Artemisinin inhibits neuronal ferroptosis in Alzheimer's disease models by targeting KEAP1.

Ferroptosis, a form of cell death characterized by lipid peroxidation, is involved in neurodegenerative diseases such as Alzheimer´s disease (AD). Recent studies have shown that a first-line antimalarial drug artemisinin is effective to counteract AD pathology. In this study, we investigated the protective effect of artemisinin against neuronal ferroptosis and the underlying mechanisms. In hippocampal HT22 cells, pretreatment with artemisinin dose-dependently protected against Erastin-induced cell death with an EC50 value of 5.032 µM, comparable to the ferroptosis inhibitor ferrostatin-1 (EC50 = 4.39 µM). We demonstrated that artemisinin (10 µM) significantly increased the nuclear translocation of Nrf2 and upregulated SLC7A11 and GPX4 in HT22 cells. Knockdown of Nrf2, SLC7A11 or GPX4 prevented the protective action of artemisinin, indicating that its anti-ferroptosis effect is mediated by the Nrf2-SLC7A11-GPX4 pathway. Molecular docking and Co-Immunoprecipitation (Co-IP) analysis revealed that artemisinin competitively binds with KEAP1, promoting the dissociation of KEAP1-Nrf2 complex and inhibiting the ubiquitination of Nrf2. Intrahippocampal injection of imidazole-ketone-Erastin (IKE) induced ferroptosis in mice accompanied by cognitive deficits evidenced by lower preference for exploration of new objects and new object locations in the NOR and NOL tests. Artemisinin (5, 10 mg/kg, i.p.) dose-dependently inhibited IKE-induced ferroptosis in hippocampal CA1 region and ameliorated learning and memory impairments. Moreover, we demonstrated that artemisinin reversed Aß1-42-induced ferroptosis, lipid peroxidation and glutathione depletion in HT22 cells, primary hippocampal neurons, and 3×Tg mice via the KEAP1-Nrf2 pathway. Our results demonstrate that artemisinin is a novel neuronal ferroptosis inhibitor that targets KEAP1 to activate the Nrf2-SLC7A11-GPX4 pathway.

Synthesis of a C2-Symmetric Chiral Borinic Acid and Its Application in Catalytic Desymmetrization of 2,2-Disubstituted-1,3-Propanediols.

Notwithstanding the common use of boronic acids in catalysis, the design and synthesis of efficient chiral boronic acids remains a formidable challenge. Herein we disclose a rational design and a concise synthesis of a series of novel C2-symmetric disubstituted boronic acids, or borinic acids. Chiral borinic acids have been found to be excellent agents that can achieve highly enantioselective desymmetrization of 2,2-disubstituted-1,3-propanediols, providing chiral diols with a quaternary stereocenter, which has been regarded in recent years as challenging. A wide range of substrates are tolerated in this reaction, providing a series of chiral diols with high enantioselectivity. The presence of the tetracoordinate borinate in the catalytic cycle has been proven by 11B NMR studies, and a stereocontrol model has been proposed.

Planar Chiral Multiple Resonance Thermally Activated Delayed Fluorescence Materials for Efficient Circularly Polarized Electroluminescence.

Chiral boron/nitrogen doped multiple resonance thermally activated delayed fluorescence (MR-TADF) emitters are promising for highly efficient and color-pure circularly polarized organic light-emitting diodes (CP-OLEDs). Herein, we report two pairs of MR-TADF materials (Czp-tBuCzB, Czp-POAB) based on planar chiral paracyclophane with photoluminescence quantum yields of up to 98 %. The enantiomers showed symmetric circularly polarized photoluminescence spectra with dissymmetry factors |gPL | of up to 1.6×10-3 in doped films. Meanwhile, the sky-blue CP-OLEDs with (R/S)-Czp-tBuCzB showed an external quantum efficiency of 32.1 % with the narrowest full-width at half-maximum of 24 nm among the reported CP-OLEDs, while the devices with (R/S)-Czp-POAB displayed the first nearly pure green CP electroluminescence with |gEL | factors at the 10-3 level. These results demonstrate the incorporation of planar chirality into MR-TADF emitter is a reliable strategy for constructing of efficient CP-OLEDs.

Enantioselective Construction of Tertiary α-Alkyl Fluoride via BTM-Catalyzed Fluorination of α-Alkynyl-Substituted Acetic Acids.

The isothiourea-catalyzed enantioselective construction of tertiary α-fluoro stereogenic centers has been demonstrated by using branched alkynyl-substituted acetic acids as starting materials, providing a broad range of optically active tertiary α-alkyl fluorides in high enantioselectivity (up to 97% ee). Furthermore, this methodology was proven to be scaled up to a Gram scale without loss of enantioselectivity.

Computational Design of Enhanced Enantioselectivity in Chiral Phosphoric Acid-Catalyzed Oxidative Desymmetrization of 1,3-Diol Acetals.

A general method for the highly enantioselective desymmetrization of 2-alkyl-substituted 1,3-diols is presented. A combination of computational and experimental studies has been utilized to understand the origin of the stereocontrol of oxidative desymmetrization of 1,3-diol benzylideneacetals. DFT calculations demonstrate that the acetal protecting group is highly influential for high enantioselectivity, and a simple but effective new protecting group has been designed. The desymmetrization reactions proceed with high enantioselectivity for a variety of substrates. Moreover, the reaction conditions are also shown to be effective for desymmetrization of 2,2-dialkyl-substituted 1,3-diols, which provides chiral products bearing acyclic all-carbon quaternary stereocenters. The method has been applied to the formal synthesis of indoline alkaloids.

Advances in asymmetric visible-light photocatalysis, 2015-2019.

Asymmetric visible-light photocatalysis has recently drawn considerable attention of the scientific community owing to its unique activation modes and significance for the enantioselective green synthesis. In this review, the recent advances in the visible-light-triggered enantioselective synthesis, classified by different catalytic strategies, are summarized. The progress achieved in this area inspires us to develop new strategies, including the combination of photocatalysis with other catalytic modes and the design and synthesis of multifunctional chiral photocatalysts, in an attempt to incorporate chirality into the photo-mediated chemical transformations.

Chiral-Organotin-Catalyzed Kinetic Resolution of Vicinal Amino Alcohols.

A highly efficient kinetic resolution of racemic amino alcohols has been achieved for the first time with a chiral tin catalyst. A chiral organotin compound with 3,4,5-trifluorophenyl groups at the 3,3'-positions of the binaphthyl framework enabled this transformation with excellent yield and high enantioselectivity. The process tolerates aryl- and alkyl-substituted amino alcohols and a variety of other substrates, affording the corresponding products in high enantioselectivity and with s factors up to >500.

Mild arylboronic acid catalyzed selective [4 + 3] cycloadditions: access to cyclohepta[b]benzofurans and cyclohepta[b]indoles.

The first example of arylboronic acid catalyzed [4 + 3] cycloaddition reaction is reported. 3,5-Bis-(trifluoromethyl) phenylboronic acid is shown to be the best catalyst in this reaction. The method has also enabled the preparation of cyclohepta[b]benzofurans and cyclohepta[b]indoles in excellent yields.

Chiral phosphoric acid catalyzed highly enantioselective desymmetrization of 2-substituted and 2,2-disubstituted 1,3-diols via oxidative cleavage of benzylidene acetals.

A highly enantioselective catalytic protocol for the desymmetrization of a wide variety of 2-substituted and 2,2-disubstituted 1,3-diols is reported. This reaction proceeds through the formation of an "ortho ester" intermediate via oxidation of 1,3-diol benzylidene acetal by dimethyldioxirane (DMDO) and the subsequent proton transfer catalyzed by chiral phosphoric acid (CPA). The mechanism and origins of enantioselectivity of this reaction are identified using DFT calculations. The oxidation by DMDO is rate-determining, and the phosphoric acid significantly accelerates the proton transfer; the attractive interactions between the benzylidene part of the substrate and the 2,4,6-triisopropyl group of CPA are the key to high enantioselectivity.

Highly enantioselective synthesis of bisoxindoles with two vicinal quaternary stereocenters via Lewis base mediated addition of oxindoles to isatin-derived ketimines.

A highly efficient asymmetric organocatalytic addition of 3-substituted oxindole to isatin-derived ketimine is reported with excellent stereocontrol (>99 : 1 dr, >99% ee) under mild conditions. This method provides access to the bisoxindole structure moiety with two vicinal quaternary stereogenic centers.

[Protective effect of rutin against oxidative injury in neuronal cells].

OBJECTIVE: To observe the protective effect of rutin (RUT) on neuronal cells against sodium nitroprusside (SNP) induced neurotoxicity. METHODS: PC12 cells were treated with different concentration of SNP for 24 h and MTT assay was applied to analyze the survival rate; PC12 cells were pretreated with rutin for 1 h, and then incubated for 24 h with SNP. MTT assay, morphological observation, as well as immunofluorescence were performed to evaluate both the SNP neurotoxicity and the protective effects of RUT, Western blot was used to analyzed the level of phosphorylated extra cellular regulated protein kinases (ERK1/2) after treatment with RUT, the results were also testified in primary cultured neurons. RESULTS: Results from MTT assay showed that SNP caused cell death in a concentration-dependent manner in PC12 cells. The effect of SNP was observed at 200 - 1 000 micromol/L and was significant at 800 micromol/L. 25 micromol/L rutin partly blocked the neurotoxicity of SNP by preventing PC12 cells from apoptosis. Hoechst and PI staining indicated that SNP treatment decreased the number of viable cells and induced shrinkage and aggregation of the nucleus, whereas RUT pretreatment attenuated the toxic effects of SNP, after treatment with RUT in PC12 cells, the phosphorylation of ERK1/2 was increased and peaked at 20 min. Most importantly, the protective effect of RUT on PC12 cells was confirmed on cultured neurons. CONCLUSION: RUT possesses protective effect against neuronal apoptosis induced by SNP and this effect may be partially related with ERK1/2 signaling.

[Protective effect and mechanisms of dihydromyricetin on PC12 cells induced by oxidative injury].

OBJECTIVE: To study the protective effect and possible mechanisms of Dihydromyricetin(DMY)on PC12 cells injury in- duced by sodium nitroprusside( SNP). METHODS: SNP toxicity cellular model was established using PC12 cells treated with SNP. Cell via- bility was determined by MTT assay. The apoptosis of treated cells was detected by Hoechst Staining. Effect of DMY on accumulation of ROS in PC12 cells induced by SNP was detected by fluorometric analysis. The pathways involved were studied by kinase specific inhibi- tors; The level of phosphorylated Akt and ERK1/2 was detected by Western blot with specific phosphor-antibodies. RESULTS: SNP in- duced the apoptosis of PC12 cells in a dose-dependent manner. DMY dose-dependently protected PC12 cells from injury induced by SNP. Hoechst staining indicated that SNP decreased the number of viable cells and induced shrinkage and aggregation of the nucleus, whereas DMY attenuiated the toxic effects of SNP. The level of ROS induced by SNP in PC12 cells was decreased gradually by DMY. PI3K specific inhibitor LY294002 and the MAPK pathway specific inhibitor PD98059 attenuated the protective effect of DMY on SNP-induced injury of PC12 cells. However, the effect of DMY could be blocked by LY294002 and PD98059 respectively. CONCLUSION: DMY possesses protective effect against apoptosis induced by SNP in PC12 cells,and its mechanisms may be partially related with Akt and ERK1/2 signaling.

Synthesis of Chiral Biphenyl Monophosphines as Ligands in Enantioselective Suzuki-Miyaura Coupling.

Herein, we describe our design and synthesis of novel chiral monophosphine ligands by the short-step addition of chiral lactates as side chains to the well-known ligand SPhos/RuPhos. The new chiral ligands were shown to be highly efficient in palladium-catalyzed Suzuki-Miyaura coupling, providing a series of axially chiral biphenyl products in high yield and high enantioselectivity. Furthermore, the gram-scale reaction and the diverse conversions of the products demonstrated the potential utility of the approach.

Mechanism and Molecular Targets of a Water-Soluble Extract of Artemisia annua on the Treatment of Alzheimer's Disease Based on Network Pharmacology and Experimental Validation.

Oxidative stress is an important contributor to the pathogenesis of Alzheimer's disease (AD). The overproduction of reactive oxygen species observed in AD patients results in the loss of mitochondrial function, altered metal ion homeostasis, lipopolysaccharide metabolism disorder, reduced anti-oxidant defense, increased release of inflammatory factors, and the aggravation and accumulation of amyloid-beta and tau hyper-phosphorylation, which directly cause synaptic and neuronal loss and lead to cognitive dysfunction. Thus, oxidative stress proves to be a fundamental part of AD development and progression, suggesting the potential benefits of anti-oxidant-based therapies for AD. In this study, we found that a water-soluble extract of Artemisia annua (WSEAA), a traditional Chinese herbal medicine, has a strong anti-oxidant function. We also found that WSEAA is able to improve the cognitive function of 3xTg AD mice. However, the mechanisms and molecular targets underlying WSEAA action are still not known. In order to uncover the potential molecular mechanisms involved, we used a combination of network pharmacology and different experimental approaches. Obtained results revealed key genes (such as AKT1, BCL2, IL-6, TNF-[Formula: see text] and BAX) and signaling pathways (like PI3K-AKT and BCL2/BAX) are closely associated with the biological processes responding to oxidative stress. Further verification of the survival/anti-oxidant effects of WSEAA in vitro and in vivo showed that the extract has anti-oxidatant/neuronal survival action against H2O2-induced damage, and is thus able to prevent the cognitive decline and pathological changes of 3xTg transgenic (3xTg) mice via the regulation of key target-genes and pathways, such as PI3K-AKT and BCL2/BAX, related to survival/apoptosis. Our findings strongly indicate the potential of WSEAA for the prevention and treatment of AD.

Induced Red Circularly Polarized Luminescence Emission Promoted by Intermolecular Förster Resonance Energy Transfer through a Cholesteric Liquid Crystal Medium.

In this paper, planar chiral helicenes based on [2.2]paracyclophane PCPH5 acted as both chiral inducers and energy donors to construct the circularly polarized luminescence (CPL)-active ternary cholesteric liquid crystals (T-N*-LCs) in a commercial nematic liquid crystal (SLC1717, N-LCs) medium. Induced red CPL emission based on the energy acceptor of the achiral polymer DTBTF8 could be successfully promoted by the intermolecular Förster resonance energy transfer mechanism. The resulting T-N*-LCs can generate intensive CPL signals with glum up to +0.70/-0.67. Interestingly, this kind of "on-off" CPL switching of T-N*-LCs can be manipulated by the applied direct current electric field.

Activation of phospholipase-Cγ and protein kinase C signal pathways helps the survival of spinal motoneurons injured by root avulsion.

The signaling transduction processes involved in avulsion-induced motoneuron (MN) death have not been elucidated. Using the brachial plexus root avulsion rat model, we showed that avulsion-activated phosphorylation of phospholipase-Cγ (PLCγ) and protein kinase C (PKC) occurred in injured spinal MNs within 72 h of injury. Moreover, some MNs positive for PLCγ and PKC are also positive for avulsion-induced neuronal nitric oxide synthase (nNOS). Inhibition of PLCγ/PKC signal pathway, either with PLCγ inhibitor, 1-[6-((17ß-3-methoxyestra-1,3,5(10)-trien-17-yl) amino)hexyl]-1H-pyrrole-2,5-dione, or with PLCγ siRNA augmented avulsion-induced MN death. 1-[6-((17ß-3-methoxyestra-1,3,5(10)-trien-17-yl) amino)hexyl]-1H-pyrrole-2,5-dione also inhibited PKC phosphorylation and exacerbated avulsion-induced reductions in the nNOS protein level in injured spinal segments. Moreover, activation of PLCγ/PKC signal pathway with PKC activator, phorbol-12-myristate-13-acetate, decreased avulsion-induced MN death. The temporal profile of PLCγ/PKC signaling appears to be crucial for the survival of spinal MNs after root avulsion. Our data suggest that PLCγ mediates, while PKC and nNOS are associated with, the avulsion-induced MN death in brachial plexus root avulsion.

A highly enantioselective approach towards optically active γ-amino alcohols by tin-catalyzed kinetic resolution of 1,3-amino alcohols.

A highly enantioselective kinetic resolution of racemic 1,3-amino alcohols via O-Acylation was achieved using a chiral organotin as the catalyst. Alkyl- and aryl-substituted 1,3-amino alcohols were resolved with excellent efficiencies to afford the recovered 1,3-amino alcohols and acylative products with high enantioselectivities, with s factors up to >600. Notably, the chiral organotin catalyst was more selective for anti-1,3-amino alcohols than for syn-isomers. A Gram-scale reaction with loading using 2 mol% catalysts demonstrated the utility of this protocol.

Kinetic Resolution of Tertiary Alcohols by Chiral Organotin-Catalyzed O-Acylation.

A novel highly enantioselective method for the kinetic resolution of racemic tertiary alcohols has been achieved through chiral organotin-catalyzed intermolecular acylation of the hydroxyl group. This process has demonstrated a broad substrate scope (both alkyl- and aryl-substituted tertiary alcohols) with high enantioselectivity under mild reaction conditions, affording the corresponding products and the recovered tertiary alcohols with high enantioselectivities, with s factors up to >200.

Inverted Circularly Polarized Luminescence Behavior Induced by Helical Nanofibers through Chiral Co-Assembly from Achiral Liquid Crystal Polymers and Chiral Inducers.

Chiral supramolecular assembly can provide a powerful strategy for developing circularly polarized luminescence (CPL)-active materials by forming helices or superhelices into single or multiple components. Herein, we chose three achiral liquid crystal polymers (LC-P1/P2/P3) and chiral binaphthyl-based inducers (R/S-M) with anchored dihedral angles to construct chiral co-assemblies and explore the induced CPL behavior from pyrenyl (Py) emitters in achiral LC polymers through the regulation of helical nanofibers during the supramolecular co-assembly process. Most interestingly, chiral co-assembly (R/S-M)0.1-(P3)0.9 emitted an inverted blue-colored CPL signal during thermal annealing treatment at the glass transition temperature due to the flexible main chain of the LC polymer (LC-P3). The strongest blue-colored CPL emission for the (R/S-M)0.1-(P3)0.9 spin-coated film (λem = 455 nm, |gem| = 6.47 × 10-2, ΦF = 48.5%) could be detected by using thermal annealing treatment at 105 °C.

Synthesis and Chiroptical Properties of Planar Chiral Azahelicenes Based on [2.2]Paracyclophane.

Three pairs of planar chiral heteroarenes were synthesized using palladium-catalyzed Buchwald-Hartwig coupling and hypervalent iodine-mediated oxidative cyclization from optically pure 4-amino[2.2]paracyclophane. Among them, an enantiomer of planar chiral azahelicene was found to have circularly polarized luminescence activity that was remarkably stronger than that of planar chiral heteroarenes.