A Network-Based Approach to Investigate the Neuroprotective Effects and Mechanisms of Action of Huangqi-Chuanxiong and Sanleng-Ezhu Herb Pairs in the Treatment of Cerebral Ischemic Stroke.

Objective: We aimed to investigate the effect and mechanisms of action of two drug pairs [Huangqi-Chuanxiong and Sanleng-Ezhu Herb (HCSE)] on the treatment of ischemic stroke. Materials and methods: We mined the current literature related to ischemic stroke and formulated a new formulation of Chinese herbs. Then, we identified the main candidate target genes of the new formulation by network pharmacology. Next, we performed enrichment analysis of the target genes to identify the potential mechanism of action of the new formulation in the treatment of ischemic stroke. Next, we experimentally validated the mechanism of action of the new formulation against ischemic stroke. Infarct volume and neurological deficits were evaluated by 2,3,5-triphenyltetrazolium (TTC) staining and Longa's score, respectively. The predicted pathways of signal-related proteins were detected by western blotting. Results: We mined the current literature and identified a new formulation of Chinese herbs for the treatment of ischemic stroke. The formulation included Huangqi, Chuanxiong, Sanleng and Ezhu. Next, we used network pharmacological analysis to identify 23 active compounds and 327 target genes for the new formulation. The key target genes were MAPK3, MAPK1, HSP90AA1, STAT3, PIK3R1, PIK3CA and AKT1. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed significant enrichment of the PI3K/AKT and MAPK/ERK signaling pathways. By performing experiments, we found that the new formulation reduced the infarct volume of middle cerebral artery occlusion (MCAO) induced mice and activated the PI3K/AKT and MAPK/ERK signaling pathways. These findings confirmed that the new formulation has a significant protective effect against ischemic stroke injury by activating the PI3K/AKT and MAPK/ERK signaling pathways. Conclusion: We identified a new treatment formulation for ischemic stroke by data mining and network pharmacological target prediction. The beneficial effects of the new formulation act by regulating multiple target genes and pathways. The mechanism of action of the new formulation may be related to the AKT and ERK signaling pathways. Our findings provide a theoretical basis for the effects of the new formulation on ischemic stroke injury.

γ-Difluoroalkylation: Synthesis of γ-Difluoroalkyl-α,ß-Unsaturated Esters via Photoredox NHC-Catalyzed Radical Reaction.

By the cooperative photoredox and N-heterocyclic carbene catalysis, the γ-difluoroalkylation of γ-preoxidized enals was developed for the synthesis of γ-difluoroalkyl-α,ß-unsaturated esters with all-carbon quaternary centers. This method provides efficient catalytic C(sp3)-CF2R bond formation at the γ-position of carbonyl compounds for the first time.

N-Heterocyclic carbene/photo-cocatalyzed oxidative Smiles rearrangement: synthesis of aryl salicylates from O-aryl salicylaldehydes.

The N-heterocyclic carbene/photo-cocatalyzed oxidative Smiles rearrangement of O-aryl salicylaldehydes was developed. Both electron-deficient and electron-rich aryls worked well as migrating groups, giving the corresponding aryl salicylates in good yields. This reaction features formation of two new C-O bonds and one C-O bond cleavage via metal-free oxidation of the Breslow intermediate using oxygen as the terminal oxidant and following the Smiles rearrangement under photocatalysis.

Visible-Light-Driven N-Heterocyclic Carbene Catalyzed γ- and ϵ-Alkylation with Alkyl Radicals.

The merging of photoredox catalysis and N-heterocyclic carbene (NHC) catalysis for γ- and ϵ-alkylation of enals with alkyl radicals was developed. The alkylation reaction of γ-oxidized enals with alkyl halides worked well for the synthesis γ-multisubstituted-α,ß-unsaturated esters, including those with challenging vicinal all-carbon quaternary centers. The synthesis of ϵ-multisubstituted-α,ß-γ,δ-diunsaturated esters by an unprecedented NHC-catalyzed ϵ-functionalization was also established.

Visible-Light-Promoted Oxo-difluoroalkylation of Alkenes with DMSO as the Oxidant.

Visible-light-promoted oxo-difluoroalkylation (acetylation and acetamidation) of alkenes with dimethyl sulfoxide as both the solvent and the oxidant was developed, affording the corresponding α,α-difluoro-γ-ketoacetates and acetamides in modest yields. Both terminal and internal alkenes worked well for the reaction. This reaction features simple starting materials, a green oxidant, mild reaction conditions, and highly functional products.

DBU-Mediated Construction of 1,3,5-Trisubstituted Benzenes via Annulation of α,ß-Unsaturated Carboxylic Acids and α-Cyano-ß-methylenones.

A DBU-mediated synthesis of 1,3,5-trisubstituted benzenes was developed via the [2 + 4] annulation of in situ activated α,ß-unsaturated carboxylic acids and α-cyano-ß-methylenones. The dual role of DBU as Brønsted base and nucleophilic Lewis base is the key for the success of the reaction.

Switchable Decarboxylative Heck-Type Reaction and Oxo-alkylation of Styrenes with N-Hydroxyphthalimide Esters under Photocatalysis.

The switchable visible-light-mediated decarboxylative Heck-type reaction and oxo-alkylation reaction of N-hydroxyphthalimide esters under photocatalysis were developed. Disubstituted or trisubstituted alkenes were obtained in good yield with high E-selectivity in the presence of Brønsted acid as the additive, while ketones resulted in the absence of the acidic additive.