BACKGROUND:In the treatment of nasopharyngeal carcinoma (NPC), there is a lack of effective assessment of the long-term effects on patients. Searching for an effective evaluation scheme and screening a reliable index for various therapeutic regimens is an urgent clinical issue that needs to be resolved. AIM:To establish an effective evaluation scheme and screen a reliable index for NPC patients across various therapeutic regimens. METHODS:This population-based retrospective cohort study included NPC survivors (n = 1142; weighted population, 100984) from the OB database of the Hunan Cancer Hospital, spanning from 2011 to 2023. The software DT Health (V 6.8) and I Medical software were utilized to extract the data. By leveraging the aforementioned database, the survival and mortality rates of NPC patients across various therapeutic regimens were analyzed. Three Cox regression models were formulated to explore the independent association of the Ferritin index with 3- and 5-year mortality risk. We used restricted cubic spline analysis to assess the potential nonlinear relationships between Ferritin-related indices and 3- and 5-year mortality. We also assessed the association between the Ferritin index and mortality using Cox proportional hazards regression models. All NPC patients were randomly divided into training and validation sets in a 3:7 ratio. Receiver operating characteristic (ROC), decision curve analysis (DCA), and calibration curves were plotted simultaneously for both training and validation sets. RESULTS:NPC patients were divided into two groups: Survivors (615, 53.85%) and non-survivors (527, 46.15%) based on their 5-year mortality. The 5-year mortality rate of males (71.35%) was higher than that of females (28.65%). The tumor stage of the non-survivors converged to TNM stages III and IV. Non-survivors displayed significantly higher levels of Ferritin, lactate dehydrogenase, and carcinoembryonic antigen than the survivors (P < 0.05). Follow-up analysis revealed that nidaplatin plus 5-fluorouracil (NF), docetaxel plus nidaplatin (TN), and docetaxel plus cisplatin (TP) regimens were associated with imporved 5-year survival in NPC patients. The 3- and 5-year rates showed a significant association with Ferritin level. When patients were stratified by Ferritin index quartiles, the tumor stages were predominantly skewed towards TNM stages III and IVa. Thus, Ferritin serves as a key novel biomarker for assessing NPC treatment efficacy. The Ferritin index was significantly associated with 3- and 5-year mortality risk. This correlation was evident in both the unadjusted and fully adjusted models. There was a minor level, S-shaped correlation between the Ferritin index and 3-year mortality. NPC patients with the Ferritin index in quartiles 1 and 3 had a higher 5-year mortality risk. Kaplan-Meier curves demonstrated that there were significant differences in mortality rates among different Ferritin quartiles. NPC patients with the Ferritin index in quartile 4 exhibited the highest 5-year survival rates. ROC curve analysis based on logistic regression predictive model revealed that the Ferritin index predicted 5-year mortality in the validation set. Additionally, the DCA curves of both the training and validation sets indicated that the Ferritin index optimized the predictive performance of the basic risk model for 5-year mortality. CONCLUSION:The chemotherapy regimens of NF, TN, and TP for NPC are associated with the prognosis of NPC. The Ferritin index is an important indicator for predicting NPC survival.

As one of head and neck tumors, nasopharyngeal carcinoma (NPC) occurs most frequently in the south of China, especially in Hunan, Guangzhou and other places, causing serious harm to people's life and health. NPC patient is mainly treated with radiotherapy in clinic, but most of them have serious side effects. At present, traditional Chinese medicine (TCM) combined with chemoradiotherapy in the treatment of NPC patient has been focused on by Chinese and Western clinicians. Although TCM syndrome differentiation has significant advantages in the treatment of nasopharyngeal cancer, the relevant syndrome type standards for TCM syndrome differentiation guidance are still not unified. Therefore, this paper summarized the clinical experience, clinical data analysis and experimental research of TCM scholars in recent years, discussed the role and influence of TCM syndrome differentiation on the treatment of NPC. It provides some guidance for the standardization of TCM syndrome differentiation of NPC patients.

The incidence of nasopharyngeal carcinoma (NPC) is related to genetic factors, and individual genetics determines the physical constitution and syndrome type. The Traditional Chinese Medicine (TCM) studies have proven that NPC patients with different TCM syndrome types should be given various TCM treatment formulas, and the patients get various effects, but the molecular mechanisms are not clear. This study used small RNA microarray sequencing to analyze differential tsRNA of serum samples from NPC patient with TCM syndrome type, and molecular expression profiles in NPC with various CTM syndrome were obtained. 3,718 tsRNAs were highly expressed in NPC patients when compared with healthy population. In the pattern of lung heat with phlegm coagulation, 47 tsRNAs were up-regulated and 11 were down-regulated. Remarkably, tRF3b-ArgACG-2, 5'tiRNA-32-ValAAC-1, mt-tRF3-21-ValTAC, mt-tRF3-24-ValTAC, and mt-tRF3-20-ValTAC exhibited up-regulation. While 5'tiRNA-36-GlnCTG-6, tRF3b-PheGAA-11, tRF5-18-AsnGTT-15, tRF5-30-GlnTTG-3, 5'tiRNA-35-LeuTAG-1 were down-regulated. In Qi stagnation with phlegm stasis, 16 tsRNAs were up-regulated and 16 tsRNAs were down-regulated. tRF-1-GluCTC-5-1, tRF3b-ArgACG-2, 5'tiRNA-32-ValAAC-2, 5'tiRNA-35-GlnTTG-6, and 5'tiRNA-34-GlnTTG-6 showed up-regulation. tRF5-18-GlnTTG-5, tRF5-18-GluTTC-9, i-tRF-29:51-Asn-GTT-1, tRF5-18-GlyCCC-6, and i-tRF-21i22:46-Lys-CTT-1 were down-regulated. For fire toxin obstruction, 19 tsRNAs were up-regulated and 32 tsRNAs were down-regulated. mt-tRF3-19-ValTAC, mt-tRF3a-ValTAC, tRF5-22-ValCAC-6, mt-tRF5-25-TyrGTA, and 5'Leader-ThrAGT-1-1 were upregulated. tRF3b-GluTTC-4, 5'tiRNA-37-LeuAAG-4, 5'Leader-ThrAGT-4-1, mt-tRF3-17-ThrTGT, and 3'tiRNA-45-AlaCGC-4 were down-regulated. The Qi-Yin deficiency group showed 6 upregulated and 1 downregulated tsRNA. i-tRF-15:32-His-GTG-1, mt-tRF5-26-LeuTAA, 5'tiRNA-37-AsnGTT-7, mt-tRF5-22-MetCAT, tRF5-30-HisGTG-1, and i-tRF-21:54-His-GTG-1 were upregulated. tRF3a-AlaAGC-10 was down-regulated. Specific tsRNA profiles for each syndrome are revealed, NPC patients with different TCM syndrome types have various tsRNA profile.

OBJECTIVE:To investigate the mechanism by which the CBX4-HDAC5-CERS6 axis regulates sphingolipid metabolism in acute myeloid leukemia (AML), with the goal of providing new theoretical foundations for the targeted therapy of AML. METHODS:This prospective study involved 50 AML patients and 50 healthy controls. The expression levels of CBX4, CERS6, and free ceramide were detected. RNA sequencing, proteomics, and lipidomics were employed to analyze CBX4's regulatory effects on sphingolipid metabolism-related genes and pathways. Using THP-1 and KG-1 cell lines, we validated the molecular mechanisms of the CBX4-HDAC5-CERS6 axis through techniques including gene knockdown (siRNA), overexpression, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. CCK-8 assay, flow cytometry, and Western blot were used to analyze the effects of CBX4 on cell proliferation, cell cycle, and key signaling pathways. RESULTS:CBX4 was significantly overexpressed in AML cells, with its expression levels markedly higher in THP-1 and KG-1 cell lines compared with CD34+ normal hematopoietic stem cells (P<0.05). Analysis of clinical samples revealed that the mRNA expression levels of CBX4 and CERS6 as well as free ceramide content were significantly lower in the AML group than the control group (all P<0.05). Mechanistic studies demonstrated that CBX4 knockdown significantly downregulated both mRNA and protein expression of CERS6 (P<0.05) and activated the PI3K/AKT and MAPK signaling pathways. Furthermore, CBX4 indirectly regulated CERS6 transcription by suppressing HDAC5 expression, and dual-luciferase reporter assays confirmed that HDAC5 directly targets the CERS6 promoter region (P<0.05). Combined use of ceramide synthesis inhibitors synergistically enhanced the activation of p-AKT/p-PI3K and p-MEK1/2/p-Raf1 signaling pathway associated proteins induced by CBX4 knockdown. CONCLUSION:The CBX4-HDAC5-CERS6 axis influences AML malignant progression by regulating sphingolipid metabolism, and targeted intervention of this axis may represent a novel therapeutic strategy for AML.

Aflatoxin B1 (AFB1) is the most toxic mycotoxin and a proven human carcinogen that requires metabolic activation, known by cytochrome P450 (CYP) 1A2 and 3A4. Previous evidence showed that AFB1 is activated by human recombinant CYP1A1 expressed in budding yeast. Yet, the toxicity, in particular the genotoxicity of the reactive metabolites formed from AFB1 remains unclear. Humans could be exposed to both AFB1 and benzo(a)pyrene (BaP) simultaneously, thus we were interested in their combined genotoxic effects subsequent to metabolic activation by CYP1A1. In this study, molecular docking of AFB1 to human CYP1A1 indicated that AFB1 is valid as a substrate. In the incubations with AFB1 in human CYP1A1-expressed microsomes, AFM1 as a marking metabolite of AFB1 was detected. Moreover, AFB1 induced micronucleus formation in a Chinese hamster V79-derived cell line and in a human lung epithelial BEAS-2B cell line, both expressing recombinant human CYP1A1, V79-hCYP1A1 and 2B-hCYP1A1 cells, respectively. Immunofluorescence of centromere protein B stained micronuclei was dominant in AFB1-treated BEAS-2B cells exposed to AFB1, suggesting an aneugenic effect. Moreover, AFB1 elevated the levels of ROS, 8-OHdG, AFB1-DNA adduct, and DNA breaks in 2B-hCYP1A1 cells, compared with those in the parental BEAS-2B cells. Meanwhile, AFB1 increased CYP1A1, RAD51, and γ-H2AX protein levels in 2B-hCYP1A1 cells, which were attenuated by the CYP1A1 inhibitor bergamottin. Co-exposure of AFB1 with BaP increased 8-OHdG, RAD51, and γ-H2AX levels (indicating DNA damage). In conclusion, AFB1 could be activated by human CYP1A1 for potent aneugenicity, which may be further enhanced by co-exposure to BaP.

Gas explosions are one of the most lethal types of coal mine safety accidents.The powerful shock waves these explosions produce can cause damage to the lung tissue of nearby individuals,resulting in symptoms including pulmonary hemorrhage and pulmonary edema[1].

Background: Hydroquinone (HQ), a major metabolite of benzene and known hematotoxic carcinogen. MicroRNA 1246 (miR-1246), an oncogene, regulates target genes in carcinogenesis including leukemia. This study in-vestigates the impact of exosomal derived miR-1246 from HQ-transformed (HQ19) cells on cell-to-cell communication in recipient TK6 cells.Methods: RNA sequencing was used to identify differentially expressed exosomal miRNAs in HQ19 cells and its phosphate buffered solution control cells (PBS19), which were then confirmed using qRT-PCR. The impact of exosomal miR-1246 derived from HQ-transformed cells on cell cycle distribution was investigated in recipient TK6 cells.Results: RNA sequencing analysis revealed that 34 exosomal miRNAs were upregulated and 158 miRNAs were downregulated in HQ19 cells compared with PBS19 cells. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses predicted that their targets are enriched in cancer development-related pathways, such as MAPK signaling, microRNAs in cancer, apoptosis, PI3K-Akt signaling, cell cycle, Ras signaling, and Chronic myeloid leukemia. Eleven miRNAs were confirmed to have differential expression through qRT-PCR, with 6 upregulated (miR-140-3p, miR-551b-3p, miR-7-5p, miR-1290, miR-92a-3p, and miR-1246) and 5 downregulated (miR-183-5p, miR-26a-5p, miR-30c-5p, miR-205-5p, and miR-99b-3p). Among these, miR-1246 exhibited the highest expression level. HQ exposure resulted in a concentration-dependent increase in miR-1246 levels and decrease Cyclin G2 (CCNG2) levels in TK6 cells. Similarly, exosomes from HQ19 exhibited similar effects as HQ exposure. Dual luciferase reporter gene assays indicated that miR-1246 could band to CCNG2. After HQ expo-sure, exosomal miR-1246 induced cell cycle arrest at the S phase, elevating the expression of genes like pRb, E2F1, and Cyclin D1 associated with S phase checkpoint. However, silencing miR-1246 caused G2/M-phase arrest.Conclusion: HQ-transformed cells' exosomal miR-1246 targets CCNG2, regulating TK6 cell cycle arrest, high-lighting its potential as a biomarker for HQ-induced malignant transformation.

Hydroquinone(HQ) is a widely used industrial raw material and is a topical lightening product found in over-the-counter products. However, inappropriate exposure to HQ can pose certain health hazards. This study aims to explore the mechanisms of DNA damage and cell apoptosis caused by HQ, with a focus on whether HQ activates the nuclear factor-κB (NF-κB) pathway to participate in this process and to investigate the correlation between the NF-κB pathway activation and poly(ADP-ribose) polymerase 1(PARP1). Through various experimental techniques, such as DNA damage detection, cell apoptosis assessment, cell survival rate analysis, immunofluorescence, and nuclear-cytoplasmic separation, the cytotoxic effects of HQ were verified, and the activation of the NF-κB pathway was observed. Simultaneously, the relationship between the NF-κB pathway and PARP1 was verified by shRNA interference experiments. The results showed that HQ could significantly activate the NF-κB pathway, leading to a decreased cell survival rate, increased DNA damage, and cell apoptosis. Inhibiting the NF-κB pathway could significantly reduce HQ-induced DNA damage and cell apoptosis and restore cell proliferation and survival rate. shRNA interference experiments further indicated that the activation of the NF-κB pathway was regulated by PARP1. This study confirmed the important role of the NF-κB pathway in HQ-induced DNA damage and cell apoptosis and revealed that the activation of the NF-κB pathway was mediated by PARP1. This research provides important clues for a deeper understanding of the toxic mechanism of HQ.

Hydroquinone (HQ), one of the metabolites of benzene in humans, has significant hepatotoxic properties. Chronic exposure to HQ can lead to leukemia. In a previous study by this group, we constructed a model of malignant transformation of human lymphoblastoid cells (TK6) induced by chronic exposure to HQ with significant subcutaneous tumorigenic capacity in nude mice. miR-92a-3p is a tumor factor whose role in HQ-induced malignant transformation is not yet clear. In the present study, raw signal analysis and dual-luciferase reporter gene results suggested that miR-92a-3p could target and regulate TOB1, and the expression level of miR-92a-3p was significantly upregulated in the long-term HQ-induced TK6 malignant transformation model, while the anti-proliferative factor TOB1 was significantly downregulated. To investigate the mechanism behind this, we inhibited miR-92a-3p in a malignant transformation model and found a decrease in cell viability, a decrease in MMP-9 protein levels, a G2/M phase block in the cell cycle, and an upregulation of the expression of G2/M phase-related proteins cyclinB1 and CDK1. Inhibition of miR-92a-3p in combination with si-TOB1 restored cell viability, inhibited cyclin B1 and CDK1 protein levels, and attenuated the G2/M phase block. Taken together, miR-92a-3p reduced the cell proliferation rate of HQ19 and caused cell cycle arrest by targeting TOB1, which in turn contributed to the altered malignant phenotype of the cells. This study suggests that miR-92a-3p is likely to be a biomarker for long-term HQ-induced malignant transformation of TK6 and could be a potential therapeutic target for leukemia caused by long-term exposure to HQ.

Objective:The study aimed to estimate the benchmark dose (BMD) of coke oven emissions (COEs) exposure based on mitochondrial damage with the mitochondrial DNA copy number (mtDNAcn) as a biomarker.Methods:A total of 782 subjects were recruited, including 238 controls and 544 exposed workers. The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction. Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95% confidence lower limit (BMDL).Results:The mtDNAcn of the exposure group was lower than that of the control group (0.60 ± 0.29 vs. 1.03 ± 0.31; P < 0.001). A dose-response relationship was shown between the mtDNAcn damage and COEs. Using the Benchmark Dose Software, the occupational exposure limits (OELs) for COEs exposure in males was 0.00190 mg/m 3. The OELs for COEs exposure using the BBMD were 0.00170 mg/m 3 for the total population, 0.00158 mg/m 3 for males, and 0.00174 mg/m 3 for females. In possible risk obtained from animal studies (PROAST), the OELs of the total population, males, and females were 0.00184, 0.00178, and 0.00192 mg/m 3, respectively.Conclusion:Based on our conservative estimate, the BMDL of mitochondrial damage caused by COEs is 0.002 mg/m 3. This value will provide a benchmark for determining possible OELs.

Hydroquinone (HQ), one of the main active metabolites of benzene in vivo, 7is commonly used as a surrogate for benzene in in vitro studies and has been shown to be cytotoxic. The aim of this study was to investigate the role of endoplasmic reticulum stress (ERS) in HQ-induced autophagy and apoptosis in human lymphoblastoid cells (TK6) and how activating transcription factor 6 (ATF-6) is involved. We treated TK6 cells with HQ to establish a cytotoxicity model and found that HQ induced cellular ERS, autophagy and apoptosis by Western blot, flow cytometry and transmission electron microscopy. In addition, inhibition of both reactive oxygen species (ROS) and ERS inhibited cellular autophagy and apoptosis, suggesting that ERS may be induced by ROS, which in turn affects autophagy and apoptosis. Our study also found that HQ could inhibit ATF6 expression and mTOR activation. Knockdown of ATF6 enhanced autophagy and apoptosis levels and further inhibited mTOR activation; activation of ATF6 by AA147 enhanced cellular activity, suggesting that ATF6 may affect cellular autophagy and apoptosis through mTOR. In conclusion, our data suggest that ROS mediated ERS may promote autophagy and apoptosis by inhibiting ATF6-mTOR pathway after HQ treatment of TK6 cells.

Coke oven emissions (COEs) exposure leads to oxidative stress, an imbalance between oxidant production and antioxidant defence in the body, which then leads to shortened relative telomere length (RTL) and reduced mitochondrial DNA copy number (mtDNAcn), ultimately leading to ageing and disease. By analysing the relationship among COEs, oxidative stress, RTL and mtDNAcn, we investigated the chain-mediating effects of oxidative stress and telomeres on mitochondrial damage and mitochondria on telomere damage in coke oven workers. A total of 779 subjects were included in the study. Cumulative COEs exposure concentrations were estimated, and the RTL and mtDNAcn of peripheral blood leukocytes were measured using real-time fluorescence quantitative PCR. Total antioxidant capacity (T-AOC) was measured to reflect the level of oxidative stress. The data were statistically analysed using SPSS 21.0 software and discussed using mediation effect analysis. After adjusting for age, sex, smoking, drinking and BMI, generalised linear model revealed dose-response associations between COEs and T-AOC, RTL and mtDNAcn, respectively. (Ptrend < 0.05). The results of chain-mediating effect showed that the proportion of the chain-mediating effect of "CED-COEs→T-AOC→ RTL→mtDNAcn" was 0.82% (β = -0.0005, 95% CI = [-0.0012, -0.0001]), and the proportion of the chain-mediating effect of "CED-COEs→T-AOC→ mtDNAcn → RTL ″ was 2.64% (β = -0.0013, 95% CI = [-0.0025, -0.0004]). After oxidative stress is induced by COEs, mitochondria and telomeres may interact with each other while leading further to potential bodily damage. This study provides clues to explore the association between mitochondria and telomeres.

Coke oven emissions (COEs) contain many carcinogenic polycyclic aromatic hydrocarbons (PAHs). Telomere damage is an early biological marker reflecting long-term COEs-exposure. Whereas, whether the genetic variations of telomere-regulated gene TNKS have an effect on the COEs-induced telomere damage is unknown. So we detected the environmental exposure levels, relative telomere length (RTL), and TNKS genetic polymorphisms among 544 COEs-exposure workers and 238 healthy participants. We found that the RTL of the wild homozygous GG genotype in rs1055328 locus was statistically shorter compared with the CG+CC genotype for the healthy participants using covariance analysis(P = 0.008). In the Generalized linear model (GLM) analysis, TNKS rs1055328 GG could accelerate telomere shortening (P = 0.011); and the interaction between TNKS rs1055328 GG and COEs-exposure had an effect on RTL (P = 0.002). In conclusion, this study was the first to discover the role of TNKS rs1055328 locus in COEs-induced telomere damage, and proved that chromosomal damage was a combined consequence of environmental and genetic factors.

Abstract The invasion and metastasis of gastric cancer pose frequent clinical challenges following standard treatment. Investigating the molecular mechanisms underpinning gastric cancer invasion and metastasis constitutes a critical research area. This study aims to pinpoint potential target molecules involved in gastric cancer metastasis. After analyzing the TCGA database, we identified overexpression of EGFR and MMP7 in gastric adenocarcinoma, which correlates with unfavorable patient outcomes. Notably, MMP7 expression is closely linked to gastric adenocarcinoma metastasis. Immunohistochemical analysis of clinical gastric adenocarcinoma tissue samples confirmed the association of both EGFR and MMP7 with metastasis, aligning with the findings from bioinformatics analysis. Moreover, our immunohistochemical results revealed a positive correlation between EGFR and MMP7 expression, providing a foundational basis for future endeavors in searching for drug targets to prevent and treat gastric cancer invasion and metastasis.

Polycyclic aromatic hydrocarbons (PAHs), which are a wide range of environmental toxicants, may act on humans through inhalation, ingestion, and skin contact, resulting in a range of toxic reactions. Epidemiological studies showed that long-term exposure to PAHs in the occupational and living environment results in a substantial rise in the incidence rate of many cancers in the population, so the prevention and treatment of these diseases have become a major worldwide public health problem. N6-methyladenosine (m6A) modification greatly affects the metabolism of RNA and is implicated in the etiopathogenesis of many kinds of diseases. In addition, m6A-binding proteins have an important role in disease development. The abnormal expression of these can cause the malignant proliferation, migration, invasion, and metastasis of cancers. Furthermore, a growing number of studies revealed that environmental toxicants are one of the cancer risk factors and are related to m6A modifications. Exposure to environmental toxicants can alter the methylation level of m6A and the expression of the m6A-binding protein, thus promoting the occurrence and development of cancers through diverse mechanisms. m6A may serve as a biomarker for early environmental exposure. Through the study of m6A, we can find the health injury early, thus providing a new sight for preventing and curing environmental health-related diseases.

The main objective of this study was to explore the value of the discharged case fatality rate (DCFR) in estimating the severity and epidemic trend of COVID-19 in China. Epidemiological data on COVID-19 in China and Hubei Province were obtained from the National Health Commission of the People’s Republic of China from January 20, 2020, to March 31, 2020. The number of daily new confirmed cases, daily confirmed deaths, daily recovered cases, the proportion of daily deaths and total deaths of discharged cases were collected, and the total discharge case fatality rate (tDCFR), daily discharge case fatality rate (dDCFR), and stage-discharge case fatality rate (sDCFR) were calculated. We used the R software (version 3.6.3, R core team) to apply a trimmed exact linear time method to search for changes in the mean and variance of dDCFR in order to estimate the pandemic phase from dDCFR. The tDCFR of COVID-19 in China was 4.16

Objective The aim of the study is to investigate the influence of work-related psychological and physical stresses on risk of cardiovascular disease (CVD). Methods A total of 5651 CVD-free participants older than 50 years from the Survey of Health, Ageing and Retirement in Europe were followed up for 13 years to detect incident CVD. Work-related stress was assessed using job strain and job reward questionnaire. Cox regression model was used to estimate the association. Results High physical demands (hazard ratio [HR], 1.30) and low reward (HR, 1.19) compared with their counterparts, as well as active physical jobs (HR, 1.41) and high physical strain (HR, 1.45) in comparison with low physical strain were associated with higher risk of incident CVD after adjusting for confounders. However, combining physically stressful jobs with low reward did not further increase the CVD risk. Conclusions Avoiding physically stressful jobs or providing appropriate reward may reduce the occurrence of CVD.

Silicosis is a disease mainly caused by pulmonary interstitial fibrosis caused by long-term inhalation of dust with excessively high content of free SiO2. Transdifferentiation of lung fibroblasts into myofibroblasts is an important cellular basis for silicosis, but the key transcription factors (TFs) involved in this process are still unclear. In order to explore the biological regulation of transcription factor PPARγ/LXRα in silica-induced pulmonary fibrosis, this study explored the molecular mechanism of PPARγ/LXRα involved in regulating transcription factors related to SiO2-induced lung injury at the cellular level and in animal models. ChIP-qPCR detected that PPARγ directly regulated the transcriptional activity of the LXRα gene promoter, while the PPARγ agonist RSG increased the expression of LXRα. In addition, we demonstrated in the cell model that upregulation of LXRα can inhibit silica-mediated fibroblast transdifferentiation, accompanied by an increase in the expression of SREBF1, PLTP and ABCA1. The results of LXRα silencing experiment matched those of overexpression experiment. These studies explored the role of LXRα in plasticity and phenotypic transformation between lung fibroblasts and myofibroblasts. Therefore, inhibiting or reversing the transdifferentiation of lung fibroblasts to myofibroblasts by intervening PPARγ/LXRα may provide a new therapeutic target for the treatment of silicosis.

The main clinical manifestations are pulmonary fibrosis, silicosis, is one of the most common types of pneumoconiosis, and its pathogenesis is still unclear. The proliferation and transdifferentiation of fibroblasts are considered to be the key link leading to pulmonary fibrosis. Type II alveolar epithelial cells can be transformed into lung fibroblasts through epithelial-mesenchymal transition (EMT) to promote lung fibrosis. Involved in the EMT process of a variety of cancers, lncRNA UCA1 (UCA1) has been shown to competitively adsorb miR-204-5p, and play an effect on the downstream target gene E-box binding zinc finger protein 1 (ZEB1), thereby promoting EMT to facilitate the invasion and migration of cancer cells. This is an important potential intervention target that affects the process of EMT, but it has not been reported in the study of EMT related to silicosis. Therefore, this study established a SiO2 dust-treated mouse silicosis model and an in vitro EMT model of A549 cells to observe the changes and effects of UCA1 and miR-204-5p, and intervene on the two respectively. The results showed that the EMT process existed in the aforementioned models, while UCA1 was upregulated in the in vitro model. Double luciferase reporter assay demonstrated the targeted binding of UCA1 and miR-204-5p. Silencing UCA1 can up-regulate the expression of miR-204-5p and reduce the level of ZEB1, thus inhibiting EMT process, while intervention of miR-204-5p can change the level of ZEB1 and regulate EMT. Therefore, UCA1 may release its target gene ZEB1 through competitive adsorption of miR-204-5p to regulate EMT process.

Immunotherapy using programmed cell death 1 (PD1) inhibitors has shown great efficacy in colorectal cancer patients harboring mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) alterations. We previously showed a negative correlation of zymogen granule protein 16 (ZG16) with programmed death-ligand 1 (PD-L1) expression in patients with colorectal cancer. However, how ZG16 regulates PD-L1 expression is unclear. In this study, we showed that ZG16 can directly bind to glycosylated PD-L1 through its lectin domain, leading to PD-L1 degradation. Mutations on the lectin domain of ZG16 largely inhibit the interaction between ZG16 and PD-L1. Importantly, ZG16 overexpression suppressed tumor growth in two syngeneic mouse models through blockage of PD-L1 expression in cancer cells meanwhile suppression of PD1 expression in T cells. We also showed that ZG16 could improve the effect of chemotherapy and may be delivered as a protein to serve as an immune checkpoint inhibitor to promote T-cell mediated immunity.