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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.

Celastrol, a friedelane-type triterpenoid isolated from the genus Triperygium, possesses antitumor, anti-inflammatory, and immunosuppressive activities. A total of 42 celastrol derivatives (1a–1t, ...

Glycosylated hemoglobin A1c (HbA1c) has been considered as a key contributor to impaired cognition in type 2 diabetes mellitus (T2DM) brains. However, how does it affect the brain and whether the glucose controlling can slow down the process are still unknown. In the current study, T2DM patients with high glycosylated hemoglobin level (HGL) and controls with normal glycosylated hemoglobin level (NGL) were enrolled to investigate the relationships between HbA1c, brain imaging characteristics and cognitive function. First, a series of cognitive tests including California Verbal Learning Test (CVLT) were conducted. Then, the functional irregularity based on resting state functional magnetic resonance imaging data was evaluated via a new data-driven brain entropy (BEN) mapping analysis method. We found that the HGLs exhibited significantly increased BEN in the right precentral gyrus (PreCG.R), the right middle frontal gyrus (MFG.R), the triangular and opercular parts of the right inferior frontal gyrus (IFGtriang.R and IFGoperc.R). The strengths of the functional connections of PreCG.R with the brainstem/cerebellum were decreased. Partial correlation analysis showed that HbA1c had a strong positive correlation to regional BEN and negatively correlated with some CVLT scores. Negative correlations also existed between the BEN of PreCG.R/IFGoperc.R and some CVLT scores, suggesting the correspondence between higher HbA1c, increased BEN and decreased verbal memory function. This study demonstrated the potential of BEN in exploring the functional alterations affected by HbA1c and interpreting the verbal memory function decline. It will help understanding the neurophysiological mechanism of T2DM-induced cognitive decline and taking effective prevention or treatment measures.

Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a-2d, 3a-3g, and 4a-4t, were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50 = 1.9 μM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 μM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.

Purpose The diagnosis of prostate transition zone cancer (PTZC) remains a clinical challenge due to their similarity to benign prostatic hyperplasia (BPH) on MRI. The Deep Convolutional Neural Networks (DCNNs) showed high efficacy in diagnosing PTZC on medical imaging but was limited by the small data size. A transfer learning (TL) method was combined with deep learning to overcome this challenge. Materials and methods A retrospective investigation was conducted on 217 patients enrolled from our hospital database (208 patients) and The Cancer Imaging Archive (nine patients). Using T2-weighted images (T2WIs) and apparent diffusion coefficient (ADC) maps, DCNN models were trained and compared between different TL databases (ImageNet vs. disease-related images) and protocols (from scratch, fine-tuning, or transductive transferring). Results PTZC and BPH can be classified through traditional DCNN. The efficacy of TL from natural images was limited but improved by transferring knowledge from the disease-related images. Furthermore, transductive TL from disease-related images had comparable efficacy to the fine-tuning method. Limitations include retrospective design and a relatively small sample size. Conclusion Deep TL from disease-related images is a powerful tool for an automated PTZC diagnostic system. In developing regions where only conventional MR scans are available, the accurate diagnosis of PTZC can be achieved via transductive deep TL from disease-related images.

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.

Glycogen synthase kinase-3β (GSK-3β) is a key enzyme in hyperphosphorylation of tau proteins and is a promising therapeutic target in Alzheimer’s disease (AD). Here, we reported, for the first time, that the stereoisomers of Schisandrin B (Sch B), (+)-1, (−)-1, (+)-2, and (−)-2, were potent GSK-3β inhibitors. They were demonstrated to selectively target GSK-3β in an orthosteric binding mode, with IC50 values of 340, 290, 80, and 70 nM, respectively. Further study showed that these stereoisomers can significantly increase the expression of p-GSK-3β (Ser9) and decrease the expressions of p-GSK-3β (Tyr216) and p-GSK-3β (Tyr279). Finally, these compounds can alleviate the cell injury induced by Aβ, and the cognitive disorders in AD mice, especially (+)-2 and (−)-2. Collectively, the stereoisomers of Sch B, especially (+)-2 and (−)-2, were found to be potential selective ATP-competitive GSK-3β inhibitors, which further affected their anti-AD effects. These promising findings explained the biological target of ...

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.

Abrus pulchellus subsp. mollis (Hance) Verdc. (Leguminosae) is a well-known edible plant usually added to soups and beverages. In this study, vicenin-2 (1), isoschaftoside (2), schaftoside (3), and their enrichment fraction, total flavonoid C-glycosides, derived from the extracts of A. mollis, were firstly found to prevent nonalcoholic fatty liver disease both in vitro and in vivo. In the in vitro study, total flavonoid C-glycosides decreased the lipid accumulation in oleic acid-treated HepG2 cells. The mechanisms of total flavonoid C-glycosides are involved in the regulation of peroxisome proliferator-activated receptor α and its downstream, and the reduction of proinflammatory cytokines. In high-fat diet-induced fatty liver rats, total flavonoid C-glycosides decreased the levels of glutamic-oxalacetic transaminease and glutamic-pyruvic transaminase, and decreased the lipid accumulation both in the liver and blood without affecting food intake. In addition, total flavonoid C-glycosides also increased the activities of the antioxidant enzyme system in vivo. In conclusion, total flavonoid C-glycosides are active components of A. mollis on nonalcoholic fatty liver disease, and can be used in functional food and supplements for nonalcoholic fatty liver disease prevention and treatment.

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.

Background Blue light can directly penetrate the lens and reach the retina to induce retinal damage, causing dry age-related macular degeneration (dAMD). Cynaroside (Cyn), a flavonoid glycoside, was proved to alleviate the oxidative damage of retinal cells in vitro. However, whether or not Cyn also exerts protective effect on blue light-induced retinal degeneration and its mechanisms of action are unclear. Purpose This study aims to evaluate the protective effects of Cyn against blue-light induced retinal degeneration and its underlying mechanisms in vitro and in vivo. Study design/methods Blue light-induced N-retinylidene-N-retinylethanolamine (A2E)-laden adult retinal pigment epithelial-19 (ARPE-19) cell damage and retinal damage in SD rats were respectively used to evaluate the protective effects of Cyn on retinal degeneration in vitro and in vivo. MTT assay and AnnexinV-PI double staining assay were used to evaluate the in vitro efficacy. Histological analysis, TUNEL assay, and fundus imaging were conducted to evaluate the in vivo efficacy. ELISA assay, western blot, and immunostaining were performed to investigate the mechanisms of action of Cyn. Results Cyn decreased the blue light-induced A2E-laden ARPE-19 cell damage and oxidative stress. Intravitreal injection of Cyn (2, 4 μg/eye) reversed the retinal degeneration induced by blue light in SD rats. Furthermore, Cyn inhibited the nuclear translocation of NF-κB and induced autophagy, which led to the clearance of overactivated pyrin domain containing 3 (NLRP3) inflammasome in vitro and in vivo. Conclusion Cyn protects against blue light-induced retinal degeneration by modulating autophagy and decreasing the NLRP3 inflammasome.

Five new phloroglucinol derivatives, eucalyptins C-G (1-5), together with 13 known analogues (6-18) were isolated from the fruits of Eucalyptus globulus. The structures and absolute configurations of 1-5 were established by means of spectroscopic data analysis, computational calculation methods, and single-crystal X-ray diffraction. Compounds 1-18 were investigated for their immunosuppressive effects in vitro, and 1, 2, 6, and 7 displayed moderate inhibitory activities with IC50 values of 11.8, 10.2, 18.2, and 19.1 μM, respectively. The stimulation index (SI) of 1 was 64.2 and was compared to that of cyclosporine A (SI = 149.57). Further study demonstrated that 1 exhibited an immunosuppressive effect through inducing apoptosis and inhibiting cytokine secretion.

Cynaroside is a flavonoid compound proved to possess antioxidant activity, but its protective effect on age-related macular degeneration still remains unclear. In this study, the protective effects of cynaroside on oxidative stress and apoptosis in retinal pigment epithelial (RPE) cells induced by hydrogen peroxide (H2 O2 ) were investigated. Results showed that cynaroside effectively attenuated the decrease of cell activity induced by H2 O2 . The total reactive oxygen species can be remitted by decreasing malondialdehyde level, as well as increasing glutathione level, and superoxide dismutase and catalase activities. In addition, Western blot analysis indicated that cynaroside protected ARPE-19 cells from apoptosis through downregulation of caspase-3 protein activation which was controlled by the upstream proteins Bcl-2 and Bax. It was finally proved that cynaroside could enhance the antioxidant and antiapoptotic ability in ARPE-19 cells by promoting the expression of p-Akt.

• In this study, seven clovamide analogues (1–7) were designed and synthesized, and the neuroprotection of 1–7 as well as 8–15 (prepared in our previous work) against H2O2-induced oxidative stress was evaluated in SH-SY5Y cells. Results showed that 1–7 with catechol groups exhibited better neuroprotective effects than 8–15, and their EC50 values ranged from 4.26 to 23.83 μM, especially 1, indicating that the moiety of catechol governed the activities of these compounds. Furthermore, oral administration of 1 (10 or 20 mg/kg) was demonstrated to possess anti-PD effect through alleviating apoptosis and oxidative stress in vitro and in vivo, and to up-regulate the expression of heme oxygenase-1 (HO-1) via PI3K/AKT/mTOR pathway. Finally, the pharmacokinetic (PK) assessment of 1 was determined in rats. These findings suggested that 1 might be an effective candidate for PD therapy.

Background Nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme in the repair of DNA and is a promising target in the development of chemosensitizers. This study first investigated the inhibitory effects of amentoflavone (AMF) and its derivatives on PARP-1 and the potentiation of AMF on carboplatin (CBP) in non-small cell lung cancer (NSCLC). Purpose This study aims to evaluate the inhibitory effect of AMF against PARP-1 and its potentiation on CBP in lung cancer both in vitro and in vivo. Study design The inhibitory effect of AMF on PARP-1 was investigated using molecular docking and cell-free model of PARP-1 assay. Its potentiation on CBP in lung cancer was also evaluated. Methods Fluorescence resonance energy transfer assay was used to detect the inhibitory effects of AMF and its analogues on PARP-1. Molecular docking was employed to predict the binding mode of AMF and PARP-1. MTT assay, isobologram analysis, Hoechst staining, and Annexin V-PI double staining were used to confirm the potentiation of AMF on CBP in vitro. siRNA (PARP-1)-A549 cells were used to reveal the action target of AMF. Western blot analysis, immunohistochemistry, and Tunnel assay were employed to evaluate the potentiation of AMF on CBP in A549 xenograft mice. Results AMF and its analogues exerted excellent inhibitory effects on PARP-1 with IC50 values ranging from 0.198 μM to 0.409 μM. Docking experiment showed that AMF can stably bind to PARP-1 with a comparable binding energy to olaparib. AMF can decrease the expression of PAR induced by H2O2 in vitro. AMF synergistically increased the CBP anti-proliferative effect in A549. However, its potentiation nearly disappeared when the cells were transfected with siRNAs against PARP-1. Oral administration of AMF (100 mg/kg), combined with CBP, remarkably inhibited A549 tumor growth and ki67 expression, and increased apoptosis compared with CBP-alone group. Conclusion All results suggest that AMF can be a potential PARP-1 inhibitor and a candidate adjuvant agent to boost the anticancer effect of CBP in NSCLC.

kV distribution network topology is complex, along the lines there are many connected power distribution transformer and branch lines, and the lines are mostly hybrid cases. Its channel transmission characteristics are complex and variable, which has caused great difficulties to the high rate NB-PLC technology frequency selection. Based on urban 10 kV distribution network topology, it emphatically analyzes the changes in the channel transmission characteristics from the carrier source to the receiving point in hybrid cases and influence rules of the length of main trunk line, the length and number of branch line and the location and quantity of distribution transformer on the channel transmission characteristics, which provide reference basis for the modulation mode and frequency selection of high rate NB-PLC technology.