Chiral phosphoric acid-catalyzed asymmetric epoxidation of alkenyl aza-heteroarenes using hydrogen peroxide.

The synthesis of chiral α-azaheteroaryl oxiranes via enantioselective catalysis is a formidable challenge due to the required complex stereoselectivity and diverse N-heterocyclic structures. These compounds play a crucial role in developing bioactive molecules, where precise chirality significantly influences biological activity. Here we show that using chiral phosphoric acid as a catalyst, our method efficiently addresses these challenges. This technique not only achieves high enantio- and diastereoselectivity but also demonstrates superior chemo- and stereocontrol during the epoxidation of alkenyl aza-heteroarenes. Our approach leverages a synergistic blend of electrostatic and hydrogen-bonding interactions, enabling the effective activation of both substrates and hydrogen peroxide. The resulting chiral oxiranes exhibit enhanced diversity and functionality, aiding the construction of complex chiral azaaryl compounds with contiguous stereocenters. Kinetic and density functional theory studies elucidate the mechanism, highlighting chiral phosphoric acid's pivotal role in this intricate enantioselective process.

Discovery of a First-in-Class GPR183 Antagonist for the Potential Treatment of Rheumatoid Arthritis.

GPR183 is required for humoral immune responses, and its polymorphisms have been associated with inflammatory autoimmune diseases. Despite increasing attention to GPR183 as a potential therapeutic target for autoimmune diseases, relatively few antagonists have been reported, and none of them have progressed to the clinical stage. In this study, we discovered a highly potent GPR183 antagonist, compound 32, with good aqueous solubility, excellent selectivity, and pharmacokinetic properties. Meanwhile, compound 32 showed exceptional efficacy for rheumatoid arthritis (RA) disease in a mouse collagen-induced arthritis (CIA) model, with an efficacious dose of 0.1 mg/kg. Functionally, compound 32 significantly reduced the swelling of paws and joints, the gene expression of proinflammatory cytokines, MCP-1, MMPs, and VEGF, inflammatory cell infiltration, cartilage damage, pannus formation, and bone erosion in the joints of CIA mice in a dose-dependent manner. Hence, these findings suggest compound 32 as a valuable molecule for further development.

Autoimmunity associates with severity of illness in elderly patients with drug-induced liver injury.

Background: Drug-induced liver injury (DILI) is a potentially serious adverse drug reaction. Due to the lack of definite etiology, specific clinical manifestations, and diagnostic methods, its prediction and diagnosis are challenging. Elderly individuals are deemed to be at high risk for DILI due to abnormal pharmacokinetics, aging tissue repair function, comorbidities, and taking multiple drugs. This study aimed to identify the clinical characteristics and explore the risk factors associated with the severity of illness in elderly patients with DILI. Methods: In the present study, the clinical characteristics at the time of liver biopsy of consecutive patients with biopsy-proven DILI who presented at our hospital from June 2005 to September 2022 were evaluated. Hepatic inflammation and fibrosis were assessed according to the Scheuer scoring system. The presence of autoimmunity was considered if IgG level >1.1 × ULN (1826 mg/dL), or high titer (>1:80) of ANA, or SMA. Results: In total, 441 patients were enrolled, and the median age was 63.3 years (IQR, 61.0-66.0); 122 (27.7%), 195 (44.2%), or 124 (28.1%) were classified as having minor, moderate, or severe hepatic inflammation, respectively; and 188 (42.6%), 210 (47.6%) or 43 (9.8%) patients presented minor, significant fibrosis or cirrhosis, respectively. Female sex (73.5%) and the cholestatic pattern (47.6%) were dominant in elderly DILI patients. Autoimmunity existed in 201 patients (45.6%). Comorbidities were not directly associated with the severity of DILI. PLT (OR: 0.994, 95% CI: 0.991-0.997; p < 0.001), AST (OR: 1.001, 95% CI: 1.000-1.003, p = 0.012), TBIL (OR: 1.006, 95% CI: 1.003-1.010, p < 0.001), and autoimmunity (OR: 1.831, 95% CI: 1.258-2.672, p = 0.002) were associated with the degree of hepatic inflammation. Meanwhile, PLT (OR: 0.990, 95% CI: 0.986-0.993, p < 0.001), TBIL (OR: 1.004, 95% CI: 1.000-1.007, p = 0.028), age (OR: 1.123, 95% CI: 1.067-1.183, p < 0.001), and autoimmunity (OR: 1.760, 95% CI: 1.191-2.608, p = 0.005) were associated with the stage of hepatic fibrosis. Conclusion: This study revealed that the presence of autoimmunity represents a more serious illness state of DILI, deserving more intensive monitoring and progressive treatment.

Enantioselective Conjugate Addition of Alkenyl Trifluoroborates to Alkenyl-Substituted Benzimidazoles Catalyzed by Chiral Binaphthols.

The enantioselective organocatalytic conjugate alkenylation of ß-substituted alkenyl benzimidazoles afforded ß-stereogenic 2-alkyl benzimidazole derivatives in excellent enantioselectivities. Chiral binaphthols were effective catalysts for promoting the nucleophilic addition of bench-stable alkenyl trifluoroborate salts under mild conditions, expanding their applications by utilizing C=N-containing azaarenes as activating groups. The synthetic utility of this strategy is demonstrated by conversions into several useful enantiomerically enriched benzimidazole building blocks.

Microencapsulation of blueberry anthocyanins by spray drying with soy protein isolates/high methyl pectin combination: Physicochemical properties, release behavior in vitro and storage stability.

Eleven anthocyanins in the blueberry anthocyanins powders (BAP) were identified and quantified by HPLC-DAD-ESI-MS. BAP microcapsules (MBAP) were produced by spray drying using high methyl pectin (HMP) combined with whey protein isolates (WPI) or soy protein isolates (SPI) in different proportions as wall materials. Generally, SPI/HMP combination was more efficient in increasing the encapsulation efficiency and Tg, and in decreasing the particle size and hygroscopicity of the microcapsules than WPI or HMP or WPI/HMP combination. Microcapsules created with 4% SPI + 2% HMP combination (MBAPc), possessed superior anthocyanin release behavior and antioxidant stability to those produced with 4% SPI alone (MBAPs). Both MBAPc and MBAPs had continuous release of anthocyanins throughout the simulated gastrointestinal digestion, and exhibited two first-order kinetics, but MBAPc exhibited higher stability than MBAPs and BAP, because it showed the longest half-life and the lowest anthocyanin degradation rate at 25 °C and 35 °C during 6-months' storage.

Behavioral analyses in mouse models of autism spectrum disorders.

Autism spectrum disorder is a group of genetically-related developmental disorders of the nervous system. Patients mainly present with core symptoms such as social behavior defects, repetitive stereotyped behaviors, and learning and memory disorders. The mouse models are critical for the studies of the pathogenic mechanisms and potential therapeutic strategies of autism spectrum disorder. The assessments of mouse behaviors provide understandings of the effects of different genetic manipulations as well as pathogenic mechanisms of these diseases. This article describes various mouse behavioral assays corresponding to the core symptoms of ASD patients and provides a detailed description of protocols, cautions, and data analysis for those assays, thereby helping researchers to establish their own experimental designs. In addition, behavioral phenotypes of currently known ASD mouse models are summarized to provide a reference for researchers in the field.

Kinetic Resolution of Tertiary Allylic Alcohols: Highly Enantioselective Access to Cyclic Ethers Bearing an α-Tetrasubstituted Stereocenter.

A chiral phosphoric acid-catalyzed kinetic resolution of tertiary allylic alcohols was developed to provide structurally valuable enantioenriched 2,2-disubstituted tetrahydrofurans, tetrahydropyrans, and oxepane. A variety of tertiary allylic alcohols were resolved with selectivity factors of ≤120. A tertiary allylic carbocationic intermediate mediates the enantioselective intramolecular substitution to achieve high regio- and enantioselectivity. A gram-scale reaction with low catalyst loading and subsequent transformations of the recovered alcohols and products demonstrated the utility of this method.

Organocatalytic Enantioselective Conjugate Alkynylation of ß-Aminoenones: Access to Chiral ß-Alkynyl-ß-Amino Carbonyl Derivatives.

Readily available potassium alkynyltrifluoroborates were used for organocatalytic asymmetric conjugate alkynylation of ß-enaminones. The interception of a modified binaphthol catalyst and in situ generated organodifluoroboranes proved important to access functionalized ß-alkynyl-ß-amino carbonyls and derivatives with improved chemo-reactivity and enantio-induction. Mechanistic studies revealed the impact of molecular sieves on efficiency and stereocontrol. The products undergo additional functionalization to yield a diverse set of valuable ß-alkynyl-ß-amino carbonyl scaffolds.

Effect of microwave radiation on antioxidant capacities of Tartary buckwheat sprouts.

This study aimed to investigate the effects of different microwave radiation power and treatment time on the antioxidant enzyme activities and radical scavenging potency in Tartary buckwheat sprouts. The results indicated that the optimal microwave irradiation conditions for superoxide dismutase, catalase, peroxidise and ascorbate peroxidise antioxidant enzymes was the power 300 W for 75 s, and their activities were all higher than those of the control and the ungerminated seeds. In addition, under the above microwave conditions, the total reducing power and the ability to scavenge DPPH, ABTS, O2- and •OH were also optimal. These results indicated that suitable microwave treatment could effectively improve the antioxidant enzyme activity in Tartary buckwheat sprouts and enhance the antioxidant capacity of sprouts.

Comparative study of gene expression profiles rooted in acute myocardial infarction and ischemic/reperfusion rat models.

Mining data in depth of genome-wide sequencing data generated from pathological target tissues under disease conditions is necessary for seeking novel functional genes, and developing more biological study directions for the field. Based on our previous published RNA-seq data generated from acute myocardial ischemia and ischemia-reperfusion in rat heart, we re-analysed these two data sets using bioinformatics tools. All these raw fastq files were extracted from Illumina BCL using the Illumina CASAVA program. Four groups were obtained: UD (genes up-regulated in MI but down-regulated in I/R injury), DU (genes down-regulated in MI but up-regulated in I/R injury), UU (genes both up-regulated in MI and I/R injury), and DD (genes both down-regulated in MI and I/R injury) groups. The results showed that 304 common genes in the UD group, 236 common genes in the DU group, 318 common genes in the UU group, and 159 common genes in the DD group detected by comparing data sets of the MI and the I/R injury. We then listed the top 30 DEGs for each group, and carried out GO and KEGG analyses for enrichment and pathway studies for those top expressed genes. Further analysis of INTERPRO Protein Domains and Features enriched by DEGs showed that 20% of the Domains enriched were related to c-type lectin, and 17% of these domains are related to neurotransmitter-gated ion-channel. 15% of PFAM Protein Domains were about Neurotransmitter-gated ion-channel. There were only 8 SMART Protein Domains DEGs enriched and 37.5% of which were concerned about leucine-rich. Collagen involvement in Reactome Pathways accounted for 22.7%. We found that only a few DEGs in these two disease conditions have been reported in the literatures, suggesting that there are many new genes would be considered in the future studies. These analyses would provide some information for seeking more novel targets of these two clinic diseases, acute myocardial ischemia and myocardial ischemia/reperfusion.

[Selenium Uptake Characteristics of Reclaimed Soil-Crop from Mining Wasteland and Its Antagonistic Effects on Heavy Metals].

To fully exploit selenium-rich land resources and ensure crop safety, the phenomenon of "double high" of Se and heavy metals in reclaimed soil of mining wasteland was studied. Soil and maize samples collected from "point-to-point" were weighted by the inverse distance weighted (IDW) method; multiple linear regression (MLR), partial least squares regression (PLSR), random forest regression (RFR), and other methods were used to predict selenium uptake by maize in a sulfur mine reclamation area in southwest China. Meanwhile, the antagonistic effects of selenium (Se) on heavy metals (Hg, As, Cd, and Cr) were analyzed. The results showed that the soil in the study area was rich in selenium resources. The average Se content in the soil reached 0.83 mg·kg-1, which was 2.87 times that of the average Se content in Chinese soil. The Se content in maize grains ranged from 0.02 mg·kg-1 to 0.16 mg·kg-1. According to correlation analysis and model prediction, the main influencing factors of selenium content in maize grains in the study area were soil selenium, pH value, organic matter, and heavy metal As. Multivariate linear regression (MLR) was the most effective method for predicting selenium content in maize grains, and the determinant coefficient R2 was 0.52. By comparing the enrichment characteristics of maize to heavy metals (Hg, As, Cd, and Cr) under different concentration gradients of Se in the soil of the study area, the results showed that Se had antagonistic effects on Hg, As, Cd, and Cr. The results can provide a basis for the development of selenium-rich agriculture in similar mining wasteland reclamation in the future.

Delirium after primary percutaneous coronary intervention in aged individuals with acute ST-segment elevation myocardial infarction: A retrospective study.

The present prospective study aimed to investigate the incidence and risk factors of delirium after primary percutaneous coronary intervention (PCI) in older adults with acute ST-segment elevation myocardial infarction (STEMI). A total of 111 patients (age, ≥65 years) with acute STEMI following primary PCI were included in the present study. Neurocognitive testing was performed using the Mini-mental State Examination on the first day of hospitalization. Post-operative delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit within the first four post-operative days. A total of 32 patients (28.8%) developed delirium after primary PCI. The independent predictors of delirium were older age [odds ratio (OR)=1.192, 95% confidence interval (CI)=1.07-1.328, P=0.001], living alone (OR=4.827, 95% CI=1.315-17.725, P=0.018), history of alcohol abuse (OR=3.875, 95% CI=1.168-12.857, P=0.026), longer duration of primary PCI (OR=1.152, 95% CI=1.077-1.232, P<0.001) and post-operative pain (current pain; OR=7.663, 95% CI=1.432-41.02, P=0.017). Compared to the patients without delirium, the participants who developed delirium had longer hospital stays and a higher rate of re-admission within 30 days after discharge. The mortality within one year after discharge (one-year mortality) was similar between patients with and without delirium. In conclusion, older patients (age, ≥65 years) with acute STEMI are at a relatively high risk of delirium following primary PCI. Higher age (≥65 years), living alone, history of alcohol dependence, longer length of primary PCI (>50 min) and post-operative pain (current pain) were determined to be risk factors for delirium after primary PCI in the present cohort.

OsSYP121 Accumulates at Fungal Penetration Sites and Mediates Host Resistance to Rice Blast.

Magnaporthe oryzae is a fungal pathogen that causes rice (Oryza sativa) blast. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are key components in vesicle trafficking in eukaryotic cells and are known to contribute to fungal pathogen resistance. Syntaxin of Plants121 (SYP121), a Qa-SNARE, has been reported to function in nonhost resistance in Arabidopsis (Arabidopsis thaliana). However, the functions of SYP121 in host resistance to rice blast are largely unknown. Here, we report that the rice SYP121 protein, OsSYP121, accumulates at fungal penetration sites and mediates host resistance to rice blast. OsSYP121 is plasma membrane localized and its expression was obviously induced by the rice blast in both the blast-resistant rice landrace Heikezijing and the blast-susceptible landrace Suyunuo (Su). Overexpression of OsSYP121 in Su resulted in enhanced resistance to blast. Knockdown of OsSYP121 expression in Su resulted in a more susceptible phenotype. However, knockdown of OsSYP121 expression in the resistant landrace Heikezijing resulted in susceptibility to the blast fungus. The POsSYP121 ::GFP-OsSYP121 accumulated at rice blast penetration sites in transgenic rice, as observed by confocal microscopy. Yeast two-hybrid results showed that OsSYP121 can interact with OsSNAP32 (Synaptosome-associated protein of 32 kD) and Vesicle-associated membrane protein714/724. The interaction between OsSYP121 and OsSNAP32 may contribute to host resistance to rice blast. Our study reveals that OsSYP121 plays an important role in rice blast resistance as it is a key component in vesicle trafficking.

TLR3 contributes to persistent autophagy and heart failure in mice after myocardial infarction.

Toll-like receptors (TLRs) are essential immunoreceptors involved in host defence against invading microbes. Recent studies indicate that certain TLRs activate immunological autophagy to eliminate microbes. It remains unknown whether TLRs regulate autophagy to play a role in the heart. This study examined this question. The activation of TLR3 in cultured cardiomyocytes was observed to increase protein levels of autophagic components, including LC3-II, a specific marker for autophagy induction, and p62/SQSTM1, an autophagy receptor normally degraded in the final step of autophagy. The results of transfection with a tandem mRFP-GFP-LC3 adenovirus and use of an autophagic flux inhibitor chloroquine both suggested that TLR3 in cardiomyocytes promotes autophagy induction without affecting autophagic flux. Gene-knockdown experiments showed that the TRIF-dependent pathway mediated the autophagic effect of TLR3. In the mouse model of chronic myocardial infarction, persistent autophagy was observed, concomitant with up-regulated TLR3 expression and increased TLR3-Trif signalling. Germline knockout (KO) of TLR3 inhibited autophagy, reduced infarct size, attenuated heart failure and improved survival. These protective effects were abolished by in vivo administration of an autophagy inducer rapamycin. Similar to the results obtained in cultured cardiomyocytes, TLR3-KO did not prevent autophagic flux in mouse heart. Additionally, this study failed to detect the involvement of inflammation in TLR3-KO-derived protection, as wild-type and TLR3-KO hearts were comparable in inflammatory activity. It is concluded that up-regulated TLR3 expression and signalling contributes to persistent autophagy following MI, which promotes heart failure and lethality.

Nicotine Suppressed Fetal Adrenal StAR Expression via YY1 Mediated-Histone Deacetylation Modification Mechanism.

Steroidogenic acute regulatory (StAR) protein plays a pivotal role in steroidogenesis. Previously, we have demonstrated that prenatal nicotine exposure suppressed fetal adrenal steroidogenesis via steroidogenic factor 1 deacetylation. This study further explored the potential role of the transcriptional repressor Yin Yang 1 (YY1) in nicotine-mediated StAR inhibition. Nicotine was subcutaneously administered (1.0 mg/kg) to pregnant rats twice per day and NCI-H295A cells were treated with nicotine. StAR and YY1 expression were analyzed by real-time PCR, immunohistochemistry, and Western blotting. Histone modifications and the interactions between the YY1 and StAR promoter were assessed using chromatin immunoprecipitation (ChIP). Prenatal nicotine exposure increased YY1 expression and suppressed StAR expression. ChIP assay showed that there was a decreasing trend for histone acetylation at the StAR promoter in fetal adrenal glands, whereas H3 acetyl-K14 at the YY1 promoter presented an increasing trend following nicotine exposure. Furthermore, in nicotine-treated NCI-H295A cells, nicotine enhanced YY1 expression and inhibited StAR expression. ChIP assay showed that histone acetylation decreased at the StAR promoter in NCI-H295A cells and that the interaction between the YY1 and StAR promoter increased. These data indicated that YY1-medicated histone deacetylation modification in StAR promoters might play an important role in the inhibitory effect of nicotine on StAR expression.

[Effect of Water and Nitrogen Fertilizer Coupling on Water Use Efficiency of Chuzhou Chrysanthemum morifolium].

Objective: To discuss the suitable water and nitrogen management modes in cultivating Chuzhou Chrysanthemum morifolium. Methods: According to two-factors quadratic regression rotation experimental designs, the effect of water and nitrogen fertilizer coupling on water consumption and water use efficiency( WUE) of Chuzhou Chrysanthemum morifolium were studied by pot experiment. Results: The water consumption of Chuzhou Chrysanthemum morifolium in different growth stages had big variation, and the water consumption rate( WCR) of squaring stage was higher. There were remarkable effect of water and nitrogen coupling on water consumption of Chuzhou Chrysanthemum morifolium in different growth stages and WUE. Effect of water on water consumption of Chuzhou Chrysanthemum morifolium in different growth stages was higher than that of nitrogen fertilizer, but effect of nitrogen fertilizer on WUE were higher than that of water, and there were significant interaction between water and nitrogen. When the soil water and nitrogen fertilizer was- 0. 2063 level and 0. 4793 level, respectively, namely, keeping 71. 35% of the field water capacity and 0. 268 N / kg of nitrogen fertilizer, the WUE reached maximum up to 3. 435 g / kg per plant. Conclusion: Considered from WUE,the suitable management mode of water and nitrogen of Chuzhou Chrysanthemum morifolium is to keep low-to-middle soil water level and middle-to-high nitrogen fertilizer.

[Effects of crop rotation and bio-organic manure on soil microbial characteristics of Chrysanthemum cropping system].

We conducted a field experiment to evaluate the effects of rotation system and bio-organic manure on soil microbial characteristics of Chrysanthemum cropping system. Taking Chrysanthemum morifolium Ramat and wheat as experimental plants, treatments under Chrysanthemum continuous cropping system (M1), conventional Chrysanthemum-wheat rotation system (M2), and Chrysanthemum-wheat rotation system receiving bio-organic manure application of 200 kg · 667 m(-2) (M3) were designed. Soil chemical properties, soil microbial biomass carbon (MBC) and nitrogen (MBN), and the amounts of different types of soil microorganisms were determined. Results showed that compared with M1, treatments of M2 and M3 significantly increased soil pH, organic matter, available N, P, and K, MBC, MBN, and the amounts of bacteria, fungi and actinomycetes, but decreased the ratio of MBC/MBN, and the relative percentage of fungi in the total amount of microorganisms. Treatment of M3 had the highest contents of soil organic matter, available N, available P, available K, MBC, MBN, and the amounts of bacteria, fungi and actinomycetes, with the values being 15.62 g · kg(-1), 64.75 mg · kg(-1), 83.26 mg · kg(-1), 96.72 mg · kg(-1), 217.40 mg · kg(-1), 38.41 mg · kg(-1), 22.31 x 10(6) cfu · g(-1), 56.36 x 10(3) cfu · g(-1), 15.90 x 10(5) cfu · g(-1), respectively. We concluded that rational crop rotation and bio-organic manure application could weaken soil acidification, improve soil fertility and microbial community structure, increase the efficiency of nutrition supply, and have a positive effect on reducing the obstacles of continuous cropping.

CXCL1 Triggers Caspase-3 Dependent Tau Cleavage in Long-Term Neuronal Cultures and in the Hippocampus of Aged Mice: Implications in Alzheimer's Disease.

Truncation of tau protein is considered an early event in Alzheimer's disease (AD) and is believed to play a major pathogenic role in sporadic AD. However, causative factors that trigger tau truncation in AD remain poorly understood. In the present study, we demonstrate that CXCL1 (C-X-C motif ligand 1), a specific ligand for the chemokine receptor CXCR2, induced cleavage of tau at ASP421 in a caspase-3-dependent manner in long-term but not short-term cultured neurons. The cleaved tau formed varicosities or bead-like structures along the neurites, an abnormal distribution of tau induced by CXCL1 that has not been observed previously. CXCL1-induced activation of GSK3ß and the subsequent phosphorylation of tau preceded and were required for caspase-3 activation and tau cleavage. Moreover, intrahippocampal microinjection of lentiviral CXCL1 induced tau cleavage in hippocampal neurons in aged (15-18 months of age) but not adult mice (5-10 months of age). Our data highlight a new role of CXCR2 in tau cleavage and suggest that targeting CXCR2 may offer therapeutic benefits to patients with AD and potentially other tauopathies.

Design of signal peptide bombyxin and its effect on secretory expression efficiency and levels of Helicobacter pylori urease subunit B in silkworm cells and larvae

This study employed a Bac-to-Bac/Bombyx mori bioreactor to mass-produce immunogenic urease subunit B (UreB) from Helicobacter pylori. The signal peptide bombyxin from B. mori was used to promote secretory expression to improve expression levels and was designed and integrated into the UreB gene to generate the Bacmid/BmNPV/(signal peptide)-UreB baculovirus expression system. To determine whether the bombyxin signal peptide resulted in secretory expression of recombinant UreB (rUreB) and to determine the secretory efficiency, we tested the secretory expression level of rUreB in Bm5 cells using ELISA. To further investigate whether secretory expression affected cell viability, cells were evaluated using 0.4% trypan blue staining, and Bacmid/BmNPV/UreB without the signal peptide served as a control. The above recombinant bacmid constructs were injected to silkworm larvae, and the secretory expression level of rUreB was detected using SDS-PAGE and semi-quantitative western blot analysis. The results indicated that the bombyxin signal peptide directed the secretory expression of rUreB and that this expression improved the viability of Bm5 cells. Moreover, the results showed that the expression level of rUreB was 1.5 times higher with the Bacmid/BmNPV constructs containing the bombyxin signal sequence than those without the signal sequence. These results demonstrate that secretory expression can enhance rUreB expression levels and is likely to aid in the large-scale expression and yield of rUreB in silkworm larvae.