Associations between immune cell phenotypes and lung cancer subtypes: insights from mendelian randomization analysis.

INTRODUCTION: Lung cancer is a common malignant tumor, and different types of immune cells may have different effects on the occurrence and development of lung cancer subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). However, the causal relationship between immune phenotype and lung cancer is still unclear. METHODS: This study utilized a comprehensive dataset containing 731 immune phenotypes from the European Bioinformatics Institute (EBI) to evaluate the potential causal relationship between immune phenotypes and LUSC and LUAD using the inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, including MR-Egger intercept, Cochran Q test, and others, were conducted for the robustness of the results. The study results were further validated through meta-analysis using data from the Transdisciplinary Research Into Cancer of the Lung (TRICL) data. Additionally, confounding factors were excluded to ensure the robustness of the findings. RESULTS: Among the final selection of 729 immune cell phenotypes, three immune phenotypes exhibited statistically significant effects with LUSC. CD28 expression on resting CD4 regulatory T cells (OR 1.0980, 95% CI: 1.0627-1.1344, p < 0.0001) and CD45RA + CD28- CD8 + T cell %T cell (OR 1.0011, 95% CI: 1.0007; 1.0015, p < 0.0001) were associated with increased susceptibility to LUSC. Conversely, CCR2 expression on monocytes (OR 0.9399, 95% CI: 0.9177-0.9625, p < 0.0001) was correlated with a decreased risk of LUSC. However, no significant causal relationships were established between any immune cell phenotypes and LUAD. CONCLUSION: This study demonstrates that specific immune cell types are associated with the risk of LUSC but not with LUAD. While these findings are derived solely from European populations, they still provide clues for a deeper understanding of the immunological mechanisms underlying lung cancer and may offer new directions for future therapeutic strategies and preventive measures.

Lafutidine Ameliorates Indomethacin-Induced Small Intestinal Damage in Rats by Modifying the Intestinal Mucosal Barrier, Inflammation, and Microbiota.

INTRODUCTION: Nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal damage is a serious and escalating clinical problem without effective treatment. Lafutidine (LAF) is a novel histamine H2 receptor antagonist with a mucosal protective action. This study aimed to investigate the protective effect of LAF on indomethacin (IND)-induced enteropathy in rats. METHODS: Rats were treated with LAF for 10 days with concomitant IND treatment on the final 5 days. Changes in metabolism and hematological and biochemical parameters were measured, and intestinal damage was blindly scored. Intestinal mucosal tissue and luminal contents were collected for transcriptome and microbiota sequencing. Intestinal inflammation and barrier function were also evaluated. RESULTS: LAF treatment prevented anorexia and weight loss in rats and ameliorated reductions in hemoglobin, hematocrit, total protein, and albumin levels. LAF reduced the severity of IND-induced intestinal damage including macroscopic and histopathological damage score. Transcriptome sequencing results indicated that LAF might have positive effects on intestinal inflammation and the intestinal mucosal barrier. Further research revealed that LAF decreased neutrophil infiltration, and IL-1ß and TNF-α expression in intestinal tissue. Besides, the treatment increased mucus secretion, MUC2, Occludin, and ZO-1 expression, and decreased serum D-lactate levels. LAF treatment also ameliorates microbial dysbiosis in small intestine induced by IND and increased the abundance of Lactobacillus acidophilus. CONCLUSION: LAF may protect against NSAID enteropathy via enhancing the intestinal mucosal barrier, inhibiting inflammation, and regulating microbiota.

[Progresses on active targeting liposome drug delivery systems for tumor therapy].

Liposome is an ideal drug carrier with many advantages such as excellent biocompatibility, non-immunogenicity, and easy functionalization, and has been used for the clinical treatment of many diseases including tumors. For the treatment of tumors, liposome has some passive targeting capability, but the passive targeting effect alone is very limited in improving the drug enrichment in tumor tissues, and active targeting is an effective strategy to improve the drug enrichment. Therefore, active targeting liposome drug-carriers have been extensively studied for decades. In this paper, we review the research progresses on active targeting liposome drug-carriers based on the specific binding of the carriers to the surface of tumor cells, and summarize the opportunities, challenges and future prospects in this field.

Anti-Carbonic Anhydrase Goldbodies by Conformational Reconstruction of the Complementary-Determining Regions of Phage-Displayed Antibodies.

It has been demonstrated that the main complementary-determining region (CDR) fragments of antibodies could be grafted onto gold nanoparticles (AuNPs) to produce artificial antibody, dubbed Goldbody. Goldbody maintains the same binding specificity with the corresponding antigen as the original antibody, but has better stability than the antibody. However, the current design of Goldbodies is mainly based on the structures of antibody-antigen complexes. To extend this promising technique to the majority of antibodies whose complexes with the corresponding antigens are not structurally solved, herein, two anti-carbonic anhydrase (CA) antibodies screened by phage display were chosen to create anti-CA Goldbodies. One of the anti-CA antibodies, cAb-CA05, has a known complex structure with CA; but the other, cAb-CA06, does not. By conformational reconstruction of the CDR3 of cAb-CA06, which is identified by sequence alignment, as well as the CDR3 of cAb-CA05, two anti-CA Goldbodies have been created. Interestingly, our results show the two Goldbodies can bind to CA simultaneously, unambiguously indicating their binding sites on CA are far away. As the CDR3 is the major binding unit for many antibodies, which can be reliably predicted by sequence alignment, it could be used as a general strategy to develop artificial antibodies by directly grafting and conformationally reconstructing the predicted CDR3 of antibodies.

Increased diurnal difference of NO2 concentrations and its impact on recent ozone pollution in eastern China in summer.

Nitrogen dioxide (NO2) is a key tropospheric O3 precursor. Since 2013, efforts to decrease air pollution in China have driven substantial declines in annual NO2 concentrations, whereas ozone (O3) concentrations have increased. Based on nationwide NO2 observations and a regional air quality model (WRF-CMAQ), we analyzed trends in the diurnal difference (DD, the difference between nighttime and daytime concentrations) of NO2 concentrations across eastern China and in five national urban agglomerations (UAs) from 2014 to 2021, and explored the factors underlying such changes and the potential impacts on O3 pollution. We found that the observed DD of NO2 has increased in most cities and UAs, and that this trend can be primarily attributed to changes in anthropogenic emissions, based on comparison with DDs simulated with fixed anthropogenic emissions, which generally showed much weaker trends and little interannual variation. A sensitivity analysis using the WRF-CMAQ model was conducted to investigate the impact of a modified diurnal cycle of nitrogen oxides (NOx) emissions on O3 concentrations. The result revealed that enhancing the DD of NO2 would increase O3 concentrations in the morning and the daily maximum 8-h O3 concentrations in the cities with high NOx concentrations, as well as downwind areas of cities, indicating that greater DDs in NO2 is one of the reasons that have led to the enhanced China's O3 pollution in recent years.

Modeling the biogenic isoprene emission and its impact on ozone pollution in Zhejiang province, China.

Isoprene is the most abundantly emitted biogenic volatile organic compound (BVOC), which plays an essential role in producing tropospheric ozone (O3). However, the simulations of isoprene emissions have not been sufficiently verified over Yangtze River Delta (YRD), and few studies have specifically addressed its impact on O3 formation. In this study, we simulated the isoprene emissions in Zhejiang Province (ZJ), a region with the largest BVOC emission in YRD, in August 2020 using the Model of Emissions of Gases and Aerosols from Nature (MEGAN) and the latest Moderate Resolution Imaging Spectroradiometer (MODIS) products, and investigated its contributions to O3 using the Weather Research and Forecasting (WRF)-Community Multiscale Air Quality (CMAQ) model. The model has a good performance on isoprene simulations over urban and suburban areas, with mean biases of -0.16-0.12 ppb, but underestimated the concentrations at forest sites (mainly due to bamboo). Regionally, the simulated formaldehyde concentrations over forests agree well with the satellite observations. In August 2020, the total isoprene emission in ZJ was 125.1 GgC, with higher emissions in western ZJ and relatively lower emissions in eastern coastal regions. The spatial pattern of isoprene concentrations is similar to its emissions, and the maximum daytime average concentrations are above 3.5 ppb. The spatial pattern of its contribution to daily maximum 8 h average O3 concentrations is significantly different from the emissions and concentrations, which shows a higher impact in northern ZJ (>6 ppb) and relatively lower impact in southern ZJ (1-3 ppb). The mean contribution over ZJ is 8.9 %, with daily variation in the range of 3.1 % to 13.4 %. For different cities, the monthly mean contribution is in the range of 4.6 % to 14.3 %, and the maximum daily contribution reaches about 25 %. These findings help understand the summertime O3 pollution in ZJ and the YRD region of China.

Conformationally engineering flexible peptides on silver nanoparticles.

Molecular conformational engineering is to engineer flexible non-functional molecules into unique conformations to create novel functions just like natural proteins fold. Obviously, it is a grand challenge with tremendous opportunities. Based on the facts that natural proteins are only marginally stable with a net stabilizing energy roughly equivalent to the energy of two hydrogen bonds, and the energy barriers for the adatom diffusion of some metals are within a similar range, we propose that metal nanoparticles can serve as a general replacement of protein scaffolds to conformationally engineer protein fragments on the surface of nanoparticles. To prove this hypothesis, herein, we successfully restore the antigen-recognizing function of the flexible peptide fragment of a natural anti-lysozyme antibody on the surface of silver nanoparticles, creating a silver nanoparticle-base artificial antibody (Silverbody). A plausible mechanism is proposed, and some general principles for conformational engineering are summarized to guide future studies in this area.

Folding of Flexible Protein Fragments and Design of Nanoparticle-Based Artificial Antibody Targeting Lysozyme.

It is generally believed that a protein's sequence solely determines its native structure, but how the long- and short-range interactions jointly determine the native structure/conformation of the protein or every local fragment of the protein is still not fully understood. Since most protein fragments are unstructured on their own, direct observation of the folding of flexible protein fragments is very difficult. Interestingly, we show that it is possible to graft the complementary-determining regions (CDRs) of antibodies onto the surface of a gold nanoparticle (AuNP) to create AuNP-based artificial antibodies (denoted as Goldbodies), such as an antilysozyme Goldbody. Goldbodies can specifically recognize the corresponding antigens like the original natural antibodies do, but direct structural evidence for the refolding or restoration of native conformation of the grafted CDRs on AuNPs is still missing and in high demand. Herein we design a new Goldbody that targets an epitope on the lysozyme different from that of the previous antilysozyme Goldbody, and the one circle of helix in the CDR makes it possible to distinguish the unfolded conformation of the free CDR and its folded conformation on AuNPs by circular dichroism (CD) spectroscopy. The refolding of flexible protein fragments on NPs provides unique evidence and inspiration for understanding the fundamental principles of protein folding.

Anthropogenic emissions estimated using surface observations and their impacts on PM2.5 source apportionment over the Yangtze River Delta, China.

Source-tagged source apportionment (SA) has advantages for quantifying the contribution of various source regions and categories to PM2.5; however, it is highly affected by uncertainty in the emission inventory. In this study, we used a Regional multi-Air Pollutant Assimilation System (RAPAS) to optimize daily SO2, NOx and primary PM2.5 (PPM2.5) emissions in the Yangtze River Delta (YRD) in December 2016 by assimilating hourly in-situ measurements. The CMAQ-ISAM model was implemented with prior and posterior emissions respectively to investigate the impacts of optimizing emissions on PM2.5 SA in the YRD megalopolis (YRDM) and three megacities of Shanghai, Nanjing, and Hangzhou in the YRDM. The results showed that RAPAS significantly improved the simulations and reduced the emission uncertainties of the different pollutants. Compared with prior emissions, the posterior emissions in the YRD decreased by 13% and 11% for SO2 and NOx respectively, and increased by 24% for PPM2.5. Compared with SA using prior emissions, the contributions from Hangzhou, northern Zhejiang, and areas outside of the YRD to the YRDM increased. The local contributions from the YRDM, Nanjing and Shanghai decreased by 1.8%, 9.7%, and 2.3%, respectively, whereas that of Hangzhou increased by 5.6%. The changes in the daily local contributions caused by optimizing emissions ranged from -18.0% to 23.6%. Generally, under stable weather conditions, the local contribution changed the most, whereas under unstable weather conditions, the contribution from upwind areas changed significantly. Overall, with optimized emissions, we found in Nanjing, Shanghai, and Hangzhou, local emissions contributed 18.2%, 39.6% and 36.8% of their PM2.5 concentrations, respectively; long-range transport from outside the YRDM contributed 59.2%, 48.1%, and 48.2%, respectively. This study emphasizes the importance of improving emission estimations for source-tagged SA and provides more reliable SA results for the main cities in the YRD, which will contribute to pollution control in these regions.

Synthesis of chitosan/TCN nanocomposites with the carbon dioxide assisted phase inversion.

The chitosan (CS)/bis(2-hydroxyethyl)methyl tallow ammonium modified montmorillonite (TCN) nanocomposites are synthesized by the phase inversion procedure via the assistance of carbon dioxide (CO2). The viscosity of CS/formic acid solution is reduced with the incorporation of CO2 owing to the formation of carbamic acid. However, the incorporation of TCN promotes the viscosity of CS solution due to the interaction between TCN and carbamic acid. The morphology of CS/TCN nanocomposites is studied by scanning electron microscopy (SEM), where the surface of the membrane is dense and non-porous. The microstructure of the synthesized CS/TCN composite is further investigated by attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and transmission electron microscopy (TEM). It is found that the incorporation of TCN without the presence of CO2 disturbs the crystallization of CS. Interestingly, the melting enthalpy of the CS/TCN composite is notably increased with the introduction of CO2, demonstrating that the interaction between the TCN and carbamic acid enhances the formation of CS crystals. XRD and TEM results show that this interaction is able to promote the homogeneous distribution of TCN in the nanoscale with the non-exfoliated form, enhancing the mechanical properties of the synthesized nanocomposites. In particular, the synthesized CS/TCN nanocomposites with the assistance of CO2 present exceptional mechanical properties, where the tensile strength (65.82 MPa) and Young's modulus (3512.48 MPa) are twice as high as that of the CO2 free system.

PEGylation of Goldbody: PEG-aided conformational engineering of peptides on gold nanoparticles.

It is still a great challenge to engineer flexible non-functional molecules into special conformations to carry out novel functions. Previously, we successfully restored the native conformations and functions of the flexible complementary-determining regions (CDRs) of antibodies on the surface of gold nanoparticles (AuNPs), and created a class of AuNP-based artificial antibodies, denoted as Goldbodies. Yet, in these Goldbodies, there are dozens of CDRs on one Goldbody. Herein, we show that the number of CDRs per Goldbody could be reduced by more than one order of magnitude, by replacing the majority of the CDRs with polyethylene glycol (PEG) with a molecular weight around 600 Da, while the native conformations and functions of the CDRs could still be restored on AuNPs. Also, we find that the PEG with two terminal -SH groups is much better than the PEG with a single -SH group for aiding the restoration of the native conformation of the CDRs on AuNPs. To demonstrate the potential generic applicability of the PEGylation in aiding conformational engineering of peptides, two PEGylated Goldbodies have been created, which can specifically recognize lysozyme and epidermal growth factor receptor, respectively. The PEGylated Goldbodies further prove the mechanism of conformational engineering and the "Confined Lowest Energy Fragments" (CLEFs) hypothesis, and pave the way for future applications of Goldbodies.

Synthesis of chitosan/silver nanocomposites by phase inversion with the assistance of carbon dioxide.

Carbon dioxide (CO2) assisted synthesis of water-soluble silver nanoparticle with a narrow particle size distribution is reported here based on the phase-inversion procedure. Bio-derived chitosan (CS) is used to stabilize the metal nanoparticles according to its abundant functional groups. Formic acid is employed as both a solvent (for the polymer) and a reductant for in-situ reducing the silver precursor along with the solvent evaporation. CO2 is utilized to combine with the amino groups of CS, reducing the viscosity of chitosan/formic acid solution and limiting the formation of hydrogen bonds. This promotes the stabilization and reduction efficiency of silver nanoparticles. In particular, 100% of Ag metal nanoparticles with the size of 7.5 ± 2.3 nm is successfully synthesized with the assistance of CO2. Interestingly, the synthesized CS/Ag nanocomposites are water-soluble owing to the formation of carbamate groups. This water-soluble silver nanoparticle presents an exceptional performance in the selective reduction of 4-nitrophenol, where the turnover frequency (TOF = 599 h-1) is even double with respect to the CO2 free system.

Lactic Acid-Producing Probiotic Saccharomyces cerevisiae Attenuates Ulcerative Colitis via Suppressing Macrophage Pyroptosis and Modulating Gut Microbiota.

Lactic acid, a metabolic by-product of host and intestinal microbiota, has been recovered as an active signal molecule in the immune system. In this study, a lactic acid biosynthesis pathway that directly produces lactic acid from glucose rather than ethanol with high production was reconstructed in Saccharomyces cerevisiae. The engineered S. cerevisiae showed anti-inflammatory activity in dextran sulfate sodium (DSS)-induced mice with improved histological damage, increased mucosal barrier, and decreased intestinal immune response. Lactic acid regulated the macrophage polarization state and inhibited the expression of pro-inflammatory cytokines in vivo and in vitro. Increasing the macrophage monocarboxylic acid transporter-mediated active lactic acid uptake suppressed the excessive activation of the NLRP3 inflammasome and the downstream caspase-1 pathway in macrophages. Moreover, lactic acid promoted histone H3K9 acetylation and histone H3K18 lactylation. Meanwhile, the engineered S. cerevisiae altered the diversity and composition of the intestinal microbiota and changed the abundance of metabolic products in mice with colitis. In conclusion, this study shows that the application of engineered S. cerevisiae attenuated DSS-induced colitis in mice via suppressing macrophage pyroptosis and modulating the intestinal microbiota, which is an effective and safe treatment strategy for ulcerative colitis.

Role of the Aryl Hydrocarbon Receptor and Gut Microbiota-Derived Metabolites Indole-3-Acetic Acid in Sulforaphane Alleviates Hepatic Steatosis in Mice.

Scope: Gut microbiome-derived metabolites are the major mediators of diet-induced host-microbial interactions. Aryl hydrocarbon receptor (AHR) plays a crucial role in glucose, lipid, and cholesterol metabolism in the liver. In this study, we aimed to investigate the role of indole-3-acetic acid (IAA) and AHR in sulforaphane (SFN) alleviates hepatic steatosis in mice fed on a high-fat diet (HFD). Methods and Results: The HFD-fed male C57BL/6 mice were intervened with SFN for 6 weeks. HFD-mice showed classical pathophysiological characteristics of hepatic steatosis. The results showed that SFN significantly reduced body weight, liver inflammation and hepatic steatosis in HFD-fed mice. SFN reduced hepatic lipogenesis by activating AHR/SREBP-1C pathway, which was confirmed in HepG2 cell experiments. Moreover, SFN increased hepatic antioxidant activity by modulating Nrf-2/NQO1 expression. SFN increased serum and liver IAA level in HFD mice. Notably, SFN manipulated the gut microbiota, resulting in reducing Deferribacteres and proportions of the phylum Firmicutes/Bacteroidetes and increasing the abundance of specific bacteria that produce IAA. Furthermore, SFN upregulated Ahr expression and decreased the expression of inflammatory cytokines in Raw264.7 cells. Conclusions: SFN ameliorated hepatic steatosis not only by modulating lipid metabolism via AHR/SREBP-1C pathway but regulating IAA and gut microbiota in HFD-induced NAFLD mice.