Search

Introduction: Asthma–chronic obstructive pulmonary (COPD) overlap (ACO) coexists with asthma and COPD syndrome characteristics, with more frequent exacerbations, heavier disease burden, higher medical utilization, and even lower quality of life. However, the ACO standard medications supported by evidence-based medicine have not yet appeared. Methods: By using an ACO mouse model established previously and LPS-stimulated RAW264.7 macrophages in vitro, a potential therapeutic candidate, EAPP-2, was screened from derivatives of 3-arylbenzofuran, and its effect and mechanism on ACO inflammation were evaluated. Results: EAPP-2 significantly alleviated airway inflammation in ACO mice and also inhibited the inflammatory reactions in LPS-induced RAW264.7 macrophages in vitro. Furthermore, EAPP-2 significantly inhibited the expression and phosphorylation of spleen tyrosine kinase (Syk), a common target regulating both eosinophils and neutrophils inflammation. In addition to this, EAPP-2 significantly down-regulates the expression of NF-κB, p-NF-κB, and NLRP3 in vivo and in vitro. Moreover, by using specific inhibitors in vitro, it was validated that EAPP-2 targeted on Syk and then regulated its downstream NF-κB and NLRP3. Conclusion: EAPP-2 is shown to be a potentially useful therapeutic candidate for ACO, and its mechanism is at least partially achieved by targeting on Syk and then inhibiting NF-κB or NLRP3. Moreover, this study suggests that Syk may be a potentially effective target for ACO therapy. [ABSTRACT FROM AUTHOR]

Chlorogenic acid (CGA) is found in many plants that are used as medicinal substances in traditional Chinese medicine injectables (TCMIs). However, to date, there is controversy as to whether CGA is the major cause of TCMIs-related hypersensitivity administered intravenously. Therefore, the aim of this study was to evaluate the potential sensitization of CGA and structure–activity differences between its isomers using an intravenous exposure mouse model. The results showed that popliteal lymph nodes proliferation was significantly induced by CGA and its isomers. Both CGA and isochlorogenic acid A (iso-CGA A) significantly enhanced the secretion of trinitrophenyl (TNP) ovalbumin-specific immunoglobulin (Ig)G1; and iso-CGA B significantly induced TNP-specific IgG1, IgM, and IgG2b secreting. Furthermore, the results of quantitative structure–activity relationship analysis suggested that chemical structure factors, including atomic mass, electronegativity, atom shape and size, atom distribution, atomic weight, and atomic polarizabilities, the ionic currents, were significantly correlated with the potential sensitization of CGA and its isomers. In summary, when administered intravenously, the strength and type of sensitization may be correlated with structure differences in the CGA family. [ABSTRACT FROM AUTHOR]

ABSTRACT Immune-mediated drug hypersensitivity is a particularly concerning health-safety issue among clinicians given its unpredictability and potentially life-threatening effects, especially with exposure to intravenous drugs. Therefore, the development of intravenous drug-exposure models for drug-hazard assessments has garnered increasing interest in recent years. In this study, we used reporter antigens popliteal lymph node assay to investigate the potential value of intravenous exposure to a selected variety of allergenic compounds, including ovalbumin (OVA), concanavalin A (ConA) and diclofenac. The trinitrophenyl (TNP)-specific antibody-forming cells were used to assess the systemic immune responses to a bystander antigen. Mice were subsequently sensitized by TNP-OVA, and then intravenous exposure to one of the selective compounds. As expected, all positive compounds induced significant popliteal lymph node (PLN) proliferation compared with the control. OVA significantly increased Cluster of Differentiation 4 receptors (CD4)+ interleukin-4 (IL-4)+ T-helper 2 (Th2) cells and, consequently, increased the ratios of IL-4/interferon- γ (IFN- γ) antibody-forming cells (AFCs) in PLNs, while bringing about a dose-dependent increase in immunoglobulin G1 (IgG1) AFCs; these findings indicate that a Th2 hypersensitivity response was induced. A Th2 response was also observed in diclofenac sodium-treated groups, and for ConA, a more mixed Th1/Th2 immune response appeared to be induced. In addition, there was no marked reaction with the negative compound. Together, it seems likely that the intravenous exposure model may be useful for drug-induced systemic hypersensitivity assessments. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract Two water-soluble polysaccharides, BSP-1 and BSP-2, were extracted and purified from the tuber of Bletilla striata. The molecular weights of BSP-1 and BSP-2 were 83.54 kDa and 12.60 kDa, respectively. The composition and proportion of BSP-1 and BSP-2 were mannose and glucose in molar ratios of 4.0:1.0 and 3.0:1.0 respectively. The two polysaccharides had a linear backbone, consisting mainly of repeating β‑1,4‑linked d ‑mannosyl residues and β‑1,4‑linked d ‑glucosyl residues. BSP-1 exhibited immunomodulatory effects by increasing the thymus and spleen indices of immunocompromised model mice. Highlights • Two polysaccharides were isolated from the tuber of Bletilla striata. • The molecular weights of BSP-1, BSP-2 were 83.54 kDa, 12.60 kDa respectively. • The backbone consisted of 1,4‑linked mannosyl and 1,4‑linked glucosyl residues. • BSP-1 was shown to have immunomodulatory effects in vivo. [ABSTRACT FROM AUTHOR]

Brusatol, a biologically active naturalproduct, was modified infour distinct positions through the covalent attachment of a furoxanmoiety, which acts as a nitric oxide (NO) donor. Forty derivativeswere synthesized and evaluated for their inhibitory effects on excessNO biosynthesis in activated macrophages. Among them, compound 75demonstrated inhibition (IC50= 0.067 μM)comparable to that of brusatol but were less cytotoxic. More importantly,even at very low doses (2 μmol/kg/day), compound 75also showed substantial inhibitory efficacy against chronic obstructivepulmonary disease (COPD)-like inflammation in the mouse model inducedby cigarette smoke (CS) and lipopolysaccharide (LPS). Particularly,this compound was over 100-fold less toxic (LD50> 3852μmol/kg) than brusatol and could be a promising lead for furtherstudies. Notably, the improved properties of this derivative are associatedwith its NO-releasing capability. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocyte (CTL), a key effector cell in aplastic anemia (AA) immune injury, is shown to be a potential target for AA drug therapy. However, there is no candidate for this target till now. Oriented by the inhibition activity of CTL and macrophage derived nitric oxide (NO), a series of novel sinomenine derivatives on rings A and C are designed, synthesized and screened. Among them, compound 3a demonstrates the best inhibitory activity on CTL with an IC 50 value of 2.3 μM, and a 97.1% inhibiton rate on macrophage NO production without significant cytotoxicity. Further, compound 3a exhibits substantial therapeutic efficacy on immune-mediated BM failure in AA model mice by improving the symptoms of anemia and the function of BM hematopoiesis, and shows more advantages in life quality improving than cyclosporine A (CsA). Its efficacy on AA at least partly comes from targeting on activated cluster of differentiation (CD)8+ T cell. Additionally, 3a also shows much less toxicity (LD 50 > 10.0 g/kg) than sinomenine (LD 50 = 1.1 g/kg) in preliminary acute toxicity assessment in mice, and has a low risk to inhibit hERG to cause cardiotoxicity. These results indicate that compound 3a merits further investigation for AA treatment by targeting on CTL. [Display omitted] • A series of novel sinomenine derivatives are designed and synthesized. • 3a shows the best in vitro inhibitory activity. • 3a shows substantial therapeutic efficacy on mice model of aplastic anemia. • The efficacy of 3a at least partly comes from targeting on activated CD8+ T cell. • 3a shows good safety in vivo. [ABSTRACT FROM AUTHOR]