Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2-mediated inflammatory disease associated with significant clinical, social, and economic burdens and high unmet therapeutic need. Dupilumab, a fully human monoclonal antibody targeting the interleukin-4 receptor α (IL-4Rα) subunit, demonstrated efficacy and acceptable safety in CRSwNP and other type 2 diseases (eg, atopic dermatitis and asthma). We now report the local effects of dupilumab on type 2 inflammatory biomarkers in nasal secretions and nasal polyp tissues of patients with CRSwNP in a randomized, placebo-controlled, phase 2 trial (NCT01920893). METHODS: Cytokines, chemokines, and total immunoglobulin E (IgE) levels were measured using immunoassay techniques in nasal secretions and nasal polyp tissue homogenates of CRSwNP patients receiving dupilumab 300 mg or placebo weekly for 16 weeks. RESULTS: With dupilumab, type 2 biomarker concentrations decreased in nasal secretions (least squares mean area under the curve from 0 to 16 weeks for the change from baseline) vs placebo for eotaxin-3 (-30.06 vs -0.86 pg/mL; P = 0.0008) and total IgE (-7.90 vs -1.86 IU/mL; P = 0.022). Dupilumab treatment also decreased type 2 biomarker levels in nasal polyp tissues at Week 16 vs baseline for eosinophilic cationic protein (P = 0.008), eotaxin-2 (P = 0.008), eotaxin-3 (P = 0.031), pulmonary and activation-regulated chemokine (P = 0.016), IgE (P = 0.023), and IL-13 (P = 0.031). CONCLUSIONS: Dupilumab treatment reduced multiple biomarkers of type 2 inflammation in nasal secretions and polyp tissues of patients with CRSwNP, demonstrating that antagonism of IL-4Rα signaling suppresses IL-4-/IL-13-dependent processes, such as mucosal IgE formation, as well as the expression of chemokines attracting inflammatory cells to the nasal mucosa.

Rh-Catalyzed Regioselective ortho-C-H Carbenoid Insertion of Diarylazines.

The Rh-catalyzed ortho-C-H carbenoid insertion reaction of diarylazines with diazo compounds has been developed. A wide range of ortho-substituted diarylazines have been obtained in moderate to high yields with high regioselectivity at room temperature. The hydrolysis of the products could release ketones or aldehydes, giving access to aromatic 1,5-keto-diesters as valuable synthons for further chemical transformations.

Tongxinluo Inhibits Renal Fibrosis in Diabetic Nephropathy: Involvement of the Suppression of Intercellular Transfer of TGF-[Formula: see text]1-Containing Exosomes from GECs to GMCs.

Glomerular mesangial cells (GMCs) activation is implicated in the pathogenesis of diabetic nephropathy (DN). Our previous study revealed that high glucose (HG)-treated glomerular endothelial cells (GECs) produce an increased number of TGF-[Formula: see text]1-containing exosomes to activate GMCs through the TGF-[Formula: see text]1/Smad3 signaling pathway. We also identified that Tongxinluo (TXL), a traditional Chinese medicine, has beneficial effects on the treatment of DN in DN patients and type 2 diabetic mice. However, it remained elusive whether TXL could ameliorate renal structure and function through suppression of intercellular transfer of TGF-[Formula: see text]1-containing exosomes from GECs to GMCs. In this study, we demonstrate that TXL can inhibit the secretion of TGF-[Formula: see text]1-containing exosomes from HG-treated GECs. Furthermore, exosomes produced by HG induced-GECs treated with TXL cannot trigger GMC activation, proliferation and extracellular matrix (ECM) overproduction both in vitro and in vivo. These results suggest that TXL can prevent the transfer of TGF-[Formula: see text]1 from GECs to GMCs via exosomes, which may be one of the mechanisms of TXL in the treatment of DN.

Construction of Fused Polyheterocycles through Sequential [4 + 2] and [3 + 2] Cycloadditions.

A method for Pd-catalyzed aerobic oxidative reaction of quinazolinones and alkynes has been developed for sequential [4 + 2] and [3 + 2] cycloadditions to assemble a novel fused-polycyclic system containing tetrahydropyridine and dihydrofuran rings. The reaction process involves C-H and N-H bond functionalization for the formation of tetrahydropyridine and an oxygen radical cyclization for the dihydrofuran ring. This atom- and step-economical synthesis is highly efficient and has good substrate tolerance, which provides a new approach for the construction of polycyclic molecules with potential pharmaceutical interest.

Resolution and contrast enhancement of subtractive second harmonic generation microscopy with a circularly polarized vortex beam.

We extend the subtractive imaging method to label-free second harmonic generation (SHG) microscopy to enhance the spatial resolution and contrast. This method is based on the intensity difference between two images obtained with circularly polarized Gaussian and doughnut-shaped beams, respectively. By characterizing the intensity and polarization distributions of the two focused beams, we verify the feasibility of the subtractive imaging method in polarization dependent SHG microscopy. The resolution and contrast enhancement in different biological samples is demonstrated. This work will open a new avenue for the applications of SHG microscopy in biomedical research.

Teriflunomide attenuates immunopathological changes in the dark agouti rat model of experimental autoimmune encephalomyelitis.

Teriflunomide is an oral disease-modifying therapy recently approved in several locations for relapsing-remitting multiple sclerosis. To gain insight into the effects of teriflunomide, immunocyte population changes were measured during progression of experimental autoimmune encephalomyelitis in Dark Agouti rats. Treatment with teriflunomide attenuated levels of spinal cord-infiltrating T cells, natural killer cells, macrophages, and neutrophils. Teriflunomide also mitigated the disease-induced changes in immune cell populations in the blood and spleen suggesting an inhibitory effect on pathogenic immune responses.

Ursolic acid induces apoptosis by suppressing the expression of FoxM1 in MCF-7 human breast cancer cells.

Ursolic acid (UA), a naturally occurring pentacyclic triterpene, is a potent in vitro anticancer agent, acting through control of growth, apoptosis, and differentiation. As the anticancer effect and the mechanism of action of ursolic acid on human breast cancer cells has not been extensively studied, we performed an evaluation of the effects of UA on apoptosis in MCF-7 cells. UA was found to inhibit the proliferation of MCF-7 cells in a concentration and time-dependent manner. After treatment, UA-induced apoptosis was accompanied by a significant decrease in CyclinD1/CDK4 expression, which can be regulated by FoxM1. Previous studies demonstrated that FoxM1 orchestrates the transcription of genes that are essential for cell cycle progression and cell proliferation. The result of Western blot suggested that ursolic acid inhibited the expression of FoxM1. Taken together, the data suggest that the proapoptotic effect of UA on MCF-7 cells is mediated by inhibition of FoxM1 and is highly correlated with inactivation of CyclinD1/CDK4.

Fluorescence ghost imaging with pseudothermal light.

We extend classical light ghost imaging to the area of fluorescence imaging and propose a new fluorescence imaging method. For the first time, we demonstrate both theoretically and experimentally that fluorescence ghost imaging can be realized with pseudothermal light. Important factors influencing the visibility and resolution of the images are discussed to improve the quality of the fluorescence ghost imaging. We hope that this work may pave the road for ghost imaging to biomedical applications.

Effects of SMYD3 over-expression on cell cycle acceleration and cell proliferation in MDA-MB-231 human breast cancer cells.

SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase that plays an important role in transcriptional regulation in human carcinogenesis. It can specifically methylate histone H3 at lysine 4 and activate the transcription of a set of downstream genes, including several oncogenes (e.g., N-myc, CrkL, Wnt10b, RIZ and hTERT) and genes involved in the control of cell cycle (e.g., CyclinG1 and CDK2) and signal transduction (e.g., STAT1, MAP3K11 and PIK3CB). To determine the effects of SMYD3 over-expression on cell proliferation, we transfected SMYD3 into MDA-MB-231 cells and found that these cells showed several transformed phenotypes as demonstrated by colony growth in soft agar. Besides, we show here that down-regulation of SMYD3 could induce G1-phase cell cycle arrest, indicating the potent induction of apoptosis by SMYD3 knockdown. These results suggest the regulatory mechanisms of SMYD3 on the acceleration of cell cycle and facilitate the development of strategies that may inhibit the progression of cell cycle in breast cancer cells.

Molecular characterization of antigen-induced lung inflammation in a murine model of asthma.

Asthma is one of the foremost contributors to morbidity and mortality in industrialized countries. Our objective was to characterize the acute response to allergen and to identify potentially novel molecular targets for pharmacological intervention in asthma. We therefore designed a study to identify genes whose regulation was altered following ovalbumin (OVA) challenge in the presence and absence of treatment with glucocorticoids in BALB/c mice. RNA was isolated from lungs for gene profiling from 8-week-old sensitized mice, 3 and 18 hours post OVA challenge on days 1, 4, and 7 of aerosol challenge. Taqman (real time RT-PCR) analysis of marker genes indicative of Th2 (IL-4, IL-13), eosinophil (RANTES, eotaxin), Th1/macrophage (IFNgamma) and epithelial cell (MUC5AC) phenotypes were used to characterize responses to allergen challenge. Histological evaluation of lungs from additional challenged animals revealed inflammatory infiltrates on days 4 and 7, but not on day 1 post challenge. We postulate that expression of IL-4, IL-13 and other genes by OVA at day 1 probably reflects activation of resident cells, whereas the fivefold increase in the number of regulated genes at day 7 reflects the contribution of recruited cells. Of the regulated genes, only a subset was counter-regulated by dexamethasone treatment. Although regulated genes included genes in many protein families, herein we report regulation of two proteases whose role in response to OVA challenge has not been characterized. This model will be used to generate disease hypotheses for which may play an important role in initiating disease pathology in this model.