Fluorinated macromolecular amphiphiles as prototypic molecular drones.

The advent of drones has revolutionized various aspects of our lives, and in the realm of biological systems, molecular drones hold immense promise as "magic bullets" for major diseases. Herein, we introduce a unique class of fluorinated macromolecular amphiphiles, designed in the shape of jellyfish, serving as exemplary molecular drones for fluorine-19 MRI (19F MRI) and fluorescence imaging (FLI)-guided drug delivery, status reporting, and targeted cancer therapy. Functioning akin to their mechanical counterparts, these biocompatible molecular drones autonomously assemble with hydrophobic drugs to form uniform nanoparticles, facilitating efficient drug delivery into cells. The status of drug delivery can be tracked through aggregation-induced emission (AIE) of FLI and 19F MRI. Furthermore, when loaded with a heptamethine cyanine fluorescent dye IR-780, these molecular drones enable near-infrared (NIR) FL detection of tumors and precise delivery of the photosensitizer. Similarly, when loaded with doxorubicin (DOX), they enable targeted chemotherapy with fluorescence resonance energy transfer (FRET) FL for real-time status updates, resulting in enhanced therapeutic efficacy. Compared to conventional drug delivery systems, molecular drones stand out for their simplicity, precise structure, versatility, and ability to provide instantaneous status updates. This study presents prototype molecular drones capable of executing fundamental drone functions, laying the groundwork for the development of more sophisticated molecular machines with significant biomedical implications.

Construction of a human cell landscape at single-cell level.

Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex systems1. However, a comprehensive single-cell atlas has not been achieved for humans. Here we use single-cell mRNA sequencing to determine the cell-type composition of all major human organs and construct a scheme for the human cell landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have not been well characterized. We established a 'single-cell HCL analysis' pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from human and mouse to identify conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, whereas differentiated cells are more distinct. Our results provide a useful resource for the study of human biology.

Construction of a cross-species cell landscape at single-cell level.

Individual cells are basic units of life. Despite extensive efforts to characterize the cellular heterogeneity of different organisms, cross-species comparisons of landscape dynamics have not been achieved. Here, we applied single-cell RNA sequencing (scRNA-seq) to map organism-level cell landscapes at multiple life stages for mice, zebrafish and Drosophila. By integrating the comprehensive dataset of > 2.6 million single cells, we constructed a cross-species cell landscape and identified signatures and common pathways that changed throughout the life span. We identified structural inflammation and mitochondrial dysfunction as the most common hallmarks of organism aging, and found that pharmacological activation of mitochondrial metabolism alleviated aging phenotypes in mice. The cross-species cell landscape with other published datasets were stored in an integrated online portal-Cell Landscape. Our work provides a valuable resource for studying lineage development, maturation and aging.

How many cell types are there in nature? How do they change during the life cycle? These are two fundamental questions that researchers have been trying to understand in the area of biology. In this study, single-cell mRNA sequencing data were used to profile over 2.6 million individual cells from mice, zebrafish and Drosophila at different life stages, 1.3 million of which were newly collected. The comprehensive datasets allow investigators to construct a cross-species cell landscape that helps to reveal the conservation and diversity of cell taxonomies at genetic and regulatory levels. The resources in this study are assembled into a publicly available website at http://bis.zju.edu.cn/cellatlas/.

Allosteric SHP2 inhibition enhances regorafenib's effectiveness in colorectal cancer treatment.

Colorectal cancer (CRC) is the third most common cancer globally. Regorafenib, a multi-target kinase inhibitor, has been approved for treating metastatic colorectal cancer patients who have undergone at least two prior standard anti-cancer therapies. However, regorafenib efficacy as a single agent remains suboptimal. A promising target at the crossroads of multiple signaling pathways is the Src homology 2 domain-containing protein tyrosine phosphatase (SHP2). However, a combination approach using SHP2 inhibitors (SHP099) and anti-angiogenic drugs (Regorafenib) has not been reported in current research. In this study, we conducted in vitro experiments combining SHP099 and regorafenib and established an MC-38 colon cancer allograft mouse model. Our results revealed that co-treatment with SHP099 and regorafenib significantly inhibited cell viability and altered the biological characteristics of tumor cells compared with treatment alone in vitro. Furthermore, the combination strategy demonstrated superior therapeutic efficacy compared to monotherapy with either drug. This was evidenced by reduced tumor size, decreased proliferation, increased apoptosis, normalized tumor microvasculature, and improved antitumor immune response in vivo. These findings suggest that the combination of an SHP2 inhibitor and regorafenib is a promising therapeutic approach for patients with colorectal cancer.

Thrombopoietin receptor agonists regulate myeloid-derived suppressor cell-mediated immunomodulatory effects in ITP.

TPO receptor agonists (TPO-RAs) are a class of clinical second-line regimens for the treatment of primary immune thrombocytopenia (ITP). It can promote megakaryocyte maturation and increase platelet production, but its effect on immunosuppressive cells in patients with ITP has not been explored. Sixty-two ITP patients and 34 healthy controls (HCs) were included in this study. The proportion and functions of myeloid-derived immunosuppressive cells (MDSCs) in ITP patients and HCs were investigated. We found that the proportion and function of MDSCs in ITP patients treated with TPO-RAs were significantly higher than those treated with glucocorticoids (GCs), which was correlated with the clinical efficacy. The proportion and function of cytotoxic Th1 cells and CD8+T cells decreased, while the proportion and immunosuppressive function of Treg cells increased in ITP patients treated with TPO-RAs. We further proved, through MDSC depletion tests, that the inhibitory effect of MDSCs on Th1 cells and the promotion of Treg cells in the original immune micro-environment of GCs-treated ITP patients were impaired; however, these MDSCs' functions were improved in TPO-RAs-treated patients. Finally, we found that the KLF9 gene in MDSCs cells of ITP patients treated with TPO-RAs was down-regulated, which contribute to the higher mRNA expression of GADD34 gene and improved function of MDSCs. These results demonstrate a novel mechanism of TPO-RAs for the treatment of ITP through the assessment of MDSCs and their subsequent impact on T cells, which provides a new basis for TPO-RAs as first-line treatment approach to the treatment of ITP.

The involvement of Sting in exacerbating acute lung injury in sepsis via the PARP-1/NLRP3 signaling pathway.

BACKGROUND: Interferon gene stimulator (Sting) is an indispensable adaptor protein that plays a crucial role in acute lung injury (ALI) induced by sepsis, and the PARP-1/NLRP3 signaling pathway may be an integral component of the inflammatory response mediated by Sting. However, the regulatory role of Sting in the PARP-1/NLRP3 pathway in ALI remains insufficiently elucidated. METHODS: Using lipopolysaccharide (LPS) to induce ALI in C57BL/6 mice and HUVEC cells, an in vivo and in vitro model was established. In vivo, Sting agonists and inhibitors were administered, while in vitro, Sting was knocked down using siRNA. ELISA was employed to quantify the levels of IL-1ß, IL-6, and TNF-α. TUNEL staining was conducted to assess cellular apoptosis, while co-immunoprecipitation was utilized to investigate the interaction between Sting and NLRP3. Expression levels of Sting, NLRP3, PARP-1, among others, were assessed via Western blotting and RT-qPCR. Lung HE staining and lung wet/dry ratio were evaluated in the in vivo mouse model. To validate the role of the PARP-1/NLRP3 signaling pathway, PARP-1 inhibitors were employed both in vivo and in vitro. RESULTS: In vitro experiments revealed that the Sting agonist group exacerbated LPS-induced pulmonary pathological damage, pulmonary edema, inflammatory response (increased levels of IL-6, TNF-α, and IL-1ß), and cellular injury, whereas the Sting inhibitor group significantly ameliorated the aforementioned injuries, with further improvement observed in the combination therapy of Sting inhibitor and PARP-1 inhibitor. Western blotting and RT-qPCR results demonstrated significant suppression of ICAM-1, VCAM-1, NLRP3, and PARP-1 expression in the Sting inhibitor group, with this reduction further enhanced in the Sting inhibitor + PARP-1 inhibitor treatment group, exhibiting opposite outcomes to the agonist. Furthermore, in vitro experiments using HUVEC cell lines validated these findings. CONCLUSIONS: Our study provides new insights into the roles of Sting and the PARP-1/NLRP3 signaling pathway in inflammatory responses, offering novel targets for the development of therapeutic interventions against inflammatory reactions.

Sulfur Vacancies in Pyrite Trigger the Path to Nonradical Singlet Oxygen and Spontaneous Sulfamethoxazole Degradation: Unveiling the Hidden Potential in Sediments.

Pharmaceutical residues in sediments are concerning as ubiquitous emerging contaminants. Pyrite is the most abundant sulfide minerals in the estuarine and coastal sediments, making it a major sink for pharmaceutical pollutants such as sulfamethoxazole (SMX). However, research on the adsorption and redox behaviors of SMX on the pyrite surface is limited. Here, we investigated the impact of the nonphotochemical process of pyrite on the fate of coexisting SMX. Remarkably, sulfur vacancies (SVs) on pyrite promoted the generation of nonradical species (hydrogen peroxide, H2O2 and singlet oxygen, 1O2), thereby exhibiting prominent SMX degradation performance under darkness. Nonradical 1O2 contributed approximately 73.1% of the total SMX degradation. The SVs with high surrounding electron density showed an advanced affinity for adsorbing O2 and then initiated redox reactions in the sediment electron-storing geobattery pyrite, resulting in the extensive generation of H2O2 through a two-electron oxygen reduction pathway. Surface Fe(III) (hydro)oxides on pyrite facilitated the decomposition of H2O2 to 1O2 generation. Distinct nonradical products were observed in all investigated estuarine and coastal samples with the concentrations of H2O2 ranging from 1.96 to 2.94 µM, while the concentrations of 1O2 ranged from 4.63 × 10-15 to 8.93 × 10-15 M. This dark-redox pathway outperformed traditional photochemical routes for pollutant degradation, broadening the possibilities for nonradical species use in estuarine and coastal sediments. Our study highlighted the SV-triggered process as a ubiquitous yet previously overlooked source of nonradical species, which offered fresh insights into geochemical processes and the dynamics of pollutants in regions of frequent redox oscillations and sulfur-rich sediments.

Depression and suicidal ideation among Chinese college students during the COVID-19 pandemic: the mediating roles of chronotype and sleep quality.

BACKGROUND: This study was intended to investigate the correlation between depression and suicidal ideation among Chinese college students during the COVID-19 pandemic and the potential mediating roles of chronotype and sleep quality in this relationship . METHODS: A sample of 4,768 college students was selected from four institutions in Anhui Province, China, and the study was conducted during the COVID-19 pandemic (November to December 2020) using a stratified, cluster, multi-stage sampling method. This study used the two-item Patient Health Questionnaire (PHQ-2) to assess depressive symptoms, the Morningness-Eveningness Questionnaire 19 (MEQ-19) to determine individual sleep chronotypes (i.e., morning or evening preference), and the Pittsburgh Sleep Quality Index (PSQI) to evaluate sleep quality. Participants were asked about suicidal ideation. MPLUS 8.3 software was used to analyze the mediating effect of chronotype and sleep quality on the relationship between depression and suicidal ideation. RESULTS: During the COVID-19 pandemic, the prevalence of suicidal ideation among Chinese college students was 5.4%. Depression was inversely correlated with chronotype (beta = - 0.346, P < 0.01) and positively correlated with sleep quality (beta = 0.846, P < 0.001), indicating that students experiencing depressive symptoms were more likely to have a later chronotype and poor sleep quality. A later chronotype (beta = - 0.019, P < 0.05) and poor sleep quality (beta = 0.066, P < 0.01) predicted suicidal ideation. Depression emerged as a direct and significant risk factor for suicidal ideation (effect value = 0.535, 95% confidence interval: 0.449 ~ 0.622). Chronotype and sleep quality were found to have potential mediating effects on the relationship between depression and suicidal ideation; however, the chain-mediating effect of chronotype and sleep quality was not statistically significant. CONCLUSIONS: Our findings suggest that during the COVID-19 pandemic, depression can precipitate suicidal ideation through its influence on sleep chronotype and quality. These compelling findings highlight the urgency of early intervention strategies intended to mitigate suicidal thoughts, particularly among students exhibiting depressive symptoms, who experience disrupted sleep patterns and poor sleep quality.

Urinary antibiotic levels and risk of overweight/obesity in preschool children: A biomonitoring-based study from eastern China.

There is limited evidence linking antibiotic exposure, particularly from contaminated food or drinking water, to childhood obesity. The study aimed to investigate the association between urinary antibiotic levels and overweight/obesity in preschool children. In the case-control study, 121 overweight/obese preschoolers and 242 controls (aged 3-6 years) from eastern China were enrolled in 2022 based on age, sex, and study site matching. Overweight/obesity was determined using body mass index (BMI) and weight for height (WFH) criteria derived from national data. A total of 50 antibiotics from 8 categories were analyzed using ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). We identified major dietary patterns using principal component analysis (PCA) and examined the associations of antibiotic exposure with childhood overweight/obesity using multivariate logistic regression. Twenty-four individual antibiotics were detected in more than 10 % of the samples, and overall detection rates were up to 100 %. Overweight/obese children had a higher exposure to veterinary antibiotics (VAs) than normal weight children. PCA analysis showed that children who were overweight/obese had higher scores of "Aquatic products preferred dietary pattern" and "Cereals preferred dietary pattern" compared to children with normal weight. Multivariate logistic regression analyses indicated that exposure to elevated levels of deoxytetracycline (OR: 1.72; 95 %CI: 1.00-2.93) and quinolones (OR: 1.63; 95 %CI: 1.04-2.57) was significantly related to an increased risk of BMI-based overweight/obesity. Quinolones exposure was also significantly associated with WFH-based overweight/obesity, primarily in boys. After adjustment for all covariates, higher exposure to ofloxacin (of the quinolones) was significantly related to overweight/obesity in girls. Exposure to certain antibiotics, especially quinolones, may increase the risk of overweight/obesity in preschoolers. More prospective, well-designed studies are needed to clarify these findings.

Elevated remnant cholesterol was associated with the increased metabolically unhealthy obesity risk in Chinese youth.

BACKGROUND AND OBJECTIVES: Metabolically unhealthy obesity is characterized by the presence of cardiovascular metabolic risks such as hypertension, dyslipidemia, and hyperglycemia. Research has shown a correlation between remnant cholesterol (RC) concentrations and abdominal obesity in children. However, the effect of RC concentration on metabolically unhealthy obesity remains unclear. METHODS AND STUDY DESIGN: This study included 3114 Chinese adolescents who received health check-ups. We used logistic regression models and receiver operating characteristic analysis to evaluate the correlation between RC concentration and metabolically unhealthy obesity in a cross-sectional design. RESULTS: After controlling for possible confounding variables, we found that individuals in the top and fourth quintiles of RC concentrations had a significantly higher likelihood of developing metabolically unhealthy obesity compared to those in the bottom quintile (ORs, 4.810 and 1.836; 95% CIs, 3.209-7.212 and 1.167-2.890, respectively). The risk of metabolically unhealthy obesity tended to increase with RC concentration (ptrend<0.001). In addition, boys showed positive associations between RC concentration and both BMI (r = 0.305, p<0.001) and waist circumference (r = 0.306, p<0.001). According to the analysis, the predictive accuracy of metabolically unhealthy obesity was 0.736 (95% CI, 0.690-0.781) for boys and 0.630 (95% CI, 0.573-0.687) for girls. The ideal prediction threshold was 0.66 for boys and 0.59 for girls. CONCLUSIONS: Our findings indicate that elevated RC concen-tration is linked to a higher likelihood of developing metabolically unhealthy obesity in young individuals, regardless of other known risk factors.

Giant, Linearly Increasing Spin-Orbit Torque Efficiency in Symmetry-Broken Spin-Orbit Torque Superlattices.

Magnetic heterostructures with high spin-orbit torque efficiency and low impedance have great promise for low-power spintronic technologies. We report a symmetry-broken spin-orbit superlattice [Pt0.75Cu0.25/Co/Ta]n, in which the dampinglike spin-orbit torque efficiency accumulates linearly with the repeat number n and achieves a giant value of >200% when n = 16, which is 100 times stronger than that of a conventional magnetic heterostructure with a clean Pt (e.g., 2% at a resistivity of 7 µΩ cm). The giant spin-orbit torque effect arises predominantly from the spin Hall effect of Pt0.75Cu0.25. The anomalous Nernst effect increases remarkably as the repeat number n increases, implying a critical need to include the thermal effect in the analysis of magnetic superlattices and multilayers. The giant spin-orbit torque, low resistivity, and strong anomalous Nernst effect suggest the great potential of the superlattice [Pt0.75Cu0.25/Co/Ta]n for low-power memory and logic technologies as well as high-performance thermoelectric battery and sensor applications.

Optimized rat models better mimic patients with irinotecan-induced severe diarrhea.

Irinotecan-induced severe diarrhea (IISD) not only limits irinotecan's application but also significantly affects patients' quality of life. However, existing animal models often inadequately represent the dynamics of IISD development, progression, and resolution across multiple chemotherapy cycles, yielding non-reproducible and highly variable response with limited clinical translation. Our studies aim to establish a reproducible and validated IISD model that better mimics the pathophysiology progression observed in patients, enhancing translational potential. We investigated the impact of dosing regimens (including different dose, infusion time, and two cycles of irinotecan administration), sex, age, tumor-bearing conditions, and irinotecan formulation on the IISD incidence and severity in mice and rats. Lastly, we investigated above factors' impact on pharmacokinetics of irinotecan, intestinal injury, and carboxylesterase activities. In summary, we successfully established a standard model establishment procedure for an optimized IISD model with highly reproducible severe diarrhea incidence rate (100%) and a low mortality rate (11%) in F344 rats. Additionally, the rats tolerated at least two cycles of irinotecan chemotherapy treatment. In contrast, the mouse model exhibited suboptimal IISD incidence rates (60%) and an extremely high mortality rate (100%). Notably, dosing regimen, age and tumor-bearing conditions of animals emerged as critical factors in IISD model establishment. In conclusion, our rat IISD model proves superior in mimicking pathophysiology progression and characteristics of IISD in patients, which stands as an effective tool for mechanism and efficacy studies in future chemotherapy-induced gut toxicity research.

Comparison of the Efficacy of Indwelling Gastric Tubes in Preoperative and Postoperative Patients With Oral and Maxillofacial Malignancies.

PURPOSE: To explore the optimal plan for the timing of indwelling gastric tube placement in oral and maxillofacial malignant tumor patients. DESIGN: A prospective randomized controlled trial. METHODS: 80 patients with oral and maxillofacial tumor were selected, and 40 patients were Pre-operative group. The remaining 40 patients were the control group, called Postoperative group. The body weight and hospital stay of the two groups were observed before and after surgery. Blood samples were taken before surgery and 1, 3 and 7 days after surgery to detect hemoglobin and plasma albumin. FINDINGS: The number of postoperative hospitalization days in the pre-operative group was significantly lower than that in the post-operative group; postoperative hemoglobin and plasma albumins were lower in both groups compared with the preoperative level. CONCLUSIONS: Preoperative nasogastric tube ensured early postoperative administration of gastrointestinal nutrition, promoted postoperative plasma albumin recovery, and shortened the days of hospitalization.

MicroRNA-27a Regulates Ferroptosis Through SLC7A11 to Aggravate Cerebral ischemia-reperfusion Injury.

Cerebral ischemia-reperfusion (I/R) injury is an inevitable issue in the treatment of ischemic stroke, which has a high disability rate and seriously threatens the living quality of patients. Previous studies have demonstrated that ferroptosis, which plays a crucial role in ischemia-reperfusion injury, can be accelerated by microRNA-27a (miR-27a). However, the mechanism by which miR-27a regulates ferroptosis in cerebral ischemia-reperfusion injury remains unknown. In this study, Male Sprague-Dawley rats were subjected to a middle cerebral artery occlusion (MCAO), then restored blood flow. Neurological function score and TTC staining were used to evaluate brain tissue injury and the infarct volume. The relative expression level of miR-27a was detected by qPCR. The relative expression levels of glutathione peroxidase 4(GPx4), solute carrier family 7 member 11 (SLC7A11) proteins were analyzed by Western Blot. The contents of GSH, Fe and malonaldehyde (MDA) were detected by corresponding detection kits, and the target gene of miR-27a was confirmed by dual luciferase reporter gene technique. It was found the relative expression level of miR-27a was increased and ferroptosis was aggravated as reperfusion time went by. Also, brain tissue injury and ferroptosis were exacerbated with agomiR-27a intervention, while these effects were reversed with antagomiR-27a intervention. In addition, the combined intervention of agomiR-27a and Fer-1 alleviated the brain tissue injury and ferroptosis. The results of dual luciferase reporter gene technique indicated SLC7A11 as the target gene of miR-27a. In the current study, miR-27a upregulates ferroptosis to aggravate cerebral ischemia-reperfusion injury by SLC7A11.

Clinical indocyanine green-based silk fibroin theranostic nanoprobes for in vivo NIR-I/II fluorescence imaging of cervical diseases.

Cervical diseases such as lymph node disease and tubal obstruction have threatened women's health. However, the traditional diagnostic methods still have shortcomings. NIR-II fluorescence imaging with advantages of low scattering, negligible autofluorescence, and high spatial resolution could be an ideal option. To obtain high quality NIR-II fluorescence imaging, selecting appropriate nanoprobes becomes the important issue. As a small molecular photothermal agent, extensive applications of ICG are rather limited because of its drawbacks. Herein, natural silk fibroin (SF) was synthesized and encapsulated ICG molecules to form SF@ICG nanoparticles (NPs). After detailed analysis, SF@ICG NPs showed excellent stability and long circulation time, as well as strong NIR-II fluorescence emission, well photo-stability, biocompatibility and well photothermal property under 808 nm laser irradiation. Furthermore, SF@ICG NPs were utilized for NIR-II fluorescence imaging of lymph node/lymphangiography and angiography of fallopian tubes. The process of fallopian tubes could be detected with high resolution and high sensitivity.

Efficacy and Adverse Reactions of Dahuang Mudan decoction Combined with Laparoscopy in the Treatment of Appendicitis: A Meta-Analysis.

Background: Appendicitis is a common acute abdominal disease. Traditional Chinese medicine believes that acute appendicitis is caused by the accumulation of heat and toxin, and the formation of carbuncle and pus in the colon due to stasis. Therefore, treatment should be carried out to clear heat and detoxify, clear the organs, and eliminate carbuncle. Dahuang Mudan Tang contains various traditional Chinese medicines for clearing heat and detoxifying, which can be used to treat appendicitis. This study observes the therapeutic effect of Dahuang Mudan Tang on patients undergoing laparoscopic surgery for acute appendicitis. Methods: Eight databases were searched by computer and inclusion criteria were pre determined before evaluation: (1) patients with appendicitis; (2) 18-70 years old; (3) Agree to this study and obtain randomized controlled trials at home and abroad on the combined treatment of appendicitis with caesarean section and rhubarb peony testing. Using RevMan 5.3 software, conduct a comprehensive evaluation of the cultivation quality and conduct data analysis. Results: The meta-analysis ultimately included 16 papers. They are all considered randomized controlled trials. The overall efficiency of the test unit and control unit was reported in 12 surveys. The total effective rate of the experimental group was significantly higher than that of the control group (Odds Ratio (OR): (1.16; 95% Cl: 1.11,1.20; P < .001), and the duration of bowel sounds was also significantly higher than that of the control group. Standardized mean deviation (SMD): (-7.39; 95% Cl: -8.48, -6.30; P < .01), defecation time SMD: (-1.60; 95% Cl: -2.07, -1.12; P < .01). Conclusion: Based on the total effective rate, defecation time, defecation time, CRP, IL-6, and adverse reactions of participants in this study, the combination of Dahuang Mudan Tang and laparoscopy in the treatment of appendicitis may be beneficial, which can improve clinical efficacy, inhibit inflammatory reactions, and promote postoperative recovery of patients. It is worth promoting and applying in clinical practice. However, these findings still require more high-quality research to confirm. Patients undergoing laparoscopic surgery for appendicitis were treated with Dahuang Mudan Tang combined with targeted intervention.

Exposure to metal mixtures and young children's growth and development: A biomonitoring-based study in Eastern China.

Exposure to metal mixtures may affect children's health but the conclusions are controversial. We aimed to investigate the associations of metal mixture exposure with children's physical and behavioral development. 15 metals were detected in the urine samples of 278 preschoolers aged 3-6 years from eastern China. Multiple linear models and restricted cubic splines were used to evaluate dose-response relationships between single metal and children's physical and behavioral development. The Bayesian Kernel Machine Regression (BKMR) models, the weighted quantile sum (WQS) models and Quantile G-Computation were applied to evaluate the joint effects of metal mixtures. The results showed that arsenic (As) was negatively associated with z score of height for age (HAZ) in individual-metal models [ß (95%CI): - 0.22 (-0.38, -0.06), P = 0.006]. Concerning children's behavioral development, multiple-metal models demonstrated a negative association with strontium (Sr) [ß (95%CI): - 0.82 (-1.38, -0.26), P = 0.004], and a positive association with tin (Sn) [ß (95%CI): 0.69 (0.16, 1.21), P = 0.010]. Notably, these associations remained significant or suggestive even after adjustments for multiple tests, sensitivity analyses, and application of different statistical models, including BKMR, WQS, and Quantile G-Computation. Furthermore, the study identified a negative joint effect of the metal mixture on HAZ, as demonstrated by BKMR and Quantile G-Computation models, with As playing an irreplaceable role in this observed impact. In summary, exposure to As appears to have adverse effects on HAZ, while exposure to Sn may hinder children's behavioral development. Conversely, exposure to Sr may have a protective effect on children's behavioral development. Additionally, the combined impact of metal mixtures is implicated in potentially impairing children's physical development, particularly in terms of HAZ.

Bulleyaconitine A is a sensitive substrate and competitive inhibitor of CYP3A4: One of the possible explanations for clinical adverse reactions.

Bulleyaconitine A (BLA), a toxic Aconitum alkaloid, is a potent analgesic that is clinically applied to treat rheumatoid arthritis, osteoarthritis and lumbosacral pain. BLA-related adverse reactions occur frequently, but whether the underlying mechanism is related to its metabolic interplay with drug-metabolizing enzymes remains unclear. This study aimed to elucidate the metabolic characteristics of BLA and its affinity action and mechanism to drug-metabolizing enzymes to reveal whether BLA-related adverse reactions are modulated by enzymes. After incubation with human liver microsomes and recombinant human cytochrome P450 enzymes, we found that BLA was predominantly metabolized by CYP3A, in which CYP3A4 had an almost absolute advantage. In vitro, the CYP3A4 inhibitor ketoconazole noticeably suppressed the metabolism of BLA. In vivo, the AUC0-∞ values, cardiotoxicity and neurotoxicity of BLA in Cyp3a-inhibited mice were all obviously enhanced (P < 0.05) compared to those in normal mice. In the enzyme kinetics study, BLA was found to be a sensitive substrate of CYP3A4, and its characteristics were consistent with substrate inhibition (Km = 39.36 ± 10.47 µmol/L, Ks = 83.42 ± 19.65 µmol/L). BLA was further identified to be a competitive inhibitor of CYP3A4 with Ki = 53.64 µmol/L, since the intrinsic clearance (CLint) of midazolam, a selective CYP3A4 substrate, decreased significantly (P < 0.05) when incubated with BLA together in mouse liver microsomes. Overall, BLA is a sensitive substrate and competitive inhibitor of CYP3A4, and clinical adverse reactions of BLA may mechanistically related to the CYP3A4-mediated drug-drug interactions.

Cardiovascular risk factors and breast cancer incidence in a large middle-aged cohort study.

BACKGROUND: Several studies have demonstrated that cardiovascular risk factors play a role in the etiology of breast cancer. However, the combined effect of cardiovascular risk factors on the risk of breast cancer is still uncertain. METHODS: Data from the Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort of middle-aged women, were used to investigate the association of individual and combined cardiovascular risk factors with breast cancer. Cox proportional hazards models were applied to calculate the hazard ratio (HR) and 95% confidence intervals (CI). RESULTS: A total of 7501 women were included. During a mean follow-up of 19.7 years, 576 women were diagnosed with breast cancer. White women and premenopausal status were independently associated with increased risk of breast cancer. Of the individual cardiovascular risk factors, only obesity was independently associated with an increased risk of breast cancer (HR 1.29, 95% CI 1.04-1.61). Compared with women without cardiovascular risk factors, women having three or greater, but not those with fewer than three cardiovascular risk factors, had a significantly higher risk of developing breast cancer (HR 1.27, 95% CI 1.06-1.53). Subgroup analyses indicated that women with three or greater cardiovascular risk factors had higher risk of breast cancer among postmenopausal Black women, but not among premenopausal Black and White women. CONCLUSIONS: Combinations of cardiovascular risk factors are associated with increased risk of breast cancer in middle-aged women, especially in postmenopausal Black women. Joint interventions to modify cardiovascular risk factors could be used to prevent breast cancer in these higher-risk individuals.

Chiral induction in a novel self-assembled supramolecular system composed of α-cyclodextrin porous liquids, chiral silver nanoparticles and planar conjugated molecules.

The newly developed porous liquids known as liquids with permanent microporosity, have considerable application potential in many unknown areas. Herein, a supramolecular system composed of α-cyclodextrin porous liquid, chiral silver nanoparticles and planar conjugated molecules (methylene blue and indigo carmine) was designed and the induced chirality of the system was observed. It was found that the induced chirality can be easily tuned by changing the pH value of the mixture solution. The induced chiral signal of methylene blue in the developed self-assembled supramolecular system occurred when the pH was between 8 and 10, and furthermore the induced chirality of indigo carmine was found when the pH was between 6.5 and 7.5. The intensity of induced chirality decreases upon increasing temperatures and ionic strength. This study may offer a new approach for the creation of a chiral supramolecular system based on host-guest and electrostatic interaction and make cyclodextrin porous liquids promising candidates for applications in chiral induction.