Enhancing the color and astringency of red wines through white grape seeds addition: Repurposing wine production byproducts.

The clear juice fermentation technique for white wines suggests that white grape seeds, rich in flavan-3-ols and proanthocyanidins, are not effectively utilized in the winemaking process. This study incorporated 'Gewürztraminer' grape seeds into 'Cabernet Sauvignon' must before cold soak to investigate how the resultant red wines' phenolic compound profiles, color, and astringency were affected. The results showed that adding seeds primarily inhibited the leaching of flavan-3-ols from both skins and seeds. A significant increase in the levels of flavan-3-ols, tannins, and phenolic acids, as well as direct and aldehyde-bridged flavan-3-ol-anthocyanin polymers, were observed in the wines with additional seeds. This led to the improvement in the wine' red hue and its resistance to SO2 bleaching. Furthermore, the wine added with seeds exhibited stronger astringency compared to those without. The findings provide a promising winemaking strategy to improve color stability and intensify the astringency of red wines through the utilization of grape seeds.

Evolution of Aroma Profiles in Vitis vinifera L. Marselan and Merlot from Grapes to Wines and Difference between Varieties.

The fermentation process has a significant impact on the aromatic profile of wines, particularly in relation to the difference in fermentation matrix caused by grape varieties. This study investigates the leaching and evolution patterns of aroma compounds in Vitis vinifera L. Marselan and Merlot during an industrial-scale vinification process, including the stages of cold soak, alcohol fermentation, malolactic fermentation, and one-year bottle storage. The emphasis is on the differences between the two varieties. The results indicated that most alcohols were rapidly leached during the cold soak stage. Certain C6 alcohols, terpenes, and norisoprenoids showed faster leaching rates in 'Marselan', compared to 'Merlot'. Some branched chain fatty-acid esters, such as ethyl 3-methylbutyrate, ethyl 2-methylbutyrate, and ethyl lactate, consistently increased during the fermentation and bottling stages, with faster accumulation observed in 'Marselan'. The study combines the Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) model based on odor activity values to elucidate the accumulation of these ethyl esters during bottle storage, compensating for the reduction in fruity aroma resulting from decreased levels of (E)-ß-damascenone. The 'Marselan' wine exhibited a more pronounced floral aroma due to its higher level of linalool, compared to the 'Merlot' wine. The study unveils the distinctive variation patterns of aroma compounds from grapes to wine across grape varieties. This provides a theoretical framework for the precise regulation of wine aroma and flavor, and holds significant production value.

Exploring Immune Redox Modulation in Bacterial Infections: Insights into Thioredoxin-Mediated Interactions and Implications for Understanding Host-Pathogen Dynamics.

Bacterial infections trigger a multifaceted interplay between inflammatory mediators and redox regulation. Recently, accumulating evidence has shown that redox signaling plays a significant role in immune initiation and subsequent immune cell functions. This review addresses the crucial role of the thioredoxin (Trx) system in the initiation of immune reactions and regulation of inflammatory responses during bacterial infections. Downstream signaling pathways in various immune cells involve thiol-dependent redox regulation, highlighting the pivotal roles of thiol redox systems in defense mechanisms. Conversely, the survival and virulence of pathogenic bacteria are enhanced by their ability to counteract oxidative stress and immune attacks. This is achieved through the reduction of oxidized proteins and the modulation of redox-sensitive signaling pathways, which are functions of the Trx system, thereby fortifying bacterial resistance. Moreover, some selenium/sulfur-containing compounds could potentially be developed into targeted therapeutic interventions for pathogenic bacteria. Taken together, the Trx system is a key player in redox regulation during bacterial infection, and contributes to host-pathogen interactions, offering valuable insights for future research and therapeutic development.

STAU1 exhibits a dual function by promoting amyloidogenesis and tau phosphorylation in cultured cells.

Staufen-1 (STAU1) is a double-stranded RNA-binding protein (RBP) involved in a variety of pathological conditions. In this study, we investigated the potential role of STAU1 in Alzheimer's disease (AD), in which two hallmarks are well-established as cerebral ß-amyloid protein (Aß) deposition and Tau-centered neurofibrillary tangles. We found that STAU1 protein level was significantly increased in cells that stably express full-length APP and the brain of APP/PS1 mice, an animal model of AD. STAU1 knockdown, as opposed to overexpression, significantly decreased the protein levels of ß-amyloid converting enzyme 1 (BACE1) and Aß. We further found that STAU1 extended the half-life of the BACE1 mRNA through binding to the 3' untranslated region (3'UTR). Transcriptome analysis revealed that STAU1 enhanced the expression of growth arrest and DNA damage 45 ß (GADD45B) upstream of P38 MAPK signaling, which contributed to STAU1-induced regulation of Tau phosphorylation at Ser396 and Thr181. Together, STAU1 promoted amyloidogenesis by inhibiting BACE1 mRNA decay, and augmented Tau phosphorylation through activating GADD45B in relation to P38 MAPK. Targeting STAU1 that acts on both amyloidogenesis and tauopathy may serve as an optimistic approach for AD treatment.

Ethylene-responsive VviERF003 modulates glycosylated monoterpenoid synthesis by upregulating VviGT14 in grapes.

Terpenoids are important contributors to the aroma of grapes and wines. Grapes contain terpenoids in both volatile free form and non-volatile glycosidic form, with the latter being more abundant. Glycosylated terpenoids are deemed as latent aromatic potentials for their essential role in adding to the flowery and fruity bouquet of wines. However, the transcriptional regulatory mechanism underlying glycosylated terpenoid biosynthesis remains poorly understood. Our prior study identified an AP2/ERF transcription factor, VviERF003, through DNA pull-down screening using the promoter of terpenoid glycosyltransferase VviGT14 gene. This study demonstrated that both genes were co-expressed and synchronized with the accumulation of glycosylated monoterpenoids during grape maturation. VviERF003 can bind to the VviGT14 promoter and promote its activity according to yeast one-hybrid and dual-luciferase assays. VviERF003 upregulated VviGT14 expression in vivo, leading to increased production of glycosylated monoterpenoids based on the evidence from overexpression or RNA interference in leaves, berry skins, and calli of grapes, as well as tomato fruits. Additionally, VviERF003 and VviGT14 expressions and glycosylated monoterpenoid levels were induced by ethylene in grapes. The findings suggest that VviERF003 is ethylene-responsive and stimulates glycosylated monoterpenoid biosynthesis through upregulating VviGT14 expression.

XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial.

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

Effects of Phenolic Evolution on Color Characteristics of Single-Cultivar Vitis vinifera L. Marselan and Merlot Wines during Vinification and Aging.

The loss of red hue in dry red wine has been a persistent issue for wine enterprises in western China. We investigated the changes in anthocyanins and non-anthocyanin phenols during the industrial-scale fermentation and one-year bottle aging of Vitis vinifera L. Merlot and Vitis vinifera L. Marselan, respectively, using the grapes in the Ningxia region. We also examined their correlation with color characterization. The study found that both anthocyanins and non-anthocyanin phenolics were rapidly extracted from grapes during alcohol fermentation. However, their concentrations decreased rapidly during malolactic fermentation. On the other hand, Vitisin A and Vitisin B were formed during alcoholic fermentation and decreased slowly from malolactic fermentation to storage period. Directly polymerized pigments (F-A and A-F), bridged polymerized pigments (A-e-F), and flavanyl-pyranoanthocyanins (A-v-F) from the reactions of anthocyanins (A) and flavan-3-ols (F), as well as pinotins were generated during the later stages of alcoholic fermentation, and remained at a high level throughout malolactic fermentation and bottle storage. Partial least squares regression and Pearson correlation analyses revealed that the red hue (a* value) of 'Merlot' and 'Marselan' wines was closely associated with monomeric anthocyanins and F-A type pigments. Furthermore, four pinotin components were positively correlated with the red hue (a* value) of 'Merlot' wine. These primary red components of the two varieties had a positive correlation with the level of flavan-3-ols. The data suggest that elevating the flavan-3-ol concentration during fermentation aids in improving the color stability of red wine.

EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses.

Aberrant N-glycosylation has been implicated in viral diseases. Alpha-(1,6)-fucosyltransferase (FUT8) is the sole enzyme responsible for core fucosylation of N-glycans during glycoprotein biosynthesis. Here we find that multiple viral envelope proteins, including Hepatitis C Virus (HCV)-E2, Vesicular stomatitis virus (VSV)-G, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-Spike and human immunodeficiency virus (HIV)-gp120, enhance FUT8 expression and core fucosylation. HCV-E2 manipulates host transcription factor SNAIL to induce FUT8 expression through EGFR-AKT-SNAIL activation. The aberrant increased-FUT8 expression promotes TRIM40-mediated RIG-I K48-ubiquitination and suppresses the antiviral interferon (IFN)-I response through core fucosylated-EGFR-JAK1-STAT3-RIG-I signaling. FUT8 inhibitor 2FF, N-glycosylation site-specific mutation (Q352AT) of EGFR, and tissue-targeted Fut8 silencing significantly increase antiviral IFN-I responses and suppress RNA viral replication, suggesting that core fucosylation mediated by FUT8 is critical for antiviral innate immunity. These findings reveal an immune evasion mechanism in which virus-induced FUT8 suppresses endogenous RIG-I-mediated antiviral defenses by enhancing core fucosylated EGFR-mediated activation.

Integrated Analysis of Transcriptome and Metabolome to Unveil Impact on Enhancing Grape Aroma Quality with Synthetic Auxin: Spotlight the Mediation of ABA in Crosstalk with Auxin.

It is widely accepted that prevéraison application of naphthaleneacetic acid (NAA) can delay the ripening of grapes and improve their quality. However, how NAA impacts grape aroma compound concentrations remains unclear. This study incorporated the analyses of aroma metabolome, phytohormones, and transcriptome of Vitis vinifera L. cv. Cabernet Sauvignon grapes cultivated in continental arid/semiarid regions of western China. The analyses demonstrated that NAA application increased ß-damascenone and 1,1,6-trimethyl-1,2-dihydronaphthalene (TDN) in the harvested grapes by delaying véraison and upregulating VvPSY1 and VvCCD4b expressions. Additionally, NAA treatment decreased 2-isobutyl-3-methoxypyrazine (IBMP) at the same phenological stage. Notably, abscisic acid (ABA) levels increased in NAA-treated grapes during véraison, which triggered further changes in norisoprenoid metabolisms. The ABA-responsive factor VvABF2 was potentially involved in VvPSY1 positive modulation, while the auxin response factor VvARF10 may play a role in VvCCD4b upregulation and VvOMT2 downregulation during NAA induction. VvARF10 possibly acts as a crosstalk node between the ABA and auxin signaling pathways following NAA treatment in regulating aroma biosynthesis.

SHMT2 Mediates Small-Molecule-Induced Alleviation of Alzheimer Pathology Via the 5'UTR-dependent ADAM10 Translation Initiation.

It is long been suggested that one-carbon metabolism (OCM) is associated with Alzheimer's disease (AD), whereas the potential mechanisms remain poorly understood. Taking advantage of chemical biology, that mitochondrial serine hydroxymethyltransferase (SHMT2) directly regulated the translation of ADAM metallopeptidase domain 10 (ADAM10), a therapeutic target for AD is reported. That the small-molecule kenpaullone (KEN) promoted ADAM10 translation via the 5' untranslated region (5'UTR) and improved cognitive functions in APP/PS1 mice is found. SHMT2, which is identified as a target gene of KEN and the 5'UTR-interacting RNA binding protein (RBP), mediated KEN-induced ADAM10 translation in vitro and in vivo. SHMT2 controls AD signaling pathways through binding to a large number of RNAs and enhances the 5'UTR activity of ADAM10 by direct interaction with GAGGG motif, whereas this motif affected ribosomal scanning of eukaryotic initiation factor 2 (eIF2) in the 5'UTR. Together, KEN exhibits therapeutic potential for AD by linking OCM with RNA processing, in which the metabolic enzyme SHMT2 "moonlighted" as RBP by binding to GAGGG motif and promoting the 5'UTR-dependent ADAM10 translation initiation.

Differences in Aroma Profile of Cabernet Sauvignon Grapes and Wines from Four Plots in Jieshi Mountain Region of Eastern China.

The Bohai Bay region is a famous wine-growing area in China, where the rainfall is concentrated in the summer due to the influence of the temperate semi-humid monsoon climate. As such, the vineyard terrain has a significant impact on the flavor quality of the grapes and the resulting wines. To explore the relationship between the 'Cabernet Sauvignon' wine style and terrain, this study takes four different plots in the Jieshi Mountain region to investigate the differences in the aroma profile of Cabernet Sauvignon grapes and wines of two consecutive vintages. Based on two-way ANOVA, there were 25 free and 8 glycosylated aroma compounds in the grapes and 21 and 10 aroma compounds with an odor activity value greater than 0.1 in the wines at the end of alcohol fermentation (AF) and malolactic fermentation (MLF), respectively, that varied among the four plots. Wines from the four plots showed a significant difference in floral and fruity aroma attributes, which were mainly related to esters with high odor activity values. The difference in concentration of these compounds between plots was more pronounced in 2021 than in 2020, and a similar result was shown on the Shannon-Wiener index, which represents wine aroma diversity. It has been suggested that high rainfall makes the plot effect more pronounced. Pearson's correlation analysis indicated that concentrations of (E)-3-hexen-1-ol in grapes and ethyl 3-methylbutanoate, ethyl hexanoate, isoamyl acetate, isopentanoic acid, and phenethyl acetate in wines were strongly positively correlated with the concentrations of N, P, K, Fe, and electrical conductivity in soil but negatively correlated with soil pH. This study laid a theoretical foundation for further improving the level of vineyard management and grape and wine quality in the Jieshi Mountain region.

Nickel-Catalyzed Reductive [4 + 1] Sila-Cycloaddition of 1,3-Dienes with Dichlorosilanes.

Transition-metal-catalyzed sila-cycloaddition has been a promising tool for accessing silacarbocycle derivatives, but the approach has been limited to a selection of well-defined sila-synthons. Herein, we demonstrate the potential of chlorosilanes, which are industrial feedstock chemicals, for this type of reaction under reductive nickel catalysis. This work extends the scope of reductive coupling from carbocycle to silacarbocycle synthesis and from single C-Si bond formation to sila-cycloaddition reactions. The reaction proceeds under mild conditions and shows good substrate scope and functionality tolerance, and it offers new access to silacyclopent-3-enes and spiro silacarbocycles. The optical properties of several spiro dithienosiloles as well as structural variations of the products are demonstrated.

Identification of SNP loci and candidate genes genetically controlling norisoprenoids in grape berry based on genome-wide association study.

Obtaining new grapevine varieties with unique aromas has been a long-standing goal of breeders. Norisoprenoids are of particular interest to wine producers and researchers, as these compounds are responsible for the important varietal aromas in wine, characterized by a complex floral and fruity smell, and are likely present in all grape varieties. However, the single-nucleotide polymorphism (SNP) loci and candidate genes genetically controlling the norisoprenoid content in grape berry remain unknown. To this end, in this study, we investigated 13 norisoprenoid traits across two years in an F1 population consisting of 149 individuals from a hybrid of Vitis vinifera L. cv. Muscat Alexandria and V. vinifera L. cv. Christmas Rose. Based on 568,953 SNP markers, genome-wide association analysis revealed that 27 candidate SNP loci belonging to 18 genes were significantly associated with the concentrations of norisoprenoid components in grape berry. Among them, 13 SNPs were confirmed in a grapevine germplasm population comprising 97 varieties, including two non-synonymous mutations SNPs within the VvDXS1 and VvGGPPS genes, respectively in the isoprenoid metabolic pathway. Genotype analysis showed that the grapevine individuals with the heterozygous genotype C/T at chr5:2987350 of VvGGPPS accumulated higher average levels of 6-methyl-5-hepten-2-one and ß-cyclocitral than those with the homozygous genotype C/C. Furthermore, VvGGPPS was highly expressed in individuals with high norisoprenoids concentrations. Transient overexpression of VvGGPPS in the leaves of Vitis quinquangularis and tobacco resulted in an increase in norisoprenoid concentrations. These findings indicate the importance of VvGGPPS in the genetic control of norisoprenoids in grape berries, serving as a potential molecular breeding target for aroma.

Clinical characteristics of pediatric cases infected with the SARS-CoV-2 Omicron variant in a tertiary children's medical center in Shanghai, China.

BACKGROUND: The number of pediatric cases of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has increased. Here, we describe the clinical characteristics of children in a tertiary children's medical center in Shanghai. METHODS: A total of 676 pediatric coronavirus disease 2019 (COVID-19) cases caused by the Omicron variant who were admitted to the Shanghai Children's Medical Center from March 28 to April 30, 2022 were enrolled in this single-center, prospective, observational real-world study. Patient demographics and clinical characteristics, especially COVID-19 vaccine status, were assessed. RESULTS: Children of all ages appeared susceptible to the SARS-CoV-2 Omicron variant, with no significant difference between sexes. A high SARS-CoV-2 viral load upon admission was associated with leukocytopenia, neutropenia, and thrombocytopenia (P = 0.003, P = 0.021, and P = 0.017, respectively) but not with physical symptoms or radiographic chest abnormalities. Univariable linear regression models indicated that comorbidities (P = 0.001) were associated with a longer time until viral clearance, and increasing age (P < 0.001) and two doses of COVID-19 vaccine (P = 0.001) were associated with a shorter time to viral clearance. Multivariable analysis revealed an independent effect of comorbidities (P < 0.001) and age (P = 0.003). The interaction effect between age and comorbidity showed that the negative association between age and time to virus clearance remained significant only in patients without underlying diseases (P < 0.001). CONCLUSION: This study describes the clinical characteristics of children infected with the Omicron variant of SARS-CoV-2 and calls for additional studies to evaluate the effectiveness and safety of vaccination against COVID-19 in children.

HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24.

BACKGROUND: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer's disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-ß protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive. OBJECTIVE: The present study was to investigate the role of HMGCS2 in Tau/p degradation. METHODS: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy. RESULTS: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or ß-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau. CONCLUSION: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role.

Nickel-Catalyzed Cross-Electrophile 1,2-Silyl-Arylation of 1,3-Dienes with Chlorosilanes and Aryl Bromides.

Catalytic, three-component, cross-electrophile reactions have recently emerged as a promising tool for molecular diversification, but studies have focused mainly on the alkyl-carbonations of alkenes. Herein, the scope of this method has been extended to conjugated dienes and silicon chemistry through silylative difunctionalization of 1,3-dienes with chlorosilanes and aryl bromides. The reaction proceeds under mild conditions to afford 1,2-linear-silylated products, a selectivity that is different to those obtained from conventional methods via an intermediary of H(C)-η3 -π-allylmetal species. Preliminary mechanistic studies reveal that chlorosilane reacts with 1,3-diene first and then couples with aryl bromide.

Regulating the Electronic Structure of Cu-Nx Active Sites for Efficient and Durable Oxygen Reduction Catalysis to Improve Microbial Fuel Cell Performance.

The efficient and durable oxygen reduction reaction (ORR) catalyst is of great significance to boost power generation and pollutant degradation in microbial fuel cells (MFCs). Although transition metal-nitrogen-codoped carbon materials are an important class of ORR catalysts, copper-nitrogen-codoped carbon is not considered a suitable MFC cathode catalyst due to the insufficient performance and especially instability. Herein, we report a three-dimensional (3D) hierarchical porous copper, nitrogen, and boron codoped carbon (3DHP Cu-N/B-C) catalyst synthesized by the dual template method. The introduced B atom as an electron donor increases the electron density around the Cu-Nx active site, which significantly promotes the efficiency of the ORR process and stabilizes the active site by preventing demetallization. Thus, the 3DHP Cu-N/B-C catalyst exhibited excellent ORR performance with the half-wave potential of 0.83 V (vs reversible hydrogen electrode (RHE)) in a 0.1 M KOH electrolyte and 0.68 V (vs RHE) in a 50 mM PBS electrolyte. Meanwhile, 3DHP Cu-N/B-C had satisfactory stability with 94.16% current retention after 24 h of chronoamperometry test, which is better than that of 20% Pt/C. The MFCs using 3DHP Cu-N/B-C not only showed a maximum power density of up to 760.14 ± 19.03 mW m-2 but also operating durability of more than 50 days. Moreover, the 16S rDNA sequencing results presented that the 3DHP Cu-N/B-C catalyst had a positive effect on the microbial community of the MFC with more anaerobic electroactive bacteria in the anode biofilm and fewer aerobic bacteria in the cathode biofilm. This study provides a new approach for the development of Cu-based ORR electrocatalysts as well as guidance for the rational design of high-performance MFCs.

Atrial Fibrillation and Depression: A Bibliometric Analysis From 2001 to 2021.

BACKGROUND: The control of diseases related to atrial fibrillation (AF) may reduce the occurrence of AF, delay progression, and reduce complications, which is beneficial to the prevention and treatment of AF. An increasing number of studies have shown that AF is associated with depression. However, to date, there has not been a bibliometric analysis to examine this field systematically. Our study aimed to visualize the publications to determine the hotspots and frontiers in research on AF and depression and provide guidance and reference for further study. METHODS: Publications about AF and depression between 2001 and 2021 were retrieved from the Web of Science Core Collection (WOSCC) database. CiteSpace 5.8. R1, VOSviewer 1.6.16, and Excel 2019 software tools were used to conduct this bibliometric study. RESULTS: In total, 159 articles and reviews were analyzed. The number of publications has been increased sharply since 2018. David D. McManus had the largest number of publications. The most prolific country was the USA with 54 publications but the centrality was <0.1. The most prolific institution was Northeastern University. Three clusters were formed based on keywords: The first cluster was composed of atrial fibrillation, depression, anxiety, symptoms, ablation, and quality of life, et al. The second cluster were risk, prevalence, mortality, heart failure, association, et al. While the third cluster included anticoagulation, impact, stroke, management, warfarin, et al. After 2019, stroke and prediction are the keywords with strongest citation bursts. CONCLUSION: Research on AF and depression is in its infancy. Cooperation and exchanges between countries and institutions must be strengthened in the future. The effect of depression on prevalence and mortality in AF, depression on ablation in AF, and impact of depression on anticoagulation treatment in AF have been the focus of current research. Stroke prevention (including anticoagulant therapy) is the research frontier, which may still be the focus of research in the future.

Discovery of triterpenoids as potent dual inhibitors of pancreatic lipase and human carboxylesterase 1.

Pancreatic lipase (PL) is a well-known key target for the prevention and treatment of obesity. Human carboxylesterase 1A (hCES1A) has become an important target for the treatment of hyperlipidaemia. Thus, the discovery of potent dual-target inhibitors based on PL and hCES1A hold great potential for the development of remedies for treating related metabolic diseases. In this study, a series of natural triterpenoids were collected and the inhibitory effects of these triterpenoids on PL and hCES1A were determined using fluorescence-based biochemical assays. It was found that oleanolic acid (OA) and ursolic acid (UA) have the excellent inhibitory effects against PL and hCES1A, and highly selectivity over hCES2A. Subsequently, a number of compounds based on the OA and UA skeletons were synthesised and evaluated. Structure-activity relationship (SAR) analysis of these compounds revealed that the acetyl group at the C-3 site of UA (compound 41) was very essential for both PL and hCES1A inhibition, with IC50 of 0.75 µM and 0.014 µM, respectively. In addition, compound 39 with 2-enol and 3-ketal moiety of OA also has strong inhibitory effects against both PL and hCES1A, with IC50 of 2.13 µM and 0.055 µM, respectively. Furthermore, compound 39 and 41 exhibited good selectivity over other human serine hydrolases including hCES2A, butyrylcholinesterase (BChE) and dipeptidyl peptidase IV (DPP-IV). Inhibitory kinetics and molecular docking studies demonstrated that both compounds 39 and 41 were effective mixed inhibitors of PL, while competitive inhibitors of hCES1A. Further investigations demonstrated that both compounds 39 and 41 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. Collectively, we found two triterpenoid derivatives with strong inhibitory ability on both PL and hCES1A, which can be served as promising lead compounds for the development of more potent dual-target inhibitors targeting on PL and hCES1A.