic disruptions in influencing IVF outcomes among women with DOR.

Background: Disinfection byproducts (DBPs) as ovarian toxicants have been documented in toxicological studies. However, no human studies have explored the effects of exposure to DBPs on diminished ovarian reserve (DOR)., Objective: To assess whether urinary biomarkers of exposure to drinking-water DBPs were associated with DOR risk., Methods: A total of 311 women undergoing assisted reproductive technology were diagnosed with DOR in the Tongji Reproductive and Environmental (TREE) cohort from December 2018 to August 2021. The cases were matched to the controls with normal ovarian reserve function by age in a ratio of 1:1. Urinary trichloroacetic acid (TCAA) and dichloroacetic acid (DCAA) were quantified as biomarkers of drinking-water DBP exposures. The conditional logistic regression and restricted cubic spline (RCS) were used to explore urinary biomarkers of drinking-water DBP exposures in associations with the risk of DOR., Results: Elevated urinary DCAA levels were associated with higher DOR risk [adjusted odds ratio (OR) = 1.87; 95 % confidence interval (CI): 1.16, 3.03 for the highest vs. lowest quartiles; P for trend = 0.016]. The association was confirmed in the RCS model, with a linear dose-response curve (P for overall association = 0.029 and P for non-linear association = 0.708). The subgroup analysis by age and body mass index (BMI) showed that urinary DCAA in association with DOR risk was observed among women ≥35 years old and leaner women (BMI < 24 kg/m 2 ), but the group differences were not statistically significant. Moreover, a U-shaped dose-response curve between urinary TCAA and DOR risk was estimated in the RCS model (P for overall association = 0.011 and P for non-linear association = 0.004)., Conclusions: Exposure to drinking-water DBPs may contribute to the risk of DOR among women undergoing assisted reproductive technology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Prenatal exposures to phthalates and bisphenols have been shown to be linked with adverse birth outcomes. Oxidative stress (OS) is considered a potential mechanism. The objective of this study was to explore the individual and mixtures of prenatal exposures to phthalates and bisphenols in associations with OS biomarkers. We measured eight phthalate metabolites and three bisphenols in the urine samples from 105 pregnant women in Wuhan, China. Urinary 8-hydroxydeoxyguanosine (8-OHdG), 8-isoprostaglandin F 2α (8-isoPGF 2α ), and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) were determined as OS biomarkers. The OS biomarkers in associations with the individual chemicals were estimated by linear regression models and restricted cubic spline (RCS) models, and their associations with the chemical mixtures were explored by quantile g-computation (qg-comp) models. In single-pollutant analyses, five phthalate metabolites including monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-(2-ethylhexyl) phthalate (MEHP), (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) were positively associated with urinary 8-OHdG levels (all FDR-adjusted P = 0.06). These associations were further confirmed by the RCS models and were linear (P for overall association ≤ 0.05 and P for non-linear association > 0.05). In mixture analyses, qg-comp models showed that a one-quartile increase in the chemical mixtures of phthalate metabolites and bisphenols was positively associated with urinary levels of 8-OHdG and 8-isoPGF 2α , and bisphenol A (BPA) and bisphenol F (BPF) were the most contributing chemicals, respectively. Prenatal exposures to individual phthalates and mixtures of phthalates and bisphenols were associated with higher OS levels., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Toxicological studies have demonstrated that disinfection byproducts (DBPs), particularly haloacetic acids, cause testicular toxicity. However, evidence from human studies is sparse and inconclusive. This study included 1230 reproductive-aged men from the Tongji Reproductive and Environmental (TREE) cohort to investigate the associations between repeated measures of DBP exposures and semen parameters. Urinary dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) as biomarkers of DBP exposures and semen parameters in up to three samples from each man were assessed. The linear mixed effect models were applied to explore the associations between urinary biomarkers of DBP exposures and semen parameters. We found inverse associations of urinary DCAA with sperm count, progressive motility, and total motility (e.g., -14.86%; 95% CI: -19.33%, -10.15% in sperm total motility for the highest vs. lowest quartiles; all P for trends < 0.05). Moreover, urinary TCAA modeled as a continuous variable was negatively associated with sperm progressive motility and total motility, while the inverse associations across increasing urinary TCAA quartiles were seen among leaner men (BMI < 25 kg/m 2 ). Exposure to DBPs reflected by urinary DCAA and TCAA was inversely associated with sperm motility and such effects were more evident among leaner men., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: Numerous studies have documented the association of self-rated health (SRH) with chronic diseases. However, few studies have investigated its association with semen quality., Objective: To examine the association of SRH with semen quality among men undergoing assisted reproductive technology (ART) in China., Design, Setting, and Participants: This cross-sectional study recruited male partners in couples undergoing ART treatment at the Center for Reproductive Medicine, Tongji Hospital, Wuhan, China. A total of 1262 men underwent 2 semen examinations and completed a questionnaire on SRH between December 2018 and January 2020. Data analysis was performed from November 20, 2022, to March 24, 2023., Exposure: SRH, including overall physical and mental health, as well as reproductive-related physical and mental health specifically, were reported at baseline recruitment., Main Outcomes and Measures: Sperm concentration, sperm progressive motility, sperm motility, and sperm count as semen quality parameters., Results: The study included 1262 men with a mean (SD) age of 32.79 (5.25) years and body mass index of 24.37 (3.68). Men with poorer SRH had lower semen quality (eg, sperm concentration among poor vs very good overall physical health: percentage variation, -14.67%; 95% CI, -23.62% to -4.66%). Among 4 components of SRH, a greater reduction in semen quality was estimated for reproductive-related SRH compared with overall SRH, whereas the greatest reduction was observed for reproductive-related physical SRH. In comparison with men with very good reproductive-related physical SRH, men with poor reproductive-related physical SRH had differences of -24.78% (95% CI, -32.71% to -15.93%) and -25.61% (95% CI, -33.95% to -16.22%) in sperm count and concentration, respectively, and regression coefficients of -9.38 (95% CI, -12.01 to -6.76) and -9.24 (95% CI, -11.82 to -6.66) for sperm motility and sperm progressive motility, respectively., Conclusions and Relevance: In this cross-sectional study of Chinese men, poorer SRH was associated with lower semen quality, and reproductive-related physical SRH was the most pronounced indicator. Our findings suggest that SRH, especially reproductive-related physical SRH, was a good indicator of semen quality, which should inform public and clinical regulatory decisions.

Background: Experimental studies have shown that disinfection byproducts (DBPs) including haloacetic acids (HAAs) can cause liver toxicity, but evidence linking this association in humans is sparse., Objectives: We aimed to explore the associations between HAA exposures and liver injury., Methods: We included 922 women between December 2018 and January 2020 from the Tongji Reproductive and Environmental (TREE) cohort study in Wuhan, China. Urinary HAA concentrations including trichloroacetic acid (TCAA) and dichloroacetic acid (DCAA) and serum indicators of liver function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) were measured. Liver injury was defined as if any of serum indicator levels were above the 90th percentile. Multivariate logistic and linear regression models were fitted to assess the associations of urinary HAA concentrations with the risk of liver injury and liver function indicators. Stratified analyses by age, body mass index (BMI), alcohol use, and passive smoking were also applied to evaluate the potential effect modifiers., Results: There is little evidence of associations of urinary TCAA concentrations with liver injury risk and liver function indicators. However, urinary DCAA concentrations were associated with a higher risk of liver injury [odds ratios (OR) for 1-interquartile range (IQR) increase in natural log (ln) transformed DCAA concentrations: 1.45; 95% confidence interval (CI): 1.07, 1.98]. This association was observed only among nondrinkers ( p interaction = 0.058 ). We also found that a 1-IQR increase in ln-transformed DCAA concentrations was positively associated with ALT levels (percentage change = 6.06 % ; 95% CI: 0.48%, 11.95%) and negatively associated with AST/ALT (percentage change = - 4.48 % ; 95% CI: - 7.80 % , - 1.04 % ). In addition, urinary DCAA concentrations in relation to higher GGT levels was observed only among passive smokers ( p interaction = 0.040 )., Conclusion: Our findings suggest that exposure to DCAA but not TCAA is associated with liver injury among women undergoing assisted reproductive technology. https://doi.org/10.1289/EHP13386.

Background: Experimental studies have shown that disinfection byproducts (DBPs) induce coagulotoxicity, but human evidence is scarce., Objective: This study aimed to explore the relationships of DBP exposures with blood coagulation parameters., Methods: Among 858 women from the Tongji Reproductive and Environmental (TREE) study, urinary dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) were detected as internal biomarkers of DBP exposures. We measured activated partial thromboplastin time (APTT), fibrinogen (Fbg), international normalized ratio (INR), prothrombin time (PT), and thrombin time (TT) as blood coagulation parameters. Multivariable linear regression models were utilized to estimate the relationships between urinary DCAA and TCAA and blood coagulation parameters. The effect modifications by demographic and lifestyle characteristics were further explored., Results: Elevated tertiles of urinary DCAA concentrations were associated with increased PT and INR (11.29%, 95% CI: 1.66%, 20.92% and 0.99%, 95% CI: 0.08%, 1.90% for the third vs. first tertile, respectively; both P for trends < 0.05). Stratification analysis showed that the positive associations were only observed among younger (< 30 years), leaner (body mass index < 24.0 kg/m 2 ), and non-passive smoking women. Moreover, elevated tertiles of urinary TCAA concentrations in positive associations with PT and INR were observed among younger women (17.89%, 95% CI: 2.50%, 33.29% and 1.82%, 95% CI: 0.34%, 3.30% for the third vs. first tertile, respectively; both P for trends < 0.05) but not among older women (both P for interactions < 0.05)., Conclusion: Higher levels of urinary DCAA and TCAA are associated with prolonged clotting time among women., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Air pollution and type 2 diabetes (T2D) are both associated with an increased risk of ischemic heart disease (IHD). Little is known about the combined effects of multiple air pollutants on IHD risk, especially among individuals with T2D. We sought to assess the association of combined exposure to multiple air pollutants with incident IHD and examine the modification effect of T2D., Methods: This study included 388780 individuals (20036 individuals with T2D) free of cardiovascular disease and cancer from the UK Biobank. The combined exposure to multiple air pollutants, including particulate matter (PM) with diameters ≤ 2.5 μm (PM 2.5 ), PM with diameters between 2.5 and 10 µm (PM coarse ), PM with diameters ≤ 10 μm (PM 10 ), nitrogen dioxide (NO 2 ), and nitrogen dioxides (NO x ), was assessed by creating a weighted air pollution score (APS), with a higher APS representing a higher level of air pollution exposure. Hazard ratios (HR) and 95 % confidence intervals (CI) for incident IHD were assessed by multivariable-adjusted Cox proportional hazard models., Results: During a median of 12.9 years of follow-up, 27333 incident IHD cases were observed. Compared with the lowest tertile of the APS, the multivariable-adjusted HR (95 % CI) of IHD risk for the highest tertile was 1.13 (1.03-1.23) among individuals with T2D, while the HR was 1.06 (1.03-1.10) among individuals without T2D. Additionally, the associations between APS and IHD incidence showed a linear relationship among individuals with T2D (nonlinearity: P = 0.37), whereas a non-linear relationship was observed among individuals without T2D (nonlinearity: P = 0.02). For the joint analysis, individuals in the highest tertile of APS and with T2D had a 54 % higher risk of IHD compared to individuals in the lowest tertile of APS and without T2D, with a significant additive interaction (P interaction  < 0.01). The proportion of relative excess risk was 17 % due to the interaction in categorical analyses., Conclusions: The combined exposure to multiple air pollutants has been associated with an elevated risk of incident IHD, and the association is more pronounced among individuals with T2D., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Phthalates have been reported to impair fertility in various studies. However, evidence exploring the associations between phthalate metabolites in follicular fluid (FF) and reproductive outcomes is lacking., Objectives: To investigate the associations between phthalate metabolite concentrations in FF and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes among women recruited from a fertility clinic., Methods: We included 641 women undergoing IVF/ICSI treatment from December 2018 to January 2020. The levels of eight phthalate metabolites, including monoethyl phthalate (MEP), mono-isobutyl phthalate (MiBP), mono- n -butyl phthalate (MBP), monobenzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), were quantified in FF collected on the oocyte retrieval day. Associations between quartiles of individual phthalate metabolite concentrations and nine IVF/ICSI outcomes, including oocyte yield, mature oocyte number, two distinct pronuclei (2PN) zygote number, fertilization rate, blastocyst formation rate, implantation, clinical pregnancy, miscarriage, and live birth, were estimated with generalized linear models. The effects of phthalate mixtures on IVF/ICSI outcomes were assessed using Bayesian kernel machine regression (BKMR) models., Results: After adjusting for relevant confounders, elevated quartiles of MBzP, MEHHP, and MEHP in FF were inversely associated with the numbers of retrieved oocytes, mature oocytes, and 2PN zygotes (all p for trends < 0.10 ). In comparison with the lowest quartile, the highest quartile of molar sum of di(2-ethylhexyl) phthalate metabolites ( Σ DEHP ) was associated with a reduction of 9.1% [95% confidence interval (CI): - 17.1 % , - 0.37 % ] and 10.3% (95% CI: - 18.8 % , - 0.94 % ) in yielded oocyte and mature oocyte numbers, respectively. Furthermore, the BKMR models revealed inverse associations between phthalate mixtures and the numbers of retrieved oocytes and mature oocytes. We generally found null results for implantation, clinical pregnancy, miscarriage, and live birth., Discussion: Certain phthalate metabolites in FF are inversely associated with the numbers of retrieved oocytes, mature oocytes, and 2PN zygotes among women undergoing IVF/ICSI treatment. https://doi.org/10.1289/EHP11998.

Purpose: Neuroblastoma (NB) is the most common solid malignancy in children. Despite current intensive treatment, the long-term event-free survival rate is less than 50% in these patients. Thus, patients with NB urgently need more valid treatment strategies. Previous research has shown that STAT3 may be an effective target in high-risk NB patients. However, there are no effective inhibitors in clinical evaluation with low toxicity and few side effects. Astaxanthin is a safe and natural anticancer product. In this study, we investigated whether astaxanthin could exert antitumor effects in the SK-N-SH neuroblastoma cancer cell line., Method: MTT and colony formation assays were used to determine the effect of astaxanthin on the proliferation and colony formation of SK-N-SH cells. Flow cytometry assays were used to detect the apoptosis of SK-N-SH cells. The migration and invasion ability of SK-N-SH cells were detected by migration and invasion assays. Western blot and RT-PCR were used to detect the protein and mRNA levels. Animal experiments were carried out and cell apoptosis in tissues were assessed using a TUNEL assay., Result: We confirmed that astaxanthin repressed proliferation, clone formation ability, migration and invasion and induced apoptosis in SK-N-SH cells through the STAT3 pathway. Furthermore, the highest inhibitory effect was observed when astaxanthin was combined with si-STAT3. The reason for this may be that the combination of astaxanthin and si-STAT3 can lower STAT3 expression further than astaxanthin or si-STAT3 alone., Conclusion: Astaxanthin can exert anti-tumor effect on SK-N-SH cells. The inhibitory effect was the higher when astaxanthin was combined with si-STAT3., (© 2023. The Author(s).)

Two new triterpenoid saponins ( 1 and 2 ), together with two known saponins ( 3 and 4 ) were isolated from Bupleurum marginatum Wall. ex DC. Their structures were elucidated by the comprehensive spectroscopic analysis. Compounds 1 and 2 represented the rare example of an oleanane-type triterpenoid with two sugar moieties at C-3 and C-28. The cytotoxic activity of four compounds was evaluated against normal heptocell BRL-3A in vitro .

Ketamine is a racemic mixture of equal amounts of R-ketamine and S-ketamine and is well known to anesthesiologists for its unique dissociative anesthetic properties. The pharmacological properties of ketamine, namely, its sympathetic excitation, mild respiratory depression, and potent analgesia, are still highly valued in its use as an anesthetic for some patients. In particular, since its advent, S-ketamine has been widely used as an anesthetic in many countries due to its increased affinity for NMDA receptors and its enhanced anesthetic and analgesic effects. However, the anesthetic and analgesic mechanisms of S-ketamine are not fully understood. In addition to antagonizing NMDA receptors, a variety of other receptors or channels may be involved, but there are no relevant mechanistic summaries in the literature. Therefore, the purpose of this paper is to review the mechanisms of action of S-ketamine on relevant receptors and systems in the body that result in its pharmacological properties, such as anesthesia and analgesia, with the aim of providing a reference for its clinical applications and research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Peng, Liang, Chen, Liu, Wang, Guo, Deng, Ye, Zhong and Wang.)

Background: Experimental studies show that disinfection byproducts (DBPs) can inhibit oocyte maturation, decrease fertilization capacity, and impair embryo development, but human evidence is lacking., Objectives: We aimed to evaluate the associations between exposure to drinking water DBPs and in vitro fertilization (IVF) outcomes., Methods: The study included 1,048 women undergoing assisted reproductive technology (ART) treatment between December 2018 and January 2020 from a prospective cohort study, the Tongji Reproductive and Environmental study in Wuhan, China. Exposure to DBPs was assessed by dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) in up to four urine samples, which were collected on the day of both enrollment and oocyte retrieval. Multivariable generalized linear mixed models, accounting for multiple IVF cycles per woman, were applied to evaluate the associations between urinary biomarkers of DBP exposures and IVF outcomes. Stratified analyses were used to explore the potential effect modifiers., Results: The included 1,048 women underwent 1,136 IVF cycles, with 960 (91.6%), 84 (8.0%), and 4 (0.4%) women contributing one cycle, two cycles, and three cycles, respectively. We found that elevated quartiles of urinary DCAA and TCAA concentrations were associated with reduced numbers of total oocytes and metaphase II oocytes and that urinary DCAA concentrations with a lower proportion of best-quality embryos (all p for trends < 0.05 ). Moreover, elevated quartiles of urinary DCAA concentrations were associated with decreased proportions of successful implantation, clinical pregnancy, and live birth (14%, 15%, and 15% decreases in adjusted means comparing the extreme quartiles, respectively; all p for trends < 0.05 ). Stratification analyses showed that the inverse associations of urinary TCAA concentrations with multiple IVF outcomes were stronger among women ≥ 30 y of age ( p for interactions < 0.05 )., Discussion: Exposure to drinking water DBPs was inversely associated with some IVF outcomes among women undergoing ART treatment. Further study is necessary to confirm our findings. https://doi.org/10.1289/EHP12447.

Phthalates are widespread endocrine disrupting chemicals that adversely affect female reproductive health. We aimed to investigate the individual and joint associations of phthalate exposures measured by repeated urinary metabolites with polycystic ovary (PCO) and polycystic ovary syndrome (PCOS) (96 PCO cases, 96 PCOS cases and 370 controls). In single-pollutant analyses, mono-isobutyl phthalate (MiBP), monobenzyl phthalate (MBzP) and the sum of di(2-ethylhexyl) phthalate (∑DEHP) were associated with increased prevalence of PCO. Mono(2-ethylhexyl) phthalate (MEHP), MBzP and ∑DEHP were associated with elevated prevalence of PCOS. In multiple-pollutant analyses, one-quartile increase of weighted quantile sum index in phthalate metabolite mixtures was associated with increased prevalence of PCO and PCOS, and MBzP was the most major contributor. Our findings suggest a potential role for phthalate exposures, both individually and in mixtures, in the development of PCO and PCOS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Epidemiological studies on phthalate exposures in associations with uterine fibroids (UF) and endometriosis (EMT) are inconsistent. The underlying mechanisms are poorly understood., Objectives: To investigate the relationships of urinary phthalate metabolites with UF and EMT risks, and further to examine the mediating role of oxidative stress., Methods: This study included 83 and 47 women separately diagnosed with UF and EMT, as well as 226 controls from the Tongji Reproductive and Environmental (TREE) cohort. Two spot urine samples from each woman were analyzed for two oxidative stress indicators and eight urinary phthalate metabolites. Unconditional logistic regression models or multivariate regression models were fitted to evaluate the associations among phthalate exposures, oxidative stress indicators, and the risks of UF and EMT. The potential mediating role of oxidative stress was estimated by the mediation analyses., Results: We observed that each ln-unit increase in urinary mono-benzyl phthalate (MBzP) concentrations was associated with increased UF risk [adjusted OR (aOR): 1.56, 95% CI: 1.20, 2.02], and that each ln-unit increase in urinary MBzP (aOR: 1.48, 95% CI: 1.09, 1.99), mono-isobutyl phthalate (MiBP) (aOR: 1.83, 95% CI: 1.19, 2.82), and mono-2-ethylhexyl phthalate (MEHP) (aOR: 1.66, 95% CI: 1.19, 2.31) concentrations were associated with increased EMT risk (all FDR-adjusted P < 0.05). Moreover, we observed that all tested urinary phthalate metabolites were positively associated with two oxidative stress indicators [4-hydroxy-2-nonenal-mercapturic acid (4-HNE-MA) and 8-hydroxy-2-deoxyguanosine (8-OHdG)], in which 8-OHdG was associated with increased risks of UF and EMT (all FDR-adjusted P < 0.05). The mediation analyses showed that 8-OHdG mediated the positive relationships of MBzP with UF risk, and of MiBP, MBzP, and MEHP with EMT risk, with the estimated intermediary proportion ranging from 32.7% to 48.1%., Conclusions: Oxidatively generated DNA damage may mediate the positive associations of certain phthalate exposures with the risks of UF and EMT. However, further investigation is warranted to confirm these findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Disinfection byproducts (DBPs) are a class of ubiquitous chemicals in drinking water and inevitably result in widespread human exposures. Potentially adverse health effects of DBP exposures, including reproductive and developmental outcomes, have been increasing public concerns. Several reviews have focused on the adverse pregnancy outcomes of DBPs. This review summarized current evidence on male reproduction health upon exposure to DBPs from toxicological and epidemiological literature. Based on existing experimental studies, there are sufficient evidence showing that haloacetic acids (HAAs) are male reproductive toxicants, including reduced epididymal weight, decreased semen parameters and sperm protein 22, and declined testosterone levels. However, epidemiological evidence remains insufficient to support a link of DBP exposures with adverse male reproductive outcomes, despite that blood and urinary DBP biomarkers are associated with decreased semen quality. Eight potential mechanisms, including germ/somatic cell dysfunction, oxidative stress, genotoxicity, inflammation, endocrine hormones, folate metabolism, epigenetic alterations, and gut microbiota, are likely involved in male reproductive toxicity of DBPs. We also identified knowledge gaps in toxicological and epidemiological studies to enhance future needs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Two new polyketides, pholiotones B and C ( 1 and 2 ), and four known compounds, trichodermatide D ( 3 ), vermistatin ( 4 ), dehydroaltenuene A ( 5 ) and terpestacin ( 6 ) were isolated from the crude extract of Pholiota sp. Their structures were identified by NMR and MS spectroscopic data. The absolute configurations of compounds 1 and 2 were elucidated by modified Mosher's method, electronic circular dichroism (ECD) calculations and 13 C NMR calculations as well as DP4+ probability analyses. All the compounds were evaluated for their antifungal and cytotoxicity.

Abstract There are many kinds of microorganisms that inhabit the environment of manned space stations. Wet wipes are a common tool used in space stations to clean and reduce microorganisms on surfaces. Here, we compared the performance of five types of wipes used by the Chinese Space Station (CSS) on orbit before 2021 in terms of microbial decontamination. In previous studies, we found that Bacillus sp. TJ-1-1 and Staphylococcus sp. HN-5 were the most abundant microorganisms in the assembly environment of the CSS. In this study, we used these two bacteria to build different microbial load models to represent the occurrence and non-occurrence of microbial outbreaks in the on-orbit CSS. The results show that the number of microorganisms that can be removed when wiping the surface with high microbial load by wet wipes was higher than that when wiping the surface with low microbial load. For on-orbit daily cleaning and keeping the microbial population within the regulation concentration range, it is suitable to use two pure water wipes per 100 cm 2 . When the number of microorganisms increases to a degree where astronauts can see the colonies with their naked eyes, the best way to eliminate the problem is to wipe them thoroughly and repeatedly with at least four quaternary ammonium-based wipes every 100 cm 2 .

Enhancing the catalytic activity of Ru metal in the hydrogen oxidation reaction (HOR) potential range, improving the insufficient activity of Ru caused by its oxophilicity, is of great significance for reducing the cost of anion exchange membrane fuel cells (AEMFCs). Here, we use Ru grown on Au@Pd as a model system to understand the underlying mechanism for activity improvement by combining direct in situ surface-enhanced Raman spectroscopy (SERS) evidence of the catalytic reaction intermediate (OH ad ) with in situ X-ray diffraction (XRD), electrochemical characterization, as well as DFT calculations. The results showed that the Au@Pd@Ru nanocatalyst utilizes the hydrogen storage capacity of the Pd interlayer to "temporarily" store the activated hydrogen enriched at the interface, which spontaneously overflows at the "hydrogen-deficient interface" to react with OH ad adsorbed on Ru. It is the essential reason for the enhanced catalytic activity of Ru at anodic potential. This work deepens our understanding of the HOR mechanism and provides new ideas for the rational design of advanced electrocatalysts.

Epidemiological studies have suggested that phthalate exposures are associated with increased risks of thyroid cancer and benign nodule, while the underlying mechanisms are largely unknown. Here, we explored the mediation effects of oxidative stress (OS) biomarkers in the associations between phthalate exposures and the risks of thyroid cancer and benign nodule. Urine samples collected from 143 thyroid cancer, 136 nodule patients, and 141 healthy controls were analyzed for 8 phthalate metabolites and 3 OS biomarkers [8-hydroxy-2-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), and 8-iso-prostaglandin F 2α (8-isoPGF 2α )]. Multivariable linear or logistic regression models were used to explore the associations of OS biomarkers with phthalate metabolite concentrations and the risks of thyroid cancer and nodule. The mediation role of OS biomarkers was also investigated. Urinary monoethyl phthalate (MEP), monomethyl phthalate (MMP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), mono (2-ethylhexyl) phthalate (MEHP), and mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) were positively associated with at least 2 OS biomarkers (all P-values<0.01), and part of these positive associations varied in different subgroups. All 3 OS biomarkers were positively associated with the risks of thyroid nodule and cancer (P-values<0.001). The mediation analysis showed that OS biomarkers significantly mediated the associations between urinary MEHOP concentration and nodule, as well as between urinary MMP, MEHP, and MEHHP concentrations and cancer and nodule, with the estimated proportions of mediation ranging from 15.8% to 85.6%. Our results suggest that OS is a potential mediating mechanism through which phthalate exposures induce thyroid carcinogenesis and nodular formation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Theasinensin A is an important quality chemical component in tea, but its taste characteristics and the related mechanism are still unclear. The bitterness quantification and simulated taste mechanism of theasinensin A were researched. The results showed that theasinensin A was significantly correlated with the bitterness of tea. The bitterness threshold of theasinensin A was identified as 65 μmol/L for the first time. The dose-over-threshold (DOT) value of theasinensin A was significantly higher than that of caffeine in black tea soup. The concentration-bitterness curve and time-intensity curve of theasinensin A were constructed. The bitterness contribution of theasinensin A in black tea was higher than in oolong and green tea. Theasinensin A had the highest affinity with bitterness receptor protein TAS2R16, which was compared to TAS2R13 and TAS2R14. Theasinensin A was mainly bound to a half-open cavity at the N-terminal of TAS2R13, TAS2R14, and TAS2R16. The different binding capacity, hydrogen bond, and hydrophobic accumulation effect of theasinensin A and bitterness receptor proteins might be the reason why theasinensin A presented different bitterness senses in human oral cavity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Cui, Feng, Wang, Zhao, Deng, Jiang, Yin and Engelhardt.)

The treatment of malignant tumors has entered the era of immunotherapy, and immune checkpoint inhibitors (ICIs) have brought significant benefits to patients. However, some patients are required to discontinue treatment with ICIs owing to factors such as disease progression and intolerable side effects. Faced with limited subsequent treatment options and complex medical needs, we searched PubMed, Embase, Cochrane library, and the NIH clinical trials database and found that ICI rechallenge could be a relevant clinical strategy. The factors that could affect the rechallenge efficacy include the patients' characteristics, therapeutic strategy selection, and the timing of treatment. Multiple factors are used to identify target population, of which clinical features and PD-L1 expression are more potential. Both single ICI rechallenge and combination therapy may have survival benefits. Patients who have tolerated initial immunotherapy well could undergo ICI rechallenge, while patients who have experienced grade 3 or higher immune-related adverse events should be carefully assessed prior to rechallenge. Interventions and the interval between two courses of ICI will clearly have an impact on the efficacy of subsequent treatment. Preliminary data evaluation supports further investigation on ICI rechallenge to identify the factors that could contribute to its efficacy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Bone loss can be noted in kidney transplantation recipients (KTRs) and can be related to fracture events. Denosumab, a potent monoclonal antibody to RANK ligand, increases lumbar bone mineral density. However, safety data for denosumab remain limited regarding transplant recipients. Hypocalcemia and increased genital tract infections have been mentioned as adverse effects in KTRs after being prescribed denosumab., Methods: We retrospectively analyzed the electronic medical records of KTRs during the recent 20 years who had been prescribed antiresorptive therapy and were >18 years old. Medical records and their clinical data were reviewed and analyzed. We compared the frequency of adverse effects between denosumab with other antiresorptive therapies., Results: A total of 70 KTRs were enrolled, with 46 patients being given denosumab and the first injection being noted on October 31, 2014. No significant differences were seen in mortality rate, opportunistic infection, pneumonia, or genitourinary tract infection. One diagnosis of osteonecrosis of the jaw was noted in the denosumab group (2.2%). A higher incidence of hypocalcemia (<8.4 mg/dL) was noted in the denosumab group (34.8%), and a higher but nonsignificant difference in the incidence of severe hypocalcemia was also noted in the group., Conclusions: Denosumab may be considered as safe as other antiresorptive therapies for KTRs. However, more hypocalcemia events have been noted, so medical personnel may need to be cautious when prescribing its use., (Copyright © 2023. Published by Elsevier Inc.)

Four new transition metal borates, [Co(1-MI) 2 ]·B 5 O 7 (OH) 3 (1, 1-MI = 1-methylimidazole), Co 2 (PZ) 8 (SO 4 ) 2 ·2H 3 BO 3 (2, PZ = pyrazole), K 7 {(BO 3 )Co[B 12 O 18 (OH) 6 ]}·H 2 O (3) and K 2 {[Ni(PY) 2 ] 2 ·[(C 4 H 2 O 6 ) 2 B]} 2 (4, PY = pyridine), have been successfully synthesized by a mild method. Their structures were determined by X-ray single crystal diffraction. These compounds were further characterized by FTIR, PXRD and UV-vis-NIR. It is worth noting that the catalytic properties of catalysts based on these four borates were explored, and that organically templated borate 1- and 2-based catalysts showed better ORR catalytic performance compared to 3- and 4-based catalysts. This may be caused by the supramolecular skeletons of 1 and 2 providing sufficient space and porosity.

Background: Parabens, as suspected endocrine disruptors, are widely used in personal care products and pharmaceuticals. However, variability, predictors, and risk assessments of human exposure to parabens are not well characterized., Objective: To evaluate within-day variability, predictors, and risk assessments of exposure to parabens among Chinese adult men., Methods: We measured four parabens including methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and butylparaben (BuP) in repeated urine samples from 850 Chinese adult men. We examined the variability by intraclass correlation coefficients (ICCs) and identified the predictors by multivariable linear mixed models. We assessed risks of paraben exposures based on the estimated daily intake (EDI)., Results: The four parabens were detected in >76% of urinary samples. We observed fair to good to high reproducibility (ICCs: 0.71 to 0.86) for urinary paraben concentrations within one day. Use of facial cleanser was associated with higher four urinary paraben concentrations. Increasing age, taking medicine, intravenous injection, and interior decoration in the workplace were related to higher urinary concentrations of specific parabens. Smoking and drinking were associated with lower urinary concentrations of specific parabens. The maximum EDIs for the four parabens ranged from 13.76 to 848.68 μg/kg bw/day, and 0.9% of participants had the hazard quotient values > 1 driven by PrP exposure., Conclusions: Urinary paraben concentrations were less variable within one day. Several lifestyle characteristics including use of facial cleanser and pharmaceuticals may contribute to paraben exposures., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Maternal exposure to regulated disinfection by-products (DBPs) during pregnancy has been linked with adverse birth outcomes. However, no human studies have focused on drinking water nitrosamines, a group of emerging unregulated nitrogenous DBPs that exhibits genotoxicity and developmental toxicity in experimental studies. This cohort study included 2457 mother-infant pairs from a single drinking water supply system in central China, and maternal trimester-specific and entire pregnancy exposure of drinking water nitrosamines were evaluated. Multivariable linear and Poisson regression models were used to estimate the associations between maternal exposure to nitrosamines in drinking water and birth outcomes [birth weight (BW), low birth weight (LBW), small for gestational age (SGA) and preterm delivery (PTD)]. Elevated maternal N-nitrosodimethylamine (NDMA) exposure in the second trimester and N-nitrosopiperidine (NPIP) exposure during the entire pregnancy were associated with decreased BW (e.g., β = -88.6 g; 95% CI: -151.0, -26.1 for the highest vs. lowest tertile of NDMA; p for trend = 0.01) and increased risks of PTD [e.g., risk ratio (RR) = 2.16; 95% CI: 1.23, 3.79 for the highest vs. lowest tertile of NDMA; p for trend = 0.002]. Elevated maternal exposure of N-nitrosodiethylamine (NDEA) in the second trimester was associated with increased risk of SGA (RR = 1.80; 95% CI: 1.09, 2.98 for the highest vs. lowest tertile; p for trend = 0.01). Our study detected associations of maternal exposure to drinking water nitrosamines during pregnancy with decreased BW and increased risks of SGA and PTD. These findings are novel but require replication in other study populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Chronic hypercortisolism leads to a phenotype resembling metabolic syndrome. We aimed to investigate the association between gut microbiota and metabolic abnormalities in endogenous hypercortisolism (Cushing's syndrome)., Methods: A total of 23 patients with Cushing's syndrome (18 female and 5 men, aged 47.24 ± 12.99 years) and 30 age-, sex-and BMI-matched healthy controls (18 female and 12 men, aged 45.03 ± 6.69 years) were consecutively recruited. Differences in gut microbiota and plasma short-chain fatty acid (SCFAs) concentrations between the Cushing's syndrome patients and controls were analyzed by 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS)., Results: Compared to the controls, the Simpson and Pielou indices of α diversity were dramatically decreased in Cushing's syndrome ( P < 0.05). The gut microbiota community structure differed significantly between Cushing's syndrome patients and controls. Compared to controls, the bacterial communities of the Cushing's syndrome patients were enriched in Proteobacteria and Escherichia-Shigella , and depleted in Firmicutes , including Agathobacter , Blautia , Anaerostipes , Eubacterium&#95;eligens&#95;group , and Lachnospira . Spearman analysis demonstrated that HbA1c, SBP, DBP, and cortisol levels were significantly positively correlated with Proteobacteria and Escherichia-Shigella , whereas negatively correlated with Agathobacter, Blautia, Anaerostipes, Eubacterium&#95;hallii&#95;group, and Lachnospira , etc. Cushing's syndrome patients also had a lower propionic acid concentration (0.151±0.054 vs. 0.205±0.032 µg/mL, P =0.039) than controls. Furthermore, the level of propionic acid was negatively correlated with systolic pressure and cortisol levels ( P <0.05)., Conclusion: Gut microbiota dysbiosis and decreased propionic acid levels were observed in patients with Cushing's, suggesting that the gut microbiota may be a potential therapeutic intervention target to improve hypercortisolism-related metabolic abnormalities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Hu, Deng, Wan, Wang and Jin.)

The incidence of hypocalcemia is high in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) undergoing denosumab treatment. Since 2018, we have carried out a "multidisciplinary integrated care program for osteoporosis among patients with CKD and ESRD" in our hospital. The aim of this study was to compare the incidence of denosumab-associated hypocalcemia among patients with advanced CKD and ESRD before and after the integrated care program. We retrospectively reviewed the records of patients on their first dose of denosumab treatment from January 2012 to December 2021. A total of 3208 patients were included in our study. Among the 3208 patients, there were 101 dialysis patients, 150 patients with advanced CKD (stage 4 and 5), and 2957 patients with an estimated glomerular filtration rate (eGFR) higher than or equal to 30. The incidence of post-treatment severe hypocalcemia (corrected calcium level less than 7.0 mg/dl) within 30 days was significantly higher in the dialysis and advanced CKD group than in patients with an eGFR higher than or equal to 30 (6.9% vs. 2.0% vs. 0.1%, respectively, p < 0.001). Based on the results of the multivariate regression model, poor renal function ( p < 0.05) and lower baseline corrected calcium level ( p < 0.05) were associated with severe hypocalcemia within 30 days following the first dose of denosumab treatment. The incidence of post-treatment severe hypocalcemia within 30 days in advanced CKD and dialysis patients was significantly lower after the integrated care program (6.8% vs. 0.8%, p < 0.05). Our study shows that multidisciplinary integrated care may reduce the incidence rate of denosumab-associated severe hypocalcemia among patients with advanced CKD and ESRD.

Phthalates, as endocrine disrupting chemicals that can alter the endogenous hormones, may be involved in the incidence of endometrial polyp, a benign hormone-dependent condition. We conducted a pilot case-control study from the Tongji Reproductive and Environmental (TREE) cohort to investigate the associations between phthalate exposures and the risk of endometrial polyp. A total of 40 endometrial polyp patients were matched to 80 controls by age and body mass index in the ratio of 1:2. Two spot urine samples from each subject were quantified for eight phthalate metabolites to enhance exposure assessment. The conditional logistic regression and quantile-based g-computation models were separately used to explore the associations between individual and mixture of urinary phthalate metabolites and the risk of endometrial polyp. After adjusting for covariates, individual chemical analyses showed that urinary monobenzyl phthalate (MBzP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethylhexyl) phthalate (MEHHP) and the sum of di(2-ethylhexyl) phthalate (ΣDEHP) were associated with increased risks of endometrial polyp, with adjusted odds ratios ranging from 2.62 (95% CI: 0.88, 7.84) for MECPP to 6.96 (95% CI: 1.87, 25.87) for ΣDEHP comparing the extreme exposure categories (all P for trends <0.05 or = 0.057). These associations still persisted when these exposures were modeled as continuous variables. Chemical mixture analyses showed that a simultaneous one-quartile increase in concentrations of eight phthalate metabolites was associated with an elevated odds ratio of 3.14 (95% CI: 1.49, 6.60) in endometrial polyp. Our data suggests that exposure to individual benzylbutyl phthalate (BBzP) and DEHP, as well as mixture of phthalates is associated with increased risk of endometrial polyp. This may inform public health recommendations and policies to avoid phthalate exposures for improving female reproductive health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The parabrachial nucleus (PBN) is an important structure regulating the sleep-wake behavior and general anesthesia. Astrocytes in the central nervous system modulate neuronal activity and consequential behavior. However, the specific role of the parabrachial nucleus astrocytes in regulating the sleep-wake behavior and general anesthesia remains unclear. Methods: We used chemogenetic approach to activate or inhibit the activity of PBN astrocytes by injecting AAV-GFAabc1d-hM3Dq-eGFP or AAV-GFAabc1d-hM4Di-eGFP into the PBN. We investigated the effects of intraperitoneal injection of CNO or vehicle on the amount of wakefulness, NREM sleep and REM sleep in sleep-wake behavior, and on the time of loss of righting reflex, time of recovery of righting reflex, sensitivity to isoflurane, electroencephalogram (EEG) power spectrum and burst suppression ratio (BSR) in isoflurane anesthesia. Results: The activation of PBN astrocytes increased wakefulness amount for 4 h, while the inhibition of PBN astrocytes decreased total amount of wakefulness during the 3-hour post-injection period. Chemogenetic activation of PBN astrocytes decreased isoflurane sensitivity and shortened the emergence time from isoflurane-induced general anesthesia. Cortical EEG recordings revealed that PBN astrocyte activation decreased the EEG delta power and BSR during isoflurane anesthesia. Chemogenetic Inhibition of PBN astrocytes increased the EEG delta power and BSR during isoflurane anesthesia. Conclusion: PBN astrocytes are a key neural substrate regulating wakefulness and emergence from isoflurane anesthesia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Yao, Chen, Su, Zheng, Yan, Deng, Shi, Liu, Gao, Lin, Zhu, Lin, Zhu, Cai, Zhang and Chen.)

Objective: To investigate the characteristics of gut microbiota in type 2 diabetes mellitus (T2DM) patients with hypertriglyceridemia (HTG). Methods: Eighty-one patients first diagnosed with T2DM were enrolled in the Third Xiangya Hospital of Central South University from January 2018 to December 2020, including 58 patients [46 males and 12 females, aged (43±13) years] with HTG [HTG group, triglyceride (TG)≥1.7 mmol/L]. There were 23 cases without HTG (NTG group), including 20 males and 3 females, aged (46±13) years. According to the severity of HTG, the patients of HTG group were divided into severe HTG group (STG group, TG ≥5.6 mmol/L) and mild HTG group (MTG group, 1.7 mmol/L≤TG<5.6 mmol/L). Thirty healthy controls were matched accordingly, including 21 males and 9 females, aged (45±6) years. Clinical laboratory indicators and feces of the subjects were collected and 16S rRNA sequencing was performed to compare the differences in intestinal flora among the groups. Results: The Shannon and Simpson indexes in HTG group were lower than those in NTG group and healthy control group (5.02±0.91 vs 5.45±0.55 and 5.60±0.63, P =0.003; 0.90±0.06 vs 0.93±0.04, 0.94±0.04, P =0.002). Compared with healthy control group and NTG group, the abundance of intestinal P&#95;Proteobacteria , g&#95;Escherichia&#95;Shigella , s&#95;Escherichia&#95;Coli and g&#95;Clostridium&#95;sensu&#95;stricto&#95;1 increased in HTG group, while the abundance of p&#95;Firmicutes , g&#95;Faecalibacterium and Faecalibacterium&#95;prausnitzii decreased. The abundance of g&#95;Clostridium&#95;sensu&#95;stricto&#95;1 in the STG group was higher than that of NTG and MTG groups, while the abundance of g&#95;Faecalibacterium decreased. Spearman correlation analysis suggested that g&#95;Clostridium&#95;sensu&#95;stricto&#95;1 was positively correlated with glycosylated hemoglobin ( r =0.22, P =0.044), fasting blood glucose ( r =0.36, P =0.001), TG ( r =0.27, P =0.015) and total cholesterol ( r =0.44, P <0.001). Logistic regression analysis indicated that g&#95;Faecalibacterium was a protective factor for T2DM with HTG( OR =0.90, 95% CI :0.83-0.97, P =0.006). Conclusions: The intestinal flora of T2DM patients with HTG was dysregulated, which was manifested as decreased diversity, increased abundance of P&#95;Proteobacteria and decreased abundance of p&#95;Firmicutes . g&#95;Faecalibacterium is a protective factor for T2DM with HTG.

Context: Urolithin A (UroA) can inhibit the growth of many human cancer cells, but it has not be reported if UroA inhibits nasopharyngeal carcinoma (NPC) cells., Objective: To explore the inhibitory effect of UroA on NPC and potential mechanism in vitro ., Materials and Methods: RNA-sequencing-based mechanistic prediction was conducted by comparing KEGG enrichment of 40 μM UroA-treated for 24 h with untreated CNE2 cells. The untreated cells were selected as control. After NPC cells were treated with 20-60 μM UroA, proliferation, migration and invasion of were measured by colony formation, wound healing and transwell experiments. Apoptosis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) were measured by flow cytometry, Hoechst 33342, Rhodamine 123, JC-1 staining and ROS assay methods, respectively. Gene and protein expression were measured by RT-qPCR and Western blotting assay., Results: RNA-sequencing and KEGG enrichment revealed UroA mainly altered the ECM receptor interaction pathway. UroA inhibited cells proliferation, epithelial-mesenchymal-transition pathway, migration and invasion with IC 50 values of 34.72 μM and 44.91 μM, induced apoptosis, MMP depolarization and increase ROS content at a concentration of 40 μM. UroA up-regulated E-cadherin, Bax/Bcl-2, c-caspase-3 and PARP proteins, while inhibiting COL4A1, MMP2, MMP9, N-cadherin, Vimentin and Snail proteins at 20-60 μM. Moreover, co-treatment of UroA (40 μM) and NAC (5 mM) could reverse the effect of UroA on apoptosis-related proteins., Discussion and Conclusions: RNA-sequencing technology based on bioinformatic analyses may be applicable for studiying the mechanism of drugs for tumour treatment.

Previous studies have reported that exposure to phthalates and polycyclic aromatic hydrocarbons (PAHs) is individually associated with altered semen quality, but no human studies have evaluated their joint effects of exposure mixtures, a more real-world scenario. We aimed to explore urinary metabolite mixtures of phthalates and PAHs in associations with semen quality. Repeated spot-urine samples gathered from 695 men attending a fertility clinic were analyzed for urinary metabolites of eight phthalates and ten monohydroxylated-PAHs (OH-PAHs). Principal component analysis (PCA)-multivariable linear regression (MLR) model, quantile g-computation (qg-comp), and Bayesian kernel machine regression (BKMR) were applied to estimate the associations of urinary mixtures of phthalate and OH-PAH metabolites with semen quality. The overall effects of urinary mixtures of phthalate and PAH metabolites on semen quality were not statistically significant. However, hydroxynaphthalene (OHNa) factor identified from PCA was monotonically associated with decreased total sperm count and sperm concentration, whereas di(2-ethylhexyl) phthalate (DEHP) factor was non-monotonically related to increased progressive sperm motility and total sperm motility. Qg-comp and BKMR models confirmed these findings and identified 2-OHNa and 2-OHFlu as the primary negative contributors, whereas MEOHP and MEHP as the primary positive contributors. Our findings suggest that exposure to mixtures of naphthalene and DEHP is associated with altered semen quality. The finding is warranted to confirm in further well-designed epidemiological studies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The small molecule chemical compound cinobufotalin (CB) is reported to be a potential antitumour drug that increases cisplatin (DDP) sensitivity in nasopharyngeal carcinoma. In this study, we first found that CB decreased DDP resistance, migration and invasion in lung adenocarcinoma (LUAD). Mechanistic studies showed that CB induced ENKUR expression by suppressing PI3K/AKT signalling to downregulate c-Jun, a negative transcription factor of ENKUR. Furthermore, ENKUR was shown to function as a tumour suppressor by binding to β-catenin to decrease c-Jun expression, thus suppressing MYH9 transcription. Interestingly, MYH9 is a binding protein of ENKUR. The Enkurin domain of ENKUR binds to MYH9, and the Myosin&#95;tail of MYH9 binds to ENKUR. Downregulation of MYH9 reduced the recruitment of the deubiquitinase USP7, leading to increased c-Myc ubiquitination and degradation, decreased c-Myc nuclear translocation, and inactivation of epithelial-mesenchymal transition (EMT) signalling, thus attenuating DDP resistance. Our data demonstrated that CB is a promising antitumour drug and may be a candidate chemotherapeutic drug for LUAD patients., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)