Impact of corrupt admission on the mental health of Chinese adolescents.

Through preferential treatment by education officials or through bribery, some adolescents can obtain admission to a junior high school. However, it is unclear whether it affects the mental health of adolescents. This study used Propensity Score Matching to examine the effects of corruption on adolescent mental health. A total of 17,254 junior high school students sample (11-18 years old; 48.7% girls and 53.1% boys) were used from the China Education Panel Survey. 14.1% of adolescents attended a junior high school by corrupt means, corruption had a significantly negative effect on the mental health of these adolescents (ATT = -0.388, p < 0.01), the reasons grounded in the fact that they received more criticisms from teachers and wanted to leave their current school. In general, corruption in the admissions process can have detrimental effects on the mental health of adolescents. This study extends the previous articles on how to improve adolescent mental health and complements the application of cognitive dissonance theory. Findings from this study revealed that anti-corruption in the education sector is necessary, and the institutional design to ensure fair enrolment in basic education will contribute to the mental health of adolescents.

Machine learning-based prediction of clinical outcomes after traumatic brain injury: Hidden information of early physiological time series.

AIMS: To assess the predictive value of early-stage physiological time-series (PTS) data and non-interrogative electronic health record (EHR) signals, collected within 24 h of ICU admission, for traumatic brain injury (TBI) patient outcomes. METHODS: Using data from TBI patients in the multi-center eICU database, we focused on in-hospital mortality, neurological status based on the Glasgow Coma Score (mGCS) motor subscore at discharge, and prolonged ICU stay (PLOS). Three machine learning (ML) models were developed, utilizing EHR features, PTS signals collected 24 h after ICU admission, and their combination. External validation was performed using the MIMIC III dataset, and interpretability was enhanced using the Shapley Additive Explanations (SHAP) algorithm. RESULTS: The analysis included 1085 TBI patients. Compared to individual models and existing scoring systems, the combination of EHR and PTS features demonstrated comparable or even superior performance in predicting in-hospital mortality (AUROC = 0.878), neurological outcomes (AUROC = 0.877), and PLOS (AUROC = 0.835). The model's performance was validated in the MIMIC III dataset, and SHAP algorithms identified six key intervention points for EHR features related to prognostic outcomes. Moreover, the EHR results (All AUROC >0.8) were translated into online tools for clinical use. CONCLUSION: Our study highlights the importance of early-stage PTS signals in predicting TBI patient outcomes. The integration of interpretable algorithms and simplified prediction tools can support treatment decision-making, contributing to the development of accurate prediction models and timely clinical intervention.

Purpurin ameliorated neuropathic allodynia and hyperalgesia by modulating neuronal mitochondrial bioenergetics and redox status in type 1 diabetic mice.

A substantial proportion of diabetic patients suffer a debilitating and persistent pain state, known as peripheral painful neuropathy that necessitates improved therapy or antidote. Purpurin, a natural anthraquinone compound from Rubia tinctorum L., has been reported to possess antidepressant activity in preclinical studies. As antidepressants have been typically used as standard agents against persistent neuropathic pain, this study aimed to probe the effect of purpurin on neuropathic pain associated with streptozotocin-induced type 1 diabetes in male C57BL6J mice. The Hargreaves test and the von Frey test were used to assess the pain-like behaviors, shown as heat hyperalgesia and mechanical allodynia respectively. Chronic treatment of diabetic mice with purpurin not only ameliorated the established symptoms of heat hyperalgesia and mechanical allodynia, but also arrested the development of these pain states given preemptively at low doses. Although purpurin treatment hardly impacted on metabolic disturbance in diabetic mice, it ameliorated exacerbated oxidative stress in pain-associated tissues, improved mitochondrial bioenergetics in dorsal root ganglion neurons and restored nerve conduction velocity in sciatic nerves. Notably, the analgesic actions of purpurin were modified by pharmacologically manipulating redox status and mitochondrial bioenergetics. These findings unveil the analgesic activity of purpurin, an effect that is causally associated with its bioenergetics-enhancing and antioxidant effects, in mice with type 1 diabetes.

Explainable machine learning for predicting neurological outcome in hemorrhagic and ischemic stroke patients in critical care.

Aim: The objective of this study is to develop accurate machine learning (ML) models for predicting the neurological status at hospital discharge of critically ill patients with hemorrhagic and ischemic stroke and identify the risk factors associated with the neurological outcome of stroke, thereby providing healthcare professionals with enhanced clinical decision-making guidance. Materials and methods: Data of stroke patients were extracted from the eICU Collaborative Research Database (eICU-CRD) for training and testing sets and the Medical Information Mart for Intensive Care IV (MIMIC IV) database for external validation. Four machine learning models, namely gradient boosting classifier (GBC), logistic regression (LR), multi-layer perceptron (MLP), and random forest (RF), were used for prediction of neurological outcome. Furthermore, shapley additive explanations (SHAP) algorithm was applied to explain models visually. Results: A total of 1,216 hemorrhagic stroke patients and 954 ischemic stroke patients from eICU-CRD and 921 hemorrhagic stroke patients 902 ischemic stroke patients from MIMIC IV were included in this study. In the hemorrhagic stroke cohort, the LR model achieved the highest area under curve (AUC) of 0.887 in the test cohort, while in the ischemic stroke cohort, the RF model demonstrated the best performance with an AUC of 0.867 in the test cohort. Further analysis of risk factors was conducted using SHAP analysis and the results of this study were converted into an online prediction tool. Conclusion: ML models are reliable tools for predicting hemorrhagic and ischemic stroke neurological outcome and have the potential to improve critical care of stroke patients. The summarized risk factors obtained from SHAP enable a more nuanced understanding of the reasoning behind prediction outcomes and the optimization of the treatment strategy.

Changes in SLITRK1 Level in the Amygdala Mediate Chronic Neuropathic Pain-Induced Anxio-Depressive Behaviors in Mice.

BACKGROUND: Comorbid chronic neuropathic pain (NPP) and anxio-depressive disorders (ADD) have become a serious global public-health problem. The SLIT and NTRK-like 1 (SLITRK1) protein is important for synaptic remodeling and is highly expressed in the amygdala, an important brain region involved in various emotional behaviors. We examined whether SLITRK1 protein in the amygdala participates in NPP and comorbid ADD. METHODS: A chronic NPP mouse model was constructed by L5 spinal nerve ligation; changes in chronic pain and ADD-like behaviors were measured in behavioral tests. Changes in SLITRK1 protein and excitatory synaptic functional proteins in the amygdala were measured by immunofluorescence and Western blot. Adeno-associated virus was transfected into excitatory synaptic neurons in the amygdala to up-regulate the expression of SLITRK1. RESULTS: Chronic NPP-related ADD-like behavior was successfully produced in mice by L5 ligation. We found that chronic NPP and related ADD decreased amygdalar expression of SLITRK1 and proteins important for excitatory synaptic function, including Homer1, postsynaptic density protein 95 (PSD95), and synaptophysin. Virally-mediated SLITRK1 overexpression in the amygdala produced a significant easing of chronic NPP and ADD, and restored the expression levels of Homer1, PSD95, and synaptophysin. CONCLUSION: Our findings indicated that SLITRK1 in the amygdala plays an important role in chronic pain and related ADD, and may prove to be a potential therapeutic target for chronic NPP-ADD comorbidity.

LPAR6 Participates in Neuropathic Pain by Mediating Astrocyte Cells via ROCK2/NF-κB Signal Pathway.

Neuropathic pain (NPP) is a common type of chronic pain. Glial cells, including astrocytes (AS), are believed to play an important role in the progression of NPP. AS cells can be divided into various types based on their expression profiles, among which A1 and A2 types have clear functions. A1-type AS cells are neurotoxic, while A2-type AS cells exert neuroprotective functions. Some types of lysophosphatidic acid receptors (LPAR) have been shown to play a role in NPP. However, it remains unclear how AS cells and LPAR6 affect the occurrence and progression of NPP. In this study, we established a mouse model of chronic constriction injury (CCI) to simulate NPP. It was found that the expression of LPAR6 in AS cells of the spinal dorsal horn was increased in the CCI model, and the thresholds of mechanical and thermal pain were elevated after knocking out LPAR6, indicating that LPAR6 and AS cells participated in the occurrence of NPP. The experiment involved culturing primary AS cells and knocking down LPAR6 by Lentivirus. The results showed that the NF-κB signal pathway was activated and the number of A1-type AS cells increased in the CCI model. However, LPAR6 knockdown inhibited the NF-κB signal pathway and A1-type AS cells. The results of the mRNA sequencing and immunoprecipitation test indicate an interaction between LPAR6 and ROCK2. Inhibiting ROCK2 by Y-27632 increased mechanical and thermal pain thresholds and alleviated NPP at the molecular level. The study presents evidence that LPAR6 activates the NF-κB pathway through ROCK2 and contributes to the progression of NPP by increasing A1-type AS and decreasing A2-type AS. This suggests that LPAR6 could be a potential therapeutic target for alleviating NPP. Clinical applications that are successful can offer new therapeutic options, enhance the quality of life for patients, and potentially uncover new mechanisms for pain modulation.

HSV-1 reactivation results in post-herpetic neuralgia by upregulating Prmt6 and inhibiting cGAS-STING.

Chronic varicella zoster virus (VZV) infection induced neuroinflammatory condition is the critical pathology of post-herpetic neuralgia (PHN). The immune escape mechanism of VZV remains elusive. As to mice have no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well established PHN mice model. Transcriptional expression analysis identified that the protein arginine methyltransferases 6 (Prmt6) was upregulated upon HSV-1 infection, which was further confirmed by immunofluorescence staining in spinal dorsal horn. Prmt6 deficiency decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load in vivo and in vitro. Overexpression of Prmt6 in microglia dampened antiviral innate immunity and increased HSV-1 load. Mechanistically, Prmt6 methylated and inactivated STING, resulting in reduced phosphorylation of TANK binding kinase-1 (TBK1) and interferon regulatory factor 3 (IRF3), diminished production of type I interferon (IFN-I) and antiviral innate immunity. Furthermore, intrathecal or intraperitoneal administration of the Prmt6 inhibitor EPZ020411 decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load. Our findings revealed that HSV-1 escapes antiviral innate immunity and results in PHN by upregulating Prmt6 expression and inhibiting the cGAS-STING pathway, providing novel insights and a potential therapeutic target for PHN.

PRMT6 deficiency or inhibition alleviates neuropathic pain by decreasing glycolysis and inflammation in microglia.

Microglia induced chronic inflammation is the critical pathology of Neuropathic pain (NP). Metabolic reprogramming of macrophage has been intensively reported in various chronic inflammation diseases. However, the metabolic reprogramming of microglia in chronic pain remains to be elusive. Here, we reported that immuno-metabolic markers (HIF-1α, PKM2, GLUT1 and lactate) were related with increased expression of PRMT6 in the ipsilateral spinal cord dorsal horn of the chronic construction injury (CCI) mice. PRMT6 deficiency or prophylactic and therapeutic intrathecal administration of PRMT6 inhibitor (EPZ020411) ameliorated CCI-induced NP, inflammation and glycolysis in the ipsilateral spinal cord dorsal horn. PRMT6 knockout or knockdown inhibited LPS-induced inflammation, proliferation and glycolysis in microglia cells. While PRMT6 overexpression exacerbated LPS-induced inflammation, proliferation and glycolysis in BV2 cells. Recent research revealed that PRMT6 could interact with and methylate HIF-1α, which increased HIF-1α protein stability. In sum, increased expression of PRMT6 exacerbates NP progress by increasing glycolysis and neuroinflammation through interacting with and stabilizing HIF-1α in a methyltransferase manner, which outlines novel pathological mechanism and drug target for NP.

Macrophage ß2-AR activation amplifies inflammation in wound healing by upregulating Trem1 via the cAMP/PKA/CREB pathway.

BACKGROUND: Inflammation is an important part of the wound healing process. The stress hormone epinephrine has been demonstrated to modulate the inflammatory response via its interaction with ß2-adrenergic receptor (ß2-AR). However, the precise molecular mechanism through which ß2-AR exerts its influence on inflammation during the wound healing process remains an unresolved question. METHODS: Transcriptome datasets of wound and macrophages from the GEO database were reanalyzed using bioinformatics. The role of ß2-AR in wound healing was explored by a mouse hind paw plantar wound model, and histological analyses were performed to assess wound healing. In vivo and in vitro assays were performed to elucidate the role of ß2-AR on the inflammatory response. Triggering receptor expressed on myeloid cells 1 (Trem1) was knocked down with siRNA on RAW cells and western blot and qPCR assays were performed. RESULTS: Trem1 was upregulated within 24 h of wounding, and macrophage ß2-AR activation also upregulated Trem1. In vivo experiments demonstrated that ß2-AR agonists impaired wound healing, accompanied by upregulation of Trem1 and activation of cAMP/PKA/CREB pathway, as well as by a high level of pro-inflammatory cytokine production. In vitro experiments showed that macrophage ß2-AR activation amplified LPS-induced inflammation, and knockdown of Trem1 reversed this effect. Using activator and inhibitor of cAMP, macrophage ß2-AR activation was confirmed to upregulate Trem1 via the cAMP/PKA/CREB pathway. CONCLUSION: Our study found that ß2-AR agonists increase Trem1 expression in wounds, accompanied by amplification of the inflammatory response, impairing wound healing. ß2-AR activation in RAW cells induces Trem1 upregulation via the cAMP/PKA/CREB pathway and amplifies LPS-induced inflammatory responses.

Polystyrene nanoplastics exacerbated Pb-induced liver toxicity in mice.

Nanoplastics are widely distributed in the environment and can adsorb heavy metals, which poses a potential threat to human health through food chain. It is necessary to assess the combined toxicity of nanoplastics and heavy metals. The adverse effect of Pb and nanoplastics on liver, single or in combination, was evaluated in this study. The results showed that the Pb content in co-exposure group of nanoplastics and Pb (PN group) was higher than the group exposed to Pb alone (Pb group). And more severe inflammatory infiltration was observed in liver sections of PN group. The level of inflammatory cytokines and malondialdehyde were increased, while the superoxide dismutase activity was decreased in liver tissues of PN group. Moreover, the gene expression level of nuclear factor-erythroid 2-related factor 2, nicotinamide adenine dinucleotide phosphate:quinine oxidoreductase 1 and catalase, which is related to antioxidation, was downregulated. And the expression level of cleaved-Caspase9 and cleaved-Caspase3 were increased. However, with the supplementation of oxidative stress inhibitor N-Acetyl-L-cysteine, liver damage shown in PN group was evidently alleviated. In summary, nanoplastics evidently exacerbated the deposition of Pb in liver and potentially aggravated the Pb-induced liver toxicity by activating oxidative stress.

Machine Learning-Based Screening of Risk Factors and Prediction of Deep Vein Thrombosis and Pulmonary Embolism After Hip Arthroplasty.

Prophylactic anticoagulation is a standard strategy for patients undergoing total hip arthroplasty (THA) to prevent deep venous thromboembolism (DVT) and pulmonary embolism (PE). Nevertheless, some patients still experience these complications during their hospital stay. Current risk assessment methods like the Caprini and Geneva scores are not specifically designed for THA and may not accurately predict DVT or PE postoperatively. This study used machine learning techniques to establish models for early diagnosis of DVT and PE in patients undergoing THA. Data were collected from 1481 patients who received perioperative prophylactic anticoagulation. Model establishment and parameter tuning were performed using a training set and evaluated using a test set. Among the models, extreme gradient boosting (XGBoost) performed the best, with an area under the receiver operating characteristic curve (AUC) of 0.982, sensitivity of 0.913, and specificity of 0.998. The main features used in the XGBoost model were direct and indirect bilirubin, partial activation prothrombin time, prealbumin, creatinine, D-dimer, and C-reactive protein. Shapley Additive Explanations analysis was conducted to further analyze these features. This study presents a model for early diagnosis DVT or PE after THA and demonstrates bilirubin could be a potential predictor in the assessment of DVT or PE. Compared to traditional risk assessment, XGBoost has a high sensitivity and specificity to predict DVT and PE in the clinical setting. Furthermore, the results of this study were converted into a web calculator that can be used in clinical practice.

Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway.

BACKGROUND: Ventilator-induced lung injury (VILI) is caused by overdistension of the alveoli by the repetitive recruitment and derecruitment of alveolar units. This study aims to investigate the potential role and mechanism of fibroblast growth factor 21 (FGF21), a metabolic regulator secreted by the liver, in VILI development. METHODS: Serum FGF21 concentrations were determined in patients undergoing mechanical ventilation during general anesthesia and in a mouse VILI model. Lung injury was compared between FGF21-knockout (KO) mice and wild-type (WT) mice. Recombinant FGF21 was administrated in vivo and in vitro to determine its therapeutic effect. RESULTS: Serum FGF21 levels in patients and mice with VILI were significantly higher than in those without VILI. Additionally, the increment of serum FGF21 in anesthesia patients was positively correlated with the duration of ventilation. VILI was aggravated in FGF21-KO mice compared with WT mice. Conversely, the administration of FGF21 alleviated VILI in both mouse and cell models. FGF21 reduced Caspase-1 activity, suppressed the mRNA levels of Nlrp3, Asc, Il-1ß, Il-18, Hmgb1 and Nf-κb, and decreased the protein levels of NLRP3, ASC, IL-1ß, IL-18, HMGB1 and the cleaved form of GSDMD. CONCLUSIONS: Our findings reveal that endogenous FGF21 signaling is triggered in response to VILI, which protects against VILI by inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis pathway. These results suggest that boosting endogenous FGF21 or the administration of recombinant FGF21 could be promising therapeutic strategies for the treatment of VILI during anesthesia or critical care.

Lyn-mediated glycolysis enhancement of microglia contributes to neuropathic pain through facilitating IRF5 nuclear translocation in spinal dorsal horn.

The pro-inflammatory phenotype of microglia usually induces neuroinflammatory reactions in neuropathic pain. Glycometabolism shift to glycolysis can promote the pro-inflammatory phenotype transition of microglia. The omics data analysis suggest a critical role for Lyn dysregulation in neuropathic pain. The present study aimed at exploring the mechanism of Lyn-mediated glycolysis enhancement of microglia in neuropathic pain. Neuropathic pain model was established by chronic constriction injury (CCI), then pain thresholds and Lyn expression were measured. Lyn inhibitor Bafetinib and siRNA-lyn knockdown were administrated intrathecally to evaluate the effects of Lyn on pain thresholds, glycolysis and interferon regulatory factor 5 (IRF5) nuclear translocation of microglia in vivo and in vitro. ChIP was carried out to observe the binding of transcription factors SP1, PU.1 to glycolytic gene promoters by IRF5 knockdown. Finally, the relationship between glycolysis and pro-inflammatory phenotype transition of microglia was evaluated. CCI led to the upregulation of Lyn expression and glycolysis enhancement in microglia of spinal dorsal horn. Bafetinib or siRNA-lyn knockdown intrathecally alleviated pain hyperalgesia, suppressed glycolysis enhancement and inhibited nuclear translocation of IRF5 in CCI mice. Also, IRF5 promoted the binding of transcription factors SP1, PU.1 to glycolytic gene promoters, and then the enhanced glycolysis facilitated the proliferation and pro-inflammatory phenotype transition of microglia and contributed to neuropathic pain. Lyn-mediated glycolysis enhancement of microglia contributes to neuropathic pain through facilitating IRF5 nuclear translocation in spinal dorsal horn.

Structure-Based Design of Novel Alkynyl Thio-Benzoxazepinone Receptor-Interacting Protein Kinase-1 Inhibitors: Extending the Chemical Space from the Allosteric to ATP Binding Pockets.

Systemic inflammatory response syndrome (SIRS), characterized by severe systemic inflammation, represents a major cause of health loss, potentially leading to multiple organ failure, shock, and death. Exploring potent RIPK1 inhibitors is an effective therapeutic strategy for SIRS. Recently, we described thio-benzoxazepinones as novel RIPK1 inhibitors and confirmed their anti-inflammatory activity. Herein, we further synthesized novel thio-benzoxazepinones by introducing substitutions on the benzene ring by an alkynyl bridge in order to extend the chemical space from the RIPK1 allosteric to ATP binding pockets. The in vitro cell and kinase assays found that compounds 2 and 29 showed highly potent activity against necroptosis (EC50 = 3.7 and 3.2 nM) and high RIPK1 inhibitory activity (Kd = 9.7 and 70 nM). Prominently, these two analogues possessed better in vivo anti-inflammatory effects than the clinical candidate GSK'772 and effectively blocked hypothermia and deaths in a TNFα-induced SIRS model.

High-fat diet in mice led to increased severity of spermatogenesis impairment by lead exposure: perspective from gut microbiota and the efficacy of probiotics.

BACKGROUND: The mechanism of multifactorial spermatogenesis impairment is unclear. This study aimed to investigate the reproductive toxicity of lead (Pb) in mice fed a high-fat diet (HFD) and to delineate the important role of gut microbiota. RESULTS: Results showed that, compared with mice fed a normal diet (ND), Pb exposure caused more severe spermatogenesis impairment in HFD-fed mice, including decreased sperm count and motility, seminiferous tubule injury, serum and intratesticular testosterone decline, and downregulated expression level of spermatogenesis-related genes. Besides, 16S sequencing indicated that HFD-fed mice had increased severity of gut microbiota dysbiosis by Pb exposure compared to ND-fed mice. With fecal microbiota transplantation, the same trend of spermatogenesis impairment occurred in recipient mice, which confirmed the important role of gut microbiota. Moreover, probiotics supplementation restored the gut microbial ecosystem, and thus improved spermatogenic function. CONCLUSION: Our work suggested that a population with HFD might face more reproductive health risks upon Pb exposure, and revealed an intimate linkage between microbiota dysbiosis and spermatogenesis impairment, accompanied by the potential usefulness of probiotics as prophylactic and therapeutic. © 2022 Society of Chemical Industry.

Detection of apoptotic cells based on in situ hybridization chain reaction using specific hairpins.

There are an increasing number of experiments to study programmed cell death/apoptosis, one of the characteristics of which is DNA fragmentation. The only current method for in situ detection of DNA fragmentation is Terminal deoxynucleotidyl transferase mediated-dUTP Nick End Labeling, TUNEL. In this study, a new method for in situ detection of apoptotic DNA fragments, namely In Situ Hybridization Chain Reaction, isHCR, was established. The principle of the assay is that the sticky end sequence of the apoptotic cell DNA fragment non-specifically initiates a hybridization chain reaction that specifically detects the apoptotic cell. The results of the combined TUNEL and isHCR method demonstrated that the majority of isHCR-positive cells were also labeled by TUNEL. In situ HCR often detect DNA fragments in the cytoplasm that the classical TUNEL method couldnot, and these cells may be in the early stages of apoptosis. It also indicates that DNA fragments are transferred to the cytoplasm during apoptosis. Because the staining process does not require terminal deoxynucleotidyl transferase as TUNEL staining does, isHCR staining cost low and can be performed on a large number of tissue specimens. It is believed that isHCR has the potential to detect DNA fragmentation of apoptotic cells in situ.

Prognosis and pain dissection of novel signatures in kidney renal clear cell carcinoma based on fatty acid metabolism-related genes.

Renal cell carcinoma (RCC) is a malignant tumor that is characterized by the accumulation of intracellular lipid droplets. The prognostic value of fatty acid metabolism-related genes (FMGs) in RCC remains unclear. Alongside this insight, we collected data from three RCC cohorts, namely, The Cancer Genome Atlas (TCGA), E-MTAB-1980, and GSE22541 cohorts, and identified a total of 309 FMGs that could be associated with RCC prognosis. First, we determined the copy number variation and expression levels of these FMGs, and identified 52 overall survival (OS)-related FMGs of the TCGA-KIRC and the E-MTAB-1980 cohort data. Next, 10 of these genes-FASN, ACOT9, MID1IP1, CYP2C9, ABCD1, CPT2, CRAT, TP53INP2, FAAH2, and PTPRG-were identified as pivotal OS-related FMGs based on least absolute shrinkage and selection operator and Cox regression analyses. The expression of some of these genes was confirmed in patients with RCC by immunohistochemical analyses. Kaplan-Meier analysis showed that the identified FMGs were effective in predicting the prognosis of RCC. Moreover, an optimal nomogram was constructed based on FMG-based risk scores and clinical factors, and its robustness was verified by time-dependent receiver operating characteristic analysis, calibration curve analysis, and decision curve analysis. We have also described the biological processes and the tumor immune microenvironment based on FMG-based risk score classification. Given the close association between fatty acid metabolism and cancer-related pain, our 10-FMG signature may also serve as a potential therapeutic target with dual effects on ccRCC prognosis and cancer pain and, therefore, warrants further investigation.

Micro(nano)plastics in food system: potential health impacts on human intestinal system.

Micro(nano)plastics (MNPs) in human food system have been broadly recognized by researchers and have drawn an increasing public attention to their potential health risks, particularly the risk to the intestinal system regarding the long-term exposure to MNPs through food consumption. This study aims to review the environmental properties (formation and composition) of MNPs and MNPs pollution in human food system following the order of food production, food processing and food consumption. The current analytic and identical technologies utilized by researchers are also summarized in this review. In fact, parts of commonly consumed food raw materials, processed food and the way to take in food all become the possible sources for human MNPs ingestion. In addition, the available literatures investigating MNPs-induced intestinal adverse effect are discussed from in vitro models and in vivo mammalian experiments, respectively. Particle translocation, cytotoxicity, damaged gut barrier, intestinal inflammation as well as microbial alteration are mostly reported. Moreover, the practical remediation strategies for MNPs pollution are also illustrated in the last section. This review is expected to provide a research insight for foodborne MNPs and arouse more public awareness of MNPs pollution in food and potential risk for human intestinal health.

Co-exposure to polystyrene microplastics and lead aggravated ovarian toxicity in female mice via the PERK/eIF2α signaling pathway.

Generally, individual microplastics (MPs) or lead (Pb) exposure could initiate ovarian toxicity. However, their combined effects on the ovary and its mechanism in mammals remained unclear. Female C57BL/6 mice were used in this study to investigate the combined ovarian toxicity of polystyrene MPs (PS-MPs, 0.1 mg/d/mouse) and Pb (1 g/L) for 28 days. Results showed that co-exposure to PS-MPs and Pb increased the accumulation of Pb in ovaries, the histopathological damage in ovaries and uterus, the serum malondialdehyde levels and decreased serum superoxide dismutase and sex hormone levels significantly when compared with single PS-MPs and Pb exposure. These observations indicated that co-exposure exerted more severe toxicity to mouse ovaries and uterus. Furthermore, co-exposure to PS-MPs and Pb caused endoplasmic reticulum (ER) stress by activating the PERK/eIF2α signaling pathway in the ovary, which resulted in apoptosis. However, the oxidative and ovarian damage were alleviated, and the mRNA levels of genes related to the PERK/eIF2α signaling pathway were down-regulated to levels of the control mice in the PS-MPs and Pb co-exposed mice administered with ER stress inhibitor (Salubrinal, Sal) or the antioxidant (N-acetyl-cysteine, NAC). In conclusion, our findings suggested that the combination of PS-MPs and Pb aggravated ovarian toxicity in mice by inducing oxidative stress and activating the PERK/eIF2α signaling pathway, thereby providing a basis for future studies into the combined toxic mechanism of PS-MPs and Pb in mammals.

Low-Stiffness Hydrogels Promote Peripheral Nerve Regeneration Through the Rapid Release of Exosomes.

A hydrogel system loaded with mesenchymal stem cell-derived exosome (MSC-Exos) is an attractive new tool for tissue regeneration. However, the effect of the stiffness of exosome-loaded hydrogels on tissue regeneration is unclear. Here, the role of exosome-loaded hydrogel stiffness, during the regeneration of injured nerves, was assessed in vivo. The results showed that the photocrosslinkable hyaluronic acid methacrylate hydrogel stiffness plays an important role in repairing nerve injury. Compared with the stiff hydrogels loaded with exosomes, soft hydrogels loaded with exosomes showed better repair of injured peripheral nerves. The soft hydrogel promoted nerve repair by quickly releasing exosomes to inhibit the infiltration of macrophages and the expression of the proinflammatory factors IL-1ß and TNF-α in injured nerves. Our work revealed that exosome-loaded hydrogel stiffness plays an important role in tissue regeneration by regulating exosome release behavior and provided important clues for the clinical application of biological scaffold materials.