Predictive potential of preoperative Naples prognostic score-based nomogram model for the prognosis in surgical resected thoracic esophageal squamous cell carcinoma patients: A retrospective cohort study.

The present study aimed to establish an effective prognostic nomogram model based on the Naples prognostic score (NPS) for resectable thoracic esophageal squamous cell carcinoma (ESCC). A total of 277 patients with ESCC, who underwent standard curative esophagectomy and designated as study cohort, were retrospectively analyzed. The patients were divided into different groups, including NPS 0, NPS 1, NPS 2, and NPS 3 or 4 groups, for further analysis, and the results were validated in an external cohort of 122 ESCC patients, who underwent surgery at another cancer center. In our multivariate analysis of the study cohort showed that the tumor-node-metastasis (TNM) stage, systemic inflammation score, and NPS were the independent prognostic factors for the overall survival (OS) and progression-free survival (PFS) durations. In addition, the differential grade was also an independent prognostic factor for the OS in the patients with ESCC after surgery (all P < .05). The area under the curve of receiver operator characteristics for the PFS and OS prediction with systemic inflammation score and NPS were 0.735 (95% confidence interval [CI] 0.676-0.795, P < .001) and 0.835 (95% CI 0.786-0.884, P < .001), and 0.734 (95% CI 0.675-0.793, P < .001) and 0.851 (95% CI 0.805-0.896, P < .001), respectively. The above independent predictors for OS or PFS were all selected in the nomogram model. The concordance indices (C-indices) of the nomogram models for predicting OS and PFS were 0.718 (95% CI 0.681-0.755) and 0.669 (95% CI 0.633-0.705), respectively, which were higher than that of the 7th edition of American Joint Committee on Cancer TNM staging system [C-index 0.598 (95% CI 0.558-0.638) for OS and 0.586 (95% CI 0.546-0.626) for PFS]. The calibration curves for predicting the 5-year OS or PFS showed a good agreement between the prediction by nomogram and actual observation. In the external validation cohort, the nomogram discrimination for OS was better than that of the 7th edition of TNM staging systems [C-index: 0.697 (95% CI 0.639-0.755) vs 0.644 (95% CI 0.589-0.699)]. The calibration curves showed good consistency in predicting the 5-year survival between the actual observation and nomogram predictions. The decision curve also showed a higher potential of the clinical application of predicting the 5-years OS of the proposed nomogram model as compared to that of the 7th edition of TNM staging systems. The preoperative NPS-based nomogram model had a certain potential role for predicting the prognosis of ESCC patients.

Therapeutic detoxification of quercetin for aflatoxin B1-related toxicity: Roles of oxidative stress, inflammation, and metabolic enzymes.

Aflatoxins (AFTs), a type of mycotoxin mainly produced by Aspergillus parasiticus and Aspergillus flavus, could be detected in food, feed, Chinese herbal medicine, grain crops and poses a great threat to public health security. Among them, aflatoxin B1 (AFB1) is the most toxic one. Exposure to AFB1 poses various health risks to both humans and animals, including the development of chronic inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, and cancer. The molecular mechanisms underlying these risks are intricate and dependent on specific contexts. This review primarily focuses on summarizing the protective effects of quercetin, a natural phenolic compound, in mitigating the toxic effects induced by AFB1 in both in vitro experiments and animal models. Additionally, the review explores the molecular mechanisms that underlie these protective effects. Quercetin has been demonstrated to not only have the direct inhibitory action on the production of AFTs from Aspergillus, both also possess potent ameliorative effects against AFB1-induced cytotoxicity, hepatotoxicity, and neurotoxicity. These effects are attributed to the inhibition of oxidative stress, mitochondrial dysfunction, mitochondrial apoptotic pathway, and inflammatory response. It could also directly target several metabolic enzymes (i.e., CYP3As and GSTA1) to reduce the production of toxic metabolites of AFB1 within cells, then reduce AFB1-induced cytotoxicity. In conclusion, this review highlights quercetin is a promising detoxification agent for AFB1. By advancing our understanding of the protective mechanisms offered by quercetin, we aim to contribute to the development of effective detoxification agents against AFB1, ultimately promoting better health outcomes.

Tris(1,3-dichloro-2-propyl) phosphate induces endoplasmic reticulum stress and mitochondrial-dependent apoptosis in mouse spermatocyte GC-2 cells.

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a frequently detected organophosphorus flame retardants (OPFRs) in various environmental media, and has been evidenced as reproductive toxicity. However, its adverse effects on spermatogenic cells are unknown. In this study, mouse spermatocyte GC-2spd (GC-2) cells were selected as an in vitro model, and the impact of mitochondrial structure and function, endoplasmic reticulum (ER) stress, cell apoptosis and the related molecular mechanisms were investigated. Our study indicated that cell viability was decreased significantly in a dose-dependent manner after TDCIPP treatment with the half lethal concentration (LC50) at 82.8 µM, 50.0 µM and 39.6 µM for 24 h, 48 h and 72 h, respectively. An apoptosis was observed by Annexin V-FITC/PI stain. In addition, fragmentation of mitochondrial structure, an increase of mitochondrial membrane potential (MMP), reduction of cellular adenosine triphosphate (ATP) content, release of cytochrome c and activation of Caspase-3 and Caspase-9 activity implicated that Caspase-3 dependent mitochondrial pathway might play a key role in the process of GC-2 cell apoptosis. Furthermore, ER stress induction was convinced by altered morphology of ER and up-regulation of ER targeting genes, including (Bip, eIF2α, ATF4, XBP1, CHOP, ATF6 and Caspase-12). Taken together, these results demonstrate that both mitochondrial apoptotic pathways and ER stress apoptotic pathways might play important roles in the process of apoptosis in GC-2 cells induced by TDCIPP treatment. Therefore, the potential reproductive toxicity of TDCIPP should not be ignored.

Glucose-Regulated Protein 78 Targeting ICG and DOX Loaded Hollow Fe3O4 Nanoparticles for Hepatocellular Carcinoma Diagnosis and Therapy.

Purpose: Liver cancer is considered as the third leading cause of cancer-related deaths, with hepatocellular carcinoma (HCC) accounting for approximately 90% of liver cancers. Improving the treatment of HCC is a serious challenge today. The primary objective of this study was to construct SP94-Fe3O4@ICG&DOX nanoparticles and investigate their potential diagnosis and treatment effect benefits on HCC. Methods: Firstly, we synthesized and characterized SP94-Fe3O4@ICG&DOX nanoparticles and confirmed their in vitro release behavior, photothermal and photodynamic performance. Moreover, the in vivo imaging capability was also observed. Finally, the inhibitory effects on Hepa1-6 in vitro and in vivo were observed as well as biosafety. Results: SP94-Fe3O4@ICG&DOX nanoparticles have a size of ~22.1 nm, with an encapsulation efficiency of 45.2% for ICG and 42.7% for DOX, showing excellent in vivo MPI and fluorescence imaging capabilities for precise tumor localization, and synergistic photo-chemotherapy (pH- and thermal-sensitive drug release) against tumors under irradiation. With the assistance of a fluorescence molecular imaging system or MPI scanner, the location and contours of the tumor were clearly visible. Under a constant laser irradiation (808 nm, 0.6 W/cm2) and a set concentration (50 µg/mL), the temperature of the solution could rapidly increase to ~45 °C, which could effectively kill the tumor cells. It could be effectively uptaken by HCC cells and significantly inhibit their proliferation under the laser irradiation (100% inhibition rate for HCC tumors). And most importantly, our nanoparticles exhibited favorable biocompatibility with normal tissues and cells. Conclusion: This versatile agent can serve as an intelligent and promising nanoplatform that integrates multiple accurate diagnoses, precise positioning of cancer tissue, and effective coordination with synergistic tumor photodynamic therapy.

A SILAC-based accurate quantification of shrimp allergen tropomyosin in complex food matrices using UPLC-MS/MS.

The carryover of trace allergens in complex food matrices poses challenges for detection techniques. Here, we demonstrate an accurate UPLC-MS/MS quantification assay for the shrimp allergen tropomyosin with a full-length isotope-labelled recombinant tropomyosin (TM-I) internal standard in complex food matrices. The TM-I, expressed based on the SILAC technique, exhibited a high isotope labelling ratio (>99%), purity, and alignment with the natural sequence. This method determined the tropomyosin ranging from 0.2 to 100 ng/mL. Mean recoveries ranged from 89 to 116%, with intra- and inter-day RSDs below 12%, for three signature peptides across three types of commercially processed food matrices. The limits of quantitation were 1 µg/g in pop food and sauce, and 10 µg/g in surimi product, respectively. This study supports the use of recombinant full-length isotope-labelled proteins rather than stable-isotope labelling peptides as internal standards to achieve more accurate quantitation of food allergens as the digestion error is corrected.

Characterizing the cumulative health risks of 19 kinds of pesticides in Chinese food from the cancer and non-cancer perspective.

Food safety is an important issue of most concern for health, while pesticides are one of the main threats to food safety. In view of the potential health hazard of pesticides in food, the cancer and non-cancer risks were assessed for 19 kinds of pesticides in Chinese food in this study. Furthermore, the health risks of different types of pesticides were compared to uncover the most polluted pesticide types in this study. Results show that methyl parathion, dichlorvos and 2,4-D residues in some food groups exceed the Chinese food standards. The cumulative disease burden of six carcinogenic pesticides for people older than 40 years ranges from 1.03 × 10-6 to 2.27 × 10-6, which exceeds the WHO recommended limit of 10-6. The non-cancer risks of 13 kinds of pesticides are all lower than 1 and will not pose appreciable health risk to the consumers. Livestock and poultry (contribution rate = 38.93%) and Milk and dairy products (contribution rate = 22.38%) are the dominate risk exposure sources for carcinogenic pesticides while staple foods (contribution rate = 31.62%) and vegetables (contribution rate = 21.5%) are the main risk exposure sources for non-carcinogenic pesticides. Comparing the risks of different pesticide types, insecticide is the most harmful category in this study, followed by herbicide and acaricide. This study characterized the health risks of pesticides in Chinese food and provided a scientific basis for pesticide management.

Association between household and outdoor air pollution and risk for metabolic syndrome among women in Beijing, China.

This study explored whether household and outdoor air pollution is associated with a greater risk for metabolic syndrome (MetS) among women. In all 11,860 women who cooked with clean energy were included in the analysis. Cooking frequency, range hood use during cooking, passive smoking exposure, and solid fuel use for heating were used to represent household air pollution. The 2-year average concentration of PM2.5, and face mask usage were used to reflect outdoor air pollution exposure. An index of air pollution exposure was also constructed. Multivariable logistic regression models were used to estimate the association between air pollution and risk for MetS, and a positive correlation was found. Our results indicated that household cooking used clean energy and exposure to a high level of outdoor PM2.5 without face mask usage may contribute to an increased risk for MetS among women.

Parkin-mediated mitophagy protects against aluminum trichloride-induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway.

Aluminum is a neurotoxic food contaminant. Aluminum trichloride (AlCl3) causes hippocampal mitochondrial damage, leading to hippocampal injury. Damaged mitochondria can release mitochondrial reactive oxygen species (mtROS) and activate nucleotide-binding oligomerization domain-like receptor-containing 3 (NLRP3) inflammasomes and apoptosis. E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy can attenuate mitochondrial damage. However, the role of mitophagy in AlCl3-induced mice hippocampal damage and its regulatory mechanism remain elusive. First, C57BL/6 N mice were treated with 0, 44.825, 89.65, and 179.3 mg/kg body weight AlCl3 drinking water for 90 d. Apoptosis, NLRP3-inflammasome activation and mitochondrial damage were increased in AlCl3-induced hippocampal damage. In addition, Parkin-mediated mitophagy peaked in the middle-dose group and was slightly attenuated in the high-dose group. Subsequently, we used wild-type and Parkin knockout (Parkin-/-) mice to investigate the AlCl3-induced hippocampal damage. The results showed that Parkin-/- inhibited mitophagy, and aggravated AlCl3-induced mitochondrial damage, NLRP3-inflammasome activation, apoptosis and hippocampal damage. Finally, we administered MitoQ (mtROS inhibitor) and MCC950 (NLRP3 inhibitor) to AlCl3-treated Parkin-/- mice to investigate the mechanism of Parkin-mediated mitophagy. The results showed that inhibition of mtROS and NLRP3 attenuated hippocampal NLRP3-inflammasome activation, apoptosis, and damage in AlCl3-treated Parkin-/- mice. These findings indicate that Parkin-mediated mitophagy protects against AlCl3-induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway.

Evaluation of the cytotoxic activity of triphenyl phosphate on mouse spermatocytes cells.

Triphenyl phosphate (TPhP) is one of the most commonly found organophosphorus flame retardants (OPFRs) in the environment and the general population. Continuous daily exposure to TPhP may adversely impact male reproductive health. However, few researches were conducted to investigate the direct effects of TPhP on the progress of sperm growth and development. In this study, mouse spermatocyte GC-2spd (GC-2) cells were selected as an in vitro model, the impact of oxidative stress, mitochondrial impairment, DNA damage, cell apoptosis and the related molecular mechanisms were investigated using high content screening (HCS) system. Our study indicated that cell viability was decreased significantly in a dose-dependent manner after TPhP treatment with the half lethal concentration (LC50) at 105.8, 61.61 and 53.23 µM for 24, 48 and 72 h. A concentration-related apoptosis occurrence was observed in GC-2 cells after TPhP exposure for 48 h. In addition, the elevated intracellular reactive oxygen species (ROS) and the total antioxidant capacity (T-AOC) also observed after exposing to 6, 30 and 60 µM of TPhP. Furthermore, based on the enhancement of pH2AX protein and alteration of nuclear morphology or DNA content, DNA damage might be induced by higher concentration of TPhP treatment. Simultaneously, alteration of mitochondrial structure, enhancement of mitochondrial membrane potential (MMP), reduction of cellular adenosine triphosphate (ATP) content, altered expression of Bcl-2 family proteins, release of cytochrome c and increase of caspase-3 and caspase-9 activity demonstrated that caspase-3 dependent mitochondrial pathway might play a key role in the process of GC-2 cell apoptosis. Taken together, these results showed that TPhP was a mitochondrial toxicant and apoptotic inducer, which might trigger alike responses in human spermatogenic cells. Therefore, the potential reproductive toxicity of TPhP should not be ignored.

High expression of RNF31 is associated with tumor immune cell infiltration and leads to poor prognosis in liver hepatocellular carcinoma.

Ring finger protein 31 (RNF31) has been found to play an important role in tumor immunity. However, the role of RNF31 in liver hepatocellular carcinoma (LIHC) has not been reported. Therefore, we investigated the expression and prognostic value of RNF31 in patients with LIHC and explored its relationship with immune cell infiltration. The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset was downloaded to analyse the impact of RNF31 on the prognosis and immune cell infiltration of LIHC. The Tumor Immune Estimation Resource (TIMER) database was used to analyse the correlation between RNF31 and tumor immune cell infiltration in LIHC. Additionally, we analysed the relationship between RNF31 and tumor necrosis factor (TNF) as well as the interferon-gamma (IFN-γ) signaling pathway. The expression of RNF31 in LIHC was significantly higher than that in normal tissues. Increased RNF31 expression was associated with decreased overall survival (OS) and relapse-free survival (RFS). An increase in RNF31 expression was closely related to the infiltration levels of immune cells (e.g., natural killer (NK) cells, CD8 + T cells, and B cells). RNF31 was also positively correlated with the expression of immune checkpoint genes in LIHC. Moreover, RNF31 may participate in TNF and IFN-γ signaling pathways. In conclusion, RNF31 is a potentially valuable prognostic biomarker in LIHC. RNF31 is also associated with immune cell infiltration in LIHC. RNF31 may be a potential target for immunotherapy of LIHC.

[Determination of 26 bisphenols in dust by ultra performance liquid chromatography-tandem mass spectrometry].

Bisphenol A (BPA) is one of the most widely produced compounds in the world and was listed as a substance of very high concern by the European Chemicals Agency in 2016. Because of its toxicity, many countries and regions, including China, have banned BPA addition in feeding-bottles. And the European Union (EU) has banned BPA use in other food contact materials and thermal paper. Restrictions on BPA have contributed to the widespread use of alternatives. As the toxicity of BPA alternatives continues to be revealed, the alternatives of BPA alternatives are being developing. As the most extensive alternative for BPA, bisphenol S (BPS) was proven to have estrogen-disrupting effects and developmental toxicity of the neuroendocrine system. Therefore, BPS alternatives are used in thermal paper. In this study, alternatives to both BPA and BPS are collectively referred to as bisphenols (BPs). As a pooling matrix of many indoor chemicals, dust is an important pathway for human exposure to BPs. BPA and its alternatives are routinely detected in dust. As BPS alternatives have been detected in recycled paper and sludge, it is also very important to detected in dust. However, common analytical methods for BPs have low sensitivity and contain few BPS alternatives. Therefore, a high-throughput, high-accuracy, and high-sensitivity method must be established for the determination of BPs in dust; this will lay the foundation for subsequent studies on the environmental behavior and exposure risk of BPs. In this study, an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of 26 variations of BPs in dust. UPLC-MS/MS parameters of the variations were optimized to compare the separation effect and response intensity in different columns and mobile phases. The influence of the extraction solvent and solid phase extraction (SPE) on the extraction efficiency and purification effect of target compounds were optimized by using the isotopic internal standard method, and the 26 variations of BPs in dust was quantitatively analyzed. Finally, the dust samples were extracted by using 3 mL of acetonitrile and 3 mL of a 50% methanol aqueous solution in an ultrasound bath. The combined extract was further purified by using an Oasis HLB cartridge (60 mg/3 mL). The cartridge was then washed with a 40% methanol aqueous solution (0.5 mL) and eluted with methanol (2 mL). The target compounds were separated on a CORTECS® UPLC® C18 column (100 mm×2.1 mm, 1.6 µm), with methanol and 1 mmol/L ammonium fluoride solution as mobile phases and a flow rate of 0.3 mL/min. Electrospray ionization (ESI) was applied in the positive, negative, and multiple reaction monitoring (MRM) modes for the mass scan. Under optimized conditions, the linear ranges of the 26 targets behaved well linearly in their respective ranges with correlation coefficients (r2)>0.999. The limits of detection (LODs) and limits of quantification (LOQs) were assessed using signal-to-noise (S/N) ratios of 3 and 10, respectively. The LODs and LOQs of the method were 0.01-0.75 µg/kg and 0.02-2.50 µg/kg, respectively. The accuracy of the method was evaluated by conducting a recovery test at three spiked levels: LOQ, two times the LOQ, and 10 times the LOQ, with the average recoveries ranging from 83.7% to 114.9%. The precision of the method was evaluated by using the relative standard deviation (RSD). The intra-day RSDs and inter-day RSDs were 0.86%-9.79% (n=6) and 5.16%-19.5% (n=6), respectively. The established method was used to determine 11 dust samples. Fifteen BPs were detected at a detection rate of 9.1%-100.0%. The detection rate for BPA, BPS, bisphenol F (BPF), 4-hydroxy-4'-isopropoxydiphenylsulfone (BPSIP), and diphenyl sulfone (DPS) was 100.0%. BPSIP, 4-allyloxy-4'-hydroxydiphenyl sulfone (BPS-MAE), and bis-(3-allyl-4-hydroxyphenyl) sulfone (TGSA) were first detected in Chinese dust, whereas 4-benzyloxy-4'-hydroxydiphenyl sulfone (BPS-MPE), 4-hydroxybenzoic acid benzyl (PHBB), and DPS were first detected in dust samples worldwide. This method is simple, rapid, and sensitive, and is suitable for the qualitative screening and quantitative analysis of the 26 BPs in dust samples.

Fibronectin-targeting and metalloproteinase-activatable smart imaging probe for fluorescence imaging and image-guided surgery of breast cancer.

Residual lesions in the tumor bed have been a challenge for conventional white-light breast-conserving surgery. Meanwhile, lung micro-metastasis also requires improved detection methods. Intraoperative accurate identification and elimination of microscopic cancer can improve surgery prognosis. In this study, a smart fibronectin-targeting and metalloproteinase-activatable imaging probe CREKA-GK8-QC is developed. CREKA-GK8-QC possesses an average diameter of 21.7 ± 2.5 nm, excellent MMP-9 protein responsiveness and no obvious cytotoxicity. In vivo experiments demonstrate that NIR-I fluorescence imaging of CREKA-GK8-QC precisely detects orthotopic breast cancer and micro-metastatic lesions (nearly 1 mm) of lungs with excellent imaging contrast ratio and spatial resolution. More notably, fluorescence image-guided surgery facilitates complete resection and avoids residual lesions in the tumor bed, improving survival outcomes. We envision that our newly developed imaging probe shows superior capacity for specific and sensitive targeted imaging, as well as providing guidance for accurate surgical resection of breast cancer.

Praziquantel promotes protection against Schistosoma japonicum infection in mice.

Praziquantel (PZQ) is the first line drug for the treatment of schistosomiasis. Several studies have confirmed that PZQ regulates host immunity, and we have recently found that pretreatment with PZQ enhances resistance against Schistosoma japonicum infection in buffaloes. We speculate that PZQ induces physiological changes in mice that prevent S. japonicum infection. To test this hypothesis and provide a practical measure to prevent S. japonicum infection, we determined the effective dose (the minimum dose), protection period and onset time of protection by comparing the worm burden, female worm burden and egg burden in PZQ-pretreated mice and blank control mice. Morphological differences between parasites were observed by measuring the total worm length, oral sucker, ventral sucker and ovary. The levels of cytokines, nitrogen monoxide (NO), 5-hydroxytryptamine (5-HT) and specific antibodies were measured using kits or soluble worm antigens. Hematological indicators on day 0 were analyzed in mice that received PZQ on days -15, -18, -19, -20, -21 and -22. The PZQ concentrations in plasma and blood cells were monitored using high performance liquid chromatography (HPLC). The effective dose was found to be two oral administrations (interval of 24 h) at 300 mg/kg body weight (BW) or one injection at 200 mg/kg BW, and the protection period of PZQ injection was 18 days. The optimal preventive effect was observed at two days post-administration, with a >92% worm reduction rate and significant worm reduction until 21 days after administration. Adult worms from PZQ-pretreated mice were runtish showing a shorter length, smaller organs and fewer eggs in the uteri of females. Detection of cytokines, NO, 5-HT and hematological indicators showed that PZQ induced immune-physiological changes, including higher levels of NO, IFN-γ and IL-2, and a lower level of TGF-ß. No significant difference in the anti-S. japonicum specific antibody levels was observed. The PZQ concentrations in plasma and blood cells 8 and 15 days post-administration were lower than the detection limit. Our results confirmed that pretreatment with PZQ promotes the protection of mice against S. japonicum infection within 18 days. Although we observed some immune-physiological changes in the PZQ-pretreated mice, the exact mechanisms involved in the preventive effect require further study.

Easily operated COF-based monolithic sponges as matrix clean-up materials for non-targeted analysis of chemical hazards in oil-rich foods.

Non-targeted analysis of chemical hazards in foods plays a crucial role in controlling food safety. However, because it brings forward high demand for sample pretreatment, materials suitable for the pretreatment of foods, especially animal foods, are rare. Herein, covalent organic frameworks (COF)-based monolithic materials were constructed by three successive steps: preparation of polydimethylsiloxane (PDMS) sponge using sugar cube as a sacrificial template, loading of a heteroporous COF on PDMS sponge via ultrasonic or in-situ growth method, coating of the obtained PDMS@COF by polydopamine (PDA) network. As-prepared PDMS@COF@PDA sponges were demonstrated to work well in sample pretreatment of animal foods for non-targeted analysis of chemical hazards. After a simple vortex treatment for about 2 min, more than 98% triglycerides, the main interfering matrix components in animal foods, could be removed from lard and pork samples, accompanied by "full recovery" (recovery efficiencies: ≥63%) of 44 chemical hazards with different physicochemical properties. Besides providing promising sample pretreatment materials for non-targeted food safety analysis, this work also paves a feasible way to improve COF-based monolithic materials and thus promote their practical applications, because we found that the introduction of PDA network on COF-based monolithic material surface could play a role in "killing three birds with one stone": enhancing the stability of the materials by overcoming the detachment of COF during operations; controllably adjusting hydrophobic and hydrogen-bonding interactions on the material surface to promote the removal of triglycerides; weakening the hydrophobic and π-π interactions between COF and chemical hazards to increase the recoveries of chemical hazards.

Organochlorine pesticides and polycyclic aromatic hydrocarbons in serum of Beijing population: Exposure and health risk assessment.

Organochlorine pesticides (OCPs) and polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants, but large-scale human biomonitoring and health risk assessment data on these contaminants remain limited. In this study, concentrations of 6 OCPs and 5 PAHs were determined by GC-MS/MS in 1268 human serum samples which were collected from the participants in 2017 Beijing Chronic Disease and Risk Factor Surveillance. The detection frequencies of OCPs and PAHs ranged from 64.7 % to 96.5 % and 89.4 % to 99.6 %, respectively. The most abundant contaminants in OCPs and PAHs were pentachlorophenol (PCP) and pyrene (Pyr) with median concentrations reaching up to 3.13 and 8.48 µg/L, respectively. Nonparametric tests were employed to assess the correlations among contaminants levels, demographic characteristics (age, gender, body mass index, residence) and serum biochemical indexes. Significantly higher serum levels of all PAHs were observed in suburb residents than that in urban residents (P < 0.001). Binary logistic regression analysis demonstrated that exposure to benzo(a)pyrene (OR 2.17 [1.29, 3.63]), phenanthrene (OR 1.06 [1.02, 1.11]), fluoranthene (OR 1.04 [1.02, 1.07]) and Pyr (OR 1.02 [1.01, 1.03]) might increase the occurrence of hyperglycemia, and exposure to hexachlorobenzene (HCB) (OR 1.53 [1.05, 2.22]) and pentachlorobenzene (OR 1.14 [1.02, 1.27]) were positively associated with hyperlipidemia. Furthermore, the hazard quotients (HQs) for serum HCB, PCP and p,p'-dichlorodiphenyldichloroethylene were calculated based on health-based guidance values to predict health risks. 0.2 % and 4.3 % of serum samples showed HQ values exceeding 1 for HCB and PCP, respectively, in case of the non-carcinogenic risk, while 23.1 % of HQs for HCB were above 1 in case of the carcinogenic risk for a risk level 10-5. Our study reveals that the body burden of the Beijing general population relative to OCPs and PAHs was nonnegligible. The past exposure of HCB and PCP might adversely affect the health status of the Beijing population.

Metabolic profiling of the fluorinated liquid-crystal monomer 1-ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl)benzene.

1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl)benzene (EDPrB) is a typical fluorinated liquid-crystal monomer (LCM). LCMs contaminants are becoming increasingly concerning due to their potential persistence, bioaccumulation, toxicity, and broad prevalence in environmental and human samples. However, LCM metabolism is poorly understood. Herein, by introducing selected EDPrB into the appropriate liver microsomes in vitro, we examined the metabolic pathways of LCM in humans, rats, pigs, Cyprinus carpio, crucian carp, and Channa argus. A total of 20 species-dependent metabolites were identified and structurally elucidated by gas and liquid chromatography-high resolution mass spectrometry for the first time. Dealkylation, H-abstraction, and hydroxylation reactions are the primary metabolic pathways. Half of these in vitro metabolites were found in the urine, serum, and fecal samples of Sprague-Dawley rats exposed to EDPrB. Toxicity predictions indicate that 17 metabolites can be classified as toxic. According to the Ecological Structure Activity Relationships (ECOSAR), a number of metabolites exhibit equivalent or greater aquatic toxicity to that of EDPrB. Toxicity Estimation Software Tool (T.E.S.T.) predicts that some metabolites exhibit developmental toxicity and mutagenicity in rats. These findings suggest that biotransformation should be particularly emphasized, and more toxicological and monitoring studies should be performed to assess the ecological and human safety of LCMs.

Tubiechong patching promotes tibia fracture healing in rats by regulating angiogenesis through the VEGF/ERK1/2 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The external use of traditional Chinese medicine (TCM) to treat fractures has a long history of clinical application and theoretical basis, and is also one of the characteristic treatment methods of TCM with significant efficacy and many advantages. Among the commonly used external Chinese medicines, Tubiechong is noteworthy. AIM OF THE STUDY: To elucidate whether local patching of Tubiechong can promote fracture healing and explore its mechanism of action. MATERIALS AND METHODS: A rat tibia fracture model was constructed by the modified Einhorn modeling method. X-ray films were taken to evaluate the progress of fracture healing. Serum bone alkaline phosphatase (BALP), osteocalcin (BGP) and the C-terminal content of collagen type I (CTX-I) were analyzed by ELISA. CD31 immunohistochemistry was used to evaluate angiogenesis in the tibia segment. The effects of Tubiechong decoction (TD) on HUVEC proliferation, migration and invasion were detected by MTT assay, wound healing assay and Transwell migration assay, respectively. RNA-seq was performed to identify differentially expressed genes (DEGs). Enrichment of functions and signaling pathway analysis were performed based on the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Quantitative real time polymerase chain reaction (qRT-PCR) was used to study gene expression levels. Western blotting (WB) was used to detect the expression of relevant regulatory proteins. RESULTS: The healing time of rat tibia fractures in the three TD dose groups was shortened. The serum levels of BALP, BGP and CTX- I in the TD-treated group were higher than those in the NC group. The X-ray results showed that on the 7th day after surgery, the fracture healing degree of the high-dose TD group was significantly better than that of the NC group, and the fracture healing degrees of each TD treatment group were significantly higher than those of the NC group on the 14th, 17th, and 21st days after the operation. The CD31 immunohistochemistry results showed that the number of blood vessels and the vascular area in the TD treatment group were higher than those in the NC group. In vitro, TD promoted the proliferation, wound healing and migration of HUVECs. GO analysis of transcriptome sequencing results showed that TD significantly altered the expression of genes related to cell growth, metabolism, and motility. According to KEGG annotations, VEGFA was upregulated. Eight DEGs were enriched in the VEGFA-VEGFR2 signaling pathway, of which six were upregulated. KEGG signaling pathway analysis showed that the most abundant DEGs were in mitogen-activated protein kinase (MAPK) signaling pathway. qRT-PCR showed that VEGFA gene expression in HUVECs was 7.8 times that of the control group after 1 mg/mL TD treatment for 24 h, and WB experiments showed that its protein expression was 3 times that of the control group. WB results showed that the phosphorylated ERK gene was highly expressed, while the expression levels of phosphorylated P38 and phosphorylated JNK protein remained unchanged. CONCLUSION: Tubechong patching therapy promotes tibia fracture healing in rats by regulating angiogenesis through the VEGF/ERK1/2 signaling pathway.

Aluminum activates NLRP3 inflammasome-mediated pyroptosis via reactive oxygen species to induce liver injury in mice.

Aluminum (Al) exposure can lead to oxidative stress and liver inflammatory injury in mice. The overproduction of reactive oxygen species (ROS) activates the NLRP3 inflammasome and further induces liver pyroptosis. However, the participation of pyroptosis in inducing Al-mediated liver injury and the underlying regulatory mechanisms remain largely unclear. Herein, a mice model of subchronic Al exposure was established to investigate the role of pyroptosis in Al-induced liver injury. Then, MCC950 and N-acetylcysteine were used to inhibit NLRP3 inflammasome-mediated pyroptosis and ROS production for exploring the role and the underlying mechanisms of pyroptosis in determining Al-induced liver injury. It was confirmed that Al induced hepatocyte pyroptosis in mice, and that NLRP3 inflammasome-mediated pyroptosis plays a damaging role in Al-induced liver injury. ROS promotes pyroptosis in an Al-induced liver injury model by activating the NLRP3 inflammasome. Collectively, it was shown that ROS promotes pyroptosis to aggravate Al-induced liver injury by activating the NLRP3 inflammasome.

Chlorinated organophosphorus flame retardants-induced mitochondrial abnormalities and the correlation with progesterone production in mLTC-1 cells.

Environmental monitoring data have indicated that three chlorinated organophosphorus flame retardants (Cl-OPFRs), including tris(2-chloroethyl)-phosphate (TCEP), tris(2-chloropropyl)-phosphate (TCPP), and tris(1,3-dichloro-2-propyl)-phosphate (TDCPP) are the predominant chemicals in various environmental matrices and exhibit reproductive endocrine disrupting activities. Currently, mitochondrial abnormality is a new paradigm for evaluating chemical-mediated cell dysfunction. However, a comprehensive correlation between these two aspects of Cl-OPFRs remains unclear. In this research, the effects of TCEP, TCPP, and TDCPP on progesterone production and mitochondrial impairment were investigated by using mouse Leydig tumor cells (mLTC-1). The half maximal inhibitory concentration (IC50) values at 48 h exposure indicated that the rank order of anti-androgenic activity was TDCPP > TCPP. Whereas, TCEP exhibited elevation of progesterone production. At concentrations close to IC50 of progesterone production by TCPP and TDCPP, the elevation of intracellular reactive oxygen species (ROS), depletion of mitochondrial membrane potential (MMP), reduction of cellular adenosine triphosphate (ATP) content, and alteration of mitochondrial structures was observed. In addition, the expression of main genes related to progesterone synthesis was dramatically down-regulated by TCPP and TDCPP treatments. These results imply that the inhibition effect of TCPP and TDCPP on progesterone production might be related to mitochondrial damage and down-regulated steroidogenic genes.