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.

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.

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.

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.

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.

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.

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.

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.

A Strategy to Design Cu2MoS4@MXene Composite With High Photothermal Conversion Efficiency Based on Electron Transfer Regulatory Effect.

Using photothermal therapy to treat cancer has become an effective method, and the design of photothermal agents determines their performance. However, due to the major radiative recombination of a photogenerated electron in photothermal materials, the photothermal performance is weak which hinders their applications. In order to solve this issue, preventing radiative recombination and accelerating nonradiative recombination, which can generate heat, has been proved as a reasonable way. We demonstrated a Cu2MoS4@MXene nanocomposite with an obviously enhanced photothermal conversion efficiency (η = 87.98%), and this improvement can be attributed to the electron migration. Then, a mechanism is proposed based on the electron transfer regulatory effect and the localized surface plasmon resonance effect, which synergistically promote nonradiative recombination and generate more heat. Overall, our design strategy shows a way to improve the photothermal performance of Cu2MoS4, and this method can be extended to other photothermal agents to let them be more efficient in treating cancer.

Artificially Intelligent Olfaction for Fast and Noninvasive Diagnosis of Bladder Cancer from Urine.

Globally, bladder cancer (BLC) is one of the most common cancers and has a high recurrence and mortality rate. Current clinical diagnostic approaches are either invasive or inaccurate. Here, we report on a cost-efficient, artificially intelligent chemiresistive sensor array made of polyaniline (PANI) derivatives that can noninvasively diagnose BLC at an early stage and maintain postoperative surveillance through ″smelling″ clinical urine samples at room temperature. In clinical trials, 18 healthy controls and 76 BLC patients (60 and 16 at early and advanced stages, respectively) are assessed by the artificial olfactory system. With the assistance of a support vector machine (SVM), very high sensitivity and accuracy from healthy controls are achieved, exceeding those obtained by the current techniques in practice. In addition, the recurrences of both early and advanced stages are diagnosed well, with the effect of confounding factors on the performance of the artificial olfactory system found to have a negligible influence on the diagnostic performance. Overall, this study contributes a novel, noninvasive, easy-to-use, inexpensive, real-time, accurate method for urine disease diagnosis, which can be useful for personalized care/diagnosis and postoperative surveillance, resulting in saving more lives.

Prenatal exposure to triphenyl phosphate activated PPARγ in placental trophoblasts and impaired pregnancy outcomes.

The health risks of triphenyl phosphate (TPhP) have increased since its widespread application. Using placental trophoblast cell line JEG-3, we demonstrated that TPhP could induce endoplasmic reticulum stress (ERS) and cell apoptosis through PPARγ-mediated lipid metabolism. However, the developmental toxicity of TPhP through the placenta is not known. In this study, prenatal TPhP exposure to mice was investigated. Pregnant mice were orally exposed to TPhP (1 and 5 mg/kg) from embryonic day 0 (E0) until delivery. The results showed that TPhP could accumulate in placenta and impair pregnancy outcomes. After exposure, at E18, placental hormone chorionic gonadotrophin and testosterone levels were significantly decreased, but progesterone and estradiol levels were significantly increased, and placental angiogenesis was activated in the low-dose exposure group. While, in the high-dose exposure group, only estradiol levels were significantly increased. Different with the effect on hormone level or angiogenesis, TPhP significantly increased PPARγ and its regulated lipid transport proteins FABP, FATP, and CD36, and induced lipid accumulation in placental trophoblasts of both low- and high-exposure group. RNA-seq analysis of the placenta identified differentially expressed genes that were mainly involved in the ERS and MAPK signaling pathways. Western blot analysis verified that the protein levels related to ERS stress and apoptosis were significantly increased. To further confirm the role of PPARγ in TPhP mediated placental toxicity, pregnant mice were orally exposed to TPhP (1 mg/kg) or TPhP (1 mg/kg) + GW9662 (PPARγ inhibitor, 2 mg/kg) from E0 until delivery. The results showed that GW9662 could ameliorate the effect of TPhP on placental lipid accumulation, ERS and cell apoptosis, suggesting that PPARγ mediated the placental toxicity of TPhP. Overall, our results indicated that prenatal TPhP exposure impaired pregnancy outcomes, at least partly through PPARγ regulated function of trophoblast.

Removal efficiencies and risk assessment of endocrine-disrupting chemicals at two wastewater treatment plants in South China.

Endocrine-disrupting chemicals (EDCs) in the effluent from wastewater treatment plants (WWTPs) are an important pollutant sources of the aquatic system. In this study, the removal efficiencies of eight typical EDCs at two domestic WWTPs in Dongguan City, China, are reported based on instrumental analysis and bioassay results. Bioactivities, including steroidogenesis-disrupting effects, estrogen receptor (ER)-binding activity, and aryl hydrocarbon receptor (AhR)-binding activity were evaluated using the H295R, MVLN, and H4IIE cell bioassays, respectively. The potential environmental risks of these residual EDCs were also evaluated. The results of instrumental analysis showed that nonylphenol was the major chemical type present among the eight tested EDCs. Meanwhile, concentrations of estrogen compounds including estrone, 17ß-estradiol (E2), estriol, 17α-ethinyl estradiol, and diethylstilbestrol were relatively low. The removal rates of all eight EDCs were relatively high. Although the chemical analysis indicated high removal efficiency, the bioassay results showed that steroidogenesis-disrupting effects as well as ER-binding and AhR-binding activities remained, with E2-equivalent values of effluent samples ranging from 0.16 to 0.9 ng·L-1, and 2,3,7,8-tetrachlorodibenzo-p-dioxin-equivalent values ranging from 0.61 to 4.09 ng L-1. Principal component analysis combined with regression analysis suggests that the chemicals analyzed in this study were partly responsible for these ER and AhR activities. Ecological risk assessment of the residual EDCs showed that estrone was the most hazardous chemical among the eight EDCs tested, with a risk quotient of 1.44-5.50. Overall, this study suggests that, despite high apparent removal efficiencies of typical EDCs, their bioactivities and potential ecological risks cannot be ignored.

CCDC137 Is a Prognostic Biomarker and Correlates With Immunosuppressive Tumor Microenvironment Based on Pan-Cancer Analysis.

BACKGROUND: The coiled-coil domain containing (CCDC) family proteins have important biological functions in various diseases. However, the coiled-coil domain containing 137 (CCDC137) was rarely studied. We aim to investigate the role of CCDC137 in pan-cancer. METHODS: CCDC137 expression was evaluated in RNA sequence expression profilers of pan-cancer and normal tissues from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. The influence of CCDC137 on the prognosis of tumor patients was analyzed using clinical survival data from TCGA. Function and pathway enrichment analysis was performed to explore the role of CCDC137 using the R package "clusterProfiler." We further analyzed the correlation of immune cell infiltration score of TCGA samples and CCDC137 expression using TIMER2 online database. RESULTS: CCDC137 was over-expressed and associated with worse survival status in various tumor types. CCDC137 expression was positively correlated with tumor associated macrophages (TAMs) and cancer associated fibroblasts (CAFs) in Lower Grade Glioma (LGG) and Uveal Melanoma (UVM). In addition, high CCDC137 expression was positively correlated with most immunosuppressive genes, including TGFB1, PD-L1, and IL10RB in LGG and UVM. CONCLUSIONS: Our study identified CCDC137 as an oncogene and predictor of worse survival in most tumor types. High CCDC137 may contribute to elevated infiltration of TAMs and CAFs and be associated with tumor immunosuppressive status.

Live-Cell Sensing of Telomerase Activity by Using Hybridization-Sensitive Fluorescent Oligonucleotide Probes.

Live-cell sensing of telomerase activity with simple and efficient strategies remains a challenging target. In this work, a strategy for telomerase sensing by using hybridization-sensitive fluorescent oligonucleotide probes is reported. In the presence of telomerase and dNTPs, the designed supporting strand was extended and generated the hairpin structure that catalyzed the next telomerase extending reaction. The special extension mechanism increased the local concentration of another supporting strand and telomerase, which resulted in enhanced telomerase activity. The hybridization-sensitive oligonucleotide probes bound to the hairpin catalyst and generated turn-on fluorescence. This method realized the sensing of telomerase activity in HeLa cell extract with a detection limit below 1.6×10-6  IU µL-1 . The real-time in situ observation of telomerase extension was achieved in living HeLa cells. This strategy has been applied to monitor the efficiency of telomerase-targeting anticancer drugs in situ.