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The fruits of Eucalyptus globulus Labill. are known to have a plenty of medicinal properties, such as anti-tumor, anti-inflammatory, and immunosuppressive activity. Our previous study found that the phloroglucinol-sesquiterpene adducts in the fruits of E. globulus were immunosuppressive active constituents, especially Eucalyptin C (EuC). Phosphoinositide 3-kinases-γ (PI3Kγ) plays a pivotal role in T cell mediated excessive immune responses. In this study, EuC was first discovered to be a novel selective PI3Kγ inhibitor with an IC50 value of 0.9 μmol·L-1 and selectivity over 40-fold towards the other PI3K isoforms. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay showed that EuC bound to PI3Kγ. Furthermore, EuC suppressed the downstream of PI3Kγ to induce the apoptosis and inhibit the activation of primary spleen cells derived from allergic contact dermatitis mice. This work highlights the role of the fruits of E. globulus as a source of bioactive plant with immunosuppressive activity.

N-Phenylpropenoyl-l-amino acids (NPAs) are inducible nitric oxide synthase (iNOS) inhibitors possessing preventive effects for Parkinson's disease (PD). Here, structural modifications for improving the iNOS inhibitory activity and blood-brain barrier (BBB) permeability of NPAs were conducted, leading to 20 optimized NPA derivatives (1-20). Compound 18, with the most potent activity (IC50 = 74 nM), high BBB permeability (Pe = 19.1 × 10-6 cm/s), and high selectivity over other NOS isoforms, was selected as the lead compound. Further studies demonstrated that 18 directly binds to iNOS. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced acute PD model, the oral administration of 18 (1 and 2 mg/kg) exerted preventive effects by alleviating the loss of dopaminergic (DAergic) neurons. Notably, in the MPTP-/probenecid-induced chronic PD model, the same dose of 18 also displayed a therapeutic effect by repairing the damaged DAergic neurons. Finally, good pharmacokinetic properties and low toxicity made 18 a promising candidate for the treatment of PD.

Amentoflavone, a biflavonoid occurring in many edible supplements, possesses some bioactivities, including antioxidant, anti-inflammation, antitumor, and neuroprotective activities. In the present study, an ultrahigh-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS) method, combined with a three-step analytical strategy, was employed to identify metabolites in vivo (rat plasma, bile, urine, and feces) and in vitro (rat liver microsomes and rat intestine microsomes). A total of 39 metabolites in rats and nine metabolites in rat microsomes were elucidated by UHPLC-Q-TOF-MS/MS analysis, and the chemical structure of some isomers was further assigned by calculated Clog P values. Oxidation, internal hydrolysis, hydrogenation, methylation, sulfation, glucuronidation, glucosylation, O-aminomethylation, and degradation were the major metabolic pathways of amentoflavone. Noteworthy, O-aminomethylation and glucosylation could be considered as unique metabolic pathways of amentoflavone. This was the first report on metabolite identification of amentoflavone in vivo and in vitro, and the metabolic findings offer novel and valuable evidence for an in-depth understanding of the safety and efficacy of amentoflavone.

Ischemic stroke is one of the leading causes of death and disability worldwide. The severe sequelae caused by ischemic thrombolysis and the narrow time window are now the main clinical challenges. Our previous study has reported 4-Trifluoromethyl-(E)-cinnamoyl]-L-4-F-phenylalanine Acid (AE-18) was a promising candidate for Parkinson's Disease. In this study, the preventive and therapeutic effects of AE-18 on focal cerebral ischemia-reperfusion injury and the mechanisms are explored. In oxygen glucose deprivation/reoxygenation (OGD/R)-induced well-differentiated PC12 cells model, AE-18 (10 or 20 μM) can significantly reduce nerve damage when administered before or after molding. In middle cerebral artery occlusion-reperfusion (MCAO/R) rat model, pre-modelling, or post-modelling administration of AE-18 (5 or 10 mg/kg) was effective in reducing neurological damage, decreasing infarct volume and improving motor disturbances. In addition, AE-18 (5 mg/kg) given by intravenous injection immediately after occlusion significantly reduce the infarct volume caused by reperfusion for different durations, indicating that AE-18 could extend the time window of thrombolytic therapy. Further studies demonstrate that AE-18 exerts the effects in the prevention, treatment, and prolongation of the time window of cerebral ischemic injury mainly through inhibiting excitotoxicity and improving BBB permeability, VEGF and BDNF. These results suggest that AE-18 is a good candidate for the treatment of ischemic stroke.

A series of clovamide analogues, namely, 1a–13a and 1b–13b, was synthesized and evaluated for their anti-neuroinflammatory activities using BV-2 microglia cells. Among these compounds, six (1b, 4b–8b) showed NO inhibition with no or weak cytotoxicity (CC50 > 100 μM), especially 4b, and showed an IC50 value of 2.67 μM. Enzyme activity and docking assay revealed that the six compounds, especially 4b, target inducible NO synthase (iNOS) and exhibit potent inhibitory effects on iNOS with IC50 values ranging from 1.01 μM to 29.23 μM 4b significantly suppressed the expression of pro-inflammatory cytokines in lipopolysaccharide-stimulated cells. Notably, the oral administration of 4b remarkably improved dyskinesia, reduced the expression of glial fibrillary acidic protein (GFAP)-a marker of neuroinflammation, and increased tyrosine hydroxylase-positive cells in 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine-induced Parkinson's disease (PD) mouse models. These observations demonstrated that 4b is an effective and promising candidate for PD therapy.

Previous studies reported that long-term nociceptive stimulation could result in neurovascular coupling (NVC) dysfunction in brain, but these studies were based mainly on unimodal imaging biomarkers, thus could not comprehensively reflect NVC dysfunction. We investigated the potential NVC dysfunction in chronic migraine by exploring the relationship between neuronal activity and cerebral perfusion maps. The Pearson correlation coefficients between these 2 maps were defined as the NVC biomarkers. NVC biomarkers in migraineurs were significantly lower in left inferior parietal gyrus (IPG), left superior marginal gyrus (SMG) and left angular gyrus (AG), but significantly higher in right superior occipital gyrus (SOG), right superior parietal gyrus (SPG), and precuneus. These brain regions were located mainly in parietal or occipital lobes and were related to visual or sensory information processing. ALFF-CBF in right SPG was positively correlated with disease history and that in right precuneus was negatively correlated with migraine persisting time. fALFF-CBF in left SMG and AG were negatively related to headache frequency and positively related to health condition and disease history. In conclusion, multi-modal MRI could be used to detect NVC dysfunction in chronic migraine patients, which is a new method to assess the impact of chronic pain on the brain.