Identification of O-arylated huperzinines as novel cholinergic anti-inflammatory pathway agonists against gout arthritis.

Lycodine alkaloids are important natural products with diverse biological effects. In this manuscript, we set out the first structural optimization of the 2-pyridone moiety of Lycodine alkaloid via selective O-arylation under metal-free conditions and obtained a series of potent bioactive molecules against monosodium urate (MSU)-induced IL-1ß production. Further investigations demonstrated that these natural product derivatives could activate the neuro-immunomodulatory cholinergic anti-inflammatory pathway (CAP) to block the initial phase of NLRP3 inflammasome activation. Compared with the clinical drugs hydrocortisone and indomethacin, as well as commercially available CAP agonists GTS-21 and pnu282987, 3k and 3q possessed greater potency against MSU-induced IL-1ß production. Meanwhile, these molecules possessed less cytotoxicity against promonocytic THP-1 macrophages when compared with colchicine. This work reports a concise strategy for direct modification of 2-pyridone moiety from natural Lycodine alkaloids, and provides novel frameworks for discovering CAP activators and drugs for gout arthritis.

Prenylated Acetophenone Derivatives from the Leaves of Acronychia pedunculata and Their Anti-proliferative Activities.

Four new prenylated acetophenone derivatives, including one acetophenone dimer [acronyrone D (1)] and three acetophenone monomers [acronyrones E-G (2-4)], along with seven known analogues (5-11) were obtained from the leaves of Acronychia pedunculata. Their structures and absolute configurations were established by analysis of HRMS and NMR data, single crystal X-ray diffraction studies and quantum chemical calculations. In addition, the isolates were tested for their anti-proliferative acivity against HCT-116, RKO and SW480 cancer cell lines. Remarkably, compound 5 exhibited significant anti-proliferative effects on the three cell lines, with IC50 values ranging from 0.24 to 5.3 µM.

[Mechanism of liver injury induced by alcohol extract of salt-processed Psoraleae Fructus based on chemical modification of protein].

Salt-processed Psoraleae Fructus is a commonly used tonic in clinical practice. However, its usage is restricted due to the inherent toxicity. The covalent modification of proteins by reactive metabolites(RMs) plays a role in the hepatotoxicity of salt-processed Psoraleae Fructus. This study delves into the protein covalent modification by RMs generated from psoralen/isopsoralen, the primary toxic components of salt-processed Psoraleae Fructus, by liquid chromatography-mass spectrometry(LC-MS), aiming to elucidate the mechanism underlying the hepatic injury induced by salt-processed Psoraleae Fructus. Biochemical methods were utilized to measure the levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), catalase(CAT), malondialdehyde(MDA), superoxide dismutase(SOD), reduced glutathione(GSH), and glutathione S-transferase(GST) in mice. The pathological changes in the liver were observed by hematoxylin-eosin(HE) staining. Subsequently, ultra performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry(UPLC-Q-TOF-MS) was employed to identify the primary toxic components of psoralen/isopsoralen and the RMs in salt-processed Psoraleae Fructus. Covalent bonding adducts of the toxic components/RMs with GSH and free amino acids were identified to investigate the effects of the toxic components on modification sites and patterns of amino acids. The modifications of RMs were incorporated into the variable modifications of Proteome Discoverer, and the target proteins of psoralen/isopsoralen were detected by liquid chromatography-quadrupole exactive-mass spectrometry. Lastly, Label-free quantitative proteomics was adopted to screen differential proteins, which were further subjected to KEGG and GO enrichment analyses and confirmed by qPCR. The results indicated that compared with the control group, salt-processed Psoraleae Fructus significantly elevated the ALT, AST, and MDA levels and lowered the SOD, CAT, GSH, and GST levels in a dose-dependent manner, while causing obvious vacuolization and inflammatory cell infiltration in mouse hepatocytes. Furthermore, the livers of mice in the salt-processed Psoraleae Fructus group showed the presence of five RMs of psoralen/isopsoralen, two adducts with GSH, and one adduct with cysteine. In addition, 10 proteins modified by the RMs of psoralen/isopsoralen were identified. A total of 133 differential proteins were detected in the livers of mice in the salt-processed Psoraleae Fructus group, including 92 with up-regulated expression and 41 with down-regulated expression. These differential proteins mainly involved ribosomes, rRNAs, and glutathione, affecting the proteasome pathway. The qPCR results were consistent with the differential proteins. These findings suggest that the RMs of psoralen/isopsoralen can covalently bind to GSH and modify cysteine and lysine residues of liver proteins. This covalent modification of proteins by harmful substances can potentially result in liver damage. Therefore, it can be inferred that the oxidative stress damage induced by salt-processed Psoraleae Fructus may be associated with the abnormality of proteasome and its complex, biosynthesis of ribosomes and their nucleoprotein complex, rRNA binding, and glutathione binding.

Five New Phenylpropanoyl Phloroglucinol Derivatives from Leptospermum scoparium.

Leptosperols C-G (1-5), five new phenylpropanoyl phloroglucinol derivatives were isolated from the leaves of Leptospermum scoparium. Compounds 1-3 are phenylpropanoyl phloroglucinol-sesquiterpene adducts with new carbon skeletons. Their structures with absolute configurations were elucidated by detailed spectroscopic analyses, single-crystal X-ray diffraction, and electronic circular dichroism (ECD) calculation. Compounds 2 and 3 exhibited moderate anti-inflammatory activity in zebrafish acute inflammatory models.

Dimeric Acylphloroglucinol Derivatives with New Skeletons from Leptospermum scoparium.

Leptosparones A-F (1-6), six new dimeric acylphloroglucinol derivatives with unprecedented skeletons, were isolated from Leptospermum scoparium. Compounds 1-3 and 5-6 are phenylpropanoyl-phloroglucinol dimers, while 4 is a phenylpropanoylphloroglucinol-isovalerylphloroglucinol hybrid. Structurally, these compounds represent the first examples of dimeric phloroglucinols with unprecedented C(7')-C(8) linkage between the phloroglucinol core and the acyl side chain. Their structures were elucidated by comprehensive analyses of spectroscopic data, single crystal X-ray diffraction and chemical calculations. In addition, all compounds showed inhibitory effects against α-glucosidase with IC50 values ranging from 39.5 to 186.8 µM.

Efficient volumetric method of moments for modeling plasmonic thin-film solar cells with periodic structures.

Metallic nanoparticles (NPs) support localized surface plasmon resonances (LSPRs), which enable to concentrate sunlight at the active layer of solar cells. However, full-wave modeling of the plasmonic solar cells faces great challenges in terms of huge computational workload and bad matrix condition. It is tremendously difficult to accurately and efficiently simulate near-field multiple scattering effects from plasmonic NPs embedded into solar cells. In this work, a preconditioned volume integral equation (VIE) is proposed to model plasmonic organic solar cells (OSCs). The diagonal block preconditioner is applied to different material domains of the device structure. As a result, better convergence and higher computing efficiency are achieved. Moreover, the calculation is further accelerated by two-dimensional periodic Green's functions. Using the proposed method, the dependences of optical absorption on the wavelengths and incident angles are investigated. Angular responses of the plasmonic OSCs show the super-Lambertian absorption on the plasmon resonance but near-Lambertian absorption off the plasmon resonance. The volumetric method of moments and explored physical understanding are of great help to investigate the optical responses of OSCs.

Acronyrones A-C, unusual prenylated acetophenones from Acronychia pedunculata.

Two novel prenylated acetophenones with new carbon skeletons, acronyrones A and B (1 and 2), and a new analogue, acronyrone C (3), together with two known compounds (4 and 5) were isolated from the leaves of Acronychia pedunculata. Their structures with absolute configurations were identified by interpretation of spectroscopic data, single crystal X-ray diffraction, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 represent the first example of prenylated acetophenones possessed a C7 (1) and a C6 (2) side chain, forming a 4-isobutylchroman-2-one unit and a 3-(2-methylpropylidene)benzofuran-2(3H)-one moiety with the acetophenone core, respectively. In addition, compound 4 exhibited significant dose-dependent transcriptional activation effect against retinoid X receptor-α (RXRα), and could be regarded as a new type of non-classical RXR ligand.

Leptosperols A and B, Two Cinnamoylphloroglucinol-Sesquiterpenoid Hybrids from Leptospermum scoparium: Structural Elucidation and Biomimetic Synthesis.

Leptosperols A and B (1 and 2), two cinnamoylphloroglucinol-sesquiterpenoid hybrids featuring unprecedented 1-benzyl-2-(2-phenylethyl) cyclodecane and 2-benzyl-3-phenylethyl decahydronaphthalene backbones, along with their biosynthetic precursor (3), were isolated from Leptospermum scoparium. Compounds 1 and 2 represent the first example of phloroglucinol derivatives biogenetically constructed by a De Mayo reaction. The biomimetic synthesis of leptosperol B (2) was achieved using the proposed biosynthetic pathway. In addition, compounds 1 and 2 showed significant anti-inflammatory effects in zebrafish acute inflammatory models.

Five new koumine-type alkaloids from the roots of Gelsemium elegans.

Five new koumine-type alkaloids (1-5) along with six known ones were isolated from the roots of Gelsemium elegans. Their structures with absolute configurations were elucidated on the basis of NMR spectroscopy and electronic circular dichroism spectral analyses. The inhibitory effects of compounds 1-11 on the viability of three tumor cell lines (A-649, HepG2, and HuH7) were evaluated by the MTT assay.