New Iridoids and Acyclic Monoterpenoids from the Roots and Rhizomes of Valeriana officinalis var. latifolia.

Five new iridoids, valeralides A-E (1-5), two new acyclic monoterpenoids, valeralides F (6) and G (7), together with two known iridoids (8 and 9), were isolated from the roots and rhizomes of Valeriana officinalis var. latifolia. Their structures were elucidated based on 1D and 2D NMR, as well as HR-ESI-MS spectroscopic data. The absolute configuration of compounds 1-4 were elucidated based on electronic circular dichroism (ECD) calculation. In addition, all the isolates were evaluated for their inhibition on nitric oxide production, cytotoxicity and anti-influenza A virus activity.

Iridoids and other constituents from the leaves and stems of Valeriana officinalis var. latifolia.

Fifty-nine compounds, including nineteen previously undescribed iridoids (valeriananols A-S) and an undescribed alkaloid (5'-isovaleryl uridine), were isolated from the leaves and stems of Valeriana officinalis var. latifolia. Their structures were elucidated based on Mass spectrometry and NMR spectroscopy. The absolute configuration of valeriananols A-C, E-N, P, Q and S was determined by experimental and calculated electronic circular dichroism. Structurally, valeriananols A and B were two 1,3-seco-iridoids with a 3,6-epoxy moiety, valeriananols K and L were a pair of C-4 epimers, while valeriananol S was a 4'-deoxy iridoid glycoside. In addition, valeriananol P, stenopterin A and patriscabioin C exhibited significant inhibition on nitric oxide production with IC50 values of 10.31, 3.93 and 8.69 µM, respectively. Furthermore, stenopterin A and patriscabioin C showed anti-proliferation activity on the MCF-7 cell line with IC50 values of 17.28 and 13.89 µM, respectively.

Complexation and evolution of cis-prenyltransferase homologues in Cinnamomum kanehirae deduced from kinetic and functional characterizations.

Eukaryotic dehydrodolichyl diphosphate synthases (DHDDSs), cis-prenyltransferases (cis-PTs) synthesizing precursors of dolichols to mediate glycoprotein biosynthesis require partners, for eample Nus1 in yeast and NgBR in animals, which are cis-PTs homologues without activity but to boost the DHDDSs activity. Unlike animals, plants have multiple cis-PT homologues to pair or stand alone to produce various chain-length products with less known physiological roles. We chose Cinnamomum kanehirae, a tree that contains two DHDDS-like and three NgBR-like proteins from genome analysis, and found that one DHDDS-like protein acted as a homodimeric cis-PT to make a medium-chain C55 product, while the other formed heterodimeric complexes with either one of two NgBR homologues to produce longer-chain products. Both complexes were functional to complement the growth defect of the yeast rer2 deficient strain at a higher temperature. From the roles for the polyprenol and dolichol biosynthesis and sequence motifs, their homologues in various species were compared to reveal their possible evolutionary paths.

Iridoids and sesquiterpenoids from Valeriana officinalis and their bioactivities.

Twenty-six iridoids, including six undescribed ones (iridoidvols A-F) and an undescribed natural one, along with ten known sesquiterpenoids were isolated from the roots and rhizomes of Valeriana officinalis. Structurally, iridoidvol A is the first example of iridoid with sesquiterpenoid acid ester. In addition, all of the isolates were evaluated for anti-inflammatory and anti-influenza virus activities. Among them, isovaltrate isovaleroyloxyhydrin exhibited a significant inhibitory effect on NO production with an IC50 value of 19.00 µM.

Synthesis, evaluation, and mechanism of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones as potent reversible SARS-CoV-2 entry inhibitors.

A class of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones were designed and synthesized via Michael addition, cyclization, aldol condensation, and deprotonation to inhibit the human transmembrane protease serine 2 (TMPRSS2) and Furin, which are involved in priming the SARS-CoV-2 Spike for virus entry. The most potent inhibitor 2f (81) was found to efficiently inhibit the replication of various SARS-CoV-2 delta and omicron variants in VeroE6 and Calu-3 cells, with EC50 range of 0.001-0.026 µM by pre-incubation with the virus to avoid the virus entry. The more potent antiviral activities than the proteases inhibitory activities led to discovery that the synthesized compounds also inhibited Spike's receptor binding domain (RBD):angiotensin converting enzyme 2 (ACE2) interaction as a main target, and their antiviral activities were enhanced by inhibiting TMPRSS2 and/or Furin. To further confirm the blocking effect of 2f (81) on virus entry, SARS-CoV-2 Spike pseudovirus was used in the entry assay and the results showed that the compound inhibited the pseudovirus entry in a ACE2-dependent pathway, via mainly inhibiting RBD:ACE2 interaction and TMPRSS2 activity in Calu-3 cells. Finally, in the in vivo animal model of SARS-CoV-2 infection, the oral administration of 25 mg/kg 2f (81) in hamsters resulted in reduced bodyweight loss and 5-fold lower viral RNA levels in nasal turbinate three days post-infection. Our findings demonstrated the potential of the lead compound for further preclinical investigation as a potential treatment for SARS-CoV-2.

Comparing PET/MRI with PET/CT for Pretreatment Staging of Gastric Cancer.

18F-FDG PET/MRI has been applied to the diagnosis and preoperative staging in various tumor types; however, reports using PET/MRI in gastric cancer are rare because of motion artifacts. We investigated the value of PET/MRI for preoperative staging compared with PET/CT in gastric cancer (GC). Thirty patients with confirmed GC underwent PET/CT and PET/MRI. TNM staging for each patient was determined from the PET/MRI and PET/CT images. The diagnostic performance of PET/MRI and PET/CT was calculated compared with the pathologic TNM stage. The two methods were compared using statistical analyses. The accuracy for T staging between PET/MRI and PET/CT was 76.9% vs. 57.7%, respectively. In T1 and T4a staging, the sensitivity and specificity for PET/MRI vs. PET/CT was 1.0 vs. 0.6 and 1.0 vs. 0.8, respectively. The area under the curve (AUC) for PET/MRI vs. PET/CT was 1.00 vs. 0.78 in the T1 stage, 0.73 vs. 0.66 in the T2 stage, 0.72 vs. 0.57 in the T3 stage, and 0.86 vs. 0.83 in the T4 stage. The accuracy for N staging of PET/MRI vs. PET/CT was 53.9% vs. 34.0%, and that for N0 vs. N+ was 85.0% vs. 77.0%. The sensitivity for PET/MRI in N3 staging was 0.67 and 0 for PET/CT. There was a statistically significant difference in the AUC for N1 staging (PET/MRI vs. PET/CT, 0.63 vs. 0.53, p = 0.03). SUVmax/ADC positively correlated with tumor volume and Ki-67. PET/MRI performs more accurately in TNM staging compared with PET/CT and is optimal for accurate N staging. SUVmax/ADC has positive correlations with tumor volume and Ki-67.

Neovascularization in the carotid atherosclerotic plaque is not associated with inflammatory cell aggregation.

BACKGROUND: Monocytes and macrophages in atherosclerotic plaque lead to plaque instability. The aim of the study was to determine if plaque neovascularization led to inflammation. METHODS: Patients were consecutively enrolled if their carotid intimal media thickness was > 2 mm, as revealed by duplex ultrasound. The patients then underwent dynamic contrast enhanced magnetic resonance imaging (DCE MRI) and fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography combined with computed tomography (PET CT). A target to background ratio (TBR) of ≥ 1.25 or < 1.25 served as the cutoff point for the presence and absence of inflammation, respectively. RESULTS: Twenty-six patients underwent bilateral carotid DCE MRI and 24 patients also underwent PET CT. One hundred and fifty-five plaques were evaluated by both DCE MRI and PET CT. There was no significant difference in plaque morphology between the TBR ≥ 1.25 (n = 61) and TBR < 1.25 (n = 94) groups. No significant differences were found in plasma volume and transfer constant between the TBR ≥ 1.25 and TBR < 1.25 groups. CONCLUSION: Our study did not find a significant correlation between plaque neovascularization and the aggregation of inflammatory cells.