Discovery of 5-(3,4-dihydroxybenzylidene)-1,3-dimethylpyrimidine- 2,4,6(1H,3H,5H)-trione as a novel and effective cardioprotective agent via dual anti-inflammatory and anti-oxidative activities.

Myocardial ischemia/reperfusion (MI/R) injury is still the huge unmet medical need without effective therapy in clinic. It is critical to develop pharmacological intervention to scavenge ROS and inhibit NLRP3 activation to have a double benefit against MI/R injury. Cinnamamide derivatives have been demonstrated to possess anti-oxidative and anti-inflammatory activities. Previously, we have reported that a cinnamamide derivative 2 exerts excellent cardioprotective effect via mediation of intracellular oxidative stress via Nrf2 up-regulation against MI/R. In the present study, seventeen compounds have been optimized using cinnamamide-barbiturate hybrid 2 as the lead compound and their cardioprotective activities against MI/R were further determined in vitro and in vivo. Among them, compound 7 showed the most potent cardioprotective effect and low cytotoxicity. While cardiomyocytes were invased by hydrogen peroxide, compound 7 exhibited more excellent cardioprotective effect than that of luteolin and metoprolol, the positive control employed in the present study, as demonstrated by dramatically elevated cell survival rate and decreased LDH leakage rate. Moreover, compound 7 markedly inhibited cardiac expressions of inflammasome activation and pro-inflammatory cytokines release (i.e. NLRP3, IL-1ß, IL-18), simultaneouly increasing endogenous antioxidative proteins (i.e. Nrf2, HO-1 and SOD) in vitro. In the rat MI/R model, compound 7 pretreatment profoundly reduced cardiac infarct size in MI/R rats and reversed abnormal changes in myocardial enzymes and lipid peroxidation levels in heart tissues. Mechanistically, compound 7 revealed significant cardioprotective effects by inhibiting NLRP3 and its downstream inflammatory chemokine IL-1ß, as well as up-regulating Nrf2 in vivo. Furthermore, at the active site of the co-crystal of NLRP3 and Nrf2, compound 7 exhibited higher binding force in the molecular docking study, which was consistent with the in vitro results. Therefore, compound 7 is expected to be a potential cardioprotective agent possessing dual anti-inflammatory and anti-oxidative activities. Our work provides an important therapeutic strategy for the treatment of ischemic-reperfused heart disease.

Whole genome analysis calls for a taxonomic rearrangement of the genus Colwellia.

Microbial taxonomy is the foundation of microbiology and rapid advancements in DNA sequencing technologies are providing new approaches to address prevailing questions in this field. The family Colwelliaceae, which currently comprises four genera, is a diverse and globally abundant group of Gamaproteobacteria. Based on 14 publically available genomes of bacteria strains labeled as members of the family Colwelliaceae, phylogenomic analyses were conducted to revisiting the taxonomic status of this family both in the genus and species level. Using genome-based phylogeny as a primary guideline and genome-based similarity indexes including average amino acid identity, percentage of conserved proteins, average nucleotide identity, and the digital DNA-DNA hybridization as supplements, the following taxonomic proposals were proposed: Colwellia polaris, Colwellia beringensis, Colwellia sediminilitoris, Colwellia aestuarii, Colwellia chukchiensis and Colwellia mytili should be reclassified into the novel genus Cognaticolwellia; Colwellia agarivorans should be reclassified into the novel genus Pseudocolwellia. Our results constitute a solid framework for current and future taxonomic decisions within this family, which will be helpful for avoiding confusion with ecological and evolutionary interpretations in subsequent studies.

Three New Polyacetylene Glycosides from the Roots of Heracleum dissectum and Their Triglyceride Accumulating Activities in 3T3-L1 Cells.

Continually phytochemical study of the roots of Heracleum dissectum had led to the isolation of three previously undescribed polyacetylene glycosides (1-3), together with seven known compounds, including one polyacetylene (8) and six coumarins (4-7 and 9-10) using diverse chromatographic methods. The structures of these three new compounds were characterized and identified as deca-4,6-diyn-1-yl ß-d-glucopyranosyl-(1→6)-ß-d-glucopyranosyl-(1→2)-ß-d-glucopyranoside (1), (8Z)-dec-8-ene-4,6-diyn-1-yl ß-d-glucopyranosyl-(1→6)-ß-d-glucopyranosyl-(1→2)-ß-d-glucopyranoside (2), and (8E)-dec-8-ene-4,6-diyn-1-yl ß-d-glucopyranosyl-(1→6)-ß-d-glucopyranosyl-(1→2)-ß-d-glucopyranoside (3) based on their physicochemical properties and extensive analyses of various spectroscopic data. Their triglycerides accumulating activities were assayed and the results showed that the three new polyacetylene glycosides (1-3) exhibited triglyceride accumulating activities in 3T3-L1 adipocytes.

A new cinnamic acid glycoside from roots of Heracleum dissectum.

From the roots of Heracleum dissectum Lebb., one new cinnamic acid glycoside derivative named dissectumoside (1), together with eight known compounds including three phenolics, three phenolic glycosides and two phenylpropanoic glycoside were isolated using various chromatographic methods. Among them compound 2-9 was isolated from the plant for the first time. Their structures were elucidated and identified on the basis of their physicochemical properties and by extensive analyses of NMR spectroscopy and high-resolution mass spectrometry. The results of triglyceride accumulation screening in 3T3-L1 cells showed that compounds 1, 5 and 9 exhibited significantly accelerating activities of adipogenesis in adipocytes.

A New Anti-Inflammatory Alkaloid from Roots of Heracleum dissectum.

Using various chromatographic methods, a new piperidinone alkaloid, (3S)-3-{4-[(1E)-3-hydroxyprop-1-en-1-yl]-2-methoxyphenoxy}piperidin-2-one (1), together with 10 known compounds, bergapten (2), xanthotoxol (3), isopimpinellin (4), isobergapten (5), heratomol-6-O-ß-d-glucopyranoside (6), scopoletin (7), apterin (8), 3-methoxy-4-ß-d-glucopyranosyloxypropiophenone, (praeroside; 9), tachioside (10) and coniferin (11), were isolated from roots of Heracleum dissectum Ledeb. Their structures were elucidated on the basis of physicochemical properties and the detailed interpretation of various spectroscopic data. All the isolated compounds were screened for anti-inflammatory activity in vitro. As the results, compound 1 and 8 showed significantly inhibitory activity on nitric oxide production in RAW264.7 cells.