Small molecule deoxynyboquinone triggers alkylation and ubiquitination of Keap1 at Cys489 on Kelch domain for Nrf2 activation and inflammatory therapy.

Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by Kelch-like ECH-associated protein 1 (Keap1) alkylation plays a central role in anti-inflammatory therapy. However, activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified. Deoxynyboquinone (DNQ) is a natural small molecule discovered from marine actinomycetes. The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1. DNQ exhibited significant anti-inflammatory properties both in vitro and in vivo. The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α, ß-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine. DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway. Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation. The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry. DNQ triggered the ubiquitination and subsequent degradation of Keap1 by alkylation of the cysteine residue 489 (Cys489) on Keap1-Kelch domain, ultimately enabling the activation of Nrf2. Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α, ß-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain, suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

Cu(ii)/SPDO complex catalyzed asymmetric Baeyer-Villiger oxidation of 2-arylcyclobutanones and its application for the total synthesis of eupomatilones 5 and 6.

A novel classical kinetic resolution of 2-aryl-substituted or 2,3-disubstituted cyclobutanones of Baeyer-Villiger oxidation catalyzed by a Cu(ii)/SPDO complex is reported for the first time, producing normal lactones in excellent enantioselectivities (up to 96% ee) and regioselectivities (up to >20/1), along with unreacted ketones in excellent enantioselectivities (up to 99% ee). The current transformation features a wide substrate scope. Moreover, catalytic asymmetric total syntheses of natural eupomatilones 5 and 6 are achieved in nine steps from commercially available 3-methylcyclobutan-1-one.

The strategies of exercise intervention for adolescent depression: A meta-analysis of randomized controlled trials.

Purpose: This study aimed to investigate the effect of exercise intervention, and analyze exercise intervention strategies for adolescent depression through a meta-analysis of RCTs. Methods: Accordance to PRISMA guidelines, PubMed, Medline, EBSCO, Web of Science, SPORTDiscus, PsycINFO, ProQuest, and CNKI were searched for eligible records. Peer-reviewed studies were included if they met the following criteria: population (mean age of 10-18 years), intervention (physical activity, sport, or exercise), and outcomes (depression, adherence, ITT, dropout, adverse events, follow-up report). The protocol of this systematic review was registered in PROSPERO (CRD42022321683). Effect sizes calculations and methodological quality of exercise intervention (TESTEX scale) were carried out. The certainty of evidence was assessed by GRADE framework. Results: Thirteen randomized controlled trials were eligible for this review, which comprised a total of 433 adolescents. Compared with the control treatment, the effect of exercise on adolescent depression was moderate (SMD = -0.65, 95%CI: -1.03 to -0.27, p < 0.01). Heterogeneity was substantial (T 2 = 0.30, I 2 = 67%, p < 0.01). The moderating effect analysis showed that exercise intervention characteristics (organization form, exercise frequency, exercise intensity, exercise type, and single exercise session duration) of included studies varied greatly revealing multiple factors that may impact the antidepressant effect of exercise on adolescent depression (I 2 > 50%, p < 0.05). Three studies show that the positive effect of exercise on reducing depression in adolescents remained 40 weeks after the intervention. Moreover, owing to the included studies contained methodological limitations, the certainty of evidence was reduced to moderate level. Conclusion: This study shows that exercise intervention has a moderate and sustained positive effect on adolescent depression. Our results recommended that adolescents with depression undertake moderate to high intensity group mixed exercise for more than 12 weeks, 20 to 60 min/time, more than 3 times/week. Additionally, our study also shows that the antidepressant effects remained for a long time after the end of exercise interventions. However, following the GRADE framework, we rated the certainty of evidence the primary meta-analysis as moderate evidence due to some limitations of included studies. Therefore, rigorous studies are still needed to verify the results. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=321683], identifier [CRD42022321683].

Copper-Nitrene-Catalyzed Desymmetric Oxaziridination/1,2-Alkyl Rearrangement of 1,3-Diketones toward Bicyclic Lactams.

Although copper-nitrene has been extensively studied as a versatile active species in various transformations, asymmetric reactions involving copper-nitrene have been limited to the aziridination of olefins. Herein, we report the novel copper-nitrene-catalyzed desymmetric oxaziridination reaction of cyclic diketones with alkyl azides and the subsequent rearrangement of the resulting highly active intermediate, which produces a synthetically challenging chiral bicyclic lactam containing a quaternary carbon center. This procedure not only enriches the copper-nitrene-catalyzed asymmetric reactions, but also provides an alternative strategy to address the inherent challenges of catalytic asymmetric Schmidt reactions. This unique reaction could inspire the investigation of novel copper-nitrene-catalyzed asymmetric transformations and their reaction mechanisms.

Rapid determination and continuous monitoring of propofol in microliter whole blood sample during anesthesia by paper spray ionization-mass spectrometry.

Propofol is a widely used intravenous anesthetic agent in sedation and general anesthesia. To improve the safety and maintain the depth of anesthesia, it is important to develop a rapid, sensitive, and reliable method to monitor the concentration of propofol in blood during anesthesia continuously. Here, we present a novel strategy based on paper spray ionization-mass spectrometry (PSI-MS) to detect propofol. Samples (in 10 µL) were mixed with methanol as protein precipitation solvent and 2,6-dimethylphenol as internal standard. Protein micro-precipitation was achieved with methanol by vortexing and centrifuging for 5 s each, and propofol was extracted to the supernatant. PSI-MS was performed in negative ionization mode, and MS signal lasted for 1 min. The analysis of a single sample was completed within 2 min. The area ratios of propofol to internal standard were calculated for quantification. Limit of detection of 5.5 ng mL-1 and limit of quantification of 18.2 ng mL-1 were achieved for propofol in whole blood. Calibration curve was linear in the range of 0.02-10 µg mL-1. The developed method was used successfully in monitoring the propofol concentration in 3 patients' whole blood during anesthesia, showing its further application in controlling and feeding-back target concentration infusion. Graphical abstract.

Catalytic Asymmetric Total Syntheses of (-)-Galanthamine and (-)-Lycoramine.

The catalytic asymmetric total syntheses of the biologically important and therapeutically valuable Amaryllidaceae alkaloids (-)-galanthamine and (-)-lycoramine have been divergently achieved from commercially available 3-butyn-1-ol. A newly developed spirocyclic pyrrolidine (SPD)-catalyzed enantioselective Robinson annulation rapidly constructs the key cis-hydrodibenzofuran core, which bears an all-carbon quaternary stereocenter of the target molecules with an excellent stereoselective control. Additionally, the current asymmetric synthetic strategy provides an alternative approach toward the syntheses of (-)-galanthamine and its analogues.

Enantioselective synthesis of cis-hydrobenzofurans bearing all-carbon quaternary stereocenters and application to total synthesis of (‒)-morphine.

(‒)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (‒)-morphine remains a long-standing challenge. Here, we disclose an efficient enantioselective total synthesis of (‒)-morphine in a longest linear sequence of 16 steps. The key transformation features a highly enantioselective Robinson annulation enabled by our spiro-pyrrolidine catalyst to rapidly construct the densely functionalized cis-hydrodibenzofuran framework containing vicinal stereocenters with an all-carbon quaternary center. This asymmetric approach provides an alternative strategy for the synthesis of (‒)-morphine and its analogues.

Pseudonocardia antitumoralis sp. nov., a deoxynyboquinone-producing actinomycete isolated from a deep-sea sediment.

An aerobic actinomycete, designated SCSIO 01299(T), was isolated from a deep-sea sediment collected from the northern South China Sea at a depth of 3258 m. The isolate was found to be a natural producer of the synthesized antitumour agent deoxynyboquinone and its three new derivatives, pseudonocardians A, B and C. A blast search based on almost-complete 16S rRNA gene sequences showed that strain SCSIO 01299(T) had high sequence similarities with members of the genus Pseudonocardia. The 16S rRNA gene sequence phylogenetic tree revealed that strain SCSIO 01299(T) was a member of the genus Pseudonocardia. Phenotypic analysis, chemotaxonomy and DNA-DNA relatedness could readily distinguish the isolate from established members in this genus. It was concluded that strain SCSIO 01299(T) represents a novel species, for which the name Pseudonocardia antitumoralis sp. nov. is proposed. The type strain is SCSIO 01299(T) ( = DSM 45322(T)  = CCTCC M 2011255(T)).

[Characteristics of soil microelements contents in the rhizospheres of different vegetation in hilly-gully region of Loess Plateau].

To explore the rhizosphere effect of the microelements in the soils under different vegetation types in Loess Plateau, this paper analyzed the organic C, total N, Mn, Cu, Fe, and Zn contents in the rhizosphere soil and bulk soil of six vegetation types in hilly-gully region of Loess Plateau. Among the six vegetation types, Caragana korshinskii, Heteropappus altaicus, and Artemisia capillaries had higher organic C and total N contents in rhizosphere soil than in bulk soil. With the exception of C. korshinskii and H. rhamnoides, all the six vegetation types had a significantly lower pH in rhizosphere soil than in bulk soil. The six vegetation types had a lower available Mn content in rhizosphere soil than in bulk soil, and the C. korshinskii, Astragalus adsurgen, and Panicum virgatum had a significantly higher available Cu content in rhizosphere soil than in bulk soil. The six vegetation types except A. adsurgens had a slightly higher available Fe content in rhizosphere soil than in bulk soil, and A. adsurgens, P. virgatum, H. altaicus, and A. capillaries had a significant accumulation of available Zn in rhizosphere soil. There existed significant positive correlations between the rhizosphere soil and bulk soil of the six vegetation types in the relationships between the organic C and total N contents and the available Mn and Zn contents and between the contents of available Mn and Zn. In rhizosphere soil, available Mn and Zn contents were significantly negative- ly correlated with pH value. Due to the differences in root growth characteristics, rhizosphere pH value, and microbial structure composition, the microelements contents in the rhizosphere soil of the six vegetation types differed, with the contents of Mn, Cu, Fe, and Zn being higher in the rhizosphere soil of H. altaicus than in that of the other vegetation types.