Upregulation of GOLPH3 mediated by Bisphenol a promotes colorectal cancer proliferation and migration: evidence based on integrated analysis.

Background: The interaction between environmental endocrine-disrupting chemicals, such as Bisphenol A (BPA), and their influence on cancer progression, particularly regarding the GOLPH3 gene in colorectal cancer, remains unclear. Methods: We performed an integrated analysis of transcriptional profiling, clinical data, and bioinformatics analyses utilizing data from the Comparative Toxicogenomics Database and The Cancer Genome Atlas. The study employed ClueGO, Gene Set Enrichment Analysis, and Gene Set Variation Analysis for functional enrichment analysis, alongside experimental assays to examine the effects of BPA exposure on colorectal cancer cell lines, focusing on GOLPH3 expression and its implications for cancer progression. Results: Our findings demonstrated that BPA exposure significantly promoted the progression of colorectal cancer by upregulating GOLPH3, which in turn enhanced the malignant phenotype of colorectal cancer cells. Comparative analysis revealed elevated GOLPH3 protein levels in cancerous tissues versus normal tissues, with single-cell analysis indicating widespread GOLPH3 presence across various cell types in the cancer microenvironment. GOLPH3 was also associated with multiple carcinogenic pathways, including the G2M checkpoint. Furthermore, our investigation into the colorectal cancer microenvironment and genomic mutation signature underscored the oncogenic potential of GOLPH3, exacerbated by BPA exposure. Conclusion: This study provides novel insights into the complex interactions between BPA exposure and GOLPH3 in the context of colorectal cancer, emphasizing the need for heightened awareness and measures to mitigate BPA exposure risks. Our findings advocate for further research to validate these observations in clinical and epidemiological settings and explore potential therapeutic targets within these pathways.

Protosappanin B enhances the chemosensitivity of 5-fluorouracil in colon adenocarcinoma by regulating the LINC00612/microRNA-590-3p/Golgi phosphoprotein 3 axis.

BACKGROUND: 5-fluorouracil (5-FU) is conventionally used in chemotherapy for colon adenocarcinomas. Acquired resistance of 5-FU remains a clinical challenge in colon cancer, and efforts to develop targeted agents to reduce resistance have not yielded success. Protosappanin B (PSB), the main component of Lignum Sappan extract, is known to exhibit anti-tumor effects. However, whether and how PSB could improve 5-FU resistance in colon cancer have not yet been established. In this study, we aimed to explore the effects and underlying mechanisms of PSB in 5-FU-induced chemoresistance in colon adenocarcinoma. METHODS: Forty-seven paired colon cancer tissue samples from patients who received 5-FU chemotherapy were collected as clinical samples. Two 5-FU resistant colon cancer cell lines were established for in vitro experiments. Reverse transcription-quantitative PCR (RT-qPCR) was performed to determine the mRNA and microRNA (miRNA) expression levels in colon adenocarcinoma tissues and cell lines. Cell Counting Kit-8 (CCK-8) and flow cytometry assays were performed to evaluate cell proliferation and apoptosis, respectively. RESULTS: LINC00612 was highly expressed in colon adenocarcinoma samples and 5-FU resistant colon cancer cells. LINC00612 knockdown enhances 5-FU chemosensitivity in 5-FU resistant cells. Notably, PSB treatment attenuated LINC00612 expression in 5-FU resistant colon adenocarcinoma cells. Moreover, PSB treatment reversed the increase in LINC00612-induced 5-FU resistance. Mechanistically, LINC00612 specifically bound to miR-590-3p, which promoted 5-FU resistance in colon adenocarcinoma cells and attenuated the inhibitory effect of LINC00612 on GOLPH3 expression. CONCLUSION: PSB attenuates 5-FU chemoresistance in colon adenocarcinoma by regulating the LINC00612/miRNA-590-3p/GOLPH3 axis.

tert-Butyl Nitrite-Induced Radical Nitrile Oxidation Cycloaddition: Synthesis of Isoxazole/Isoxazoline-Fused Benzo 6/7/8-membered Oxacyclic Ketones.

A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through Csp3-H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the simultaneous formation of isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketones to form polycyclic architectures by using tert-butyl nitrite (TBN) as a non-metallic radical initiator and N-O fragment donor.

Intrauterine and early postnatal exposures to submicron particulate matter and childhood allergic rhinitis: A multicity cross-sectional study in China.

BACKGROUND: Airborne particulate matter pollution has been linked to occurrence of childhood allergic rhinitis (AR). However, the relationships between exposure to particulate matter with an aerodynamic diameter ≤1 µm (PM1) during early life (in utero and first year of life) and the onset of childhood AR remain largely unknown. This study aims to investigate potential associations of in utero and first-year exposures to size-segregated PMs, including PM1, PM1-2.5, PM2.5, PM2.5-10, and PM10, with childhood AR. METHODS: We investigated 29286 preschool children aged 3-6 years in 7 Chinese major cities during 2019-2020 as the Phase II of the China Children, Families, Health Study. Machine learning-based space-time models were utilized to estimate early-life residential exposure to PM1, PM2.5, and PM10 at 1 × 1-km resolutions. The concentrations of PM1-2.5 and PM2.5-10 were calculated by subtracting PM1 from PM2.5 and PM2.5 from PM10, respectively. Multiple mixed-effects logistic models were used to assess the odds ratios (ORs) and 95% confidence intervals (CIs) of childhood AR associated with per 10-µg/m3 increase in exposure to particulate air pollution during in utero period and the first year of life. RESULTS: Among the 29286 children surveyed (mean ± standard deviation, 4.9 ± 0.9 years), 3652 (12.5%) were reported to be diagnosed with AR. Average PM1 concentrations during in utero period and the first year since birth were 36.3 ± 8.6 µg/m3 and 33.1 ± 6.9 µg/m3, respectively. Exposure to PM1 and PM2.5 during pregnancy and the first year of life was associated with an increased risk of AR in children, and the OR estimates were higher for each 10-µg/m3 increase in PM1 than for PM2.5 (e.g., 1.132 [95% CI: 1.022-1.254] vs. 1.079 [95% CI: 1.014-1.149] in pregnancy; 1.151 [95% CI: 1.014-1.306] vs. 1.095 [95% CI: 1.008-1.189] in the first year of life). No associations were observed between AR and both pre- and post-natal exposure to PM1-2.5, indicating that PM1 rather than PM1-2.5 contributed to the association between PM2.5 and childhood AR. In trimester-stratified analysis, childhood AR was only found to be associated with exposure to PM1 (OR = 1.077, 95% CI: 1.027-1.128), PM2.5 (OR = 1.048, 95% CI: 1.018-1.078), and PM10 (OR = 1.032, 95% CI: 1.007-1.058) during the third trimester of pregnancy. Subgroup analysis suggested stronger PM-AR associations among younger (<5 years old) and winter-born children. CONCLUSIONS: Prenatal and postnatal exposures to ambient PM1 and PM2.5 were associated with an increased risk of childhood AR, and PM2.5-related hazards could be predominantly attributed to PM1. These findings highlighted public health significance of formulating air quality guideline for ambient PM1 in mitigating children's AR burden caused by particulate air pollution.

Exploring the impact of awe on the multifaceted construct of empathy.

Empathy helps us navigate social interactions and promotes prosocial behaviors like caregiving and helping. Here, we explored whether awe, a key self-transcendent and epistemic emotion, could encourage greater empathy across seven diverse student and community samples collected between 2020 and 2022. Empathy is a multifaceted construct; thus, we assessed performance on a range of empathy measures including perspective taking accuracy (Study 2), empathic accuracy (Study 3; preregistered), emotion contagion and compassion (Study 4). We also directly tested whether awe motivated people to empathize with others (Study 5; preregistered). Although dispositional awe was positively correlated with trait measures of empathy (Study 1), experimental inductions of awe did not improve performance on empathy measures or motivate people to empathize, compared to a control (Studies 2-5). However, a moderation effect emerged in which awe had divergent effects on empathy depending on participants' self-reported dispositional levels of cognitive empathy. Although effects only reached significance in two studies (Studies 3; preregistered and 4), an internal meta-analysis revealed that awe improved empathy for those high in dispositional cognitive empathy, while marginally reducing it among those low in dispositional cognitive empathy, compared to a control. These results suggest that awe may have polarizing effects on empathy depending on one's dispositional level of cognitive empathy and reveal a potentially important role of cognitive processes in linking awe and empathy. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Residential greenness mitigates mortality risk from short-term airborne particulate exposure: An individual-level case-crossover study.

BACKGROUND: Studies suggested that greenness could reduce death risks related to ambient exposure to particulate matter (PM), while the available evidence was mixed across the globe and substantially exiguous in low- and middle-income countries. By conceiving an individual-level case-crossover study in central China, this analysis primarily aimed to quantify PM-mortality associations and examined the modification effect of greenness on the relationship. METHODS: We investigated a total of 177,058 nonaccidental death cases from 12 counties in central China, 2008-2012. Daily residential exposures to PM2.5 (aerodynamic diameter <2.5 µm), PMc (aerodynamic diameter between 2.5 and 10 µm), and PM10 (aerodynamic diameter <10 µm) were assessed at a 1 × 1-km resolution through satellite-derived machine-learning models. Residential surrounding greenness was assessed using satellite-derived enhanced vegetation index (EVI) and normalized difference vegetation index (NDVI) at multiple buffer sizes (250, 500, and 1000 m). To quantify the acute mortality risks associated with short-term exposure to PM2.5, PMc, and PM10, a time-stratified case-crossover design was utilized in conjunction with a conditional logistic regression model in our main analyses. To investigate the effect modification of greenness on PM-mortality associations, we grouped death cases into low, medium, and high greenness levels using cutoffs of 25th and 75th percentiles of NDVI or EVI exposure, and examined potential effect heterogeneity in PM-related mortality risks among these groups. RESULTS: Mean concentrations (standard deviation) on the day of death were 73.8 (33.4) µg/m3 for PM2.5, 43.9 (17.3) µg/m3 for PMc, and 117.5 (44.9) µg/m3 for PM10. Size-fractional PM exposures were consistently exhibited significant associations with elevated risks of nonaccidental and circulatory mortality. For every increase of 10-µg/m3 in PM exposure, percent excess risks of nonaccidental and circulatory mortality were 0.271 (95% confidence interval [CI]: 0.010, 0.533) and 0.487 (95% CI: 0.125, 0.851) for PM2.5 at lag-01 day, 0.731 (95% CI: 0.108, 1.359) and 1.140 (95% CI: 0.267, 2.019) for PMc at lag-02 day, and 0.271 (95% CI: 0.010, 0.533) and 0.386 (95% CI: 0.111, 0.662) for PM10 at lag-01 day, respectively. Compared to participants in the low-level greenness areas, those being exposed to higher greenness were found to be at lower PM-associated risks of nonaccidental and circulatory mortality. Consistent evidence for alleviated risks in medium or high greenness group was observed in subpopulations of female and younger groups (age <75). CONCLUSIONS: Short-term exposure to particulate air pollution was associated with elevated risks of nonaccidental and circulatory death, and individuals residing in higher neighborhood greenness possessed lower risk of PM-related mortality. These findings emphasized the potential public health advantages through incorporating green spaces into urban design and planning.

Intraday exposure to ambient ozone and emergency department visits among children: a case-crossover study in southern China.

Most existing studies have investigated short-term associations between ozone exposure and acute disease events among children at a daily timescale, which might neglect risk effects happening within several hours after ozone exposure. In this research, we aimed to depict intraday associations between pediatric emergency department visits (PEDVs) and exposure to ozone in order to better detect ultra-short-term effects of ozone exposure on children. We obtained hourly data of all-cause PEDVs, air pollutants, and meteorological factors in Shenzhen and Guangzhou, China, 2015-2018. We applied time-stratified case-crossover design and conditional logistic regression models to estimate odds ratios per 10-µg/m3 rise of ozone concentrations at various exposure periods (e.g., 0-3, 4-6, 7-12, 13-24, 25-48, and 49-72 h) prior to PEDVs, controlling for hourly relative humidity and temperature. Subgroup analyses divided by gender, age, and season were undertaken to identify the potential susceptible population and period. A total of 358,285 cases of PEDVs were included in two cities, and hourly average concentration of ozone was 45.5 µg/m3 in Guangzhou and 58.9 µg/m3 in Shenzhen, respectively. Increased risks of PEDVs occurred within a few hours (0-3 h) after exposure to ozone and remained up to 48 h. Population risks for PEDVs increased by 0.8% (95% confidence interval, 0.6 to 1.0) in Shenzhen and 0.7% (0.5 to 0.9) in Guangzhou for a 10-µg/m3 increase in ozone concentrations at lag 4-6 h and lag 7-12 h, respectively. These findings were robust to co-exposure adjustments in our sensitivity analyses. Significantly greater ozone-associated risks were consistently observed during cold months (October to March of the following year) in both cities, while we did not identify evidence for effect modification of children's age and gender. This study provided novel evidence for increased risks of acute disease events among children within several hours after ozone exposure, highlighting the significant implications for policymakers to establish hourly air quality standards for better protecting children's health.

Ambient PM2.5, ozone and mortality in Chinese older adults: A nationwide cohort analysis (2005-2018).

BACKGROUND: Cohort evidence linking long-term survival with exposure to multiple air pollutants (e.g., fine particulate matter [PM2.5] and ozone) was extensively sparse in low- and middle-income countries, especially among older adults. This study aimed to investigate potential associations of long-term exposures to PM2.5 and ozone with all-cause mortality in Chinese older adults. METHODS: A dynamic nationwide prospective cohort comprising 20,352 adults aged ≥65 years were enrolled from the Chinese Longitudinal Healthy Longevity Study and followed up through 2005-2018. Participants' annual exposures to warm-season ozone and year-round PM2.5 were assigned using satellite-derived spatiotemporal estimates. A directed acyclic graph (DAG) was developed to identify confounding variables. Associations of annual mean exposures to PM2.5 and ozone with mortality were evaluated using single- and two-pollutant Cox proportional hazards models, adjusting for time-dependent individual risk factors and ambient temperature. RESULTS: During 100 thousand person-years of follow-up (median: 3.6 years), a total of 14,313 death events occurred. The participants were averagely aged 87.1 years at baseline and exposed to a wide range of annual average concentrations of warm-season maximum 8-hour ozone (mean, 54.4 ppb; range, 23.3-81.6 ppb) and year-round PM2.5 (mean, 65.5 µg/m3; range, 10.1-162.9 µg/m3). Approximately linear concentration-response relationship was identified for ozone, whereas significant increases in PM2.5-associated mortality risks were observed only when concentrations were above 60 µg/m3. Rises of 10 ppb in ozone and 10 µg/m3 in PM2.5 above 60 µg/m3 were associated with increases in all-cause mortality of 13.2% (95% confidence interval [CI]: 10.2-16.2%) and 6.2% (95% CI: 4.6-7.7%) in DAG-based single-pollutant model, and of 9.7% (95% CI: 6.6-13.0%) and 5.3% (95% CI: 3.7-6.9%) in DAG-based two-pollutant model, respectively. We detected significant effect modification by temperature in associations of mortality with ozone (P <0.001 for interaction), suggesting greater ozone-related risks among participants in warmer locations. CONCLUSIONS: This study provided longitudinal evidence that long-term exposure to ambient PM2.5 and ozone significantly and independently contributed to elevated risks of all-cause mortality among older adults in China.

Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9.

Osteoarthritis (OA) is a type of common degenerative joint disorder, in which adipose mesenchymal stem cells (ADSCs) and the secreted exosomes play an important role. The purpose of this study was to investigate the role and mechanism of exosomes derived from ADSCs (ADSC-exos) in OA. The gradient of IL-1ß concentration was designed to construct the articular chondrocyte model of arthritic mice. The expression of miR-93-5p and ADAMTS9 in articular chondrocytes was detected by reverse transcription quantitative polymerase chain reaction. Dual luciferase reporter gene assay was performed to verify the interaction between them. Monodansylcadaverine staining was used to visualize the autophagosome formation and cell apoptosis was analyzed by flow cytometry. ADSC-exos were authenticated by transmission electron microscope and western blot assay. miR-93-5p was found to be downregulated in IL-1ß-treated articular chondrocytes compared with OA cartilage while ADAMTS9 was upregulated, which was identified as a direct target gene of miR-93-5p. Silencing of ADAMTS9 attenuated the effects of miR-93-5p. Exosomal miR-93-5p can reduce the release of inflammatory factors in mouse arthritis cell models. This study first described the mechanism under that ADSC-exos inhibited inflammation and alleviated OA through the innovative targets miR-93-5p/ADAMTS9 signal axis. This provided a new method for the treatment of OA.

Emergency Department Visits in Children Associated with Exposure to Ambient PM1 within Several Hours.

BACKGROUND: Emerging evidence has integrated short-term exposure to PM1 with children's morbidity and mortality. Nevertheless, most available studies have been conducted on a daily scale, ignoring the exposure variations over the span of a day. OBJECTIVE: The main intention of this study was to examine the association between pediatric emergency department visits (PEDVs) and intra-day exposures to PM1 and PM2.5. We also aimed to investigate whether a high PM1/PM2.5 ratio elevated the risk of PEDVs independent from PM2.5 exposure within several hours. METHODS: We collected hourly data on aerial PM1 and PM2.5 concentrations, all-cause PEDVs, and meteorological factors from two megacities (i.e., Guangzhou and Shenzhen) in southern China during 2015-2016. Time-stratified case-crossover design and conditional logistic regression analysis were used to assess the associations of PEDVs with exposures to PM1 and PM2.5 at different lag hours. The contribution of PM1 to PM2.5-associated risk was quantified by introducing PM1/PM2.5 ratio as an additional exposure indicator in the analysis adjusting for PM2.5. Subgroup analyses were performed stratified by sex, age, and season. RESULTS: During this study period, 97,508 and 101,639 children were included from Guangzhou and Shenzhen, respectively. PM1 and PM2.5 exposures within several hours were both remarkably related to an increased risk of PEDVs. Risks for PEDVs increased by 3.9% (95% confidence interval [CI]: 2.7-5.0%) in Guangzhou and 3.2% (95% CI: 1.9-4.4%) in Shenzhen for each interquartile range (Guangzhou: 21.4 µg/m3, Shenzhen: 15.9 µg/m3) increase in PM1 at lag 0-3 h, respectively. A high PM1/PM2.5 ratio was substantially correlated with increased PEDVs, with an excess risk of 2.6% (95% CI: 1.2-4.0%) at lag 73-96 h in Guangzhou and 1.2% (95% CI: 0.4-2.0%) at lag 0-3 h in Shenzhen. Stratified analysis showed a clear seasonal pattern in PM-PEDVs relationships, with notably stronger risks in cold months (October to March of the following year) than in warm months (April to September). CONCLUSIONS: Exposures to ambient PM1 and PM2.5 within several hours were related to increased PEDVs. A high PM1/PM2.5 ratio may contribute an additional risk independent from the short-term impacts of PM2.5. These findings highlighted the significance of reducing PM1 in minimizing health risks due to PM2.5 exposure in children.

Higher benefit-risk ratio of COVID-19 vaccination in patients with schizophrenia and major depressive disorder versus patients with bipolar disorder when compared to controls.

Patients with major psychiatric disorders (MPD) that include schizophrenia (SCH), bipolar disorder (BP), and major depressive disorder (MDD) are at increased risk for coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccines in MPD patients have not been fully evaluated. This study aimed to investigate adverse events (AEs)/side effects and efficacy of COVID-19 vaccines in MPD patients. This retrospective study included 2034 patients with SCH, BP, or MDD who voluntarily received either BBIBP-CorV or Sinovac COVID-19 vaccines, and 2034 matched healthy controls. The incidence of AEs/side effects and the efficacy of COIVD-19 vaccinations among the two groups were compared. The risk ratio (RR) of side effects in patients with MPD was 0.60 (95% confidence interval [CI]: 0.53-0.68) after the first dose and 0.80 (95% CI: 0.65-0.99) following the second dose, suggesting a significantly lower risk in the MPD group versus healthy controls. The RRs of AEs did not differ between patients and controls. Notably, fully vaccinated patients exhibited a decreased risk of influenza with or without fever compared with controls (RR=0.38, 95% CI: 0.31-0.46; RR=0.23, 95% CI: 0.17-0.30; respectively). Further subgroup comparisons revealed a significantly lower risk of influenza with fever in MDD (RR=0.13, 95% CI: 0.08-0.21) and SCH (RR=0.24, 95% CI: 0.17-0.34) than BP (RR=0.85, 95% CI: 0.69-1.06) compared to controls. We conclude that the benefit-risk ratio of COVID-19 vaccination was more favorable in SCH or MDD versus BP when compared with controls. These data indicate that COVID-19 vaccines are safe and protective in patients with MPD from COVID-19.

Comprehensive analysis of triphenyl phosphate: An environmental explanation of colorectal cancer progression.

Organophosphate flame retardants (OPFRs) are alternatives to brominated flame retardants (BFRs) and have recently gained wide acceptance in various materials. For the treatment and prevention of diseases, it is also important to clarify the relationship between OPFRs and tumors, despite the fact that OPFRs are less toxic than BFRs. This research used the TCGA and CTD databases for transcriptome profiling and identifying OPFRs-related genes. GO and KEGG analyses suggested that OPFRs may be closely related to colorectal cancer (CRC), and genes correlated with OPFRs were significantly and differently expressed between tumor and normal group. Further, OPFRs-related genes were associated with a good prognosis in CRC patients. The deeper research demonstrated that one of the OPFRs-triphenyl phosphate could significantly increased the viability and proliferation of CRC cell lines compared with the control group. In addition, Our research also found that melatonin at 50 µM could significantly impact CRC cell proliferation and migration ability induced by TPP.

Analysis and Research on Influencing Factors of College Students' Satisfaction with Physical Education.

Physical education is an important part of a university, and the satisfaction of college students for physical education directly determines the teaching effect of physical education. Therefore, it is of great significance to understand college students' satisfaction with physical education and its influencing factors for improving the level of physical education. In this paper, by means of multistage sampling, probability sampling according to scale and random equidistant sampling, 7 main campuses, including 36 subcampuses, are selected for data entry, cleaning, and calculation by using the college physical education teaching system. Through the investigation of 1752 students, the results show that there are significant differences in grade, gender, cognition, credit, sense of responsibility, and teaching content (P > 0.05), which are all factors affecting college students' satisfaction. Cognition, grades, credits, and make-up test rate are the main influencing factors, with the influence degree ranging from 1 to 3, and there are significant differences in OR value and P value. Therefore, in the process of physical education, we should pay attention to the above-mentioned influencing factors, effectively reduce the occurrence rate of make-up examination and reexamination, adjust unreasonable teaching content, and improve students' satisfaction with physical education.

Effectiveness of acupuncture for irritable bowel syndrome: Protocol for a scoping review of systematic reviews and meta-analyses.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional bowel disorder. Many systematic reviews/meta-analyses indicate that acupuncture and related therapies are effective for IBS. However, the robustness of the results in the systematic reviews and meta-analyses has not been evaluated. This scoping review aims to ascertain the credibility of current evidence of acupuncture therapy for IBS, to provide clinical research investigators with reliable information. METHODS: Searches of China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), China Biology Medicine disc (CBMdisc), and Wanfang Database since the establishment of the database to February 2022. Study selection and data extraction will be conducted by 2 reviewers, and the quality will be assessed by 2 trained reviewers. We will use Assessment of Multiple Systematic Reviews-2 (AMSTAR2) for methodological quality assessment, Preferred Reporting Items for Systematic Reviews and Meta-Analyses for report quality assessment, Grading of Recommendations, Assessment, Development, and Evaluation for the quality of evidence assessment, and the Risk of Bias in Systematic Reviews for the bias assessment. RESULTS: The results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: INPLASY202210117. CONCLUSION: This scoping review will provide comprehensive evidence of acupuncture for patients with irritable bowel syndrome. ETHICS AND DISSEMINATION: This scoping review does not require ethical approval as it is a secondary assessment of available literature.

Infection microenvironment-activated core-shell nanoassemblies for photothermal/chemodynamic synergistic wound therapy and multimodal imaging.

The development of intelligent designs of new antibacterial modalities for diagnosing and treating chronic multidrug-resistant bacterial infections is an urgent need, but achieving the precisive theranostic in response to specific inflammatory microenvironments remains a great challenge. This paper describes our work designing and demonstrating infection microenvironment-activated core-shell Gd-doped Bi2S3@Cu(II) boron imidazolate framework (Bi2S3:Gd@Cu-BIF) nanoassemblies. Upon exposure to a single beam of 808 nm laser, Bi2S3:Gd@Cu-BIF nanoassemblies showed exceptional photothermal conversion (η = 52.6%) and produced several cytotoxic reactive oxygen species, such as singlet oxygen and hydroxyl radicals, by depleting the intracellular glutathione and in-situ catalyzing the decomposition of endogenous hydrogen peroxide in the inflammatory microenvironment. The broad-spectrum antibacterial properties of nanoassemblies were confirmed to be effective against Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) with an inhibition rate of 99.99% in vitro. Additionally, in vivo wound-healing studies revealed that Bi2S3:Gd@Cu-BIF nanoassemblies could serve as an effective wound spray to accelerate healing following MRSA infections via photothermal/chemodynamic (PTT/CDT) synergistic therapy. The effective wound healing rate in the synergistic treatment group was 99.8%, which is higher than the 69.5% wound healing rate in the control group. Furthermore, magnetic resonance and computed tomography dual-modal imaging mediated by Bi2S3:Gd@Cu-BIF nanoassemblies also exhibits promising potential as an integrated diagnostic nanoplatform. Overall, this work provides useful insights for developing all-in-one theranostic nanoplatforms for clinical treatment of drug-resistant bacterial infections. STATEMENT OF SIGNIFICANCE: New treatments and effective diagnostic strategies are critical for fighting drug-resistant bacterial infections. Infection microenvironment-activated Bi2S3@Cu-BIF nanoassemblies can simultaneously increase eigen temperature and generate cytotoxic reactive oxygen species, such as singlet oxygen and hydroxyl radicals, under near-infrared laser irradiation, achieving the synergistic effect of photothermal and chemodynamic therapy, which has been proven to be highly effective for inhibiting bacterial activity and speeding wound healing from methicillin-resistant Staphylococcus aureus infection. More importantly, the nanoassemblies could enable early precise visualized detection of bacterial abscess using magnetic resonance/computed tomography dual-modal bio-imaging techniques.

Human cytochrome P450 3A-mediated two-step oxidation metabolism of dimethomorph: Implications in the mechanism-based enzyme inactivation.

Dimethomorph (DMM), an effective and broad-spectrum fungicide applied in agriculture, is toxic to environments and living organisms due to the hazardous nature of its toxic residues. This study aims to investigate the human cytochrome P450 enzyme (CYP)-mediated oxidative metabolism of DMM by combining experimental and computational approaches. Dimethomorph was metabolized predominantly through a two-step oxidation process mediated by CYPs, and CYP3A was identified as the major contributor to DMM sequential oxidative metabolism. Meanwhile, DMM elicited the mechanism-based inactivation (MBI) of CYP3A in a suicide manner, and the iminium ion and epoxide reactive intermediates generated in DMM metabolism were identified as the culprits of MBI. Furthermore, three common pesticides, prochloraz (PCZ), difenoconazole (DFZ) and chlorothalonil (CTL), could significantly inhibit CYP3A-mediated DMM metabolism, and consequently trigger elevated exposure to DMM in vivo. Computational studies elucidated that the differentiation effects in charge distribution and the interaction pattern played crucial roles in DMM-induced MBI of CYP3A4 during sequential oxidative metabolism. Collectively, this study provided a global view of the two-step metabolic activation process of DMM mediated by CYP3A, which was beneficial for elucidating the environmental fate and toxicological mechanism of DMM in humans from a new perspective.

Regioselective hydroxylation of carbendazim by mammalian cytochrome P450: A combined experimental and computational study.

Carbendazim (CBZ), a broad-spectrum pesticide frequently detected in fruits and vegetables, could trigger potential toxic risks to mammals. To facilitate the assessment of health risks, this study aimed to characterize the cytochrome P450 (CYPs)-mediated metabolism profiles of CBZ by a combined experimental and computational study. Our results demonstrated that CYPs-mediated region-selective hydroxylation was a major metabolism pathway for CBZ in liver microsomes from various species including rat, mouse, minipig, dog, rabbit, guinea pig, monkey, cow and human, and the metabolite was biosynthesized and well-characterized as 6-OH-CBZ. CYP1A displayed a predominant role in the region-selective hydroxylation of CBZ that could attenuate its toxicity through converting it into a less toxic metabolite. Meanwhile, five other common pesticides including chlorpyrifos-methyl, prochloraz, chlorfenapyr, chlorpyrifos, and chlorothalonil could significantly inhibit the region-selective hydroxylation of CBZ, and consequently remarkably increased CBZ exposure in vivo. Furthermore, computational study clarified the important contribution of the key amino acid residues Ser122, and Asp313 in CYP1A1, as well as Asp320 in CYP1A2 to the hydroxylation of CBZ through hydrogen bonds. These results would provide some useful information for the metabolic profiles of CBZ by mammalian CYPs, and shed new insights into CYP1A-mediated metabolic detoxification of CBZ and its health risk assessment.

Identification of Escherichia coli β-glucuronidase inhibitors from Polygonum cuspidatum Siebold & Zucc

Abstract Gut bacterial β-glucuronidase (GUS) can reactivate xenobiotics that exert enterohepatic circulation- triggered gastrointestinal tract toxicity. GUS inhibitors can alleviate drug-induced enteropathy and improve treatment outcomes. We evaluated the inhibitory effect of Polygonum cuspidatum Siebold & Zucc. and its major constituents against Escherichia coli GUS (EcGUS), and characterized the inhibitory mechanism of each of the components. Trans-resveratrol 4'-O-β-D-glucopyranoside (HZ-1) and (-)-epicatechin gallate (HZ-2) isolated from P. cuspidatum were identified as the key components and potent inhibitors. These two components displayed strong to moderate inhibitory effects on EcGUS, with Ki values of 9.95 and 1.95 μM, respectively. Results from molecular docking indicated that HZ-1 and HZ-2 could interact with the key residues Asp163, Ser360, Ile 363, Glu413, Glu504, and Lys 568 of EcGUS via hydrogen bonding. Our findings demonstrate the inhibitory effect of P. cuspidatum and its two components on EcGUS, which supported the further evaluation and development of P. cuspidatum and its two active components as novel candidates for alleviating drug-induced damage in the mammalian gut.

Disturbance of the Dlk1-Dio3 imprinted domain may underlie placental Dio3 suppression and extracellular thyroid hormone disturbance in placenta-derived JEG-3 cells following decabromodiphenyl ether (BDE209) exposure.

Decabromodiphenyl ether (BDE209) has been widely used as a flame retardant in the past four decades, leading to human health consequences, especially neurological impairments. Our previous in vivo studies have suggested that developmental neurotoxicity in offspring may be the result of BDE209-induced placental type III iodothyronine deiodinase (Dio3) disturbance and consequent thyroid hormone (TH) instability. Dio3 is paternally imprinted gene, and its balanced expression is crucial in directing normal development and growth. In this study, we used placenta-derived cells to investigate how BDE209 affected Dio3 expression through interfering imprinting mechanisms in the delta-like homolog 1 (Dlk1)-Dio3 imprinted region. Gene chip analysis and RT-qPCR identified miR409-3p, miR410-5p, miR494-3p, miR668-3p and miR889-5p as potential candidates involved in Dio3 deregulation. The sodium bisulfite-clonal sequencing revealed the BDE209 affect methylation status of two differentially methylated regions (DMRs), intergenic-DMR (IG-DMR) and maternally expressed gene 3-DMR (MEG3-DMR). Our data indicate that placental Dio3 may be a potential molecular target for future study of BDE209 developmental toxicity. In particular, miRNAs, IG-DMR and MEG3-DMR in the Dlk1-Dio3 imprinted locus may be informative in directing studies in TH disturbance and developmental toxicity induced by in utero exposure to environmental persistent organic pollutants (POPs), and those candidate miRNAs may prove to be convenient and noninvasive biomarkers for future large-scale population studies.