Chronic obstructive pulmonary disease (COPD) is a major inflammatory lung disease characterized by irreversible and progressive airflow obstruction. Although corticosteroids are often used to reduce inflammation, steroid therapies are insufficient in patients with refractory COPD. Both serum amyloid A (SAA) and IL-33 have been implicated in the pathology of steroid-resistant lung inflammation. Picroside II isolated from Pseudolysimachion rotundum var. subintegrum (Plantaginaceae) is a major bioactive component of YPL-001, which has completed phase-2a clinical trials in chronic obstructive pulmonary disease patients. In this study, we investigated whether picroside II is effective in treating steroid refractory lung inflammation via the inhibition of the SAA-IL-33 axis. Picroside II inhibited LPS-induced SAA1 expression in human monocytes, which are resistant to steroids. SAA induced the secretion of IL-33 without involving cell necrosis. Picroside II, but not dexamethasone effectively inhibited SAA-induced IL-33 expression and secretion. The inhibitory effect by picroside II was mediated by suppressing the mitogen-activated protein kinase (MAPK) p38, ERK1/2, and nuclear factor-κB pathways. Our results suggest that picroside II negatively modulates the SAA-IL-33 axis that has been implicated in steroid-resistant lung inflammation. These findings provide valuable information for the development of picroside II as an alternative therapeutic agent against steroid refractory lung inflammation in COPD. Full article

Twenty eight 7-substitued fangchinoline analogues, of which twenty two were novel, were synthesized and evaluated for their effect to inhibit lipopolysaccharide/nigericin (LPS/NIG)-induced IL-1β release at both cell and protein levels at the concentration of 5 μM. Among them, compound 6 exhibited promising inhibitory potency against IL-β activation with an IC₅₀ value of 3.7 μM. Preliminary mechanism study revealed that 6 might target NLRP3 protein, and then block ASC pyroptosome formation with-NLRP3, rather than acting on the activation of the NLRP3 inflammasome (NF-κB and MAPK pathways) or caspase-1 protein. Our current study supported the potential role of compound 6 against IL-β activation, and provided powerful information for developing fangchinoline derivatives into a novel class of anti-inflammatory agents. Full article

In this study, we developed and validated a new proposed parameter quantifying the interaction strength between natural and/or synthetic molecules with paramagnetic metal ions. The Metal ion Recognition Index, Miri, is a quantitative parameter to describe the proton environment and to define their involvement in the inner and/or outer sphere of the paramagnetic metal ion. The method is based on the analysis of NMR proton spin-lattice relaxation rates of a specific ligand in both the diamagnetic and paramagnetic conditions. The proposed procedure is also useful to calculate the ligand proton spin-lattice relaxation rate in the paramagnetic bound conditions, which is typically very difficult to determine experimentally. Miri was used to compare the ligand proton involvement toward different paramagnetic species, in particular the Copper(II)-Piroxicam system. Copper(II)-Piroxicam complex is one of the most active anti-inflammatory and anti-arthritic species. Miri provides an opportunity to improve our knowledge of metal-ligand complexes that play a fundamental role in bioinorganic interactions. Full article

Inflammation is a complex phenomenon that results as a healing response of organisms to different factors, exerting immune signaling, excessive free radical activity and tissue destruction. Lipoxygenases and their metabolites e.g., LTB₄, are associated with allergy, cell differentiation and carcinogenesis. Lipoxygenase 12/15 has been characterized as a mucosal-specific inhibitor of IgA and a contributor to the development of allergic sensitization and airway inflammation. Development of drugs that interfere with the formation or effects of these metabolites would be important for the treatment of various diseases like asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer and blood vessel disorders. In this study we extended our previous research synthesizing a series of multi-target cinnamic acids from the corresponding aldehydes with suitable 4-OH/Br substituted phenyl acetic acid by Knoevenagel condensation. The final products 1i, 3i, 3ii, 4i, 6i, 6ii, and 7i were obtained in high yields (52–98%) Their structures were verified spectrometrically, while their experimentally lipophilicity was determined as R_M values. The novel derivatives were evaluated for their antioxidant activity using DPPH, hydroxyl radical, superoxide anion and ABTS^+•, anti-lipid peroxidation and soybean lipoxygenase inhibition assays. The compounds presented medium interaction with DPPH (30–48% at 100 µM). In contrast all the synthesized derivatives strongly scavenge OH radicals (72–100% at 100 µM), ABTS^+• (24–83% at 100 µM) and presented remarkable inhibition (87–100% at 100 µM) in linoleic acid peroxidation (AAPH). The topological polar surface of the compounds seems to govern the superoxide anion scavenging activity. Molecular docking studies were carried out on cinnamic acid derivative 3i and found to be in accordance with experimental biological results. All acids presented interesting lipoxygenase inhibition (IC₅₀ = 7.4–100 µM) with compound 3i being the most potent LOX inhibitor with IC₅₀ = 7.4 µM combining antioxidant activities. The antioxidant results support the LOX inhibitory activities. The recorded in vitro results highlight compound 3i as a lead compound for the design of new potent lipoxygenase inhibitors for the treatment of asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer and blood vessel disorders. Full article

Given that the peculiar redox behavior of ergothioneine involves a rapid regeneration process, the measurement of its precursor and redox metabolite hercynine could be particularly useful in assessing its role in oxidative stress or other biological processes. Thus, a LC-MS/MS method for the determination of hercynine concentrations in whole blood was developed. After lysis of red blood cells by cold water, samples were filtered on micro concentrators at a controlled temperature of 4 °C. The clear filtered fluid was then treated with diethylpyrocarbonate to derivatize hercynine for the analysis by LC-MS/MS. The derivatized analyte was isocratically separated as a carbethoxy derivative on a C18 column with a mobile phase of an aqueous 0.1% v/v formic acid and acetonitrile (95:5). Effluents were monitored by MRM transitions at m/z 270.28→95 and 273.21→95 for hercynine and its deuterated counterpart, respectively. No cross-talk between MRM transitions was observed and a good linearity was found within a range of 35–1120 nmol/L. The LOD and LOQ were, respectively, 10.30 and 31.21 nmol/L with an intraday and intermediate precision below 7%. The average hercynine concentration in whole blood from 30 healthy male volunteers (aged 77 ± 12 years) was 178.5 ± 118.1 nmol/L. Overall, the method is easy to perform, allowing a rapid and accurate assessment of whole blood concentrations of hercynine. Full article

Suppressing canonical NOD-like receptor protein 3 (NLRP3) inflammasome-mediated interleukin (IL)-1β secretion is a reliable strategy for the development of nutraceutical to prevent chronic inflammatory diseases. This study aimed to find out the functional group responsible for the inhibitory effects of cinnamaldehyde-related compounds on the canonical IL-1β secretion. To address this, the suppressing capacities of six cinnamaldehyde-related compounds were evaluated and compared by using the lipopolysaccharide (LPS)-primed and adenosine 5′-triphosphate (ATP)-activated macrophages. At concentrations of 25~100 μM, cinnamaldehyde and 2-methoxy cinnamaldehyde dose-dependently inhibited IL-1β secretion. In contrast, cinnamic acid, cinnamyl acetate, cinnamyl alcohol and α-methyl cinnamaldehyde did not exert any inhibition. Furthermore, cinnamaldehyde and 2-methoxy cinnamaldehyde diminished expressions of NLRP3 and pro-IL-1β. Meanwhile, cinnamaldehyde and 2-methoxy cinnamaldehyde prevented the ATP-induced reduction of cytosolic pro-caspase-1 and increase of secreted caspase-1. In conclusion, for cinnamaldehyde-related compounds to suppress NLRP3 inflammasome-mediated IL-1β secretion, the propenal group of the side chain was essential, while the substituted group of the aromatic ring played a modifying role. Cinnamaldehyde and 2-methoxy cinnamaldehyde exerted dual abilities to inhibit canonical IL-1β secretion at both stages of priming and activation. Therefore, there might be potential to serve as complementary supplements for the prevention of chronic inflammatory diseases. Full article

Acne vulgaris (acne) is a common inflammatory skin disorder, and Propionibacterium acnes plays a major role in the development and progression of acne inflammation. Herbs possessing antimicrobial and anti-inflammatory activity have been applied as a medical option for centuries. In this study, we examined the suppressive effect of ethanolic oregano (Origanum vulgare) extract on live P. acnes-induced in vivo and in vitro inflammation. Following ethanol extraction of oregano leaves, four compounds with strong antioxidant activity, including rosmarinic acid, quercetin, apigenin, and carvacrol, were identified by high-performance liquid chromatography. Using the mouse ear edema model, we demonstrated that ethanol oregano extracts (EOE) significantly suppressed P. acnes-induced skin inflammation, as measured by ear thickness (32%) and biopsy weight (37%). In a separate study, using the co-culture of P. acnes and human THP-1 monocytes, EOE reduced the production of interleukin (IL)-8, IL-1β and tumor necrosis factor (TNF)-α up to 40%, 37%, and 18%, respectively, as well as the expression of these three pro-inflammatory mediators at the transcriptional level. Furthermore, EOE inhibited the translocation of nuclear factor-kappa B (NF-κB) into the nucleus possibly by inactivating toll-like receptor-2 (TLR2). The suppressive effect of EOE on live P. acnes-induced inflammatory responses could be due, in part, to the anti-inflammatory and antioxidant properties, but not the anti-microbial effect of EOE. Full article