Methyl salicylate 2-O-β-D-lactoside, a novel salicylic acid analogue, acts as an anti-inflammatory agent on microglia and astrocytes

<p>Abstract</p> <p>Background</p> <p>Neuroinflammation has been known to play a critical role in the pathogenesis of Alzheimer's disease (AD). Activation of microglia and astrocytes is a characteristic of brain inflammation. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) delays the onset of AD and suppresses its progression. Methyl salicylate-2-<it>O</it>-<it>β</it>-<smcaps/><smcaps>D</smcaps>-lactoside (DL0309) is a new molecule chemically related to salicylic acid. The present study aimed to evaluate the anti-inflammatory effects of DL0309.</p> <p>Findings</p> <p>Our studies show that DL0309 significantly inhibits lipopolysaccharide (LPS)-induced release of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α; and the expression of the inflammation-related proteins iNOS, COX-1, and COX-2 by microglia and astrocytes. At a concentration of 10 μM, DL0309 prominently inhibited LPS-induced activation of NF-κB in glial cells by blocking phosphorylation of IKK and p65, and by blocking IκB degradation.</p> <p>Conclusions</p> <p>We demonstrate here for the first time that DL0309 exerts anti-inflammatory effects in glial cells by suppressing different pro-inflammatory cytokines and iNOS/NO. Furthermore, it also regulates the NF-κB signaling pathway by blocking IKK and p65 activation and IκB degradation. DL0309 also acts as a non-selective COX inhibitor in glial cells. These studies suggest that DL0309 may be effective in the treatment of neuroinflammatory disorders, including AD.</p

Salvianolic Acid A Inhibits PDGF-BB Induced Vascular Smooth Muscle Cell Migration and Proliferation While Does Not Constrain Endothelial Cell Proliferation and Nitric Oxide Biosynthesis

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Multiple process microstructure evolution simulation of ultrasonic assisted rolling directed energy deposition

Directed energy deposition (DED) has a widely application prospect, but dendrite and component segregation are not easily controlled and predicted. In this study, the method of applying ultrasonic assisted rolling was introduced to the DED to eliminate above phenomenon. A multiple process microstructure evolution simulation (involved melting, solidification, dynamitic recrystallization and grain growth) was also carried out, which introduced ultrasonic effect in the form of energy. The influence of ultrasonic amplitude (A), distance between laser focus point and ultrasonic roller (d0) on microstructure of Pb-Sn alloy deposition layer were explored. There is a good consistency between experiment and simulation with relative error of 4.33%. The results show that the roundness of grains is improved significantly after rolling, and the grain are refined with the increase of A and d0. In all tests of this study, comprehensive effect of ultrasonic rolling achieves the best when d0 is taken as 24 mm and A is taken as 20 μm, the average grain diameter (D0) in grain size counted zone is 18.8 μm which is 23.23% lower than that without rolling. This study laid a foundation for the development of ultrasonic assisted rolling DED and provide a multiple process microstructure simulation method

Effect of in-situ rolling and heat treatment on microstructure, mechanical and corrosion properties of wire-arc additively manufactured 316L stainless steel

Post-heat treatment and in-situ rolling, both can be used to improve the coarse grains and anisotropy that are prevalent in metallic materials, fabricated by wire and arc additive manufacturing (WAAM). In this study, the effect of in-situ rolling and heat treatment on the microstructure, mechanical and corrosion behaviors of WAAM 316L was investigated. The results showed that the microstructure of WAAM 316L changed considerably due to the introduction of rolling deformation, as it was observed that the ferrite was distributed in a reticulated or equiaxed morphology instead of dendritic distribution, columnar grains were found to be engulfed, while a large number of low angle grain boundaries (LAGBs) with high dislocation density were introduced. After heat treatment at 650 °C, there was no significant change in grain morphology, ferrite gradually transformed into σ phase, the tensile strength increased, yield strength and elongation decreased. After heat treatment above 1000 °C, the strength and ductility of the rolled WAAM 316L were higher than those of the unrolled WAAM 316L. As the heat treatment temperature increased, the corrosion resistance first decreased and then increased. In-situ rolling resulted in a decrease in the corrosion current density of the steel and also reduced the stability of the passive film

C19-Diterpenoid alkaloid arabinosides from an aqueous extract of the lateral root of Aconitum carmichaelii and their analgesic activities

Eight new C19-diterpenoid alkaloid arabinosides, named aconicarmichosides E–L (1–8), were isolated from an aqueous extract of the lateral roots of Aconitum carmichaelii (Fu Zi). Their structures were determined by spectroscopic and chemical methods including 2D NMR experiments and acid hydrolysis. Compounds 1–8, together with the previously reported four neoline 14-O-arabinosides from the same plant, represent the only examples of glycosidic diterpenoid alkaloids so far. At a dose of 1.0 mg/kg (i.p.), as compared with the black control, compounds 1, 2, and 4–6 exhibited analgesic effects with >65.6% inhibitions against acetic acid-induced writhing of mice. Structure–activity relationship was also discussed. KEY WORDS: Ranunculaceae, Aconitum carmichaelii, C19-diterpenoid alkaloid, Arabinoside, Aconicarmichosides E−L, Analgesic effect, Structure–activity relationshi

Aconicarmisulfonine A, a Sulfonated C₂₀-Diterpenoid Alkaloid from the Lateral Roots of <i>Aconitum carmichaelii</i>

A novel sulfonated C₂₀-diterpenoid alkaloid with an unprecedented carbon skeleton and significant analgesic activity (46.7% inhibition at 0.1 mg/kg, i.p.), named aconicarmisulfonine A (<b>1</b>), was isolated from an aqueous extract of the lateral roots of <i>Aconitum carmichaelii</i>. Its structure was determined by comprehensive analysis of spectroscopic data, especially by 2D NMR spectroscopic data combined with ECD calculation and single-crystal X-ray diffraction. The plausible biosynthetic pathways of compound <b>1</b> are also discussed

Methyl Salicylate Lactoside Protects Neurons Ameliorating Cognitive Disorder Through Inhibiting Amyloid Beta-Induced Neuroinflammatory Response in Alzheimer’s Disease

Neuroinflammatory reactions mediated by microglia and astrocytes have been shown to play a key role in early progression of Alzheimer’s disease (AD). Increased evidences have demonstrated that neurons exacerbate local inflammatory reactions by producing inflammatory mediators and act as an important participant in the pathogenesis of AD. Methyl salicylate lactoside (MSL) is an isolated natural product that is part of a class of novel non-steroidal anti-inflammatory drugs (NSAID). In our previous studies, we demonstrated that MSL exhibited therapeutic effects on arthritis-induced mice and suppressed the activation of glial cells. In the current study, we investigated the effects of MSL on cognitive function and neuronal protection induced by amyloid-beta peptides (Aβ) and explored potential underlying mechanisms involved. Amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice were used to evaluate the effects of MSL through behavioral testing and neuronal degenerative changes. In addition, copper-injured APP Swedish mutation overexpressing SH-SY5Y cells were used to determine the transduction of cyclooxygenase (COX) and mitogen-activated protein kinase (MAPK) pathways. Our results indicated that at an early stage, MSL treatment ameliorated cognitive impairment and neurodegeneration in APP/PS1 mice. Moreover, in an in vitro AD model, MSL treatment protected injured cells by increasing cell viability, improving mitochondrial dysfunction, and decreasing oxidative damage. In addition, MSL inhibited the phosphorylated level of c-Jun N-terminal kinase (JNK) and p38 MAPK, and suppressed the expression of COX-1/2. As a novel NSAIDs and used for the treatment in early stage of AD, MSL clearly demonstrated cognitive preservation by protecting neurons via a pleiotropic anti-inflammatory effect in the context of AD-associated deficits. Therefore, early treatment of anti-inflammatory therapy may be an effective strategy for treating AD