In Vitro and In Vivo Biotransformation Profiling of 6PPD-Quinone toward Their Detection in Human Urine.

The antioxidant N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its oxidized quinone product 6PPD-quinone (6PPD-Q) in rubber have attracted attention due to the ecological risk that they pose. Both 6PPD and 6PPD-Q have been detected in various environments that humans cohabit. However, to date, a clear understanding of the biotransformation of 6PPD-Q and a potential biomarker for exposure in humans are lacking. To address this issue, this study presents a comprehensive analysis of the extensive biotransformation of 6PPD-Q across species, encompassing both in vitro and in vivo models. We have tentatively identified 17 biotransformation metabolites in vitro, 15 in mice in vivo, and confirmed the presence of two metabolites in human urine samples. Interestingly, different biotransformation patterns were observed across species. Through semiquantitative analysis based on peak areas, we found that almost all 6PPD-Q underwent biotransformation within 24 h of exposure in mice, primarily via hydroxylation and subsequent glucuronidation. This suggests a rapid metabolic processing of 6PPD-Q in mammals, underscoring the importance of identifying effective biomarkers for exposure. Notably, monohydroxy 6PPD-Q and 6PPD-Q-O-glucuronide were consistently the most predominant metabolites across our studies, highlighting monohydroxy 6PPD-Q as a potential key biomarker for epidemiological research. These findings represent the first comprehensive data set on 6PPD-Q biotransformation in mammalian systems, offering insights into the metabolic pathways involved and possible exposure biomarkers.

Fetal Origin of Abnormal Glucose Tolerance in Adult Offspring Induced by Maternal Bisphenol A Analogs Exposure.

With the widespread use of bisphenol A (BPA) analogs, their health risks have attracted attention. The effects of maternal BPA analogs exposure on glucose homeostasis in adult offspring and the underlying fetal origins require further exploration. Herein, we exposed pregnant mice to two types of BPA analogs─BPB and BPAF; we evaluated glucose homeostasis in adult offspring and maternal-fetal glucose transport by testing intraperitoneal glucose tolerance, determining glucose and glycogen contents, conducting positron emission tomography (PET)/computed tomography (CT), detecting expression of placental nutrient transport factors, and assessing placental barrier status. We observed that adult female offspring maternally exposed to BPB and BPAF exhibited low fasting blood glucose in adulthood, with even abnormal glucose tolerance in the BPAF group. This phenomenon can be traced back to the elevated fetal glucose induced by the increased efficiency of placenta glucose transport in late pregnancy. On the other hand, the expression of genes associated with vascular development and glucose transport was significantly altered in the placenta in the BPAF group, potentially contributing to enhanced fetal glucose. These findings provide preliminary insights into potential mechanisms underlying the disturbance of glucose metabolism in adult female offspring mice induced by maternal exposure to BPA analogs.

Producing high value unsaturated fatty acid by whole-cell catalysis using microalga: A case study with Tribonema minus.

High value unsaturated fatty acids can be produced by de novo synthesis in microalgal cells, especially via heterotrophic cultivation. Unfortunately, the lipid accumulation of heterotrophic microalgae cannot be improved efficiently in conventional ways. Here we reported heterotrophic Tribonema minus, a promising resource for the production of palmitoleic acid which has increasing demands in health service for patients with metabolic syndrome, as whole-cell biocatalyst to develop a novel way of shifting low value exogenous saturated fatty acids to high value ones. Results showed that myristic acid is the best precursor for whole-cell catalysis; it elevated the lipid content of T. minus to 42.2%, the highest among the tried precursors. The influences of cultivation condition on the utilization of extrinsic myristic acid and lipid accumulation were also determined. Under the optimized condition, the lipid content reached as high as 48.9%. In addition, our findings showed that ~13.0% of C16:1 in T. minus is derived from extrinsic myristic acid, and 30.1% of metabolized precursor is converted into heterologous fatty acids. Thus, a feasible approach for both increasing the value of low value saturated fatty acid by bioconversion and enhancing the lipid accumulation in microalgae is proposed by supplementing extrinsic myristic acid.

Bisphenol A Analogs Induce Cellular Dysfunction in Human Trophoblast Cells in a Thyroid Hormone Receptor-Dependent Manner: In Silico and In Vitro Analyses.

Bisphenol A (BPA) and its analogs are frequently detected in human daily necessities and environmental media. Placental thyroid hormone plays an important role in fetal development. Herein, we followed the adverse outcome pathway (AOP) to explore the toxic mechanisms of BPA and its analogs toward placental thyroid hormone receptor (TR). First, the TOX21 database was used, and the interactions between BPA analogs and the ligand-binding domains (LBDs) of two subtypes of TR (TRα and TRß) were subjected to in silico screening using molecular docking (MD) and molecular dynamics simulation (MDS). Fluorescence spectra and circular dichroism (CD) showed that BPA and its analogs interfere with TRs as a molecular initiation event (MIE), including static fluorescence quenching and secondary structural content changes in TR-LBDs. Key events (KEs) of the AOP, including the toxicity induced in placental chorionic trophoblast cells (HTR-8/SVneo) by an inverted U-shaped dose effect and changes in ROS levels, were tested in vitro. BPA, BPB, and BPAF significantly changed the expression level of TRß, and only BPAF significantly downregulated the expression level of TRα. In conclusion, our study contributes to the health risk assessment of BPA and its analogs regarding placental adverse outcomes (AOs).

Gestational exposure to NO2 aggravates placental senescence.

Placental senescence is a normal physiological process of placenta, while premature placental senescence has been confirmed to be associated with some adverse pregnancy complications. Epidemiological studies indicate that NO2 exposure can aggravate placental senescence which is represented by fibrosis and abnormal telomere homeostasis, etc. In this study, pregnant C57BL/6 mice were exposed to NO2 (2.5 ppm, 5 h/day) daily in a dynamic exposure chamber throughout the gestation period, and were sacrificed at embryonic day 13.5 (E13.5), E15.5 and E18.5. Placenta were harvested and conducted for histopathological examination and telomere evaluation. Our results showed that gestational NO2 exposure significantly aggravated placental fibrosis and calcification, and up-regulated the related bio-markers (connective tissue growth factor (Ctgf) and transforming growth factor-ß1 (Tgf-ß1)) at E18.5. In addition, gestational exposure to NO2 also activated senescence related pathway (p53/p21) at E18.5. Furthermore, gestational NO2 exposure significantly shortened telomere length at E18.5, and the expression of telomere homeostasis regulation genes telomeric repeat binding factor 1 (Trf1), protection of telomeres 1a (Pot1a) and Pot1b were significantly increased while telomerase reverse transcriptase (Tert) was suppressed after NO2 exposure at E13.5 or E18.5, respectively. Importantly, DNA methylation status of the 22nd at E13.5 and 32nd at E18.5 site in sub-telomeric region of chromosome 1 was significantly altered. Based on the above results, our present study indicated that gestational NO2 exposure could lead to premature placental senescence during the late trimester of pregnancy via aggravation of fibrosis and telomere length shortening regulated by telomere regulatory enzyme and DNA methylation.

Maternal NO2 exposure disturbs the long noncoding RNA expression profile in the lungs of offspring in time-series patterns.

Gestation is a sensitive window to nitrogen dioxide (NO2) exposure, which may disturb fetal lung development and lung function later in life. Animal and epidemiological studies indicated that long noncoding RNAs (lncRNAs) participate in abnormal lung development induced by environmental pollutant exposure. In the present study, pregnant C57BL/6J mice were exposed to 2.5 ppm NO2 (mimicking indoor occupational exposure) or clean air, and lncRNAs expression profiles in the lungs of offspring mice were determined by lncRNA-seq on embryonic day 13.5 (E13.5), E18.5, postnatal day 1 (P1), and P14. The lung histopathology examination of offspring was performed, followed by weighted gene coexpression network analysis (WGCNA), prediction of lncRNAs-target genes, and the biological processes enrichment analysis of lncRNAs. Our results indicated that maternal NO2 exposure induced hypoalveolarization on P14 and differentially expressed lncRNAs showed a time-series pattern. Following WGCNA and enrichment analysis, 2 modules participated in development-related pathways. Importantly, the expressions of related genes were altered, some of which were confirmed to be related to abnormal vascular development and even lung diseases. The research points out that the maternal NO2 exposure leads to abnormal lung development in offspring that might be related to altered lncRNAs expression profiles with time-series-pattern.

CircRNAs as promising biomarker in diagnostic and prognostic of lung cancer: An updated meta-analysis.

BACKGROUND: As a class of endogenous non-coding RNAs with closed-loop structure, circular RNAs (circRNAs) are receiving more and more attention. CircRNAs have been reported to be widely expressed in various human cancers and are implicated in tumorigenesis and progression. The present study aimed to systematically evaluate the clinicopathological, diagnostic and prognostic values of circRNAs in lung cancer. METHODS: We searched literature from PubMed, Web of science, Cochrane Library, EMBASE and Ovid online databases up to May 29, 2020. Statistical analyses were undertaken based on Stata 11.0, Meta-DiSc 1.4, and RevMan 5.3 software. RESULTS: Finally, a total of 63 eligible articles were included in our meta-analysis, including 18 studies for diagnosis, 22 studies for prognosis and 57 studies for clinicopathological features. In terms of diagnostic values, circRNAs could discriminate between lung cancer patients and the normal individuals with a relatively high pooled area under the curve (AUC) of 0.83 (95%CI, 0.80-0.86). For the prognostic values, we found that elevated expression of oncogenic circRNAs could predict poor survival outcomes based on multivariate analysis (HR = 2.430, 95%CI = 2.003-2.948, P < 0.001 for OS; HR = 2.228, 95%CI = 1.289-3.853, P = 0.004 for DFS) while tumor-suppressor circRNAs was correlated with better OS in univariate analysis (HR = 0.627, 95%CI = 0.519-0.757, P < 0.001). The pooled results suggested that elevated expression of carcinogenic circRNAs was associated with tumor size (OR = 1.676, 95%CI = 1.209-2.323, P = 0.002), smoking statue (OR = 1.260, 95%CI = 1.062-1.494, P = 0.008), TNM stage (OR = 2.345, 95%CI = 1.617-3.399, P < 0.001), differentiation grade (OR = 1.843, 95%CI = 1.228-2.765, P = 0.003), and lymphatic metastasis (OR = 2.097, 95%CI = 1.482-2.967, P < 0.001). Moreover, the expression of tumor-suppressor circRNAs was related to the improved clinicopathological features (lymphatic metastasis: OR = 0.536, 95%CI = 0.311-0.926, P = 0.025). CONCLUSIONS: Our meta-analysis demonstrated that circRNAs could be used as feasible and important biomarkers for diagnosis, prognosis and clinicopathological features in lung cancer.

[Virtual screening and antiepileptic activity evaluation of COX-2 inhibitory components in Trachelospermi Caulisetfolium].

This study investigated the potential active components against cyclooxygenase-2(COX-2) from Trachelospermi Caulisetfolium and explored the pharmacodynamic material basis.A pharmacophore-based virtual screening method was adopted to establish a COX-2 ligands-based HipHop pharmacophore model on the basis of the information on compounds with COX-2 inhibitory activity reported in published research articles.The reported components in Trachelospermi Caulisetfolium were collected to establish the compound library and matched with the pharmacophores.Subsequently, the matched small molecule compounds underwent molecular docking with COX-2 targets(PDB ID: 3 LN1), and the interaction of potential active monomers and COX-2 was further explored by molecular dynamics.The antiepileptic effect of active monomer arctigenin(15) was determined based on the pentylenetetrazole(PTZ)-induced seizure model, and its modulatory effect on the COX-2 level was evaluated.A compound library containing 118 chemical constituents in Trachelospermi Caulisetfolium was established by literature retrieval.The preferred pharmacophore 04 was selected through test set verification for virtual screening of the compound library of Trachelospermi Caulisetfolium.After matching, six potential constituents with COX-2 inhibitory activity were obtained.The interaction of five compounds with COX-2 and COX-1 was analyzed by molecular docking, and 10 ns molecular dynamics was performed on two compounds.Compound 15 could prolong the latent time of PTZ-induced seizures at medium and high doses, improve the anxiety-and depression-like behaviors induced by PTZ, reduce the expression level of COX-2, and decrease the number of COX-2 immuno-posi-tive cells in the hippocampal CA1 region.The results showed that it was reasonable to investigate the components in Trachelospermi Caulisetfolium with COX-2 inhibitory activity based on virtual screening and activity evaluation.

Research progress in biological activities of succinimide derivatives.

Succinimides are well recognized heterocyclic compounds in drug discovery which produce diverse therapeutically related applications in pharmacological practices. Researches in medicinal chemistry field have isolated and synthesized succinimide derivatives with multiple medicinal properties including anticonvulsant, anti-inflammatory, antitumor and antimicrobial agents, 5-HT receptor ligands and enzyme inhibitors. Simultaneously, SAR (Structure-Activity Relationship) analysis has been gradually possessed, along with a great deal of derivatives have been derived for potential targets. In this article, we comprehensively summarize the biological activities and SAR for succinimide derivatives, along with the featuring bioactive molecules reported in patents, wishing to provide an overall retrospect and prospect on the succinimide analogues.

Maternal PM2.5 exposure and abnormal placental nutrient transport.

Epidemiological studies of human and animal experiments indicated that gestational exposure to atmospheric pollutants could be followed by the abnormal placental development. However, the effects of this exposure on the placental transportation for nutrients have not been systematically investigated. In this study, fine particulate matters (PM2.5) samples were collected in Taiyuan and pregnant rodent models were administered with 3 mg/kg b.w. PM2.5 by oropharyngeal aspiration every other day starting on embryonic day 0.5 (E0.5). Then the pregnant mice were sacrificed and their placentas were collected at different time points. The results showed that maternal PM2.5 exposure (MPE) disrupted the expression of proliferating cell nuclear antigen (PCNA) at all time points and inhibited the cell proliferation in placenta. Following that, the capacity for placental nutrient transport was impaired. The changes at E18.5 were observed most significantly, showing the altered mRNA expression of amino acid, long-chain polyunsaturated fatty acid (LCPUFA), glucose and folate transporters. In addition, the glycogen content was elevated at E18.5, and the triglyceride content was increased at E13.5 and E15.5 and decreased at E18.5 in the placenta after MPE. In a word, the adverse effect induced by MPE revealed that MPE led tothe disruption on the nutrient supply to the developing fetus via modulating the abundance of placental nutrient transporters (PNT).