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Abstract Previous studies revealed that MIR155HG possessed an oncogenic role in many types of tumors including lung adenocarcinoma (LUAD), along with higher expression in tumors. However, in our study, we observed a positive correlation between MIR155HG expression and overall survival across different cohorts. The transferred PBMC on the NCG mouse model abrogated the tumor intrinsic oncogenic role of MIR155HG in LUAD. Upregulation of MIR155HG positively correlated with CD8+ T cell infiltration both in vitro and in vivo, as well as LUAD tissues. Mechanistically, we revealed that MIR155HG increased the cytokine CCL5 expression at the transcriptional level, which depended on the interaction between MIR155HG and YBX1 protein, a novel transcription factor of CCL5, resulting in the more protein stability of YBX1 through dampening ubiquitination. Additionally, we also observed that MIR155 could increase PD-L1 expression to hamper the activity of recruited CD8+ T cells, which could be rescued through PD-L1 mAb addition. Finally, we uncovered that patients with high MIR155HG expression had a higher response rate to immunotherapy, and the combination of MIR155HG overexpression and PD-L1 mAb increased the efficacy of PD-L1 mAb. Together, our study provides a novel biomarker and potential combination treatment strategy for patients who received immunotherapy.

Abstract Osimertinib (Osi) is a widely used epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the emergence of resistance is inevitable, partly due to the gradual evolution of adaptive resistant cells during initial treatment. Here, we find that Osi treatment rapidly triggers adaptive resistance in tumor cells. Metabolomics analysis reveals a significant enhancement of oxidative phosphorylation (OXPHOS) in Osi adaptive-resistant cells. Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA4-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.

Background: Malignant tumours, particularly non-small cell lung cancer (NSCLC), pose a significant threat to human health due to their prevalence and lethality. Treatment methods for NSCLC vary greatly among individuals, making it crucial to identify predictive markers. Moreover, during tumour initiation and progression, tumour cells can release signaling molecules to induce polarization of macrophages towards a more tumour friendly M2 phenotype, which can promote tumour growth, metastasis, and drug resistance. Methods: We employed a comprehensive approach, combining bulk RNA-seq and single-cell sequencing analysis. Results: In our study, we used bulk RNA-seq and single-cell sequencing methods to analyze differential cells in NSCLC and adjacent tissues, searching for relevant marker genes that can predict prognosis and drug efficacy. We scrutinized biological phenomena such as macrophage-related gene methylation, copy number variation, and alternative splicing. Additionally, we utilized a co-culture technique of immune and tumour cells to explore the role of these genes in macrophage polarization. Our findings revealed distinct differences in macrophages between cancerous and adjacent tissues. We identified ANP32A, CCL20, ERAP2, MYD88, TMEM126B, TUBB6, and ZNF655 as macrophage-related genes that correlate with NSCLC patient prognosis and immunotherapy efficacy. Notably, ERAP2, TUBB6, CCL20, and TMEM126B can induce macrophage M0 to M2 polarization, promoting tumour proliferation. Conclusion: These findings significantly contribute to our understanding of the NSCLC tumour immune microenvironment. They pave the way for further research into the potential of these genes as targets for regulating tumour occurrence and development.

Abstract Background Biopsies obtained from primary oesophageal squamous cell carcinoma (ESCC) guide diagnosis and treatment. However, spatial intra‐tumoral heterogeneity (ITH) influences biopsy‐derived information and patient responsiveness to therapy. Here, we aimed to elucidate the spatial ITH of ESCC and matched lymph node metastasis (LNmet). Methods Primary tumour superficial (PTsup), deep (PTdeep) and LNmet subregions of patients with locally advanced resectable ESCC were evaluated using whole‐exome sequencing (WES), whole‐transcriptome sequencing and spatially resolved digital spatial profiling (DSP). To validate the findings, immunohistochemistry was conducted and a single‐cell transcriptomic dataset was analysed. Results WES revealed 15.72%, 5.02% and 32.00% unique mutations in PTsup, PTdeep and LNmet, respectively. Copy number alterations and phylogenetic trees showed spatial ITH among subregions both within and among patients. Driver mutations had a mixed intra‐tumoral clonal status among subregions. Transcriptome data showed distinct differentially expressed genes among subregions. LNmet exhibited elevated expression of immunomodulatory genes and enriched immune cells, particularly when compared with PTsup (all P

Abstract Tertiary lymphoid structures (TLSs) are considered to have a good prognosis in multiple solid tumors. However, the prognostic value of TLS in esophageal squamous cell carcinoma (ESCC) is unknown. In this study, we retrospectively enrolled 185 ESCC patients who underwent surgical resection. Hematoxylin and eosin staining was performed to investigate the presence, the abundance, the maturation, and the location of TLSs. We explored the cellular composition of TLSs using traditional immunohistochemistry in serial sections. The prognostic value of TLSs was investigated by univariate and multivariate analyses. A nomogram was constructed to predict the prognosis. TLS‐positive tumors were infiltrated with more CD45+ leukocytes, CD20+ B cells, CD4+ and CD8+ T cells, and CD11c+ dendritic cells（DCs） compared with negative tumors. Kaplan–Meier curves showed that the presence and the abundance of TLSs were associated with longer disease‐free survival (DFS) (p = 0.0130) and overall survival (OS) (p = 0.0164). In addition, patients with tumors containing more CD20+ B cell infiltration had longer DFS (p = 0.0105) and OS (p = 0.0341). Multivariate analyses demonstrated that the presence of TLSs was an independent prognostic factor for DFS (hazard ratio [HR] = 0.384, p

Background It has been reported that smoking history as a predictor of immunotherapy efficacy in patients with advanced lung cancer, however, the underlying mechanisms of this phenomenon remain largely unknown.Methods The patients with lung adenocarcinoma’s (LUAD) cohort and the orthotopical transplanted mouse model were used to explore the correlation between smoking status and tertiary lymphoid structure (TLS) and chemokine CCL21, respectively. Cell adhesion and co-immunoprecipitation assays were performed to explore the interaction between CD4+T cells and CD20+B cells under tobacco exposure. Chromatin immunoprecipitation-PCR was used to dissect the mechanism of upregulated CCL21 secretion in tobacco treatment. Serum CCL21 level was recorded in patients with LUAD treated with immunotherapy.Results Here we observed that individuals with a smoking history exhibit an increased quantity and maturation level of TLS compared with non-smokers, along with higher levels of CCL21 secretion. Tobacco exposure promoted CCL21 expression in an epithelial cell-intrinsic manner, of which BaP, the main component of tobacco, facilitated the nuclear retention of the aryl hydrocarbon receptor that occupied the promoter of CCL21. Additionally, the activated CCL21/CCR7 axis increased the CD11a expression of CD4+T cells, boosting the interaction with CD20+B cells dependent on ICAM1, which potentially induced the TLSs formation. Patients with elevated serum levels of CCL21 benefited more from immunotherapy.Conclusions Patients with a smoking history exhibited higher levels of TLS via the CCL21-dependent mechanism, serum CCL21 was identified as a reliable biomarker for predicting the efficacy of immunotherapy.

Objective: To investigate the genetic mutation characteristics of non-small cell lung cancers (NSCLC) with and without lymph node metastasis.Methods: Primary lesions and metastatic lymph node lesions of 36 Chinese NSCLC patients were tested for somatic mutations, tumor mutation burden, phylogenetic and clonal evolutional analysis using a 1021-gene panel by next-generation sequencing (NGS) with an average sequencing depth of 671X.Results: In this study, eighteen patients with lung adenocarcinoma (LUAD) and 18 with lung squamous cell carcinoma (LUSC) were included. Different groups had distinct characteristics of gene mutations. CTNNB1 gene mutations were only present in Nome_LC LUAD patients (p < 0.05). ARID1A mutation was however the only gene with significant alterations (p < 0.05) in Nome_LC in LUSC. Phylogenetic trees of mutated genes were also constructed. Linear and parallel evolutions of metastatic lymph nodes were observed both in LUAD and LUSC.Conclusion: LUSC exhibited more genetic mutations than LUAD. Intriguingly, there was significant difference in gene mutations between Meta_LC and Nome_LC. CTNNB1 gene alteration was the key mutation in LUAD that seems to promote proliferation of the tumor and then determine T stage. On the other hand, proliferation of the tumor was characterized by ARID1A missense mutation in LUSC, thus influencing the T stage as well. Lymph node metastasis could display both linear and parallel evolutionary characteristics in NSCLC. Different metastatic lymph nodes might have exactly the same or different mutated genes, underlining the heterogeneous genomic characteristics of these cancer types.

Abstract Background Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers. The two major lethal causes of ESCC are diagnosis at an advanced stage and lymph node metastasis (LNM). Circular RNAs (circRNAs) play critical regulatory roles in cancer progression, though, largely through unclear mechanisms. However, the character of circRNAs in the malignant progression of ESCC remains unclear. Methods The circRNA microarray was used to explore the circRNAs that were differentially expressed between ESCC and paired adjacent normal tissues. The function of circIMMP2L was validated by gain or loss of function assays. Pull‐down, RNA immunoprecipitation assays were used to demonstrate the biological mechanism of circIMMP2L. Tissue microarray (TMA), specimen, and paired plasma were investigated to evaluate the clinical significance of circIMMP2L. Results CircIMMP2L, commonly upregulated in tumor and plasma from advanced‐stage ESCC patients and LNM patients, predicts poorer patient survival. CircIMMP2L was also found to be a significant indicator for LNM, even in the T1 stage of ESCC. CircIMMP2L depletion suppressed the malignant progression of ESCC both in vitro and in vivo. Mechanistically, cytoplasmic circIMMP2L interacted with CtBP1 and facilitated the nuclear retention of CtBP1 in a CtBP2‐independent manner. Moreover, circIMMP2L promoted the interaction of CtBP1 with HDAC1 in the nucleus, which is essential for epigenetic remodeling and transcriptional suppression of E‐cadherin and p21. Conclusions These findings demonstrated that circIMMP2L promotes the malignant progression of ESCC mediated by CtBP1 nuclear retention and is a robust biomarker for the diagnosis, prognosis, and LNM in ESCC. Further, the findings extend our knowledge about the mechanism of circRNA regulation of gene transcription through epigenetics.

The microstructure and mechanical properties of X70 pipeline steel with a ferrite/martensite dual-phase microstructure produced by thermo-mechanical controlled processing were investigated by tensile tests, Charpy V-notched (CVN) impact tests, drop-weight tear tests, guided-bend tests, scanning electron microscopy and transmission electron microscopy combined with thermodynamic simulation analysis. All the mechanical properties met the strength, ductility, toughness and deformability properties requirements of X70 grade pipeline steel with strain-based design. The shear fracture area and absorbed energy of CVN at −10 °C were >97% and >205 J in base metal (BM), weld metal (WM) and heat affected zone (HAZ) with low transition temperature, indicating adequate resistance to propagating fracture. The microstructure of WM was mainly intragranular acicular ferrite that can guarantee high strength, toughness and over matching requirements of the welded joint. Because of being exposed to successive heat inputs, the ferrite plus martensite/bainite microstructure of BM was heated between Ac1 and Ts forming the HAZ. However, a high CVN impact toughness of 345 J at −10 °C in HAZ was obtained, which indicated that the excellent mechanical properties of BM would not be seriously deteriorated during the welding thermal cycles with the reasonable addition of Ti and Nb.

This study aims to investigate the effect of initial microstructures on the properties of ferrite-martensite dual-phase pipeline steels with strain-based design. For this purpose, the as-received acicular ferrite steels were first austenitized at 920 ºC for 15 minutes followed by air cooling and water quenching to produce ferrite-pearlite and ferrite-martensite microstructure, respectively. Subsequently, the steels with ferrite-pearlite, ferrite-martensite and as-received acicular ferrite microstructure were intercritically annealed at 820 ºC for 10 minutes followed by water quenching to produce three different ferrite-martensite dual-phase microstructures. Tensile tests, Vickers hardness and Charpy impact tests were carried out to investigate the mechanical properties. Scanning electron microscope was used to analyze the microstructures and tensile fractographs. The results showed that all the tensile specimens of these three different ferrite-martensite dual-phase steels fractured in ductile mode, however, their microstructures and mechanical properties varied significantly. By contrast, the ferrite-martensite dual-phase steel derived from acicular ferrite initial microstructure had optimal combination of the strength, toughness and deformability, which provided a good candidate for the pipeline steels with strain-based design used in severe geological environments.

Mycoplasma gallinarum (MG) can cause infectious respiratory diseases in poultry that are chronic. Arbutin (AR) possesses anti-inflammatory, bacteriostatic, antitussive, and expectorant pharmacological effects, but whether it exerts regulatory effects on MG-induced pneumonia and fibrosis remains unclear. The study results unveiled that pulmonary connective tissue hyperplasia, pulmonary capillary congestion, and inflammatory cell infiltration, as well as serum levels of cytokines (i.e., TNF-α, IL-1β, IL-6, and IL-10), were elevated after MG infection. Collagen fibers were significantly deposited in the lung tissue from MG-infected chicks. Furthermore, the expression levels of key factors in the JAK2/STAT3 and TGF-β/Smad pathways markedly increased. AR intervention significantly alleviated MG-induced pneumonic injury, and reduced collagen deposition and the expression of fibrosis markers in the lung tissue. AR reduced the degree of pulmonary fibrosis by regulating key factors of the JAK2/STAT3 signaling pathway in the MG-infected HD11 cells. Thus, AR effectively reduced the expression of inflammatory factors by regulating the JAK2/STAT3 signaling pathway, thereby improving lung inflammation and fibrosis.

Abstract Objective Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) are considered gold standards for measuring visceral fat area (VFA). However, their relatively high prices and potential radiation exposure limit their widespread use in clinical practice and everyday life. Therefore, our study aims to develop a VFA estimated equation based on sagittal abdominal diameter (SAD) and transverse abdominal diameter (TAD) using anthropometric indexes. To the best of our knowledge, there have been limited studies investigating this aspect thus far. Methods This study was designed as a cross-sectional, retrospective cohort survey. A total of 288 patients (167 males and 121 females) aged 18–80 with type 2 diabetes (T2D) were consecutively collected from a multicenter hospital, and VFA was measured by CT. Subsequently, variables highly correlated with VFA were screened through general linear correlation analysis. A stepwise regression analysis was then conducted to develop a VFA estimated equation. Discrepancies between the estimated and actual VFA values were assessed using the Bland-Altman method to validate the accuracy of the equation. Results In the female T2D population, triglyceride (TG), SAD, TAD were found to be independently correlated with VFA; in the male T2D population, BMI, TG, SAD and TAD showed independent correlations with VFA. Among these variables, SAD exhibited the strongest correlation with VFA (r = 0.83 for females, r = 0.88 for males), followed by TAD (r = 0.69 for females, r = 0.79 for males). Based on these findings, a VFA estimated equation was developed for the T2D population: VFA (male) =-364.16 + 15.36*SAD + 0.77*TG + 9.41*TAD − 5.00*BMI (R2 = 0.75, adjusted R2 = 0.74); VFA(female)=-170.87 + 9.72*SAD-24.29*(TG^-1) + 3.93*TAD (R2 = 0.69, adjusted R2 = 0.68). Both models demonstrated a good fit. The Bland-Altman plot indicated a strong agreement between the actual VFA values and the estimated values, the mean differences were close to 0, and the majority of differences fell within the 95% confidence interval. Conclusions In the T2D population, a VFA estimated equation is developed by incorporating SAD and TAD along with other measurement indices. This equation demonstrates a favorable estimated performance, suggesting to the development of novel and practical VFA estimation models in the future study.

Abstract Few research discuss whether the body measurement indexs of obesity in general populations is applicable to patients with type 2 diabetes. We explore the optimal cutoffs of visceral fat area (VFA) and subcutaneous fat area (SFA) in the diagnosis of central obesity and the cutoffs of corresponding waist circumference (WC) and body mass index (BMI) in patients with Type 2 Diabetes (T2D). Cross-sectional cohort study. 1057 patients with T2D (550 males and 507 females) aged 18 or above that satisfied the criteria were included. The definition and diagnostic criteria of Metabolic syndrome (Mets) were analyzed according to the 2020 Chinese Diabetes Society (CDS) Guideline. The VFA and SFA were measured by bioelectrical impedance analysis (BIA). The optimal VFA and SFA cutoffs and corresponding WC and BMI when two or more nonadipose components of MetS (without central obesity) were met were analyzed by ROC curve. Among all of the T2D patients, the optimal VFA cutoff for identifying two or more nonadipose components of MetS was 73.30 cm2 for females and 69.20 cm2 for males, while the optimal SFA cutoff was 186.70 cm2 for females and 123.30 cm2 for males. The ROC area under curve (AUC) of VFA for identifying two or more nonadipose components of MetS was higher than that of SFA (Female: 0.65 vs. 0.58, P = 0.01). The VFA cutoff of newly diagnosed T2D patients (females = 86.10 cm2, males = 69.00 cm2) was higher than that of non-newly diagnosed T2D patients (females = 73.30 cm2, males = 65.40 cm2). A stratification analysis of gender and whether newly diagnosed with T2D or not showed that the WCs corresponding to VFA were 85.00 cm and BMI was about 24.00 kg/m2. VFA measured by BIA can be a non-invasive method to detect central obesity in patients with T2D, the corresponding WC were 85.00 cm and BMI was 24.00 kg/m2.

Abstract Background Early neurological deterioration (END) sometimes occurs in patients with penetrating artery territory infarction (PATI) and leads to poor prognosis. In this study, we analyzed clinical and neuroimaging characteristics of PATI, and focused on the infarct patterns on diffusion-weighted imaging (DWI). We tried to investigate whether the “island sign” pattern is associated with END. Methods We enrolled consecutive patients admitted with acute PATI within 48 h after onset from May 2020 to July 2022. They were divided into with and without the “island sign” pattern on DWI. According to infarct location, all the patients were classified into two groups: the territories of the lenticulostriate arteries (LSA) and paramedian pontine arteries (PPA). The patients in each group were further divided into two groups according to whether they developed END or not. Through analyzing the clinical and neuroimaging characteristics of the patients, we tried to identify the factors that might associated with the “island sign” pattern and the potential predictors of END within the LSA and PPA groups. Results Out of the 113 patients enrolled in this study, END was found in 17 patients (27.9%) in the LSA group and 20 patients (38.5%) in the PPA group. The “island sign” was found in 26 (23%) patients. In the multivariate analysis, the independent predictors of END in the LSA group were the “island sign” (OR 4.88 95% CI 1.03–23.2 P = 0.045) and high initial National Institute of Health Stroke Scale (NIHSS) (OR 1.79 95% CI 1.08–2.98 P = 0.024) and in the PPA group was the presence of lesions extending to the ventral pontine surface (OR 7.53 95% CI 1.75–32.37 P = 0.007). Conclusions The predictive factors for END were different in the LSA and PPA groups. The “island sign” was particularly associated with END in the LSA group.

DNA N6-methyladenine (6mA) modification is widespread in organisms and plays an important functional role in the regulation of cellular processes. As a model organism in biohydrometallurgy, Acidithiobacillus ferrooxidans can obtain energy from the oxidation of ferrous iron (Fe2+) and various reduced inorganic sulfides (RISCs) under acidic conditions. To determine the linkage between genomic DNA methylation and the switching between the two oxidative metabolic pathways in A. ferrooxidans, the 6mA landscape in the genome of A. ferrooxidans cultured under different conditions was evaluated by using 6mA-IP-seq. A total of 214 and 47 high-confidence peaks of 6mA were identified under the Fe2+ and RISCs oxidizing conditions, respectively (P

Micro/nanoplastics (MPs/NPs) are ubiquitous in the environment and living organisms have been exposed to these substances for a long time. When MPs/NPs enter different organisms, they transport various pollutants, including heavy metals, persistent organic pollutants, drugs, bacteria, and viruses, from the environment. On this basis, this paper summarizes the combined toxicity induced by MPs/NPs accumulating contaminants from the environment and entering organisms through a systematic review of 162 articles. Moreover, the factors influencing toxic interactions are critically discussed, thus highlighting the dominant role of the relative concentrations of contaminants in the combined toxic effects. Furthermore, for the first time, we describe the threats posed by MPs/NPs combined with other pollutants to human health, as well as their cytotoxic behavior and mechanism. We found that the “Trojan horse” effect of nanoplastics can increase the bioaccessibility of environmental pollutants, thus increasing the carcinogenic risk to humans. Simultaneously, the complex pollutants entering the cells are observed to be constantly dissociated due to the transport of lysosomes. However, current research on the intracellular release of MP/NP-loaded pollutants is relatively poor, which hinders the accurate in vivo toxicity assessment of combined pollutants. Based on the findings of our critical review, we recommend analyzing the toxic effects by clarifying the dose relationship of each component pollutant in cells, which is challenging yet crucial to exploring the toxic mechanism of combined pollution. In the future, our findings can contribute to establishing a system modeling the complete load-translocation toxicological mechanism of MP/NP-based composite pollutants.

Context A growing body of evidence demonstrates that gastrointestinal motility disorder (GIMD) and gastric stress ulcers can be induced by restraint stress, while melatonin (MT) elicits anti-inflammation and antioxidant effects. Objective The present study investigated the mechanisms of MT-mediated protection effects on restraint stress-induced GIMD. Materials and methods 144 8-week-old male ICR mice were divided into four groups: control, restraint stress, restraint stress + MT and MT (positive control). 20 mg/kg MT or vehicle were intraperitoneally injected 60 min before restraint stress (10 h/day) once daily for 3 days. Biochemical parameters, intestinal mucosal integrity, tissues antioxidant ability and autophagic proteins levels were determined. Results Mice subjected to restraint stress elevated NE level by 141.41% and decreased MT content by 38.82% in plasma. Consistent with the decrease in MT level, we observed a reduction in the antioxidant ability and an increase in autophagic proteins by 14.29–46.74% in the gut, resulting in injury to intestinal mucosa which was manifested by reductions in villus height and villus height/crypt depth (V/C) ratio, number of goblet and PCAN-positive cells, and expression of tight junction protein (ZO-1, occludin and claudin-1). In contrast, MT reversed these changes caused by restraint stress and improved the intestinal mucosal injury. However, there was no significant difference between MT (positive control) and control group. Discussion and conclusion Our results suggest that MT effectively mitigates psychological stress-induced injury to intestinal mucosa, providing evidence demonstrating the potential for using MT as therapy against intestinal impairment associated with psychological stress.

Indene (IND) is a kind of important aromatic hydrocarbon that is extracted from coal tar and has important applications in industry and biology. In the process of production and utilization, it is easy to enter the soil and produce toxic effects on the soil or organisms. The earthworm is an important organism in the soil. The toxicity of indene on earthworm coelomocytes is rarely studied, and the oxidative stress effects of IND on earthworm coelomocytes remain unclear. In this study, coelomocytes from earthworms and antioxidant enzymes were selected as the research targets. In addition, IND caused oxidative stress, and its related toxic effects and mechanisms were systematically studied and evaluated at the cellular and molecular levels. The results showed that IND destroyed the redox balance in earthworm coelomocytes, and the large accumulation of reactive oxygen species (ROS) significantly inhibited the activities of the antioxidant system, including superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), and caused lipid peroxidation and membrane permeability changes, resulting in a decrease in cell viability to 74.5% of the control group. At the molecular level, IND was bound to SOD by the arene-H bond, and the binding constant was 4.95 × 103. IND changed the secondary structure of the SOD and led to a loosening of the structure of the SOD peptide chain. Meanwhile, IND caused SOD fluorescence sensitization, and molecular simulation showed that IND was mainly bound to the junction of SOD subunits. We hypothesized that the changes in SOD structure led to the increase in SOD activity. This research can provide a scientific basis for IND toxicity evaluation.

This paper investigated the toxic effect and mechanism of ultrafine carbon black (UFCB) on splenocytes and enzymes in the digestive system. It was found that the toxicity of UFCB to splenocytes was dose-dependent. UFCB with a low concentration (15 μg/mL) induced significant oxidative damage with increased content of reactive oxygen species (ROS) (134%) and malonaldehyde (MDA) (222.3%) along with the decreased activity of superoxide dismutase (SOD) (55.63%) and catalase (CAT) (87.73%). Analysis combined cellular and molecular levels indicated that UFCB induced splenocyte toxicity through oxidative stress. The interactions of UFCB with two important digestive enzymes, α-amylase and lipase, were also studied respectively. Results showed that the interaction of UFCB and the two enzymes altered the particle size and fluorescence intensity in both experimental systems. The formation of protein corona also resulted in the contraction of the polypeptide skeleton in both enzymes, which further inhibited their activity. Our work provided basic data on the toxicity of UFCB in the spleen and digestive system and fills the gap in the study of UFPs toxicity. Capsule: UFCB induced splenocyte toxicity and enzyme dysfunction through oxidative stress and protein corona formation respectively.

Awareness of risks posed by widespread presence of nanoplastics (NPs) and bioavailability and potential to interact with organic pollutants has been increasing. Inhalation is one of the more important pathways of exposure of humans to NPs. In this study, combined toxicity of concentrations of polystyrene NPs and various phthalate esters (PAEs), some of the most common plasticizers, including dibutyl phthalate (DBP) and di-(2-ethyl hexyl) phthalate (DEHP) on human lung epithelial A549 cells were investigated. When co-exposed, 20 μg NPs/mL increased viabilities of cells exposed to either DBP or DEHP and the modulation of toxic potency of DEHP was greater than that of DBP, while the 200 μg NPs/mL resulted in lesser viability of cells. PAEs sorbed to NPs decreased free phase concentrations (Cfree) of PAEs, which resulted in a corresponding lesser bioavailability and joint toxicity at the lesser concentration of NPs. The opposite effect was observed at the greater concentration of NPs, which may result from the dominated role of NPs in the combined toxicity. Furthermore, our data showed that oxidative stress and inflammatory reactions were mechanisms for combined cytotoxicities of PAEs and NPs on A549 cells. Results of this study emphasized the combined toxic effects and mechanisms on human lung cells, which are helpful for assessing the risk of the co-exposure of NPs and organic contaminants in humans.

Whole body vibration (WBV) is a non-invasive physical therapy that has recently been included in the hospital's patient rehabilitation training catalog, but its health effects have not been sufficiently studied. In the present study, to examine the possible effects of WBV on immune cell differentiation, the IFN, IL-4,−17, F4/80 and CD3,−4,−8,−11b,−11c,−19 markers were used to characterizing the cells in mouse spleen. The results showed that the CD4 and CD25 positive lymphocytes in the spleen were significantly increased in the WBV group, and the population of Treg cells was enhanced significantly in response to WBV. Since the differentiation in immune cells is usually associated with microbiota, therefore the intestinal flora was characterized in mice and human individuals. The results indicated that WBV significantly reduced the α-diversity of mouse intestinal microbiota. Moreover, the principal coordinate analysis (PCoA) results indicated that the β-diversities of both mice and human fecal microbiota increased after WBV. Analysis of the bacterial composition indicated that the contents of a variety of bacteria changed in mice upon the stimulation of vibration, such as Lactobacillus animalis in mice, and Lactobacillus paraplantarum and Lactobacillus sanfranciscensis in human. The succeeding correlation analysis revealed that some bacteria with significant content variations were correlated to the regulatory T cell differentiation in mice and physical characteristics in human. Our research will provide the basis for future non-invasive treatment of microbial and immune related diseases.

A novel banana-shaped molecule using 2,8-Dimethyl-6H,12H-5,11-methanodibenzo [b,f] [1,5]diazocine (Tröger’s base) as bent-core was synthesized via double Carbon-Carbon cross-coupling reaction. The double Sonogashira cross-coupling reaction was optimized by using Pd(PPh3)2Cl2 as catalyst, CuI as cocatalyst and diisopropylamine as base in place of triethylamine. The structure of this compound was confirmed by 1H-NMR, 13C-NMR, Fourier transform infrared (FT-IR) spectroscopy and mass spectrometry.

The study investigated the effect of oxytetracycline (OTC) on the anti-oxidative defense system, the structure (hemolysis rate and morphology) and function (ATP enzyme activity) of human red blood cells (hRBCs) to investigate the possible toxic mechanism of OTC to hRBCs. The experimental results indicate that OTC can cause a decline in the function of the antioxidant defense system of hRBCs, resulting in oxidative stress. OTC can bring about morphological changes to hRBCs, and further leads to hemolysis, when the concentration of OTC is over 8×10(-5) M (about 164 µg/ml). At a low OTC concentration, below 4×10(-5) M (82 µg/ml), OTC can enhance the activity of ATP enzyme of hRBCs, known as hormesis. However, at a high concentration, above 4×10(-5) M (about 82 µg/ml), the ATP enzymatic activity was inhibited, affecting the function of hRBCs. The estalished mechanism of toxicity of OTC to hRBCs can facilitate a deeper understanding of the toxicity of OTC in vivo.

Tetracycline (TC) and chlortetracycline (CTC) are common members of the widely used veterinary drug tetracyclines, the residue of which in the environment can enter human body, being potentially harmful. In this study, we establish a new strategy to probe the binding modes of TC and CTC with trypsin based on spectroscopic and computational modeling methods. Both TC and CTC can interact with trypsin with one binding site to form trypsin-TC (CTC) complex, mainly through van der Waals' interactions and hydrogen bonds with the affinity order: TC>CTC. The bound TC (CTC) can result in inhibition of trypsin activity with the inhibition order: CTC>TC. The secondary structure and the microenvironment of the tryptophan residues of trypsin were also changed. However, the effect of CTC on the secondary structure content of trypsin was contrary to that of TC. Both the molecular docking study and the trypsin activity experiment revealed that TC bound into S1 binding pocket, competitively inhibiting the enzyme activity, and CTC was a non-competitive inhibitor which bound to a non-active site of trypsin, different from TC due to the Cl atom on the benzene ring of CTC which hinders CTC entering into the S1 binding pocket. CTC does not hinder the binding of the enzyme substrate, but the CTC-trypsin-substrate ternary complex can not further decompose into the product. The work provides basic data for clarifying the binding mechanisms of TC (CTC) with trypsin and can help to comprehensively understanding of the enzyme toxicity of different members of tetracyclines in vivo.