NLRP4 negatively regulates type I interferon response and influences the outcome in anti-programmed cell death protein (PD)-1/PD-ligand 1 therapy.

The challenge to improve the clinical efficacy and enlarge the population that benefits from immune checkpoint inhibitors (ICIs) for non-small-cell lung cancer (NSCLC) is significant. Based on whole-exosome sequencing analysis of biopsies from NSCLC patients before anti-programmed cell death protein-2 (PD-1) treatment, we identified NLRP4 mutations in the responders with a longer progression-free survival (PFS). Knockdown of NLRP4 in mouse Lewis lung cancer cell line enhanced interferon (IFN)-α/ß production through the cGAS-STING-IRF3/IRF7 axis and promoted the accumulation of intratumoral CD8+ T cells, leading to tumor growth retardation in vivo and a synergistic effect with anti-PD-ligand 1 therapy. This was consistent with clinical observations that more tumor-infiltrating CD8+ T cells and elevated peripheral IFN-α before receiving nivolumab treatment were associated with a longer PFS in NSCLC patients. Our study highlights the roles of tumor-intrinsic NLRP4 in remodeling the immune contextures in the tumor microenvironment, making regional type I IFN beneficial for ICI treatment.

CD4+ T Cells Promote IgG Production in MHC-Independent and ICAM-1-Dependent Manners in Pristane-Induced Lupus Mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and chronic inflammation. The etiology and pathogenesis of SLE are complicated in which dysfunction of CD4+ T cells is largely engaged. In this study, we investigated the manners of CD4+ T cells in antibody production in a lupus-like mouse model through peritoneal injection of pristane reagent. With the increase in total IgG/IgM and autoantibody production after 6 months, CD4+ T cells exhibited activated phenotypes with the elevated CD44, ICOS, OX40, and PD-1 expression. Pristane injection induced the increase in IgM levels in both wild-type and T cell-deficient TCRα -/- mice whereas IgG, IgG1, and IgG2a production was impaired. When adoptively transferring CD4+ T cells into T cell-deficient mice or coculturing CD4+ T cells and B cells in vitro, it was found that CD4+ T cells derived from pristane-treated mice could help the production of total IgG as well as IgG1/IgG2a in a more efficient manner both in vivo and in vitro. While MHC was dispensable for IgG production, ICAM-1 likely functioned as an attenuating factor for IgG production. Our study thus reveals that CD4+ T cells in pristane-treated mice play important roles in IgG production, which implies the critical roles in the induction of pathological autoantibodies in MHC-independent and ICAM-1-dependent manners.

Formation and migration of α-dicarbonyl compounds during storage and reheating of a sugary food simulation system.

BACKGROUND: The thermal processing of food results in the formation of α-dicarbonyl compounds (α-DCs) such as glyoxal (GO), methylglyoxal (MGO), 2,3-butanedione (2,3-BD), and 3-deoxyglucosone (3-DG), which are precursors of potentially harmful advanced glycation end products. Some of the α-DCs found in food products might result from chemical deterioration reactions during storage and reheating. A range of sugary food simulation systems were stored at three different temperatures (4, 25, and 37 °C) and reheated using three different processing methods to investigate the formation and migration of α-DCs. RESULTS: During 20 days of storage, the concentration of α-DCs declined, following which the concentration remained approximately constant. Methylglyoxal was the major α-DC affected during storage, its relative content decreasing from 233.71 to 44.12 µg mL-1 in the glucose-lysine system. The concentration of α-DCs decreased with increasing temperature. Microwave reheating increased the formation of α-DC compounds. The largest increases in 3-DG concentrations were observed in the maltose-lysine systems (24.94 to 35.74 µg mL-1 ). The concentration of α-DCs only changed a little in response to reheating at 100 °C, but declined when reheated at 150 °C. CONCLUSION: The concentration of α-DCs following storage and reheating depends on the type of sugar, lysine content, temperature, and method of reheating. © 2020 Society of Chemical Industry.

Accelerated Glomerular Cell Senescence in Experimental Lupus Nephritis.

BACKGROUND The aim of this study was to determine whether senescence in renal glomeruli is involved in lupus nephritis (LN); the expression of senescence-associated ß-galactosidase (SA-ß-Gal) and its association with glomerular lesions were investigated in a mouse model of LN. MATERIAL AND METHODS Eighteen MRL/lpr mice with severe proteinuria were randomly divided into 2 equal groups and intraperitoneally injected with dexamethasone (DEX) or saline; 4 age-matched mice with mild proteinuria served as controls. Serum creatinine and urinary protein levels were analyzed, and kidney histological changes were observed by periodic acid-Schiff and Sirius Red staining. SA-ß-Gal was detected via histochemistry. Glomerular expression of collagen IV, α-SMA, and nephrin was analyzed by immunohistochemistry, and glomerular complement C3 deposition was tested by immunofluorescence. The relationships between SA-ß-Gal expression and renal function or glomerular lesion markers were determined by Spearman's correlation analysis. RESULTS Mice with severe proteinuria exhibited glomerular segmental sclerosis and endothelial cell proliferation. DEX administration suppressed these lesions but had no significant effect on 24-hour urinary protein levels. The elevated glomerular expression of SA-ß-Gal in proteinuric mice was attenuated by DEX treatment. In addition, DEX treatment markedly downregulated glomerular C3 deposition and collagen IV and α-SMA expression, while significantly increasing nephrin expression. Furthermore, SA-ß-Gal expression was positively correlated with urinary protein levels and expression of α-SMA. CONCLUSIONS Accelerated senescence of glomerular cells may contribute to glomerular injury in LN.

[Optimization of method for determination of Forsythia Fructus and discussion on the establishment of quality control standard for green (old) Forsythia Fructus].

In order to obtain the optimum method for content determination of Forsythia Fructus (FF), a variety methods for the sample preparation of FF were evaluated by the content determination methods of Chinese Pharmacopoeia. And an optimum method was screened and as follows: 30 times with 70% ethanol solution in ultrasonic extractor for half an hour. The method can achieve the best effect of simultaneously extracting forsythoside A and forsythin. Then, a HPLC method for simultaneous determination of forsythoside A and forsythin was established by methodology. The HPLC chromatographic conditions: the mobile phase consisted of acetonitrile (A)-0.4% acetic acid solution (B) with gradient elution [0-33 min，15%A，33-43 min，15%-25%A，43-60 min，25% A] was at the flow rate of 1 mL·min⁻¹, the column temperature was 25 °C, and the detection wavelength was 330 and 277 nm. Moreover, the contents of forsythoside A and forsythin for 10 Green Forsythia Fructus (GF) and 5 Old Forsythia Fructus (OF) were determined by this method and Chinese Pharmacopoeia. The result not only displayed that the established method is effective, rapid, and simple, but also showed that the contents of forsythoside A and forsythin for GF and OF were significantly different. Which implied that the forsythoside A and forsythin limit standard for GF and OF should be controled by different values. This studies provide an important basis for the establishment of the content determination of FF and the quality control standard for GF and OF.

[The Near Infrared Spectral Bands Optimal Selection in the Application of Liquor Fermented Grains Composition Analysis].

In order to improve the technical level of the rapid detection of liquor fermented grains, in this paper, use near infrared spectroscopy technology to quantitative analysis moisture, starch, acidity and alcohol of liquor fermented grains. Using CARS, iPLS and no information variable elimination method (UVE), realize the characteristics of spectral band selection. And use the multiple scattering correction (MSC), derivative and standard normal variable transformation (SNV) pretreatment method to optimize the models. Establish models of quantitative analysis of fermented grains by PLS, and in order to select the best modeling method, using R2, RMSEP and optimal number of main factors to evaluate models. The results showed that the band selection is vital to optimize the model and CARS is the best optimization of the most significant effect. The calculation results showed that R2 of moisture, starch, acidity and alcohol were 0.885, 0.915, 0.951, 0.885 respectively and RMSEP of moisture, starch, acidity and alcohol were 0.630, 0.519, 0.228, 0.234 respectively. After optimization, the model prediction effect is good, the models can satisfy the requirement of the rapid detection of liquor fermented grains, which has certain reference value in the practical.

Preparation and Characterization of Folate Targeting Magnetic Nanomedicine Loaded with Gambogenic Acid.

To engineer multifunctional nanomedicines for simultaneous imaging and therapy of cancer cells, we have prepared Gambogenic acid (GNA) loaded folic acid (FA) armed MNPs (FA-GNA-MNPs) to target the folate receptor (FR) positive cancer cells. The FA-GNA-MNPs have been prepared by a facile method, which have been further characterized by SEM, TEM, IR and UV-vis spectra. And the cytotoxicity of FA-GNA-MNPs to HeLa and A549 cells was assessed using the MTT assay. The FA-GNA-MNPs (with loading efficiency of 4.35%) showed sustained liberation of GNA molecules (with 73.46% release in 96 h). The mean particle diameter (MD) of FA-GNA-MNPs and the polydispersity index (PDI) are 254.3 nm and 0.139, respectively. The cytotoxicity of free GNA and FA-GNA-MNPs toward HeLa cells showed that FA-GNA-MNPs was more cytotoxic than GNA. Based on these findings, it suggests that FA-GNA-MNPs would be as a novel multifunctional nanomedicine/theranostic for concurrent targeting, imaging and therapy of the FR-positive cancer cells.

[Roles of the cross talk between MAP kinases and Keap1-Nrf2-ARE signaling pathways in chronic obstructive pulmonary disease].

Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is characterized by airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways. Its main pathological manifestations include airway inflammation, mucus hypersecretion, oxidative stress and apoptotic epithelial cells. Recent research suggests that MAP kinases and Keap1-Nrf2-ARE signaling pathway are involved in the pathological process of inflammation and oxidative stress. This review explores the potential role of the cross talk of these signaling pathways in airway inflammation, mucus hypersecretion, oxidative stress and apoptotic epithelial cells. To clarify the roles of cross talk between MAP kinases and Keap1-Nrf2-ARE signaling pathway, we also focus on the drugs related to that in the treatment of COPD, and it provides ideas for more drug research in the treatment of COPD.

Encapsulated human hepatocellular carcinoma cells by alginate gel beads as an in vitro metastasis model.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and often forms metastases, which are the most important prognostic factors. For further elucidation of the mechanism underlying the progression and metastasis of HCC, a culture system mimicking the in vivo tumor microenvironment is needed. In this study, we investigated the metastatic ability of HCC cells cultured within alginate gel (ALG) beads. In the culture system, HCC cells formed spheroids by proliferation and maintained in nuclear abnormalities. The gene and protein expression of metastasis-related molecules was increased in ALG beads, compared with the traditional adhesion culture. Furthermore, several gene expression levels in ALG bead culture system were even closer to liver cancer tissues. More importantly, in vitro invasion assay showed that the invasion cells derived from ALG beads was 7.8-fold higher than adhesion cells. Our results indicated that the in vitro three-dimensional (3D) model based on ALG beads increased metastatic ability compared with adhesion culture, even partly mimicked the in vivo tumor tissues. Moreover, due to the controllable preparation conditions, steady characteristics and production at large-scale, the 3D ALG bead model would become an important tool used in the high-throughput screening of anti-metastasis drugs and the metastatic mechanism research.

Infantile hemangioma-like vascular lesion in a 26-year-old woman after abortion.

A 26-year-old woman (G2P1A1) presented with a 5-week history of multiple red marks on her body after a therapeutic abortion. A physical examination found 15 palpable red marks on her head, neck, chest, arms and legs. Proliferating endothelial cells, which expressed CD31, CD34, von Willebrand factor, but not Glut-1 and merosin, were observed in the lesional area by histopathological analyses. Histocompatibility antigen typing of 2 lesions was identical to a sample from peripheral blood. Accelerated regression was observed in 2 lesions treated by intralesional injection of betamethasone, while spontaneous regression was observed within 9 months in the remaining lesions without any treatment. Rapid growth, spontaneous regression and histological analyses in this case support the diagnosis of 'infantile hemangioma-like vascular lesion'.