The effects of micro- and nanoplastics on the central nervous system: A new threat to humanity?

Given the widespread production and use of plastics, poor biodegradability, and inadequate recycling, micro/nanoplastics (MNPs) have caused widespread environmental pollution. As a result, humans inevitably ingest MNPs through various pathways. However, there is still no consensus on whether exposure to MNPs has adverse effects on humans. This article aims to provide a comprehensive overview of the knowledge of MNPs and the potential mechanisms of their impact on the central nervous system. Numerous in vivo and in vitro studies have shown that exposure to MNPs may pass through the blood-brain barrier (BBB) and lead to neurotoxicity through impairments in oxidative and inflammatory balance, neurotransmitter alternation, nerve conduction-related key enzymes, and impact through the gut-brain axis. It is worth noting that MNPs may act as carriers and have more severe effects on the body when co-exposed with other substances. MNPs of smaller sizes cause more severe harm. Despite the scarcity of reports directly relevant to humans, this review brings together a growing body of evidence showing that exposure to MNPs disturbs neurons and has even been found to alter the memory and behavior of organisms. This effect may lead to further potential negative influence on the central nervous system and contribute to the development of other diseases such as central nervous system inflammation and Parkinson 's-like neurodegenerative disorders. There is a need further to investigate the threat of MNPs to human health.

Effect of aspirin on blood pressure in hypertensive patients: a systematic review and meta-analysis.

INTRODUCTION: Aspirin is widely used for secondary prevention in patients with hypertension. However, previous studies mainly focused on the preventive effects of aspirin, and there has been a lack of reliable evidence on whether taking aspirin affects blood pressure This study aimed to investigate whether aspirin would affect the blood pressure in patients with hypertension. METHODS: PubMed, Cochrane database, Embase, Scopus and Medline databases were searched until September 2023. For continuous variables (e.g., blood pressure reduction), the mean difference (MD) was selected as the effect magnitude indices. We used the Cochrane Collaboration's Risk of Bias tool to assess the risk of bias. RESULT: A total of five studies were included, comprising 20,312 patients. We found that aspirin did not affect SBP (MD = -0.78, 95% CI: - 2.41, 0.84). A similar result was found for DBP (MD = -0.86, 95% CI: - 2.14, 0.42). CONCLUSION: This study showed no significant difference in blood pressure between the aspirin and control groups, suggesting that aspirin does not affect blood pressure.

The application of two-phase composite absorbent systems consisting of BAD and seawater resources in the wet treatment of ship exhaust gas.

The impact of ship emissions on the environment cannot be ignored and should be controlled. The possibility of applying seawater electrolysis technology and a novel amide absorbent (BAD, C12H25NO) to the simultaneous desulfurization and denitrification of ship exhaust gas is entirely confirmed by using various seawater resources. Concentrated seawater (CSW) with high salinity can effectively reduce the heat generated during electrolysis and the escape of chlorine. The initial pH of the absorbent can greatly affect the NO removal capacity of the system, and the BAD could keep the pH range suitable for NO oxidation in the system for a long time. The use of fresh seawater (FSW) to dilute the electrolysis of concentrated seawater (ECSW) to make an aqueous oxidant is a more reasonable scheme; the average removal efficiencies of SO2, NO, and NOx were 97.10%, 75.41%, and 74.28%, respectively. The synergistic effect of HCO3 -/CO3 2- and BAD was shown to further restrict NO2 escape.

circMMD reduction following tumor treating fields inhibits glioblastoma progression through FUBP1/FIR/DVL1 and miR-15b-5p/FZD6 signaling.

BACKGROUND: Tumor treating fields (TTF) is the latest treatment for GBM. Circular RNA (circRNA) has been demonstrated to play critical roles in tumorigenesis. However, the molecular mechanism of TTF remained largely unknown and the role of circRNA in TTF was not reported. The aim of this study was to elucidate the role and mechanism of circMMD in TTF treatment of GBM. METHODS: Divergent primer was designed to verify the existence of circMMD in GBM cells. The prognostic role of circMMD was explored in glioma specimens. The knockdown and overexpressed plasmids were used to evaluate the effect of circMMD on GBM cell proliferation and TTF efficacy. RNA pull-down and RNA immunoprecipitation were performed to identify binding proteins of circMMD. Subcutaneous and intracranial tumor models were established to validate findings in vivo. RESULTS: The expression of circMMD was elevated in GBM and its high expression indicated poor prognoses. TTF intervention could reduce circMMD synthesis, which suppressed GBM proliferation and increased TTF-mediated apoptosis. The reduction of circMMD promoted the interaction between FUBP1 and FIR, which decreased DVL1 transcription. Meanwhile, decreased circMMD would promote the activity of miR-15b-5p to degrade FZD6. Finally, the diminished expression of DVL1 and FZD6 expression suppressed the activation of Wnt/ß-catenin pathway. CONCLUSIONS: Our study revealed a novel mechanism of TTF that TTF-mediated reduction of circMMD could inhibit Wnt/ß-catenin pathway to suppress GBM proliferation.

Prognostic significance of ING3 expression in patients with cancer: A systematic review and meta-analysis.

Background: It has been reported that ING3 inhibits the progression of various cancers. However, some studies have shown that it promotes the development of prostate cancer. The purpose of this study was to investigate whether ING3 expression is associated with the prognosis of patients with cancer. Materials and methods: PubMed, Cochrane Database, Embase, Medline, ScienceDirect, Scopus and Web of Science were searched until September 2022. The hazard ratio (HR)/odds ratio (OR) and 95% confidence interval (95% CI) were calculated using Stata 17 software. We used the Newcastle-Ottawa Scale (NOS) to assess the risk of bias. Result: Seven studies involving 2371 patients with five types of cancer were included. The results showed that high expression of ING3 was negatively associated with a more advanced TNM stage (III-IV vs. I-II) (OR=0.61, 95% CI: 0.43-0.86), lymph node metastasis (OR=0.67, 95% CI: 0.49-0.90) and disease-free survival (HR=0.63, 95% CI: 0.37-0.88). However, ING3 expression was not associated with overall survival (HR=0.77, 95% CI: 0.41-1.12), tumor size (OR=0.67, 95% CI: 0.33-1.37), tumor differentiation (OR=0.86, 95% CI: 0.36-2.09) and gender (OR=1.14, 95% CI: 0.78-1.66). Conclusion: This study showed that the expression of ING3 was associated with better prognosis, suggesting that ING3 may be a potential biomarker for cancer prognosis. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier (CRD42022306354).

Whole transcriptome and proteome analyses identify potential targets and mechanisms underlying tumor treating fields against glioblastoma.

Glioblastoma (GBM) is one of the most malignant types of brain cancer. Tumor treating fields (TTFields) is the up-to-date treatment for GBM. However, its molecular mechanism requires additional investigation. Herein, a novel TTFields system was developed (CL-301A) and its efficiency in suppressing GBM cell proliferation and inducing cell apoptosis was demonstrated. Through the whole proteomic and transcriptomic analyses, a multitude of differentially expressed proteins (1243), mRNAs (4191), miRtNAs (47), lncRNAs (4286), and circRNAs (13,903) were identified. Bioinformatic analysis indicated that TTFields mainly affected nuclear proteins and interrupt cell mitosis-related events. Moreover, the inhibition of autophagy could significantly enhance the anti-GBM activity of TTFields. And CDK2-AS1 might be a target of TTFields to mediate cell cycle arrest via regulating CDK2 mRNA stability. This study provided valuable resources for understanding the mechanism of TTFields, which might further assist the investigation of TTFields in GBM treatment.

A Nanoparticle-Conjugated Anti-TBK1 siRNA Induces Autophagy-Related Apoptosis and Enhances cGAS-STING Pathway in GBM Cells.

BACKGROUND: Gene therapy shows considerable clinical benefit in cancer therapy, in which single-stranded ribonucleic acid (siRNA) is a promising strategy in the treatment of glioblastoma (GBM). TANK-binding kinase 1 (TBK1) is critical in tumorigenesis and development, which lays a foundation for an ideal target for tumor therapy. However, the practical application of free siRNA is limited. It is urgent to develop novel strategies to deliver TBK1 siRNA to activate apoptosis and cGAS-STING pathway as a therapeutic strategy for GBM. METHODS: The expression and prognostic value of TBK1 were evaluated in the TCGA, CGGA, and GTEx databases. A novel gene delivery system was designed here via PEGylated reduced graphene oxide (rGO-PEG) to targeted delivery of anti-TBK1 siRNA efficiently. The efficacy of TBK1si/rGO-PEG was evaluated in GBM cells. The underlying pathways were explored by Western blot. RESULTS: TBK1 was highly expressed in glioma samples, and its high expression indicated poor prognoses in glioma patients. The rGO-PEG presented great efficiency in targeted delivery of TBK1si RNA into GBM cells with up to 97.1% transfection efficiency. TBK1si/rGO-PEG exhibited anti-GBM activities by inhibiting TBK1 and autophagy, as well as activating apoptosis and cGAS-STING pathway. CONCLUSION: The rGO-PEG could be an efficient system facilitating the delivery of specific siRNA. TBK1si/rGO-PEG could be a novel strategy for the treatment of GBM.

Hypoxia-Related lncRNA Correlates With Prognosis and Immune Microenvironment in Lower-Grade Glioma.

Background: Hypoxia-related genes are demonstrated to correlate with the prognosis of various cancers. However, the role of hypoxia-related long non-coding RNAs (HRLs) in lower-grade glioma (LGG) remains unclear. Methods: A total of 700 LGG samples were extracted from TCGA and CGGA databases. Pearson correlation analysis was used to identify HRLs. Lasso analysis was adopted to construct the HRL signature. TIDE algorithm was used to predict responses to immune checkpoint inhibitors. Cell proliferation was estimated by cell counting kit-8 assay, colony formation assay, and EdU assay. Results: We identified 340 HRLs and constructed a novel risk signature composed of 19 HRLs. The risk score exhibited potent value in predicting the prognosis of LGG patients and was significantly associated with the prognosis of LGG patients. Moreover, HRL signature could distinguish patients with similar expression levels of immune checkpoints and might predict the efficacy of immune checkpoint inhibitors. Additionally, hypoxia-related pathways and immune pathways were enriched in high-risk group, and high risk score indicated low tumor purity and high immune infiltration. Two major HRLs, LINC00941 and BASP1-AS1, could significantly affect the proliferation of glioma cells. Conclusions: Our study constructed a novel HRL signature that could predict the prognosis and immunotherapy response of LGG patients. HRLs could be novel biomarkers to predict the prognosis of LGG patients and potential targets for LGG treatment.

CD74 Correlated With Malignancies and Immune Microenvironment in Gliomas.

Background: Cluster of differentiation 74 (CD74) is found to be highly involved in the development of various types of cancers and could affect the activities of infiltrated cells in the tumor microenvironment. However, these studies only focus on a few types of immune cells. Our study aims to comprehensively explore the role of CD74 in glioma prognosis and immune microenvironment. Methods: A total of 40 glioma specimens were collected in this study. We extracted data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene-Expression Omnibus (GEO) databases to explore the expression pattern of CD74 in gliomas. gene sets enrichment analysis and gene set variation analysis analyses were conducted to characterize the immune features of CD74. ESTIMATE, ssGSEA, Tumor IMmune Estimation Resource, and CIBERSORT algorithms were applied to assess the immune infiltration. Kaplan-Meier analysis was used for survival analysis. Receiver operating characteristic analysis was used to evaluate the predictive accuracy of CD74 in glioma diagnosis and prognosis. Results: A total of 2,399 glioma patients were included in our study. CD74 was highly expressed in glioma tissue compared to normal brain tissue and its expression was significantly higher in the high-grade glioma compared to the lower grade glioma at transcriptional and translational levels. Besides, CD74 was positively associated with immune checkpoints and inflammatory cytokines as well as immune processes including cytokine secretion and leukocyte activation. The high expression of CD74 indicated a high infiltration of immune cells such as macrophages, dendritic cells, and neutrophils. Moreover, patients with high expression of CD74 had poor prognoses. CD74 had moderate predictive accuracy in the diagnosis of glioblastoma and prediction of survival. Conclusions: In conclusion, our study revealed that the high expression of CD74 was associated with poor prognosis and high immune infiltration. CD74 could be used as a potential target for glioma treatment and as a biomarker to predict the prognosis of glioma patients.

Bioinformatic Analyses Identify a Prognostic Autophagy-Related Long Non-coding RNA Signature Associated With Immune Microenvironment in Diffuse Gliomas.

BACKGROUND: Autophagy and long non-coding RNA (lncRNA) play a critical role in tumor progression and microenvironment. However, the role of autophagy-related lncRNAs (ARLs) in glioma microenvironment remains unclear. METHODS: A total of 988 diffuse glioma samples were extracted from TCGA and CGGA databases. Consensus clustering was applied to reveal different subgroups of diffuse gliomas. Kaplan-Meier analysis was used to evaluate survival differences between groups. The infiltration of immune cells was estimated by ssGSEA, TIMER, and CIBERSORT algorithms. The construction of ARL signature was conducted using principal component analysis. RESULTS: Consensus clustering revealed two clusters of diffuse gliomas, in which cluster 1 was associated with poor prognosis and enriched with malignant subtypes of gliomas. Moreover, cluster 1 exhibited high apoptotic and immune characteristics, and it had a low purity and high infiltration of several immune cells. The constructed ARL signature showed a promising accuracy in predicting the prognosis of glioma patients. ARL score was significantly elevated in the malignant subtype of glioma and the high ARL score indicated a poor prognosis. Besides, the high ARL score notably indicated low tumor purity and high infiltration of macrophages and neutrophils. CONCLUSION: Our study developed and validated a novel ARL signature for the classification of diffuse glioma, which was closely associated with glioma immune microenvironment and could serve as a promising prognostic biomarker for glioma patients.

A Novel Mice Model for Studying the Efficacy and IRAEs of Anti-CTLA4 Targeted Immunotherapy.

BACKGROUND: Patient-derived orthotopic xenograft (PDOX) is a popular animal model for translational cancer research. Immunotherapy is a promising therapy against glioblastoma (GBM). However, the PDOX model is limited to evaluating immune-related events. Our study aims to establish GBM humanized PDOX (HPDOX) mice models to study the mechanism of anti-CTLA4 immunotherapy and immune-related adverse events (IRAEs). METHODS: HPDOX models were established by culturing GBM tissues and intracranially implanting them in NSG mice. Meanwhile, peripheral blood mononuclear cells (PBMCs) were separated from peripheral blood and of GBM patients and administrated in corresponding mice. The population of CD45+, CD3+, CD4+, CD8+, and regulatory T (Treg) cells was estimated in the peripheral blood or tumor. RESULTS: T cells derived from GBM patients were detected in HPDOX mice models. The application of anti-CTLA4 antibodies (ipilimumab and tremelimumab) significantly inhibited the growth of GBM xenografts in mice. Moreover, residual patient T cells were detected in the tumor microenvironment and peripheral blood of HPDOX mice and were significantly elevated by ipilimumab and tremelimumab. Additionally, Treg cells were decreased in mice with IRAEs. Lastly, the proportion of CD4+/CD8+ T cells dramatically increased after the administration of ipilimumab. And the degree of IRAEs may be related to CD56+ expression in HPDOX. CONCLUSIONS: Our study established HPDOX mice models for investigating the mechanism and IRAEs of immunotherapies in GBM, which would offer a promising platform for evaluating the efficacy and IRAEs of novel therapies and exploring personalized therapeutic strategies.

Competing risk model to determine the prognostic factors and treatment strategies for elderly patients with glioblastoma.

The prognostic factors and optimal treatment for the elderly patient with glioblastoma (GBM) were poorly understood. This study extracted 4975 elderly patients (≥ 65 years old) with histologically confirmed GBM from Surveillance, Epidemiology and End Results (SEER) database. Firstly, Cumulative incidence function and cox proportional model were utilized to illustrate the interference of non-GBM related mortality in our cohort. Then, the Fine-Gray competing risk model was applied to determine the prognostic factors for GBM related mortality. Age ≥ 75 years old, white race, size > 5.4 cm, frontal lobe tumor, and overlapping lesion were independently associated with more GBM related death, while Gross total resection (GTR) (HR 0.87, 95%CI 0.80-0.94, P = 0.010), radiotherapy (HR 0.64, 95%CI 0.55-0.74, P < 0.001), chemotherapy (HR 0.72, 95%CI 0.59-0.90, P = 0.003), and chemoRT (HR 0.43, 95%CI 0.38-0.48, P < 0.001) were identified as independently protective factors of GBM related death. Based on this, a corresponding nomogram was conducted to predict 3-, 6- and 12-month GBM related mortality, the C-index of which were 0.763, 0.718, and 0.694 respectively. The calibration curve showed that there was a good consistency between the predicted and the actual mortality probability. Concerning treatment options, GTR followed by chemoRT is suggested as optimal treatment. Radiotherapy and chemotherapy alone also provide moderate clinical benefits.

The adaptive transition of glioblastoma stem cells and its implications on treatments.

Glioblastoma is the most malignant tumor occurring in the human central nervous system with overall median survival time <14.6 months. Current treatments such as chemotherapy and radiotherapy cannot reach an optimal remission since tumor resistance to therapy remains a challenge. Glioblastoma stem cells are considered to be responsible for tumor resistance in treating glioblastoma. Previous studies reported two subtypes, proneural and mesenchymal, of glioblastoma stem cells manifesting different sensitivity to radiotherapy or chemotherapy. Mesenchymal glioblastoma stem cells, as well as tumor cells generate from which, showed resistance to radiochemotherapies. Besides, two metabolic patterns, glutamine or glucose dependent, of mesenchymal glioblastoma stem cells also manifested different sensitivity to radiochemotherapies. Glutamine dependent mesenchymal glioblastoma stem cells are more sensitive to radiotherapy than glucose-dependent ones. Therefore, the transition between proneural and mesenchymal subtypes, or between glutamine-dependent and glucose-dependent, might lead to tumor resistance to radiochemotherapies. Moreover, neural stem cells were also hypothesized to participate in glioblastoma stem cells mediated tumor resistance to radiochemotherapies. In this review, we summarized the basic characteristics, adaptive transition and implications of glioblastoma stem cells in glioblastoma therapy.

Immune-related genes with APA in microenvironment indicate risk stratification and clinical prognosis in grade II/III gliomas.

Tumor microenvironment and alternative polyadenylation (APA) have drawn more attention in cancer research. However, their roles in grade II and III gliomas, termed as lower-grade glioma (LGG) in this study, remain to be fully elucidated. Here, we conducted this study and found that stromal and immune scores were elevated in higher grade and isocitrate dehydrogenase (IDH) wild-type glioma. Besides, higher stromal and immune scores indicated a poor prognosis in patients with LGG. APA events in immune-related genes were associated with overall survival, RNA expression, IDH mutation, and disease-free survival. Patients in the high-risk group had poor prognoses, and the risk score could be used to predict the survival rate. The risk score was positively correlated with the expression of immune checkpoints, inflammatory cytokines, and infiltrated immune cells. Moreover, risk stratification could predict the efficacy of radiotherapy and provide a reference for the treatment of grade III glioma. Our study revealed that immune-related genes with APA events in the microenvironment could predict risk stratification and clinical prognosis in patients with LGG.

Expression of m6A Regulators Correlated With Immune Microenvironment Predicts Therapeutic Efficacy and Prognosis in Gliomas.

BACKGROUND: N6-methyladenosine (m6A) RNA methylation and tumor immune microenvironment played crucial roles in cancer development. However, their association in gliomas remains to be fully elucidated. METHODS: A total of 2144 glioma patients from CGGA, TCGA, and Rembrandt databases were extracted in our study, in which 325 were set as the training cohort and 1819 were defined as the validation cohort. Survival differences evaluated by Kaplan-Meier analysis between groups. Patients were clustered into subgroups by consensus clustering. ESTIMATE algorithm was applied to calculate immune and stroma scores. The infiltration of immune cells was characterized by TIMER algorithm. The risk signature was constructed by multivariate Cox regression analysis. RESULTS: Nineteen m6A regulators were highly expressed in glioma tissues. The expression of m6A regulators was associated with prognoses, grade, isocitrate dehydrogenase (IDH) status, and 1p19q status of gliomas. Two subgroups were identified by consensus clustering, in which cluster 1 was associated with favorable prognosis, high stroma and immune scores, and high immune infiltration. When the patients were divided into high risk and low risk groups based on their risk scores, we found that patients in the high risk group had poor prognoses. Besides, patients in the high risk group had a higher stroma and immune scores, and higher abundance of immune infiltration. These results were further verified in the validation cohort, which contained three independent datasets. Moreover, patients in the low risk group enjoyed better prognoses without chemoradiotherapy or single chemotherapy. CONCLUSION: Our study revealed that m6A regulators could predict the prognosis and therapeutic efficacy, and were also associated with the immune microenvironment in gliomas.

Downregulation of CyclophilinA/CD147 Axis Induces Cell Apoptosis and Inhibits Glioma Aggressiveness.

Gliomas are the most common primary tumors in the brain with poor prognosis. Previous studies have detected high expression of Cyclophilin A (CyPA) and CD147, respectively, in glioma. However, the correlation between their expressions and glioma prognosis remains unclear. Here, we investigated the expression of CyPA and CD147 in different types of glioma and characterized their relationships with clinical features, prognosis, and cell proliferation. Results showed that CyPA and CD147 expressions were elevated in higher grade gliomas. Moreover, the knockdown of CyPA and CD147 by RNA interference significantly induced cell express apoptosis biomarkers such as Annexin V and inhibited proliferation biomarkers like EdU in glioma cells. In summary, our findings revealed that high expression of CyPA and CD147 correlated with glioma grades. Moreover, downregulation of the Cyclophilin A/CD147 axis induces cell apoptosis and inhibits glioma aggressiveness. Those indicating CyPA and CD147 could be used as both potential predictive biomarkers and a potential therapeutic target.

Tumor treating fields for high-grade gliomas.

High-grade gliomas (HGG) are the most common malignant intracranial tumors with poor prognosis. Current treatments have not yielded optimal remission rates; there are no standard treatments for recurrent and drug-resistant gliomas. Tumor treating fields, which was recently approved by the Food and Drug Administration (FDA), could significantly improve progression free survival and the overall survival of glioma patients. In this review, we elaborate on the mechanism of tumor treating fields in tumor cells and detail various preclinical and clinical studies on gliomas. Tumor treating fields could be a promising option for patients with malignant tumors for which there are no standard treatment plans. Moreover, we identify several potential problems for the practical application of tumor treating fields and predict future directions for further studies. Tumor treating fields may be a potential therapy with high efficacy, fewer adverse effects, and high cost-effectiveness.

Immunotherapy for glioma: Current management and future application.

Gliomas are intrinsic brain tumors that originate from neuroglial progenitor cells. Conventional therapies, including surgery, chemotherapy, and radiotherapy, have achieved limited improvements in the prognosis of glioma patients. Immunotherapy, a revolution in cancer treatment, has become a promising strategy with the ability to penetrate the blood-brain barrier since the pioneering discovery of lymphatics in the central nervous system. Here we detail the current management of gliomas and previous studies assessing different immunotherapies in gliomas, despite the fact that the associated clinical trials have not been completed yet. Moreover, several drugs that have undergone clinical trials are listed as novel strategies for future application; however, these clinical trials have indicated limited efficacy in glioma. Therefore, additional studies are warranted to evaluate novel therapeutic approaches in glioma treatment.