Placental inflammatory injury induced by chlorinated polyfluorinated ether sulfonate (F-53B) through NLRP3 inflammasome activation.

Chlorinated polyfluorinated ether sulfonate, commercially known as F-53B, has been associated with adverse birth outcomes. However, the reproductive toxicology of F-53B on the placenta remains poorly understood. To address this gap, we examined the impact of F-53B on placental injury and its underlying molecular mechanisms in vivo. Pregnant C57BL/6 J female mice were randomly allocated to three groups: the control group, F-53B 0.8 µg/kg/day group, and F-53B 8 µg/kg/day group. After F-53B exposure through free drinking water from gestational day (GD) 0.5-14.5, the F-53B 8 µg/kg/day group exhibited significant increases in placental weights and distinctive histopathological alterations, including inflammatory cell infiltration, heightened syncytiotrophoblast knots, and a loosened trophoblastic basement membrane. Within the F-53B 8 µg/kg/day group, placental tissue exhibited increased apoptosis, as indicated by increased caspase3 activation. Furthermore, F-53B potentially induced the NF-κB signaling pathway activation through IκB-α phosphorylation. Subsequently, this activation upregulated the expression of inflammatory cytokines and components of the NLRP3 inflammasome, including activated caspase1, IL-1ß, IL-18, and cleaved gasdermin D (GSDMD), ultimately leading to pyroptosis in the mouse placenta. Our findings reveal a pronounced inflammatory injury in the placenta due to F-53B exposure, suggesting potential reproductive toxicity at concentrations relevant to the human population. Further toxicological and epidemiological investigations are warranted to conclusively assess the reproductive health risks posed by F-53B.

Exposure to Neighborhood Greenness and Hypertension Incidence in Adults: A Longitudinal Cohort Study in Taiwan.

BACKGROUND: There are few studies on the health effects of long-term exposure to neighborhood greenness in a longitudinal setting, especially in Asian countries with high population densities. OBJECTIVES: This study investigates the association between long-term exposure to neighborhood greenness and hypertension among adults in Taiwan. METHODS: We selected 125,537 participants (≥18 years of age) without hypertension from Taiwan who had joined the standard medical examination program between 2001 and 2016. Neighborhood greenness was estimated using the normalized difference vegetation index (NDVI), derived from satellite images at a resolution of 250 m2. The 2-y average NDVI value within a 500-m circular buffer around participants' residences was calculated. A time-varying Cox regression model was used to investigate the association between neighborhood greenness and incident hypertension. Mediation analyses were performed to examine whether the association was explained by air pollution, leisure-time physical exercise, or body mass index (BMI). RESULTS: Compared with living in areas within the first quartile of neighborhood greenness, living in areas within the second, third, and fourth quartiles of neighborhood greenness was found to be associated with a lower risk of hypertension, with hazard ratios (HRs) and 95% confidence intervals (CIs) of 0.95 (95% CI: 0.91, 1.00), 0.95 (95% CI: 0.90, 0.99), and 0.93 (95% CI: 0.88, 0.97), respectively. Each 0.1-unit increase in the NDVI was associated with a 24% lower risk of developing hypertension (HR=0.76; 95% CI: 0.66, 0.87), with this associations being stronger among males and those with higher education levels. This association was slightly mediated by BMI but not by air pollution or leisure-time physical exercise. DISCUSSION: Our findings suggest the protective effects of neighborhood greenness on hypertension development, especially in males and well-educated individuals. Our results reinforced the importance of neighborhood greenness for supporting health. https://doi.org/10.1289/EHP13071.

Protocol for induction of human kidney cell fibrosis.

Here, we present a protocol for inducing fibrosis in human kidney-2 (HK2) cells followed by quantitative real-time PCR analysis of fibrosis-related genes. We describe steps for growing and expanding cells, inducing HK2 fibrosis, and collecting cells for downstream applications. Given the limited cell quantity in culture flasks and the challenges of cell collection, we utilized 10-cm Petri dishes for cell harvesting, with each experimental group comprising five replicate samples. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

Novel Carrier-Free Nanodrug Enhances Photodynamic Effects by Blocking the Autophagy Pathway and Synergistically Triggers Immunogenic Cell Death for the Efficient Treatment of Breast Cancer.

Photosensitizers have been widely used to cause intratumoral generation of reactive oxygen species (ROS) for cancer therapy, but they are easily disturbed by the autophagy pathway, a self-protective mechanism by mitigating oxidative damage. Hereby, we reported a simple and effective strategy to construct a carrier-free nanodrug, Ce6@CQ namely, based on the self-assembly of the photosensitizer chlorin e6 (Ce6) and the autophagy inhibitor chloroquine (CQ). Specifically, Ce6@CQ avoided the unexpected toxicity caused by the regular nanocarrier and also ameliorated its stability in different conditions. Light-activated Ce6 generated cytotoxic ROS and elicited part of the immunogenic cell death (ICD). Moreover, CQ induced autophagy dysfunction, which hindered self-healing in tumor cells and enhanced photodynamic therapy (PDT) to exert a more potent killing effect and more efficient ICD. Also, Ce6@CQ could effectively accumulate in the xenograft breast tumor site in a mouse model through the enhanced permeability and retention (EPR) effect, and the growth of breast tumors was effectively inhibited by Ce6@CQ with light. Such a carrier-free nanodrug provided a new strategy to improve the efficacy of PDT via the suppression of autophagy to digest ROS-induced toxic substances.

Adipose Tissue Targeting Ultra-Small Hybrid Nanoparticles for Synergistic Photodynamic Therapy and Browning Induction in Obesity Treatment.

Photodynamic therapy (PDT), as a means of locally and rapidly inducing adipocyte death via light illumination, in combination with adipose browning induction, a more gradual and widespread effect that could transform white adipose tissue into thermogenic adipose tissue, manifests a promising approach to combat obesity. Herein, adipose-targeting ultra-small hybrid nanoparticles (Pep-PPIX-Baic NPs) composed of an adipose-targeting peptide, Fe3+, a photosensitizer (protoporphyrin IX), and a browning agent (baicalin) are introduced. Pep-PPIX-Baic NPs have been designed to simultaneously enhance the photodynamic effect and induce browning. After intravenous injection in obese mice, the hybrid nanoparticles can specifically accumulate in white adipose tissues, especially those rich in blood supply, and drive adipose reduction owing to the synergy of the PDT effect and baicalin browning induction. Overall, Pep-PPIX-Baic NPs exhibited superior anti-obesity potential through PDT synergistic with adipose browning induction. The designed multifunctional adipose-targeting hybrid nanoparticles present a prospective nanoplatform for obesity treatment.

Global, regional, and national burden of ischemic heart disease attributable to ambient PM2.5 from 1990 to 2019: An analysis for the global burden of disease study 2019.

Information on the spatio-temporal patterns of the burden of ischemic heart disease (IHD) caused by ambient ambient fine particulate matter (PM2.5) in the global level is needed to prioritize the control of ambient air pollution and prevent the burden of IHD. The Global Burden of Disease Study (GBD) 2019 provides data on IHD attributable to ambient PM2.5. The IHD burden and mortality attributable to ambient PM2.5 were analyzed by year, age, gender, socio-demographic index (SDI) level, geographical region and country. Estimated annual percentage change (EAPC) was calculated to estimate the temporal trends of age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life years rate (ASDR) from 1990 to 2019. Globally, the ASMR and ASDR for ambient PM2.5-related IHD tended to level off generally, with EAPC of -0.03 (95% CI: -0.06, 0.12) and 0.3 (95% CI: 0.22, 0.37), respectively. In the past 30 years, there were obvious differences in the trend of burden change among different regions. A highest increased burden was estimated in low-middle SDI region (EAPC of ASMR: 3.73 [95% CI: 3.56, 3.9], EAPC of ASDR: 3.83 [95% CI: 3.64, 4.02]). In contrast, the burden in high SDI region (EAPC of ASMR: -4.48 [95% CI: -4.6, -4.35], EAPC of ASDR: -3.98 [95% CI: -4.12, -3.85]) has declined most significantly. Moreover, this burden was higher among men and older populations. EAPCs of the ASMR (R = -0.776, p < 0.001) and ASDR (R = -0.781, p < 0.001) of this burden had significant negative correlations with the countries' SDI level. In summary, although trends in the global burden of IHD attributable to ambient PM2.5 are stabilizing, but this burden has shifted from high SDI countries to middle and low SDI countries, especially among men and elderly populations. To reduce this burden, the air pollution management prevention need to be further strengthened, especially among males, older populations, and middle and low SDI countries.

A Spatiotemporal and Machine-Learning Platform Accelerates the Manufacturing of hPSC-derived Esophageal Mucosa.

Human pluripotent stem cell-derived tissue engineering offers great promise in designer cell-based personalized therapeutics. To harness such potential, a broader approach requires a deeper understanding of tissue-level interactions. We previously developed a manufacturing system for the ectoderm-derived skin epithelium for cell replacement therapy. However, it remains challenging to manufacture the endoderm-derived esophageal epithelium, despite both possessing similar stratified structure. Here we employ single cell and spatial technologies to generate a spatiotemporal multi-omics cell atlas for human esophageal development. We illuminate the cellular diversity, dynamics and signal communications for the developing esophageal epithelium and stroma. Using the machine-learning based Manatee, we prioritize the combinations of candidate human developmental signals for in vitro derivation of esophageal basal cells. Functional validation of the Manatee predictions leads to a clinically-compatible system for manufacturing human esophageal mucosa. Our approach creates a versatile platform to accelerate human tissue manufacturing for future cell replacement therapies to treat human genetic defects and wounds.

Influence of Air Pollution Exposures on Cardiometabolic Risk Factors: a Review.

PURPOSE OF REVIEW: The increasing prevalence of cardiometabolic risk factors (CRFs) contributes to the rise in cardiovascular disease. Previous research has established a connection between air pollution and both the development and severity of CRFs. Given the ongoing impact of air pollution on human health, this review aims to summarize the latest research findings and provide an overview of the relationship between different types of air pollutants and CRFs. RECENT FINDINGS: CRFs include health conditions like diabetes, obesity, hypertension etc. Air pollution poses significant health risks and encompasses a wide range of pollutant types, air pollutants, such as particulate matter (PM), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O2). More and more population epidemiological studies have shown a positive correlation between air pollution and CRFs. Although various pollutants have diverse effects on specific cellular molecular pathways, their main influence is on oxidative stress, inflammation response, and impairment of endothelial function. More and more studies have proved that air pollution can promote the occurrence and development of cardiovascular and metabolic risk factors, and the research on the relationship between air pollution and CRFs has grown intensively. An increasing number of studies are using new biological monitoring indicators to assess the occurrence and development of CRFs resulting from exposure to air pollution. Abnormalities in some important biomarkers in the population (such as homocysteine, uric acid, and C-reactive protein) caused by air pollution deserve more attention. Further research is warranted to more fully understand the link between air pollution and novel CRF biomarkers and to investigate potential prevention and interventions that leverage the mechanistic link between air pollution and CRFs.

Comprehensive analysis of the relationship between xanthine oxidoreductase activity and chronic kidney disease.

Chronic kidney disease (CKD) is a common disease that seriously endangers human health. However, the potential relationship between xanthine oxidoreductase (XOR) activity and CKD remains unclear. In this study, we used clinical data, CKD datasets from the Gene Expression Omnibus database, and untargeted metabolomics to explain the relationship between XOR activity and CKD. First, XOR activity showed high correlation with the biomarkers of CKD, such as serum creatinine, blood urea nitrogen, uric acid, and estimated glomerular filtration rate. Then, we used least absolute shrinkage and selection operator logical regression algorithm and random forest algorithm to screen CKD molecular markers from differentially expressed genes, and the results of qRT-PCR of XDH, KOX-1, and ROMO1 were in accordance with the results of bioinformatics analyses. In addition, untargeted metabolomics analysis revealed that the purine metabolism pathway was significantly enriched in CKD patients in the simulated models of kidney fibrosis.

Discovery of dolutegravir-1,2,3-triazole derivatives against prostate cancer via inducing DNA damage.

Prostate cancer (PCa) is the second most frequently diagnosed cancer among men, causing a huge number of deaths each year. Traditional chemotherapy for PCa mostly focused on targeting androgen receptors. However, some of the patients would develop resistance to hormonal therapy. In these cases, it is suggested for these patients to administer treatments in combination with other chemotherapeutics. Current chemotherapeutics for metastatic castration-resistant PCa could hardly reach satisfying effects, therefore it is crucial to explore novel agents with low cytotoxicity. Herein, a common drug against the human immunodeficiency virus (HIV), the dolutegravir (DTG) was modified to become a series of dolutegravir-1,2,3-triazole derivatives. Among these compounds, the 4d and 4q derivatives were verified with high anti-tumor efficiency, suppressing the proliferation of the prostate cancer cells PC3 and DU145. These compounds function by binding to the poly (adenosine diphosphate-ribose) polymerase (PARP), inactivating the PARP and inducing DNA damage in cancer cells. It is noteworthy that the 4d and 4q derivatives showed almost no impact on normal cells and mice. Thereby, the results reveal that these dolutegravir-1,2,3-triazole compounds are potential chemotherapeutics for PCa treatment.

A carrier-free supramolecular nano-twin-drug for overcoming irinotecan-resistance and enhancing efficacy against colorectal cancer.

Irinotecan (Ir) is commonly employed as a first-line chemotherapeutic treatment for colorectal cancer (CRC). However, tremendous impediments remain to be addressed to surmount drug resistance and ameliorate adverse events. Poly-ADP-Ribose Polymerase (PARP) participates in the maintenance of genome stability and the repair of DNA damage, thus playing a critical role in chemotherapy resistance. In this work, we introduce a novel curative strategy that utilizes nanoparticles (NPs) prepared by dynamic supramolecular co-assembly of Ir and a PARP inhibitor (PARPi) niraparib (Nir) through π-π stacking and hydrogen bond interactions. The Ir and Nir self-assembled Nano-Twin-Drug of (Nir-Ir NPs) could enhance the therapeutic effect on CRC by synergistically inhibiting the DNA damage repair pathway and activating the tumor cell apoptosis process without obvious toxicity. In addition, the Nir-Ir NPs could effectively reverse irinotecan-resistance by inhibiting the expression of multiple resistance protein-1 (MRP-1). Overall, our study underscores the distinctive advantages and potential of Nir-Ir NPs as a complementary strategy to chemotherapy by simultaneously overcoming the Ir resistance and improving the anti-tumor efficacy against CRC.

The association between childhood adiposity in northeast China and anthropogenic heat flux: A new insight into the comprehensive impact of human activities.

Anthropogenic heat has been reported to have significant health impacts, but research on its association with childhood adiposity is still lacking. In this study, we matched the 2008-2012 average anthropogenic heat flux, as simulated by a grid estimation model using inventory methods, with questionnaire and measurement data of 49,938 children randomly recruited from seven cities in Northeast China in 2012. After adjusting for social demographic and behavioral factors, we used generalized linear mixed-effect models to assess the association between anthropogenic heat flux and adiposity among children. We also examined the effect modification of various social demographic and behavioral confounders. We found that each 10 W/m2 increase in total anthropogenic heat flux and that from the industry source was associated with an increase of 5.82% (95% CI = 0.84%-11.05%) and 6.62% (95% CI = 0.87%-12.70%) in the odds of childhood adiposity. Similarly, the excess rate of adiposity among children were 5.26% (95% CI = -1.33%-12.29%) and 8.51% (95% CI = 2.24%-15.17%) per 1 W/m2 increase in the anthropogenic heat flux from transportation and buildings, and was 7.94% (95% CI = 2.28%-13.91%) per 0.001 W/m2 increase in the anthropogenic heat flux from human metabolism. We also found generally greater effect estimates among female children and children who were exposed to passive smoking during pregnancy, born by caesarean section, non-breastfed/mixed-fed, or lived within 20 m adjacent to the main road. The potential deleterious effect of anthropogenic heat exposure on adiposity among children may make it a new but major threat to be targeted by future mitigation strategies.

Role of interneuron subtypes in controlling trial-by-trial output variability in the neocortex.

Trial-by-trial variability is a ubiquitous property of neuronal activity in vivo which shapes the stimulus response. Computational models have revealed how local network structure and feedforward inputs shape the trial-by-trial variability. However, the role of input statistics and different interneuron subtypes in this process is less understood. To address this, we investigate the dynamics of stimulus response in a cortical microcircuit model with one excitatory and three inhibitory interneuron populations (PV, SST, VIP). Our findings demonstrate that the balance of inputs to different neuron populations and input covariances are the primary determinants of output trial-by-trial variability. The effect of input covariances is contingent on the input balances. In general, the network exhibits smaller output trial-by-trial variability in a PV-dominated regime than in an SST-dominated regime. Importantly, our work reveals mechanisms by which output trial-by-trial variability can be controlled in a context, state, and task-dependent manner.

An ultrasmall PVP-Fe-Cu-Ni-S nano-agent for synergistic cancer therapy through triggering ferroptosis and autophagy.

Photothermal therapy (PTT) is an emerging field where photothermal agents could convert visible or near-infrared (NIR) radiation into heat to kill tumor cells. However, the low photothermal conversion efficiency of photothermal agents and their limited antitumor activities hinder the development of these agents into monotherapies for cancer. Herein, we have fabricated an ultrasmall polyvinylpyrrolidone (PVP)-Fe-Cu-Ni-S (PVP-NP) nano-agent via a simple hot injection method with excellent photothermal conversion efficiency (∼96%). Photothermal therapy with this nano-agent effectively inhibits tumor growth without apparent toxic side-effects. Mechanistically, our results demonstrated that, after NIR irradiation, PVP-NPs can induce ROS/singlet oxygen generation, decrease the mitochondrial membrane potential, release extracellular Fe2+, and consume glutathione, triggering autophagy and ferroptosis of cancer cells. Moreover, PVP-NPs exhibit excellent contrast enhancement according to magnetic resonance imaging (MRI) analysis. In summary, PVP-NPs have a high photothermal conversion efficiency and can be applied for MRI-guided synergistic photothermal/photodynamic/chemodynamic cancer therapy, resolving the bottleneck of existing phototherapeutic agents.

Nanodrugs systems for therapy and diagnosis of esophageal cancer.

With the increasing incidence of esophageal cancer, its diagnosis and treatment have become one of the key issues in medical research today. However, the current diagnostic and treatment methods face many unresolved issues, such as low accuracy of early diagnosis, painful treatment process for patients, and high recurrence rate after recovery. Therefore, new methods for the diagnosis and treatment of esophageal cancer need to be further explored, and the rapid development of nanomaterials has brought new ideas for solving this problem. Nanomaterials used as drugs or drug delivery systems possess several advantages, such as high drug capacity, adjustably specific targeting capability, and stable structure, which endow nanomaterials great application potential in cancer therapy. However, even though the nanomaterials have been widely used in cancer therapy, there are still few reviews on their application in esophageal cancer, and systematical overview and analysis are deficient. Herein, we overviewed the application of nanodrug systems in therapy and diagnosis of esophageal cancer and summarized some representative case of their application in diagnosis, chemotherapy, targeted drug, radiotherapy, immunity, surgery and new therapeutic method of esophageal cancer. In addition, the nanomaterials used for therapy of esophageal cancer complications, esophageal stenosis or obstruction and oesophagitis, are also listed here. Finally, the challenge and the future of nanomaterials used in cancer therapy were discussed.

Cortical Pyramidal and Parvalbumin Cells Exhibit Distinct Spatiotemporal Extracellular Electric Potentials.

Highlighted Research Paper: L. J. Sukman and E. Stark, "Cortical pyramidal and parvalbumin cells exhibit distinct spatiotemporal extracellular electric potentials." eNeuro (2022).

Maternal transfer of F-53B inhibited neurobehavior in zebrafish offspring larvae and potential mechanisms: Dopaminergic dysfunction, eye development defects and disrupted calcium homeostasis.

Maternal exposure to environment toxicants is an important risk factor for neurobehavioral health in their offspring. In our study, we investigated the impact of maternal exposure to chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs, commercial name: F-53B) on behavioral changes and the potential mechanism in the offspring larvae of zebrafish. Adult zebrafish exposed to Cl-PFESAs (0, 0.2, 2, 20 and 200 µg/L) for 21 days were subsequently mated their embryos were cultured for 5 days. Higher concentrations of Cl-PFESAs in zebrafish embryos were observed, along with, reduced swimming speed and distance travelled in the offspring larvae. Molecular docking analysis revealed that Cl-PFESAs can form hydrogen bonds with brain-derived neurotropic factor (BDNF), protein kinase C, alpha, (PKCα), Ca2+-ATPase and Na, K - ATPase. Molecular and biochemical studies evidenced Cl-PFESAs induce dopaminergic dysfunction, eye developmental defects and disrupted Ca2+ homeostasis. Together, our results showed that maternal exposure to Cl-PFESAs lead to behavioral alteration in offspring mediated by disruption in Ca2+ homeostasis, dopaminergic dysfunction and eye developmental defects.

Environmental pollutant pre- and polyfluoroalkyl substances are associated with electrocardiogram parameters disorder in adults.

Environmental pollutants exposure might disrupt cardiac function, but evidence about the associations of per- and polyfluoroalkyl substances (PFASs) exposure and cardiac conduction system remains sparse. To explore the associations between serum PFASs exposure and electrocardiogram (ECG) parameters changes in adults, we recruited 1229 participants (mean age: 55.1 years) from communities of Guangzhou, China. 13 serum PFASs with detection rate > 85% were analyzed finally. We selected 6 ECG parameters [heart rate (HR), PR interval, QRS duration, Bazett heart rate-corrected QT interval (QTc), QRS electric axis and RV5 + SV1 voltage] as outcomes. Generalized linear models (GLMs) and Bayesian kernel machine regression (BKMR) model were conducted to explore the associations of individual and joint PFASs exposure and ECG parameters changes, respectively. We detected significant associations of PFASs exposure with decreased HR, QRS duration, but with increased PR interval. For example, at the 95th percentile of 6:2 Cl-PFESA, HR and QRS duration were - 6.98 [95% confidence interval (CI): - 9.07, - 4.90] and - 6.54(95% CI: -9.05, -4.03) lower, but PR interval was 7.35 (95% CI: 3.52, 11.17) longer than those at the 25th percentile. Similarly, significant joint associations were observed in HR, PR interval and QRS duration when analyzed by BKMR model.

Smart Wearable Systems for Health Monitoring.

Smart wearable systems for health monitoring are highly desired in personal wisdom medicine and telemedicine. These systems make the detecting, monitoring, and recording of biosignals portable, long-term, and comfortable. The development and optimization of wearable health-monitoring systems have focused on advanced materials and system integration, and the number of high-performance wearable systems has been gradually increasing in recent years. However, there are still many challenges in these fields, such as balancing the trade-off between flexibility/stretchability, sensing performance, and the robustness of systems. For this reason, more evolution is required to promote the development of wearable health-monitoring systems. In this regard, this review summarizes some representative achievements and recent progress of wearable systems for health monitoring. Meanwhile, a strategy overview is presented about selecting materials, integrating systems, and monitoring biosignals. The next generation of wearable systems for accurate, portable, continuous, and long-term health monitoring will offer more opportunities for disease diagnosis and treatment.

Airway basal cells show regionally distinct potential to undergo metaplastic differentiation.

Basal cells are multipotent stem cells of a variety of organs, including the respiratory tract, where they are major components of the airway epithelium. However, it remains unclear how diverse basal cells are and how distinct subpopulations respond to airway challenges. Using single cell RNA-sequencing and functional approaches, we report a significant and previously underappreciated degree of heterogeneity in the basal cell pool, leading to identification of six subpopulations in the adult murine trachea. Among these, we found two major subpopulations, collectively comprising the most uncommitted of all the pools, but with distinct gene expression signatures. Notably, these occupy distinct ventral and dorsal tracheal niches and differ in their ability to self-renew and initiate a program of differentiation in response to environmental perturbations in primary cultures and in mouse injury models in vivo. We found that such heterogeneity is acquired prenatally, when the basal cell pool and local niches are still being established, and depends on the integrity of these niches, as supported by the altered basal cell phenotype of tracheal cartilage-deficient mouse mutants. Finally, we show that features that distinguish these progenitor subpopulations in murine airways are conserved in humans. Together, the data provide novel insights into the origin and impact of basal cell heterogeneity on the establishment of regionally distinct responses of the airway epithelium during injury-repair and in disease conditions.