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Abstract There are increasing concerns regarding the rapid expansion of polystyrene nanoplastics (PS-NPs), which could impact human health. Previous studies have shown that nanoplastics can be transferred from mothers to offspring through the placenta and breast milk, resulting in cognitive deficits in offspring. However, the neurotoxic effects of maternal exposure on offspring and its mechanisms remain unclear. In this study, PS-NPs (50 nm) were gavaged to female rats throughout gestation and lactation to establish an offspring exposure model to study the neurotoxicity and behavioral changes caused by PS-NPs on offspring. Neonatal rat hippocampal neuronal cells were used to investigate the pathways through which NPs induce neurodevelopmental toxicity in offspring rats, using iron inhibitors, autophagy inhibitors, reactive oxygen species (ROS) scroungers, P53 inhibitors, and NCOA4 inhibitors. We found that low PS-NPs dosages can cause ferroptosis in the hippocampus of the offspring, resulting in a decline in the cognitive, learning, and memory abilities of the offspring. PS-NPs induced NOCA4-mediated ferritinophagy and promoted ferroptosis by inciting ROS production to activate P53-mediated ferritinophagy. Furthermore, the levels of the antioxidant factors glutathione peroxidase 4 (GPX4) and glutathione (GSH), responsible for ferroptosis, were reduced. In summary, this study revealed that consumption of PS-NPs during gestation and lactation can cause ferroptosis and damage the hippocampus of offspring. Our results can serve as a basis for further research into the neurodevelopmental effects of nanoplastics in offspring. Graphical Abstract

Abstract Background Although immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, only a minority of colorectal cancer (CRC) patients respond to them. Enhancing tumor immunogenicity by increasing major histocompatibility complex I (MHC-I) surface expression is a promising strategy to boost the antitumor efficacy of ICIs. Methods Dual luciferase reporter assays were performed to find drug candidates that can increase MHC-I expression. The effect of nilotinib on MHC-I expression was verified by dual luciferase reporter assays, qRT-PCR, flow cytometry and western blotting. The biological functions of nilotinib were evaluated through a series of in vitro and in vivo experiments. Using RNA-seq analysis, immunofluorescence assays, western blotting, flow cytometry, rescue experiments and microarray chip assays, the underlying molecular mechanisms were investigated. Results Nilotinib induces MHC-I expression in CRC cells, enhances CD8+ T-cell cytotoxicity and subsequently enhances the antitumor effects of anti-PDL1 in both microsatellite instability and microsatellite stable models. Mechanistically, nilotinib promotes MHC-I mRNA expression via the cGAS-STING-NF-κB pathway and reduces MHC-I degradation by suppressing PCSK9 expression in CRC cells. PCSK9 may serve as a potential therapeutic target for CRC, with nilotinib potentially targeting PCSK9 to exert anti-CRC effects. Conclusion This study reveals a previously unknown role of nilotinib in antitumor immunity by inducing MHC-I expression in CRC cells. Our findings suggest that combining nilotinib with anti-PDL1 therapy may be an effective strategy for the treatment of CRC.

Abstract Background Extracellular ATP–AMP–adenosine metabolism plays a pivotal role in modulating tumor immune responses. Previous studies have shown that the conversion of ATP to AMP is primarily catalysed by Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39), a widely studied ATPase, which is expressed in tumor-associated immune cells. However, the function of ATPases derived from tumor cells themselves remains poorly understood. The purpose of this study was to investigate the role of colon cancer cell–derived ATPases in the development and progression of colon cancer. Methods Bioinformatic and tissue microarray analyses were performed to investigate the expression of ATPase family members in colon cancer. An ATP hydrolysis assay, high-performance liquid chromatography (HPLC), and CCK8 and colony formation assays were used to determine the effects of ENTPD2 on the biological functions of colon cancer cells. Flow cytometric and RNA-seq analyses were used to explore the function of CD8+ T cells. Immunoelectron microscopy and western blotting were used to evaluate the expression of ENTPD2 in exosomes. Double-labelling immunofluorescence and western blotting were used to examine the expression of ENTPD2 in serum exosomes and colon cancer tissues. Results We found that ENTPD2, rather than the well-known ATPase CD39, is highly expressed in cancer cells and is significantly positively associated with poor patient prognosis in patients with colon cancer. The overexpression of ENTPD2 in cancer cells augmented tumor progression in immunocompetent mice by inhibiting the function of CD8+ T cells. Moreover, ENTPD2 is localized primarily within exosomes. On the one hand, exosomal ENTPD2 reduces extracellular ATP levels, thereby inhibiting P2X7R-mediated NFATc1 nuclear transcription; on the other hand, it facilitates the increased conversion of ATP to adenosine, hence promoting adenosine-A2AR pathway activity. In patients with colon cancer, the serum level of exosomal ENTPD2 is positively associated with advanced TNM stage and high tumor invasion depth. Moreover, the level of ENTPD2 in the serum exosomes of colon cancer patients is positively correlated with the ENTPD2 expression level in paired colon cancer tissues, and the ENTPD2 level in both serum exosomes and tissues is significantly negatively correlated with the ENTPD2 expression level in tumor-infiltrating CD8+ T cells. Conclusion Our study suggests that exosomal ENTPD2, originated from colon cancer cells, contributes to the immunosuppressive microenvironment by promoting ATP–adenosine metabolism. These findings highlight the importance of exosome-derived hydrolytic enzymes as independent entities in shaping the tumor immune microenvironment.

Micro(nano)plastic, as a new type of environmental pollutant, have become a potential threat to the life and health of various stages of biology. However, it is not yet clear whether they will affect brain development in the fetal stage. Therefore, this study aims to explore the potential effects of nanoplastics on the development of fetal rat brains. To assess the allocation of NPs (25 nm and 50 nm) in various regions of the fetal brain, pregnant rats were exposed to concentrations (50, 10, 2.5, and 0.5 mg/kg) of PS-NPs. Our results provided evidence of the transplacental transfer of PS-NPs to the fetal brain, with a prominent presence observed in several cerebral regions, notably the cerebellum, hippocampus, striatum, and prefrontal cortex. This distribution bias might be linked to the developmental sequence of each brain region. Additionally, we explored the influence of prenatal exposure on the myelin development of the cerebellum, given its the highest PS-NP accumulation in offspring. Compared with control rats, PS-NPs exposure caused a significant reduction in myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) expression, a decrease in myelin thickness, an increase in cell apoptosis, and a decline in the oligodendrocyte population. These effects gave rise to motor deficits. In conclusion, our results identified the specific distribution of NPs in the fetal brain following prenatal exposure and revealed that prenatal exposure to PS-NPs can suppress myelin formation in the cerebellum of the fetus.

Uncertainty exists regarding the mechanisms by which hypoxia-inducible factors (HIFs) control CD8+T-cell migration into tumor microenvironments. Here, we found that HIF-1α knockdown or overexpression resulted in increased or decreased CXCL9, −10, and −11 expression in vitro, respectively. Gene Set Variation Analysis revealed that elevated HIF-1α levels correlated with a poor prognosis, severe pathological stage, and an absence of CD8+ T cells in the tumor microenvironment in colorectal cancer (CRC) patients. HIF-1α was inversely associated with pathways beneficial to anti-tumor immunotherapy and cytokine/chemokine function. In vivo, inhibiting HIF-1α or its upstream regulator BIRC2 significantly suppressed tumor growth and promoted CD8+ T-cell infiltration. CXCR3 neutralizing antibodies reversed these effects, implicating the involvement of CXCL9, −10, and −11/CXCR3 axis. The presence of HIF-1α weakened the upregulation of CXCL9, −10, and −11 by bleomycin and doxorubicin. Combining HIF-1α inhibition with bleomycin promoted CD8+ T-cell infiltration and tumor suppression in vivo. Moreover, doxorubicin could upregulate CXCL9, −10 and −11 by suppressing HIF-1α. Our findings highlight the potential of HIF-1α inhibition to improve CRC microenvironments and increase chemotherapy sensitivity.

Previous studies have shown that early-life exposure to fine particulate matter (PM2.5) is associated with an increasing risk of autism spectrum disorder (ASD), however, the specific sensitive period of ASD is unknown. Here, a model of dynamic whole-body concentrated PM2.5 exposure in pre- and early-postnatal male offspring rats (MORs) was established. And we found that early postnatal PM2.5 exposed rats showed more typical ASD behavioral characteristics than maternal pregnancy exposure rats, including poor social interaction, novelty avoidance and anxiety disorder. And more severe oxidative stress and inflammatory responses were observed in early postnatal PM2.5 exposed rats. Moreover, the expression level of phosphatase and tensin homolog deleted on chromosome ten (PTEN) was down-regulated and the ratios of p-PI3K/PI3K and p-AKT/AKT were up-regulated in early postnatal PM2.5 exposed rats. This study suggests that early postnatal exposure to PM2.5 is more susceptible to ASD-like phenotype in offspring than maternal pregnancy exposure and the activation of PI3K-AKT signaling pathway may represent underlying mechanisms.

Abstract Background Autophagy is involved in nasopharyngeal carcinoma (NPC) radioresistance. Replication protein A 1 (RPA1) and RPA3, substrates of the RPA complex, are potential therapeutic targets for reversing NPC radioresistance. Nevertheless, the role of RPA in autophagy is not adequately understood. This investigation was performed to reveal the cytotoxic mechanism of a pharmacologic RPA inhibitor (RPAi) in NPC cells and the underlying mechanism by which RPAi-mediated autophagy regulates NPC radiosensitivity. Methods and results We characterized a potent RPAi (HAMNO) that was substantially correlated with radiosensitivity enhancement and proliferative inhibition of in vivo and in NPC cell lines in vitro. We show that the RPAi induced autophagy at multiple levels by inducing autophagic flux, AMPK/mTOR pathway activation, and autophagy-related gene transcription by decreasing glycolytic function. We hypothesized that RPA inhibition impaired glycolysis and increased NPC dependence on autophagy. We further demonstrated that combining autophagy inhibition with chloroquine (CQ) treatment or genetic inhibition of the autophagy regulator ATG5 and RPAi treatment was more effective than either approach alone in enhancing the antitumor response of NPC to radiation. Conclusions Our study suggests that HAMNO is a potent RPAi that enhances radiosensitivity and induces autophagy in NPC cell lines by decreasing glycolytic function and activating autophagy-related genes. We suggest a novel treatment strategy in which pharmacological inhibitors that simultaneously disrupt RPA and autophagic processes improve NPC responsiveness to radiation.

Apolipoprotein E (apoE) has previously been reported to play vital roles in tumor progression. However, the impact of apoE on colorectal cancer (CRC) metastasis remains largely unexplored. This study aimed to investigate the role of apoE in CRC metastasis and to identify the transcription factor and receptor of apoE involved in regulation of CRC metastasis. Bioinformatic analyses were conducted to examine the expression pattern and prognosis of apolipoproteins. APOE-overexpressing cell lines were utilized to explore the effects of apoE on proliferation, migration and invasion of CRC cells. Additionally, the transcription factor and receptor of apoE were screened via bioinformatics, and further validated through knockdown experiments. We discovered that the mRNA levels of APOC1, APOC2, APOD and APOE were higher in lymphatic invasion group, and a higher apoE level indicated poorer overall survival and progression-free interval. In vitro studies demonstrated that APOE-overexpression did not affect proliferation but promoted the migration and invasion of CRC cells. We also reported that APOE-expression was modulated by the transcription factor Jun by activating the proximal promoter region of APOE, and APOE-overexpression reversed the metastasis suppression of JUN knockdown. Furthermore, bioinformatics analysis suggested an interaction between apoE and low-density lipoprotein receptor-related protein 1 (LRP1). LRP1 was highly expressed in both the lymphatic invasion group and the APOEHigh group. Additionally, we found that APOE-overexpression upregulated LRP1 protein levels, and LRP1 knockdown attenuated the metastasis-promoting function of APOE. Overall, our study suggests that the Jun-APOE-LRP1 axis contributes to tumor metastasis in CRC.

Air pollution is highly associated with respiratory diseases. However, the influence and mechanism of particulate matter with aerodynamic equal to or less than 2.5 μm (PM2.5) in lung homeostasis remain unclear. Herein, we demonstrated the induction of pulmonary fibrosis (PF) by PM2.5 exposure. The animal model showed that PM2.5 exposure could activate the oxidative stress and inflammation response, promoting epithelial-mesenchymal transition and accumulation of collagen, high expression of pro-fibrotic factors, and pathological characteristics of fibrosis. The proteomic analysis indicated that PM2.5 exposure decreased the expression of caveolin-1 (Cav-1), and many differential proteins were enriched in the TGF-β1/Smad, endoplasmic reticulum stress (ERS) and autophagy pathways. Combining in vivo and in vitro experiments, it was found that PM2.5 exposure could reduce Cav-1 protein levels and activate TGF-β1/Smad3 signaling pathways through ERS and autophagy pathways, thereby inducing cell apoptosis and promoting pulmonary fibrosis. However, inhibiting ERS could alleviate the occurrence of autophagy, and blocking the autophagy system could increase the level of Cav-1 protein and inhibit TGF- β 1/Smad3 signaling pathway to improve pulmonary fibrosis. Therefore, we demonstrated that the exposure of PM2.5 could enhance the ERS induced-autophagy-mediated Cav-1 degradation, thus activating the TGF-β1/Smad3 axis to promote pneumonocytes apoptosis and overproduction of extracellular matrix (ECM), finally aggravating PF. Moreover, our findings revealed that intermittent exposure to high doses of PM2.5 was more toxic than continuous exposure to low dose.

Summary: Background: Pyrimidine nucleotides fuel the growth of colorectal cancer (CRC), making their associated proteins potential targets for cancer intervention. Uridine-Cytidine Kinase Like-1(UCKL1) is an enzyme involved in the pyrimidine salvage pathway. It is highly expressed in multiple cancers. But the function and underlying mechanism of UCKL1 in CRC are yet to study. Methods: Large-scale genomic analysis was performed to search for potential CRC players related to pyrimidine metabolism. The function of UCKL1 in CRC were examined by RNA interference coupled with in vitro and in vivo assays. GSH/GSSG assay, NADP+ assay, ROS, and Lipid peroxidation assays were performed to check the function of UCKL1 in ferroptosis. Metabolomics analyses, RNA sequencing, western blotting, and rescue assays were done to reveal the underlying mechanisms of UCKL1. Xenograft mouse model was used to examine the therapeutic potential of UCKL1 as a target in combination with other ferroptosis inducers. Findings: UCKL1 was identified to repress ferroptosis in CRC cells. It was highly expressed in CRC. It regulated CRC cells proliferation and migration. Downregulation of UCKL1 led to enhanced tumour lipid peroxidation. Intriguingly, UCKL1 reduction-mediated ferroptosis was not related to its role in catalyzing uridine monophosphate (UMP) and cytidine monophosphate (CMP) synthesis. Instead, UCKL1 stabilized Nrf2, which in turn promoted the expression of SLC7A11, a classical repressor of ferroptosis. Moreover, downregulation of UCKL1 sensitized CRC cells to GPX4 inhibitors in vitro and in vivo. Interpretation: Our study demonstrates that UCKL1 plays a non-canonical role in repressing ferroptosis through a UCKL1-Nrf2-SLC7A11 axis in CRC cells. Combinatorial strategy in targeting ferroptosis by depletion of UCKL1 and application of GPX4 inhibitors may serve as a new effective method for CRC treatment. Funding: This study was supported in part by fund from National Natural Science Foundation of China (Grant No. 31970674 to PY), by the Basic and Applied Basic Research Program of Guangdong Province (Grant No. 2023A1515030245 to KL), by the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), and by National Key Clinical Discipline.

Rapid social and industrial development has resulted in an increasing demand for fossil fuel energy, which increases particulate matter (PM) pollution. In this study, we employed a simple one-step electrospinning technique to fabricate polysulfone (PSF) fiber membranes for PM filtration. A 0.3 g/mL polymer solution with an N,N-dimethylformamide:tetrahydrofuran volume ratio of 3:1 yielded uniform and bead-free PSF fibers with a diameter of approximately 1.17 μm. The PSF fiber membrane exhibited excellent hydrophobicity and mechanical properties, including a tensile strength of 1.14 MPa and an elongation at break of 116.6%. Finally, the PM filtration performance of the PSF fiber membrane was evaluated. The filtration efficiencies of the membrane for PM2.5 and PM1.0 were approximately 99.6% and 99.2%, respectively. The pressure drops were 65.0 and 65.2 Pa, which were significantly lower than those of commercial air filters. Using this technique, PSF fiber membrane filters can be easily fabricated over a large area, which is promising for numerous air filtration systems.

Perinatal air pollution plays an important role in the development of autism. However, research on the pathogenic mechanism remains limited. In this study, the model of systemic inhalation of concentrated approximately 8-fold the level (mean concentration was 224 μg/m3) reported in ambient outdoor air of PM2.5 (particulate matters that are 2.5 μm or less in diameter)in early-postnatal male Sprague-Dawley (SD) rats was established. Through a series of autism-related behavioral tests, it was identified that young rats (postnatal day 1-day21, named PND1-PND21) exposed to PM2.5 exhibited typical autistic phenotypes, such as impaired language communication, abnormal repetitive and stereotyped behaviors, and impaired social skills. Moreover, synaptic abnormalities have been found in the brain tissues of young rats exposed to PM2.5. In terms of the molecular mechanism, we found that the levels of SH3 and multiple ankyrin repeat domains 3 (SHANK3) expression and key molecular proteins in the downstream signaling pathways were decreased in the brain tissues of the exposed rats. Finally, at the epigenetic level, SHANK3 methylation levels were increased in young rats exposed to PM2.5. In conclusion, the study revealed that PM2.5 exposure might induce the early postnatal autism through the SHANK3 signaling pathway by affecting the SHANK3 methylation levels and reducing the SHANK3 expression levels. The study could provide new ideas for autism etiology and a theoretical basis for the prevention and treatment of autism in children.

Summary: Antibody-secreting B cells have long been considered the central element of gut homeostasis; however, tumor-associated B cells in human colorectal cancer (CRC) have not been well characterized. Here, we show that the clonotype, phenotype, and immunoglobulin subclasses of tumor-infiltrating B cells have changed compared to adjacent normal tissue B cells. Remarkably, the tumor-associated B cell immunoglobulin signature alteration can also be detected in the plasma of patients with CRC, suggesting that a distinct B cell response was also evoked in CRC. We compared the altered plasma immunoglobulin signature with the existing method of CRC diagnosis. Our diagnostic model exhibits improved sensitivity compared to the traditional biomarkers, CEA and CA19-9. These findings disclose the altered B cell immunoglobulin signature in human CRC and highlight the potential of using the plasma immunoglobulin signature as a non-invasive method for the assessment of CRC.

Exposure to PM2.5 can aggravate the occurrence and development of bronchial asthma and fibrosis. Here, we investigated the differences in bronchial injury caused by different exposure modes of PM2.5 (high concentration intermittent exposure and low concentration continuous exposure), and the mechanism of macrophage activation and respiratory immune imbalance induced by PM2.5, leading to bronchial asthma and airway fibrosis using animal and cell models. A ''PM2.5 real-time online concentrated animal whole-body exposure system'' was used to conduct PM2.5 respiratory exposure of Wistar rats for 12 weeks, which can enhance oxidative stress in rat bronchus, activate epithelial cells and macrophages, release chemokines, recruit inflammatory cells, release inflammatory factors and extracellular matrix, promote bronchial mucus hypersecretion, inhibit the expression of epithelial cytoskeletal proteins, destroy airway barrier, and induce asthma. Furthermore, PM2.5 induced M2 polarization in lung bronchial macrophages through JAK/STAT and PI3K/Akt signaling pathways, and compared with low concentration continuous exposure, high concentration intermittent exposure of PM2.5 could regulate significantly higher expression of TIPE2 protein through promoter methylation of TIPE2 DNA, thereby activating PI3K/Akt signaling pathway and more effectively inducing M2 polarization of macrophages. Additionally, activated macrophages release IL-23, and activated epithelial cells and macrophages released TGF-β1, which promoted the differentiation of Th17 cells, triggered the Th17 dominant immune response, and activated the TGF-β1/Smad2 signaling pathway, finally causing bronchial fibrosis. Moreover, when the total amount of PM2.5 exposure was equal, high concentration-intermittent exposure was more serious than low concentration-continuous exposure. In vitro experiments, the co-culture models of PM2.5 with BEAS-2B, WL-38 and rat primary alveolar macrophages further confirmed that PM2.5 could induce the macrophage activation through oxidative stress and TIPE2 DNA methylation, and activate the TGF-β1/Smad2 signaling pathway, leading to the occurrence of bronchial fibrosis.

The molecular mechanisms of PM2.5 exposure in the male reproductive system, have scarcely been studied. Here, we demonstrate the possible relationship and molecular mechanisms between endoplasmic reticulum stress (ERS), oxidative stress, and reproductive toxicity caused by PM2.5. A ''PM2.5 real-time online concentrated animal whole-body exposure system'' was employed to expose male Wistar rats to PM2.5 for 12 weeks, which could induce sperm quality decline, apoptosis, inflammation, oxidative stress, ERS, and histopathological damage in the testis. In vitro study on cultured primary testicular spermatogonia and Leydig cells confirmed that treatment with PM2.5 (0–320 μg/mL) for 24 h decreased cell survival rate, increased reactive oxygen species, lactate dehydrogenase and 8-hydroxydeoxyguanosine levels, induced DNA damage, ERS and apoptosis, and inhibit the secretion and synthesis of testosterone in Leydig cells. These results clarified that ERS pathways triggered by oxidative stress could significantly induce CHOP and caspase-12 activation, which are significantly associated with cell apoptosis. However, oxidative stress and ERS inhibitors significantly inhibited the occurrence of these injuries. In conclusion, PM2.5 triggers the ERS pathway and induces DNA damage in rat testicular cells through oxidative stress, ultimately leading to cellular apoptosis. Furthermore, high-concentration intermittent inhalation was more harmful than low-concentration continuous inhalation when the total mass of PM2.5 exposure was the same.

Exposure to nanoplastics can induce toxicity on organisms at both parental generation (P0-G) and the offspring. However, the underlying mechanism remains unknown. Using Caenorhabditis elegans as a model organism, exposure to 20-nm polystyrene nanoparticle (PS-NP) (1–100 μg/L) upregulated the expressions of insulin ligands (INS-39, INS-3, and DAF-28), and this increase could be further detected in the offspring after PS-NP exposure. Germline ins-39, ins-3, and daf-28 RNAi induced resistance to transgenerational toxicity of PS-NP, indicating that increase in expression of these three insulin ligands mediated induction of transgenerational toxicity. These three insulin ligands transgenerationally activated function of insulin receptor DAF-2 to control transgenerational toxicity of PS-NP. Exposure to 1–100 μg/L PS-NP further upregulated DAF-2, AGE-1, and AKT-1 expressions and downregulated DAF-16 expression. During transgenerational toxicity control, DAF-16/AKT-1/AGE-1 was identified as downstream signaling cascade of DAF-2. Moreover, transcriptional factor DAF-16 activated two downstream targets of HSP-6 (a mitochondrial UPR marker) and SOD-3 (a mitochondrial SOD) to modulate transgenerational toxicity of PS-NP. Our findings indicate a crucial link between activation of insulin signaling and induction of transgenerational toxicity of nanoplastics at low concentrations in organisms.

The possible toxicity caused by nanoplastics or microplastics on organisms has been extensively studied. However, the unavoidably combined effects of nanoplastics and microplastics on organisms, particularly intestinal toxicity, are rarely clear. Here, we employed Caenorhabditis elegans to investigate the combined effects of PS-50 (50 nm nanopolystyrene) and PS-500 (500 nm micropolystyrene) at environmentally relevant concentrations on the functional state of the intestinal barrier. Environmentally, after long-term treatment (4.5 days), coexposure to PS-50 (10 and 15 μg/L) and PS-500 (1 μg/L) resulted in more severe formation of toxicity in decreasing locomotion behavior, in inhibiting brood size, in inducing intestinal ROS production, and in inducting intestinal autofluorescence production, compared with single-exposure to PS-50 (10 and 15 μg/L) or PS-500 (1 μg/L). Additionally, coexposure to PS-50 (15 μg/L) and PS-500 (1 μg/L) remarkably caused an enhancement in intestinal permeability, but no detectable abnormality of intestinal morphology was observed in wild-type nematodes. Lastly, the downregulation of acs-22 or erm-1 expression and the upregulation expressions of genes required for controlling oxidative stress (sod-2, sod-3, isp-1, clk-1, gas-1, and ctl-3) served as a molecular basis to strongly explain the formation of intestinal toxicity caused by coexposure to PS-50 (15 μg/L) and PS-500 (1 μg/L). Our results suggested that combined exposure to microplastics and nanoplastics at the predicted environmental concentration causes intestinal toxicity by affecting the functional state of the intestinal barrier in organisms.

Oil mist particulate matter (OMPM) causes acute and chronic diseases and exacerbations. Owing to the characteristics of poor ventilation, high oil mist concentration, and a relatively closed working environment, the existence of OMPM in the cabin is inevitable, and its impact on the health of occupations on ships cannot be ignored. However, compared with several studies that summarized the health effects of OMPM from traditional sources, few studies have focused on the occupational exposure risk of OMPM from oil pollution sources in ships. In this study, we collected OMPM from oil pollution in cabins and assessed the exposure to OMPM from oil pollution and the corresponding health risks through acute exposure experiments in rats. OMPM exposure induces protein regulation in the extracellular matrix and immune responses, leading to severe inflammatory responses. The abundance and composition of the lung microbial community changed significantly. It interferes with the lung metabolite levels. However, more research is needed to fully understand the extent of health risks associated with OMPM exposure. Further research on vulnerable groups exposed to OMPM from ships is needed to inform public health interventions.

Objective: To study the regulatory relationship between ozone-induced mitophagy and pyroptosis in lung epithelial cells. Results: First, type I primary alveolar epithelial cells and male Wistar rats were treated with ozone at different dosages. The ATP content and mitochondrial membrane potential significantly decreased in type I primary alveolar epithelial cells. The mitophagy-related markers and PINK1/Parkin pathway-related proteins, and the co-localization of LC3, Parkin, and mitochondria in type I alveolar epithelial cells indicated that ozone exposure triggered mitophagy. On the other hand, the reactive oxygen species (ROS) inhibitor NAC could significantly alleviate mitophagy in epithelial cells. After treatment with the mitophagy inhibitor MDIVI-1, the levels of the NLRP3 inflammasome, cleaved caspase-1, and N-gasdermin D (N-GSDMD) significantly decreased in the cells. Altogether, these results indicated that mitophagy can be triggered by ozone exposure, and subsequently induces cell death mediated by the NLRP3 inflammasome. Finally, the overexpression and knockdown of NLRP3 confirmed this conclusion. Conclusion: Ozone exposure induced oxidative damage, leading to mitochondrial structural and functional damage. Ozone-induced ROS triggered mitophagy through the activation of the PINK1/Parkin signaling pathway, then pyroptosis through activation of the NLRP3 inflammasome.

Abstract Background tRNA-derived small RNAs (tDRs), which are widely distributed in human tissues including blood and urine, play an important role in the progression of cancer. However, the expression of tDRs in colorectal cancer (CRC) plasma and their potential diagnostic values have not been systematically explored. Methods The expression profiles of tDRs in plasma of CRC and health controls (HCs) are investigated by small RNA sequencing. The level and diagnostic value of 5′-tRF-GlyGCC are evaluated by quantitative PCR in plasma samples from 105 CRC patients and 90 HCs. The mechanisms responsible for biogenesis of 5′-tRF-GlyGCC are checked by in vitro and in vivo models. Results 5′-tRF-GlyGCC is dramatically increased in plasma of CRC patients compared to that of HCs. The area under curve (AUC) for 5′-tRF-GlyGCC in CRC group is 0.882. The combination of carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) with 5′-tRF-GlyGCC improves the AUC to 0.926. Consistently, the expression levels of 5′-tRF-GlyGCC in CRC cells and xenograft tissues are significantly greater than that in their corresponding controls. Blood cells co-cultured with CRC cells or mice xenografted with CRC tumors show increased levels of 5′-tRF-GlyGCC. In addition, we find that the increased expression of 5′-tRF-GlyGCC is dependent on the upregulation of AlkB homolog 3 (ALKBH3), a tRNA demethylase which can promote tRNA cleaving to generate tDRs. Conclusions The level of 5′-tRF-GlyGCC in plasma is a promising diagnostic biomarker for CRC diagnosis.

Background: Current diagnostic methods for colorectal cancer (CRC) are colonoscopy and sigmoidoscopy, which are invasive and complex procedures with possible complications. This study aimed to determine models for CRC identification that involve minimally invasive, affordable, portable, and accurate screening variables. Methods: This was a retrospective study that used data from electronic medical records of patients with CRC and healthy individuals between July 2017 and June 2018. Laboratory data, including liver enzymes, lipid profiles, complete blood counts, and tumor biomarkers, were extracted from the electronic medical records. Five machine learning models (logistic regression, random forest, k-nearest neighbors, support vector machine [SVM], and naïve Bayes) were used to identify CRC. The performances were evaluated using the areas under the curve (AUCs), sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV). Results: A total of 1164 electronic medical records (CRC patients: 582; healthy controls: 582) were included. The logistic regression model achieved the highest performance in identifying CRC (AUC: 0.865, sensitivity: 89.5%, specificity: 83.5%, PPV: 84.4%, NPV: 88.9%). The first four weighted features in the model were carcinoembryonic antigen (CEA), hemoglobin (HGB), lipoprotein (a) (Lp(a)), and high-density lipoprotein (HDL). A diagnostic model for CRC was established based on the four indicators, with an AUC of 0.849 (0.840-0.860) for identifying all CRC patients, and it performed best in discriminating patients with late colon cancer from healthy individuals with an AUC of 0.905 (0.889-0.929). Conclusions: The logistic regression model based on CEA, HGB, Lp(a), and HDL might be a powerful, noninvasive, and cost-effective method to identify CRC.

There is an urgent need for novel agents for colorectal cancer (CRC) due to the increasing number of cases and drug-resistance related to current treatments. In this study, we aim to uncover the potential of chaetocin, a natural product, as a chemotherapeutic for CRC treatment. We showed that, regardless of 5-FU-resistance, chaetocin induced proliferation inhibition by causing G2/M phase arrest and caspase-dependent apoptosis in CRC cells. Mechanically, our results indicated that chaetocin could induce reactive oxygen species (ROS) accumulation and activate c-Jun N-terminal kinase (JNK)/c-Jun pathway in CRC cells. This was confirmed by which the JNK inhibitor SP600125 partially rescued CRC cells from chaetocin induced apoptosis and the ROS scavenger N-acetyl-L-cysteine (NAC) reversed both the chaetocin induced apoptosis and the JNK/c-Jun pathway activation. Additionally, this study indicated that chaetocin could down-regulate the expression of CD47 at both mRNA and protein levels, and enhance macrophages phagocytosis of CRC cells. Chaetocin also inhibited tumor growth in CRC xenograft models. In all, our study reveals that chaetocin induces CRC cell apoptosis, irrelevant to 5-FU sensitivity, by causing ROS accumulation and activating JNK/c-Jun, and enhances macrophages phagocytosis, which suggests chaetocin as a candidate for CRC chemotherapy.

Inhibitor of β-catenin and T-cell factor (ICAT) was first found as a polypeptide that blocks β-catenin–TCF interaction. Abundant evidence has shown that ICAT has different functions in diverse cancers’ progression. Nevertheless, the roles it plays in colorectal cancer (CRC) have not been described. Here, we documented that ICAT expression was higher in CRC tissue than in the adjacent normal tissue and that prognosis was better in high-ICAT expression patients. The overexpression of ICAT inhibited CRC cell proliferation both in vitro and in vivo. Wnt pathway transcriptional activity was suppressed in the CRC cells with ICAT overexpression, where the CCND1 and MYC expression, which occurs downstream of the Wnt signaling pathway, was inhibited. Co-immunoprecipitation experiments showed that ICAT bound with β-catenin in stable overexpression cell lines; immunofluorescence showed the co-localization of ICAT and β-catenin in the cytoplasm. Overall, our study reveals that ICAT inhibits CRC cell proliferation by binding to cytoplasm-located β-catenin, and prevents its translocation, which results in Wnt signaling pathway inactivation. It may provide a scientific foundation for focusing on ICAT in treatments for CRC.

Oil-mist particulate matter (OMPM) refers to oily particles with a small aerodynamic equivalent diameter in ambient air. Since the pathogenesis of pulmonary fibrosis (PF) has not been fully elucidated, this study aims to explore the potential molecular mechanisms of the adverse effects of exposure to OMPM at different concentrations in vivo and in vitro on PF. In this study, rats and cell lines were treated with different concentrations of OMPM in vivo and in vitro. Sirius Red staining analysis shows that OMPM exposure could cause pulmonary lesions and fibrosis symptoms. The expression of TGF-β1, α-SMA, and collagen I was increased in the lung tissue of rats. The activities of MMP2 and TIMP1 were unbalanced, and increased N-Cadherin and decreased E-Cadherin upon OMPM exposure in a dose-dependent manner. In addition, OMPM exposure could activate the TGF-β1/Smad3 and TGF-β1/MAPK p38 signaling pathways, and the differentiation of human lung fibroblast HFL-1 cells. Therefore, OMPM exposure could induce PF by targeting the lung epithelium and fibroblasts, and activating the TGF-β1/Smad3 and TGF-β1/MAPK p38 signaling pathways.

Metabolic reprogramming is one of the most common characteristics of cancer cells. The metabolic alterations of glucose, amino acids and lipids can support the aggressive phenotype of cancer cells. Exosomes, a kind of extracellular vesicles, participate in the intercellular communication through transferring bioactive molecules. Increasing evidence has demonstrated that enzymes, metabolites and non-coding RNAs in exosomes are responsible for the metabolic alteration of cancer cells. In this review, we summarize the past and recent findings of exosomes in altering cancer metabolism and elaborate on the role of the specific enzymes, metabolites and non-coding RNAs transferred by exosomes. Moreover, we give evidence of the role of exosomes in cancer diagnosis and treatment. Finally, we discuss the existing problems in the study and application of exosomes in cancer diagnosis and treatment.

Neurotransmission related signals are involved in the control of response to toxicants. We here focused on the tyramine and the glutamate related signals to determine their roles in regulating nanoplastic toxicity in Caenorhabditis elegans. In the range of μg/L, exposure to nanopolystyrene (100 nm) increased the expression of tdc-1 encoding a tyrosine decarboxylase required for synthesis of tyramine, and decreased the expression of eat-4 encoding a glutamate transporter. Both TDC-1 and EAT-4 could act in the neurons to regulate the nanopolystyrene toxicity. Meanwhile, neuronal RNAi knockdown of tdc-1 induced a susceptibility to nanopolystyrene toxicity, and neuronal RNAi knockdown of eat-4 induced a resistance to nanopolystyrene toxicity. In the neurons, TYRA-2 functioned as the corresponding receptor of tyramine and acted upstream of MPK-1 signaling to regulate the nanopolystyrene toxicity. Moreover, during the control of nanopolystyrene toxicity, GLR-4 and GLR-8 were identified as the corresponding glutamate receptors, and acted upstream of JNK-1 signaling and DBL-1 signaling, respectively. Our results demonstrated the crucial roles of tyramine and glutamate related signals in regulating the toxicity of nanoplastics in organisms.

Abstract Background Indoleamine 2,3-dioxygenase 1 (IDO1) is a critical regulator of T cell function, contributing to immune tolerance. Upregulation of IDO1 has been found in many cancer types; however, the regulatory mechanisms and clinical significance of IDO1 in colon cancer are still unclear. Here, we investigated the role of dysregulated microRNA (miRNA) targeting IDO1 in the colon cancer microenvironment. Methods We elucidated IDO1 function by performing cell-based assays and establishing transplanted tumor models in BALB/c mice and BALB/c nude mice. We evaluated IDO1 protein expression by immunohistochemistry (IHC) in a tissue microarray (TMA) and analyzed IDO1 mRNA expression with The Cancer Genome Atlas (TCGA). We screened miRNAs targeting IDO1 by using a dual luciferase reporter assay. We tested the function of microRNA-448 (miR-448) by using western blotting (WB) and fluorescence-activated cell sorting (FACS). Results We demonstrated that stable IDO1 overexpression enhanced xenograft tumor growth in BALB/c mice but not in BALB/c nude mice. We also revealed the involvement of posttranscriptional regulation of IDO1 in colon cancer by observing IDO1 protein levels and mRNA levels. Furthermore, ectopic expression of miRNA mimics suggested that miR-448 could significantly downregulate IDO1 protein expression. Notably, we proved that miR-448 suppressed the apoptosis of CD8+ T cells by suppressing IDO1 enzyme function. Conclusion Our findings indicated that IDO1 suppressed the CD8+ T cell response in colon cancer. miR-448, as a tumor-suppressive miRNA, enhanced the CD8+ T cell response by inhibiting IDO1 expression. The results provide a theoretical basis for the development of new immunotherapy for the treatment of colon cancer.

Abstract Background Acquired resistance remains a limitation of the clinical use of 5-fluorouracil (5-FU). Because exosomes, are important vesicles participating in intercellular communication, their contribution to the development of acquired 5-FU resistance needs to be elucidated. In this study, we aimed to examine the underlying mechanisms of exosomes from 5-FU resistant cells (RKO/R) in sustaining acquired 5-FU resistance in sensitive cells (RKO/P). Methods Exosomes from a 5-FU-resistant cell line (RKO/R) and its parental cell line RKO/P were isolated and co-cultured with 5-FU-sensitive cells. Real-time cellular analysis (RTCA) and FACS analysis were used to examine cell viability and apoptosis. Exosomal protein profiling was performed using shotgun proteomics. Inhibitors and siRNAs were applied to study the involvement of selected proteins in 5-FU resistance. The effect of exosomal p-STAT3 (Tyr705) on the caspase cascade was examined by western blotting (WB) and high content analysis. Xenograft models were established to determine whether exosomal p-STAT3 can induce 5-FU resistance in vivo. Results Our results indicated that exosomes from RKO/R cells significantly promoted cell survival during 5-FU treatment. Proteomics and WB analysis results indicated that GSTP1 and p-STAT3 (Tyr705) were enriched in exosomes from RKO/R cells. Inhibition of p-STAT3 re-sensitized RKO/P cells to 5-FU via caspase cascade. Furthermore, p-STAT3 packaged by exosomes from RKO/R cells increased resistance of tumor cells to 5-FU in vivo. Conclusions Our results reveal a novel mechanism by which p-STAT3-containing exosomes contribute to acquired 5-FU resistance in CRC. This study suggests a new option for potentiating the 5-FU response and finding biomarkers for chemotherapy resistance.

Background: Increased frequency of CCR9+ CD4+ T cells in peripheral blood is linked to several gastrointestinal inflammatory diseases; however, its relationship with necrotizing enterocolitis (NEC) is not understood. We investigated whether the frequencies of CCR9+ CD4+ T cells and related subsets were increased in peripheral blood of both patients and mice with NEC. Methods: CCR9+ CD4+ T cells and related subsets were evaluated by flow cytometry in peripheral blood collected from both patients and mice with NEC and controls. The suppressive function of CCR9+ regulatory T (Treg) cells in NEC was assessed via in vitro suppression assay. An in vitro T cell polarization assay was performed to investigate the role of proinflammatory cytokines in Treg cell polarization. In vivo Treg cell polarization analysis was performed using NEC mice treated with anti-interleukin-6 (IL-6) receptor antibody. Findings: A higher proportion of CCR9+ CD4+ T cells occurred in peripheral blood of both patients and mice with NEC than in controls. Elevated CCR9+ CD4+ T cells were primarily CCR9+ IL-17-producing Treg cells, possessing features of conventional Treg cells, but their suppressive activity was seriously impaired and negatively correlated with the severity of intestinal tissue injury. IL-6 promoted polarization of CCR9+ Treg cells to CCR9+ IL-17-producing Treg cells, and blocking IL-6 signalling inhibited this conversion in vitro and ameliorated experimental NEC in vivo. Interpretation: Collectively, these data suggested that CCR9+ IL-17-producing Treg cells may be a biomarker of severity and highlight the possibility that antibodies targeting IL-6R could ameliorate NEC by modulating lymphocyte balance. Fund: This work was supported by the Science and Technology Planning Project of Guangdong Province, China (2017A020215100), the Science and Technology Foundation of Guangzhou, China (201704020086 and 201604020154), the Medical Scientific Research Foundation of Guangdong Province, China (A2017304 and A2014704), and the Social Science and Technology Development Foundation of Dongguan, China (2016108101037). Keywords: CCR9, Interleukin-6, IL-17-producing Treg cell, Necrotizing enterocolitis

Abstract Background Long noncoding RNAs (lncRNAs) have emerged as critical players in cancer progression, but their functions in colorectal cancer (CRC) metastasis have not been systematically clarified. Methods lncRNA expression profiles in matched normal and CRC tissue were checked using microarray analysis. The biological roles of a novel lncRNA, namely RP11-138 J23.1 (RP11), in development of CRC were checked both in vitro and in vivo. Its association with clinical progression of CRC was further analyzed. Results RP11 was highly expressed in CRC tissues, and its expression increased with CRC stage in patients. RP11 positively regulated the migration, invasion and epithelial mesenchymal transition (EMT) of CRC cells in vitro and enhanced liver metastasis in vivo. Post-translational upregulation of Zeb1, an EMT-related transcription factor, was essential for RP11-induced cell dissemination. Mechanistically, the RP11/hnRNPA2B1/mRNA complex accelerated the mRNA degradation of two E3 ligases, Siah1 and Fbxo45, and subsequently prevented the proteasomal degradation of Zeb1. m6A methylation was involved in the upregulation of RP11 by increasing its nuclear accumulation. Clinical analysis showed that m6A can regulate the expression of RP11, further, RP11 regulated Siah1-Fbxo45/Zeb1 was involved in the development of CRC. Conclusions m6A-induced lncRNA RP11 can trigger the dissemination of CRC cells via post-translational upregulation of Zeb1. Considering the high and specific levels of RP11 in CRC tissues, our present study paves the way for further investigations of RP11 as a predictive biomarker or therapeutic target for CRC.

The underlying mechanisms of microRNAs (miRNAs) in regulating nanoplastic toxicity are still largely unclear in organisms. In nanopolystyrene (NPS) exposed Caenorhabditis elegans, the expression of mir-76 (a neuronal miRNA) was significantly decreased, and the mir-76 mutant was resistant to the toxicity of NPS. The aim of this study was to determine the molecular basis of mir-76 in controlling NPS toxicity in nematodes. The mir-76 mutation increased expression of glb-10 encoding a globin protein in NPS (1 μg/L) exposed nematodes. Exposure to NPS (1–100 μg/L) increased the glb-10 expression, and the glb-10(RNAi) worm was susceptible to NPS toxicity in inducing reactive oxygen species (ROS) production and in decreasing locomotion behavior. Using ROS production and locomotion behavior as endpoints, mutation of glb-10 inhibited resistance of mir-76 mutant to NPS toxicity, and neuronal overexpression of mir-76 inhibited the resistance to NPS toxicity in nematodes overexpressing neuronal glb-10 containing 3’ untranslated region (3’UTR). Thus, GLB-10 functioned as a target of mir-76 in the neurons to regulate the NPS toxicity. Moreover, a signaling cascade of HRG-7-HRG-5 required for the control of heme homeostasis was identified to function downstream of neuronal GLB-10 to regulate the NPS toxicity. In this signaling cascade, the neuronal HRG-7 regulated the NPS toxicity by antagonizing function of intestinal HRG-5. Furthermore, in the intestine, HRG-5 controlled NPS toxicity by inhibiting functions of hypoxia-inducible transcriptional factor HIF-1 and transcriptional factor ELT-2. Our results highlight the crucial function of heme homeostasis related signaling in regulating the NPS toxicity in organisms.

Abstract Background Patient-derived xenografts (PDX) have a biologically stable in tumor architecture, drug responsiveness, mutational status and global gene-expression patterns. Numerous PDX models have been established to date, however their thorough characterization regarding the tumor formation and rates of tumor growth in the established models remains a challenging task. Our study aimed to provide more detailed information for establishing the PDX models successfully and effectively. Methods We transplanted four different types of solid tumors from 108 Chinese patients, including 21 glioblastoma (GBM), 11 lung cancers (LC), 54 gastric cancers (GC) and 21 colorectal cancers (CRC), and took tumor tissues passaged for three successive generations. Here we report the rate of tumor formation, tumor-forming times, tumor growth curves and mortality of mice in PDX model. We also report H&E staining and immunohistochemistry for HLA-A, CD45, Ki67, GFAP, and CEA protein expression between patient cancer tissues and PDX models. Results Tumor formation rate increased significantly in subsequent tumor generations. Also, the survival rates of GC and CRC were remarkably higher than GBM and LC. As for the time required for the formation of tumors, which reflects the tumor growth rate, indicated that tumor growth rate always increased as the generation number increased. The tumor growth curves also illustrate this law. Similarly, the survival rate of PDX mice gradually improved with the increased generation number in GC and CRC. And generally, there was more proliferation (Ki67+) in the PDX models than in the patient tumors, which was in accordance with the results of tumor growth rate. The histological findings confirm similar histological architecture and degrees of differentiation between patient cancer tissues and PDX models with statistical analysis by GraphPad Prism 5.0. Conclusion We established four different types of PDX models successfully, and our results add to the current understanding of the establishment of PDX models and may contribute to the extension of application of different types of PDX models.

Abstract Background Estrogenic signals are suggested to have protection roles in the development of colorectal cancer (CRC). The G protein-coupled estrogen receptor (GPER) has been reported to mediate non-genomic effects of estrogen in hormone related cancers except CRC. Its expression and functions in CRC were investigated. Methods The expression of GPER and its associations with clinicopathological features were examined. The mechanisms were further investigated using cells, mouse xenograft models, and clinical human samples. Results GPER was significantly (p

The discovery of new bioactive compounds from marine natural sources is very important in pharmacological research. Here we developed a Wnt responsive luciferase reporter assay to screen small molecule inhibitors of cancer associated constitutive Wnt signaling pathway. We identified that gliotoxin (GTX) and some of its analogues, the secondary metabolites from marine fungus Neosartorya pseufofischeri, acted as inhibitors of the Wnt signaling pathway. In addition, we found that GTX downregulated the β-catenin levels in colorectal cancer cells with inactivating mutations of adenomatous polyposis coli (APC) or activating mutations of β-catenin. Furthermore, we demonstrated that GTX induced growth inhibition and apoptosis in multiple colorectal cancer cell lines with mutations of the Wnt signaling pathway. Together, we illustrated a practical approach to identify small-molecule inhibitors of the Wnt signaling pathway and our study indicated that GTX has therapeutic potential for the prevention or treatment of Wnt dependent cancers and other Wnt related diseases.

Racemic new cyclohexenone and cyclopentenone derivatives, (±)-(4R*,5S*,6S*)-3-amino-4,5,6-trihydroxy-2-methoxy-5-methyl-2-cyclohexen-1-one (1) and (±)-(4S*,5S*)-2,4,5-trihydroxy-3-methoxy-4-methoxycarbonyl-5-methyl-2-cyclopenten-1-one (2), and two new xanthone derivatives 4-chloro-1,5-dihydroxy-3-hydroxymethyl-6-methoxycarbonyl-xanthen-9-one (3) and 2,8-dimethoxy-1,6-dimethoxycarbonyl-xanthen-9-one (4), along with one known compound, fischexanthone (5), were isolated from the culture of the mangrove endophytic fungus Alternaria sp. R6. The structures of these compounds were elucidated by analysis of their MS (Mass), one and two dimensional NMR (nuclear magnetic resonance) spectroscopic data. Compounds 1 and 2 exhibited potent ABTS [2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)] scavenging activities with EC50 values of 8.19 ± 0.15 and 16.09 ± 0.01 μM, respectively. In comparison to Triadimefon, compounds 2 and 3 exhibited inhibitory activities against Fusarium graminearum with minimal inhibitory concentration (MIC) values of 215.52 and 107.14 μM, respectively, and compound 3 exhibited antifungal activity against Calletotrichum musae with MIC value of 214.29 μM.

ObjectiveE-selectin (SELE) mediates the rolling and adhesion of leukocytes on activated endothelial cells and plays a critial role in the pathogenesis of coronary artery disease (CAD). Associatons between the A561C and G98T polymorphisms of the SELE gene and CAD risk were investigated broadly, but the results were inconsistent. In the present study, we performed a meta-analysis to systematically evaluate the associations between the two polymorphisms and the risk of CAD.MethodsComprehensive research was conducted to identify relevant studies. The fixed or random effect model was selected based on the heterogeneity among studies, which was evaluated with Q-test and Ι(2). Meta-regression was used to explore the potential sources of between-study heterogeneity. Peters's linear regression test was used to estimate the publication bias.ResultsOverall, 24 articles involving 3694 cases and 3469 controls were included. After excluding articles deviating from Hardy-Weinberg equilibrium in controls and sensitive analysis, our meta-analysis showed a significant association between the A561C ploymprphism and CAD in dominant (OR= 1.84, 95% CI = 1.56-2.16) and codominant (OR= 1.74, 95% CI= 1.49-2.03) models. As for the G98T polymorphism, significantly increased CAD risk was observed in dominant (OR = 1.47, 95% CI= 1.16-1.87) and codominant (OR= 1.48, 95% CI = 1.18-1.86) models, but after subgroup analysis, the association was not significant among Caucasians in dominant (OR= 1.58, 95% CI= 0.73-3.41) and codominant (OR= 1.58, 95% CI= 0.79-3.20) models.ConclusionsDespite some limitations, our meta-analysis suggested that the SELE gene polymorphisms (A561C, G98T) were significantly associated with increased risk of CAD. However, after subgroup analysis no significant association was found among Caucasians for the G98T polymorphism, which may be due to the small sample size and other confounding factors. Future investigations with multicenter, large-scale, and multi-ethnic groups are needed.

Programmed death ligand-1 (PD-L1) has been identified as a factor associated with poor prognosis in a range of cancers, and was reported to be mainly induced by PTEN loss in gliomas. However, the clinical effect of PD-L1 and its regulation by PTEN has not yet been determined in colorectal cancer (CRC). In the present study, we verified the regulation of PTEN on PD-L1 and further determined the effect of PTEN on the correlation between PD-L1 expression and clinical parameters in CRC.RNA interference approach was used to down-regulate PTEN expression in SW480, SW620 and HCT116 cells. It was showed that PD-L1 protein, but not mRNA, was significantly increased in cells transfected with siRNA PTEN compared with the negative control. Moreover, the capacity of PTEN to regulate PD-L1 expression was not obviously affected by IFN-γ, the main inducer of PD-L1. Tissue microarray immunohistochemistry was used to detect PD-L1 and PTEN in 404 CRC patient samples. Overexpression of PD-L1 was significantly correlated with distant metastasis (P

Background: The similarity between Crohn's disease (CD) and non-CD, especially with ulcerative colitis (UC) or intestinal tuberculosis (ITB), makes the diagnostic error rate not low. Therefore, there is an urgent need for an efficient, fast, and simple predictive model that can be applied in clinical practice. The purpose of this study is to establish the risk prediction model for CD based on five routine laboratory tests by logistic-regression algorithm, to construct the early warning model for CD and the corresponding visual nomograph, and to provide an accurate and convenient reference for the risk determination and differential diagnosis of CD, in order to assist clinicians to better manage CD and reduce patient suffering. Methods: Using a retrospective analysis, a total of 310 cases were collected from 2020 to 2022 at The Sixth Affiliated Hospital, Sun Yat-sen University, who were diagnosed by comprehensive clinical diagnosis, including 100 patients with CD, 50 patients with ulcerative colitis (UC), 110 patients with non-inflammatory bowel disease (non- IBD) diseases (65 cases of intestinal tuberculosis, radioactive enterocolitis 39, and colonic diverticulitis 6), and 50 healthy individuals (NC) in the non-CD group. Risk prediction models were established by measuring ESR, Hb, WBC, ALb, and CH levels in hematology. The models were evaluated and visualized using logistic-regression algorithm. Results: 1) ESR, WBC, and WBC/CH ratios in the CD group were higher than those in the non-CD group, while ALb, Hb, CH, WBC/ESR ratio, and Hb/WBC ratio were lower than those in the non-CD group, and the differences were statistically significant (all p < 0.05). 2) CD occurrence had a strong correlation with the WBC/CH ratio, with the correlation coefficient exceeding 0.4; CD occurrence was correlated with other indicators. 3) A risk prediction model containing age, gender, ESR, ALb, Hb, CH, WBC, WBC/CH, WBC/ESR, and Hb/WBC characteristics was constructed using a logistic-regression algorithm. The sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve of the model were 83.0%, 76.2%, 59.0%, 90.5%, and 0.86, respectively. The model based on the corresponding index also had high diagnostic accuracy (AUC = 0.88) for differentiating CD from ITB. Visual nomograph based on the logistic-regression algorithm was also constructed for clinical application reference. Conclusions: In this study, a CD risk prediction model was established and visualized by five conventional hematological indices: ESR, Hb, WBC, ALb, and CH, in addition to a high diagnostic accuracy for the differential diagnosis of CD and ITB. [ABSTRACT FROM AUTHOR]