Anchoring of Fe-MIL-101-NH2 to the Polymer Membrane Matrix through the Hinsberg Reaction to Promote Conductivity of SPEEK Membranes.

SCPEEK@MOF proton exchange membranes, where SCPEEK is sulfinyl chloride polyether ether ketone and MOF is a metal-organic framework, were prepared by doping Fe-MIL-101-NH2 into polymers. The amino group in the MOF and the -SOCl2 group in thionyl chloride polyether ether ketone cross-link to form a covalent bond through the Hinsberg reaction, and the prepared composite membrane has stronger stability than other electrostatic interactions and simple physical doping composite membranes. The formation of covalent bonds improves the water absorption of the composite membrane, which makes it easy for water molecules to form hydrogen bonds. Moreover, SPEEK as a proton conductive polymer and the synergy of MOFs improve the proton conductivity of composite membranes. The composite membranes were characterized by Fourier transform infrared spectroscopy, powder X-ray diffraction, scanning electron microscopy, and atomic force microscopy. The swelling rate, water absorption, mechanical stability, ion exchange capacity, and proton conductivity of the pure sulfonated polyether ether ketone (SPEEK) membrane were compared with those of the mechanically doped SPEEK/MOF membrane and the composite membrane SCPEEK@MOF doped with different ratios of Fe-MIL-101-NH2, and all of the SCPEEK@MOF showed superior performance. When the Fe-MIL-101-NH2 loading rate of the composite membrane is 2%, the proton conductivity of the composite membrane can reach 0.202 S cm-1 at 363 K and a 98% relative humidity, which is much higher than that of the SPEEK/MOF membrane obtained by simple physical doping under the same conditions.

Identification of lignans as ATP citrate lyase (ACLY) inhibitors from the roots of Pouzolzia zeylanica.

A new lignan, named pouzolignan P (1), together with 14 known ones (2 - 15) were isolated from the roots of Pouzolzia zeylanica (L.) Benn. Their structures were deduced based on the detailed spectroscopic analysis. All the isolates were evaluated for their inhibitory activities toward the ATP citrate lyase (ACLY). Among them, four lignans, isopouzolignan K (3), gnemontanins E (5), gnetuhainin I (6), and styraxlignolide D (15) showed excellent ACLY inhibitory effect with IC50 values of 9.06, 0.59, 2.63, and 7.62 µM, respectively. These compounds were further evaluated for their cholesterol-lowing effects on ox-LDL-induced high-cholesterol HepG2 cells. Compound 15 emerges as the most potent ACLY inhibitor, which significantly decreased the TC level in a dose-dependent manner. In addition, molecular docking simulations elucidated that 15 formed a strong hydrogen-bond interaction with Glu599 of ACLY, which was an important site responsible for the enzyme catalytic activity.

Silica Nanoparticle Size Determines the Mechanisms Underlying the Inhibition of Iron Oxide Nanoparticle Uptake by Daphnia magna.

Aquatic environments are complicated systems that contain different types of nanoparticles (NPs). Nevertheless, recent studies of NP toxicity, and especially those that have focused on bioaccumulation have mostly investigated only a single type of NPs. Assessments of the environmental risks of NPs that do not consider co-exposure regimes may lead to inaccurate conclusions and ineffective environmental regulation. Thus, the present study examined the effects of differently sized silica NPs (SiO2 NPs) on the uptake of iron oxide NPs (Fe2O3 NPs) by the zooplankton Daphnia magna. Both SiO2 NPs and Fe2O3 NPs were well dispersed in the experimental medium without significant heteroaggregation. Although all three sizes of SiO2 NPs inhibited the uptake of Fe2O3 NPs, the underlying mechanisms differed. SiO2 NPs smaller than the average mesh size (∼200 nm) of the filtering apparatus of D. magna reduced the accumulation of Fe2O3 NPs through uptake competition, whereas larger SiO2 NPs inhibited the uptake of Fe2O3 NPs mainly by reducing the water filtration rate of the daphnids. Overall, in evaluations of the risks of NPs in the natural environment, the different mechanisms underlying the effects of NPs of different sizes on the uptake of dissimilar NPs should be considered.

Persistent Halogenated Organic Pollutants in Deep-Water-Deposited Particulates from South China Sea.

POP data are limited in the marine environment; thus, this study aimed to investigate background persistent organic pollutant (POP) levels in oceanic deep-water-deposited particulates in the South China Sea (SCS). Six POPs, including polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs), dioxin-like polychlorinated biphenyls (DL-PCBs), polybrominated diphenyl ethers (PBDEs), polybrominated dibenzo-p-dioxins/dibenzofurans (PBDD/Fs), polychlorinated diphenyl ethers (PCDEs), and polybrominated biphenyls (PBBs), were investigated in eight pooled samples from the SCS from 20 September 2013 to 23 March 2014 and 15 April 2014 to 24 October 2014 at depths of 2000 m and 3500 m. PBDEs were the most predominant compounds, with the highest mean Σ14PBDE of 125 ± 114 ng/g dry weight (d.w.), followed by Σ17PCDD/F, Σ12PBDD/F, and Σ12DL-PCB (275 ± 1930, 253 ± 216, and 116 ± 166 pg/g d.w., respectively). Most PBDD/F, PBB, and PCDE congeners were below the detection limits. PCDDs had the highest toxic equivalency (TEQ), followed by PBDDs and DL-PCBs. Among the six POPs, PBDEs were the major components of the marine-deposited particles, regarding both concentrations and mass fluxes. Compared to 3500 m, PBDE levels were higher at a depth of 2000 m. PBDE mass fluxes were 20.9 and 14.2 ng/m2/day or 68.2 and 75.9 ng/m2/year at deep-water 2000 and 3500 m, respectively. This study first investigated POP levels in oceanic deep-water-deposited particles from existing global data.

Design and synthesis of oridonin derivatives as cytotoxic agents.

Oridonin is one of the ent-kaurane diterpenes that have been studied extensively for various bioactivities. In an effort to expand natural scaffold-based library as anticancer agents, we have designed and synthesised a number of novel oridonin derivatives and evaluated their bioactivities on a panel of human cancer cell lines (HCT116, A375, MCF-7, HepG2, and A549). Compound 4b bearing a 4-fluorophenyl moiety was found to be the most active compound with an IC50 value of 0.3 µM against MCF-7 cells, which was 7.4-fold more active than oridonin. This study could provide some insightful information for further synthesis of oridonin derivatives as anticancer agents.

Silica nanoparticle accumulation in plants: current state and future perspectives.

With their excellent biocompatibility, adjustable size, and high specific surface area, silica nanoparticles (SiO2 NPs) offer an alternative to traditional bulk fertilizers as a means to promote sustainable agriculture. SiO2 NPs have been shown to promote the growth of plants and to reduce the negative effects of biotic and abiotic stresses, but their bioaccumulation is a crucial factor that has been overlooked in studies of their biological effects. In this review, the techniques to quantify and visualize SiO2 NPs in plants were examined first. We then provide a summary of the current state of knowledge on the accumulation, translocation, and transformation of SiO2 NPs in plants and of the factors (e.g., the physicochemical properties of SiO2 NPs, plant species, application mode, and environmental conditions) that influence SiO2 NP bioaccumulation. The challenges in analyzing NP-plant interactions are considered as well. We conclude by identifying areas for further research that will advance our understanding of NP-plant interactions and thus contribute to more sustainable, eco-friendly, nano-enabled approaches to improving crop nutrient supplies. The information presented herein is important to improve the delivery efficiency of SiO2 NPs for precision and sustainable agriculture and to assess the safety of SiO2 NPs during their application in agriculture.

Isolation and Anticancer Progression Evaluation of the Chemical Constituents from Bridelia balansae Tutcher.

The dichloromethane extract of the roots of Bridelia balansae Tutcher (Phyllanthaceae) was found to show potential anticancer activity against HCT116 colorectal cancer cell. Our bioassay-guided phytochemical investigation of the roots of B. balansae led to the identification of 14 compounds including seven lignans (1-7), three phenylbenzene derivatives (8-10), two flavanone (11-12), and two triterpenoids (13-14). Among them, 4'-demethyl-4-deoxypodophyllotoxin (1) is the first aryltetralin lignan compound identified from this plant species. In addition, the stereochemistry of 1 was validated by X-ray crystallography for the first time, and its distinguished cytotoxic effect on HCT116 cells with an IC50 value at 20 nM was induced via an apoptosis induction mechanism. Compound 1 could also significantly decrease the migration rate of HCT116 cells, indicating its potential application against cancer metastasis. The western blot analysis showed that 1 has the potential to inhibit cell proliferation and metastasis. Treatment of 1 resulted in the downregulation of matrix metalloproteinases 2 (MMP2) and p-Akt, while p21 was upregulated. Collectively, the present study on the phytochemical and biological profile of B. balansae has determined the plant as a useful source to produce promising anticancer lead compounds.

Accumulation of nanoplastics in human cells as visualized and quantified by hyperspectral imaging with enhanced dark-field microscopy.

Nanoplastic (NP) pollution is receiving increasing attention regarding its potential effects on human health. The identification and quantification of intracellular NPs are prerequisites for an accurate risk assessment, but appropriate methods are lacking. Here we present a label-free technique to simultaneously visualize and quantify the bioaccumulation of NPs based on hyperspectral imaging with enhanced dark-field microscopy (HSI-DFM). Using polystyrene NPs (PS NPs) as representative particles, the construction of a hyperspectral library was optimized first with more accurate NP identification achieved when the library was based on intracellular instead of extracellular PS NPs. The PS NPs used herein were labeled with a green fluorescent dye so that the accuracy of HSI-DFM in identifying and quantifying intracellular NPs can be evaluated, by comparing the results with those obtained by fluorescence microscopy and flow cytometry. The validation of HSI-DFM for use in determinations of the NP concentration at the single-cell level allows analyses of the accumulation kinetics of NPs in single living cells. The utility of HSI-DFM in different cell lines and with NPs differing in their chemical composition was also demonstrated. HSI-DFM therefore provides a new approach to studies of the accumulation and distribution of NPs in human cells.

Identification and bioactivity evaluation of miliusanes from Miliusa sinensis.

Miliusanes are a class of anticancer lead molecules belonging to meroterpenoids with an 18-carbon skeleton isolated from Miliusa plants. A phytochemical study of the plant M. sinensis was carried out to discover new miliusanes with diverse structural features in order to better understand their structure-activity relationship. As a result, 20 compounds including 12 new ones (7-14 and 17-20) belonging to two sub-classes of miliusanes were isolated and identified from the twigs and leaves of this plant. Their structures, including absolute configurations, were determined by spectroscopic analyses and electronic circular dichroism. The absolute stereochemistry of miliusane structures has also been confirmed for the first time through the single crystal X-ray diffraction analysis of miliusol (1). Bioactivity evaluation showed that some of the miliusane isolates potently inhibit cell growth of several human derived cancer cell lines with IC50 values ranging from 0.52 to 23.5 µM. Compound 11 demonstrated more potent cytotoxic activity than the known miliusol (1) in stomach cancer cells though its structure contains an unconjugated 1, 4-diketone system, which added a new structure-activity feature to miliusanes. The preliminary mechanism of action studies revealed that they could be a class of dual cell migration inhibitor and senescence inducer.

Dihydro-Resveratrol Attenuates Oxidative Stress, Adipogenesis and Insulin Resistance in In Vitro Models and High-Fat Diet-Induced Mouse Model via AMPK Activation.

Management of obesity has become a prevalent strategy for preventing the diseases closely integrated with excess body weight such as diabetes over the last half century. Searching for therapeutic agents acting on oxidative stress, adipogenesis and insulin resistance is considered as an efficient approach to control obesity-related diseases. The present study was designed to examine the in vitro and in vivo effects of dihydro-resveratrol (DR2), a naturally occurring compound from Dendrobium medicinal plants, on oxidative stress aggravation, adipogenesis, lipogenesis and insulin sensitivity. We utilized an in vitro 3T3-L1 adipocyte differentiation model to show that DR2 could reduce pre-adipocyte maturation by activation of AMPK/SIRT1 signaling proteins to inhibit p38MAPK proteins. With the use of in vitro oxidative-stress-induced hepatocytes and myoblasts models, DR2 was also shown to be able to reduce oxidative stress aggravation through mediation of Nrf2-related antioxidative cascade, reduce intracellular lipid accumulation through phosphorylation of ACC protein, reduce lipid peroxidation in hepatocytes and promote insulin sensitivity via activation of AKT protein in the insulin-resistant HepG2 cells and C2C12 cells. The effects of DR2 on adipogenesis, lipid accumulation, insulin resistance and blood glucose clearance were further demonstrated in the high-fat diet-induced obesity mouse model. Our in vitro and in vivo studies determined that DR2 could contain therapeutic potential for the treatment of obesity and type 2 diabetes.

Identification of an Arylnaphthalene Lignan Derivative as an Inhibitor against Dengue Virus Serotypes 1 to 4 (DENV-1 to -4) Using a Newly Developed DENV-3 Infectious Clone and Replicon.

Dengue virus (DENV) is the most widespread arbovirus, causing symptoms ranging from dengue fever to severe dengue, including hemorrhagic fever and shock syndrome. Four serotypes of DENV (DENV-1 to -4) can infect humans; however, no anti-DENV drug is available. To facilitate the study of antivirals and viral pathogenesis, here we developed an infectious clone and a subgenomic replicon of DENV-3 strains for anti-DENV drug discovery by screening a synthetic compound library. The viral cDNA was amplified from a serum sample from a DENV-3-infected individual during the 2019 epidemic; however, fragments containing the prM-E-partial NS1 region could not be cloned until a DENV-3 consensus sequence with 19 synonymous substitutions was introduced to reduce putative Escherichia coli promoter activity. Transfection of the resulting cDNA clone, plasmid DV3syn, released an infectious virus titer of 2.2 × 102 focus-forming units (FFU)/mL. Through serial passages, four adaptive mutations (4M) were identified, and addition of 4M generated recombinant DV3syn_4M, which produced viral titers ranging from 1.5 × 104 to 6.7 × 104 FFU/mL and remained genetically stable in transformant bacteria. Additionally, we constructed a DENV-3 subgenomic replicon and screened an arylnaphthalene lignan library, from which C169-P1 was identified as exhibiting inhibitory effects on viral replicon. A time-of-drug addition assay revealed that C169-P1 also impeded the internalization process of cell entry. Furthermore, we demonstrated that C169-P1 inhibited the infectivity of DV3syn_4M, as well as DENV-1, DENV-2, and DENV-4, in a dose-dependent manner. This study provides an infectious clone and a replicon for the study of DENV-3 and a candidate compound for future development against DENV-1 to -4 infections. IMPORTANCE Dengue virus (DENV) is the most prevalent mosquito-transmitted virus, and there is no an anti-dengue drug. Reverse genetic systems representative of different serotype viruses are invaluable tools for the study of viral pathogenesis and antiviral drugs. Here, we developed an efficient infectious clone of a clinical DENV-3 genotype III isolate. We successfully overcame the instability of flavivirus genome-length cDNA in transformant bacteria, an unsolved issue for construction of cDNA clones of flaviviruses, and adapted this clone to efficiently produce infectious viruses following plasmid transfection of cell culture. Moreover, we constructed a DENV-3 subgenomic replicon and screened a compound library. An arylnaphthalene lignan, C169-P1, was identified as an inhibitor of virus replication and cell entry. Finally, we demonstrated that C169-P1 exhibited a broad-spectrum antiviral effect against the infections with DENV-1 to -4. The reverse genetic systems and the compound candidate described here facilitate the study of DENV and related RNA viruses.

Natural Compounds Targeting the Autophagy Pathway in the Treatment of Colorectal Cancer.

Autophagy is a highly conserved intracellular degradation pathway by which misfolded proteins or damaged organelles are delivered in a double-membrane vacuolar vesicle and finally degraded by lysosomes. The risk of colorectal cancer (CRC) is high, and there is growing evidence that autophagy plays a critical role in regulating the initiation and metastasis of CRC; however, whether autophagy promotes or suppresses tumor progression is still controversial. Many natural compounds have been reported to exert anticancer effects or enhance current clinical therapies by modulating autophagy. Here, we discuss recent advancements in the molecular mechanisms of autophagy in regulating CRC. We also highlight the research on natural compounds that are particularly promising autophagy modulators for CRC treatment with clinical evidence. Overall, this review illustrates the importance of autophagy in CRC and provides perspectives for these natural autophagy regulators as new therapeutic candidates for CRC drug development.

Bioactive icetexane and abietane diterpenes from Isodon phyllopodus.

A new icetexane diterpenoid, 11, 12, 20α-trihydroxyl-7ß-methoxyicetexa-8, 11, 13-triene-19, 10-lactone [Phyllane A (1)], and a new abietane diterpenoid, 7ß, 20-epoxy-3ß, 17-acetoxy-abieta-8, 11, 13-teriene-11, 12-diol [phyllane B (2)], along with two known compounds (3 and 4) were isolated from the methanol (MeOH) extract of twigs and leaves of the folk medicinal Isodon phyllopodus. Their structures were determined by spectroscopic analyses including 2 D NMR spectral data, and further confirmed by X-ray single crystal diffraction. Moreover, the compounds were evaluated for their cytotoxicity and anti-HIV activities, and phyllane A showed anti-HIV activity with an IC50 value of 15.7 µM, but phyllane B was found to be cytotoxic to the A549 host cells with a CC50 value of 108.5 µM.

Investigation of Factors Influencing the Fear of Cancer Recurrence in Breast Cancer Patients Using Structural Equation Modeling: A Cross-Sectional Study.

Objective: This study aimed to investigate the fear of cancer recurrence (FCR) in breast cancer patients and develop a structural equation model of influencing factors to help formulate clinical intervention strategies. Methods: A convenience sample of 325 patients was surveyed using a general and disease-related data questionnaire, which combined the Fear of Progression Questionnaire-Short Form, Mishel Uncertainty in Illness Scale, Perceived Social Support Scale, and Medical Coping Modes Questionnaire. Results: The total score of FCR in breast cancer patients was 35.06 ± 10.83, and 53.8% of patients reached the clinical level. The structural equation model demonstrated that illness uncertainty had a direct positive impact on FCR (ß = 0.275, p < 0.05), and it could have an indirect impact through social support and resignation coping methods (ß = 0.254, p < 0.05). Conclusion: The fear of cancer recurrence in breast cancer patients needs further understanding. Medical staff can reduce or buffer FCR in breast cancer patients by strengthening positive influences, such as social support, or weakening negative influences, such as illness uncertainty and resignation coping.

Bromo-protopine, a novel protopine derivative, alleviates tau pathology by activating chaperone-mediated autophagy for Alzheimer's disease therapy.

Emerging evidence from Alzheimer's disease (AD) patients suggests that reducing tau pathology can restore cognitive and memory loss. To reduce tau pathology, it is critical to find brain-permeable tau-degrading small molecules that are safe and effective. HDAC6 inhibition has long been considered a safe and effective therapy for tau pathology. Recently, we identified protopine as a dibenzazecine alkaloid with anti-HDAC6 and anti-AD activities. In this study, we synthesized and tested novel protopine derivatives for their pharmacological action against AD. Among them, bromo-protopine (PRO-Br) demonstrated a two-fold increase in anti-HDAC6 activity and improved anti-tau activities compared to the parent compound in both in vitro and in vivo AD models. Furthermore, molecular docking results showed that PRO-Br binds to HDAC6, with a ∆G value of -8.4 kcal/mol and an IC50 value of 1.51 µM. In neuronal cell lines, PRO-Br reduced pathological tau by inducing chaperone-mediated autophagy (CMA). In 3xTg-AD and P301S tau mice models, PRO-Br specifically decreased the pathogenic hyperphosphorylated tau clumps and led to the restoration of memory functions. In addition, PRO-Br treatment promoted the clearance of pathogenic tau by enhancing the expression of molecular chaperones (HSC70) and lysosomal markers (LAMP2A) via CMA in AD models. Our data strongly suggest that administration of the brain-permeable protopine derivative PRO-Br, could be a viable anti-tau therapeutic strategy for AD.

Inflammation-targeted nanomedicine against brain cancer: From design strategies to future developments.

Brain cancer is an aggressive type of cancer with poor prognosis. While the immune system protects against cancer in the early stages, the tumor exploits the healing arm of inflammatory reactions to accelerate its growth and spread. Various immune cells penetrate the developing tumor region, establishing a pro-inflammatory tumor milieu. Additionally, tumor cells may release chemokines and cytokines to attract immune cells and promote cancer growth. Inflammation and its associated mechanisms in the progression of cancer have been extensively studied in the majority of solid tumors, especially brain tumors. However, treatment of the malignant brain cancer is hindered by several obstacles, such as the blood-brain barrier, transportation inside the brain interstitium, inflammatory mediators that promote tumor growth and invasiveness, complications in administering therapies to tumor cells specifically, the highly invasive nature of gliomas, and the resistance to drugs. To resolve these obstacles, nanomedicine could be a potential strategy that has facilitated advancements in diagnosing and treating brain cancer. Due to the numerous benefits provided by their small size and other features, nanoparticles have been a prominent focus of research in the drug-delivery field. The purpose of this article is to discuss the role of inflammatory mediators and signaling pathways in brain cancer as well as the recent advances in understanding the nano-carrier approaches for enhancing drug delivery to the brain in the treatment of brain cancer.

3,4-Seco-Isopimarane Diterpenes from the Twigs and Leaves of Isodon Flavidus.

Three isopimarane diterpenes [fladins B (1), C (2), and D (3)] were isolated from the twigs and leaves of Chinese folk medicine, Isodon flavidus. The chemical structures were determined by the analysis of the comprehensive spectroscopic data, and the absolute configuration was confirmed by X-ray crystallographic analysis. The structures of 1-3 were formed from isopimaranes through the rearrangement of ring A by the bond break at C-3 and C-4 to form a new δ-lactone ring system between C-3 and C-9. This structure type represents the first discovery of a natural isopimarane diterpene with an unusual lactone moiety at C-9 and C-10. In the crystal of 1, molecules are linked to each other by intermolecular O-H···O bonds, forming chains along the b axis. Compounds 1-3 were evaluated for their bioactivities against different diseases. None of these compounds displayed cytotoxic activities against HCT116 and A549 cancer cell lines, antifungal activities against Trichophyton rubrum and T. mentagrophytes, or antiviral activities against HIV entry at 20 µg/mL (62.9-66.7) µM. Compounds 1 and 3 did not show antiviral activities against Ebola entry at 20 µg/mL either; only 2 was found to show an 81% inhibitory effect against Ebola entry activity at 20 µg/mL (66.7 µM). The bioactivity evidence suggested that this type of compound could be a valuable antiviral lead for further structure modification to improve the antiviral potential.

Exploring the role of senescence inducers and senotherapeutics as targets for anticancer natural products.

During the last few decades, cancer has remained one of the deadliest diseases that endanger human health, emphasizing urgent drug discovery. Cellular senescence has gained a great deal of attention in recent years because of its link to the development of cancer therapy. Senescent cells are incapable of proliferating due to irreversibly inhibition of the initiation of the cell cycle pathways. However, senescent cells aggregate in tissues and produce a pro-inflammatory secretome called senescence-associated secretory phenotype (SASP) that can cause serious harmful effects if not managed properly. There is mounting evidence that senescent cells lead to various phases of tumorigenesis in various anatomical sites, owing mostly to the paracrine activities of the SASP. Therefore, a new treatment field called senotherapeutics has been established. Senotherapeutics are newly developed anticancer agents that have been demonstrated to inhibit cancer efficiently. In light of recent findings, several promising natural products have been identified as senescence inducers and senotherapeutics, including, miliusanes, epigallocatechin gallate, phloretin, silybin, resveratrol, genistein, sulforaphane, quercetin, allicin, fisetin, piperlongumine, berberine, triptolide, tocotrienols and curcumin analogs. Some of them have already been validated through preclinical trials and exert an enormous potential for clinical trials. This review article focuses on and summarizes the latest advances made on cellular senescence and its potential as a target for cancer treatment and highlights the well-known natural products as senescence inducers and senotherapeutics for cancer treatment.

Ebola Entry Inhibitors Discovered from Maesa perlarius.

Ebola virus disease (EVD), a disease caused by infection with Ebola virus (EBOV), is characterized by hemorrhagic fever and a high case fatality rate. With limited options for the treatment of EVD, anti-Ebola viral therapeutics need to be urgently developed. In this study, over 500 extracts of medicinal plants collected in the Lingnan region were tested against infection with Ebola-virus-pseudotyped particles (EBOVpp), leading to the discovery of Maesa perlarius as an anti-EBOV plant lead. The methanol extract (MPBE) of the stems of this plant showed an inhibitory effect against EBOVpp, with an IC50 value of 0.52 µg/mL, which was confirmed by testing the extract against infectious EBOV in a biosafety level 4 laboratory. The bioassay-guided fractionation of MPBE resulted in three proanthocyanidins (procyanidin B2 (1), procyanidin C1 (2), and epicatechin-(4ß→8)-epicatechin-(4ß→8)-epicatechin-(4ß→8)-epicatechin (3)), along with two flavan-3-ols ((+)-catechin (4) and (-)-epicatechin (5)). The IC50 values of the compounds against pseudovirion-bearing EBOV-GP ranged from 0.83 to 36.0 µM, with 1 as the most potent inhibitor. The anti-EBOV activities of five synthetic derivatives together with six commercially available analogues, including EGCG ((-)-epigallocatechin-3-O-gallate (8)), were further investigated. Molecular docking analysis and binding affinity measurement suggested the EBOV glycoprotein could be a potential molecular target for 1 and its related compounds.

Corynoxine B derivative CB6 prevents Parkinsonian toxicity in mice by inducing PIK3C3 complex-dependent autophagy.

Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural alkaloid named corynoxine B (Cory B) as a neuronal autophagy inducer. However, its brain permeability is relatively low, which hinders its potential use in treating PD. Thus we synthesized various derivatives of Cory B to find more potent autophagy inducers with improved brain bioavailability. In this study, we evaluated the autophagy-enhancing effect of CB6 derivative and its neuroprotective action against PD in vitro and in vivo. We showed that CB6 (5-40 µM) dose-dependently accelerated autophagy flux in cultured N2a neural cells through activating the PIK3C3 complex and promoting PI3P production. In MPP+-treated PC12 cells, CB6 inhibited cell apoptosis and increased cell viability by inducing autophagy. In MPTP-induced mouse model of PD, oral administration of CB6 (10, 20 mg· kg-1· d-1, for 21 days) significantly improved motor dysfunction and prevented the loss of dopaminergic neurons in the striatum and substantia nigra pars compacta. Collectively, compound CB6 is a brain-permeable autophagy enhancer via PIK3C3 complex activation, which may help the prevention or treatment of PD.